key: cord-252708-88s32x0v authors: hawkins, devan title: differential occupational risk for covid‐19 and other infection exposure according to race and ethnicity date: 2020-06-15 journal: am j ind med doi: 10.1002/ajim.23145 sha: doc_id: 252708 cord_uid: 88s32x0v background: there are racial and ethnic disparities in the risk of contracting covid‐19. this study sought to assess how occupational segregation according to race and ethnicity may contribute to the risk of covid‐19. methods: data about employment in 2019 by industry and occupation and race and ethnicity were obtained from the bureau of labor statistics current population survey. this data was combined with information about industries according to whether they were likely or possibly essential during the covid‐19 pandemic and the frequency of exposure to infections and close proximity to others by occupation. the percentage of workers employed in essential industries and occupations with a high risk of infection and close proximity to others by race and ethnicity was calculated. results: people of color were more likely to be employed in essential industries and in occupations with more exposure to infections and close proximity to others. black workers in particular faced an elevated risk for all of these factors. conclusion: occupational segregation into high‐risk industries and occupations likely contributes to differential risk with respect to covid‐19. providing adequate projection to workers may help to reduce these disparities. whether they were likely or possibly essential during the covid-19 pandemic and the frequency of exposure to infections and close proximity to others by occupation. the percentage of workers employed in essential industries and occupations with a high risk of infection and close proximity to others by race and ethnicity was calculated. results: people of color were more likely to be employed in essential industries and in occupations with more exposure to infections and close proximity to others. black workers in particular faced an elevated risk for all of these factors. conclusion: occupational segregation into high-risk industries and occupations likely contributes to differential risk with respect to covid-19. providing adequate projection to workers may help to reduce these disparities. americans, are at an elevated risk both for contacting the disease, being hospitalized and dying from it. 1,2 different explanations have been provided to account for these disparities including people of color being more likely to live in densely populated areas, and, due to structural factors like discrimination and racism, being more likely to be socioeconomically disadvantaged and have comorbid health conditions that contribute to the risk of covid-19. 3, 4 discrimination within the healthcare system may also contribute to worse outcomes when covid-19 is contracted. occupational exposures are an important factor to consider in explaining these racial and ethnic health disparities. it has already been established that some occupations and industries are an elevated risk for covid-19, especially those employed in healthcare and other essential industries. 5, 6 some of these differences may be related to different characteristics of the occupation worked, including exposures to infections and close proximity to others. 7, 8 due to occupational segregation, people of color are often employed in an occupation that tends to be at a higher risk for occupational injuries, illnesses and fatalities. 9 to assess how this occupation segregation may contribute to racial and ethnic disparities for covid-19, this study sought to determine whether there were racial and ethnic disparities in workers employed in essential industries and in occupations with a higher risk of exposure to infections and close proximity to others. data showing employment by industry and occupation according to race and ethnicity were obtained from the bureau of labor statistics (bls) current population survey (cps) for the year 2019. 10 the only race and ethnicities included in this data were white, black, asian, and hispanic. the hispanic category included all those indicating that they were hispanic regardless of race and the individual race categories included those who indicated that they were hispanic. the brookings institute performed an analysis in which they characterized industries according to whether they were either likely or possibly part of the essential workforce according to guidelines published by the department of homeland security. 11 we matched this data with the employment data from the bls cps and calculated the percentage of workers likely or possibly employed in essential industries according to race and ethnicity. we also provide data about employment to select essential industries. based on previous analyses, 7, 8 we obtained data about the occupational risk for infections and close proximity other from the occupational information network (o*net). 12 the data for exposure to infections is based on a survey that is sent to workers that ask, "how often does this job require exposure to disease/infections?" the data for proximity to others is based on another question that asks, "to what extent does this job require the worker to perform job tasks in close physical proximity to other people?" based on the responses to this question, occupations are given a score between 0 and 100 that corresponds to their frequency of exposure to infections/proximity to others. for this analysis, high-risk occupations for infections were categorized as those with a score of 51 or higher and higher risk for proximity to others was categorized as 76 or higher. we combined these occupational scores with the employment data from the bls cps and calculated the percentage of workers with a high risk of exposure to infections and proximity to others according to race and ethnicity. we also provide data about select occupations with high exposure to infections and close proximity to others. finally, we categorized some occupations as high risk for both exposure to infections and proximity to others if they were in the high-risk group for both variables. again we calculated the percentage of workers who fell into this high-risk category by race and ethnicity and provide data about select high-risk occupations. this project was considered exempt from review by the mcphs university institutional review board because it was conducted with previously collected, deidentified data. possibly essential industries can be seen in table s1 . black and asian workers were also more likely to be employed in occupations with a high risk of infections. both black and asian workers were more likely to be employed as respiratory therapists. asian workers were more likely to be employed as registered nurses and black workers were more likely to be employed as licensed practical and vocational nurses. black workers were most likely to be employed in occupations frequently requiring close proximity to others. with respect to some of the occupations that require the most frequent proximity to others, white and asian workers were most likely to be employed as physical therapists. black, hispanic, and asian workers were most likely to be employed as personal care aids, and black and hispanic workers were most likely to be employed as medical assistants. black and asian workers were most likely to be employed in occupations with both frequent exposures to infections and proximity to others. two occupations that fell into this category-bus drivers and flight attendants-had black workers more likely to be employed in them. employment in all occupations with data available according to the risk of infection and proximity to others can be seen in table s2 . protecting frontline workers is essential in the current crisis because these workers are particularly vulnerable to the disease. such protection may also help to reduce racial and ethnic disparities in the burden of covid-19. these protections should include personal protective equipment to limit exposure to the virus, as well as protections for if a worker becomes sick, including paid sick leave and worker's compensation benefits. the author declares that there is no conflict of interest. john d. meyer declares that he has no conflict of interest in the review and publication decision regarding this article. devan hawkins conceived of this study, acquired data, and drafted the paper. he approves this version of the manuscript and agrees to be accountable for all aspects of the work. this project was considered exempt from review by the mcphs university institutional review board because it was conducted with previously collected, deidentified data. devan hawkins http://orcid.org/0000-0002-7823-8153 hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-covid-net, 14 states age-adjusted rates of lab-confirmed covid-19 non hospitalized cases, estimated non-fatal hospitalized cases, and total persons known to have died (lab-confirmed and probable) per 100,000 by race/ethnicity group covid-19 and racial disparities disparities in the population at risk of severe illness from covid-19 by race/ethnicity and income risk factors of healthcare workers with corona virus disease 2019: a retrospective cohort study in a designated hospital of wuhan in china italian workers at risk during the covid-19 epidemic estimating the burden of united states workers exposed to infection or disease: a key factor in containing risk of covid-19 infection the workers who face the greatest coronavirus risk. the new york times workers are people too: societal aspects of occupational health disparities-an ecosocial perspective labor force statistics from the current population survey how to protect essential workers during covid-19 supporting information additional supporting information may be found online in the supporting information section how to cite this article: hawkins d. differential occupational risk for covid-19 and other infection exposure according to race and ethnicity key: cord-024378-po1bu4v3 authors: chakraborty, sweta title: how risk perceptions, not evidence, have driven harmful policies on covid-19 date: 2020-04-20 journal: nan doi: 10.1017/err.2020.37 sha: doc_id: 24378 cord_uid: po1bu4v3 covid-19 hits all of the cognitive triggers for how the lay public misjudges risk. robust findings from the field of risk perception have identified unique characteristics of a risk that allow for greater attribution of frequency and probability than is likely to be aligned with the base-rate statistics of the risk. covid-19 embodies these features. it is unfamiliar, invisible, dreaded, potentially endemic, involuntary, disproportionately impacts vulnerable populations such as the elderly and has the potential for widespread catastrophe. when risks with such characteristics emerge, it is imperative for there to be trust between those in governance and communication and the lay public in order to quell public fears. this is not the environment in which covid-19 has emerged, potentially resulting in even greater perceptions of risk. receive significant media attention, especially compared to other disease states that are known (eg cardiovascular disease, cancer or alzheimer's disease). 11 this was true of h1ni, 12, 13 and has anecdotally so far proven true of risks are amplified or attenuated through the media through social amplification stations, which can range from individuals to the news media. amplification happens in two stages: in the initial transfer of information about the risk; and in the response mechanisms in society. 14 it is through these amplification stations that public perceptions of risks are shaped. 15, 16 these amplifications are exceptionally poignant in cases where first-hand knowledge is not tenable, such as with covid-19, and the public is therefore reliant on the media to help ascertain the risk. 17, 18 research shows that media coverage of a public health risk such as covid-19 can introduce particular risk characteristics that influence public perceptions and therefore become a factor in itself in how the risk is viewed. 19, 20 in addition to the extent of media coverage is the way a public health risk is framed in the media. as mentioned above, a new, unfamiliar disease will be prescribed far higher dread than a more familiar disease (eg lou-gehrig's disease), even if the more familiar disease is actually deadlier. 21 h1n1 was also referred to in south korean media as shin-jong or new flu. 22 before covid-19 was named, it was widely referred to in the media as the novel coronavirus. this media attention to a "new" or "novel" infectious disease frames diseases as unfamiliar and potentially catastrophic, which trigger cognitive over-attributions of frequency and probability. this along with the social amplification of risk amplifies risk perceptions and can result in the inaccurate overemphasis of primary public health impacts. given heightened public awareness of the primary public health impacts associated with the novel coronavirus, media coverage has acted as a feedback loopreinforcing the generated public awareness of these impacts. mass media have showcased epidemiological, medical and public health perspectives on the impacts 11 of covid-19primarily the lives lostat a serious detriment to understanding the big picture. observationally, there has been rare inclusion of risk or behavioural science expertise in the media. analysis of mass global media and social media coverage in the coming months and years will surely verify this observation. even being several months into the covid-19 outbreak, a comprehensive cost-benefit analysis of the various policies and combinations of policies put in place around the world has yet to be produced. policies have been based on historical data, models and disproportionate emphasis on mitigating against primary public health impacts. practitioners in risk analysis know all too well the dangers of risk analysis and policy-making in silos, and yet there has been no mainstream thorough costbenefit analysis on covid-19 in the context of a complex, global interconnected risk landscape. the global risk analysis community collectively holds a plethora of knowledge and data, as well as knowledge of where data are lacking, on the primary risks related to infectious disease (eg deaths caused by the disease), as well as secondary and tertiary impacts (eg mental health impacts, lost productivity). yet, the risk and behavioural science community has hardly been included in real-time analysis of covid-19 and its impacts. policies designed after the emergence of an outbreak carry inherent risk stemming from analysis of data that are fluid and rapidly evolving. these risks can and should be minimised by ensuring that policies across various outcome scenarios are well thought out and ready for implementation long before a crisis hits. the need for proactive preparedness for an inevitable infectious disease outbreak has been consistently maintained by the infectious disease community. this lack of preparedness has resulted in disjointed policies reacting to public perceptions of risk. specifically, a proactive risk communication plan ahead of an outbreak would have allowed for clear, consistent communication that would have quelled public fears and presumably have allowed evidence-based containment and mitigation policies to take hold. 23 because of a variety of factors (eg resource restrictions, varying country priorities, general complacency when there is not an outbreak), not only are evidencebased policies not dictating nation-state responses within and beyond political borders, they are rather being replaced with fear-based measures. consistent, clear and credible messaging helps to quell public fears. fischhoff et al found in a survey of the us public's understanding of ebola following the 2014 outbreak in west africa that the public is less likely to horribly misjudge risk when information is effectively and accurately communicated. people also have clear preferences about how they like to receive information and what sources are viewed as trustworthy. 24 while risk tolerance varies across cultures around the globe, the public generally demands governments ensure low exposure to risks, especially if they are new or unfamiliar. knowledge of this expectation is why proactive preparedness for anticipated risks is so critical. it has become painfully evident that this has not been the case for covid-19. the disjointed communication response following the outbreak has most definitely perpetuated distrust in the usa and around the world. what the risk perception and communication community has urged since the development of the us centers for disease control and prevention (cdc) crisis communication lifecycle 25honest, accurate information (ideally researched and tested) from trusted spokespeoplehas clearly been ignored at any meaningful level. the consequences of such poor preparedness and policies have real-world implications. governance decisions made in reaction to public fears err on quelling short-term hysteria at the expense of worse overall outcomes. the secondary and tertiary impacts stemming from covid-19 will go well beyond the primary public health impacts. reactive policies such as prolonged quarantines and isolations may very well increase the odds of negative outcomes. for example, brooks et al found negative psychological effects of severe social distancing measures, including posttraumatic stress symptoms, confusion and anger. they recommended for policymakers to minimise such measures and to communicate consistently throughout in order to reduce harm. 26 the ripple effects of the policies put in place to mitigate against the primary public health impacts of covid-19 may very well produce a worse overall outcomes picture. the role of the media in contributing to public perceptions of heightened risk and the reaction of policy-makers to govern based on public fears and not base-rate statistics of the disease (however fluid) will present several research opportunities in the future across multiple disciplines. this need not have been the case. it is evident that existing risk communication research has not been consistently consulted in managing the covid-19 outbreak, nor has a comprehensive risk-benefit analysis been conducted to prevent worse overall outcomes. these measures might have offset the power of the media in shaping risk perceptions, which might have in turn resulted in preventing potentially harmful policies and misallocation of precious resources in battling this global disaster. hopefully, the takeaways from covid-19 will prove helpful for the next inevitable disease outbreak. crisis and emergency risk communication as an integrative model media and social amplification of risk: bse and h1n1 cases in south korea" (2013) 22 disaster prevention & management 148 attention cycles and the h1n1 pandemic: a cross-national study of u.s. and korean newspaper coverage" (2012) 22 asian journal of communication 214. 14 re kasperson et al communication and health beliefs: mass and interpersonal influences on perceptions of risk to self and others the influence of mass media and interpersonal communication on societal and personal risk judgments communicating about emerging infectious disease: the importance of research public perceptions of everyday food hazards: a psychometric study risk analysis 487. 20 oh et al, supra again, sing-jong flu? key: cord-018907-c84t1bo5 authors: bin-hussain, ibrahim title: infections in the immunocompromised host date: 2012 journal: textbook of clinical pediatrics doi: 10.1007/978-3-642-02202-9_68 sha: doc_id: 18907 cord_uid: c84t1bo5 nan infections are considered a major cause of morbidity and mortality in immunocompromised children. the survival rate in this particular population has increased over the last 3 decades. this is mainly due to the advancement in medical technology leading to improvement in diagnosis capabilities as well as supportive care including antimicrobial therapy. immunodeficiency can be divided into primary and secondary immunodeficiency disorders. primary immunodeficiency disorders including combined t-cell and b-cell immunodeficiencies, antibody deficiency, disease of immune dysregulation, congenital defects of phagocyte number or function or both, defects in innate immunity, autoimmunity disorders, complement deficiencies, and cytokine defects. secondary immunodeficiency disorders include human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) -both of which lead to altered cellular immunity -dysgammaglobulinemia, defective phagocytic function or neutropenia. cancer leading to neutropenia, lymphopenia, humoral deficiencies and altered physical integrity especially with the use of chemotherapeutic agents leading to disruption barrier integrity with mucositis leading to easy access of microorganisms, solid organ transplant leading to deficiencies in cellular and phagocytic immunity, malnutrition which leads to impaired immunity, and complement activity. fever is the main manifestation and occasionally the only sign of infection in immunocompromised children. when approaching a patient with immunodeficiency in the context of infection, one needs to look at the net state of immunosuppression. the net state of immunosuppression can be evaluated by the host defense defects caused by the primary disease, dose and duration of the immunosuppressive therapy (the longer duration of immunosuppressive therapy, the higher risk of infection), presence of neutropenia, and anatomical and functional integrity because defect in the skin or mucosa can lead to easy access for the microorganisms, metabolic factors, and infection with immunomodulating viruses (hiv, hbv, hcv, cmv, ebv, and hhv-6). risk of infections can be classified as high, intermediate, and low. high risk includes hematologic malignancies, aids, hsct, splenectomized patient, and congenital immunodeficiency especially severe combined immune deficiency (scid). intermediate risk includes solid tumors, hiv/aids, and solid organ transplantation. low-risk patients include patients with corticosteroid therapy, local defects, and diabetes. the pathogens in immunocompromised patients can be predicted based on the immune defect. for example, if there is an anatomical disruption in the oral cavity it lead to infections caused by alpha hemolytic streptococci, anaerobes, candida species, and herpes simplex virus (hsv). patients with urinary catheters will be at risk for infection caused by gram negative bacteria including pseudomonas spp., enterococci, and possibly candida. if there is a skin defect including central venous catheter (cvc), the patient will be at risk of staphylococcus species (both coagulase-negative staphylococci and staphylococcus aureus, bacillus species, atypical mycobacterium, and gram-negative organism. if a defect in the phagocytic function, either quantitative or qualitative, predispose what to invasive diseases like invasive pneumonia caused by bacterial pathogens: gram-positive (staphylococci, streptococci, and nocardia species) and gram-negative bacilli (escherichia coli, klebsiella pneumoniae, p. aeruginosa), other enterobacteriaceae, and fungal pathogens like candida species and aspergillus species. patients with defective cell-mediated immunity are at risk of infections caused by intracellular pathogens (i.e., viral, fungi, mycobacterial, and intracellular bacteria). intracellular pathogens include legionella species, salmonella species, mycobacteria, and listeria species, histoplasma capsulatum, coccidioides immitis, cryptococcus neoformens, candida species, pneumocystis jiroveci, cytomegalovirus, varicella-zoster virus, epstein-barr virus, live viral vaccines (measles, mumps, rubella, and polio) and protozoal, toxoplasma gondii, strongyloides stercoralis, cryptosporidia, microsporidia, and isospora species. patients with immunoglobulin deficiencyo are at risk of sinupulmonary infection caused by s. pneumoniae, haemophilus influenzae, and cns infection from viral infections, especially enterovirus, leading to chronic meningoencephalitis as well as gastrointestinal infection due to giardiasis. patients with complement deficiency are at risk of diseases caused by s. pneumoniae, h. influenzae, and neisseria species. splenectomized patients are at risk of invasive diseases (e.g., sepsis, meningitis) caused by encapsulated organism including s. pneumoniae, h. influenzae, and neisseria meningitidis. in evaluating patients with immunodeficiency, one can predict the pathogen based on the primary immune defects, the organs involved, and the clinical presentation of the patient. for instance, staphylococcus aureus, burkholderia cepacia, serratia marcescens, pseudomonas and aspergillous infection should be considered for a chronic granulomatous diseased (cgd) patient with soft tissue infection, lymphadenitis, liver abscess, osteomyelitis, pneumonia, and sepsis. in centers dealing with immunocompromised patients, the microbiology laboratory as well as the radiology service need to be well equipped and trained in diagnosing these patients. patients with fever should be worked up with complete blood count with differential, renal, and hepatic profile, blood culture from central line (if present), and peripheral culture. chest x-rays are not done routinely unless the patients have respiratory symptoms. other investigations need to be guided by the presentation of the patient. patients with diarrhea should have stool checked for bacterial culture, ova and parasite, viral culture, rotavirus, and electron microscopy for viral studies, in addition to microspora, cryptosporidium, and isospora. in addition to chest x-ray, patients with respiratory symptoms required nasopharyngeal aspirate for rapid test for viruses and pcr multiplex -a newly developed laboratory procedure that can screen multiple viruses and other respiratory pathogens in the same setting. patients with skin lesions should have skin biopsy from the lesion, which will be sent for culture (bacterial, fungal, and mycobacterium) in addition to histopathology for gram-stain and special staining for fungal as well as acid fast stain (afb stain). there are several objectives in managing infections in immunocompromised patients. the first and foremost objective is to assure patients' survival and prevent infectious morbidity. decrease days of hospitalization and decrease exposure to multidrug resistance organism, decrease number of days of antibiotic use to minimize selection of resistance organism. modification of antimicrobial therapy in immunocompromised patients is the rule rather than the exception. timely modification of antibiotic therapy is very important to control breakthrough infection. there are several questions to be addressed to choose the effective antimicrobial therapy when evaluating patients. in addition to history and physical examination, it is important to determine which arm/arms of the immune systems that is/are affected? what the clinical syndrome/site of infection is? (to predict what are the likely pathogens), what clinical specimen(s) should be obtained (empiric/definitive therapy)? and which antimicrobial agents have predictable activity against pathogens? with these in mind, one can predict pathogen and choose the right antimicrobial agents. patients with wiskott-aldrich syndrome are at risk of bacterial pneumonia as well as sepsis with gram-positive organisms including mrsa. in this situation, medication should include agents active against gram-negative pathogen plus anti-staphylococcus agents, for example, cefotaxime or ceftriaxone plus naficillin; if mrsa or penicillin resistant s. pneumonia is suspected, one can use vancomycin. the pathogen in immunocompromised patients can be predicted by the system involved during the presentation. for example, the presentation and etiological agents in pneumonia in immunocompromised patients are different than immunocompetent persons. in evaluating pneumonia in immunocompromised patients, one needs to know that the pulmonary complication is present in up to 60% of immunocompromised patients and mortality is up to 80% of those who require mechanical ventilation. the initial evaluation needs rapid assessment of the vital signs including oxygen saturation, complete blood count with differential, renal profile, blood culture, and imaging of the lung either chest x-ray or ct scan. the organism can be predicted based on the primary immune defect. at certain point in the history, the defect in the immune system, the presence or absence of neutropenia, history of antimicrobial exposure, the presence of potential pulmonary pathogens in previous cultures, and the presence of indwelling catheters should be looked at. the pattern and distribution of radiological abnormalities can predict the pathogen and the time and the rate of progression and time to resolution of pulmonary abnormalities. for definitive diagnoses invasive procedures may be needed including bronchoalveolar lavage (bal), transbronchial biopsy, needless biopsy, thorascopic biopsy, and open lung biopsy. in obtaining the biopsy from this patient, it is very important to send it for histopathology for special staining, for viruses, bacteria, fungi, pneumocystis, mycobacterial pathogen, and also culture for viral, fungal, bacterial, and mycobacterium. other laboratory tests that will help in diagnosing pneumonia are nasal washings or swabs for direct fluorescent antibody, pcr for respiratory viruses and atypical pneumonia, culture and staining, cmv antigenemia or cmv viral load testing, aspergillus galactomannan assay, and 1,3 beta d glucan. the radiological finding in immunocompromised patient can be focal (lobar or segmental infiltrate), diffuse interstitial infiltrate or nodular (with or without cavitation). focal infiltrate can be due to gram-positive or gram-negative bacteria, legionella, mycobacteria, and fungal infection. also the noninfectious etiology includes infarction, radiation, and drug-related bronchiolitis obliterans organizing pneumonia (boop). diffuse interstitial infiltrate is caused by viral infection, pneumocystis jiroveci, less likely mycobacterium, disseminated fungal infection, atypical pneumonium including chlamydia, legionella, and mycoplasma. other noninfectious etiology causing diffuse interstitial infiltrate include edema, acute respiratory distress syndrome (ards), and drug-related radiation. for nodular infiltrate with or without cavitation the infectious etiology include aspergillus infection, and other mycoses, nocardia, bacteria either gram-positive or gram-negative, anaerobes, and mycobacterium tb, as well as noninfectious etiology including disease progression like metastasis and drug toxicity. the management of immunocompromised patients with pulmonary infiltrate will depend on the patient presentation. if the patient is acutely ill, it is very important to begin empiric therapy to cover the likely pathogen based on the presentation of the patient and the primary immune defect with simultaneously comprehensive evaluation. subsequently, therapy should be adjusted based on culture and clinical response. in providing empirical antibiotic therapy in patient with pulmonary infiltrate and defect in cell-mediated immunity one need to consider pneumocystis jiroveci, nocardia, legionella, mycoplasma, in addition to aerobic gram-positive cocci and gram-negative bacilli therefore it is advised to use trimethoprim-sulfamethoxazole, macrolides including erythromycin or clarithromycin and agent active against gram-positive and gram-negative; for example, thirdgeneration cephalosporin with or without aminoglycoside with anti-gram-positive either nafcillin or vancomycin based on the incidence of methicillin-resistant staphylococcus aureus (mrsa) and penicillin resistant streptococcus pneumoniae. the fever is defined in the context of febrile neutropenia as a single oral temperature of more than 38.3 c or more than 38.0 c for at least 1 h and is not related to the administration of pyrexial agents including blood, blood product, ivig, and pyrogenic drugs, especially ara c. neutropenia is defined as absolute neutrophil count (anc) less than 500/mm 3 or less than 1,000/mm 3 with predictive decline to less 500/mm 3 48 h. the most important risk factor is the presence of neutropenia as well as the degree and duration of neutropenia. the lower the neutrophil count, the higher the risk of infection. the longer the duration of neutropenia, the higher the risk of infection. usually, neutropenia is considered high risk if 7 days and low risk < 7 days. other risk factors include associated medical comorbidity, primary disease, and status (remission or relapse). low-risk patients are clinically defined by neutropenia as anticipated lasting less than 7 days, clinically stable, and having no medical comorbid conditions. about 50% of neutropenic patients who become febrile have established or occult infections and about 25% of patients with anc less than 100 cells/mm 3 have bacteremia. the risk varies depending on the underlying disease, for example, patients post allogenic bone marrow transplantation are at higher risk than autologous bone marrow transplantation while aml has the higher risk than all. the lowest risk is in patients with cyclic neutropenia. in evaluating a patient with fever and neutropenia, it is important to keep in mind that signs and symptoms can be muted or subtle. profoundly neutropenic patients can sometime have life-threatening infections and yet be afebrile especially if they presented with abdominal pain. careful and comprehensive physical examination is critical and should be repeated at least daily because these patients are dynamic and their condition can change rapidly. other important points in the history include the nature of chemotherapeutic agents, steroids, or other immunosuppressive agents because these can predict the degree of immunosuppression, the duration of neutropenia, and the severity of neutropenia. the history of antibiotic prophylaxis is also important because the antibiotic used as prophylaxis should be avoided in treating these patients. reviewing the recent documented infection with susceptibility can help in determining the empiric therapy. for example, if the patient has a previous infection with multidrug resistance pathogen, empiric therapy can be used to cover these pathogens. if the patient had recent surgical procedure, this means there is break of the skin and is at risk for certain pathogens including grampositive cocci (coagulase negative staphylococci and staphylococcus aureus). allergy history is an important factor in selecting empirical therapy as allergic medications need to be avoided. detailed and thorough physical examination is important with focus on certain sites that can be a portal of entry of pathogens including periodontium, pharynx, lower esophagus, lung, skin, perineum, bone marrow aspiration site, and catheter entry and exit sites. after history and thorough physical examinations, blood culture from central and peripheral lines should done in order to identify the source of infection. for example, if the blood culture is positive from the central culture but negative from peripheral culture, the likely source is the central line. if both are positive, time is needed to positively determine the source of infection. routine surveillance culture is not indicated as it is not cost effective and has low predictive value. other cultures should be guided by the sites of infection. for example, a patient with respiratory symptoms needs to have nasapharyngeal aspirate for viral study, pcr multiplex, and atypical pneumonia. patients with gastrointestinal symptoms, for example, with diarrhea, the stool needs to be sent for viral study, culture and sensitivity, ova and parasite. chest x-ray should not be done routinely in all patients with fever and neutropenia because it has low yield in patients without respiratory symptoms. it is only done in children who have respiratory symptoms. if negative, a chest ct scan to be considered to better evaluate patient not responding to therapy. most patients with fever and neutropenia have no identifiable site of infection and no positive culture results. bloodstream infection is documented in about 20% of patients with fever and neutropenia. disruption of the skin or soft tissue including vascular access or catheter insertion site can be a point of entry. in those centers, who are dealing with cancer patients, it is very important to monitor the infection rate and pathogen as well as the resistance pattern in the same center. the local data will help to select the appropriate empirical antimicrobial therapy (> table 68 .1). there is no ideal regimen because there are variables which include the risk status of the patient, microflora and their sensitivity patterns, toxicity indication, preference, and the cost. prompt initiation of broad-spectrum therapy when neutropenic patients became febrile is the key to successful management. in 1960 the mortality rate was up to 80% initially but with the introduction of empiric therapy against gram-negative organism the mortality rate now is close to 5%. there is no ideal regimen because this can be determined based on the isolate and its susceptibility in the same center as each center for example, one cannot extrapolate from different centers the likely pathogen, the same thing that a center can have a different pathogen and different susceptibility pattern in adult versus pediatric population with febrile neutropenia ( > table 68 .2). monotherapy and combination therapy has equal efficacy. the monotherapy needs to have antipseudomonal activities including antipseudomonal penicillin with or without beta-lactamase inhibitor, carbapenem, and third-or fourth-generation antipseudomonal cephalosporins. the combination therapy includes antipseudomonal betalactam with aminoglycoside. both monotherapy and combination therapy have equal efficacy but it is important to look at the local data to be able to predict the empiric therapy either combination therapy or monotherapy. it is worth stressing that vancomycin should not be used routinely for empiric therapy in febrile neutropenia and there is a special indication for vancomycin. the vancomycin indication includes hemodynamic instability or other evidence of severe sepsis, pneumonia documented radiographically, positive blood culture for gram-positive bacteria before final identification and susceptibility testing is available, clinically suspected catheter-related infections (e. g., chills or rigors with infusion through catheter and cellulitis around the catheter entry/exit site), skin or soft-tissue infection at any site, colonization with methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococcus, or penicillin-resistant streptococcus pneumoniae, and severe mucositis, if fluoroquinolone prophylaxis has been given and ceftazidime is employed as empirical therapy. if the patient started empirically on vancomycin the need for continuation of vancomycin should be re-assessed on daily basis. overuse of vancomycin in more than 90%, and selection for resistant organism and emergence of vancomycin resistance enterococci. the factors influencing antimicrobial selection include the types of bacterial isolates found in the institution, antibiotic susceptibility patterns, drug allergies, presence of organ dysfunction, chemotherapeutic regimen whether the patient was receiving prophylactic antibiotics, and condition of the patient at diagnosis, for example, presence of signs and symptoms at initial evaluation and presence of documented sites requiring additional therapy. the center-specific factors include the patterns of resistance, effect on microbial ecology, high presence of vancomycin resistance enterococci (vre), or extended spectrum beta-lactamase (esbl) producing organism. the patient-specific factors including recent antibiotic use such as current prophylaxis as drug allergy, and the underlying organ dysfunction. the signs and symptoms present at the initial evaluation determine. in the recent year more interest in the outpatient therapy for patient with fever and neutropenia. the advantages of ambulatory management of febrile patients with neutropenia especially those at low risk include lower cost particularly with oral outpatient therapy, fewer superinfections caused by multidrug-resistant nosocomial pathogens, improved quality of life for patient, greater . not recommended for routine use *other antimicrobials (aminoglycosides, fluoropuinolone, and/or vancomycin) may be added to initial regimen for complicated presentation or if resistance is suspected or proven infections in the immunocompromised host convenience for family or other caregivers, and more efficient utilization of valuable and expensive resources. the disadvantage includes the potential risk for developing serious complications such as septic shock at home, risk of noncompliance particularly with oral therapy, false sense of security or inadequate monitoring for response to therapy or toxicity, and the need to develop a team and infrastructure capable of treating substantial numbers of low-risk patients. there are several requirements for successful outpatient treatment programs for patients with febrile neutropenia which include institutional infrastructure and support, a dedicated and experienced team of healthcare providers, availability of institution-specific epidemiological data and susceptibility and resistance data, microbiologically appropriate treatment regimen, frequent follow-up monitoring of outpatient, adequate transportation and communication capabilities, and access to management team 24 h a day, 7 days a week. there are certain clinical events or manifestations that require modifying the initial antimicrobial therapy; for example, if a patient has breakthrough bacteremia and if gram-positive is isolated (add vancomycin especially if there is a risk of mrsa or pneumococcal resistance penicillin). if gram-negative organism is isolated consider resistant gram-negative and can change the regimen or broaden the coverage (carbapenems if the data in the center showed that the carbapenems has better sensitivity than cephalosporin or beta-lactam antibiotic). if the patient has catheter-associated soft tissue infection, vancomycin should be added. patients with severe oral mucositis or necrotizing gingivitis are at risk of anaerobic bacteria as well as viruses; add agent that is active against beta-lactamase-producing anaerobic bacteria including clindamycin, metronidazole, and acyclovir should be considered. if the patient has diffuse pneumonia, continue with the broad-spectrum anti-gramnegative coverage (add trimethoprim-sulfamethoxazole and macrolide to the therapy). increasing neutrophil count on patients who developed new infiltrates while on antibiotic can be related to the recovery of neutropenia. if the patient is stable observe if the neutrophil count is not rising, antifungal therapy should be considered as the patient is at risk for fungal infection. in addition to other evaluation aspergillus galactomannan and b-d glucan (fungitell) should be done with chest ct scan. depending on the ct scan findings bronchoalveolar lavage or lung biopsy should be considered. patient with prolonged fever and neutropenia needs to be observed if recovery of neutropenia is not imminent. antifungal therapy can include either regular amphotericin b, or lipid formulation of amphotericin b including liposomal amphotericin b (ambisome) or amphotericin b lipid complex (ablc), caspofungin or voriconazole depending of the availability of medications and epidemiology of the institution. infections in the immunocompromised low risk episodes of fever and neutropenia in pediatric oncology: is outpatient oral antibiotic therapy the new gold standard care? predicting events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter spog 2003 fn study cefepime and death: reality to rescue clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious society of america etiology and clinical course of febrile neutropenia in children with cancer risk prediction in pediatric cancer patients with fever and neutopenia advances in the management of primary immunodeficiency immunocompromised children: conditions and infectious agents emprical oral antibiotic therapy for low risk febrile cancer patients with neutropenia meta-analysis of a possible signal of increased mortality associated with cefepime use febrile neutropenia: a critical review of the initial management fever and neutropenia in pediatric patients with cancer ) b lactam monotherapy versus b lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systemic review and meta-analysis of randomized trials fever in immunocompromised patients bloodstream infections in hematology: risks and new challenges for prevention pediatric cancer patients in clinical trials of sepsis: factors that predispose to sepsis and stratify outcome key: cord-266526-8csl9md0 authors: li, shuai; xu, yifang; cai, jiannan; hu, da; he, qiang title: integrated environment-occupant-pathogen information modeling to assess and communicate room-level outbreak risks of infectious diseases date: 2020-10-24 journal: build environ doi: 10.1016/j.buildenv.2020.107394 sha: doc_id: 266526 cord_uid: 8csl9md0 microbial pathogen transmission within built environments is a main public health concern. the pandemic of coronavirus disease 2019 (covid-19) adds to the urgency of developing effective means to reduce pathogen transmission in mass-gathering public buildings such as schools, hospitals, and airports. to inform occupants and guide facility managers to prevent and respond to infectious disease outbreaks, this study proposed a framework to assess room-level outbreak risks in buildings by modeling built environment characteristics, occupancy information, and pathogen transmission. building information modeling (bim) is exploited to automatically retrieve building parameters and possible occupant interactions that are relevant to pathogen transmission. the extracted information is fed into an environment pathogen transmission model to derive the basic reproduction numbers for different pathogens, which serve as proxies of outbreak potentials in rooms. a web-based system is developed to provide timely information regarding outbreak risks to occupants and facility managers. the efficacy of the proposed method was demonstrated by a case study, in which building characteristics, occupancy schedules, pathogen parameters, as well as hygiene and cleaning practices are considered for outbreak risk assessment. this study contributes to the body of knowledge by computationally integrating building, occupant, and pathogen information modeling for infectious disease outbreak assessment, and communicating actionable information for built environment management. this study aims to develop a framework for room-level outbreak risk assessment based on 105 integrated building-occupancy-pathogen modeling to mitigate the spread of infectious disease in 106 buildings. the rationale is twofold. first, buildings are highly heterogeneous with a variety of 107 compartments of distinctive functionalities and characteristics, providing diverse habitats for 108 humans and various pathogens [17, 18] . modeling the pathogen transmission and exposure 109 within a building at the room level will provide useful information at an unprecedented resolution 110 to implement appropriate disease control strategies. second, the spread of infectious diseases 111 can be mitigated if occupants and facility managers have adequate and timely information 112 regarding the outbreak risks within their buildings. communicating actionable information to 113 occupants and facility managers through an easily accessible interface will help occupants to 114 follow hygiene and social distancing practice, and help facility managers to schedule disinfection 115 for rooms with high outbreak risks. 116 117 to address the knowledge gaps, a novel environment-occupant-pathogen modeling framework 119 and a web-based information visualization system are developed to assess the outbreak risks 120 and mitigate the spread of infectious diseases in buildings ( fig. 1) . first, to assess the outbreak 121 risks, the fomite-based pathogen transmission model proposed in [24] is adopted in this study. 122 the limitation of the model is that the environmental parameters and occupant characteristics 123 are not automatically extracted and incorporated in the model, hindering the computation of the 124 spatially-varying environmental infection risks in buildings. to overcome this limitation, bim is 125 exploited to automatically retrieve venue-specific parameters including building characteristics 126 and occupancy information that are relevant to pathogen transmission and exposure. then, the 127 extracted building and occupant parameters are used with pathogen-specific parameters in a 128 human-building-pathogen transmission model to compute the basic reproduction number r 0 for 129 each room in a building. r 0 is used as a proxy to assess the outbreak risks of different infectious 130 diseases. second, a web-based system is developed to enable information visualization and 131 communication in an interactive manner to provide guidance for occupants and facility 132 managers. this study innovatively establishes the computational links among building, occupant, 133 and pathogen modeling to predict outbreak risks. the risk prediction for spatially and 134 functionally distributed rooms in a building provides useful information for end-users to combat 135 and respond to the spread of infectious diseases, including the seasonal flu and covid-19. the 136 developed method and system add a health dimension to transform the current building 137 management to a user-centric and bio-informed paradigm. 138 139 fig. 1 in this study, a computational tool is developed based on dynamo [29] to extract the geometry 232 and properties of each room in a building, and to compute the corresponding venue-specific 233 parameters. fig. 4 shows the workflow of the information retrieval process. lines in fig the workflow for information retrieval is detailed as follows. 241 242 the steps for extracting room parameters are: thereafter, the total furniture area in each room (named ) is calculated by summing 282 up the surface area of all furniture inside the room. in epidemiology literature, r 0 is one of the most widely used indicators of transmission intensity 384 to demonstrate the outbreak potential of an infectious disease in a population. commonly, r 0 > 385 1 means the epidemic begins to spread in the population, r 0 < 1 means the disease will 386 gradually disappear, and r 0 = 1 means the disease will stay alive and reach a balance in the 387 population. with the increase of r 0 , the outbreak risk will increase, and more severe control 388 measures and policies will be needed [37] . in this study, we categorize the level of outbreak risk 389 into low, mild, moderate, and severe based on the range of r 0 . specifically, the risk is low when 390 r 0 < 1; the risk is mild when 1 ≤ r 0 < 1.5 because there is a fair chance that the transmission 391 will fade out as , is not much larger than 1 [38]; the risk is moderate when 1.5 ≤ r 0 < 2, 392 indicating an epidemic can occur and is likely to do so [39, 40] ; and the risk is severe when r 0 > 393 2 and immediate actions should be taken by facility managers, such as cleaning the surfaces, to 394 reduce the risk. 395 396 to better communicate the infection risk to occupants and facility managers, a web-based 398 system was developed to visualize the outbreak risk of different pathogens in each room within 399 a building. fig. 5 illustrates the architecture of the web-based system, which consists of four 400 modules, i.e., data management, model derivative, web application, and user. three add-in functions were developed to help users visualize the interior layout of the building 441 and color-coded rooms with their corresponding risk levels, as well as search specific room-442 related disease outbreak risk information. the first add-in function is "vertical explode", which is 443 used to view each level of the building. this function can help the user visualize the interior and 444 room layout. the facility users can also use this function to visualize the outbreak risk of rooms 445 on each floor and take appropriate practices. for facility managers, the "vertical explode" 446 function enables them to obtain a holistic view of risk distribution at each level and take 447 informed actions, such as limiting the number of occupants and implementing cleaning and 448 disinfection protocols, to control the spread of the disease. this function is integrated with the 449 web-based system, and clicking buttons were created to activate and deactivate it. the second 450 function is "room filtering", which is used to highlight rooms at different risk levels for a specific 451 pathogen. the user needs to first select one of the three pathogens from the dropdown menu: 452 sars-cov-2, influenza, and norovirus. thereafter, the user can set a risk threshold to highlight 453 rooms with r 0 greater than a specific value. in addition, different highlighting colors are used to 454 represent different infection risk levels. low, mild, moderate, and severe risks are represented 455 by color green, blue, celery, and red, respectively. the third function is "room query", which 456 enables the user to search for a specific room and retrieve infection risk for the three pathogens. 457 the "room query" function is displayed as a search box on the web-based system. the users 458 can easily find the potential risk of a specific room using this function. finally, end users can 459 access the web-based information communication system and obtain information about 460 outbreak risk in each room of the building through various channels, including laptops, 461 smartphones, and tablets. 462 463 a hypothetical case study is used as an example to demonstrate the efficacy of the proposed 465 framework and the newly developed web-based system. the building information model of a 466 six-floor school building with 221,000 square feet is used. the building contains classrooms and 467 faculty and graduate assistant offices. 468 469 the room types considered in the case study include offices and classrooms. five offices and 471 five classrooms were selected. the venue-specific parameters of the rooms are extracted and 472 listed in table 3 , and the computed r 0 values of the three diseases are listed in table 4. 473 474 table 3 venue-specific parameters in representative rooms 475 from table 4 , the values of r 0 vary across different rooms and different diseases. r 0 values in 482 offices are smaller than the values in classrooms, which stems from the small occupancy and 483 the low rate of fomite touching in offices compared to those in classrooms. for influenza, the r 0 484 values in all the rooms are less than 1, indicating that influenza is unlikely to outbreak in the 485 building through the fomite-mediated transmission. this could be partially explained by the 486 relatively short infectious period, high inactivation rate in hands, low hand-to-fomite pathogen 487 transmission efficiency, and relatively low infectiousness with the same amount of pathogens. 488 for covid-19, the r 0 values in all rooms are higher than those of influenza, and the risk in 489 classroom 4 reaches a moderate level, indicating that covid-19 has the potential to outbreak 490 in the classroom. covid-19 has a relatively high outbreak risk in most cases because it has a 491 high shedding rate, small surface inactivation rate, and high transfer efficiency from fomites to 492 hands. for norovirus, the r 0 values are high in most classrooms, which might be because of its 493 high infectivity, long infection period, and high hand-to-fomite transmission efficiency compared 494 to the other two diseases. this finding also aligns with the trend obtained in [24]. the above 495 results prove that the outbreak risk of an infectious disease is influenced by both venue-specific 496 and pathogen-specific parameters, which highlights the significance of integrating bim and the 497 pathogen transmission model in assessing spatial-varying disease outbreak risk. 498 499 sensitivity analysis was further conducted to evaluate the influence of the rate of fomite 500 touching (+ e ) and the shedding rate (%) of sars-cov-2 on r 0 based on the estimated ranges 501 of the two parameters (listed in table 2 ). fig. 6 illustrates the changes in r 0 with the increase of 502 + e for all three diseases in both classrooms and offices. from fig. 6 , the disease outbreak risk 503 increases as the increase of + e . the values of r 0 for norovirus and covid-19 in classroom 1, 2, 504 and 4 may exceed 1 with the increase of + e . on the other hand, the infection risk in offices and 505 that for influenza in classrooms will remain low even occupants touch objects in the rooms more 506 frequently. therefore, it is particularly important to educate students in classrooms with 507 relatively high occupancy to not touch the common areas frequently. fig. 7 illustrates the 508 changes in r 0 of covid-19 with varying shedding rates. from the figure, % has a significant 509 impact on the outbreak risk of covid-19 in classroom 1, 2, and 4. therefore, for classrooms 510 with relatively large occupancy, control strategies should be taken to reduce pathogen shedding 511 from the occupants, such as using face masks, and covering the mouth when coughing. applied to different rooms to reduce the risks to an acceptable low level. cleaning the surface 532 five times per day will decrease r 0 by over 50%, compared to no surface cleaning. considering 533 the ongoing outbreak of covid-19, classrooms with high occupancy (e.g., classroom 4) should 534 be given particular attention on surface cleaning. cleaning surfaces at least two times per day is 535 needed to achieve a low risk level. for norovirus, classrooms with relatively large occupancy 536 (e.g., classroom 1, 2, and 4) will require more frequent surface cleaning to reduce the outbreak 537 risk to the low level. other complementary strategies, such as increasing hand washing and 538 limiting occupancy, should be adopted to maintain a low level of outbreak risks. 539 540 as shown in fig. 10 , room filtering and room query functions can help the user easily locate 556 rooms with high risk and query risk information for a specific room. specifically, fig. 10 (a) 557 shows an exemplary output of the room filtering function that highlights the rooms with r 0 value 558 greater than 1 for covid-19. fig. 10 (b) displays an example of the room query function in the 559 web system. the pathogen risk information for influenza, norovirus, and covid-19 is retrieved 560 with corresponding recommendations. with the web-based information communication system, 561 facility managers can take important measures to control the spread of diseases, such as 562 designing appropriate cleaning and disinfection strategies, promoting hand hygiene, reducing 563 maximum occupancy, and accommodating facility usage schedule based on risk distribution 564 across rooms within the building. for instance, deep cleaning and disinfection are required for 565 rooms with severe outbreak risk. in addition, facility managers can post signs at these high-risk 566 areas to remind occupants to take essential practices such as social distancing and hand 567 hygiene. the web-based system will also keep facility users, including teachers, students, and 568 other staff, aware of up-to-date outbreak risk information within the building, and thus taking 569 informed actions to avoid further spread of diseases. for example, facility users can avoid 570 entering rooms with high outbreak risk. 571 572 4. discussion 573 the results and insights derived from the analysis have important implications on adaptive built 574 environment management to prevent infectious disease outbreak and respond to on-going 575 pandemic. due to varying building characteristics, occupancy levels, and pathogen parameters, 576 the microbial burdens and outbreak risks differ significantly even in the same building, 577 highlighting the need for spatially-adaptive management of the built environment. the proposed 578 method automates the batch process for simulation and prediction of outbreak risks for different 579 pathogens at the room level, and visualizes the risks for adaptive management. the results on 580 outbreak risks at room level enables the paradigm for spatially-adaptive management of the 581 built environment. with the new streams of risk information, customizable interventions can be 582 designed. for instance, in consistent with the practice during the covid-19 pandemic, reducing 583 the accessible surfaces in rooms and restricting the occupancy in the room are some of the 584 effective strategies to reduce the outbreak risks. the spatially-varying risk information can also 585 guide the facility managers to pay close attention to high-risk areas by adopting more frequent 586 disinfection practices. 587 588 a bim-based information system is developed to extract the necessary information for modeling 589 infection within buildings, and to visualize the derived information in an easy-to-understand and 590 convenient way through web pages. as such, the information-driven interventions could 591 alleviate the pathogenic burdens in the buildings to prevent the spread of infectious diseases. 592 providing information to end-users is critically important for them to change behaviors. human 593 behavior plays an important role in the transmission of pathogens such as the sars-cov-2. 594 changing behaviors is critical to preventing transmission. providing timely and contextual 595 information can be a promising option to motive the change of human behaviors. with the room-596 level outbreak risk information, the users could be motivated or persuaded by the visualized 597 risks to practice appropriate behaviors such as wearing a mask, social distancing, and hand-598 washing. the facility managers can use the information to conduct knowledge-based 599 management, such as limiting the occupancy in the room, managing crowd traffic, and 600 rearranging room layout. 601 602 this study has some limitations that deserve future research. first, the model does not consider 603 factors such as sunlight exposure, humidity, and airflow that may impact the persistence and 604 transmission of pathogens in built environments. this is mainly because the quantitative 605 impacts of these factors on pathogen persistence and transmission are largely ambiguous, if not 606 unknown. if these impacts can be quantified and the environmental parameters can be 607 monitored and modeled in bim, our proposed framework can be extended to incorporate these 608 factors. second, the computation of r 0 only considers the fomite-mediated transmission, and 609 does not consider the airborne and close contact transmission. microbial pathogens may have 610 different transmission routes, including airborne, close-contact, and fomite-based transmission. 611 this study focused on fomite-based transmission to illustrate the modeling approach for 612 assessing the outbreak risks, and demonstrate the efficacy of the developed information system 613 to guide infection control practices and building operations. to fully assess the exposure risks 614 and outbreak potentials, all important routes need to be considered. in addition, the outbreak 615 potentials of a variety of pathogens can be considered together to develop an aggregate index, 616 which could be more intuitive for occupants and facility managers who are not public health 617 experts. third, the system mainly relies on static models and does not make full use of dynamic 618 and real-time data regarding built environments and occupant behaviors such as presence and 619 interactions with objects. in future studies, the internet of things sensors can be installed in the 620 buildings and algorithms can be developed to retrieve dynamic data for integration with the 621 models for accurate and robust risk estimation. fourth, the web-based system can be further 622 improved by connecting it with smart devices such as robots for automated cleaning and 623 disinfection and smartphones for precision notifications. 624 625 this study creates and tests a computational framework and tools to explore the connections 627 among built environment, occupant behavior, and pathogen transmission. using bim-based 628 simulations, building-occupant characteristics, such as occupancy and accessible surface, are 629 extracted as venue-specific parameters. the fomite-mediated transmission model is used to 630 predict the contamination risks in the built environment by calculating a room-by-room basic 631 reproductive number r 0 , based on which the level of infection risk at each room is characterized 632 into low, mild, moderate, and severe. a web-based system is then created to communicate the 633 infection risk and outbreak potential information within buildings to occupants and facility 634 managers. the case study demonstrated the efficacy of the proposed methods and developed 635 systems. practically, the method and system can be used in a variety of built environments, 636 especially, schools, hospitals, and airports, where transmission of infectious pathogens is of 637 particular concern. the outbreak risks predicted at room resolutions can inform the facility 638 managers to determine room disinfection and cleaning frequency, schedule, and standard. in 639 addition, appropriate operational interventions including access control, occupancy limits, social 640 distancing, and room arrangement (e.g. reducing the number of tables and chairs) can be 641 designed based on the derived information. the occupants can access the useful information 642 via webpage to plan their visit and staying time in the facilities, and practice appropriate 643 personal hygiene and cleaning practice based on the information. microbial exchange via fomites and implications for human health how quickly viruses can contaminate buildings --from just a single 658 doorknob the occurrence of influenza a virus on household and day care 661 center fomites an interactive web-based dashboard to track covid-19 in 663 real time prolonged infectivity of 666 sars-cov-2 in fomites exaggerated risk of transmission of covid-19 by fomites role of fomite contamination during an 671 outbreak of norovirus on houseboats epidemiologic and molecular trends of "norwalk-like viruses" 675 associated with outbreaks of gastroenteritis in the united states microbiology of the built environment model analysis of fomite 680 mediated influenza transmission informing 683 optimal environmental influenza interventions: how the host, agent, and environment 684 alter dominant routes of transmission dynamics and control of infections 687 transmitted from person to person through the environment bacterial transfer to fingertips during 691 sequential surface contacts with and without gloves, indoor air. (2020) ina.12682 evaluating a transfer gradient 695 assumption in a fomite-mediated microbial transmission model using an experimental and 696 bayesian approach physical factors that affect 699 microbial transfer during surface touch architectural design drives the biogeography of indoor bacterial communities architectural design influences the diversity and 708 structure of the built environment microbiome the diversity and distribution of fungi on 711 residential surfaces microbiota of the indoor environment: 713 a meta-analysis bacterial communities on classroom surfaces 716 vary with human contact what have we learned about the microbiomes of indoor environments? bim handbook: a guide to building 720 information modeling for owners, managers, designers, engineers and contractors a conceptual framework 723 for integrating building information modeling with augmented reality fomite-mediated transmission as a sufficient pathway: a 727 comparative analysis across three viral pathogens 11 medical and health sciences 1117 728 public health and health services building information modeling (bim) for existing 731 buildings -literature review and future needs determining the level of development for bim implementation in 734 large-scale projects: a multi-case study transmission of influenza a in a student office based on realistic 737 person-to-person contact and surface touch behaviour risk of fomite-mediated transmission of sars-cov-2 in child 741 daycares, schools, and offices: a modeling study visual scripting environment for designers -dynamo 747 predicting infectious sars-cov-2 from diagnostic samples deducing the dose-response relation for coronaviruses from 750 covid-19, sars and mers meta-analysis results estimated surface decay of sars-cov-2 (virus that causes covid-753 19) a study of the probable transmission routes of 756 mers-cov during the first hospital outbreak in the republic of korea, indoor air cov-2: clinical presentation, infectivity, and immune responses pandemic potential of a strain of 769 influenza a (h1n1): early findings, science on the definition and the computation of 772 the basic reproduction ratio r0 in models for infectious diseases in heterogeneous 773 populations unraveling r0: considerations for public health 775 applications assessing the pandemic potential of mers-cov nuanced risk assessment for emerging infectious 780 diseases 782 interventions to mitigate early spread of sars-cov-2 in singapore: a modelling study web development with mongodb and nodejs hand hygiene and surface cleaning should be paired 789 for prevention of fomite transmission, indoor air key: cord-011325-r42hzazp authors: stowe, julia; andrews, nick; miller, elizabeth title: do vaccines trigger neurological diseases? epidemiological evaluation of vaccination and neurological diseases using examples of multiple sclerosis, guillain–barré syndrome and narcolepsy date: 2019-10-01 journal: cns drugs doi: 10.1007/s40263-019-00670-y sha: doc_id: 11325 cord_uid: r42hzazp this article evaluates the epidemiological evidence for a relationship between vaccination and neurological disease, specifically multiple sclerosis, guillain–barré syndrome and narcolepsy. the statistical methods used to test vaccine safety hypotheses are described and the merits of different study designs evaluated; these include the cohort, case-control, case-coverage and the self-controlled case-series methods. for multiple sclerosis, the evidence does not support the hypothesized relationship with hepatitis b vaccine. for guillain−barré syndrome, the evidence suggests a small elevated risk after influenza vaccines, though considerably lower than after natural influenza infection, with no elevated risk after human papilloma virus vaccine. for narcolepsy, there is strong evidence of a causal association with one adjuvanted vaccine used in the 2009/10 influenza pandemic. rapid investigation of vaccine safety concerns, however biologically implausible, is essential to maintain public and professional confidence in vaccination programmes. vaccination is one of the most effective public health interventions successfully controlling many serious infectious diseases and saving millions of lives globally each year [1] . however, as with any medical treatment or drug, vaccination can never be entirely risk free in terms of unwanted side effects. an important feature of vaccination is that unlike most therapeutic drugs, vaccines are given prophylactically to healthy individuals, often young children. when an event occurs shortly after vaccination in an otherwise healthy individual without an obvious cause, it is tempting to attribute its occurrence to the preceding vaccination. the assumption of a causal association with a vaccine from purely a temporal association is often incorrect as unrelated events will occur by chance irrespective of vaccination. it can be hard to disentangle these temporal associations when there is a strong perception that a temporal association is necessarily evidence of a causal association and the onset of the condition is insidious and its timing relies on patient or parental recall [2] . even if only based on a temporal sequence of events, it is important that such safety concerns are rapidly investigated with robust epidemiological studies to allow mitigation procedures to be put in place if an association is confirmed or, if unfounded, to have the necessary evidence to sustain public confidence in the vaccination programme without which coverage drops and disease control is lost. in this article, which focusses on the evaluation of the relationship between vaccination and neurological diseases, the statistical approaches to causality assessment are first discussed and their relative merits evaluated, followed by an overview of a selection of vaccine safety studies involving neurological disease with differing conclusions; some of the included studies have shown a small elevated risk, others none, two lack evidence to draw any definitive conclusion and one provides robust evidence of causal association. to establish whether the signal seen is associated with the vaccine and to quantify the risk, a formal epidemiological study is usually needed. this requires a pre-specified protocol detailing the population under study, the period after vaccination for which an elevated risk is suspected, and the methods for case identification and statistical analysis. most importantly, the ascertainment of the condition of interest must be unbiased with respect to vaccination history [3] . the following statistical methods have been used most commonly to address vaccine safety questions and to control for the inherent biases in the population and data under study. although these methods aim to address confounding, it can be difficult to fully control for this in an observational study. an assessment of the likelihood of residual confounding/ bias and its potential extent is an important consideration when weighing up the strength of a study and drawing a conclusion with regard to causality. in a cohort study, the risk of developing the condition is compared in the vaccinated and unvaccinated individuals in the study population. cohort studies need to be very large to detect rare vaccine adverse events and this often makes them impractical for a prospective study. retrospective cohort designs can use routinely collected data and cases identified by clinical coding but this study design may be disadvantaged by the need to collect a large number of confounding variables. factors such as underlying illnesses, sociodemographic characteristics, and propensity to consult may differ between unvaccinated and vaccinated individuals and would therefore need to be adjusted for in the analysis as they can independently determine the likelihood of the adverse event under study. the advantage is that an entire population is studied and relative and absolute incidence estimates can be reported. in addition, once the cohort is defined, several outcomes can be assessed within the same study design. when studying a vaccine that is given as part of a national schedule and high coverage is achieved, the small unvaccinated group may differ from the vaccinated group in ways that are difficult to capture and control for in an adjusted analyses. additionally, care must be taken to ensure unvaccinated cases are indeed unvaccinated and the data are not missing. this can occur when regional vaccine datasets are used and the transfer and sharing of data are not comprehensive. cohort studies are feasible for vaccine safety studies when data from a whole country or region can be used. an example of this is in denmark where danish residents contribute to a large linked dataset consisting of demographic factors that are linked to health information including potential confounding variables [4] . the self-controlled case-series method (sccs) was designed for rapid unbiased assessment in vaccine safety studies using available disease surveillance data that may not be amenable to cohort analysis. the method only requires information on the timing of cases during a defined observation period and their vaccination status [5] . the cases act as their own controls as the incidence of the event in pre-defined risk periods following vaccination is compared to the incidence outside the risk period generating a relative incidence (ri) measure ( fig. 1) . a significant advantage of the method is that confounding factors that do not vary over the observation period, such as co-morbidities or sociodemographic status, are automatically controlled for. adjustment for timevarying confounders such as age is also possible by dividing up the observation period further into age categories. it has been demonstrated that the power of the sccs method is nearly as good as a cohort study when uptake is high and risk intervals are short, and it is superior to that of a casecontrol study [6] . the self-controlled case-series method has been used by public health england to address many pertinent vaccine safety concerns [7] [8] [9] [10] . this design has been chosen both because of its simplicity and ability to control for individual level confounding and also because a national cohort of cases cannot be easily defined using the national hospital data as no national immunisation register is available. unlike a cohort study, the sccs method does not provide absolute risk estimates. however, if the number of doses given to the population from which the cases are derived is known and if ascertainment is complete, then absolute risks can be estimated and the cases attributable to vaccination estimated from the magnitude of the ri. a case-control study requires smaller numbers than a cohort study but the same confounding and bias can occur and it also has the added difficulty of selecting the correct controls for comparison. for vaccinations given in the short age range in the first and second year of life or during a short calendar period to target ages, close matching of the controls on date of birth is required. prior vaccination status is then compared between cases and controls using the date of onset in cases as a reference date. to obtain enough power to assess the required risk, multiple controls per case are often needed and defining appropriate criteria for the selection of controls can be problematic. while it is important to ensure that controls are similar to cases on characteristics such as age and geographical location that can independently affect vaccination status, over matching is a risk if too many extraneous variables are included in the matching, resulting in loss of efficiency and potentially introducing bias. a case-control study does not provide absolute risk estimates, rather it measures the odds of vaccination in cases compared to controls. however, as with the sccs method, if the number of doses given to the population from which the cases are derived is known and if ascertainment is complete, then absolute risks can be estimated and the cases attributable to vaccination estimated from the magnitude of the odds ratio. the case-control design has been used where controls can be selected from the same population as cases and can be readily matched on the relevant variables. as a case-control approach is more efficient than the cohort approach, it is often used on large databases that could be used for a cohort analysis. examples include the vaccine safety datalink in the usa, which accesses complete patient records from health maintenance organisations, or studies using hospital admission data bases linked to national immunisation registers such as the australian childhood immunisation register [11] [12] [13] . the case-coverage design has recently been used in vaccine safety studies [14, 15] . it is similar to the screening method, which until recently has been primarily used for vaccine effectiveness assessment [16] , although it is more limited in terms of adjustment for possible confounders than the sccs method. each case is matched to a population coverage estimate and this is then used to see if the number of cases vaccinated is greater than expected. the method uses logistic regression on the odds of vaccination with an offset for the log-odds of the matched population coverage, thus it is similar to a case-control study with thousands of controls per individual. this design has been used by public health england to assess the risk between as03 adjuvanted h1n1 pandemic vaccine pandemrix™ and narcolepsy. because pandemrix™ was rolled out over a short period of time in the winter season of 2009/10 targeting children of different ages according to whether they had certain co-morbid conditions, it was necessary to have detailed information on dates of vaccination and dates of birth to estimate the population coverage for each narcolepsy case by age and time period. this was available from a representative subset of general practices in england, which also provided information on co-morbidities, the only other variable considered as a potential confounder [14] . in the first study assessing the risk of narcolepsy in children [14] , both the sccs method and the case-coverage design was used. the results from the sccs method were found not to be clear as this method requires the incidence in a pre-specified risk period after vaccination relative to the baseline incidence to be compared. because the duration of the risk period had not been defined at the time, the postvaccination interval was found to be too short and resulted in the inclusion in the baseline period of four patients with symptoms more than 6 months after vaccination. the choice of study design to answer a vaccine safety question will depend on the hypothesis to be tested, the available data sources and the extent to which confounding variables are likely to bias the results. the sccs method has now become the gold standard design in vaccine safety studies, owing to the benefits highlighted above, but for each study question the methods should be adapted and potential biases considered in the context of the population under study, the dataset being utilised and the hypothesis being tested. it will inevitably be a trade-off between the ideal and the practical and the best designs will vary according to setting. when many studies are performed to answer the same question, the key to demonstrating causality is consistency in the results from well-designed studies [17] . neurological conditions have a long history of causal associations with vaccination being inferred from temporally related onsets. an example is the damage that was made to the uk whole-cell pertussis vaccination programme in the late 1970s when neurological damage was wrongly attributed to the vaccine based on case reports of infants with onset of encephalopathy shortly after vaccination. these reports of permanent brain damage following vaccination attracted intense and sustained professional and media interest causing vaccination rates to fall from 79% in 1973 to 31% in 1978. following this, three national epidemics of pertussis occurred with an estimated 5000 hospital admissions, 200 cases of pneumonia, 83 cases of convulsions and 38 deaths [18, 19] . neurological vaccine safety concerns can be broadly assigned to either being biologically plausible or unsubstantiated and unexpected. the biologically plausible group are often a direct effect from a component of the vaccine. for example, in the case of a live attenuated vaccine, the adverse reaction could mimic, at a lower frequency, what the non-attenuated wild virus would do. this is demonstrated in the rare risk of acute flaccid paralysis following the oral polio vaccine after a reversion to virulence or with the risk of aseptic meningitis after the attenuated urabe mumps strain in the measles-mumps-rubella vaccine due to retention of some neurovirulent characteristics [20, 21] . the unsubstantiated and unexpected group occurs usually because of the timing of the vaccine, which coincides with the diagnosis of the condition and has no immediate biologically plausible explanation. examples of this are measles-mumps-rubella and autism [22] , gait disturbance and measles-mumps-rubella [23] , and thiomersal and developmental delay [24] . although a signal may not have a clear biological basis for its causation, it still needs to be fully investigated using robust epidemiological methods. neurological diseases for which a causal association with vaccination has been suspected have some common features. first, they are often serious conditions that are rare, second, their aetiology and pathophysiology are poorly understood, and third, immune stimulation is thought to play a role in the pathogenesis of the condition. because vaccines provoke an immune response, albeit targeted to a specific antigen, it can be tempting to invoke a superficially plausible causal pathway when adverse events with a suspected immune aetiology arise shortly after vaccination. universal hepatitis b vaccine was recommended by the world health organization in the early 1990s to protect against the hepatitis b virus, which can cause chronic liver damage and cancer. following this recommendation, france carried out a mass vaccine campaign in 1994. shortly after, reports of cases of multiple sclerosis (ms) with onset or relapse after vaccination were reported, leading to the hypothesis that the vaccine could cause an acute autoimmune reaction in susceptible persons soon after administration. with a lack of adequate background rates of ms in the vaccinated population to put the reported cases into perspective, mistrust in the vaccine soon grew and the vaccine programme was subsequently suspended. a systematic review and meta-analysis by mouchet et al. published in 2018 that included 13 studies with a control group found no evidence of an increased risk. the overall adjusted risk ratios for ms was 1.19 (95% confidence interval [ci] 0.93-1.52) and for central demyelination was 1.25 (95% ci 0.97-1.62) [25] . within the systematic review, there was one study that found a significant association using a primary care database from england [26] . this study was unable to adjust for all risk factors and additionally no routine hepatitis b vaccination programme was in place at the time with most of the vaccine delivered via occupational health departments whose records may not be routinely transferred to primary care databases. france continues to have suboptimal vaccine coverage [27, 28] and has the lowest level of confidence in vaccine safety in europe [29, 30] . this demonstrates the need to have robust methods in place to rapidly respond to such scares because once confidence is lost in a vaccine it is difficult to restore and may generate a more general lack of confidence in vaccine safety. guillain-barré syndrome (gbs) is the most common cause of acute neuromuscular paralysis in the developed world resulting in muscle weakness and sometimes paralysis, which can lead to respiratory failure and a death rate in up to 13% [31] . the strongest evidence of a causal link with a vaccine was obtained during the 1976 us swine influenza vaccine programme in military personnel, which was found to be associated with a risk of one case per 100,000 and resulted in the suspension of the vaccine programme [32] . since then, gbs has been a potential vaccine-associated adverse event of interest particularly for vaccines given in adolescence, an age coinciding with the age at which autoimmune diseases are often diagnosed. 1.20-1.66) . the overall relative risk for gbs after seasonal vaccine was marginally increased at 1.22 (95% ci 1.01-1.48), with a somewhat larger relative risk of 1.84 (1.36-2.50) for the 2009 h1n1 pandemic vaccine but this was not significantly higher than the relative risk for seasonal vaccine [33] . the authors did not find any statistically significant differences by geographical region nor between adjuvanted and unadjuvanted vaccines. an earlier meta-analysis of studies using the sccs method also found a small elevated risk of gbs after the monovalent h1n1 pandemic vaccine, with an ri of 2.42 (95% ci 1.58-3.72) in the 42 days following vaccination [34] . similarly, salmon et al. found an ri of 2.35 (95% ci 1.42-4.01) in a large study in the usa [35] . in contrast, a strong association between gbs and a preceding influenza-like-illness was shown in a study in england using primary care data and the sccs method. no association was seen with influenza vaccine in the 0-90 days after administration (ri 0.76 [95% ci 0.41-1.40]) but a significantly increased risk was found in the 90 days after influenza-like illness (ri 7.35 [95% ci 4.36-12.38]) [36] . these studies show that a small overall risk of gbs after influenza vaccine probably does exist with a slightly larger risk after the 2009 monovalent pandemic vaccine. the mechanism may be multi-factored with the risk varying with the vaccine used, co-circulation of other infections and the inherent susceptibility to developing gbs. however, the small risk that exists does not outweigh the risk of developing gbs after influenza itself. human papilloma virus vaccine is given at an age when autoimmune disorders are often diagnosed. following a french study reporting a signal for gbs after human papilloma virus vaccination, a study was conducted in england identifying gbs cases in a national hospital discharge database (hospital episode statistics) [37] . primary care practitioners were then contacted for the vaccination history and asked to confirm gbs diagnosis and provide an onset date and send supporting documentation. in a selfcontrolled case-series analysis of 101 cases with a record of human papilloma virus vaccination, there were episodes in the 0-to 91-day risk period after any dose with no significant increased risk, ri 1.04 (95% ci 0.47-2.28). the analysis was also stratified by manufacturer (of either the quadrivalent or bivalent product); there was no difference in the ri between products and no significant increased risk for either manufacturer. the pandemic influenza vaccine, pandemrix™, was the most widely used vaccine in europe during the 2009 pandemic. it was a monovalent h1n1 pdm 09 vaccine containing as03, a powerful oil-in-water adjuvant. uptake of the vaccine varied between countries with high coverage of 75% in children in finland [38] and lower coverage in england where children in a risk group eligible for the seasonal influenza vaccine and later all children under 5 years of age were targeted, with uptake being 37% and 24%, respectively. in england, pandemrix™ was also used in the influenza season 2010/11 because of a shortage of seasonal influenza vaccine. in august 2010, concerns were raised in finland and sweden, where vaccine coverage was high, about a possible association between narcolepsy and pandemrix ™ when a large increase in cases of narcolepsy in vaccinated cases was reported by sleep centres [38, 39] . a subsequent cohort study in finland reported a 13-fold increased risk of narcolepsy following pandemrix™ in children aged 4-19 years, the majority of whom had onset within 3 months of vaccination and almost all within 6 months [38, 40] . narcolepsy was a totally unexpected adverse event and the early reports were met with initial scepticism in the global vaccine community. the world health organization global advisory committee in vaccine safety issued a statement in april 2011 stating "no excess of narcolepsy has been reported from several other european states where pandemrix was used" and "it seems likely that some as yet unidentified additional factor was operating in sweden and finland". however, it was unlikely that narcolepsy would be identified by passive surveillance systems in other countries where pandemrix™ coverage was low given the low background incidence of the condition and the complexity and frequent delays in diagnosis. to assess this risk identified in finland, the health protection agency (now public health england) performed a study in sleep centres in england where the majority of children with sleep disorders are seen. this study identified a 14-fold increased risk in those vaccinated with pandem-rix™ [14] with the attributable risk estimated to be 1.9 per 100,000 doses. this demonstrated that even in a country were vaccine coverage was low, the association can be demonstrated using robust epidemiological methods. the study of the relationship between narcolepsy and pandemrix™ has been an epidemiological challenge in terms of identifying the cases and their vaccine histories in a non-biased manner. not only can the diagnosis be lengthy and complex, but admitted patient care databases, which are widely used for a non-biased ascertainment of cases in vaccine safety studies, are incomplete as patients experiencing narcolepsy may not be admitted and if they are admitted, the admission date is not an accurate reflection of the onset of the narcolepsy symptoms leading to misclassification bias. an important consideration when selecting cases is the awareness of the hypothesised association. this awareness may lead to an increased reporting of cases known to be vaccinated and has two aspects; public awareness and professional awareness. first, this heightened awareness may lead to vaccinated individuals presenting to healthcare institutions and being diagnosed earlier than unvaccinated cases leading to ascertainment bias. if a condition has an insidious onset making the recall of the first symptom difficult to determine, media attention may lead to a differential recall of the symptom-onset date in the vaccinated cases. using source documents, which were created prior to any media attention in the country of study, can address this potential recall bias. professional awareness is likely to occur even if media attention is low, as health professionals in the specialty will be aware of current topics of interest through professional bodies and literature. differential misclassification bias will occur if cases known to have been vaccinated are more likely to be assigned a diagnosis of narcolepsy than unvaccinated cases. in the study from england, public awareness of the association was assessed by analysing google searches for "narcolepsy" in the period of interest and found there was little activity in the uk compared to sweden (fig. 2) [14] . even with these practical challenges, there has now been a consistent strong association demonstrated in countries that used pandemrix™ but no association has been seen with other pandemic or seasonal vaccines [17] . as with all vaccine safety studies, but particularly in the case of narcolepsy and pandemrix™ where the association was completely unexpected, the key to demonstrating causality was consistency of results from well-designed studies in different settings. the answer to the question of whether vaccination can cause neurological disease is multifaceted. the evidence does not support an association between ms and the hepatitis vaccine, while for gbs and influenza vaccines the evidence suggests a small increased risk though it is much smaller than the risk from a natural influenza virus infection. the now established association between narcolepsy and pan-demrix™ should act as a lesson for the vaccine safety community that sometimes unexpected but serious conditions can arise and need to be investigated rapidly however biologically implausible. the neurological vaccine safety issues outlined here demonstrate that rapid assessments of safety signals are needed to ensure that public confidence is maintained in national immunisation programmes. the confirmation of a signal and estimation of the magnitude of vaccine-attributable risk will require consistent results from a number of well-designed epidemiological studies, preferably conducted in different settings. as the experience with narcolepsy has shown, not all vaccine safety concerns can be anticipated on the basis of biologically plausible and thus predictable effects. as new vaccines are introduced, the basis of discussions on vaccine safety should be the acceptance that vaccination can carry a small risk but that this risk needs to be balanced against the enormous individual and public health benefits. funding public health england, national infection service, immunisation and countermeasures division has provided vaccine manufacturers with post-marketing surveillance reports, which the marketing authorisation holders are required to submit to the uk licensing authority in compliance with their risk management strategy. a cost recovery charge is made for these reports. world health organization. the power of vaccines: still not fully utilized recall bias, mmr, and autism vaccine safety surveillance postlicensure epidemiology of childhood vaccination: the danish experience control without separate controls: evaluation of vaccine safety using case-only methods statistical assessment of the association between vaccination and rare adverse events post-licensure autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association guillain-barre syndrome and h1n1 (2009) pandemic influenza vaccination using an as03 adjuvanted vaccine in the united kingdom: self-controlled case series idiopathic thrombocytopenic purpura and mmr vaccine the risk of intussusception following monovalent rotavirus vaccination in england: a self-controlled case-series evaluation population-based study of rotavirus vaccination and intussusception intussusception risk and disease prevention associated with rotavirus vaccines in australia's national immunization program mmr vaccine and idiopathic thrombocytopaenic purpura risk of narcolepsy in children and young people receiving as03 adjuvanted pandemic a/h1n1 2009 influenza vaccine: retrospective analysis risk of narcolepsy after as03 adjuvanted pandemic a/ h1n1 2009 influenza vaccine in adults: a case-coverage study in england estimation of vaccine effectiveness using the screening method incidence of narcolepsy after h1n1 influenza and vaccinations: systematic review and meta-analysis pertussis immunisation and control in england and wales, 1957 to 2012: a historical review the pertussis vaccine controversy in great britain risk of aseptic meningitis after measles, mumps, and rubella vaccine in uk children risks of convulsion and aseptic meningitis following measlesmumps-rubella vaccination in the united kingdom autism and mmr vaccination in north london; no causal relationship no evidence of an association between mmr vaccine and gait disturbance thiomerosal exposure in infants and developmental disorders: a retrospective cohort study in the united kingdom does not support a causal association hepatitis b vaccination and the putative risk of central demyelinating diseases: a systematic review and metaanalysis. vaccine recombinant hepatitis b vaccine and the risk of multiple sclerosis: a prospective study estimates of national immunization coverage european centre for disease prevention and control. measles vaccination coverage (second dose the state of vaccine confidence 2016: global insights through a 67-country survey vaccine hesitancy among general practitioners and its determinants during controversies: a national cross-sectional survey in france guillain-barre syndrome guillain-barre syndrome following vaccination in the national influenza immunization program guillain-barre syndrome and influenza vaccines: a meta-analysis international collaboration to assess the risk of guillain barre syndrome following influenza a (h1n1) 2009 monovalent vaccines association between guillain-barre syndrome and influenza a (h1n1) 2009 monovalent inactivated vaccines in the usa: a meta-analysis investigation of the temporal association of guillain-barre syndrome with influenza vaccine and influenzalike illness using the united kingdom general practice research database no increased risk of guillain-barre syndrome after human papilloma virus vaccine: a self-controlled case-series study in england increased incidence and clinical picture of childhood narcolepsy following the 2009 h1n1 pandemic vaccination campaign in finland risks of neurological and immune-related diseases, including narcolepsy, after vaccination with pandemrix: a population-and registry-based cohort study with over 2 years of follow-up as03 adjuvanted ah1n1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in finland key: cord-024982-4f6m3kfc authors: che huei, lin; ya-wen, lin; chiu ming, yang; li chen, hung; jong yi, wang; ming hung, lin title: occupational health and safety hazards faced by healthcare professionals in taiwan: a systematic review of risk factors and control strategies date: 2020-05-18 journal: sage open med doi: 10.1177/2050312120918999 sha: doc_id: 24982 cord_uid: 4f6m3kfc background: healthcare professionals in taiwan are exposed to a myriad of occupational health and safety hazards, including physical, biological, chemical, ergonomic, and psychosocial hazards. healthcare professionals working in hospitals and healthcare facilities are more likely to be subjected to these hazards than their counterparts working in other areas. objectives: this review aims to assess current research literature regarding this situation with a view to informing policy makers and practitioners about the risks of exposure and offer evidence-based recommendations on how to eliminate or reduce such risks. methods: using the preferred reporting items for systematic reviews and meta-analyses review strategy, we conducted a systematic review of studies related to occupational health and safety conducted between january 2000 and january 2019 using medline (ovid), pubmed, pmc, toxline, cinahl, plos one, and access pharmacy databases. results: the review detected 490 studies addressing the issue of occupational health and safety hazards; of these, 30 articles were included in this systematic review. these articles reported a variety of exposures faced by healthcare professionals. this review also revealed a number of strategies that can be adopted to control, eliminate, or reduce hazards to healthcare professionals in taiwan. conclusion: hospitals and healthcare facilities have many unique occupational health and safety hazards that can potentially affect the health and performance of healthcare professionals. the impact of such hazards on healthcare professionals poses a serious public health issue in taiwan; therefore, controlling, eliminating, or reducing exposure can contribute to a stronger healthcare workforce with great potential to improve patient care and the healthcare system in taiwan. eliminating or reducing hazards can best be achieved through engineering measures, administrative policy, and the use of personal protective equipment. implications: this review has research, policy, and practice implications and provides future students and researchers with information on systematic review methodologies based on the preferred reporting items for systematic reviews and meta-analyses strategy. it also identifies occupational health and safety risks and provides insights and strategies to address them. according to the world health organization (who), 1 an estimated 59 million people work in healthcare facilities globally, accounting for roughly 12% of the working population. the who 2 also reports that all healthcare workers, including healthcare professionals, are exposed to occupational hazards. the international labour organization (ilo) 3 reported that millions of healthcare workers suffer from work-related diseases and accidents, and many succumb to occupational hazards. scholars and practitioners in the field of healthcare and occupational health and safety (ohs) are striving to raise awareness of the risk factors and importance of workplace health and safety among this population. 1, 3, 4 schulte et al. 5 defined an occupational hazard as the shortterm and long-term dangers or risks associated with unhealthy workplace environments. tullar et al. 6 and joseph and joseph 7 stated that the healthcare workers at greatest risk are doctors, healthcare professionals, nurses, laboratory technicians, and medical waste handlers. occupational hazards pose health and safety risks and have negative impact on the economy, which accounts for roughly a 4% loss in global annual gross domestic product (i.e. $2.8 trillion annually). 3 the who, 2 ilo, 3 and nelson et al. 8 noted a lack of universally applicable data on the impact of occupational hazards. ohs hazards, and their negative impacts on health and well-being among healthcare professionals, is an issue of growing concern in the asia and pacific region, particularly in taiwan; however, research in this area has been somewhat limited. according to the taiwanese ministry of health and welfare (mohw) 9 in taiwan, 182,019 health and medical personnel are working at health care organizations in taiwan, including 33,516 healthcare professionals and 15,016 pharmacist assistants. the healthcare professionals serve a taiwanese population of 23,590,744 in 22,384 medical care institutions (490 hospitals and 21,894 clinics). 10 of the 490 hospitals, 81 are public and 409 are privately owned; of the 21,894 clinics, 440 are public and 21,454 are privately owned. 10 taiwanese healthcare professionals face a variety of ohs hazards, which increase the incidences of work-related disease, the country's burden of disease, the total number of accidents, the incidences of job-related health problems, and the number of cases involving incapacitation or disablement. 9 this study reviewed previous works on ohs hazards, as well as their risk factors and control strategies, with a focus on healthcare professionals in taiwan. cochrane 11 identified eight steps of a systematic review, which are adopted in this study. this study employed the preferred reporting items for systematic reviews and meta-analyses (prisma) protocol to organize the flow of information through the various steps of the review. we used the following key words in our literature search: occupational health and safety, risk factors, healthcare professionals, control strategies, and taiwan to ensure specificity and exclude irrelevant studies, we employed boolean logic (and, or, not) in combining terms as search strings. 12 the operator and was used to reduce the search yield for two key terms (e.g. "healthcare professionals (p) and occupational health and safety"). the operator or was used to increase the search yield (e.g. "healthcare professionals and occupational health and safety or risk factors"). note that in this example, the two search terms are synonyms. the operator "not" was used to exclude specific terms or term combinations. 13 this research obtained a large number of initial articles (n initial = 490); however, the application of inclusion and exclusion criteria considerably reduced the number of articles for inclusion in the review (n = 30 articles). the 30 articles focused on ohs, occupational hazards, and healthcare professionals in taiwan. figure 1 presents a flow diagram depicting the application of eligibility criteria, the process of identification and screening, and the reasons for inclusion and exclusion. in documenting and assessing individual publications, we collected key information from the relevant studies to populate an evidence table (see appendix c) and conducted a critical appraisal of the included studies. 12 the study population included adult pharmacy workers (male and female). data were extracted only from studies that included samples that were deemed significant given the justification of the authors of the studies. a critical appraisal of all studies was performed to assess their quality in terms of validity and reliability, as based on performance bias, information bias, selection bias, and detection bias. cochrane 11 and khan et al. 16 reported that biases tend to exaggerate or underestimate the "true" outcome of exposure to an occupational hazard. our ultimate objective was to compare (without any form of bias) groups that were exposed to occupational hazards and those that were not exposed in terms of risk factors and outcomes. 16 for the sake of validity and reliability, all of the studies selected for inclusion were prospective in nature and included data pertaining to exposure and outcomes, while controlling confounding factors. we also looked for studies with high internal reliability (consistency across items within a test) and high external reliability (consistency in agreeability between uses/rates). 12 in our final analysis, we considered whether the research had been conducted in an appropriate manner (internal validity). 13 we also considered the generalizability of the results, that is, whether the results were pertinent to other situations (external validity). data synthesis. the final step involved the synthesis of evidence from the included studies; that is, organized into homogeneous categories, under which the results were to be summarized. the evidence was also graded (i.e. assessed in terms of quality) and integrated (i.e. weighted across categories to address the multidisciplinary nature of ohs research). 12 in this review, the synthesis, grading, integration, interpretation, and summary of the evidence were presented in narrative form, due to difficulties in textual and statistical pooling. after completing our systematic review, we employed the prisma reporting scheme, which is endorsed for ohs studies by hempel et al. 12 briefly, the prisma structure is laid out in the following format: topic, summary/abstract, introduction, methods, results, conclusion, and recommendations. 12 a meta-analysis was not conducted. the ilo categorizes ohs hazards that affect healthcare professionals as biological, chemical, physical, ergonomics, and psychosocial. 17 from the 30 studies in this review, this study identified the ohs hazards, injuries, and diseases affecting healthcare professionals working in hospitals and healthcare facilities. this section provides the biological hazards, as identified in the review, as the most commonly encountered in hospitals and healthcare facilities in taiwan. according to who, the managers and administrators of hospital and healthcare facilities, in our case those in taiwan, should carefully assess the potential for exposure to biohazards and put effective biohazard control plans in place. the following chart provides a summary of the identified biological hazards, their risk factors, and control strategies (table 1) . the review established some of the most commonly faced chemical hazards present in hospitals and healthcare immunization and vaccines; 18 and biological safety cabinets, needleless systems or safety-engineered needles, suitable ventilation, and an appropriate medical waste management system. 15 administrative controls: written and documented infection control plans; decontamination procedures; enforcement of these systems; and the training of hospital staff in the implementation of occupational health and safety measures. 20 immunization programs; detection and followup of infections; periodic screening; codes of practice; and staff orientation. designing all work systems with the aim of minimizing the risk of exposure. personal protective equipment (ppe): includes devices for the protection of the eyes (e.g. face shields, goggles), respiratory system (e.g. surgical masks), and skin (e.g. latex gloves, protective aprons, gown. 20 based on risk assessments and careful training. [21] [22] [23] infection from human immunodeficiency virus (hiv), hepatitis b virus (hbv), and hepatitis c virus (hcv) 14 needle-stick injuries (nsi) and accidents with other sharp objects: occupational exposure resulting in hiv, hbv surface antigen-positive, or hcv transmission is largely due to inoculation of pathogens into cutaneous abrasions, lesions, scratches, or burns, as well as mucocutaneous exposure involving inoculation or accidental splashes onto non-intact mucosal surfaces of the nose, mucous membranes, mouth, or eyes. 24 facilities, as well as the documented control strategies, which are summarized in table 2 . physical hazards, which are defined as environmental risk factors that can harm the body without contact, were found to account for a substantial proportion of risks among healthcare professionals in taiwan. 4, [42] [43] [44] the physical hazards, risk factors, and control strategies are summarized in table 3 . the review established that healthcare professionals are exposed to musculoskeletal disorders and injuries, such as low back pain due to the nature of their work, such as lifting patients. 44 table 4 summarizes the risk factors and control strategies for this hazard. psychosocial hazards have attracted considerable attention in the research community, as well as among policy makers and practitioners in healthcare. [53] [54] [55] this study found that in taiwan, psychosocial hazards have prompted a larger number of studies combining physical, chemical, and biological hazards. the who 56 reported that psychosocial hazards are closely linked to work-related stress, workplace violence (e.g. violent patients), and other workplace stressors. table 5 provides a summary of the risk factors and control strategies of psychosocial hazards. this review provides detailed information regarding the ohs hazards that affect healthcare professionals working in hospitals and healthcare facilities in taiwan. the review summarizes the risk factors for hazards, as well as the control strategies to control, eliminate, or reduce them. from the reviewed studies, it was clear that ohs hazards can potentially result in a number of injuries, sickness, and harm. a wide range of ohs hazards were identified, including biological hazards 14 chemical hazards, 65 ergonomic hazards, psychosocial hazards, and physical hazards. 59, 62 the review has shown that healthcare professionals are at a significantly high risk of occupational related hazards. 56 injuries and sickness prevent healthcare workers from discharging their duties effectively, which can have negative impact on the overall healthcare system in taiwan. physical hazards, such as falls, noise, and mechanical hazards, could have long-term physiological effects, such as hearing impairments; therefore, there is need to introduce various control strategies, such as engineering noise control measures. there should be the provision of good ppe for healthcare professionals to protect themselves from physical harms in the workplace. according to our findings, it is evident that healthcare professionals are exposed to chemical hazards, some of which can be carcinogenic. there is also the risk of exposure to occupational dermatitis. it is therefore important that healthcare professionals are screened for cancer on a regular basis. the workers can also be trained about skin care and be provided with safety equipment and other useful interventions, such as sunscreen cream. such efforts can help in early detection, prevention, and intervention. as part of their routine occupation, biological hazards can affect healthcare professionals due to contact with patients and visitors. the review of healthcare professionals on duty demonstrates how important it is to manage blood borne and airborne biological pathogens in the healthcare workforce. 20 there should be administrative guidance and training on how healthcare professionals can deal with biological hazards, and these professionals should be encouraged to report work-related incidents as soon as they occur or are suspected to have occurred to aid early intervention. ergonomic hazards in healthcare professionals tend to arise from lifting patients and hospital equipment. this requires careful prevention, assessment, and intervention, as the impact of ergonomic hazards on the musculoskeletal system of the affected healthcare professionals cannot be ignored. 34 hospital administrators need to alleviate frequent job pressures by providing the necessary safe and ergonomic equipment, and hiring an adequate number of personnel. the professionals can work in properly planned shifts and teams to reduce fatigue, they should be trained in the correct techniques for lifting patients and equipment, and policies should be enforced to ensure compliance. the findings on psychosocial hazards show that healthcare professionals can be affected by mental and psychological hazards, such as stress, as it is evident that healthcare professionals who suffer from stress are likely to suffer from fatigue and exhaustion. healthcare professionals are trained to show less emotion, and thus, find it difficult to seek medical intervention. there is need for counseling and stress management for healthcare professionals, and the workers should be trained to manage stress. the workplace should be designed in such a manner as to prevent invasion, harassment, and violence against healthcare professionals. overall, hospital administrations and healthcare professionals should focus on evidence-based strategies (engineering, administrative, and ppe) to manage ohs hazards. the increasing prevalence of occupational hazards and work-related diseases among healthcare professionals in taiwan is a concern. 66 risk factors include exposure to hazards and a failure to follow hierarchical control strategies. health care workers and administrators must work together to eliminate or minimize these hazards through the introduction of and strict adherence to engineering, administrative, and personal protective equipment (ppe) controls. the the main routes of exposure to chemical hazards include ingestion, injection, skin contact or absorption, and inhalation. 34, 35 contamination and exposure are both affected by the duration and frequency of exposure, the quantity of drugs undergoing preparation, and the use of ppe. 23 the adverse health effects can be attributed to compounds deemed carcinogenic (cancer causing), mutagenic (promoting mutations), teratogenic (causing birth defects), or toxic to various organs. 36 alcohol hand sanitizers commonly used by healthcare professionals are flammable and harmful to the skin. there have also been reports on the dangers of detergents used to clean surfaces, which can lead to irritation and promote allergies of the skin, eyes, and respiratory tract. 35, 37 there is also evidence that some detergents can react with other products commonly stocked in healthcare facilities to produce toxic vapors. 31, 35, 38 it has been found that low concentration disinfectants, such as quaternary ammonium salts, alcohols, hydrogen peroxide, iodophors, and phenolic and chlorine compounds, can have toxic effects and irritate the skin, eyes, and respiratory system. 23 the inhalation of powdered medications and vapors exposes healthcare professionals to the risk of poisoning and allergic reactions. 39, 40 engineering control strategies: isolating and segregating hospital or healthcare facility areas and equipment; providing exhaust hoods to provide local ventilation when compounding and mixing drugs; providing biological safety cabinets to safeguard chemicals; and providing containers to prevent needle stick injuries. flammable chemicals should be stored away from sources of ignition and dangerous chemicals substituted with less harmful ones. 36 cuts, burns, hearing loss, motion sickness, and muscle cramps. 47 engineering controls: minimize the use of sharp tools, use machine guarding, use quality sockets, and close water faucets when not in use. 48 administrative controls: promote and practice safe work procedures, such as when using electrical equipment (e.g. cords). 18 educating workers about the cleaning equipment and cleaning up broken glass is also recommended. 49 ppe: use of appropriate footwear, gloves, eye and nose protection, and protective clothing 18 3. tripping, slipping, cuts, and falling poor housekeeping, poor layout, and slippery tiled floors. 50 open power cables, live wires, broken glassware, lancets, knives, scissors, and scalpels. 47 bruised skin, cuts, broken bones, and muscular injuries. 50 engineering control: proper lighting, the construction of safe stairwells, and regular building maintenance (e.g. floors and workspaces). 44 ppe: use of appropriate footwear, gloves, eye and nose protection, and protective clothing 18 4. exposure to microwave radiation, and ionizing and non-ionizing radiation. 50 risks imposed by radiation from x-ray machines and other diagnostic imaging systems, and the radionuclides used in nuclear medicine and radiation therapy. workers face risks from nonionizing radiation, lasers, ultraviolet rays, and magnetic resonance imaging. 51 the risk increases when using heat sealers and poorly maintained or insulated radio-diagnostic equipment. 48 tissue damage, risk of cancer, and abnormal cell mutation (e.g. abnormal leukocytes). 48,51 engineering control: reducing the time of exposure, increasing the distance to x-ray machines, and increasing the amount of shielding. 20 ppe: use of appropriate footwear, gloves, eye and nose protection, and protective clothing 18 perceptions of workers can greatly affect their implementation of risk-mitigation strategies. 20 selection bias is a concern here, despite the fact that we selected published and peer-reviewed articles, as well as unpublished but authoritative gray articles; the fact is that other unverifiable but potentially valuable reports were no doubt excluded. 67 our reliance on observational studies (to the exclusion of intervention studies) and the heterogeneity of the included articles (in terms of methodology) posed a risk of bias and limited standardization. 68 this study discovered relatively little research focusing on hospital workers in taiwan, and thus, further empirical studies focusing on this group of healthcare givers are required and recommended. 68 researchers should focus on the health status, work performance, and workplace retention of healthcare professionals, including the prevalence of morbidity and mortality. 67 the insights in this review provide a valuable reference for policy makers in establishing goals to deal with workplace hazards. 68 hazard control strategies must be based on objective assessments of existing risks and the most appropriate measures to deal with them. 20 this systematic review confirmed a positive correlation between ohs hazards (biological, physical, chemical, and psychosocial), and work-related injuries, occupational health problems, and work-related diseases. the burden of disease and attributable fraction of work-related diseases and occupational injuries has been shown to cause considerable social and economic losses for employees, families, companies, countries, and societies at large. 8 generally, the burden of disease is assessed using disease/disability adjusted life years. the burden of disease is measured as the impact of morbidity and premature mortality within a given area. 2, 69 scholars and professionals agree that reducing, substituting, or eliminating ohs hazards in healthcare facilities is important for healthcare workers, helps to ensure patient safety, and enhances the overall quality of healthcare. 7 many researchers have used the "hierarchy of controls," which is based on the assumption that interventions are most effective when implemented at the source and least effective when applied at the worker level. 20 gorman et al. listed control interventions from most to least effective as follows: elimination, substitution, engineering, administrative, and ppe. researchers have also emphasized the importance of eliminating hazards or substituting hazardous materials with less hazardous materials. 20, 70 taimela et al. 71 argued that administrative controls, such as training and ensuring adequate staffing, are crucial to eliminating or minimizing occupational hazards. engineering controls, such as redesigning work spaces, ensuring adequate ventilation, and introducing automated systems for repetitive tasks, were emphasized by liberati et al. 72 ppe, such as the use of gloves, clothing, and eye wear, are considered the least effective and have the most profound consequences in the event of failure by exposing the individual directly to the hazard. 20 nonetheless, many researchers and professionals agree that all such controls should be applied collectively, in order to minimize the effects of hazards. 20,70-72 musculoskeletal disorders (msds) due to repetitive actions, less than optimal computer equipment, and a poorly engineered workspace in which healthcare professionals are forced to overreach and/or sit while maintaining an awkward posture. 43 healthcare professionals are tasked with lifting and transferring equipment, tools, and instruments. one's physical fitness level and demographic background were shown to affect the risk of developing msds. 52 workplace and job-related demands, poor administrative and team support, and a negative attitude toward job tasks were all strongly correlated with msds. 47 ergonomic hazards can lead to chronic pain in the arms, back, or neck. frequently, they lead to msds, such as carpel tunnel syndrome, which tends to reduce work performance and productivity and can have a serious detrimental effect on one's health-related quality of life. 50 strained movement due to localized pain, stiffness, sleep disturbances, twitching muscles, burning sensations, and feelings of overworked muscles. 47 engineering control strategies: redesign workstations with appropriate chairs and computer equipment. 43 workstations should be configurable to a wide range of medical personnel with different body shapes and sizes. it is also recommended that lifting and handling equipment, such as trolleys, be installed in areas requiring heavy lifting. automation should be adopted when resources and practicability allow. 46 59 healthcare professionals also face violence during robberies and the theft of addictive prescription pain killers, such as oxycontin and vicodin. 54 we also identified organizational culture and structure, interpersonal relationships at work, job content and satisfaction, homework balance, and the changing nature of work as important psychosocial hazard risk factors among healthcare professionals. 54, 57, 60 work-related stressors have a detrimental impact on worker's health and safety, in terms of mental, musculoskeletal, chronic degenerative disorders, metabolic syndrome diabetes, and cardiovascular diseases. 61 psychological hazards at work were associated with heart disease, depression, physical health problems, and psychological strain. 54 low back pain was the most common work-related ailment among healthcare workers in taiwan. 53 employees who experience job insecurity and/or workplace injustice were more likely to suffer from burnout. 54 job demands and the level of control experienced by the worker were significantly associated with fatigue; exposure to workplace violence affects psychological stress, sleep quality, and subjective health status among healthcare professionals. 59 engineering control strategies: creation of isolation areas for agitated patients and designing an office layout that prevents the healthcare professionals from coming into direct contact with customers/patients or being trapped. 57 spaces should be well lit and separated to ensure that client-care provider contact is controlled and access is allowed only when absolutely necessary. proper working communication devices and video surveillance, as well as panic buttons and alarm systems. 62 administrative control: management policies make unequivocal declarations of non-violence/anti-abuse. 63 management can encourage workers to participate in the design of forwardrotating (day-evening-night) shifts and work schedules that impose gradual shift changes and ease the adaptation to nonregular work shifts to ensure that all concerned get adequate sleep. 61 educate healthcare professionals about the risks associated with shift work. 20 well-trained security personnel should be hired to deal with unruly customers. 59 training in conflict management and problem-solving could also help workers to prevent or de-escalate violence. 60, 64 nametags should be used by employees, and reporting and response procedures should be enhanced. the manuscript has not previously been published and is not under consideration by another journal. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the ethical approval was not sought for this study because this is a systematic review and all the literature has been published. the author(s) received no financial support for the research, authorship, 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important in evaluating and developing disease control programs. this study aims to describe an accurate spatiotemporal pattern of influenza at the prefecture level and explore the risk factors associated with influenza incidence risk in mainland china from 2005 to 2018. the incidence data of influenza were obtained from the chinese notifiable infectious disease reporting system (cnidrs). the besag york mollié (bym) model was extended to include temporal and space-time interaction terms. the parameters for this extended bayesian spatiotemporal model were estimated through integrated nested laplace approximations (inla) using the package r-inla in r. a total of 702,226 influenza cases were reported in mainland china in cnidrs from 2005–2018. the yearly reported incidence rate of influenza increased 15.6 times over the study period, from 3.51 in 2005 to 55.09 in 2008 per 100,000 populations. the temporal term in the spatiotemporal model showed that much of the increase occurred during the last 3 years of the study period. the risk factor analysis showed that the decreased number of influenza vaccines for sale, the new update of the influenza surveillance protocol, the increase in the rate of influenza a (h1n1)pdm09 among all processed specimens from influenza-like illness (ili) patients, and the increase in the latitude and longitude of geographic location were associated with an increase in the influenza incidence risk. after the adjusting for fixed covariate effects and time random effects, the map of the spatial structured term shows that high-risk areas clustered in the central part of china and the lowest-risk areas in the east and west. large space-time variations in influenza have been found since 2009. in conclusion, an increasing trend of influenza was observed from 2005 to 2018. the insufficient flu vaccine supplements, the newly emerging influenza a (h1n1)pdm09 and expansion of influenza surveillance efforts might be the major causes of the dramatic changes in outbreak and spatio-temporal epidemic patterns. clusters of prefectures with high relative risks of influenza were identified in the central part of china. future research with more risk factors at both national and local levels is necessary to explain the changing spatiotemporal patterns of influenza in china. influenza is associated with notable mortality and morbidity worldwide, as well as in china 1-3 . the behaviours of major epidemics and pandemics of influenza were complicated due to dramatic genetic changes, subtype circulation, wave patterning and virus replacement 4 . influenza vaccination is the most effective means to prevent infection, severe disease and mortality 5 . the world health assembly recommends vaccinating 75% of key risk groups against influenza 6 . although seasonal influenza vaccination was introduced in 1998, influenza vaccination is not yet included on the national immunization program (nip) in china 7 . the average national vaccination coverage was reported to be just 1.5-2.2% between 2004 and 2014 7, 8 . the overall number of flu vaccines approved for sale by china's national institute for food and drug control (nifdc) has decreased in recent years 9, 10 . the low coverage rate and reduction in flu vaccine supplementation have raised much concern about the increased risk of influenza incidence in china. although new emerging influenza virus types and subtypes, such as avian influenza a h5n1 [11] [12] [13] [14] , influenza a (h1n1)pdm09 [15] [16] [17] , and influenza a h7n9 18, 19 , have been reported continuously in china, the disease burden of influenza has been dominated by a(h3n2), a(h1n1)pdm2009 influenza viruses, pre-pandemic a(h1n1) or influenza b in recent years, which account for the majority of cases 20 . the influenza a(h1n1)pdm2009 virus was first introduced to mainland china on may 9, 2009 21 , and has been one of the dominant viruses in the seasonal influenza epidemics since then 20 . the effect of newly emerging influenza a(h1n1)pdm2009 viruses on the geographic patterns and temporal trends of influenza across the whole country is still unknown. covariates associated with the reported incidence cases of influenza. the table 2 . the crude odds ratios (ors) and adjusted ors in both the univariate poisson models and multivariate adjusted poisson model are statistically significant. after adjusting for other covariates, a spatially unstructured random effect term (v i ), a spatially structured conditional autoregression term (υ i ), a first-order random walk-correlated time variable (γ 1j ), and an interaction term for time and place (δ ij ) in the multivariate adjusted spatiotemporal model, the flu vaccines (per million doses), flu surveillance protocols, rate of influenza a (h1n1)pdm09, latitude and longitude still remain statistically significant. holding all other covariates to zero and adjusting for spatiotemporal variation, every one million increase in the number of influenza vaccines for sale approved by the china food and drug administration was associated with a 12.7% decrease in the influenza incidence risk (95% ci = 0.825-0.923). similarly, the new update of the influenza surveillance protocol in 2017 was related to a 65.6% increase in the influenza incidence risk (95% ci = 1.097-2.496) compared to the protocol used in 2005 to 2008. for every 10% increase in the rate of influenza a (h1n1)pdm09 among all processed specimens from ili patients, there was a 19.5% increase in the influenza incidence risk (95% ci = 1.005-1.413). every one degree increase in the latitude and longitude was associated with a 1.5% (95% ci = 0.980~0.991) and 0.2% (95% ci = 0.997~0.999) increase in the influenza incidence risk, respectively. the spatial and temporal effects in spatiotemporal models with covariates. the spatial effects. the map of the spatially structured conditional autoregression term demonstrated areas of spatial patterning and similarity among prefectures. the spatially structured relative risk and posterior probabilities of spatially structured relative risk greater than 1.0 are presented in figs. 3 and 4, respectively. table 1 . deviance information criterion (dic) for five spatiotemporal models. abbreviations: d, posterior mean of the deviance; pd, the number of effective parameters; dic, the deviance information criterion, as a measure of the trade-off between model fit and complexity. note: model terms used in four models include an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); uncorrelated time (γ j ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ 1j ). θ ij represents the relative risk of area i at time j. * model 1, convolution + uncorrelated time (time iid), e.g., θ α ν table 2 . risk analysis of covariates associated with reported cases of influenza. abbreviations: or, odds ratio; ci, confidence interval. * univariate poisson analysis models. ** multivariate adjusted poisson analysis model, which included all variables in the univariate analysis models. † multivariate adjusted spatiotemporal models, which included all variables in the univariate analysis models; an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). ‡ total number of flu vaccines approved for sale by china's national institute for food and drug control (nifdc), which were rescaled to one million doses as one unit. data were collected from nifdc. # the convolutional spatial risk term, which includes both the spatially structured conditional autoregression term (υ i ) and the spatially unstructured random effect term (ν i ) at the prefecture level, identified areas at increased risk of influenza throughout the 14-year study period (fig. 5) . posterior probabilities for an area's spatial risk estimate exceeding 1.0 are presented in fig. 6 . the proportion of the total spatial heterogeneity explained by the spatially structured conditional autoregression term was 73.51%. after adjusting for fixed covariate effects and time random effects, both the map of the spatial structured term and the convolutional spatial term show that high-risk areas clustered in the central part of china and the lowest-risk areas in the east, northwest and southwest. the higher-risk prefectures were mostly distributed in guangdong, guangxi, guizhou, hunan, jiangxi, zhejiang, hubei, anhui, henan, hebei, beijing, tianjin, gansu, ningxia, and inner mongolia. the lower-risk areas in the east included some prefectures in the shandong peninsula and the prefectures of heilongjiang, liaoning, and jilin provinces in the northeast. the northwest areas are composed of prefectures in tibet, qinghai and xinjiang, while the southwest areas include chongqing and prefectures in sichuan and yunnan provinces. the temporal trend. the relative risks of the 14-year study period, holding the covariates and spatial risk constant, were calculated by exponentiating the marginal first-order random walk-correlated time term (γ 1j ) in the spatiotemporal models of influenza risk with and without covariates. for the spatiotemporal model without . ** adjusted by convolutional spatial term, space-time interaction term, and covariates, e.g., . figure 3 . map of the spatially structured relative risk ( υ e i ), spatiotemporal model of influenza incidence risk with covariates, china prefectures, 2005-2018. note: the linear terms in the model of spatiotemporal model of influenza incidence risk with covariates were , which included all variables in the univariate analysis models; an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). www.nature.com/scientificreports www.nature.com/scientificreports/ covariates, an overall increasing trend was found in the temporal trend term in the 14-year study period. the risk of influenza remained low between 2005 and 2008. a steep increase was observed in 2009. it dropped slightly back to a low level and remained stable in 2010 and 2011. a rapid increase was obvious in the last 3 years (table 3) (fig. 7) . for the temporal trend term in the spatiotemporal model with covariates, the relative risks in the years from 2005 to 2016 were not significantly different from that in the spatiotemporal model with covariates. the relative risks in the model with covariates in 2017 and 2018 were significantly lower than those in the model without covariates. the lower boundary of the 95% confidence intervals in the model with covariates showed some levelling off in recent years. the differences between the spatiotemporal model with and without covariates indicated that the recent increases in influenza incidence risks could be partially explained by the fixed covariate effects. space-time interactions. the probability exceedances for the yearly space-time interactions are presented for the study period (fig. 8) . these identify areas with residual spatial risk greater than 1.0 compared to the prefecture-wide risk after the fixed effects, unstructured, spatially structured, and time random effects are held constant. changing patterns and large variations among the yearly specific spatial distributions are shown in fig. 8 . it is interesting that most of the higher-risk areas were western areas of china before 2009, and most of the higher-risk areas are eastern or northern areas of china after 2009. , which included all variables in the univariate analysis models; an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). , which included all variables in the univariate analysis models; an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). (2019) 9:19650 | https://doi.org/10.1038/s41598-019-56104-8 www.nature.com/scientificreports www.nature.com/scientificreports/ based on the incidence data of influenza gained from the chinese notifiable infectious disease reporting system, we used the bayesian spatiotemporal model in this study to assess the space-time patterns of the influenza epidemic at the prefecture level in mainland china from 2005 to 2018 and explored several factors that may be associated with the changing spatial and temporal patterns in the influenza incidence risk. several potential factors may be associated with the rapid increasing trend of influenza in china. first, insufficient flu vaccine supplements and a low uptake rate might be associated with an increase in influenza incidence. the results of the final spatiotemporal model showed that every million increase in the number of influenza vaccines approved for sale by the china food and drug administration was associated with a 12.7% decrease in the influenza incidence risk (95% ci = 0.825-0.923). the rapidly increased crude rates of influenza from 2016 to 2018 coincided with a large reduction in the numbers of vaccines approved for sale at the same time. the reductions in the numbers of vaccine supplements were mostly due to the outcomes of vaccine scandals related to improper vaccine storage and production in 2016 and 2018, respectively 9,10,37 . previous studies reported that uptake figures of the influenza vaccine averaged 1.9% nationally and 4.3% among urban elderly aged 60 years and above in 9 cities of china during the 2008-2009 and 2011-2012 influenza seasons, respectively 7, 8, 20 . it is expected that the uptake may be even lower, as people lost their faith in the safety of domestically produced vaccines after the vaccine scandals in china 38 . our results are consistent with the study in italy, which reported an association between vaccination coverage decline and influenza incidence among italian elderly 39 . , which included all variables in the univariate analysis models; an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). www.nature.com/scientificreports www.nature.com/scientificreports/ second, currently circulating influenza strains in humans include influenza a (h1n1)pdm09, influenza a (h3n2) and influenza b viruses, (b/victoria and b/yamagata) 5, 40, 41 . influenza a (h1n1)pdm09 has been reported to be the predominant subtype in recent years according to ili surveillance and is more likely to be the major cause of regional and widespread outbreaks 40 . our study showed that for every 10% increase in the rate of influenza a (h1n1)pdm09 among all processed specimens from ili patients, there was a 19.5% increase in the influenza incidence risk (95% ci = 1.005-1.413). shu et al. reported that the predominant subtype of seasonal influenza a (h1n1) and b/yamagata could circulate from the south to the north of china from 2006 to 2009 34 . our study also found that every one degree increase in latitude and longitude was associated with a 1.5% (95% ci = 0.980~0.991) and 0.2% (95% ci = 0.997~0.999) increase in the influenza incidence risk, respectively. this result was consistent with the role of climatic factors in influenza transmission dynamics 20, 42 . third, the greater effort in influenza surveillance and the use of new technologies may account for the rise in influenza incidence. in recent years, especially after the 2009 pandemic season, influenza surveillance has been expanded worldwide, as recommended by the world health organization (who) [43] [44] [45] 33, 34, 41 . as cnidrs includes all sentinel hospitals, sentinel hospitals are likely to report more cases of influenza to cnidrs. in addition, more hospitals have used electronic health information systems, which may improve both the quantity and quality of data collection and exchange from hospitals to cnidrs [46] [47] [48] [49] . fourth, the reporting on influenza a (h1n1)pdm09, avian influenza a (h7n9), highly pathogenic avian influenza (hpai) h5n1 and avian h6 influenza has increased in recent years 12 , which included all variables in the univariate analysis models; which included all variables in the univariate analysis models; an intercept (α); a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). www.nature.com/scientificreports www.nature.com/scientificreports/ media and public health campaigns against the new emerging virus have caused both the government and the public to be more concerned about influenza. the improved public perception of influenza may change people's health-seeking behaviours, especially in the epidemic seasons 52, 53 . furthermore, enlarged coverage of health care insurance in both urban and rural areas in recent years in china may also induce people to use more health services 54, 55 . a rapid increase in the numbers of airlines and high-speed railway transports in china has been reported in recent years 56 . these factors would make it easy to transmit the influenza virus at a larger scale and in a shorter time across the country 56-58 . the spatial pattern. the bym model includes both a spatial conditional autoregression component and a heterogeneous random effect component. this structure allows us to know how much of the residual disease risk is due to spatially structured variation and how much is unstructured overdispersion 22 . the spatially structured conditional autoregression term demonstrated areas of spatial patterning and similarity among prefectures. the results of spatially structured variation show a distinguished spatial pattern of risk of influenza across prefectures in china. the highest-risk areas clustered in the middle part of china, while the lowest-risk areas were distributed in the east, northwest and southwest. different patterns of influenza between the north and south in china were well reported 3, 16, 20, 34, 41, 59 . in china, the line following the qinling mountain range in the west and the huaihe river in the east is often used to split the mainland into the north and the south 34 . in this study, we observed clustering in both the north and the south in the middle part of china. the unique structured spatial patterns may be attributed to the shared risk factors among the neighbouring areas. this may be associated with similarities in the climatic zone, the predominant subtype of the virus at the time of epidemics, socioeconomic background or lifestyles. the last important factor should not be ignored. some studies reported that clustering of diseases may be a consequence of spatial heterogeneity in surveillance efforts 60,61 . the space-time interaction. the space-time interaction is a random effect term, which is interpreted as the residual effect after the unstructured, spatially structured and time effects are modelled and represent sporadic short-term outbreaks or clusters. the changes and circulations of virus subtypes may determine the characteristics of the space-time interaction terms. the year 2009 was the critical point according to the results of the spatiotemporal analysis. there are four types of ili activities: sporadic, local outbreak, regional outbreak and widespread outbreak in flunet (www. who.int/flunet), global influenza surveillance and response system (gisrs) 62, 63 . since the first case of influenza a (h1n1)pdm09 was reported on may 9, 2009, in mainland china, the type a (h1n1)pdm09 virus has been detected in all ili activities according to the data from flunet. the yearly ili activities may be partially associated with the changes and similarities in the patterns of the space-time interactions from 2005 to 2018. from the flunet data mentioned above, we found that sporadic ili activities were dominant in 2005, 2006, 2007 and 2008. correspondently, we found more areas with high relative risk in these 4 years in the space-time term. this implies that the more sporadic the activities are, the larger the variations in the spatiotemporal distribution of the risk of influenza. in contrast, the large outbreaks account for most ili activities in the years 2009, 2010, 2017 and 2018. few prefectures were observed to have a relative risk greater than 2 or 3 during that period. large outbreaks, especially large regional and widespread outbreaks, may reduce the differences in the incidence risk of influenza among the areas and times on a large scale. strengths. this work adds to the existing research on influenza epidemiology in the following ways. first, the study initially presents the spatiotemporal distributions with higher-resolution spatial data than has been reported in china for the last 14 years, which allows more opportunity for focused investigations and interventions. next, we used the exceedance probabilities instead of the observed risk estimates to identify those areas for which the increased risk was highly unlikely to be due to chance. then, this study also provided a baseline model that can be extended to include social, economic, ecological, and environmental factors, as well as intervention measures to explore their associations with influenza. finally, the methods in this study offer practical tools for spatial analysis of other notifiable infectious diseases in cnidrs. there are some limitations to this study. cnidrs is a passive surveillance system, and accessibility to health facilities and patient visit behaviour may affect the number of cases reported. we collected both clinically diagnosed and laboratory-confirmed cases in cnidrs, so misdiagnosis and misreporting are unavoidable because it is difficult to distinguish influenza from other respiratory viruses without laboratory testing, especially in the non-epidemic seasons. this paper outlined the application of the bayesian spatiotemporal model to assess the relative disease risk of influenza at the prefecture level in mainland china. we observed an increased incidence trend of influenza from 2005 to 2018 that was fairly steady in the first 4 years and increased rapidly in the last 3 years. clusters of prefectures with high relative risk values concerning influenza incidence were identified in the central part of china. the identification of high-risk areas is especially a priority in china because the limited resources available for disease control need to be focused on the places most in need. we hypothesize that the insufficient flu vaccine supplements, low vaccine uptake, the newly emerging influenza a (h1n1)pdm09 and expansion of influenza surveillance efforts might be the major causes of the dramatic changes in outbreak and spatiotemporal epidemic patterns. future research with more risk factors at the national and local levels is necessary to explain the changing spatiotemporal patterns of influenza in china. model specifications for spatiotemporal analysis. the besag york mollié (bym) convolution model was used as a baseline model 22 . using the notation of banerjee et al. 65 , the bym model is as follows: • n is the number of areas. the y i counts of influenza cases in area i are independently identically poisson distributed. θ i is the risk for area i. e i is the number of expected cases of influenza in area i, which acts as an offset. • α quantifies the average incidence risk of influenza in all the prefectures. • ν i is a spatially unstructured random effects component that is i.i.d normally distributed with mean zero. • υ i is a spatially structured component using an intrinsic conditional autoregressive structure (icar). the random effect for each area ζ i is thus the sum of a spatially structured component υ i and an unstructured component ν i . it is termed a convolution prior 22, 66 . the bym model was extended to include a linear term for space-time interaction and a nonparametric spatiotemporal time trend. possible random effects specifications for the temporal term include a linear time trend (β j ), a random time effect (γ j ), a first-order random walk (γ 1j ), a second-order autoregression (γ 2j ), etc. 25 . four types of interactions are proposed in knorr-held (2000) 28 , see knorr-held (2000) 28 for a detailed description. in this study, we assume no spatial and temporal structure on the interaction, and therefore, δ ij ∼ normal(0; τ δ ). four candidate models were tested and compared: in model 4, the space-time interaction is a random effect term and is interpreted as the residual effect after the unstructured, spatially structured and time effects are modelled and represent sporadic short-term outbreaks or clusters. model selection was based on deviance information criteria (dic), which take into consideration the posterior mean deviance, a bayesian measure of model fit, and the complexity of the model. a smaller dic indicates a better fit of the model 67 . the final linear model consisted of an intercept (α); a vector of national-level explanatory variables ∑ β = ( x ) k 1 n k k for the yearly total number of lot release of influenza vaccines by the china food and drug administration, the positive rate of influenza a (h1n1)pdm09 among the number of ili specimens processed, the percentage of influenza a (h1n1)pdm09 among all the positive influenza specimens, and protocol changes; a spatially unstructured random effect term (ν i ); a spatially structured conditional autoregression term (υ i ); a first-order random walk-correlated time variable (γ 1j ); and an interaction term for time and place (δ ij ). the prefecture-specific structured and unstructured spatial risks of influenza compared to the whole spatial risk of all prefectures are obtained by applying an exponential transformation to the components of ν i and υ i , respectively. the relative risk of space-time interaction is computed by the exponentiation of the term δ ij . the exceedance probabilities of spatial risk and risk of space-time interaction were also calculated. the exceedance probability represents the posterior probabilities for an area's spatial risk estimate exceeding some pre-set value and has been proposed as a bayesian approach to hotspot identification 68, 69 . all spatial models were computed using integrated nested laplace approximations (inla), which have been developed as a computationally efficient alternative to mcmc 70 . all spatial analyses were conducted within microsoft r open version 3.5 using the r-inla package (version 18.07.12). ethics approval. the authors assert that all of the procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and the helsinki declaration of 1975 as revised in 2008. this article does not contain any studies of human or animal subjects performed by any of the authors. since this analysis was based on anonymous aggregated statistical data, patient informed consent and ethical committee approval were not required in china. disclaimer. the views expressed are those of the authors and do not necessarily represent the official policy of the chinese center for disease control and prevention. the burden of influenza: a complex problem the substantial hospitalization burden of influenza in central china: surveillance for severe, acute respiratory infection, and influenza viruses estimates of global seasonal influenza-associated respiratory mortality: a modelling study pandemic influenza: certain uncertainties temporal patterns of influenza a and b in tropical and temperate countries: what are the lessons for influenza vaccination? plos one 11, e0152310 seasonal influenza vaccine supply and target vaccinated 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models: development and evaluation with a focus on cluster detection approximate bayesian inference for latent gaussian models by using integrated nested laplace approximations this study was supported by grants from the key joint project for data center of the national natural science j.q. ma. conceived, designed, and supervised the study. y.w. zhang., x.f. wang. and y.f. li. collected and cleaned the data. y.w. zhang. analysed the data and wrote the drafts of the manuscript. j.q. ma. and y.w. zhang. interpreted the findings. all authors read and approved the final manuscript. the authors declare no competing interests. correspondence and requests for materials should be addressed to j.m. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. key: cord-026384-ejk9wjr1 authors: crilly, colin j.; haneuse, sebastien; litt, jonathan s. title: predicting the outcomes of preterm neonates beyond the neonatal intensive care unit: what are we missing? date: 2020-05-19 journal: pediatr res doi: 10.1038/s41390-020-0968-5 sha: doc_id: 26384 cord_uid: ejk9wjr1 abstract: preterm infants are a population at high risk for mortality and adverse health outcomes. with recent improvements in survival to childhood, increasing attention is being paid to risk of long-term morbidity, specifically during childhood and young-adulthood. although numerous tools for predicting the functional outcomes of preterm neonates have been developed in the past three decades, no studies have provided a comprehensive overview of these tools, along with their strengths and weaknesses. the purpose of this article is to provide an in-depth, narrative review of the current risk models available for predicting the functional outcomes of preterm neonates. a total of 32 studies describing 43 separate models were considered. we found that most studies used similar physiologic variables and standard regression techniques to develop models that primarily predict the risk of poor neurodevelopmental outcomes. with a recently expanded knowledge regarding the many factors that affect neurodevelopment and other important outcomes, as well as a better understanding of the limitations of traditional analytic methods, we argue that there is great room for improvement in creating risk prediction tools for preterm neonates. we also consider the ethical implications of utilizing these tools for clinical decision-making. impact: based on a literature review of risk prediction models for preterm neonates predicting functional outcomes, future models should aim for more consistent outcomes definitions, standardized assessment schedules and measurement tools, and consideration of risk beyond physiologic antecedents. our review provides a comprehensive analysis and critique of risk prediction models developed for preterm neonates, specifically predicting functional outcomes instead of mortality, to reveal areas of improvement for future studies aiming to develop risk prediction tools for this population. to our knowledge, this is the first literature review and narrative analysis of risk prediction models for preterm neonates regarding their functional outcomes. preterm infants have long been recognized as a population at high risk for mortality and adverse functional outcomes, including cerebral palsy and intellectual impairment. 1 as mortality rates for preterm neonates decline and more survive to childhood, 2,3 attention has increasingly turned towards measuring longer-term morbidities and related functional impairments during childhood and young-adulthood, as well as identifying risk factors related to these complications. 4, 5 while child-specific characteristics, such as gestational age, birth weight, and sex, are well established as predictors of adverse neurodevelopmental outcomes, 6-8 recent work has identified additional factors, including bronchopulmonary dysplasia and family socioeconomic status, that are correlated with relevant outcomes, such as poor neuromotor performance and low intelligence quotient at school age. 9 in clinical settings, the assessment of prognosis can vary widely across neonatologists, 10 making a valid and reliable predictive model for long-term outcomes a highly sought-after clinical tool. moreover, predicting outcomes is vital when making decisions regarding which therapeutic interventions to apply, when providing critical data to parents for informed decision-making, and when matching infants with outpatient services to best meet their needs. in addition, prediction models are useful in evaluating neonatal intensive care unit (nicu) performance and allowing for between-center comparisons with proper adjustment for the severity of cases being treated. 11 numerous prediction tools have been developed to quantify the risk of death for preterm neonates in the nicu setting, including the score for neonatal acute physiology (snap) and the clinical risk index for babies (crib). 12 the national institute of child health and human development (nichd) risk calculator, predicting survival with and without neurosensory impairment, is widely used to counsel families in the setting of threatened delivery at the edges of viability. 13 furthermore, there are numerous other models that use clinical data from the nicu stay to predict risk for poor functional outcomes in infancy and school age. 14, 15 while several studies have categorized and evaluated the risk prediction models developed and validated in recent decades for mortality, 12, 16 no studies have compared and contrasted risk prediction models for non-mortality outcomes. recently, linsell et al. 17 published a systematic review of risk factor models for neurodevelopmental outcomes in children born very preterm or very low birth weight (vlbw). however, this review focused primarily on overall trends in model development and validation rather than a detailed consideration of individual models. in this article, we conduct an in-depth, narrative review of the current risk models available for predicting the functional outcomes of preterm neonates, evaluating their relative strengths and weaknesses in variable and outcome selection, and considering how risk model development and validation can be improved in the future. towards this, we first provide an overview of the different risk models developed since 1990. we then frame our review of these models in terms of the outcomes predicted, the range of predictors considered, and the statistical methods used to select the variables included in the final model, as well as to assess the predictive performance of the model. finally, the ethical implications of integrating risk stratification into standard clinical care for preterm neonates are considered. we conducted a manual search for relevant literature via pubmed, entering combinations of key terms synonymous with "prediction tool," "preterm," and "functional outcome" and reading the abstracts of resulting studies (table 1 ). studies with abstracts that appeared related to our review were then read in full to identify prediction models that were eligible for inclusion. reference lists of included studies were also reviewed, as were articles that later cited these original studies. prediction tools were defined as multivariable risk factor analyses (>2 variables) aiming to predict the probability of developing functional outcomes beyond 6 months corrected age. models that solely investigated associations between individual risk factors and outcomes were excluded, as were models that were not evaluated for predictive ability in terms of either a validation study or an assessment for performance, discrimination, or calibration. tests used to evaluate a model's overall performance were r 2 , adjusted r 2 , and the brier score. the use of a receiver operating characteristic (roc) curve or a c-index evaluated a model's discrimination, and the hosmer-lemeshow test was considered to evaluate a model's calibration. 18 preterm neonates were defined as <37 weeks of completed gestational age. models with vlbw neonates <1500 g were also included, since in the past birth weight served as a substitute for measuring prematurity when gestational age could not be accurately determined. models were excluded if they used a cohort entirely composed of infants born prior to 1 january 1990; those born after 1990 were likely to have had surfactant therapy available in the event of respiratory distress syndrome, which significantly reduced the morbidity and mortality rates among preterm neonates nationwide. 19, 20 models were also excluded if they limited their prediction to the outcome of survival, if they incorporated variables measured after initial nicu discharge, or if they included subjects who were not necessarily transferred to a nicu for further care following delivery. finally, we excluded tools that only predicted outcomes to an age of <6 months corrected age, as well as case reports, narrative reviews, and tools reported in languages other than english. overview of risk prediction models table 2 lists all 32 studies with risk prediction models that meet the inclusion and exclusion criteria. [13] [14] [15] from these, a total of 43 distinct models were reported. from mortality to neurodevelopmental impairment since 1990, several mortality prediction tools have been evaluated in regards to their ability to predict the likelihood of neurodevelopmental impairment (ndi) among neonates surviving to nicu discharge. one such model is the crib, which incorporates six physiologic variables collected within the first 12 h of the preterm infant's life: birth weight, gestational age, presence of congenital malformations, maximum base excess, and minimum and maximum fio 2 requirement. 50 fowlie et al. 24 evaluated how crib models obtained at differing time periods over the first 7 days of life predicted severe disability among a group of infants born >31 weeks gestational age or vlbw. in another study, fowlie et al. 25 incorporated cranial ultrasound findings on day of life 3 along with crib scores between 48 and 72 h of life into their prediction model. subsequent studies analyzed the crib in its original 12-h form and, with only one exception, 23 determined that it was not a useful tool for predicting long-term ndi or other morbidities. [26] [27] [28] [29] a second example is the snap score. 51 snap uses 28 physiologic parameters collected over the first 24 h of life to predict survival to nicu discharge, and was modified to predict ndi at 1 year and 2-3 years of age. a subsequent assessment of both the snap and the snap with perinatal extension 42 showed a poor predictive value for morbidity at 4 years of age for children born vlbw and/or with gestational age ≤31 weeks. 28 finally, the neonatal therapeutic intervention scoring system, a comprehensive exam-based prediction tool for mortality, 52 was found to have a poor predictive value for adverse outcomes at 4 years of age in children born very preterm or vlbw. 28 shortened forms of the early physiology-based scoring systems were developed and assessed for their ability to predict outcomes in childhood. application of the crib-ii on a small cohort (n = 107) of infants born <1250 g predicted significant ndi at 3 years of age. 39 however, a subsequent evaluation in a much larger cohort (n = 1328) of preterm infants <29 weeks gestational age concluded that the crib-ii did no better than gestational age or birth weight alone in predicting moderate to severe functional disability at 2-3 years of age. 40 studies have supported an association between the snap-ii and snappe-ii scores and neurodevelopmental outcomes and small head circumference at 24 months corrected age. high snap-ii scores were shown to correlate with adverse neurological, cognitive, and behavioral outcomes up to 10 years of age within a large cohort (n = 874) of children born very preterm. 43 antenatal risk factors several groups have used data from the nichd's neonatal research network (nrn) to design and test various risk prediction models for extremely low birth weight (elbw) newborns. one of the most widely used risk prediction tools developed from this cohort was by tyson et al., 13 postnatal morbidity a large cohort study (n = 910) from schmidt et al. 15, 32 used data from elbw neonates 500-999 g enrolled in the international trial of indomethacin prophylaxis in preterms (tipp). they found that the presence of three morbidities at 36 weeks post-menstrual age -bronchopulmonary dysplasia, serious brain injury, and severe retinopathy of prematurity-had a significant and additive effect on the risk for death or poor neurologic outcome at 18 months corrected age. they developed a model from this relationship that has been corroborated in two studies with smaller samples and by schmidt et al. 15 in a separate, large cohort in which the definition of poor outcome was expanded from solely ndi to "poor general health." 33, 34 letting the machines decide some innovative work has been recently performed by ambalavanan et al. 14, 35 in creating several risk prediction models. 45 along with studies developing risk prediction tools with data from the nrn and the tipp to predict the outcomes of death and ndi or solely ndi, the group made the only risk prediction tool for the outcome of rehospitalization, both general and specifically for respiratory complications, using a combination of physiologic and socioeconomic variables incorporated into a decision tree approach. they have also been the only group to create neural network-trained models, using the same small cohort to predict major handicap, low mental development index (mdi), or low psychomotor development index (pdi). the advantage of using neural networks-algorithms that can "learn" mathematical relationships between a series of independent variables and a set of outcomes-is the ability to model complex or nonlinear relationships that can be elucidated by the model without having to consider these relationships a priori (as is typically required when using multiple regression models). despite the use of innovative approaches, however, none of these models differed from other studies in predictive strength or even had high predictive efficacy. 31 limitations of prior approaches the above literature review highlights the substantial interest in developing a clinically useful risk prediction model and the limits of efforts to date. notwithstanding their differing inclusion and exclusion criteria, existing risk prediction models are relatively similar in terms of variables selected, outcomes analyzed, and statistical strategies employed. with few exceptions, the limitations of existing risk prediction models are especially apparent in their reliance on solely biologic variables and traditional analytic methods ill-equipped to handle the statistical complexity necessary for risk modeling. identifying important outcomes. the majority of risk prediction models defined ndi as their primary outcome of interest. making a determination of impairment often relies on standardized measures of cognition in concert with neurosensory deficits. yet, researchers often define ndi in different ways, making betweenstudy comparisons difficult. ndi is a construct relating to global abilities encompassing cognition, language, motor function, and vision and hearing. while the tools used to identify ndi are often also used to make diagnoses of developmental delay, ndi is not a clinical term or diagnosis in and of itself. many of the remaining studies also predicted functional outcomes, such as academic performance, executive function, language ability, and autism spectrum disorder (asd). these outcomes may be more meaningful to parents and providers than ndi. 54 to date, only four studies have considered outcomes unrelated to neurodevelopment, such as impaired pulmonary function, "poor general health," and rehospitalization rates. 15, 28, 45, 49 while the emphasis on ndi is unsurprising given the high-risk population, moderate to severe ndi only affects a minority of the preterm population. 55, 56 studies have revealed numerous additional adverse outcomes that preterm individuals are more likely to experience compared to their full-term counterparts, such as impaired respiratory, cardiovascular, and metabolic function. [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] neurodevelopment has been linked to chronic health problems in later childhood. 67 limiting risk prediction to moderate to severe ndi therefore ignores other, more common complications that preterm infants are likely to face that have an impact on neurodevelopment. this represents a missed opportunity for researchers to better understand what variables influence the likelihood that these problems occur. the impact of developmental disability on the child and family is completely absent from current risk models. health-related quality of life (hrql), which distinguishes itself as a personal rather than third-party valuation of a patient's physical and emotional well-being, is being increasingly appreciated as an important metric necessary to fully understand the impact of prematurity. 68 in a french national survey, the majority of neonatologists, obstetricians, and pediatric neurologists stated that predicting hrql in the long term for preterm infants would be beneficial for consulting parents about what additional responsibilities they can anticipate in caring for their child. 69 the trajectory of hrql from childhood to young-adulthood appears to improve in both vlbw and extremely low gestational age populations. 70 prediction modeling might aid in determining which factors could positively or negatively impact hrql in this vulnerable population. finally, we must consider the age at which outcomes are being predicted. it is evident that lower gestational age is inversely proportional to rates of ndi and academic achievement in adolescence. 71, 72 however, the vast majority of risk prediction models assessed outcomes at the age of 3 years or less, with only three studies doing so at 10 years of age or above. although early childhood outcomes may give clues about later development, many problems do not manifest until later in childhood, such as learning disabilities and certain psychiatric disorders. developmental disability severity can fluctuate throughout childhood, with catch-up occurring in early preterm children and worsening delay in some moderate and late preterm children. 73, 74 although cohorts of preterm infants are not usually followed for more than several years, likely due to lack of resources and expense, recent studies have used data from national registries to link neonatal clinical data to sampled adults, providing evidence of increased rates of adverse neurodevelopmental, behavioral, and educational outcomes among adults born preterm. 75, 76 opportunities are therefore available to use long-term data to extend risk prediction models beyond the first few years of life. variable selection. most of the risk models reviewed relied primarily on physiologic and clinical measures obtained during the nicu stay. while an emphasis on biologic risk factors is clearly reasonable given the known associations between perinatal morbidities and long-term outcomes, there is strong evidence in the literature suggesting associations between sociodemographic factors like parental race, education, and age, and outcomes such as cognitive impairment, cerebral palsy, and mental health disorders in children born preterm. more specific socioeconomic variables such as lower parental education, maternal income, insurance status, foreign country of birth by a parent, and socioeconomic status as defined by the elly-irving socioeconomic index have been repeatedly correlated with reduced mental development index, psychomotor development index, intelligence quotient, and social competence throughout childhood. 71, 72, [77] [78] [79] [80] [81] [82] the geographic area in which preterm neonates are raised could also have a profound influence on their development. neighborhood poverty rate, high school dropout rate, and place of residence (metropolitan vs. non-metropolitan) have all been correlated with academic skills and rate of mental health disorders among low birth weight children. 83, 84 only 12 of the 43 models reviewed included socioeconomic variables. this may be due, at least in part, to the difficulty in obtaining social, economic, and demographic data; these variables are often not collected upon hospital admission. additionally, socioeconomic information is often poorly, inaccurately, and variably recorded or is largely missing. 85 some risk prediction models collected socioeconomic variables at the follow-up visit when outcomes were assessed. this is an imperfect method given that factors such as household setting and family income may change substantially in the years following nicu discharge and affect children's health. 86, 87 in some models, socioeconomic variables were not included because they did not significantly improve the model's predictive ability. 45 testing the effects of social factors on infant and child outcomes requires samples that are socially and economically diverse. even large, diverse study populations may become more homogeneous over time, as subjects of lower socioeconomic status and non-white race are more likely to drop out of studies dependent on long-term follow-up. 41 and treating socioeconomic variables as statistically independent factors rather than interrelated might minimize the impact of contextual information on neurodevelopmental outcomes. model development. of the 32 papers included in the review, 12 reported on de novo risk prediction tools. the other 20 studies either evaluated a previous model or adjusted a prior model by changing the times at which data were collected or by adding additional variables. the approach to prediction tool development was almost uniform among the studies, with nine of the models solely using regression techniques to select variables. ambalavanan et al. deviated from this method in three separate studies: two using classification tree analysis, 35, 45 and one using a four-layer back-propagation neural network. 31 each new model-with the exception of the neural networkbased model by ambalavanan et al. 35, 45 -depended on an approach in which individual variables were selected and treated as independent of one another as they were analyzed in their ability to predict the outcome of interest. yet, variables may, in fact, not act independently. while parsing the roles of potential interrelationships may be computationally onerous and treating them independently may lead to a more parsimonious model, this may be at the expense of accuracy. alternative computational approaches are needed to account for the differential likelihoods of certain outcomes on the causal pathway from preterm birth to later childhood outcome. nonlinear statistical tools should be further utilized in risk prediction model development to examine the relationships between variables and outcomes of interest. machine learning, for instance, is a method of inputting a group of variables and generating a predictive model without making assumptions of independence between the factors or that specific factors would contribute the most to the model. 88 different forms of machine learning have already been employed in nicu's to extract the most important variables for predicting outcomes such as days to discharge. 89 the non-independence of risk factors is also complicated by the role of time in models of human health and development. the lifecourse framework describes how an accumulation or "chains" of risk experienced over time and at certain critical periods impact later health outcomes. 90 in the context of preterm birth, the risk of being born early is not uniform across populations and dependent on a given set of maternal risks. in turn, the degree of prematurity imparts differential risk for developing complications such as bronchopulmonary dysplasia, necrotizing enterocolitis, or retinopathy of prematurity. these morbidities then, in turn, increase risks for further medical and developmental impairment. these time-varying probabilities can be modeled and incorporated into prediction tools to more accurately capture the longitudinal and varying relationships between exposures and outcomes and improve thereby estimations of risk. [91] [92] [93] a final methodological concern regarding model development is whether and how the competing risk of death is considered when the outcome being predicted is non-terminal. consider, for example, the task of developing a model for the risk of ndi at 10 years of age. how one handles death can have a dramatic effect on the model, especially since mortality is relatively high among preterm infants. moreover, if death is treated simply as a censoring mechanism, as it is often done in time-to-event analyses such as those based on the cox model, then the overall risk of ndi will be artificially reduced; those children who die before being diagnosed with ndi will be viewed as remaining at risk even though they cannot possibly be subsequently diagnosed with ndi. while an alternative to this would be to use a composite outcome of time the first of ndi or death, doing so may result in a model that is unable to predict either event well. instead, one promising avenue is to frame the development of a prediction model for ndi within the semi-competing risks paradigm. 94, 95 briefly, semicompeting risks refer to settings where one event is a competing risk for the other, but not vice versa. this is distinct from standard competing risks, where each event is competing for the other (e.g., death due to one cause or another). to the best of our knowledge, however, semi-competing risks have not been applied to the study of long-term outcomes among preterm infants. model evaluation. waljee et al. 18 provide a summary of methods for assessing the performance of a predictive model, categorizing them into three types: overall model performance, which focuses on the extent of variation in risk explained by the model; calibration, which assesses differences between observed and predicted event rates; and discrimination, which assesses the ability to distinguish between patients who do and do not experience the outcome of interest. the majority of studies in our review assessed their models with roc curve analysis, a method of assessing discrimination. while widely used, there is some debate with regard to roc-based assessments, specifically in regard to its lack of sensitivity in assessing differences between good predictive models. 96 although several novel performance measures for comparing discrimination among models have been proposed, none have been employed in the context of comparing risk prediction tools for preterm neonates. 97, 98 few studies employed analyses other than roc. only six in our review assessed overall performance with r 2 or partial r 2 , and five evaluated calibration using the hosmer-lemeshow test. another four studies assessed internal validation with either an internal validation set or bootstrapping techniques. 99 there were nine studies meeting inclusion criteria solely because they had models that were externally validated via other studies. schmidt et al. 32 reported odds ratio associations for their 3-morbidity model, which are not a reliable method of determining the strength of risk prediction tools. 100 future risk model assessments for preterm neonates should at minimum include an roc curve analysis, although assessments of overall performance and calibration would also be helpful. validation with a different sample from the development set is also advised, ideally with a population outside the original cohort. 18 conclusion risk assessment and outcomes prediction are valuable tools in medical decision-making. fortunately, infants born prematurely enjoy ever-increasing likelihood of survival. research over the past several decades has highlighted the many influences, physiologic and psychosocial, affecting neurodevelopment, hrql, and health services utilization. yet, the wealth of knowledge gained from longitudinal studies of growth and development is not reflected in current risk prediction models. moreover, some of the most wellknown and widely used tools today, such as tyson et al.'s 13 fivefactor model, were developed nearly two decades ago. as advances in neonatal intensive care progressively reduce the risk of certain outcomes, it is clear that these older models require updating if they are to be of continued clinical use. it should be recognized that there are potential ethical ramifications to incorporating more psychosocial factors and outcomes into risk prediction models, such as crossing the line from risk stratification to "profiling" patients and offering different treatment decisions based on race or class. 101 however, physician predictions without the aid of prediction tools are highly inconsistent during counseling at the margins of viability, and further research is needed regarding the level of influence that physicians actually have on caregiver decision-making during counseling, as well as the extent to which risk prediction tools would change their approach to counseling. 10 in addition, despite recent innovation in statistical approaches to risk modeling, such as machine learning, most prediction tools rely on standard regression techniques. insofar that risk prediction models will continue to be developed for preterm neonatal care, making use of the clinical data available in most modern electronic health records and taking into consideration the analytic challenges related to unequal prior probabilities of exposures, non-independence of variables, and semi-competing risk can only strengthen our approach to predicting outcomes. we therefore recommend taking a broader view of risk, incorporating these concepts in creating stronger risk prediction tools that can ultimately serve to benefit the long-term care of preterm neonates. c.j.c. and j.s.l. designed and carried out this literature review. c.j.c., j.s.l., and s.h. worked jointly in the analysis and interpretation of the literature review results, as well as the drafting and revision of this article. all three authors gave final approval of the version to be published. on the 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of prediction models: a framework for traditional and novel measures novel metrics for evaluating improvement in discrimination: net reclassification and integrated discrimination improvement for normal variables and nested models multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker just health: on the conditions for acceptable and unacceptable priority settings with respect to patients' socioeconomic status auc: 0.703 sensitivity: 27.6% specificity: 87.3% competing interests: the authors declare no competing interests.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-256432-53l24le2 authors: yang, honglin; pang, xiaoping; zheng, bo; wang, linxian; wang, yadong; du, shuai; lu, xinyi title: a strategy study on risk communication of pandemic influenza: a mental model study of college students in beijing date: 2020-09-04 journal: risk manag healthc policy doi: 10.2147/rmhp.s251733 sha: doc_id: 256432 cord_uid: 53l24le2 purpose: to understand the characteristics of risk perception of influenza pandemic in college students with prominent frequency and the differences between these risk perceptions and professionals. then, offering a proposal for the government to improve the efficiency of risk communication and health education. methods: according to the mental model theory, researchers first draw a framework of key risk factors, and then they ask these students about the understanding of the framework with questionnaire and then making concept statistics and content analysis on the respondents’ answers. results: researchers find some students’ misunderstanding of pandemic including excessive optimism to the consequences of a pandemic, a lack of detailed understanding of mitigation measures, and negative attitudes towards health education and vaccination. most students showed incomplete and incorrect views about concepts related to the development and exposure factors, impact and mitigation measures. once threatened, it may lead to the failure of decision-making. the majority of students we interviewed had positive attitudes towards personal emergency preparedness for a pandemic influenza and specialized health education in the future. conclusion: researchers suggest that the government should make a specific pandemic guidance plan by referring to the risk cognitive characteristics of college students shown in the research results, and update the methods of health education to college students. influenza, which is a highly variable infectious disease that can quickly evolve into a pandemic, can pose a significant threat to people's health. 1 the corresponding emergency response measures require the active cooperation of the public to work effectively. because of its wide range of impact and potential mortality, effective risk communication will help the public understand information related to influenza. 2 compared to risk communication in other fields, when public health events occur, the government often turns to experts to ask them what the public should know. so, it is a challenge that how to effectively transform scientific knowledge into useful structures and non-professional backgrounds. 3 our researchers use influence diagrams from mental model interview to analyze the critical risk factors of flu, which can improve student`s ability of decision-making to maintain their physical health. [4] [5] [6] [7] [8] morgan et als monograph on mental model theory argues that everyone relies on their mental models to understand information. it grows into a unique and intrinsic pattern as individuals grow, similar to a workflow chart. splitting the outside world into multiple components to help us understand may not be perfect; however, it affects our way of thinking and behavior choice. 3, 9, 10 a person's mental model is influenced by various factors, including personal experience, acquired learning, and living environment, and these factors are changeable and also important in affecting our health-related behaviors. 3, [11] [12] [13] [14] [15] therefore, targeted education can help an individual correct misunderstanding in their mental models and then improve their risk management. in china, there is no application of mental model theory in the field of health education and no special pandemic preparedness guideline for the general public. however, in western countries, particularly the united states, many scholars have conducted substantial research in this area. lazrus et al have studied the public mountain flood communication framework in boulder county, colorado state. 16 casman et al 17 used the influence map to establish a dynamic risk model for waterborne cryptosporidiosis, which defines "key awareness variables" in risk communication and assigns scores for evaluation. our researchers hope to use the mental model theory to analyze the most critical risk factors of influenza pandemic from a broader perspective and find out college students` risk perception of these factors. the understanding and cognitive characteristics help improve the communication work of the government, which is the aim of this article. this study refers to the impact map formed by morss et al in the flood risk communication of boulder county 18 and draws the risk factor framework of the influenza pandemic. the entire frame is an analysis of disaster events from a macro perspective, including "causes," "development," "response," "event impact" and "risk information dissemination." then, through literature research and expert consultation, the researchers summarized the concept of the communication framework and initially formed its content suitable for the influenza epidemic. the content of the whole frame consists of the causes of influenza epidemics, the impact of pandemics, emergency preparedness and strategies of different groups, risk information, and emergency response decisions, as shown in figure 1 . the researchers subsequently searched for the corresponding supporting documents according to the content of the framework and conducted expert seminars. combined with the materials of the literature and expert opinions, the authors initially wrote identical concept items under each part of the frame. finally, we used the delphi method to invite 18 experts from the related fields to judge the structure, importance and scientific nature of these items. 19 the purpose of mental model interviews is to determine which concepts or beliefs are "out there" with sufficient frequency such that in smaller samples, these concepts or beliefs become reasonable. there is no standard method for determining sample size in relevant theories and research practice. 3 according to professor morgan's monograph and related research examples, the sample size for a mental model interview should be 20~30, at which point new information has reached saturation. 3 based on these research facts, combined with the research design of lazrus and morss, 16, 18 we recruited the first 30 respondents from 5 randomly selected non-medical college by telephone and posters. to avoid confounding bias, these students are also from non-medical majors (including russian, finance, urban planning and marketing) and have not studied medical related professional courses. after all the investigations have been completed, we discussed the results and deleted two poor interview results, and then drew a line chart of information saturation according to the number of concepts mentioned by the respondents in figure 2 . we found that after the 22nd interviewee, information saturation began to show a downward trend, and subsequent respondents did not propose new concepts. we believe that the information provided by these 28 respondents can meet the sample size required for the analysis of this study, because the purpose of mental model study is not to use statistical methods to analyze the distribution of some risk cognition in the population, but to find out which concepts or beliefs, are "out there" with some reasonable frequency, 3 so as to help government departments identify what should be focused on when developing guidance programs and health education materials for this population. the interview began with an open question, such as "please tell us about the pandemic." our investigators guided the respondents to elaborate on their main concepts, then details of the outbreak, as well as the mitigation measures that should be employed. if the interviewer had experienced emergencies, then they were encouraged to talk about the decision or idea at that time. the interview results were subsequently transcribed, encoded and classified using the coding software atlas.ti. we also conducted a quantitative analysis of the results of the compilation, then created a statistical chart, observed the degree of attention of the respondents, and compared these results with the risk perception of experts to determine the interviewee's understanding of the related concepts and other features. the questions used in this interview refer to a questionnaire in the study of skarlatidou et al. 20 the interview covers the content in figure 1 . two researchers simultaneously coded the results of the interviews. the classification consistency index (holsti reliability) of the coder was subsequently calculated, 21 which fluctuated between 0.624 and 0.965, and the average reliability statistic was 0.749. according to the study of boyatzis and burrus, the coding reliability of trained different coders ranges from 0.74 to 0.80; 22 therefore, the reliability of the coder was within the normal range and displayed adequate consistency. information saturation trend provided by 28 respondents. for each of the respondents' answers to the number of concepts noted, the researchers first mapped the scatter plots. then, to better show the increase and decrease in the information provided by the respondents, polylines were used to connect the points. the content of the concept is derived from the framework of figure 3 and is described by the responses of all 28 respondents. here is the result of two rounds of delphi expert consultation. the value of the authority coefficient is 0.885 (>0.70), which indicates that the study has a good expert score. 19, 23, 24 as shown in table 1 , in the first round of expert consultation, the coordination coefficient of each item was 0.291 (p<0.001), and in the second round of expert consultation, the coordination coefficient was 0.324 (p<0.001), which was better than the first round and indicates that the opinions of the experts are consistent from the perspective of significance test. 25 finally, we created a communication framework for an influenza pandemic, as shown in figure 3 . it serves as the basis for our investigation of the problem content of college students and can also be regarded as a kind of "standardized communication content". the respondent may have a higher probability of taking the correct protective measures if he has a good understanding of the entire framework. communication framework of pandemic influenza. the frame is composed of six main conceptual dimensions; the central concept is the bold label, and the 2ndlevel concept in the box is the part. more complicated concepts in the framework are omitted; refer to the coding manual in the appendix. the whole frame contains 79 concepts, and the arrowhead represents the influence relationship of each part. the analogy part is listed separately to describe the events associated with the respondents. note: table 1 shows the statistical coefficient calculation results of the two delphi studies, and the p values of the two coefficients all meet the requirements. the researchers counted the percentage of respondents that mentioned a concept item. also, this study used a stacked bar chart to show the number of concepts mentioned by the 28 respondents ( figure 3 ). as shown in the graph, we distinguish the concept of different attributes in terms of dimensions (risk factors). the richness of the color can visually distinguish the depth of the mental model of each interviewee [the number of concepts mentioned by an interviewee], and we can determine which dimensions of the expert`s risk perception the public is highly aware of and in which areas the public lacks awareness. furthermore, the length of the bar graph reflects the number of concepts mentioned in the dimension: a taller bar graph reflects more relevant concept items indicated by the respondents and a deeper degree of understanding of the related content. for example, respondents 12, 16 and 21 knew more about the emergency response decisions during the pandemic, whereas interviewee #24 was less aware in this regard. figure 4 shows the differences in thinking about the risk of and coping with the influenza pandemic among different groups. even with a higher education level, each college student interviewee displayed a significant difference in the depth and detail of their mental model. some of the respondents' mental models appear particularly "scarce" (such as respondents #2 and 25). nearly all respondents discussed less information than the risk perception of experts. only one interviewee (interviewee #9) cited concepts that reflected almost all the parts of the communication framework in figure 2 . the other students did not suggest many more new concepts in the interview. their conceptual descriptions reflect the concern for specific content and common cognitive deficiencies and misunderstandings. the following sections discuss these best features of the interview answers. the interactions between multiple factors may affect the formation and development of pandemic influenza. several factors mentioned by our respondents are shown in table 2 ; 39% of the respondents believed that influenza virus variation was an essential cause of the pandemic. they used statements such as "new virus," "virus mutation," and "an unknown virus." additionally, 32% of the respondents referred to disease surveillance, which included "poor supervision of the source of infection" and "unchecked work", and they were more inclined to use terms to express their views (for example, "gene mutation", "isolation treatment", "infrared surveillance", and "take the body temperature"). forty-six percent of the respondents cited characteristics related to the international spread of the pandemic. interviewee #6 indicated "foreign virus carriers from foreign places into beijing." however, some respondents believed that climate factors could lead to flu cases because they confused pandemic influenza with seasonal flu, such as interviewee #7, who answered "when the seasons change, people may catch a cold easily. if they do not pay attention, a pandemic will happen if they don`t do that." many respondents (46%) also cited the impact of population density, including densely populated places and more floating cities with higher risk areas for influenza. other factors were less frequently cited by less than 17% of interviewee, including virus resistance, viral power, avian influenza immunity, and a human lack of immunity to new viruses. compared to the experts, the mental models of many of the students interviewed contained only part of the communication framework. although some key factors were cited by most of the respondents, other essential factors were rarely cited or were misunderstood by the respondents. for example, interviewee #16 believed that the flu was a "foodborne disease" and "caused by drugs." for individuals infected with influenza, no respondents discussed the impact of vulnerable groups on the development of the pandemic, and there was no further detailed description of the virus variation. a full understanding of these information can help people to evaluate the risk level in the environment, including which situations may have a higher risk of infectious diseases. another neglected concept is the lethality of the virus. no respondents mentioned this concept or discuss the content related to us. in fact, the lethal rate is also an important indicator of a new infectious virus. 26 from the perspective of scientific disease control, the lethal rate affects whether the virus has the characteristics of limited regional transmission (for example, ebola virus, its lethal rate is 50-90%, making the virus only intermittently epidemic in individual countries and regions, with certain limitations in time and space.) 27 from the perspective of promoting public participation in disease response, highrisk events can promote individual polar to make protective decisions. 28 knowing the virulence of the virus can avoid the negative attitude to personal disease prevention caused by fluke psychology. as shown in table 3 , approximately 29% of the respondents discussed the fatality of the flu, while only 14% of the respondents described the severe symptoms that could occur after the infection, such as interviewee #5: " . . . if there goes a pandemic, it would be more than a common cold. runny nose and sneezing or, maybe, pneumonia?" none of the respondents cited complications related to influenza infection. even if a real pandemic is only composed of common symptoms of fever and fatigue, complications such as pneumonia, myocarditis, and bronchitis are the real causes of death in some vulnerable patients. 29, 30 therefore, although most of the respondents understood that the flu could have serious health threats, they did not understand how people die as a result of the flu. these misunderstandings may be related to some respondents' personal and onesided understanding of the pandemic and the lack of targeted health education. for example, interviewee #10 stated "that is, people usually do not pay attention to clothes, then they catch a cold. it is quite a normal situation every year." most respondents also discussed the social and economic impacts of the pandemic, and 46% of the respondents referred to negative effects on schools, shops, public transport, and other infrastructure during the pandemic, such as interviewee #14: "schools may shut down . . . the shops outside may be closed because of this disease, and the economy may be seriously affected because everyone will hide at home." most of the types of infrastructure, of which transportation was the most frequently cited, were generally quoted as examples of people during the sars or bird flu period, such as interviewee #11 who stated, "everyone is not going out at the time of the outbreak . . . wearing a mask if you have to go outside." thirty-two percent of the respondents were worried about overburdened hospital patients during the pandemic. some of the respondents (28%) also imagined disastrous consequences, including the impact of the pandemic on the community. according to interviewee #16, for a long time . . . our life may be threatened, many people steal food and drugs and will be locked inside their house . . . not just the direct impact, it will bring other serious problems. although the respondents mentioned the relevant concepts in the communication framework, they fail to understand the severe damage that pandemic influenza could cause to individual health; moreover, they are not fully aware of panic actions during the outbreak. the most common panic behavior is to escape from the epidemic area. to avoid disaster is people's instinctive behavior, especially in the outbreak of infectious diseases. 31 in fact, during the outbreak of the novel coronavirus (covid-19) in china, people in some areas fled the outbreak area. and it happened to be the chinese new year's holiday. lots of college students returned home to celebrate festival, which strongly increased the risk of virus transmission. although these situations have not caused irreparable serious consequences, they have also brought great interference to the case investigation and disease monitoring in all provinces of the country. surprisingly, there are 30% of the respondents believed that a negative impact of a flu pandemic would be minimal or more positive, and nearly all of them stated that it "feels like the pandemic is far away from me." according to interviewee #23, it "is a kind of epidemic disease, but speaking of cold and flu, what is generally not a major disease, easier to treat the feeling, plus the pandemic, it is only a larger scope of infection, right?" the content reflects that some students do not pay substantial attention to public health and their health. more people choose to passively wait and accept the strategies and measures employed by the school or the state government; they lack the initiative to understand the relevant information and take preventive actions. the coping strategies in table 4 are essential to pandemic emergency work and a necessary part of the communication framework in figure 2 . twenty-nine percent of the respondents cited the importance of personal hygiene habits, such as wearing masks and isolating patients; however, there are not many people who provided detail regarding these aspects. a few respondents described these strategies on the government, organization, and individual levels. most of them referred to "masks" and "be far away from the cough" in the relevant description and noted details of whether to use a special mask or separate the patient from the family. for example, interviewee #6 stated: "if it is a more serious situation, we will wear a mask, and then the hospital will be more nervous about the flu . . . " another 18% of the respondents believed that there was no need to isolate the suspected patients, such as interviewee #19: "you cannot go to the hospital first because most of the cases are not true flu, to the hospital may be isolated, so look first." for the government's decision-making, 57% of the respondents cited health education and counseling. most of them were willing to accept the necessary emergency response; over 1/4 of the respondents referred to influenza surveillance, public disinfection, and hospital treatment. these answers demonstrate these students still make mistakes and lack of understanding of the most effective protection decisions, although they have better educational backgrounds and a high degree of potential coordination. moreover, although vaccination is the most effective way to prevent the flu, only two of the respondents said they were willing to receive the flu vaccine, and the other respondents said they would not vaccinate themselves if it were not compulsory. "there is no need for voluntary vaccination" (respondents 3 and 17), "some vaccines may have side effects . . . it will hurt me" (interviewee 26). notably, interviewee #9, who originated from hong kong, was able to describe all the individual and government contingency strategies and discussed his own experience of avian influenza in hong kong in addition to elaborating on the entire process of emergency work. this fully embodies the maturity and perfection of the hong kong government in the risk communication of emergencies and the higher risk awareness. thus, the related communication and publicity strategies are worth referencing. the risk of pandemic influenza can be reduced by timely warning, access to correct information, and attitudes towards communication and interest in the face of threats. as shown in table 5 , 50% of the respondents had a specific information identification ability; 43% of the respondents chose to obtain their information on pandemic risk from the official channels. all respondents were willing to take several methods to search for risk information, including using the internet. however, although knowing first-hand influenza warning and decision support information originates from the cdc, very few of the respondents (10%) were able to clarify what types of communicators can provide help and detailed descriptions on this topic, including the specific types of early warning information that is available, where the information is, and how it is transmitted. individuals have only mastered the general concept, such as interviewee #11: " . . . go to the official website or wechat (to) find how to prevent." for health education and publicity, most of the respondents indicated that they would not take the initiative to participate in similar activities. the reasons were "traditional lectures are boring," "the publicity manual was not attractive". moreover, as interviewee #25 indicated, "i think all of them are theoretical knowledge which can be seen on the internet. if they can tell us something that you need to deal with when an event comes, it would be better." regarding suggestions for future risk communication. most of the respondents were satisfied with the current government's work and had a positive attitude towards the emergency plan of the official guide form; they were more focused on "the details of the emergency work" (cited by 25% of the respondents) and "hope to get official plan" (cited by 21% of the respondents). for example, interviewee 20 indicated that " . . . the way must be change, not as before, because the flu is not like a common cold, people will not pay much attention to it. communication, whether it is a family or school, it is best to have some specific suggestions, such as how to wash hands and disinfection, everyone can refer to themselves to do it." in general, there was a clear difference in the breadth and depth of the overall understanding of the pandemic-related information and communication framework among each student interviewed. as expected, in the context of the communication framework, most of the students' mental models were not as rich as those of the experts. they were more concerned with the critical information necessary to make individual decisions in the interpretation of risk information, for example, interviewee #10 says: "now, i want to know what type of impact will it cause, and what type of protection measures can protect me?" most respondents only referred to the critical concepts in the communication framework, without a detailed description or in an inaccurate or unclear manner; therefore, these gaps may reduce the ability of people to manage their behavior and their compliance with expert opinions. compared to the communication framework in figure 2 , the respondents used personal experience and analogies to produce more related concepts to establish the information base they needed to make decisions. table 5 the discussion of related items complete negation of self-media 5 18% dialectical view of self-media 14 50% willing to participate in publicity 8 29% refusing to participate in publicity 20 71% access to information from the authority 12 43% access to information from other mass media 14 50% obtaining information from other trusted sources 13 46% differences between pandemic and seasonal influenza 4 14% the influence of rumors 7 25% note: table shows the concept of risk information mentioned by respondents and their suggestions on current government risk communication. the infection of flu often brings many complications, in the heart and lung systems, to those who have low immunity, such as infants and young children, and these are also the significant causes of virus' potential lethality. 30, 32 the interview results show that some students do not pay sufficient attention to the impact of pandemic influenza and remain optimistic, particularly the lethality of virus, serious complications, and identification of vulnerable populations. our respondents trust in the country's sound epidemic prevention system. however, because we still have a lot of unknown information to explore about the virus, the outbreak of a new virus often brings challenges to the health system of a region. for example, virus identification, targeted program formulation, and information release all need time. for the existence of these time lags between case generation and interventions, if we want to carry out successful disease control actions, it is more important for the public to actively carry out personal protection rather than passively wait for the intervention of government departments. moreover, the desalination of the history of the epidemic, and the lack of targeted health education may also be reasons for the over-optimism of the pandemic. consequently, those who have inaccurate risk perception will estimate themselves as "the strongest young people" or "a person who having enough understanding about the flu." once a new virus outbreaks, these people may also bring misleading information to other individuals in their social circle, which will affect others' emergency decisions. in particular, for those who have experienced influenza pandemic without being negatively affected, luck may cause them to have a more positive response to future pandemics. 33, 34 furthermore, although the h1n1, h5n1, and other influenza outbreaks have been derived from new viruses following mutation, the repetition of the old virus and the prevention of the flu season risk becoming a pandemic. 31 being able to distinguish the key differences between the pandemic and common flu can effectively improve the level of personal risk cognition. among the respondents, we found that some students remained confusion: they believed that a pandemic is the mass spread of seasonal influenza or a pandemic is an almost impossible "super calamity". moreover, a pandemic is often unpredictable and generally involves international outbreak. therefore, it is important for the public to understand that the pandemic is not far away from us. we need to pay attention to our own prevention during the flu season, and at the same time, we need to be alert to unusual cold symptoms, especially when we go abroad. otherwise, patients may mistakenly think that they are suffering from common influenza, choose to place or take medicine, thus delaying the diagnosis and treatment time, infecting others and causing serious consequences. finally, concerning vaccination, our respondents have negative views regarding this issue. only 2 of the 28 respondents cited the importance of the vaccine and had a history of active vaccination, and the reasons mainly focused on the conventional "i feel good and don`t need vaccination" and "doubts about the safety of vaccines." therefore, our risk communication at present seems inadequate in promoting the necessity of vaccination. the public is not aware of the importance of the vaccine for influenza prevention or the misperceptions caused by its one-sided understanding of the pandemic, as discussed in "the countermeasures of the pandemic". in an investigation of the willingness of the elderly to be vaccinated, shaoliang geng 35 found that the primary sources of influenza and related knowledge in elderly adults were family, relatives, friends, and television, and the most trusted means of knowledge were doctors. there are cracks in clinical and public health knowledge, and patients lack knowledge about the importance of vaccination. the correction of this misunderstanding is vital for college students and because it can promote the dissemination of inoculation knowledge of young students in the family, thus improving the injection of the recommended groups (old people and young children). as discussed in the acquisition of risk information and public suggestion, in the absence of relevant knowledge and information, the respondents applied personal experiences and analogies to compose the foundation of their mental model and help themselves understand the risk of the pandemic. understanding differences in causality between risk factors can also lead to substantial differences in risk perception and coping between individuals. 33 many students only know a few general concepts and have not formed a complete emergency preparedness mode of thinking in a communication framework, knowing what one can do during the pandemic but not much about what to do and what is truly meaningful. for example, although nearly all respondents cited wearing masks and bringing in patients in time for medical treatment, the most basic measures can be limited in the presence of a real pandemic, which is only a result of a personal experience analogy (compared to a cold or related disease). what ` s more, for those in the outbreak area, especially those with suspected symptoms, it is the right and effective decision to stay at home and seek the help of local medical institutions to protect personal health than to conceal facts and escaping from outbreak area in panic. but none of our respondents know that. also, most respondents have only basic concepts (the government and the health department) regarding the types of communicators who provide the relevant risk information. these overly broad understandings may limit their ability to rapidly identify critical information or influence their knowledge of specific report under the threat of severe flu, mainly when their typical sources of information or communication channels are not available, or the necessary information is not provided. if the government is unable to offer exact messages or be out of protection from the spread of information. public trust in official authority may be reduced. students always prefer health education with new styles and systematic content. the appeal of traditional lectures and guideline books full of academic words is far less attractive, and it is hoped that the government will "reduce the over the generality of the description" and "release relevant data to increase persuasion" in future communication work. foltz's research confirms that it is necessary to use various mechanisms in the risk communication of emergencies. individuals with nonprofessional backgrounds tend to think in more specific terms, their vocabulary is less expansive, and subtle expressions cannot be well understood. bright colors and charts easily attract them. complex text information transmission will make people feel tired and irritable. 2 if possible, two student respondents also suggested organizing practical exercises, which they think is more helpful to deepen the impression and understand self-protection measures used to cope with the pandemic. information consistency is the decisive factor in understanding and perceiving personal risk. in terms of communication effectiveness, multiple sources of consistent messages are typically more effective than messages from a single source or with different contents. 36 the earlier the warning people receive and the higher the threat of information is, the higher the possibility that people take active preventive measures. therefore, the government department should incorporate the outbreak situational information and the proposed measures into influenza warnings, while maintaining the consistency of multiple communication messages. first, the results of this research reflect some misunderstanding in the respondents with a more prominent frequency: 1) influenza virus mutation and seasonal influenza have the potential to evolve into a pandemic, and the prevention of common influenza cannot be ignored. 2) the impact of an influenza pandemic is often unprecedented, and influenza virus infection can be lethal; in addition to severe cold symptoms, it also results in severe complications in patients. 3) influenza vaccination plays an active role in pandemic prevention and should be actively vaccinated, particularly children with low immunity and elderly adults, a vulnerable group. 4) for suspected patients in the family, the first choice is a social isolate, and it is very dangerous for family members to remain in close contact with their protection work. it is imperative for individuals to have common knowledge regarding influenza, the correct personal response and the degree of risk in our area for making the right decisions. therefore, we suggest that the government should put the above content as the focus of communication when communicating the risks related to the pandemic, or formulating the corresponding health education materials, so as to improve the compliance of the audience. on the other hand, the content of government risk communication should not be limited to medical advice. the public health department should develop a response plan for individuals and organizations. in terms of organization, a pandemic does not directly damage related facilities in contrast to many other catastrophic events. however, the regular work of employees within the organization will be affected. the absence of ill employees in central positions will have a severe impact on the regular operation of the organization. therefore, we need to develop a "continuous work plan" for these particular circumstances. the government should release relevant risk information on an influenza pandemic in the form of a preparation plan, or, use the network for distance health education or guiding emergency response work through local radio or television stations. finally, we should update the channels and methods of risk communication and health education. the government should strengthen the application of new media to adapt to young people's information acquisition preferences. in the form of communication, it can be gradually changed from traditional lectures to novel approaches, such as public welfare videos, songs, and scene construction experiences. moreover, scene effects can play an essential role in enhancing the personal experience because analogies are encountered in the event of a risk event to facilitate their correct risk assessment and response behavior. risk communication for public health emergencies the perception of risk risk communicaiton: a mental models approach rational choice and the framing of decisions a warning shot: influenza and the 2004 flu vaccine shortage the determinants of trust and credibility in environmental risk communication: an empirical study news influence on our pictures of the world health information on the internet: accessibility, quality, and readability in english and spanish? best practices in public health risk and crisis communication? risk perception and communication unplugged: twenty years of progress risk society. ho po wen translation acceptable risk the nature of explanation rating the risk know what to do if you encounter a flash flood": mental models analysis for improving flash flood risk communication and public decision making an integrated risk model of a drinking-water -borne cryptosporidiosis outbreak flash flood risks and warning decisions: a mental models' study of forecasters, public officials, and media broadcasters in application of delphi method in screening self-rated health evaluation index system what do lay people want to know about the disposal of nuclear waste? a mental model approach to the design and development of an online risk communication validity in the qualitative research interview the competent manager: a model for effective performance delphi method and its application in medical research and decision making research on the structure of public risk communication ability of influenza pandemic in health sector coordination coefficient w test and its spss implementation influenza century: review and enlightenment of influenza pandemic in the 20th century discrete logistic dynamic model and its parameter identification for the ebola epidemic modern epidemiology methods and applications beijing: beijing medical university peking union medical college joint publishing house research on monitoring and evaluation index system of national essential medicine system in primary health care institutions. hubei: hua zhong university of science and technology analysis of the clinical characteristics of influenza a (h1n1) how does the general public evaluate risk information? the impact of associations with other risks prevalence and characteristics of children at increased risk for complications from influenza analysis of the information demand characteristics of public health emergencies of infectious diseases investigation on knowledge and willingness of influenza vaccination among the elderly over 60 years old in xuchang city social and hydrological responses to extreme precipitations: an interdisciplinary strategy for post-flood investigation the authors would like to acknowledge linxian wang for helping compiling interview questionnaires, making suggestions on interview skills and finding supporting documents. we also express the sincere gratitude to students involved in the interviews of this research. this research did not involve any experiments or investigation which need ethical approval, and did not receive any specific funding too. the authors report no conflicts of interest for this work. risk management and healthcare policy is an international, peerreviewed, open access journal focusing on all aspects of public health, policy, and preventative measures to promote good health and improve morbidity and mortality in the population. the journal welcomes submitted papers covering original research, basic science, clinical & epidemiological studies, reviews and evaluations, guidelines, expert opinion and commentary, case reports and extended reports. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord-034832-uvjjmt1p authors: shi, yong; zheng, yuanchun; guo, kun; jin, zhenni; huang, zili title: the evolution characteristics of systemic risk in china’s stock market based on a dynamic complex network date: 2020-06-02 journal: entropy (basel) doi: 10.3390/e22060614 sha: doc_id: 34832 cord_uid: uvjjmt1p the stock market is a complex system with unpredictable stock price fluctuations. when the positive feedback in the market amplifies, the systemic risk will increase rapidly. during the last 30 years of development, the mechanism and governance system of china’s stock market have been constantly improving, but irrational shocks have still appeared suddenly in the last decade, making investment decisions risky. therefore, based on the daily return of all a-shares in china, this paper constructs a dynamic complex network of individual stocks, and represents the systemic risk of the market using the average weighting degree, as well as the adjusted structural entropy, of the network. in order to eliminate the influence of disturbance factors, empirical mode decomposition (emd) and grey relational analysis (gra) are used to decompose and reconstruct the sequences to obtain the evolution trend and periodic fluctuation of systemic risk. the results show that the systemic risk of china’s stock market as a whole shows a downward trend, and the periodic fluctuation of systemic risk has a long-term equilibrium relationship with the abnormal fluctuation of the stock market. further, each rise of systemic risk corresponds to external factor shocks and internal structural problems. the stock market is a typical complex system with multiple stock prices fluctuating from equilibrium to deviation and to equilibrium again. a large number of heterogeneous investors buy and sell stocks frequently, making the relationships between different stocks unpredictable. in most scenarios, owing to some factors like herd effect, investors' investment strategies converge [1, 2] ; when some investors buy a stock, other investors tend to buy the same one, and furthermore, when the vast majority of investors buy or sell stocks, other investors usually follow this action. at the same time, different listed companies are another heterogeneous agent in the stock market. on the one hand, the economic exchanges between listed companies will lead to the linkage of their stock prices. on the other hand, similar actions by investors on similar stocks can cause herd behavior between different stock prices. when the prices of a large number of stocks in the market tend to be consistent, it means that the herd effect in the market is higher, and the stock market is more likely to fluctuate excessively and consistently, leading to higher market systemic risks [3, 4] . in former studies, the capital asset pricing model (capm) framework was usually used to analyze financial systematic risks as a basic theory [5] [6] [7] [8] . according to capm, risks can be divided into systematic risk (or market risk) and non-systematic risk, while the latter can be diminished through investment portfolios. the systematic risk often refers to pervasive, far-reaching, perpetual market risk, which can be measured by the variance of the portfolio (beta) altogether. therefore, most studies on systematic risk are based on beta values. although this theory is widely adopted, it usually comes with a number of hypotheses, such as homogenous investors in capital markets. however, in modern financial markets, different investors generally have different degrees of rationality, ability to obtain information, and sensitivity to prices, that is, investors are usually heterogenous. hence, capm may not be a reasonable model in the real complex world [9, 10] . more importantly, this paper focuses on the systemic risk, which reflects the stability of the system and the characteristics of risk transmission among individuals in a certain complex system. a complex network, which is based on physics and mathematics theory, can tackle complicated practical problems [11] . it is especially suitable for modeling, analysis, and calculation in complex finance systems [12] . nowadays, the literature on applying complex networks to finance is growing in size, and complex networks have become important tools in the finance field [13] . after 30 years of development, china's stock market is growing in scale and vitality, while the market operation mechanism and management system are constantly improving. nevertheless, there have been several typical bear and bull markets in recent years, and systemic risk in the stock market has risen periodically. therefore, a dynamic complex network of individual stocks in china's stock market is constructed in this paper to measure the dynamic systemic risk of china's stock market. then, the tendency evolution and cycle change characteristics of systemic risk are explored. the structure of this paper is as follows. section 2 summarizes the applications of complex networks in the field of economy and finance; section 3 introduces the data and methodology used in this paper; section 4 proposes the empirical results and analysis; and the conclusions and some discussion are given in section 5. construction of the network consists of two important steps, defining nodes and defining edges. in previous studies, nodes are usually represented by different agents in the financial market, that is, stocks or bonds, and edges are symbolized by the relationship between such agents. pearson's correlation coefficient is the most common and easiest way to measure the correlation between two entities in the financial market [14] [15] [16] [17] [18] [19] [20] . for example, mcdonald et al. used pearson correlation coefficient to construct a currency-related network in the global foreign exchange market and obtained temporary dominant or dependent currency information [16] . in addition, other correlation coefficients, such as spearman rank-order correlation coefficient [21] , multifractal detrended cross-correlation analysis (mfcca) [22, 23] , multifractal detrended fluctuation analysis (mfdca) [24] , and cophenetic correlation coefficient (ccc) [25] , have also been put forward. furthermore, correlation can also be defined by some econometric methods, such as the granger causality test [26, 27] , cointegration test [28] , dynamic correlation coefficient with garch (dcc-garch) [29] , and so on. after the definition of edges, some filter methods for choosing the important edges should be applied. otherwise, the complex network will be very large and complicated, which is not conducive to subsequent analysis. minimum spanning tree (mst) can be used for this purpose. after mst operation, the complex network will retain only n − 1 edges, where n is the number of the nodes, which greatly facilitates the study of the network topology. at present, mst is most commonly used to simplify the financial complex network [14, 15, [18] [19] [20] 22, [29] [30] [31] . for example, in 1999, mantegna first proposed that mst could be used to search for important edges in the stock market network, and a stock market topology with economic significance could be obtained [14] . except for mst, other 90 days and 1 day for step. then, the average weight and structural entropy of the network in each day can be obtained. the ratio of the stocks with weight in the top 10% to the average weight in each window period can also be calculated and defined as the concentration ratio of important stock. therefore, four network indexes could be derived. next, these four network indexes were combined with the stock market index and 0-1 standardization before empirical mode decomposition (emd) was performed. through the above process, the original sequences were divided into a number of intrinsic mode functions (imfs). then, the results were reconstructed with grey relational analysis (gra), making each sequence have three items, that is, tendency, cycle, and disturbance. finally, the statistical analysis of the three components was conducted in order to explore the development of china's stock market and the evolution characteristics of systemic risk. modeling of the complex network, emd, and gra is introduced as follows. window period can also be calculated and defined as the concentration ratio of important stock. therefore, four network indexes could be derived. next, these four network indexes were combined with the stock market index and 0-1 standardization before empirical mode decomposition (emd) was performed. through the above process, the original sequences were divided into a number of intrinsic mode functions (imfs). then, the results were reconstructed with grey relational analysis (gra), making each sequence have three items, that is, tendency, cycle, and disturbance. finally, the statistical analysis of the three components was conducted in order to explore the development of china's stock market and the evolution characteristics of systemic risk. modeling of the complex network, emd, and gra is introduced as follows. a complex network consists of several nodes and edges linking them. the node is the basic element of a complex network, which is the abstract expression of an "individual" in the real world. the edge is an expression of the relationship between the elements and can be given weight according to the extent of the relationships. here, represents the weight of the edge linking node and node , where , = 1,2,3, . . . , and is the number of nodes in a certain network. for an undirected network, (1) we can also use the weighted degree to represent the importance of nodes, which is defined as where ( ) is the set of nodes linking to node . the larger the weighted degree, the stronger the degree of correlation with other nodes and the more important the node. we use the return rates of a-share stocks on china's stock market as the network nodes and construct the network using correlation coefficient as the edge weight. a complex network consists of several nodes and edges linking them. the node is the basic element of a complex network, which is the abstract expression of an "individual" in the real world. the edge is an expression of the relationship between the elements and can be given weight according to the extent of the relationships. here, w ij represents the weight of the edge linking node i and node j, where i, j = 1, 2, 3, . . . , n and n is the number of nodes in a certain network. for an undirected network, we can also use the weighted degree to represent the importance of nodes, which is defined as where v (i) is the set of nodes linking to node i. the larger the weighted degree, the stronger the degree of correlation with other nodes and the more important the node. we use the return rates of a-share stocks on china's stock market as the network nodes and construct the network using correlation coefficient ρ ij as the edge weight. here, {x it , i = 1, 2, · · · , n; t = 1, 2, · · · , t} is the original stock return rates data and < · · · > indicates a time-average over the t data points for each time series. after we get w ij , we calculate the average weight, top 10 nodes weight, and concentration ratio below: top 10 nodes = 1 10 concentration ratio = top 10 nodes average weight (6) where top (i) means the nodes i with the top 10 weights (dw i ). furthermore, we calculate the network's structural entropy, which is often used to measure the complexity of the complex network system [37] . however, as the structural entropy of the all-connected network is constant, it is meaningless for our analysis, so we need to remove the edge of weak correlation to get a non-all-connected network for calculating the structural entropy. the threshold value of the correlation coefficient is set at 0.4. if the absolute value of the correlation coefficient ρ ij , that is, w ij , is less than 0.4, this edge will be cut off, and we will get a non-fully connected network to calculate the structural entropy e deg under each window [37] : where n is the total number of nodes in the network; k is boltzmann's constant; and p i can be calculated by the number of edges connecting to node i, namely, the degree of node i: combining the three network indexes with china's stock market index gives four input data, named as {y kt , k = 1, 2, 3, 4; t = 1, 2, · · · , t}. y kt have to be 0-1 standardized, owing to significant differences at the numerical level, that is, for the signal z(t), the upper and lower envelopes are determined by local maximum and minimum values of the cubic spline interpolation. m 1 is the mean of envelopes. subtracting m 1 from z(t) yields a new sequence h 1 . if h 1 is steady (does not have a negative local maximum or positive local minimum), it is denoted as the intrinsic mode function (im f 1 ). if h 1 is not steady, it is decomposed again, until steady series is attained, which is denoted as im f 1 . then, m 1 replaces the original z(t) and m 2 is the mean of the envelopes of m 1 , and m 1 is similarly decomposed. repeating these processes k times gives im f k , that is, finally, let res denote the residual of z(t) and all im f s: where im f s and res could be extracted for the gra process. the grey relational analysis was first put forward by deng j l in 1989 [38] . his grey relational degree model, which is usually called the grey relative correlation degree, mainly focused on the influence of distance between points in the system. the grey relative correlation degree formula is given by equation (12). where d i (t) is the reference series; d j (t) is the compared series; and ρ is the distinguishing coefficient, which is usually equal to 0.5. in order to overcome the weakness of the grey relative correlation degree, the absolute correlation degree was proposed by mei (1992) [39] . the formula is given by equation (13). considering the weakness and strength, we used the grey comprehensive relational degree to classify the noise terms and market fluctuation terms. the formula of the grey comprehensive relational degree is given by equation (14): where β is the weight of the grey relative relational degree, which is valued as 0.5. figure 2a compares the three average weight related indicator of the dynamic complex network with the dynamic evolution of the shanghai composite index standardized by setting it as 1000 on the first trading day of 1997. it can be seen that the average weight of the complex network and the average weight of the top 10 stocks have strong synchronization, with a high correlation of 0.9896. therefore, both of them can be used as proxy indicators of systemic risk. however, the concentration ratio is not consistent with the overall systemic risk. the concentration of risk is relatively low when the systemic risk is high, which means the risk is relatively decentralized. furthermore, the concentration ratio and the average weight are significantly negatively correlated with a correlation coefficient of −0.91329. in this way, we will focus on using the index of the average weight to measure the systemic risk of the chinese stock market. it can also be seen from figure 2a that, although there is a correlation between two average weight indexes (all and top 10) and the stock index, the coefficients, −0.1370 and −0.0829, are relatively small. this proved that the level of systemic risk is not determined by the move of overall price trend. in order to further investigate the relationship between the systemic risk represented by the average weight, the beta value (β) obtained by the capm model, and the stock average variance (v), we estimated β t and v t as follows: where n is the total number of stocks; t is the length of the sliding window; r f is the risk-free interest rate, which was set to 3%; x kt is the return of the kth stock in the sliding window t; y t is the return of the stock index, which is symbolized for market return and is represented by 000001.sh; β kt is calculated by mls with y t and x kt ; e kt is the error term; β t is the average of all individual stocks' beta; and v t is the average variance of all stocks in sliding window t. in figure 2b , we compare the systemic risk with beta and stock variance, finding that these three have different moving trends, which shows that our systemic risk index can catch unique market fluctuations. furthermore, the systemic risk index was ahead of beta in several stages, such as from june 2006 to july 2008 or from july 2015 to august 2017, which shows that our systemic risk index has a certain risk pre-warning ability. it can also be seen from figure 2a that, although there is a correlation between two average weight indexes (all and top 10) and the stock index, the coefficients, −0.1370 and −0.0829, are relatively small. this proved that the level of systemic risk is not determined by the move of overall price trend. in order to further investigate the relationship between the systemic risk represented by the average weight, the beta value ( ) obtained by the capm model, and the stock average variance ( ), we further compared the systemic risk represented by average weight with the volatility index (vix) of china and the u.s. stock market. considering the chinese vix cannot cover the above research range, the u.s. vix was selected for comparison purposes. the correlation coefficient between the two vix in this range is significantly positive, but the coefficient is only 0.5626. figure 3a presents the great differences in the trend of vix between china and the united states. it can be seen that the correlation coefficient between average weight and chinese vix is 0.4763 during the interval since the chinese vix launched. it is noteworthy that the volatility index leads the systemic risk index to a certain extent. this is confirmed by the results obtained from the cross-correlation analysis with the maximum coefficient of 0.7469, corresponding to lags of 55 days (which means current systemic risk is highly related to the vix from 55 days prior). however, this is mainly because the systemic risk index constructed in this paper was compiled using the sliding window method, with the window length of 90 days, so the systemic risk index of a certain time, t actually represents the systemic risk of the previous 90 days. between the two vix in this range is significantly positive, but the coefficient is only 0.5626. figure 3a presents the great differences in the trend of vix between china and the united states. it can be seen that the correlation coefficient between average weight and chinese vix is 0.4763 during the interval since the chinese vix launched. it is noteworthy that the volatility index leads the systemic risk index to a certain extent. this is confirmed by the results obtained from the crosscorrelation analysis with the maximum coefficient of 0.7469, corresponding to lags of 55 days (which means current systemic risk is highly related to the vix from 55 days prior). however, this is mainly because the systemic risk index constructed in this paper was compiled using the sliding window method, with the window length of 90 days, so the systemic risk index of a certain time, , actually represents the systemic risk of the previous 90 days. in fact, the complex network characteristics of individual stocks are effective at reflecting the systemic risk of the market. to verify this, we calculated the 90-day averages for vix, which are shown in figure 3b . it can be seen that the systemic risk index constructed in this paper is consistent with the 90-day average trend for china's vix, and the systemic risk is ahead of china's vix after 2017 and is more sensitive, which proves the effectiveness of the systemic risk index derived from the complex network. figure 4 shows the comparison between the structural entropy and the number of nodes in a complex network. it can be seen that the structural entropy is highly correlated with the number of nodes, and the correlation coefficient reaches 0.9302. in other words, the increase in system complexity of china's stock market is mainly caused by the increase in the number of listed companies. nevertheless, we can also find that, in addition to the overall upward trend, structural entropy also has periodic fluctuations. therefore, multi-scale analysis is required to determine whether the system complexity represented by structural entropy is related to systemic risk. in fact, the complex network characteristics of individual stocks are effective at reflecting the systemic risk of the market. to verify this, we calculated the 90-day averages for vix, which are shown in figure 3b . it can be seen that the systemic risk index constructed in this paper is consistent with the 90-day average trend for china's vix, and the systemic risk is ahead of china's vix after 2017 and is more sensitive, which proves the effectiveness of the systemic risk index derived from the complex network. figure 4 shows the comparison between the structural entropy and the number of nodes in a complex network. it can be seen that the structural entropy is highly correlated with the number of nodes, and the correlation coefficient reaches 0.9302. in other words, the increase in system complexity of china's stock market is mainly caused by the increase in the number of listed companies. nevertheless, we can also find that, in addition to the overall upward trend, structural entropy also has periodic fluctuations. therefore, multi-scale analysis is required to determine whether the system complexity represented by structural entropy is related to systemic risk. figure 5 presents the emd results of the standardized systemic risk index, structural entropy, and stock price index, respectively. it can be seen that the two original sequences are divided into seven imfs and one residual term, among which the residual term can represent the overall trend of indexes' evolution to a certain extent, while the imf of lower frequency can describe the periodic fluctuation of indexes in different time scales, and the imf of highest frequency represents the stochastic perturbation. figure 5 presents the emd results of the standardized systemic risk index, structural entropy, and stock price index, respectively. it can be seen that the two original sequences are divided into seven imfs and one residual term, among which the residual term can represent the overall trend of indexes' evolution to a certain extent, while the imf of lower frequency can describe the periodic fluctuation of indexes in different time scales, and the imf of highest frequency represents the stochastic perturbation. through emd, it can be found that the residual term, also known as the trend term, decomposed by structural entropy, represents the growth in the number of network nodes, and the correlation coefficient between this residual term and the number of network nodes can be further improved to 0.9428. when removing the trend term from the original sequence and comparing it to the systemic risk series represented by the average weight, as shown in figure 6 , the highly consistent fluctuations between the two series can be seen, and the correlation coefficient of the two reaches 0.7572. therefore, adjusted structural entropy, that is, removing the trend term of the network size, can also measure the systemic risk. nevertheless, owing to the high correlation between these two series, the following analysis only focuses on the systemic risk represented by average weight. 0.9428. when removing the trend term from the original sequence and comparing it to the systemic risk series represented by the average weight, as shown in figure 6 , the highly consistent fluctuations between the two series can be seen, and the correlation coefficient of the two reaches 0.7572. therefore, adjusted structural entropy, that is, removing the trend term of the network size, can also measure the systemic risk. nevertheless, owing to the high correlation between these two series, the following analysis only focuses on the systemic risk represented by average weight. in order to further observe the systemic risk evolution of the chinese stock market, several imfs and residual terms obtained from emd decomposition were combined using the method of grey correlation degree. figures 7 and 8 present the trend term, cycle term, and random term of systemic risk (average weight) and the stock price index. then, we focused on the overall trend change and cycle fluctuation of systemic risk in china's stock market. in order to further observe the systemic risk evolution of the chinese stock market, several imfs and residual terms obtained from emd decomposition were combined using the method of grey correlation degree. figures 7 and 8 present the trend term, cycle term, and random term of systemic risk (average weight) and the stock price index. then, we focused on the overall trend change and cycle fluctuation of systemic risk in china's stock market. 0.9428. when removing the trend term from the original sequence and comparing it to the systemic risk series represented by the average weight, as shown in figure 6 , the highly consistent fluctuations between the two series can be seen, and the correlation coefficient of the two reaches 0.7572. therefore, adjusted structural entropy, that is, removing the trend term of the network size, can also measure the systemic risk. nevertheless, owing to the high correlation between these two series, the following analysis only focuses on the systemic risk represented by average weight. in order to further observe the systemic risk evolution of the chinese stock market, several imfs and residual terms obtained from emd decomposition were combined using the method of grey correlation degree. figures 7 and 8 present the trend term, cycle term, and random term of systemic risk (average weight) and the stock price index. then, we focused on the overall trend change and cycle fluctuation of systemic risk in china's stock market. for the long-term tendency, we found that the overall trend of the stock price rose steadily, while the systemic risk has been declining slowly throughout the evolution of the chinese stock market since 1997. this means that, although there is still phased systemic risk in the chinese stock market, the overall level of systemic risk is declining as the operating mechanism and related regulations are constantly improving. for the long-term tendency, we found that the overall trend of the stock price rose steadily, while the systemic risk has been declining slowly throughout the evolution of the chinese stock market since 1997. this means that, although there is still phased systemic risk in the chinese stock market, the overall level of systemic risk is declining as the operating mechanism and related regulations are constantly improving. for the cycle fluctuation, the rise of systemic risk is usually caused by the joint action of external shocks and internal operations, which is manifested in the excessive rise and fall in the stock market. therefore, the cyclical characteristics of systemic risk have no direct relationship with the fluctuations of the stock market. thus, we converted the cycle fluctuation of the stock market into the difference from the price mean using (18) . considering that cycle_abs_stock and cycle_risk are both non-stationary, we calculated their firstorder differences. the results of augmented dickey-fuller (adf) tests show that both variables are an integrated of order one. therefore, cointegration tests can be proposed on the original sequences. the results of johnson trace tests show that there are at least two cointegration relationships between the two variables, which confirms that there is a long-term equilibrium relationship between stock price volatility and systemic risk. the equilibrium equation is all the coefficients are significant at the 5% significance level, so the volatility of the stock market is positively related to systemic risk from the perspective of long-term equilibrium, which means that, while the stock price deviates from the theoretical value of equilibrium, the systemic risk will be at a high level. in figure 9 , when the blue line is above 0, the systemic risk is large, while when the blue line is below 0, the systemic risk is small. the red line represents the absolute value of stock price movements, and the red line is clearly ahead of the above-zero parts of the blue line. for the cycle fluctuation, the rise of systemic risk is usually caused by the joint action of external shocks and internal operations, which is manifested in the excessive rise and fall in the stock market. therefore, the cyclical characteristics of systemic risk have no direct relationship with the fluctuations of the stock market. thus, we converted the cycle fluctuation of the stock market into the difference from the price mean using (18) . considering that cycle_abs_stock and cycle_risk are both non-stationary, we calculated their first-order differences. the results of augmented dickey-fuller (adf) tests show that both variables are an integrated of order one. therefore, cointegration tests can be proposed on the original sequences. the results of johnson trace tests show that there are at least two cointegration relationships between the two variables, which confirms that there is a long-term equilibrium relationship between stock price volatility and systemic risk. the equilibrium equation is all the coefficients are significant at the 5% significance level, so the volatility of the stock market is positively related to systemic risk from the perspective of long-term equilibrium, which means that, while the stock price deviates from the theoretical value of equilibrium, the systemic risk will be at a high level. in figure 9 , when the blue line is above 0, the systemic risk is large, while when the blue line is below 0, the systemic risk is small. the red line represents the absolute value of stock price movements, and the red line is clearly ahead of the above-zero parts of the blue line. entropy 2020, 22, x for peer review 13 of 16 figure 9 . cycle evolution of systemic risk. figure 9 shows the cycle evolution of systemic risk, the lead-lag relationship between systemic risk and stock volatility is dynamic owing to the sliding window processing. from the perspective of the whole cycle evolution, we found that there were several periods of high systemic risk in the chinese stock market since 1997, as described below. 1997-1998: the stock market was in a shock stage during this period. on the one hand, the chinese stock market was impacted by external factors such as the asian financial crisis; on the other hand, the operating mechanism at that time was not perfect enough, with frequent insider trading and market manipulation. the systemic risk was at a high level during this period and, therefore, the stock market began to comprehensively reform its trading mechanism in 1998. although the market fluctuation was not violent from the current perspective, it actually contained many factors causing systemic risk. 2001-2002: the stock market was in a declining bear stage during this period. owing to the poor performance of high-tech companies, resulting from the burst of the global internet bubble and the launch of the policy reducing the state-owned shares holding of listed companies, the stock market had a big crash in china. related departments issued a series of favorable strategies such as reducing interest rates and trading commissions; however, the imperfection of the market led to a number of "black markets", which brought a high systemic risk. 2007-2008: this period includes both excessive rise and fall of the market. the reform of nontradable shares in 2005, together with a series of positive policies such as the entry of insurance funds and the appreciation of renminbi (rmb), promoted the rise of the chinese stock market. however, a lot of speculation by inexperienced individual investors caused a more and more serious herding effect, and the systemic risk was maintained at a high level for a long time. followed by the global financial crisis brought by the u.s. subprime crisis, with the launch of stock index futures, the chinese stock market began to reverse to a bear stage, and the systemic risk in this stage also remained at a high level. 2011-2012: this stage was another volatile bear market; the fluctuation of stock price was much smaller than that of the previous stage, but the systemic risk still remained at a similar level. even though the chinese economy maintained a high growth rate during this period, the stock market was influenced by the global financial markets, as well as the european debt crisis. the low volatility of the stock market still contained large systemic risks, which were reinforced by the frequent occurrence of black swan events such as a rear-end collision of bullet trains, clenbuterol, and so on. figure 9 shows the cycle evolution of systemic risk, the lead-lag relationship between systemic risk and stock volatility is dynamic owing to the sliding window processing. from the perspective of the whole cycle evolution, we found that there were several periods of high systemic risk in the chinese stock market since 1997, as described below. 1997-1998: the stock market was in a shock stage during this period. on the one hand, the chinese stock market was impacted by external factors such as the asian financial crisis; on the other hand, the operating mechanism at that time was not perfect enough, with frequent insider trading and market manipulation. the systemic risk was at a high level during this period and, therefore, the stock market began to comprehensively reform its trading mechanism in 1998. although the market fluctuation was not violent from the current perspective, it actually contained many factors causing systemic risk. 2001-2002: the stock market was in a declining bear stage during this period. owing to the poor performance of high-tech companies, resulting from the burst of the global internet bubble and the launch of the policy reducing the state-owned shares holding of listed companies, the stock market had a big crash in china. related departments issued a series of favorable strategies such as reducing interest rates and trading commissions; however, the imperfection of the market led to a number of "black markets", which brought a high systemic risk. 2007-2008: this period includes both excessive rise and fall of the market. the reform of non-tradable shares in 2005, together with a series of positive policies such as the entry of insurance funds and the appreciation of renminbi (rmb), promoted the rise of the chinese stock market. however, a lot of speculation by inexperienced individual investors caused a more and more serious herding effect, and the systemic risk was maintained at a high level for a long time. followed by the global financial crisis brought by the u.s. subprime crisis, with the launch of stock index futures, the chinese stock market began to reverse to a bear stage, and the systemic risk in this stage also remained at a high level. 2011-2012: this stage was another volatile bear market; the fluctuation of stock price was much smaller than that of the previous stage, but the systemic risk still remained at a similar level. even though the chinese economy maintained a high growth rate during this period, the stock market was influenced by the global financial markets, as well as the european debt crisis. the low volatility of the stock market still contained large systemic risks, which were reinforced by the frequent occurrence of black swan events such as a rear-end collision of bullet trains, clenbuterol, and so on. 2015-2016: the market price was rising rapidly in 2015 and the systemic risk was also in a climbing stage. however, a high level of risk still appeared in 2016, which was a stage of rapid and frequent fluctuations. the issuing scale of new stocks increased significantly, driving frequent market shocks such as thousands of shares rising or falling together, two triggering circuit breaker events in a day, and so on. thus, the overall capital presents a large-scale net outflow, and the investor sentiment fluctuates abnormally. to summarize, the systemic risk of the stock market will significantly increase in the irrational stages of rise, fall, and frequent shocks. however, extremely high systemic risk is more likely in the cases of collapse and frequent shocks. complex networks have been widely used in the field of socio-economic analysis. most of them focus on the risk contagion of banks and international economic or trade exchanges; however, studies on the stock market are limited. in fact, a complex network provides an important tool for the study of the stock market, which is a self-organizing complex system with multi-agent interactions. the average weight of the complex network can be used to measure the aggregation of positive feedback in the market, so as to measure the overall systemic risk. on the basis of the data of all a-shares in china, this paper constructs a dynamic complex network of stock correlation, and the change of average weight as well as adjusted structural entropy of the network are used to measure the evolution of systemic risk in china's stock market. although, owing to the use of a sliding window, the average weight or structural entropy in fact presents the average systemic risk level in the past 90 days, it also reflects the evolution of systemic risk in china's stock market for more than 20 years as a whole. the results show that the systemic risk of china's stock market shows a downward trend on the whole, which is closely related to the continuous improvement of the management system and operation mechanism of the financial market. in addition, there is a long-term equilibrium relationship between the cycle fluctuation of systemic risk and the excessive fluctuation of the stock market. since 1997, the stages with high systemic risk have appeared with excessive increases, excessive falls, and frequent fluctuations of the stock market. meanwhile, it can also be seen from figure 1 that the global stock market began to fluctuate significantly under the influence of the novel coronavirus pneumonia. the chinese stock market is relatively stable at present, but the systemic risk has been climbing rapidly since the beginning of february. therefore, we must be alert to the further expansion of the systemic risk of the chinese stock market under the double impact of internal and external factors. herd behavior and investment herd behavior in financial markets the low-volatility anomaly: market evidence on 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the foreign currency exchange market topology of correlation-based minimal spanning trees in real and model markets a global network of stock markets and home bias puzzle complex networks in a stock market an approach to hang seng index in hong kong stock market based on network topological statistics explaining what leads up to stock market crashes: a phase transition model and scalability dynamics pathways towards instability in financial networks singular cycles and chaos in a new class of 3d three-zone piecewise affine systems introduction to grey system theory the concept and computation method of grey absolute correlation degree the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. key: cord-011824-4ge9i90s authors: andrews, jack l.; foulkes, lucy e.; bone, jessica k.; blakemore, sarah-jayne title: amplified concern for social risk in adolescence: development and validation of a new measure date: 2020-06-23 journal: brain sci doi: 10.3390/brainsci10060397 sha: doc_id: 11824 cord_uid: 4ge9i90s in adolescence, there is a heightened propensity to take health risks such as smoking, drinking or driving too fast. another facet of risk taking, social risk, has largely been neglected. a social risk can be defined as any decision or action that could lead to an individual being excluded by their peers, such as appearing different to one’s friends. in the current study, we developed and validated a measure of concern for health and social risk for use in individuals of 11 years and over (n = 1399). concerns for both health and social risk declined with age, challenging the commonly held stereotype that adolescents are less worried about engaging in risk behaviours, compared with adults. the rate of decline was steeper for social versus health risk behaviours, suggesting that adolescence is a period of heightened concern for social risk. we validated our measure against measures of rejection sensitivity, depression and risk-taking behaviour. greater concern for social risk was associated with increased sensitivity to rejection and greater depressed mood, and this association was stronger for adolescents compared with adults. we conclude that social risks should be incorporated into future models of risk-taking behaviour, especially when they are pitted against health risks. adolescence is a sensitive period of development, characterised by significant changes in both the biological and social environment. in particular, adolescence is a time of social reorientation, greater susceptibility to peer influence and heightened sensitivity to social rejection [1] . adolescents are also stereotyped as risk takers, which is likely due to evidence that risk behaviours, such as binge drinking, risky driving and smoking, are heightened during this period of life [2, 3] . this commonly held perspective, that adolescence is a period of heightened risk taking, conceals a more nuanced reality. social context significantly affects adolescents' engagement in health risk behaviours. for example, evidence from car accidents shows that, for young drivers, the risk of engaging in a fatal car accident increases with the number of passengers in the car [4] . this is reflected in the experimental literature, with one study finding that, when playing alone, adolescents and adults take a similar number of risks on an incentivised computerised driving task (the stop light task). however, when adolescents played the same driving game in the presence of friends, they took significantly more risks, which was not the case for adults [5] . adolescents are also more likely to smoke, binge drink and take illicit substances with their peers, compared to when alone [6] . however, not all adolescents take risks, and recent work has led to the suggestion that adolescence is in fact a time of increased sensitivity to risk, characterised by wide variation in risk seeking and risk averse sit at the extreme end of concern for social risk, when the environmental cues potentially signal that one's social burden is significantly greater than one's social value. however, few studies have directly investigated whether adolescence is a period of heightened concern for social risk, and the extent to which concern for social risk predicts depressive symptomatology. current questionnaire measures of risk-taking behaviour do not uniformly include social risks as a risk-taking domain, and instead focus on the domains of health (e.g., taking illicit substances), financial (e.g., gambling) or legal (e.g., stealing) risk. one adult risk-taking questionnaire, the domain-specific risk-taking questionnaire (dospert) includes a social risk subscale, but this includes items that are not applicable to adolescent populations. for example, the social-risk items in this measure include 'approaching your boss to ask for a raise' and 'taking a job that you enjoy over one that is prestigious but less enjoyable' [22] . another issue with current questionnaire measures of risk taking is the conflation between health and social risk. many health risks carry with them some degree of social risk, e.g., smoking may carry with it both health and social risk considerations. further, it is unclear whether concerns about social risk are independent of concerns for other risk domains, such as health risk behaviours, so whether or not an individual's propensity to take risks is uniform across risk domains. given these issues, we developed and validated a measure of concern for health and social risk, which is suitable for both adolescents and adults. in this measure, we conceptualised a social risk as any behaviour that marks individuals as being different from their peers-for example, openly endorsing music that friends do not like, or befriending an unpopular peer. we attempted to isolate the social-risk items by including social risks that involve little or no obvious health risk. we conceptualised a health risk as risks to one's physical wellbeing, such as crossing a street on a red light. we included health risk behaviours that have as little conflation with social risk as possible. we had four primary hypotheses. we first hypothesised that concern for social risk would be distinct from health risk concerns. in order to establish this, we developed a measure using exploratory and confirmatory factor analysis (efa; cfa) to assess whether health and social risk domains are distinct constructs. second, and in order to validate our measure, we hypothesised that higher concern for social risk would be associated with greater sensitivity to rejection and lower mood. we hypothesised that this relationship would be stronger for adolescents compared with adults. third, we hypothesised that greater concern for each risk domain would be positively related to risk perception and negatively related to engagement in that risk domain. finally, we hypothesised that concern for social risk would decrease with age from early adolescence to late adulthood, relative to concern for health risk. sample 1 (exploratory factor analysis: efa; adults). participants (n = 500) were recruited from two sources: the university participant pool (n = 177) and prolific, an online participant recruitment and data collection platform (n = 323). participants (295 females, 204 males, one did not disclose gender) were aged 18-60 years (mean = 32.2, sd = 10.72). sample 2 (confirmatory factor analysis: cfa; adults). participants (n = 415) were recruited via prolific. participants (284 females, 129 males, two did not disclose gender) were aged 18-77 years (mean = 36.53, sd = 13.10). sample 3 (confirmatory factor analysis: cfa; adolescents). participants (n = 484) were recruited from schools in the greater london area, as part of ongoing research projects in our lab. participants (333 females, 107 males, four did not disclose gender) were aged 11-17 years (mean = 13.54, sd = 1.91). all participants were from the united kingdom and all completed the questionnaires online. ethical approval was obtained from the university ethics board (7199/001; 3453/001). participants were paid at a rate of approximately £10 per hour for their time. we developed a questionnaire measure in order to assess the degree to which adolescents and adults are concerned about engaging in health and social risk behaviours. given that many social risks also incur health risks, we developed items with as little conflation between the two as possible. we developed a list of social-risk items, e.g., "spend time with someone your friends don't like", and health risk items, e.g., "cross a main road when the crossing light is red". a panel of five researchers with expertise in adolescent social development reviewed an initial list of items and provided feedback on the content and suitability for individuals aged 11 and above, with the aim of making sure each item was distinct from the opposing type of risk. following this, a total list of 16 items was included in the scale validation: eight health and eight social (see table 1 ). in the version of the questionnaire given to participants, individuals were asked: "for each statement please rate how worried you would feel doing this behaviour. (if you have never done it, imagine how you would feel)." answers were given on a sliding scale from, "not worried at all (0)" to "very worried (100)". the questionnaire was administered online and the numbers (0-100) were visible along a slider (see supplementary materials for final questionnaire). all participants completed a number of additional measures in order to assess the construct validity of the hsrq. all participants included in the adult cfa completed each additional measure (n = 415). however, due to time constraints imposed by testing sessions, a subset of the participants in the adolescent cfa completed the rejection sensitivity (c-rsq; n = 207) and depressed mood (mfq; n = 281) measures only. questionnaire is a validated measure of sensitivity to actual or perceived rejection [23] . individuals were presented with nine scenarios such as "you approach a close friend to talk after doing or saying something that seriously upset him/her" and are asked to rate their rejection concern and level of acceptance expectancy. scores are computed by reversing the level of acceptance expectancy and multiplying this by the level of rejection concern. scores across the nine items are then averaged to create a total rejection sensitivity score; higher scores indicate higher rejection sensitivity. we hypothesised that higher scores on the social subscale of the hsrq would be positively associated with higher scores on the a-rsq. adolescents: children's rejection sensitivity questionnaire (c-rsq). participants completed the anxious expectations subscale of the children's rejection sensitivity questionnaire, which is a valid measure of rejection sensitivity in children [24] . participants were presented with six scenarios and were asked to report on a scale of 0-6 their expected likelihood of the outcome of the scenario and how nervous they would be given the content of the scenario. their expected likelihood was multiplied by their nervous expectation for each scenario and then a mean score was derived across all items. higher scores relate to greater rejection sensitivity. we hypothesised that higher scores on the social subscale of the hsrq would be positively associated with higher scores on the c-rsq. adults: personal health questionnaire depression scale (phq-8). the phq-8 is a validated eight item measure of depression [25] . participants were asked how often over the past two weeks they have experienced eight different symptoms, such as "how often were you bothered by feeling down, depressed, or hopeless?" participants were asked to report on a 4-point scale (0 = "not at all" [ . . . ] 3 = "nearly every day"). we hypothesised that higher scores on the social subscale of the hsrq would be positively associated with higher scores on the phq-8. the mfq [26] is a depression screening tool for individuals aged 6 to 17 years old. it is a validated measure of depression in children and young people [27] . individuals were presented with 13 questions, such as "i felt miserable or unhappy" in the past two weeks. responses were scored on a 3-point scale (0 = "not true", 1 = "somewhat true", 2 = "true"). we hypothesised that higher scores on the social subscale of the hsrq would be positively associated with higher scores on the mfq. adults: domain-specific risk-taking (dospert) scale. participants completed the health and social risk subscales of the 30 item dospert scale, a validated risk-taking measure for adults [22] . individuals were asked to report on a 5-point scale their likelihood of engaging in each activity or behaviour such as "speaking your mind about an unpopular issue in a meeting at work" ("1= "very unlikely" to 5= "very likely") and their assessment of how risky each situation or behaviour was ("1= "not at all risky" to 5= "extremely risky"). we hypothesised that higher scores on the social subscale of the hsrq would be negatively associated with the social risk engagement subscale of the dopsert and positively associated with the social risk perception subscale of the dospert, with the same being true for the health risk subscales. adolescents. note that adolescents did not complete a social risk-taking measure because the items from the dospert are not appropriate for this age group (e.g., "approaching your boss to ask for a raise") and there is no existing social risk-taking measure for adolescents. all data was analysed primarily using the laavan (version 0.6-5), psych (version 1.9.12.3) and semtools (version 0.5-2) packages in r (version 3.62; r core team, 2013). we first conducted an exploratory factor analysis (efa) using oblique (oblimin) rotation on the initial 16 items relating to health and social risks (eight health, eight social) on a sample of 500 adults. we determined the suitability of our sample size and data for efa based on the kaiser-meyer-olkin (kmo) index (>0.70) and bartlett's test (<0.05) [28] . we determined the number of factors to retain based on examination of the scree plot, retention of factors with eigenvalues of 1 or greater and factors with at least three items. items with factor loadings of <0.4 were removed. following factor and item reduction based on the above criteria, we subjected the same data to a confirmatory factor analysis (cfa) to assess the strength of the proposed factor structure. we then used cfa to assess the strength of this factor structure in two new samples: one adult group (aged 18-77; n = 415) and one adolescent group (aged 11-17, n = 485). in line with the recommendations outlined by [29] , our primary measure of model fit was root mean squared error of approximation (rmsea). an rmsea of around <0.08 indicates reasonable fit [29] . we also assessed the model fit with the standardised root mean square residual (srmr; <0.08 reasonable fit), comparative fit index (cfi; >0.9 reasonable fit), and the tucker-lewis index (tli; >0.9 reasonable fit). we computed measures of internal consistency using cronbach's alpha and mcdonalds omega. we further tested the fit of each two-factor cfa using aic, by comparing a one-factor solution (where all items are loaded onto one higher order risk factor) with the two-factor solution (health and social risk). a lower aic represents a better fit to the data. to assess convergent and divergent validity, we assessed the relationship between the new hsrq, rejection sensitivity [23, 24] and depressed mood [25, 27] across both cfa samples using pearson r correlations. we then compared the strength of the relationship between the adolescent and adult sample with a z statistic. one additional risk-taking questionnaire, the dospert [22] , was used to brain sci. 2020, 10, 397 6 of 14 relate the hsrq to risk perception and engagement health and social risks, in the adult sample only. in order to establish the test-retest reliability of the hsrq, we invited 100 participants from the adult cfa sample to complete the questionnaire a second time 11-12 days after the first completion. we used pearson r correlations to establish the relationship between these individuals' scores at time point 1 and 2. using all the data collected (n = 1399), we computed a mean score of the validated health and social subscale. we determined the relationship between age and the two subscales of the hsrq using multiple linear regression. we included age, gender and risk domain (health, social) in the model, as well as an age*risk domain interaction, to predict risk concern. we used aic to compare between linear, quadratic and cubic models, with a lower aic representing a better fit. analyses showed that the sample size (n = 500) was suitable for conducting factor analysis (kmo = 0.88, bartlett's test <0.001). factor loadings of each item are presented in table 1 . three factors showed eigenvalues above our threshold of 1: 5.92, 2.53, 1.14, respectively. a fourth factor with an eigenvalue of 0.88 was removed. the third factor (eigenvalue 1.14) only consisted of two items and so was removed. this resulted in a two-factor, 11-item solution. the two factors contained items pertaining to health risks (5 items) and social risks (6 items). we tested the strength of this two-factor solution on the same sample with cfa. the two-factor solution fit the data well (rmsea = 0.07 (0.06-0.08), srmr = 0.05, cfi = 0.95, and tli = 0.93). we conducted a cfa on a new sample of 415 adults. the sample size was deemed appropriate for testing a model comprising of 24 parameters (11 factor loadings, 11 error variances and 2 factor correlations). the model approximates to a 17:1 subject to parameter ratio, above the recommended 10:1 [30] . the two-factor structure adequately fit the data according to our primary fit index; rmsea = 0.08 (0.07-0.09). other model fit indices were good (srmr = 0.06) or fell just below the suggested cut off (cfi = 0.87 and tli = 0.83). factor loadings of each item (see table 2 ) were medium to high (0.42-0.76) except for one item (loading of 0.28). although this item loading was low, we decided to retain it in order to maintain consistency with the factor structure in the adolescent sample and given its good loading in the adult efa and the adolescent cfa sample. there was a positive correlation between the health and social subscale of the hsrq (r(482) = 0.21, p < 0.001). measures of internal consistency were good (see table 3 ). an additional cfa to assess a one-factor structure did not achieve good model fit (rmsea = 0.12 (0.11-0.13), srmr = 0.10, cfi = 0.72, and tli = 0.70), indicating that concern about risk taking is not a unitary construct and is instead domain specific (health, social). the aic of the two-factor model (42983.13) was lower than the aic of the one-factor model (43126.50), suggesting that the two-factor model provided a better fit. to measure the test-retest reliability of the hsrq, 100 adult participants were invited to complete the questionnaire a second time, 11-12 days later; 68 participants responded. pearson r correlation between the two time points indicated good test-retest reliability (social risk subscale: r(66) = 0.62, p < 0.001; health subscale: r(66) = 0.74, p < 0.001). to assess convergent and divergent validity, participants also completed measures of rejection sensitivity (a-rsq), depressed mood (phq-8) and risk taking (dospert). association with rejection sensitivity. the social risk subscale positively correlated with rejection sensitivity (r(413) = 0.22, p < 0.001) such that individuals who scored high on concern for social risk also scored high in rejection sensitivity (see figure 1, panel b) . the health risk subscale did not significantly correlate with rejection sensitivity (r(413) = −0.00, p = 0.99). association with depressed mood. the social risk subscale positively correlated with depressed mood (r (413) = 0.13, p = 0.009) such that individuals who scored high on concern for social risk also scored high in depressed mood (see figure 1 , panel d). the health risk subscale did not significantly correlate with depressed mood (r(413) = −0.05, p = 0.27). association with risk taking. the social risk subscale of the hsrq negatively correlated with the likelihood of engaging in social risks subscale of the dospert (r(413) = −0.32, p < 0.001) and was positively correlated with the perception of social risks subscale of the dospert (r(413) = 0.29, p < 0.001). in other words, individuals who scored high on concern for social risk on the hsrq were less likely to engage in social risk behaviours and more likely to rate social risk behaviours as risky. the health risk subscale of the hsrq was negatively correlated with the likelihood of engaging in health risks subscale of the dospert (r(413) = −0.18, p < 0.001) and was positively correlated with the perception of health risks subscale of the dospert (r(413) = −0.29, p < 0.001). thus, individuals who scored high on concern for health risks were less likely to engage in health risk behaviours and more likely to rate health risk behaviours as risky. we conducted a cfa on a new sample of 484 adolescents. the sample size was deemed appropriate for testing a model comprising of 24 parameters (11 factor loadings, 11 error variances and 2 factor correlations). the model approximates to a 20:1 subject to parameter ratio, above the recommended 10:1 [30] . the two-factor structure fit the data well (rmsea = 0.07 (0.06-0.08), srmr = 0.05, cfi = 0.95, and tli = 0.93). factor loadings of each item were medium to high (0.54-0.79) (see table 2 ). there was a positive correlation between the health and social subscale of the hsrq (r(482) = 0.21, p < 0.001). measures of internal consistency were good (see table 3 ). an additional cfa to assess a one-factor structure did not achieve good model fit (rmsea = 0.18 (0.17-0.19), srmr = 0.16, cfi = 0.60, and tli = 0.50), indicating that concern about risk taking is not a unitary construct across domains, and is instead domain specific (health, social), as in the adult sample. the aic of the two-factor model (49696.51) was lower than the aic of the one-factor model (50280.89), suggesting that the two-factor model provides a better fit. validation to assess convergent and divergent validity, a subset of the adolescent participants completed measures of rejection sensitivity (c-rsq; n = 207) and depressed mood (mfq; n = 281). association with rejection sensitivity. the social risk subscale positively correlated with rejection sensitivity (r(205) = 0.52, p< 0.001) such that individuals who scored high on concern for social risk also scored high in rejection sensitivity (see figure 1 , panel a). the health risk subscale did not significantly correlate with rejection sensitivity (r(205) = −0.01, p = 0.83). association with depressed mood. the social risk subscale positively correlated with depressed mood (r(279) = 0.31, p < 0.001) such that individuals who scored high on concern for social risk also scored high in depressed mood (see figure 1 , panel c). the health risk subscale did not significantly correlate with depressed mood (r(279) = −0.11, p = 0.06). we compared the strength of the correlations between concern for social risk, rejection sensitivity and depression between the adolescent cfa and adult cfa sample. the strength of the correlations between concern for social risk and rejection sensitivity and depression was stronger for adolescents than for adults (rejection sensitivity: z = 4.12, p < 0.001; depression: z = 2.45, p = 0.007). we conducted a multiple regression to assess the relationship between the hsrq and age, using data collected across all participants (n = 1399; aged 11-77). the outcome was risk concern (i.e., the mean score of the health and social subscales) and the predictor variables were age, gender, risk domain (health, social), and an age by risk domain interaction. the overall regression model was significant (r 2 = 0.14, f(3,2793) = 113.2, p < 0.001; see table 4 for estimates). there was a significant main effect of age (β = −0.15; 95% ci: −0.23-0.07; p < 0.001) and risk domain (β = −11.69; 95% ci: −15. 18-8.19 ; p < 0.001) and a significant interaction between age and risk domain (β = −0.16; 95% ci: −0.27-0.04; p < 0.001). there was no main effect of gender (β = 1.07 95% ci: −0.54-2.69; p < 0.19). . the strength of the correlations between concern for social risk and rejection sensitivity and depression was stronger for adolescents than for adults (rejection sensitivity: z = 4.12, p < 0.001; depression: z = 2.45, p = 0.007). we conducted a multiple regression to assess the relationship between the hsrq and age, using data collected across all participants (n = 1399; aged 11-77). the outcome was risk concern (i.e., the mean score of the health and social subscales) and the predictor variables were age, gender, risk domain (health, social), and an age by risk domain interaction. the overall regression model was significant (r 2 = 0.14, f(3,2793) = 113.2, p < 0.001; see table 4 for estimates). there was a significant main effect of age (β = −0.15; 95% ci: −0.23-0.07; p < 0.001) and risk domain (β = −11.69; 95% ci: −15. 18-8.19 ; p < 0.001) and a significant interaction between age and risk domain (β = −0.16; 95% ci: −0.27-0.04; p < 0.001). there was no main effect of gender (β = 1.07 95% ci: −0.54-2.69; p < 0.19). to explore the interaction between age and risk domain, we plotted the relationship ( figure 2 ) and used simple slope analyses. the slope for both risks was significant (social: β = −0.31, p < 0.001); health: β = −0.15, p < 0.001). there was a significant difference between the gradient of these slopes (t(2794) = 2.7, p = 0.008), driven by a steeper decline across age in concern for social risk compared to concern for health risk. this linear model (aic: 25125.34) outperformed a quadratic model (aic: 25142.67) and cubic model (aic: 25156.83). relationship between concern for social risk and rejection sensitivity for adolescents (r(205) = 0.52, p < 0.001; panel (a) and adults (r(413) = 0.22, p < 0.001; panel (b). relationship between risk concern and depression for adolescents (r(279) = 0.31, p < 0.001; panel (c) and adults (r(413) = 0.13, p = 0.009; panel (d). the strength of the correlations between concern for social risk and rejection sensitivity and depression was stronger for adolescents than for adults (rejection sensitivity: z = 4.12, p < 0.001; depression: z = 2.45, p = 0.007). to explore the interaction between age and risk domain, we plotted the relationship ( figure 2 ) and used simple slope analyses. the slope for both risks was significant (social: β = −0.31, p < 0.001); health: β = −0.15, p < 0.001). there was a significant difference between the gradient of these slopes (t(2794) = 2.7, p = 0.008), driven by a steeper decline across age in concern for social risk compared to concern for health risk. this linear model (aic: 25125.34) outperformed a quadratic model (aic: 25142.67) and cubic model (aic: 25156.83). −0.016 0.06 −2.7 0.008 note: *= an interaction term; β= beta coefficient; se= standard error; t = t statistic (the β divided by the se); p = significance. relationship between age and concern for health risk (slope: β = −0.15, p < 0.001) and social risk (slope: β = −0.31, p < 0.001). there was a significant difference between the gradient of these slopes (t(2794) = 2.7, p = 0.008), driven by a steeper decline across age in concern for social risk than for concern for health risk. in this study, we developed a questionnaire measure of concern for health and social risk behaviours for use in adolescents and adults. our results showed that concerns related to engaging in social risks are distinct from concerns related to engaging in health risks. overall, we found that people reported greater concern for health risk compared with social risk. we investigated age differences in concern for health and social risk, and found that concern for both health and social risk decreased with age, from adolescence through adulthood. however, concern for social risk decreased to a greater extent than concern for health risk. this suggests that, relative to adults, adolescents are more concerned about social risks than health risks. this heightened concern for social risk in adolescence has implications for understanding why adolescents engage in health and legal risks. one hypothesis is that adolescents are motivated to avoid what they consider to be a greater immediate risk, the social risk of being rejected or excluded by their peers [13] . avoiding social risks can be considered an important goal during adolescence, a period when social status and friendships provide psychological and physical health benefits [14, 15] . the association between our new measure, the health and social risk questionnaire (hsrq), rejection sensitivity and depression indicate the potential relevance of social risk for understanding adolescent behaviour and mental health. individuals who report greater concern for social risk were relationship between age and concern for health risk (slope: β = −0.15, p < 0.001) and social risk (slope: β = −0.31, p < 0.001). there was a significant difference between the gradient of these slopes (t(2794) = 2.7, p = 0.008), driven by a steeper decline across age in concern for social risk than for concern for health risk. in this study, we developed a questionnaire measure of concern for health and social risk behaviours for use in adolescents and adults. our results showed that concerns related to engaging in social risks are distinct from concerns related to engaging in health risks. overall, we found that people reported greater concern for health risk compared with social risk. we investigated age differences in concern for health and social risk, and found that concern for both health and social risk decreased with age, from adolescence through adulthood. however, concern for social risk decreased to a greater extent than concern for health risk. this suggests that, relative to adults, adolescents are more concerned about social risks than health risks. this heightened concern for social risk in adolescence has implications for understanding why adolescents engage in health and legal risks. one hypothesis is that adolescents are motivated to avoid what they consider to be a greater immediate risk, the social risk of being rejected or excluded by their peers [13] . avoiding social risks can be considered an important goal during adolescence, a period when social status and friendships provide psychological and physical health benefits [14, 15] . the association between our new measure, the health and social risk questionnaire (hsrq), rejection sensitivity and depression indicate the potential relevance of social risk for understanding adolescent behaviour and mental health. individuals who report greater concern for social risk were more likely to report greater sensitivity to rejection (adolescents: c-rsq; adults: a-rsq). social rejection is an unpleasant feeling and therefore it makes sense that individuals with a heightened degree of sensitivity to the negative effects of social rejection would be more concerned with engaging in situations that could lead to, or indicate a possibility of, social rejection. within the adult sample, individuals who scored high on concern for social risk were less likely to engage in socially risky behaviours and were more likely to rate social risk behaviours as risky. this finding indicates that higher concern for social risk is related to an increase in rejection sensitivity and an increase in socially risk-averse behaviour. concern for social risk was also related to depressive symptomatology (adolescents: mfq; adults: phq-8), such that individuals with greater concern for social risk were more likely to report higher levels of depressive symptoms. this finding supports the predictions made by the social risk hypothesis of depression [20] . this hypothesis proposes that, when cues in the environment signal that one's social burden is significantly greater than their social value, depression manifests as an adaptive mechanism to remove the individual from social situations which might confer further risk of social rejection. we showed that concern for social risk was more strongly associated with rejection sensitivity in adolescents (11-17 years) , than in adults (18+ years). during adolescence, individuals are particularly sensitive to social evaluative concerns [11] , and peer perceptions influence adolescents' social and personal worth [31] . adolescents are also hypersensitivity to social rejection relative to adults [10] . this fits with our finding that concerns for social risk are more tightly linked to rejection sensitivity among adolescents, relative to adults. in addition, and as previously discussed, adolescents with good quality friendships and higher social status have more favourable psychological and physical outcomes later in life. thus, it is potentially beneficial and adaptive for adolescents to try to avoid the risk of social rejection [14, 15] . additionally, the association between concern for social risk and depressive symptoms was stronger in adolescents than adults. this suggests that the social environment may be particularly salient for mental health during this developmental period [18, 32] . this is important because the incidence of many mental health problems, including depression, increases significantly during adolescence [33] . our findings have a number of implications. at the theoretical level, the way in which risk behaviours have been traditionally conceptualised has focused heavily on the health, financial, legal and recreational domains. our results suggest that social risk should be incorporated into our understanding of risk-taking behaviour. for some individuals, taking a social risk, and placing themselves at risk of social rejection, is a real and 'risky' decision. at the practical level, interventions aimed at reducing health and legal risk behaviours should recognise the importance of concerns surrounding social risks. one promising approach is to focus on peer-led interventions, which work to influence social norms surrounding unhealthy or illegal behaviours [34] . this approach encourages healthy behaviours by reducing the social risk of being ostracised by peers. interventions using a peer-led approach have shown positive results for unhealthy behaviours such as bullying [35] and smoking [36] . the hsrq is a valid measure for individuals aged 11+. however, this measure has not been validated for children below 11 and very little is known about social risk in this younger age group. future work should explore the extent to which the current items and factor structure are valid for use in children below this age. additionally, we did not test the relationship between our measure of concern for social risk and engagement in real-life social risks in the adolescent sample (11-17 years) because of a lack of appropriately validated scales for this age group. this is a limitation when making comparisons with the adult sample (18+) and future work should explore the relationship between our concern for social risk measure and engagement in real-life social risks among adolescents. further, our sample was collected from the united kingdom and therefore this measure should be cross-culturally validated for use in other socio-cultural environments. in addition, the hsrq is based on self-report, and an important line of subsequent work is to relate responses on this questionnaire measure to a task-based assessment of social risk. finally, the present study was not designed to investigate the degree to which individuals weigh up the health vs. social consequences of a given 'risky' decision. therefore, an important outstanding question is the degree to which individual variation in concern for health and social risk impacts involvement in 'risky' behaviours, especially when individuals are presented with risks that often carry both social and health consequences, such as smoking or dangerous driving. in the current study, we developed a self-report measure of concern for health and social risk for use with adolescents and adults. we found that heightened concern for social risk was related to increased sensitivity to rejection and depression, with this relationship being stronger for adolescents compared to adults. this supports the body of evidence that adolescence is a period of heightened sensitivity to the social environment. in addition, both concern for health and social risk decreased with age, but the rate of decrease was steeper for social versus health risk, suggesting that adolescence is a period of amplified concern for social risk. practically, these findings have potential implications for policy. within an educational context, an understanding of social risk may offer insight into why adolescents are more or less motivated to engage with school work. for example, if individuals who try hard at school are perceived as unpopular or uncool, then being openly motivated in the classroom could be a social risk [37] . within a legal context, concerns surrounding social risk may be a factor in adolescents' decisions to engage in criminal behaviour, particularly in peer contexts when opting out of a group behaviour could risk being excluded from the group. together, these findings highlight the importance of social risk in adolescent behaviour and suggest that interventions to reduce risk-taking behaviours in this age group should consider the role of social risk. the following are available online at http://www.mdpi.com/2076-3425/10/6/397/s1, table s1 : health and social risk questionnaire (hsrq). is adolescence a sensitive period for sociocultural processing? the relationship between early age of onset of initial substance use and engaging in multiple health risk behaviors among young adolescents clustering of health-compromising behavior and delinquency in adolescents and adults in the dutch population carrying passengers as a risk factor for crashes fatal to 16-and 17-year-old drivers peer influence on risk taking, risk preference, and risky decision making in adolescence and adulthood: an experimental study is it all in the reward? peers influence risk-taking behaviour in young adulthood neural correlates of expected risks and returns in risky choice across development age-related differences in social influence on risk perception depend on the direction of influence social influence on risk perception during adolescence social brain development and the affective consequences of ostracism in adolescence the teenage brain: sensitivity to social evaluation risk-taking and social exclusion in adolescence: neural mechanisms underlying peer influences on decision-making avoiding social risk in adolescence peer status in school and adult disease risk: a 30-year follow-up study of disease-specific morbidity in a stockholm cohort goodyer, i. the nspn consortium adolescent friendships predict later resilient functioning across psychosocial domains in a healthy community cohort peripheral ingroup membership status and public negativity toward outgroups how intragroup dynamics affect behavior in intergroup conflict: the role of group norms, prototypicality, and need to belong the role of peer rejection in adolescent depression peer relationships in adolescence the social risk hypothesis of depressed mood: evolutionary, psychosocial, and neurobiological perspectives darwinian models of depression: a review of evolutionary accounts of mood and mood disorders a domain-specific risk-taking (dospert)scale for adult populations rejection sensitivity and disruption of attention by social threat cues rejection sensitivity and children's interpersonal difficulties the phq-8 as a measure of current depression in the general population development of a short questionnaire for use in epidemiological studies of depression in children and adolescents: factor composition and structure across development criterion validity of the mood and feelings questionnaire for depressive episodes in clinic and non-clinic subjects statistical methods for health care research conceptions and perceived influence of peer groups: interviews with preadolescents and adolescents social support and mental health in late adolescence are correlated for genetic, as well as environmental lifetime prevalence and age-of-onset distributions of mental disorders in the world health organization's world mental health survey initiative peer influence in adolescence: public-health implications for covid-19 changing climates of conflict: a social network experiment in 56 schools an informal school-based peer-led intervention for smoking prevention in adolescence (assist): a cluster randomised trial role theory of schools and adolescent health this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors declare no conflicts of interest. key: cord-017883-6a4fkd5v authors: dutta, ankhi; flores, ricardo title: infection prevention in pediatric oncology and hematopoietic stem cell transplant recipients date: 2018-07-16 journal: healthcare-associated infections in children doi: 10.1007/978-3-319-98122-2_16 sha: doc_id: 17883 cord_uid: 6a4fkd5v pediatric patients with malignancies and transplant recipients are at high risk of infection-related morbidity and mortality. children at the highest risk for infections are those with acute myeloid leukemia (aml), relapsed acute lymphoblastic leukemia (all), and hematopoietic stem cell transplant recipients (hsct). these patients are at high risk for life-threatening bacterial, viral, and fungal infections which are associated with prolonged hospital stay, poor quality of life, and increased healthcare cost and death. recognition of risk factors which predisposes them to infections, early identification of signs and symptoms of infections, prompt diagnosis, and empiric/definitive treatment are the mainstay in reducing infection-related morbidity and mortality. infection control and prevention programs also play a crucial role in preventing hospital-acquired infections in these immunosuppressed hosts. there are various factors which contribute to the increased susceptibility to infections in pediatric hematology/oncology (pho) and hsct patients, most prominent of them being disruption of cutaneous and mucosal barriers (oral, gastrointestinal, etc.), microbial gastrointestinal translocation, defects in cell-mediated immunity, and insufficient quantities and inadequate function of phagocytes. goals of infection control and prevention in this population are based on mitigating the risk inherent with the underlying malignancy and associated treatments (i.e., chemotherapy, radiation). this chapter discusses infection control and prevention measures specifically in patients with hematological malignancies as well as hsct recipients. hand hygiene and standard precautions during the care of pho and hsct patients are key components in reducing the risk of infections. additional isolation precautions may also be undertaken depending on the pathogen isolated and/or symptoms that the patient is experiencing (e.g., contact precautions would be appropriate in patients experiencing diarrhea). further information on general infection prevention measures can be found in chap. 1. minimizing injury to mucosal surfaces and decreasing heavy colonization of the skin reduce the likelihood of microbial invasion through these sites. thus, the importance of meticulous skin care and daily inspection in pho and hsct patients is paramount and provides opportunities to identify areas of inflammation or breakdown early. skin inspection should be done routinely, with special attention to highrisk areas like intravascular catheter insertion sites and the perineum. rectal thermometers, digital rectal examinations, and suppositories should be avoided to prevent mucosal breakdown. as part of an effort to reduce colonization of cutaneous surfaces, daily chlorhexidine baths have been shown to reduce hais and transmission of multidrug-resistant organisms (mdro) in oncology patients [1, 2] . chlorhexidine gluconate (chg) is a cationic bisbiguanide that serves as a topical antiseptic. chg binds to negatively charged bacterial cell wall proteins altering the bacterial cell wall equilibrium and helps in reducing bacterial colonization of the skin [1] . education of patients, families, and staff on the importance of these practices is key to compliance with this preventative strategy and should be made a priority. many experts recommend a complete periodontal examination be performed prior to initiation of chemotherapy with reevaluations throughout the treatment course and after completion [3, 4] . oral mucositis, which can be considered an acute inflammation and/or ulceration of the oral/oropharyngeal mucus membranes, is a common adverse effect of chemotherapeutic agents. it can cause oral pain/discomfort as well as difficulties in eating, swallowing, and speech. mucositis is most commonly caused by chemotherapeutic agents which prevent dna synthesis such as methotrexate, 5-fluorouracil, and cytarabine, particularly in hsct recipients. oral rinses with normal saline or chg-containing products are recommended 4-6 times per day to prevent oral mucositis [2, 3] . patients with painful mucositis might not comply with oral care regimens, however, putting them at increased risk for infections from oral flora such as bacteremia due to viridans streptococci. mouth rinses containing alcohol should be avoided because they can aggravate mucositis. neutropenic patients should also be instructed to brush their teeth carefully in order to prevent gingival injury [3] . a regular soft toothbrush or an electric brush can be used to minimize trauma [3] . any elective dental procedure should be ideally performed prior to starting chemotherapy and after discussion with the primary medical team. the absolute neutrophil count, platelet count, and stage of treatment should be considered before performing any dental procedures in this vulnerable population [2, 3] . the presence of central venous catheters (cvc) in this population puts them at risk for central line-associated bloodstream infection (clabsi) and its related complications. clabsi is the most commonly reported hai in most pediatric series. among all the pediatric hai reported to national healthcare surveillance network (nhsn), 15% were from oncology units; streptococcus viridans (15%) and klebsiella pneumoniae/oxytoca (12%) were the two most common pathogens in this study [5] . in the nhsn report, antibiotic resistance was noted to be high in oncology units, including ampicillin and/or vancomycin resistance for enterococcus faecium and fluoroquinolone resistance for escherichia coli [5] . although less than 4% of enterobacteriaceae were reported to have carbapenem resistance, the emergence of such organisms in this population is of significant concern [6]. among candida infections in this population, fluconazole resistance among non-c. albicans and non-c. parapsilosis isolates was up to 41%, whereas fluconazole resistance in c. albicans and c. parapsilosis was <4% [5] . mucosal barrier injury (mbi)-associated laboratory-confirmed bloodstream infections (mbi-lcbi) have gained attention in recent years [7, 8] . these are clabsis related primarily to mucosal barrier injury (i.e., mucositis) and not due to the direct presence of the cvc per se. in the nhsn definition, a positive blood culture would qualify as a mbi-lcbi if it results from one or more groups of selected commensal organisms of the oral cavity or gastrointestinal tract and occurred in the presence of signs and symptoms consistent with mucosal barrier injury (mbi) in pho or hsct patients [7] . eligible organisms for mbi-lcbi include candida species, enterococcus, enterobacteriaceae, viridans group streptococci, other streptococcus species, and anaerobes [7] . specific guidelines for central line insertion and maintenance bundles have been proposed by the centers for disease control and prevention (cdc) and the infectious diseases society of america (idsa) to reduce the clabsi rates and healthcare costs [9, 10] . several studies have demonstrated that a multifaceted approach reduces clabsi rates in this population [11, 12] and includes standardizing cvc insertion practices and maintenance bundles, tracking cvc infections using standardized definitions, and using dedicated nursing staff or "cvc champions" specifically trained in cvc maintenance and tracking in conjunction with other infection control methods (including oral and hand hygiene, optimizing nurse/patient ratio, etc.). clabsi is discussed in greater detail in chap. 6. the american society for blood and marrow transplantation recommends a low microbial diet for hsct recipients [13] . there is little evidence, however, to suggest that this helps in pho patients. routine safety in handling and preparing food should be practiced by patients and parents. in general, eating unpasteurized milk/ cheese, undercooked meat, and raw fruits and vegetables is discouraged during periods of neutropenia to reduce incidence of infection. the need to minimize risk of infection, however, should be balanced with the nutritional needs and quality of life of the patient [2, 13] . pets can be a great source of companionship and comfort to children; however, there are several diseases that can be transmitted by pets to these immunosuppressed hosts [14] [15] [16] . certain animals like reptiles, birds, rodents, or other exotic animals that cannot be immunized and could carry unusual human pathogens should not be kept as pets in households with pho or hsct patients. immunosuppressed patients should avoid petting zoos due to the risk of diseases secondary to enteric pathogens (such as salmonella or campylobacter) [13] [14] [15] [16] . dogs and cats, preferably more than 1 year old, are generally considered safe for pho and hsct patients. they should be routinely evaluated by veterinarians for diseases and their immunizations kept up-to-date. extreme care should be taken to maintain hand hygiene during and after handling the pets [13] [14] [15] [16] . further information regarding pet therapy is available in chap. 4. studies performed in adult oncology patients have consistently shown the benefit of using prophylactic antibiotics in reducing the incidence of bacterial infections [17] . levofloxacin prophylaxis in adults has been shown to reduce the incidence of fever, bacterial infection, hospitalization rates, and all-cause mortality [18, 19] . based upon such data in adults, the idsa guidelines for the use of antimicrobial agents in neutropenic patients with cancer state that fluoroquinolone prophylaxis should be considered for high-risk patients with prolonged severe neutropenia [20] . pediatric studies on antibiotic prophylaxis are limited. a pediatric pilot study on the use of ciprofloxacin prophylaxis for pediatric patients receiving delayed intensification therapy for acute lymphoblastic leukemia (all) showed a reduction in hospitalization, intensive care admission, and bacteremia when compared to controls [21] . in another study, levofloxacin prophylaxis in patients with all reduced the odds of febrile neutropenia, possible bacterial infection, and confirmed bloodstream infection by ≥70%. it also reduced the use of other broad-spectrum antibiotics and the incidence of c. difficile infections [22] . in other studies, however, ciprofloxacin prophylaxis did not decrease the incidence of overall bacteremia or duration of fever or mortality in pediatric acute myelogenous leukemia (aml) patients [23] . furthermore, increasing quinolone resistance among gram-negative organisms is a concern recently observed in the nhsn database of pediatric oncology patients with clabsi [5] . in addition, the use of antimicrobial prophylaxis in pho could increase the possibility of developing other mdros, invasive fungal infections, or drug-related toxicities. though some authors suggest that antibiotic prophylaxis should be considered in children undergoing induction chemotherapy for all, there is currently insufficient data to inform definitive guidelines for antibiotic prophylaxis to prevent bacterial infections in pediatric oncology patients [19] [20] [21] . notably, an open-label randomized clinical trial was recently conducted of levofloxacin prophylaxis vs. no prophylaxis in children with aml, relapsed all, and hsct recipients. among patients with aml and relapsed all, prophylaxis was associated with a reduction in rates of bacteremia; there was a numeric reduction in bacteremia in the hsct recipients, but this did not achieve statistical significance. it is unclear at this time how these new findings will influence practice and future guidelines [24] . infections with common respiratory and gastrointestinal viruses can result in significant morbidity and mortality in pho and hsct patients. the most common respiratory viruses encountered include rhinovirus, coronavirus, adenovirus, rsv, parainfluenza, human metapneumovirus, and influenza. common gastrointestinal viruses affecting both healthy and immunocompromised children include norovirus, rotavirus, enteric adenoviruses, and enteroviruses among others. infection prevention strategies should include education provided to the patient and the family about hand hygiene, prevention techniques, avoidance of ill visitors, disease surveillance in the community and hospital, vaccination against influenza and prompt identification, and testing and treatment (if possible) of any respiratory viral illness. implementation of routine infection control prevention policies on oncology wards should reduce transmission of common respiratory and gastrointestinal viruses. all visitors should be screened for any signs and symptoms of acute viral illness and restricted from visitation on the unit or contact with any immunocompromised hosts. chapter 4 outlines infection control guidance for hospital visitors in greater detail. immunization of healthcare workers and household contacts needs special consideration in settings with pho and hsct patients. given the immunosuppressed status of children with malignancy and/or hsct, immunization of those closest to them at home and those caring for them in the hospital is critically important in preventing infections. live attenuated vaccines contain a theoretical risk of being transmitted to an immunocompromised host. live oral polio vaccine, which is no longer administered in the united states, is an absolute contraindication for people taking care of this high-risk population. however, data suggests that measles, mumps, and rubella (mmr), varicella zoster, and herpes zoster vaccines can be safely provided to healthcare workers and household contacts [25] . if healthcare personnel develop a rash that cannot be covered within the first 42 days following receipt of the varicella vaccine, they should avoid any contact with immunocompromised patients until all rash has crusted to avoid the potential risk of transmitting vaccine strain varicella to patients [25] . infants living in households with persons who are immunocompromised including pho and hsct patients may be safely immunized against rotavirus; it is recommended, however, that immunocompromised persons avoid contact with the infant's diapers/stool for 4 weeks following vaccination to minimize risk of acquiring vaccine strain rotavirus infection [26] . an inactivated influenza vaccine is preferred for personnel taking care of immunocompromised children as opposed to live attenuated influenza vaccine [25] . vaccination against other non-viral pathogens (such as pneumococcus or pertussis) by family members is another important method to minimize the risk of serious infection in pho patients. hospital environments are designed to minimize the potential for fungal disease in the highest-risk patients. high efficiency particulate air (hepa) filters have been shown to reduce nosocomial infection in hsct patients, and the cdc recommends hepa filters in hsct recipient's rooms. the rooms should also have directed airflow and positive air pressure and be properly ventilated (≥12 air changes per hour) [2] . avoidance of carpets and upholstery is also recommended. since outbreaks secondary to aspergillus have been reported during hospital renovation or construction, appropriate containment should be in place, and strict precautions should be taken to prevent exposure to patients during such periods [2] . infection control and prevention departments should be involved in risk assessment, planning, and approval of all construction or renovation projects in healthcare facilities including inpatient units, clinics, and infusion centers caring for these patients [27] . cytotoxic chemotherapies and radiation therapy used in the treatment of malignancies are myelosuppressive and result in variable duration and severity of neutropenia. in addition, certain malignancies that originate from bone marrow precursors (i.e., leukemia) or metastasize to the bone marrow (e.g., lymphoma, neuroblastoma, and sarcomas) can result in a decreased number of normal blood cell precursors and consequent neutropenia. hence, pediatric cancer and hsct patients are frequently immunosuppressed and at risk for a wide range of pathogens. febrile neutropenia is a common condition in the pho/hsct population. with regard to this entity, fever is defined as a single temperature >38.3 °c (101 °f) or a temperature ≥38.0 °c (100.4 °f) on two occasions 1 hour apart. neutropenia is classified as mild (absolute neutrophil count [anc] >500-1000/mm 3 ), moderate (anc ≥200-500/mm 3 ), or severe (anc <200/mm 3 ). febrile neutropenia (also known as fever and neutropenia) is the combination of these two events in the patient with malignancy or hsct and is a common complication of cancer treatment. it has been estimated that 10-50% of patients with solid tumors and up to 80% of patients with hematologic malignancies will develop fever during at least one chemotherapy cycle associated with neutropenia [28] . moreover, fever may be the only indication of a severe underlying infection as other signs and symptoms are often absent or minimized due to an inadequate inflammatory response. therefore, physicians must be particularly aware of the infection risks, diagnostic methods, and antimicrobial therapies required for the management of febrile neutropenia in cancer patients. in the majority of febrile episodes, a pathogen is not identified, with a clinically documented infection occurring in only 20-47% of cases. of these patients, bacteremia occurs in 10-25%, with most episodes seen in the setting of prolonged and/or profound neutropenia (anc < 100 neutrophils/mm 3 ) [29, 30] . on the other hand, the most common sites of focal infection include the gastrointestinal tract, lung, and skin [31] . over the past five decades, the rates, antibiotic resistance, and epidemiologic spectrum of bloodstream pathogens isolated from febrile neutropenic patients have changed substantially under the selective pressure of broad-spectrum antimicrobial therapy and/or prophylaxis [32, 33] . early in the development of cytotoxic chemotherapies, during the 1960s and 1970s, gram-negative pathogens predominated in febrile neutropenia. subsequently, during the 1980s and 1990s, gram-positive organisms became more common as use of indwelling plastic venous catheters became more prevalent, which can allow for colonization and subsequent infection by gram-positive skin flora [31, 34] . gram-positive bacteria currently account for 60-70% of culture-positive infections in pediatric cancer patients [5] . importantly, a recent systematic review of the epidemiology and antibiotic resistance of pathogens causing bacteremia in cancer patients since 2008 showed a recent shift from gram-positive to gram-negative organisms [35] . the main causes for this new trend are to be determined, but the use and duration of antibiotic prophylaxis are an important factor to consider as the incidence of gram-negative bacteria was significantly higher in groups who did not receive antibiotic prophylaxis. the use of antibiotic prophylaxis, however, may conceivably select for resistant organisms; increasing rates of antibiotic resistance in both gram-negative and gram-positive bacteria have been reported in the global community as well as the cancer population and are of significant concern [5, 31, 35] . overall, the most common blood isolate in the setting of febrile neutropenia is coagulase-negative staphylococci. other less common blood isolates include enterobacteriaceae, non-fermenting gram-negative bacteria (such as pseudomonas), s. aureus, and streptococci (see table 16 .1). providers should review the local data at their institution for prevalent blood isolates and antimicrobial susceptibility profiles. management of febrile neutropenia continues to evolve given the awareness that interventions previously considered standard of care (such as inpatient treatment with intravenous broad-spectrum antibiotics) may not be necessary nor appropriate for all patients [36] . it has become increasingly important to identify patients at high risk of infectious complications requiring more aggressive management and monitoring (i.e., inpatient setting with intravenous antibiotics). in addition, clinicians may be able to identify low-risk patient populations who may be managed in a less aggressive and more cost-effective manner (i.e., outpatient setting and/or with oral antibiotics). in order to address these issues, algorithmic approaches to neutropenic fever, infection prophylaxis, diagnosis, and treatment have been developed [20, [37] [38] [39] . it is well established that stratification of patients to determine the risk for complications of severe infection should be undertaken at presentation of fever [20, 37] . this determines the type of empiric antibiotic therapy (oral vs. intravenous), venue of treatment (inpatient vs. outpatient), and duration of antibiotic therapy. generally, the risk for serious infection is directly related to the degree and duration of neutropenia. pediatric patients with mild (anc ≥500) and brief periods of neutropenia (<7 days) are less likely to have infectious complications than those [20, 29, 30] a. dutta and r. flores with moderate to severe neutropenia (anc ≤500) lasting more than 7 days. similarly, the risk for bacteremia and septicemia increases dramatically when the anc is <200. infectious complications that are more common with severe and prolonged neutropenia include bacteremia, pneumonitis, cellulitis, and abscess formation. it is important to consider individual patient risk incorporating the latest recommendations for the management of neutropenic fever in children with cancer and hsct [37, 38] . patients are generally stratified as either high or low risk as follows: 1. high-risk patients -anticipated prolonged (>7 days duration) and profound neutropenia (anc <100 cells/mm 3 following cytotoxic chemotherapy) and/or significant medical comorbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes [20] 2. low-risk patients -anticipated brief (<7 days duration) neutropenic periods in those with no or few comorbidities [20] in addition, risk classification may be based on the multinational association for supportive care in cancer (mascc) score (table 16. 2) [40] . a mascc risk score of ≥21 is recommended as the threshold for definition of low risk, with 6% of such patients developing serious medical complications compared to 39% of those scoring <21 [40] . however the mascc score was developed and validated in adults and has not been validated in a pediatric population. the consensus in the field is for all patients considered to be at high risk by mascc or by clinical criteria to be treated as inpatients with empiric iv antibiotic therapy. carefully selected low-risk patients may be candidates for oral and/or outpatient empiric antibiotic therapy. table 16 .3 summarizes the recommendation for the management of febrile neutropenia based on recommendations of the idsa and the international pediatric fever and neutropenia guideline panel. importantly, in neutropenic febrile patients with an obvious source of infection on clinical exam, management should be tailored to that source. of note, adequate antibiotic stewardship is of utmost importance during the treatment of neutropenic patients in order to decrease the incidence of antibiotic-related adverse drug events, prevalence of antibiotic resistance, and decrease treatment costs. blood cultures must be closely monitored, and once a microorganism has been identified, an appropriate plan for antibiotic de-escalation and/or treatment duration should be promptly instituted. invasive fungal diseases (ifd) are one of the leading causes of morbidity and mortality in pho and hsct patients and present many diagnostic and therapeutic challenges. one of the principal risk factors contributing to the development of ifd relates to the patient's oncologic diagnosis. patients with aml and high-risk and relapsed all, recipients of allogenic hsct, and those with chronic or severe acute graft-versushost disease (gvhd) are at the highest risk of ifd [42, 43] . often a combination of other risk factors is present in these patients which may include prolonged neutropenia, high-dose corticosteroid use, immunosuppressive therapy, parenteral nutrition, presence of a cvc, preceding antibiotic therapy, presence of bacterial coinfection, oral mucositis, and admission to an intensive care unit [44, 45] . the highest risk of ifd is during periods of profound neutropenia which for hsct recipients occurs during the first 30 days posttransplant and during neutrophil engraftment [46] ; for pho patients, the highest risk period is during induction chemotherapy [46] . high-risk patients use monotherapy with an antipseudomonal β-lactam, a fourth generation cephalosporin, or a carbapenem as empirical therapy in pediatric high-risk fn depending on the local prevalence of multidrug-resistant gram-negative rods strong recommendation high-quality evidence reserve addition of a second gram-negative agent or a glycopeptide for patients who are clinically unstable, when a resistant infection is suspected, or for centers with a high rate of resistant pathogens in an era of growing prophylactic antifungal use, children receiving mold-active agents have been shown to be at higher risk of non-aspergillus species fungal infection [43] . voriconazole prophylaxis in adults has been shown to be an independent risk factor for mucormycoses [47] . likewise, breakthrough trichosporonosis has also been reported in patients receiving micafungin as prophylaxis [48] . these phenomena are likely in part related to the selection of fungi with reduced intrinsic susceptibility to the prophylactic agent. the most common ifd are invasive aspergillosis (ia) and invasive candidiasis (ic), with a recent upward trend seen in non-aspergillus mold infections [43] [44] [45] . among aspergillus species, a. fumigatus is the most common, followed by a. flavus and a.niger [45] . among non-aspergillus molds, mucormycoses (rhizopus, mucor, absidia) are most frequently reported followed by a number of other species (e.g., fusarium, scedosporium, curvularia, exserohilum, etc.) [45] . among ic, c. albicans is the single most common candida species, but nonalbicans candida species (especially c. parapsilosis and c. tropicalis) have been increasingly reported among this population [49] . ifd should be suspected in patients with fever and neutropenia lasting for more than 4 days without any identifiable cause [20] . ic can present as septic shock or may have more non-specific findings such as fever, cough, nausea/vomiting, abdominal pain, and cutaneous lesions depending on the site of involvement. in children, the most common sites of ic are the lungs, liver, and spleen, but dissemination can occur to the other organs including the heart, eyes, or brain. disseminated disease is an independent risk factor for death in children with ic [50] . the primary sites of ia are the lungs, skin, and sinuses [45] . the clinical presentation of fungal rhinosinusitis may include fever, rhinorrhea, nasal congestion, and facial pain; many cases, however, may not present with any symptoms and may be diagnosed based on imaging performed in a persistently febrile patient with profound and prolonged neutropenia. cutaneous lesions can present as macules, papules, or nodular ulcerative lesions with or without surrounding erythema and tenderness. clinical presentation secondary to other molds, such as fusarium or scedosporium, is indistinguishable from ia. mucormycoses deserve special mention since dissemination and death are higher due to ifd caused by these species when compared to ia [51] . early recognition and prompt treatment of ifd are crucial for optimal management. diagnostic tests should include blood cultures (though often with low sensitivity), cultures of appropriate sterile sites (such as urine or csf), and diagnostic biopsies of involved sites for culture and histopathology. fungal biomarkers can be used as both a screening test during high-risk periods and adjunct diagnostic test in patients with suspected ifd, especially during the periods of prolonged fever and neutropenia. galactomannan (gm) is a cell wall component released by aspergillus species which can be detected in blood, bronchoalveolar lavage fluid, and cerebrospinal fluid. a cutoff value of a gm optical index of ≥0.5 in blood and a bronchoalveolar lavage fluid level of ≥1 is considered a positive test, though an optimum cutoff value is not well defined in children [52, 53] . invasive fungal disease due to fungi other than aspergillus species may have negative galactomannan tests. β-d-glucan is a cell wall component found in many (but not all) species of fungi, and an elevated serum β-d-glucan assay can be caused by ic, ia, and other molds [53, 54] . the optimum cutoff value of β-dglucan for a positive test is unknown in children, but ≥80 pg/ml is used in most studies [54] . both gm and β-d-glucan assays have variable sensitivity and specificity among children and should be interpreted with caution. the sensitivity of gm has been reported to range from 65 to 82% in children with malignancy and ia [55, 56] ; by contrast the β-d-glucan assay has high sensitivity for ifd (~90%) but suffers from poor specificity [57] . false-positive β-d-glucan can be due to systemic bacterial or viral coinfection, receipt of antibiotics (such as piperacillin-tazobactam or amoxicillinclavulanate), hemodialysis, receipt of albumin or intravenous immunoglobulin, material containing glucan, oral mucositis, and other gi mucosal breakdowns [54] . other pcr-based fungal diagnostic tests are under investigation but have low sensitivity and specificity. gm and β-d-glucan monitoring twice weekly is suggested to evaluate treatment response in those with confirmed/probable disease and as a screening tool in patients at high risk for ifd [52, 53] . all pho and hsct patients with febrile neutropenia that persists beyond 4 days and/or those with suspected ifd should undergo computed tomography of the chest, abdomen, and pelvis and of other areas if indicated [53] . the most common findings on imaging suggestive of ifd are pulmonary nodules, especially those with a halo sign, air crescent sign, or cavitations. hepatosplenic and renal nodules should also raise suspicion of ifd. other studies to consider include an echocardiogram and dilated retinal examination, especially in patients with disseminated candidiasis. if symptoms of sinusitis or new lesions on the palate are present, a prompt nasal endoscopic examination and ct of sinuses are warranted. there are three main classes of antifungals used in patients with ifd: (1) polyenes, which include amphotericin b (amb) and its lipid formulations (liposomal amb is most commonly used in pho and hsct patients); (2) triazoles (fluconazole, itraconazole, voriconazole, and posaconazole); and (3) echinocandins (caspofungin, micafungin, anidulafungin). antifungal prophylaxis should be considered in patients who are at high risk for ifd including hsct recipients and those undergoing intensive remission-induction therapy or salvage-induction therapy [46, 53] . a high incidence of ifd has been reported in children with aml (newly diagnosed and relapsed) [58] and patients with relapsed all [46] , and such patients may be considered candidates for prophylaxis. among hsct recipients, those with an unrelated donor or a partially matched donor are at higher risk of ifd [46] . recent studies show that children with aml receiving antifungal prophylaxis have reduced rates of induction mortality and resource utilization compared to those who did not receive prophylaxis [59] . posaconazole was found to be superior to fluconazole or itraconazole in reducing incidence of ifd in children [60] . echinocandins have been shown to be as or more effective for ifd prophylaxis than triazoles, especially in hsct recipients, with less adverse effects and can be an alternative option for prophylaxis [46] . the idsa and the european conference on infections in leukemia (ecil-4) recommend using posaconazole, voriconazole, or micafungin during prolonged neutropenia to prevent ifd [20, 53] . posaconazole is recommended for prophylaxis in patients with gvhd who are at high risk of ia [53] . variable absorption of oral azoles in children should be taken into consideration when choosing oral antifungals. for patients with prolonged fever and neutropenia without an alternative explanation, consideration must be given to the possibility of an active fungal infection. empiric antifungal therapy should be considered for neutropenic patients with persistent or recurrent fevers after 4-7 days of antibiotic therapy and whose overall duration of neutropenia is expected to be >7 days [20] . in low-risk patients, routine use of empiric antifungals is not recommended [20] . liposomal amphotericin b or an echinocandin, both of which are fungicidal, are the first-line therapy for empiric antifungal treatment [20] . there is insufficient data to provide specific guidance for patients with concern for a new fungal infection who are already receiving moldactive (i.e., anti-aspergillus) prophylaxis; however, some experts suggest switching to a different mold-active antifungal [18] . surgical debridement of any fungal lesions or abscesses and prompt removal of cvc in the event of fungemia are crucial to reduce the progression of ifd. therapeutic drug monitoring (tdm) should be performed for patients receiving voriconazole, itraconazole, and posaconazole. there is extreme variability in triazole serum levels among pediatric patients owing to diversity in bioavailability in this population. for voriconazole tdm, a serum trough level between 1 and 5 mcg/dl has been considered safe and effective in preventing breakthrough ifd in children [53] . for posaconazole, a trough level of 0.7 mg/l-1 mg/l has been shown to be effective [53] . due to increased toxicity associated with vinca alkaloids, high doses of cyclophosphamide, and anthracyclines, azoles should not be co-administered with these agents. the antifungal agents most commonly used in children with pho and hsct and their indications are noted below (table 16 .4). although combination antifungals are not well studied in children, they are used frequently in this population. pediatric data are variable regarding the benefit of combination antifungal therapy but overall report an increase in adverse events [45] ; the risk of systemic toxicity must therefore be taken into account when considering the use of antifungal combinations. combination therapy could be considered in patients with refractory disease or as salvage therapy. granulocyte transfusions for profound or persistent neutropenia, adjunctive cytokines (e.g., granulocyte colony-stimulating factor [gcsf]), and reduction of immunosuppression and tapering of steroids are recommended as an adjunct to antifungal agents in the treatment of ifd [20] . in summary, children and adolescents with malignancy have additional risk factors for healthcare-associated infections. meticulous attention to personal and oral hygiene, diet, environmental safety, and appropriate immunizations should be practiced in this high-risk population. the use of antimicrobial prophylaxis should be considered in periods of severe neutropenia to prevent bacterial and fungal infections as necessary. prompt diagnosis and management strategies to prevent infectious complications are key to preventing morbidity and mortality in these immunocompromised hosts. daily bathing with chlorhexidine and its effects on nosocomial infection rates in pediatric oncology patients infection prevention in the cancer center oral and dental considerations in pediatric leukemic patient guideline on dental management of pediatric patients receiving chemotherapy, hematopoietic cell transplantation, and/or radiation pathogen distribution and antimicrobial resistance among pediatric healthcareassociated infections reported to the national healthcare safety network antibiotic use during infectious episodes in the first 6 months of anticancer treatment-a swedish cohort study of children aged 7-16 years mucosal 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malignancy: american society of clinical oncology and infectious diseases society of america clinical practice guideline update summary the multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america invasive mycoses in children receiving hemopoietic sct a prospective, international cohort study of invasive mold infections in children epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a singlecentre study with focus on emerging pathogens invasive mold infections in pediatric cancer patients reflect heterogeneity in etiology, presentation, and outcome: a 10-year, single-institution, retrospective study antifungal prophylaxis in pediatric hematology/oncology: new choices & new data. pediatr blood cancer breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants trichosporonosis in pediatric patients with a hematologic disorder results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates risk factors for mortality in children with candidemia invasive mucormycosis in children: an epidemiologic study in european and non-european countries based on two registries practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america ecil-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of america threshold of galactomannan antigenemia positivity for early diagnosis of invasive aspergillosis in neutropenic children galactomannan antigenemia in pediatric oncology patients with invasive aspergillosis beta-d-glucan screening for detection of invasive fungal disease in children undergoing allogeneic hematopoietic stem cell transplantation guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients antifungal prophylaxis associated with decreased induction mortality rates and resources utilized in children with new-onset acute myeloid leukemia antifungal prophylaxis with posaconazole vs. fluconazole or itraconazole in pediatric patients with neutropenia key: cord-252870-52fjx7s4 authors: xie, kefan; liang, benbu; dulebenets, maxim a.; mei, yanlan title: the impact of risk perception on social distancing during the covid-19 pandemic in china date: 2020-08-27 journal: int j environ res public health doi: 10.3390/ijerph17176256 sha: doc_id: 252870 cord_uid: 52fjx7s4 social distancing is one of the most recommended policies worldwide to reduce diffusion risk during the covid-19 pandemic. based on a risk management perspective, this study explores the mechanism of the risk perception effect on social distancing in order to improve individual physical distancing behavior. the data for this study were collected from 317 chinese residents in may 2020 using an internet-based survey. a structural equation model (sem) and hierarchical linear regression (hlr) analyses were conducted to examine all the considered research hypotheses. the results show that risk perception significantly affects perceived understanding and social distancing behaviors in a positive way. perceived understanding has a significant positive correlation with social distancing behaviors and plays a mediating role in the relationship between risk perception and social distancing behaviors. furthermore, safety climate positively predicts social distancing behaviors but lessens the positive correlation between risk perception and social distancing. hence, these findings suggest effective management guidelines for successful implementation of the social distancing policies during the covid-19 pandemic by emphasizing the critical role of risk perception, perceived understanding, and safety climate. as the number of global coronavirus cases explodes rapidly, threatening millions of lives, the covid-19 pandemic has become the fastest spreading, most extensive, and most challenging public health emergency worldwide since world war ii [1] . compared to seasonal influenza, this coronavirus appears to be more contagious and transmits much faster. for example, the basic reproduction rate r 0 for seasonal influenza is approximately 1.28, while for covid-19, this value comprises 3.3 on average [2] [3] [4] . with no efficacious treatments and vaccines available yet, social distancing measures are still one of the common approaches to reduce the rate of infection. moreover, for the foreseeable multiple waves of the pandemic, covid-19 prevention will continue to rely on physical distancing behaviors until safe vaccines or effective pharmacological interventions become accessible. accordingly, social distancing has been implemented by authorities across the globe to prevent diffusion of the disease. facing this global pandemic, even each government has issued advice about mobility restriction, the definition of social distancing, and distancing rules. however, the guidance documents differ social distancing has received increasing attention in numerous studies over recent decades, especially since the covid-19 outbreaks. in order to explore critical points and network patterns of these prior research studies, a co-word analysis was conducted. the literature keywords present the relationship between the study subjects and a concentration of the research content [18] . hence, the application of a co-word analysis on the existing literature can provide generic knowledge and network patterns in the studies on social distancing. an integrated search was conducted given the topic of social distancing, such as "physical distancing", "social isolation", "lockdown", etc. subsequently, 978 related papers published from 1 january 2000 through 28 june 2020 were retrieved using the web of science core database. then, using citespace software, which is designed as a tool for progressive knowledge domain visualization [19] , the co-occurrence matrix of keywords was calculated and visualized, as shown in figure 1 . the size of the keywords presents the frequency of co-occurrence and the connection shows the significance of co-occurrence [20] . based on the co-word analysis, the major research focus and inner bibliometric characteristics of social distancing were concluded from four perspectives, such as how social distancing affects the pandemic, the additional effects and challenges caused by social distancing, modeling and simulation of social distancing, and influencing factors. most of the previous studies [21] confirmed that social distancing has positive effects on the pandemic slowdown while several studies [22] seem not to confirm this. some studies believe that social distancing cuts off the transmission path of the virus, thereby reducing r 0 [23] . moreover, different mathematical models and simulations have displayed a good correlation with the data showed in biomedical studies, which offered a high level of evidence for the impact of social distancing measures to contain the pandemic [24, 25] . for example, based on simple stochastic simulations, cano et al. [26] evaluated the efficiency of social distancing measures to tackle the covid-19 pandemic. okuonghae and omame [27] found if at least 55% of the population would implement social distancing measures, the pandemic will eventually disappear according to the numerical simulations of the model. nevertheless, a systematic review and meta-analysis demonstrated that the social distancing regulation showed a non-significant protective effect, which can be caused by the persisting knowledge gaps in disparate population groups [22] . although various cohort studies and modeling simulations have found that the social distance regulations can effectively prevent the spread of the pandemic, the additional effects and challenges caused by social distancing cannot be ignored. for instance, anxiety associated with social distancing may have a long-term effect on mental health [28] and social inequality. furthermore, loneliness pandemics are arising from physical isolation as well [29] . as a form of reduced movement and face-to-face connections between people, social distancing has changed residents' conventional health behaviors, which may lead to increasing obesity, accidental pregnancies, and other health risks [30, 31] . a national survey carried out in italy demonstrated that individual needs shifted towards the three bottom levels of the maslow's pyramid (i.e., belongingness and love needs, safety needs, and physiological needs) due to the social isolation [32] . compared with the impact of social distancing, more previous studies focused on its influencing factors. first, at the national and cultural dimension levels, akim and ayivodji [33] concluded that certain economic and fiscal interventions were associated with higher compliance with social distancing. huynh [5] found that countries with higher "uncertainty avoidance index" indicate a lower proportion of public gatherings. likewise and moon [34] explored the role of cultural orientations and showed that vertical collectivism predicted stronger compliance with social distancing norms. then, at the level of public society, aldarhami et al. [35] conducted a survey indicating that the high level of public awareness affects social distancing implementation. besides, public health authorities and experts alike pointed out that mass media and information played an important role in developing public awareness and constructing social distancing behaviors among social populations [36] . lastly, from the perspective of individual behaviors and psychological factors, oconnell et al. [1] reported that more antisocial individuals may pose a health risk to the public and engage in fewer social distancing regulations. based on a cross-sectional online survey, yanti et al. [37] identified that the respondents who had sufficient knowledge and a good attitude would positively comply with safety behaviors, such as keeping a physical distance from others and wearing face masks in public places. although the evidence unambiguously supported that implementing the social distancing regulations has a crucial effect on restraining the pandemic [38] , recent studies found that mobility restrictions do not lead to an expected reduction of coronavirus cases [8, 39] . previous literature has conducted various analyses regarding the different factors motivating social distancing behaviors. however, facing the current enormous gap between the method and the existing practice, limited research has paid attention to the key factors from the perspective of risk management. because of the significant role that individuals and public awareness play in compliance with social distancing, this study focuses on the mechanism of the risk perception effect on social distancing. individual's perceived understanding and safety climate are also examined to identify their effectiveness in the relationship between risk perception and social distancing. based on a quantitative online survey with a sample size of 317 participants from china over the period of may 2020, we built the structural equation model (sem) and conducted hierarchical linear regression (hlr) analysis to examine how the selected moderators influence social distancing behavior. the remainder of the paper is organized as follows. section 2 will review the risk perception theories and develop several hypotheses with the conceptual framework. section 3 describes the research methodology, data collection, and measurement of latent variables. then, we analyze the data and examine hypotheses (section 4) and finally, discuss the implications and limitations of our findings (section 5) as well as draw the main conclusions (section 6). risk exists objectively, but distinct people will take different behavioral decisions when they perceive risk differently [40] . hence, even many medical experts stressed the importance of maintaining physical distancing amid the covid-19 pandemic and people's risk perception still colors beliefs about facts. the concept of risk perception differs among different disciplines [41] . in this study, risk perception in the context of the pandemic is defined as the psychological processes of subjective assessment of the probability of being infected by the coronavirus, an individual's perceived health risk, and available protective measures [42, 43] . compared to the concept of risk perception in other fields, the health risk perception and the severity caused by the consequences of subsequent behavioral decisions are the most prominent features. empirical evidence has indicated that health risk perception may significantly affect people's self-protective behaviors and increase negative consequences of health risks [44] . dionne et al. [45] found that risk perception associated with medical activities was a critical predictor of the epidemic prevention behaviors. accordingly, as reported, underestimation of the pandemic knowledge and health risks could lead to decreasing implementation of social distancing. most previous research focused on identifying influencing factors for people's health risk perception as risk perception largely determines whether individuals would take protective measures during the pandemic. also, there are various factors that reduce the substantial deviation between the actual objective risk and subjective feelings. perceived understanding is just one of the crucial factors that refers to situational awareness for the adoption of healthcare protections when facing the pandemic [46] . according to the theory of planned behavior, only when people realize that they are in a health risk or even death risk will they have the situational awareness to take further healthcare protections. effective and timely perceived understanding will greatly promote people to translate risk perception into actual actions [47] . perceived understanding plays a vital role in the adoption of healthcare behaviors. therefore, the following four hypotheses were developed, considering the findings from previous studies. perceived understanding about the covid-19 pandemic plays a mediating role between risk perception and social distancing behavior. facing huge economic pressure and public opinion, many companies and organizations gradually re-opened. at the same time, these institutions require their employees to implement the social distancing policies strictly. similarly, when people go out to eat, shop, and entertain, many public places remind people to maintain a physical distance. regardless of whether it is a social organization or a public place, this kind of a reminder message released through information media has virtually created a safe climate to require people to take necessary measures and reduce the spread of the virus. generally, the safety climate refers to individuals' perception of safety regulations, procedures, and behaviors in the workplace [48] . from the perspective of pandemic prevention and control, the safety climate relates to a consensus created by the work environment which will promote people consciously or unconsciously to take the appropriate safety measures. namely, safety climate reflects common awareness among employees on the importance of organizational safety issues [49] . numerous observations and studies attest to the relationship between safety climate and protective behavior. bosak et al. [50] found that a good safety climate was negatively related to people's risk behaviors. moreover, another study showed that safety climate completely mediated the effect of risk perception on safety management [49] . however, few studies focused on the influence of safety climate on people's self-protection behavior during the pandemic. taking protective measures, such as social distancing, wearing face masks, and other self-prevention behaviors, are instrumental to avoid the spread of the infection. an organization with a good safety climate can carry out relevant safety training and drills, so as to suppress the potential risk tendency and promote their employees' safety behaviors. therefore, if the working environment can strengthen the education and publicity of pandemic knowledge, people are more willing to take correct protective measures, such as maintaining a social distance. additionally, koetke et al. [51] also pointed out that safety climate (trust in science) played a moderating role in the relationship between conservative and social distancing intentions. to conclude, based on the above literature reviews, the conceptual framework of this study is illustrated in figure 2 . our last two hypotheses read as follows: according to the 44th china statistical report on internet development, which was announced by the china internet network information center (cnnic), in 2019, there were 854 million internet users in china. several studies exploring some physical or psychological influencing mechanisms, such as risk perception, showed no significant difference between internet users and non-users [52] . therefore, online questionnaires were randomly collected from internet users through wenjuan.com. a total of 317 completed responses were received with an effective rate of 94.63%, after excluding suspected unreal answers completed in less than 60 s. additionally, participants were first directed to review and provide their consent using an online informed consent form, which was pre-approved by a panel of experts and the institutional review board, before answering the survey questionnaire. the data collection was anonymously conducted throughout may 2020. the female participants constituted 48.3% of the sample, while 51.7% of the sample were male participants. among the respondents, most of them were young people, 31.9% belonged to the age group of 18-24 years, while 40.7% belonged to the age group of 25-39 years. a total of 84.5% of the participants had a college degree or above and only 6% had a lower level education than high school. out of the total sample, 48.6% reported to be living in rural areas and 51.4% lived in urban communities. it should be noticed that there were 15.14% of the participants living in hubei province, which used to be the epicenter of the covid-19 pandemic in china. the initial questionnaire contained 22 questions to measure these 4 latent variables, including risk perception-rp (7 items), perceived understanding-pu (4 items), social distancing-sd (5 items), and safety climate-sc (6 items). all the measurement items were prepared based on the review of related literature and methods (table 2) . for example, initial items for rp were generated following previous questionnaires conducted by dionne et al. [45] and kim et al. [53] . measurement items of pu were compiled based on the infectious disease-specific health literacy scale [54] and the study by qazi et al. [46] . the sc instrument statements were taken from the literature review and previously completed research [51, 55, 56] . based on the studies of swami et al. [57] and gudi et al. [58] , initial measurement questions of sd were developed. additionally, to ensure the validity of the draft questionnaire, the original survey instrument statements were revised based on the suggestions from a panel of experts, including 5 professionals of risk management, 5 public health specialists, and 5 community managers. then, necessary modifications were made by simplifying, rewording, and replacing several items after 15 experts reviewed the survey structure, wording, and item allocation. according to the expert panel's feedback, the item-level content validity index (i-cvi) of the 18 items were all greater than 0.78 and the scale-level cvi (s-cvi) is 0.97 (>0.90), indicating an excellent validity of this scale (see supplementary materials ). an initial survey with 22 items was first pilot tested among a randomly selected sample of 100 internet users. after conducting cognitive interviews with the pilot sample participants and analyzing the reliability and correlations, 4 measurement items (rp5, rp6, rp7, and sd5) with a item-to-total correlation below 0.5 were removed. finally, a formal questionnaire containing 18 items was developed. the response scale for all the survey items was a 5-point likert scale with categories ranging from 1 = "strongly disagree" to 5 = "strongly agree". all of the items were phrased positively, so that a higher score represented stronger agreement. table 2 displays an overview of the scale and questionnaire items. avoid contact with individuals who have influenza. avoid traveling within or between cities/local regions. avoid using public transport due to covid-19. avoid going to crowded places due to covid-19. * safety climate the government is concerned about the health of people. koetke et al. [51] ; neal et al. [55] ; wu et al. [56] sc2 i trust the covid-19 information provided by the government. there is a clearly stated set of goals or objectives for covid-19 prevention. people consciously follow the pandemic prevention regulations. being able to provide necessary personal protective equipment for workers during the pandemic. offering to workers as much safety instruction and training as needed during the pandemic. note: * items removed from the initial questionnaire. descriptive statistics and correlation analyses of the latent variables were first examined. then, the exploratory factor analysis (efa) and the confirmatory factor analysis (cfa) were conducted to verify the unidimensionality and reliability of the measurement items. the sem can be applied to control for measurement errors as well as to use parameters to identify interdependencies [2, 50] . hence, this approach is appropriate to test the hypotheses by conducting the path analyses. in addition, to examine the moderating effect, hlr was carried out to verify hypotheses h5 and h6. amos version 24.0 software was applied for cfa and sem (hypotheses h1-h4) . the remaining analyses, e.g., efa and hlr (hypotheses h5 and h6) , were done using spss 22.0. (ibm, armonk, ny, usa) the means, standard deviations (s.d.), and inter-correlations of all the measures are contained in table 3 . there are significant positive correlations between the four variables. rp has significant positive correlations with sd and pu, suggesting a partial support for hypotheses h1 and h2, respectively. moreover, both pu and sc showed a significant positive correlation with sd, indicating that hypotheses h3 and h5 were partially supported as well. reliability can be formally defined as the proportion of observed score variance, which is attributable to the true score variance. there exist several approaches to evaluate the reliability of a measuring item and internal consistency is the most widely used method in research with a cross-sectional design. the cronbach's alpha (î±) can be used to estimate the internal consistency [59] . a standard value for cronbach's alpha is 0.70 or above, which indicates strong internal consistency of adopted scales [60] . table 4 indicates that all four latent variables have good reliability (cronbach's î± > 0.7), suggesting that the measurement items are appropriate indicators of their respective constructs. the validity analysis is used to examine the accuracy of the measurement instrument, namely the validity of the scale. the validity analysis mainly includes the content validity and the construct validity, of which the content validity has been supported by the expert panel's recommendations and pre-tests, while the construct validity requires a combination of efa and cfa. first, the kaiser-meyer-olkin (kmo) test value was 0.888. in addition, the result of the bartlett test (ï� 2 = 3135.94, df = 153, p < 0.001) was large and significant. hence, the data shown in table 4 were suitable for cfa. then, the measurement items identified four factors that exactly correspond to four latent variables. these four factors explained 66.41% of the total variance. similarly, the cfa results confirmed the four-factor model. in this study, the goodness-of-fit statistics were found to be x 2/ df = 2. (1) and (2): where î» i and ï� 2 e i represent the regression weight (factor loading) and measure variance estimate of the measurement item i, respectively, and k is the number of measurement items. cr and ave are other effective measures to evaluate the construct validity. correspondingly, according to jobson [61] , the acceptable value of cr is 0.7 and above, while ave should be 0.5 and above. table 4 demonstrates that most of the values of cr and ave met the standards, suggesting an acceptable goodness-of-fit for the further sem analysis. based on the conceptual framework, the sem analysis was conducted to explore the relationship between rp, sd, and pu (as the mediator). the hypothesized model shown in figure 3 was first examined. table 5 summarizes the fit indices of the model, which indicates an excellent goodness-of-fit for the data based on the majority of indices. in this model, several path analyses were developed to test hypotheses h1, h2, and h3. as shown in table 6 , rp has significant positive relationships with pu (î² = 0.296, c.r. = 4.435, p < 0.001) and sd (î² = 0.238, c.r. = 4.421, p < 0.001). likewise, pu plays a significant positive role on sd (î² = 0.581, c.r. = 8.426, p < 0.001) as well. thus, it implies that hypotheses h1, h2, and h3 are supported. bias-corrected (bc) and percentile (pc) bootstrapping approaches were carried out to verify the mediating effect of pu. previous studies have found that bootstrapping was a proper method that can provide a robust test of mediating hypotheses [62] . accordingly, the significant effect of risk perception on social distancing could be assessed through perceived understanding by using the bootstrapping of 5000 sub-samples. as can be seen from table 7 , the values of the lower and upper limits (95% bc and pc bootstrap confidence intervals) for the indirect effect (î² = 0.100) were all greater than zero. moreover, the value of z (indirect effect/standard error) equals 2.5 (>1.96). subsequently, similar to an indirect effect, it was found that there were no zero values between the lower and upper limits (95% bc and pc bootstrap confidence intervals) for the direct effect (î² = 0.138, z = 3.45). therefore, perceived understanding partially mediates the positive effects of risk perception on social distancing. in other words, perceived understanding did not completely offset the effect of risk perception, which partially explains the social distancing. in summary, these results confirmed hypothesis h4. hypothesis h6 predicted that safety climate positively moderates the impact of risk perception on social distancing. to test the moderation effects, the hlr analysis was conducted. model 1 serves as a baseline with independent variables rp and sc. then, model 2 incorporated additional variables rpã�sc. table 8 presents the significant interaction effects of the two-way interaction effect between rp and sc on sd (model 2, rpã�sc, î² = â��0.242, p < 0.001). as shown in table 8 , while risk perception is positively associated with social distancing regardless of the value of safety climate, the safety climate further reduces the positive effect. thus, hypothesis h6 is partially supported. additionally, whether sc is in model 1 (î² = 0.566, p < 0.001) or model 2 (î² = 0.4689, p < 0.001), it presents a statistically significant positive relationship with sd, which further supports hypothesis h5. note: *** p < 0.001. vif represents variance inflation factor (vif = 1/tolerance), vif < 5 (acceptable). this study has continued to demonstrate that social distancing behaviors play a critical role in preventing the diffusion of the covid-19 pandemic. in identifying influencing factors that lead to social distancing, previous studies have highlighted risk perception as a leading indicator of protective behaviors [42, 44, 45] . people should be encouraged to promote risk perception in order to identify and rectify infection risks and health issues related to unprotected behaviors during the covid-19 pandemic. however, limited research has examined whether different risk perception of individuals affects their interpretation of the social distancing regulations in an equivalent manner. by investigating the measurement scales of risk perception, perceived understanding, safety climate, and social distancing across populations of internet users in china, this study addressed the mechanism of the risk perception effect on social distancing to improve individuals' physical distancing behaviors. this study provided evidence that risk perception and perceived understanding can significantly affect people's social distancing behaviors during the covid-19 pandemic. the results of the path analysis supported hypotheses h1, h2, and h3. it is evident from figure 3 , tables 5 and 6 that the path coefficients are significant and the overall hypothesized model has a good fit for the investigation. these findings are in line with aldarhami et al. [35] , zhong et al. [63] , and machida et al. [64] . a key principle of social distancing behavior is that risk perception is a critical condition for protective action. the results support the finding that higher risk perception motivates people to comply with social distancing. only by enhancing risk perception can people truly remain vigilant against the pandemic and take protective measures. therefore, when the government implements social distancing and other prevention measures, it must take into account the public risk perception and improve public environmental awareness through various means, such as social media, press conferences, standard therapy, and guidelines for the outbreak response. in particular, it is necessary to rectify pandemic rumors to prevent incorrect information that can potentially reduce public risk perception. besides, we confirmed a dual effect of perceived understanding on social distancing. first, perceived understanding was found to predict social distancing directly. these results are consistent with other studies [1, 46] which have shown that increased perceived understanding can encourage people to gain more knowledge about the pandemic and health risks, so that they would engage more in the social distancing regulations. then, we identified that perceived understanding as a factor showed an incomplete mediating effect on the relationship between risk perception and social distancing. previous literature regarding perceived understanding shows that it affects the social distancing behaviors related to the sources of information [46] . on the other hand, our results confirm an indirect positive effect of risk perception on social distancing through perceived understanding. hence, with the help of the authority of medical experts, we should promptly popularize scientific knowledge of the pandemic and prevention measures among communities to enhance public perceived understanding. in addition, the increase in risk perception can promote public desire to understand the pandemic and pay more attention to their own health risks. the authorities should improve pandemic information release channels. moreover, we identified that a positive perception of safety climate (î² = 0.566, p < 0.001) would promote adherence to social distancing and that this effect would be stronger than the risk perception (î² = 0.165, p < 0.001). this finding concurs with the study conducted by kouabenan et al. [49] . the achievement of a consensus on a safe climate requires the joint efforts of the organization and society. first, workplaces such as shops, cafeterias, office spaces, and public transit systems have to strengthen pandemic prevention and control drills. then, it is necessary to support community propaganda and scientific knowledge popularization and gather the individual consensus on self-protective behaviors. it is also strongly recommended to wear a face mask, keep a 2 m physical distance between workers, and use sanitary measures in public venues. finally, we demonstrated that safety climate, risk perception, and social distancing are the interacting factors, supporting our hypothesis that a moderating effect of safety climate on the relationship between risk perception and social distancing exists, as found in kouabenan et al. [49] , bosak et al. [50] , and koetke et al. [51] (see hypothesis h6). however, we did not find that safety climate increased the degree to which the risk perception positively affects social distancing. as shown in figure 4 , risk perception was positively related to social distancing under the conditions of a high safety climate as well as under the conditions of a low safety climate. more importantly, we found that safety climate is a factor that lessens the positive correlation between risk perception and social distancing. this moderating effect improves our understanding of the contexts in which risk perception affects social distancing. yet, as described by kouabenan et al. [49] , the safety climate was viewed as the key factor because it completely mediated the effect of perceived risk on safety behavior. one potential explanation for this difference of findings is the complex content of safety climate measurement items, because it actually includes three clauses. compared to the previous studies, we regarded the safety climate as the whole of social consciousness. the overall promotion of social protection awareness will replace the role of risk perception and may lead to compliance with social distancing through the public herd effect. therefore, while focusing on the importance of risk perception, we cannot ignore the positive incentives for social distancing brought by a good safety climate. in addition to enhancing employees' consensus on pandemic prevention, qualified organizations can physically isolate workspaces and public venues in time and space. for example, people should avoid going out for mass gatherings (lunches, shopping, traveling, education, leisure, etc.). then, for management commitment, they should physically divide the restaurant space, office space, and other public areas to ensure that people have sufficient isolation distance. flexible work scheduling, online office hours, and e-learning are encouraged for implementation. conclusively, application of innovating social distance management technologies (e.g., technologies that are based on an emerging range of ict technologies [65] like bluetooth, radio frequency identification, cloud mobile, and others) can assist with achieving an accurate measurement of the physical distance between individuals and momentarily reminding people to maintain a social distance as needed. in public venues, such as dining areas, using multimedia, posters, and ground stickers with social distancing reminders can create a good safety climate. although substantial efforts were put into this study to ensure the reliability and validity of the results, a few limitations still exist, which might be explored in further research. first, our sample does consist of chinese internet users but may not have all the attributes that perfectly match the characteristics of the current chinese population. without collecting data from other regions and having a representative sample, the generalizability of our findings is limited to a certain extent. a cross-regional, more representative study with a bigger sample size could be used in future studies in order to improve accuracy and generalizability of the results. second, we measured all the latent variables with a simple one-dimensional factor by using a cross-sectional design. the results could neither exclude the possibility of reverse causation nor prove the exact cause-and-effect relationships from a cross-sectional survey design. hence, further study could be extended by collecting longitudinal data through multiple rounds of experiments. furthermore, several previous studies measured risk perception from a multi-dimensional perspective. therefore, it would be meaningful to present risk perception as a multi-dimension construct, developing a multi-item scale to promote reliability and validity. moreover, this study takes into consideration risk perception that creates social distancing for the adoption of risk management. some other factors, like knowledge and beliefs of the covid-19 pandemic, mask-wearing, self-awareness in prevention of covid-19, number of confirmed covid-19 cases in a given region, death rate in a given region, and percentage of elderly population in a given region, can also be included in further research. finally, we considered the mediating and moderating effects of perceived understanding and safety climate. as contingent factors, these effects may interact with other factors, shifting the results conducted in the present study. besides, several control variables that are associated with population demographics, such as gender, age, and education level, did not show a significant impact on the relationships among these latent variables. this subject, however, is worth exploring in further research. this study investigated the impact of risk perception on social distancing during the covid-19 pandemic. based on the data collected from an online survey among 317 participants in china throughout may 2020, our analyses indicate that positive changes in social distancing behaviors are associated with increased risk perception, perceived understanding, and safety climate. the individual's perceived understanding partly plays a positive mediating role in the relationship between risk perception and social distancing behaviors. furthermore, the safety climate plays a negative role in the relationship between risk perception and social distancing because the safety climate seems to mitigate the effects of risk perception on social distance. hence, effective health promotion strategies directed at developing or increasing positive risk perception, perceived understanding, and safety climate should be conducted to encourage people to comply with the social distancing policies amid these unprecedented times. finally, these results are expected to contribute to management guidelines at the level of individual perception and public opinions as well as to assist with effective implementation of the social distancing policies in countries with a high risk of the covid-19 pandemic. pandemic is associated with antisocial behaviors in an online united states sample tracking changes in sars-cov-2 spike: evidence that d614g increases infectivity of the covid-19 virus early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia the reproductive number of covid-19 is higher compared to sars coronavirus does culture matter social distancing under the covid-19 pandemic? social distancing: how religion, culture and burial ceremony undermine the effort to curb covid-19 in south africa airborne or droplet precautions for 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korea study on the development of an infectious disease-specific health literacy scale in the chinese population the impact of organizational climate on safety climate and individual behavior core dimensions of the construction safety climate for a standardized safety-climate measurement analytic thinking, rejection of coronavirus (covid-19) conspiracy theories, and compliance with mandated social-distancing: direct and indirect relationships in a nationally representative sample of adults in the united kingdom knowledge and beliefs towards universal safety precautions during the coronavirus disease (covid-19) pandemic among the indian public: a web-based cross-sectional survey coefficient alpha and the internal structure of tests introduction to psychometric theory applied multivariate data analysis: volume ii categorical and multivariate methods testing mediation and suppression effects of latent variables: bootstrapping with structural equation models knowledge, attitudes, and practices towards covid-19 among chinese residents during the rapid rise period of the covid-19 outbreak: a quick online cross-sectional survey adoption of personal protective measures by ordinary citizens during the covid-19 outbreak in japan social distancing 2.0 with privacy-preserving contact tracing to avoid a second wave of covid-19 the authors declare no conflict of interest. key: cord-024824-lor8tfe6 authors: asgary, ali; ozdemir, ali ihsan; özyürek, hale title: small and medium enterprises and global risks: evidence from manufacturing smes in turkey date: 2020-02-12 journal: int j disaster risk sci doi: 10.1007/s13753-020-00247-0 sha: doc_id: 24824 cord_uid: lor8tfe6 this study investigated how small and medium enterprises (smes) in a country perceive major global risks. the aim was to explore how country attributes and circumstances affect sme assessments of the likelihood, impacts, and rankings of global risks, and to find out if sme risk assessment and rankings differ from the global rankings. data were gathered using an online survey of manufacturing smes in turkey. the results show that global economic risks and geopolitical risks are of major concern for smes, and environmental risks are at the bottom of their ranking. among the economic risks, fiscal crises in key economies and high structural unemployment or underemployment were found to be the highest risks for the smes. failure of regional or global governance, failure of national governance, and interstate conflict with regional consequences were found to be among the top geopolitical risks for the smes. the smes considered the risk of large-scale cyber-attacks and massive incident of data fraud/theft to be relatively higher than other global technological risks. profound social instability and failure of urban planning were among the top societal risks for the smes. although the global environmental and disaster risks were ranked lowest on the list, man-made environmental damage and disasters and major natural hazard-induced disasters were ranked the highest among this group of risks. overall, the results show that smes at a country level, for example turkey, perceive global risks differently than the major global players. small and medium enterprises (smes) face many small and large internal and external risks. while they can better control much of the internal risks through risk management and treatment measures, they are more vulnerable to external risks because these risks are often beyond their control, influence, radar, and capacity to manage. the world economic forum (wef) has created, assessed, and monitored 30 global risks since 2005, using a survey of about 1000 major global stakeholders and players. by the wef definition, a global risk is ''an uncertain event or condition that, if it occurs, can cause significant negative impact for several countries or industries within the next 10 years'' (world economic forum 2019, p. 100). small and medium enterprises are playing a vital role in local, national, and global economies and are very important in job and income generation (chowdhury 2011; oecd 2014; chatterjee et al. 2015) . at least 90% of the firms in both developed and developing countries are smes (mbuyisa and leonard 2017) . they account for 40-60% of gdp in developed and developing countries (igwe et al. 2018 ) and generate about 40% of the global industrial production and 35% of the world's exports (sharma and bhagwat 2006; mbuyisa and leonard 2017) . small and medium enterprises are the backbone of the european economy, with more than 99.8% of all non-financial businesses, 58% of total value added, and 66.8% of total employment (briozzo and cardone-riportella 2012; european commission 2015) . in japan, more than 99.7% of all firms are smes, they employ more than 70% of the workforce, and create more than 50% of all added value of the manufacturing industry (yoshino and taghizadeh-hesary 2018) . small and medium enterprises comprised 99.8% of the firms in turkey in 2014 and were involved in 55.1% of export and 37.7% of import (kaya and uzay 2017) . considering their size and roles in the national and global economies and the fact that the enhancement of the private sector's resilience depends on risk reduction by smes (chatterjee et al. 2015) , more studies are needed to better understand various aspects of sme risk management. small and medium enterprises, like large corporations, face a significant number of risks, and their survival and resilience are important for national and global economies. however, smes are less prepared to manage the risks, and the institutional supports for them are rather weak (han and nigg 2011) . small and medium enterprises around the world, particularly in developing and emerging economies do not have strong risk management, business continuity, and crisis management cultures and systems in place (asgary et al. 2013; yuwen et al. 2016; kaya and uzay 2017) . most of smes not have the resources and expertise to focus on these activities and therefore are more vulnerable to internal and external risks and disruptive shocks (leopoulos et al. 2006; marks and thomalla 2017) . to minimize the impacts, it is important that smes become more aware of global risks, as well as assess, monitor, and enhance their risk management and business continuity management capacities (güneş and teker 2010; brustbauer 2016; kaya and uzay 2017) . the goals of this study were twofold: (1) to examine whether country attributes and circumstances affect sme assessments of the likelihood, impacts, and rankings of global risks; and (2) to find out if sme risk assessment and rankings differ from global rankings. small and medium enterprises in manufacturing in an emerging economy with global footprints were selected because, unlike the wef that takes its samples from large international players, the sample smes are small individual players in the global economy and it is important to see how they view the global risks. the 2019 global risk report by the world economic forum (wef 2019) examines 30 important global risks that are classified into five categories: economic, environmental, geopolitical, societal, and technological (table 1) . these risks are evaluated annually based on 1000 global players and stakeholder views of the risks. according to the 2019 wef global risk report, extreme weather events, failure of climate-change mitigation and adaptation, natural disasters, data fraud or theft, cyber-attacks, man-made environmental damages and disasters, large-scale involuntary migration, biodiversity loss and ecosystem collapse, water crises, and asset bubbles in a major economy were ranked the top 10 global risks in terms of likelihood. weapons of mass destruction, failure of climate-change mitigation and adaptation, extreme weather events, water crises, natural disasters, biodiversity loss and ecosystem collapse, cyber-attacks, critical information infrastructure breakdown, man-made global economic risks have significant implications for smes, particularly those in the manufacturing sector. asset bubbles in a major economy can increase the production costs through inflation, wage increases and labor shortages, and access to financial resources that will impact the global economy (zheng et al. 2010) . global financial crises cause substantial downturn in the formation of new smes, their performance, and their existence in the market. the 1997-1998 world financial and economic crisis severely impacted smes. as interest rates started to rise, many smes were bankrupted due to the credit crunch, tight monetary policies, and decline in domestic and international demands (filardo 2011; wehinger 2014) . the number of bankrupted smes in south korea, for example, particularly in the manufacturing sector, increased by nearly 100% from 1996 to 1998 (gregory et al. 2002) . the 2008 economic crisis induced severe socioeconomic impacts worldwide and impacted smes in almost every economy, far beyond expectations, through fast domino effects that caused massive sme closures, downsizing, and reduced the number of new ventures (chowdhury 2011; sannajust 2014). small and medium enterprises were under extreme pressures and experienced devastating decrease in demand and revenues, increased lay-offs, and stressful working environments (kossyva et al. 2014 ). close to 50% of the smes in belgium and the netherlands, for example, experienced extended delays in their receivables (kossyva et al. 2014) . small and medium enterprises in the united states lost 2.8 million jobs (gagliardi et al. 2013) . during this global turmoil, turkish smes were also impacted heavily (karadag 2016) . during an economic crisis, smes are more vulnerable because of weak cash flow and financial structures, low equity reserves, limited adaptation potential and flexibility for downsizing, liquidation problems, too much dependency on external financial resources, tightened credit lines, payment delays on receivables, lack of resources, and lack of necessary skills to adopt or make necessary strategic decisions (ates et al. 2013; sannajust 2014; wehinger 2014; karadag 2016) . failure of aging and insecure energy, transportation, and communications infrastructure can have major short-and long-term risks for sme performance and competitiveness. high structural unemployment lowers demand for goods and services and impacts smes significantly (alegre and chiva 2013) . illicit trade reduces sme competitiveness in the global market. in countries with higher levels of economic risk, smes have less of a chance to flourish (mekinc et al. 2013) . energy is an important input for sme production and logistics. if energy prices are not manageable or controlable, smes face major uncertainties about energy costs and availability (mulhall and bryson 2014) . energy price shocks raise sme production costs (kilian 2008 ) and compromise their individual and collective competitiveness in the global economy. it is mainly because smes are usually less flexible with respect to their energy sources and smes in the manufacturing sector are very energy intensive, that unpredicted fluctuations in energy prices impact them extensively. energy price shock events have become more frequent and a consistent feature of the energy markets in recent years (mulhall and bryson 2014) . as the global demand for energy increases, more shock events in the energy prices are expected. finally, unmanageable high inflation rates at national and global levels pose risks to smes through higher interest rates (cefis and marsili 2006; gül et al. 2010 ). small and medium enterprises around the globe, particularly those that are part of the global supply chains, are exposed to various types of global environmental and disaster risks that can have devastating impacts on smes (auzzir et al. 2018 ). these enterprises are highly vulnerable to and not well prepared for most of the global environmental and disaster risks (crichton 2006; schaefer et al. 2011) . they are vulnerable to environmental disaster risks on four fronts: capital, labor, logistics, and markets (ballesteros and sonny 2015) . environmental and disaster risk events can damage and disrupt the supply chain networks in which many smes are embedded. they can also damage sme assets, premises, and inventories, disrupt their operations, increase their production costs, and reduce their revenues and long-term growth potentials (snyder and shen 2006; griffiths 2010, 2012; asgary et al. 2012) . small and medium enterprises have limited capabilities to recover from these events and bring their operations, revenue, and profit back to pre-event conditions (asgary et al. 2013) . considering the links that exist between climate change and extreme events, it is expected that these events will increase in the future (ipcc 2013). small and medium enterprises face significant climate change-related environmental and regulatory risks (schaefer et al. 2011) . major costly floods, severe heat and cold waves, heavy rains and extreme storms with higher frequency and intensity are observed globally. extreme events not only cause disruptions and destruction to smes, but also create major challenges for their continuity of operations and future planning (gunawansa and kua 2014; gasbarro et al. 2018 studies show that overall about 25% of smes do not reopen following a major disaster (ballesteros and sonny 2015) . of the us companies that experience disasters, for example, 43% never reopen, and another 29% close within 2 years (weinhofer and busch 2013; ballesteros and sonny 2015) . small and medium enterprises are worse off after disaster events compared to before disaster because they are relatively resource constrained, less resilient, are mainly informal and some of them do not fully comply or are not requested to follow standards and codes, lack necessary insurance, do not carry out risk assessments, and are often without business continuity plans (ye and abe 2012; undp 2013; ballesteros and sonny 2015; halkos et al. 2018) . being prone to multiple natural hazards such as flooding, earthquakes, and drought, natural hazards and disasters have affected smes in turkey as well. the 1999 earthquake had significant economic impacts on the enterprise sector, ranging from usd 1.1 to 4.5 billion in damages (oecd 2000) , most of it from the loss in manufacturing (usd 600 to 700 million). about 63.2% of the total manufacturing industry were damaged in five provinces, and 31,000 smes suffered heavy physical damages. ezgi (2014) reported that the vast majority of smes had little preparedness before the earthquake and only 30% of them invested in insurance before the earthquake. a world of geopolitical instability and uncertainty is a major concern for all sectors and businesses, but more so for smes. many of these risks are cross border with global consequences. while existing international political and economic agreements such as those of the world trade organization (wto) are weakened by unilateralism, there is little evidence that new and better multilateralism agreements are replacing them (pascual-ramsay 2015; asgary and ozdemir 2019). rather these agreements are being replaced by fragmentation, bilateralism, regionalism, as well as local and short-term interests (pascual-ramsay 2015; asgary and ozdemir 2019). the international economy and its key players, including smes, are becoming more exposed and vulnerable to existing and emerging geopolitical risks and uncertainties (pascual-ramsay 2015) . studies show that terrorist attacks, for example, even though they are very small in terms of direct physical impact zones, have economic impacts that are often substantial and very extensive. repeated terrorist attacks in one country not only impact the economy of that country but create spillover impacts for neighboring countries and the global economy. terrorist attacks discourage foreign investments and capital inflows and cause significant loss of economic activities and international trade (abadie and gardeazabal 2008; araz-takay et al. 2009 ). these risks can also increase insurance, transaction, transportation, and security costs for smes. turkey as an emerging economy located in a geopolitically complex region (middle east and north africa), with several potentially failing neighboring states, and as a member of various types of regional agreements, has a unique situation in terms of geopolitical risks. turkey has been suffering from terrorism and dealing with regional conflicts, both of which have had various impacts on the smes. the presence of terrorist activities has impacted the emergence and growth of smes and the overall economic performance in the country. bilgel and karahasan (2017) found that after the rise of terrorism, the per capita real gdp in eastern and southeastern anatolia declined by about 6.6%. other studies also found that terrorism has a major negative impact on foreign direct investments in turkey (omay et al. 2013 ). global societal risks have specific implications for smes. failure of urban planning leads to declining cities, informal urban growth or sprawl, and poor and fragile infrastructure with significant social, environmental, and health issues (asgary and ozdemir 2019). such urban environments are not able to adequately support enterpreneurship activities that can compete at national and global levels. cities without efficient and interconnected transportation systems, with significant air pollution, and unaffordable land and housing prices are not attractive for entrepreneurship growth (tursab and tuader 2017). but sme engagement in risk management and critical infrastructure protection is an effective way to reduce the impact of future disasters in urban areas (chatterjee et al. 2015; chatterjee et al. 2016) . food and water crises are other important global risks that can affect smes in several ways, particularly those in the agri-food business and those that are in water-intensive manufacturing sectors. social instability as another global risk is not healthy for sme growth and competitiveness. global pandemics such as the 2003 severe acute respiratory syndrome (sars) pandemic and the 2009 h1n1 pandemic can have immediate direct and indirect impacts on smes. for example, sars had major impacts on smes, particularly those in the tourism and hospitality sector in heavily impacted countries such as china, canada, thailand, and hong kong (kuo et al. 2008) . studies have found that many smes do not recognize pandemics as a meaningful risk. although governments have tried to raise awareness and provide resources to enhance pandemic preparedness by smes, awareness or concern and actual preparedness have not changed much, and most smes do not have appropriate preparedness and continuity plans for future pandemics (watkins et al. 2008) . armed conflicts, interstate wars, natural hazards and disasters, and climate change are creating widespread involuntary and forced displacement around the globe. population displacements have a range of economic, social, and political impacts on both source and host countries (tumen 2016; salgado-gálvez 2018) . the impacts of forced migration on smes have not been studied yet, but it may have both positive and negative impacts. at least smes can be considered a solution for some of these problems by providing job opportunities for displaced people. turkey has received more than 4 million displaced people from syria since the start of conflict in 2012 (onur 2018). adverse consequences of technological advances could be very diverse and consequential for smes, especially those in the manufacturing sector. new technologies such as robotics, autonomous vehicles and drones, automation, smart phones, artificial intelligence, 3-d printing, cloud computing and big data, and new materials are among the new technologies that can have unintended consequences and risks for manufacturing smes. these technologies have the potential to reduce outsourcing. studies predict that 47% of the jobs in the united states (much of them in smes) are at high risk of being automated over the next 20 years, especially in manufacturing, logistics, and administrative support (pascual-ramsay 2015). these advances will possibly reduce employment opportunities for workers in manufacturing smes and will challenge smes survival. while information technology brings significant growth opportunities for smes through knowledge and information availability, business communication, cost savings and efficiency, improving decision making, responsiveness, and overall flexibility (mbuyisa and leonard 2017) , technology also introduces risks, including data theft, disruptions, and cyber-attacks (chacko and harris 2006) . like other institutions, smes are dependent on internet and information technology and a substantial number of their sales and orders are handled through cyberspace and networks. any major failure and disruption of the national and global information infrastructure and networks due to large-scale disaster events can have significant negative impacts on smes. such disruptions can have severe consequences for smes that are very vulnerable and without adequate protection. small and medium enterprises use these technologies in production and service delivery, distribution, sales, and marketing. data breaches, cyber security, and intentional or accidental technological failures can disrupt or significantly damage the short-and long-term operation as well as the existence of smes. following the wef (2019), this study uses a qualitative risk assessment (qra) approach. this will allow us to compare the results of the study with the global risk report results. qualitative risk assessment is one of the most widely used risk assessment approaches because of its low cost and ease of use and it is quick to perform (modarres 2006) . in qra, potential likelihoods and consequences are assessed using qualitative scales such as low, medium, and high. qualitative risk assessment uses subjective likelihood and consequence values collected from experts and decision makers and, as such, they are not always perfect estimates and are subject to biases and heuristics (talbot 2011) . assessed likelihoods and consequences for selected risks are then ploted in a two-dimensional space to generate a risk matrix. various risk matrix forms and sizes have been reported in risk assessment reports. a risk matrix is used to visualize, compare, and rank different risks based on their locations in the matrix. color coding is mostly used to show the importance of each risk. the risk matrix approach is also used for indicating possible risk control measures and to record the inherent, current, and target levels of risk (hopkin 2012) . a risk matrix provides some basis for risk treatments and management. risks that are located in the top righthand corner of the risk matrix (often colored in red) have higher likelihoods and impacts. these risks are very critical and need to be controled. risks that are in the lower (colored in green) and middle part (colored in orange or yellow) of the matrix should be monitored and checked regularly. although the risk matrix method has been criticized by scholars and professionals (cox 2008; ni et al. 2010; bao et al. 2017) , it is an invaluable tool for fast, effective, and practical risk assessment (talbot 2011) . data were collected from a sample of manufacturing smes in turkey. small and medium enterprises in turkey are categorized into three groups of micro, small, and medium-sized enterprises based on their employee numbers and annual revenues. micro firms are those with less than 10 employees and less than usd 430,000 annual turnover. small firms are those with less than 50 employees and less than usd 3.4 million annual turnover, and medium-sized firms are those with less than 250 employees and less than usd 17.2 million annual turnover (karadag 2016) . to assess and evaluate the risks, a questionnaire survey, including 19 questions, was developed. several questions collected general information about the production type, years in operation, city of operation, position of responder in the business, percent of production for export, percent of imported production materials, and export countries. in two sets of questions sme representatives provided their opinion about the consequences and likelihoods of global risks. samples of a risk likelihood question and a risk consequences question are: 6. review the following global economic risks and give your opinion on the likelihood of these risks occurring in the manufacturing sector in turkey over the next 10 years. • critical infrastructure failure: • very unlikely • unlikely • somewhat likely • likely • very likely 7. please review the following global economic risks and give your opinion about the potential impacts/consequences of these risks on the manufacturing sector in turkey over the next 10 years. • critical infrastructure failure: the questionnaire was designed and distributed using google form. small and medium enterprises operating in the manufacturing sector (nace revision.02 in c class through 10-33) were included in the population framework. these are smes in the nace classes that are registered with the kosgeb (small and medium industry development organization, turkey) and had an approved kobi̇ (sme) certificate in 2017. the survey link was emailed to about 40,000 smes on 19 april 2019. potential respondents were asked to complete the online survey by 3 may 2019. by the deadline, 217 completed responses had been received. the sample covers smes in different manufacturing areas. after the unspecified ''other'' manufacturing subgroup (39), smes in food products (22), textiles (22), machinery and equipment (22), furniture (20), fabricated metal (13), basic metal (9), wood products (9), rubber and plastic (9), electrical equipment (8), and chemical products (8) had the highest number of participants in this study. the questionnaire was completed by various individuals within each sample business, including managers (36), owners (20), accounting managers (13), financial managers (9), business partners (10), board members (3), engineers (6), and other employees (9). sample smes are operating in 50 different cities and 7 geographic regions in turkey, including marmara (72), central anotolia (47), aegean (29), black sea (24), mediterranean (23), eastern anotolia (11), and southeastern anotolia (11). the majority of the sample businesses (132) have been in operation for less than 10 years, only 34 have been in operation for 11 to 20 years, 29 between 21 and 30 years, and the rest (22) have been in business for more than 31 years. about 39.6% of the sample businesses were micro businesses, 37.8% small businesses, and about 22.6% were medium-sized enterprises. more than 60% of the smes export their products to varying degrees. they export to a large list of neighboring and european countries in particular. the sample smes also import some of their raw materials and equipment, and about 85% use imported products in their productions. using the methodology on collected data respondents perceived likelihood of the global risks and their impacts were identified and risk values were calculated, and risk matrix was generated using the risk values. this section presents the key findings. almost all global economic risks are perceived to have very high and high likelihoods by the sample turkish smes (fig. 1a) . however, fiscal crises in key economies, high structural unemployment or underemployment, and severe energy price shock are among the most likely risks according to the sample enterprises. a majority of the smes thought that catastrophic and severe impacts can be expected from the economic risks, particularly unmanageable inflation, high structural unemployment or underemployment, and fiscal crises in key economies (fig. 1b) . global environmental risks seem to have relatively lower likelihoods to the sample smes, compared with the global economic risks (fig. 2a) . man-made environmental damages caused by human and major natural hazards and disasters show higher perceived likelihood. the perceived impacts from these risks were scored lower as well. among these risks, environmental damages caused by human are perceived to have slightly higher impacts for the sample businesses (fig. 2b) . figure 3a and b show the sample sme respondents' opinion about the likelihoods and the consequences of the global geopolitical risks. failure of national governance and failure of regional or global governance, and largescale terrorist attacks have the highest average perceived likelihood in this risk category. however, the impacts are assessed to be higher for interstate conflicts with regional consequences, followed by the failure of national governance, and failure of regional or global governance. among global societal risks failure of urban planning and profound social instability were perceived to have the highest likelihood and impact averages among the sample businesses (fig. 4a, b) figure 5a and b present the stated likelihoods and consequences of the global technological risks. while the likelihood of all these risks is perceived to be high, largescale cyber-attacks and large data fraud are among the top in this risk group. although the means of the impacts are lower for most of these risks, except for the negative consequences of technological developments, more smes stated that the consequences of large-scale cyber-attacks and large-scale data fraud are expected to be severe and catastrophic. risks can be calculated as the multiplication of likelihood by impacts (table 2) . using the mean values of each risk category, economic and technological risks are perceived to have the highest likelihood levels followed by geopolitical risks (fig. 6a) . in terms of impacts, however, economic risks and geopolitical risks take the first and second ranks followed by technological risks. societal and environmental risks are considered to have lower impacts (fig. 6b) . in terms of the overall risk, the results show that economic risks and geopolitical risks take the first and second place, followed by technological risks (fig. 6c) . using the qualitative risk analysis methodology and perceived likelihood and impact data, a risk matrix was generated. although the horizontal and vertical axes take the values 1 to 5, the matrix axes have been rescaled for better visualization. this risk matrix displays the means of stated likelihoods and consequences for each risk. risks at the top right and in the red colored area are risks with higher than average likelihoods and consequences. risks in the lower left part of the matrix and colored green are considered to be low. figure 7 presents the resulting risk matrix for the 217 businesses and the 30 risks. most economic risks are in the upper part of the risk matrix, followed by some geopolitical risks. large-scale data fraud is the only technological risk that falls into the same area. majority of environmental and societal risks, although scattered diagonally in the risk matrix, are in the lower part of the matrix. this study examined the global risks from the perspective of manufacturing smes with global footprints in the emerging economy of turkey. the main aim was to understand whether and to what extent country-and industry-specific contexts and conditions affect smes perceptions of the global risks. key findings are discussed here. first, overall the results suggest that regardless of the ranking, the global risks are of high concern for smes in turkey. the average likelihood for all global risks is 3.56 and the average impact is 3.1. the minimum perceived likelihood (infectious desease) is 3.05 and the minimum perceived impact (severe weather events) is 2.7. these figures confirm that all global risks are of concern for the smes and have significant implications for them, particularly those in the manufacturing sector (zheng et al. 2010) . second, findings indicate that the smes' perceived risks at the country level (turkey) significantly varied from those perceived by the global companies in the global risk report (world economic forum 2019) (table 3) . while this study does not examine the underlying causes of these differences, it is evident that the smes' major concerns are global economic and geopolitical risks, both in terms of the likelihoods and the impacts. individual smes in turkey have been exposed and impacted more by the global economic risks than other risks. our findings are consistent with a few different but related research conducted by gül et al. (2010) , topçu (2013) , and deloitte (2017) that economic and financial risks such as devaluation of the turkish lira, interest rate risk, breakdown in cash flow or liquidity risk, credit risk, and increase in input prices were the key risks that businesses are facing in turkey. third, it is not surprising that smes' highest perceived risks are economic and geopolitical risks. studies demonstrate that financial and economic crises cause substantial (gregory et al. 2002; zheng et al. 2010; chowdhury 2011; filardo 2011; kossyva et al. 2014) . small and medium enterprises are very vulnerable to economic and financial crises as they are forced to close, downsize, and reduce the number of new ventures due to sharp decrease in demand and revenues (ates et al. 2013; sannajust 2014; wehinger 2014) . in today's global economy, turkish smes are not exempt from this, and they have been frequently impacted by such risks in the past two decades as well (karadag 2016) . moreover, giving high likelihood and high impact values for financial crises and other economic risks can be explained by the fact that turkish economy has deficit in international trade (abbasoglu et al. 2019 ) and highly rely on external energy sources such as oil and natural gas. fourth, failure of regional or global governance and failure of national governance are the geopolitical risks that are among the top perceived risks by the smes in this study. these risks have been largely felt by turkish smes in recent years. turkey has been in close proximity to a number of regional conflicts with potential impacts on the smes (omay et al. 2013; bilgel and karahasan 2017) and because of their vulnerability (pascual-ramsay 2015) and awareness of these risks, such risks are perceived highly both in terms of the likelihoods and the impacts. fifth, the sample smes also consider the likelihood of large data fraud/theft and large-scale cyber-attacks to be high. this is possibly due to the increasing dependency of the smes to the internet and the increasing number of cyber attacks and data theft in recent years (mbuyisa and leonard 2017) . while smes do not consider the impacts of these risks as high as their likelihoods, still these risks can cause disruptions and severe consequences to them, particularly because they are not well equipped to manage these risks. a recent report published by allianz (2019) confirms that smes in turkey increasingly recognize their cyber vulnerability and risks. finally, the relatively lower perceived likelihoods and impacts of the global risks by the sample smes can be attributed to the fact that small businesses may not be directly and highly impacted by distance environmental risks such as major natural hazard-induced disasters and that the awareness about some of the environmental risks among the smes may be lower than other risks. moreover, turkey has not experienced a major natural hazard-induced disaster in the past 20 years, and major weather events have been very local. the results of this study indicate the importance of addressing global risk assessments by smes. as more and more smes are connected with the national and global economies, their awareness about theses risks and the impacts that they could have for them will increase. this awareness can help smes to take these risks into consideration and prepare themselves for such risks. this study highlighted that smes' perceptions of the global risks are different from the businesses that operate at large scale at the global level. it also demonstrated that country's circumstances can affect smes' assessments of the likelihood, impacts, and rankings of global risks. it demonstrated that smes are more concerned about economic risks and risks that directly impact economic systems and variables, particularly geopolitical risks. environmental risks, while important, are not at the top of the list for smes. considering the significant role that smes play in local and national economies and the fact that they are concerned most about global economic and geopolitical risks, it can be argued that efforts towards lowering global economic and geopolitical risks can significantly benefit smes. since turkey's smes have been in a relatively unique situation in the past two decades with respect to some of the major global risks, similar studies in countries in other parts of the world may shed more light on how country contexts and type and size of businesses impact smes' perceptions of global risks. it was beyond the scope of this study to examine the smes' risk and business continuity actions taken to manage and mitigate the risks. future studies can also investigate whether and how smes prepare themselves for global risks. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/. terrorism and the world economy the turkish current account deficit linking entrepreneurial orientation and firm performance: the role of organizational learning capability and innovation performance allianz risk baromter 2019 sme business risks the endogenous and non-linear relationship between terrorism and economic performance: turkish evidence global risks and tourism industry in turkey 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analysing the vulnerability of micro, small, and medium enterprises to natural hazards and their capacity to act as drivers of community recovery. background paper for the global assessment report on disaster risk reduction tackle the problem when it gets here: pandemic preparedness among small and medium businesses building up resilience of construction sector smes and their supply chains to extreme weather events smes and the credit crunch: current financing difficulties, policy measures and a review of literature corporate strategies for managing climate risks the global risks report 2019 the impacts of natural disasters on global supply chains. artnet working paper series the role of smes in asia and their difficulties in accessing finance. asian development bank institute controlling town industry explosion hazard in china towards a system of open cities in china: home prices, fdi flows and air quality in 35 major cities acknowledgements this research has been partially supported by the scientific and technological research council of turkey (tubitak) through the 2221-fellowship program for visiting scientists and scientists on sabbatical leave. the project has been also supported in part by york university's advanced disaster, emergency, and rapid response simulation (adersim) funded by ontario research fund. key: cord-033655-16hj7sev authors: miroudot, sébastien title: reshaping the policy debate on the implications of covid-19 for global supply chains date: 2020-10-12 journal: j int bus policy doi: 10.1057/s42214-020-00074-6 sha: doc_id: 33655 cord_uid: 16hj7sev disruptions in global supply chains in the context of the covid-19 pandemic have re-opened the debate on the vulnerabilities associated with production in complex international production networks. to build resilience in supply chains, several authors suggest making them shorter, more domestic, and more diversified. this paper argues that before redesigning global supply chains, one needs to identify the concrete issues faced by firms during the crisis and the policies that can solve them. it highlights that the solutions that have been proposed tend to be disconnected from the conclusions of the supply chain literature, where reshoring does not lead to resilience, and could further benefit from the insights of international business and global value chain scholars. lastly, the paper discusses the policies that can build resilience at the firm and global levels and the narrative that could replace the current one to reshape the debate on the policy implications of covid-19 for global supply chains. with covid-19, the debate has re-emerged on the vulnerabilities of an interconnected world where goods are produced in complex value chains that span across borders. international production and supply chains were criticized because of the economic disruptions they allegedly created when a pandemic interrupted trade and the movement of people across countries, adding to existing fears and concerns about globalization (kobrin, 2020) . reshaping global supply chains, and possibly making them shorter, more domestic, or more diversified, were therefore proposed to bring some resilience into production networks (coveri, cozza, nascia, & zanfei, 2020; javorcik, 2020; lin & lanng, 2020; o'leary, 2020; o'neil, 2020; shih, 2020) . this debate builds on several concepts used in supply chain risk management, starting with 'resilience' 1 . however, some of the solutions proposed, such as reshoring or diversifying production away from china, may be motivated by a different policy agenda than risk mitigation (evenett, 2020) . in this paper, i argue that before reshaping global supply chains, the debate itself needs to be reframed and more solidly grounded in business reality and in lessons from the literature. there is an important corpus of knowledge in the supply chain and risk management literature that tells firms what to do to improve the resilience of their own production networks. however, there are fewer answers on what resiliency means at the country or global level and what global value chain-oriented policies can be adopted to strengthen it. this is where the international business (ib) and global value chain (gvc) literature can provide further insights. for the ib community, covid-19 can be seen as an opportunity to bring to policy circles the knowledge on firms and the organization of multinational enterprises (mnes) that can help to shape the debate on the resilience of supply chains, in line with the ambition of the journal of international business policy (van assche, 2018; van assche & lundan, 2020). as noted by lorenzen, mudambi and schotter (2020) , studying mne risk mitigation strategies in the context of covid-19 can be a fruitful avenue for ib research. strange (2020) already provides some interesting thoughts about how gvcs may be reorganized once the crisis is over. the concept of resilience is not new in the gvc literature. it was used for example to highlight the recovery of trade networks after the great financial crisis in 2008 (cattaneo, gereffi, & staritz, 2010) . more recently, gereffi (2020) addresses the issue of the resilience of medical supply gvcs. however, as policymakers now seem to associate resilience with a specific type of organization of gvcs where mnes produce mostly through more localized or shorter supply chains, new questions arise on the type of governance that would allow such organization and on the way policymakers could influence the design of gvcs. the main risk with the current debate on the economic policy implications of covid-19 is that it can lead to the use of supply chain concepts by policymakers and international organizations in a way that departs from business reality, thus leading to wrong policy choices. the idea that reshoring unambiguously improves the resilience of supply chains, for example, is not supported by academic research. if there is a case for linking reshoring to higher resiliency, it should be brought up based on evidence, on a deeper discussion of the specific circumstances where it might be a strategy mitigating risks, and one would also need to disentangle the different policy rationales (e.g., bringing jobs back home versus creating more resilient supply chains). what is at stake in this debate are three decades of productivity gains and innovation driven by the internationalization of production, as well as higher levels of income in many emerging economies (world bank, 2019). building more resilient supply chains should not lead to the dismantlement of gvcs. it should also not replace the risks related to covid-19 by new policy hazards and a higher level of uncertainty for companies. against this backdrop, the paper suggests that the debate on the policy implications of covid-19 for international supply chains can be improved in three ways. first, there is a need to better understand the 'vulnerabilities' of global supply chains during covid-19. that is, the primary step in reshaping the debate is to identify what went wrong during covid-19. second, one needs to compare the current policy proposals to established insights from the business literature. i illustrate this with a discussion of the effects of building redundancy in suppliers, just-in-case management, and domestic supply chains. the literature indicates that these strategies are not the best suited to boost resilience in gvcs. still, their analysis is useful to point to better and more realistic policy options and to see where ib research can help. lastly, as the literature suggests that it is at the firm level that resilience is built (or at the level of mnes or lead firms in gvcs), the question is what resilience means at the country or global level and what governments can do to strengthen it. answering these questions can set the stage for a new narrative on the policy implications of covid-19 for global supply chains. prescribing the solution unlike the great financial crisis of 2008-2009 that provoked a collapse of trade financing, covid-19 has prompted an economic crisis that is not specifically a trade crisis. the most affected industries are services that do not rely on long and complex value chains but involve movements of people (benz, gonzales, & mourougane, 2020) . as china was the first country to put a lockdown into effect in january, there was initially the fear that many manufacturing gvcs would be disrupted because key inputs from china would not be delivered. this immediately triggered a series of papers warning about the vulnerabilities of international supply chains and the risk of producing in china (braw, 2020; gertz, 2020; linton & vakil, 2020, among others) . 2 many manufacturing value chains indeed rely on inputs produced in china and calculations with international input-output tables suggest that not having access to chinese inputs can have a high economic impact on the rest of the world (baldwin & freeman, 2020) . however, there is a lack of evidence at this stage of how serious disruptions were related to the (partial) lockdown of the chinese economy. the reason is that large parts of the world also implemented lockdowns a few weeks later, and demand for most manufacturing goods started to fall at the same time. the chinese lockdown was also relatively short, and china was the first country to restart its economy. macro calculations can give an indication of how important a country is as a supplier of inputs for others. however, since companies have risk management strategies and inventories, the actual impact of china temporarily shutting down its exports is not known. figure 1 compares the projected fall in gdp in 2020 according to the latest oecd economic outlook (oecd, 2020a) with the import intensity of production in g20 economies (an indicator of the reliance on imported inputs all along the value chain). 3 there is no apparent correlation between the two. the country that is the most dependent on gvcs is korea, which happens to be the economy with the lowest projected fall in gdp for 2020. at the opposite side of fig. 1 are eu economies that are dependent on their regional supply chains (but not so much on china) and were severely hit by covid-19. the idea that dependence on china or some other country creates supply chain vulnerabilities and that covid-19 has somehow materialized this fear would need to be substantiated by strong quantitative evidence, and this evidence would have to point to the size of economic losses rather than just the existence of disruptions. 4 when analyzing the evidence, it is also important to propose some counterfactuals. using a quantitative model of production and trade, bonadio, huo, levchenko and pandalai-nayar (2020) find, for example, that there is a high drop in world gdp due to the transmission of the covid-19 shock through gvcs. however, the drop in gdp is higher under the scenario of a 'renationalization' of global supply chains. also using a quantitative model, oecd (2020b) highlights that in addition to higher costs, the re-localization of supply chains also leads to higher volatility in output, as there are fewer channels for economic adjustments. therefore, the right question might not be whether there are vulnerabilities associated with international sourcing but whether these vulnerabilities are higher than if production were concentrated domestically. while the jury is still out on the actual vulnerabilities of gvcs during covid-19, there are nonetheless three types of concrete issues that have been highlighted and that deserve to be addressed from a policy perspective. the chinese supply shock at the end of january and beginning of february 2020 is an example of international supply chain risk. whether it is a pandemic or a natural disaster, production can suddenly halt in a region of the world and induce a contagion effect to other regions through international supply chains. this was observed in 2011 with the tōhoku earthquake and tsunami in japan and the chao phraya floods in thailand, or in 2005 with hurricane katrina in the united states. many companies have learned to deal with such country-specific shocks by reinforcing their risk management strategies to mitigate the impact on their production processes. if building more resilient supply chains simply means improving the capacity of firms to face country-or region-specific supply chain risks, there is already abundant literature that indicates how this can be done (christopher & peck, 2004; sheffi, 2005a; manuj & mentzer, 2008; pettit, fiksel, & croxton, 2010; kamalahmadi & parast, 2016) . from the experience of firms at the beginning of 2020, it might be possible to revisit this literature and to draw new conclusions from additional case studies, as the field is always evolving (pettit, croxton, & fiksel, 2019) . such case studies would be particularly useful to give insights on what exactly went wrong with global supply chains beyond the supply and demand shocks that have affected all firms during covid-19. the second type of disruption that has triggered the debate on gvcs is those related to the production of medical supplies and more particularly personal protective equipment (ppe). the shortage in face masks, a key product to fight the coronavirus, was also quickly turned into an international supply chain issue. however, the story behind face mask shortages was an exceptional surge in demand (oecd, 2020c; gereffi, 2020) . the country that was concentrating half of the production of face masks in the world (china) also faced a shortage, suggesting that domestic production or not, the way to deal with a surge in demand is not by asking where production takes place but how production capacity can be rapidly ramped up. the shortage was also exacerbated by export restrictions put in place by some countries and by the fierce competition between governments to get access to existing stocks of face masks (fiorini, hoekman, & yildirim, 2020) , highlighting that the problem is not limited to the organization of supply chains. china and gvcs provided the solution to the shortage with massive exports from china to the rest of the world in april-may and one can wonder whether what seemed to be the issue (international sourcing from china) was not retrospectively the solution. if building more resilient supply chains means preventing future shortages in essential products, the answer might lie in a discussion of stockpiling strategies, contingency plans and public-private partnerships, as well as addressing export restrictions put in place by governments (oecd, 2020c). like companies, governments need to assess risks and have risk management strategies that include plans for the production of essential goods (dasaklis, pappis, & rachaniotis, 2012). a closer look at supply chains from an ib perspective could nonetheless bring additional insight on how companies themselves can be prepared for a surge in demand and more generally the volatility in demand (as the surge in demand is followed by a fall when the crisis is finished, leaving many companies with excess production capacity). the supply chain risk and the issue of volatility in demand are not new and may not require the 'world after' to be radically different from the world of yesterday. although not necessarily making the headlines when they are unrelated to major natural disasters or a pandemic, disruptions in value chains are frequent (logistics incidents, fire in a warehouse, bankruptcy of a supplier, etc.). not all companies are well prepared to face risks (mckinsey global institute, 2020), but some are (sheffi, 2015) , and building on advances in supply chain and risk management, companies should come up with sensible answers to the question of resilience of their supply chains. new advances in big data analytics and the internet of things (iot) are also likely to provide new answers (birkel & hartmann, 2020) . the third type of disruption, and maybe the most prevalent during covid-19, is those related to the functioning of international trade networks. trade did not come to a halt at the height of the crisis but it was definitely more complicated (and more costly) for firms to export and to import because of tensions in transport services and issues with border controls (oecd, 2020d; wto, 2020). with travel bans, the supply of air cargo services was reduced, as half of air cargo shipments are on passenger flights. longer delays at the border were observed for customs procedures due to new health regulations and tighter controls, also affecting maritime and land transport. new port procedures and rules on the disembarkation of crews were also responsible for reduced capacity in the shipping industry. while transport companies are the ones that can mitigate the impact of such disruptions, it should be noted that they are the consequence of measures put in place by governments and that making border processes faster and safer is the basis of trade facilitation policies. addressing these types of issues does not require a reorganization of gvcs. once the problems faced by firms are clearly identified, it becomes easier to move to an evidence-based policy discussion and to see what type of policies or cooperation across countries could actually bring answers to supply chain risks or volatility in demand. and domestic supply in addition to not having properly identified the issues to be solved, the debate on covid-19 and global supply chains has started with strong statements about solutions, relying on concepts from the business literature. these concepts tend to be used without actually referring to academic work, which can be explained by the fact that what the literature has to say is quite different from the recommendations made. this can be illustrated with three concepts used in the papers telling us about the new normal of supply chains in the post-covid-19 world: redundancy, just-in-case inventories, and domestic supply chains. a new word that has appeared in the supply chain vocabulary of policymakers is 'redundancy'. in order to build more robust value chains, there should be some redundancy in suppliers (or supplier diversification) 5 , so that in case of failure of one, others can step in and provide the required inputs. redundancy is part of the toolkit of risk management strategies and can be applied not only to suppliers but also to inventories or production capacity (kamalahmadi & parast, 2016) . however, it is generally regarded as a costly solution to mitigate risk. as summarized by yossi sheffi, one of the leading experts in organizational resilience: ''companies can develop resilience in three main ways: increasing redundancy, building flexibility, and changing the corporate culture. the first has limited utility; the others are essential.'' (sheffi, 2005b) . in an empirical study looking at 4000 us firms, jain, girotra and netessine (2016) found that supply chains with more diversified sourcing (i.e., the same products are sourced from different suppliers) have slower recovery after a disruption than supply chains relying on single sourcing. one of the reasons for this is that single sourcing is associated with long-term relationships with suppliers. these long-term relationships ensure faster recovery because suppliers are more committed to mitigating risks, are ready to go beyond their contractual obligations to address disruptions, and are more integrated in the production processes of the firm with more information sharing. redundancy also means having some extra inventory or additional production capacity to face crises. however, the cost of holding a large inventory or maintaining spare production capacity often outweighs the gains from mitigating risks, particularly in the case of low-probability events. for companies that regularly face hurricanes or adverse climate conditions, for example, redundancy can make sense (sheffi, 2015) , but one cannot expect companies to invest in extra production capacity and inventories for a once-ina-century pandemic. the issue of redundancy is clearly one where ib research can help to shape the policy debate. the multinational enterprise has been analyzed as a network of subsidiaries operating in different countries with the objective of managing risks, such as exchange rate volatility or policy risk (kogut & kulatilaka, 1994) . even if there are switching costs, covid-19 has illustrated that some companies used their network to reallocate production, such as samsung moving temporarily the production of its high-end mobile phones from korea to vietnam when its factory was threatened by the coronavirus (financial times, 2020). this type of redundancy is more related to flexibility and does not imply duplicating capacity or multiplying the number of suppliers on a permanent basis. however, it is one advantage that mnes have over companies operating in a single market. explaining what type of redundancy is useful to build resilience in gvcs and how this redundancy is related to international production could improve the terms of the debate. the discussion on inventories is related to 'just-intime' strategies that have contributed to reducing the size of buffer stocks. just-in-time (jit) inventories management was introduced in the 1970s by toyota and was quickly adopted by many manufacturing companies in the world as an effective strategy to reduce costs, shorten lead times, and improve the quality of production (keller & kazazi, 1993) . jit is part of lean manufacturing strategies aimed at reducing all costs and waste in the production process (bhamu & singh sangwan, 2014) . now the idea would be to switch to 'justin-case' management where a loss in economic efficiency would be traded-off for increased security in supply of inputs. but what exactly is the underlying management strategy? 'just-in-case' is an expression used in the literature to describe what was before jit or in the risk management literature to discuss whether higher inventories are needed (srinidhi & tayi, 2004) . but it is not a specific type of management model that could be mainstreamed to make supply chains more resilient, unless the idea is to come back to the management of inventories as it was before the ict revolution and modern logistics. 'just in case' is a very vague proposal that maybe only suggests adjusting jit to better take into account risk management. however, this is already the case, as risk management strategies and jit generally go together. firms that invest in reducing inventories and making their production process as efficient as possible all along the value chain are also the ones investing in the monitoring and management of risks. this can be illustrated with cisco's supply chain risk management that is often mentioned as an example of best practices. cisco aims at identifying the right level of inventories to achieve both resilience and efficiency (miklovic & witty, 2010) . in may, in the middle of the covid-19 crisis, 3m -one of the main manufacturers of face masks -announced that it plans to reduce the cost of its inventories by usd 500 million in the coming years in order to operate its supply chains more efficiently (supply management, 2020) . this highlights that companies producing essential goods are also looking for lean inventories and do not see it as a contradiction with their risk management and business continuity objectives. a point made by pisch (2020) is also that jit companies have lower costs for inventories. therefore, if there is a need to increase inventories to reduce risks, they are also better placed to do it in a more competitive way. a related consideration is that when there is a fall in demand, like in the current covid-19 crisis, companies with low inventories have smaller losses than those with high inventories. the paradox is that if 'just-incase' was currently the predominant strategy of firms, more of them could become bankrupt with covid-19. finally, it should be noted that the manufacturing paradigm has also recently shifted from 'lean manufacturing' to 'agile manufacturing' (potdar, routroy, & behera, 2017) . while some firms may still follow jit and lean production, new business models put more emphasis on the capacity of firms to adapt to change and to produce in uncertain environments. some ib scholars suggest that the international business environment is now characterized by volatility, uncertainty, complexity, and ambiguity (vuca) and that, in this new vuca world, firms need to develop dynamic capabilities to remain competitive (bennett & lemoine, 2014; teece, 2014; van tulder, verbeke, & jankowska, 2019) . what authors reacting to covid-19 are calling for is already something under way (and where efficiency does not have to be sacrificed to achieve resilience). further insights on the new paradigms of firms and what they do and intend to do as a consequence of the covid-19 pandemic could also help to bring the policy debate closer to the decisions of firms. the idea that domestic production is more resilient than international production is also not something found in the risk management literature. 6 the main reason for this is that there are many risks in the domestic economy as well and this literature does not try to identify where is the safest place to produce but what strategies can companies put in place to mitigate risks. for example, companies producing in japan will always face a high risk of earthquakes. some countries may be less exposed to natural disasters but will face other risks such as exchange rate volatility, strikes, social unrest, or a pandemic. there are also risks that are not related to the location of production, such as bankruptcy. if a supplier goes bankrupt (which is a high risk during the covid-19 recession), it does not matter whether it produces in the domestic economy or not. inputs will no longer be supplied. another type of risk that has recently gained attention is cyber risk (ghadge, weiß, caldwell, & wilding, 2019) . as supply chains increasingly rely on information and communication technologies, they are more vulnerable than before to cyber-attacks and it failures, a risk that is not lower when production is domestic (and potentially higher if domestic firms all use the same it infrastructure). risk management is about looking at the whole portfolio of risks, which can lead to different decisions in terms of the location of production. domestic production might indeed be the strategy in some cases, but it would be the result of a decision integrating a variety of risks -and risk is only one determinant of the location of production among others. until recently, the concept of reshoring could not be found in the business literature and was mentioned more as a hypothetical case when discussing offshoring. some anecdotal evidence on companies actually reshoring their activities has prompted new research. however, the literature does not regard supply chain risk as one of the main determinants of reshoring (wiesmann, snoei, hilletofth, & eriksson, 2017) . minimizing disruptions in supply chains and reducing delivery times might be a driver but studies generally emphasize the limits of reshoring (bailey & de propris, 2014) . some further insights that could be brought from the ib literature are what firms have to lose (or to change) when being disconnected from the most efficient suppliers or from international knowledge networks. there are advantages in producing locally, such as not supporting all the additional costs related to cross-border transactions and managing activities abroad. the question is what kind of location advantages from offshored places are traded for these domestic location advantages. more generally, there are important insights from the ib literature that can help policymakers to develop a better understanding of the relationship between the organization of global supply chains and risk. risk is part of the location advantages in dunning's eclectic theory (dunning, 1980) . the policy or institutional risk in the host country of mnes has always been regarded as an important determinant of fdi, with heterogeneous responses (buckley, chen, clegg, & voss, 2018) . volatility in real exchange rates is another risk specific to international production that can lead firms to look for options and the flexibility of switching production across countries (kogut & kulatilaka, 1994) . real options theory provides a theoretical basis for this type of diversification strategy and can be applied to a variety of other risks beyond exchange rates (chi, trigeorgis, & tsekrekos 2019) . internalization theory can also potentially address the issue of risks in supply chains with an answer not limited to the geographical location of activities but also the boundaries of firms and what they decide to outsource or not (strange, 2020) . the geography of mnes is the result of complex strategic decisions (mudambi et al., 2018) . a new imperative related to the mitigation of supply chain risks can affect these decisions and change the geography and boundaries of firms, but the idea of reshoring seems simplistic as compared to the sophisticated location decisions described in the ib literature and the constraints faced by firms to remain competitive. help to know what to do now that it seems accepted that covid-19 has revealed the vulnerabilities of international supply chains, governments are under pressure to show that they are taking some action to fix gvcs. this is why it is dangerous to leave an analytical vacuum where the solutions proposed would only be the ones analyzed in the previous section. reshaping the debate and introducing a different set of answers derived from the business literature and supported by empirical evidence requires addressing three questions. one is a matter of communication, and the two others are more fundamental. while there is some convergence in the risk management literature on what can improve the resilience of supply chains, the first question is how to communicate the results of this research to policymakers. one issue is the diversity in the concepts used to describe what firms need to achieve. under the list of 'capabilities' to be developed are the concepts of flexibility, agility, visibility, adaptability, and collaboration (kamalahmadi & parast, 2016) . each concept casts light on a different aspect of what makes firms able to quickly react to a crisis and mitigate its impact, but there is also some overlap between them. as concepts, they also carry some level of abstraction and both businesses and policymakers might regard them as a bit disconnected from their daily work. it would be useful to simplify the message and to synthesize these different aspects. one reason why the concept of 'resilience' is successful (while not always properly used) is that it sounds like a reasonable and simple objective. as the pendulum seems to be right now more on the side of limiting international supply, increasing inventories and diversifying suppliers, there is a need to move it more in the direction of flexibility and agility where firms do not have to become less efficient to mitigate risks. the role of collaboration (scholten & schilder, 2015) , which is related to visibility, might also be interesting to emphasize from a policy perspective (having in mind governments as potential actors in this collaboration). the second question is whether solutions are at the firm level or the gvc level. the risk management literature focuses on making firms resilient, and this can be measured by the time they take to recover from a disruption. according to martins de sá et al. (2020) , resilience in the value chain does not depend on the organizational features of the supply chain but rather on efficient risk management strategies in firms that are able to reconfigure the value chain to mitigate the disruptions. here it might be useful to refer to gvc analysis and to the different models of governance of supply chains (gereffi, humphrey, & sturgeon, 2005) . if a lead firm controls the whole value chain (captive value chain or vertically integrated value chain), ensuring that the lead firm has the capabilities needed for effective risk mitigation might be enough to create resilience all along the supply chain. it might also be the case in some relational value chains where the same is achieved through collaboration. in the case of market linkages and modular value chains, one may have to distinguish the resilience of the supply chain from the resilience of specific firms. moving from policy proposals focusing mainly on the design of supply chains (e.g., to make them shorter, more domestic, and more diversified) to proposals enhancing the capabilities of firms (e.g., to help them to develop flexibility and agility, as well as visibility in their supply chains) requires clarifying the intersection between firms and gvcs (pananond, gereffi and pedersen, 2020) . on the one hand, the concept of resilience at the gvc level (the way policymakers understand it, i.e., value chains for a large range of final producers belonging to the same broad industry, such as medical supplies or food) is more difficult to define, as different firms will recover at a different pace after a disruption (and not all of them might be affected in the first place). in theory, the production of final goods can only resume when production all along the value chain starts again, but it can still leave some final producers and input suppliers at different stages of recovery when considering gvcs of a whole industry. on the other hand, the type of resilience that is discussed by policymakers (and which is more about reducing and diversifying risks rather than shortening the time to recover from a disruption) might be easier to achieve at the gvc level. for example, reducing the dependence on inputs from a specific partner country can be the result of different firms sourcing from different countries while not asking each firm to diversify suppliers (ferrarini & hummels, 2014) . the third question is how governments can influence sourcing decisions or capabilities of firms, as well as the organization of gvcs. it should be noted that this question is the same whether one is promoting reshoring or agility. it is a traditional question in the literature in relation to the design of gvc-oriented industrial policy (gereffi & sturgeon, 2013) , the public/private governance of value chains (bair, 2017) , the role of the state in gvcs (horner & alford, 2019) , as well as the impact of investment and trade regimes on decisions of mnes (buckley, 2018; rugman & verbeke, 2017) . it may receive different answers based on whether governments want to encourage or constrain firms in adopting specific strategies. leaving aside the option where governments themselves become actors in gvcs (through government ownership), constraints (e.g., tariffs, taxes) or incentives to firms (e.g., subsidies, tax breaks) inevitably lead to economic distortions. it would be a paradox to resort to such mechanisms when the origin of current trade tensions and policy uncertainties for investment lies in market-distorting government support and when several countries highlight the need for levelling the playing field (oecd, 2019). some governments might still follow this path, but a more coherent policy framework that would not suggest increasing policy risks and costs for companies in order to build resilience would have to rely on a two-pronged approach. first, as highlighted before, there are a series of policies, such as trade facilitation or the regulation of transport and infrastructure services, where the government is directly in charge of setting the rules and can create the conditions for firms to mitigate risks and increase their agility (e.g., by eliminating red tape, creating emergency certification procedures, etc.). the reduction of policy uncertainties, including at the global level, is also in the hands of governments, although more dependent on the success of international cooperation (which is not warranted in the current geopolitical environment). second, some dialogue with the private sector and possibly the organization of public-private platforms at the level of gvcs (hoekman, 2014) can allow governments to encourage firms to put more emphasis on the issue of resilience, while not introducing financial constraints or incentives. different types of incentives can be provided, such as with the organization of 'stress tests' that would put companies in the position of proving that they have taken the necessary steps to be resilient, particularly in the context of the production of essential goods (simchi-levi & simchi-levi, 2020) . such stress tests could also provide information to governments to organize their own risk management strategies (e.g., the right level of national stockpiling to meet a surge in demand beyond the capacity of firms to ramp up their production) and to improve their policies (e.g., information on policy-related costs encountered by firms in their operations). a gvc-level dialogue would also allow firms to cooperate among themselves to be better prepared for risks. the basis for developing and promoting such policy proposals would be a new narrative with the following elements: (1) covid-19 has confirmed interdependencies between economies. there are risks inherent to these interdependencies but they are also the source of growth and development. at this stage, there is no reason to believe that reducing interdependencies would reduce the exposure of economies to risks. on the contrary, simulations suggest that not only the income of countries would be lower but also more volatile. (2) there are concrete issues that can be addressed by policymakers at the gvc level for economies to be better prepared for risks in the future. these issues do not require a new paradigm for gvcs but may involve their restructuring in a process driven by companies and tailored to the specific conditions they operate in. three of them were discussed in the first section of the paper: international supply chain risks and contagion effects, surges in demand for essential goods, and disruptions in trade and transport networks. in these three areas, a gvc perspective makes sense and a combination of actions by firms and governments can mitigate the impact of the next crises. (3) there is no trade-off between efficiency and lower risk. there are trade-offs between different types of risks and firms have to balance the costs and benefits of risk management. however, the most efficient firms are also the ones that are the best at mitigating risks (sheffi, 2015) . promoting agility and flexibility is an agenda that can serve both the objective of resilience and economic recovery after covid-19. (4) the location of production is a complex issue where risk is one determinant among others. there is no rationale for suggesting a specific organization of gvcs that would create resilience, but one type of risk that governments can control is policy risk. they can diminish uncertainties within their domestic economy and rely on international cooperation to reduce international policy risks and trade tensions. conclusion in its 2020 world investment report, unctad (2020) is already predicting that reshoring, diversification, and regionalization will drive the restructuring of gvcs in the coming years. it might be premature, as these strategies have been proposed in columns or opinion pieces and are not grounded in business experience, research, and analytical work. calls for more resilient supply chains have been heard before, after 2001 when the emphasis was on risks related to terrorism or after 2011 when the emphasis was on natural disasters. businesses that nowadays are described to be focused too much on efficiency and insufficiently prepared for risks related to hyper-globalization have already been through many crises that have prompted them to act. still, covid-19 is an unprecedented crisis, and its global scale might lead more companies to rethink their strategies and to put more emphasis on risk management. companies that have been through this process in the past have not resorted to reshoring or regionalization and have not significantly diversified their supply chains. what could be different this time is that firms also have to adjust to deep changes in their environment, such as the digital transformation, climate change, or rising protectionism and trade tensions. therefore, we will see some structural shifts in the organization of global supply chains and covid-19 might be an accelerator of these shifts in some cases. it is too early, however, to predict what solutions will lead businesses to thrive in this uncertain environment. still, it is useful to have the current debate on the policy implications of covid-19 for global supply chains. first, this debate can prevent governments from making the wrong policy choices in the future. that is, there is an opportunity for researchers to convey to policymakers relevant knowledge that will improve their policies or prevent them from making mistakes. second, the overlap between the debate on the resilience of supply chains and the debate on protectionism and economic nationalism can also offer new ways of addressing concerns about globalization. while building more resilient gvcs could be used as a pretext for protectionist policies, it is a two-edged sword. demonstrating that domestic value chains are increasing certain types of risks or that international sourcing can improve the access to essential goods would not only reduce the appeal of protectionist policies but do it on different grounds than just pointing at a welfare loss. third, new research on global supply chains and risk mitigation during covid-19 could provide novel insights, as well as new policy recommendations. different questions could also be examined, not being constrained by the initial emphasis on reshoring and redundancy. for example, the reshoring debate focuses on resilient value chains for developed countries and does not take into account developing and emerging economies. these countries would not only lose some economic activity if reshoring was the new normal, but would also face a more difficult access to essential goods when they are produced by mnes from developed countries. the author is writing in a strictly personal capacity. the views expressed do not reflect those of the oecd secretariat or the member countries of the oecd. the author is grateful to the editor, ari van assche, and to two anonymous referees for their many helpful comments and suggestions. in the risk management literature, resilience is defined as ''the ability of a system to return to its original state or move to a new more desirable state after being disturbed'' (christopher & peck, 2004) . in the supply chain, resilience is about reducing the time it takes for companies to resume normal production once a disruption has occurred. it is different from 'robustness', which is the ability of supply chains to maintain their function despite internal or external disruptions (brandon-jones, squire, autry, & petersen, 2014). authors who ask for more resilient supply chains in the context of covid-19 are often mistaking resilience for robustness. they focus on the description of the disruptions but do not report how quickly international supply chains have generally adjusted, which is the sign of their resilience. on the policy implications of robustness versus resilience in gvcs, see miroudot (2020). the debate on china overlaps with another type of risk that is not related to covid-19 but to trade tensions between the united states and china. there is evidence that an increasing number of companies are moving their production out of china to avoid trade barriers imposed on chinese exports or potential political pressures (baker mckenzie, 2020) . the fact that reshoring and domestic production are suggested to build more resilient supply chains is likely to be linked to economic nationalism and the anti-globalization sentiment. the issue of concentration of production, which is relevant for supply chain disruptions, is also generally analyzed only in relation to china. 3 see timmer et al. (2016) for the calculation of the import intensity of production. the ratio indicates for each dollar of output the value of all intermediate inputs traded upstream in the value chain. it was calculated for 2015 (latest year available) with data from the oecd trade in value added (tiva) database. data for the eu are based on the euro area only. 4 business surveys generally indicate high rates of disruptions but without an indication of the consequences of these disruptions (e.g., whether firms have stopped producing or not). see for example the surveys conducted by the institute for supply management (www.instituteforsupply management.org), the data collected on firmlevelrisk.com and mckinsey global institute (2020). 5 the expression 'supplier diversification' is only partially a synonym for redundancy. redundancy suggests that there are (at least) two suppliers for the same input (in different locations). supplier diversification can also be understood as diversifying the sources of supply by working with different suppliers in different countries but each of them providing different inputs (i.e., maintaining single sourcing). it can spread the supply chain risk but does not offer the same level of business continuity when one of these suppliers fails to provide the inputs. 6 the argument is also about shorter supply chains, which can be understood as a regionalization of production and not just relying on domestic suppliers. the relationship between distance and risk is linked to regional integration and economic cooperation among countries, which can reduce the policy and institutional risk. cultural factors could also play a role with lower transaction costs and easier co-operation between firms when there is some cultural proximity. see e.g., shenkar (2012) for a discussion of cultural distance. trade in value-added terms, the relationship between trade and investment, and the trade policy implications of global value chains. he holds a phd in international economics from sciencespo. supply chains reimagined: recovery and renewal in asia pacific and beyond manufacturing reshoring and its limits: the uk automotive case contextualising compliance: hybrid governance in global value chains supply chain contagion waves: thinking ahead on manufacturing 'contagion and reinfection' from the covid concussion what a difference a word makes: understanding threats to performance in a vucaworld the impact of covid-19 international travel restrictions on services-trade costs: some illustrative scenarios lean manufacturing: literature review and research issues internet of things -the future of managing supply chain risks. supply chain management global supply chains in the pandemic a contingent resource-based perspective of supply chain resilience and robustness blindsided on the supply side towards a theoretically-based global foreign direct investment policy regime risk propensity in the foreign direct investment location decision of emerging multinationals global value chains in a post-crisis world: a development perspective real options theory in international business building the resilient supply chain supply chain contagion and the role of industrial policy toward an eclectic theory of international production: some empirical tests chinese whispers: covid-19, supply chains in essential goods, and public policy asia and global production networks: implications for trade, incomes and economic vulnerability covid-19: expanding access to essential supplies in a value chain world inside samsung's fight to keep its global supply chain running what does the covid-19 pandemic teach us about global value chains? the case of medical supplies the governance of global value chains global value chain-oriented industrial policy: the role of emerging economies the coronavirus will reveal hidden vulnerabilities in complex global supply chains managing cyber risk in supply chains: a review and research agenda supply chains, mega-regionals and multilateralism: a roadmap for the wto the roles of the state in global value chains recovering from supply interruptions: the role of sourcing strategies global supply chains will not be the same in the post-covid-19 world a review of the literature on the principles of enterprise and supply chain resilience: major findings and directions for future research just-in-time' manufacturing systems: a literature review how globalization became a thing that goes bump in the night operating flexibility, global manufacturing, and the option value of a multinational network here's how global supply chains will change after covid-19 coronavirus is proving we need more resilient supply chains international connectedness and local disconnectedness: mne strategy, city-regions and disruption global supply chain risk management supply chain resilience: the whole is not the sum of the parts risk, resilience, and rebalancing in global value chains case study: cisco addresses supply chain risk management resilience versus robustness in global value chains: some policy implications zoom in, zoom out: geographic scale and multinational activity the modern supply chain is snapping. the atlantic how to pandemic-proof globalization: redundancy, not re-shoring, is the key to supply chain security oecd. 2020a. oecd economic outlook 2020 oecd. 2020b. shocks, risks and global value chains: insights from the oecd metro model the face mask global value chain in the covid-19 outbreak: evidence and policy lessons trade facilitation and the covid-19 pandemic levelling the playing field an integrative typology of global strategy and global value chains: the management and organization of cross-border activities the evolution of resilience in supply chain management: a retrospective on ensuring supply chain resilience ensuring supply chain resilience: development of a conceptual framework managing global production: theory and evidence from just-in-time supply chains agile manufacturing: a systematic review of literature and implications for future research global corporate strategy and trade policy the resilient enterprise: overcoming vulnerability for competitive advantage building a resilient supply chain the power of resilience. how the best companies manage the unexpected cultural distance revisited: towards a more rigorous conceptualization and measurement of cultural differences is it time to rethink globalized supply chains? sloan management review collaboration in supply chain resilience we need a stress test for critical supply chains just in time or just in case? an explanatory model with informational and incentive effects the 2020 covid-19 pandemic and global value chains 3m cuts inventory by $370m a dynamic capabilities-based entrepreneurial theory of the multinational enterprise an anatomy of the global trade slowdown based on the wiod 2016 release world investment report, 2020 -international production beyond the pandemic from the editor: steering a policy turn in international business -opportunities and challenges from the editor: covid-19 and international business policy international business in a vuca world: the changing role of states and firms drivers and barriers to reshoring: a literature review on offshoring in reverse world development report 2020 -global value chains: trading for development trade in services in the context of covid-19 about the author sébastien miroudot is senior trade policy analyst in the trade in services division of the oecd trade and agriculture directorate. he was previously a research assistant at groupe d'economie mondiale and taught in the master's degree programme at sciencespo, paris. during 2016-2017, he was visiting professor at the graduate school of international studies of seoul national university. at the oecd, his current work is on the measurement of key: cord-001781-afg1nmib authors: saksena, sumeet; fox, jefferson; epprecht, michael; tran, chinh c.; nong, duong h.; spencer, james h.; nguyen, lam; finucane, melissa l.; tran, vien d.; wilcox, bruce a. title: evidence for the convergence model: the emergence of highly pathogenic avian influenza (h5n1) in viet nam date: 2015-09-23 journal: plos one doi: 10.1371/journal.pone.0138138 sha: doc_id: 1781 cord_uid: afg1nmib building on a series of ground breaking reviews that first defined and drew attention to emerging infectious diseases (eid), the ‘convergence model’ was proposed to explain the multifactorial causality of disease emergence. the model broadly hypothesizes disease emergence is driven by the co-incidence of genetic, physical environmental, ecological, and social factors. we developed and tested a model of the emergence of highly pathogenic avian influenza (hpai) h5n1 based on suspected convergence factors that are mainly associated with land-use change. building on previous geospatial statistical studies that identified natural and human risk factors associated with urbanization, we added new factors to test whether causal mechanisms and pathogenic landscapes could be more specifically identified. our findings suggest that urbanization spatially combines risk factors to produce particular types of peri-urban landscapes with significantly higher hpai h5n1 emergence risk. the work highlights that peri-urban areas of viet nam have higher levels of chicken densities, duck and geese flock size diversities, and fraction of land under rice or aquaculture than rural and urban areas. we also found that land-use diversity, a surrogate measure for potential mixing of host populations and other factors that likely influence viral transmission, significantly improves the model’s predictability. similarly, landscapes where intensive and extensive forms of poultry production overlap were found at greater risk. these results support the convergence hypothesis in general and demonstrate the potential to improve eid prevention and control by combing geospatial monitoring of these factors along with pathogen surveillance programs. two decades after the institute of medicine's seminal report [1] recognized novel and reemerging diseases as a new category of microbial threats, the perpetual and unexpected nature of the emergence of infectious diseases remains a challenge in spite of significant clinical and biomedical research advances [2] . highly pathogenic avian influenza (hpai) (subtype h5n1) is the most significant newly emerging pandemic disease since hiv/aids. its eruption in southeast asia in 2003-4 and subsequent spread globally to more than 60 countries fits the complex systems definition of "surprise" [3] . in this same year that iom had published its final report on microbial threats which highlighted h5n1's successful containment in hong kong in 1997 [4] , massive outbreaks occurred in southeast asia where it remains endemic, along with egypt's nile delta. since 2003, hpai h5n1 has killed millions of poultry in countries throughout asia, europe, and africa, and 402 humans have died from it in sixteen countries according to who data as of january 2015. the threat of a pandemic resulting in millions of human cases worldwide remains a possibility [5] . lederberg et al. [1] first pointed to the multiplicity of factors driving disease emergence, which later were elaborated and described in terms of 'the convergence model' [6] . the model proposes emergence events are precipitated by the intensifying of biological, environmental, ecological, and socioeconomic drivers. microbial "adaptation and change," along with "changing ecosystems" and "economic development and land use" form major themes. joshua lederberg, the major intellectual force behind the studies summed-up saying "ecological instabilities arise from the ways we alter the physical and biological environment, the microbial and animal tenants (humans included) of these environments, and our interactions (including hygienic and therapeutic interventions) with the parasites" [6] . combining such disparate factors and associated concepts from biomedicine, ecology, and social sciences in a single framework remains elusive. one approach suggested has been to employ social-ecological systems theory that attempts to capture the behavior of so-called 'coupled natural-human systems', including the inevitable unexpected appearance of new diseases, themselves one of the "emerging properties" of complex adaptive systems (cas) [7, 8] . the convergence model can be so adapted by incorporating the dynamics of urban, agricultural, and natural ecosystem transformations proposed with this framework. these associated multifaceted interactions including feedbacks that affect ecological communities, hosts and pathogen populations, are the proximate drivers of disease emergence. the initial hpai h5n1 outbreaks in vietnam represent an ideal opportunity to adapt and test a cas-convergence model. emergence risk should be highest in the most rapidly transforming urban areas, peri-urban zones where mixes of urban-rural, modern-traditional land uses and poultry husbandry coincide most intensely. specifically we hypothesized a positive association between the presence of hpai outbreaks in poultry at the commune level and: 1) peri-urban areas, as defined by saksena et al. [9] , 2) land-use diversity, and 3) co-location of intensive and extensive systems of poultry. we used the presence or absence at the commune level of hpai h5n1 outbreaks in poultry as the dependent variable. vietnam experienced its first hpai h5n1 outbreak in late 2003, since then, there have been five waves and sporadic outbreaks recorded over the years [10, 11] . we chose to study the first wave (wave 1) that ended in february 2004 and the second wave (wave 2) that occurred between december 2004 and april 2005. we used data from the viet nam 2006 agricultural census to develop an urbanicity classification that used data collected at a single point in time (2006) but across space (10,820 communes) to infer processes of change (urbanization, land-use diversification, and poultry intensification) [9] . the 58 provinces in vietnam (not counting the 5 urban provinces that are governed centrally) are divided into rural districts, provincial towns, and provincial cities. rural districts are further divided into communes (rural areas) and towns, and provincial towns and cities are divided into wards (urban subdistricts) and communes. a commune in viet nam is thus the third level administrative subdivision, consisting of villages/hamlets. for the purpose of simplicity we will henceforth use the term "commune" to refer to the smallest administrative unit whether it is a commune, town, or ward. we included risk factors documented in previous work. we also aimed to understand the differences, if any, in risk dynamics at different scales; comparing risks at the national scale to those at two sub-national agro-ecological zones. for this purpose we chose to study the red river and mekong river deltas, well known hot spots of the disease. hence we conducted two sets of analyses (waves 1 and 2) for three places (nation, red river delta, and mekong delta) producing a total of 6 wave-place analyses. data on outbreaks were obtained from the publicly available database of viet nam's department of animal health. given the highly complex dynamics of the epidemics and in keeping with recent methodological trends, we used multiple modeling approaches-parametric and non-parametric-with a focus on spatial analysis. we used both 'place' oriented models that can take into account variations in factors such as policies and administration as well as 'space' oriented models that recognize the importance of physical proximity in natural phenomenon [12] . very few empirical studies have attempted to determine whether urbanization is related to eid outbreaks or whether urbanization is associated primarily with other factors related to eid outbreaks. one immediate problem researchers face is defining what is rural, urban, and transitional (i.e., peri-urban). some studies have used official administrative definitions of urban and rural areas, but this approach is limited in its bluntness [13] . other studies prioritized human population density as a satisfactory surrogate [11, [14] [15] [16] [17] [18] [19] [20] , but this approach ignores the important fact that density is not a risk factor if it is accompanied by sufficient infrastructure to handle the population. spencer [21] examined urbanization as a non-linear characteristic, using household-level variables such as water and sanitation services. he found evidence that increased diversity in water supply sources and sanitation infrastructure were associated with higher incidences of hpai. these studies employed a limited definition of urbanization that lacked a well-defined characterization of peri-urbanization. still other studies have mapped the relative urban nature of a place, a broad concept that is often referred to as 'urbanicity' [22] [23] [24] [25] . while these studies show differences in the rural/ urban nature of communities across space and time, they have been limited to small-to medium-scale observational studies; and they have failed to distinguish between different levels of "ruralness". perhaps the best known model of peri-urbanization is mcgee's concept of desakota (indonesian for "village-town") [26] . mcgee identified six characteristics of desakota regions: 1) a large population of smallholder cultivators; 2) an increase in non-agricultural activities; 3) extreme fluidity and mobility of population; 4) a mixture of land uses, agriculture, cottage industries, suburban development; 5) increased participation of the female labor force; and 6) "grey-zones", where informal and illegal activities group [26] . saksena et al. [9] built on mcgee's desakota concepts and data from the 2006 viet nam agricultural census to establish an urbanicity classification. that study identified and mapped the 10,820 communes, the smallest administrative unit for which data are collected, as being rural, peri-urban, urban, or urban core. this project used the saksena classification to assess associations between urbanicity classes, other risks factors, and hpai outbreaks. researchers have estimated that almost 75% of zoonotic diseases are associated with landcover and land-use changes (lcluc) [27, 28] . lcluc such as peri-urbanization and agricultural diversification frequently result in more diverse and fragmented landscapes (number of land covers or land uses per unit of land). the importance of landscape pattern, including diversity and associated processes, which equate to host species' habitat size and distribution, and thus pathogen transmission dynamics is axiomatic though the specific mechanisms depend on the disease [29, 30] . landscape fragmentation produces ecotones, defined as abrupt edges or transitions zones between different ecological systems, thought to facilitate disease emergence by increasing the intensity and frequency of contact between host species [31] furthermore, fragmentation of natural habitat tends to interrupt and degrade natural processes, including interspecies interactions that regulate densities of otherwise opportunistic species that may serve as competent hosts [32] , although it is not clear if reduced species diversity necessarily increases pathogen transmission [33] . rarely has research connected land-use diversification to final health endpoints in humans or livestock; this study attempts to link land-use diversity with hpai h5n1 outbreaks. human populations in the rapidly urbanizing cities of the developing world require access to vegetables, fruits, meat, etc. typically produced elsewhere. as theorized by von thünen in 1826 [34] , much of this demand is met by farms near cities [35] , many in areas undergoing processes of peri-urbanization [26] . due to the globalization of poultry trade, large-scale chicken farms raising thousands of birds have expanded rapidly in southeast asia and compete with existing small backyard farmers [36] . large, enterprise-scale (15,000-100,000 birds) operations are still rare in viet nam (only 33 communes have such a facility). on the other hand, domestic and multinational companies frequently contract farmers to raise between 2,000 and 15,000 birds. recent studies have examined the relative role of extensive (backyard) systems and intensive systems [15, [17] [18] [19] 37] . in much of asia there is often a mix of commercial and backyard farming at any one location [36] . experts have suggested that from a biosecurity perspective the co-location of extensive and intensive systems is a potential risk factor [38] . intensive systems allow for virus evolution (e.g. low pathogenic avian influenza to hpai) and transformation, while extensive systems allow for environmental persistence and circulation [39] . previous studies of chicken populations as a risk factor have distinguished between production systems-native chickens, backyard chickens; flock density; commercial chickens, broilers and layers density, etc. [15, [17] [18] [19] 37] . in isolation, however, none of these number and/or density based poultry metrics adequately measures the extent of co-location of intensive and extensive systems in any given place. intensive and extensive systems in viet nam have their own fairly well defined flock sizes. a diversity index of the relative number of intensive and extensive systems of poultry-raising can better estimate the effect of such co-location; this study attempts to link a livestock diversity index with the presence or absence of hpai h5n1 outbreaks at the commune level. this study investigated for the 10,820 communes of viet nam a wide suite of socio-economic, agricultural, climatic and ecological variables relevant to poultry management and the transmission and persistence of the hpai virus. many of these variables were identified based on earlier studies of hpai (as reviewed in gilbert and pfeiffer [40] ). three novel variables were included based on hypotheses generated by this project. all variables were measured or aggregated to the commune level. the novel variables were: • degree of urbanization: we used the urbanicity classification developed by saksena et al. [9] to define the urban character of each commune. the classification framework is based on four characteristics: 1) percentage of households whose main income is from agriculture, aquaculture and forestry, 2) percentage of households with modern forms of toilets, 3) percentage of land under agriculture, aquaculture and forestry and 4) the normalized differentiated vegetation index (ndvi). the three-way classification enabled testing for non-linear and non-monotonous responses. • land-use diversity: we measured land-use diversity using the gini-simpson diversity index [41] . the gini-simpson diversity index is given by 1-λ, where λ equals the probability that two entities taken at random from the dataset of interest represent the same type. in situations with only one class (complete homogeneity) the gini-simpson index would have a value equal to zero. such diversity indices have been used to measure land-use diversity [42] . we used the following five land-use classes: annual crops, perennial crops, forests, aquaculture and built-up land (including miscellaneous uses) for which data were collected in the 2006 agricultural census. the area under the last class was calculated as the difference between the total area and the sum of the first four classes. the following variables are listed according to their role in disease introduction, transmission and persistence, though some of these factors may have multiple roles. • human population related transmission. human population density [11, 14-16, 18, 19, 44, 45] . • poultry trade and market. towns and cities were assumed to be active trading places [10, 18, 37, 44, 46] . so, the distance to the nearest town/city was used as indicator of poultry trade. trade is facilitated by access to transportation infrastructure [37, 47, 48] . so, the distance to the nearest a) national highway and b) provincial highway was used as indicator of transportation infrastructure. • disease introduction and amplification. the densities of chicken were calculated based on commune area [15, 19, 37, 49] . • intermediate hosts. duck and geese densities were calculated using total commune area [11, 19, 49] . as previous studies have shown a link between scavenging in rice fields by ducks and outbreaks, we also calculated duck density using only the area under rice. • agro-ecological and environmental risk factors. previous studies have shown that the extent of rice cultivation is a risk factor, mainly due its association with free ranging ducks acting as scavengers [10] . we used percentage of land under rice cultivation as a measure of extent. rice cropping intensity is also a known risk factor [11, 17, 37] . we used the mean number of rice crops per year as a measure of intensity. the extent of aquaculture is a known risk factor [10] , possibly because water bodies offer routes for transmission and persistence of the virus. the percentage of land under aquaculture was used as a metric. proximity to water bodies increases the risk of outbreaks [47, [50] [51] [52] , possibly by increasing the chance of contact between wild water birds and domestic poultry. we measured the distance between the commune and the nearest: a) lake and b) river. climatic variables-annual mean temperature and annual precipitation-have been associated with significant changes in risk [48, 53] . elevation, which is associated with types of land cover and agriculture, has been shown to be a significant risk factor in vietnam [10] . compound topographical index (cti, also known as topographical wetness index) is a measure of the tendency for water to pool. studies in thailand and elsewhere [54] have shown that the extent of surface water is a strong risk factor, possibly due to the role of water in long-range transmission and persistence of the virus. in the absence of reliable and inexpensive data on the extent of surface water we used cti as a proxy. cti has been used in ecological niche models (enm) of hpai h5n1 [55, 56] . however, given the nature of enm studies, the effect of cti as a risk factor has been unknown so far. cti has been used as a risk factor in the study of other infectious and non-infectious diseases [57] . some studies have shown that at local scales, the slope of the terrain (a component of cti) was significantly correlated with reservoir species dominance [58] . cti is a function of both the slope and the upstream contributing area per unit width orthogonal to the flow direction. cti is computed as follows: cti = ln (a s / (tan (β)) where; a s = area value calculated as ((flow accumulation + 1) ã (pixel area in m 2 )) and β is the slope expressed in radians [59] . though previous studies have indicated that normalized difference vegetation index (ndvi) is a risk factor [10, 20, 55, 60, 61], we did not include it explicitly in our models, as the urban classification index we used included ndvi [9] . we obtained commune level data on hpai h5n1 outbreaks from the publicly available database of the department of animal health [10] . viet nam experienced its first major epidemic waves between december 2003 and february 2006 [10] . we chose to study the first wave (wave 1) that ended in february 2004 and the second wave (wave 2) that occurred between december 2004 and april 2005. in wave 1, 21% of the communes and in wave 2, 6% of the communes experienced outbreaks. we used data from the 1999 population census of viet nam to estimate human population per commune. we relied on data from two agriculture censuses of viet nam. this survey is conducted every five years covering all rural households and those peri-urban households that own farms. thus about three-fourths of all of the country's households are included. the contents of the survey include number of households in major production activities, population, labor classified by sex, age, qualification, employment and major income source; agriculture, forestry and aquaculture land used by households classified by source, type, cultivation area for by crop type; and farming equipment by purpose. commune level surveys include information on rural infrastructure, namely electricity, transportation, medical stations, schools; fresh water source, communication, markets, etc. detailed economic data are collected for large farms. we used the 2006 agriculture census for most variables because the first three epidemic waves occurred between the agricultural censuses of 2001 and 2006 but were closer in time to the 2006 census [10] . however, for data on poultry numbers we used the 2001 agriculture census data set because between 1991 and 2003 the poultry population grew at an average rate of 7% annually. however, in 2004, after the first wave of the h5n1 epidemic, the poultry population fell 15%. only by mid-2008 did the poultry population return close to pre-epidemic levels. thus, we considered the poultry population data from the 2001 census to be more representative. we aggregated census household data to the commune level. a three-way classification of the rural-to-urban transition was based on a related study [9] . raster data on annual mean temperature and precipitation were obtained from the world-clim database and converted to commune level data. the bioclimatic variables were compiled from the monthly temperature and precipitation values and interpolated to surfaces at 90m spatial resolution [62] . this public database provides data on the average climatic conditions of the period 1950-2000. elevation was generated from srtm 90 meter digital elevation models (dem) acquired from the consortium for spatial information (cgiar-csi). compound topographical index (cti) data were generated using the geomorphometry and gradient metrics toolbox for arc-gis 10.1. prior to risk factor analysis we cleaned the data by identifying illogical values for all variables and then either assigning a missing value to them or adjusting the values. illogical values occurred mainly (less than 1% of the cases) for land-related variables such as percentage of commune land under a particular type of land use. next we tested each variable for normality using the bestfit software (palisade corporation). most of the variables were found to follow a log-normal distribution and a log-transform was used on them. we then examined the bi-variate correlations between all the risk factors (or their log-transform, as the case may be). correlations were analyzed separately for each place. certain risk factors were then eliminated from consideration when |r| ! 0.5 (r is the pearson correlation coefficient). when two risk factors were highly correlated, we chose to include the one which had not been adequately studied explicitly in previously published risk models. notably, we excluded a) elevation (correlated with human population density, chicken density, duck density, percentage land under paddy, annual temperature and compound topographical index), b) human population density (correlated with elevation and cti), c) chicken density (only at national level, correlated with cti), d) duck and goose density (correlated with elevation, chicken density, percentage land under paddy, land use diversity index and cti), e) annual temperature (correlated with elevation and cti) and f) cropping intensity (correlated with percentage land under paddy). considering the importance of spatial autocorrelation in such epidemics, we used two modeling approaches: 1) multi-level generalized linear mixed model (glmm) and 2) boosted regression trees (brt) [63, 64] with an autoregressive term [65] . glmm is a 'place' oriented approach that is well suited to analyzing the effect of administrative groupings, while brt is a 'space' oriented approach that accounts for the effects of physical proximity. we began by deriving an autoregressive term by averaging the presence/absence among a set of neighbors defined by the limit of autocorrelation, weighted by the inverse of the euclidean distance [65] . the limit of the autocorrelation of the response variable was obtained from the range of the spatial correlogram ρ (h) [66] . to determine which predictor variables to include in the two models, we conducted logistic regression modeling separately for each of them one by one but included the autoregressive term each time. we finally included only those variables whose coefficient had a significance value p 0.2 (in at least one wave-place combination) and we noted the sign of the coefficient. this choice of p value for screening risk factors is common in similar studies [15, 18, 45, 67] . we used a two-level glmm (communes nested under districts) to take account of random effects for an area influenced by its neighbors, and thus, we studied the effect of spatial autocorrelation. we used robust standard errors for tests of fixed effects. boosted regression trees, also known as stochastic gradient boosting, was performed to predict the probability of hpai h5n1 occurrence and determine the relative influence of each risk factor to the hpai h5n1 occurrence. this method was developed recently and applied widely for distribution prediction in various fields of ecology [63, 64] . it is widely used for species distribution modeling where only the sites of occurrence of the species are known [68] . the method has been applied in numerous studies for predicting the distribution of hpai h5n1 disease [16, 51, [69] [70] [71] . brt utilizes regression trees and boosting algorithms to fit several models and combines them for improving prediction by performing iterative loop throughout the model [63, 64] . the advantage of brt is that it applies stochastic processes that include probabilistic components to improve predictive performance. we used regression trees to select relevant predictor variables and boosting to improve accuracy in a single tree. the sequential process allows trees to be fitted iteratively through a forward stage-wise procedure in the boosting model. two important parameters specified in the brt model are learning rate (lr) and tree complexity (tc) to determine the number of trees for optimal prediction [63, 64] . in our model we used 10 sets of training and test points for cross-validation, a tree complexity of 5, a learning rate of 0.01, and a bag fraction of 0.5. other advantages of brt include its insensitivity to co-linearity and non-linear responses. however, for the sake of consistency with the glmm method, we chose to eliminate predictors that were highly correlated with other predictors and to make log-transforms where needed. in the glmm models we used p 0.05 to identify significant risk factors. the predictive performances of the models were assessed by the area under the curve (auc) of the receiver operation characteristic (roc) curve. auc is a measure of the overall fit of the model that varies from 0.5 (chance event) to 1.0 (perfect fit) [72] . a comparison of auc with other accuracy metrics concluded that it is the most robust measure of model performance because it remained constant over a wide range of prevalence rates [73] . we used the corrected akaike information criteria (aicc) to compare each glmm model with and without its respective suite of fixed predictors. we used spss version 21 (ibm corp., new york, 2012) for glmm and r version 3.1.0 (the r foundation for statistical computing, 2014) for the brt. for calculating the spatial correlogram we used the spdep package of r. the fourteen predictor variables we modeled (see tables) were all found to be significantly associated with hpai h5n1 outbreaks (p 0.2) in at least one wave-place combination based on univariate analysis (but including the autoregressive term) ( table 1) . land-use diversity, chicken density, poultry flock size diversity and distance to national highway were found to have significant associations across five of the six wave-place combinations. power of the glmm models, as measured by the auc, is very good with auc values ranging from 0.802 to 0.952 (tables 2-7 ). the predictive power of the national models was higher than that of the delta models. the predictive power of the brt models is good, with aucs ranging from 0.737 to 0.914. the brt models also had a better predictive power at the national level than at the delta level. these values are higher than those reported for wave 1 (auc = 0.69) and wave 2 (auc = 0.77) by gilbert et al. [11] . both gilbert et al. [11] and this study found that at the national level the predictive performance for wave 2 was higher than that for wave 1. wave 2 mainly affected the mekong river delta. previous studies indicated the duck density was an important predictor [11] ; our results, however, indicated that the diversity of duck flock size was a more important predictor than duck density. both the glmm and brt models found annual precipitation to be a significant factor. the glmm model indicated a negative association; similar to what was found by studies in china [51] and in the red river delta [53] . a global study of human cases also found occurrence to be higher under drier conditions [74] . generally, the role of precipitation was found to be far more significant in the deltas than for the country as a whole. the unadjusted relative risk (rr) of peri-urban areas in comparison with non-peri-urban areas was 1.41 and 1.60 for waves 1 and 2, respectively. in terms of urbanicity, we found that chicken density, percentage of land under rice, percentage of land under aquaculture, flock size diversity for duck and geese, and the compound topographical index (cti) to be highest in peri-urban areas (fig 1a-1e) . we also found that land-use diversity was higher in rural areas, but peri-urban areas had diversity levels only marginally lower (fig 1f) . the urbanicity variable alone, however, was not found to be significantly associated with hpai h5n1 in any place according to the glmm model except for the urban level in red river delta for wave 2 and in the mekong river delta for wave 1. the brt model ranked urbanicity as one of the least influential variables. land-use diversity was found to be significantly associated with hpai h5n1 in both waves for viet nam according to the glmm model, but at the delta level the association was significant only for wave 2 in the mekong river delta. the brt model indicated that land-use diversity highly influenced hpai h5n1 at the national level in wave 2. for the remaining waveplace combinations land-use diversity had middle to below-middle rank of influence. both the glmm and brt models indicated that the diversity of chicken flock-size had a strong association with hpai h5n1 for both waves at the national level. this was generally found to be true at the delta levels with some exceptions. the diversity of duck and goose flock size was also significantly associated with hpai h5n1 in all places, but the associations were much stronger in wave 2 than in wave 1. the glmm model indicated that the cti had a very strong association with hpai h5n1 at the national level in both waves although this was not true in the two deltas. the cti is a steady state wetness index commonly used to quantify topographic control on hydrological processes. accumulation numbers in flat areas, like deltas, are very large; hence the cti was not a relevant variable in the glmm model in these areas. the brt model however indicated that cti had middle to low influence in all waves and places. we found very high spatial clustering effects as indicated by the fact that in all waves and places the brt model found the spatial autocorrelation term to have the highest rank of influence. as expected, the relative influence of the autocorrelation term at the national level was higher (60-78%) than at the delta levels (14-35%). in the glmm models we found the akaike information criterion (aic) using the entire set of 14 variables to be much lower than the aics of a glmm model without fixed effects. this indicated that though clustering effects were significant, our theory driven predictor variables improved model performance. a limitation of using surveillance methods for the dependent variable (poultry outbreaks) is that the data may have reporting/detection biases [11] . under-reporting/detection in rural areas as compared to peri-urban areas is possible. we believe that the urbanicity and the shortest distance to nearest town risk factors serve as rough proxies for reporting/detection efficiency. previous studies have tended to use human population density as a proxy for this purpose. in our study we found a strong association between human population density and urbanicity. but we acknowledge that a categorical variable such as urbanicity may provide less sensitivity than a continuous variable such as human population density in this specific context. this study explored the validity of a general model for disease emergence that combined the iom 'convergence model' [6] and the social-ecological systems model [7, 8] , for investigating the specific case of hpai in vietnam. we sought to test the hypotheses that measures of urbanization, land-use diversification, and poultry intensification are correlated with outbreaks in poultry. our results generally support the hypothesis that social-ecological system transformations are associated with h5ni outbreaks in poultry. the results presented here highlight three main findings: 1) when relevant risk factors are taken into account, urbanization is generally not a significant independent risk factor; but in peri-urban landscapes emergence factors converge, including higher levels of chicken densities, duck and geese flock size diversities, and fraction of land under rice or aquaculture; 2) high land-use diversity landscapes, a variable not previously considered in spatial studies of hpai h5n1, are at significantly greater risk for hpai h5n1 outbreaks; as are 3) landscapes where intensive and extensive forms of poultry production are co-located. only one other study has explicitly examined urbanicity in the context of hpai h5n1. loth et al. [17] found peri-urban areas in indonesia were significantly associated with hpai h5n1 cases, even based on multivariate models. our study, however, attempted both to associate hpai h5n1 with degree of urbanicity and to determine the features of peri-urban areas that place them at risk. when those features (i.e., chicken densities, duck and geese flock size diversities, and the fraction of land under rice or aquaculture) are included in multivariate models, the role of the urbanization variable per se diminishes. we found in the main river deltas in viet nam (red river and mekong), urbanization had no significant association with hpai h5n1. this may be due to the fact that the deltas are more homogenous, in terms of urbanization, than the country as a whole. this is the first study to examine land-use diversity as a risk factor for hpai h5n1. measured by the gini-simpson diversity index of the five land-use classes on which data were collected in the 2006 viet nam agricultural census, and the presence or absence of hpai outbreaks at the commune level, our results indicate a strong association between land-use diversity and hpai h5n1 at the national level and in the mekong river delta. this metric captures both the variety of habitats and of the complexity of geospatial patterning likely associated with transmission intensity. our results are similar to what has been observed by studies of other eids using fragmentation metrics (e.g. [75] [76] [77] . this is one of the few studies, however, to link landscape fragmentation to an eid disease in poultry and not just to the vector and/or hosts of the eid. previous studies have focused on poultry production factors such as type of species, size of flocks, and extent of commercialization (e.g. [15, [17] [18] [19] . this study expands on those findings by providing evidence that when intensive and extensive systems of chicken and/or duck and geese production co-exist in the same commune, the commune experiences higher risk of disease outbreak. future studies need to examine the biological causal mechanisms in this context. we suggest that national census data (particularly agricultural censuses) compiled at local levels of administration provide valuable information that are not available from remotely sensed data (such as poultry densities) or require a large amount of labor to map at national to larger scales (land-use diversity). mapping land-use classes at the national scale for local administrative units (i.e., the 10,820 communes in viet nam) is not an insignificant task. future studies, however, could examine the correlation between a census-based metric with metrics derived from remote sensing used to measure proportional abundance of each landcover type within a landscape [78] . vietnam is relatively advanced in making digital national population and agricultural census data available in a format that can be linked to administrative boundaries. while other nations are beginning to develop similar capacities, in the short term the application of this method to other countries may be limited. ultimately, both census and remotely sensed data can be used independently to map the urban transition and diversity of land use; these tools, however, may provide their greatest insights when used together. another important contribution of this study was the discovery of the importance of cti. so far cti had been used only in ecological niche modeling studies of hpai h5n1; the specific role and direction of influence of cti had has so far been unknown. our study, the first to use cti as a risk factor, found it had a large positive influence on hpai h5n1 risk at the national level. previous studies have highlighted the role of surface water extent in the persistence and transmission of the hpai h5n1 virus. these studies measured surface water extent as area covered by water, magnitude of seasonal flooding, distance to the nearest body of water, or other variables that are often difficult to map using remotely sensed data, especially for large area studies. cti on the other hand has the potential to serve as an excellent surrogate which can easily be measured in a gis database. the national and regional (delta) models differed quite considerably, both in terms of performance and significant risk factors. in the deltas we commonly found only chicken density, duck flock size diversity and annual precipitation to be significant. this suggests dynamics of risk at the commune level are strongly dependent on the spatial range of analysis, consistent with another study in the mekong delta [61] . though that study's model initially included three dozen commonly known risk factors, the significant risk factors were limited to poultry flock density, proportion households with electricity, re-scaled ndvi median may-october, buffalo density and sweet potato yield. another study in the red river delta [79] found that in addition to the typical poultry density metrics, only the presence of poultry traders was significant. we speculate that for smaller regions, especially for known hot-spots, the relevant risk factors are those that reflect short-range, short-term driving forces such as poultry trading, presence of live bird markets and wet markets etc. improving model performance for smaller regions would require highly refined and nuanced metrics for poultry trading, road infrastructure, water bodies, etc.-data that are typically not available through census surveys. the differences between the national and regional models suggest that our results can inform planners making decisions at different hierarchical levels of jurisdiction: national, region and local. our study has the potential to inform the design of future research related to the epidemiology of other eids in viet nam and elsewhere. for example, we speculate that in southeast asia, japanese encephalitis, the transmission of which is associated with rice cultivation and flood irrigation [80] , may also show a strong association with peri-urbanization. in some areas of asia these ecological conditions occur near, or occasionally within, urban centers. likewise, hantaan virus, the cause of korean hemorrhagic fever, is associated with the field mouse apodemus agrarius and rice harvesting in fields where the rodents are present [80] . our work has demonstrated that the percentage of land under rice in peri-urban areas and rural areas is similar. hence diseases associated with rice production are likely to peak in peri-urban areas given other risk factors such as land-use diversity, cti, and distance to infrastructure. our poultry flock-size diversity findings may also be relevant to understanding the dynamics of other poultry related infections such as newcastle disease. finally, these results suggest the validity of a general model of zoonotic disease emergence that integrates iom's convergence model with the subsequently proposed social-ecological systems and eid framework. 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on the accuracy of distribution models: ecological phenomenon or statistical artefact? seasonal patterns in human a (h5n1) virus infection: analysis of global cases integrated mapping of establishment risk for emerging vector-borne infections: a case study of canine leishmaniasis in southwest france fragmentation analysis for prediction of suitable habitat for vectors: example of riverine tsetse flies in burkina faso the impact of habitat fragmentation on tsetse abundance on the plateau of eastern zambia spatial pattern analysis program for quantifying landscape structure risk factors of highly pathogenic avian influenza h5n1 occurrence at the village and farm levels in the red river delta region in vietnam factors in the emergence of infectious diseases we thank nargis sultana, university of hawaii, manoa for assistance with compiling a gis database. we thank the following for giving us advice and suggestions on the statistical model key: cord-004091-gex0zvoa authors: abdulkareem, shaheen a.; augustijn, ellen-wien; filatova, tatiana; musial, katarzyna; mustafa, yaseen t. title: risk perception and behavioral change during epidemics: comparing models of individual and collective learning date: 2020-01-06 journal: plos one doi: 10.1371/journal.pone.0226483 sha: doc_id: 4091 cord_uid: gex0zvoa modern societies are exposed to a myriad of risks ranging from disease to natural hazards and technological disruptions. exploring how the awareness of risk spreads and how it triggers a diffusion of coping strategies is prominent in the research agenda of various domains. it requires a deep understanding of how individuals perceive risks and communicate about the effectiveness of protective measures, highlighting learning and social interaction as the core mechanisms driving such processes. methodological approaches that range from purely physics-based diffusion models to data-driven environmental methods rely on agent-based modeling to accommodate context-dependent learning and social interactions in a diffusion process. mixing agent-based modeling with data-driven machine learning has become popularity. however, little attention has been paid to the role of intelligent learning in risk appraisal and protective decisions, whether used in an individual or a collective process. the differences between collective learning and individual learning have not been sufficiently explored in diffusion modeling in general and in agent-based models of socio-environmental systems in particular. to address this research gap, we explored the implications of intelligent learning on the gradient from individual to collective learning, using an agent-based model enhanced by machine learning. our simulation experiments showed that individual intelligent judgement about risks and the selection of coping strategies by groups with majority votes were outperformed by leader-based groups and even individuals deciding alone. social interactions appeared essential for both individual learning and group learning. the choice of how to represent social learning in an agent-based model could be driven by existing cultural and social norms prevalent in a modeled society. a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 when facing risks, people go through a complex process of collecting information, deciding what to do, and communicating with others about the effectiveness of their actions. social influence may interfere with personal experiences, making peer groups and group interactions important factors. this is especially important in understanding disease diffusion and the emergence of epidemics, as these phenomena annually take thousands of lives worldwide [1] . hence, good responsive and preventive strategies at both the individual and government levels are vital for saving lives. a choice of strategy depends on behavioral aspects, complex interactions among people [2] , and the information available about a disease [3] . perceiving the risk of an infectious disease may trigger behavioral change, as during the 2003 sars epidemic [4] . gathering information and experience through multiple sources is essential for increasing disease risk awareness about the disease and taking protective measures [5] . to help prevent epidemics, we need advanced tools that identify the factors that help spread of information about life-threatening diseases and that change individual behavior to curbs the diffusion of disease. various scientific approaches have been developed to tackle this challenge. network science is prominent in studying how epidemics propagate and how different awareness mechanisms can help to prevent the outbreak of disease. some researchers propose a framework with different mechanisms for spreading awareness about a disease as an additional contagion process [6] . others model populations as multiplex networks where the disease spreads over one layer and awareness spreads over another [7] . the influence of the perception of risk on the probability of infection also has been studied [8] . several recent studies have shown how information spreads in complex networks [9, 10] . however, a different approach is needed to account for individual heterogeneity (such as income and education levels), the richness of the information on social and spatial distance or media influence. here, a combination of modeling with data-driven machine learning becomes particularly attractive. simulation tools are commonly used to assess the effects of policy impacts in the health domain [3, 11, 12] . among the models for policy-making, agent-based modeling (abm) is recommended as the most promising modeling approach [13] . abm studies the dynamics of complex systems by simulating an array of heterogeneous individuals that make decisions, interact with each other, and learn from their experiences and the environment. the method is widely used to analyze epidemics [14] [15] [16] [17] . its advantage is in analyzing the factors that influence the spread of infectious diseases and the actions of individual actors [18] . as a bottom-up method, abm integrates micro-macro relationships while accommodating agents' heterogeneity and their adaptive behavior. it ensures that the interaction between the spatial environment and the behavior agents can integrate a variety of data inputs including aggregated, disaggregated and qualitative data [19] [20] [21] [22] . two processes are essential in representing agents' health behavior and disease dynamics, the evolution of risk perception, and selection of a coping strategy. hence, the core of a disease abm lies in defining the learning methods that steer these two processes. sensing of information (global, from the environment, and social, i.e., from other agents), exchanging information (i.e., interactions between agents), and processing of information (i.e., decision making) are critical. machine learning (ml) techniques can support these three elements and offer a more realistic way to adjust agents' behavior in abm [23] [24] [25] [26] . as more data become available in the analysis of the spread of disease, supporting abm with data-driven approaches becomes a prominent research direction. ml has the potential to enhance abm performance, especially when the number of agents is large (e.g., pandemics) and the decision-making process is complex (e.g., depending on both past experience and new information from the environment and peers). ml approaches in abm can provide agents with the ability to learn by adapting their decision-making process in line with new information. people make decisions both as individuals and as members of a group who imitate the decisions taken by the group or its leader [27] . information about social networks is becoming increasingly available, e.g., through social media analysis. it may reveal collective behavior in various domains, including health [28] . for example, people are not entirely rational and imitate others in their views about vaccines [29] . many abms rely solely on the decisions of individuals, paying little attention to group behavior [30] . yet, mirroring emotions, beliefs, and intentions in an abm with the collective decision making of crowds affects social contagion in abms [31] . agents-individuals and groups-may learn in isolation or through interactions with others, such as their neighbors [32] . in isolated learning, agents learn independently, requiring no interaction with other agents. in interactive learning, several agents are engaged in sensing and processing information and communicating and cooperating to learn effectively. interactive learning can be done in multiple ways, i.e., based on different social learning strategies [33] . agents might be represented as members of local groups, learning together and mimicking behavior from other group members (i.e., collective learning) [34] . yet, the impact of different types of interactive learning in groups compared to learning by an individual is an under-explored domain in the development of abms of socio-environmental systems. this article examines the influence of individual vs group learning on a decision-making process in abms enhanced with ml. to illustrate the implications of individual and collective intelligence in abms, we used a spatially explicit disease model of cholera diffusion [35] as a case study. bayesian networks (bns) steer agents' behavior when judging on risk perception (rp) and coping appraisal (ca). we quantitatively tested the influence of agents' ability to learn-individually or in a group-on the dynamics of disease. the main goal is, therefore, methodological: to introduce ml into a spatial abm with a focus on comparing individual learning to collective learning. the added value of the analysis of alternative implementations of learning in abms goes beyond the domain of disease modeling. it illustrates the effects of individuals learning and collective learning on the field of abms of socio-environmental systems as a whole. therefore, our main objectives are to (1) simulate the learning processes of agents on a gradient of learning from individual to collective, and (2) understand how these learning processes reveal the dynamics of social interactions and their emergent features during an epidemic. to address these objectives, the article aims to answer the following research questions: (rq1) what is the impact of social interactions on the perceptions and decisions of intelligent individuals facing a risk? (rq2) how do different implementations of group learning-deciding by majority voting vs by leaders-impact the diffusion process? (rq3) what are the implications of implementing collective learning for risk assessment combined with individual coping strategies? by answering these methodological questions for our case study, we reveal whether individuals perform better than groups at perceiving risks and at coping during epidemics. to explore the implications of intelligent learning on the gradient from individual to collective, we advance the existing cholera abm (cabm) originally developed to study cholera diffusion [35] . in cabm, mls steer agents' behavior [23, 35, 36] , helping them to adjust risk perception and coping during an epidemic outbreak. for this study, we ran eight abms to test various combinations of individual and group learning, using different information sources-with or without interactions among agents-as factors in the bns. we investigate the extent to which the epidemic spreads, depending on these different learning approaches regarding risk perception and coping decisions. s1 appendix provides a technical description of the model and the mls. below we briefly outline the processes in cabm essential to understand the performed simulation experiments. nowadays, 69 countries worldwide are labeled as cholera-endemic, with 2.8 million cases each year leading to 91,000 deaths [37] . people in urban slums and refugee camps are at high risk of cholera because of limited or no access to clean water and adequate sanitation. cabm is an empirically and theoretically grounded model developed to study the 2005 cholera outbreak in kumasi, ghana [35] . the open-source code for the model code is available online. cabm is grounded in the protection motivation theory (pmt) in psychology [23, 38] . the empirically-driven bns model a two-stage decision process of people facing a disease risk: learning to update risk perceptions (threat appraisal, bn1 in fig 1) and making decisions about how to adapt their behavior during the epidemic (coping appraisal, bn2 in fig 1) . according to pmt, threat appraisal depends on individual perceptions of the severity of the disease (evaluating the state of the environment and observing what happens to others) and one's own susceptibility. the coping appraisal is driven by the perceived response efficacy (the belief that the recommended behavior will protect) and one's own self-efficacy (the ability to perform the recommended behavior). cabm simulates individuals who are spatially located in a city. these agents differ by income and education level. individual agents form households and neighborhood groups and are susceptible to cholera at the beginning of the simulation. cabm implements an adjusted seir model [39] as explained in fig 2 below . instead of going directly from susceptible to exposure, we introduced an awareness component in which agents can assess their risk. options included: no risk perception in which the agent will be exposed (arrow 1, fig 2) ; no risk perception yet no exposure (arrow 2, fig 2) ; and risk perception leading agents to the coping phase (arrow 3, fig 2) . exposure to cholera takes place through the use of unsafe river water. agents can influence their exposure by selecting alternative water sources. these alternative water sources can either reduce their exposure to zero (arrow 5, fig 2) or have no effect on their infection risk (arrow 4, fig 2) . their actions are contingent on income and education levels, as well as on the information that they retrieve from their own experience, information received from others, or observations of the environment. it is not possible to judge by sight whether surface water is infected with cholera, but the agents use other types of visual pollution, e.g., floating garbage, as a proxy. when household agents find the visual pollution level too high, they may decide on an alternative. household agents with high incomes do not take a risk and will buy safe water. in cabm, the risk perception was updated using bn1, which depends on the agent memory (me), the visual pollution at the water fetching point (vp), and the evidence of the severity of the epidemic based on communication from the media (m) and potentially with neighbor households (cnh). media broadcast news about cholera starting on day 21 onward (see: ghana news archive). during a simulation, household agents may also interact with their neighbors zero to seven times a day (applied randomly) [40] . when interactive learning was activated, social interactions among household agents helped to share information on cholera cases that occurred in their communities and on the effectiveness of coping decisions. if risk perception was positive (bn1 returns a value above 0.5), household agents activate bn2 to decide which action (d1 -d4, fig 1) to take given their income (i) and education (e) level, the experience of their own household with cholera (oe), and possibly their neighbors' experiences with cholera (ne) [22] . s1 appendix provides further details on how the bns are implemented, together with tables of the parameters. sensitivity analysis of the aggregated model dynamics on the bns inputs and training alternatives can be found in [23, 36] . a feeling of risk among individuals is fueled by the type of information, the amount of information communicated, and the attention to specific information that may trigger fear and stimulate a learning process regarding a new response strategy [41] . gained information helps individuals (i) to estimate the severity of the emerging event, (ii) to assess the probability of being exposed to infection, and (iii) to evaluate the efficiency of their coping responses. we used a complex network approach to illustrate the gradual processes from individual to collective learning in cabm (fig 3) . each stage is presented as a single network over which a given learning process spreads. each network in fig 3 had the same set of nodes and connections to show how different processes can lead to different outcomes in the same network structure when different information is used to make decisions. in individual learning (fig 3, process 1a and process 1b), agents depend on their prior knowledge (memory, experience, and/or the perceived risk of the environment, such as visual pollution). such learning is the process of gaining skills or knowledge, which an agent pursues individually to support a task [42] . group learning is the process of acquiring new skills or knowledge that is undertaken collectively in a group of several individual agents and driven by a common goal [32] . group learning can be realized by making all group members use their own ml algorithms to gather information to perform a specific sub-task (decentralized), and then pool their opinions collectively by making one decision for the entire group (fig 3, process 2a and process 2b). here, we adopt a "majority vote" as the resolution mechanism in the decentralized group decision-making. however, group learning can also be realized by introducing a single agent (leader) who uses ml to learn for the whole group to help it accomplish its group task (centralized). in the centralized group learning, agents in the group copy the decisions of their leader. in both cases, all agents that belong to a group share the same decision, but the information on which this decision is based on varies considerably (fig 3, process 3a and process 3b). both individuals and groups may learn by either by taking information from their social networks (i.e., have it as an additional source of information in their ml algorithms) or not. when individual agents are isolated learners (fig 3, process 1a) , they do not have a social network but use only their own information to make a decision in an isolated environment using the information they possess. when individuals learn in an interactively (fig 3, process 1b) , https://doi.org/10.1371/journal.pone.0226483.g003 they gain new skills or knowledge by perceiving information, experience, and the performance of other agents through their social network. like individual agents, groups can also learn in isolation or interactively. in isolated learning, agents learn independently within their groups, without exchanging any information with each other or with their neighbors (fig 3, process 2a and process 3a). in interactive learning, agents communicate with their neighbors to learn effectively within their groups (fig 3 process 2b and process 3b). neighbors could be members of the same group or belong to other income/education groups but live in the same community and share the water collection points. therefore, there might be communication across the groups (fig 3, process 2b and process 3b). groups can be defined in different ways and at different hierarchical levels. this model uses three levels of an organization, the individual agent, groups of agents and communities that comprise several groups. in cabm, household agents living in the same community are grouped based on their income and education level since their coping behavior depends on these factors. agents' behavior in the disease abm also is contingent on their geographic location. hence, all neighbors that share the same water fetching point may contact and exchange information between their groups in cabm. the size and compilation of the groups impact the results of the different learning strategies. when applying interactive learning, a group's decision can be influenced by information retrieved from neighbors inside the group and neighbors outside the group but inside the community. for interactive groups, process 2b (fig 3) shows a situation in which individual household agents make decisions that account for interactions in their social networks (as in process 1b). then each household conducts a majority vote, allowing it to proceed with the option chosen by the majority of its members. process 3b (fig 3) shows a situation in which the leaders of each group make decisions based on their interactions with others (nodes a, b, and c are leaders of groups g1, g2, and g3 respectively in fig 3) . the decisions of group leaders are adopted by the household agent of the group. we designed eight simulation scenarios to answer the research questions about the influence of isolated vs interactive individual learning (rq1); centralized vs decentralized learning in processes-during both the risk perception (rp, bn1) and coping appraisal (ca, bn2) processes (rq2); and collective learning about risk perception combined with individual coping appraisal (rq3) on the dynamics of the epidemic and the performance of the model (table 1) . we systematically vary cabm settings following the steps in fig 4 to change the gradient of intelligent learning (steps 2 and 3) in different cognitive stages corresponding to our decisions of interest: risk and coping appraisal (step 1). table 1 shows the setup of the eight scenarios that reflects the three stages shown in fig 4. the area of the case study captured in cabm is 19.2 km 2 and comprises of 21 communities. we assumed that high-income households bought water, so they were excluded from intelligent learning. communities can have up to four groups based on their income and education levels. ten to fifteen percent of the household agents in the case study area usually fetch water from the river. two communities in our dataset (#11 and #20) hosted only high-income households, so they were excluded from the intelligent learning. hence, we simulated 76 groups spread over 19 communities. each simulation was run for 90 days with a time step equal to one hour. given the inherent randomness of abms, we ran each model for 100 times, generating a new synthetic population every 10 runs. besides the extensive gis data and aggregated data on disease dynamics, we ran a survey via a massive open online course (mooc) geohealth in two rounds (2016 and 2017) to gain data on individual behavior. the participants-primarily students from developing countrieswere introduced to the problem of cholera disease, saw pictures of water, and were asked if they would use the water as it is (d1 in fig 1) , walk to a cleaner water point (d2), or use the water after boiling it (d3). the survey data were used to construct and train our bns [36] . we also used these data to evaluate the results of expert-driven bns in cabm [43] . table 2 shows that trust in boiled water was much higher than trust in un-boiled water. agents also changed their behavior and began boiling water in the model. to evaluate the impact of individual and social intelligence on agents' learning processes regarding risk perception and coping appraisal and the resulting patterns of disease spread, we used four output measures: disease diffusion, risk perception, spatial patterns, and model performance. these aspects are described in more detail in the odd protocol (s1 appendix). we also measured the performance of models m1 -m8 in terms of run time and the number of intelligent decision steps, i.e., when agents called their bn1 and/or bn2. given the stochastic nature of abms, we ran each of the eight models 100 times. the average and standard deviations of the results of these runs for each output measure were listed in table 3 . behavioral changes can lead to different duration times of the epidemic and reduce the number of infected cases [44] . this was shown by running cabm with the eight models. models m5, m6, m7, and m8 recorded a longer duration of active infection during the epidemic (75-79 days, table 3 ). these results are closer to the real duration of the epidemic in 2005 (75 days, table 3 ). m5, m6, and m8 applied centralized learning, while m7 applied decentralized learning, but only for the risk perception stage. m2, which is individual learning with social interactions, also recorded a shorter duration when compared to the real data of 2005 (68 days in m2). however, isolated learning and decentralized learning for both risk perception and coping appraisals recorded shorter epidemic duration, with an average difference of -25% compared to the empirical data (table 3) . all eight scenarios generated more infected cases than the empirical data. this was because infection with cholera bacteria leads to a clinical spectrum that ranges from asymptomatic cases to symptomatic cholera cases. asymptomatic cases are not reported, although they represent roughly half of all cases [45] . in our simulations, we did not differentiate between symptomatic and asymptomatic cases; we considered all infected cases are considered to be symptomatic cases. therefore, following [45] , in table 3 , we reported that 57% of the total infected cases occurred when running the eight models. m8, which uses centralized learning for risk perception and individual interactive learning for coping appraisal, reported the fewest infected cases (2,107 against 1,621 in reality). this was followed by m2 (individual social learning) with 2,279 cases and m1 (individual isolated learning) with 2,457 occurrences. these three values reflect the fact that when household agents learned to cope and make decisions individually, they were more efficient than when they were in groups. when these decisions were combined with social interactions, they lead to better protection (m2 and m8). in general, group behavior had a negative effect, although centralized groups had a less negative impact compared to decentralized ones. finally, in m7, where household agents learned risk perception in decentralized groups and learned to cope individually, 2,911 infected cases were recorded (table 3) . hence, cabm household agents' engagement in decentralized groups for appraising disease risk hindered the perception of risk, lowering agents' motivation to change their behavior to more protective alternatives. the spatial distribution of infected cases (spi) of m8 reported the closest spi over the communities (0.75) compared to 1 in the empirical data. this was followed by m5, with 0.7 ( table 3 ). the spatial patterns of the two collective learning models (m8 and m5) reflected their similarity to the spatial patterns in the empirical data. the correlation between the peak of the epidemic and the peak of risk perception reflects the responsiveness of the household agents' risk perception of the epidemic. scenarios m2, m5, m6, and m8 were more responsive. that is, the peak of risk perception in m2 came three days after its epidemic peak, and the peaks in m5, m6, and m8 came seven days after their epidemic peaks (table 3) . m1, m3, m4 and m7 showed peaks for risk perception near the end of the simulation time. individuals in m1 were isolated, along with individuals in m3; therefore, they kept following their usual behavior of fetching water and using it as it is. in m4 and m7, household agents depended on majority votes in their groups to make their decisions on risk and to change behavior. more explanations are represented visually in the next sections. table 4 shows the number of steps and the time required to run one simulation of each model. the number of agents that were supposed to go for risk perception daily was 15% of the total number of household agents (which totaled 8,500). this percentage was derived from national statistical data from ghana statistical services [35] . over the 90 days of the epidemic, 114,750 agents appraised their risk perception (use their bn1). table 4 also shows the number of steps, during which agents perceived the risk of disease (i.e., risk perception equals 1). notably, in m3 -m8, if a group at large assessed the risk perception as zero, then none of its members did the coping appraisal, i.e., the number of steps when bn2 was activated is zero. in such cases, only the total number of steps with activated bn1 assessing risk perceptions was included in table 4 . models with centralized learning required the shortest computation times (table 4) . for example, m5, where only the isolated leaders with the centralized learning consult their bns, had the best performance with the shortest runtime. moreover, m5 and m6 recorded the fewest steps across all models. although the average number of agents with risk perception per simulated day was high (410 agents), there were only 6,840 steps in risk perception and the same number of steps when coping appraisal mls were activated. that is, only leaders activated their bn1 and bn2. this is only 22% compared to what it would be if agents decided individually. without voting, only one agent per group assessed the situation and made decisions. this made m5 and m6 time-efficient. on the opposite end, m4 recorded the highest computational time because of the intensive calculations required in the individual agents' network and the decentralized group network. among all models, m4 recorded the longest process time. agents individually perceived risk (bn1) before going back to their groups to negotiate a final decision on risk perception and then repeating the same individual-group sequence for the coping appraisal. in models m5, m6, and m8 only one agent per group-a total of 76 leaders-assessed risk perception daily, leading to 6,840 steps over the 90-day epidemic. in m5 and m6 only the 76 leaders also went for coping appraisal, while in m8, the group members individually assessed the coping appraisal (26,370 steps in m8 vs 6,840 steps in m5 and m6). calibration of the original model was conducted in two steps: first the hydrological submodel was calibrated, followed by a calibration of the complete model [35] . after the calibration, a stability check was performed [35] . for the current work, the objective of this epidemic model is not to reproduce the real data. it is focusing on the impact of social interactions (present or not, on the level of individual or groups) on both risk perception and coping appraisal of the individual agent. to calibrate a scenario further, one would need risk perception data for that area for the duration of the epidemic. however, such data are very scarce, not only for kumasi but worldwide. hence, risk perception was randomized at initialization. therefore, the eight models cannot be calibrated individually because they need to be comparable at initialization. s2 appendix shows the statistical analysis that was performed on the output data of the eight models to show and analyze the distribution of the obtained results. when household agents evaluated the risks of getting cholera and made coping decisions individually (m1), they relied only on their own experience. that is, each had individual bn1 and bn2 and did not communicate with neighbors. scenario m2 extends this stylized isolated benchmark case by assuming that while agents continued to make decisions individually, they table 4 risk perception and behavioural change during epidemics did share information with neighbors about the perception of risk and protective behavior. that is, both bn1 and bn2 included neighbors' experiences among the information input nodes. fig 5 shows the epidemic curves and the dynamics of risk perception for all scenarios. in the absence of social interactions, more agents became infected with cholera. the peak of the epidemic curve in m1 (in-i) is higher than m2 (in-n), leading to 11% more cases of disease ( fig 5 and table 3 ). overlaying risk perception and epidemic curves suggests that when agents made decisions in isolation (m1: in-i), the dynamics of risk perception were hardly realistic (fig 5a) . namely, when the epidemic was at its peak, household agents in m1 responded very slowly, with bn1 delivering a wrong evaluation of risk perception (fig 5a) . they became aware of the risks very late, so when the epidemic vanished, the number of agents with risk perception = 1 kept increasing. in the absence of communication and experience sharing among peers (in-i), the information about disease spread slowly and there was a significant time-lag between the occurrence of the disease and people's awareness. the small stepwise increase, around day 21, was because the media started to broadcast information about the epidemic on that day. in m2, household agents behaved according to the expected pattern: risk perception became amplified by media coverage and social interactions and then vanished as disease cases became rare (fig 5b) . only those who experienced cholera infection in their households remained alert. household agents in m2 after day 21 had more responses to the media's news compared to isolated agents. media supported the agents' social interactions with their risk perception and behavioural change during epidemics neighbors, which led to more agents perceiving risk, especially when the number of infected cases reached their peak (fig 5b) . even in m2, there were limitations of making decisions about risk perceptions individually: risk perception fell too quickly, implying that people stopped worrying about the epidemics although they continued. since household agents in m1 did not have interactions with other agents, running this model required less time than m2 (creating a 10% increase in performance, table 3 ). the interaction between household agents required time to process the information exchanged between agents. in addition, (m1: in-i) and (m2: in-n) were approximately the same in terms of the realistic spatial distribution of infected cases over the communities, with values of 0.65 and 0.66, respectively (table 3) . fig 6 presents the spatial distribution of decision types over the study area in both m1 (in-i) and m2 (in-n). the household agents in isolated learning were not aware of the cholera-infected cases in their neighbors' household. household agents in m1 took an unsecured decision and trusted more in using the water fetched from the river as it is (d1 in fig 6a) . household agents in m2 were more rational and mostly boiled the water that they fetched from the river (d3 in fig 6b) . in decentralized learning, groups of household agents vote for risk perception and coping appraisal. the final decision of the group is the output of the majority votes. thus, all group members follow the final decision of the group. these groups represent the democratic system, which depends very much on the composition of the group. the decentralized groups with a majority vote can lead to a negative perception of risk. besides, a coping appraisal that depends on a majority vote can lead to inappropriate decisions regarding protection from cholera. when individuals are engaged in social groups, their behaviors are not independent anymore https://doi.org/10.1371/journal.pone.0226483.g006 [46] . this leads to an increase in the randomization of decentralized learning models (m3 and m4). these two models had higher standard deviations in all measures ( table 3) . the qualitative patterns of the three scenarios (m3, m4, and m7) were the same regardless of the social interactions that added new information to ml (fig 5) . for the development of the disease, the voting mechanisms seemed to overwrite individual judgments. the m3 scenario assumes that household agents were isolated when performing risk perception and coping appraisals. in contrast, m4 and m7 allowed household agents to communicate with neighbors during the process of risk perception and before making a coping decision. as a result, m4 and m7 generated greater risk perception than m3 (fig 5c, 5d and 5e ). this suggests that the social interactions still amplify both the awareness of risks and the diffusion of preventive actions. given approximately the same peak heights, the epidemic curves in the three majority voting scenarios reported more infected cases than the other models. among the majority votes, m7 reported the fewest infected cases, since household agents in their coping appraisal relied on themselves rather than their decentralized groups. overall, it seems that all three models-m3, m4, and m7 -got the process of disease risk evaluation wrong. in those cases, risk perception slowly grew in the days when the epidemic was peaking (fig 5c, 5d and 5e) and did not react to the peak in any way, which is unrealistic. moreover, risk perception in the three models continued to grow when the epidemics were almost over. risk perception peaked when there was no longer a risk, i.e., in the last days of the simulation, as shown in table 3 . hence, group voting on risk perception operated with a major time lag: household agents ignored early signals of disease that occurred in just a few households. then they increased their awareness about risk only when most of them were already infected, and they continue to be falsely alerted when the epidemic was over. in m3, the small stepwise increase in risk perception represents the response to media, and it is similar to m1 (in-i) in its development (fig 5c) . the household agents in their decentralized groups did not have contact with neighbors, therefore, no cases were reported to them from their neighborhoods. as such, they were disconnected from what is happening around them. in m4 and m7, which included social interactions, the development of risk perception seems more responsive, especially after the activation of media on day 21. nevertheless, their response time was still slow (fig 5d and 5e ). in these models, the group decisions were very much dependent on the composition of the group members' opinions. these varied from one another and had different information sources for the final decisions about risk perception (in both m4 and m7) and coping appraisal (in m4). thus, majority voting led to unsecured decisions. groups in these models were heterogeneous in that household agents had different levels of exposure to the group members with which they voted. decentralized groups with isolated input information (m3) led household agents to vote to use the water fetched from the river (d1) most of the time (fig 7, map a) . because of their lack of communication with neighbors, household agents missed the opportunity to get information about the infection in their neighborhoods. this explains the higher numbers of infected cases in the majority vote models. social interactions in both m4 and m7 helped agents make better decisions, although following the majority still biased their choices. for instance, in m4 high-income communities (upper communities in maps b and c, fig 7) , household agents mostly used the river water as it was even though they were rich enough to boil it before using it (d3) or to buy bottled water (d4). the opposite also occurred when a majority vote forced low-income households to buy bottled water, which is an expensive decision for them. the group voting on the coping appraisal in m4 might have made individual members uncomfortable when they followed the decisions of their groups even though they might not protect. in reality, household agents sought a balance between preventive behavior and their capability to implement it. moreover, there is always the possibility of routinely changing one's mind based on daily updates of information regarding the epidemic and updates from neighbors. as in m4, the household agents in m7 relied on their decentralized groups for risk perception. this, often led to risk ignorance (fig 5e) . however, since the agents in m7 decided on coping appraisals individually, more agents adopted d1 (fig 7c) . when they perceived risk during the last days of the epidemic, household agents in the middle-income level switched to boiling water or buying bottled water (d3, d4 in fig 7c) . those in the low-income level walked to another water fetching point (d2). in centralized groups, one household agent is randomly selected to be the group leader. the leader is responsible for risk perception and the coping appraisal of the group. group members copy the risk perception and disease preventive decisions of their leaders. it is argued that group leaders may improve their group's performance if they model the responses to the situation the group faces [47] . in this article, we considered two types of leaders: a dictator making top-down decision about risk perception and coping strategy (m5 and m6), and an opinion leader evaluating risk perception top-down but giving group members the freedom to pursue their own disease coping behavior (m8). the qualitative trends of all three models coincided with what is expected: peaks caused by amplification of risk perception followed by a gradual decrease when epidemics plateau (fig 5f, 5g and 5h) . the centralized group learning on average represented the processes well, as the leader alerted the group members about the disease. however, since no real data are available on risk perception dynamics or the actual coping behaviors that people pursued during the epidemic, we cannot determine which of the models m5, m6, and m8 is the best. the following subsections compare models with a leader-dictator (m5, and m6) to one with an opinion leader (m8). a dictator-leader decides on behalf of his group regarding disease risk and coping strategies, and both decisions are adopted top-down. a dictator leader learns either in isolation (m5) or in interaction with her/his neighbors (m6). isolated dictators in m5 are overestimated disease risks (fig 5f) . for example, if such a leader had his/ her own bad experience with cholera, s/he would keep warning the group. with social interactions (m6), there is less uncertainty in the process of updating the risk perception than in m5. for example, compare risk perception assessments around the epidemic peak (fig 5g) . fig 8 illustrates the impact of social interactions on the dictator's decisions regarding coping appraisal. isolated leaders guided their groups to various types of decisions (fig 8a) , which were sometimes less secure decisions (e.g., d1). with social interactions, leaders relied on their neighbors and decided more often to walk to a point along the river where the water was cleaner (d2). very few dictators directed their groups to boil the fetched water (d3) or buy bottled water (d4) (fig 8b) . this shows how centralized decisions making undermines heterogeneity in individual circumstances, such as disease exposure or coping capacity. in m8, the leaders in the centralized groups were responsible for evaluating disease risks for their groups, but they interacted with neighbors during the risk perception process. for the coping appraisal, the group members made their own decisions, using the information from their social networks. as a result of this combination of centralized speed alertness about risk perception and individual coping strategies, m8 generated the fewest infections. the shape of the epidemic curve (except for its height) is very close to the empirical data of 2005, (fig 5h) . as in m6, the uncertainty in the process of risk perception in m8, is lower than in m5 (fig 5h) . the risk perception curve developed around the epidemic peak followed the dynamics of the epidemic (fig 5g) . when group members relied on social interaction to learn about the effectiveness of various coping strategies but eventually chose one themselves (m8), there was a diversity of coping strategies. fig 8c shows the spatial distribution of different types of decisions during the simulation. more household agents went for d3 and d4, which were considered to be the most protective decisions. consequently, communities pursued at least three types of decisions, reflecting the disease coping diversity so important for resilience. the goal of this paper is to perform a systematic comparison of individual vs group learning. the methodological advancements showed that different implementations of individual and collective decision-making in agents' behavior led to different model outcomes. in particular, the stepwise approach of testing how learning (on a gradient from individual learning-without any interactions-to collective-with social networks) affects an abm's dynamics is generic and can be used for other models. to illustrate the subtle difference in implementing learning in abms, we used the example of the spatial empirical abm of cholera diffusion with intelligent agents that employ ml to assess disease risk and decide on protective strategies, which define the dynamics of the epidemic. interactive learning, which assumes that agents share information about risks and potential protective actions, outperformed isolated learning both for individuals and in groups. this underlines the fact that social learning in the decision-making process is very important in abms. while we used disease modeling as a case study, the results may be contingent on the endogenous dynamics of this particular cholera abm. notably, simulation results may differ for abms with other underlying dynamics. this calls for further scrutiny in testing and reporting cases of intelligent social and individual learning in other models. the results indicate that decentralized groups with majority votes are less successful than groups with leaders, whether dictators or opinion leaders. when evaluating current disease risks, majority voting appears to be the worst mechanism for group decisions, often arriving at a wrong decision because of time lags compared to the dynamics of objective disease risks. perceiving risk is a very personal decision-making process [48] . in contrast, when leaders develop risk perception and propose it to the group, such groups perform better in terms of risk appraisal. moreover, opinion leaders are very effective in helping their group members be alert about disease while giving them the freedom to make coping decisions that accommodate heterogeneity in their socio-economic status and geographical locations. in contrast, dictatorleaders and majority votes that impose a decision that all group members must follow are less effective in reducing the incidence of disease. in our simulation experiments, the structure of the groups is simple and is formed based on the spatial and socio-demographic characteristics of the agents. as grouping seems to have an impact on the spatio-temporal diffusion of the disease, the importance of disease modeling stresses the fact that for this type of model a careful evaluation of the social structures in the case study area should be conducted, to generate trustworthy results. future research should focus on constructing groups based on different variables (family ties, religion, tribes). also, in our abm the leaders had no particular knowledge but were randomly selected and assigned to groups. in reality, this may not be the case. leaders may have access to better information or have already earned the group's trust and respect. in addition, decentralized groups can be improved by giving greater weights to more trusted partners to make wise decisions. the model's performance can be a strong argument when the number of agents is massive, e.g., when simulating a pandemic or epidemics within a very large population is needed to detect a worldwide diffusion mechanism. in that case, social group learning, as described in model m5, is a very good alternative to individual interactive behavior. moreover, m5 shortens the computation time by 73% while maintaining a good quality model output. the number of contacts each household agent has when they are in their collective learning may impact the diffusion of cholera. however, running a fat tail distribution of the number of contacts would be an interesting topic for future study. different considerations steer the ultimate decision on which type of social behavior to use. besides the technical model performance metrics discussed here, the choice of a particular type of social behavior can also be based on the society that is being modeled. different political systems, the presence of tribes, and different ethnic groups or religious leaders require careful considerations of the social interactions in a model. one should make sure that the actual situation regarding social learning represents the cultural and social norms of the society being modeled. in this article, it was not possible to define, which implementation (m1 -m8) represented the situation in kumasi most closely. to validate the risk perception-behavior, one would need risk perception data for that area for the duration of the epidemic. however, such data are very scarce, not only for kumasi but worldwide. as we illustrated in this study, many different implementations of social behavior using ml are technically possible, but data are needed to validate alternative implementations. yet, research on risk perception during epidemics is often conducted too late (when the peak is over) or at distance (not in the area where the disease spreads). hence, researches provide little empirical proof of people's behavior and risk perception. more research on risk perception during epidemics, including other variables such as cultural aspects and group behavior, can be very helpful in generating a model that represents a specific society realistically. on a technical note, agent-based modeling software does not always include ml toolkits and libraries. this complicates the implementation of different types of social intelligence. hence, better integration of abm and ml in one software package or linkable libraries could eliminate this problem in the future. finally, an important direction of future research is to implement other ml techniques besides bns, such as decision trees and genetic algorithms. in addition, modeling groups with different ml algorithms may lead to different results since groups will be heterogeneous in terms of members' learning algorithms. several developments in health research drew our attention to the implementation of learning in disease models. one is the 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of household contacts of patients with cholera in behavioral modeling and simulation risk perception and human behaviors in epidemics risk perception it's personal. environmental health perspectives. national institute of environmental health science key: cord-016982-qt25tp6t authors: fong, i. w. title: litigations for unexpected adverse events date: 2010-11-30 journal: medico-legal issues in infectious diseases doi: 10.1007/978-1-4419-8053-3_8 sha: doc_id: 16982 cord_uid: qt25tp6t a 53-year-old iranian female who immigrated to canada about 3.5 years before was referred to an internist for a positive mantoux skin test (11 mm in diameter). the subject was previously well with no symptoms indicative or suggestive of active tuberculosis. a routine tuberculosis skin test was performed because the patient had applied to be a volunteer at a local hospital. she had no significant past illness or known allergies, and she was never diagnosed with nor had known contact with anyone with active tuberculosis. the subject never ingested alcohol and was not known to have hepatitis or be a carrier of any hepatitis virus. baseline investigations performed by the internist included routine complete blood count, routine biochemical tests (liver enzymes, creatinine, and glucose), serum ferritin, and thyroid-stimulating hormone – all of which were normal. a chest radiograph was reported to be normal. creatinine, glucose and electrolytes; but the bilirubin had risen to 219 mmol/l, the sgot was 978 m/l, the serum alanine aminotransferase (alt) was 641 m/l (normal 10-45 m/l), alp 300 m/l, and the prothrombin time 2.2 s. a repeat ultrasonography of the abdomen revealed large ascites and a liver of 13 cm in length with normal contour. over the next 2 weeks, she became drowsy and encephalopathic, and was transferred to a tertiary care hospital where a liver transplantation was successfully performed (live donor from the patient's daughter). pathology of the liver showed a markedly shrunken liver with signs of fulminant hepatitis, with negative stains for hepatitis b antigens. a lawsuit was subsequently launched by the patient (plaintiff) against the physician who prescribed the isoniazid. the statement of claim alleged the following: (1) isoniazid was directly responsible for the plaintiff's fulminant hepatitis which resulted in the need for a liver transplant, (2) informed consent was never obtained to prescribe the drug, as the plaintiff was never counseled on the adverse effects, nor given a choice of treatment, (3) use of the isoniazid was never indicated, as the patient had no symptoms or signs of active disease, (4) the physician should have realized that the positive mantoux test was due to a previous bcg vaccination as a child (the defendant was informed of this fact) and therefore there was no need to treat the plaintiff for latent tuberculosis. based on the above facts, the internist was negligent in prescribing isoniazid and he should have monitored her liver enzymes after initiation of treatment (according to the statement of claims). the lawyer for the plaintiff further stipulated that if his client were never treated unnecessarily for latent tuberculosis, she would not have suffered from fulminant hepatitis or required a liver transplant. hence, the treating physician provided substandard care and compensation was sought for pain and suffering of the plaintiff, as well as for the daughter who underwent partial hepatectomy for liver donation. the case under discussion does not fall into the high-risk category for treatment of latent tuberculosis, but may be considered as an intermediate risk on cursory assessment. although employees and staff of healthcare facilities, especially those involved in direct patient contact, should be offered treatment of latent tuberculosis, there is no such stipulation for volunteers in hospitals. most healthcare facilities screen volunteers for active tuberculosis by mantoux skin test and chest radiograph for those with positive reaction. another category under which the subject could be considered is an indication for treatment of latent tuberculosis include persons from highly endemic countries within 5 years of immigration with a positive mantoux test (10 mm), irrespective of previous bcg vaccination. this group of people represent one of the largest segment of newly diagnosed patients with active tuberculosis in north america and europe. 2, 3 in 2006, 57% of all tuberculosis cases in the united states were among foreign-born persons, 4 and in several european countries >50% of tuberculosis case occur among foreign-born people. 5 there are 22 countries with a high burden of tuberculosis (tb) that account for 80% of the tb cases globally. 6 these countries are located predominantly in asia (south east asia and western pacific regions) africa, brazil (south america), the russian federation (eastern europe), and afghanistan (middle east). the estimated new tb cases (all forms) per 100,000 people per year in iran is 22, which falls in the low risk category (0-24) as present in north america and western europe. 6 the incidence and prevalence of tb in the middle east varies from country to country, and iran actually falls into the relatively lower risk group the indication for treatment of latent tb in this case is borderline or very debatable, but most physicians (including internists) may not be aware of this fact. the treatment of choice for latent tb is now standardized to a 9-month course of isoniazid (inh) 300 mg once daily for adults, with or without pyridoxine (vitamin b6) to prevent peripheral neuritis. this is believed to be about 90% effective in preventing future reactivation of tb; but it does not prevent re-infection (with a new strain), which is a risk mainly in highly endemic countries. the main worrisome adverse effect of inh is clinical hepatitis, which can be fatal or lead to fulminant hepatitis that requires liver transplantation. there are two types of hepatic toxicity seen in inh; a common transient elevation of the transaminases seen in 10-30% of patients that occurs within 4-6 months and is benign and asymptomatic, and clinical hepatitis (symptomatic) which is much less common, age-related, and only occurs in about 1% of treated patients. clinical hepatitis with inh is rare under 20 years of age and increases to about 2-2.3% above 50 years, and in persons >65 years, the risk increases to about 4.5%. 1 about 50% of inh hepatitis occurs in the first few months of treatment and the remainder occurs later up to 12 months (if still on inh). 7 the prognosis of overt inh hepatitis is usually very good if the drugs are discontinued promptly with the first sign of clinical hepatitis. the overall mortality is about 10% or 4.2 per 100,000 patients treated with inh. 7 middle-aged black women seem to have the worst prognosis from this complication. in the majority of patients, there is clinical and biochemical resolution of signs and laboratory abnormality within 1-2 months of stopping the drug. occasionally, patients can present or develop a sub-acute, more protracted course that mimics chronic viral hepatitis and leads to cirrhosis. 7 the pathogenesis of inh hepatotoxicity was initially considered to be an idiosyncratic reaction, but there is increasing evidence that this is a direct toxic effect of metabolite(s). there appears to be a higher risk and greater severity with higher doses, and higher incidence in slow acetylators. 8, 9 animal experiments show that inh metabolism leads to acetyl hydrazine, which after oxidation forms toxic intermediates. these are thought to produce damaging effects by acetylating or alkylating macromolecules within liver cells, but the exact mechanism of liver cell injury is unknown. 7 in slow acetylators, acetyl hydrazine accumulates and predisposes to hepatotoxicity. another metabolic pathway involves hydrolysis of inh to hydrazine and isonicotinic acid. hydrazine is known to be directly hepatotoxic and hydrolysis of inh is increased by alcohol and rifampin. 9 the mechanism of agerelated hepatotoxicity is unclear, but could possibly be related to the slowing of acetylation with advancing age. most guidelines and recommendations of latent tb strongly discourage treatment with inh in patients with active liver disease. close clinical and biochemical monitoring for liver toxicity are mainly recommended for subjects with high risk for clinical hepatitis, such as older people (65 years), those with history of liver disease, chronic carriers of hepatitis b and c, alcohol abusers, concomitant users of other hepatotoxic drugs, and subjects who suffer from malnutrition or aids. current textbooks of medicine do not recommend routine biochemical monitoring for healthy adults being treated with inh. 10 in these circumstances, baseline liver tests are performed and patients should be counseled on symptoms of clinical side effects and should be monitored clinically. some experts and the manufacturer recommend biochemical monitoring for persons >35 years old, pregnant women, (and those within 3 months post-partum), monthly for 3 months, then afterwards at 1-3 month intervals. 1, 11 inh should be discontinued promptly at the first sign of clinical hepatitis. symptoms of hepatitis may include fatigue, weakness or fever >3 days, malaise, unexplained anorexia, right upper quadrant pain or discomfort, and jaundice. if the alt is 3-5 times the upper limit of normal, the drug should be discontinued, even if the patient is asymptomatic. restarting inh at a small dose has been recommended by some experts in asymptomatic patients. it is of interest to note that the american thoracic society, the british thoracic society, and the task force of the european respiratory society only recommend regular biochemical monitoring of liver function on multidrug treatment for tb in patients with chronic liver disease or increased serum transaminases prior to treatment. 12 in the case of symptoms of hepatotoxicity, the liver function should be examined. this may be based on the fact that there is no good evidence that routine monitoring of liver function will decrease the chance of fulminant hepatitis or fatality, and prompt discontinuation of medications with first onset of symptoms usually results in full recovery in those with clinical hepatitis. the defendants' lawyer raised a critical question. is it absolutely certain that the fulminant hepatitis suffered by the patient was due to isoniazid? with any serious adverse event, to make an assessment requires several steps and investigations to reach a valid conclusion. this involves a process of deduction and exclusion of other etiologies (such as hepatitis virus), other agents, and use of bayes theorem to assess overall probability (definite, probable, or possible), as well as posterior and prior probability (based on known literature reports). other considerations include temporal relationship with use of the medication, compatibility of clinical features and laboratory data, histopathology data and previous reports, and reproduction of the event by re-challenge with the putative agent. although this is the most definitive method of proving cause and effect, it is the least used because of the potential risk of harm to the patient and the ethical and moral issues. the temporal relationship, clinical features, laboratory data, and histology of the liver are all compatible with inh -induced hepatitis. however, the investigation excluded well-known causes of viral hepatitis. the patient was also receiving diclofenac, which started 5 weeks before the clinical diagnosis of hepatitis and 2-3 weeks before the onset of symptoms. thus, there is a temporal relationship with diclofenac treatment and the onset of clinical hepatitis. nsaids in general are known, but rare causes of drug-induced hepatitis. 7 the incidence of diclofenac-induced clinical hepatitis is about 1-5 per 100,000 users, and the incubation period varies from 3 to 12 weeks (consistent with the present case). 7 data from the diclofenac monograph (novartis pharmaceuticals) indicates that there is a higher incidence of moderate to severe (3-8 times upper limit of normal) and marked (>8 times normal) elevation of transaminases when compared to other nsaids. in addition, rare causes of severe hepatic reactions, including liver necrosis, jaundice, and fulminant fatal hepatitis (or requiring liver transplant) have been reported with diclofenac. to date, there is no evidence of enhanced risk of clinical hepatitis in patients receiving both inh and diclofenac or other nsaids. elderly women are more susceptible to nsaids-induced hepatitis. histopathology of the liver usually reveals zone 3 or 5 spotty acute hepatocellular necrosis, but there can be granulomas, cholestasis, hepatic eosinophilia, and even chronic active hepatitis with overuse of nsaids. 7 the prognosis is usually very good from withdrawal of nsaids. there is no evidence that concurrent treatment with inh and nsaids increased the risk or severity of hepatitis. treatment for latent tb in the case under discussion was not indicated, but the circumstances could be interpreted as representing a borderline indication to use inh. however, the patient should have been offered the choice of no treatment versus therapy for latent tb. the risk versus benefit should have been discussed and the potential side effects explained to the patient. the patient should have been counseled to discontinue the medication at the first symptoms suggestive of clinical hepatitis. monitoring for liver disturbance by biochemical tests is not routinely recommended for patients at low risk for clinical hepatitis, and the physician should not be held responsible for his failure to order these tests. clinical monitoring however is standard and the physician can be held responsible for either failure to recognize the manifestations of hepatitis, or his failure to promptly withdraw all drugs once these signs appear. it cannot be concluded that inh was irrefutably culpable for the fulminant hepatitis, but based on the relative risk and incidence, it was more likely the cause than diclofenac. in any case, both drugs should have been discontinued immediately with the first signs of clinical hepatitis. for 2 years, a 35-year-old male had suffered from recurrent bouts of nasal congestion, nasal discharge, and post-nasal drip with only partial, temporary relief from decongestants, antihistamines, and topical corticosteroids. his fp referred him to an internist and clinical allergist for further management. his past history was negative for any significant medical illness, but the patient had previous surgery for nasal septal deviation, and had stopped smoking 2 years before. examination by the allergist revealed inflamed edematous nasal mucosa with some purulent discharge, and a radiograph of the sinuses demonstrated mucosal thickening of both maxillary antra. based on these findings, the consultant made a diagnosis of chronic rhino-sinusitis with an allergic and infectious component. the consultant prescribed intranasal corticosteroids and a 2-week course of trimethoprim-sulfamethoxazole (tmp-smx). the patient reported that he was treated by his fp 2 months before with triple sulfonamide antibiotics (trisulphamine) for 7 days without any side effects. he had no known drug allergies before this visit. towards the end of the 2-week course of tmp-smx, the patient developed malaise, low-grade fever, and a body rash that started on the face and trunk. this rash rapidly progressed over the next 48 h to involve his limbs, mouth, and eyes, with blistering of the skin. he was admitted to the emergency department of a hospital with a diagnosis of sulfonamide-induced toxic epidermal necrolysis (ten). further care was performed in the burn unit. as a consequence of this adverse reaction, the patient developed bilateral corneal ulcerations requiring repeated corneal transplants. despite this, he remained blind in the left eye and had severe visual impairment on the right side. medico-legal actions were launched by the patient's lawyer claiming medical malpractice against the allergist in failing to warn the patient of the potential adverse effects of tmp-smx. moreover, the plaintiff claimed that antibiotics were never needed in the first place and if he had known of these potential side effects, he would not have agreed to be treated with the tmp-smx. the defense retorted that the adverse reaction suffered by the patient was extremely rare, and that the patient had previously been treated with sulfonamides, without any reaction. they claimed this reaction could not have been predicted and that it was not the standard medical practice for physicians to list all the rare side effects of licensed drugs on the market. the first relevant issue in this case is the following question: should any antibiotic have been prescribed? if antibiotics were indicated, was the choice of the tmp-smx appropriate? current consensus is that antibiotics are overused and prescribed unnecessarily for sinus disease. sinusitis is commonly due to respiratory viruses and allergic reaction (as in hay fever), and antibiotics are of no value in these situations. the presence of purulent nasal discharge can be seen in the above conditions, but is not diagnostic or indicative of bacterial sinusitis. 13 radiographs of sinuses showing thickened mucosa or fluid in the chambers are non-specific and not diagnostic of bacterial sinusitis, as these changes can also be seen in viral infection and allergic sinusitis. the etiology of chronic sinusitis is complex and there is a lack of consensus of the pathogenesis. multiple factors may predispose to chronic sinusitis and allergy appears to play a prominent role, with or without polyps. 13 other factors include structural abnormalities (outflow obstruction, retention cysts, etc.) and irritants such as smoking. chronic sinusitis is usually defined as having symptoms of sinus inflammation lasting longer than 12 weeks, with documented inflammation (by imaging techniques) at least 4 weeks after appropriate therapy with no intervening acute infection. 14 computerized tomography (ct) is the preferred imaging technique to identify any obstruction and polyps. although antibiotics are commonly used in chronic sinusitis, their benefits have not been established by randomized trials, and the role of bacterial superinfection has not been well-defined. 13 the best microbiological data from patients with chronic sinusitis have found aerobic (52.2%) and anaerobic pathogens (47.8%) are common in these cases. 15 the most common aerobes were streptococcus species and hemophilus influenzae (nontypable strains), and the most common anaerobes were prevotella species, anaerobic streptococci and fusobacterium species. management of chronic sinusitis is challenging and involves combined medical and surgical therapy. for surgical cases where there is good clinical and imaging evidence of chronic bacterial sinusitis, empiric antibiotics should be effective against streptococci, h. influenzae and anaerobes. amoxicillin-clavulanate would be a suitable choice, and for b-lactam allergic patients, a new fluoroquinolone with anaerobic activity (moxifloxacin) would be an acceptable alternative. 13 failure to respond usually indicates the need for surgery which can be performed by endoscopy, and in these cases, antibiotic treatment should be guided by sinus culture (by puncture or endoscopy-guided). although antimicrobials are commonly used for extended periods (3-4 weeks) for acute superinfection or exacerbation, no studies have addressed the issue of duration of therapy. although the case under discussion may not meet the diagnostic criteria for chronic bacterial sinusitis, making this diagnosis and instituting antibiotic therapy (although a judgment error) should not be considered gross negligence, or represent substandard care to merit malpractice litigation. the choice of antibiotic (even if the diagnosis of chronic sinusitis were correct), however, would not be a suitable selection. for acute bacterial sinusitis, amoxicillin/ampicillin is considered the drug of choice and tmp-smx is recommended as an alternative agent for subjects allergic to penicillin. what counseling should patients receive when prescribing an antibiotic, and specifically tmp-smx? most physicians do not spend time to inform their patients about the adverse effects of prescribed medications. on the other hand, most pharmacists do provide written information on new prescriptions. physicians cannot depend on this fact though, nor rely on this service for defense in a court of law. in most situations, physicians may counsel patients on drugs with known high risk of toxicity or side effects. for frequently prescribed medications (such as most oral antibiotics), counseling often is neglected, or only the common adverse effects are mentioned. the incidence of uncomplicated skin reaction (allergic skin rash) to tmp-smx (mainly due to the sulfonamide component) in the general population is about 1-4% of recipients. 16 this consists of mainly toxic erythema, a maculopapular eruption, infrequently urticaria, erythema nodosum, and fixed drug eruption. 16 severe skin reactions in tmp-smx recipients are rare and include steven's-johnson syndrome (sjs), toxic epidermal necrolysis (ten), exfoliative dermatitis, and necrotizing cutaneous vasculitis. previous estimates of severe skin reaction were 1 in 100,000 recipients. 16 patients with hiv infection have a much higher incidence of cutaneous reaction to tmp-smx (especially those with aids). epidermal necrolysis (en) is a rare and life-threatening reaction, mainly drug induced, which encompasses sjs and ten. these two conditions represent severity variants of identical process and differ only in the percentage of body surface involved. 17 the incidence of sjs and ten are estimated at 1.6 per million person-years and 0.4-1.2 cases per million person-years, respectively. 17 although en can occur at any age, it increases in prevalence after the fourth decade, and is more frequent in women. there is some evidence that the risk of en increases with hiv, collagen vascular disorders, and cancers. the clinical features of en are characterized by skin and mucous membrane involvement. initially, the skin reaction begins with macules (mainly localized to the trunk, face, and proximal limbs), and then progresses to involve the rest of the body and become confluent with flaccid blisters leading to epidermal detachment. 17 patients may become systematically ill with fever, dehydration, hypovolemia, secondary bacterial infection, esophageal and pulmonary involvement, and complications and death from sepsis. the pathogenesis of en is not completely understood, but studies indicate cell mediated cytotoxic reaction against keratinocytes leading to massive apoptosis. early in the process, there is a predominance of cd 8 killer t lymphocytes in the epidermis and dermis of bullous lesions, and later monocytes develop. cytotoxic cd 8 t cells express a-b tcell receptors are able to kill cells through production of perforin and granzyme b. drugs are the most important causes of en and ten and >100 different drugs are implicated. cd 8 oligoclonal expansion corresponds to a drug specific, major histocompatibility complex (mhc) -restricted cytotoxicity against keratinocytes. 17 pro-inflammatory cytokines il-6, tnfa, and fas ligand are also present in skin lesions. genetic susceptibility appears to be important, and there is strong association with han chinese with hla-b5802 leucocyte antigen and sjs induced by carbamazepine, and hla-b5801 antigen and sjs induced by allopurinol. 17 high-risk drugs (about 12) from six different classes, account for 50% of en reactions. these include allopurinol, sulfonamides, anticonvulsants (carbamazepine, phenobarbital, lamotrigine), nevirapine (non-nucleoside analog), oxicam nsaids, and thiacetazone. 18 the incubation period for en ranges from 4 to 30 days, but most cases occur within 8 weeks of starting the medication. rare cases can appear within hours of use, or same day if they had prior reaction. early, non-specific symptoms (fever, headache, rhinitis, myalgias) may precede mucocutaneous lesions by 1-3 days. some patients may also present with pain on swallowing or stinging of the eyes. about one third of patients begin with non-specific symptoms, another third with primary mucous membrane involvement, and the rest present with an exanthema. 17 progression from a localized area to full body involvement can vary from hours to days. the classification of en depends on areas of detachable epidermidis by a positive nikolsky sign (dislodgement of epidermidis by lateral pressure) and flaccid blisters. the diagnosis of sjs is made when there is less than 10% body surface area (bsa) involvement; sjs/ten overlaps with 10-30% bsa, and ten for >30% bsa involvement. 17 in severe cases of en, the mucous membranes (buccal, ocular, genital) are involved in about 90%, and 85% have conjunctival affliction consisting mainly of hyperemia, erosions, chemosis, photophobia, and excessive lacrimation. severe form of eye involvement can result in shedding of eyelashes, corneal ulceration (as in case 2), anterior uveitis, and purulent conjunctivitis. 17 extra-cutaneous complications mainly seen in severe ten may include pulmonary disease (25%) with hypoxia, hemoptysis, bronchial mucosal casts, interstitial changes, and acute respiratory distress syndrome (ards), which carries a poor prognosis. the gastrointestinal tract involvement is less common, but can include esophageal necrosis, small bowel disease with malabsorption, and colonic disease (diffuse diarrhea and bleeding). renal involvement is mainly proteinuria and hematuria, but proximal renal tubular damage can sometimes cause renal failure. late ophthalmic complications occur in about 20-75% and consist of abnormal lacrimation with dry eyes, trichiasis (ingrowing eyelashes), entropion (inversion of eyelid), and visual impairment or blindness from scarring of the cornea. prognosis of en varies with the severity of illness and prompt withdrawal of the offending agent. the overall mortality of en is 20-25%, but for sjs it is lower, at 5-12%, and higher for ten >30%. development of a prognostic scoring system (scorten) for ten, 19 has recently been found useful, but the performance of the score in prediction is best on day 3 of hospitalization. 20 the prognostic factors that are each given one point include the following: age >40 years, heart rate >120/min, cancer, or hematologic malignancy, bsa involved >10%, serum bicarbonate of <20 mm/l, and serum glucose of >14 mm/l. the mortality rate in ten increases with accumulation of points as follows: 0-1 point has a mortality rate of 3.2%, 2 points has a mortality rate of 12.1%, 3 points has a mortality rate of 35.8%, 4 points result in a mortality rate of 58.3%, and >5 points result in nearly uniform mortality of 90%. 19 management of en or ten consists of prompt removal of the offending agent and symptomatic therapy. patients with a scorten of 0-1 can be managed on the regular medical wards, whereas those with >2 points should be transferred to a burn center or intensive care unit (icu). 17 it is most important to maintain hemodynamic support with adequate fluids and electrolyte balance. central venous lines should be avoided because the risk of superinfection is high, and so peripheral intravenous access should be used. moreover, the rash and blistering is greatest proximally. nutritional support should be maintained orally or by nasogastric tube, and use of prophylactic heparin is warranted, and also an air-fluidized mattress preferable. unlike severe burns, extensive and aggressive debridement of necrotic epidermidis is not recommended. 17 there is no indication for prophylactic antibiotics, but patients should be monitored diligently for infection and treated promptly when present. there is no standard protocol for skin dressing, and antiseptic is used depending on the individualized center's experience. eye care should consist of a daily examination, artificial tears, antiseptic and vitamin a drops every 2 h. regular mouth rinse with antiseptic solution several times a day is recommended. there is no proven specific therapy for any form of en. steroids were initially considered for sjs, but their value is unproven, controversial, and they are not routinely recommended. intravenous immunoglobulin (ivig) is also very controversial, and although initial retrospective studies suggested benefit, recent prospective, non-randomized studies have not confirmed any definite value, and some studies showed increased renal failure and mortality with ivig. 21 in one of the largest studies from a single center, ivig was assessed in a prospective noncomparative study of 34 patients with en, and 20 subjects with ten. there was no evidence of improvement in mortality, progression of detachment, nor reepidermalization. most deaths occurred in elderly patients with initially impaired renal function. thus, ivig is not recommended for en unless being assessed in a randomized clinical trial. the death rate with ivig was 32%, which was higher than the historical death rate in the same center (20%), in historical controls with ten not treated with ivig. 22 thus, ivig may be harmful in patients with en. one of the issues raised by the plaintiff was that he was not counseled on the potential severe side effects of the tmp-smx, and that if he were aware of the risk, he would not have agreed to take it. is it the responsibility of the physicians to explain all potential albeit rare adverse effects of any treatment? the courts may take in consideration the standard practice of the physician's peers, or what is considered accepted practice. most physicians (if they do counsel patients on medications) would mention the most common side effects, but would not usually mention rare adverse effects. for instance, it would be justifiable to mention that a drug rash could be seen with tmp-smx, if the patient happens to be allergic to the drug (which should be discontinued as soon as this occurs). as physicians, we would not usually mention that there is a rare risk of shedding of the skin, blindness, or death. similarly, when prescribing penicillin in patients not known allergic to the drug, we generally do not counsel that there is a 1:50,000 to 1:300,000 risk of dying from anaphylaxis (which is treatable). yet, if we were to order or prescribe chloramphenicol, it is expected that we should counsel the patient that there is a 1:50,000 to 1:300,000 risk of aplastic anemia, which is not treatable except by bone marrow transplantation. hence, it may be asked; what is the best method of informing patients on medication toxicity? it is acceptable to leave this to pharmacists to provide literature on these drugs as the sole form of counseling. it is the prescriber's responsibility to obtain informed consent before ordering the medications. it may be the best policy for prescribers to list the most common side effects, then occasional severe adverse reactions, and mention a possibility of other rare unforeseen adverse reaction (without specifying these latter reactions unless requested by the patient). the details of the counseling may vary on several factors, such as the relative safety profile (therapeutic to toxic ratio), enhanced risk factor for side effects (which may depend on underlying comorbidities or genetic predisposition), and the expected duration of treatment; as the longer an individual is exposed to a drug, the greater the potential for some side effects. the cmpa have provided some guidelines for risk management considerations in prescribing opioids 23 that are useful for all medication orders and may curtail medico-legal cases from drug adverse events. these medico-legal considerations are: 1. is there an appropriate indication for this drug? 2. is the starting dose and need for continuation appropriate? 3. have you considered the need for monitoring that would be reasonable for your patient? 4. have you considered the potential effect of any concomitant medication that might influence the dosing, monitoring, and side effects? 5. have you considered other factors such as comorbidity that might influence the dosing and monitoring? 6. are you prepared to diagnose and manage any adverse event? 7. have you counseled the patient on potential side effects, how to recognize early signs, and necessary actions? 8. when discharging patients, have you provided reasonable information about the risks of adverse reactions, precautions to be observed, and person to notify? patients who suffer from adverse effects may be willing to forgive a physician's failure to provide informed consent when that therapy is indicated. however, in situations where the treatments were not indicated, or of questionable value, then any adverse event would likely be unacceptable to the plaintiff or courts. a 38-year-old male with steroid-dependent crohn's colitis (diagnosed 6 years before) called his fp for advice regarding chickenpox from his young son who was recently diagnosed with it at a daycare center. the patient was experiencing retrosternal and epigastric pain on swallowing. the fp prescribed omeprazole 20 mg once daily and ibuprofen over the phone, without seeing the patient. later in the night of the same day, the man presented to the emergency department of a local hospital. the er physician noted that the patient was chronically on methylprednisolone 8 mg once daily for crohn's disease, and that he had developed local pustules consistent with early varicella within the past 4 days. however, the main concern of the patient was severe retrosternal, mid-chest pain on swallowing and radiating through his back for 24 h. the recorded vital signs showed a temperature of 38.3 c, blood pressure of 155/110 mmhg, heart rate of 81/min, and respiratory rate of 20/min. the examination revealed scattered vesicles/pustules on the patient's face, soft palate, and pharynx. treatment on discharge consisted of liquid bupivacaine swish and swallow (topical anesthetic), oxycodone-acetaminophen, and metoclopramide. an electrocardiogram was normal and the discharge diagnosis listed possible esophageal involvement with varicella. within 72 h, the subject returned to the same er with worsening symptoms, and was seen by the same physician. the symptoms consisted of swelling of his face, fever, sweats, productive cough of blood-streaked sputum, and persistent chest pain. examination reports revealed a very ill looking male with a temperature of 39.5 c, heart rate of 169/min, blood pressure of 131/87 mmhg, and respiratory rate of 30/min. his face was swollen and edematous with closure of the right eye, extensive vesicles and pustules on the face, soft palate with edema and inflammation of the gingivae, and numerous skin lesions over the trunk and proximal limbs. oxygen saturation on room air was 92% and the chest radiograph was reported as normal. investigations revealed anemia, thrombocytopenia, liver disturbance, and evidence of disseminated intravascular coagulopathy. intravenous acyclovir was started and the patient was transferred to the icu of a tertiary care center, where he died within 38 h after the second presentation. autopsy revealed disseminated varicella with involvement of the brain, lung, heart, liver, esophagus, and stomach. the wife and family of the deceased man launched medical malpractice litigation against the fp, er attending physician, and the local hospital. charges against the fp were as follows: (1) substandard care reasonably expected of a general practitioner, (2) he should have advised or warned the patient and provided early treatment, especially since he knew that his son had chickenpox, (3) he knew, or ought to have known that the deceased was immunosuppressed from chronic steroids and therefore at increased risk, (4) he failed to provide medical assistance and prescribe the correct drug (acyclovir) on presentation, (5) he failed to make the patient aware of the potential complications of his long-term steroid use, and (6) he failed to refer the deceased to an appropriate specialist. the accusations against the er attending physician were similar: (1) his negligence was the direct cause of the deceased's death, (2) his medical care fell below the standard reasonably expected from an er physician, (3) he ought to have known that the patient was immunosuppressed from steroids, and therefore at high risk for complications from chickenpox, (4) he failed to provide proper medical assistance and treatment, (5) he failed to appropriately admit the patient on initial presentation and institute intravenous acyclovir, and (6) he failed to consult an appropriate specialist (internist or infectious disease specialist). damages were sought by the plaintiffs for pain and suffering, deprivation of a husband and father, loss of economic benefit afforded to the family from potential employment earnings of the deceased over the next 27 years (assuming retirement at age 65). counsel for the defendants requested expert opinion on two key issues: (1) was the steroid dose the deceased received sufficient to cause immunosuppression? (2) if appropriate therapy with acyclovir were started at initial presentation with chickenpox, would the outcome have been any different? chickenpox (varicella) has dramatically declined in all age groups, but most markedly in children since the introduction of varicella vaccine in 1995 in north america and developed countries. since the introduction of the vaccine, the decline in varicella-related hospitalization in the us was greatest among 0-4 year-old children, but rates also declined in older youths (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) year) and adults. 24 in temperate regions, 90% of cases of varicella occur in children <10 years of age, 5% occur in individuals >15 years old, and adults (>20 year) only account for 2%. the risk of hospitalization and death is greater in young infants and adults than children, and most varicella-related deaths occur in previously healthy people. 25 although varicella is much less common in adults than children, 47% of the deaths from complications occur in adults. 26 in tropical and subtropical countries, the mean age of patients with varicella is higher than in temperate regions, and up to 40% of immigrants from these areas are susceptible to varicella. healthy children rarely suffer from complications of varicella, with the most common one being secondary bacterial infection (streptococcus and staphylococcus) of the skin and soft tissue. immunocompromised children are predisposed to more severe and progressive diseases (up to one third) with multiple organ involvement, lungs, liver, and central nervous system issues being the most frequent. 27 mortality in these children range from 15% to 18% and those with lympho-proliferative malignancies on chemotherapy have the greatest risk. bone marrow transplant recipients also have a high risk of varicella zoster virus (vzv) infection, with a probability of vzv infection at 30% by 1 year after transplant. 28 in a series of 231 cases of vzv infection, 36 presented with chickenpox and 195 with herpes zoster. the overall vzv infection mortality was 9.7% (23 of 231) -all with disseminated infection in the first 9 months. however, the mortality in those with herpes zoster was only 6.6% versus 27.7% of those with varicella. 28 high dose corticosteroids are also associated with significant complications of varicella and herpes zoster. 29 immunosuppression is most commonly seen with high daily dose of 1 mg/kg of prednisone or moderate doses for prolonged periods. rates of infectious complication were not increased in patients given a daily dose of less than 10 mg daily, or a cumulative dose of less than 700 mg prednisone in a meta-analysis of 73 controlled trials. 30 many experts consider prolonged daily dose 15 mg prednisone or equivalent to be immunosuppressive. the us food and drug administration (fda) states that low doses of prednisone (or similar agents) for prolonged periods may also increase the risk of infection. 31 corticosteroids can suppress several stages of the immune response that leads to inflammation, but the main immunosuppressive effect is on the cellular immunity. thus, steroids can increase the risk and severity of a variety of infectious agents (virus, bacteria, fungi, and parasites). most notable are agents that require intact cellular immunity for control and eradication, such as herpes viruses, mycobacteria, listeria, nocardia, pneumocystis, candida, cryptococci, toxoplasma, and strongyloides, etc., are increased in patients on prolonged corticosteroids. the effect of corticosteroids on the inflammatory and immune responses is pleomorphic. an earlier study in guinea pigs demonstrated that similar levels of lymphocytopenia were induced by acute and chronic corticosteroid administration, but only chronic treatment was associated with depression of certain cell-mediated lymphocyte functions. 32 chronic cortisone treatment resulted in marked decrease in both antigen-induced migration inhibitory factor (mif) and proliferation, although mitogen responses remained normal. over the last few decades, corticosteroids have been found to inhibit the function of various cell types: (1) macrophage/monocytesinhibit cyclooxygenase-2 and phospholipase a 2 (interrupting prostaglandin and leukotriene pathways), and suppress cytokine production and release of interleukin (il)-1, il-6, tumor necrosis factor (tnf)-a, (2) endothelial cells -impair endothelial leucocyte adhesion molecule-i (elam-i), and intracellular adhesion molecule-i (icam-i), that are critical for leucocyte localization, (3) basophils -block histamine and leukotriene 4c ige-dependent release, (4) fibroblast -inhibit arachidonic pathway (as with monocytes) and suppress growth factor-induced dna synthesis and fibroblast proliferation, (5) lymphocytes -inhibit cytokines il-1, il-2, il-3, il-6, tnf-a, gm-csf, and interferon g production or expression. 33 the association of steroid therapy and increased risk, severity and complications of vzv infections has been well established for decades. 34 patients receiving highdose corticosteroids are at risk for disseminated disease and fatality, whereas patients on low-dose schedules are not at increased risk. 34, 35 esophagitis and gastrointestinal involvement of vzv are distinctly rare and have been described in both immunocompromised hosts and apparently healthy subjects as complications of chickenpox or herpes zoster. disseminated varicella in autopsy studies of children with acute lymphoblastic leukemia or lymphoma on chemotherapy had demonstrated involvement of the esophagus, small bowel, colon, liver, spleen, and pancreas. 36 fulminant and fatal cases of varicella hepatitis have been described predominantly in immunosuppressed children and adults, but also in healthy people. 37 rare cases of adult varicella on chronic steroids (for asthma) have been reported with small bowel involvement presenting with abdominal pain and gastrointestinal bleeding. 38 however, it appears that the patient may have been on moderately high dose of methylprednisolone (40 mg daily). in an immunocompetent young adult on inhaled steroids for asthma, varicella has been reported to cause diffuse abdominal pain and tenderness with hepatic, esophageal, and pulmonary involvement, with recovery after acyclovir therapy. 39 bullous and necrotic ulcerative lesions of the esophagus and stomach have been described in the pathology literature of fatal varicella as early as 1940. 40 stomach and small bowel changes detected by radiological imaging has also been reported in a case of chickenpox. 41 occasionally healthy adults with varicella may have mild symptoms of esophagitis that respond to antihistamine-h2 blockers, suggesting temporary esophageal reflux. 42 shingles esophagitis have also been seen on endoscopy in patients without widespread dissemination of herpes zoster and benign course. 43 the deceased patient (case 3) was receiving 8 mg daily of methylprednisolone prior to his presentation with chickenpox. this dose is equivalent to 10 mg prednisone and normally would not be considered to be immunosuppressive. however, the course of the disease and widespread dissemination with fatality resembles that of an immunocompromised host. how can we explain this reaction? the possibilities include: (1) inaccurate history of the steroid dose provided by the patient, (2) rarely, dissemination and fatality can occur in healthy adults, (3) unrecognized immunocompromised state such as hiv infection or rare genetic mutations, or polymorphisms in genes involved in cellular immunity, and (4) higher free active concentration of the drug than would be expected. methylprednisolone (medrol) is 70% bound to protein, mainly albumin, and decrease in serum albumin by 30-50% could increase the active unbound drug almost to the same proportion. on admission to hospital, the patient's serum albumin was 15 g/l (lower limit of normal 35 g/l), 42% of the normal lower limit. although the serum albumin can decrease in acute illness from varicella, the half-life of circulating albumin is 15 days and thus, even after 7 days of chickenpox, it should not decrease more than 25% below normal, even if his liver stopped producing any protein (which is not likely). hence, the patient probably had a chronically low serum albumin from his chronic colitis. his free concentration of corticosteroid should have been greater than 50% of his expected active drug, which is equivalent to 15 mg prednisone/day. can this information absolve the defendants from responsibility of the patient's adverse outcome? it could be argued by the defendants that it is not common knowledge or usual practice to consider the protein binding effects of drugs on their toxicity. furthermore, it would not be expected that the fp and er physicians be cognizant of these facts. the defendants maintain that their management did not fall below the expected standard of care, and most reasonable physicians would not have considered the patient immunocompromised on such a low dose of prednisolone. the outcome was unpredictable and only in hindsight was it evident that the deceased was likely immunocompromised and susceptible to a higher risk for adverse outcome. experts' opinions for the plaintiffs' side argued that the involved physicians should have been aware that adults (even normal hosts) are at a greater risk of severe disease and complications than children from chickenpox are. therefore, the fp and er physician were remiss in not prescribing antiviral drug (acyclovir). the er physician should have admitted the deceased at the first presentation and started intravenous acyclovir, as he suspected visceral dissemination (esophagitis) with varicella, irrespective of the immune state of the patient. previous randomized control trial (rct) of oral acyclovir therapy for uncomplicated varicella in healthy adults have reported mild clinical benefit (decrease of symptoms, fever and time to cutaneous healing), but only in those initiating treatment within 24 h of the rash. 44 late treatment (25-72 h) had no benefit. the low frequency of serious complications (pneumonia, encephalitis, or death) precluded any evaluation of acyclovir on these outcomes. in immunocompromised patients with vzv infection, later initiation of therapy (72 h after onset of rash) may be of value. 45, 46 although there is no rct to prove the benefit of intravenous acyclovir in normal adults with varicella complicated by visceral involvement, observational and cohort studies suggest benefit. 47 thus, intravenous acyclovir continues to be the standard therapy for healthy adults and immunocompromised hosts with clinically significant visceral disease (pneumonia, encephalitis) or dissemination. chronic corticosteroid therapy can have numerous side effects and complications. it is important for physicians to counsel their patients on these potential adverse events, and provide a risk-benefit assessment. many organs and systems in the body can be adversely affected by chronic steroid therapy (endocrine, bone, eyes, muscle, brain, immune system, skin, etc.). it is important to counsel on potential increased risk of infectious diseases and certain precautions should be taken before embarking on chronic therapy. these include a mantoux skin test and treatment for latent tuberculosis in those with positive reactions and about to receive prednisone 15 mg/day for 30 days. 48 a baseline chest radiograph for active or inactive disease should be performed beforehand. it is also recommended that steroid dependent children should undergo vzv antibody test, and if this were negative, then varicella vaccination should be offered. 33 it seems prudent to apply these guidelines to adults as well on chronic steroid therapy. for patients with previous chickenpox or adequate antibodies, varicella zoster vaccine may be considered to reduce the risk and severity of shingles. this vaccine, a live attenuated vaccine has been found effective and is recommended for persons 60 years of age to reduce the burden of illness and incidence of postherpetic neuralgia. 49 presently, this vaccine is not indicated in immunocompromised adults, so it should be administered before starting prolonged steroids. the product monograph of zostavax tm (merck), states that the varicella zoster vaccine is contraindicated in patients receiving high-dose corticosteroid, but not contraindicated for individuals on inhaled or low-dose steroids. the varicella vaccine has been found safe in children with moderate immune deficiency, 50 but it is contraindicated in those with substantial suppression of cellular immunity (as with high-dose steroid). 51 what should have been the appropriate steps of action in this case? once the fp was notified that the patient's child had chickenpox, he should have counseled the father and determined his previous past history or antibody level against vzv. for patients considered non-immune and severely immunosuppressed (moderate to high-dose corticosteroid (20 mg/day) vzv immune globulin should be offered and treatment with acyclovir should be instituted at the first sign of varicella. 33 since the deceased was considered to be receiving a low dose of steroid, then it was more appropriate to offer treatment with acyclovir at the first sign of a typical rash, or provide a prescription to be filled within 24 h of onset of varicella. ahfs drug information changes in the transmission of tuberculosis in the new york city from 1990 to 1999 advanced survey of tuberculosis transmission in a complex socioepidemiologic scenario with a high proportion of cases in immigrants trends in tuberculosis incidence -united states the global plan to stop tb 2006-2015. world health organization global tuberculosis control: epidemiology strategy, financing. world health organization report drug-induced liver disease and environmental toxins hepatic toxicity of antitubercular agents. role of different drugs, 199 cases risk factor for isoniazid (inh)-induced liver dysfunction harrison's principles of internal medicine isoniazid antituberculosis drug-induced hepatotoxicity: concise up-to-date review emergency issues in head and neck infections. in: emerging issues and controversies in infectious disease infectious rhinosinusitis in adults: classification, etiology and management bacteriologic finding associated with chronic bacterial maxillary sinusitis in adults adverse reactions to trimethoprim-sulfamethoxazole epidermal necrolysis (stevens-johnson syndrome and toxic epidermal necrolysis) medication use and the risk of stevens-johnson syndrome or toxic epidermal necrolysis scorten: a severity-of-illness score for toxic epidermal necrolysis performance of the scorten during the first five days of hospitalization to predict the prognosis of epidermal necrolysis toxic epidermal necrolysis: does immunoglobulin make a difference? intravenous immunoglobulin treatment for steven-johnson syndrome and toxic epidermal necrolysis: prospective non-comparative study showing no benefit in mortality or progression adverse events -physician-prescried opioids. risk identification for all physicians fitzpatrick's dermatology in general medicine the epidemiology of varicella and its complications varicella complications and cost varicella in children with cancer.: seventy seven cases infection with varicella zoster virus after marrow transplantation varicella and herpes zoster: changing concepts of the natural history, control and importance of a not-so-benign virus (first of two parts) glucocorticoids and infection hormones and synthetic substitutes: adrenals immunosuppressive effects of glucocorticosteroids: differential effects of acute vs chronic administration on cell-mediated immunity adrenocorticotropic hormone, adrenocortical steroids and their synthetic analogs: inhibitors of synthesis and actions of adrenocortical hormones varicella and herpes zoster: changes in concepts of natural history, control and importance of a not-so-benign virus (second of two parts) the human herpesviruses: an interdisciplinary perspective disseminated varicella at autopsy in children with cancer varicella hepatitis in the immunocompromised adult: a case report and review of the literature fatal varicella in an adult: case report and review of gastrointestinal complications of chickenpox digestive manifestations in an immunocompetent adult with varicella visceral lesions associated with varicella cimetidine in "chickenpox esophagitis shingles esophagitis: endoscopic diagnosis in two patients treatment of adult varicella with acyclovir. a randomized placebo-controlled trial acyclovir halts progression of herpes zoster in immunocompromised patients treatment of varicella-zoster virus infections in severely immunocompromised patients early treatment with acyclovir for varicella pneumonia in otherwise healthy adults: retrospective controlled study and review in the clinic: tuberculosis for the shingles prevention study group a vaccine to prevent herpes zoster and postherpetic neuralgia in older patients varicella vaccine in children with acute lymphoblastic leukemia and non-hodgkin lymphoma general recommendations on immunization. recommendations of the advisory committee on immunization practices (acip) key: cord-200147-ans8d3oa authors: arimond, alexander; borth, damian; hoepner, andreas; klawunn, michael; weisheit, stefan title: neural networks and value at risk date: 2020-05-04 journal: nan doi: nan sha: doc_id: 200147 cord_uid: ans8d3oa utilizing a generative regime switching framework, we perform monte-carlo simulations of asset returns for value at risk threshold estimation. using equity markets and long term bonds as test assets in the global, us, euro area and uk setting over an up to 1,250 weeks sample horizon ending in august 2018, we investigate neural networks along three design steps relating (i) to the initialization of the neural network, (ii) its incentive function according to which it has been trained and (iii) the amount of data we feed. first, we compare neural networks with random seeding with networks that are initialized via estimations from the best-established model (i.e. the hidden markov). we find latter to outperform in terms of the frequency of var breaches (i.e. the realized return falling short of the estimated var threshold). second, we balance the incentive structure of the loss function of our networks by adding a second objective to the training instructions so that the neural networks optimize for accuracy while also aiming to stay in empirically realistic regime distributions (i.e. bull vs. bear market frequencies). in particular this design feature enables the balanced incentive recurrent neural network (rnn) to outperform the single incentive rnn as well as any other neural network or established approach by statistically and economically significant levels. third, we half our training data set of 2,000 days. we find our networks when fed with substantially less data (i.e. 1,000 days) to perform significantly worse which highlights a crucial weakness of neural networks in their dependence on very large data sets ... while leading papers on machine learning in asset pricing focus on predominantly returns and stochastic discount factors (chen, pelger & zhu 2020; gu, kelly & xiu 2020) , we are motivated by the global coid-19 virus crisis and the subsequent stock market crash to investigate if and how machine learning methods can enhance value at risk (var) threshold estimates. in line with gu, kelly & xiu's (2020: 7) , we like to open by disclaiming our awareness that " [m] achine learning methods on their own do not identify deep fundamental associations" .without human scientists designing hypothesized mechanisms into an estimation problem. 1 nevertheless, measurement errors can be reduced based on machine learning methods. hence, machine learning methods employed as means to an end instead of as end in themselves can significantly support researchers in challenging estimation tasks. 2 in their already legendary paper, gu, kelly & xiu (gkx in the following, 2020) apply machine learning to a key problem in academic finance literature: 'measuring asset risk premia'. they observe that machine learning improves the description of expected returns relative to traditional econometric forecasting methods based on (i) better out-ofsample r-squared and (ii) forecasts earning larger sharpe ratios. more specifically, they compare four 'traditional' methods (ols, glm, pcr/pca, pls) with regression trees (e.g. random forests) and a simple 'feed forward neural network' based on 30k stocks over 720 months , using 94 firm characteristics, 74 sectors and 900+ baseline signals. crediting inter alia (i) flexibility of functional form and (ii) enhanced ability to prioritize vast sets of baseline signals, they find the feed forward neural networks (ffnn) to perform best. contrary to results reported from computer vision, gkx further observe that "'shallow' learning outperforms 'deep' learning" (p.47), as their neural network with 3 hidden layers excels beyond neural networks with more hidden layers. they interpret this result as a consequence of a relatively much lower signal to noise ratio and much smaller data sets in finance. interestingly, the outperformance of nns over the other 5 methods widens at portfolio compared to stock level, another indication that an understanding of the signal to noise ratio in financial markets is crucial when training neural networks. that said, while classic ols is statistically significantly weaker than all other models, nn3 beats all others but not always at statistically significant levels. gkx finally confirm their results via monte carlo simulations. they show that if one generated two hypothetical security price datasets, one linear and un-interacted and one nonlinear and interactive, ols and glm would dominate in former, while nns dominate in the latter. they conclude by attributing the "predictive advantage [of neural networks] to accommodation of nonlinear interactions that are missed by other methods." (p.47) following gkx, an extensive literature on machine learning in finance is rapidly emerging. chen, pelger and zhu (cpz in the following, 2020) introduce more advanced (i.e. recurrent) neural networks and estimate a (i) non-linear asset pricing model (ii) regularized under no-arbitrage conditions operationalized via a stochastic discount factor (iii) while considering economic conditions. in particular they attribute the time varying dependency of the stochastic discount factor of about ten thousand us stocks to macroeconomic state processes via a recurrent long short term memory (lstm) network. in cpz's (2020: 5) view "it is essential to identify the dynamic pattern in macroeconomic time series before feeding them into a machine learning model". avramov et al. (2020) replicate the approaches of gkx's (2020) , cpz (2020) , and two conditional factor pricing models: kelly, pruitt, and su's (2019) linear instrumented principal component analysis (ipca) and gu, kelly, and xiu's (2019) nonlinear conditional autoencoder in the context of real-world economic restrictions. while they find strong fama french six factor (ff6) adjusted returns in the original setting without real world economic constraints, these returns reduce by more than half if microcaps or firms without credit ratings are excluded. in fact, when avramov et al. (2020: 3) are "[e]xcluding distressed firms, all deep learning methods no longer generate significant (valueweighted) ff6-adjusted return at the 5% level." they confirm this finding by showing that the gkx (2020) and cpz (2020) machine learning signals perform substantially weaker in economic conditions that limit arbitrage (i.e. low market liquidity, high market volatility, high investor sentiment). curiously though, avramov et al. (2020: 5) find that the only linear model they analyse kelly et al.'s (2019) ipca -"stands out … as it is less sensitive to market episodes of high limits to arbitrage." their finding as well as the results of cpz (2020) imply that economic conditions have to be explicitly accounted for when analysing the abilities and performance of neural networks. furthermore, avramov et al. (2020) as well as gkx (2020) and cpz (2020) make anecdotal observations that machine learning methods appear to reduce drawdowns. 1 while their manuscripts focused on return predictability, we devote our work to risk predictability in the context of market wide economic conditions. the covid-19 crisis as well as the density of economic crisis in the previous three decades imply that catastrophic 'black swan' type risks occur more frequent than predicted by symmetric economic distributions. consequently, underestimating tail risks can have catastrophic consequences for investors. hence, the analysis of risks with the ambition to avoid underestimations deserves, in our view, equivalent attention to the analysis of returns with its ambition to identify investment opportunities resulting from mispricing. more specifically, since a symmetric approach such as the "mean-variance framework implicitly assumes normality of asset returns, it is likely to underestimate the tail risk for assets with negatively skewed payoffs" (agarwal & naik, 2004:85) . empirically, equity market indices usually exhibit, not only since covid-19, negative skewness in its return payoffs (albuquerque, 2012 , kozhan et al. 2013 . consequently, it is crucial for a post covid-19 world with its substantial tail risk exposures (e.g. second pandemic wave, climate change, cyber security) that investors provided with tools which avoid the underestimation of risks best possible. naturally, neural networks with their near unlimited flexibility in modelling non-linearities appear suitable candidates for such conservative tail risk modelling that focuses on avoiding giglio & xiu (2019) , and kozak, nagel & santosh (2020) as also noteworthy, as are efforts by fallahgouly and franstiantoz (2020) and horel and giesecke (2019) to develop significant tests for neural networks. our paper investigates is basic and/or more advanced neural networks have the capability of underestimating tail risk less often at common statistical significance levels. we operationalize tail risk as value at risk which is the most used tail risk measure in both commercial practice as well as academic literature (billio et al. 2012 , billio and pellizon, 2000 , jorion, 2005 , nieto & ruiz, 2015 . specifically, we estimate var thresholds using classic methods (i.e. mean/variance, hidden markov model) 1 as well as machine learning methods (i.e. feed forward, convolutional, recurrent), which we advance via initialization of input parameter and regularization of incentive function. recognizing the importance of economic conditions (avramov et al. 2020 , chen et al. 2020 , we embed our analysis in a regime-based asset allocation setting. specifically, we perform monte-carlo simulations of asset returns for value at risk threshold estimation in a generative regime switching framework. using equity markets and long term bonds as test assets in the global, us, euro area and uk setting over an up to 1,250 weeks sample horizon ending in august 2018, we investigate neural networks along three design steps relating (i) to the initialization of the neural network's input parameter, (ii) its incentive function according to which it has been trained and which can lead to extreme outputs if it is not regularized as well as (iii) the amount of data we feed. first, we compare neural networks with random seeding with networks that are initialized via estimations from the best-established model (i.e. the hidden markov). we find latter to outperform in terms of the frequency of var breaches (i.e. the realized return falling short of the estimated var threshold). second, we balance the incentive structure of the loss function of our networks by adding a second objective to the training instructions so that the neural networks optimize for accuracy while also aiming to stay in empirically realistic regime distributions (i.e. bull vs. bear market frequencies). this design features leads to better regularization of the neural network, as it substantially reduces extreme outcomes than can result from a single incentive function. in particular this design feature enables the balanced incentive recurrent neural network (rnn) to outperform the single incentive rnn as well as any other neural network or established approach by statistically and economically significant levels. third, we half our training data set of 2,000 days. we find our networks when fed with substantially less data (i.e. 1,000 days) to perform significantly worse which highlights a crucial weakness of neural networks in their dependence on very large data sets. our contributions are fivefold. first, we extend the currently return focused literature of machine learning in finance (avramov et al. 2020 , chen et al. 2020 gu et al. 2020) to also focus on the estimation of risk thresholds. assessing the advancements that machine learning can bring to risk estimation potentially offers valuable innovation to asset owners such as pension funds and can better protect the retirement savings of their members. 2 second, we advance the design of our three types of neural networks by initializing their input parameter with the best established model. while initializations are a common research topic in core machine learnings fields such as image classification or machine translation (glorot & bengio, 2010 , we are not aware of any systematic application of initialized neural networks in the field of finance. hence, demonstrating the statistical superiority of an initialized neural network over itself non-initialized appears a relevant contribution to the community. third, while cpz (2020) regularize their neural networks via no arbitrage conditions, we regularize via balancing the incentive function of our neural networks on multiple objectives (i.e. estimation accuracy and empirically realistic regime distributions). this prevents any single objective from leading to extreme outputs and hence balances the computational power of the trained neural network in desirable directions. in fact, our results show that amendments to the incentive function maybe the strongest tool available to us in engineering neural networks. fourth, we also hope to make a marginal contribution to the literature on value at risk estimation. whereas our paper is focused on advancing machine learning techniques and is therefore following billio and pellizon (2000) anchored in a regime based asset allocation setting 1 to account for time varying economic states (cpz, 2020), we still believe that the nonlinearity and flexible form especially of recurrent neural networks maybe of interesting to the var (forecasting) literature (billio et al. 2012 , nieto & ruiz, 2015 , patton et al. 2019 . fifth, our final contribution lies in the documentation of weaknesses of neural networks as applied to finance. while avramov et al. (2020) subjects neural networks to real world economic constraints and finds these to substantially reduce their performance, we expose our neural networks to data scarcity and document just how much data these new approaches need to advance the estimation of risk thresholds. naturally, such long data history may not always be available in practice when estimating asset management var thresholds and therefore established methods and neural networks are likely to be used in parallel for the foreseeable future. in section two, we will describe our testing methodology including all five competing models (i.e. mean/variance, hidden markov model, feed forward neural network, convolutional neural network, recurrent neural network). section three describes data, model training, monte carlo simulations and baseline results. section four then advances our neural networks via initialization and balancing the incentive functions and discusses the results of both features. section five conducts robustness tests and sensitivity analyses before section six concludes. 1 we acknowledge that most recent statistical advances in value at risk estimation have concentrated on jointly modelling value at risk and expected shortfall and were therefore naturally less focused on time varying economic states (patton et al. 2019 , taylor 2019 , 2020 ). value at risk estimation with mean/variance approach when modelling financial time series related to investment decisions the asset return of portfolio (p) at time (t) as defined in equation (1) below is the focal point of interest instead of asset price , since investors earn on the difference between the price at which they sold. value-at-risk (var) metrics are an important tool in many areas of risk management. our particular focus on var measures as a means to perform risk budgeting in asset allocation. asset owners such as pension funds or insurances as well as asset managers often incorporate var measures into their investment processes (jorion, 2005) . value at risk is defined as in equation (2) as the lower bound of a portfolio's return, which the portfolio or asset is not expected to fall short off with a certain probability (a) within the next period of allocation (n). pr ( + < − ( )) = for example, an investment fund indicates that, based on the composition of its portfolio and on current market conditions, there is a 95% or 99% probability it will not lose more than a specified amount of assets over the next 5 trading days the var measurement can be interpreted as a threshold (billio and pellizon 2000) . if the actual portfolio or asset return falls below this threshold, we refer to this a var breach. the classic mean variance approach of measuring var values is based on the assumption that asset returns follow a (multivariate) normal distribution. var thresholds can then be measured by estimating the mean and covariance ( , σ) of the asset returns by calculating sample mean and sample covariance of the respective historical window. the 1% or 5% percentile of the resulting normal distribution will be an appropriate estimator of the 95% or 99% var threshold. we refer to this way of estimating var thresholds as being the "classical" approach and use it as baseline of our evaluation. this classic approach, however, does not sufficiently reflect the skewness of real world equity markets and the divergences of return distributions across different economics regimes. in other words, the classic approach does not take into account longer term market dynamics, which express themselves as phases of growth or of downside, also commonly known as bull market and bear markets. for this purpose, regime switching models have grown in popularity well before machine learning entered finance (billio and pellizon 2000) . in this study, we model financial markets inter alia using neural networks while accounting for shifts in economics regimes (avramov et al. 2020 , chen et al., 2020 . due to the generative nature of these networks, they are able to perform monte-carlo simulation of future returns, which could be beneficial for var estimation. in asset manager's risk budgeting it is advantageous to know about the current market phase (regime) and estimate the probability that the regime changes (schmeding et al., 2019) . the most common way of modelling market regimes is by distinguishing between bull markets and bear markets. unfortunately, market regimes are not directly observable, but are rather to be derived indirectly from market data. regime switching models based on hidden markov models are an established tool for regime based modelling. hidden markov models (hmm)which are based on markov chains -are models that allow for analysing and representing characteristics of time series such as negative skewness (ang and bekaert, 2002; timmerman, 2000) . we employ the hmm for the special case of two economic states called 'regimes' in the hmm context. specifically, we model asset returns y t ∈ n (we are looking at n ≥ 1 assets) at time t to follow an n-dimensional gaussian process with hidden states s ∈ {1, 2} as shown in equation (3): the returns are modelled to have state dependent expected returns μ ∈ as well as covariance σ ∈ . the dynamic of is following a homogenous markov chain with transition probability matrix with = ( = 1 | | −1 = 1 ) and = ( = 2 | | −1 = 2 ) . this definition describes if and how states are changing over time. it is also important to note the 'markov property' that the probability of being in any state at the next point in time only depends on the present state, not the sequence of states that preceded it. furthermore, the probability of being in a state at a certain point in time is given as π = ( = 1) and (1 − π ) = ( = 2). this is also called smoothed state probability. by estimating the smoothed probability πt of the last element of the historical window as the present regime probability, we can use the model to start from there and perform monte-carlo simulations of future asset returns for the next days. 1 this is outlined for the two-regimes case in figure 1 below. 2 figure 1 : algorithm for the hidden markov monte-carlo simulation (for two regimes) 1: estimate = ( 0 , , , σ) from history when graves [13] successfully made use of a long short-term memory (lstm) based recurrent neural network to generate realistic sequences of handwriting, he followed the idea of using a mixture density network (mdn) to parametrize a gaussian mixture predictive distribution (bishop, 1995) . compared to standard neural networks (multi-layer perceptron) as used by gkx (2020), this network does not only predict the conditional average of the target variable as point estimate (in gkx' case expected risk premia), but rather estimates the conditional distribution of the target variable. given the autoregressive nature of graves' approach, the output distributions are not assumed to be static over time, but dynamically conditioned on previous outputs, thus capturing the temporal context of the data. we consider both characteristics as being beneficial for modelling financial market returns, which experience a low signal to noise ratio as highlighted by gkx' results due to inherently high levels of intertemporal uncertainty. the core of the proposed neural network regime switching framework is a (swappable) neural network architecture, which takes as input the historical sequence of daily asset returns. at the output level, the framework computes regime probabilities and provides learnable gaussian mixture distribution parameters, which can be used to sample new asset returns for monte-carlo simulation. a multivariate gaussian mixture model (gmm) is a weighted sum of k different components, each following a distinct multivariate normal distribution as shown in equation (5): a gmm by its nature does not assume a single normal distribution, but naturally models a random variable as being the interleave of different (multivariate) normal distributions. in our model, we interpret k as the number of regimes and φi explains how much each regime contributes to the (current output). in other words, φi can be seen as the probability that we are in regime i. in this sense the gmm output provides a suitable level of interpretability for the use case of regime based modelling. with regard to the neural network regime switching model, we extend the notion of a gaussian mixture by conditioning φi via a yet undefined neural network f on the historic asset returns within a certain window of a certain size. we call this window receptive field and denote its size by r: this extension makes the gaussian mixture weights dependent on the (recent) history of the time varying asset returns. note that we only condition φ on the historical returns. the other parameters of the gaussian mixture ( , σ ), are modelled as unconditioned, yet optimizable parameters of the model. this basically means we assume the parameters of the gaussians to be constant over time (per regime). this is in contrast to the standard mdn, where ( , σ ) are also conditioned on and therefore can change over time. 1 keeping these remaining parameters unconditional is crucial to allow for a fair comparison between the neural networks and the hmm, which also exhibits time invariant parameters ( , σ ) in its regime shift probabilities. following graves (2013), we define the probability given by the network and the corresponding sequence as shown in equation (7) and (8), respectively: since financial markets operate in weekly cycles with many investors shying away from exposure to substantial leverage during the illiquid weekend period, we are not surprised to observe that model training is more stable when choosing the predictive distribution to not only be responsible for the next day, but for the next 5 days (hann and steuer, 1995) . we call this forward looking window the lookahead. this is also practically aligned with the overall investment process, in which we want to appropriately model the upcoming allocation period, which usually spans multiple days. it also fits with the intuition that regimes do not switch daily but have stability at least for a week. the extended sequence probability and sequence loss are denoted accordingly in equations (9) and (10): an important feature of the neural network regime model is how it simulates future returns. we follow graves (2013) approach and conduct sequential sampling from the network. when we want to simulate a path of returns for the next n business days, we do this according to the algorithm displayed in figure 2 . in accordance with gkx (2020) we first focus our analysis on traditional "feed-forward" neural networks before engaging in more sophisticated neural network architectures for time series analysis within the neural network regime model. the traditional model of neural networks, also called multi-layer perceptron, consists of an "input layer" which contains the raw input predictors and one or more "hidden layers" that combine input signals in a nonlinear way and an "output layer", which aggregates the output of the hidden layers into a final predictive signal. the nonlinearity of the hidden layers arises from the application of nonlinear "activation functions" on the combined signals. we visualise the traditional feed forward neural network and its input layers in figure 4 . we setup our network structure in alignment with gkx's (2020) best performance neural network 'nn3'. the setup of our network is thus given with 3 hidden layers with decreasing number of hidden units (32, 16, 8) . since we want to capture the temporal aspect of our time series data, we condition the network output on at least a receptive field of 10 days. even though the receptive field of the network is not very high in this case, the dense structure of the network results in a very high number of parameters (1698 in total, including the gmm parameters). in between layers, we make use of the activation function tanh. convolutional neural networks (cnns) can also be applied within the proposed neural network regime switching model. recently, cnns gained popularity for time series analysis, as for example van den oord et al. (2015) successfully applied convolutional neural networks on time series data for generating audio waveforms, the state-ofthe-art text-to-speech and music generation. their adaption of convolutional neural networkscalled wavenethas shown to be able to capture long ranging dependencies on sequences very well. in its essence, a wavenet consists of multiple layers of stacked convolutions along the time axis. crucial features of these convolutions are that they have to be causal and dilated. causal means that the output of a convolution only depends on past elements of the input sequence. dilated convolutions are ones that exhibit "holes" in their respective kernel, which effectively means that its filter size increases while being dilated with zeros in between. wavenet typically is constructed with increasing dilation factor (doubling in size) in each (hidden) layer. by doing so, the model is capable of capturing an exponentially growing number of elements from the input sequence depending on the number of hidden convolutional layers in the network. the number of captured sequence elements is called the receptive field of the network (and in this sense is equal to the receptive field defined for the neural network regime model). 1 the convolutional neural network (cnn), due to its structure of stacked dilated convolutions, has a much greater receptive field than the simple feed forward network and needs much less weights to be trained. we restricted the number of hidden layers to 3 to illustrate the idea. our network structure has 7 hidden layers. each hidden layer furthermore exhibits a number of channels, which are not visualized here. figure 5 illustrates the networks basic structure as a combination of stacked causal convolutions with a dilation factor of d = 2. the backing model presented in this investigation is inspired by wavenet, we restrict the model to the basic layout, using causal structure and increasing dilation between layers. the output layer comprises the regime predictive distributions by applying a softmax function to the hidden layers' outputs. our network consists of 6 hidden layers, each layer having 3 channels. the convolutions each have a kernel size of 3. in total, the network exhibits 242 weights (including gmm parameters), the receptive field has a size of 255 days. as graves (2013) was very successful in applying lstm for generating sequences, we also adapt this approach for the neural network regime switching model. originally introduced by hochreiter and schmidhuber (1997), a main characteristic of lstmswhich are a sub class of recurrent neural networks -is its purpose-built memory cells, which allows it to capture long range dependencies in the data. from a model perspective, lstms differ from other neural network architectures in that they are applied recurrently (see figure 6 ). the output from a previous sequence of the network function servesin combination with the next sequence element -as input for the next application of the network function. in this sense, the lstm can be interpreted as being similar to an hmm, in that there is a hidden state which conditions the output distribution. however, the lstm hidden state not only depends on its previous states, but it also captures long term sequence dependencies through its recurrent nature. maybe most notably, the receptive field size of an lstm is not bound architecture wise as in case of simple feed forward network and cnn. instead, the lstm's receptive field depends solely on the lstms ability to memorize the past input. in our architecture we have one lstm layer with a hidden state size of 5. in total, the model exhibits 236 parameters (including the gmm parameters). the potential of lstms was noted by cpz (2020: 6) who note that "lstms are designed to find patterns in time series data and … are among the most successful commercial ais". 3 assessment procedure we obtain daily price data for stock and bond indices globally for three major global markets (i.e. eu, uk, us) to study the presented regime based neural network approaches on a variety of stock markets and bond markets. for each stock market, we focus on one major stock index. for bond markets, we further distinguish between long term bond indices (7-10 years) and short term bond indices (1-3 years). the markets in scope are (1) the data dates back to at least january 1990 and ends with august 2018, which means covering almost 30 years of market development. hence, the data also accounts for crises like the dot-com bubble in the early 2000s as well as the financial crisis of 2008. this is especially important for testing the regime based approaches. the price indices are given as total return indices (i.e. dividends treated as being reinvested) to properly reflect market development. the data is taken from refinitiv's datastream. descriptive statistics are displayed in table 1 , whereby panel a displays a daily frequency and panel b a weekly frequency. mean returns for equities exceed the returns for bond whereby the longer bond return more than the shorter one. equities have naturally a much higher standard deviation and a far worse minimum return. in fact, equity returns in all four regions lose substantially more money than bond return even at the 25 th percentile, which highlights that the holy grail of asset allocation is the ability to predict equity market drawdowns. furthermore, equity markets tend to bequite negatively skewed as expected while short bonds experience a positive skewness, which reflects previous findings (albuquerque, 2012 , kozhan et al. 2013 ) and the inherent differential in the riskiness of both asset's payoffs. [insert table 1 about here] the back testing is done on a weekly basis via a moving window approach. at each point in time, the respective model is fitted by providing the last 2,000 days (which is roughly 8 years) as training data. we choose this long range window, because neural networks are known to need big datasets as inputs and it is reasonable to assume that over eight years include simultaneously times of (at least relative) crisis and times of market growth. covering both bull and bear markets in the training sample is crucial to allow the model to "learn" these types of regimes. 1 for all our models we set the number of regimes to k = 2. as we back test an allocation strategy with a weekly re-allocation, we set the lookahead for the neural network regime models to 5 days. we further configured the back testing dates to always align with the end of a business week (i.e. fridays). the classic approach does not need any configuration, model fitting is same as computing sample mean and sample covariance of the asset returns within the respective window. the hmm also does not need any more configuration, the baum-welch algorithm is guaranteed to converge the parameters into a local optimum with respect to the likelihood function (baum, 1970) . for the neural network regime models, additional data processing is required to learn network weights that lead to meaningful regime probabilities and distribution parameters. an important pre-processing step is input normalization, as it is considered good practice for neural network training (bishop, 1995) . for this purpose, we normalize the input data by ' = ( − ( )) / ( ) . in other words, we demean the input data and scale them by their variance but without removing the interactions between the assets. we train the network by using the adamax optimizing algorithm (kingma & ba, 2014) and at the same time applying weight decay to reduce overfitting (krogh & hertz, 1992) . learning rate and number of epochs configured for training vary depending on the model. in general, estimating parameters of a neural network model is a non-convex optimization problem. thus, the optimization algorithm might become stuck in an infeasible local optimum. in order to mitigate this problem, it is common practice to repeat the training multiple times, starting off having different (usually randomly chosen) parameter initializations, and then averaging over the resulting models or picking the best in terms of loss. in this paper, we follow a best-out-of-5 approach, that means each training is done five times with varying initialization and the best one is selected for simulation. the initialization strategy, which we will show in chapter 4.1, further mitigates this problem by starting off from an economically reasonable parameter set. we observe that the in-sample regime probabilities learned by the neural network regime switching models as compared to those estimated by the hmm based regime switching model generally show comparable results in terms of distribution and temporal dynamics. when we set k = 2 and the model fits two regimes with nearly invariably one having a positive corresponding equity means and low volatility, and the other experiencing a low or negative equity mean and high volatility. these regimes can be interpreted as bull and bear market, respectively. the respective insample regime probabilities over time also show strong alignment with growth and drawdown phases. this holds true for the vast majority of seeds and hence indicates that the neural network regime model is a valid practical alternative for regime modelling when compared to a hidden markov model. after training the model for a specific point in time, we start a monte carlo simulation of asset returns for the next 5 days (one week -monday to friday). for the purpose of calculating statistically solid quantiles of the resulting distribution, we simulate 100,000 paths for each model. we do this for at least 1093 (emu), and at most 1250 (globally) points in time within the back-test history window. as soon as we have simulated all return paths, we calculate a total (weekly) return for each path. the generated weekly returns follow a non-trivial distribution, which arises from the respective model and its underlying temporal dynamics. based on the simulations we compute quantiles for value at risk estimations. for example, the 0.01 and 0.05 percentile of the resulting distribution represent the 99% and 95% -5 day -var metric, respectively. we evaluate the quality of our value at risk estimations by counting the number of breaches of the asset returns. in case, the actual return is below the estimated var threshold, we count this as a breach. assuming an average performing model, it is e.g. reasonable to expect 5% breaches for a 95% var measurement. we compared the breaches of all models with each other. we classify a model as being superior to another model, if the number of var breaches is less than those from the compared model. a value comparison comp = 1.0(= 0.0) indicates that the row model is superior (inferior) to the column model. we performed significance tests by applying paired t-tests. we further evaluated a dominance value which is defined as shown in equation (11): in our view the three most crucial design features of neural networks in finance, where the sheer number of hidden layers appears less helpful due to the low signal to noise ratio (gkx, 2020), are: amount of input data, initializing information and incentive function. big input data is important for neural networks, as they need to consume sufficient evidence also of rarer empirical features to ensure that their nonlinear abilities in fitting virtually any functional form are used in a relevant instead of an exotic manner. similarly, the initialization of input parameters should be as much as possible based on empirically established estimates to ensure that the gradient descent inside the neural network takes off from a suitable point of departure, thereby substantially reducing the risks that a neural network confuses itself into irrelevant local minima. on the output side, every neural network is trained according to an incentive (i.e. loss) function. it is this particular loss function which determines the direction of travel for the neural network, which has no other ambitions than to minimize its loss best possible. hence, if the loss function only represents one of several practically relevant parameters, the neural network may come to results with bizarre outcomes for those parameters not included in its incentive function. in our case, for instance, the baseline incentive is just estimation accuracy which could lead to forecasts dominated much more by a single regime than ever observed in practice. in other words, after a long bull market, the neural network could "conclude" that bear markets do not exist. metaphorically spoken, a unidimensional loss function in a neural network has little decency (marcus, 2018) . commencing with the initialization and the incentive functions, we will assess our three neural networks in the following vis a vis classic and hmm approach, where each of the three networks is once displayed with an advanced design feature and once with a naïve design feature. if no specific initialization strategy for neural networks is defined, it occurs entirely random, normal via a computer generated random number. where established econometric approaches use naïve priors (i.e. mean), neural networks originally relied on brute force computing power and a bit of luck. hence, it is unsurprising that initializations are a common research topic in core machine learnings fields such as image classification or machine translation (glorot & bengio, 2010 nowadays. however, we are not aware of any systematic application of initialized neural networks in the field of finance. hence, we compare naïve neural networks, which are not initialized with neural networks that have been initialized with the best available prior. in our case, the best available prior for , σ of the model is the equivalent hmm estimation based on the same window. 1 such initialization is feasible, since the structure of the neural network -due to its similarity with respect to , σis broadly comparable with the hmm. in other words, we make use of already trained parameters from hmm training as starting parameters for the neural network training. in this sense, initialized neural networks are not only flexible in their functional form, they are also adaptable to "learn" from the best established model in the field if suitably supervised by the human data scientists. metaphorically spoken, our neural networks can stand on the shoulders of the giant that hmm is for regime based estimations. table 2 presents the results by comparing breaches between the two classic approaches (mean/variance, hmm) and the non-initialized and hmm initialized neural networks across all four regions. panel a and b display the 1% var threshold for equities and long bonds, respectively, while panels c and d show the equivalent comparison for 5% var thresholds. 2 note that for model training we apply a best-out-of-5 strategy as described in section 3.2. that means we repeat the training five times, starting off with random parameter initializations each time. in case of the presented hmm initialized model, we apply the same strategy, with the exception that , σ of the model are initialized the same for each of the five iterations. all residual parameters are initialized randomly as fits best according to the neural network part of the model. xxx findings are observable: first, not a single var threshold estimation process in a single region and in either of the two asset classes was able uphold its promise in that an estimated 1% var threshold should be breached no more than 1% of the time. this is very disappointing and quite alarming for institutional investors such as pension funds and insurance since it implies that all approachesestablished and machine learning basedfail to sufficiently capture downside tail risks and hence underestimate 1% var thresholds. the vast majority of approaches estimate var thresholds that occur in more than 2% of the cases and the lstm fails entirely if not initialised. in fact, even the best method, the hmm for us equities, estimates var thresholds which are breached in 1.34% of the cases. second, when inspecting the ability of our eight methods to estimate 5% var thresholds, the result remains bad but is less catastrophic. the mean/variance approach, the hmm and the initialised lstm display cases where their var thresholds were breaches in less than the expected 5%. the mean/variance and hmm approach make their thresholds in 3 out of 8 cases and the initialised lstm in 1 out of 8. overall, this is still a disappointing performance, especially for the feed forward neural network and the cnn. 1 even though we initialize , σ from hmm parameters, we still have weights to be initialized arising from the temporal neural network part of the model. we do this on a per layer level by sampling uniformly as where i is the number of input units for this layer. 2 we focus our discussion of results on the equities and long bonds since these have more variation, lower skewness and hence risk. results for the short bonds are available upon request from the contact author. third, when comparing the initialised with the non-initialised neural networks, the performance is like day vs. night. the non-initialised neural networks perform always worse and the lstm performs entirely dismal without a suitable prior. when comparing across all eight approaches, the hmm appears most competitive which means that we either have to further advance the design of our neural networks or their marginal value add beyond classic econometric approaches appears inexistent. to advance the design of our neural networks further, we aim to balance its utility function to avoid extreme unrealistic results possible in the univariate case. [insert table 2 about here] whereas cpz (2020) regularize their neural networks via no arbitrage conditions, we regularize via balancing the incentive function of our neural networks on multiple objectives. specifically, we extend the loss function to not only focus on accuracy of point estimates but also give some weight to eventually achieving empirically realistic regime distributions (i.e. in our data sample across all four regions no regimes display more than 60% frequency on a weekly basis). this balanced extension of the loss function prevents the neural networks from arriving at bizarre outcomes such as the conclusion that bear markets (or even bull markets) barely exist. technically, such bizarre outcomes result from cases where the regime probabilities φi(t) tend to converge globally either into 0 or 1 for all t, which basically means the neural network only recognises one-regime. to balance the incentive function of the neural network and facilitate balancing between regime contributions, we introduced an additional regularization term reg into the loss function which penalizes unbalanced regime probabilities. the regularization term is displayed in equation (13) below. if bear and bull market have equivalent regime probabilities the term converges to 0.5, while it converges towards 1 the larger the imbalance between the two regimes. substituting equation (13) into our loss function of equation (10), leads to equation (14) below, which doubles the point estimation based standard loss function in case of total regime balance inaccuracy but adds only 50% of the original loss function in case of full balance. conditioning the extension of the loss function on its origin is important to avoid biases due to diverging scales. setting the additional incentive function to initially have half the marginal weight of the original function also seems appropriate for comparability. the outcome of balancing the incentive functions of our neural networks are displayed in table 3 , where panels a-d are distributed as previously in table 2 . the results are very encouraging, especially with regards to the lstm. the regularized lstm is in all 32 cases (i.e. 2 thresholds, 2 asset classes, 4 regions) better than the non-regularized lstm. for the 5% var thresholds, it reaches realized occurrences of less than 4% in half the cases. this implies that the regularized lstm can even be more cautious than required. the regularized lstm also sets a new record for the 1% [insert table 4 about here] to measure how much value the regularized lstm can add compared to alternative approaches, we compute the annual accumulated costs of breaches as well as the average cost per breach. they are displayed in table 5 for the 5% var threshold. the regularized lstm is for both numbers in any case better than the classic approaches (mean/variance ad hmm) and the difference is economically meaningful. for equities the regularized lstm results in annual accumulated costs of 97-130 basis points less than the classic mean/variance approach, which would be up to over one billion us$ avoid loss per annum for a > us$100 billion equity portfolios of pension fund such as calpers or pggm. compared to the hmm approach, the regularized lstm avoids annual accumulated costs of 44-88 basis points, which is still a substantial amount of money for the vast majority of asset owners. with respect to long bonds, where total returns are naturally lower, the regularized lstm's avoided annual costs against the mean/variance and the hmm approach range between 23-30 basis points, which is high for bond markets. [insert table 5 about here] these statistically and economically attractive results have been achieved, however, based on 2,000 days of training data. such "big" amounts of data may not always be available for newer investment strategies. hence, it is natural to ask if the performance of the regularized neural networks drop when fed with just half the data (i.e. 1,000 days). apart from reducing statistical power, a period of over 4 years also may comprise less information on downside tail risks. indeed, the results displayed in table 6 show that in all context of var thresholds and asset classes, the regularized networks trained on 2,000 days substantially outperform and usually dominate their equivalently designed neural networks with half the training data. hence, the attractive risk management features for hmm initialised, balanced incentive lstms are likely only available for established discretionary investment strategies where sufficient historical data is available or for entirely rules-based approaches whose history can be replicated ex-post with sufficient confidence. [insert table 6 about here] we further conduct an array of robustness tests and sensitivity analysis to challenge our results and the applicability of neural network based regime switching models. as first robustness test, we extend the regularization in a manner that the balancing incentive function of equation (13) has the same marginal weight than the original loss function instead of just half the marginal weight. the performance of both types of regularized lstms is essentially equivalent second, we study higher var thresholds such as 10% and find the results to be very comparable to the 5% var results. third, we estimate monthly instead of weekly var. accounting for the loss of statistical power in comparison tests due to the lower number of observations, the results are equivalent again. we conduct two sensitivity analysis. first, we set up our neural networks to be generalized by two balancing incentive functions but without hmm initialisation. the results show the regularization enhances performance compared to the naïve non-regularized and non-initialized models but that both design features are needed to achieve the full performance. in other words, initialization and regularization seem additive design features in terms of neural network performance. second, we run analytical approaches with k > 2 regimes. adding a third or even fourth regime when asset prices only know two directions leads to substantial instability in the neural networks and tends to depreciate the quality of results. inspired by gkx (2020)'s and cpz (2020) to outperform the single incentive rnn as well as any other neural network or established approach by statistically and economically significant levels. third, we half our training data set of 2,000 days. we find our networks when fed with substantially less data (i.e. 1,000 days) to perform significantly worse which highlights a crucial weakness of neural networks in their dependence on very large data sets. hence, we conclude that well designed neural networks, i.e. a recurrent lstm neural network initialized with best current evidence and balanced incentivescan potentially advance the protection offered to institutional investors by var thresholds through a reduction in threshold breaches. however, such advancements rely on the availability of a long data history, which may not always be available in practice when estimating asset management var thresholds. descriptive statistics of the daily returns of the main equity index (equity), the main sovereign bond with (short) 1-3 years maturity (sb1-3y) and the main sovereign bond (long) with 7-10 year maturity (sb7-10). descriptive statistics include sample length, the first three moments of the return distribution and 11 thresholds along the return distribution. risks and portfolio decisions involving hedge funds skewness in stock returns: reconciling the evidence on firm versus aggregate returns can machines learn capital structure dynamics? working 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networks autoencoder asset pricing models much ado about nothing? exchange rate forecasting: neural networks vs. linear models using monthly and weekly data j. long short-term memory towards explainable ai: significance tests for neural networks improving earnings predictions with machine learning. working paper jorion, p.. value at risk characteristics are covariances: a unified model of risk and return adam: a method for stochastic optimization shrinking the cross-section the skew risk premium in the equity index market a simple weight decay can improve generalization advances in financial machine learning deep learning: a critical appraisal frontiers in var forecasting and backtesting dynamic semiparametric models for expected shortfall (and value-at-risk) maschinelles lernen bei der entwicklung von wertsicherungsstrategien. zeitschrift für das gesamte kreditwesen deep learning for mortgage risk forecasting value at risk and expected shortfall using a semiparametric approach based on the asymmetric laplace distribution forecast combinations for value at risk and expected shortfall moments of markov switching models verstyuk, s. 2020. modeling multivariate time series in economics: from auto-regressions to recurrent neural networks. working paper fixup initialization: residual learning without normalization. interantional conference on learning representations (iclr) paper acknowledgments: we are grateful for comments from theodor cojoianu, james hodson, juho kanniainen, qian li, yanan, andrew vivian, xiaojun zeng and participants at 2019 financial data science association conference in san francisco the international conference on fintech and financial data science at university college dublin (ucd). the views expressed in this manuscript are not necessarily shared by sociovestix labs, the technical expert group of dg fisma or warburg invest ag. authors are listed in alphabetical order, whereby hoepner serves as the contact author (andreas.hoepner@ucd.ie). any remaining errors are our own. key: cord-001064-59i3jert authors: ashbolt, nicholas j.; amézquita, alejandro; backhaus, thomas; borriello, peter; brandt, kristian k.; collignon, peter; coors, anja; finley, rita; gaze, william h.; heberer, thomas; lawrence, john r.; larsson, d.g. joakim; mcewen, scott a.; ryan, james j.; schönfeld, jens; silley, peter; snape, jason r.; van den eede, christel; topp, edward title: human health risk assessment (hhra) for environmental development and transfer of antibiotic resistance date: 2013-07-09 journal: environ health perspect doi: 10.1289/ehp.1206316 sha: doc_id: 1064 cord_uid: 59i3jert background: only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. objective: we examined possible approaches and sought to identify research needs to enable human health risk assessments (hhra) that focus on the role of the environment in the failure of antibiotic treatment caused by antibiotic-resistant pathogens. methods: the authors participated in a workshop held 4–8 march 2012 in québec, canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. we focused on key elements of environmental-resistance-development “hot spots,” exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. discussion: various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. these include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (arb); b) identifying and describing rates of horizontal gene transfer (hgt) in the relevant environmental “hot spot” compartments; and c) modifying traditional dose–response approaches to address doses of arb for various health outcomes and pathways. conclusions: we propose that environmental aspects of antibiotic-resistance development be included in the processes of any hhra addressing arb. because of limited available data, a multicriteria decision analysis approach would be a useful way to undertake an hhra of environmental antibiotic resistance that informs risk managers. citation: ashbolt nj, amézquita a, backhaus t, borriello p, brandt kk, collignon p, coors a, finley r, gaze wh, heberer t, lawrence jr, larsson dg, mcewen sa, ryan jj, schönfeld j, silley p, snape jr, van den eede c, topp e. 2013. human health risk assessment (hhra) for environmental development and transfer of antibiotic resistance. environ health perspect 121:993–1001; http://dx.doi.org/10.1289/ehp.1206316 a workshop (antimicrobial resistance in the environment: assessing and managing effects of anthropogenic activities), held in march 2012 in québec, canada, focused on anti biotic resistance in the environment and approaches to assessing and managing effects of anthropogenic activities. the human health concern was identified as environmentally derived antibioticresistant bacteria (arb) that may adversely affect human health (e.g., reduced efficacy in clinical anti biotic use, more serious or prolonged infection) either by direct exposure of patients to antibiotic resistant pathogen(s) or by exposure of patients to resistance determinants and subsequent horizontal gene transfer (hgt) to bacterial pathogen(s) on or within a human host, as conceptualized in figure 1 . arb hazards develop in the environment as a result of direct uptake of antibioticresistant genes (arg) via various mechanisms (e.g., mobile genetic elements such as plasmids, integrons, gene cassettes, or transposons) and/or proliferate under environmental selection caused by anti biotics and coselecting agents such as biocides, toxic metals, and nanomaterial stressors (qiu et al. 2012; taylor et al. 2011) , or by gene mutations (gillings and stokes 2012) . depending on the presence of recipient bacteria, these processes generate either environmental antibioticresistant bacteria (earb) or pathogens with antibioticresistance (parb) (figure 1 ). human health risk assessment (hhra) is the process used to estimate the nature and probability of adverse health effects in humans who may be exposed to hazards in contaminated environmental media, now or in the future [u.s. environmental protection agency (epa) 2012]. in this review we focus on how to apply hhra to the risk of infec tions with pathogenic arb because they are an increasing cause of morbidity and mor tality, particularly in developing regions background: only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. objective: we examined possible approaches and sought to identify research needs to enable human health risk assessments (hhra) that focus on the role of the environment in the failure of anti biotic treatment caused by antibiotic-resistant pathogens. methods: the authors participated in a workshop held 4-8 march 2012 in québec, canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. we focused on key elements of environmental-resistance-development "hot spots," exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. discussion: various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. these include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibioticresistant bacteria (arb); b) identifying and describing rates of horizontal gene transfer (hgt) in the relevant environmental "hot spot" compartments; and c) modifying traditional dose-response approaches to address doses of arb for various health outcomes and pathways. conclusions: we propose that environmental aspects of antibiotic-resistance development be included in the processes of any hhra addressing arb. because of limited available data, a multicriteria decision analysis approach would be a useful way to undertake an hhra of environmental antibiotic resistance that informs risk managers. citation: ashbolt nj, amézquita a, backhaus t, borriello p, brandt ). an antimicrobial resistant micro organism has the ability to mul tiply or persist in the presence of an increased level of an anti microbial agent compared with a susceptible counter part of the same species. for this review, we limited the resistant group of micro organisms to bacteria and therefore to anti biotic resistance, an area in which the term "antibiotic" is used synonymously with "antibacterial." it is important to understand the contribution that the environment has on the development of resistance in both human and animal pathogens because therapeutic resistant infections may lead to longer hos pitalization, longer treatment time, failure of treatment therapy, and the need for treatment with more toxic or costly antibiotics, as well as an increased likelihood of death. a vast amount of work has been under taken to understand the contribution and roles played by hospital and community settings in the dissemination and maintenance of arb infections in humans. a particular area of focus in terms of exposure in a community setting has been anti biotic use in livestock produc tion and the presence of earb and parb in food of animal origin. in 2011, the codex alimentarius commission [established in 1963 by the food and agriculture organization of the united nations (fao) and the world health organization (who) to harmonize international food standards, guidelines, and codes of practice to protect the health of con sumers and ensure fair trade practices in the food trade] released guidelines on processes and methodologies for applying risk analy sis methods to foodborne anti microbial resis tance related to the use of anti microbials in veterinary medicine and agriculture (codex alimentarius commission 2011). other sources of anti biotics and other anti microbials in the environment are human sewage (dolejska et al. 2011) , intensive ani mal husbandry, and waste from the manu facture of pharmaceuticals (larsson et al. 2007 ). the environmental consequences from the use and release of anti biotics from various sources (kümmerer 2009a (kümmerer , 2009b and the hgt of antibioticresistance genes (arg) between indigenous environmental and pathogenic bacteria and their resistance determinants (börjesson et al. 2009; chagas et al. 2011; chen et al. 2011; cummings et al. 2011; forsberg et al. 2012; gao et al. 2012; qiu et al. 2012 ) has yet to be quanti fied, but is of global concern (finley et al. 2013; who 2012a) . the genetic elements encoding for the ability of micro organisms to withstand the effects of an anti microbial agent are located either chromosomally or extra chromosomally and may be associated with mobile genetic elements such as plas mids, integrons, gene cassettes, or transpo sons, thereby enabling horizontal and vertical transmission from resistant to previously susceptible strains. from an hhra point of view, the emergence of arb in source and drinking water (de boeck et al. 2012; isozumi et al. 2012; shi et al. 2013 ) further highlights the need to place these emerging environmental risks in perspective. yet, assess ing the range of environmental contribu tions to anti biotic resistance may not only be complicated by lack of quantitative data but also by the need to coordinate efforts across different agencies that may have jurisdiction over environmental risks versus human and animal health. a key consideration for arb develop ment in the environment is that resistance genes can be present due to natural occur rence (d'costa et al. 2011 ). further, the use of anti microbials in crops, animals, and humans provides a continued entry of anti biotics to the environment, along with pos sible novel genes and arb. a summary of the fate, transport, and persistence of antibiotics and resistance genes after land application of waste from food animals that received antibiotics or following outflow to surface water from sewage treatment has emphasized the need to better understand the environ mental mechanisms of genetic selection and gene acquisition as well as the dynamics of resistance genes (resistome) and their bacte rial hosts (cheesanford et al. 2009; crtryn 2013) . for example, the presence of anti biotic residues in water from pharma ceuti cal manufacturers in certain parts of the world (fick et al. 2009 ), ponds receiving intensive animal wastes (barkovskii et al. 2012) , aqua culture waters (shah et al. 2012) , and sewage outfalls (dolejska et al. 2011 ) are important sources, among others, leading to the pres ence of arg in surface waters. in particu lar, the comparatively high concentrations of anti biotics found in the effluent of pharma ceuti cal production plants have been asso ciated with an increased presence of arg in surface waters (kristiansson et al. 2011; li et al. 2009 li et al. , 2010 . most recently, 100% sequence identity of arg from a diverse set of clinical pathogens and common soil bacte ria (forsberg et al. 2012 ) has highlighted the potential for environ mental hgt between earb and parb. despite these concerns, few risk assess ments have evaluated the combined impacts of anti biotics, arg, and arb in the environ ment on human and animal health (keen and montforts 2012) . recent epidemiological stud ies have included evaluation of arb in drink ing water and the susceptibility of commensal escherichia coli in household members. for example, coleman et al. (2012) reported that water, along with other factors not directly related to the local environment, accounted for the presence of resistant e. coli in humans. in many studies, native bacteria in drinking water systems have been shown to accumulate arg (vazmoreira et al. 2011) . in addition to addressing environmental risks arising from the development of anti biotic resistance, we should also consider the or development and enrichment of parb low probability but high impact "onetime event" type of risk. this exceedingly rare event that results in the transfer of a novel (to clinically important bacteria) resistance gene from a harmless environmental bacterium to a pathogen need happen only once if a human is the recipient of the novel parb. unlike the emergence of sars (severe acute respira tory syndrome) and similar viruses where, in hindsight, the risk factors are now well under stood (swift et al. 2007 ), the conditions for a "onetime event" could occur in a range of "normal" habitats. once developed, the resis tant bacterium/gene has a possibility to spread between humans around the world [such as seen with the spread of ndm1 (new delhi metallobetalactamase1) resistance (wilson and chen 2012) ], promoted by our use of anti biotics. although it seems very difficult to quantify the probability for such a rare event (including assessing the probability for where it will happen and when), there is consider able value in trying to identify the risk factors (such as pointing out critical environments for hgt to occur, or identifying pharmaceutical exposure levels that could cause selection pres sures and hence increase the abundance of a given gene). after such a critical hgt event, we may then move into a more quantitative kind of hhra. the overall goal of the workshop (anti microbial resistance in the environment: assessing and managing effects of anthropogenic activities) was to identify the significance of arb within the environment and to map out some of the complexities involved in order to identify research gaps and provide statements on the level of scientific understanding of various arb issues. a broad range of international delegates, including aca demics, government regulators, industry mem bers, and clinicians, discussed various issues. the focus of this review arose from discussions of improving our understanding of human health risks-in addition to epidemiological studies-by developing hhras to explore potential risks and inform risk manage ment. because the end goal of an assessment depends on the context (e.g., research, regulation), we provide a generic approach to under taking an hhra of environmental arb that can be adapted to the users' interest (conceptualized in figure 1 ). given the many uncertainties, we also highlight identified research gaps. understanding other on going relevant inter national activities and the types of anti biotics used provide good starting points to aid in framing a risk assessment of arb. the codex alimentarius commission (2011) described eight principles that are specific to risk analysis for foodborne anti microbial resistance, several of which are generally applicable to a hhra of environ mental arb. examples include the recommendations of the joint fao/who/ oie expert meeting on critically important antimicrobials (food and agriculture organization of the united nations/world health organization/world organisation for animal health 2008) and the who advisory group on integrated surveillance of antimicrobial resistance (who 2012b), which provided information for setting the priority anti biotics for a human risk assess ment. it should be noted that there are sig nificant national and regional differences in anti biotic use, resistance patterns, and human exposure pathways. in general, risk assessments are framed by identifying risks and management goals, so the assessment informs the need for possible management options and enables evaluation of management success. the consensus of workshop participants was that manage ment could best be applied at points of anti biotic manufacturing and use, agricultural operations including aquaculture, and wastewater treat ment plants (pruden et al. 2013) . assessing the relative impact of managing any particular part of a system is hampered by the lack of knowledge on the relative importance of each part of the system for the overall risk. that is, as recently stated by the who (2013), "amr is a complex problem driven by many inter connected factors so single, isolated interventions have little impact and coordi nated actions are required." hence, a start ing point for an assessment of environmental anti bioticresistance risks intended to aid risk management is a theo retical risk assessment pathway based on a) local surveillance data on the occurrence and types of anti biotics used in human medi cine, crop production, animal husbandry, and companion animals; b) infor mation on arg and arb in the various environmental compartments (in particular, soil and aquatic systems including drinking water); and c) related disease information. this assessment should be amended by discussion with the relevant stakeholders, which requires extensive risk communication and could form part of the multi criteria decision analysis (mcda) approach discussed in detail below. as a result of the workshop, pruden et al. (2013) also advocate coupling environ mental manage ment and mitigation plans with tar geted surveillance and monitoring efforts in order to judge the relative impact and success of the interventions. to undertake a useful human health risk assessment, some details require quantitative measures. thus, the key issue is how experi mental and modeling approaches can be used to derive estimates. furthermore, haz ard concentration, time, and environ mental compartmentdependent aspects should also be taken into account. first, the current understanding is that for nonmutation derived antibiotic resistance to develop in environmental bacteria (including pathogens that may actively grow outside of hosts) to develop into earb/parb ( figure 1 , pro cesses 1 and 2), a selective pressure (i.e., pres ence of anti biotics or antibioticresistance determinants) must be maintained over time in the presence of arg; for existing parb released into the environment, sur vival in environmental media is the critical factor. however, the exact mechanisms and quantitative relationships between selective pressures and arb development have yet to be elucidated, and they may be different depending on the anti biotic, bacterial spe cies, and resistance mechanisms involved. in cases where selective pressure is removed, the abundance of antibioticresistance arb may be reduced, but not to extinction. hughes 2010, 2011; cottell et al. 2012) . even a small number of arb at the com munity level represents a reservoir of arg for horizontal transfer once pressure is reap plied. because it seems inevitable that arb will eventually develop against any anti biotic (levy and marshall 2004) , the key manage ment aim seems to be to delay and confine such a development as much as possible. second, a robust quantitative risk assess ment will require rates of hgt and/or gene mutations in the relevant compartments ( figure 1 , processes 3-5) to be described for different combinations of donating earb strains and receiving parb strains. the lack of quantitative estimates for mutation/hgt of arg is a major data gap. third, traditional microbial risk assess ment dose-response approaches (figure 1, processes 6 and 8) could be used to address the likeli hood of infection [codex alimentarius commission 2011; u.s. epa and u.s. department of agriculture/food safety and inspection service (usda/fsis) 2012], but the novel aspect required here-in addition to hgt and arb selection-would be to address quantitative dose-response relation ships for earb (in the presence of a sensitive pathogen in or on a human) (figure 1 , pro cesses 3 and 6). importantly, the key difference from traditional hhra undertaken in some jurisdictions is that it is essential to include environmental processes to fully assess human risks associated with anti biotic resistance. therefore, the type of information that should be documented for a human healthoriented risk assessment of environmental arb includes the following [adapted from codex alimentarius commission (2011)]: • clinical and environmental surveillance programs for anti biotics, arb, and their determinants, with a focus on regional data volume 121 | number 9 | september 2013 • environmental health perspectives reporting the types and use of anti biotics in human medicine, crops, and commercial and companion animals, as well as globally where crops and food animals are produced • epidemiological investigations of outbreaks and sporadic cases associated with arb, including clinical studies on the occurrence, frequency, and severity of arb infections • identification of the selection pressures (time and dose of selecting/coselecting agents) required to select for resistance in differ ent environments, and subsequent hgt to humanrelevant bacteria, both based on reports describing the frequency of hgt and uptake of arg into environmental bac teria, including environmental pathogens, in previously identified hot spots • human, laboratory, and/or field animal/crop trials addressing the link between anti biotic use and resistance (particularly regional data) • investigations of the characteristics of arb and their determinants (ex situ and in situ) • studies on the link between resistance, viru lence, and/or ecological fitness (e.g., surviv ability or adaptability) of arb • studies on the environmental fate of anti biotic residues in water and soil and their bioavailability associated with the selection of arb in any given environmental com partment, animal, or human host result ing in parb • existing risk assessments of arb and related pathogens. in summary, many sources of data are required to undertake a human health risk assessment for environ mental arb, and much of the data may be severely limited (particularly for a quantitative assessment). thus, the final risk assessment report should emphasize the importance of the evidence trail and weight of evidence for each finding. furthermore, when models are constructed, previously unused data sets should be consid ered for model verifications where possible. human health risk assessment of anti biotics in the environment builds on traditional chemical risk assessments (national research council 1983), starting, for example, with an accept able daily intake (adi) based on resistance data (vich steering committee 2012). a corresponding metric for environ mental anti biotic concentration could be developed based on the concept of the minimum selective concentration (msc) (gullberg et al. 2011) , defined as the minimum concentration of an anti biotic agent that selects for resistance. unlike the traditional chemical risk assess ment approach, with the msc assay it would be necessary to address the human health effects arising from args and the resistance determinants that give rise to arb, including resistance associated with mutations (figure 1 , processes 1 and 2). in the absence of specific data, an msc assay could inform a risk asses sor of the selective concentration of a pharma ceutical or complex mixture of compounds in a matrix of choice, allowing description of thresholds for significant arb development. pathogen risks may be evaluated through microbial risk assessment (mra), a struc tured, systematic, sciencebased approach that builds on the chemical risk assessment paradigm; the mra involves a) problem for mulation (describing the hazards, risk setting, and pathways), b) exposure assessment of the hazard (arb, arg), c) dose-response assess ment that quantifies the relationship between hazard dose and parb infection in humans (figure 1, processes 6 and 7) , and d) com bination of these procedures to characterize risk for the various pathways of exposure to pathogens identified to be assessed. an mra is used qualitatively or quantitatively to evalu ate the level of exposure and subsequent risk to human health from microbiological haz ards. in the context of anti bioticresistant micro organisms, environmental mra is in its infancy but is needed to address resistant bac teria and/or their determinants. the mra was originally developed for fecal pathogen hazards in food and water [ilsi (international life sciences institute) 1996], with more recent modifications to include biofilmassociated environmental pathogens such as legionella pneumophila (schoen and ashbolt 2011) . some human pathogens can grow in the envi ronment (and may become parb; figure 1 , processes 1 and 2), and many will infect only compromised individuals (generally termed opportunistic pathogens). over the past 20 years, the mra has largely evolved by input from the inter national food safety community, and it is now a wellrecognized and accepted approach for food safety risk analysis. in 1999, the codex alimentarius adopted the principles and guidelines for the conduct of microbiological risk assessment (cac/gl30) (codex alimentarius commission 2009). the most recent codex alimentarius guidelines for risk analysis of foodborne antimicrobial resistance include eight principles (codex alimentarius commission 2011), and in the united states, mra guidelines for food and water (u.s. epa and usda/fsis 2012) continue to use the fourstep framework originally described for chemical risk assessment. several arb risk assessments have been published and reviewed in recent years (geenen et al. 2010; mcewen 2012; snary et al. 2004) . however, nearly all of these studies focus on foodborne transmis sion; human health risk assessments dealing with arb transmission via various environ mental routes or direct contact with arg are sparse. for example, geenen et al. (2010) studied extendedspectrum betalactamase (esbl) producing bacteria and identified the following risk factors: previous admission to healthcare facilities, use of anti microbial drugs, travel to highendemic countries, and having esbl positive family members. the authors con cluded that an environ mental risk assessment would be helpful in addressing the problem of esblproducing bacteria but that none had been performed. hazard identification and hazard charac terization. unfortunately, we are unaware of data that quantitatively link arg uptake and human health effects (figure 1 , processes 3 and 6). what data do exist and are rapidly improving in quality, however, are on the presence of args within various environ mental compartments (allen et al. 2009; cummings et al. 2011; ham et al. 2012) , specifically on clinically rele vant resistance genes within soils (forsberg et al. 2012 ) (figure 1 , process 1). precursors that lead to the develop ment of arb hazards include arg and mecha nisms to mobilize these genes, anti biotics, and coselecting agents (qiu et al. 2012; taylor et al. 2011 ) along with gene mutations (gillings and stokes 2012) . depending on the presence of recipient bac teria, these processes generate either earb or parb (figure 1, processes 1 and 2) . in regard to the numerous parameters rele vant to individual environmental compart ments, we are not aware of the availability of comprehensive data on a) anti biotic resistance development by anti biotics and other coselect ing agents; b) the flow of arg (resistome) and acquisition elements (e.g, integrons) in native environmental compartment bacteria; or c) the likely range in rates of horizontal and vertical gene transfer within environ mental compartments. nonetheless, factors that are considered important include the range of potential pathways involving the release of anti biotics, arg, and arb into and amplify ing in environmental compartments such as the rhizosphere, bulk soil, compost, biofilms, wastewater lagoons, rivers, sedi ments, aqua culture, plants, birds, and wildlife. with respect to anti biotics, in general, the following information is required to aid haz ard characterization: a) a list of the local anti biotic classes of concern, b) what is known of their environmental fate, and c) where they may accumulate, in particular, environmental compartments (e.g., the rhizosphere, general soil, compost, biofilms, wastewater lagoons, rivers, sediments, aquaculture, plants, birds, wildlife, farm animals, or companion ani mals). selection for arb (figure 1 , process 2) will depend on the type and in situ bio availability of selecting/coselecting agents, the abundance of bacterial host, and the abun dance of ar determinants. selection for arb is further modulated by the nutritional status of members of the rele vant bacterial community because high meta bolic activity and high cell density promote bacterial community succession and hgt (brandt et al. 2009; sørensen et al. 2005) . in contrast, hgt is relatively independent of anti biotics-although anti biotics and arb may be cotransported (chen et al. 2013 )and increases in hgt rates are thought to occur in stressed bacteria. for example, integrase expression can be upregulated (increased) by the bacterial sos response (process for dna repair) in the presence of certain anti biotics (guerin et al. 2009 ). although quantitative data that describe the development of parb in the environment are lacking, ample evidence exists for the co uptake by an antibioticsensitive pathogen in the presence of an anti biotic, arg (such as on a plasmid with metal resistance), and/or carbon utilization genes (knapp et al. 2011; laverde gomez et al. 2011) , or as demon strated in vitro for a disinfectant/nanomaterial (qiu et al. 2012; soumet et al. 2012) . the spatial distribution of organisms (opportunity for close proximity) may also affect gene transfer, which results from inher ent patchi ness, soil structure, presence of substrates, and so forth. in considering gene transfer rates, there may be hot spots of activ ity; for example, there is evidence for hgt of clinically rele vant resistance genes between bacteria in manureimpacted soils (forsberg et al. 2012 ) and in association with the rhi zosphere because of its organicrich condi tions (pontiroli et al. 2009 ). in addition, selection pressures for subsequent prolifera tion of earb may be higher in these hot spot environments (brandt et al. 2009; li et al. 2013) . therefore, it is important to reco gnize likely zones of high activity during the prob lem formulation and hazard characterization stages of a risk assessment, and when using sampling to identify in situ exchange rates. as an example marker of anthropogenic impact with potential to predict the impact on the mobile resistome, class 1 integrons could be used because of their ability to integrate gene cassettes that confer a wide range of anti biotic and biocide resistance (gaze et al. 2011) . in semipristine soils, prevalence may be two or three orders of magnitude lower than in impacted soils and sedi ments (0.001 vs. 1%, respectively) (gaze et al. 2011; zhu et al. 2013) . in addition to a huge diversity of earb hazards, there are several pathogens that could be evaluated in microbial risk assess ments: a) foodborne and waterborne fecal pathogens represented by campylobacter jejuni, salmonella enterica, or various patho genic e. coli; and b) environ mental pathogens, such as respiratory, skin, or wound pathogens represented by legionella pneumophila, staphylococcus aureus, and pseudomonas aeruginosa. each of these fecal and environmental pathogens is well known to be able to acquire arg; thus, given further data on environmen tal hgt rates, they could be used as refer ence pathogens in microbial risk assessments. however, what is much more problematic for risk assessment-and a current limiting factor-is the rate at which the indigenous bacteria transfer resistance to these pathogens within each environmental compartment and within the human/animal host (figure 1 , pro cesses 3-5). methods to model and experi mentally derive relevant information on these environmental issues are discussed below in "environmental exposure assessment." data on hgt within the human gastro intestinal tract have been summarized by hunter et al. (2008) . dose-response relationships. to properly charac terize human risks, it is typical to select hazards for which there are dose-response health data described either deterministically or stochastically, as available for the refer ence enteric pathogens (e.g., campylobacter jejuni, salmonella enterica, e. coli) (schoen and ashbolt 2010) , but these dose-response health data have yet to be quantified for the skin/wound reference pathogens (mena and gerba 2009; rose and haas 1999) . however, as noted above for processes 1-5, (figure 1 ), an important difference for arb is the need to account for the phenomena associated with selective environmental pressures for the development of arb, and ultimately that form the human infective dose of either earb or parb. the exact mechanisms and doseresponse relationships have yet to be eluci dated, and may be different depending on the bacterial species and resistance mechanisms involved. nevertheless, it seems reasonable for the non compromised human exposed to a parb to fit the published dose-response/ infection relationship (e.g., derived from "feeding" trials with healthy adults or from information collected during outbreak inves tigations) for strains of the same pathogen without antibiotic resistance. what appears more limiting are dose-response models that describe the probability of illness based on the conditional probability of infection and including people who are already compro mised, such as those under going anti biotic therapy. although there is definitive data on parb being more pathogenic or causing more severe illness than their antimicrobial susceptible equivalents (barza 2002; helms et al. 2004 helms et al. , 2005 travers and barza 2002) , that may not always be the case (evans et al. 2009; wassenaar et al. 2007) . clear examples of excess mortality include associ ated blood stream infections for methicillin resistant staphylococcus aureus (mrsa) and from third generation cephalosporinresistant e. coli (g3crec). in 2007 in participating european countries, 27,711 cases of mrsa were associated with 5,503 excess deaths and 255,683 excess hospital days, and 15,183 epi sodes of g3crec blood stream infections were responsible for 2,712 excess deaths and 120,065 extra hospital days (de kraker et al. 2011) . the authors predicted that the combined burden of resistance of mrsa and g3crec will likely lead to a pre dicted incidence of 3.3 associated deaths per 100,000 inhabitants in 2015. yet for many regions of the world, such predictions are less well understood. the final step of mra is risk charac teriza tion, which integrates the outputs from the hazard identification, the hazard charac terization, dose response, and the exposure assessment with the intent to generate an overall estimate of the risk. this estimate may be expressed in various measures of risk, for example, in terms of individual or popula tion risk, or an estimate of annual risk based on exposure to specific hazard(s). depending on the purpose of the risk assessment, the risk characterization can also include the key scientific assumptions used in the risk assessment, sources of variability and uncer tainty, and a scientific evalua tion of risk management options. based on our conceptualization of the pro cesses important to undertake hhra of arb (figure 1 ), most elements related to arb development in environmental media (pro cesses 1, 2, and 4) have been addressed above in "hazard identification and hazard charac terization." here we focus on describing important environmental compartments for and human exposure to arb (figure 1 , pro cesses 3 and 6). concentrations of environ mental factors (such as anti biotics) and arb, along with their fate and transport to points of human uptake, are critical to exposure assessment. for a particular human health risk assessment of arb, it would be impor tant to select/expand on individual pathway scenarios (identifying critical environmental compartments to human contact) relevant to the anti biotic/resistance determinants identi fied in the problem formulation and hazard characterization stages. compartments of potential concern include soil environments receiving animal manure or biosolids, compost, and lagoons, rivers, and their sediments receiving waste waters (chen et al. 2013 ). more traditional routes of human exposures to contaminants that could include earb and parb are drinking water, recreational and irrigation waters impacted by sewage and/or anti biotic volume 121 | number 9 | september 2013 • environmental health perspectives production wastewaters, food, and air affected by farm buildings and exposure to farm ani mal manures, as discussed by pruden et al. (2013) . what is emerging as an important research gap is the in situ development of arb within biofilms (boehm et al. 2009) and their associated freeliving protozoa that may protect and transport arb (abraham 2010) to and within drinking water systems (schwartz et al. 2003; silva et al. 2008 ). this latter route could be particularly problem atic for hospital drinking water systems where an already vulnerable population is exposed. in addition, with the increasing use and exposure to domestically collected rainwa ter, atmospheric fallout of arb may "seed" household systems (kaushik et al. 2012) . after identifying anti biotic concentra tions and pathogen densities in the environ ment, as well as possible levels and rates of arb generation in each environmental compartment, a range of fate and transport models are available to estimate the amounts of anti biotics, pathogens, arb, and arg at points of human contact (figure 1 , pro cesses 3 and 6). such models are largely based on hydro dynamics, with pathogenspecific parameters to account for likely inactivation/ predation in soil and aquatic environments, such as sunlight inactiva tion (bradford et al. 2013; cho et al. 2012; ferguson et al. 2010) . a key aspect of the fate and transport models is the ability to account for the inherent vari ability of any system component. in addition, our uncertainties in assessing model parameter values should be factored into fate and trans port models such as by using bayesian syn thesis methods (albert et al. 2008; williams et al. 2011) . to better account for param eter uncertainties, more recent models are including bayesian learning algorithms that help to integrate information using meteo rologic, hydrologic, and microbial explana tory variables (dotto et al. 2012; motamarri and boccelli 2012) . overall, these models also help to identify management opportunities to mitigate exposures to arb and anti biotics and are an important aspect in describing the path ways of hazards to points of human exposure in any risk assessment. considering the complexity of exposure path ways associated with environmental arb risks and the large uncertainty in the input data for some nodes along the various exposure path ways, outputs would inevitably be difficult for decision makers to interpret and could in fact be counter productive. thus, there is merit in considering decision analysis approaches to prioritize risks, guide resource allocation and data collection activities, and facilitate decision making. although there is a range of ranking options, uses of weightings, and selection criteria (cooper et al. 2008; pires and hald 2010) , as well as failure mode and effects analysis (pillay and wang 2003) , in the overall area of microbial risk assessment, there is a consolidation to mcda approaches that may include bayesian algorithms (lienert et al. 2011; ludwig et al. 2013; ruzante et al. 2010) . approaches such as mcda are designed to provide a structured framework for mak ing choices where multiple factors need to be considered in the decisionmaking pro cess. mcda is a wellestablished tool that can be used for evaluating and document ing the importance assigned to different fac tors in ranking risks (lienert et al. 2011) , albeit heavily dependent on expert opinion. in the context of mra, mcda has been used to rank foodborne microbial risks based on multiple factors, including public health, market impacts, consumer perception and acceptance, and social sensitivity (ruzante et al. 2010) , as well as to prioritize and select inter ventions to reduce pathogen exposures (fazil et al. 2008) . examples of mcda applications in structuring decisions for man aging eco toxico logi cal risks have also been reported (linkov et al. 2006; semenzin et al. 2008 ) and provide useful mcda approaches. mcda could be used, for example, to evalu ate and rank the relative risks between habi tats highly polluted with anti biotics, arg, and arg determinants, as described above for possible hot spots for hgt and develop ment of arb. mcda could be applied to evaluate the relative contribution of coselect ing agents (e.g., detergents, biocides, met als, nano materials) from various sources to the overall risk of arb in the environment. moreover, for a range of anti biotics consid ered to be of environmental concern, mcda approaches could be used for risk ranking according to criteria based on relevant con tributing factors (e.g., mobility of resistance determinants in genetic elements, antibiotic resistance transfer rates in different environ mental compartments, accumulation levels of anti biotics in environmental compartments, environmental fate and transport to expo sure points). in the mcda process, it is also important to identify low probability but high impact "onetimeevent" types of risk. because mcda techniques rely on expert opinion (which is often regarded as a limi tation of such approaches), wellstructured and recognized elicitation practices should be used in order to avoid introduction of biases and errors by subjective scoring. in contrast, one of the main advantages of mcda tech niques is that they capture a consensus opin ion among an expert group about the most relevant criteria and their relative weight on the decision. there are several research gaps that need to be addressed. in particular, specific atten tion should be paid to contaminated habitats (hot spots) in which anti biotics, coselecting agents, bacteria carrying resistance determi nants on mobile genetic elements, and favor able conditions for bacterial growth and activity-all conditions expected to favor hgt-prevail at the same time. however, because these data are currently very limited, workshop participants evaluated alternative ways and possible experimental methods to address these data gaps for hhra as they relate to the processes identified in figure 1 . assays to determine msc (processes 1, 2, and 4) . assays could be developed to mea sure msc (gullberg et al. 2011 ) for a range of anti biotics and environmental conditions. for example, assays could be developed and validated in sandy and clay soils, different sediments, and water types, with isogenic pairs of the model organism inoculated into the matrix of choice and subjected to a titra tion of the selective agent to sufficiently high dilution. selection at sub inhibitory concen trations and assay development for environ mental matrices are key areas of research that need to be addressed. however, overall care is needed when interpreting ex situ studies and extrapolating to in situ environmental condi tions, as well as in dealing with illdefined hazard mixtures in the environment. (processes 1, 2, and 4) . hot spots, locations where a highlevel of hgt and anti biotic resistance develop, may, for instance, include aquatic environments affected by pharma ceutical industry effluents, aqua culture, or sewage discharges, as well as terrestrial environments affected by the deposition of biosolids or animal manures. the degree of persistence of anti biotic resistance (i.e., the rate by which resistance disappears without having an environ mental selection pressure for resistance) must also be considered for risk assessment and will depend on the fit ness cost of resistance. however, the fitness costs within complex and variable environ ments are difficult to assess. furthermore, standard methods have not been developed for evaluating environ mental selection pres sures in complex microbial communities, but several experimental approaches are possible and have been described elsewhere (berg et al. 2010; brandt et al. 2009 ). the approaches identified by berg et al. (2010) and brandt et al. (2009) could be labo ra tory based (to assess the potency of known compounds/mixtures) or applied in the field to assess whether the environment in question (with, for example, its unknown mixture of chemicals) is a hot spot. defining "critical exposure levels" is therefore an important hhra output to aid manage ment activities, which will likely vary between and within environmental compartments, depending on the location. screening for novel resistance determinants (to reduce process 2). screening procedures could be introduced early in the development cycle of novel anti biotics to ensure that exist ing resistance determinants are not prevalent in environmental compartments. marked recipient strains could be inoculated into environmental matrices [e.g., soil, biosolids, or fecal slurry (with sterilized matrix equiva lents as negative controls)], incubated, and then seeded onto media containing the study compound along with a selective anti biotic to recover marked recipient strains demon strating resistance. plasmids, or the entire genome of the recipient, could then be cloned into small insert expression vectors, transformed into e. coli or other hosts, and seeded back onto media containing the study compound. in this way, novel resistance determinants would be identified. alternatively, functional meta genomics could be used to identify novel resistance determinants in meta genomic dna (allen et al. 2009 ). in brief, dna would be extracted from an environmental sample, cloned into an expression vector, and trans formed into a bacterial host such as e. coli. transformants could then be screened on the study compound and resistance genes identi fied using transposon muta genesis followed by sequencing and bio informatic analyses. this would allow detection of novel resistance determinants that may not be plasmid borne but may transfer to other pathogens. dose-response data needs (processes 3, 5, and 6). we were unaware of dose-response data representing a combined arg and a recipient, previously susceptible pathogen dose, and human or animal disease (figure 1 , processes 3 and 5). in contrast, various exam ples illustrate increased morbidity and mor tality when humans are exposed to parb, as described above in "dose-response rela tionships." hence, existing published doseresponse models for non resistant pathogens may not be appropriate to use beyond the end point of infection, and further dose-response models that address people of various lifestages need to be described and summarized to facilitate parb risk assessments. there is also a need to develop dose-response information for sec ondary illness end points (sequelae) resulting from parb infections. regarding anti biotic concentration and time of exposure giving rise to selection of parb within a human (for couptake of earb and a sensitive pathogen), safety could be based on the effective concentration for the specific anti biotic under consideration. in other words, screening values to determine whether further action is warranted could be derived from the acute or mean daily anti biotic intake, with uncertainty factors applied as appropriate, until future research is under taken on pathogen anti bioticresponse changes in the presence of specific anti biotic treatment. alternatively, epidemiological data from exist ing clones of anti bioticresistant strains (e.g., ndm1) could provide useful data for doseresponse and exposure assessments. options for ranking risks (overall hhra). in the absence of fully quantitative data to undertake a hhra, riskranking approaches based on exposure assessment modeling could be adopted and developed to inform allocation of resources for data generation as part of an hhra of arb. evers et al. (2008) presented one such approach in the context of food safety for estimating the relative contribution of campylobacter spp. sources and transmis sion routes on exposure per personday in the netherlands. their study included 31 transmis sion routes related to direct contact with animals and ingestion of food and water, and resulted in a ranking of the most significant sources of exposure. although their study focused on foodborne transmission routes and did not deal with anti bioticresistant campylobacter strains, a similar approach could be applied to estimate human exposure to arb hazards using the environmental exposure pathways described by evers et al. (2008) . this would require data on the prevalence of arg and arb, as well as lev els of anti biotics present in all exposure routes to be considered in the risk assessment. although such an approach is probably not currently fea sible, improved environmental data for a select number of pathogen-gene combinations could be developed in the future. an alternative approach to capturing knowledge of experts and other stakeholders could be to develop a bayesian network based on expert knowledge and add to that as data become available, as described for campylo bacters in foods by albert et al. (2008) . because we are addressing an inter national problem and because the precautionary approach is used in many jurisdictions, there are many risk management approaches that can be implemented now, before anti biotic resistance issues worsen, as noted in the related risk management paper resulting from the workshop (pruden et al. 2013) . furthermore, many current risk management schemes start the process from a management perspec tive and delve into quantitative assessments as needed in order to improve risk manage ment actions, such as in the who water safety plans (who 2009) . we propose that environmental aspects of anti bioticresistance development be included in the processes of any hhra addressing arb. in general terms, an mra appears suitable to address environ mental human health risks posed by the envi ronmental release of anti biotics, arb, and arg; however, at present, there are still too many data gaps to realize that goal. further development of this type of approach requires data mining from previous epidemiological studies to aid in model development, param eterization, and validation, as well as in the collection of new information, particularly that related to conditions and rates of arb development in various hot spot environ ments, and for various human health doseresponse unknowns identified in this review. in the nearterm, options likely to provide a firstpass assessment of risks seem likely to be based on mcda approaches, which could be facilitated by bayesian network models. once these mra models gain more acceptance, they may facilitate scenario testing to deter mine which control points may be most effec tive in reducing risks and which riskdriving attributes should be specifically considered and minimized during the development of novel anti biotics. megacities as sources for pathogenic bacteria in rivers and their fate downstream quantitative risk assessment from farm to fork and beyond: a global bayesian approach concerning 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management for drinking-water suppliers. geneva:world health organization 2012a. report of the 3rd meeting of the who advisory group on integrated surveillance of antimicrobial resistance the evolving threat of antimicrobial resistance: options for action. geneva:world health organization antimicrobial resistance. fact sheet no. 194 framework for microbial food-safety risk assessments amenable to bayesian modeling ndm-1 and the role of travel in its dissemination diverse and abundant antibiotic resistance genes in chinese swine farms key: cord-018001-ris02bff authors: garrido, guillermo; dhillon, gundeep s. title: medical course and complications after lung transplantation date: 2018-06-23 journal: psychosocial care of end-stage organ disease and transplant patients doi: 10.1007/978-3-319-94914-7_26 sha: doc_id: 18001 cord_uid: ris02bff lung transplant prolongs life and improves quality of life in patients with end-stage lung disease. however, survival of lung transplant recipients is shorter compared to patients with other solid organ transplants, due to many unique features of the lung allograft. patients can develop a multitude of noninfectious (e.g., primary graft dysfunction, pulmonary embolism, rejection, acute and chronic, renal insufficiency, malignancies) and infectious (i.e., bacterial, fungal, and viral) complications and require complex multidisciplinary care. this chapter discusses medical course and complications that patients might experience after lung transplantation. the lungs normally have a dual blood supply, consisting of 1) large pulmonary arteries that provide desaturated blood under low pressure for alveolar gas exchange and 2) smaller bronchial arteries that provide oxygenated blood under systemic pressure for nutrition and oxygenation of the bronchi and lung tissue. as the only solid organ transplant that does not undergo primary systemic (i.e., bronchial) arterial revascularization at the time of surgery, lung transplants rely on the deoxygenated pulmonary arterial circulation and are especially vulnerable to the effects of injury and ischemia [4] . it has been hypothesized that the absence of the bronchial system in the lung allograft increases susceptibility to microvascular injury and chronic airway ischemia, which may be implicated in the genesis of chronic rejection and other complications [5] . similarly, the native lymphatics and the neural supply to lung allografts are disrupted at the time of trans-plantation. the impact of these disruptions on lung transplant outcomes remains unclear, though it is possible that these changes lead to higher susceptibility to the development of pulmonary edema and infections, worse airway clearance, and ineffective cough [6] . lastly, the lung allografts have higher exposure to immunogenic compounds, as compared to other organs, by ventilation. the ongoing exposure to various inhaled injurious agents may also predispose lung allografts to develop chronic rejection. there is a vast array of complications from lung transplantation. broadly these complications can be divided into noninfectious and infectious complications and have been summarized in table 26 .1. these complications arise at different times in the postoperative period [7] . the understanding of timing of various complications post-lung transplant can lead to early recognition and management of these complications. epithelium, and alveolar macrophages. the interaction between these cells leads to release of cytokines, reactive oxygen intermediates, and proteolytic enzymes leading to graft dysfunction [9] . the severity of pgd falls along a spectrum, ranging from mild dysfunction to severe lung injury. pgd can affect 10-25% of transplanted patients, and the 30-day mortality can be as high as 50%. furthermore, severe pgd after lung transplantation has been associated with development of subsequent chronic rejection and graft dysfunction [10] . the management of pgd is largely supportive and includes lung-protective ventilation strategies (low tidal volume, high positive end-expiratory pressure), judicious fluid management, inhaled nitric oxide or other inhaled pulmonary vasodilators to improve oxygenation, and extracorporeal life support (ecls) for the most severe cases. re-transplantation is an option for highly selected cases, but it is generally not recommended due to suboptimal outcomes [11] . lung transplant recipients are at increased risk of vte. the risk factors include major surgery status, hypercoagulable state, high dose of corticosteroids, immobility, and indwelling vascular access. the reported incidences of pulmonary embolism (pe) and deep venous thrombosis (dvts) postlung transplantation are approximately 5-15% and 20-45%, respectively [12] . the pulmonary embolism in setting of limited pulmonary reserve due to pgd, postoperative atelectasis, and single-lung transplantation can have catastrophic consequences, thus underscoring the need for early and appropriate vte prophylaxis after lung transplantation [13] . the diagnosis can be made with computed tomography (ct) pulmonary angiography, ventilation-perfusion scan, or by documentation of dvt by doppler ultrasonography. the treatment is the same as for vtes in general, although the risk of postoperative bleeding needs to be weighed against the risk of pe. the choice of anticoagulant is based on kidney function, periprocedural reversibility of anticoagulant effect, and drug interactions, with unfractionated heparin, low-molecular-weight heparin, and/or warfarin being by far the most common agents used. in case of ongoing bleeding or high risk of bleeding, inferior vena cava filters can be used as a temporizing measure. inadvertent injury to various intrathoracic nerves during lung transplantation is a well-recognized and common complication. the most commonly affected structures are the phrenic and vagus nerves. the reported rates of phrenic nerve injury have ranged from 3% to 9% in lung transplant cases. this rate can be as high as 40% in combined heart-lung transplantation [14, 15] . diaphragmatic dysfunction as a consequence of phrenic nerve injury can present clinically with dyspnea, hypoventilation and hypercapnia, and hypoxemia or as difficult wean from the ventilator. diaphragmatic paralysis can lead to increased length of stay and ventilator dependence. diagnosis can be confirmed by documenting paradoxical movement of affected diaphragm during quiet and deep breathing, using fluoroscopy or ultrasound visualization. the vagal nerve injury post-lung transplantation can lead to gastroparesis with associated risk of gastroesophageal reflux (gerd) and aspiration events. these in turn can place lung allograft at risk for recurrent infections, bronchiectasis, and possibly chronic allograft dysfunction [16] [17] [18] . common symptoms of gastroparesis include early satiety, decreased appetite, abdominal pain, and bloating. a diagnosis is usually made by a nuclear medicine gastric emptying study. the potential management strategies include minimizing transit delaying medications (e.g., opioids), the use of pro-motility agents, placement of post-pyloric feeding tubes, botulinum toxin injection to the pylorus, and surgical fundoplication in conjunction with pyloroplasty [17] . the pleural complications in early post-lung transplantation period include pleural effusions, hemothorax, pneumothorax, empyema, chylothorax, and interpleural communication. these complications usually arise as a result of the pleural disruption from the surgery itself, though rejection and immunosuppressive regimens may also play a role. the risk factors for the development of pleural complications include previous thoracic surgery, pleural adhesions, and donor-recipient size mismatch [19, 20] . pleural effusions are extremely common in the early postlung transplant period. the reported incidence has been 100% in some series [19, 20] . all patients have chest tubes in place immediately post-operation to allow lung re-expansion, pleural air, and fluid drainage. the increased amount of pleural fluid post-lung transplantation is related to capillary leak due to allograft ischemia reperfusion, fluid overload, bleeding, and surgical interruption of allograft lymphatics at the time of explantation [19, 20] . late pleural effusions can be a consequence of infection, acute rejection, trapped lung physiology from pleural fibrosis, or malignancy [21, 22] . in general, all pleural effusions need to be evaluated to rule out complicated effusions such as hemothorax, empyema, and chylothorax. these entities have all been associated with negative patient outcomes and are treated with a range of medical and surgical procedures depending on the condition and severity. for example, a chylothorax might necessitate mechanical interruption of thoracic duct, or hemothorax may need thoracotomy for control of bleeding. pneumothoraxes are common after lung transplantation. they can result from donor-recipient size mismatch, bronchopleural fistulas that occur secondary to operative injury or bronchial anastomoses dehiscence, or as a consequence of transbronchial biopsies performed in the course of allograft evaluation. small and stable pneumothoraxes after lung transplantation can be managed by watchful waiting, though larger or symptomatic pneumothorax may require chest tube drainage. an inadequately drained, hemodynamically significant pneumothorax can be a medical emergency necessitating urgent drainage [23, 24] . in patients who have undergone sequential bilateral lung transplantation (bslt) or heart-lung transplantation (hlt), interpleural communication due to surgical severance of the pleural recesses that separate the left and right pleural spaces can develop. this entails that pleural issues in these patients must be managed aggressively as pneumothoraxes can be bilateral and life threatening, and empyema can spread quickly. vascular anastomotic complications can arise either early or late in the post-transplant course and can have very severe adverse consequences. pulmonary artery stenosis can be secondary to mechanical kinking, disruption, or narrowing of the anastomosis, sometimes due to the particulars of donor anatomy or due to thrombosis [25] . the clinical picture is usually consistent with pulmonary hypertension and right ventricular failure. diagnosis can be made through pulmonary angiography and can be managed with interventions such as balloon dilation and stent deployment. occasionally, patients may require surgery for definitive management of the stenosis. pulmonary vein occlusion post-lung transplantation is a rare but serious complication. the commonest cause of pulmonary vein occlusion is the development of thrombosis at the anastomotic junction of the pulmonary veins and the left atrium, though inadvertent narrowing or ligation of pulmonary veins has also been reported. the potential clinical consequences include hypoxic respiratory failure, pulmonary edema, and cardio-embolic events. this entity should be included in the differential diagnosis of a patient with acute pulmonary edema post-lung transplantation. diagnosis is usually made by transesophageal echocardiography or ct angiography [26, 27] . the airway complications after lung transplantation can be classified by time of occurrence. early anastomotic complications, usually within 1 month of transplantation, include infection, dehiscence, and necrosis at the anastomotic sites. later complications include bronchopleural, bronchovascular and bronchomediastinal fistulae, excessive granulation tissue, bronchomalacia, and airway stenosis. airway anastomotic complications do not seem to be associated with decreased survival; however, they do negatively impact quality of life and significantly increase healthcare resource utilization [28] . the risk factors for airway anastomotic complications include colonization with burkholderia cepacia and aspergillus fumigatus, pgd, acute rejection, prolonged mechanical ventilation, and sirolimus use prior to anastomotic healing [29, 30] . bronchial necrosis and dehiscence occur 1-2 weeks after transplant. they can present with dyspnea, difficulty weaning from the ventilator, persistent air leak on the water seal, pneumomediastinum, and subcutaneous emphysema and infection, with symptoms ranging from mild to severe. depending on the severity, management can range from observation and antibiotics to minimally invasive or surgical repair. bronchial stenosis is the narrowing of the airway lumen, usually at the site of the anastomosis. patients can present with wheezing, cough, post-obstructive pneumonias, decline in pulmonary function tests (pfts), and stridor. the bronchial narrowing can also present distal to the anastomosis causing lobar lobe collapse. this syndrome occurs 2-6 months post-transplant but can present as late as 12 months. treatment options include close monitoring, bronchial dilatation with or without stent placement, and re-transplantation [31] . allograft rejection is a major cause of morbidity and mortality post-lung transplantation. at least a third of patients are reported to have acute rejection in the first year after transplant. acute rejection in itself seldom leads to mortality, but it is a main risk factor for the development of chronic rejection. the chronic rejection of lung allograft is the major hurdle to long-term survival after transplantation. despite the use of potent and novel immunosuppressive regimens, the incidence of chronic rejection and long-term survival post-transplant has remained essentially unchanged over the last two decades [1, 32] . acute cellular rejection (acr) is the most common kind of acute lung transplant rejection and is mediated by t lymphocytes. symptoms and signs of acr include dyspnea, cough, fever, and hypoxia. high-grade rejection may be associated with respiratory failure. mild acr can be asymptomatic and frequently detected on surveillance pulmonary function testing and/or transbronchial biopsies. current imaging modalities are not diagnostic but may reveal useful findings such as infiltrates and ground-glass opacities [32, 33] . flexible bronchoscopy with transbronchial biopsies is the gold standard for diagnosis. histologically, acr is characterized by the presence of perivascular and/or peribronchiolar (grade b) lymphocytes in the absence of infectious etiologies [32, 34, 35] . risk factors for acr include the number of hla mismatches between donor and recipient, although it is unclear which specific hlas have more impact. other reported risk factors are age, with older patients having more rejection, immunosuppressive regimen used (tacrolimus regimens reject less), other genetic factors such as il-10 production, and documented gerd. acr has also been documented following infections with certain viruses, such as rhinovirus, parainfluenza virus, influenza virus, human metapneumovirus, coronavirus, and respiratory syncytial virus. the treatment for acr is not uniform, and high-quality randomized controlled trials are lacking. there is wide agreement that severe cases of acr must be treated, but there is variability among transplant centers on whether to treat milder cases. the mainstay of therapy is high-dose corticosteroids. in cases that are refractory or recurrent, usually the immunosuppressive regimen gets intensified or altered, and medications such as anti-thymocyte globulin (atg), antiinterleukin 2-receptor (il-2r) antagonists, muromonab-cd3 (okt3), and alemtuzumab (anti-cd52 monoclonal antibody), among others, can be used [36, 37] . antibody-mediated rejection (amr) is believed to be mediated by donor-specific antibodies (dsa) against human leukocyte antigens (hla) and other donor antigens. these antibodies may have been present in the recipient prior to transplant, although most appear to develop after transplantation. amr is described as the combination of the following: donor-specific anti-hla antibodies, evidence of complement deposition in allograft biopsies, histologic tissue injury, and clinical allograft dysfunction [38] . once the aforementioned antibodies bind their receptors in the graft, they are capable of binding complement, specifically c1q. this can trigger complement-mediated cell destruction and inflammation. the development of de novo anti-hla antibodies is associated with poor prognosis [39, 40] . the mainstay of amr management involves depletion and/or neutralization of anti-hla antibodies by plasma exchange or intravenous immunoglobulin (ivig), followed by rituximab infusion. rituximab is an anti-cd-20 chimeric antibody that targets b-cell function and can decrease production of antibodies. in cases of refractory amr, newer agents such as bortezomib (anti-proteasome 26s) and the anticomplement antibody eculizumab have been tried with limited success. successful clearance of anti-hla antibodies has been associated with decreased risk of development of chronic rejection following amr [32] . the term chronic lung allograft dysfunction (clad) encompasses pathologies that lead to chronic dysfunction of lung allograft. clad is predominantly a consequence of chronic rejection and is a major hurdle to long-term survival. the two major phenotypes of clad include (i) bronchiolitis obliterans syndrome (bos) and (ii) restrictive allograft syndrome (ras) [41, 42] . bos is the predominant form of clad and is the number one cause of death after 1 year of transplantation. it is reported to occur in up to 76% of lung transplant recipients at 10 years post-transplant, and it is a major cause of morbidity, negative impact in quality of life, and increased costs. bos is defined by a sustained (>3 weeks) decline in the forced expiratory volume in the first second of expiration (fev1); provided alternative causes of pulmonary dysfunction have been excluded. at the tissue level, the hallmark of bos is obliterative bronchiolitis (ob), which is an inflammatory/fibrotic process affecting the small non-cartilaginous airways (membranous and respiratory bronchioles) characterized by subepithelial fibrosis causing partial or complete luminal occlusion [43, 44] . risk factors include prior episodes of acute rejection, cytomegalovirus infection (cmv), community-acquired respiratory viruses (carv) infection, history of pgd, isolation of aspergillus fumigatus and pseudomonas aeruginosa, the presence of gerd, and other immune-mediated factors [44] . the diagnosis can be made conditionally without histopathology (bos) or definitively with histopathology (bo). transbronchial biopsy is an insensitive method for detecting bo, and the clinical use of bos is the favored method for diagnosis and monitoring. the treatment of bos is disappointing in terms of outcomes; often success is measured in slowing the decline or stabilizing it. beyond augmentation of immunosuppression, azithromycin, extracorporeal photopheresis, montelukast, methotrexate, aerosolized cyclosporine, alemtuzumab, and total lymphoid irradiation have been used with limited success [44, 45] . ras has been more recently described and occurs in less than a third of patients with clad. these patients present with predominant restriction, and the survival is worse as compared to patients with bos. the median survival postdiagnosis is 8 months. ct scan shows interstitial opacities, ground-glass opacities, upper lobe-dominant fibrosis, and honeycombing. the only identified risk factor for the development of ras is late-onset diffuse alveolar damage (dad), occurring later than 3 months after lung transplant. there is no proven treatment for this condition, and re-transplantation remains technically challenging [46, 47] . lung transplant and associated immunosuppression are an established risk factor for development of cancer [48] . the commonest malignancy post-lung transplant is the squamous cell cancer of the skin. the single-lung transplant recipients are at higher risk of development of lung cancer in their native lungs. this increased risk is in part related to the increased risk of cancer due to underlying disease (e.g., emphysema, idiopathic pulmonary fibrosis) [49, 50] . similarly, the transplant recipients with cystic fibrosis remain at an elevated risk for development of gastrointestinal malignancies [49] . it is imperative that transplant recipients adhere to age-appropriate health screening after transplant. additionally, all lung transplant recipients should undergo skin cancer screening annually. the risk is especially high for of viral infection associated malignancies such as lymphoma, kaposi sarcoma, and anogenital cancers [49] . post-transplant lymphoproliferative disorders (ptld) encompass an array of diseases involving clonal expansion of b lymphocytes, ranging from polyclonal benign disorders to aggressive malignant lymphomas. the reported incidence of non-hodgkin lymphoma post-lung transplant has been as high as 28 cases/100,000 person-years [49] . there is a significant association between ptld and epstein-barr virus (ebv) infection, especially in patients who acquire infection the novo after being transplanted. ptld is managed by reducing the intensity of immunosuppression if possible, with specific chemotherapy for more severe and refractory cases. hyperammonemia affects 1-4% of the lung transplant population; it is a rare but potentially fatal complication. it can be secondary to systemic infection with mycoplasma hominis and ureaplasma, which break down urea as an energy source, generating ammonia as a waste product. this likely represents a donor-derived infection and can respond to early appropriate antibiotic treatment [51] . postoperative liver dysfunction and urea-cycle enzyme deficiencies can also cause hyperammonemia. diabetes mellitus (dm) is common in lung transplant recipients, with 25-30% of patients developing it in the first year post-transplant and up to 40% at 5 years. the use of glucocorticoids, calcineurin inhibitors, obesity, and advanced age is a significant risk factor for the development of dm. the development of dm in lung transplant recipients is associated with decreased survival. a close and judicious glycemic control is indicated in this patient population [52, 53] . patients who undergo lung transplantation have multiple risk factors to develop acute kidney injury (aki) post-transplant, including decreased renal perfusion before, during, and/or after surgery, drug toxicities, and systemic infections. aki affects as many as 70% of patients with approximately 8% patients requiring renal replacement therapy (rrt). the postoperative renal failure necessitating the use of rrt is associated with increased risk of early mortality [54, 55] . by 3 years, 25% of surviving lung transplant recipients develop severe renal dysfunction (serum creatinine >2.5 mg/ dl), and that percentage rises to 40% at 10-year mark [1] . the risk factors for development of chronic kidney disease (ckd) include older age, dm, hypertension, smoking history, and use of nephrotoxic drugs. ckd is also associated with higher mortality in lung transplant recipients [56] . recipients of lung transplant are at risk for development of osteopenia and osteoporosis due to multiple factors such as malnutrition, immobility, chronic corticosteroid use, calcineurin inhibitor use (e.g., tacrolimus), and other comorbidities. the strategies to prevent and reverse bone losses after transplant need to be proactively implemented. treatment includes adequate supplementation of calcium, vitamin d, use of bisphosphonates, enhancing physical activity, and minimizing contributing medications, if possible [57, 58] . dyslipidemia is also very common in lung transplant recipients, as high as 59%, and it may be related to the aforementioned metabolic risk factors. treatment usually entails lifestyle modifications and cholesterol lowering medications. there are multiple cardiac complications after lung transplantation, both short and long term. atrial dysrhythmias are very frequent in the early postoperative period, likely related to stress of major surgery, catecholamine surge, medication side effects, and mechanical stresses related to vascular anastomoses. the reported incidence has been as high as 25-35% [59, 60] . these arrhythmias are usually managed with medications aimed at rate and rhythm control. hemodynamically significant and/or refractory arrhythmias may require electric cardioversion. atrial dysrhythmias are associated with increased length of hospital stay and increased mortality [59, 60] . over the long term, lung transplant recipients are at increased risk for developing coronary artery disease (cad). as they progress into long-term survival, these patients have cumulative impact from risk factors previously discussed in this chapter, namely, dm, dyslipidemia, ckd, hypertension, chronic corticosteroid use, and other immunosuppressive medication. these risk factors should be carefully managed to decrease the impact of cad and related complications, with a combination of lifestyle modifications and specific medical therapies [61] . lung transplant recipients experience a decrease in skeletal muscle strength and function, including respiratory and limb muscles. this is likely related to reduced activity postoperatively and deconditioning, corticosteroid-induced myopathy, critical illness-related weakness (neuropathy/myopathy), and in the case of the diaphragm, phrenic nerve injury. this issue seems to be consistent in lung transplant recipients and independent of pre-transplant diagnosis and surgery type. muscle weakness, deconditioning, and sarcopenia are associated with adverse outcomes and decrease in quality of life. aggressive rehabilitation is standard and important in the post-transplant care [62, 63] . lung transplant recipients are at an increased risk for acquiring infections due to the immunosuppressed state, constant environmental pathogen exposure, decreased cough reflex, impaired mucociliary clearance, and lymphatic disruption. infectious complications are responsible for about a quarter of post-transplant deaths [64] . pneumonias are the most significant bacterial infection in lung transplant recipients, and the highest risk is in the first 30 days post-transplant. in the early period, they are more likely to be caused by hospital-acquired organisms, which tend to be more virulent and more resistant to antibiotics. the patients with cystic fibrosis are frequently colonized by multidrug-resistant organisms and are at increased risk of pneumonia post-transplant. in later stages, community-acquired organisms become more prevalent. moreover, throughout the post-transplant period, the patients are susceptible to numerous opportunistic infections [65] . other commonly encountered bacterial infections in this patient population include pleural space infections, blood stream infections (bsis), and soft tissue infections. the bsis and empyema carry a high risk of morbidity and mortality [66, 67] . pseudomonas aeruginosa, burkholderia cepacia, staphylococcus aureus (including methicillin-resistant), and other gram-negative organisms are common causes of serious infections in post-lung transplant period. these organisms have high rates of antibiotic resistance and are associated with worse outcomes [68] [69] [70] . streptococcus pneumoniae is the most common cause of communityacquired pneumonia, and immunosuppressed patients have increased risk of disseminated infection [71] . clostridium difficile associated diarrhea is a major complication in hospitalized, immunosuppressed and debilitated patients and is associated with increased hospital length of stay and mortality [72] . molds are common fungal entities affecting lung allografts. aspergillus spp. are the most common and have a predilection for the respiratory tract [73] . lung transplants have the highest incidence of invasive aspergillosis among solid organ transplant recipients, and it is the most common invasive fungal infection in lung transplant. aspergillus is ubiquitous in the environment and is acquired by inhalation. there are three main described presentations: invasive pulmonary disease, tracheobronchial aspergillosis, and disseminated disease, all of which are associated with varying degrees of increased mortality. other implicated molds include fusarium, scedosporium, and mucormycosis. these infections are difficult to treat and are associated with poor clinical outcomes [73] . candida spp. are another common pathogen in lung transplant setting. oral candidiasis is the most common manifestation of this infection. however, candida infections can also manifest as candidemia, empyema, surgical wound infection, and disseminated disease. serious candida infections have been associated with increased mortality, though rates have been declining over time [74] . other fungal infections in this patient population include opportunistic infections, such as pneumocystis jiroveci and cryptococcus, as well as endemic fungi, such as histoplasma capsulatum, coccidioides immitis, and blastomyces dermatitidis [75, 76] . viral infections contribute to morbidity and mortality from acute infection and have been associated with an increased risk of rejection, chronic allograft dysfunction, lymphoproliferative and other neoplastic diseases, and other extra pulmonary organ damage [77] . cytomegalovirus (cmv) is the most significant viral infection occurring in solid organ transplant recipients and is the second most common infection, after bacterial pneumonia. cmv infection can range from latent infection, to asymptomatic viremia, to cmv disease manifested with clinical symptoms and end-organ involvement. severity of disease may range from mild to life threatening. when there is organ damage, affected organs can include the lungs, pancreas, intestines, retina, kidney, liver, and brain. cmv disease is associated with increased mortality [77, 78] . other notable dna viruses from the herpesviridae family include epstein-barr virus (ebv), which is associated with increased risk of ptld and other malignancies, herpes simplex virus (hsv) 1 and 2, varicella-zoster virus (vzv), and human herpesvirus 6, 7, and 8 [77] . community-acquired respiratory viruses, including influenza, are a major source of respiratory symptoms and mor-bidity after lung transplantation. these infections may also be associated with development of chronic allograft dysfunction [79] . currently, the median survival for all adult lung transplant recipients is 6 years [1] . bilateral lung recipients appear to have a better median survival compared to single-lung recipients (7 versus 4.5 years) [1] . overall lung transplantation confers clinically meaningful and statistically significant improvements in health-related quality of life (hrqol). greater than 80% of lung transplant recipients report no activity limitations [80] . the care of lung transplant recipients is multidisciplinary, labor intensive, and comprehensive. it includes management of immunosuppression regimen, opportunistic infection prophylaxis, prevention and management of various comorbidities, and complications. a typical medication regimen consists of three classes of immunosuppression drugs (i.e., calcineurin inhibitor, cell-cycle inhibitor, and corticosteroids), as well as opportunistic infection prophylaxis against pneumocystis jiroveci, other fungal infections, and cmv. in early postoperative period and after hospital discharge, the recipients are closely monitored in outpatient setting. typical clinic visits include thorough medication reconciliation, clinical exam, pulmonary function testing, chest radiographs, and laboratory examinations. the role of surveillance bronchoscopies with transbronchial biopsies in monitoring of lung allograft remains unclear. while lung transplantation improves survival and quality of life in patients with end-stage lung disease, it is associated with multitude of noninfectious and infectious complications. lung transplant recipients have one of the shortest survival rates among other solid organ recipients, due to some unique characteristics of the lung allograft, including its unique blood supply and risk for ischemia, disruption of the native lymphatics and the neural supply during the transplant surgery, and exposure to immunogenic entities via ventilation. among noninfectious complications, pgd, vte, and rejection are the most important ones. clad affects most patients long term and remains a significant clinical concern and contributor to early mortality in lung transplant recipients. lung transplant recipients are also at increased risk for a variety of malignancies, due to their underlying disease, comorbidities, and immunosuppressed status; thus they require vigilant monitoring and screening for cancer. infectious complications (i.e., bacterial, fungal, viral) are also important contributors to morbidity and mortality, with bacterial pneumonias and cmv most commonly seen. patients require multidisciplinary and intensive follow-up and aftercare, ongoing vigilance, early recognition and treatment, and open and frequent communication between recipients, caregivers, and healthcare team providers. the registry of the international society for heart and lung transplantation: thirtieth adult lung and heart-lung transplant report--2013; focus theme: age long-term health status and quality of life outcomes of lung transplant recipients the registry of the international society for heart and lung transplantation: thirty-fourth adult heart transplantation report-2017; focus theme: allograft ischemic time every allograft needs a silver lining lung transplant airway hypoxia: a diathesis to fibrosis? a critical role for airway microvessels in lung transplantation pulmonary complications of lung transplantation report of the ishlt working group on primary lung graft dysfunction, part i: definition and grading-a 2016 consensus group statement of the international society for heart and lung transplantation report of the ishlt working group on primary lung graft dysfunction part iii: mechanisms: a 2016 consensus group statement of the international society for heart and lung transplantation report of the international society for heart and lung transplantation working group on primary lung graft dysfunction, part ii: epidemiology, risk factors, and outcomesa 2016 consensus group statement of the international society for heart and lung transplantation report of the ishlt working group on primary lung graft dysfunction part iv: prevention and treatment: a 2016 consensus group statement of the international society for heart and lung transplantation venous thromboembolic complications of lung transplantation: a contemporary single-institution review pulmonary embolectomy after single-lung transplantation diaphragmatic paralysis: a complication of lung transplantation leuven lung transplant g. phrenic nerve dysfunction after heart-lung and lung transplantation post-surgical and obstructive gastroparesis gastroparesis is common after lung transplantation and may be ameliorated by botulinum toxin-a injection of the pylorus upper gastrointestinal dysmotility in heart-lung transplant recipients acute and chronic pleural complications in lung transplantation pleural space complications associated with lung transplantation pleural effusion from acute lung rejection mesothelioma after lung transplantation frequency and management of pneumothoraces in heart-lung transplant recipients shifting pneumothorax after heart-lung transplantation endovascular management of early lung transplant-related anastomotic pulmonary artery stenosis four-year prospective study of pulmonary venous thrombosis after lung transplantation pulmonary venous obstruction after lung transplantation. diagnostic advantages of transesophageal echocardiography primary graft dysfunction and other selected complications of lung transplantation: a single-center experience of 983 patients airway complications and management after lung transplantation: ischemia, dehiscence, and stenosis airway complications after lung transplantation: treatment and long-term outcome segmental nonanastomotic bronchial stenosis after lung transplantation acute cellular and antibody-mediated allograft rejection are symptom reports useful for differentiating between acute rejection and pulmonary infection after lung transplantation? heart lung the role of transbronchial lung biopsy in the treatment of lung transplant recipients. an analysis of 200 consecutive procedures revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection acute allograft rejection: cellular and humoral processes transplant/immunology network of the american college of chest p. a survey of clinical practice of lung transplantation in north america antibody-mediated rejection of the lung: a consensus report of the international society for heart and lung transplantation acute antibody-mediated rejection after lung transplantation acute antibody-mediated rejection after lung transplantation chronic lung allograft dysfunction phenotypes and treatment update on chronic lung allograft dysfunction bronchiolitis obliterans syndrome: the achilles' heel of lung transplantation an international ishlt/ats/ers clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome therapy options for chronic lung allograft dysfunction-bronchiolitis obliterans syndrome following first-line immunosuppressive strategies: a systematic review neutrophilic reversible allograft dysfunction (nrad) and restrictive allograft syndrome (ras) restrictive allograft syndrome (ras): a novel form of chronic lung allograft dysfunction comparison of the incidence of malignancy in recipients of different types of organ: a uk registry audit spectrum of cancer risk among us solid organ transplant recipients bronchogenic carcinoma complicating lung transplantation disseminated ureaplasma infection as a cause of fatal hyperammonemia in humans risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients prevalence and predictors of diabetes after lung transplantation: a prospective, longitudinal study short-term and long-term outcomes of acute kidney injury after lung transplantation incidence and outcomes of acute kidney injury following orthotopic lung transplantation: a population-based cohort study chronic kidney disease after lung transplantation: incidence, risk factors, and treatment osteoporosis and fractures after solid organ transplantation: a nationwide population-based cohort study bone loss and fracture after lung transplantation contemporary analysis of incidence of post-operative atrial fibrillation, its predictors, and association with clinical outcomes in lung transplantation atrial arrhythmias after lung transplant: underlying mechanisms, risk factors, and prognosis new-onset cardiovascular risk factors in lung transplant recipients skeletal muscle force and functional exercise tolerance before and after lung transplantation: a cohort study maximal exercise capacity and peripheral skeletal muscle function following lung transplantation pneumonia after lung transplantation in the resitra cohort: a multicenter prospective study nocardia infections in solid organ transplantation significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients empyema complicating successful lung transplantation multidrug-resistant gram-negative bacteria infections in solid organ transplantation the impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral centre methicillinresistant, vancomycin-intermediate and vancomycin-resistant staphylococcus aureus infections in solid organ transplantation invasive pneumococcal infections in adult lung transplant recipients clostridium difficile in solid organ transplant recipients mold infections in lung transplant recipients fungal infections in lung transplant recipients endemic fungal infections in solid organ transplantation cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome dna viral infections complicating lung transplantation cytomegalovirus and lung transplantation community-acquired respiratory viral infections in lung transplant recipients: a single season cohort study quality of life in lung transplantation key: cord-029226-eagbwk7j authors: williamson, brian title: beyond covid‐19 lockdown: a coasean approach with optionality date: 2020-06-29 journal: nan doi: 10.1111/ecaf.12414 sha: doc_id: 29226 cord_uid: eagbwk7j nan maintaining across-the-board restrictions is socially and economically costly, has adverse distributional impacts, and is poorly targeted in terms of protecting health and health care provision. instead a win-win 'coasean' social contract could be forged to protect older people and other atrisk groups coupled with freedom from lockdown for everyone else. the social contract could involve a period of support and extra payments to older age groups to commit to home quarantine, but with the possibility of opting out. younger cohorts would be given the option of taking greater risks in return for liberty, fraternity, and greater economic participation. by doing so they would benefit themselves, but also support society economically and through acquired immunity. a few countries, such as new zealand and australia, which acted early and had a limited number of covid-19 cases, may be able to eliminate covid-19 and reopen their societies with ongoing strict border controls. however, given that covid-19 transmission is well established in most countries, near-term options in other countries are limited to mitigation. in the longer term, immunity acquired via infection, or ideally a vaccine, offers the prospect of a solution. however, the timing and effectiveness of vaccines are uncertain, and this is not a nearterm option. in the near term, mitigation options include hygiene measures, physical distancing, testing and contact tracing to limit transmission, in addition to improved clinical care. however, physical distancing (especially via lockdown) is very costly in terms of liberty as well as economics. elimination strategies. a number of studies do not consider such differences, for example barro (2020) . first, unlike an influenza pandemic, which may involve waves over a period of months but typically evolves into less serious seasonal strains, covid-19 is expected to persist. influenza also has a lower reproduction number (r 0 ) than covid-19 (biggerstaff, cauchemez, reed, gambhir, & finelli, 2014) , so population immunity could be acquired at a lower level of infection. a short-term quarantine can therefore be effective in avoiding or limiting the impact of an influenza pandemic but not covid-19, though it buys valuable time. second, unlike influenza, covid-19 is very unusual in its markedly disproportionate risk of killing older people, in addition to those at risk due to chronic health conditions. in contrast, mortality during the 1918-19 influenza pandemic was u-shaped or w-shaped with age; that is, many younger people died in addition to older people (taubenberger, 2006) . this difference is relevant to the economic impact in terms of reduction in workforce participation due to deaths or fear of deaths. a further consideration is immunity. covid-19 infection produces immunity, but the longevity of such immunity and the extent of cross-immunity with other coronaviruses is unknown. the nature of immunity, which may differ from that for influenza, will impact the dynamics of the covid-19 infection (kissler, tedijanto, goldstein, grad, & lipsitch, 2020) . figure 1 shows the marked variation in the infection-fatality ratio by age group. the risk of death if infected in the 80-plus age group is around 250 times that for 20-29 year-olds; more broadly, the risk of death if infected in the under-60 age group is 0.145 per cent, versus 3.28 per cent in the 60-plus age group, a 23-fold difference. while younger people are at greatly reduced risk from covid-19, they are on the other hand likely to suffer some of the more severe impacts in terms of forgone education, employment, and social and longer-term opportunities from measures to increase physical distancing. economic harm, particularly unemployment, can in turn be expected to have an adverse impact on mental health in particular. the combination of low health risk for younger people from covid-19 with disproportionately high economic and social costs from the current policy response suggests that a more targeted policy response is desirable. given that the risk of dying from covid-19 is a sharply increasing function of age, two broad suggestions have been put forward in the uk: • extend the stay-at-home recommendation for those aged over 70 to those aged over 60 (osama, pankhania, & majeed, 2020) . • release the under-30s from lockdown (oswald & powdthavee, 2020) . however, while these proposals better reflect population risk, neither is sustainable or sufficient to restart the economy and protect the most vulnerable. a larger group than those under 30 need to be released, and some, but not all, of those aged 50-60 are at significant risk and account for a significant fraction of years of life lost. sustainable responses that can bridge the gap to longer-term solutions are required which do not involve the high costs of lockdown in terms of liberty, employment, education, income, and broader physical and mental health outcomes. this is a pressing challenge, in particular for those at the start of their adult lives. in this article, building on a blog post where the idea was first suggested (williamson & wilson, 2020) , what is proposed is a coasean social contract that recognises the reciprocal nature of the problem of mitigating the risk of harm to health, welfare, and the economy from the covid-19 pandemic. the bargain is 'coasean' in recognising that social costs (externality) can be reciprocalan idea developed by ronald coase, the nobel prize-winning economist. coase analysed the case of sparks from trains setting fire to crops where the train company could mitigate sparks while the farmer could avoid cultivation of crops close to railways; and an efficient bargain between the two could in principle be struck (coase, 1960) . externalities arise because individual actions have consequences for others in terms of infection (from contact), in terms of reduced population immunity (from avoiding contact), and in terms of the risk that health care resources are redirected to treat those with covid-19. a functioning economy is also required to support society, and economic harm can be expected to have health implications (case & deaton, 2015) . reciprocity arises because either those at higher risk can isolate themselves or those who might infect them but are at lower risk can be locked down to reduce the spread of covid-19. however, while some risk factors can be identified, individuals will have information about their own risk, risk preferences, and opportunity cost of lockdown that is not available to central authority but which should inform decisions about who is isolated. what is proposed is a combination of central design and individual decisionsa coasean social contractthat recognises the reciprocal nature of the problem and allows individuals to opt in or out of defined categories in return for receiving or forgoing social and financial support. reflecting different individual preferences, there would be optionality for those at low risk to isolate without payment (they are not contributing to the societal good of a build-up of population immunity), while those at higher risk could opt out of isolation but would forgo support and payment. research on individual preferences could be conducted to inform the choice of default thresholds and incentives for a coasean social contract. a further option would be to require those at risk who opt out of self-isolation to pay a riskadjusted health insurance surcharge reflecting the broader risk they pose in terms of health care costs and the risk of overloading the health care system (in contrast to the moral hazard involved with health insurance opt-in those choosing to pay an insurance surcharge to opt out of isolation might be at lower risk than average for their cohort). however, a surcharge for opting out may be considered inequitable. this approach may also have the benefit of permitting an additional feedback loop as the load on the health system evolves, namely by changing the eligibility cohort and/or by changing the payment in return for isolation or potentially holding an online auction to achieve a given level of additional opt-in. the ability to influence r 0 via modest distancing measures and to keep the growth in covid-19 cases manageable would also be enhanced by growth in the proportion of people with a degree of immunity (well short of herd immunity) as younger cohorts re-enter education and work and socialise. again, the covid-19 health risk for this group, while non-zero, is low. this approach may also have lower costs to the economy than turning off or on distancing measures for everyone as epidemic spread subsides or picks up again, since the ongoing uncertainty associated with such epidemic dynamics limits individuals' ability to plan and invest, and may make some businesses non-viable, for example in hospitality and tourism. while financial incentives could undermine incentives for voluntary sacrifice and compliance for behavioural reasons, they are also more tuneable. it can be difficult, for example, to communicate clearly to the public the changes in the detailed rules in relation to home quarantine and physical distancing, or potentially to maintain a high level of compliance while extending the period of compliance (briscese, lacetera, macis, & tonin, 2020) . centralised and decentralised responses to covid-19 can, and would, both play a part in mitigating overall harm under a coasean social contract. the proposed approach could substantially reduce the economic and social cost of the covid-19 policy response while limiting mortality and the risk of overloading the health-care system. the degree of heterogeneity in terms of risk and preferences across individuals in the age group most at risk may be very large. some of those at increased risk may be highly productive or simply value outside economic and social opportunities highly, others less so. some may have a diminished quality of life, and/or may have died in the near term irrespective of covid-19. others who are healthy may consider the increased risk of premature death to be a small price to pay in return for freedom. this is relevant to the trade-offs individuals might make and to a societal assessment of alternative policy options. for deaths involving covid-19 that occurred in march 2020 in the uk, there was at least one pre-existing condition in 91 per cent of cases (ons, 2020). neil ferguson (2020) , director of the mrc centre for global infectious disease analysis at imperial college london, considered that it might be that as many as half to two-thirds of those who had died from covid-19 in the uk early in 2020 would have died by the end of the year from other causes. however, a study of hospital cases (excluding care homes) found that stratifying by age and multimorbidity counts showed that average years of life remaining were rarely below three (hanlon et al., 2020) . infection-fatality ratios can be combined with expected years of life remaining from life tables (ons, 2019) to obtain expected years of life lost, conditional on catching covid-19. these estimates can also be adjusted based on estimated health-adjusted life years remaining. covid-19 infection, on the assumption that years of life lost are 50 per cent lower for those aged 50-69 and two-thirds lower for those aged 70-plus. those most at risk face an expected loss of around six months of life on the assumption of typical health, and around two months of life if the assumed impact of comorbidity is allowed for. compared with the reduced quality of life associated with lockdown, some might regard this risk as modest, though individuals tend to be risk-averse. individuals are likely to have very different attitudes to this uncertain prospect. there are, therefore, grounds for not only moving to an age-specific policy response to covid-19, but also moving from mandates to incentives given large variations in individual trade-offs and private information about such trade-offs. what is proposed is a shift to an agespecific set of policy defaults, but with optionality and incentives to allow individuals to make individual choices. developing an approach which recognises individual heterogeneity and the importance of private information and preferences to individual and socially efficient trade-offs is more likely to prove sustainable, since it more closely aligns with individual preferences and incorporates support and compensation for those bearing the greatest burden in terms of isolation. the approach is intended as a bridge to a time when population immunity develops, ideally via an effective vaccine. the novel social contract set out here could be explored further by governments who have pursued mitigation via physical distancing but find that population fatigue is limiting its effectiveness or that the economic and social cost for younger cohorts in particular is simply too high. the approach seeks to recognise both individual preferences and two particular social benefits. first, society as a whole would benefit from getting younger cohorts back into education, training and work; and from the immunity this group would build up. they should therefore be not only allowed to return to 'normal' life but encouraged to do so, via a reduction in financial support to pre-existing safety net levels. second, society as a whole would also benefit by encouraging those groups considered to be at high risk to stay at home for the medium term. compulsion may not be sustainable, may be regarded as discriminatory, and is not ideal as some individuals may have low risk or high productivity or simply prefer liberty alongside the risk from covid-19. a combination of support and financial incentives coupled with the option to opt out is preferable to compulsion. the goal of this possible 'third way' is not to minimise deaths per se, but to go beyond a health optimisation approach to a broader well-being-maximising one, taking account of individual preferences and trade-offs. the proposed approach places greater weight on individual choice coupled with incentives rather than mandates, in part because such an approach may be more likely to have legitimacy over an extended time frame than the prevailing lockdown approach. it also recognises that individuals have more information about their risks and preferences, and these will differ across individuals. it also has the benefit of representing a social contract which, in contrast to across-the-board restrictions, recognises the contribution everyone is making while improving intergenerational equity. the views expressed in this article are the author's own and not those of communications chambers, which has no collective view. non-pharmaceutical interventions and mortality in u.s. cities during the great influenza pandemic, 1918-1919. nber working paper 27049 estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. bmc infectious diseases compliance with covid-19 social-distancing measures in italy: the role of expectations and duration rising morbidity and mortality in midlife among white non-hispanic americans in the 21st century the problem of social cost science and technology committee. parliamentlive.tv covid-19 -exploring the implications of long-term condition type and extent of multimorbidity on years of life lost: a modelling study projecting the transmission dynamics of sars-cov-2 through the postpandemic period national life tables: uk. 25 september deaths involving covid-19, england and wales: deaths occurring in protecting older people from covid-19: should the united kingdom start at age 60? the case for releasing the young from lockdown: a briefing paper for policymakers the origin and virulence of the 1918 'spanish' influenza virus estimates of the severity of coronavirus disease 2019: a model-based analysis. the lancet might a 'coasean' social contract mitigate overall societal harm from covid-19? public health expert how to cite this article: williamson b. beyond covid-19 lockdown: a coasean approach with optionality key: cord-254436-89zf41xr authors: singer, professor donald rj title: health policy implications of the links between cardiovascular risk and covid-19 date: 2020-09-03 journal: health policy technol doi: 10.1016/j.hlpt.2020.09.001 sha: doc_id: 254436 cord_uid: 89zf41xr nan influenza by immunization now have reduced confidence in leaving home. they are therefore much less likely to be prepared to access community health services to receive an influenza immunization. an epidemic of simultaneous influenza and covid-19 is therefore a serious concern. this would result in higher morbidity and mortality in vulnerable people and greater pressure on acute medical services. approaches to improving outcomes of covid-19 include development of effective vaccines. in the meantime, public health measures are the mainstay for containing spread of infection with sars-cov-2, complemented by access to high quality supportive treatment and efforts to develop targeted approaches to reduce infection and disease severity in people at high risk of serious morbidity and death from covid-19. however, eight months since this new respiratory syndrome was first reported to international authorities, effective test and trace systems have not yet been internationally implemented, even across all well-developed healthcare systems. for example, in the uk, reporting of test results has fallen to below 50% within 24 hours and one in seven home testing kits are reported to fail to yield a result [3] . there are major global efforts underway to develop vaccines against covid-19, with 19 candidates as of 31 july 2020 entered into clinical studies, including phase 2 and 3 trials [4] . however, their short and long-term effectiveness and safety remain to be established. the usual questions for a new vaccine remain to be answered. will vaccines prevent covid-19 or at least improve prognosis from the infection? will groups at higher risk from covid-19 respond as well as the often healthier volunteers in clinical trials? the timeline also remains uncertain for widespread public protection if and when safe and effective vaccines become available. international networks for pharmacovigilance against adverse effects of covid-19 vaccines are needed, with for example utrecht university in the netherlands being commissioned by the european medicines agency as a hub for a europe-wide network [5] . people with comorbidities are more likely to be infected with sars-cov-2, especially those with hypertension, coronary heart disease, diabetes mellitus and obesity. they are also more likely to have worse outcomes from covid-19, with similar associations in reports for example from china, the usa and italy [6, 7] . people with cardiovascular risk factors or established cardiovascular disease also experience a high case-fatality rate from covid-19 [5, 6] . for example, hypertension was reported in 40% of patients who died [odds ratio for death, 3.05 (95% ci: 1.57-5.92)] in a meta-analysis of over 40,000 confirmed covid19 patients in china [6] . in the same report, cardiovascular disease [cvd] was associated with a 5-fold increase in risk of death from covid-19 [6] . although the elderly are at greater risk of infection and death, younger adults are also at risk, especially those who are obese [8] and/or from black and asian ethnic minorities [9] . a recent meta-analysis of almost 400,000 subjects [8] reported that patients with a bmi over 30 kg/m 2 were ~50% more likely to develop covid-19and for those with covid-19, over twice as likely to be admitted to hospital for treatment, ~75% more likely to be admitted to an intensive care unit and had a ~50% greater mortality than the less overweight. for patients from bame groups, a lower bmi threshold of over 25 kg/m 2 appeared associated with worse severity from covid-19. in addition to being at increased risk of covid-19, obese patients also appear less likely to respond effectively to the influenza immunization [10] . there are therefore concerns that obese people may also respond less well to immunization against sars-cov2. however, as an example of the global health challenge, despite international efforts, including sustainable development goals for health adopted by g20 countries [11] , obesity remains an international epidemic, despite its being recognized as a disease by many organisations [12] including by the american medical association since 2013, and the long-established role of obesity as a major contributor to serious disorders of the heart, brain and circulation, as well as many cancers, joint disease and poor mental health. the who estimates that obesity has tripled since 1975 and that by 2016 there were 650 million obese people globally (1.6 billion overweight) [13] . reasons why black and ethnic minorities (bame) are more at risk of infection with sars-cov2 and of worse outcomes from covid-19 are unclear [8] . for example, in one study in the uk, one third of patients admitted to icu due to covid-19 were from an ethnic minority [14] with similar reports from the usa. possible reasons include a higher prevalence in bame populations of cardiovascular risk factors e.g. hypertension, diabetes mellitus, insulin resistance and obesity, socioeconomic, cultural, or lifestyle factors and genetic predisposition. there may also be pathophysiological differences in susceptibility or response to infection due for example to increased prevalence of vitamin d deficiency. an increased inflammatory burden may also contribute to worse outcomes. ace-2 (angiotensin converting enzyme ii) is the key docking protein by which the covid-19 virus binds to cells [15] . this is also the key cell entry receptor used by the initial sars-cov [14] . ace-2 is mainly found on vascular endothelial cells, the renal tubular epithelium and the leydig cells of the testis. copies of the ace-2 protein are present in increased numbers in patients with risk factors for heart disease. ace-2 could thus be a therapeutic target in the treatment of covid-19. however enzymatic activity of ace2 controls activation of the renin-angiotensin-aldosterone system (raas), a current therapeutic target in cardiovascular and renal disease. there were concerns that common medicines such as ace inhibitors (acei) or angiotensin receptor blockers (arbs) used to treat hypertension or heart failure by inhibiting the renin-angiotensin system could adversely affect ace2 expression. however, studies to date in sars-cov-2-infected patients do not suggest that these raas modulators influence susceptibility to the infection or cause more severe covid-19. indeed, in a meta-analysis of almost 29,000 patients with covid-19, use of raas inhibitors for any conditions showed a trend to lower risk of death or critical events (odds ratio 0.67, 95% ci 0.43 to 1.03, p = 0.07). within the hypertensive cohort, treatment with acei or arbs was associated with one third less mortality from covid-19 (odds ratio 0.66, ci 0.46 to 0.96, p = 0.03) and a one third reduction in the combined end-point of death and critically severe outcomes (odds ratio 0.67, ci 0.50 to 0.91, p = 0.01) [16] . this was however an observational study and there is as yet no evidence as to whether adding an acei or arb to treatment would influence the outcome of covd-19. myocardial injury is found in >25% of critical cases of covid-19 and presents in 2 patterns: acute myocardial injury and dysfunction on presentation and delayed myocardial injury that develops as illness severity intensifies [5] . there are also potentially serious drug-cardiac disease interactions affecting patients with covid-19 and associated cardiovascular disease, for example from empirical anti-inflammatory treatments. [6] . sars-cov2 may also cause hypercoagulability, resulting in unexpectedly severe lung damage from widespread thromboses and disseminated intravascular coagulation adding to lung injury from covid-19 pneumonia [17] . these features suggest complement-mediated thrombotic microangiopathy as a contributory factor and may give clues to treatment beyond anticoagulation to prevent life-threatening microangiopathy [17, 18] . an indirect factor in covid-19-related increased severity of cardiovascular disease is malnutrition in patients self-isolating at home. this may directly increase risk of falls, heart attack and stroke, especially when patients continue diuretics and other blood pressure-lowering medicines despite reduced oral intake of food and drinka recognized cause of hypotension and falls. other indirect reasons for concern about increased prevalence and severity of cardiovascular disease because of the covid-19 pandemic include poorer recognition and control of cardiovascular risk factors and established serious disorders of the heart, brain and circulation due to reduced access to medical services. particularly in less developed countries, public transport is vital for access to health care facilities. both public transport services and medical facilities have been seriously limited during covid-19 restrictions and availability of funds to pay for medical services has been severely reduced. for example, in india, over 75% of the country's substantial workforce of 100 million migrant workers lost their jobs overnight, public transport services were critically reduced, and many healthcare facilities closed [19] . increasing recognition of these links between cardiovascular risk and disease and severity of covid-19, including mortality, offer opportunities to improve outcomes of covid-19 in the large number of patients with these common disorders. understanding the pathophysiology and exploring potential solutions and treatments to reverse worse outcomes in patients at increased cardiovascular risk is a priority for health researchers and clinical health services around the world. this is all the more pressing as there is an international epidemic of the preventable cardiovascular risk factors which have been linked to increased severity of covid-19. health policy makers also need to take steps to extend influenza immunization to all groups now recognized to be at risk of more serious covid-19, including the obese, others with increased cardiovascular risk and people from black and other at risk ethnic minorities. policy makers will need to make extra efforts to make sure that these vulnerable people take part in influenza immunization programmes. this requires measures to make sure that accessing points of care will not put people at risk of acquiring covid-19. policy makers also need to build public awareness of the current extra importance of influenza immunization and confidence in the safety of accessing medical services. the involvement of policy makers to ensure sustained financial and social solutions for covid-19 is urgently needed, to complement the efforts against covid-19 of health professionals, regulators and the pharmaceutical and biotechnology industries. these efforts will not be successful without also addressing the cardiovascular and other factors that contribute to higher risk from covid-19. links to the severity of covid-19 make it all the more pressing for policy makers and public health agencies to address underlying causes and to reduce the incidence and severity of preventable cardiovascular risk. situation updates. website for the european centre for disease prevention and control. accessed 27 th a pneumonia outbreak associated with a new coronavirus of probable bat origin uk coronavirus live: daily cases tally jumps by nearly 500 to reach 1,522. uk guardian news website vaccines and treatment of covid-19. european centre for disease prevention and control ema to monitor real world use of covid-19 treatments and vaccines covid-19 and cardiovascular disease: from basic mechanisms to clinical perspectives clinical determinants for fatality of 44,672 patients with covid-19. crit care individuals with obesity and covid-19: a global perspective on the epidemiology and biological relationships asian and minority ethnic groups in england are at increased risk of death from covid-19: indirect standardisation of nhs mortality data obesity impairs the adaptive immune response to influenza virus soft power and global health: the sustainable development goals (sdgs) era health agendas of the g7, g20 and brics. bmc public health regarding obesity as a disease: evolving policies and their implications is ethnicity linked to incidence or outcomes of covid-19? ace2 as a therapeutic target for covid-19; its role in infectious processes and regulation by modulators of the raas system effect of renin-angiotensin-aldosterone system inhibitors in patients with covid-19: a systematic review and meta-analysis of 28 covid-19 cytokine storm: the interplay between inflammation and coagulation emerging evidence of a covid-19 thrombotic syndrome has treatment implications the author has no conflict of interest to declare. he is the president of the fellowship of postgraduate medicine, for which health policy and technology is an official journal.during 2014 he was a physician and pharmacologist in rwanda within the us aid and us cdc human resources for health program. key: cord-017479-s4e47bwx authors: pulcini, elena title: spectators and victims: between denial and projection date: 2012-03-16 journal: care of the world doi: 10.1007/978-94-007-4482-0_6 sha: doc_id: 17479 cord_uid: s4e47bwx this chapter goes into the unproductive metamorphosis of fear, and analyses the defence mechanisms that it generates: namely denial and projection. in the case of global risks, fear provokes self-defensive strategies based on denial (in the face of the nuclear challenge) and self-deception (in the face of global warming); and, in the case of the threat of the other, projective and persecutory strategies based on reactivating the dynamic of the ‘scapegoat’. they are two contrasting but specular responses which, at the emotional level, reflect the divarication between (unlimited) individualism and (endogamous) communitarianism. the first, implosive response converts into an absence of fear, attested to above all by the figure of the global spectator, while the second, explosive response converts into an excess of fear (fear of the other, fear of contamination), fuelled by forms of reinventing community. these responses are defined as irrational since in the first case they inhibit the spectator’s capacity to recognize himself as also a potential victim of the threats, thus preventing his mobilization, and in the second case they give rise to dynamics of demonization-dehumanization of the other, which result in a spiral of violence and impede forms of solidarity. this case a subjective factor comes into play, linked to the capacity and manner of perceiving the threats. it is telling that sociology and psychology converge on the importance of this aspect, underlining the fact that the very characteristics of the risk have a de fi nite in fl uence on the way in which it is perceived. 4 ulrich beck had already stressed the fact that the often invisible nature of the global risks, the unforeseeability of their effects and the only potential character of the damage which they provoke mean that they are removed from our perception and require the intervention of a re fl exive attitude interpreting the new scenarios through a knowledge that is equal to the new challenges. but in reality the problem is more complex still, since rather than an absence, we are faced with processes that distort the perception and assessment of the risk, which affect both the emotional and the cognitive spheres, and above all how they interact together. among the approaches sensitive to this problem, the one which seems to dwell on it most is cognitive psychology. starting from the classic studies by chauncey starr and then fischoff and slovic, 5 and on the basis of the so-called psychometric paradigm, cognitive psychology has built complex cognitive maps aimed at providing as exhaustive a list as possible of the variables that in fl uence the subjective perception of risk. the conclusions that have emerged from this interpretative approach show, for example, that concern in the face of threats (whether they derive from particular activities, substances or technologies) grows in correspondence to certain characteristics, amongst which the involuntary nature of the risks, the impossibility of controlling them, their capacity to cause irreversible damage and their originating from an unknown source. but above all, the results stress the fact that individuals are subject to distorted assessments and judgements in relation to the risks they are exposed to. for example, they tend to overestimate threats publicized by the media even if they are infrequent; to consider dangers dealt with voluntarily as more acceptable compared to those to which we are subjected or which are completely unprecedented or not very familiar; to feel fear in the face of very vivid events (11 september 2001), at the same time being quite incapable of a historical memory that links these same events together. while the merit of this approach is that it accepts and recognizes the presence of the subjective aspect and the uncertainty factor in de fi ning the concept of risk, pointing out the presence of non-rational responses, its limits lie, however, in its still strongly assuming the notion of probability. 7 namely, it ignores what is instead underlined by mary douglas, that is, the social and institutional context and the symbolic-cultural factors that in fl uence the perception of the threats, 8 and reproposes the idea of an essentially individualistic and de-contextualized social actor based on an abstract idea of rationality. finally, what we are most interested in here, in part deriving from the latter aspect, the limit of this approach lies in its failure to account for the why , the deep reasons that pollute a correct perception and assessment of the risks. in this connection, based on the reassessment of the role of emotions that has greatly questioned the hegemonic paradigm of rationality 9 over the last few decades, some authors have underlined that cognitive and emotional factors have to go together in order to recognize the existence of a risk and to weigh up its possible consequences. 10 they have put forward the idea that the information that enters our cognitive system can only have an effective impact on our action if it succeeds in creating images laden with emotion in our psyche. in other words, this means that we can be perfectly aware of particular threats without this involving us emotionally. put differently, only if this converts into the capacity to 'feel', to react emotionally and imagine its possible effects can our knowledge of the risk be effectively said to be knowledge, and therefore produce apt mobilization. now, the problem with regard to global risks seems to be prompted, as günther anders had already perfectly grasped in his diagnosis of fear in the age of technology, by the very imbalance between knowing and feeling. this imbalance is none other than one of the many variants of the psychic split that characterizes the contemporary subject and that anders, as has already been hinted, calls the 'promethean gap'. with this expression, he alludes in general to the detachment between the faculties, fi rst of all between the power to do and the capacity to foresee, which characterizes contemporary homo faber , or rather homo faber who has become homo creator . paradoxically what corresponds to the immense human power to 115 6.1 global risks and absence of fear produce and create permitted by developments in technology is man's inability to imagine its consequences: the faculties have got further and further away from each other so now they can no longer see each other; as they cannot see each other, they no longer come into contact, they no longer do each other harm. in short: man as such no longer exists, there only exists he who acts or produces on one hand, and he who feels on the other; man as producer and man as feeling, and only these specialized fragments of men have a reality. 11 no more are our imagination and our emotions equal to our unlimited power; at this point man's soul is irreparably 'outdated' with respect to what he produces and his colossal performances. in short, no more can we keep up-to-date with our promethean productivity and with the world that we ourselves have built: we are about to build a world that we cannot keep up with, and, in order to "catch" it, demands are made that go way beyond our imagination, our emotions and our responsibility. 12 this 'schizophrenia', 13 which is where the fundamental pathology of our time resides, prompts the paradoxical and ambivalent combination of power and impotence, activity and passivity, knowledge and unawareness that exposes the contemporary prometheus not only to previously inconceivable risks, but, also and above all, to the impossibility to recognize their destructive potential. this pathological drift appears particularly evident in the risk par excellence of the age of technology, which undermines not only the quality of individuals' lives (like in the case of the possible effects of the biotechnologies), but humankind's very survival on the planet: namely, the risk produced by the creation of the nuclear bomb, which we can recognize as the fi rst effectively global challenge. 14 before the horror of hiroshima and the spectre of humankind's self-destruction anders says: we really have gained the omnipotence that we had been yearning for so long, with promethean spirit, albeit in a different form to what we hoped for. given that we possess the strength to prepare each other's end, we are the masters of the apocalypse. we are in fi nity . 15 but the inability of our imagination to be equal to our unlimited power makes the latter mortally dangerous and transforms us into potential victims of what we ourselves have built: we, the men of today, are the fi rst men to dominate the apocalypse, hence we are also the fi rst to be endlessly subject to its threat. we are the fi rst titans, hence we are also the fi rst dwarves or pygmies -or whatever else we care to call ourselves, we beings with our collective deadline -we are no longer mortal as individuals, but as a group; whose existence is exposed to annulment. 16 suf fi ce it to think that it is impossible to see the bomb simply a means; an impossibility generated by the fact that if someone used the bomb… the means would not be extinguished in the purpose, but, on the contrary, the effect of the presumed "means" would put an end to the purpose. and it would not be one effect, but an unforeseeable chain of effects, in which the end of our life would be but one link among the many. 17 the gap between the power to do and the power to foresee, therefore, gives rise to the paradoxical coexistence of omnipotence and vulnerability, which exposes future humankind and the whole of civilization to the risk of extinction, thereby con fi guring the apocalyptic scenario of a 'world without man'. 18 but the problem does not stop here. indeed, if men, even when faced with the loss of foresight and projectuality caused by their own action, were capable of recognizing the reality of the danger, a change of direction could be set in motion to restore their control over their future. or, to put it in terms that allow us to return to our theme, if people felt fear in the face of the spectre of self-destruction and the enormity of the risks ahead, they would probably manage to break that promethean spiral of unlimitedness and restore sense and purpose to their action. furthermore, this is the normative premise at the basis of hans jonas's whole line of argument in favour of an ethics of responsibility. he starts from a similar diagnosis to that of anders on the drifts of technological power and the threats, for the whole living world, produced by a ' fi nally unbound prometheus' to suggest what he de fi nes as a 'heuristics of fear', as the precondition for ethically responsible action. ' […] it is an anticipated distortion of man,' he says, 'that helps us to detect that in the normative conception of man which is to be preserved from that threat […] . we know the thing at stake only when we know that it is at stake .' 19 this means that only the fear of 'losing the world' can push us to responsibly take on the problem of how to preserve it. i shall come back to the nexus between fear and responsibility later on. 20 but the problem, which anders strongly underlines -showing, unlike jonas, its complex anthropological and psychic roots -is that today we are in the presence of the unavailability of fear ; in actual fact it is paradoxically absent, due to the additional and deeper manifestation of the promethean gap which is the imbalance between knowing and feeling . indeed, there is no one who does not know what the bomb is and who does not know its possible, catastrophic consequences, but, anders adds, 'most people indeed only "know" it: in the emptiest of manners'. 21 namely, this 17 22 this asynchrony, anders points out, is something that pertains to human nature as a matter of fact. in general, in itself this is not bad, since it only shows that feeling is slower to transform. however, so to speak, it degenerates into a pathology when the gap between the faculties becomes too wide, as is happening today. as a consequence, it breaks all bonds and communication between them, 23 and reduces contemporary men to the 'most dissociated, most disproportionate in themselves, most inhuman that have ever existed.' 24 therefore, it is here, in the inadequacy of our emotional resources with respect to our productive power, that the anthropological root of our 'blindness to the apocalypse' lies. 25 and this inadequacy, which is true for all the emotions in general, concerns fear fi rst of all. everyone, in however confused a manner and in spite of the minimization strategies implemented by those who produce it, realize that the bomb is not a pure means whose function ends in the ful fi lment of a purpose, but a monstrous ' unicum ' that, together with our lives and the lives of future generations, can put an end to all purposes tout court . 26 yet, surprisingly, there is no fear : if today we were to seek out fear ( angst ),* real fear in vienna paris, london, new yorkwhere the expression ' age of anxiety ' is very much in use -, the booty would be extremely modest. of course, we would fi nd the word 'fear', in swarms even, in whole reams of publications […] . because today fear has become a commodity; and these days everyone is talking about fear. but those talking out of fear these days are very few. 27 if we are to observe our present-day situation, we could even claim that the more fear becomes the subject of talk in the newspapers and mass media, the more it is withdrawn from emotional perception and is anaesthetized by the reassuring urgency of routine and day-to-day concerns. the anaesthetizing mechanism also works in a directly proportionate manner to the enormity of the risk and the stake at play. while it may be true that at best we 22 ibid., i, 269. 23 ibid., i, 267-68. 24 ibid., i, 271-72. 25 see ibid., part iv, i, 234ff. anders underlines its historical roots, such as trust in progress that prevents man from thinking of an 'end', and above all, the con fi guration at the anthropological level of what he de fi nes as the 'medial man', whose passive and conformist action ends up removing his ability to project himself into the future, together with all sense and purpose. see ibid., part 5, i, 276ff. 26 ibid., i, 254ff. * translator's note: anders only uses one term -angst -and does not distinguish between anxiety and fear. since, however, the meaning with which he uses the term angst coincides more with 'fear' in the acceptation put forward by elena pulcini, i have decided to translate it with 'fear' so as to distinguish it from 'anxiety'. 27 ibid., i, 264. are able to imagine our own death, but not that of tens or thousands of people, and that we may be able to destroy a whole city without batting an eyelid while not managing, however, to imagine the actual, terrible scenario of 'smoke, blood and ruins', it is inevitable that we are totally incapable of perceiving the destruction of all humankind 28 : 'before the thought of the apocalypse, the soul remains inert. the thought remains a word.' 29 even though today the end of humankind has entered the sphere of possibility and even though man himself is responsible for this, the psyche removes the thought of this possibility, thus preventing fear from arising. hence, we are illiterate in fear -'analphabeten der angst' -and 'if one had to seek a motto for our age, the most appropriate thing to call it would be "the era of the inability to feel fear"'. 30 anders's diagnosis concerning the anaesthetizing of fear and the imbalance between knowing and feeling seems to fi nd a perfect correspondence in that distinctive defence mechanism that freud de fi ned as 'denial of reality'. 31 more complex and subtle than repression ( verdrängung ), which indicates the operation with which the subject pushes particular representations linked to an instinct to the unconscious, and which for freud becomes a sort of prototype of defence mechanisms, denial ( verleugnung ) causes the self, despite rationally recognizing a painful and dif fi cult situation, to prevent this reaching the emotional sphere. 32 in other words, while repression is a defence against internal instinctual demands , denial is a defence against the claims of external reality , 33 which is rationally recognized, but not emotionally felt or participated. this converts into that distinctive ambivalence of 'knowing and not-knowing' which, as has recently been 28 ibid., i, 268-69. 29 ibid., i, 269. 30 in his recent sociological valuation of the concept of 'denial', stanley cohen stresses this ambivalence, pointing this out as the most interesting side of the concept, 36 and above all the most suited to accounting for a series of phenomena that characterize contemporary reality. explicitly drawing from psychoanalysis, whose worth he acknowledges -if nothing else against the reductive simpli fi cations of cognitive psychology 37 -as more than any other approach having grasped the elusive quality of the concept of denial, cohen offers a de fi nition that fi rst of all takes into account the meaning that is more general and common to the various forms: […] people, organizations, governments or whole societies are presented with information that is too disturbing, threatening or anomalous to be fully absorbed or openly acknowledged. the information is therefore somehow repressed, disavowed, pushed aside or reinterpreted. or else the information "registers" well enough, but its implications -cognitive, emotional or moral -are evaded, neutralized or rationalized away.' 38 on the basis of this premise, cohen analyses the many forms of denial. it can occur in good faith or be deliberate and intentional; it changes in relation to the subjects' different positions, that is, whether they are victims, guilty parties or witnesses; it depends on how the object is evaluated, which can be expressed through a simple refusal to acknowledge the facts, through a different interpretation or through a rationalization that aims to prevent its psychological, political and moral implications. but the most disconcerting and problematic form, since it can affect whole cultures -as is the case today -is what makes the subjects of the denial aware and unaware at the same time, that is, placed on the threshold between consciousness and unconsciousness. here they do have access to the reality, but in such a way as to ignore it since it is too frightening or painful, or simply too unpleasant to accept. 'we are vaguely aware,' cohen says, 'of choosing not to look at the facts, but not quite conscious of just what it is we are evading. we know, but at the same time we don't know.' 39 for example, much more than the intentional denial which is often 34 ibid, 22. 35 anders, die antiquiertheit des menschen , i, 269-70. 36 cohen, states of denial . 37 'the cognitive revolution of the last thirty years has removed all traces of freudian and other motivational theories. if you distort the external world, this means that your faculties of information processing and rational decision making are faulty.' (ibid., 42) . 38 ibid., 1. 39 ibid., 5. moreover, this is the core of the freudian concept, which evidently presupposes the idea of splitting the ego ( ichspaltung ): 'freud,' says cohen, 'was fascinated by the idea that awkward facts of life could be handled by simultaneous acceptance and disavowal. they are too threatening to confront, but impossible to ignore. the compromise solution is to deny and acknowledge them at the same time.' (ibid., 27) . implemented by political actors and institutional authorities to cover up regrettable facts and unpopular decisions, this is the frame of mind that most interests us and disturbs us because it can explain the widespread and paradoxical indifference with which common people react to situations of suffering, atrocities and violence. 40 tellingly, the focus of cohen's whole and documented analysis seems to be the fi gure of the 'passive bystander' who, when faced with other people's suffering (whether this is experienced in a direct manner like a rape or episode of bullying, or is distant like genocide or torture), defensively withdraws from all involvement, pretending not to see and not to know, inhibiting emotional reactions, minimizing the event's capacity or changing channel if the information is transmitted through mass media images. hence the bystander withdraws from facing up to painful and embarrassing situations and avoids all possible mobilization. therefore, cohen seems, quite rightly, to rediscover denial above all as a reaction of defence in the face of other people's suffering where this assumes such proportions as not to be acceptable by the psyche. as a consequence, he fi nds it to be the root of the emotional indifference that today seems to be permeating contemporary societies. nevertheless, as we have seen, anders's re fl ection allows us to grasp another aspect of denial that sharpens its paradoxical nature, since it concerns the tendency to ignore, wipe out or minimize something that not only concerns other people's destinies, but that threatens our own lives: like in the exemplary case of denying the global challenge par excellence , the nuclear risk. consistent with anders's diagnosis, a few decades ago the psychoanalysis of war had already re fl ected on the radical changes caused by the nuclear threat with respect to the traditional forms of war con fl ict, and hence explained, more or less indirectly, the psychic roots of this speci fi c case of denial. while underlining the abstract or phantasmal nature of the danger at the objective level -due to the invisibility and intangibility of nuclear weapons, the distance of the target, as well as the bureaucratic 'normality' of those who hold the actual decision-making powersome authors have singled out the unprecedented nature of the nuclear con fl ict in its split and autonomization from the individual's instinctual sphere. 41 that is, unlike traditional war, based on mobilizing aggressive instincts, nuclear war (its destructive potential) appears as a mechanical event, or rather, a psychologically unreal event, in which the 'enemy' himself, far from being the object of projective dynamics, becomes an inanimate abstraction with whom all emotional bonds are lost. 42 this sort of 'dehumanization' of war, which affects the relationship with the other and the relationship with oneself to the same extent, thereby producing its 40 'the grey areas between consciousness and unconsciousness are far more signi fi cant in explaining ordinary public responses to knowledge about atrocities and suffering' (ibid., 6). 41 'devitalization', 43 is at the root, together with the enormity of the risk and the impossibility to 'think the unthinkable', 44 of the denial of the danger, which immunizes individuals from emotional involvement, and, therefore, from true awareness. it is telling that, in addition to denial, martin wangh spoke of a 'narcissistic withdrawal', 45 as he alluded to the entropic and self-defensive strategy of individuals reduced to passive and indifferent 'spectators' of events. individuals who, with respect to events, preclude any form of effective reaction and thus inhibit the insurgence of fear at the outset. i will return to the 'spectator phenomenon' shortly. 46 as i have already hinted, this phenomenon is one of the most disturbing pathologies of contemporary individualism. first, however, it is interesting to dwell on one of the -so to speakmore active variants of denial, which consists not only of withdrawal from a reality that is uncomfortable or painful for the psyche, sheltering in a sort of emotional indifference, but of lying to ourselves in order to believe something that does not respond to our rational evaluations, but to our desires. this is self-deception , a defence mechanism that has tellingly been de fi ned as 'the most extreme form of the paradox of irrationality'. 47 without going into the (at times muddled) analytical controversies relating to a concept that is without doubt slippery and problematic, 48 we can, however, try to sum up the characteristics -shared by many authors -which prove fruitful in further extending the picture relating to the metamorphosis of fear in the global age. self-deception is what pushes individuals to form a belief that contrasts with the information and proof at their disposal, since their desires end up interfering with their vision of reality and cause them to act in a different way from what their rational judgement would suggest. in other words, it consists of believing something because one desires it to be true, 49 hence it converges, despite some differences, with 43 martin wangh speaks of 'dehumanization' and 'devitalization' (meant as the impoverishment of the ability to feel) in 'narcissism in our time: some psychoanalytic re fl ections on its genesis," psychoanalytic quarterly 52 (1983). 44 the allusion is to the text by herman kahn, thinking about the unthinkable (new york: horizon press, 1962). 45 martin wangh, "the nuclear threat: its impact on psychoanalytic conceptualizations," psychoanalytical inquiry , no. 6 (1986). 46 the expression ( zuschauer-phänomen ) is by martin wangh, "die herrschaft des thanatos," in zur psychoanalyse der nuklearen drohung. vorträge einer tagung der deutchsen gesellschaft für psychotherapie, psychosomatik und tiefenpsychologie , ed. carl nedelmann (göttingen: verlag für medizinische psychologie, 1985). 47 david pears, "the goals and strategies of self-deception," in the multiple self , ed. elster, 60; giovanni jervis, fondamenti di psicologia dinamica (milan: feltrinelli, 1993) and massimo marraffa, "il problema dell'autoinganno: una guida per il lettore," sistemi intelligenti , no. 3 (1999): 373-403. 48 '[…] self-deception,' davidson says, 'is a problem for philosophical psychology. for in thinking about self-deception, as in thinking about other forms of irrationality, we fi nd ourselves tempted by opposing thoughts.' (donald davidson, "deception and division," in the multiple self , ed. elster, 79). 49 ibid., 86. the dynamic of wishful thinking. 50 like denial, meant in its pure form, so to speak, self-deception implies ichspaltung , no matter what name may be given to what freud identi fi ed as the splitting of the ego. 51 finally, like denial, it is an ambivalent phenomenon since it acts in that threshold between consciousness and unconsciousness which, as cohen stresses in this case too, creates a paradoxical situation of knowing and not-knowing. 52 but while denial appears, as we have seen, effective in explaining the lack of perception and the anaesthetizing of fear in the face of the nuclear threat, selfdeception can prove pertinent in order to understand the complex emotional response that individuals give to the other global risk already brought up above: that is, the twofold environmental risk of global warming and the depletion of the ozone layer, which by no means seems to generate that mobilization of the whole of humankind which it would instead -urgently -require. 53 from this point of view, the recently proposed de fi nition of 'global risks in the making' or 'potentially global' risks, which tends to distinguish them from the global risk par excellence represented by nuclear power, 54 can prove to be extremely useful in explaining the however blurred difference in the subject's reaction and in further enlightening the phenomenology of fear. the inde fi nite nature that without doubt also pertains to the nuclear risk is greatly stressed here, due to the fact that global warming and depletion of the ozone layer have wider margins of uncertainty created by their inertial nature, the impossibility to measure and foresee their future development, and therefore to calculate with certainty, together with their possible effects, the last deadline for possible countermeasures. their ungraspable and invisible nature, further fuelled by the dif fi culty to point the fi nger of blame mean that, in spite of the alarming international reports on the climate and reliable scienti fi c forecasts on the devastating future damage, moreover given increasing mass media coverage, individuals mostly seem 50 in paradoxes of irrationality (in richard a. wollheim and james hopkins, eds., philosophical essays on freud , (cambridge: cambridge university press, 1982)), davidson upholds that in wishful thinking desire produces a belief without providing any proof in its favour, so that in this case the belief is evidently irrational. however, he underlines the differences between self-denial and wishful thinking: unlike the second, the fi rst requires the agent's intervention, that is, the agent has to 'do' something to change his way of seeing things; in the second the belief always takes the direction of positive effect, never of negative, while in the fi rst the thought that it triggers can be painful (see 'deception and division', 85ff.). 51 in this connection pears speaks of 'functional insulation', "goals and strategies of self-deception", 71; davidson speaks of 'boundaries': '[…] i postulate such a boundary somewhere between any (obviously) con fl icting beliefs. such boundaries are not discovered by introspection; they are conceptual aids to the coherent description of genuine irrationalities.' "deception and division", 91-92. on self-denial and splitting of the ego, see herbert fingarette, self-deception (london : henley-routledge, 1969) . 52 see cohen, states of denial , 37ff. 53 it is important to point out that the second problem (the one relating to the risk of ozone layer depletion) nevertheless found some solutions as of the montreal protocol in 1987, made possible due to the fact that they did not require costs or relinquishments in terms of economics or lifestyle. 54 d'andrea, "rischi ambientali globali e aporie della modernità". to fail to suitably perceive the phenomenon. instead, it is often shrugged off with detached irony towards the excessive catastrophism, with resigned declarations of impotence, or the expression of enlightened trust in the capacities of technology to repair the situation. 55 in other words, despite being rationally known and recognized, the risk does not produce such emotional involvement as to give rise to effective answers. at most it produces a widespread and generic feeling of anxiety which ends up imploding, sucked in by the much more real worries of everyday life. the causes of this paradoxical situation can be traced fi rst of all to within the same dynamic of fear of which, as i will recall, hobbes's diagnosis had grasped an essential aspect. namely, fear as a necessary and vital passion that allows us to respond to the immediate danger (of death) loses its ef fi cacy when the danger, and the damage it could cause, are shifted to the future, that is, when a time gap inserts itself between the present action (based on destructive passions) and its possible consequences. thus all certainty and inexorability are taken away from the evil, enabling individuals to imagine it as a remote and avoidable possibility, for which it makes no sense to mobilize themselves immediately. in other words, in this case, fear does not manage to overcome the passions of the present. hobbes's intuition is all the more valid in the case of global risks, whose possible damage is even more remote and does not concern current individuals, but future generations. that is, fear does not have the strength to change present action (and therefore the underlying desires and passions) when the damage that this action can cause is not an evil for ourselves but for 'others': anonymous, generic and distant in time. in short, by weakening fear, the future nature of the damage makes it easy for essentially selfpreserving and narcissistic individuals to deceive themselves as to the actual entity of the risk and therefore to minimize or deny the possible consequences. in this case, the aim is not so much for individuals to defend themselves emotionally from events that are too painful to bear (like in the case of nuclear con fl ict), but to carry on with a manner of acting that allows them to legitimize and satisfy their current desires, preserve their lifestyles and not lose consolidated privileges. to once again recall the pathologies of the global self, we could say that the acquisitive voracity of homo creator , orientated towards unlimited growth, combines with the parasitic bent of a consumer individual anchored solely to the present, to prevent access -through the cunning of self-deception -to a correct perception of the catastrophic effects of climate change, global warming, the greenhouse effect and depletion of the ozone layer. this appears all the more paradoxical where these effects start to be dramatically visible: tropicalization of the climate, deserti fi cation, destruction of the ecosystem, lethal viruses and infective diseases are no longer only remote possibilities but the disturbing proof of environmental risks. by now scattered all over the planet, 56 they affect whole geographical areas and populations, damaging the illusion of individuals and states' immunity more and more. indeed, despite not just abstract information and forecasts, but a more and more invasive state of affairs that is starting to concern them at close quarters, guaranteed and supported by the instrumental interests of local politics and the global economy, individuals prefer to deceive themselves in order not to pay the costs of relinquishing their current desires, assets and pleasures; further eased, in this self-defensive operation, by the morally innocent, innocuous and banally everyday nature of the action that produces the risks. 57 moreover, the absence of a 'productive' fear, inhibited by denial and self-deception, is not belied by the cyclical outbursts of panic and collective hysteria in the face of the sudden appearance of threats (as has always been the case, from chernobyl, to sars and bird fl u). on the contrary, the absence and the excess of fear are nothing but two sides of the same coin, 58 the two extreme and 'unproductive' manifestations of what i de fi ned as global fear . both denial and self-deception leave individuals in the passive position of spectators of events. thus they are enclosed in the immunitarian circuit of a self-defensive and self-preserving individualism which anaesthetizes fear and is incapable of converting into effective action, practice or political participation. alongside the two extroverted pathologies, so to speak, of unlimited individualism, represented by the insatiable voracity of the consumer individual and the omnipotence of homo creator , appears a third, paradoxically introverted con fi guration, namely a passive and impotent individual, who helplessly watches the destructive effects of his own action, over which he seems to have lost all capacity for orientation and control. against the loss of objective spaces of protection and security, increasingly eroded by the global diffusion of the risks, he seems to seek shelter, as i have already hinted , 59 in a sort of interior immunity , entrenching himself in the emotional indifference that is just one of the many manifestations of narcissism. in addition, the yearning for immunity becomes more tenacious and obstinate the more it is felt to be ineffective and illusory. thus a new condition is outlined, which to recall the metaphorical fi gures proposed by hans blumenberg in his shipwreck with spectator , 60 is neither the premodern and 'lucretian' condition of the spectator watching the shipwreck from a safe place, sheltered from the danger, nor the modern and 'pascalian' condition of being the actors of our own lives, ' être embarqués ', involved in the things of the world and ready to put ourselves at stake fi rst of all by recognizing the constitutive precariousness of the human condition and accepting the very risk of existence. while modernity had rati fi ed the decline of the spectator fi gure, and enhanced the moments of practice and action, involvement and commitment; and while late modernity had radicalized his condemnation by emphasizing the need to expose oneself to risk and accept the uncertainty and fl uidity of the human condition, 61 the global age seems to be objectively bringing the spectator up-to-date, which nevertheless coincides with a deep and disturbing change with respect to the fi gure of the lucretian wise man. the erosion of boundaries and disappearance of an 'elsewhere'redrawing global space, cancelling out the distinction between inside and out -is turning into the loss of free areas from where the shipwreck can be observed. at this point, due to the end of every real guarantee of immunity, deprived of the possibility of a safe harbour where he can feel sheltered from the world's dangers, the global self withdraws into the only space apparently able to protect him from events and threats that he is not able to deal with: namely, the wholly interior space of an emotional indifference, an anaesthetizing of emotions , generated by implementing sophisticated and for the most part unconscious defence mechanisms. in other words, the spectator fi gure is undergoing a process of interiorization , which replaces the spatial distance from the shipwreck and the contemplative safety of the lucretian subject with the apathetical extraneousness and obstinate blindness of he who refuses to recognize the very risk of the shipwreck, and encloses himself in the entropic space of an inert solitude. moreover, the spectator phenomenon seems to pervade the whole social structure, due to the spectacularization of reality that, as jacques debord had already masterfully diagnosed a few decades ago, deeply upsets the very nature of social relations. 62 by denouncing the erosion of the boundaries between real and virtual and the pervasive power of images (mass media images fi rst of all), and by diagnosing life's 'total colonization' by commodi fi cation processes and the indistinctive overlapping of true and false as the effects of the 'society of the spectacle', debord had indeed grasped the spectator fi gure as the symptom and symbol of a new form of alienation that invades the individual's whole relationship with the world. passiveness and submission to the totalitarianism of images, prioritization of appearance, loss of contact with one's desires and genuine needs, atomism and isolation are among the most evident and disturbing characteristics of the spectator-individual, who thus ends up losing all capacity to be involved and to grasp reality. in short, the emotional indifference in which individuals shelter in order to cancel out the awareness of the risks surrounding them, unconsciously implementing powerful defence mechanisms, seems to be a sort of inevitable outcome of a widespread anthropological condition. or rather, it seems to be the extreme form of a general tendency towards apathy and inertia, produced by a spectacular society that empties reality of its contents and thus deprives individuals of pathos and action. suf fi ce it to think of the de-realizing effects, with respect to the effective drama of events, produced by mass media images (for example the fi rst gulf war), 63 or the narcotizing addiction that they cause to dangers and catastrophes of all kinds (from tsunamis to sars). the images deprive events of the fl esh and blood of the experience and neutralize them in the aseptic and equalizing space of the screen. however, the problem today is no longer the subject's passivization and atomization alone, nor his a-pathetical detachment from reality: aspects which, moreover, sociological re fl ection on narcissism had already underlined some time ago, and to which the most recent and sagacious sociological diagnoses do not fail to draw attention. 64 the problem, as we have seen, regards above all the negation of reality and the possible destructive effects of this denial on the very survival of individuals and the whole of humankind. by withdrawing into the immunitarian space of a selfdefensive apathy, the global spectator performs a dangerously illusory operation which precludes the possibility to perceive and understand what the unprecedented risk of the global age is: namely, that he himself is the potential victim of events from which there is no shelter, or rather, from which there is no other possible shelter than active and universal mobilization. 65 while it may be true that the hallmark of global challenges is that they cross boundaries and no perimeter can be drawn around or circumscribe them, it is also true that everyone, in every corner of the planet, is always potentially exposed to their effects, that everyone is always potentially a victim of a shipwreck which, for the fi rst time, could affect and sweep away humankind and all living beings. by anaesthetizing fear, the denial (and self-deception) strategy paradoxically ends up betraying the very same purpose that it had been implemented for: namely, self-preservation. or rather, in order to pursue an entropic and defensive selfpreservation that preserves them from all emotional and active involvement, not only are individuals undermining the quality of their lives, but the very preservation of humankind and the world. 63 see antonio scurati, televisioni di guerra. il con fl itto del golfo come evento mediatico e il paradosso dello spettatore totale (verona: ombre corte, 2003), who observes how the increase in media exposure of the war phenomenon corresponds to a lesser ability, on the part of the spectator, to grasp its reality. as a result, on the part of the citizen there is less possibility to decide and act. in other words, the 'total visibility' offered by the television medium corresponds, in an only apparent paradox, to the blindness and impotence of the 'total spectator'. 64 this unwillingly nihilistic outcome could perhaps be interpreted as a radical and extreme manifestation of the immunitarian paradigm recognized as the very emblem of modernity, owing to which the preservation of life is paradoxically turned around into its negation. 66 however, what i would like to stress, to go back to anders's diagnosis, is the fact that -in this case at least -this worrying reversal originates in the pathologies of feeling and the denial of fear, which prevent individuals from recognizing their paradoxical condition of spectators and victims at the same time. denial, however, is just one of the unproductive metamorphoses of fear in the global age, and only one of the strategies that the global individual uses to contrast the anxious perception of new risks. denial sums up the individualistic and implosive response to the inde fi nite and unintentional threats produced by techno-economic globalization. in parallel to this there emerges, as i had mentioned, another defence strategy, which responds to what is perceived as the second, fundamental source of danger, essentially generated by economic-cultural globalization: that is, defence against the other . this strategy is specular to the fi rst since it converts more into an excess rather than an absence of fear, and i have suggested de fi ning it as communitarian and explosive . 67 it is based on reducing insecurity and inde fi niteness through the defence mechanism of projection : namely, the fear is displaced onto indirect and specious objects since these appear easier to de fi ne and identify. many of the ethnoreligious con fl icts that are traversing the planet can at least in part be traced back to this basic defence mechanism which converts inde fi nite anxiety into de fi nite fear. in this case too, we are dealing with a strategy that is anything but new since, as we will see, it results in the classic mechanism of building a 'scapegoat'. however, the novelty lies in the fact that, like in the denial strategy, this strategy seems to be resulting in substantial ineffectiveness . if, as suggested to us by rené girard's enlightening diagnosis, the fundamental goal of creating scapegoats has always been, since the origins of civilization, to keep check on and resolve violence in defence of a given community, today we are instead faced with an escalation in violence which attests to the substantial failure of the scapegoat dynamic. through a fascinating thesis that i can only brie fl y recall here, 68 girard claims that in truth this loss of effectiveness has distant roots, since it coincides with the end of the processes which made violence ritual and sacred, and with the revelation of the 66 see esposito, immunitas . 67 here there is a generic allusion to bauman's 'explosive communities' in liquid modernity . 68 of great use for the issues that follow is the essay by stefano tomelleri, "il capro espiatorio. la rivelazione cristiana e la modernità," studi perugini , no. 10 (2000): 147-57. victimage mechanism brought on by the advent of christianity. 69 in other words, while archaic societies had entrusted the rite of sacri fi cing the scapegoat with the function of providing a remedy to internal violence in order to found and preserve social order and peaceful coexistence among men, the revelation of christ radically damaged this mechanism since, by disclosing the victim's innocence, for the fi rst time it made people aware of the victimizing and persecutory dynamics. by unmasking the nexus between violence and the sacred, the christian message led to the breakdown of the mythical-ritual universe, and placed people before the unavoidable truth of their violence. thus it weakened the possibility of resolving the violence through the sacri fi cial mechanism and opened totally new scenarios, affected by a fundamental ambivalence. on one hand, by depriving men of all external justi fi cation for their violence, the christian revelation of the victim's innocence opened up the possibility of renouncing the scapegoat logic and resolving the problem of the social bond, without any exclusion or sacri fi ce; on the other hand, in the absence of ritual antidotes and their power to create order, it exposed men to the spreading of violence and the persistence -in more ambiguous, disguised and clandestine forms -of the victimage mechanism. that this second scenario is the one which, unfortunately, has ended up prevailing is manifestly undeniable; and, paradoxically, it can be pinpointed as originating above all in modernity. while it may be true that modernity -the time of rights, democracy and equality -seems to offer the possibility of transforming violence into 'soft', peaceful and even emancipatory forms of competition and rivalry, it is also true that, for the same reasons, it can provide a breeding ground which favours the heightening of violence. indeed modernity produces an ampli fi cation of the mimetic dynamic that girard recognized as the constitutive source of violent con fl ictuality among men. as has been underlined, the same equality that, à la tocqueville, can be interpreted as a loss of differences, frees the mimetic desire, which becomes unlimited 70 and inevitably exacerbates rivalry among people. in other words, in a society of equals the desire to be according to the other which pushes the mimetic actor to see the other as model and rival at the same time, triggers a spiral of competitive comparison. even the smallest difference becomes the opportunity for resentment, envy and hate, and can always provide the opportunity for violent clashes. while on one hand democratic indifferentiation and, we could add, narcissistic and postmodern intolerance towards every difference -which tocqueville had prophetically diagnosed 71 -provoke the continuance of rivalry and con fl ict, on the other hand the sacri fi cial dynamic, to which premodern societies had entrusted the function of keeping check on violence, seems to have lost its traditional ef fi cacy due to its irreversible disclosure. this means that modern and contemporary societies are exposed to a radical 'crisis of the sacri fi cial system' which, since it is impossible to fi nd a solution in the scapegoat mechanism, can result in a multiplication of violence and its manifestation in increasingly crude and destructive forms. 72 the loss of the victimage mechanism's ef fi cacy, due to the deritualization process, does not equate to its disappearance, however. on the contrary, girard once again observes that phenomena of 'sacri fi cial substitutions' reappear 'in a shameful, furtive, and clandestine manner' so as to avert moral condemnation (and selfcondemnation). 73 they take on the shape of psychological violence which is easier to conceal, or they re-explode in the exacerbated form of immolating victims to evil ideologies, as was the case of the genocides in the twentieth century. these mechanisms continue in our world usually as only a trace, but occasionally they can also reappear in forms more virulent than ever and on an enormous scale. an example is hitler's systematic destruction of european jews, and we see this also in all the other genocides and near genocides that occurred in the twentieth century. 74 of course the reference to the nazi genocide is not random, but extremely emblematic of the modern and contemporary reappearance of the victimage mechanism in spite of its disclosure. a fi rst formulation of this can be found in the diagnosis of totalitarianism that franz neumann was already suggesting in the 1950s, as he traced its psychic origins back to the transformation of fear into 'persecutory anxiety'. 75 every time, neumann says, over the course of history a particular social group (whether it can be de fi ned on the basis of class, religion or race) feels threatened by objective dangers which, together with material survival, compromise its prestige and identity, the deriving anxiety is displaced onto groups and people, who are given the requirements ad hoc , 76 and the guilt made to converge on them. if we are to take up the freudian distinction between 'realistic anxiety' and 'neurotic anxiety ', 77 neumann shows how fear and uncertainty are transformed into persecutory anxiety through the projective and hence specious creation of an enemy who becomes the subject of hate and aggression. as a result, the masses threatened with disintegration can rediscover their internal cohesion. in the case of nazism and the persecution of the jews, political and ideological manipulation linked up to this social dynamic, took advantage of the mass anxiety and pushed the masses towards 'caesaristic' and regressive identi fi cation 78 with a leader libidinally attributed the task of resolving the anxiety by expelling the evil and its presumed carriers. 79 by recognizing the victimage mechanism as originating in the persecutory transformation of anxiety, neumann allows us to see its emotional roots, which girard evidently considers less essential for his so-to-speak ontological diagnosis of violence. however, at the same time, while neumann particularly stresses the totalitarian outcomes of the scapegoat dynamic, 80 girard underlines its persistence in 'all the phenomena of nonritualized collective transference that we observe or believe we observe around us.' 81 although deritualized -and indeed all the more violent for this precise reason -the victimage mechanism continues to act in the same modern democratic societies in all creeping and disguised phenomena of exclusion and discrimination, or in the cyclical explosions of reciprocal aggression and disdain that are fuelled by identity con fl icts: we easily see now that scapegoats multiply wherever human groups seek to lock themselves into a given identity -communal, local, national, ideological, racial, religious, and so on. 82 evidently, here we are coming back to the topic of identity con fl ict which, as we have seen, is proliferating inside and outside the west, bringing the scapegoat strategy back up-to-date: a strategy which becomes all the more aggressive the more the perception of the threat grows in a global society. by eroding territorial and cultural boundaries, globalization is producing, fi rst of all in western societies, a disturbing proximity of the other. as a result, the other can increasingly be identi fi ed with the simmelian fi gure of the 'stranger within', who challenges the order and cohesion of a given community through a swarming and liminal presence that is felt, as suggested 78 neumann stresses the regressive nature of this identi fi cation mechanism for the very masses who implement it, since it involves alienation and the relinquishment of one's self: 'since the identi fi cation of the masses with the leader is an alienation of the individual member, identi fi cation always constitutes a regression'. ( anxiety and politics , 277). 79 'caesaristic identi fi cations may play a role in history when the situation of masses is objectively endangered, when the masses are incapable of understanding the historical process, and when the anxiety activated by the danger becomes neurotic persecutory (aggressive) anxiety through manipulation.' (ibid . , . 80 it is interesting to see how neumann indeed also alludes to the unconscious nature of the persecutory dynamic: 'hatred, resentment, dread, created by great upheavals, are concentrated on certain persons who are denounced as devilish conspirators. nothing would be more incorrect than to characterize the enemies as scapegoats […] for they appear as genuine enemies whom one must extirpate and not as substitutes whom one only needs to send into the wilderness.' (ibid., 279) . 81 girard, i see satan fall like lightning , 160. 82 ibid., 160. by mary douglas, as potentially contaminating. coming forth in response to the siege of a hybrid and unstemmable multitude that is penetrating the protected spaces of our identity citadels is the ancestral fear of a 'contamination' endangering the need for 'purity' upon which, douglas says, every culture and civilization builds its reassuring separations and classi fi cations. 83 the other (the stranger, he who is different, the migrant, the illegal immigrant) becomes the target upon whom to displace our fears, upon whom to project a persecutory anxiety that transforms him into the person responsible for the dangers threatening a society that is increasingly deprived of the traditional control structures. 84 hence this enables that blaming process which is indispensable for social cohesion and which, however, the anarchic and anonymous logic of globalization seems to be progressively eroding. 85 but since it is no longer possible to rely on ritual expulsion practices or strategies to con fi ne the other to a spatial and territorial elsewhere clearly divided by a de fi nite boundary that traces the separation between an inside and an outside, the exclusion mechanism becomes interiorized and acts at an eminently symbolic level. the exclusion dynamic, as has been underlined, is shifted into the conscience: 'defence and exclusion, no longer possible towards the outside, will be shifted into the conscience, the imagination, the social mythologies and into the self-evident that these hold up.' 86 thus immunity is ensured through dehumanization processes that transform the stranger within (the metoikos ) into an 'inside being' in such a way that he remains an 'outside being' all the same. 87 all this can take place in the insidious and hidden forms of psychological violence and everyday discrimination towards those who have crossed the territorial boundaries of a state and broken the taboo of distance and separation, therefore representing a constant challenge to consolidated privileges and to the 'purity' of identity. or it can occur through cyclical collective mobilization against the weak and marginalized in the attempt to deal with insecurity by displacing the fear onto problems of personal safety, which politics does not then hesitate to exploit, in selflegitimation, in the name of defending public order. 88 but, as we have already seen, it can also convert into a real and proper 'attack on the minorities', in which it is perhaps legitimate to recognize, as suggested by arjun appadurai, the distinctive form of violence spreading to the global level. when global insecurity is added to the delirious fantasy of national purity which appadurai de fi nes as an 'anxiety of incompleteness', the majorities in every single state whose hegemony is threatened tend to transform into 'predatory identities'. their aim becomes to defend the purity of the ethnos by eliminating the element of disturbance represented by the 'minor differences'. the minorities 'are embarrassments to any state-sponsored image of national purity and state fairness. they are thus scapegoats in the classical sense.' more speci fi cally in the global age they 'are the major site for displacing the anxieties of many states about their own minority or marginality (real or imagined) in a world of a few megastates, of unruly economic fl ows and compromised sovereignties.' 89 from iraq to ex-yugoslavia, from indonesia to chechnya, from palestine to rwanda, to the emblematic case of the clash between hindus and muslims within a modern democracy like india, the victimage mechanism seems to reassert itself with a fresh violence that tellingly -testimony to the obsession with purity at its origin -seems to repeat itself in particular towards the body . indeed, as appadurai underlines by taking on douglas's perspective, the body becomes subject to unheardof violations and atrocities (bodies massacred, decapitated, tortured, raped) in view of punishing the minorities for the fact that they 'blur the boundaries between "us" and "them," here and there, in and out, healthy and unhealthy, loyal and disloyal, needed but unwelcome.' 90 nevertheless, it is precisely this obsessive, punitive and puri fi catory nature that announces the danger that the violence may assume an unstemmable drift. 91 far from producing a stop to the violence, the scapegoat strategy causes its proliferation, through a sort of perverse up-the-ante that seems to bring the brutality of archaic practices, such as sacri fi ce, and of the starkest materiality back inside the abstract and impersonal space of globalization. 92 but that is not all. today the spiral of violence is further fuelled by a new factor that upsets the logic -to date essentially one-way -of the persecutors-victims relationship. what happens, unlike for example the emblematic case of nazism, is that the other tries to overturn his position as victim, and in turn becomes the persecutor, giving rise to a dynamic of hostility and aggression that potentially becomes unlimited owing to its reciprocal and specular nature. suf fi ce it to think of islamic terrorism and the projection it puts upon the west as the image of the other and evil, against which, by fuelling passions of resentment , 93 a compact and endogamous us is condensed together and built. indeed this proves the fact that the scapegoat, as girard warns, is not only necessarily embodied in the weak and oppressed but also in the rich and powerful. 94 hence, in the grip of dehumanization on one hand and demonization on the other, 95 the world becomes a theatre, through the reciprocal invention of an enemy, of an escalation in violence that has much to do with the persecutory metamorphosis of insecurity and anxiety and very little to do with a presumed 'clash of civilizations'. 96 shifted to the inner self, the victimage mechanism continues to act, hidden from view. nonetheless, it ultimately becomes ineffective since it fails in its original purpose to resolve the fear and keep a check on violence. orphaned of ritualization processes and deprived of an 'elsewhere' that permits the other's spatial and territorial exclusion, the construction of the enemy/victim generates forms of identity cohesion that are as aggressive as they are regressive, fuelled by a reciprocal persecutory projection. far from restoring cohesion and security to a given community, the scapegoat dynamic gives rise to endogamous and reciprocally exclusive processes of building an us , whose foremost and manifest effect is to form what i have de fi ned as immunitarian communities : 97 whether they are the 'voluntary ghettoes' and 'communities of fear' that explode cyclically in a west frightened by the siege of the other and anything but free from regressive phenomena, or ethno-religious communities entrenched around the obsession of identity and homogeneity, willing to reactivate atrocious forms of excluding the other, or lastly global communities that come together around the war/terrorism polarization. the metamorphosis of fear in the global age therefore seems to con fi rm, at the emotional level, the pathological split between an unlimited individualism and an endogamous communitarianism , which originates in the implementation of defence mechanisms leading to not only the polarization of an absence and excess of pathos , but also, it needs to be stressed, in their substantial inef fi cacy . on one hand, the denial of fear, we have seen, pushes individuals towards forms of apathy and narcissistic entropy that prevents them from recognizing the new risks produced by global challenges. as a consequence, this produces the individuals' incapacity to perceive their unprecedented condition of spectators and potential victims at the 94 same time, and fuels the illusion of immunity: which means that in the name of entropic self-preservation we end up delivering the whole of humankind to the danger of self-destruction. on the other hand, the persecutory conversion of fear generates perverse and endogamous forms of alliance and solidarity, which thereby result in the reactivation of destructive communities driven by 'primordial loyalties'. this gives rise to the explosive drift of identity con fl icts and to an unlimited escalation of violence at the planetary level. between self-obsession and us-obsession , as the specular polarities of the same immunitarian strategy, we run the risk of not grasping the chance 98 that the global age could actually be capable of offering through the very transformations that it produces and the very challenges that it contains. on one hand, as we will see, the risks that are bearing down on humankind for the fi rst time mean we can think of the latter as a new subject, as a set of individuals linked by their common vulnerability and weakness . therefore, they are able to take care of the world in the sense of the planet, the 'loss' of which would coincide with the disappearance of the only dwelling of living beings that we know of. on the other hand, the multiplication of differences and the slide of the idea of 'other' towards the notion of 'difference', which can neither be assimilated nor expelled into an elsewhere, for the fi rst time makes it possible to rethink the social bond as the solidaristic coexistence of a plurality of individuals, genders, cultures, races, religions, capable of forming a 'world', à la arendt, since they are capable of recognizing not only the necessity but also the potential vitality of reciprocal contamination . these real possibilities are, however, only a chance. insofar as it is a chance, the subjects have the task of knowing how to grasp it. to recall a successful suggestion by andré gorz, we could say that to pro fi t from the chance in the fi rst place means 'to learn to discern the unrealized opportunities which lie dormant in the recesses of the present' 99 ; or, in a word, to lay a wager on the ability to build alternative scenarios and create possibilities that may not yet have been taken up but are still latent. 98 the expression is inspired by georges bataille who, as already remembered above, proposes the idea of chance meant as the 'possibility of openness', see on nietzsche (london: athlone, 1992), originally published as "sur nietzsche," in oeuvres complètes, vol. 6 (paris: gallimard, 1976). 99 gorz, reclaiming work , 1. originally published as des choses cachées depuis la fondation du monde we haven't given up having scapegoats, but our belief in them is 90 percent spoiled. the phenomenon appears so morally base to us, so reprehensible, that when we catch ourselves "letting off steam" against someone innocent, we are ashamed of ourselves originally published as je vois satan tomber comme l'éclaire democratic and authoritarian state neumann says, there must always be a core of truth that makes this choice particularly dangerous: so in the case of the jews, the core of truth is given by their being 'concrete symbols of a so-called parasitical capitalism, through their position in commerce and fi nance on this see part ii purity and danger. an analysis of concepts of pollution and taboo mary douglas underlines that risk itself becomes a resource at the moral and political level and speaks of a 'forensic theory of danger': 'disasters that befoul the air and soil and poison the water are generally turned to political account: someone already unpopular is going to be blamed for it.' ( risk and blame , 5) risk and blame appadurai continues, 'are metaphors and reminders of the betrayal of the classical national project. and it is this betrayal -actually rooted in the failure of the nation-state to preserve its promise to be the guarantor of national sovereignty -that underwrites the worldwide impulse to extrude or to eliminate minorities originally published as orrorismo fear of small numbers , chap. 3 again underlines the nexus between the abstract logic of globalization and the brutality of physical violence 519-33; for an interesting treatment of the topic see stefano tomelleri key: cord-018328-t3ydu75l authors: shi, peijun title: hazards, disasters, and risks date: 2019-06-05 journal: disaster risk science doi: 10.1007/978-981-13-6689-5_1 sha: doc_id: 18328 cord_uid: t3ydu75l in this chapter, we will elaborate on three basic terms in the field of disaster risk science: hazards, disasters, and risks. we will also discuss the classification, indexes, temporal and spatial patterns, and some other fundamental scientific problems that are related to these three terms. atmospheric hazard: tropical cyclone, tornado, hail, snow, lightning and thunderstorm, long-term climatic change, and short-term climatic change. biophysical hazard: wildfire. space hazard: geomagnetic storm and extra impact events. the hazard groups proposed by joel c. gill et al. are almost equivalent to the hazard families of icsu-irdr classification except for two differences. one difference is that the meteorological and climatological families of icsu-irdr were combined into a single atmospheric group in gill's classification. the other difference is that the hazard group of shallow earth processes was added in gill's classification in order to emphasize the hazardous impacts of shallow earth changes (table 1.1). gill and malamud (2014) hazard group code definition component hazards (where applicable) geophysical earthquake eq the sudden release of stored elastic energy in the earth's lithosphere, caused by its abrupt movement or fracturing along zones of preexisting geological weakness and resulting in the generation of seismic waves ground shaking, ground rupture, and liquefaction tsunami ts the displacement of a significant volume of water, generating a series of waves with large wavelengths and low amplitudes. as the waves approach the shallow water, their amplitude increases through wave shoaling volcanic eruption vo the subterranean movement of magma and its eruption and ejection from volcanic systems together with associated tephra, ashes, and gases, under the influence of the confining pressure and superheated steam and gases gas and aerosol emission, ash and tephra ejection, pyroclastic and lava flows in the book regions of risk by hewitt (1997) , hazards were divided into the following categories: natural hazards include four types (meteorological, hydrological, geological and geomorphological, biological and disease hazards) technological hazards include hazardous materials, destructive processes, and hazardous designs. social violence hazards include weapons, crime, and organized violence. compound hazards include fog, dam failure, and gas explosion. complex disasters include famine, refugees, poisonous flood, nuclear wastes and explosion of nuclear power plants (table 1 .2). famine (drought + poor harvest + food hoarding + poverty) refugee crisis (famine + war) toxic floods (tailings dams + toxic waste + flood) harmful nuclear tests and power plant explosions (nuclear explosion and pollution + atmospheric circulation + rain and atomic dust + migration) another way to categorize hazards is based on the environment where hazards occur (also called disaster-formative environment). the classification based on causes emphasizes the origin of hazards, that is, whether the hazards are caused by natural factors, human factors, or the interaction between natural and human factors. in contrast, the classification based on disaster-formative environment lays stress on the environmental basis of hazards, especially the distinctions among different spheres of the earth, and relatively ignores the causes. actually, different kinds of hazards nowadays contain effects from both the natural and human factors to different degrees. and this is one of the important reasons why un changed the goal of the global disaster reduction activities from natural disaster reduction to disaster risk reduction. (1) classification of hazards by peijun shi in shi's paper (1991) published on the journal of nanjing university (natural sciences, special issue on natural hazards), hazards were divided into four levels: systems, groups, types, and kinds. this classification highlights not only the occurrence environment but also the causes of hazards (shi 1991) . the first level of this classification is focused on the causes, the second level the environments, the third level the types, and the fourth level the detailed hazards. the hazard system is composed of three systems: nature, human, and environment. the natural hazard system is then divided into four groups: atmosphere, lithosphere, hydrosphere, and biosphere. the hazards are mainly caused by natural environmental factors. the human hazard system includes three groups: technology, conflicts, and wars. the hazards are mainly caused by human environmental factors. the environmental hazard system is made up of five groups: global change, environmental pollution, desertification, vegetation degradation, and environmental diseases. the hazards are due to integrated natural and human factors. (2) classification of hazards in zhang lansheng and liu enzhen the atlas of natural hazards in china edited by zhang and liu, as a result of the cooperation between beijing normal university and the people's insurance company of china, was published by china science press (beijing) in 1992. based on the atlas, the paper a research on regional distribution of major natural hazards in china by wang et al. (1994) was published, and the classification system of major natural hazards in china consisting of types and subtypes (table 1. 3) was built. the major natural hazards in china can be divided into 5 environments, 31 types, and 108 subtypes based on the differences in disaster-formative environments. atmosphere including nine natural hazards-drought, typhoon, rainstorm, hailstorm, extreme low temperatures, frost, ice and snow, sandstorm, and dry-hot wind. hydrosphere including five natural hazards-flood, waterlogging, storm surge, sea wave, and tsunami. lithosphere including five natural hazards-earthquake, landslide, debris flow, subsidence, and wind-drift sand. biosphere including six natural hazards-crop diseases, crop pests, forest diseases and pests, rodents, poisonous weeds, and red tide. geosphere including six natural hazards-soil erosion, desertification, soil salinization, frozen soil, endemic disease, and environmental pollution. (1) intensity classification of single hazard the intensity classification of single hazard is based on the measurement specifications and standards of hazards. hazards of different origins and in different environments are measured by different indicators. for example, earthquakes are measured in magnitude, rainstorms in rainfall intensity, typhoons in maximum sustained wind, and floods in flood stage. those hazard measurement specifications and classification standards can be found on the web sites of international or national departments of measurement standards. generally speaking, meteorological departments set up the measurement specifications and classification standards for atmospheric hazards; hydrological or water resources, and oceanic administrations for hydrosphere hazards; geological and a large number of observations show that there is a negative correlation between hazard intensity and frequency. in other words, the higher the intensity is, the lower the occurring frequency is and the longer the repeating period is. there is a power function relationship between the hazard intensity and the occurring frequency (chen and shi 2013) . refer to textbooks or monographs on geoscience, life science and resources and environmental science for the intensity classification of single hazard. (2) intensity classification of multi-hazards the regional and integrated disaster risk research requires scientists to understand the diversity of hazards of different spatial and temporal scales and classify the intensities of multi-hazards. because the measurement indicators vary among different hazards and there is no universal indicator, the intensity classification method for single hazard mentioned in the previous section will not be able to meet the needs of the regional and comprehensive studies of the diversity of hazards. based on current data, it is very difficult to synthesize various hazard intensities measured in different indicators. one way to get around this problem is to divide each kind of hazard intensity into relative levels and then calculate the average of levels weighted by the area that respective type of hazard covers during a certain period of time. this method can approximately reflect the regional overall hazard intensities in a certain space and a certain period of time. but there is one problem with this method; that is, different hazards with the same level of relative intensity might have different impacts on hazard-affected bodies. therefore, in order to eliminate this effect, another term is added-the weighted average of the loss rate of each hazard in a certain space and time period. referring to the quadrat method in the vegetation investigation, we proposed to use multiple degree to describe the abundance of hazards in a region. another way to do this is similar to the multiple cropping index calculation in land-use research. based on wang et al.'s paper (1994) , in this book, we propose to use multiple degree and covering index of hazards to express the clustering degree and influence of multiple hazards in a region. multiple degree (h d ): the clustering degree of hazards in a certain region. as a relative value changing with the compared region, it can be expressed as where h d is the multiple degree of hazards in a region (%), n is the number of hazards in the region, and n is the number of hazards in a higher level of region (e.g., world, asia, china). the value of n is set to be 108 (table 1. 3) for the calculation of county-level multiple degree of natural hazards in china. relative intensity (h i ): the relative destructive or damaging ability of hazards. relative intensity is a relative value and only a quantity of the hazard per se. it is not an obvious positive correlation with the disaster loss or damage but is the basic reason (condition) for the regional loss. it can be calculated as follows: where h i is the relative intensity (level) of hazards in a region, p i is the relative intensity of hazard i, and s i is the area ratio of hazard i, ranging from 0.01 to 1.0, i.e., 1-100% and i is the number of hazard types. covering index of hazards (h c ): the percentage of covering area of hazards in a region. it can be expressed as where s i is the percentage of covering area of a type of hazard in a region and i is the number of hazard types. composite index (h): the sum of the three indexes mentioned above divided by the respective maximum values. the formula is where h d is the hazard multiple degree, h i is the relative intensity, h c is the covering index of a hazard in a region, and max () is the maximum value of the respective index. we will use the calculated results in wang et al.'s paper (1994) to demonstrate the practical application of the four indexes-multiple degree, relative intensity, covering index, and composite index of hazards. multiple degree of natural hazards. in fig. 1 .1, the maximum value of the natural hazard multiple degree is about eight times as large as the minimum value in china. the value ranges from below 0.04 to above 0.30. this large variation shows that there is an obvious spatial clustering feature of natural hazards in china. generally speaking, the high values are centered in north china and decrease toward northeast, northwest, and southeast. ninety percent of the districts and counties with h d value greater than 20% are located in the middle latitude belt (25°-45°n). in southwest china where the h d values are relatively low, the h d value increases in some topography-transition areas. thus, it can be seen that natural hazards relatively cluster in natural environment transition zones, such as the middle latitude belt, sea-land transition zones, topography-transition areas, and semiarid farming-pastoral ecotone. in the transition regions of several natural environments, there exist continuous areas with high h d values. north china is right in such location and thus becomes the most concentrated area of natural hazards in china, also an important part of the pacific rim and mid-latitude multiple hazard belt. therefore, regional natural hazards' factors are of important value to the degree of regional natural environmental change. covering index of natural hazards. figure 1 .2 shows that there is a large variation in covering index of natural hazards in china, ranging from less than 0.02 to more than 11.0 and indicating obvious regional differences. on the whole, the trapezoid region with qiqihar, harbin, tianshui, and hangzhou as four vertexes has the highest h c values (>8.0) in the country. in this high-value region, the northeast china plain and the north china plain have values usually greater than 9.0. the regions with h c values greater than 10 display a lambda-shaped layout; that is, one line is qiqihar-tongliao-beijing-taiyuan-baoji-tianshui, and the other line stretches from southern hebei province to hangzhou along the grand canal. the low-value regions are centered in the northern tibetan plateau, from which h c value increases outwards. in regions south of the yangtze river, there are two high-value belts: southeast coastal belt and southwestern provinces including yunnan, guizhou, and sichuan. there is a positive correlation between the h c value and the h d value. it can be seen from figs. 1.1 and 1.2 that h c values and h d relative intensity of natural hazards. figure 1 .3 shows that h i values are within the range of 0.8-24.0. regions with a h i value greater than 19.0 are sparsely distributed. one high-intensity area (h i > 16.0) stretches from the northeast to the southwest, and another one is in the southeastern side of the first one-hunan and jiangxi provinces. the relative intensities in the vast north-central tibetan plateau and northwest china are relatively low. the regional differentiation of relative intensity is tightly associated with the regional distribution of several major hazards. first of all, the seismically active belts of china, i.e., the pacific rim belt and himalayan seismic belt, have the correspondingly high intensities. seismic regions, once having an earthquake with a magnitude greater than 8, usually become small high-intensity centers, such as west china, tangshan. secondly, the high-intensity regions are overlapped with the regions concentrated with cloudbursts. for example, the coastal typhoon belt, the northern hebei mountains-taihang mountains-dabie mountains cloudburst belt, and the cloudburst belts in western sichuan and (shi 2011) western hunan. thirdly, the frequently flooded areas also correspond to high relative intensity areas. these areas include liaohe plain, north china plain, northern jiangsu plain, and hubei and hunan plains. finally, areas with frequent debris flows and landslides, mainly in the "second step" east to tibetan plateau, have high values of relative intensity. therefore, the overall relative intensity of natural hazards is controlled by several major natural hazards. however, these major natural hazards may also interact in the same region, which makes the regional differentiation of relative intensity of china's natural hazards more complicated and also expands the high-intensity regions. in every high relative intensity area, there is at least one dominant natural hazard. relationships among multiple degree, relative intensity, and covering index. the interaction of the three indexes varies among regions. figure 1 .4 shows the regional distribution of the composite index of natural hazards in china. north china has the highest values of all three indexes and thus is affected by frequent and catastrophic hazards. coastal areas have the second highest values of three indexes and are subject to frequent and severe hazards. the third highest value regions include the farming-pastoral ecotone in northern and western sichuan, yunnan, western guizhou, and southeastern tibetan plateau in the southwest. whereas, the northern tibet is a low-value region. the above outlines the basic regional differentiation of natural hazards in mainland china. (shi 2011) there are differences in natural hazards between eastern and western china and between southern and northern china. as for east-west differentiation, the values of multiple degree, relative intensity, and covering index are higher in the east and lower in the west. the high values in the east are centered in north china while the low values in the west are centered in northern tibet. as for north-south differentiation, the vast area within 25°to 45°n in the east has values of all three indexes higher than areas to its south and north. among this vast area, the highest values exist in range of 30°to 40°n. however, the north-south differentiation in the west is not obvious, since there are incomplete data records, especially in the border area among tibet, qinghai, and xinjiang, or the hoh xil region. due to inadequate data, this region has the lowest values of all three indexes nationwide. the regional differentiation of natural hazards is closely associated with the environments where hazards develop. the environmental evolution-sensitive zones usually have high multiple degree, high relative intensity, and high covering index, suffering frequent or severe hazards. however, a small number of ecologically vulnerable areas have low values of multiple degree and intensity. one outstanding example is eastern guizhou. in areas with harsh environment, such as the vast west china, the multiple degree and relative intensity are not necessarily high. therefore, there is no direct relationship between environmental conditions and the impacts of natural hazards. disasters are direct or indirect results of hazards. disaster impacts include human losses, property losses, resources and environmental destruction, ecological damages, disruption of social order, and threats to the normal functioning of lifelines and production lines. the classification of disasters is closely associated with hazards and disaster-affected bodies. in chinese literatures, "zaihai" is used to refer to both hazards and disasters. however, in western literatures, hazard and disaster are two terms used separately. most researches in the west are focused on the classification of hazards, rarely on the classification of disasters. whereas, in chinese literatures, the classification of disasters takes the place of the classifications of both hazards and disasters. this confusion of hazards with disasters, or the confusion of hazard science with disaster science (e.g., seismology substitutes for earthquake catastrophology, and rainstorm meteorology for rainstorm catastrophology), negatively affects the development of disaster risk science. with the development of human society, the types of disaster-affected bodies (exposure) have increased and the distribution of disaster-affected bodies has expanded. at the same time, human's ability of disaster prevention has also been improved. therefore, even the same hazard could induce varying degrees of disasters. when analyzing the disasters, people stress on the disaster-affected bodies; namely, focus on human's disaster prevention level, which is referred as the vulnerability, resilience, and adaptation of human beings to hazards in the western literatures. as mentioned above, in western research there is more of an emphasis on the classification of hazards than that of disasters. in chinese official documents or research literatures, the majority is the classification of disasters based on the causes and scales of disasters. the genetic classification of disasters according to the causes in chinese literatures is basically the same as that of hazards in western literatures. ( in the book introduction to catastrophology by ma (1998) , according to the causes, disasters can be divided into natural disasters and man-made disasters. natural disasters can be further categorized into natural disasters and man-made natural disasters, while man-made disasters are composed of man-made disasters and natural man-made disasters. when the management of disasters is taken into account at the same time, disasters can be divided into 5 classes and further 30 types. in the book, the author also clearly pointed out the administration departments in charge of each type of disaster (table 1. 4) . this classification is different from others in the classification of the disaster-formative environments, with an inclusion of ocean sphere instead of hydrosphere. another difference is that sources of flood and drought are attributed to the atmosphere in ma's classification (ma 1994) . besides, this classification is basically in accordance with the classifications in prc disaster reduction report (1993) and major natural disasters and disaster reduction in china (1994) (table 1.5). similar to the classification of introduction to catastrophology, in the book natural disasters by chen (2013) , based on the differences between the internal, external, and gravitational energy of the earth, natural disasters were divided into seven major categories: earthquakes, tsunamis, volcanos, meteorological disasters, floods, landslide and debris flow, and spatial disasters. this classification does not only reflect the holistic view of disasters but also emphasizes the timescales of disasters and environmental processes of the earth system. (2) classification of disasters in chinese state standards for the dual purposes of comprehensive prevention, reduction and relief of disasters and counting the losses and damages caused by natural disasters, experts organized by state disaster reduction center of ministry of civil affairs drew up the classification standards of natural disasters in china, in which the definition and code of each disaster are also given. in this classification, natural disasters in china are divided into 5 groups and 40 specific types, including 13 specific meteorological and hydrological disasters, 9 seismic and geological disasters, 6 ocean disasters, 7 biological disasters, and 5 eco-environmental disasters (table 1.6). natural disasters resulting from the abnormal or anomalous quantity, intensity, temporal and spatial distribution, and combination of meteorological and hydrological elements, causing adverse impacts on people's lives and properties, industrial and agricultural production, and ecological environment 010100 drought a deficiency in precipitation and/or a shortage in river runoff or other kinds of water resources, causing adverse impacts on people's life, industrial and agricultural production, and ecological environment 010200 flood an overflow of water from rivers or other water bodies onto land which is usually dry, caused by excessive rainfall, melting snow and ice, levee breach and storm surge, resulting in life losses, property losses, and disruption in social functioning 010300 typhoon a tropical cyclone that develops in a wide area over tropical or subtropical oceans, accompanied with heavy winds, rainstorm, storm surge and huge waves, bringing out damages to human lives and properties 010400 rainstorm rainstorm happens when the precipitation rate is more than 16 mm per hour, or more than 30 mm for 12 h or 50 mm for 24 h, causing damages to human lives and properties (continued) hail hail is a type of solid precipitation formed in thunderstorm clouds and controlled by strong convective weather, causing damages to human lives and properties and to crops and animals 010700 thunder disaster thunder disaster is an electric discharge, directly or indirectly striking human and animals, resulting in damages to human lives and properties 010800 low-temperature disaster intrusion of strong cold front or constant low temperatures, causing freezing injury and damages to crops, animals, human beings, and infrastructures, disrupting normal life and production 010900 snow and ice disaster due to snowfall, a wide area is covered with snow or affected by snowstorm, avalanche, frozen road, and other infrastructures. it severely disturbs the lives of human beings and animals and causes damages to traffic, power, and communication systems 011000 high-temperature disaster high temperatures cause harms to the health of animals, plants and human beings and damages to production and environment 011100 sandstorm a strong wind blows loose sand and dirt that later mix with air from a dry surface, causing damages to human lives and properties. horizontal visibility is usually less than 1 km 011200 fog a visible mass composed of cloud water droplets and ice crystals suspended in the air or near the earth's surface, causing damages to human lives and properties and especially harms to the traffic safety. horizontal visibility is usually less than 1 km 019900 other m&h disasters meteorological and hydrological disasters that are not mentioned above 020000 seismic and geological disasters natural disasters resulting from the sudden energy release or violent mass transport in the lithosphere of the earth or long-term accumulative geological changes, causing damages to human lives and properties and ecological environment 020100 earthquake the strong shaking of the earth's surface and the accompanying ground rupture, resulting from the sudden release of energy in the earth's crust. it causes damages to human lives, buildings and infrastructures, social functioning, and eco-environment (continued) the sudden occurrence of a violent discharge of the interior materials of the earth, causing direct damages to human lives and properties. the erupted material is referred to as lava. other impacts include pyroclastic flow, lava flow, volcanic gases and ashes, and eruption-induced debris flow, landslide, earthquake, and tsunami 020300 collapse the sudden fall of unstable materials occurring at the edge of a steep cliff, causing damages to human lives and properties 020400 landslide a slide of a large mass of dirt and rock down a slope under the action of gravity, causing damages to human lives and properties 020500 debris flow a special water flow, entraining objects such as fragmented rocks, muds, branches in the path, rapidly rushes down mountain valleys or slopes. it results from heavy rains, reservoir or pond breach, or a sudden melting of snow and ice, causing damages to human lives and properties 020600 surface collapse a surface depression due to abandoned mines or karst processes, causing damages to human lives and properties 020700 ground subsidence a large-area land subsidence due to excessive extraction of groundwater or gas and oil, causing damages to human lives and properties. it occurs in unconsolidated or semi-consolidated soil areas 020800 ground fracture a linear fissure on the ground surface cracking through the rocks or soils, causing damages to human lives and properties 029900 other geological disasters geological disasters that are not mentioned above 030000 ocean disasters disasters resulting from the abnormal or drastic change of the ocean environment and occurring on the sea or coast 030100 strom surge a coastal flood caused by non-periodic abnormal rising of water over part of the sea that results from tropical cyclone, extratropical cyclone or cold front, causing damages to human lives and properties along the coast 030200 sea wave sea waves with wave height of more than 4 meters, causing damages to ships, offshore oil drilling facilities, fishery, aquaculture, harbors and ports, seawalls, or other ocean and coastal engineering 030300 sea ice it blocks channels and causes damages to ships, offshore facilities and coastal engineering (continued) tsunami sea waves with wavelength up to hundreds of kilometers, induced by seafloor earthquakes, volcanic eruptions, underwater landslide, and subsidence, producing a sudden upward displacement of seawater and forming a "water wall" on the coast, devouring farmlands and villages, causing damages to human lives and properties 030500 red tide a sudden increase or high concentration of aquatic planktons and microorganisms changing the water body color to red or brown. it disrupts the normal aquatic ecology and causes damages to human lives and properties and eco-environment. see also the red tide disaster in the biological disasters 039900 other ocean disasters ocean disasters that are not mentioned above 040000 biological disasters natural disasters in the forest or grassland resulting from activities of living being, lightning, or spontaneous combustion, causing damages to crops, woods, cultivated animals and related facilities 040100 plant diseases and pests an outbreak of pathogenic microorganisms and pests, harming the farming and forestry 040200 pandemic disease an epidemic of infectious disease caused by microorganisms or parasites that rapidly spreads through human or animal populations, usually resulting in a high morbidity or mortality. it causes great damages to animal husbandry and harms to human health and life safety 040300 rodents an outbreak of rodent-related disasters, causing damages to plantation, animal husbandry, forestry and properties 040400 weeds weeds cause severe damages to plantation, animal husbandry, forestry, and human health 040500 red tide a sudden increase or high concentration of aquatic planktons and microorganisms changing the water body color to red or brown. it disrupts the normal aquatic ecology and causes damages to human lives and properties and eco-environment 040600 forest/grassland fire a fire in a forest or grassland caused by lightning, spontaneous combustion or human beings under combustible conditions. it causes damages to human lives and properties and eco-environment 049900 other biological disasters biological disasters that are not mentioned above 050000 natural disasters induced by the damage to ecosystem or ecological imbalance, bringing out negative impacts on the harmony between human beings and nature and on the living environment of human beings (continued) from the comparison between the classification of the twelfth five-year special plan and that of the state standards, it can be seen that they share the same five big groups of natural disasters, but the latter one has 15 more specific types than the former one. besides, an emergency incident is defined as "a natural disaster, accidental disaster, public health incident or social safety incident, which takes place by accident, has caused or might cause serious social damage and needs the adoption of emergency response measures" in emergency response law of the people's republic of china (2007). there is no universal standard for the classification of disaster scale. although there are different standards in different fields, the major factor considered is the scale of the hazardous event-induced disasters. generally, the classification indicators include the number of casualties, the amount of property loss, disaster-affected area, and hazard intensity. (1) indicator system of unisdr in the sendai framework for disaster risk reduction 2015-2030, there are seven disaster reduction indicators, four of which are related to the measuring of disasters, namely disaster mortality, disaster-affected people, direct disaster mortality. number of people killed or missing from a hazardous event. the death toll refers to the number of death population during or after the event, while the missing toll only refers to the total number of missing people during the event. besides counting the total number of dead and missing people, it is also important to calculate the percentage of killed and missing people per 100,000 people. thus, the effect of population base can be eliminated in temporal and spatial comparison of mortality. affected people. it refers to the total population that are affected directly or indirectly by disasters. directly affected people are those whose health was affected, such as injured and sick people, and those evacuated, displaced or relocated, and those who suffered from the disaster-induced direct damages to livelihoods, infrastructure, social culture, environment, and properties. at the same time, disaster statistics also need to include people whose houses were destroyed or collapsed and people who receive food aid. indirectly affected population are those suffered from the additive effects of disasters, namely people affected by disaster-induced disruption or modification of economy, critical facilities, basic services, business, work, society, and health. in practice, due to the difficulty in counting indirectly affected population, only directly affected population are included in the disaster statistics. likewise, it is also worth calculating the percentage of affected people per 100,000 people. in addition to counting the killed and missing people and affected people, it is also common to specify their ages, genders, residence addresses, and disabilities. direct economic loss. direct economic loss refers to disaster-induced loss of materials or properties, such as houses, factories, and infrastructures. usually after the occurrence of a disaster, it is advised to assess the property loss as soon as possible to facilitate the cost estimation for disaster recovery and insurance claims processing. it is also recommended to calculate the percentage of direct economic loss accounting for the global or national gross domestic product (gdp). direct economic loss can be further divided into agriculture loss, loss of industrial and commercial facilities, houses, critical infrastructure damaged or destroyed by disasters. direct agriculture loss: it refers to crop and livestock losses and also includes the losses of poultry, fishery, and forestry. industrial facilities damaged or destroyed: it refers to the loss of manufacturing and industrial facilities damaged or destroyed by hazardous events. commercial facilities damaged or destroyed: it refers to the loss of commercial facilities (including storage, warehouse, cargo terminal, etc.) that are damaged or destroyed by hazardous events. houses damaged: it refers to the loss of houses slightly affected by hazardous events and subject to no structural or architectural damages. after repair or cleanup, these damaged houses can still be habitable. houses destroyed: it refers to the loss of houses that collapsed or were burnt, washed away, and severely damaged and are no longer suitable for long-term habitation. critical infrastructure damaged or destroyed: it refers to the loss of educational and health facilities, and roads damaged or destroyed by hazardous events. educational facilities damaged or destroyed: it refers to the number of educational facilities damaged or destroyed by hazardous events. educational facilities include children's playroom, kindergarten, elementary school, high school (junior and senior), vocational school, college, university, training center, adult education school, military school, and prison school. health facilities damaged or destroyed: it refers to the number of health facilities damaged or destroyed by hazardous events. health facilities include health centers, clinics, local or regional hospitals, outpatient centers, and facilities that provide basic health services. roads damaged or destroyed: it refers to the length of road networks in kilometers that are damaged or destroyed by hazardous events. infrastructure damaged or destroyed: it refers to the loss of infrastructures other than the critical infrastructures, such as railways, ports, airports. railways damaged or destroyed: it refers to the length of railway networks in kilometers that are damaged or destroyed by hazardous events. ports damaged or destroyed: it refers to the number of ports that are damaged or destroyed by hazardous events. airports damaged or destroyed: it refers to the number of airports that are damaged or destroyed by hazardous events. basic services. basic services refers to the disruption of public services or time loss due to low-quality services, which are caused by hazardous events. basic services include health facilities, educational facilities, transportation system (including train and bus terminals), ict system, water supply, solid waste management, power supply system, emergency responses, etc. the health facilities, educational facilities, transportation system are mentioned above in the critical infrastructure loss and infrastructure loss sections. ict system refers to communications and the associated equipment network, including radio and tv stations, post offices, public information offices, internet, landline and mobile telephones. water supply includes drinking water supply and sewerage systems. drinking water supply system includes drainage system, water processing facilities, water transporting channels (channels and aqueducts) and canals, water tank, or tower. sewerage system includes public sanitary facilities, sewerage treatment system, collection and treatment of solid wastes from public sanitation. solid waste management refers to collection and treatment of solid wastes that are not from public sanitation. power/energy system includes power facilities, electrical substations, power control centers, and other power services. emergency response includes disaster management offices, fire departments, police stations, military, and emergency control centers. (2) indicator system of statistical system of damages and losses of large-scale natural disasters in china the ministry of civil affairs and national bureau of statistics of china jointly introduced the regulation statistical system of damages and losses of large-scale natural disasters in 2013, which brought the comprehensive assessment of natural disaster loss into the regulation system (shi and yuan 2014) . this statistical system explains the purpose and meaning of statistics of large-scale disasters and defines the statistical scope and major indicators. other contents described in this regulation include the submission procedure, forms of organization and data collection, 26 loss statistical report forms (1 of which is the loss summary table), 1 basic report, and 738 indicators. some examples of these indicators are affected people, houses damaged and destroyed, household property loss, agriculture loss, industry loss, service loss, infrastructure loss, loss of public service system, resources and environmental loss, and so on (table 1.8) . figure 1 .5 shows the changes in the percentage of direct economic loss accounting for gdp and human mortality caused by disasters in china (1990 china ( -2012 which wenchuan earthquake data are not included). the overall decreasing trends of the two items demonstrate a good result of comprehensive disaster reduction. compared to the disaster indicators in sendai framework for disaster risk reduction 2015-2030 that incorporates both the human-made and natural disasters, the statistical system can only be applied to natural disasters. in contrast to the emphasis of the latter one on the comprehensiveness, the former one only highlights the key points. another difference between these two is that the latter one includes report of rural residential houses damaged and destroyed b02 report of urban residential houses damaged and destroyed b03 report of non-residential houses damaged and destroyed c01 report of household property loss d01 report of agriculture loss e01 report of industry loss f01 report of service loss g01 report of infrastructure (transportation) loss g02 report of infrastructure (communications) loss g03 report of infrastructure (energy) loss g04 report of infrastructure (water conservancy) loss amount of materials damaged and destroyed g05 report of infrastructure (municipal service) loss economic loss g06 report of infrastructure (living facilities in rural area) loss g07 report of infrastructure (geological hazard prevention) loss h01 report of public service (educational system) loss h02 report of public service (technology system) loss h03 report of public service (health system) loss h04 report of public service (culture system) loss h05 report of public service (media system) loss h06 report of public service (sports system) loss h07 report of public service (social security and service system) loss h08 report of public service (social management system) loss h09 report of public service (cultural heritage system) loss report of resources and environmental loss amount of materials damaged and destroyed j01 report of basic indicators the resources and environmental damages caused by natural disasters, while the former one stresses on the effectiveness and quality losses of infrastructure and services caused by disasters. therefore, there are similarities in the disaster indicators of these two regulations, and there are also differences due to social and cultural differences. even though some indicators share the same name in two systems, the actual meanings might be different. in practice, people need to be cautious in choosing the right indicator(s). at present, the classification of disaster grade mainly adopts the standardized division method of disaster risk factors of each disaster, while there is no standard division for multi-hazard classification. the qualitative approach is usually used to classify disaster intensity levels, that is, the use of continuous quantitative or semiquantitative indicators, such as applied multi-risk mapping of natural hazards for impact assessment (armonia) that categorizes a disaster into high, medium, or low level according to its intensity. another example is hazard score proposed by odeh engineers inc. (2001) that takes into account the level, frequency, and percentage of the affected area in the total research area. a higher score means the hazard has a higher intensity. the world natural disaster hotspots identified by the world bank are based on 2.5°â 2.5°grid cells for risk assessment. in each grid cell, the hazard indexes of all types of hazards occurred are summed to give a score for the determination of hotspots. the hazard index of each type of hazard is established according to the corresponding data. the term very large-scale disaster emerged in the beginning of the twenty-first century. at the end of the twentieth century, a series of disasters happened worldwide and caused great impacts on the human society and economy. for example, hurricane andrew occurred in usa in 1992 claimed 65 lives and caused 26-billion-dollar definition of very large-scale disaster. the chinese word "juzai" appeared in 1986 in china for the first time and was used to mistranslate the word "catastrophic disaster" in the western literatures. the appearance of "juzai" in chinese media and academia is closely related to the founding and explanation of the catastrophic disaster insurance funds. according to the statistical data from cnki.com.cn, as of the end of december 2011, there were up to 1359 literatures that include "juzai" in the titles. and the number of papers increased annually with the peak of 504 publications in the year 2008. more than half of these 504 papers are related to the catastrophic disaster insurance. due to the frequent occurrences of very large-scale disasters in recent years, the new words such as "juzai prevention," "juzai relief," and "juzai assessment" are becoming more and more widely used in scientific publications. in the chinese academic literatures, it is the author of this book that first introduced the word "dazai" for "large-scale disaster" and "juzai" for "very large-scale disaster" in the western literatures after attending the high level advisory board seminar of financial management of large-scale catastrophes held by oecd in paris in the july 2006 (shi et al. 2006 (shi et al. , 2007 . although a lot of work has been done in the definition and classification of very large-scale disasters, there are no well-recognized definition and classification standards of very large-scale disasters in the fields of academia or finance. different scholars have their own angles. in western literatures, the following definitions have great influences. in the book large-scale disasters-lessons learned published by oecd in 2004, the terms large-scale disasters (or megadisasters) and very large-scale disasters were used, but the specific quantitative criterion was not provided. in oecd's opinion, very large-scale disasters can cause a great number of casualties, property losses, and widespread infrastructure damage. the impacts are so great that governments of the affected area and neighboring regions become unable to cope with; even public panic occurs. oecd also emphasizes the importance of cooperation and assistance among the member countries in response to the very large-scale disasters (oecd 2004) . in the book large-scale disaster-prediction, control, reduction by mohamed gad-el-hak (2008), disasters are divided into large-scale and very large-scale disasters based upon the disaster scope and death toll ( fig. 1.6) . a very large-scale disaster is defined as a disaster with the death toll more than 10,000 or the affected area over 1000 km 2 . the definition of catastrophic disaster is usually based on the scale of the insured property losses by experts on insurance and financial management and development. the insurance services office (iso) of usa defines a catastrophic disaster as an event that causes insured property losses of 25 million dollars or more and affects a significant number of property/casualty policyholders and insurers. swiss re uses losses more than 38.7 million us dollars as a standard. from the amount of property losses, it can be seen that the scale of a catastrophic disaster cannot reach that of a large-scale disaster or megadisaster, let alone a very large-scale disaster. this also shows that the term "juzai" mentioned in the chinese literatures in the late 1980s has a scale of the catastrophic disaster and was only paid attention to by experts on insurance and financial management and development. therefore, before the use of large-scale disasters or megadisasters and very large-scale disasters in the western literatures in the early twenty-first century, the term "juzai" in the chinese literatures only refers to a catastrophic disaster. from the angle of geoscientists, very large-scale disasters are usually defined according to the hazard intensity, casualties, property losses, and affected scope. a very large-scale disaster in ma's opinion must reach two of the following criteria: over 10,000 deaths, direct economic losses of more than 10 billion chinese yuan of 1990, economic losses of more than the average annual fiscal revenue of the previous three years of a chinese province, drought disaster rate more than 70%, or flood disaster rate more than 70%, crop losses of more than 36% of the average annual crop production of the previous three years of a chinese province, more than 300,000 houses collapsed, and livestock death toll of more than 1 million (ma et al. 1994 ). shi et al. defines a very large-scale disaster as a great disaster caused by a 100-year hazard (e.g., a 7.0-magnitude or stronger earthquake) and resulting in a great number of casualties and large and widespread property losses (shi et al. 2010) . also in shi's definition, the impacts of a very large-scale disaster are so great that the affected area is unable to respond by itself and has to resort to outside help (table 1 .9). according to the classification standard in table 1 .9, the very large-scale disasters caused by natural hazards worldwide between 1990 and 2015 are listed in table 1 .10. from table 1 .10, we can see that one of the characteristics of the very large-scale disasters is the big hazard intensity. a very large-scale disaster can be a disaster chain composed of a very large hazard and its induced secondary disasters. it can also be a superposition of multiple types of disasters that are triggered by multiple hazards in a specific region and during a specific period of time. besides, very large-scale disasters usually cause a great number of deaths and injuries, a huge amount of property losses, severe impacts on economy, society and natural large-scale 6.5-7.0 (earthquake) or 1/50a-1/100a 1000-9999 10.0-99.9 10,000-99,999 medium-scale 6.0-6.5 (earthquake) or 1/10a-1/50a 100-999 1.0-9.9 1000-9999 small-scale below 6.0 (earthquake) or below 1/10a 99 1.0 1000 note (1) for each disaster level, at least two of the four criteria must be met. (2) death toll includes both the people dead and people missing over 1 month. (3) direct economic loss is the value of actual disaster-caused property loss of the year. (4) the affected area is the area where there are casualties, property losses, or damages to ecosystems approx. 14 environment, and a large disaster area. the emergency aids and reconstruction when or after the occurrence of the very large-scale disasters usually need help from a larger region or the whole country. in some cases, even international aids are indispensable. all the very large-scale disasters mentioned so far are caused by sudden hazards. the indicators and classification standards for disasters caused by the accumulation of gradual hazards should be different (zhang et al. 2013) . however, there are few discussions about the classification standards of gradually generated very large-scale disasters. drought is one of the major natural disasters in both china and the world. since 1949, a number of severe droughts causing great number of casualties and huge property losses have happened in china. for example, more than tens of thousands of people were killed due to the three-year great drought from 1959 to 1961. based on the case of drought, we will discuss the classification standard of gradual very large-scale disasters below. we cannot use hazard intensity to measure or to classify very large-scale droughts. this is because the forming process of a drought is very complicated. a drought hazard could be meteorological, or hydrological. it can also be soil drought or socioeconomic drought. the indicators and measurement criteria vary among different types of droughts. the data and studying methods are also different. what's more, there is no linear relationship between the drought intensity and drought losses. and there is no definite relationship between the drought hazards and the formation of drought disasters neither. the impacts of a very large-scale drought disaster can be represented in crop losses and population in need of aids. drought could result in a bad harvest or total crop failure and water shortage for both human beings and livestock. industrial production, urban water supply, and ecological environment could also be affected to varying degrees if a drought lasts for a long time. in the statistical system of damages and losses of natural disasters by prc ministry of civil affairs (2013), the following items are included in the statistics of droughts: affected population, population affected by water shortage, number of livestock affected by water shortage, affected crop area, crop disaster area, total crop failure area, affected grassland area, and population in need of food and water aids. the inclusion of population affected by water shortage and population in need of aids in this statistical system demonstrates the "people-oriented" disaster relief philosophy. in the state-level contingency plan for natural disaster relief by general office of the state council of prc, it is mentioned that when the number of people in need of food and water aids from governments accounts for a certain percentage of the agricultural population or reaches a designated magnitude, the state will initiate emergency response of the corresponding level (table 1 .11). based on the severe droughts in china in table 1 .11, five criteria are used to define very large-scale drought disaster, crop disaster ratio, crop disaster area, disaster population, population in need of aids ratio, and direct economic loss (table 1.12). (2) indicator explanation. affected crop area is the crop area that has a reduction of more than 10% of production. crop disaster area is the crop area that has a reduction of more than 30% of production. crop disaster ratio is the ratio of crop disaster area over affected crop area. population affected is the number of people who suffer from losses caused by natural disasters (including non-permanent residents). disaster population is the population that are affected by the crop disaster. in this table, it is estimated from the crop disaster area and the cultivated area per capita in the disaster province. population in need of aids is the number of people who are directly affected by natural disasters and are in need of food and water supply or medical treatment from the government (including non-permanent residents). population in need of aids ratio is the ratio of population in need of aids to the population affected. direct economic loss is the value of depreciated of the disaster-bearing bodies or the value of the disaster-bearing bodies forfeited. in this table, it is the value of actual property damages of the year when the disaster happened. (3) the disaster population in events 1-11 was estimated from the crop disaster area and the cultivated area per capita in the disaster province. forum are fiscal crises in key economies, structurally high unemployment/ underemployment, water crises, severe income disparity, failure of climate change mitigation and adaptation, greater incidence of extreme weather events (e.g., floods, storms, fires), global governance failure, food crises, failure of a major financial mechanism/institution, and profound political and social instability. it can be seen from the above that, besides the continuing focus on the traditional risks, we need to accelerate the study of response to a series of non-traditional risks. the five categories of risks were not changed in the global risk report 2016, but the number of specific risks was decreased from 31 to 29 (global risk 2016). in this report, a global risk is an uncertain event or condition, if occurring, which can cause significant negative impact for several countries or industries within the next 10 years. a global trend is a long-term pattern that is currently taking place and that could contribute to amplifying global risks and/or altering the relationship between them (table 1 .14). the global risks landscape 2016 was proposed in the global risk report 2016. from the landscape, it can be seen that the risks with the highest impact and likelihood are failure of climate change mitigation and adaptation, water crises, large-scale involuntary migration, fiscal crises, interstate conflict, profound social instability, cyber attacks, and unemployment or underemployment (global risk 2016). in the global risks interconnections map 2016, the most strongly connected risks are failure of climate change mitigation and adaptation, profound social instability, large-scale involuntary migration, and unemployment or underemployment (global risk 2016). the davos world economic forum reports involve a wide range of global risks covering the fields of economy, politics, culture, society, and ecology and could be corresponding to the economic development, political development, cultural development, social development, and ecological development proposed by the chinese government, respectively. thus, it can be seen that the risk classification of the world economic forum emphasizes the combination with practice. the risk taxonomy of irgc is from the perspective of hazards, similar to the disaster classification in sect. 1.2. this classification stresses on the causes of risks and thus lacks in combination with practice. however, it pays attention to emerging risks and slow-developing catastrophic risks, including the governance of very large-scale disaster risks. at the same time, it provides the framework for systematic risk assessment and governance. in china, the classification of risks is tightly associated with the security and disaster classifications. for example, the overall national security concept proposed by the chinese government is in a one-to-one correspondence with the global risks in the world economic forum report. in detail, the political security, homeland security, and military security correspond to geopolitical risks; economic and resource security to economic risks; cultural and societal security to societal risks; technology, information, and nuclear security to technological risks; ecological security to environmental risks (xi 2016) . another example is the four public securities proposed by the chinese government corresponding to five of the six risk categories of irgc, that is, natural disaster of the former corresponds to the natural forces of the latter, accidental disasters to physical risks, public health accidents to chemical and biological risks, and social security incidents to social-communicative hazards. the complex hazards are usually related to the four public securities proposed by the chinese government, and also to the integrated disasters. the classification system of risks is built upon the hazard and disaster classifications in china. for example, if hazards are divided into natural, man-made, and environmental ones, risks can be classified into the corresponding three types. in the same way, risks can also be divided into four categories of natural, accidental, public health, and social security ones based on the four-type classification of hazards. the natural disaster risk level is usually expressed in exceedance probability or return period, the same way as the intensity level of natural hazards. for example, the meteorological, hydrological, and ocean disaster risks can be divided into 10-year level (small-scale disaster), 20-year level (medium-scale disaster), 50-year level (large-scale disaster), and 100-year level (very large-scale disaster). the earthquake disaster risk level is usually expressed in earthquake magnitude. for example, a magnitude 7.0 or above earthquake poses a very large-scale disaster risk, 6.5-7.0 large-scale, 6.0-6.5 medium-scale, and 6.0 or below small-scale disaster risks. the natural disaster risk level does not only depend on the natural hazard intensity but also count on the vulnerability and exposure of the hazard-bearing bodies. in practice, the classification of natural disaster risk levels is even more complicated and thus usually resorts to the relative levels such as the first-level risk, the second-level risk, the third-level risk, the fourth-level risk, and the fifth-level risk. the larger the number is, the higher the risk level is. in the atlas of natural disaster risk of china by peijun shi (chinese-english bilingual version, shi 2011) and the world atlas of natural disaster risk by peijun shi and roger kasperson 1.3 risks (shi et al. 2015) , the temporal and spatial patterns of natural disaster risks of china and the world are displayed by using indicators including risks, risk grades, and risk levels (qin et al. 2015; shi 2011 shi , 2015 . it is more difficult to classify man-made and environmental risk levels by using quantitative criteria. a common way is to use relative level, or using the trends and changes of man-made and environmental risks to describe their levels. the global risk trends 2015 in the davos world economic forum risk report is an example of this kind of way of reflecting global risk levels. in detail, increasing global risk levels at 2015 are aging population, changing landscape of international governance, climate change, environmental degradation, growing middle class in emerging economies, increasing national sentiment, increasing polarization of societies, rise of chronic diseases, rise of cyber dependency, rising geographic mobility, rising incoming and wealth disparity, shifts in power, and urbanization (wef 2015) . the top three most likely global risks in 2016 in each region are reported in the global risk report 2016 of wef (wef 2015) . in north america, the top three are cyber attacks, extreme weather events, and data fraud or theft. in latin america and the caribbean, the top three are failure of national governance, profound social instability, and unemployment/underemployment. in europe, the three are large-scale involuntary migration, unemployment/underemployment, and fiscal crisis. in the middle east and north africa, they are water crises, unemployment/ underemployment, failure of national governance, and profound social instability. in sub-saharan africa, they are failure of national governance, unemployment/ underemployment, and failure of critical infrastructure. in central asia (including russia), they are energy price shock, interstate conflict, and failure of national governance. in east asia and the pacific, they are natural catastrophes, extreme weather events, and failure of national governance. in south asia, the top three are water crises, unemployment/underemployment, and extreme weather events. the exceedance probability mentioned previously, a concept usually used in the study of natural disaster risks, refers to the likelihood of the intensity or motion parameters of an earthquake, or the flood level, or the maximum wind speed at the center of a typhoon exceeding a designated value or values in a specific location and during a certain period of time. in other words, it is the probability of the required value exceeding the given value and can be mathematically expressed as where p exceed is the likelihood of the required value (u) of a data series exceeding the limit value (u limit ). for example, a set of data x (x 1 , x 2 ,…x n ) have n raw data points that are arranged from the lowest to the highest. the exceedance probability of data point x i is p ¼ n à i þ 1 n â 100% ð1:6þ the following takes the earthquake as an example for the calculation of exceedance probability. within t years, the probability of earthquake occurrence for n times p(n) in a region is p n ð þ ¼ f n ð þ ð1:7þ in the same way, within t years, the likelihood of no earthquake happening in this region is then, the likelihood of at least one earthquake within t years, or the exceedance probability, is the probability density is poisson distribution is widely used in earthquake studies. within t years, the probability p(n) of n earthquakes occurring in a region can be expressed in the poisson distribution form as below: p n ð þ ¼ e àu â vt n n! ð1:11þ then, within t years, the likelihood of no earthquake happening in this region is p 0 ð þ ¼ e àvt â vt 0 0! ¼ e àvt ð1:12þ so the likelihood of at least one earthquake happening or the exceedance probability within t years is f t ð þ ¼ 1 à p 0 ð þ ¼ 1 à e àvt ð1:13þ the corresponding probability density is :14þ the variable v mentioned above is the annually averaged occurrence probability of earthquake in a region, which has an inverse relationship with the return period t 0 : from here, we can see that the relationship between the return period t 0 and the exceedance probability f(t) can be expressed as based on the equation above, we can calculate the return periods of different exceedance probabilities for a period of time. for example, the exceedance probability of 63% for 50 years is equivalent to a 50-year disaster, 10% means a 474-year disaster, and 2-3% means a 1600-2500-year disaster. in summary, hazards are negative factors to human beings, and the temporal and spatial patterns of hazards can be studied by comparing with historical observed data. disasters are the impacts of hazards on human beings and can be measured in terms of losses and damages. risks are future hazard-induced disasters in a specific location. in short, disaster risk science is a discipline studying the mechanics, processes, and dynamics of the interactions among hazards, disasters, and risks, as well as disaster risk prevention and reduction. the relationships among hazards, disasters, and risks are shown in fig. 1.7 . greater incidence of man-made environmental catastrophes (e.g., oil spills failure of climate change mitigation and adaptation geopolitical 1. global governance failure 2. political collapse of a nation of geopolitical importance 3. increasing corruption 4. major escalation in organized crime and illicit trade 5. large-scale terrorist attacks 6. deployment of weapons of mass destruction 7. violent interstate conflict with regional consequences 8. escalation of economic and resource nationalization (continued) and sabotage • human violence (criminal activities) • humiliation, mobbing consumer products (chemical, physical, etc • technologies (physical, chemical • large constructions, like buildings, dams, highways, and bridges • critical infrastructures, in terms of physical, economic, social-organizational and communicative severe acute respiratory syndrome (sars) china international decadal commission for disaster reduction china's extreme weather events and disaster risk management and adaptation assessment report gb/t28921. 2012. natural disaster classification and code notice on the emergency plan for the issuance of natural disaster relief in china beijing: ministry of civil affairs, people's republic of china reviewing and visualizing the interactions of natural hazards regions of risk: a geographical introduction to disasters risk governance: towards an integrative approach. white paper no. 1, author o. renn with an annex by a research on regional distribution of major natural hazards in china remarks on national security the atlas of natural hazards in china large-scale disaster prediction, control, and mitigation notice on statistical regulations of natural disasters. ministry of civil affairs, people's republic of china notice of "twelfth five-year" special plan on disaster prevention and reduction large-scale disasters -lessons learned theory and practices on disaster science world atlas of natural disaster risk on integrated disaster risk governance: seeking for adaptive strategies for global change on the classification standards of catastrophe and catastrophe insurance: the perspective from wenchuan earthquake and southern freezing rain and snowstorm disaster, china [c]. international integrated disaster prevention and mitigation and sustainable development forum integrated governance of natural disaster risk integrated assessment of large scale natural disasters in china theory on disaster science and disaster dynamics china atlas of natural disaster risk integrated risk governance: ihdp comprehensive risk prevention science program and comprehensive catastrophe risk prevention research integrated risk governance: ihdp integrated scientific plan and integrated catastrophe risk governance research death toll exceeded 70000 in europe during the summer of the law on response to emergencies. bulletin of the standing committee of the national people's congress of the people's republic of china terminology on disaster risk reduction disaster risk reduction for sustainable development. guidelines for mainstreaming disaster risk assessment in development. a publication of the united nations' international for disaster reduction integrated research on disaster risk. peril classification and hazard glossary united nations office for disaster risk reduction study on definition and division criteria of a large-scale disaster: analysis of typical disasters in the world in recent years global risks report global risks china's major natural disasters and mitigation measures (overview introduction to natural disasters hunan people's press (in chinese) risk is the probability of disaster loss in a future period of time in a region, or the future disaster. essentially, risk is the probability of occurrence of a future hazardous event and its impacts (loss and/or damage). unisdr (2004) defines risk as the probability of harmful consequences resulting from interactions between natural or human-induced hazards and vulnerable conditions. two aspects that need special attention are the influence of social factors on risk and the estimation of hazard intensity and distribution.disaster risk usually refers to natural disaster or environmental risk that is associated with natural factors. the wide attention which disaster risk receives is related to the disaster (especially catastrophic disaster) insurance and the risk governance of emerging risks and very large-scale disasters.the international risk governance council, founded in 2003 in geneva, switzerland, paid high attention to the governance of emerging risk and slow-developing catastrophic risks and also established the transition from risk management to risk governance.in 2006, chinese national committee for the international human dimensions program on global environmental change (cnc-ihdp) proposed to ihdp to undertake the integrated risk governance (irg) research under the background of global environmental change. this international scientific program proposal was approved by the scientific committee of ihdp and launched in 2010 (shi et al. key: cord-103784-f8ac21m2 authors: campbell, c.; wang, t.; mcnaughton, a. l.; barnes, e.; matthews, p. c. title: risk factors for the development of hepatocellular carcinoma (hcc) in chronic hepatitis b virus (hbv) infection: a systematic review and meta-analysis date: 2020-08-24 journal: nan doi: 10.1101/2020.08.21.20179234 sha: doc_id: 103784 cord_uid: f8ac21m2 background: hepatocellular carcinoma (hcc) is one of the leading contributors to cancer mortality worldwide and is the largest cause of death in individuals with chronic hepatitis b virus (hbv) infection. it is not certain how the presence of other metabolic factors and comorbidities influences hcc risk in hbv. therefore we performed a systematic review and meta-analysis to seek evidence for significant associations. methods: medline, embase and web of science databases were searched from 1st january 2000 to 24th june 2020 for english studies investigating associations of metabolic factors and comorbidities with hcc risk in individuals with chronic hbv infection. we extracted data for meta-analysis and report pooled effect estimates from a fixed-effects model. pooled estimates from a random-effects model were also generated if significant heterogeneity was present. results: we identified 40 observational studies reporting on associations of diabetes mellitus, hypertension, dyslipiaemia and obesity with hcc risk. meta-analysis was possible for only diabetes mellitus due to the limited number of studies. diabetes mellitus was associated with >25% increase in hazards of hcc (fixed effects hazards ratio [hr] 1.26, 95% ci 1.20-1.32, random effects hr 1.36, 95% ci 1.23-1.49). this association was attenuated towards the null in sensitivity analysis restricted to studies adjusted for metformin use. conclusions: in adults with chronic hbv infection, diabetes mellitus is a significant risk factor for hcc, but further investigation of how antidiabetic drug use and glycaemic control influence this association is needed. enhanced screening of individuals with hbv and diabetes may be warranted. hepatitis b virus (hbv) is a hepatotropic virus responsible for substantial morbidity and mortality worldwide. infection can be acute or chronic, with most of the hbv disease burden attributable to chronic disease. the world health organisation (who) estimated a chronic hbv (chb) global prevalence of 257 million for 2015, with 887,000 hbv-attributable deaths reported in the same year (1), making hbv the second highest viral cause of daily deaths (with first being the agent of the global covid-19 pandemic, sars-cov-2) (2,3) of which the burden has increased in recent decades (4). most chb deaths are due to primary liver cancer and cirrhosis; these conditions were responsible for over 40% of all viral hepatitis-attributable deaths. a gbd study on the global hcc burden reported a 42% increase in incident cases of hcc attributable to chronic infection between 1990 and 2015 (5), among which chb infection was the largest contributor, responsible for more than 30% of incident cases in 2015 (5). multiple risk factors for hcc in chb-infected individuals have been established, including sex, age, cirrhosis, and co-infection with human immunodeficiency virus (hiv) or other hepatitis viruses (including hepatitis c and d). previous studies have investigated associations of comorbidities, such as diabetes mellitus (dm) (8-11) and hypertension (12, 13) , with risk of hcc in the general population, and the european association for the study of the liver (easl) recognises dm as a risk factor for hcc in chb (7). as the global prevalence of comorbidities such as dm (14) , renal disease (15) , hypertension (16) and coronary heart disease (chd) (17) continues to rise, these conditions are increasingly relevant to the development of hcc. various risk scores have been developed to predict hcc risk: the page-b risk score was developed to predict hcc risk in caucasian patients on antiviral treatment (18) , with hcc risk. therefore, we undertook a systematic review, aiming to summarise and critically appraise studies investigating associations of relevant comorbidities and metabolic factors with risk of hcc in chb-infected individuals. in june 2020 we systematically searched three databases (web of science, embase and medline) in accordance with prisma guidelines (28); search terms are listed in table s1 . we searched all databases from 1 st january 2000 until 24 th june 2020, without application of any restrictions for study design applied to search terms or results, but including only full-text human studies published in english. we combined and deduplicated search results from the three databases, prior to screening for eligibility. we excluded articles not investigating associations of comorbidities with risk of hcc and/or not restricted to chb-infected participants. we also searched reference lists of relevant systematic reviews/meta-analyses and studies identified for inclusion to identify additional studies for inclusion. search terms were constructed and agreed on by three authors (pm, tw and cc) and articles were screened and selected by one author (cc). investigated, number of participants, number of hcc cases, sex, age at baseline, risk ratio and covariates adjusted for. we carried out meta-analysis in r (version 3.5.1) using the "meta" package (version 4.12-0) (29), including only hazard ratios (hrs) minimally adjusting for age and sex. we calculated pooled summary effect estimates using the inverse-variance weighting of hrs on the natural logarithmic scale, and quantified between-study heterogeneity using the i 2 statistic; significance of heterogeneity was investigated using cochran's q test (p threshold=0.05). where i 2 was >0 and heterogeneity was significant, we present both fixed-and random-effects summary estimates. we undertook multiple sensitivity analyses whereby analyses were restricted to studies adjusting for various additional confounders and for dm treatment, and stratified by dm type, in order to investigate robustness of observed associations. for diabetes, we considered diagnoses of type 1 and type 2 diabetes, as well as unspecified diabetes mellitus, for pooling the effect, followed by further stratification by subtypes of diabetes if enough studies were eligible. hypertension (ht), was defined by either a diagnosis of ht recorded as part of the medical history or current health assessment, or a measurement with mean arterial pressure (map) above a specified threshold. obesity was based on bmi values, by referring the cut-off in the included studies, where 25, 27, 30 kg/m 2 were the common threshold values used. cvd was defined broadly as an umbrella term including any of the following disease subtypes: ischeamic heart disease (ihd)/coronary heart disease(chd), cerebrovascular disease. dyslipidaemia was defined according to serum lipid concentrations above a certain threshold (thresholds may vary depending on healthcare setting). exposure/outcome ascertainment. studies with scores of <5, 5-7 and >7 points were considered to be of low, sufficient and high quality, respectively. in total our search identified 1,814 articles (899 from medline, 407 from embase and 508 from web of science) (figure 1 ). after deduplication, we screened 1,136 individual articles by title/abstract, from which 140 full texts were identified for full-text assessment. after exclusion of ineligible articles and reference list searching of relevant articles, we identified 40 articles for inclusion in this review. summary characteristics of included studies are reported in table s2 . all studies were observational in design, with 33 cohort and 7 case-control studies included (table s2) . thirty-two studies were conducted in asian countries. four studies were restricted to male cohorts and 36 were undertaken in mixed-sex cohorts. all studies recruited participants from health centres, healthcare or prescription databases, or pre-existing cohorts or cancer screening programmes. all studies were undertaken in adults, with mean/median ages of cohorts ranging between 40 and 65 years in 33 studies. thirty-three studies investigated dm/insulin resistance/fasting serum glucose, 11 studies investigated blood hypertension/blood pressure, 7 investigated dyslipidaemia, 5 investigated obesity and cardiovascular disease. less than 5 studies investigated other factors including renal disease, statin use and use of antidiabetic drugs. in the 40 studies including 536,456 adults, >30,500 hcc events occurred (we are unable to report an exact number, because one study did not report a precise number of hcc cases (31)). sample sizes of cohort studies varied widely, ranging from 102 to among 40 studies, 39 had quality scores ≥5 (tables s3 and s4 ). all cohort studies were of sufficient quality with 13 of these being scored as high-quality. six case-control studies were of sufficient quality and one of poor quality. inclusion criteria varied widely and therefore study populations were heterogeneous. in most studies, exposures and outcomes were ascertained using health assessment, imaging or record linkage. twenty-three cohort studies and 7 case-control studies accounted for age and sex. hcc typically arise after long durations of infection, and therefore prolonged follow up allows for detection of more hcc events; among 23 cohort studies identified, only 5 cohort studies had lengths of follow-up ≥ 10 years). thirty-six studies investigated the association of dm with risk of chb progression to hcc, comprising 7 case-control studies (table 1a) and 29 cohort studies (table 1b) . four studies were restricted to males and the others included both sexes (table s2) . mean ages at baseline in all studies were ≥40 years, respectively. study populations were heterogeneous with variable inclusion criteria, and definitions of dm were not consistent between studies. four case-control and four cohort studies investigated type 2 dm/insulin resistance, three case-control and seven cohort studies investigated unspecified dm, and one case-control and three cohort studies investigated both type 1 and 2 dm as a composite potential risk factor. of the 7 case-control studies that reported effect estimates, there was directional inconsistency between effect estimates reported in case-control studies, with 4 studies reporting an increased risk of hcc in those with dm as compared to those without, 3 studies reporting a decreased risk of hcc in those with dm, and one study failing to provide an effect estimate. risk ratios (rrs) >1 ranged from 1.35 to 2.04, and all were statistically significant. rrs <1 ranged from 0.19 to 0.80, of which two were statistically significant. among 28 cohort studies providing effect estimates (27 hrs and 1 or), there was directional consistency with 27 of the reported rrs >1. effect sizes >1 ranged from 1.05 to 6.80, with 15 rrs being statistically significant. the single rr that was <1 was nonsignificant. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . most case-control studies adjusted for age, sex, hcv coinfection, hiv coinfection and cirrhosis. twenty cohort studies minimally adjusted for age and sex. of these, 15 adjusted for hcv coinfection, 13 for cirrhosis, 12 for antiviral treatment, 10 for hiv coinfection, 9 for alcohol consumption, 7 each for hbv viral dna load and cigarette smoking and 6 for other liver disease (including alcoholic liver disease). eight studies excluded participants who developed hcc within the first 3 to 12 months of follow-up in their main analyses. one study did so in sensitivity analysis and found this did not modify associations observed. dm was associated with an increased risk of progression to hcc by meta-analysis restricted to hrs minimally adjusted for age and sex ( figure 2 ). as there was significant heterogeneity (i 2 =49%, p<0.01), results from both fixed-and randomeffects analyses are presented. in random-effects analysis risk of hcc was 36% (summary rr 1.36; 95% ci 1.23-1.49) significantly higher in dm compared to non-dm. we performed sensitivity analyses in order to investigate the robustness of pooled estimates to additional adjustment for hcv or hiv coinfection, cirrhosis, and dm treatment. after restricting meta-analysis to 16 studies adjusting for hcv coinfection in addition to age and sex ( figure s1 ), pooled hrs did not change materially. considering 8 studies adjusting for hiv and antiviral treatment ( figure s2 ), pooled hr from the fixed-effects analysis was attenuated towards the null slightly but still remained significant. to investigate the robustness of the association of dm with hcc to adjustment for cirrhosis, a potential mediator, we restricted meta-analysis to studies adjusting for cirrhosis ( figure s3 ). this did not change pooled hrs materially. to investigate heterogeneity between type 2 dm and unspecified dm, sensitivity analysis was performed whereby studies were stratified by dm type. amongst studies investigating type 2 dm, heterogeneity was 33% (p=0.18) ( figure s4 ). however the the association of dm with hcc risk was attenuated towards the null in studies that adjusted for metformin use, with risk of hcc 16% higher in dm participants as compared to non-dm (random effects hr 1.16, 95% ci 1.04-1.29) in analysis restricted to studies adjusting for metformin use ( figure s5 ). after restricting to studies adjusting to dm treatment, pooled hrs remained statistically significant. eleven studies investigated the association of ht with risk of chb progression to hcc, one case-control study and 10 cohort studies ( table 2 ). all studies were mixedsex samples in which mean/median age at baseline was ≥40 years (table s2) . definitions of ht were heterogeneous; most studies ascertained hypertension via record linkage, but others used health assessment or interview. few studies defined clinical thresholds for hypertension classification. "higher" map was the primary exposure of interest in the case-control study, for which a threshold was not defined. among 10 studies reporting hazards of hcc associated with ht, only three identified significantly increased risks, with two unadjusted and one adjusted for age. another five studies reported an effect in the same direction, but effect sizes were not statistically significant. adjusted hrs >1 ranged from 1.19 to 1.70 and <1 from 0.04 to 0.96. adjustment for confounders was poor, with only four hrs minimally adjusted for age and sex. seven studies investigated the association of dyslipidaemia with hcc risk in chb patients (table 3) . all studies reported reduced risks of hcc in participants with dyslipiaemia as compared to those without, however only one hr was statistically significant. clinical definitions of dyslipidaemia were often not reported, and only four studies minimally adjusted for age and sex. six studies investigated the association of obesity with hcc risk. clinical definitions of obesity varied greatly, and out of four studies reporting increased risks of hcc with obesity, only one hr was statistically significant. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint three studies investigated the association of statin use with hcc risk in chb. all studies reported hrs <1, and two of these hrs were statistically significant. hrs reported in 5 studies for hcc risk associated with cvd varied, likely due to the variable definitions of cvd used across studies. associations for other variables, including respiratory disease and renal disease, were reported by <2 studies each. our meta-analysis suggests that dm is a risk factor for hcc in chb infected individuals, with hazards of hcc >20% higher in the presence of dm; however, we report significant between-study heterogeneity. this association did not materially change after restriction to studies adjusting for relevant confounders, but did suggest a favourable impact of dm treatment with metformin. pooled effect estimates remained significant in sensitivity analyses. few studies investigated other comorbidities, and some comorbidity search terms included in our systematic literature search returned few or no results. this highlights the need for future investigation of these comorbidities, as antiviral treatment cannot eliminate the risk of hcc entirely and therefore novel risk factors must be identified in order to inform interventions. although easl (7) and apasl (32) guidelines recognise this association, it is not currently consistently described in other recommendations (e.g. aasld guidelines (33) do not list dm as a risk factor for hcc). some studies investigating comorbidities and their metabolic risk factors reported significantly reduced hazards of participants with these conditions as compared to those without. this association may be confounded by the requirement for treatment in secondary care, whereby chb-infected individuals may be more likely to receive screening and antiviral treatment. findings from case-control and cohort studies were not consistent; whilst the majority of cohort studies reported increased risks of hcc associated with dm, case-control findings were inconsistent, and indeed three studies reported a significant reduction of hcc risks in association with dm. explanations for such findings including all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . confounding, selection bias associated with the study of hospital control groups that enrich for dm (34,35), and chance, especially in small studies (34-37). our findings are consistent with a previous meta-analysis (38); we provide a comprehensive review of all cohort studies and include a larger number of studies. we restricted to studies reporting hrs minimally adjusted for age and sex. however, adjustment for covariates and inclusion criteria varied considerably between studies, and this may explain some of the between-study heterogeneity. substantial heterogeneity remained in sensitivity analyses restricted to studies adjusting for additional key confounders, as adjustment for confounders was variable within these studies and populations may not have been comparable. although baseline age and sex characteristics were comparable across studies, there was variability regarding exclusion of those with additional comorbidities and those on antiviral treatment. we noted variable definitions of dm, with some studies restricting investigation to type 2 dm whereas others included participants with unspecified dm. risk factors for types 1 and 2 diabetes mellitus vary, and heterogeneity in dm definitions could therefore contribute to variable study populations and outcomes. global prevalence and incidence estimates for specific dm types do not exist, as distinguishing between types often requires expensive laboratory resources that are not available in many settings. however most cases of type 1 diabetes are found in europe and north america, and the large majority of studies included in this systematic review and meta-analysis were conducted in asian countries (39). it is possible that varied lengths of follow-up also contributed to between-study heterogeneity, although hrs did not significantly vary with length of follow-up in sensitivity analysis. this is because cancer is a chronic disease with a slow development, and preclinical disease can be present for many years before clinical manifestation; follow-up times <10 years may be insufficient to detect hcc outcomes. we were unable to provide effect estimates across most potential patient subgroups because the subgroups contained small numbers of studies, putting subgroup analyses at greater risk of chance findings as well as being subject to the influence of multiple testing. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint the association we report in this meta-analysis is weaker than those observed in patients with chronic hcv infection. in previous studies of individuals with chronic hcv infection, risk of hcc was elevated ~2-fold in the presence of dm (40,41). previous studies also report increased risks of dm in hcv-infected individuals as compared to non-infected individuals (76) (77) (78) (79) . however, this is likely due to the various extrahepatic manifestations of hcv which are not present in hbv infection. in sensitivity analysis restricted to studies adjusting for cirrhosis, the observed association of dm with hcc was attenuated towards the null. this may be explained by a confounding of the association by cirrhosis, accounted for by an independent association of cirrhosis with both dm and hcc, and the absence of cirrhosis from the causal pathway that associates dm with hcc. however, if cirrhosis is located along this causal pathway, then it can be characterised as a mediator rather than a confounder. if cirrhosis is a mediator then adjusting for it would be incorrect. past studies support a positive association of dm with hcc risk in non-chb patients three studies adjusted for metformin use (53-55), and in sensitivity analysis restricted to these studies, the association between dm and hcc remained significant but was attenuated towards the null. it is not known the extent to which this is a result of glucoregulation by metformin, accomplished by inhibition of hepatic gluconeogenesis and improvement of insulin sensitivity in tissues leading to reduced oxidative stress in all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint the liver (56), and/or a direct impact of metformin in reducing cancer risk via regulation of cellular signalling. evidence from observational studies (57-59) and randomised controlled trials (rcts) (60) supports a protective effect of metformin against the development and progression of cancer in diabetic individuals. there is also some rct evidence for protective effects of metformin against progression of certain cancer types in non-diabetic individuals (61) although this is not consistent. multiple largescale phase iii rcts are currently underway (62-65) and will provide further information regarding the roles of dm and metformin in cancer development. we included all studies investigating the association of comorbidities with risk of chb progression to hcc that minimally adjusted for age and sex in order to provide a comprehensive review of available evidence. however, few studies investigated non-dm comorbidities, preventing meta-analysis for these comorbidities. additionally we were unable to restrict our meta-analysis of dm and hcc to studies adjusting for confounders other than age and sex, as few studies minimally adjusted for all relevant factors. publication bias may influence the outcome, as we restricted our search to peer-reviewed literature, and studies that do not report an association of dm with hcc may be less likely to be published. our results may not be generalisable to the global chb population, as there were a limited number of studies from non-asian countries. the lack of studies from any african countries is of concern, given that the region carries both the highest hbv prevalence (3) and largest mortality burdens for cirrhosis and hcc (66,67). our finding that dm is a risk factor for hcc in chb-infected individuals suggests that enhanced cancer surveillance may be justified in patients with chb and dm to enable early detection and treatment. improvements in guidelines could help to inform more consistent approaches to risk reduction. after adjustment for metformin use, this association remained significant, but was attenuated suggesting a potential benefit of metformin that warrants further study. ongoing investigation is required in order to identify and characterise risk factors for hcc, to extend these analyses to diverse global populations, and to elucidate disease mechanisms in order to inform prevention, screening and therapeutic intervention. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . stanaway preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint assessing the quality of nonrandomised studies in meta-analyses [internet] . [cited 2020 jun 17] . available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint tables table 1a . effect estimates for case-control studies investigating the association of diabetes mellitus with hepatocellular carcinoma risk. ahr, adjusted hazards ratio; uhr, unadjusted hazards ratio; bmi, body mass index; cvd, cardiovascular disease; ihd, ischaemic heart disease; acs, acute coronary syndrome; nafld, non-alcoholic fatty liver disease; copd, chronic obstructive pulmonary disease. † adjusted risk ratios are minimally adjusted for age and sex. ‡ defined specifically as hyperlipidaemia. § defined specifically as hypertriglyceridaemia. ¶ defined specifically as hypercholesteraemia. † † adjusted for age but not sex. † † † metabolic risk factors (obesity, diabetes, hypertriglyceridemia and ht), with exposure groups split into groups of 0, 1, 2 and ≥3 risk factors. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint hr, hazard ratio; ci, confidence interval; dm, diabetes mellitus. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted august 24, 2020. . https://doi.org/10.1101/2020.08.21.20179234 doi: medrxiv preprint association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma diabetes increases the risk of hepatocellular carcinoma in the united states: a population based case control study metabolic syndrome and hepatocellular carcinoma risk metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the global burden of disease study global burden of hypertension and systolic blood pressure of at least 110 to 115mmhg global burden of cvd: focus on secondary prevention of cardiovascular disease the effects of metformin on the survival of colorectal cancer patients with diabetes mellitus metformin and reduced risk of cancer in diabetic patients metformin associated with lower cancer mortality in type 2 diabetes: zodiac-16. diabetes care metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial neoadjuvant chemotherapy with or without metformin in early breast cancer. -full text view -clinicaltrials.gov [internet the metformin active surveillance trial (mast) study -full text view -clinicaltrials.gov [internet a phase iii randomized trial of metformin vs placebo in early stage breast view of hepatocellular carcinoma: trends, risk, prevention and management the global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study diabetes poses a higher risk of hepatocellular carcinoma and mortality in patients with chronic hepatitis b: a population-based cohort study diabetes mellitus is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis b virus infection in china association between hepatocellular carcinoma and type 2 diabetes mellitus in chinese hepatitis b virus cirrhosis patients: a case-control study statin use and the risk of hepatocellular carcinoma in patients with chronic hepatitis b real-world effectiveness from the asia pacific rim liver consortium for hbv risk score for the prediction of hepatocellular carcinoma in chronic hepatitis b patients treated with oral antiviral therapy -pubmed radiologic nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with suppressed chronic hepatitis b the influence of metabolic syndrome on the risk of hepatocellular carcinoma in patients with chronic hepatitis b infection in mainland china stratification of hepatocellular carcinoma risk through modified fib-4 index in chronic hepatitis b patients on entecavir therapy effects of diabetes and glycemic control on risk of hepatocellular carcinoma after seroclearance of hepatitis b surface antigen hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis b virus infection insulin resistance and the risk of hepatocellular carcinoma in chronic hepatitis b patients prognosis of patients with chronic hepatitis b in france (2008-2013): a nationwide, observational and hospitalbased study liver cirrhosis stages and the incidence of hepatocellular carcinoma in chronic hepatitis b patients receiving antiviral therapy the impact of pnpla3 (rs738409 c>g) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis b patients. liver int increased risk of hepatocellular carcinoma in chronic hepatitis b patients with new onset diabetes: a nationwide cohort study type 2 diabetes: a risk factor for liver mortality and complications in hepatitis b cirrhosis patients determinants virological response to entecavir on the development of hepatocellular carcinoma in hepatitis b viral cirrhotic patients: comparison between compensated and decompensated cirrhosis diabetes mellitus, metabolic syndrome and obesity are not significant risk factors for hepatocellular carcinoma in an hbv-and hcv-endemic area of southern taiwan risk factors for hepatocellular carcinoma in a cohort infected with hepatitis b or c the impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis b/c infection: a follow-up study in taiwan body-mass index and progression of hepatitis b: a population-based cohort study in men type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection obesity and hepatocellular carcinoma in patients receiving entecavir for chronic hepatitis b thiazolidinediones reduce the risk of hepatocellular carcinoma and hepatic events in diabetic patients with chronic hepatitis b influence of metabolic risk factors on risk of hepatocellular carcinoma and liver-related death in men with chronic hepatitis b: a large cohort study adapting a clinical comorbidity index for use with icd-9-cm administrative databases all rights reserved. no reuse allowed without permission. perpetuity preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in key: cord-021959-1y67126b authors: madanoglu, melih title: state-of-the-art cost of capital in hospitality strategic management date: 2009-11-16 journal: handbook of hospitality strategic management doi: 10.1016/b978-0-08-045079-7.00006-5 sha: doc_id: 21959 cord_uid: 1y67126b nan making well-informed and effective capital investment decisions lies at the heart of any successful business organization. however, prior to investing in a project, an executive/manager should make three key estimates to ensure the viability of a business project: economic useful life of the asset, future cash flows that the project will generate, and the discount rate that properly accounts for the time value of the capital invested and compensates the investors for the risk they bear by investing in that project ( olsen et al. , 1998 ) . although the first two items are fairly challenging to estimate, the last one is even more challenging. in their book related to cost of capital, ogier et al. (2004) provided an excellent example which i would like to use to provide a practical introduction to this chapter. i take the liberty to modify the story in accordance with the needs of this chapter. imagine yourself at the edge of a river where your goal is to pass the river getting minimally wet in the least possible time. before making your move you need to turn to a local inhabitant who knows which stepping stones are safe, what the velocity and the viscosity of the water are, what the turning moments are, and what the probability of loose stones on the stream bed is. this situation is similar to the world of today's business investments. that is, executives need to make informed decisions about their investments and find out the minimum acceptable rate of return their shareholders expect as a compensation for the risks investors undertake. in addition, when an investment consists of both debt and equity, then the executives need to estimate the total cost of capital employed in this project to be able to pay their debt holders. this chapter intends to serve as a field guide or handbook of the cost of capital estimation for hospitality executives and practitioners. however, before getting into the practical aspects of cost of capital, some relevant concepts will be discussed from a theoretical perspective to better understand the background of this important topic. prior to getting into the core of the subject of estimating cost of capital, it is useful to define what risk is and describe the role it plays in investment decisions. in the hospitality field, risk is often defined as the variation in returns (probable outcomes) over the life of an investment project ( choi, 1999 ; olsen et al. , 1998 ) . the concept of risk is at the foundation of every firm as it seeks to compete in its business environment. financial theory states that shareholders face two types of risk: systematic and unsystematic. the examples of systematic risk could be changes in monetary and fiscal policies, the cost of energy, tax laws, and the demographics of the marketplace. finance scholars refer to the variability of a firm's stock returns that moves in unison with these macroeconomic influences as systematic, or stockholder, risk ( lubatkin and chatterjee, 1994 ) . stated differently, the level of a firm's systematic risk is determined by the degree of uncertainty associated with general economic forces and the responsiveness, or sensitivity, of a firm's returns to those forces ( helfat and teece, 1987 ) . in other words, these types of risk are external to the company and are outside of its control. however, a loss of a major customer as a result of its bankruptcy represents one source of unsystematic, or firmspecific risk (idiosyncratic or stakeholder risk). other sources of unsystematic risk include the death of a high-ranking executive, a fire at a production facility, and the sudden obsolescence of a critical product technology ( lubatkin and chatterjee, 1994 ) . unsystematic risk is a type of risk that can be eliminated by an individual investor by investing his/her funds in multiple companies ' stocks. the same rule may not be applied by company executives, since the success of a single project determines their tenure within their firms. the traditional financial theory looks at investment in securities from a portfolio perspective by assuming that investors are risk-averse and can eliminate the unsystematic risks (variance) associated with investing in any particular firm by holding a diversified portfolio of stocks ( markowitz, 1952 ( markowitz, , 1959 . markowitz pioneered the application of decision theory to investments by contending that portfolio optimization is characterized by a trade-off of the reward (expected return) of that individual security against portfolio risk. since the key aspect to that theory is the notion that a security's risk is the contribution to portfolio risk, rather than its own risk, it presumes that the only risks that matter to investors are those that are systematically associated with market-wide variance in returns ( lubatkin and schulze, 2003 ; rosenberg, 1981) . investors, it argues, should only be concerned about the impact that an alternative investment might have on the risk-return properties of their portfolio. however, the capital asset pricing model (capm) ( lintner, 1965 ; sharpe, 1964 ) (to be discussed in detail later) does not explicitly explain what criteria investors should use to select the alternative investments and how they should assess the risk features of these investments. moreover, the capm assumes that because investors can eliminate the risks they do not wish to bear, at relatively low costs to them, through diversification and other financial strategies, there is little need, therefore, for managers to engage in risk-management activities ( lubatkin and schulze, 2003 ) . in contrast, the field of strategic management is based on the premise that to gain competitive advantage, firms must make strategic, or hard-to-reverse, investments in competitive methods (portfolios of products and services) that create value for their shareholders, employees, and customers in ways that rivals will have difficulty imitating ( olsen et al ., 1998 ) . these investments enable the firms to protect their earnings from competitive pressure, and allow firms to increase the level of their future cash flow, while simultaneously reducing the uncertainty associated with them. the management of firmspecific risk lies at the heart of strategic management theories ( bettis, 1983 ; lubatkin and schulze, 2003 ) , and, from this perspective, management must work hard at avoiding investments that create additional levels of risk for the firm. bettis (1983) further affirms that the capm's emphasis on the equilibration of returns across firms (i.e., systematic risk) relegates to a secondary role strategy's central concern with managerial actions that seek to delay the calibration of returns (i.e., unsystematic risks). thus, the claim that systematic risk is paramount to the firm is undermined by the two arguable assumptions from portfolio theory: stockholders are fully diversified, and the capital markets operate without such imperfections as transaction costs and taxes. some stockholders, however, are not fully diversified, particularly the corporate managers, who have heavily invested, both financially and personally, in a single company ( vancil, 1987 ) . also, transaction costs, such as brokerage fees, act as a minor impediment, inhibiting other stockholders from completely eliminating unsystematic risk ( constantinides, 1986 ) . finally, taxes make all stockholders somewhat concerned with unsystematic risk (amit and wernerfelt, 1990; hayn, 1989 ) because interest on debt financing is tax deductible, thereby allowing firms to pass a portion of the cost of capital from their stockholders to the government. thus, firms can create value for their stockholders, within limits, by financing investments with debt rather than equity (kaplan, 1989; smith, 1990) . the limits are determined in part by the amount a firm is allowed to borrow and the terms of such debt, both of which are contingent upon the unsystematic variation in the firm's income streams. lubatkin and chatterjee (1994) contend that the debt markets favour firms with low unsystematic risk because they are less likely to default on their loans (this is particularly the case of the hospitality industry firms). in summary, the discussion of partially diversified stockholders, transaction costs, and leverage suggests that some stockholders may be concerned with unsystematic risk and factor it along with market risk to determine the value of a firm's stock (amit and wernerfelt, 1990; aron, 1988 ; lubatkin and schulze, 2003 ; marshall et al. , 1984 ) . cost of capital is defined as the rate of return a firm must earn on its investment projects in order to maintain its market value and continue attracting needed funds for its operations ( fields and kwansa, 1993 ; gitman, 1991 ) . consequently, a firm adds shareholder wealth when it undertakes the projects that generate a return higher than the cost of capital of the project. cost of capital is an anchor in firm valuation, project valuation, and capital investment decisions. cost of capital is generally referred to as weighted average cost of capital (wacc): where e is the market value of equity, d the market value of debt (and thus v ϭ e ϩ d ), t c the corporate tax rate, r e the cost of equity, and r d the cost of debt ( copeland et al. , 2000 ) . both of these items ( r d and r e ) are difficult to estimate and require some careful deliberations. the cost of debt is relatively simpler to calculate when a hypothetical firm issues bonds that are rated by the major bond-rating agencies such as standard & poor's and moody's. thus, these ratings may be used as a guide in computing the cost of debt. in addition, an investor may use the bond's yield to maturity or the rate of return that is in congruence with the rating of a bond. averaging the interest rates of long-term obligations of a firm is another method to calculate the cost of debt. the cost of debt estimation becomes difficult when a given firm has no bonds and no outstanding long-term debt. the cost of equity is difficult to estimate in its own right. first, cost of equity is generally estimated using historical data, which may be confounded by business cycles and abnormal • • • events affecting firm stock returns (e.g., fire in a hotel property) and industry returns (e.g., the terrorism events of 11 september 2001). second, although several methods were developed in the last 40 years, there is not one single method that produces consistent and reliable estimates. last, a hypothetical executive/ entrepreneur will face greater challenges as he/she needs to estimate the required rate of a single restaurant/hotel unit. the next section covers some of the common methods that are used by practitioners in the fields of financial and strategic management. cost of equity can be defined as the rate of return a firm must deliver to its shareholders who have foregone other investment opportunities and elected to invest in this particular company. however, cost of equity is a complex concept because firms do not promise paying a certain level of dividends and delivering a certain level of stock returns. thus, since there is no contractual agreement between the shareholders and the firm, the expected rate of return on invested equity is extremely challenging to estimate. fortunately, there are some models that can help us in tackling this challenging task. the next section will cover the major cost of equity models that gained prominence among practitioners and researchers in the last four decades. one of the early forward-looking methodologies is the dividend growth model (dgm) originally developed by gordon (1962) . it offers a very parsimonious method for estimating discount rate and thus accounts for risk. the dividend growth approach to cost of equity states that where, k e is the cost of common equity, dps the projected dividend per share, p the current market price per share, and g the projected dividend growth rate. the model assumes that over time, successful reinvestment of the value received by retained earnings will lead to growth and growing dividends. the approach suffers from oversimplification because firms vary greatly in their rate of dividend payout ( helfert, 2003 ) . this is due to the fact that common stockholders are the residual owners of all earnings not reserved for other obligations, and dividends paid are usually only a portion of the earnings accruing to common shares. the other major difficulty in applying this model lies in determining the specific dividend growth rate, which is based on future performance tempered by past experience. another key issue is that the model becomes unusable when a firm is not a dividend payer. the capm ( lintner, 1965 ; sharpe, 1964 ) is based on the assumption of a positive risk-return trade-off and asserts that the expected return of an asset is determined by three variables: β (a function of the stock's responsiveness to the overall movements in the market), the risk-free rate of return, and the expected market return ( fama and french, 1992 ) . the model assumes that investors are risk-averse and, when choosing among portfolios, they are only concerned about the mean and variance of their one-period investment return. this argument is, in essence, the cornerstone of the capm. the model can be stated as where, r m is the market return of stocks and securities, r f the risk-free rate, β the coefficient that measures the covariance of the risky asset with the market portfolio, and e ( r i ) the expected return of i stock. although the capm is touted for its relatively simple application, several other studies ( lakonishok and shapiro, 1986 ; reinganum, 1981 ) present evidence that the positive relationship between β and returns could not be demonstrated for the period of . particularly over the last two decades, even stronger evidence has been developed against the capm by fama and french (1992 , 1997 , and roll and ross (1994) . these researchers challenged the model by contending that it is difficult to find the right proxy for the market portfolio and that capm does not appear to accurately reflect the firm size in the cost of equity calculation, and that not all systematic risk factors are reflected in returns of the market portfolio. from the strategic management perspective, business executives face the following issues. implicit to the capm is the recommendation that managers should focus on managing their firm's overall market risk by focusing on β or the firm's • • • systematic risk and not be concerned with what strategists may focus on: firm-specific (unsystematic) risk. chatterjee et al. (1999) claim that herein lie two dilemmas: first, decreasing β requires managers to reduce investors ' exposure to macroeconomic uncertainties at a cost lower than what investors could transact on their own by diversifying their own portfolio; and second, to downplay the importance of firm-specific risk that not only is contrary to the strategic management field but also tempts corporate bankruptcy ( bettis, 1983 ) . therefore, an executive of a given company has to take into account the total risk of the project because, unlike investors holding stocks of multiple companies, the executive may not be able to diversify the risk of his/her company's investment by investing in multiple projects. another prominent cost of equity model is the arbitrage pricing theory (apt) developed by ross (1976) . the model states that actors other than β affect the systematic risk. the apt is based on the assumption that there are some major macroeconomic factors that influence security returns. the apt states that no matter how thoroughly investors diversify, they cannot avoid these factors. thus, investors will " price " these factors precisely because they are sources of risk that cannot be diversified away. that is, they will demand compensation in terms of expected return for holding securities exposed to these risks ( goetzmann, 1996 ) . although the model does not explicitly specify the risk factors, the apt depicts a world with many possible sources of risk and uncertainty, instead of seeking for equilibrium in which all investors hold the same portfolio. more formally, the apt is based on the assumption that there are some major macroeconomic factors that influence security returns. the apt states that no matter how thoroughly investors diversify, they cannot avoid these factors. thus, investors will " price " these factors precisely because they are the sources of risk that cannot be diversified away. that is, they will demand compensation in terms of expected return for holding securities exposed to these risks. just like the capm, this exposure is measured by a factor β ( goetzmann, 1996 ) . chen et al. (1986) managed to identify five macroeconomic factors that, in their view, explain the expected asset returns: the industrial production index, which is a measure of state of the economy based on the actual physical output; the shortterm interest rate, measured by the difference between the yield on treasury bills (tb) and the consumer price index (cpi); short-term inflation, measured by unexpected changes in cpi; long-term inflation, measured as the difference between the yield to maturity on long-and short-term u.s. government bonds; and default risk, measured by the difference between the yield to maturity on aaa-and baa-rated long-term corporate bonds (chen et al ., 1986; copeland et al. , 2000 ) . the apt describes a world in which investors behave intelligently by diversifying, but they may choose their own systematic profile of risk and return by selecting a portfolio with its own peculiar array of β s. the apt allows a world where occasional mispricings occur. investors constantly seek information about these mispricings and exploit them as they find them. in other words, the apt somewhat realistically reflects the world in which we live ( goetzmann, 1996 ) . although the apt provides the benefits explained above, these benefits come with some drawbacks. the apt demands that investors perceive the risk sources, and that they reasonably estimate factor sensitivities. in fact, even professionals and academics are yet to agree on the identity of the risk factors, and the more β s they have to estimate, the more statistical noise they have to put up with. last, this model does not offer much guidance to business executives as it focuses primarily on investors. one of the major proponents of the capm fama and french (1993) found that the relationship between average returns and β was flat and there was a strong size effect on stock returns. as a result, they developed a model that has gained popularity in recent years among the scholars and practitioners in the hospitality industry. the fama-french (ff) model is a multifactor model that argues that factors other than the movement of the market and the risk-free rate impact security prices. the ff is a multiple regression model that incorporates both size and financial distress in the regression equation. the ff model is typically stated as where β is the coefficient that measures the covariance of the risky asset with the market portfolio, r m the market return, r f , the risk-free rate, s the slope coefficient, and small minus big (smb) the difference between the returns on portfolios of small and big company stocks (below or above the nyse median), h the slope coefficient, and high minus low (hml) the difference between the returns on portfolios of high-and low-be/me (book equity/market equity) stocks (above and below the 0.7 and 0.3 fractiles of be/me) ( fama and french, 1993 ) . the size factor is denoted as smb premium where size is measured by market capitalization. smb is the average return on three small portfolios minus the average return on three big portfolios as described by fama and french (1993) . hml is the average return on two value portfolios minus the average return on two growth portfolios ( fama and french, 1993 ) . high be/me (value) stocks are associated with distress that produces persistently low earnings on book equity which result in low stock prices. in practice, the ff model shows that investors holding stocks of small capitalization companies and firms with high bookto-market value ratios ( annin, 1997 ) need to be compensated for the additional risk they are bearing. the size argument is supported by barad (2001) who reports that small stocks have outperformed their larger counterparts by an average of 5.4% over the last 75 years . however, fama and french (1993) find that the book-to-market factor (hml) produces an average premium of 0.40% per month ( t ϭ 2.91) for the 1963-1990 period, which, in the authors ' view, is large both in practical and statistical terms. the starting point for selecting the best method for the estimation of the cost of equity can be achieved by reviewing the relevant studies undertaken in the fields of hospitality and tourism. fields and kwansa (1993) conducted the first study that directly looked into the cost of equity and suggested the use of pureplay technique for estimating the cost of equity for the divisions of a diversified firm. later, several studies investigated how macroeconomic variables affect security returns in the hospitality industry (hotels and restaurants). the first study was conducted by barrows and naka (1994) . their study encompassed the 27-year period between 1965 and 1991 and employed five factors that were slightly different than the five factors of chen et al . (1986) . barrows and naka postulated that the return of the stocks is a function of the following five factors: where einf is the expected inflation, m1 the money supply, conn the domestic consumption, term the term structure of interest rates, and ip the industrial production. the results revealed that none of the macroeconomic factors was significant in explaining the variance of u.s. hotel stocks at 0.05 level and the factors accounted for the 7.8% of the variance in the lodging stocks. however, einf, m1, and conn had significant effect on the variation of the stock returns in the u.s. restaurant industry. in terms of the signs of the β coefficients einf had a negative whereas m1 and conn had a positive relationship with the restaurant stock returns . the postulated model explained 12% of the variance in the restaurant stocks. the authors cautioned that the results should be interpreted with care due to the small sample size of both restaurant and hotel portfolios, which were represented by five and three stocks, respectively. the second study was undertaken by chen et al. (2005) who used hotel stocks listed on taiwan stock exchange. the macroeconomic variables included in their study were ip, cpi, unemployment rate (uep), money supply (m2), 10-year government bond yield (lgb), and 3-month tb rate. these variables were used in the following way: cpi was utilized to estimate einf, and lgb, and tb were used for the computation of the yield spread (spd). based on the six time-series data the authors arrived at the common five macroeconomic variables which were predominantly used in the literature, namely, ip (change in ip), einf uep (change in unemployment rate), m2 (change in money supply), and spd (rate of the yield spread). these five variables explained merely 8% of the variation in hotel stock returns while only two of these variables were significant at the 0.05 level (m2 and uep). the regression coefficient of change in money supply had a positive relationship with hotel stock returns, whereas the relationship between change in uep and lodging returns was negative. in madanoglu and olsen (2005) proposed a conceptual framework that called for the inclusion of some of the intangible variables into the cost of equity estimation in the lodging industry. some of these variables were human capital, brand, technology, and safety and security. it is common knowledge that these variables were relevant for the lodging industry; however, there exists no time-series data to include them in the cost of equity estimations. publicly traded multinational lodging companies tend to differ on some key points regarding how assets are treated on their balance sheets. many of these companies do not actually own assets and produce their future cash flows from management contracts or franchise agreements. in many cases, they may also lease hotels or restaurants and the leases do not appear on their balance sheets. instead, these firms hold an equity position in a different company that holds these leases. therefore, it is almost unfeasible to properly assess the book value of the hospitality firms, which confounds the application of the ff model. sheel (1995) was the first researcher in the hospitality industry to point out that capm does not seem to meet the industry needs and called for further research into industry-specific factors. in the mainstream financial economics, downe (2000) argued that in a world of increasing returns, risk cannot be considered a function of only systematic factors, and thus β . he pointed out that the position of the firm in the industry, as well as the nature of the industry itself become a risk factor. thus, firms with a dominant position in the industry that succeed to adapt to the complexities of the business environment, will have a different risk profile than their competitors. this argument is particularly well fitting in the context of the hospitality industry where companies such as mcdonald's and marriott may demonstrate a different risk profile based on their market share in their segments. as for ff factors, professionals in the lodging industry are sceptical about such measures as the book-to-market value ratio (hml). some hospitality industry experts argue that hml is an inappropriate measure for the industry and attribute it to the fact that the difference between the firms whose value is captured by the assets they own and the firms whose value is derived from their intangible assets is not as distinct as in some manufacturing firms. while jagannathan and wang's study (1996) added a human capital variable to their cost of equity capital model, it measured human capital effects from the macroeconomic perspective as opposed to a micro level where most hotel firms operate. in other words, the overall labour index may not properly reflect the state of the human capital in the hospitality industry. as fama and french (1993) stated, their work (ff model) leaves many open questions. the most important missing piece of the puzzle is that fama and french (1993) have not shown how the size and book-to-market factors in security returns are driven by the stochastic behaviour of firm earnings. this implies that it is not yet known how firm fundamentals such as profitability or growth produce common variation in returns associated with size and be/me factors and this variation is not captured by the market return itself. these authors further query whether specific fundamentals can be identified as state variables (variables that describe variation in the investment opportunity set) and these variables are independent of the market and carry a different premium than general market risk. this question is of utmost importance for lodging industry executives who are aiming to identify the major drivers of their companies ' stock returns in their effort to create value for their stockholders. in their current state, the cost of equity models are far from satisfying the needs of the hospitality industry. as fama and french (1997) pointed out, the cost of equity estimates yielded by these models are distressingly imprecise. standard errors of more than 3% per year were typical when the capm and ff models were used to estimate industry costs of equity in their study ( fama and french, 1997 ) . they stated that large standard errors are driven primarily by uncertainty about true factor risk premiums. since the hospitality industry is really the aggregate of individual units that all have their own unique business environments and return on equity structures, this means that the standard errors, and thus, cost of equity capital on a per-company, single-unit (a hotel property or a restaurant) basis, or for a new project will be even more imprecise. therefore, the risk determinants of cost of equity and risk factor loadings for individual operating units will be even more difficult to estimate. thus, it is very important to consider the purpose for which the cost of equity is estimated (e.g., a single project, business division, or an entire corporation). particularly, in the case of single project cost of equity estimations there might be several factors that need to be considered before arriving at the proper discount rate of the project. these factors might be location of the project, local/regional competition, political risk, credit risk, and other risk idiosyncratic to a given project. consequently, as ogier et al. (2004) suggest when estimating a cost of equity for a given project the risk of the project will be much more important than the risk level of the corporation making the investment. in other words, when marriott corporation makes a capital investment decision in nairobi, kenya, the marriott corporation executives will be much more concerned with the risks surrounding that project. unlike cost of equity, cost of debt does not require the use of sophisticated theoretical models. rather, cost of debt is simply the rate at which a given company can borrow capital from a lender (e.g., bank) or the rate at which the aforementioned company can issue bonds. some experts caution that the • • • promised and the expected yields of debt are two different concepts. in other words, when a firm makes contracted debt payments on time it meets " the promised yield " to its lender. however, in reality, there is always a possibility for default and thus the difference between the promised yield and the probability for default equals the expected yield. the expected yield can be regarded as true cost of debt since it is more realistic. although many textbooks calculate the cost of debt as promised yield, it should be noted that expected yield is more meaningful since it includes not only the systematic risk of the market but also the firm-specific risk of a given firm. another challenge for calculating the cost of debt might occur when a firm uses multiple debt instruments (e.g., bank loans, commercial papers, bonds). in this case, it may be fruitful to average the rate of these instruments based on their weight in the debt portfolio. however, an easier and more simplistic approach would be to use the " generic long-term debt " rate which can be calculated from the current rate of a company's bond or current rate at which the company can borrow a longterm loan ( ogier et al ., 2004 ) . last, to estimate the cost of debt, the issue of tax shield should be given a close consideration. for instance, although the majority of the finance textbooks use 35 or 40% as an average for corporate tax rate in the united states, it is common occurrence to observe companies whose effective corporate tax rate is often lower than the statutory rate. here, an executive should assess the situation and decide whether the effective tax rate trend is expected to continue to be below the statutory corporate tax rate in the long term. if that is the case, then he/she should use the effective tax rate in calculating the cost of debt. however, if a low effective tax rate is a short-term occurrence, then a given firm should use the statutory corporate tax rate instead ( ogier et al ., 2004 ) . hospitality industry is part of the overall service sector and is dependent on human capital in order to maintain and grow its operations. in an increasingly competitive environment, the human factor becomes one of the keys in creating sustainable competitive advantage. therefore, murphy (2003) stated that the hospitality industry should learn to view its employees from a new paradigm that human capital is a strategic intangible asset (knowledge, experience, skills, etc.). this implies that, like other assets, it is an important determinant of firm value. however, studies have concluded that " the research of human resources expenditures " is in its infancy and is seriously hampered by the absence of publicly disclosed corporate data on human resources ( lev, 2001 ) . caroll and sikich (1999) argued that keeping track of at least a 3-year history of labour costs would serve to identify the dollar value of " premium " labour-related costs, which could be thought of as all labour/benefit costs above federally mandated minimum wage. other techniques proposed by the authors were (1) to design a scoring system that illustrates productivity versus both baseline and premium labour/benefit costs by departments, and (2) to establish metrics to determine a productivity level for guest experience standards, facilities standards, and targeted revenue improvements on a department-by-department basis. bloxham (2003) advocated adjustments to certain human resource expenditures to capitalize them over the time of the investment. in that approach, one-time human resources costs are amortized and capitalized in the value creation equation in an effort to demonstrate that human capital investments go beyond being a cost item in the firms ' operations. these costs can include recruiting, interviewing, and hiring costs; one-time hiring bonuses and relocation expenses; and training costs. the costs are capitalized and amortized over the average employee tenure with the company. in this case, if employee turnover is high, these costs would be amortized over a shorter time period (thus the costs will be higher), whereas the longer tenure of the workforce will enable the firm to spread the costs over a longer period of time. kalafut and low (2001) reported that in a study of the airline industry conducted by cap gemini ernst & young's center for business innovation (cbi), the employee category was the single greatest value driver that had an impact on the firm's market value. the employee factor had a positive correlation of 0.68 with the firm value. thus, kalafut and low (2001) conclude that in the aggregate, quality and the talent of the workforce, quality of labour management relations, and diversity are critically important in the value creation process of the airline companies. the arguments above can be justified on the grounds that higher-quality human resources decrease labour turnover and increase employee productivity. this results in better organizational performance that results in stabilization of cash flows which in turn decreases the uncertainty of firms ' stock returns. therefore, one would expect that hospitality firms that have institutionalized quality human resource management practices would achieve a more realistic cost of equity estimates that reflect the lower risk associated with these practices. although definitions of the concept of brand differ across the professional and trade literature, the underlying notion is that of a distinctive name with which the customer has a higher level of awareness and a willingness to pay a higher-thanotherwise average price or make a higher-than-otherwise purchase frequency ( barth et al ., 1998 ) . a brand is the product or service of a particular supplier which is differentiated by its name and perceived expectations on the part of the consumer. brands are important and valuable because they provide a " certainty " as to future cash flows ( murphy, 1990 ) . however, since the task of estimating brand value is yet an improbable one, its value is not specifically reflected on the company's balance sheet. yet, the lodging industry has made much of the importance of the value of the brand but has not been able to unequivocally substantiate the role of the brand in reducing the variance in firm cash flows, and thus contributing to lower cost of capital for the firm. srivastava et al. (1998) provided an analytical example of how successful market-based assets (the term authors use in lieu of intangibles) lower costs by building superior relationships with customers, enable firms to attain price premiums, and generate competitive barriers (via customer loyalty and switching costs). all these factors lead to the conclusion that a strong brand reduces the uncertainty pertaining to the future cash flows which in turn decreases the required return by the investors for the risk they bear by investing in a particular firm. in attempts to value the brand in the manufacturing industries, the use of the following methods has been cited by murphy (1990) : • valuation based on the aggregate cost of all marketing, advertising, and research and development expenditures devoted to the brand over a stipulated period. • valuation based on premium pricing of a branded product over a non-branded product. • valuation at market value. • valuation based on various consumer-related factors such as esteem, recognition, or awareness. • valuation based on future earning potential discounted to present-day value. in further analysis, the investigators rejected these methods because, if indeed, brand values were the function of its cost of development, then failed brands would be attributed high values. in addition, brand valuation based solely on the consumer esteem or awareness factor would bear no relationship to commercial reality ( murphy, 1990 ) . in an effort to link the firm's security returns with brand value, simon and sullivan (1993) proposed a technique to estimate the firm's brand equity based on its value. this was done by estimating the cost of tangible assets and then subtracting it from the market capitalization of the firm to obtain the value of intangible assets. as a second step, the researchers tried to break down the intangible assets into brand value and nonbrand value components. the authors utilized the aaker and jacobson (1994) equitrend brand quality measure to evaluate the quality of 100 major brands. they examined associations between measures of brand quality and stock returns and reported that the relationship is positive. according to murphy (1990) , the only logical and consistent way to develop a multiple for brand profit was through the brand strength concept. brand strength is a composite of six weighted factors: leadership, stability, market, trend, support, and protection. the brand is scored on each of these factors according to different weightings and the resultant total known as " brand strength score. " a further addition to the brand strength concept came from prasad and dev (2000) who developed a hypothetical brand equity index via customer ratings of the brand using five key brand attributes in two sets of indicators-brand performance and brand awareness. brand performance was measured by overall satisfaction with the product or service, return intent, price-value perception, and brand preference, while brand awareness was measured as top-of-mind brand recall. olsen (1996) proposed brand-related value drivers specific to the lodging industry such as brand dilution and brand sincerity ratio. brand dilution is related to the question of how many new corporate sub-brands must be introduced in order to maintain growth, whereas, brand duration deals with what percentage of hotels in the portfolio currently meet the brand standards or promise. as a result, it is argued that hospitality companies that possess higher-brand strength will be able to achieve a lower cost of equity capital. according to connolly (1999) , one of the greatest issues plaguing the advancement of technology in the hospitality industry is the difficulty of calculating return on investment. until recently, most technology investment decisions have been considered using a support or utility mentality that stems from a manufacturing paradigm. current policies rely more on faith than on a rational business assessment. as a result, the hotel industry is perceived to be lagging behind the rival industries in the use of technology ( sangster, 2001 ) . in part, this is attributed to the fragmented nature of the hotel business itself; however, it is also believed to be closely related to hoteliers ' lack of experience and understanding in technology investments ( sangster, 2001 ) . connolly further argued that " today's financial models are inadequate for estimating the financial benefits for most of the technology projects under consideration. while the hospitality industry has disciplined models and sufficient history to determine the financial gains or success of opening a new property in a given city, it lacks the same rigorous models and historical data for technology, especially since each technology projects are unique. although this problem is not specific to the hospitality industry, it is particularly problematic since the industry tends to be technologically conservative and unwilling to adopt new technology applications based on the promises of their long-term merits especially if it cannot quantify the results and calculate a defined payback period. when uncertainty surrounds the investment, when the timing of the cash flows is unpredictable, and when the investment is perceived as risky, owners and investors will most likely channel their investment capital to projects with more certain returns and minimal risk. thus, under this thinking, technology will always take a back seat to other organizational priorities and initiatives. efforts must be made to change this thinking and to develop financial models that can accurately predict and capture the financial benefits derived from technology ( connolly, 1999; p. iii) . " although there are no hard and fast rules to facilitate the valuations of technology investments, it is common knowledge that technology is transforming the way business is conducted in the lodging industry. particularly the surge in internet usage in the early years of the new millennium brought about the issue of capacity control for hotel room inventory holders. therefore, firms that are more adaptive to utilize technology to market and sell their perishable product (hotel rooms) may accomplish a lower variation in their future cash flows, since they are able to retain greater control over pricing. the author would like to acknowledge the fact that the body of literature does not offer a direct causal relationship between the cost of equity capital and the technology utilization. however, based on the arguments discussed above, the author contends that firms that invest in technology wisely may achieve a higher average daily rate or revpar in their properties which in turn will lead to a decrease in the variance in firm's cash flows. thus, better utilization of information technology can possibly reduce the uncertainty surrounding the future earnings of the firm. as a result, capital markets will assign a lower risk premium to hospitality firms that successfully utilize and deploy technology into their operations. guest safety and security topics in the lodging industry can vary from building safety codes and bacterial contamination of hotel whirlpools to restaurant food safety and hotel crime statistics ( olsen and merna, 1991 ) . the need for greater commitment to safety and security for the hospitality industry became evident in 1990 after the san francisco earthquake and hurricane hugo occurred ( olsen and merna, 1991 ) . the culmination of these events and all the other events sparked an effort by the hotel industry to manage the risk and liability related to guest safety and security. ray ellis, the director of risk management and operations in the american hotel & motel association (at that time in 1991), contended that after the end of the gulf war the benefits of increased security for the industry go far beyond intangibles such as peace of mind ( jesitus, 1991 ) . ellis stressed that improved safety and security will significantly decrease the insurance premiums of the properties, and thus enable the companies to have more resources to invest in their operations. although ellis said that chances of terrorist attacks on the united states post gulf war were fairly remote, he warned that the hotels, particularly those serving international markets, be most wary of arson and bomb threats. the international hotel and restaurant association in 1995 identified safety and security as one of the major forces driving change in the global hospitality industry ( olsen, 1995 ) . with the destruction of the world trade center in 2001, and subsequent terrorist attacks in bali and kenya, it is clear that force has emerged now as a major risk factor for all tourismrelated enterprises. in february 2003, the federal bureau of investigation (fbi) alerted its law enforcement partners that " soft targets, " such as hotels, can be subject to terrorist attacks ( arena et al. , 2003 ) . this report simply reaffirms the argument proposed by olsen (1995 olsen ( , 2000 that lodging properties which are situated in an area exposed to terrorist attacks, should factor that risk into their cost of capital estimates. therefore, lodging property executives should apply this risk factor into their future capital investment decisions. in addition, outbreaks related to food-borne diseases, infectious bacteria occurrences on cruise ships, increased crime, and the growing threats of human immunodeficiency virus (hiv), and other viral infections such as severe acute respiratory syndrome (sars) have created a significant challenge for hospitality managers worldwide. these must be considered as important risk variables that will no doubt have an impact on the estimates of cost of capital. although the factors mentioned above are critical in estimating the cost of capital of a given project, there are no methods that can quantify these factors and apply them to the cost of equity models. however, executives are advised to consider these industryspecific risk factors before making a capital investment decision. the models covered thus far do not provide any guidance for estimating the cost of equity in a global setting or multinational projects. in order to fill this void, academics and practitioners developed adjustment models to account for differences in cost of equity among markets in developing and emerging countries. the adjustment models are primarily concerned with whether the emerging markets are segmented or integrated with the world markets. that is, in a completely segmented market, assets will be priced based on local market return. the local expected return is a product of the local β times and the local market risk premium (mrp) ( bekaert and harvey, 2002 ) . bekaert and harvey (2002) developed a modified model after researching 18 emerging markets for the pre-1990 and post-1990 periods and reported that the correlation of the emerging markets with the morgan stanley capital international (msci) world index increased noticeably. for instance, turkey is one of the countries whose market correlation with msci world index increased from less than 0.10 to more than 0.35. based on this, turkey may be considered an integrated capital market where the expected return is determined by the β with respect to the world market portfolio multiplied by the world risk premium. this is the core argument of the bekaert-harvey mixture model ( bekaert and harvey, 2002 ) . in cases when integrated markets assumption does not apply, investment banks and business advisory firms use a method called " the sovereign spread model (goldman model). " this is conducted by regressing an individual stock against the standard & poor's 500 stock price index returns to obtain the risk premium. then, an additional " factor " is added which is called the " sovereign spread " (ss). this spread between respective country's lgb for bonds denominated in u.s. dollars and the u.s. treasury bond yield is " added in. " the bond spread serves as a tool to increase an " unreasonably low " country risk premium ( harvey, 2005 ) . this section offers a practical example for managers to estimate the wacc of their projects. in addition, this section breaks down the wacc into its respective components in order to assist executives in the capital investment decisions. the major components of the wacc estimations are a firm's stock return, market return, risk-free rate, regression coefficients ( β , s , and h ), smb, hml and equity market risk premium (emrp) (which is r m ϫ r f ), capital structure (proportion of debt and equity), corporate tax rate, and cost of borrowed debt. if you are an executive of a company that is not publicly traded, you have two options to estimate the cost of equity. you can either use the industry average for cost of equity or locate two or three comparable firms that compete in the same line of business and estimate their cost of equity. however, even if you are an executive of a large restaurant corporation that is traded publicly, it is still recommended that you estimate the cost of equity for the entire restaurant industry because the standard error of regression coefficients for a single firm is fairly high, which decreases the reliability of these coefficients. my past research experience has showed me that at times using a single firm may create a situation in which cost of equity cannot be even estimated. more often than not, i obtained distressing results when running a regression for small-or medium-size hospitality firms. as a result, in the practical example, i will estimate the restaurant industry's cost of equity. since the cost of equity calculation process may be a fairly complex process for someone who is not familiar with data analysis, i will offer a step-by-step procedure, which should better clarify this process: step 1: obtaining a 5-year monthly stock return for your company/industry and the market • • • ideally, you need 5 years of monthly stock return data for your firm and the 5-year market return. the issue of selecting the best index of all traded assets in the world is a very challenging and sometimes a controversial issue. based on seminal • • • studies in financial management, the market index that yields most reliable results in the united states is center of research in security prices value weight (crspvw) index housed at the university of chicago. both your company's stock and market return should be used as excess return (i.e., return less risk-free rate which is 1-month tb rate) in order to measure the cost of equity in real units (i.e., after accounting for inflation). for reasons mentioned before, i will be estimating the u.s. restaurant industry's cost of equity and leave the decision to restaurant industry executives to adjust this value to their specific projects at hand. in order to be able to observe the accuracy of cost of equity models, we estimate the restaurant industry cost of equity by using the capm and ff model. the observation period of this example is between 2000 and 2004. the reason for not selecting a longer observation period is that the values of β and other variables become unstable over extended periods. the sample is developed from the nation's restaurant news (nrn) index, which entails 81 restaurant firms. in cases when executives are not familiar with building stock portfolios, they can alternatively use monthly returns of hospitality indices for lodging and restaurant industries from data providers such as yahoo! finance, wall street journal, or industry publications such as nrn. step 2: estimating β and fama-french factor coefficients • • • the capm's β can be computed by regressing excess stock return of a firm over the excess market return. the monthly returns for ff factors (smb and hml) can be retrieved from eventus database housed in the wharton school at the university of pennsylvania or from kenneth french's website at dartmouth college. by regressing monthly smb and hml returns on market returns you can obtain " s " and " h " coefficients that can later be inserted into the equation to estimate the cost of equity. in our practical example, the results indicate that the ff model explains more than half (51.8%) of the variation in the returns of the nrn index. in addition, the ff model results in a significant r 2 change over the capm, which showed that the two ff variables (smb and hml) explained some extra variance over and above the capm which accounted for 19.6% of the variation in the restaurant industry stock returns. the analysis at the variable level indicates that the market index variable ( β ) and the hml are significant at 0.01 level (see table 6 .1 ). however, the smb was not significant at the 0.05 level, which means that the size factor does not affect the restaurant industry stock returns while controlling for β and hml. in practice, this means that restaurant industry portfolio behaves as a large company stock, and therefore there is no size premium when considering the overall cost of equity for the restaurant industry. it should be remembered that if you are an executive of a small restaurant company there is a high possibility that your stock returns will have a size premium. step 3: the risk-free rate, market, size and distress premiums • • • there are certain rules of thumb that executives should be aware of before inserting the regression coefficients into the cost of equity calculation. first, it should be pointed out that there are two risk-free rates ( r f ) in the capm and ff models. the first r f is used in order to demonstrate the level of risk-free rate that a firm needs to exceed to compensate its investors for the risk they undertake. the second r f should ideally match the life of an asset. in other words, if the asset in this project is expected to last at least 10 years, then a given investor/executive should use a 10-year government bond as its risk-free rate to obtain the mrp ( r m ϫ r f ). another important issue is calculating market, size and distress premiums. executives/investors may often face challenges when the 5-year mrp (which equals r m ϫ r f ) is negative or extremely low, or when size premium (smb) and distress premium (hml) figures are negative. in these cases, i would recommend that executives/investors use the longterm equity premium ( r m ϫ r f ) figure of 5% ( siegel, 1998 ) , 1992-2001, 1993-2002, 1994-2003 , and so on) until 2006 and verified that in all instances smb, and hml premiums were positive. step 4: solving cost of equity equation • • • since the market index (vwcrsp) has a very low return (0.21%) for the 5-year period, i will use the long-term equity premium of 5% ( siegel, 1998 ) . next, by using the obtained regression coefficients in table 6 .1 , the regression equations provide the following results: as it can be seen from the results above, the restaurant industry cost of equity is considerably higher when estimated by using the ff model. in basic terms, this means that a hypothetical investor will expect a return of 18% from the u.s. restaurant industry in order to invest his/her funds in the u.s. restaurant portfolio. however, if a restaurant executive believes that 18% is a fairly high rate of return and his/her restaurant company does not have the same risk profile as the overall u.s. restaurant industry, he/she may elect to use the average of the capm and ff estimates, which is around 12%. next, a restaurant executive may adjust the rate of his/ her firm's project by considering whether the project will be riskier than the restaurant industry's expected return. here one should consider factors such as competition, life of the project, and the events that may have an impact on the risk of the project by influencing forces driving change in firm's external (e.g., economic, political, technological) and internal (e.g., industry, local) environment. the next step in estimating the cost of capital is to estimate the cost of debt. unlike cost of equity, cost of debt does not require consideration of the average cost of debt for the hospitality industry. this is because in simple terms, cost of debt denotes an interest rate at which a given company can borrow. therefore, a given company can calculate the cost of debt for a given project in a relatively simple manner. the situation is little more complex in cases when a corporation has multiple projects to invest in and has to estimate its corporate cost of debt. this is because some of the projects may be expansion projects that are already financed by loans obtained in the past. consequently, executives need to average out the interest rate of the outstanding debt related to this project and also consider the interest rate at which the company can borrow new funds. in this particular example, we will assume that a hypothetical company plans to issue bonds which mature in 10 years and will also secure a 10-year loan to finance a portion of the project. in this scenario, we assume that both the bond issuance and the loan will have equal contribution to the funding of the project (e.g., 50% each). let us assume that the hypothetical company in this example issues 10-year bonds whose expected yield-to-maturity is 8%. this rate is assumed based on the present bond rating of this company. we also assume that the rate of a 10-year bank loan is 7% and the corporate tax rate 38%. thus, the cost of debt can be calculated as follows: before entering the values from previous sections we assume that the current project will be financed with 60% equity and 40% debt. we use the average cost of equity estimate (12.25%) and the cost of debt (4.65%) we obtained before. consequently, the weighted cost of capital for this project can be calculated as follows: . % 12 25 0 6 4 65 0 4 7 5 2 16 9 68 it should be noted that the executive of this hypothetical firm needs to make adjustments to this project if the project carries any specific risk such as political risk, divisional risk (if the firm has multiple divisions), risk of early termination, stiff competition, and so on. this section considers a case when the cost of equity needs to be estimated for an international project. here i use a hypothetical scenario where a thai investor plans to make a hotel in line with the suggestions made by annin (1997) , and barad and mcdowell (2002) , a minimum of 36 months ' stock market trading is the criterion for a hospitality firm to be included in the turkish tourism index. in addition, crspwv index is used as a market portfolio index for the united states. this is in congruence with the previous seminal studies related to asset pricing models ( fama and french, 1992 , 1997 jaganathan and wang, 1996 ) . however, imkb ulusal 100 index is utilized as a market portfolio for turkey. β is computed by regressing excess return of the four seasons and turkish tourism index over the excess market return; therefore, both variables are analysed in real units (e.g., after subtracting inflation). excess market return (mrp) for the united states is computed by subtracting 1-month tb rate from the monthly vwcrsp index return. the mrp for turkey is calculated by subtracting the turkish government's tb from the monthly ise ulusal 100 index return. the data for the five apt variables are obtained from global insight database. the apt variables are calculated as in chen et al. (1986) . einf is estimated following the method of fama and gibbons (1984) . country risk premium is adapted from aswath damodaran at new york university. damodaran (2006) explains the estimation procedure as " to estimate the long term country risk premium, i start with the country rating (from moody's: www.moodys.com ) and estimate the default spread for that rating (us corporate and country bonds) over the treasury bond rate. this becomes a measure of the added country risk premium for that country. i add this default spread to the historical risk premium for a mature equity market (estimated from us historical data) to estimate the total risk premium. " both direct and indirect approaches are used to estimate the expected return (indirect and direct) of an investment. in this method, i first compute the expected rate of return for the u.s. stock (in this case four seasons) by using the average estimates for the capm and apt. then i adjust for country risks of turkey and thailand based on moody's country risk ratings as reported by damodaran (2006) . this method assumes that the turkish stock market is integrated and thus using the u.s. market indices to estimate the cost of equity for four seasons is equivalent to using ulusal 100 market index for the turkish tourism portfolio. first, i run a regression of the monthly returns of four seasons over the crspvw return for the 2001-2005 period. the results show that the β for four seasons is 1.6. next, the 5-year annualized return for the crsp was calculated in order to estimate the mrp. the 5-year historical return for crsp was 4.3%. the riskfree rate for the 2001-2005 period was 2.16%. as a result, the cost of equity estimate based on the capm for four seasons is as follows: . % ϭ ϩ ϫ ϫ ϭ 2 1 1 6 4 3 2 1 5 4 in an effort to have less biased estimates, i also use the five apt variables (chen et al. , 1986) to calculate the expected return for four seasons. the results reveal that, among the five apt variables, only the default risk variable (upr) is significant at the 0.05 level. however, it is not feasible to use this variable to estimate the expected return because the regression coefficient for upr is a negative number. as a result, the four seasons is likely to have a negative expected return based on the apt. as a consequence, i elect not to use the apt results in the final stage of the direct approach, since the results of the apt are in conflict with the contemporary financial theories. therefore, i use the capm's estimate of 5.4% and adjust this estimate with the country risk of turkey and thailand. according to damodaran (2006) , the historical risk premium for the united states is 4.80%. turkey's country risk premium is 5.60% above the united states value and that for thailand is 1.65% above the risk premium for the united states. this denotes that turkey's country risk premium is 3.95% over that of thailand. these figures result in an expected return of 9.35% (5.4 ϩ 3.95%) for the thai entrepreneur who is undertaking an equity investment in a hotel in turkey. in the direct approach, i estimate the nominal required rate of return for the portfolio of turkish tourism and hospitality stocks. as a next step, i adjust for the sovereign spreads of turkey and thailand as it is assumed that the thai investor will repatriate the returns from an investment to his/her home country. in this method, i regress the monthly return of the turkish tourism index over the return of the ise. the β for the tourism index was merely 0.17. the 5-year average for the risk-free rate (turkish government's tb) for the 2001-2005 period was 46.4%. the annualized return of the market index (ise) for the 2001-2005 period was 37.7%. the expected return for the tourism portfolio was calculated by applying the capm and it provided the following results: . % ϭ ϩ ϫ ϫ ϭ ϩ ϭ 37 7 0 17 46 4 37 7 37 7 1 5 39 2 the next step entails the addition of the sovereign spread between thailand and turkey to arrive at the estimate for the cost of equity capital for the thai investor. the sovereign spreads are obtained from fuentes and godoy (2005) . the spread for turkey was 11.875% and that of thailand 7.750%. based on these figures, the cost of equity for the direct approach was 43.3% (39.2 ϩ 4.1%). as it can be seen from both the examples of cost of equity estimation (the united states and international), the expected returns (costs of equity) varied widely. in the example of united states, the use of the capm resulted in a cost of equity that was fairly low (less than 6%). it is worth asking, would a given investor invest in a u.s. restaurant portfolio of stocks for less than 6% a year? the answer would probably be " no. " however, if one elects to use ff as its main cost of equity model then the possibility of obtaining more relevant results is likely to increase. as it can be seen in this example, the cost of equity by using the ff model yielded a fairly logical return which far exceeds the historical equity premium for the united states. for the international example, one of the main reasons for the stark difference in cost of equity estimates using the two approaches (direct and indirect) is the high historical inflation in turkey. this is demonstrated by the gap in the tb rates for this country (82.3% for 2001 and 16.3% for 2005). hence, if a hypothetical investor elects to use the " going-rate (16.3%) in 2005 then the new expected return for the turkish tourism portfolio would be at least twice lower than the original estimate of 43.3%. another challenge in the direct approach for international cost of equity estimations is the low β estimate for the turkish tourism portfolio (0.17). does this mean that the tourism portfolio is five times less risky than the overall ise index? what if the real risk of tourism stocks is twice higher than that of the market? (this is quite likely as the β for four seasons in the united states was 1.6.) if that is the case, then the thai investor needs to require a rate of return that is more than 50% in thai currency. how can the investor hedge his investments against the large swings in the cost of equity estimates? as the results indicated thus far, cost of equity estimations for hospitality investments in emerging and developed markets are beset with uncertainty. the main shortcomings stem from the challenge of applying the seminal models such as the capm, ff, and the apt. the second set of challenges arises when countries such as turkey tend to have high historical rates of inflation but now are entering a more stabilized period of fiscal reforms. thus, should an investor use the historical data or try to forecast the future interest rates in turkey? although the practical examples provided some answers to these questions, few more questions are left for future research. hence, i suggest two interim solutions for this cost of equity conundrum in the emerging markets: (1) the investors and academics should either solely focus on future cash flows of the project, or (2) use simulations such as monte carlo in order to create multiple scenarios that approximate the investment realities of the emerging markets. otherwise, the expected return remains to be a " gut feeling " estimate for foreign investors in emerging markets. the financial information content of perceived quality why do firms reduce business risk? fama-french and small company cost of equity calculations preparations for possible attacks gear up: new flight restrictions planned around washington ability, moral hazard, firm size, and diversification technical analysis of the size premium. business valuation alert capturing industry risk in a buildup model use of macroeconomic variables to evaluate selected hospitality stock returns in the u brand values and capital market valuation research in emerging markets finance: 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theory of market equilibrium under conditions of risk an empirical analysis of anomalies in the relationship between earnings ' yield and returns of common stocks: the case of lodging and hotel firms stocks for the long run the measurement and determinants of brand equity: a financial approach corporate ownership structure and performance: the case of management buyouts marketbased assets and shareholder value: a framework for analysis passing the baton: managing the process of ceo succession key: cord-253135-0tun7fjk authors: robin, charlotte; bettridge, judy; mcmaster, fiona title: zoonotic disease risk perceptions in the british veterinary profession date: 2017-01-01 journal: prev vet med doi: 10.1016/j.prevetmed.2016.11.015 sha: doc_id: 253135 cord_uid: 0tun7fjk in human and veterinary medicine, reducing the risk of occupationally-acquired infections relies on effective infection prevention and control practices (ipcs). in veterinary medicine, zoonoses present a risk to practitioners, yet little is known about how these risks are understood and how this translates into health protective behaviour. this study aimed to explore risk perceptions within the british veterinary profession and identify motivators and barriers to compliance with ipcs. a cross-sectional study was conducted using veterinary practices registered with the royal college of veterinary surgeons. here we demonstrate that compliance with ipcs is influenced by more than just knowledge and experience, and understanding of risk is complex and multifactorial. out of 252 respondents, the majority were not concerned about the risk of zoonoses (57.5%); however, a considerable proportion (34.9%) was. overall, 44.0% of respondents reported contracting a confirmed or suspected zoonoses, most frequently dermatophytosis (58.6%). in veterinary professionals who had previous experience of managing zoonotic cases, time or financial constraints and a concern for adverse animal reactions were not perceived as barriers to use of personal protective equipment (ppe). for those working in large animal practice, the most significant motivator for using ppe was concerns over liability. when assessing responses to a range of different “infection control attitudes”, veterinary nurses tended to have a more positive perspective, compared with veterinary surgeons. our results demonstrate that ipcs are not always adhered to, and factors influencing motivators and barriers to compliance are not simply based on knowledge and experience. educating veterinary professionals may help improve compliance to a certain extent, however increased knowledge does not necessarily equate to an increase in risk-mitigating behaviour. this highlights that the construction of risk is complex and circumstance-specific and to get a real grasp on compliance with ipcs, this construction needs to be explored in more depth. veterinary professionals can encounter a variety of occupational health risks. a high prevalence of injury has been reported, predominantly in relation to large animal work (beva, 2014; fritschi et al., 2006; lucas et al., 2009) , dog and cat bites and/or scratches and scalpel or needle stick injuries (nienhaus et al., 2005; phillips et al., 2000; soest and van fritschi, 2004) . in addition to the risk of injury, the profession is also at risk of other occupational hazards including exposure to chemicals, car accidents (phillips et al., 2000) and infec-tious diseases from zoonotic pathogens (constable and harrington, 1982; dowd et al., 2013; epp and waldner, 2012; gummow, 2003; jackson and villarroel, 2012; lipton et al., 2008; weese et al., 2002) . work days lost because of zoonotic infections are less frequent than days lost to injury (phillips et al., 2000) ; however, because of the potential seriousness of some zoonotic infections and increasing reports of occupationally-acquired antimicrobial resistant bacteria in veterinary professionals (cuny and witte, 2016; groves et al., 2016; hanselman et al., 2006; jordan et al., 2011; weese et al., 2006) , zoonotic risk in the veterinary profession deserves attention. there are no recent data on the risk of zoonotic infections in the british veterinary profession. one study published over 30 years ago estimated 64.1% of veterinary surgeons working for government agencies reported one or more zoonotic infections during their career (constable and harrington, 1982) . research from veterinary populations overseas indicates a substantial risk of http://dx.doi.org/10. 1016/j.prevetmed.2016.11 .015 0167-5877/© 2017 elsevier b.v. this is an open access article under the cc by license (http://creativecommons.org/licenses/by/4.0/). infection within the profession, with incidence of reported infections during their career ranging from 28% in the united states (lipton et al., 2008) , 45% in australia (dowd et al., 2013) , 47.2% in canada (jackson and villarroel, 2012) to 64% in south africa (gummow, 2003) . in both medical and veterinary professions, infection prevention and control (ipc) practices are fundamental to reduce the risk of healthcare-associated infections in patients, as well as occupationally-acquired infections in practitioners. in the united kingdom (uk), universal and standard precautions are recommended by the department of health. in human medicine, research has highlighted sub-optimal compliance with ipc practices. in one uk study, observed hand hygiene adherence in nurses was 20.4% and 60.1%, before and after contact with patients, respectively. in doctors in the same study, the compliance was much lower, at 8.1% and 51.4%, before and after patient contact (jenner et al., 2006) . non-adherence to guidelines is a global issue, with reported hand hygiene compliance rates of 58% in hospitals in finland (laurikainen et al., 2015) , 41.2% in an infectious diseases care unit in france (boudjema et al., 2016) and 40% in paediatric hospitals in new york (løyland et al., 2016) . in veterinary medicine in the uk, there are no enforceable national policies for ipc practices. for veterinary practices in the royal college of veterinary surgeons (rcvs) accreditation scheme, guidelines are available and specific standards have to be met to retain accreditation status. only 51% of practices are members of the accreditation scheme (rcvs, 2014) and although guidelines and recommendations are available for non-members, they tend to be practice-specific. additionally, the emphasis is on patient, rather than practitioner health. other countries have developed national standards for ipc in veterinary medicine, specifically related to occupationallyacquired zoonotic infections. these include the australian veterinary association guidelines for veterinary personal biosecurity and the compendium of veterinary standard precautions for zoonotic disease prevention in veterinary personnel, developed by the national association of state public health veterinarians in the united states (nasphv). even when national guidelines exist, not all practices have ipc programmes (lipton et al., 2008; murphy et al., 2010) . where effective procedures and resources are available, their effectiveness is dependent on uptake (dowd et al., 2013) . decision-making surrounding ipc practices will depend on a number of different factors. there are few data available focussing on awareness and perceptions of zoonotic diseases within the veterinary profession in the uk, however from studies that have been conducted overseas it appears that awareness is poor and compliance with ipc guidelines is low (dowd et al., 2013; lipton et al., 2008; nakamura et al., 2012; wright et al., 2008) . in a survey of american veterinary medicine associationregistered veterinary surgeons, under half (48.4%) of small animal vets washed or sanitised their hands between patients and this proportion was even lower in large and equine vets (18.2% for both). in addition, only a small proportion of large and equine vets washed their hands before eating, drinking or smoking at work (31.1% and 28.1%, respectively), compared with 55.2% in small animal vets. veterinary surgeons who worked in a practice that had no formal infection control policy had lower awareness, as did male veterinary surgeons (wright et al., 2008) . in a smaller survey of american veterinary professionals, although 77% of respondents agreed it was important for veterinary surgeons to inform clients about the risk of zoonotic disease transmission, only 43% reported they initiated these discussions with clients (lipton et al., 2008) . in a study of veterinary technicians and support staff, only 41.7% reported washing their hands regularly between patients (nakamura et al., 2012) . in a sample of australian veterinary surgeons, 43.4% wore no personal protective equipment (ppe) for handling clinically sick animals and the majority (67.4%) wore inadequate ppe for handling animal faeces and urine (dowd et al., 2013) . in the veterinary profession, the dichotomy between a professional status and increased risk of infection has been viewed as counterintuitive (baker and gray, 2009) , as it could be expected a comprehensive understanding of zoonotic disease risks would manifest in more risk-averse behaviour. in both medical and veterinary medicine, education has been identified as a key intervention to increase compliance (dowd et al., 2013; ward, 2011) ; however good knowledge does not necessarily lead to good practice (jackson et al., 2014) . compliance is influenced by many factors, including motivation, intention, social pressure and how individuals understand or 'construct' risk (jackson et al., 2014) . understanding of risk and why people engage in risk-mitigating behaviour (or not) is complex and perceived knowledge of the disease is only one factor that should be considered. a better understanding of how veterinary professionals in britain understand the risks surrounding zoonotic diseases will aid in the development of effective and sustainable ipc practices, reducing the risk of zoonotic infections within the profession. this paper examines how the veterinary profession in britain understand zoonotic risk and motivators and barriers for using ppe. a cross-sectional study was conducted october to december 2014; the sampling frame was all 3416 veterinary practices in great britain registered in the rcvs database. the rcvs database holds information on registered veterinary businesses, including private practice, referral hospitals, veterinary teaching hospitals and veterinary individuals. sample size calculations indicated that information from 348 veterinary practices was required for an expected prevalence of 50%, with a precision of 5%. assuming a 30% response rate, 1000 practices were selected from the rcvs database by systematically selecting every third practice. the principle veterinary surgeon and head nurse were identified at each practice using the rcvs register and sent a postal questionnaire. a total of 2000 questionnaires were posted to 1000 veterinary practices. for non-responders, reminder emails were sent out from four weeks after the initial posting and a second reminder, including an electronic copy of the questionnaire was sent out a further four weeks after the first reminder, to any remaining non-responders. the questionnaire was developed based on a similar study in australian veterinary professionals (dowd et al., 2013) and a larger, multi-country risk perception study on severe acute respiratory syndrome (de zwart et al., 2009) . the questionnaire was an a4 8page booklet (available in supplementary information), containing four sections including veterinary qualifications and experience, disease risk perceptions, infection control practices and management of zoonotic diseases. the questionnaire included both closed and open-ended questions and was piloted on a small convenience sample of veterinary surgeons, but not veterinary nurses, prior to being finalised. questionnaires were designed in automatic data capture software (cardiff teleform v 9.0), which allowed completed questionnaires to be scanned and verified and the data imported directly into a custom-designed spreadsheet (microsoft excel, redmond, wa, usa). the clinical scenarios respondents were asked to assess the risk from included contact with animal faeces/urine; contact with animal blood; contact with animal saliva or other bodily fluid; performing post mortem examinations, assisting conception and parturition for animals, contact with healthy animals; contact with clinically sick animals and accidental injury. * post mortem examination. descriptive statistics were performed using commercial software (ibm spss version 22, armonk, ny, usa). proportions were calculated for categorical data; median and interquartile ranges (iqr) for continuous data. a "risk perception score" was calculated as the mean value of the scores (high risk = 3; medium risk = 2; low risk = 1), based on the participant's opinion of the risk (high, medium or low) of contracting a zoonosis from eight different clinical scenarios detailed in fig. 2 . scores for ppe use in five clinical scenarios were calculated using pearson's correlation coefficient to compare reported use of gloves, masks and gowns/overalls to the recommendations in the nasphv guidelines. these guidelines were chosen because no uk equivalent that applies across all veterinary species could be found, but the nasphv standards are likely to be considered as reasonable levels of protection in the uk situation. the clinical scenarios included handling healthy animals (no specific protection advised: possible scores 0-3); handling excreta and managing dermatology cases (gloves and protective outerwear advised: possible scores −2 to 1); performing post mortems and performing dental procedures (gloves, coveralls and masks advised: possible scores −3 to 0). a score of 0 indicated compliance, <0 indicated less ppe than recommended was used and >0 more ppe than recommended was used. redundancy analysis (rda) was used to determine if demographic or other factors accounted for any observed clustering of the motivators or barriers to use of ppe, or for the reported ppe use in different scenarios. redundancy analysis is a form of multivariate analysis that combines principal component analysis with regression, to identify significant explanatory variables. this was performed using the r package "vegan" (oksanen et al., 2016) , based on the methods described by (borcard et al., 2011) . the adjusted r 2 value was used to test whether the inclusion of explanatory variables was a significantly better fit than the null model and a forward selection process was used to select the significant variables that explained the greatest proportion of the variance in the response data (borcard et al., 2011) . permutation tests were used to test how many rda axes explained a significant proportion of the variation. barriers and motivators to use of ppe were assessed by asking respondents to grade the influence of certain factors on their use of ppe (see fig. 4 for a full description of the barriers and motivators). the response options "not at all", "a little" and "extremely" were ranked as 0, 1 and 2, respectively. redundancy analyses, as described above, were used to determine if demographic or other factors accounted for any observed clustering of a) barriers or b) motivators to use of ppe. explanatory variables investigated were gender, age, length of time in practice, position (veterinary surgeon or nurse; owner or employee); type(s) of veterinary work undertaken (small, large/equine or exotics/wildlife); previous experience of treating a zoonotic case; level of concern over risk (for themselves or clients). additional explanatory variables investigated in the redundancy analysis for reported ppe use were the barrier and motivator scores and the attitude and belief scores (described below). participants were also asked about their level of agreement with certain statements describing their attitudes and beliefs around zoonotic disease risk and ppe use (see fig. 5 for a full description of the statements); the responses "disagree", "agree" and "strongly agree" were scored as −1, 1 and 2, respectively. principal component analysis was used to investigate clustering of these "attitude" statements. as only two axes contributed variation of interest (according to the kaiser-guttman criterion, which compares each axis to the mean of all eigenvalues), the attitude statements were grouped into two subsets; those that contributed principally to pca1 (seven statements) and those that contributed to pca2 (three statements). cronbach's alpha was calculated on these subsets of the attitude statements, using the "psy" package in r (falissard, 2011) , to test whether any of these variables may indicate an underlying latent construct. where correlation was judged to be acceptable or better (cronbach's alpha coefficient >0.7), the principal component scores were used as a proxy measure for this latent construct. potential explanatory variables, including the same demographic variables used for the redundancy analyses, and responses to motivators and barriers, were tested using linear regression modelling. multivariable regression models were fitted using the base and stats packages in r software (r core team, 2015). a manual stepwise selection of variables was performed based on knowledge of expected potential associations and confounders that made biological sense. variables were added one by one to the null model. two-way interactions were tested and variables or interactions were retained if likelihood ratio tests showed a significant improvement in model fit (p < 0.05). non-significant variables were removed, including variables that later became non-significant when additional variables were added. over the 12-week study period, a total of 252 useable questionnaires were returned from the invited individuals, giving an overall response rate of 12.6%. for a number of questions, there were some missing data; therefore the denominator for all results was 252 unless otherwise stated. a summary of demographic characteristics of the respondents is presented in table 1 . the majority of respondents had managed a zoonotic case within the 12 months prior to completing the questionnaire (93.1%; n = 230/247). the most commonly reported infections treated were campylobacter (n = 111), dermatophytosis (n = 99) and sarcoptes scabeii (n = 86). overall, 24.6% (n = 62/248) of respondents reported they had previously contracted at least one confirmed occupationallyacquired episode of zoonotic disease. when including suspected zoonotic diseases, this increased to 44.7% (n = 111/248). the most common zoonotic disease experienced by respondents who reported confirmed or suspected zoonotic infection was dermatophytosis (58.6%; n = 65/111). the relative frequency of reported zoonotic infections (confirmed and suspected) is reported in fig. 1 , showing the reported frequency in respondents who had qualified or practised outside of britain, compared with veterinary professionals with exclusively british experience. overall, the majority (57.5%; n = 145/251) of respondents were not concerned that they or their colleagues would contract an occupationally-acquired zoonotic disease, however a considerable proportion were (34.9%; n = 88/251). only a small proportion (7.1%; n = 18/251; 4.0-10.4) stated they had not thought about the risk of infection. in total, 84.6% (n = 209/247) of respondents agreed or strongly agreed they had a high level of knowledge regarding zoonotic diseases. based on the eight different clinical scenarios respondents were asked to assess, the highest risk situation for zoonotic disease transmission was considered to be accidental injury, such as a needle stick injury, bite or scratch. coming into contact with animal faeces/urine was also considered high risk for zoonotic disease transmission. these scenarios were classified as high risk by 18.3% (n = 46/245) and 17.1% (n = 43/246) of respondents, respectively. the aspect of the job considered to represent the lowest risk of exposure to zoonoses was contact with healthy animals, with 83.3% (n = 210/250) of respondents considering this to involve low risk of exposure to disease (fig. 2) . the amalgamated risk perception scores ranged from 1 (all scenarios considered low risk) to 3 (all scenarios considered high risk), with a median of 1.5 (iqr 1.25-1.75). the majority of respondents reported they were aware of their practice having standard operating procedures (sops) related to infection control practices (75.0%; n = 189/236). all workplaces provided ppe for members of staff, although 12.3% did not provide training on how to use it. the majority provided separate eating areas (92.9%; n = 234/247) and restricted access from staff and visitors to patients in isolation (92.5%; n = 225/233). when asked about what level of ppe was used in five different clinical settings, 68.3% (n = 168/246) reported they would not use any specific ppe for handling healthy animals, in line with the nasphv guidelines. when handling dermatology cases, 23% (n = 56/243) reported using no ppe. only 2.4% (n = 8/331) reported not using any ppe for handling urine or faeces; one respondent did not use any ppe for post mortem examination (n = 230; 0.4%), and 2% (n = 5/244) did not use any for performing dentistry work. correlation between the ppe scores for the different scenarios was low, the greatest correlation (r = 0.39) was between the scores for handling excreta and for handling dermatology cases. there was no evidence that respondents who wore more ppe than required in the guidelines (i.e. gloves and/or masks) for handling healthy animals would correctly select the appropriate level of ppe (i.e. gloves, masks and a protective coverall) for post mortem or dentistry. a redundancy analysis indicated that greater ppe use (a higher ppe score) was negatively correlated with a fatalistic attitude for the two higher risk scenarios. belief that sops acted as a motivating factor to use ppe and agreement that "i consciously consider using ppe in every case i deal with" were positively correlated with greater ppe use in dermatological cases, handling healthy animals and excreta (fig. 3) . all respondents indicated that perceived risk would have some effect on their motivation to use ppe, either a little (n = 63/248; 25.4%) or extremely (n = 186/248; 74.6%). respondents were also strongly motivated by previous experience with similar cases (n = 135/248; 54.5%) and a high profile or recent disease outbreak (n = 132/245; 53.9%). few respondents indicated any of the suggested barriers to ppe would have a strong influence as a deterrent to using ppe; safety concerns was most frequently cited, with 7.1% (n = 18) respondents stating this would be an extreme deterrent to using ppe. when combining both positive responses (extreme and a little influence), time constraints and safety concerns were the most frequently cited barriers, with 56.0% (n = 139/248) and 56.9% (n = 141/248) of respondents indicated these barriers would affect their decision not to use ppe, respectively. potential barriers that most respondents considered had no influence on their decision to use ppe were negative client perceptions and ppe availability, with 78.2% (n = 194/248) and 76.9% (n = 190/247) of respondents stating this, respectively. demographic variables that had significant associations with responses regarding motivators and barriers towards the use of ppe are illustrated in fig. 4 . the explanatory variables in the model were statistically significant, however they only explained a small amount of the variation in the respondents' perceptions of barriers (adjusted r-square 3.2%) and motivators (adjusted r-square 3.4%). respondents with previous experience of treating a case of zoonotic disease were less likely to regard time or financial constraints, or concern for adverse animal reactions as a deterrent to using ppe (fig. 4a) . veterinary surgeons were more likely than nurses to be deterred from using ppe because of concerns about negative client perceptions (fig. 4a) ; although positive client perceptions were marginally more likely to act as encouragement in both vets and nurses who reported themselves concerned about zoonotic risk in relation to clients (fig. 4b) . those working in large animal practice were more likely to be motivated to use ppe by concerns over liability and nurses tended to be more motivated than veterinary surgeons by sops and concern over the perceived risk to themselves. respondents were asked to state their level of agreement with 10 "attitude" statements (see fig. 5 for a description of the statements) reflecting different aspects of zoonotic disease risk control in the workplace. all respondents agreed that using ppe and practising good equipment hygiene was an effective way of reducing the risk of zoonotic disease transmission. the majority thought they had a high level of knowledge regarding zoonoses (n = 209/247; 84.6%) and that they were expected to demonstrate rigorous infection control practices (n = 229/247; 92.7%). however, 45 respondents (18.2%) stated they just hoped for the best when trying to avoid contracting a zoonotic disease and 37 (14.9%) were concerned their colleagues would think they were unnecessarily cautious if they used ppe in their workplace. responses to seven of these "attitude" statements tended to cluster together along the first pca axis (fig. 5 , statements a to g). cronbach's alpha coefficient for these statements was 0.76, suggesting an acceptable level of internal consistency and a potential underlying latent construct (interpreted here as a "positive attitude" towards ipcs) for these responses. statements h to k, whilst all contributing greater weight to pca axis 2, had an alpha coefficient of below 0.5 and were therefore evaluated individually. respondents' scores from the first principal component axis (fig. 5) were used as a proxy to represent this potential underlying "positive attitude" towards zoonotic disease risk reduction and a multivariable linear regression model was used to investigate potential explanatory factors. the only demographic variable that significantly altered model fit was profession, with veterinary surgeons tending to score lower than nurses in this "positive attitude". some of the factors identified as motivators and barriers also had a statistically significant association with the outcome. those who agreed that sops, positive client perceptions and risk to themselves motivated them to use ppe scored more highly; whereas those who regarded time constraints as a barrier to ppe use tended to have lower positive attitude scores (table 2) . there were 18.2% (n = 45/247) of respondents who agreed or strongly agreed with the statement, "i just hope for the best when it comes to trying to avoid contracting a zoonotic disease". a multivariable model suggested that respondents who had spent less time in practice tended to agree more with this "fatalistic" attitude, as did those who held the opinion that negative client perceptions deterred them from using ppe. furthermore, individuals with higher risk perception scores (i.e. who believed they tended to have a medium to high risk of exposure to zoonoses from clinical work) were more likely to agree that they "just hope for the best" (table 2) . a regression model was also constructed for the statement, "if i use ppe, others in my workplace think that i am being unnecessarily cautious". explanatory variables included an interaction between gender and profession; nurses, particularly male nurses, were more likely to agree, whereas there was no significant gender difference in veterinary surgeons. the aim of this research was to explore zoonotic disease risk perceptions within a cross-section of the veterinary profession in britain, and to identify barriers and motivators towards infection control practices and the use of ppe to minimise the risk of disease transmission. the large proportion of respondents (44.0%) who had contracted either a confirmed or suspected occupationallyacquired zoonotic infection highlights the level of occupational risk encountered by veterinary surgeons and veterinary nurses. a substantial proportion of respondents stated they were concerned about the risk of zoonoses (35%), and the majority thought the highest risk of transmission was through accidental injury, despite few reported zoonoses in the study being transmitted this way. this dissonance may be reflecting other occupational risks encountered by veterinary professionals, of which zoonotic diseases only represent a small proportion. data from studies conducted overseas suggests veterinary medicine is a high risk profession. in one survey of australian veterinary professionals, 71% reported at least one physical injury over a 10 year period (phillips et al., 2000) . in addition to practice-acquired injuries, such as dog and cat bites, scalpel blade cuts and lifting of heavy dogs, the risk of car accidents was also noted (phillips et al., 2000) . further research in the german veterinary profession highlighted workplace accidents as the most prevalent occupational hazard (87.7%), followed by commuting accidents (8.2%). occupationally-acquired zoonoses only represented 4.1% of the total hazards in the study (nienhaus et al., 2005) . practitioners are clearly working in a risky environment, particularly large animal vets, where farm environments are known to be inherently dangerous. a total of 7 fatal injuries and 292 major injuries were reported in british farmers or farmworkers in -2014 (hse, 2014 , and a recent survey by the british equine veterinary association revealed that on average, equine vets sustain seven to eight work-related injuries during a 30 year period (beva, 2014), highlighting just how hazardous these environments can be. few data are available on occupational injuries in the british veterinary profession; however, when working in what could be interpreted as a high-risk environment, a constant exposure to risk for those living or working in these types of environment may lead to habituation to, or normalisation of risk (clouser et al., 2015) . individuals in this study who tended to grade common clinical scenarios as posing a moderate to high risk of zoonosis exposure were also more likely to "just hope for the best", perhaps suggesting they have normalised these situations and do not perceive them as requiring additional precautions. within the veterinary environment, it is also possible that risks are rationalised; when faced with a very tangible risk of accident or injury, the more imperceptible risk of zoonotic infection becomes less important. this rationalisation of risk is also noted in the healthcare profession, where healthcare workers are more careful when handling sharps, compared with demonstrating compliance with ipc practices for infectious diseases (nicol et al., 2009) . the invisibility of the disease also plays a role here; the pathogens are not visible therefore the perception of the risk they pose is more abstract. in addition, there is often a time lapse between exposure to the pathogen and onset of clinical signs, making an association between suboptimal ipc behaviour and outcome difficult (cioffi and cioffi, 2015) . in the uk, personal risk receives little attention in the veterinary profession's media, especially when compared with issues such as mental health, with reports of high levels of psychological distress and suicide in the profession (bartram et al., 2010) and inclusion of issues around stress and mental wellbeing in surveys (vet futures, 2015) and veterinary curricula. this makes zoonotic disease risk less visible and may subject it to an availability heuristic, where the likelihood of an event is judged based on how easily an instance comes to mind (tversky and kahneman, 1974) . the absence of diseases such as rabies from the uk may also mean that veterinary professionals underestimate the risk of zoonoses because they consider the impacts to be relatively minor, short-term and treatable. this affect heuristic may be especially pronounced when decisions are made under time pressure (finucane et al., 2000) , perhaps reflected in this study's finding that those who viewed time constraints as a barrier to their use of ppe had less positive attitudes towards it. the disconnect between risk perception and health protective behaviour in the present study could be explained by perceived vulnerability. a risk might be acknowledged, yet if an individual does not feel vulnerable to this risk, there is no motivation or intention to change their behaviour. this perceived vulnerability is one of the factors considered in the protection motivation theory, where concern about a potential threat influences perception of the risk i.e. the more concerned an individual is about a disease, the higher risk they perceive it poses. if an individual feels vulnerable, this acts as a motivator for behaviour change (schemann et al., 2013 ). this behavioural model has been applied to horse owners following the equine influenza outbreak in australia where different levels of perceived vulnerability were identified in a cross section of the equine sector (schemann et al., 2013 (schemann et al., , 2011 . perceived vulnerability may be influencing health protective behaviour in the present study. it is possible that veterinary professionals, because they feel knowledgeable about zoonotic diseases, feel less vulnerable to the risks they pose. this lack of perceived vulnerability may account for the substantial proportion of respondents who stated they would not use ppe when handling clinically sick animals; perhaps because they are confident in their ability to identify those cases with potentially zoonotic or infectious aetiologies. identification of risk to self as a motivating factor was associated with a more "positive attitude" towards ppe use, but being a nurse was independently correlated with both of these variables. possibly because nurses often have less influence in decisions over diagnostics or handling of cases, they may feel more vulnerable. the protection motivation theory is only one of numerous health behaviour models that have been applied to both medical and veterinary research. these models are useful for explaining behaviour change in relation to infection control or biosecurity however they have had limited success in practice (pittet, 2004) . the main criticism of these models is that they make an assumption that behaviour is rational, controllable and therefore modifiable (cioffi and cioffi, 2015) . in reality, behaviour is affected by many external influences such as culture and society. society and culture are fluid, constantly changing concepts and consequently it makes incorporating them into behavioural models problematic. so while these models of behaviour are useful in explaining behaviour change to a certain extent, to gain a full understanding of what drives or inhibits behaviour change, social psychology and qualitative research is essential for making real impacts on practice. in the current study, individuals motivated by sops were found to have more positive attitudes towards ppe and also to report better compliance with ppe guidelines for medium-risk scenarios, such as dermatology cases and handling excreta. the "positive attitude" construct, related to self-efficacy, knowledge and confidence in equipment and practices, also clustered with a feeling that there is an expectation to demonstrate good practice. this could be a reflection of the influence of the practice culture on behaviour. in human healthcare, organisational factors, have been identified as one of the main drivers behind poor compliance with ipc practices (cumbler et al., 2013; de bono et al., 2014) . as compliance with infection control intersects individual behaviour and the cultural norms of the practice, the culture of veterinary practice will also be influencing behaviour surrounding infection control. it appears from the present study that when veterinary practices promote a culture of positive health behaviour and have high expectations of employees, this acts as a motivator for compliance with ipc practices. this highlights that behaviour change should also be implemented at an organisational level, rather than just focussing on individual behaviour. veterinary surgeons were more concerned than nurses that using ppe would be perceived negatively by clients. this attitude could be reflecting the importance of the vet-client relationship in veterinary practice. this is particularly relevant in farm animal practice, where vet-farmer relationships are often cultivated over extended time periods and each individual agricultural client represents a significant proportion of practices' income. respondents working in large animal practice were more likely to be motivated to use ppe by liability concerns, again potentially a reflection of the pressure felt by veterinary professionals from their clients. this is an interesting dichotomy, as the use of ppe not only protects the practitioner, but also the animal from zoonotic disease transmission. educating farm clients as to what infection control practices they should expect during clinical work on the farm may help mitigate concerns about negative client perceptions. choices around ppe use appear to be specific both to individuals and contexts, demonstrated by the low correlation between ppe scores in different clinical scenarios. this finding that protocols are often adapted to a specific situation has been observed previously in veterinary professionals (enticott, 2012) . the models that people construct to inform their behavioural decision making are highly individual and influenced by their biology and environment, but also their past experiences (kinderman, 2014) . in the present study, previous experiences of treating zoonotic cases were correlated with lower concern about potential barriers to ppe use. this may suggest that practical experience of dealing with zoonoses is more influential than the theoretical knowledge in negating negative attitudes to ppe use. a limitation of this study, as with any questionnaire based study, is that self-reported behaviours may not necessarily reflect actual practice. this discrepancy between reporting behaviours and actually performing them has been observed previously, particularly in relation to infection control practices and hand hygiene. one ukbased study highlighted no association between self-reported and observed hand-hygiene practices in a sample of healthcare professionals (jenner et al., 2006) , reflecting how self-reported behaviour should be interpreted with caution in any context. observation is considered the gold standard method of assessing behavioural practices, however is still subject to bias in the form of observer bias (racicot et al., 2012) and video recording has been used recently to monitor hand hygiene practices (boudjema et al., 2016) . these methods could also be effectively applied in a veterinary context and qualitative research methods, such as ethnography, would also provide valuable insights into the culture and practices of infection control and health protective behaviours in veterinary practice. the veterinary practices invited to take part in this study were randomly selected, using systematic random sampling, from the rcvs database. this system of using the rcvs database to sample the veterinary profession has been used previously for other research studies and is an established method of sampling this target population (nielsen et al., 2014) . the selection of practices was random, however the selection of participants at each practice may have been subject to selection bias. to facilitate a greater response rate, where data were available, individual respondents at each practice were selected from the rcvs register. to ensure this was consistent, the principal veterinary surgeon and head nurse were selected for each practice. using individual names may have increased the likelihood of the participant responding, however this may have introduced some selection bias as the selected participants are likely to be a more experienced professional. our results suggested that some workplace factors, such as sops and expectations of colleagues, influenced respondents' perceptions and attitudes to ppe use. these might be expected to cluster within practice; the response from a veterinary surgeon and nurse from the same practice might not be completely independent. however, it was not feasible to introduce practice as a random effect, as not enough practices returned two responses (22.2% returned responses from a veterinary nurse and veterinary surgeon from the same practice). as with any questionnaire-based research, this study will be subject to an element of responder bias, and the relatively low response rate of this study may accentuate this bias. this is particularly evident with male nurses, who are few in number, making them difficult to target using random selection methods. according to the latest rcvs annual report, male nurses represented just 2.1% of the total veterinary nurse population in the uk (rcvs, 2014), in the present study, 6% (95% ci 1.7-10.4) of respondents were male nurses. the rcvs database used to sample the veterinary population for this study does not contain information on specialism or type of practice, therefore it is not possible to assess whether this sample is representative of the wider veterinary profession. however, the demographic data on respondents are similar to data from the rcvs annual report; the mean age in our study was 42 years, compared with 41 years in the annual report. in addition, the gender split was similar; in our study, 61.1% (95% ci 55.1-67.1) of respondents were female and the rcvs reported 57.1% were female (rcvs, 2014) . despite similarities between the respondents and the veterinary population in the uk, the low response rate means the results from this sample may not necessarily be generalisable to the wider veterinary population, however this study is the first to provide these baseline data on attitudes and beliefs regarding zoonoses in the british veterinary population, which can be built on with future studies. the majority of respondents worked in small animal practice, which partly reflects the distribution of british practice types, but as the questionnaire was posted to the practice, this may have made it easier for small animal practitioners to respond as the majority of their time is spent within the practice premises. this means the study may be more representative of small animal veterinary professionals, rather than large and equine practice. to negate this in future studies, the use of stratified sampling would be a useful sampling method to ensure representative samples from each sector of the veterinary profession. this study aimed to investigate risk perceptions of zoonotic disease transmission in the veterinary profession in britain. the high infection rate within the profession suggests transmission of zoonotic infections from patient to clinician should be of concern. this study identified a few concepts that were reported to influence the use of ppe including a fatalistic attitude, the social environment and an individual's position within the practice. improving education provided to veterinary professionals may help improve compliance with sops and infection control practices to a certain extent, however this study has highlighted that increased knowledge does not necessarily equate to exhibiting riskmitigating behaviour. this suggests construction of risk is complex, circumstance-specific and can be influenced by a number of different internal and external factors. a qualitative study, using mixed qualitative methods including in-depth interviews and focus group discussions, to explore the construction of risk in the veterinary profession, is currently being developed to understand these concepts in more depth. survey reveals high risk of injury to equine vets a review of published reports regarding zoonotic pathogen infection in veterinarians interventions with potential to improve the mental health and wellbeing of uk veterinary surgeons numerical ecology with r journal of nursing & care hand hygiene analyzed by video recording challenging suboptimal infection control keeping workers safe: does provision of personal protective equipment match supervisor risk perceptions? risks of zoonoses in a veterinary service culture 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-nonparasitic zoonotic diseases suspected transmission of methicillin-resistant staphylococcus aureus between domestic pets and humans in veterinary clinics and in the household infection control practices and zoonotic disease risks among veterinarians in the united states perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey the authors gratefully acknowledge all participating veterinary nurses and veterinary surgeons, and dr j.l. ireland for her guidance and advice. this work was supported by the national institute for health research health protection research unit (nihr hpru) in emerging and zoonotic infections at university of liverpool in partnership with public health england (phe), in collaboration with liverpool school of tropical medicine. charlotte robin is based at the university of liverpool. the views expressed are those of the author(s) and not necessarily those of the nhs, the nihr, the department of health or public health england. no competing interests were declared. approval for this study was agreed by anglia ruskin university faculty of health, social care and education research ethics' panel. key: cord-016173-ro7nhody authors: louis, mariam; oyiengo, d. onentia; bourjeily, ghada title: pulmonary disorders in pregnancy date: 2014-08-13 journal: medical management of the pregnant patient doi: 10.1007/978-1-4614-1244-1_11 sha: doc_id: 16173 cord_uid: ro7nhody pregnancy is associated with some profound changes in the cardiovascular, respiratory, immune, and hematologic systems that impact the clinical presentation of respiratory disorders, their implications in pregnancy, and the decisions to treat. in addition, concerns for fetal well-being and safety of various interventions complicate the management of these disorders. in many circumstances, especially life-threatening ones, decisions are based upon a careful assessment of the risk benefit ratio rather than absolute safety of drugs and interventions. in this chapter, we review some of the common respiratory disorders that internists or obstetricians may be called upon to manage. asthma is the most common respiratory disease during pregnancy. asthma affects 4-8 % of pregnancies in the united states and up to 12 % in the united kingdom and australia. difference in prevalence around the world may be related to reporting methods, diagnostic methods, or possibly some environmental or genetic infl uences. pregnancy is a state of important physiological changes in the respiratory system. these physiological changes vary across the course of the pregnancy and are summarized in table 11 .1 . • 105-106 in fi rst trimester and 101-106 by third trimester paco 2 (mmhg) • 28-29 in fi rst trimester and 26-30 by third trimester ph • 7.43 hco 3 (meq/l) • 17-18 tlc total lung capacity, erv expiratory reserve volume, rv residual volume, frc functional residual capacity, vc vital capacity, ic inspiratory capacity, irv inspiratory reserve volume, fev1 forced expiratory volume in 1 s, fvc forced vital capacity, pao 2 partial arterial pressure of oxygen, paco 2 partial arterial pressure of carbon dioxide the course of asthma during pregnancy is variable. the majority of patients who improve in pregnancy tend to worsen in the postpartum period and vice versa [ 1 ] . in general, asthma improves toward the end of the pregnancy, including labor and delivery. however, the rate of asthma exacerbations is increased between gestational weeks 17 and 32 [ 1 , 2 ] . this may in part be due to medication noncompliance during the earlier part of the pregnancy upon discovery of the pregnancy but may also have to do with other pregnancy-related factors such as esophageal refl ux, nasal congestion, hormonal factors, and alterations in immunity that may result in increased susceptibility to infections. the major predictor of disease course is the severity of asthma prior to the pregnancy, but race and obesity may also play a role. african american and hispanic women are more likely to have asthma exacerbations. poor compliance with medications and diffi culties with access to medical services may be important confounders. additionally, obese women tend to have more severe asthma as both asthma and obesity share a common infl ammatory pathway at the cellular level. asthma also tends to behave in a similar fashion in subsequent pregnancies. while well-controlled asthma does not appear to have adverse consequences during pregnancy, poorly controlled asthma may negatively impact some maternal and fetal outcomes. in the largest study performed to date on over 37,000 women with asthma and over 280,000 controls, asthmatic women were more likely to have pregnancies complicated by miscarriage, antepartum and postpartum hemorrhage, anemia, and depression [ 3 ] . however, the risk of other negative outcomes such as gestational hypertensive disorders and stillbirths was not signifi cant in this study. in other large studies, a small, but statistically signifi cant risk of perinatal mortality, preeclampsia, and preterm deliveries have been reported [ 4 , 5 ] . a more recent retrospective cohort study performed in 12 clinical centers in the united states has shown increased risk of preeclampsia, gestational diabetes, and all preterm births [ 6 ] . secondary analysis of a recent randomized controlled trial showed that women with perception of good asthma control had a reduced risk of planned cesarean deliveries, asthma exacerbations, and preterm birth [ 7 ] . in the same study, women with increased anxiety had a higher risk of exacerbations. there is some evidence suggesting that poorly controlled asthma also confers an increased risk of small for gestational age, and low birth weight [ 8 ] . growth restriction may, however, be confounded by smoking. babies born to severe asthmatics are possibly more likely to have congenital anomalies [ 5 ] . the treatment of asthma involves assessment and management from preconception to the postpartum period. please refer to table 11 .3 and figure 11 .1 for a general overview of the classifi cation and management of chronic asthma. there are four general components of asthma care, irrespective of gestational age. these are (1) monitoring of respiratory status, (2) avoidance of possible triggers, (3) patient education, and (4) pharmacological treatment. patients should get a baseline spirometry and be instructed in how to follow their peak expiratory fl ow rate (pefr) at home. ideally, this should be done twice a day in patients with persistent disease. since pregnancy does not affect fl ow rates, reductions in these numbers usually indicate a worsening degree of airfl ow obstruction and should prompt quick medical evaluation. second, it is critical that patients avoid their known triggers to asthma including tobacco, dust, extreme temperatures, and allergens such as pollen and pet dander. third, patients need to be educated about their disease. pregnancy constitutes a perfect window to educate women given the multiple contacts with providers increased motivation due to concerns for fetal well-being. trigger control from washing bed sheets to vacuuming to rodent control are important strategies to review, especially since in most circumstances, women are more likely to be exposed to these triggers. important topics that need to be reviewed also include inhaler technique, early recognition of symptoms of worsening asthma, an action plan for acute asthma exacerbations, as well as an overview of how poorly controlled asthma can affect the pregnancy. patients should also be provided with the opportunity to express their concerns and ask questions. in a multi-institutional prospective study, lower forced expiratory volume in 1 s (fev1), but not asthma symptom frequency, was shown to be associated with adverse perinatal outcomes [ 9 ] . these data may be a refl ection of the effect of asthma severity or poor asthma control on perinatal outcomes and emphasize the possibility of discrepancies between symptom-based assessment and more objective measurement of lung function in pregnant women with asthma. finally, women with asthma need to receive the appropriate pharmacological treatment to achieve disease control. populationbased data do show that well-controlled asthmatics without exacerbations have better outcomes than women with exacerbations, but for obvious reasons, there are no randomized controlled trials evaluating this particular question. although most clinical practices use symptom-based, guideline-directed assessments to decide on medication use, recent data from a randomized controlled trial suggest lower rates of exacerbation, improved quality of life, and reduced neonatal hospitalization when management decisions were based on measurements of exhaled nitric oxide in pregnancy [ 10 ] . it is likely that this improvement in outcomes is due to improved control, rather than the method of assessment itself. table 11 .2 provides an overview of the asthma medications that are used in pregnancy. as in the nonpregnant population, the choice of pharmacological agent depends on disease severity. a frank discussion with the expectant mother and her partner should occur to encourage them to voice their concerns regarding asthma treatment in pregnancy. most women are told to stop their inhalers at the time of pregnancy diagnosis because of fda category listing. for that reason, a good amount of time should be spent on counseling about the use of asthma drugs in pregnancy. explaining to women that asthma control is key to the health of the pregnancy and their baby is an important part of counseling and may have to be done repeatedly during the course of pregnancy. in general, most asthma medications are justifi able in pregnancy, and some have adequate safety data. as noted in table 11 .2 , many of the drug choices are category c according to the fda classifi cation; however, these drugs are used routinely in the care of pregnant women with asthma. in addition, although leukotriene inhibitors are listed as category b, safety data are less reassuring than other drugs classifi ed as category c. omalizumab is classifi ed as category b by the fda despite the fact that all of the initial trials have excluded pregnant women. these safety data are based on animal studies which are limited by the fact that teratogenicity may be species specifi c. in addition, although prednisone may be associated with a small risk of cleft palate when administered in early pregnancy, the benefi t of this drug in an acute exacerbation of asthma by far outweighs the small risk of malformation. table 11 .3 reviews the classifi cation of asthma severity, which includes not only symptoms but also peak fl ow meter measurements. other coexisting diseases may worsen asthma and may have to be treated in order to achieve optimal control. the most common of these disorders are allergic rhinitis, gastroesophageal refl ux disease (gerd), sleep apnea, and psychiatric illnesses. allergic rhinitis occurs in 80-90 % of nonpregnant asthmatics and worsens asthma symptoms. management of the allergic rhinitis with drugs such as steroidal nasal sprays often improves asthma symptoms. women who are pregnant can also develop a different form of rhinitis, called rhinitis of pregnancy. this typically occurs in the latter part of pregnancy and resolves completely within 2 weeks after delivery. the prevalence of gerd among nonpregnant asthmatics varies between 30 and 90 %. in pregnant women with asthma, this number is likely higher given that gerd has been reported to be present in nearly 75 % of all pregnant women [ 11 ] . gerd can worsen bronchoconstriction via increased vagal tone, heightened bronchial reactivity, and microaspiration of gastric contents into the upper airway. patients who have symptoms of gerd benefi t from treatment. although proton pump inhibitors are not expected to increase the risk of congenital malformation in experimental animal studies and limited human pregnancy exposures, ranitidine constitutes a safer fi rst choice. finally, asthma and psychiatric comorbidities may coexist. stress and mental illness can worsen asthma in the pregnant women and may also complicate compliance. during labor, the general management of asthma is not signifi cantly different than above. most patients with asthma do not require a labor and delivery plan. however, patients with more severe disease or those who suffered an exacerbation close to term would require a detailed plan. stress dosing with steroids during labor can be considered in patients who have been on prolonged periods of systemic steroids during the pregnancy. patients with active symptoms or more severe asthma may benefi t from regional anesthesia. epidural anesthesia reduces minute volume and oxygen consumption and may help prevent hyperinfl ation in patients with active symptoms and reduce oxygen consumption. if general anesthesia is to be considered, then ketamine and halogenated anesthetics are preferred. it is safe to use oxytocin and prostaglandin e2. however, ergotamine and ergot derivatives, 15-methyl prostaglandin f2 alpha, morphine, and meperidine should be avoided in pregnant women with asthma as they may be associated with an increased risk of bronchospasm. an overview of the management of acute asthma exacerbations in the pregnant woman is detailed in fig. 11 .2 . more detailed information can be found in national heart lung and blood institute guidelines on asthma and pregnancy published in 2004. the treatment is similar to nonpregnant women with a few key differences that need to be highlighted. the fi rst is to remember that during pregnancy, the normal paco 2 is lower than in the nonpregnant state. therefore, a normal or high paco 2 heralds worsening respiratory failure and should be acted upon quickly. second, hypoxia during asthma exacerbations can lead to fetal distress and decelerations. therefore, immediate bronchodilators and supplemental oxygen should be administered. finally, it should be noted that while the indications for airway intubation are the same in the pregnant asthmatic as the nonpregnant asthmatic, intubation during pregnancy, especially in the third trimester, can be more diffi cult. this is due to increased airway edema, low frc and oxygen reserve, and a more profound response to sedatives from decreased venous return. hence, the most experienced member of the team should perform the intubation and be familiar with diffi cult airway management procedures. airway intubation is discussed in more detail in the critical care chap. 2 . pneumonia is one of the leading causes of non-obstetric maternal deaths in the united states [ 12 ] . there are several categories of pneumonia based on the likely spectrum of pathogens: community-acquired pneumonia (cap), healthcareassociated pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia as well as pneumonia in the immune-compromised host. as pregnant women are usually young and healthy, cap predominates. the overall rate of cap in pregnant women is 0.5-1/1,000 pregnancies depending on the population being studied [ 13 -15 ] . the risk of pneumonia is notably increased in gravidas with comorbid conditions such as asthma, anemia, and human immunodefi ciency virus [ 16 ] . tobacco and substance abuse have also been independently associated with an increased risk for pneumonia. infl uenza increases the risk for development of bacterial pneumonia by denuding the respiratory epithelium and predisposing the host to infection. in adults, the causative agents for cap are identifi ed in 40-60 % of cases when advanced testing techniques are utilized [ 17 , 18 ] . the yield is much lower, in the range of 10-25 %, with regular testing. though specifi c studies in pregnant women are lacking, the likely pathogens are not considered to be signifi cantly different • less severe symptoms • pefr between 50-80% predicted [ 19 ] . pregnant women may be more likely to contract viral infections and tend to have more severe disease than the nonpregnant population. therefore, the estimates above may be somewhat different in pregnancy. gingival hyperplasia in pregnancy may promote changes in oral fl ora and promote growth of anaerobic bacteria. aspiration risk and heartburn [ 11 ] may be increased in pregnancy, especially when undergoing sedative procedures or general anesthesia. whether these changes and increased gastroesophageal refl ux disorders are associated with increased risk of pneumonia is not clear. immune alterations in pregnancy that promote maternal tolerance to the fetus may impair optimal function of host defense mechanisms and increase the risk of infections. pregnant women have decreased lung capacity and decreased erv and rv resulting in a reduction in functional residual capacity. a state of compensated respiratory alkalosis is established by increasing minute ventilation. this is largely secondary to an increase in tidal volume and to a lesser extent an increase in respiratory rate. healthy gravid subjects have increased cardiac output and decreased oncotic pressure which peaks in the third trimester that promotes transudation of fl uid into the pulmonary interstitium. these changes diminish oxygen reserve, increase the risk of development of pulmonary edema with fl uid resuscitation, and predispose to respiratory failure and predispose women to more severe disease. pneumonia may be complicated by hypoxia, respiratory failure, or death, and preterm delivery appears to be the most common obstetric complication associated with maternal pneumonia. while intrauterine infection is known to cause preterm delivery, a causal relationship between pneumonia in pregnancy and preterm delivery is not well established. it is possible that higher levels of cytokines and other mediators such as tnf-α and prostaglandin f2 reported in bacterial infections may lead to preterm delivery and low birth weight. other reported complications include placental abruption, preeclampsia and eclampsia, and low apgar scores [ 20 -22 ] . it is unclear, however, whether these complications are related to the actual infection or to other host factors. common causes for respiratory distress in pregnancy include infection such as urinary tract infection, pulmonary edema, asthma, aspiration, and pulmonary embolus. the clinical spectra of pneumonia caused by different pathogens overlap considerably. thorough history and examination along with microscopic examination of respiratory secretions may narrow the differential diagnosis and identify the offending pathogen. urine pneumococcal and legionella antigen may also aid in guiding antibiotic therapy and should be considered for patients requiring admission. during infl uenza seasons, respiratory viral panel should be sent. though blood cultures are usually negative and of low yield, they may add value in the patient requiring admission to the intensive care unit (icu). arterial blood gas should be done for all patients with hypoxia or those requiring admission to the icu and interpreted according to pregnant status. chest x-ray should be performed in patients suspected of having pneumonia and helps confi rm the diagnosis or show evidence of a complicated pneumonia such as lung abscess or pleural effusion. computed tomography scan is unlikely to add value in the management of pneumonia, unless empyema is suspected. ultrasound guidance likely reduces the risk of complications with thoracentesis in pregnancy given the cranial displacement of the diaphragm in pregnancy. bronchoscopy though rarely needed can be performed safely in pregnancy and should not be withheld when indicated. general supportive measures are similar in patients with various types of pneumonia. for patients with a viable fetus who require admission, the obstetric team should be consulted for fetal monitoring as well as timing of delivery in the event of fetal distress. hypoxia, acidosis, and fever should not be tolerated as they are independently associated with poor fetal outcomes. oxygen should be supplemented for goal saturations > 95 % or pao 2 above 70. fever should be treated aggressively for a goal temp of less than 38 °c. in cases of severe pneumonia associated with respiratory failure, early intubation should be considered. intubations in pregnancy have a higher failure rate than the general surgical population (see chap. 2 on airway intubation ). attempts to maintain co 2 within an acceptable range may be challenging in the event of acute respiratory distress syndrome (ards) and the use of lung protective strategies. low tidal volume ventilation strategy with a target tidal volume of 6 ml/kg is recommended for ards [ 23 ] . though pregnant women were excluded in the acute respiratory distress network studies on lung protective strategies, low tidal volume ventilation should be attempted, initially with a higher respiratory rate to maintain ventilation given the survival benefi t observed in the nonpregnant population. however, higher tidal volumes may be required to correct acidosis that may compromise the fetus, in such instances attempts should still be made to keep the plateau pressure below 30 cm of water as barotrauma is thought to contribute signifi cantly to lung injury. paco 2 levels need to be watched closely, and given the 10 mmhg gradient between fetal and maternal, maternal paco 2 should be kept at 55 mmhg or lower. use of bicarbonate to correct the ph has been suggested in the nonpregnant population though clinical studies to support this approach are limited. it is thought that the transfer of bicarbonate across the placenta is slow and may not be adequate to correct fetal acidosis. while the decision to admit patients to the icu is complex and should be individualized, clinicians should have a lower threshold when evaluating pregnant mothers. antibiotic therapy should be initiated empirically while awaiting confi rmatory tests that may aid in narrowing the antimicrobial coverage. in infl uenza season, antiviral (usually oseltamivir) should be started empirically as well. decisions about antibiotic choice should address the most likely pathogen, adverse effect on the mother, and should also weigh the risk of the specifi c drug to the fetus against the risk of inappropriately treated disease. an optimal drug would be one with maximal efficacy against the known pathogen and no risk to the fetus. however, such drugs are scarce, and in most circumstances, a drug with more benefi t than risk can be selected. other than concern for fetal safety, preferred antibiotics are not different from those in nonpregnant women, but dosing should take into account increased hepatic and renal clearance and increased volume of distribution. there is a theoretical concern that aminoglycosides and vancomycin may be associated with hearing and kidney dysfunction in the offspring, but this possibility has not been confi rmed clinically. penicillins, clindamycins, and most macrolides except clarithromycin have a good safety profi le. fluoroquinolones are usually avoided in pregnancy due to a theoretical risk of arthropathy in the offspring. however, some experts argue that this issue is not clinically signifi cant in humans. tetracyclines should be avoided as they may cause permanent dental discoloration. varicella (chicken pox) is caused by varicella zoster virus (vzv). varicella is predominantly a childhood illness that is usually self-limited and rarely results in severe disease. in adults, however, it is much more likely to be severe. vzv is not only likely to have increased morbidity and mortality in pregnancy but may also be associated with congenital abnormalities and poor fetal outcomes. varicella pneumonia is among the most severe maternal complication of vzv infection [ 24 -27 ] . viral particles are shed from varicella-associated vesicles and get airborne. inhalation or contact with the conjunctiva results into contraction of the infection with entry of the virus through the respiratory mucosa. crusting over of the last crop of vesicles usually marks the end of the contagious period. patients are known to be infectious 2-3 days prior to development of the vesicular rash; for this reason, an alternative viral shedding site such as the respiratory tract is believed to exist [ 28 ] . varicella is highly contagious with seasonal variation in incidence, being most prevalent in the winter and spring. it has a very high clinical attack rate of 65-86 % following exposure to susceptible individuals [ 29 ] . following a primary infection with varicella, lifelong immunity is usually established in the majority of subjects; in a few people, however, second attacks of varicella may occur [ 30 ] . while varicella follows a benign course in children, adults have up to 25 times increased risk of severe disease [ 31 ] . pregnant women are at a uniquely increased risk for infection. in the united states, the incidence of primary varicella averages 0.7-3 cases/1,000 pregnancies. varicella pneumonia complicates 10-20 % of all cases, and 40 % of mothers with pneumonia require mechanical ventilation [ 32 , 33 ] . maternal mortality from varicella pneumonia used to be high at 20-45 % before the introduction of antiviral therapy but is currently estimated at less than 3-14 % [ 34 , 35 ] . changes in physiology and immunity associated with pregnancy may increase the risk of infection and severe outcomes in the pregnant women. in an effort to promote maternal tolerance to fetal antigens, pregnancy is associated with a shift from th1 to th2 lymphocyte responses and associated cytokines at the maternal fetal interface. macrophage and lymphocyte-secreted th2 cytokines stimulate b lymphocytes promoting a humoral response while suppressing cytotoxic lymphocytes. while pregnancy may not necessarily be an immune-suppressed state in the real sense, immunity against vzv infection is primarily cell mediated, and a systemic shift away from cell-mediated immunity may increase susceptibility to intracellular viral pathogens, parasites, and bacteria. primary varicella (chicken pox) is associated with several adverse effects in pregnancy such as preterm delivery and low birth weight. in one study involving 106 pregnant women with varicella compared to a similar number of noninfected controls, 14.3 % of pregnant women with chicken pox had a preterm delivery as compared to 5.6 % of controls [ 36 ] . low birth weight and intrauterine growth restriction have been described. nearly 1-2 % of cases of maternal primary vzv infection result in congenital varicella syndrome (cvs), which is associated with a mortality of up to 30 % in the fi rst few months of life and severe disability in survivors. primary vzv infection prior to the 20th week of pregnancy is associated with the highest risk for cvs [ 24 , 36 ] . clinical features of cvs include skin lesions in a dermatomal distribution that may lead to eventual scarring in up to 70 % of cases, muscle and limb hypoplasia in up to 72 % of cases, chorioretinitis and cataracts in up to 52 % of cases, and abnormalities of gastrointestinal, genitourinary, and cardiovascular system in 7-24 % of cases [ 37 , 38 ] . neurological abnormalities such as mental retardation, microcephaly, and hydrocephalus occur in 48-62 % of cases resulting in learning diffi culties and developmental delays [ 39 ] . the pathobiology of cvs is thought to be in utero reactivation similar to that of herpes zoster with a shortened latency period that is likely due to immature fetal cell-mediated immunity. while up to 25 % of babies born to mothers with primary vzv infection have serologic evidence of infection, there is no serologic evidence of infection in babies born to mothers with herpes zoster. similarly, infants do not appear to be at risk of infection if maternal zoster occurs near delivery [ 40 ] . unless disseminated, herpes zoster is thus not associated with a signifi cant increase in adverse fetal outcomes [ 37 , 41 ] . peripartum varicella infection places the infant at risk for neonatal varicella, which is associated with mortality rate as high as 20 %. following a 2-to 3-week incubation period, fever, headache, malaise, anorexia, and other constitutional symptoms precede the occurrence of the rash by 2-3 days. the rash is typically vesicular, generalized, and intensely pruritic. varicella pneumonia can develop anywhere from day 1 to day 6 after the onset of the rash. late onset of respiratory symptoms with recurrence of fevers is suggestive of bacterial coinfection rather than primary viral pneumonia. skin superinfection with staphylococcal bacteremia and neurological involvement with encephalitis may occur. a thorough history and skin exam may strongly suggest the diagnosis of varicella. chest radiograph pattern in varicella pneumonia is nonspecifi c and may be normal or show unilateral or patchy areas of consolidation or nodular opacities. ct fi ndings include multicentric hemorrhage and necrosis centered around the airways and small nodular opacities surrounded by ground glass which may coalesce to form consolidations. healed and calcifi ed pulmonary nodules may persist [ 42 ] . skin lesion (rather than bronchoscopic) sampling offers a high yield and should be attempted fi rst. the base of newly erupted vesicles has the highest yield and should be sampled. specimens can then be sent for viral culture, polymerase chain reaction (pcr), and immunofl uorescence (dfa). direct fl uorescent antibody test is rapidly available in most institutions. though bronchoscopy in most cases is not necessary, varicella may be recovered from bronchial washings by viral pcr and viral culture techniques. pregnant women suspected of having varicella should be admitted for initiation of antivirals and other supportive treatment. chest imaging should be performed on admission to evaluate for pulmonary involvement. antiviral therapy is associated with a reduction in the duration of symptoms when initiated within the fi rst 24 h of onset of the varicella rash. due to the high risk of varicella pneumonia in pregnancy, empiric antiviral therapy should be initiated while awaiting confi rmatory results. acyclovir or valacyclovir are the antivirals of choice. oral acyclovir has low bioavailability that requires it to be administered in frequent doses to achieve therapeutic levels. valacyclovir has high oral bioavailability and less frequent dosing intervals and is an alternative oral formulation. there is however less experience with valacyclovir compared to acyclovir. presence of pulmonary symptoms should prompt admission to the icu and initiation of intravenous acyclovir which has a guaranteed and higher bioavailability. antiviral therapy is associated with significantly less morbidity and mortality when initiated prior to 72 h. late presentation with varicella pneumonia should not obviate the initiation of antiviral therapy. a dose of 10-15 mg/kg intravenously every 8 h for 5-10 days is recommended for vzv pneumonia. pulmonary bacterial superinfection may occur. studies characterizing bacterial pathogens likely to cause superinfection are lacking. thus, empiric broad-spectrum antibiotic coverage should be initiated in pregnant women with pneumonia. despite acyclovir crossing the placenta in signifi cant amounts, there appears to be no reduction in congenital varicella syndrome with treatment. the neonate should be isolated from the mother in the peripartum period until the mother is deemed noncontagious. consultation with high-risk obstetrics and neonatology would be useful given the risk of preterm labor and growth restriction. immunity to varicella consists of both vzv-specifi c neutralizing antibodies and cell-mediated immunity. immunity against vzv can be assessed by the use of antibody serologic assays. though there are no adequate controlled trials examining the effectiveness of vzig prophylaxis, vzig is associated with more than 40-50 % reduction in risk of contracting varicella and a signifi cant reduction in risk of severe disease [ 40 ] . vzv can be prevented by vaccination. vzv vaccine is a live attenuated vaccine and is generally not recommended in pregnancy and in immune-suppressed individuals. varicella can be contracted from herpes zoster lesions as well. family members with such lesions should minimize contact and cover their lesions to decrease the risk of transmission. healthcare workers who deal with pregnant women should be screened and vaccinated, and similarly pregnant healthcare workers should avoid contact or exposure to patients with varicella. infection with infl uenza virus can result in an acute respiratory illness of varying severity. the majority of healthy individuals infected with infl uenza is asymptomatic or has minimal symptoms. however, adults with comorbidities, elderly subjects, and healthy pregnant women are at increased risk of severe disease and death. in addition, infl uenza infection during pregnancy increases the risk of adverse fetal outcomes. in a regular endemic season, infl uenza is estimated to result in 200,000 hospitalizations and 36,000 deaths in the united states. pregnant women are at increased risk for morbidity (including cardiorespiratory complications) and mortality from infl uenza compared with nonpregnant controls [ 43 -46 ] that is more pronounced in the second and third trimester of pregnancy [ 47 ] . in 2010, the pandemic h1n1 infl uenza in pregnancy working group reported on 788 pregnant women in the united states with 2009 infl uenza a(h1n1). among those, 30 died (5 % of all reported 2009 infl uenza a (h1n1) infl uenza deaths in this period). most hospitalizations and deaths occurred in the third trimester [ 47 ] . pregnant women with comorbidities or those who smoke have an increased risk for severe disease requiring hospital admission compared to those without comorbidities [ 48 , 49 ] . as discussed above, these physiological changes make pregnant women more susceptible to acquiring viral infections and subsequent development of severe disease. apart from direct effects to the mother, infl uenza has been associated with undesirable effects to the fetus. risks of adverse fetal outcomes vary with the severity of maternal disease. preterm delivery appears to be the most common and consistent complication associated with infl uenza pandemics. in the pandemic of 1918 and 1957, higher rates of pregnancy loss, premature delivery, preterm deliveries, as well as other adverse effects were reported. in several reports during the pandemic infl uenza of 2009 among pregnant women requiring admission, preterm delivery was close to 30 % and was even higher among mothers who were admitted to the icu [ 48 , 50 , 51 ] . several other adverse fetal outcomes of maternal infl uenza have been reported especially during pandemics, including abortion, fetal distress, and placenta abruption [ 50 , 52 ] . symptoms of infl uenza in pregnancy are similar to symptoms outside of pregnancy. infl uenza virus-mediated leukopenia may make the host more susceptible to bacterial infections. secondary bacterial pneumonia is characterized by the appearance of a new fever and productive cough during early convalescence. radiologic fi ndings are generally similar to other viral pneumonias, and more extensive fi ndings are associated with more severe complications. tree in bud opacities may also be seen. laboratory fi ndings may include an elevated or low white count, lymphopenia, and hyponatremia. myoglobinuria and renal failure can occur rarely. cardiac muscle damage with associated electrocardiographic changes, disturbances of rhythm, and high levels of cardiac enzymes have been reported after infl uenza virus infection. sputum cultures may be revealing in the event of bacterial superinfection. streptococcus pneumoniae , staphylococcus aureus , haemophilus infl uenzae , and group a hemolytic streptococci are the bacterial pathogens most commonly isolated in adults with infl uenza. a defi nitive diagnosis of infl uenza requires laboratory confi rmation. diagnostic tests for infl uenza fall into four broad categories: virus isolation [culture], detection of viral proteins, detection of viral nucleic acid, and serological diagnosis. detection of viral nucleic acid allows for typing and subtyping of the specifi c virus strain. treatment of infl uenza consists of supportive management and specifi c antiviral therapy. optimizing supportive treatment is central to the management of infl uenza and probably of more benefi t than specifi c antiviral therapy. supportive therapy is similar to other types of pneumonia as discussed above. as with most drugs, information about safety and effectiveness of anti-infl uenza drugs during pregnancy is scarce. in view of potential severe maternal disease from infl uenza and adverse fetal outcomes, benefi ts of treatment with antivirals likely outweigh the potential risks to the fetus. there are two classes of antiviral drugs currently in general clinical use: adamantanes, (examples of which include amantadine and rimantadine) and neuraminidase inhibitors such as oseltamivir, zanamivir, and peramivir . adamantanes are active against infl uenza a only, increase infl uenza a resistance to adamantanes, and are associated with embryotoxicity in animal studies. as such they are not recommended in pregnancy. neuraminidase inhibitors are active against infl uenza a and b viruses. they are preferred in all adults and in pregnancy. though studies in pregnancy are inadequate, extensive use of oseltamivir in pregnancy during the 2009 hin1 pandemic was not associated with adverse effects specifi c to the drug. neuraminidase inhibitors reduce the duration and severity of symptoms and duration of viral shedding when initiated within 48 h of symptom onset [ 43 , 48 , 53 , 54 ] . there is also evidence to support reduction in complication rate, duration of hospitalization, and mortality in adults. observational studies published during the 2009 pandemic demonstrated that, among pregnant women hospitalized with pandemic h1n1 infection, treatment with oseltamivir was associated with fewer intensive care unit admissions, less use of mechanical ventilation, and decreased mortality [ 43 , 48 ] . empiric treatment should always be initiated in the gravid woman when infl uenza is suspected while awaiting confi rmatory results as delay in initiation of treatment is associated with an increased risk of severe outcomes, icu admission, and death [ 48 , 49 , 55 ] . pregnant mothers presenting after 48 h of symptom onset should still be initiated on therapy as there is evidence of benefi t even when initiated after 2 days of symptom onset. initiation of antiviral therapy within the fi rst 48 h is associated with the most benefi t [ 43 , 48 , 49 , 53 , 56 ] . there is less experience with zanamivir which is administered by inhalation route. zanamivir is also contraindicated in patients with asthma as it has a potential of worsening respiratory symptoms [ 57 ] . for patients requiring admission to icu for infl uenza pneumonia or in cases of suspected secondary bacterial infection, empiric antibiotic therapy should be initiated. sputum culture may be helpful in the case of isolation of resistant bacteria that may warrant changes or broadening of antibiotic coverage. in pregnant women, infl uenza vaccination induces an antibody response similar to that in nonpregnant women. cdc and who recommend pregnant women or women who will be pregnant during the winter or peak infl uenza season to be prioritized for vaccination. in addition to protection to the mothers, infl uenza vaccination may offer protection to the neonate as well as contribute to herd immunity in other family members. pregnant mothers who have not been vaccinated or those with comorbidities such as asthma who have been exposed to infl uenza may benefi t from antiviral prophylaxis. oseltamivir is preferred for prophylaxis due to its ease of administration. sleep-disordered breathing (sdb) is a spectrum of disorders that encompasses snoring and upper airway resistance, obstructive sleep apnea (osa), and other disorders. osa is a disorder characterized by periodic and recurrent collapse of the upper airway during sleep. obesity, age, and upper airway and facial abnormalities are the most recognized risk factors for the disorder. osa is prevalent in patients with chronic hypertension, cardiovascular disease, and metabolic disorders such as diabetes mellitus. the pregnant population appears to be at risk for the disorder given anatomic upper airway changes that occur in pregnancy as well as physiological changes and hormones. snoring occurs in close to 35 % of pregnant women [ 58 ] . the prevalence of osa in pregnancy is not well known, but preliminary data suggest that close to 60 % of loud snorers in pregnancy have at least mild osa. the natural history of snoring around pregnancy is, however, unclear. there are some data suggesting that osa actually improves in untreated postpartum women around 3 months after delivery. data on osa predating pregnancy is missing and pregestational and gestational osa may have different clinical consequences. there is a signifi cant lack in screening for the disorder by obstetric providers according to a recent study, even in obese patients [ 59 ] . notably, the berlin questionnaire, a widely used screening tool in the nonpregnant population, appears to have poor positive and negative predictive values in pregnancy [ 60 ] . snoring and excessive daytime sleepiness may be important predictors [ 61 ] . chronic hypertension, age, obesity, and snoring appear to have a good predictive value for osa in high-risk populations [ 62 ] . further validation of this potential predictive model in different pregnant populations is needed. snoring and osa have been shown to be associated with a variety of adverse pregnancy outcomes including gestational hypertension, gestational diabetes, and cesarean deliveries. gestational hypertension is the most studied link with numerous studies on snoring as well as osa showing a two-to threefold increased risk of gestational hypertension in snorers, even after adjusting for confounders such as body mass index [ 63 ] . mechanistic studies are lacking and the directionality of the association not well clarifi ed, but it is possible that intermittent hypoxia, fl ow limitation, poor sleep, and arousals may play a role in causing endothelial dysfunction, infl ammation, and hypercoagulability that are common to the two disorders. a few studies to date have also shown worse abnormalities in glucose metabolism and a higher prevalence of gestational diabetes in women complaining of loud snoring and poor sleep [ 58 , 64 ] . gestational diabetes has been associated with a fi vefold increase in the risk of type ii diabetes at 5 years and a ninefold risk at 9 years [ 65 ] . snoring, poor sleep, and osa have all been associated with a higher risk of unplanned cesarean deliveries. this association may be harder to explain and may depend on the actual reason leading to unplanned cesarean delivery such as obstetric, fetal, or medical causes. the impact of sdb on fetal and neonatal outcomes has also been studied, but the results of such studies have been more confl icting. growth restriction has been reported to be associated with snoring in some studies but not in others. the effect on apgar scores also appears to be controversial. there are some case reports and case series suggesting fetal decelerations secondary to sleep apnea, but a recent study evaluating synchronized limited sleep studies and fetal monitors have failed to show a signifi cantly higher prevalence of late decelerations [ 60 ] . once diagnosed, treatment of osa is approved in patients with an apnea hypopnea index ahi >15 or those with ahi >5 who have symptoms that are known to respond to therapy such as daytime sleepiness. there are no specifi c guidelines on therapy initiation in pregnancy yet for various reasons. as stated above, the natural history of the disorder around the perinatal period is not well known. thus, it is possible that, with weight loss and reversal of pregnancy physiology, the disorder may resolve or at least improve in the postpartum period. in addition, there have been no trials to date that have shown that treatment of osa in pregnancy would improve pregnancy or fetal outcomes. this reason likely contributes to the fact that the disorder remains underscreened and underdiagnosed [ 59 ] . based on current data, weight loss is unlikely to be an option in pregnancy because of concern that it may affect the nutritional status of the mother and therefore fetal well-being. alcohol and cigarette smoking avoidance is another therapeutic strategy in pregnancy that carries additional pregnancy-specifi c benefi ts. outside of pregnancy, cpap therapy has been shown to improve quality of life and daytime sleepiness with some data suggesting improvement in cardiovascular outcomes such as hypertension. it is likely that these effects of cpap are also true in pregnancy. observational studies have shown improvement in daytime fatigue and daytime somnolence in pregnant women with osa treated with cpap and re-titrated around midpregnancy [ 66 ] . in women with preeclampsia, small, randomized trials have shown that in-laboratory positive airway pressure therapy improves hemodynamics, uric acid, and cardiac output compared to untreated women [ 67 , 68 ] . until future studies of cpap therapy are available in pregnancy, indications for therapy are likely the same as in the nonpregnant population. we are awaiting trials evaluating the effect of pap therapy on pregnancy-specifi c outcomes to be able to determine the "urgency" of starting pap therapy in pregnancy. the type of pap therapy that is most benefi cial in pregnancy is unknown. however, auto-titrating pap therapy has the advantage of avoiding repeat re-titration of pressure requirements. in summary, pregnant women with the above disorders need to be managed with pregnancy physiology and fetal effects of the disease and the therapy in mind. the course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis acute asthma during pregnancy a comprehensive analysis of adverse obstetric and pediatric complications in women with asthma asthma during pregnancy-a population based study infant and maternal outcomes in the pregnancies of asthmatic women obstetric complications among us women with asthma psychosocial variables are related to future exacerbation risk and perinatal outcomes in pregnant women with 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sleep-disordered breathing patient and provider perceptions of sleep disordered breathing assessment during prenatal care: a survey-based observational study prospective trial on obstructive sleep apnea in pregnancy and fetal heart rate monitoring excessive daytime sleepiness in late pregnancy may not always be normal: results from a cross sectional study development of a pregnancy-specifi c screening tool for sleep apnea sleep-disordered breathing in pregnancy glucose intolerance and gestational diabetes risk in relation to sleep duration and snoring during pregnancy: a pilot study type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis pregnancy, sleep disordered breathing and treatment with nasal continuous positive airway pressure reduced nocturnal cardiac output associated with preeclampsia is minimized with the use of nocturnal nasal cpap nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in preeclampsia key: cord-016704-99v4brjf authors: nicholson, felicity title: infectious diseases: the role of the forensic physician date: 2005 journal: clinical forensic medicine doi: 10.1385/1-59259-913-3:235 sha: doc_id: 16704 cord_uid: 99v4brjf infections have plagued doctors for centuries, in both the diagnosis of the specific diseases and the identification and subsequent management of the causative agents. there is a constant need for information as new organisms emerge, existing ones develop resistance to current drugs or vaccines, and changes in epidemiology and prevalence occur. in the 21st century, obtaining this information has never been more important. population migration and the relatively low cost of flying means that unfamiliar infectious diseases may be brought into industrialized countries. an example of this was an outbreak of severe acute respiratory syndrome (sars), which was first recognized in 2003. despite modern technology and a huge input of money, it took months for the agent to be identified, a diagnostic test to be produced, and a strategy for disease reporting and isolation to be established. there is no doubt that other new and fascinating diseases will continue to emerge. infections have plagued doctors for centuries, in both the diagnosis of the specific diseases and the identification and subsequent management of the causative agents. there is a constant need for information as new organisms emerge, existing ones develop resistance to current drugs or vaccines, and changes in epidemiology and prevalence occur. in the 21st century, obtaining this information has never been more important. population migration and the relatively low cost of flying means that unfamiliar infectious diseases may be brought into industrialized countries. an example of this was an outbreak of severe acute respiratory syndrome (sars), which was first recognized in 2003. despite modern technology and a huge input of money, it took months for the agent to be identified, a diagnostic test to be produced, and a strategy for disease reporting and isolation to be established. there is no doubt that other new and fascinating diseases will continue to emerge. for the forensic physician, dealing with infections presents two main problems. the first problem is managing detainees or police personnel who have contracted a disease and may be infectious or unwell. the second problem is handling assault victims, including police officers, who have potentially been exposed to an infectious disease. the latter can be distressing for those involved, compounded, in part, from an inconsistency of management guidelines, if indeed they exist. with the advent of human rights legislation, increasing pressure is being placed on doctors regarding consent and confidentiality of the detainee. therefore, it is prudent to preempt such situations before the consultation begins by obtaining either written or verbal consent from the detainee to allow certain pieces of information to be disclosed. if the detainee does not agree, then the doctor must decide whether withholding relevant details will endanger the lives or health of those working within custody or others with whom they may have had close contact (whether or not deliberate). consent and confidentiality issues are discussed in detail in chapter 2. adopting a universal approach with all detainees will decrease the risk to staff of acquiring such diseases and will help to stop unnecessary overreaction and unjustified disclosure of sensitive information. for violent or sexual assault victims, a more open-minded approach is needed (see also chapter 3) . if the assailant is known, then it may be possible to make an informed assessment of the risk of certain diseases by ascertaining his or her lifestyle. however, if the assailant is unknown, then it is wise to assume the worst. this chapter highlights the most common infections encountered by the forensic physician. it dispels "urban myths" and provides a sensible approach for achieving effective management. the risk of exposure to infections, particularly blood-borne viruses (bbvs), can be minimized by adopting measures that are considered good practice in the united kingdom, the united states, and australia (1) (2) (3) . forensic physicians or other health care professionals should wash their hands before and after contact with each detainee or victim. police officers should be encouraged to wash their hands after exposure to body fluids or excreta. all staff should wear gloves when exposure to body fluids, mucous membranes, or nonintact skin is likely. gloves should also be worn when cleaning up body fluids or handling clinical waste, including contaminated laundry. single-use gloves should only be used and must conform to the requirements of european standard 455 or equivalent (1) (2) (3) . a synthetic alternative conforming to the same standards should also be available for those who are allergic to latex. all staff should cover any fresh wounds (<24 hours old), open skin lesions, or breaks in exposed skin with a waterproof dressing. gloves cannot prevent percutaneous injury but may reduce the chance of acquiring a bloodborne viral infection by limiting the volume of blood inoculated. gloves should only be worn when taking blood, providing this does not reduce manual dexterity and therefore increase the risk of accidental percutaneous injury. ideally, a designated person should be allocated to ensure that the clinical room is kept clean and that sharps containers and clinical waste bags are removed regularly. clinical waste must be disposed of in hazard bags and should never be overfilled. after use, the clinical waste should be doublebagged and sealed with hazard tape. the bags should be placed in a designated waste disposal (preferably outside the building) and removed by a professional company. when cells are contaminated with body fluids, a professional cleaning company should be called to attend as soon as possible. until such time, the cell should be deemed "out of action." there is a legal requirement in the united kingdom under the environmental protection act (1990) and the control of substances hazardous to health regulations 1994 to dispose of sharps in an approved container. in the united states, the division of health care quality promotion on the centers for disease control and prevention (cdc) web site provides similar guidance. in custody, where sharps containers are transported off site, they must be of an approved type. in the united kingdom, such a requirement is contained within the carriage of dangerous goods (classification, packaging and labelling) and use of transportable pressure receptacles regulations 1996. these measures help to minimize the risk of accidental injury. further precautions include wearing gloves when handling sharps and never bending, breaking, or resheathing needles before disposal. sharps bins should never be overfilled, left on the floor, or placed above the eye level of the smallest member of staff. any bedding that is visibly stained with body fluids should be handled with gloves. there are only three acceptable ways of dealing with contaminated bedding: the bbvs that present the most cross-infection hazard to staff or victims are those associated with persistent viral replication and viremia. these include hbv, hcv, hepatitis d virus (hdv), and hiv. in general, risks of transmission of bbvs arise from the possible exposure to blood or other body fluids. the degree of risk varies with the virus concerned and is discussed under the relevant sections. figure 1 illustrates the immediate management after a percutaneous injury, mucocutaneous exposure, or exposure through contamination of fresh cuts or breaks in the skin. hbv is endemic throughout the world, with populations showing a varying degree of prevalence. approximately two thousand million people have been infected with hbv, with more than 350 million having chronic infection. worldwide, hbv kills about 1 million people each year. with the development of a safe and effective vaccine in 1982, the world health organization (who) recommended that hbv vaccine should be incorporated into national immunization programs by 1995 in those countries with a chronic infection rate of 8% or higher, and into all countries by 1997. although 135 countries had achieved this goal by the end of 2001, the poorest countries-often the ones with the highest prevalence-have been unable to afford it. in particular these include china, the indian subcontinent, and sub-saharan africa. people in the early stages of infection or with chronic carrier status (defined by persistence of hepatitis b surface antigen [hbsag] beyond 6 mo) can transmit infection. in the united kindgom, the overall prevalence of chronic hbv is approx 0.2-0.3% (6, 7) . a detailed breakdown is shown in table 1 . the incubation period is approx 6 weeks to 6 months. as the name suggests, the virus primarily affects the liver. typical symptoms include malaise, anorexia, nausea, mild fever, and abdominal discomfort and may last from 2 days to 3 weeks before the insidious onset of jaundice. joint pain and skin rashes may also occur as a result of immune complex formation. infections in the newborn are usually asymptomatic. * in the united kingdom, written consent from the contact must be sent with the sample, countersigned by the health care practitioner and, preferably, an independent police officer. the majority of patients with acute hbv make a full recovery and develop immunity. after acute infection, approx 1 in 300 patients develop liver failure, which may result in death. chronic infection develops in approx 90% of neonates, approx 50% of children, and between 5 and 10% of adults. neonates and children are usually asymptomatic. adults may have only mild symptoms or may also be asymptomatic. approximately 15-25% of chronically infected individuals (depending on age of acquisition) will develop cirrhosis over a number of years. this may also result in liver failure or other serious complications, including hepatocellular carcinoma, though the latter is rare. the overall mortality rate of hbv is estimated at less than 5%. a person is deemed infectious if hbsag is detected in the blood. in the acute phase of the illness, this can be as long as 6 months. by definition, if hbsag persists after this time, then the person is deemed a carrier. carriers are usually infectious for life. the degree of infectivity depends on the stage of disease and the markers present table 2 . the major routes include parenteral (e.g., needlestick injuries, bites, unscreened blood transfusions, tattooing, acupuncture, and dental procedures where equipment is inadequately sterilized), mucous membrane exposure (including mouth, eyes, and genital mucous membranes), and contamination of broken skin (especially when <24 hours old). hbv is an occupational hazard for anyone who may come into contact with blood or bloodstained body fluids through the routes described. saliva alone may transmit hbv. the saliva of some people infected with hbv contains hbv-dna concentrations 1/1000-1/10,000 of that found in their serum (8) . this is especially relevant for penetrating bite wounds. infection after exposure to other body fluids (e.g., bile, urine, feces, and cerebrospinal fluid) has never been demonstrated unless the fluids are contaminated with blood. intravenous drug users who share needles or other equipment are also at risk. hbv can also be transmitted through unprotected sexual contact, whether homosexual or heterosexual. the risk is increased if blood is involved. sexual assault victims should be included in this category. evidence has shown that the virus may also be spread among members of a family through close household contact, such as through kissing and sharing toothbrushes, razors, bath towels, etc. (9) (10) (11) . this route of transmission probably applies to institutionalized patients, but there are no available data. studies of prisoners in western countries have shown a higher prevalence of antibodies to hbv and other bbvs than the general population (12) (13) (14) ; the most commonly reported risk factor is intravenous drug use. however, the real frequency of transmission of bbvs in british prisons is unknown owing to the difficulty in compiling reliable data. hbv can be transmitted vertically from mother to baby during the perinatal period. approximately 80% of babies born to mothers who have either acute or chronic hbv become infected, and most will develop chronic hbv. this has been limited by the administration of hbv vaccine to the neonate. in industrialized countries, all prenatal mothers are screened for hbv. vaccine is given to the neonate ideally within the first 12 hours of birth and at least two more doses are given at designated intervals. the who recommends this as a matter of course for all women in countries where prevalence is high. however, the practicalities of administering a vaccine that has to be stored at the correct temperature in places with limited access to medical care means that there is a significant failure of vaccine uptake and response. in industrialized countries, hbv vaccination is recommended for those who are deemed at risk of acquiring the disease. they include the following: 1. through occupational exposure. 2. homosexual/bisexual men. 3. intravenous drug users. 4. sexual partners of people with acute or chronic hbv. 5. family members of people with acute or chronic hbv. 6. newborn babies whose mothers are infected with hbv. if the mother is hbsag positive, then hepatitis b-specific immunoglobulin (hbig) should be given at the same time as the first dose of vaccine. 7. institutionalized patients and prisoners. ideally, hbv vaccine should be administered before exposure to the virus. the routine schedule consists of three doses of the vaccine given at 0, 1, and 6 months. antibody levels should be checked 8-12 weeks after the last dose. if titers are greater than10 miu/ml, then an adequate response has been achieved. in the united kingdom, this is considered to provide protection for 5-10 years. in the united states, if an initial adequate response has been achieved, then no further doses of vaccine are considered necessary. vaccine administration after exposure varies according to the timing of the incident, the degree of risk involved, and whether the individual has already been partly or fully vaccinated. an accelerated schedule when the third dose is given 2 months after the first dose with a booster 1 year later is used to prevent postnatal transmission. where risks are greatest, it may be necessary to use a rapid schedule. the doses are given at 0, 7, and 21-28 days after presentation, again with a booster dose at 6-12 months. this schedule is currently only licensed with engerix b. hbig may also be used either alone or in conjunction with vaccine. the exact dose given is age dependent but must be administered by deep intramuscular injection in a different site from the vaccine. in an adult, this is usually into the gluteus muscle. hbig is given in conjunction with the first dose of vaccine to individuals who are deemed at high risk of acquiring disease and the incident occurred within 72 hours of presentation. it is also used for neonates born to mothers who are hbeag-positive. between 5 and 10% of adults fail to respond to the routine schedule of vaccine. a further full course of vaccine should be tried before deeming the patients as "nonresponders." such individuals involved in a high-risk exposure should be given two doses of hbig administered 1 mo apart. ideally, the first dose should be given within 48 hours after exposure and no later than 2 weeks after exposure. other measures include minimizing the risk of exposure by adopting the safe working practices outlined in subheading 2. any potential exposures should be dealt with as soon as possible. in industrialized countries blood, blood products, and organs are routinely screened for hbv. intravenous drug users should be encouraged to be vaccinated and to avoid sharing needles or any other drug paraphernalia (see subheading 6.9.2.). for staff or victims in contact with disease, it is wise to have a procedure in place for immediate management and risk evaluation. an example is shown in fig. 1 . although forensic physicians are not expected to administer treatment, it is often helpful to inform persons concerned what to expect. tables 3 and 4 outline treatment protocols as used in the united kingdom. detainees with disease can usually be managed in custody. if the detainee is bleeding, then the cell should be deemed out of action after the detainee has left until it can be professionally cleaned. contaminated bedding should be dealt with as described in subheading 2.2. if the detainee has chronic hbv and is on an antiviral agent (e.g., lamivudine), then the treatment course should be continued, if possible. hcv is endemic in most parts of the world. approximately 3% (200 million) of the world's population is infected with hcv (15) . for many countries, no reliable prevalence data exist. seroprevalence studies conducted among blood donors have shown that the highest prevalence exists in egypt (17-26%). this has been ascribed to contaminated needles used in the treatment of schistosomiasis conducted between the 1950s and the 1980s (16) . intermediate prevalence (1-5%) exists in eastern europe, the mediterranean, the middle east, the indian subcontinent, and parts of africa and asia. in western europe, most of central america, australia, and limited regions in africa, including south africa, the prevalence is low (0.2-0.5%). previously, america was included in the low prevalence group, but a report published in 2003 (17) indicated that almost 4 million americans (i.e., 1.8% of the population) have antibody to hcv, representing either ongoing or previous infection. it also states that hcv accounts for approx 15% of acute viral hepatitis in america. the lowest prevalence (0.01-0.1%) has been found in the united kingdom and scandinavia. however, within any country, there are certain groups that have a higher chance of carrying hcv. these united kingdom figures are given in table 5 . after an incubation period of 6-8 weeks, the acute phase of the disease lasts approx 2-3 years. unlike hepatitis a (hav) or hbv, the patient is usually asymptomatic; therefore, the disease is often missed unless the individual has reported a specific exposure and is being monitored. other cases are found by chance, when raised liver enzymes are found on a routine blood test. a "silent phase" follows the acute phase when the virus lies dormant and the liver enzymes are usually normal. this period lasts approx 10-15 years. reactivation may then occur. subsequent viral replication damages the hepatocytes, and liver enzymes rise to moderate or high levels. eighty percent of individuals who are hcv antibody-positive are infectious, regardless of the levels of their liver enzymes. approximately 80% of people develop chronic infection, one-fifth of whom progress to cirrhosis. there is a much stronger association with hepatocellular carcinoma than with hbv. an estimated 1.25-2.5% of patients with hcv-related cirrhosis develop liver cancer (18) . less than 2% of chronic cases resolve spontaneously. approximately 75% of cases are parenteral (e.g., needle-stick, etc.) (19) . transmission through the sexual route is not common and only appears to be significant if there is repeated exposure with one or more people infected with hcv. mother-to-baby transmission is considered to be uncommon but has been reported (20) . theoretically, household spread is also possible through sharing contaminated toothbrushes or razors. because the disease is often silent, there is a need to raise awareness among the general population on how to avoid infection and to encourage high-risk groups to be tested. health care professionals should also be educated to avoid occupationally acquired infection. an example of good practice blood or blood-stained body fluids need to be involved for a risk to occur. saliva alone is not deemed to be a risk. the risk from a single needlestick incident is 1.8% (range 0-7%). contact through a contaminated cut is estimated at 1%. for penetrating bite injuries, there are no data, but it is only considered a risk if blood is involved. blood or blood-stained body fluids have to be involved in transmission through mucous membrane exposure. this may account for the lower-than-expected prevalence among the gay population. follow the immediate management flow chart, making sure all available information is obtained. inform the designated hospital and/or specialist as soon as possible. if the contact is known and is believed to be immunocompromised and he or she has consented to provide a blood sample, it is important to tell the specialist, because the antibody tests may be spuriously negative. in this instance, a different test should be used (polymerase chain reaction [pcr] , which detects viral rna). the staff member/victim will be asked to provide a baseline sample of blood with further samples at 4-6 weeks and again at 12 weeks. if tests are negative at 12 weeks but the risk was deemed high, then follow-up may continue for up to 24 weeks. if any of the follow-up samples is positive, then the original baseline sample will be tested to ascertain whether the infection was acquired through the particular exposure. it is important to emphasize the need for prompt initial attendance and continued monitoring, because treatment is now available. a combination of ribavirin (antiviral agent and interferon a-2b) (18) or the newer pegylated interferons (15) may be used. this treatment is most effective when it is started early in the course of infection. unless they are severely ill, detainees can be managed in custody. special precautions are only required if they are bleeding. custody staff should wear gloves if contact with blood is likely. contaminated bedding should be handled appropriately, and the cell cleaned professionally after use. this defective transmissible virus was discovered in 1977 and requires hbv for its own replication. it has a worldwide distribution in association with hbv, with approx 15 million people infected. the prevalence of hdv is higher in southern italy, the middle east, and parts of africa and south america, occurring in more than 20% of hbv carriers who are asymptomatic and more than 60% of those with chronic hbv-related liver disease. despite the high prevalence of hbv in china and south east asia, hdv in these countries is rare. hdv is associated with acute (coinfection) and chronic hepatitis (superinfection) and can exacerbate pre-existing liver damage caused by hbv. the routes of transmission and at-risk groups are the same as for hbv. staff/victims in contact with a putative exposure and detainees with disease should be managed as for hbv. interferon-î± (e.g., roferon) can be used to treat patients with chronic hbv and hdv (21) , although it would not be practical to continue this treatment in the custodial setting. hiv was first identified in 1983, 2 years after the first reports were made to the cdc in atlanta, ga, of an increased incidence of two unusual diseases (kaposi's sarcoma and pneumocystis carinii pneumonia) occurring among the gay population in san francisco. the scale of the virus gradually emerged over the years and by the end of 2002, there were an estimated 42 million people throughout the world living with hiv or acquired immunodeficiency syndrome (aids). more than 80% of the world's population lives in africa and india. a report by the joint united nations programme on hiv/aids and the who in 2002 stated that one in five adults in lesotho, malawi, mozambique, swaziland, zambia, and zimbabwe has hiv or aids. there is also expected to be a sharp rise in cases of hiv in china, papua new guinea, and other countries in asia and the pacific during the next few years. in the united kingdom, by the end of 2002, the cumulative data reported that there were 54,261 individuals with hiv, aids (including deaths from aids) reported, though this is likely to be an underestimate (22) . from these data, the group still considered at greatest risk of acquiring hiv in the united kingdom is homosexual/bisexual men, with 28,835 of the cumulative total falling into this category. among intravenous drug users, the overall estimated prevalence is 1%, but in london the figure is higher at 3.7% (6, 23) . in the 1980s, up to 90% of users in edinburgh and dundee were reported to be hiv positive, but the majority have now died. individuals arriving from africa or the indian subcontinent must also be deemed a risk group because 80% of the world's total cases occur in these areas. the predominant mode of transmission is through unprotected heterosexual intercourse. the incidence of mother-to-baby transmission has been estimated at 15% in europe and approx 45% in africa. the transmission rates among african women are believed to be much higher owing to a combination of more women with end-stage disease with a higher viral load and concomitant placental infection, which renders it more permeable to the virus (24, 25) . the use of antiretroviral therapy during pregnancy, together with the advice to avoid breastfeeding, has proven efficacious in reducing both vertical and horizontal transmission among hiv-positive women in the western world. for those in third-world countries, the reality is stark. access to treatment is limited, and there is no realistic substitute for breast milk, which provides a valuable source of antibodies to other life-threatening infections. patients receiving blood transfusions, organs, or blood products where screening is not routinely carried out must also be included. the incubation is estimated at 2 weeks to 6 months after exposure. this depends, to some extent, on the ability of current laboratory tests to detect hiv antibodies or viral antigen. the development of pcr for viral rna has improved sensitivity. during the acute phase of the infection, approx 50% experience a seroconversion "flu-like" illness. the individual is infectious at this time, because viral antigen (p24) is present in the blood. as antibodies start to form, the viral antigen disappears and the individual enters the latent phase. he or she is noninfectious and remains well for a variable period of time (7-15 years). development of aids marks the terminal phase of disease. viral antigen reemerges, and the individual is once again infectious. the onset of aids has been considerably delayed with the use of antiretroviral treatment. parenteral transmission included needlestick injuries, bites, unscreened blood transfusions, tattooing, acupuncture, and dental procedures where equipment is inadequately sterilized. risk of transmission is increased with deep penetrating injuries with hollow bore needles that are visibly bloodstained, especially when the device has previously been in the source patient's (contact) artery or vein. other routes include mucous membrane exposure (eyes, mouth, and genital mucous membranes) and contamination of broken skin. the higher the viral load in the contact, the greater the risk of transmission. this is more likely at the terminal stage of infection. hiv is transmitted mainly through blood or other body fluids that are visibly blood stained, with the exception of semen, vaginal fluid, and breast milk. saliva alone is most unlikely to transmit infection. therefore, people who have sustained penetrating bite injuries can be reassured that they are not at risk, providing the contact was not bleeding from the mouth at the time. the risk from a single percutaneous exposure from a hollow bore needle is low, and a single mucocutaneous exposure is even less likely to result in infection. the risk from sexual exposure varies, although it appears that there is a greater risk with receptive anal intercourse compared with receptive vaginal intercourse (26). high-risk fluids include blood, semen, vaginal fluid, and breast milk. there is little or no risk from saliva, urine, vomit, or feces unless they are visibly bloodstained. other fluids that constitute a theoretical risk include cerebrospinal, peritoneal, pleural, synovial, or pericardial fluid. management in custody of staff/victims in contact with disease includes following the immediate management flow chart (fig. 1 ) and contacting the designated hospital/specialist with details of the exposure. where possible, obtain a blood sample from the contact. regarding hbv and hcv blood samples in the united kingdom, they can only be taken with informed consent. there is no need for the forensic physician to go into details about the meaning of the test, but the contact should be encouraged to attend the genitourinary department (or similar) of the designated hospital to discuss the test results. should the contact refuse to provide a blood sample, then any information about his or her lifestyle, ethnic origin, state of health, etc., may be useful for the specialist to decide whether postexposure prophylaxis (pep) should be given to the victim. where only saliva is involved in a penetrating bite injury, there is every justification to reassure the victim that he or she is not at risk. if in doubt, then always refer. in the united kingdom, the current recommended regime for pep is combivir (300 mg of zidovudine twice daily plus 150 mg of lamivudine twice daily) and a protease inhibitor (1250 mg of nelfanivir twice daily) given for 4 weeks (27) . it is only given after a significant exposure to a high-risk fluid or any that is visibly bloodstained and the contact is known or is highly likely to be hiv positive. ideally, treatment should be started within an hour after exposure, although it will be considered for up to 2 weeks. it is usually given for 4 weeks, unless the contact is subsequently identified as hiv negative or the "victim" develops tolerance or toxicity occurs. weekly examinations of the "victim" should occur during treatment to improve adherence, monitor drug toxicity, and deal with other concerns. other useful information that may influence the decision whether to treat with the standard regimen or use alternative drugs includes interaction with other medications that the "victim" may be taking (e.g., phenytoin or antibiotics) or if the contact has been on antiretroviral therapy or if the "victim" is pregnant. during the second or third trimester, only combivir would be used, because there is limited experience with protease inhibitors. no data exist regarding the efficacy of pep beyond occupational exposure (27) . pep is not considered for exposure to low-or no-risk fluids through any route or where the source is unknown (e.g., a discarded needle). despite the appropriate use and timing of pep, there have been reports of failure (28, 29) . unless they are severely ill, detainees can be kept in custody. every effort should be made to continue any treatment they may be receiving. apply universal precautions when dealing with the detainee, and ensure that contaminated cells and/or bedding are managed appropriately. cases of this highly infectious disease occur throughout the year but are more frequent in winter and early spring. this seasonal endemicity is blurring with global warming. in the united kingdom, the highest prevalence occurs in the 4-to 10-years age group. ninety percent of the population over the age of 40 is immune (30) . a similar prevalence has been reported in other parts of western europe and the united states. in south east asia, varicella is mainly a disease of adulthood (31) . therefore, people born in these countries who have moved to the united kingdom are more likely to be susceptible to chicken pox. there is a strong correlation between a history of chicken pox and serological immunity (97-99%). most adults born and living in industrialized countries with an uncertain or negative history of chicken pox are also seropositive (70-90%). in march 1995, a live-attenuated vaccine was licensed for use in the united states and a policy for vaccinating children and susceptible health care personnel was introduced. in summer 2002, in the united kingdom, glaxosmithkline launched a live-attenuated vaccine called varilrix. in december 2003, the uk department of health, following advice from the joint committee on vaccination and immunisation recommended that the vaccine be given for nonimmune health care workers who are likely to have direct contact with individuals with chicken pox. any health care worker with no previous history of chicken pox should be screened for immunity, and if no antibodies are found, then they should receive two doses of vaccine 4-8 weeks apart. the vaccine is not currently recommended for children and should not be given during pregnancy. following an incubation period of 10-21 days (this may be shorter in the immunocompromised), there is usually a prodromal "flu-like" illness before the onset of the rash. this coryzal phase is more likely in adults. the lesions typically appear in crops, rapidly progressing from red papules through vesicles to open sores that crust over and separate by 10 days. the distribution of the rash is centripetal (i.e., more over the trunk and face than on the limbs). this is the converse of small pox. in adults, the disease is often more severe, with lesions involving the scalp and mucous membranes of the oropharynx. in children, the disease is often mild, unless they are immunocompromised, so they are unlikely to experience complications. in adults (defined as 15 yr or older), the picture is rather different (32) . secondary bacterial infection is common but rarely serious. there is an increased likelihood of permanent scarring. hemorrhagic chicken pox typically occurs on the second or third day of the rash. usually, this is limited to bleeding into the skin, but lifethreatening melena, epistaxis, or hematuria can occur. varicella pneumonia ranges from patchy lung consolidation to overt pneumonitis and occurs in 1 in 400 cases (33) . it can occur in previously healthy individuals (particularly adults), but the risk is increased in those who smoke. immunocompromised people are at the greatest risk of developing this complication. it runs a fulminating course and is the most common cause of varicella-associated death. fibrosis and permanent respiratory impairment may occur in those who survive. any suspicion of lung involvement is an indication for immediate treatment, and any detainee or staff member should be sent to hospital. involvement of the central nervous system includes several conditions, including meningitis, guillain-barre, and encephalitis. the latter is more common in the immunocompromised and can be fatal. this is taken as 3 days before the first lesions appear to the end of new vesicle formation and the last vesicle has crusted over. this typically is 5-7 days after onset but may last up to 14 days. the primary route is through direct contact with open lesions of chicken pox. however, it is also spread through aerosol or droplets from the respiratory tract. chicken pox may also be acquired through contact with open lesions of shingles (varicella zoster), but this is less likely because shingles is less infectious than chicken pox. nonimmune individuals are at risk of acquiring disease. approximately 10% of the adult population born in the united kingdom and less than 5% of adults in the united states fall into this category. therefore, it is more likely that if chicken pox is encountered in the custodial setting, it will involve people born outside the united kingdom (particularly south east asia) or individuals who are immunocompromised and have lost immunity. nonimmune pregnant women are at risk of developing complications. pneumonia can occur in up to 10% of pregnant women with chicken pox, and the severity is increased in later gestation (34) . they can also transmit infection to the unborn baby (35) . if infection is acquired in the first 20 weeks, there is a less than 3% chance of it leading to congenital varicella syndrome. infection in the last trimester can lead to neonatal varicella, unless more than 7 days elapse between onset of maternal rash and delivery when antibodies have time to cross the placenta leading to either mild or inapparent infection in the newborn. in this situation, varicella immunoglobulin (vzig) should be administered to the baby as soon as possible after birth (36). staff with chicken pox should stay off work until the end of the infective period (approx 7-14 days). those in contact with disease who are known to be nonimmune or who have no history of disease should contact the designated occupational health physician. detainees with the disease should not be kept in custody if at all possible (especially pregnant women). if this is unavoidable, then nonimmune or immunocompromised staff should avoid entering the cell or having close contact with the detainee. nonimmune, immunocompromised, or pregnant individuals exposed to chickenpox should seek expert medical advice regarding the administration of vzig. aciclovir (or similar antiviral agent) should be given as soon as possible to people who are immunocompromised with chicken pox. it should also be considered for anyone over 15 years old because they are more likely to develop complications. anyone suspected of severe complications should be sent straight to the hospital. after chicken pox, the virus lies dormant in the dorsal root or cranial nerve ganglia but may re-emerge and typically involves one dermatome (37) . the site of involvement depends on the sensory ganglion initially involved. shingles is more common in individuals over the age of 50 years, except in the immunocompromised, when attacks can occur at an earlier age. the latter are also more susceptible to secondary attacks and involvement of more than one dermatome. bilateral zoster is even rarer but is not associated with a higher mortality. in the united kingdom, there is an estimated incidence of 1.2-3.4 per 1000-person years (38). there may be a prodromal period of paraesthesia and burning or shooting pains in the involved segment. this is usually followed by the appearance of a band of vesicles. rarely, the vesicles fail to appear and only pain is experienced. this is known as zoster sine herpete. in individuals who are immuno-compromised, disease may be prolonged and dissemination may occur but is rarely fatal. shingles in pregnancy is usually mild. the fetus is only affected if viremia occurs before maternal antibody has had time to cross the placenta. the most common complication of shingles is postherpetic neuralgia, occurring in approx 10% of cases. it is defined as pain lasting more than 120 days from rash onset (39) . it is more frequent in people over 50 years and can lead to depression. it is rare in children, including those who are immunocompromised. infection of the brain includes encephalitis, involvement of motor neurones leading to ptosis, paralysis of the hand, facial palsy, or contralateral hemiparesis. involvement of the oculomotor division of the trigeminal ganglion can cause serious eye problems, including corneal scarring. shingles is far less infectious than chicken pox and is only considered to be infectious up to 3 days after lesions appear. shingles is only infectious after prolonged contact with lesions. unlike chickenpox, airborne transmission is not a risk. individuals who are immunocompromised may reactivate the dormant virus and develop shingles. people who have not had primary varicella are at risk of developing chickenpox after prolonged direct contact with shingles. despite popular belief, it is untrue that people who are immunocompetent who have had chicken pox develop shingles when in contact with either chicken pox or shingles. such occurrences are merely coincidental, unless immunity is lowered. staff with shingles should stay off work until the lesions are healed, unless they can be covered. staff who have had chickenpox are immune (including pregnant women) and are therefore not at risk. if they are nonimmune (usually accepted as those without a history of chicken pox), they should avoid prolonged contact with detainees with shingles. pregnant nonimmune women should avoid contact altogether. detainees with the disease may be kept in custody, and any exposed lesions should be covered. it is well documented that prompt treatment attenuates the severity of the disease, reduces the duration of viral shedding, hastens lesion healing, and reduces the severity and duration of pain. it also reduces the likelihood of developing postherpetic neuralgia (40) . prompt treatment with famciclovir (e.g., 500 mg three times a day for 7 days) should be initiated if the onset is 3 d ays or less. it should also be considered after this time if the detainee is over age 50 years. pregnant detainees with shingles can be reassured that there is minimal risk for both the mother and the unborn child. expert advice should be given before initiating treatment for the mother. this tiny parasitic mite (sarcoptes scabiei) has infested humans for more than 2500 years. experts estimate that in excess of 300 million cases occur worldwide each year. the female mite burrows into the skin, especially around the hands, feet, and male genitalia, in approx 2.5 min. eggs are laid and hatch into larvae that travel to the skin surface as newly developed mites. the mite causes intense itching, which is often worse at night and is aggravated by heat and moisture. the irritation spreads outside the original point of infection resulting from an allergic reaction to mite feces. this irritation may persist for approx 2 weeks after treatment but can be alleviated by antihistamines. crusted scabies is a far more severe form of the disease. large areas of the body may be involved. the crusts hide thousands of live mites and eggs, making them difficult to treat. this so-called norwegian scabies is more common in the elderly or the immunocompromised, especially those with hiv. after a primary exposure, it takes approx 2-6 weeks before the onset of itching. however, further exposures reduce the incubation time to approx 1-4 days. without treatment, the period of infectivity is assumed to be indefinite. with treatment, the person should be considered infectious until the mites and eggs are destroyed, usually 7-10 days. crusted scabies is highly infectious. because transmission is through direct skin-to-skin contact with an infected individual, gloves should be worn when dealing with individuals suspected of infestation. usually prolonged contact is needed, unless the person has crusted scabies, where transmission occurs more easily. the risk of transmission is much greater in households were repeated or prolonged contact is likely. because mites can survive in bedding or clothing for up to 24 hour, gloves should also be worn when handling these items. bedding should be treated using one of the methods in subheading 2.2. professional cleaning of the cell is only warranted in cases of crusted scabies. the preferred treatment for scabies is either permethrin cream (5%) or aqueous malathion (0.5%) (41) . either treatment has to be applied to the whole body and should be left on for at least 8 hours in the case of permethrin and 24 hours for malathion before washing off. lindane is no longer considered the treatment of choice, because there may be complications in pregnancy (42) . treatment in custody may not be practical but should be considered when the detainee is believed to have norwegian scabies. like scabies, head lice occur worldwide and are found in the hair close to the scalp. the eggs, or nits, cling to the hair and are difficult to remove, but they are not harmful. if you see nits, then you can be sure that lice are also present. the latter are best seen when the hair is wet. the lice bite the scalp and suck blood, causing intense irritation and itching. head lice can only be passed from direct hair-to-hair contact. it is only necessary to wear gloves when examining the head for whatever reason. the cell does not need to be cleaned after use, because the lice live on or near skin. bedding may be contaminated with shed skin, so should be handled with gloves and laundered or incinerated. the presence of live lice is an indication for treatment by either physical removal with a comb or the application of an insecticide. the latter may be more practical in custody. treatment using 0.5% aqueous malathion should be applied to dry hair and washed off after 12 hours. the hair should then be shampooed as normal. crabs or body lice are more commonly found in the pubic, axillary, chest, and leg hair. however, eyelashes and eyebrows may also be involved. they are associated with people who do not bath or change clothes regularly. the person usually complains of intense itching or irritation. the main route is from person to person by direct contact, but eggs can stick to fibers, so clothing and bedding should be handled with care (see subheading 6.5.3.). staff should always wear gloves if they are likely to come into contact with any hirsute body part. clothing or bedding should be handled with gloves and either laundered or incinerated. treatment of a detainee in custody is good in theory but probably impractical because the whole body has to be treated. fleas lay eggs on floors, carpets, and bedding. in the united kingdom, most flea bites come from cats or dogs. the eggs and larvae fleas can survive for months and are reactivated in response to animal or human activity. because animal fleas jump off humans after biting, most detainees with flea bites will not have fleas, unless they are human fleas. treatment is only necessary if fleas are seen. after use, the cell should be vacuumed and cleaned with a proprietary insecticide. any bedding should be removed wearing gloves, bagged, and either laundered or incinerated. bedbugs live and lay eggs on walls, floors, furniture, and bedding. if you look carefully, fecal tracks may be seen on hard surfaces. if they are present for long enough, they emit a distinct odor. bedbugs are rarely found on the person but may be brought in on clothing or other personal effects. bedbugs bite at night and can cause sleep disturbance. the detainee does not need to be treated, but the cell should deemed out of use until it can be vacuumed and professionally cleaned with an insecticide solution. any bedding or clothing should be handled with gloves and disposed of as appropriate. staphylococcus aureus is commonly carried on the skin or in the nose of healthy people. approximately 25-30% of the population is colonized with the bacteria but remain well (43) . from time to time, the bacteria cause minor skin infections that usually do not require antibiotic treatment. however, more serious problems can occur (e.g., infection of surgical wounds, drug injection sites, osteomyelitis, pneumonia, or septicemia). during the last 50 years, the bacteria have become increasingly resistant to penicillin-based antibiotics (44) , and in the last 20 years, they have become resistant to an increasing number of alternative antibiotics. these multiresistant bacteria are known as methicillinresistant s. aureus (mrsa). mrsa is prevalent worldwide. like nonresistant staphylococci, it may remain undetected as a reservoir in colonized individuals but can also produce clinical disease. it is more common in individuals who are elderly, debilitated, or immunocompromised or those with open wounds. clusters of skin infections with mrsa have been reported among injecting drug users (idus) since 1981 in america (45, 46) , and more recently, similar strains have been found in the united kingdom in idus in the community (47) . this may have particular relevance for the forensic physician when dealing with idus sores. people who are immunocompetent rarely get mrsa and should not be considered at risk. the bacteria are usually spread via the hands of staff after contact with colonized or infected detainees or devices, items (e.g., bedding, towels, and soiled dressings), or environmental surfaces that have been contaminated with mrsa-containing body fluids. with either known or suspected cases (consider all abscesses/ulcers of idus as infectious), standard precautions should be applied. staff should wear gloves when touching mucous membranes, nonintact skin, blood or other body fluids, or any items that could be contaminated. they should also be encouraged to their wash hands with an antimicrobial agent regardless of whether gloves have been worn. after use, gloves should be disposed of in a yellow hazard bag and not allowed to touch surfaces. masks and gowns should only be worn when conducting procedures that generate aerosols of blood or other body fluids. because this is an unlikely scenario in the custodial setting, masks and gowns should not be necessary. gloves should be worn when handling bedding or clothing, and all items should be disposed of appropriately. any open wounds should be covered as soon as possible. the cell should be cleaned professionally after use if there is any risk that it has been contaminated. during the last decade, there has been an increasing awareness of the bacterial flora colonizing injection sites that may potentially lead to life-threatening infection (48) . in 1997, a sudden increase in needle abscesses caused by a clonal strain of group a streptococcus was reported among hospitalized idus in berne, switzerland (49) . a recent uk study showed that the predominant isolate is s. aureus, with streptococcus species forming just under one-fifth (50% î²-hemolytic streptococci) (50) . there have also been reports of both nonsporing and sporing anerobes (e.g., bacteroides and clostridia species, including clostridia botulinum) (51, 52) . in particular, in 2000, laboratories in glasgow were reporting isolates of clostridium novyi among idus with serious unexplained illness. by june 12, 2000, a total of 42 cases (18 definite and 24 probable) had been reported. a definite case was defined as an idu with both severe local and systemic inflammatory reactions. a probable case was defined as an idu who presented to the hospital with an abscess or other significant inflammation at an injecting site and had either a severe inflammatory process at or around an injection site or a severe systemic reaction with multiorgan failure and a high white cell count (53) . in the united kingdom, the presence of c. botulinum in infected injection sites is a relatively new phenomenon. until the end of 1999, there were no cases reported to the public health leadership society. since then, the number has increased, with a total of 13 cases in the united kingdom and ireland being reported since the beginning of 2002. it is believed that these cases are associated with contaminated batches of heroin. simultaneous injection of cocaine increases the risk by encouraging anerobic conditions. anerobic flora in wounds may have serious consequences for the detainee, but the risk of transmission to staff is virtually nonexistent. staff should be reminded to wear gloves when coming into contact with detainees with infected skin sites exuding pus or serum and that any old dressings found in the cell should be disposed of into the yellow bag marked "clinical waste" in the medical room. likewise, any bedding should be bagged and laundered or incinerated after use. the cell should be deemed out of use and professionally cleaned after the detainee has gone. the health care professional managing the detainee should clean and dress open wounds as soon as possible to prevent the spread of infection. it may also be appropriate to start a course of antibiotics if there is abscess formation or signs of cellulites and/or the detainee is systemically unwell. however, infections can often be low grade because the skin, venous, and lymphatic systems have been damaged by repeated penetration of the skin. in these cases, signs include lymphedema, swollen lymph glands, and darkly pigmented skin over the area. fever may or may not be present, but septicemia is uncommon unless the individual is immunocompromised (e.g., hiv positive). co-amoxiclav is the preferred treatment of choice because it covers the majority of staphylococci, streptococci, and anerobes (the dose depends on the degree of infection). necrotizing fasciitis and septic thrombophlebitis are rare but life-threatening complications of intravenous drug use. any detainee suspected of either of these needs hospital treatment. advice about harm reduction should also be given. this includes encouraging drug users to smoke rather than inject or at least to advise them to avoid injecting into muscle or skin. although most idus are aware of the risk of sharing needles, they may not realize that sharing any drug paraphernalia could be hazardous. advice should be given to use the minimum amount of citric acid to dissolve the heroin because the acid can damage the tissue under the skin, allowing bacteria to flourish. drugs should be injected at different sites using fresh works for each injection. this is particularly important when "speedballing" because crack cocaine creates an anerobic environment. medical help should be requested if any injection site become painful and swollen or shows signs of pus collecting under the skin. because intravenous drug users are at increased risk of acquiring hbv and hav, they should be informed that vaccination against both diseases is advisable. another serious but relatively rare problem is the risk from broken needles in veins. embolization can take anywhere from hours to days or even longer if it is not removed. complications may include endocarditis, pericarditis, or pulmonary abscesses (54, 55) . idus should be advised to seek medical help as soon as possible, and should such a case present in custody, then send the detainee straight to the hospital. the forensic physician may encounter bites in the following four circumstances: a detailed forensic examination of bites is given in chapter 4. with any bite that has penetrated the skin, the goals of therapy are to minimize soft tissue deformity and to prevent or treat infection. in the united kingdom and the united states, dog bites represent approximately three-quarters of all bites presenting to accident and emergency departments (56) . a single dog bite can produce up to 220 psi of crush force in addition to the torsional forces as the dog shakes its head. this can result in massive tissue damage. human bites may cause classical bites or puncture wounds (e.g., impact of fists on teeth) resulting in crush injuries. an estimated 10-30% of dog bites and 9-50% of human bites lead to infection. compare this with an estimated 1-12% of nonbite wounds managed in accident and emergency departments. the risk of infection is increased with puncture wounds, hand injuries, full-thickness wounds, wounds requiring debridement, and those involving joints, tendons, ligaments or fractures. comorbid medical conditions, such as diabetes, asplenia, chronic edema of the area, liver dysfunction, the presence of a prosthetic valve or joint, and an immunocompromised state may also increase the risk of infection. infection may spread beyond the initial site, leading to septic arthritis, osteomyelitis, endocarditis, peritonitis, septicemia, and meningitis. inflammation of the tendons or synovial lining of joints may also occur. if enough force is used, bones may be fractured or the wounds may be permanently disfiguring. assessment regarding whether hospital treatment is necessary should be made as soon as possible. always refer if the wound is bleeding heavily or fails to stop when pressure is applied. penetrating bites involving arteries, nerves, muscles, tendons, the hands, or feet, resulting in a moderate to serious facial wound, or crush injuries, also require immediate referral. if management within custody is appropriate, ask about current tetanus vaccine status, hbv vaccination status, and known allergies to antibiotics. wounds that have breached the skin should be irrigated with 0.9% (isotonic) sodium chloride or ringer's lactate solution instead of antiseptics, because the latter may delay wound healing. a full forensic documentation of the bite should be made as detailed in chapter 4. note if there are clinical signs of infection, such as erythema, edema, cellulitis, purulent discharge, or regional lymphadenopathy. cover the wound with a sterile, nonadhesive dressing. wound closure is not generally recommended because data suggest that it may increase the risk of infection. this is particularly relevant for nonfacial wounds, deep puncture wounds, bites to the hand, clinically infected wounds, and wounds occurring more than 6-12 hours before presentation. head and neck wounds in cosmetically important areas may be closed if less than 12 hours old and not obviously infected. â�¢ dog bites-pasteurella canis, pasteurella multocida, s. aureus, other staphylococci, streptococcus species, eikenella corrodens, corynebacterium species, and anerobes, including bacteroides fragilis and clostridium tetani â�¢ human bites-streptococcus species, s. aureus, e. corrodens, and anerobes, including bacteroides (often penicillin resistant), peptostreptococci species, and c. tetani. tuberculosis (tb) and syphilis may also be transmitted. â�¢ dog bites-outside of the united kingdom, australia, and new zealand, rabies should be considered. in the united states, domestic dogs are mostly vaccinated against rabies (57) , and police dogs have to be vaccinated, so the most common source is from racoons, skunks, and bats. â�¢ human bites-hbv, hbc, hiv, and herpes simplex. antibiotics are not generally needed if the wound is more than 2 days old and there is no sign of infection or in superficial noninfected wounds evaluated early that can be left open to heal by secondary intention in compliant people with no significant comorbidity (58) . antibiotics should be considered with high-risk wounds that involve the hands, feet, face, tendons, ligaments, joints, or suspected fractures or for any penetrating bite injury in a person with diabetes, asplenia, or cirrhosis or who is immunosuppressed. coamoxiclav (amoxycillin and clavulanic acid) is the first-line treatment for mild-moderate dog or human bites resulting in infections managed in primary care. for adults, the recommended dose is 500/125 mg three times daily and for children the recommended does is 40 mg/kg three times daily (based on amoxycillin component). treatment should be continued for 10-14 days. it is also the first-line drug for prophylaxis when the same dose regimen should be prescribed for 5-7 days. if the individual is known or suspected to be allergic to penicillin, a tetracycline (e.g., doxycycline 100 mg twice daily) and metronidazole (500 mg three times daily) or an aminoglycoside (e.g., erythromycin) and metronidazole can be used. in the united kingdom, doxycycline use is restricted to those older than 12 years and in the united states to those older than 8 years old. specialist advice should be sought for pregnant women. anyone with severe infection or who is clinically unwell should be referred to the hospital. tetanus vaccine should be given if the primary course or last booster was more than 10 years ago. human tetanus immunoglobulin should be considered for tetanus-prone wounds (e.g., soil contamination, puncture wounds, or signs of devitalized tissue) or for wounds sustained more than 6 hours old. if the person has never been immunized or is unsure of his or her tetanus status, a full three-dose course, spaced at least 1 month apart, should be given. penetrating bite wounds that involve only saliva may present a risk of hbv if the perpetrator belongs to a high-risk group. for management, see subheadings 5.1.6. and 5.1.7. hcv and hiv are only a risk if blood is involved. the relevant management is dealt with in subheadings 5.2.5. and 5.4.6. respiratory tract infections are common, usually mild, and self-limiting, although they may require symptomatic treatment with paracetamol or a nonsteroidal antiinflammatory. these include the common cold (80% rhinoviruses and 20% coronaviruses), adenoviruses, influenza, parainfluenza, and, during the summer and early autumn, enteroviruses. special attention should be given to detainees with asthma or the who are immunocompromised, because infection in these people may be more serious particularly if the lower respiratory tract is involved. the following section includes respiratory pathogens of special note because they may pose a risk to both the detainee and/or staff who come into close contact. there are five serogroups of neisseria meningitidis: a, b, c, w135, and y. the prevalence of the different types varies from country to country. there is currently no available vaccine against type b, but three other vaccines (a+c, c, and acwy) are available. overall, 10% of the uk population carry n. meningitidis (25% in the 15-19 age group) (59) . in the united kingdom, most cases of meningitis are sporadic, with less than 5% occurring as clusters (outbreaks) amongst school children. between 1996 and 2000, 59% of cases were group b, 36% were group c, and w135 and a accounted for 5%. there is a seasonal variation, with a high level of cases in winter and a low level in the summer. the greatest risk group are the under 5 year olds, with a peak incidence under 1 year old. a secondary peak occurs in the 15-to 19-year-old age group. in sub-saharan africa, the disease is more prevalent in the dry season, but in many countries, there is background endemicity year-round. the most prevalent serogroup is a. routine vaccination against group c was introduced in the united kingdom november 1999 for everybody up to the age of 18 years old and to all firstyear university students. this has since been extended to include everyone under the age of 25 years old. as a result of the introduction of the vaccination program, there has been a 90% reduction of group c cases in those younger than under 18 years and an 82% reduction in those under 1 year old (60, 61) . an outbreak of serogroup w135 meningitis occurred among pilgrims on the hajj in 2000. cases were reported from many countries, including the united kingdom. in the united kingdom, there is now an official requirement to be vaccinated with the quadrivalent vaccine (acwy vax) before going on a pilgrimage (hajj or umra), but illegal immigrants who have not been vaccinated may enter the country (62). after an incubation period of 3-5 days (63,64) , disease onset may be either insidious with mild prodromal symptoms or florid. early symptoms and signs include malaise, fever, and vomiting. sever headache, neck stiffness, photophobia, drowsiness, and a rash may develop. the rash may be petechial or purpuric and characteristically does not blanche under pressure. meningitis in infants is more likely to be insidious in onset and lack the classical signs. in approx 15-20% of cases, septicemia is the predominant feature. even with prompt antibiotic treatment, the case fatality rate is 3-5% in meningitis and 15-20% in those with septicemia. (65). a person should be considered infectious until the bacteria are no longer present in nasal discharge. with treatment, this is usually approx 24 hour. the disease is spread through infected droplets or direct contact from carriers or those who are clinically ill. it requires prolonged and close contact, so it is a greater risk for people who share accommodation and utensils and kiss. it must also be remembered that unprotected mouth-to-mouth resuscitation can also transmit disease. it is not possible to tell if a detainee is a carrier. nevertheless, the risk of acquiring infection even from an infected and sick individual is low, unless the individual has carried out mouth-to-mouth resuscitation. any staff member who believes he or she has been placed at risk should report to the occupational health department (or equivalent) or the nearest emergency department at the earliest opportunity for vaccination. if the detainee has performed mouth-to-mouth resuscitation, prophylactic antibiotics should be given before receiving vaccination. rifampicin, ciprofloxacin, and ceftriaxone can be used; however, ciprofloxacin has numerous advantages (66) . only a single dose of 500 mg (adults and children older than 12 years) is needed and has fewer side effects and contraindications than rifampicin. ceftriaxone has to be given by injection and is therefore best avoided in the custodial setting. if the staff member is pregnant, advice should be sought from a consultant obstetrician, because ciprofloxacin is not recommended (67) . for anyone dealing regularly with illegal immigrants (especially from the middle east or sub-saharan africa) (e.g., immigration services, custody staff at designated stations, medical personnel, and interpreters), should consider being vaccinated with acwy vax. a single injection provides protection for 3 years. detainees suspected of disease should be sent directly to the hospital. human tb is caused by infection with mycobacterium tuberculosis, mycobacterium bovis, or mycobacterium africanum. it is a notifiable disease under legislation specific to individual countries; for example, in the united kingdom, this comes under the public health (control of disease) act of 1984. in 1993, the who declared tb to be a global emergency, with an estimated 7-8 million new cases and 3 million deaths occurring each year, the majority of which were in asia and africa. however, these statistics are likely to be an underestimate because they depend on the accuracy of reporting, and in poorer countries, the surveillance systems are often inadequate because of lack of funds. even in the united kingdom, there has been an inconsistency of reporting particularly where an individual has concomitant infection with hiv. some physicians found themselves caught in a dilemma of confidentiality until 1997, when the codes of practice were updated to encourage reporting with patient consent (68) . with the advent of rapid identification tests and treatment and the use of bacillus calmette-guã©rin (bcg) vaccination for prevention, tb declined during the first half of the 20th century in the united kingdom. however, since the early 1990s, numbers have slowly increased, with some 6800 cases reported in 2002 (69) . in 1998, 56% of reported cases were from people born outside the united kingdom and 3% were associated with hiv infection (70, 71) . london has been identified as an area with a significant problem. this has been attributed to its highly mobile population, the variety of ethnic groups, a high prevalence of hiv, and the emergence of drug-resistant strains (1.3% in 1998 ) (phls, unpublished data-mycobnet). a similar picture was initially found in the united states, when there was a reversal of a long-standing downward trend in 1985. however, between 1986 and 1992, the number of cases increased from 22,201 to 26,673 (72) . there were also serious outbreaks of multidrug-resistant tb (mdr-tb) in hospitals in new york city and miami (73) . factors pertinent to the overall upswing included the emergence of hiv, the increasing numbers of immigrants from countries with a high prevalence of tb, and perhaps more significantly, stopping categorical federal funding for control activities in 1972. the latter led to a failure of the public health infrastructure for tb control. since 1992, the trend has reversed as the cdc transferred most of its funds to tb surveillance and treatment program in states and large cities. from 1992 to 2001, the annual decline averaged by 7.3% (74) , but the following year this was reduced to 2%, indicating that there was no room for complacency. the who has been proactive and is redirecting funding to those countries most in need. in october 1998, a global partnership called stop tb was launched to coordinate every aspect of tb control, and by 2002, the partnership had more than 150 member states. a target was set to detect at least 70% of infectious cases by 2005. the acquisition of tb infection is not necessarily followed by disease because the infection may heal spontaneously. it may take weeks or months before disease becomes apparent, or infection may remain dormant for years before reactivation in later life especially if the person becomes debilitated or immunocompromised. contrary to popular belief, the majority of cases of tb in people who are immunocompetent pass unnoticed. of the reported cases, 75% involve the lung, whereas nonrespiratory (e.g., bone, heart, kidney, and brain) or dissemination (miliary tb) are more common in immigrant ethnic groups and individuals who are immunocompromised (75) . they are also more likely to develop resistant strains. in the general population, there is an estimated 10% lifetime risk of tb infection progressing to disease (76) . there has been an increase in the number of cases of tb associated with hiv owing to either new infection or reactivation. tb infection is more likely to progress to active tb in hiv-positive individuals, with a greater than50% lifetime risk (77) . tb can also lead to a worsening of hiv with an increase in viral load (78) . therefore, the need for early diagnosis is paramount, but it can be more difficult because pulmonary tb may present with nonspecific features (e.g., bilateral, unilateral, or lower lobe shadowing) (79). after an incubation period of 4-12 weeks, symptoms may develop (see table 6 ). the main route is airborne through infected droplets, but prolonged or close contact is needed. nonrespiratory disease is not considered a risk unless the mycobacterium is aerosolized under exceptional circumstances (e.g., during surgery) or there are open abscesses. a person is considered infectious as long as viable bacilli are found in induced sputum. untreated or incompletely treated people may be intermittently sputum positive for years. after 2 weeks of appropriate treatment, the individual is usually considered as noninfectious. this period is often extended for treatment of mdr-tb or for those with concomitant hiv. patient compliance also plays an important factor. the risk of infection is directly proportional to the degree of exposure. more severe disease occurs in individuals who are malnourished, immunocompromised (e.g., hiv), and substance misusers. people who are immunocompromised are at special risk of mdr-tb or mycobacterium avium intracellulare (mai). staff with disease should stay off work until the treatment course is complete and serial sputum samples no longer contain bacilli. staff in contact with disease who have been vaccinated with bcg are at low risk of acquiring disease but should minimize their time spent in the cell. those who have not received bcg or who are immunocompromised should avoid contact with the detainee wherever possible. detainees with mai do not pose a risk to a staff member, unless the latter is immunocompromised. any staff member who is pregnant, regardless of bcg status or type of tb, should avoid contact. anyone performing mouth-to-mouth resuscitation with a person with untreated or suspected pulmonary tb should be regarded as a household contact and should report to occupational health or their physician if no other route exists. they should also be educated regarding the symptoms of tb. anyone who is likely to come into repeated contact with individuals at risk of tb should receive bcg (if he or she has not already done so), regardless of age, even though there is evidence to suggest that bcg administered in adult life is less effective. this does not apply to individuals who are immunocompromised or pregnant women. in the latter case, vaccination should preferably be deferred until after delivery. detainees with disease (whether suspected or diagnosed) who have not been treated or treatment is incomplete should be kept in custody for the minimum time possible. individuals with tb who are immunocompromised are usually too ill to be detained; if they are, they should be considered at greater risk of transmitting disease to staff. any detainee with disease should be encouraged to cover his or her mouth and nose when coughing and sneezing. staff should wear gloves when in contact with the detainee and when handling clothing and bedding. any bedding should be bagged after use and laundered or incinerated. the cell should be deemed out of action until it has been ventilated and professionally decontaminated, although there is no hard evidence to support that there is a risk of transmission from this route (70). on march 14, 2003 , the who issued a global warning to health authorities about a new atypical pneumonia called sars. the earliest case was believed to have originated in the guandong province of china on november 16, 2002. the causative agent was identified as a new corona virus-sars-cov (80, 81) . by the end of june 2003, 8422 cases had been reported from 31 different countries, with a total of 916 deaths. approximately 92% of cases occurred in china (including hong kong, taiwan, and macao). the case fatality rate varied from less than 1% in people younger than 24 years, 6% in persons aged 25-44 years, 15% in those aged 44-64 years, and more than 50% in persons 65 years or older. on july 5, 2003, the who reported that the last human chain of transmission of sars had been broken and lifted the ban from all countries. however, it warned that everyone should remain vigilant, because a resurgence of sars is possible. their warning was well given because in december 2003, a new case of sars was detected in china. at the time of this writing, three more cases have been identified. knowledge about the epidemiology and ecology of sars-cov and the disease remains limited; however, the experience gained from the previous outbreak enabled the disease to be contained rapidly, which is reflected in the few cases reported since december 2003. there is still no specific treatment or preventative vaccine that has been developed. the incubation period is short, approx 3-6 days (maximum 10 days), and, despite the media frenzy surrounding the initial outbreak, sars is less infectious than influenza. the following clinical case definition of sars has been developed for public health purposes (82) . a person with a history of any combination of the following should be examined for sars: â�¢ fever (at least 38â°c); and â�¢ one of more symptoms of lower respiratory tract illness (cough, difficulty in breathing, or dyspnea); and â�¢ radiographic evidence of lung infiltrates consistent with pneumonia or respiratory distress syndrome or postmortem findings of these with no identifiable cause; and â�¢ no alternative diagnosis can fully explain the illness. laboratory tests have been developed that include detection of viral rna by pcr from nasopharyngeal secretions or stool samples, detection of antibodies by enzyme-linked immunosorbent assay or immunofluorescent antibody in the blood, and viral culture from clinical specimens. available information suggests that close contact via aerosol or infected droplets from an infected individual provide the highest risk of acquiring the disease. most cases occurred in hospital workers caring for an index case or his or her close family members. despite the re-emergence of sars, it is highly unlikely that a case will be encountered in the custodial setting in the near future. however, forensic physicians must remain alert for the sars symptoms and keep up-to-date with recent outbreaks. information can be obtained from the who on a daily basis from its web site. if sars is suspected, medical staff should wear gloves and a surgical mask when examining a suspected case; however, masks are not usually available in custody. anyone suspected of sars must be sent immediately to the hospital, and staff who have had prolonged close contact should be alerted as to the potential symptoms. the most consistent feature of diseases transmitted through the fecaloral route is diarrhea (see table 7 ). infective agents include bacteria, viruses, and protozoa. because the causes are numerous, it is beyond the remit of this chapter to cover them all. it is safest to treat all diarrhea as infectious, unless the detainee has a proven noninfectious cause (e.g., crohn's disease or ulcerative colitis). all staff should wear gloves when in contact with the detainee or when handling clothing and bedding, and contaminated articles should be laundered or incinerated. the cell should be professionally cleaned after use, paying particular attention to the toilet area. this viral hepatitis occurs worldwide, with variable prevalence. it is highest in countries where hygiene is poor and infection occurs year-round. in temperate climates, the peak incidence is in autumn and winter, but the trend is becoming less marked. all age groups are susceptible if they are nonimmune or have not been vaccinated. in developing countries, the disease occurs in early childhood, whereas the reverse is true in countries where the standard of living is higher. in the united kingdom, there has been a gradual decrease in the number of reported cases from 1990 to 2000 (83, 84) . this results from, in part, improved standards of living and the introduction of an effective vaccine. the highest incidence occurs in the 15-to 34-year-old age group. approximately 25% of people older than 40 years have natural immunity, leaving the remainder susceptible to infection (85) . small clusters occur from time to time, associated with a breakdown in hygiene. there is also an increasing incidence of hav in gay or bisexual men and their partners (86) . an unpublished study in london in 1996 showed a seroprevalence of 23% among gay men (young y et al., unpublished). the clinical picture ranges from asymptomatic infection through a spectrum to fulminant hepatitis. unlike hbv and hcv, hav does not persist or progress to chronic liver damage. infection in childhood is often mild or asymptomatic but in adults tends to be more severe. after an incubation period of 15-50 days (mean 28 days) symptomatic infection starts with the abrupt onset of jaundice anything from 2 days to 3 weeks after the anicteric phase. it lasts for approximately the same length of time and is often accompanied by a sudden onset of fever. hav infection can lead to hospital admission in all age groups but is more likely with increasing age as is the duration of stay. the overall mortality is less than 1%, but 15% of people will have a prolonged or relapsing illness within 6-9 months (cdc fact sheet). fulminant hepatitis occurs in less than 1% of people but is more likely to occur in individuals older than 65 years or in those with pre-existing liver disease. in patients who are hospitalized, case fatality ranges from 2% in 50-59 years olds to nearly 13% in those older than 70 years (84). the individual is most infectious in the 2 weeks before the onset of jaundice, when he or she is asymptomatic. this can make control of infection difficult because the disease is not recognized. the main route is fecal-oral through the ingestion of contaminated water and food. it can also be transmitted by personal contact, including homosexuals practicing anal intercourse and fellatio. there is a slight risk from blood transfusions if the donor is in the acute phase of infection. it should not be considered a risk from needlestick injuries unless clinical suspicion of hav is high. risk groups include homeless individuals, homosexuals, idus, travellers abroad who have not been vaccinated, patients with chronic liver disease and chronic infection with hbv and hcv, employees and residents in daycare centers and hostels, sewage workers, laboratory technicians, and those handling nonhuman primates. several large outbreaks have occurred among idus, some with an epidemiological link to prisons (87, 88) . transmission occurs during the viremic phase of the illness through sharing injecting equipment and via fecal-oral routes because of poor living conditions (89) . there have also been reports of hav being transmitted through drugs that have been carried in the rectum. a study in vancouver showed that 40% of idus had past infection of hav, and they also showed an increased prevalence among homosexual/bisuexual men (90). staff with disease should report to occupational health and stay off work until the end of the infective period. those in contact with disease (either through exposure at home or from an infected detainee) should receive prophylactic treatment as soon as possible (see subheading 8.3.7.). to minimize the risk of acquiring disease in custody, staff should wear gloves when dealing with the detainee and then wash their hands thoroughly. gloves should be disposed of only in the clinical waste bags. detainees with disease should be kept in custody for the minimum time possible. they should only be sent to the hospital if fulminant hepatitis is suspected. the cell should be quarantined after use and professionally cleaned. any bedding or clothing should be handled with gloves and laundered or incinerated according to local policy. detainees reporting contact with disease should be given prophylactic treatment as soon as possible (see subheading 8.3.7.). contacts of hav should receive hav vaccine (e.g., havrix monodose or avaxim) if they have not been previously immunized or had disease. human normal immunoglobulin (hnig), 500 mg, deep intramuscular in gluteal muscle should be used in the following circumstances: â�¢ has the detainee traveled to africa, south east asia, the indian subcontinent, central/south america, or the far east in the last 6-12 months? â�¢ ascertain whether he or she received any vaccinations before travel and, if so, which ones. â�¢ ask if he or she took malaria prophylaxis, what type, and whether he or she completed the course. â�¢ ask if he or she swam in any stagnant lakes during the trip. â�¢ if the answer to any of the above is yes, ask if he or she has experienced any of the following symptoms: a fever/hot or cold flushes/shivering. diarrhea â± abdominal cramps â± blood or slime in the stool. a rash. persistent headaches â± light sensitivity. nausea or vomiting. aching muscles/joints. a persistent cough (dry or productive) lasting at least 3 weeks. â�¢ take temperature. â�¢ check skin for signs of a rash and note nature and distribution. â�¢ check throat. â�¢ listen carefully to the lungs for signs of infection/consolidation. staff at higher risk of coming in to contact with hav should consider being vaccinated before exposure. two doses of vaccine given 6-12 months apart give at least 10 years of protection. there is no specific treatment for hav, except supportive measures and symptomatic treatment. although the chance of encountering a tropical disease in custo1dy is small, it is worth bearing in mind. it is not necessary for a forensic physician to be able to diagnose the specific disease but simply to recognize that the detainee/staff member is ill and whether he or she needs to be sent to the hospital (see tables 8-10) . this is best achieved by knowing the right questions to ask and carrying out the appropriate examination. tables 8-10 should be used as an aide to not missing some more unusual diseases. guidance for clinical health care workers: protection against infection with blood-borne viruses; recommendations of the expert advisory group on aids and the advisory group on hepatitis guidelines for hand hygiene in health care settings. recommendations of the healthcare infection control practices advisory committee and the hicpac/ shea/apic/idsa hand hygiene task force national model regulations for the control of workplace hazardous substances. commonwealth of australia, national occupational health and safety committee good practice guidelines for forensic medical examiners and the hospital infection control practices advisory committee. 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antischistosomal therapy in the spread of hepatitis c virus in egypt chronic hepatitis c: disease management. nih publication no. 03-4230. february department of health hepatitis c virus: eight years old laboratory surveillance of hepatitis c virus in england and wales: 1992-1996 last update aids/hiv quarterly surveillance tables provided by the phls aids centre (cdsc) and the scottish centre for infection and environmental health hiv and aids in the uk in 2001. communicable disease surveillance centre. an update mode of vertical transmission of hiv-1. a metanalysis of fifteen prospective cohort studies vertical transmission rate for hiv in the british isles estimated on surveillance data hiv post-exposure prophylaxis after sexual assault: the experience of a sexual assault service in london guidance from the uk chief medical officer's expert advisory group on aids. uk health department failures of zidovudine post exposure prophylaxis seroconversion to hiv-1 following a needlestick injury despite combination post-exposure prophylaxis department of health, immunisation against infectious disease. united kingdom: her majesty's stationery office chickenpox-disease predominantly affecting adults in rural west bengal prevention of varicella: recommendations of the advisory committee on immunization practices varicella-zoster virus epidemiology. a changing scene? use of acyclovir for varicella pneumonia during pregnancy outcome after maternal varicella infection in the first 20 weeks of pregnancy outcome in newborn babies given anti-varicella zoster immunoglobulin after perinatal maternal infection with varicella zoster virus varicella-zoster virus dna in human sensory ganglia epidemiology and natural history of herpes zoster and post herpetic neuralgia clinical applications for changepoint analysis of herpes zoster pain treatment of scabies with permethrin versus lindane and benzoyl benzoate treatment of ectoparasitic infections; review of the english-language literature nasal carriage of staphylococcus aureus: epidemiology and control measures centers for disease control and prevention. community-acquired methicillinresistant staphylococcus aureus infections-michigan methicillinresistant staphylococcus aureus, epidmiologic observations during a community acquired outbreak emergence of pvl-producing strains of staphylococcus aureus bacteriology of skin and soft tissue infections: comparison of infections in intravenous drug users and individuals with no history of intravenous drug use outbreak among drug users caused by a clonal strain of group a streptococcus. dispatchesemerging infectious diseases bacteriological skin and subcutaneous infections in injecting drug users-relevance for custody wound botulism associated with black tar heroin among injecting drug users isolation and identification of clostridium spp from infections associated with injection of drugs: experiences of a microbiological investigation team greater glasgow health board, scifh. unexplained illness among drug injectors in glasgow embolization of illicit needle fragments right ventricular needle embolus in an injecting drug user: the need for early removal departments of emergency medicine and pediatrics, lutheran general hospital of oak brook, advocate health system. emedicine-human bites prevention and treatment of dog bites human bites. department of plastic surgery guidelines for public health management of meningococcal diseases in the uk planning, registration and implementation of an immunisation campaign against meningococcal serogroup c disease in the uk: a success story efficacy of meningococcal serogroup c conjugate vaccine in teenagers and toddlers in england quadrivalent meningoimmunisation required for pilgrims to saudi arabia risk of laboratory-acquired meningococcal disease cluster of meningococcal disease in rugby match spectators immunisation against infectious disease. her majesty's stationery office ciprofloxacin as a chemoprophylactic agent for meningococcal diseaselow risk of anaphylactoid reactions joint formulary committee 2002-03. british national formulary notification of tuberculosis an updated code of practice for england and wales statutory notifications to the communicable disease surveillance centre. preliminary annual report on tuberculosis cases reported in england, wales, and the prevention and control of tuberculosis in the united kingdom: uk guidance on the prevention and control of transmission of 1. hiv-related tuberculosis 2. drug-resistant, including multiple drug-resistant, tuberculosis. department of health, scottish office control and prevention of tuberculosis in the united kingdom: code of practice epidemiology of tuberculosis in the united states nosocomial transmission of multi-drug resistant tuberculosis among hiv-infected persons-florida the continued threat of tuberculosis tuberculosis-a clinical handbook the white plague: down and out, or up and coming? a prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection influence of tuberculosis on human immunodeficiency virus (hiv-1): enhanced cytokine expression and elevated b 2 -microglobulin in hiv-1 associated tuberculosis the chest roenterogram in pulmonary tuberculosis patients seropositive for human immunodeficiency virus type 1 coronavirus as a possible cause of severe acute respiratory syndrome epidemiological determinants of spread of causal agents of severe acute respiratory syndrome in hong kong alert, verification and public health management of sars in post-outbreak period age-specific antibody prevalence to hepatitis a in england: implications for disease control phls advisory committee on vaccination and immunisation. guidelines for the control of hepatitis a infection control of a community hepatitis a outbreak using hepatitis a vaccine seroprevalence of and risk factors for hepatitis a infection among young homosexual and bisexual men outbreaks of hepatitis a among illicit drug users identifying target groups for a potential vaccination program during a hepatitis a community outbreak multiple modes of hepatitis a transmission among metamphetamine users past infection with hepatitis a among vancouver street youth, injection drug users and men who have sex with men implications for vaccination programmes key: cord-264542-0hu5twhp authors: mueller, siguna title: facing the 2020 pandemic: what does cyberbiosecurity want us to know to safeguard the future? date: 2020-09-25 journal: biosaf health doi: 10.1016/j.bsheal.2020.09.007 sha: doc_id: 264542 cord_uid: 0hu5twhp as the entire world is under the grip of the coronavirus diseases 2019 (covid-19), and as many are eagerly trying to explain the origins of the virus and cause of the pandemic, it is imperative to place more attention on related potential biosafety risks. biology and biotechnology have changed dramatically during the last ten years or so. their reliance on digitization, automation, and their cyber-overlaps have created new vulnerabilities for unintended consequences and potentials for intended exploitation that are largely under-appreciated. herein, i summarize and elaborate on these new cyberbiosecurity challenges, (1) in terms of comprehending the evolving threat landscape and determining new risk potentials, (2) in developing adequate safeguarding measures, their validation and implementation, and (3) specific critical dangers and consequences, many of them unique to the life-sciences. drawing upon expertise shared by others as well as my previous work, this article aims to summarize and critically interpret the current situation of our bioeconomy. herein, the goal is not to attribute causative aspects of past biosafety or biosecurity events, but to highlight the fact that the bioeconomy harbors unique features that have to be more critically assessed for their potential to unintentionally cause harm to human health or environment, or to be re-tasked with an intention to cause harm. i conclude with recommendations that will need to be taken into consideration to help ensure converging and emerging biorisk challenges, in order to minimize vulnerabilities to the life-science enterprise, public health, and national security. ever since the coronavirus diseases 2019 (covid19) pandemic, (laboratory) biosafety and biosecurity concerns are even more rigorously scrutinized. this article uses the lens of the current pandemic to evaluate biological risks from biological research, particularly those that are amplified by the digitization of biological information and biotechnology automation. the cyberphysical nature of biotechnology has led to fascinating advances throughout the bioscience field. only recently, concerns have been raised regarding new risks that may lead to unintended consequences or unrecognized potentials for misuse. just as the emergence of the internet some decades ago led to a major revolution -which, by necessity was paralleled by the field of cybersecurity -we are now facing the era of cyber biosecurity 2 with its own security vulnerabilities. the dna synthesis industry has worked proactively for many years to ensure that synthesis is carried out securely and safely 3 . these efforts have been complemented by the growing desire and capability to resynthesize biological material using digital resources [1, 2] . yet, the convergence of technologies at the nexus of life and medical sciences, cyber, cyberphysical, supply chain and infrastructure systems [3] , has led to new security problems that have remained elusive to the majority of the scientific, agricultural, and health communities. it has only been during the last few years, that awareness of these new types of vulnerabilities is growing, especially related to the danger of intended manipulations. as these concerns have spawned the emergence of cyberbiosecurity as a new discipline, it is important to realize that its focus is not merely on traditional cyber-attacks (sect. 2 and fig. 1 below). due to the increased reliance of the bioscience fields on cyberphysical systems (cps, fig. 3 below), potentials for exploitation exist at each point where bioengineered or biomanufactured processes or services interface with the cyber and the physical domain, whereby attackers may exploit unsecured networks and remotely manipulate biologic data, exploit biologic agents, or affect physical processing involving biological materials, that result (whether intentionally or unintentionally) in unwanted or dangerous biological outcomes [4, 5, 6, 7] . great efforts have been put into place to rigorously assess the new risks and threats (see in particular [3] and the recent national academy of sciences, engineering, and medicine report "safeguarding the bioeconomy" [7, pp.204-211] ). nonetheless, cyberbiosecurity is still in its infancy. there is still limited expertise to fully characterize and assess the emerging cyberbio risks [8] , and it has been recognized that generic cyber and information security measures are insufficient [8, 9, 10, 11, 12, 13, 14] . triggered by the covid-19 pandemic, enormous amounts of resources have been devoted to identify its exact genesis. a goal of this article is to challenge this narrow focus by concentrating on the larger context of cyberbiosecurity, to illuminate serious new concerns for a wide audience. i will highlight distinct challenges and suggest specific steps to help support risk deterrence efforts. most broadly, cyberbiosecurity aims to identify and mitigate security risks fostered by the digitization of biology and biotechnology automation. fig. 1 gives a summary how this new paradigm evolved. while others, including the author, began to investigate these challenges almost a decade ago [15, 16, 17, 18, 19, 13] , the term cyberbiosecurity was first (informally) used in [20] . these authors warned of security issues resulting from the cyberphysical interface of the bioeconomy, as it was recognized that all biomanufacturing processes are in fact cps (see also incomplete awareness. during the last few years, the biotechnology industry has fallen prey to serious attacks (see e.g. [7, table 7 -1]), although there is no broad awareness of this. this important observation and the compelling need to question the "naive trust" throughout the life-science arena were key drivers to establish cyberbiosecurity as a new discipline [20] . additional sobering criminal cases that have affected the bioscience field are now emerging, even during the current pandemic (e.g. [10, 23, 24, 21, 25, 26] ). as noted in [23] , these encompass three critical areas of attack -sabotage, corporate espionage, and crime/extortion. yet, people in the life-sciences are largely ignorant of the dangers as they are barely trained in security issues -or not at all. research and healthcare industries are vulnerable to cyberbiosecurity attacks because they have not kept up with threats [27, 8] . capitalizing on a common misconception. generally, it is widely accepted that cybersecurity attacks and data breaches are a matter of when, not if. very recently, ransomware attacks have been recognized as "the primary threat" to healthcare organizations [28] . statements like these seem to support the understanding that cyberbio concerns in the bioeconomy could be dealt with by using it solutions alone (and possibly optimized for life-science demands). unfortunately, the reliance on cps generates unrecognized convergence issues. it is important to understand that due to cross-over effects, neither cyber nor physical security concepts alone are sufficient to protect a cps. "separate sets of vulnerabilities on the cyber and physical sides do not simply add up, they multiply" [29] . notably, cyber-attacks on critical automated (computer-based) processes (e.g., workflow or process controls) may lead to dire real-world consequences, similar to direct physical attacks. for instance, a 2008 explosion in the highly secure 1,099-mile baku-tbilisi-ceyhan pipeline was caused by computer sabotage. the main weapon for this cyberphysical act of terrorism was "a keyboard" [30, 29] . in general, the term "physical" in cps (fig. 3 , central box) is applied to the "engineering, physical and biological" [31] components of the system, or more generally, any components of the physical world which are connected through cyber elements. (e.g. the hazard analysis control point system for the fd+ag sector or, more generally, the infrastructure survey tool [36] or nist guidelines [37] ), it is recognized that fully scoping all the cyberbio risks, not to mention their relative likelihood and impact, is rather challenging [23, 22, 8] . although some of the cyberbio vulnerabilities share compelling similarities to the early days of the internet [38] , there are critical differences [9, 10, 11, 12, 14] . while most responders to the above mentioned survey of international experts [8] agreed that their organizations had "considered" cyberbio issues, some noted "insufficient time" or "no idea" how to address them, and all pinpointed the lack of available resources. this section describes some of the difficulties. the problem of identifying what needs to be protected: -many of the novel cyberbio risks and threats (table 1) have not been fully scoped. they are difficult to characterize, and envisioning the complete risk landscape continues to be a challenge [39, 8, 40, 14, 23] . -identifying and hierarchizing the extent, impact and severity of various (including, hypothetical) new vulnerabilities is difficult. -there is no comprehensive model to effectively capture, assess, and address the motivations, capabilities, and approaches of those who may cause harm (see also sect. 4.2). • how protection is achieved and enforced: -existing solutions from the cyber domain are only geared at specific aspects of biosecurity and cybersecurity but do not address the overlap and the issues arising from this convergence [8, 40, 14] . -due to variations in types of threats, targets and potential impacts, it is not straightforward to determine the applicability and effectiveness of a possible solution. -as "there is no one model" to secure the use of information systems across the bioeconomy [7] , weak or premature solutions may only help address a distinct problem but be misapplied in a different context, or even become a source for exploitation (sect. 4.2 and fig. 4 below). j o u r n a l p r e -p r o o f standards and guidelines [11, 22, 34] are a serious issue to achieve comprehensive and international protection. very recent publications and programs [33, 41, 7, 42, 43, 44, 45, 46, 47] ) undoubtedly have increased cyberbiosecurity awareness and large corporations will have been able to enhance their infrastructure. yet, the 2020 pandemic has shifted r & d priorities and budget and has hampered many efforts to better comprehend the new risks and to develop solutions. pharma and medtech professionals and companies are overwhelmed with covid-19 mitigation and crisis resolution while the industry sprints to develop new therapeutics and vaccines. on the other hand, the pandemic has led to a huge rise in cyber-attacks, with some reporting an 800% increase compared to pre-coronavirus levels [48] . as cybersecurity professionals are struggling to target this surge in cyber-crime, wfh (work from home) has impacted the ability of many cybersecurity professionals to support new business applications or initiatives [49] . as companies and organizations struggle to maintain stability and security, new research areas such as cyberbiosecurity have received inadequate attention and support. in addition to the known cyberbio challenges described above, the context of the bioscience fields leads to distinct problems that are not well understood. the context of the life-sciences involves unique concerns and unknowns. cyber-based attacks targeting the biological and medical sciences involve living entities, with networks of connections, combinatorial interactions and a dynamic range of outcomes. future and timed effects can be achieved by various technologies (e.g., non-volatile memory devices and electronic circuits). yet, with biotechnology products there is a decreased ability to control exposure [50] : they are often designed to be easily dispersed (e.g., with agricultural technologies directly in the field [51] ), reach high scalability [50] , can be delivered in different states (including water [52] ), and can be activated by simple environmental agents (temperature, light, wind [53, 54, 55] ). a critical issue with active biologicals is that they can be transferred by contact, ingestion, j o u r n a l p r e -p r o o f journal pre-proof or inhalation [50] . while concerns about unintended consequences and ill-intended applications of these and related technologies have been raised recently (see e.g., [50, 56, 57, 18, 33, 13, 7] ), types of biotechnologies that not merely have a cyber-overlap, but which constitute artificial systems themselves, have been even less assessed. these include artificially generated self-replicating systems [58] , artificial cells that mimic the ability of natural cells to communicate with bacteria [59], or artificially generated processes to interact with one another and initiate various signaling cascades [60] . the consequences of an ill-intended or accidental release of such systems into the environment are not understood. one of the most complex issues may be that "information" in the biological context is of a different kind than what is meant in the information sciences. identifying "biological information" is not always straightforward and may evade available technology from time to time: consider, for instance, the situation of recessive alleles of a gene. these can be phenotypically invisible over a huge proportion of a population and known for their frequency using tools such as the hardy weinberg equilibrium equation; as dna sequencing and synthesizing technologies developed over decades they could be detected and linked to individuals. while such invisibility features are of potential benefit in the area of steganography, [61] describes critical concerns that analogously apply to cyberbiosecurity. for instance, biological information can be stored and transmitted in a virtually undetectable way: "no x-ray, infra-red scanner, chemical assay or body search will provide any immediate evidence" of it [61] . further, biological media can survive much longer than anticipated [51] , which in this context leads to the worrisome situation that data (or biologic "information") can "literally run off on its own" [61] . notably, critical vulnerabilities also arise in the context of devices and mechanisms. among others, the above mentioned survey [8] identified "elevated or severe risk" potentials for an unauthorized actor to (1) take control of infrastructure (e.g., lab equipment, lab control systems, or even a fully automated robot lab), (2) interrupt the functioning of lab systems, or (3) circumventing security controls. the cyber-physical nature of biotechnology is one of the key concerns in cyberbiosecurity ( fig. 3 and table 1 ). with increased automation, dangers arise, for example, in the context of sterilization methods used in the healthcare and laboratory setting. for some methods, a very recent study [62] demonstrates that "integrity of released dna is not completely compromised," which is leading to the "danger of dissemination of dna and xenogenic elements across waterways." these findings were linked to temperature and time (e.g., journal pre-proof short microwave exposure times or short exposure time to glutaraldehyde treatment were least effective). parameters like these are both highly malleable and susceptible to manipulation, which will become an even bigger concern with "smart labs" of the future [21] . in the context of food and agricultural systems, cyberphysical interconnections lead to the danger of "[m]anipulation of critical automated (computer-based) processes (e.g., thermal processing time and temperature for food safety)" and "[l]ack of ability to perform vulnerability assessment" [34] . traditionally, the reliance on tacit knowledge and direct hands-on processes and applications has shielded the bioscience field from many forms of attack. beyond doubt, the digitization of biology and biotechnology automation are key drivers that enable the bioeconomy. nonetheless, these are creating yet a different type of risk than described above. the internet makes it easier to bypass our existing controls (be they personal intuitions, company procedures or even laws) [63] . we have evolved social and psychological tools over millions of years to help us deal with deception in face-to-face contexts. but when we lose both physical and human context (as in online communication), forgery and intrusion become more of a risk. it is now known that in the cyber fields "deception, of various kinds, is now the principal mechanism used to defeat online security" [63] . online frauds are often easier to do, and harder to stop, than similar real-world frauds. and according to [64] , "more and more crimes involve deception; as security engineering gets better, it"s easier to mislead people than to hack computers or hack through walls." while only recently recognized as one of the most important factors in security engineering [63] , the entire life-science enterprise is not adequately prepared for attacks that exploit psychology (social engineering attacks, table 2 ). at the same time, hackers are getting better at technology: "designers learn how to forestall the easier technical attacks..." [63] . thus, through various forms of fraud and deception, attackers may be able to circumvent many of the existing cyber-based safeguarding mechanisms and get direct access to their victim"s system. once they have entry to a target system, this may allow them to exploit not only the data and cyber side; it could also facilitate attacks on control and processes underlying various cyber-physical applications ( fig. 3) with consequences that directly affect biophysical components (fig. 4) . cyberbiosecurity is highly cross-disciplinary and will benefit from integrating existing capabilities and proven methodologies from a wide range of fields (e.g. security engineering, physical security and privacy, infrastructure resilience, and security psychology), with requirements from the life-science realm. as cyberbiosecurity may profit the most from lessons learned in the information security domains, this section focuses on this arena. several suggestions have been made to secure specific new cyberbio challenges via various cyber applications (e.g. [66, 12, 38, 14, 21, 5, 10] ). nonetheless, their practical realization is not always straightforward as even most basic information security notions still need to be better adapted to the bioscience framework (see e.g. [14, table 1 ]). similarly, it will be necessary to refine and extend the classic cia triad (which long has been the heart of information security), to extend the suggestions made previously (e.g. [14, fig. 3 ]), to optimally align them with the new demands. j o u r n a l p r e -p r o o f as argued (sect. 4.1), not all of the new problems can be linked to traditional cyber issues. thus, it will be important to distinguish which challenges could, or could not, be identified/safeguarded by existing cyber-approaches (or slight modifications thereof). to aid this distinction and develop a hierarchy of risk severity, it will be helpful to pinpoint the following. identify challenges to assure authenticity and integrity. the cyber-based interface to measure and assess a bioengineered product or service creates a gap, potentially allowing a range of vulnerabilities, from falsifiable entries of biological databases and sequence errors [38, 12] -which in a context like pathogens could lead to entry errors with rather disturbing effects -the intentional tampering of data related to forensics [67] , cyber-enabled attacks on systems monitoring water security [68] , to the actual exchange of the purported actual (cps produced) entity. the latter may enable the distribution of accidentally exchanged/counterfeit products such as plasmids [20] . which give rise to unique concerns where, e.g. some undeclared and "invisible" protein or nucleic acid in a suspended formulation contacts the stated product on release from the packaging or in the retail chain (see [50] ). "information" in the biological sciences [61] , the information life-cycle at large, logically-based game strategies, mechanisms for dual-use appropriation, end-to-end assessments, "routes to harm," context, and multiple exposure pathways [57, 13, 66, 40, 10, 35, 50] . identify the possibility of future and off-target effects. these are situations where clear predictions as required for various "if-then" paradigms employed in the cyber domains are inapplicable. deterrence measures will need to consider emerging actors and their pathways of action, including interactions between synthetic and natural entities, as well as mechanisms, vesicles and actions that can be activated by various physical and mechanical forces or combinations thereof [68, 50] . cyberbio efforts will benefit from the cps arena as these provide unique insights relative to "hardware" (incl. devices and systems) and "software" interdependencies. the cyber-interactions and the interconnectedness of such systems necessitate a drastic modification of previous security principles (see e.g., [29, 72] ). analogously, for cyberbio systems and mechanisms, it will be necessary to refine a list of security principles and goals, by incorporating cps lessons, to optimally align them with the bioscience fields. cyberbiosecurity is an evolving paradigm that points to new gaps and risks, fostered by the cyber-overlaps of modern biotechnologies. the enormous increase in computational capabilities, artificial intelligence, automation and use of engineering principles in the bioscience field have created a realm with a glaring gap of adequate controls. vulnerabilities exist within biomanufacturing, cyber-enabled laboratory instrumentation and patient-focused systems, "big data" generated from "omics" studies, and throughout the farm-to-table enterprise..." [39] . numerous security risks in the biological sciences and attack potentials based on psychology have not been adequately assessed, let alone captured. they will require completely new approaches towards their protection to avoid emergencies at the scale of covid-19 or more. yet, the current situation regarding cyberbiosecurity is sobering (fig. 5) . the private sector, small and moderate-sized companies, and the larger diy community itself are particularly vulnerable [7, 34, 11] . rather than spending enormous amounts of resources in looking back to identify the exact j o u r n a l p r e -p r o o f journal pre-proof genesis of sars-cov-2, cause of the pandemic, and the emphasized singularity of our current global situation, a concerted effort to better understand and mitigate the emerging cyberbio challenges faced by the entire bioeconomy sector should be a top priority. this paper summarizes existing critical issues that must be considered. it also suggests steps that can be leveraged to help assess and ensure that the many bioscience capabilities remain dependable in the face of malice, error, or mischance. the author confirms sole responsibility for the following: conceptualization, investigation, methodology, validation, visualization, writing -original draft, writing-reviewing and editing. the author declares there is no conflict of interest. i would like to thank the reviewers who provided expertise and comments that greatly improved this paper. • the attacker was able to view personal information including email addresses and phone numbers, which are displayed to some users of twitter"s internal support tools [73] . • these credentials can give them access to internal network tools and enable them to sabotage cyber-based controls of cps (figs. 3 and 4) . exploratory fact-finding scoping study on "digital sequence information" on genetic resources for food and agriculture., report on the exploratory fact-finding scoping study on comments of third 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authentication, united states patent a reference model of information assurance & security an update on our security incident key: cord-011688-8g0p3vtm authors: wang, ting-ting; zhou, ming; hu, xue-feng; liu, jiang-qin title: perinatal risk factors for pulmonary hemorrhage in extremely low-birth-weight infants date: 2019-11-04 journal: world j pediatr doi: 10.1007/s12519-019-00322-7 sha: doc_id: 11688 cord_uid: 8g0p3vtm background: pulmonary hemorrhage (ph) is a life-threatening respiratory complication of extremely low-birth-weight infants (elbwis). however, the risk factors for ph are controversial. therefore, the purpose of this study was to analyze the perinatal risk factors and short-term outcomes of ph in elbwis. methods: this was a retrospective cohort study of live born infants who had birth weights that were less than 1000 g, lived for at least 12 hours, and did not have major congenital anomalies. a logistic regression model was established to analyze the risk factors associated with ph. results: there were 168 elbwis born during this period. a total of 160 infants were included, and 30 infants were diagnosed with ph. risk factors including gestational age, small for gestational age, intubation in the delivery room, surfactant in the delivery room, repeated use of surfactant, higher fio(2) during the first day, invasive ventilation during the first day and early onset sepsis (eos) were associated with the occurrence of ph by univariate analysis. in the logistic regression model, eos was found to be an independent risk factor for ph. the mortality and intraventricular hemorrhage rate of the group of elbwis with ph were significantly higher than those of the group of elbwis without ph. the rates of periventricular leukomalacia, moderate-to-severe bronchopulmonary dysplasia and severe retinopathy of prematurity, and the duration of the hospital stay were not significantly different between the ph and no-ph groups. conclusions: although ph did not extend hospital stay or increase the risk of bronchopulmonary dysplasia, it increased the mortality and intraventricular hemorrhage rate in elbwis. eos was the independent risk factor for ph in elbwis. pulmonary hemorrhage (ph) is a life-threatening respiratory complication of newborns [1] , especially in extremely lowbirth-weight infants (elbwis) who are vulnerable to conditions that require invasive ventilation and intensive care after birth. the incidence of clinical ph is estimated to be 1-12 per 1000 live births [2] , whereas the rate of ph in very-lowbirth-weight infants (vlbwis) varies from 4-12% [1] [2] [3] [4] . the variation in its incidence is mainly due to the unclear etiology and diagnostic criteria of ph. the pathophysiology of ph in newborns is hemorrhagic edema [1, 5] . the severity may vary from a mild, self-limited disorder to a massive, deteriorating and end-stage syndrome. it is associated with significant morbidity and high mortality. usually, infants with ph need aggressive positive pressure ventilation, high oxygen supplementation, critical circulatory support and blood transfusions. asphyxia, prematurity, intrauterine growth restriction, infection, hypoxia and coagulopathy are considered as perinatal risk factors for ph in many studies [1, 3, 6] . a few case reports have indicated that healthy term infants with ph are associated with inborn errors of metabolism. furthermore, risk factors associated with the care of preterm infants, including surfactant replacement, the management of patent ductus arteriosus (pda) and the fluid intake of ph, might be prominent in elbwis with ph [7] [8] [9] . however, the risk factors for ph in elbwis are controversial, and more studies are needed to further enhance the understanding of the pathophysiology 1 3 of ph in these extremely premature infants. therefore, the purpose of this study was to analyze the perinatal risk factors and short-term outcomes of ph in elbwis. this is a retrospective cohort study. infants were eligible for the analysis with birth weight less than 1000 g, living for at least 12 hours and no extreme cogenital anomalies at a hospital between january 1st, 2014 and december 31st, 2017. elbwis were excluded from the study if their parents decided to withdraw treatment of their newborns within the first 12 hours of life due to extreme prematurity. infants transferred to other children's hospitals due to cardiac, gastrointestinal or other abnormalities within the first week of life were also excluded. this study was approved by the ethics committee of the hospital. all medical records/information were anonymized and deidentified prior to analysis. all elbwis were resuscitated by a pediatric team led by an attending pediatric physician according to the management guidelines of elbwis. briefly, the elbwis were wrapped with plastic bags under a radiant warmer and with respiratory support by a t-piece resuscitator. a peep 5 cm h 2 o and/or pip 20 cm h 2 o was provided through a face mask immediately after birth. intubation and/or prophylactic surfactant replacement was provided at the discretion of the attending physician in the delivery room. oxygen supplementation was given and adjusted according to the target saturation on a pulse oximeter [10] . when the infants were transferred into the neonatal intensive care unit (nicu) and put on a ventilator or nasal continuous positive airway pressure (ncpap), a physician on duty at the nicu evaluated the respiratory severity and decided to extubate the infant to ncpap after giving surfactant if required. an umbilical venous catheter was inserted, and total parenteral nutrition (tpn) infusion was given. ph was defined as bright red blood secretion from the endotracheal tube that was associated with clinical deterioration, including increased ventilator support with a fraction of inspired oxygen (fio 2 ) increase of > 0.3 from the baseline [1] or an acute drop in hematocrit (> 10%) [4] , in addition to multilobular infiltrates on chest radiography. the record of ventilation of every infant was reviewed by two attending neonatologists independently and confirmed the diagnosis of ph. when a clinical diagnosis of ph was made, the infant was intubated and ventilated with high-frequency oscillatory ventilation (hfov). the ventilation parameters were adjusted appropriately according to the oxygen saturation, the results of arterial blood gas assessment and the chest x-ray. surfactant replacement was considered if necessary. the perinatal data of all infants and their mothers were collected by retrospective chart review that contained sex, gestational age (ga), birth weight (bw), small for gestational age (sga), apgar score at 1 and 5 minutes, delivery method, maternal age, prenatal infection, pregnancy hypertension, gestational diabetes (gdm), prenatal antibiotics and corticosteroids, cause of premature birth, cervical cerclage, surgery during pregnancy, and placental abruption. the short-term outcomes of the infants were also recorded. neonatal respiratory distress syndrome (nrds) and its severity were diagnosed by the neonatologists of the nicu based on the clinical profile and chest radiograph. early onset sepsis (eos) was defined as infectious diseases within 72 hours after birth as confirmed by blood culture. brain injury, including grade iii-iv intraventricular hemorrhage (ivh) and periventricular leukomalacia (pvl), was identified by serial head ultrasounds. bronchopulmonary dysplasia (bpd) was defined as the requirement for supplemental oxygen at 36 weeks postmenstrual age among infants who survived to nicu discharge. retinopathy of prematurity (rop) was screened by an ophthalmologist. echocardiography was performed between days 3 and 7 by a cardiologist and repeated as appropriate. the hemodynamically significant pda was managed by neonatologists, and ibuprofen was given to close the patent ductus. the treatment was withheld if there was identification of gastrointestinal bleeding or oliguria (urine output of less than 1 ml/kg/hour) according to the protocol for pda management in our nicu. the decision was made by the neonatologists to transfer the elbwi for surgical ligation if more than two courses of oral ibuprofen were given and the pda was still significant [11] . the data were analyzed with spss version 22.0. descriptive statistic analysis were used to describe the characteristics of mothers and infants. the normally distributed results are reported as the mean and standard deviation (sd); the remaining results are reported as the median, interquartile range (iqr) or percentage. chi-squared test, student's t-test and logistic regression model were used for statistical analysis. a total of 168 elbwis were born in this hospital and admitted to the nicu between january 1st, 2014, and december 31st, 2017. six infants were transferred to other hospitals for surgical diseases, and two infants died (they were identical twins who were born at 25 weeks and 5 days of ga; their birth weights were 840 g and 675 g, respectively). their parents withdrew care within 12 hours of life due to concerns about adverse long-term outcomes. among the 160 infants included in this study, 30 infants were diagnosed with ph (ph group), leading to an incidence of ph in these elbwis of 18.75%. the median age of infants with ph occurrence was 3 (iqr 2-4.5) days. one elbwi had ph occurred within 24 hours, on day 5, day 7 and day 12 after birth, respectively; 21 had ph that occurred on day 2-3 after birth, three on day 6 and two on day 11. the perinatal risk factors of ph are listed in table 1 and 2. the ga of the infants with ph was significantly lower than that of the non-ph infants. there were fewer sga infants in the ph group than no-ph group. because most cases of ph occurred within 3 days of life and the majority occurred in the first week of life, the average fluid intake within the first 3 and 7 days of life was also compared between the ph and no-ph group. unsurprisingly, the infants with ph were more likely to be intubated and treated with surfactant and oxygen supplementation. a multivariate analysis (including ga, sga, intubation in the delivery room, surfactant in the delivery room, repeated use of surfactant, higher fio 2 during the first day, invasive ventilation during the first day, and eos) was performed by using the logistic regression model, which found that eos was an independent risk factor for ph (table 3 ). the mortality of infants with ph was 43.3% (13/30), which was significantly higher than that of infants without ph (17.7%, 23/130). the rate of major ivh was higher in the ph group than that in the no-ph group. however, the rates of pvl, moderate-to-severe bpd, and severe rop were not significantly different between the ph and no-ph group (table 4) . among the 124 patients who were discharged home (17 in the ph group and 107 in the no-ph group), there were no significant differences of the duration of assisted ventilation, invasive mechanical ventilation, oxygen supplementation, hospital stay, or moderate-to-severe bpd between the two groups (table 5 ). in this study, we found that elbwis with ph were likely to be intubated and require surfactant therapy, invasive ventilation and oxygen supplementation, whereas the mortality and major ivh rates were also increased. logistic regression analysis showed that eos could increase the risk of the incidence of ph is significantly higher in elbwis than that in other neonatal populations, and the precise etiology remains unclear. a 10-year retrospective study has shown that the rate of ph in vlbwis is 4% [3] . another study reported that the rate of ph was approximately 8% in vlbwis but was 11-16.6% in elbwis [2, 9] . in our cohort, the rate of ph in elbwis was 18.8%. it has been shown that sga, eos, low birth weight (lbw), lower apgar scores at 1 and 5 minutes, severe rds and surfactant replacement are risk factors for ph [12] . usually, smaller gestational age and lower birth weight increase the odds of eos in preterm infants. ph may occur as a result of unstable hemodynamics and coagulopathy in elbwis with eos. it has been proven that delayed cord clamping reduces the risk of ph [13] . circulatory stabilization is the fundamental management strategy for elbwis and reduces the risk not only for pulmonary disease but also of mortality and ivh. many studies have shown that pda is associated with the occurrence of ph [6, 8, 14] . as a result of decreased pulmonary vascular resistance, left-to-right shunting through pda increases blood flow and the pressure state of the pulmonary vessels, which may compromise cardiac function with an increased risk of ph [5] . in our cohort, the rates of pda and requirement of treatment were higher in infants with ph than in those without, but the differences were not statistically significant. interestingly, the time of ph occurrence in our cohort was earlier than that of the development of hemodynamically significant pda [15] . the other reason might be the active management of pda in elbwis [16] . in our study, 71.4% of the infants with pda in the ph group and 65.8% in the no-ph group required oral ibuprofen or ligation. in addition, there was no significant gastrointestinal bleeding or oliguria observed in either the ph or no-ph group when ibuprofen was given, while the side effects of ibuprofen were fewer than those of indomethacin [17] . in addition, the overload of fluid intake within the first week was associated with pda and ph [18, 19] . polglase et al. [20] demonstrated that immediately after an intravenous volume overload, lambs had increases in pulmonary blood flow and the left ventricular ejection volume; 50% of them developed ph. the elevation in pulmonary capillary pressure can lead to alveolar capillary wall injury, causing pulmonary edema due to increased permeability with the passage of proteins [21] . in our study, the fluid intake of these elbwis was restricted to an average of 110-120 ml/kg/day to reduce the risk of bpd and hemodynamically significant pda [22] and showed no difference between infants with ph and those without ph. surfactant replacement is a standard treatment for rds. it has been shown that surfactant replacement increases the risk of ph [23] . in contrast, some studies have reported that the rates of ph are not different before or after surfactant replacement therapy [9] . it is reasonable to postulate that the infants who need surfactant are sicker and more likely to have ph than those who do not need surfactant. although an in vitro study showed that the presence of surfactant impaired coagulation function [24] , this finding was not proven clinically. on the other hand, infants with ph can be treated with surfactant because of the inhibition of surfactant function by blood. few retrospective and observational reports have demonstrated the benefits of surfactant on ph. however, the effect of this therapy remains to be established [25] . it seems that the chemical composition of different surfactant types affects the risk of ph [26] . infants given poractant alfa have a significantly higher rate of ph (21%) than infants treated with surfactant-ta (10%) [26] . however, the clinical risk index for babies scores were higher in infants treated with poractant alfa than in infants treated with poractant alpha. in our cohort, the infants with ph were similar to the infants without ph in terms of surfactant administration in the delivery room or nicu. however, the infants with ph needed multiple doses of surfactant. infants who were given surfactant prophylactically in the delivery room did not have an increased risk of ph. ph is a life-threatening condition of hemorrhagic pulmonary edema with high mortality. in our study, the mortality of elbwis with ph was 43% (vs. 18% in the no-ph group), similar to previous reports [9] . the rate of major intraventricular hemorrhage was significantly higher in the ph infants than in the non-ph infants (10% and 2%, respectively, p < 0.05). both ph and intraventricular hemorrhage are related to perinatal hemodynamic instability [13] . the effective management of ph includes positive pressure ventilation [4] , blood transfusion and circulation support. however, there were no significant differences in mechanical ventilation, oxygen supplementation, or hospital stay between surviving infants in the ph and no-ph groups, mainly because these factors, in addition to ph, are independently related to prematurity. this is a retrospective study in a single center of shanghai, which may not be able to highlight all the risk factors of ph in elbwis due to the limited data and small sample size. however, analyzing the risk factors of ph will help physicians to better understand why ph occurs and how to prevent it. in summary, ph is an adverse pathophysiological event of elbwis that occurs mostly within the first 72 hours of life. ph increases the risk of mortality and major intraventricular hemorrhage, and early onset sepsis is an independent risk factor for ph. funding no funding was received. ethical approval this study was approved by ethics committee of the shanghai first maternity and infant hospital, tongji university school of medicine. no financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. open access this article is distributed under the terms of the creative commons attribution 4.0 international license (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. pulmonary hemorrhage clinical course and outcomes among very low-birth-weight infants prevalence, risk factors and outcomes associated with pulmonary hemorrhage in newborns pulmonary hemorrhage in very low-birthweight infants: risk factors and management short-term outcome of pulmonary hemorrhage in very-low-birthweight preterm infants improvement in mortality of very low birthweight infants and the changing pattern of neonatal mortality: the 50-year experience of one perinatal centre risk factors of pulmonary hemorrhage in very low birth weight infants: a two-year retrospective study early versus delayed neonatal administration of a synthetic surfactant: the judgment of osiris ductal shunting, high 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syndrome: a retrospective study acknowledgements we thank dr. po-yin cheung for his professional guidance for the preparation of this paper.author contributions ttw collected and analyzed the data, and drafted the manuscript. mz and xfh collected the data. jql designed the study. all authors approved the final version of the manuscript. key: cord-002906-llstohys authors: you, shu-han; chen, szu-chieh; liao, chung-min title: health-seeking behavior and transmission dynamics in the control of influenza infection among different age groups date: 2018-03-06 journal: infect drug resist doi: 10.2147/idr.s153797 sha: doc_id: 2906 cord_uid: llstohys background: it has been found that health-seeking behavior has a certain impact on influenza infection. however, behaviors with/without risk perception on the control of influenza transmission among age groups have not been well quantified. objectives: the purpose of this study was to assess to what extent, under scenarios of with/without control and preventive/protective behaviors, the age-specific network-driven risk perception influences influenza infection. materials and methods: a behavior-influenza model was used to estimate the spread rate of age-specific risk perception in response to an influenza outbreak. a network-based information model was used to assess the effect of network-driven risk perception information transmission on influenza infection. a probabilistic risk model was used to assess the infection risk effect of risk perception with a health behavior change. results: the age-specific overlapping percentage was estimated to be 40%–43%, 55%–60%, and 19%–35% for child, teenage and adult, and elderly age groups, respectively. individuals perceive the preventive behavior to improve risk perception information transmission among teenage and adult and elderly age groups, but not in the child age group. the population with perceived health behaviors could not effectively decrease the percentage of infection risk in the child age group, whereas for the elderly age group, the percentage of decrease in infection risk was more significant, with a 97.5th percentile estimate of 97%. conclusion: the present integrated behavior-infection model can help health authorities in communicating health messages for an intertwined belief network in which health-seeking behavior plays a key role in controlling influenza infection. it has been found that health-seeking behavior has a certain impact on influenza infection. 1 therefore, to facilitate public health decisions about intervention and management in controlling the spread of infectious diseases, it is crucial to assess to what extent, under scenarios of with/without control and preventive/protective behaviors, the age-specific network-driven risk perception influences influenza infection. 2 to control respiratory infectious diseases, the development of vaccination, contact tracing, isolation, and the promotion of protective behaviors are the important measures. indeed, the effectiveness of control measures fundamentally depends greatly on human beliefs on public infection awareness and risk perception for driving the change in self-behavior. 3 infection and drug resistance 2018:11 submit your manuscript | www.dovepress.com you et al risk perception can be referred to as an awareness or belief about the potential hazard and/or harm, which plays an important role in shaping health-related behaviors to reducing susceptibility and infectivity. 4 generally, risk perception is affected by social factors such as media release by health authorities, observation or interaction with relation-specific groups, past experiences of similar hazards, habits, and culture. 5 these factors result in variation in risk perception among individuals. epidemiological studies have found that variances in risk perception can be observed by examining the behavioral responses among different age groups. steelfisher et al 6 indicated that 60% of the adult population said that they did not intend to acquire the h1n1 vaccine for themselves. in addition, perception of vaccine safety and personal vulnerability were the major reasons for vaccine acceptance. allison et al 7 indicated that children could use accurate protective behavior; for example, they could use hand gel for preventing influenza. on the other hand, childhood vaccination is more likely to depend on parental decision making. moreover, researchers have suggested assessment of the risk perception and behavior across different age groups. 8, 9 a social network could be an important social structure in which people could exchange information about risk-related events to spur the health behavior change. 10 scherer and cho 11 suggested that individual perceptions could be affected by self-perception in the social network. researchers have explored the interactions between epidemic spreading and risk perception in the network. 12, 13 however, the influence of risk perception on the risk of infectious disease is controversial, because the perceptual capacity of individuals may both create and reduce the disease risks. therefore, the behavior-disease dynamics in the social network structure may result in amplification or attenuation of the disease outbreak. most epidemic modeling techniques have used a simple epidemic model such as the susceptible-infected-recovered (sir) model for describing a homogeneous disease network. moreover, the effects the network with human responses to disease spreading were studied extensively and attracted substantial attention. funk et al 12 used sirbased perceptual-influenza model for examining the effects of risk perception on behavioral change and susceptibility reduction. they also indicated that the effects within a disease network can induce health behavioral changes in the population. in turn, the influence of risk perception could result in a feedback signal to alter the progress of the disease dynamics. 12, 14 recently, information theoretical approaches have been applied to infer the relations in diseases or social networks. 15, 16 zhao et al 15 developed a model to quantify the effects of a dynamic network, indicating that the behavior responses correspond to the entropy derived from different information content of the dynamic social network. greenbaum et al 17 proposed an information theoretic model to assess pandemic risk. they indicated that mutual information was a key determinant in minimizing risk of the pandemic threats. we have previously incorporated the information-theoretic framework into a behavior-influenza (bi) transmission dynamic system to understand the effect of individual behavioral change on influenza epidemics. 18, 19 here we assess that if, how, and to what extent, under different scenarios of with/without control and preventive/protective behaviors, the age-specific network-driven risk perception influences influenza infection. in this study, we analyzed the emergency admission rates from the weekly ili visits, which were obtained from taiwan centers for disease control (tcdc) by sentinel primary care physicians. the ili cases were detected through the real-time outbreak and taiwan national infectious disease statistics system. 21 the definition of an ili case must meet three criteria: 1) fever (ear temperature ≥37.8°c) and respiratory tract symptoms (including rhinorrhea, nasal congestion, sneezing, sore throat, cough, and dyspnea), 2) one of the symptoms of muscle ache, headache, and extreme fatigue; and 3) exclusion of simple running nose, tonsillitis, and bronchitis. data on emergency admission rates for six influenza seasons in the period from week 8 of 2007 to week 13 of 2013 were adopted to test how health-seeking behavior influences the influenza infection dynamics. influenza season was defined from july 1 (week 26) to june 30 (week 25) of the following year in taiwan. the ili-related emergency admission rates were detected by using the icd-9-cm codes for influenza and pneumonia (480-487). we also estimated the age-specific admission infection fraction (if) for each age group, including child (0-14 years), teenage and adult (15-64 years) , and elderly (65+ years), for different human behaviors or influenza risk perceptions. we multiplied the annual mid-year population estimates 20 health-seeking behavior in the control of influenza infection 100,000 and then divided the result by the number of ili visits to estimate if, which is given as 21 mid-year population incidence rate where i is the different age groups (child, teenage and adult, and elderly) and j is the yearly based time period in the period of 2007-2013. the concept of the bi model developed in our previous studies 18, 19 mainly incorporated the sir-based perception model 12 into an information-theoretic framework, which was used to simulate the information flow of risk perception in response to an influenza outbreak. briefly, the bi model uses six compartments to represent the disease states of susceptible, infected, and recovered by dividing the population into a with/without perception structure. 12 the description of input parameters for the bi model is given in table 1 . basic reproduction number (r 0 ) can be used to quantify disease infection severity, defined as the average number of secondary cases produced successfully by an infected individual in a totally susceptible population. 22 therefore, based on the bi model, we can also estimate r 0 with the perception state (r a 0 ) and without perception state (r d 0 ). it can be described as input source information with perception s a = r a 0 = a / λ , where a is the rate of perception spread and l is the rate of perception loss. on the other hand, input source information can be described without perception is the infection rate describing contact between infected and susceptible populations and g is the recovery rate from infected to recovered populations. 19 we assumed that r 0 can be treated as the basic reproduction number resulting from individuals with risk perception information (r 0,rpi ) for each age group in the period of 2007-2013. thus, r 0,rpi can be estimated as: 19 . furthermore, to better characterize perception spread rate for different age groups during each year (a ij ) on the bi transmission dynamics, we adopted a ij from an epidemic equilibrium structure. 12 the equilibrium information flow of risk perception from population without perception r d where r a 0e is the basic reproduction number at equilibrium with information flow of risk perception from population without perception, s i is the reduced infectivity factor from infected with perception to susceptible without perception, w is the rate of infected becoming with perception, a is the perception spread rate, and g w/o is the recovery rate of infected without perception. moreover, we assumed that people may make the decision to change behavior based on r 0,rpi in the previous year. based on equation 3, a can then be rewritten as; where r ij 0,pri, and r i j 0 1 ,pri, + ( ) are the basic reproduction numbers with/without risk perception, respectively, for each age group in the period of 2007-2013. to assess the effect of network-driven risk perception information transmission on influenza infection, we applied an information theoretic model referred to as the multiple access channel (mac) that is used to capture a signal r 0 transmitting through multiple channels to the responses i 1 , i 2 , …, i n . we considered the network-driven risk perception information model (nm) with information bottleneck (ib). 19 the maximum mutual risk perception information (mi max ) resulting from the nm can be estimated as; 23 where n e is the effective information from contact numbers of individuals, s r 0 2 is the variance of the r 0 signal distribution, s ib→i 2 is the variance introduced in each access channel through the ib to response i, and the s r 0 2 →ib is the variance introduced to the ib. the ratio s s s is the signal-to-noise ratio. 23 on the other hand, the nm model with a negative feedback was considered to explore the effect of perceived different health behaviors on reducing susceptibility. 19 here, we used the correlation coefficient (r) and the overlapping percentage (i o ) to associate r 0 and i from the published data (table s1 ) to calculate s s s in equation 5. we estimated the r based on the relationship between viral titer-based i and viral tier-based r 0 corresponding to with/ without perceived different health behaviors. briefly, we selected published papers (table s1) where health behaviors treated with vaccinations and antiviral drugs for different subtypes of influenza were included. two protective behaviors (i.e., perceived of carrying the disease to vaccine and antiviral taking) were adopted in a state of greater alert. the value of r can be used to associate the amount of observed variability that is attributable to the overall biological variability and experimental noise. on the other hand, i o describes the age-specific overlapping percentage between the infected population with/ without perception adjusted by the fractions of initial infected population with perceptual state over those without perceptual state. here, we used three perceptual scenarios to assess our model with the initial infected population ratios of <1, =1, and >1. the i o can then be estimated as algebraic manipulation of probability density functions (pdfs) of s a and s d as; 19 thus, followed by the information-theoretic theorem with known values of r, i o , and s r 0 2 , the s s can be computed as 1 2 23 therefore, the nm model with a negative feedback in equation 5 can be rewritten as; health-seeking behavior in the control of influenza infection where i represents the individuals perceived with/without health behaviors. we further incorporated the estimated probability distributions of the model parameter with age-specific initial population sizes in the period of 2007-2013 (table 2) and a into the bi model, to estimate the age-specific overlapping percentages. to parameterize the reduced susceptibility factor with regard to adopting preventive behaviors, including using masks, avoiding visiting crowded places, and hand washing 24 (s s,pre ), and protective behaviors of vaccination 26 (s s,pro ), we applied a standard logistic regression-based equation for mathematically expressing the components of the healthbehavior model (hbm). the hbm-based health behavior with the standard logistic regression-based equation has been applied to estimate with/without preventive/protective health behaviors in respiratory infectious diseases such as severe acute respiratory syndrome (sars), influenza, 24-26 and other diseases. [27] [28] [29] the estimates are equivalent to the decisions of rational individuals with influenza knowledge. here, s s can be expressed in terms of odds ratios (ors) depending on health behaviors perceived to be associated with each hbm variable. 26 where s s is the probability of the hbm-based health behaviors (such as preventive behavior, s s,pre , and protective behavior, s s,pro ) and x is a binary variable with a value of 1 indicating a "high" state and a value of 0 indicating a "low" state. or 0 is a calibration factor when all hbm variables are in a "low" state. s s represents that an individual engages in a particular behavior, and it could be calculated from equation 8 . s s ≥0.5 indicates that an individual engages in a specific health behavior. r 0 perception-based probabilistic risk assessment to develop a probabilistic risk model, a dose-response model describing the relationship between transmission potential quantified by signal r 0 and the total proportion of the infected population (i) has to be constructed. in a previous study, 18 we have successfully employed the joint probability distribution to assess the risk profile. it can be expressed mathematically as; where r(i) is the cumulative distribution function describing the probabilistic infection risk in a susceptible population at specific r 0 signal, p(r 0 ) is the probability distribution of r 0 signal (the prior probability), and p(i|r 0 ) is the conditional response distribution describing the dose-response relationship between i and r 0 . the exceedance risk profile can be obtained by 1 -r(i). in view of equation 2, we can relate p(i, r 0 ) to r(i) in equation 9 . thus, the mutual information in these interdependences between belief of risk perception and infection risk can then be expressed as a mechanism of interpersonal influence described in equation 10 . in table 1 , the numbers of ili visits were 2.4 × 10 4 ± 1 × 10 4 (mean ± standard deviation [sd]), 2.8 × 10 4 ± 1.1 × 10 4 , and 8.4 × 10 3 ± 1.7 × 10 3 per month for child, teenage and adult, and elderly age groups, respectively. figure 1 shows the ili-related emergency admission rates and if among the three age groups, child (0-14 years), teenage -2013) , the ili-related emergency admission rates were estimated to be 16.8 ± 7.3 (mean ± sd), 1.2 ± 0.8, and 3.5 ± 1.3 per 10,000 population for child, teenage and adult, and elderly age groups, respectively. overall, the ili-related emergency admission rate was the highest in the child age group (6.4-67.3 per 10,000 population, minimum-maximum), whereas the lowest one was observed in the teenage and adult age group (0.4-8.8 per 10,000 population; figure 1a ). on the other hand, the highest ili-related emergency admission if was in the child age group (0.7 ± 0.1%), followed by teenage and adult (0.2 ± 0.1%) and elderly (0.03 ± 0.01%) age groups ( figure 1b ). to model the bi model, the age-specific perception spread rate (a) has to be determined (equation 4). we first calculated age-specific r 0 , pri based on the age-specific ili-related admission if. our results indicated that lognormal (ln) distribution with a geometric mean (gm) and a geometric standard deviation (gsd), ln (gm, gsd), was the most suitable fitted model for r 0 , pri distributions of ln (1.78, 1.08), ln (1.14, 1.04), and ln (1.00, 1.01) for child, teenage and adult, and elderly, age groups, respectively (table 1 ). figure 2 demonstrates age-specific overlapping percentage (i o ) between infected population with/without perception adjusted by fractions of initial infected population with perceptual state over those without perceptual state. we used three different scenarios of initial infected population fraction: i + /i -< 1 (figure 2a-c) , i + /i -= 1 ( figure 2d-f) , and i + /i -> 1 ( figure 2g-i) . we showed that i + /i -> 1 results in the lowest estimates of i o in child and elderly age groups ( figure 2g and i), whereas for teenage and adult age groups, the estimate was the highest in the case of i + /i -= 1 ( figure 2e ). generally, i o estimates range from 40% to 43%, 55% to 60%, and 19% to 35% for child, teenage and adult, and elderly age groups, respectively ( figure 2 ). thus, we used i o based on justified initial infected population fraction to further examine the mi max among each age group. health-seeking behavior in the control of influenza infection generally, the individual with risk perceptual status is more likely to have the communicable belief among the population. in the case of effective information from contact numbers of individuals (n e = 1; figure 3a ), when i + /i -< 1 and i + /i -= 1, the mi max was <1 bit. on the other hand, when i + /i -> 1, as the perceptual information increased in the population, mi max was >1 bit, indicating that the network-based information reflected cooperativity. our results showed that mi max -n e profile featured a smooth shape ( figure 3b ). in the elderly group, as the strength of n e increased, mi max -n e profile experienced a nearly smooth curve. on the other hand, in the child and elderly groups, when n e was >6, mi max was >1 bit. our results indicated that mi max ranged from 0.4 to 1.2 bits, 0.5 to 1.4 bits, and 1.2 to 2.4 bits for child, teenage and adult, and elderly age groups, respectively, given n e ranging from 1 to 6 ( figure 3b ). to explore the impact of n e -varying perceived health behavior information on mi max , we estimated correlation coefficient (r) based on the relationship between viral titerbased i and viral tier-based r 0 corresponding to, with and without, perceived different health behaviors. the resulting estimates were r w = 0.7 and r w/o = 0.4 ( figure s1 ). we further used equation 7 to calculate mi max based on overlapping percentage (i o ) and r affected by n e . the results indicated that mi max ranged from 0.9 to 1.9 bits, 1.0 to 2.1 bits, and 1.2 to 2.4 bits for without control, and preventive, and protective behaviors in the child age group, respectively ( figure 4a ). for the teenage and adult age group, mi max ranged from 1.1 to 1.5 bits, 0.8 to 1.9 bits, and 3.5 to 4.8 bits for without control, and preventive, and protective behaviors, respectively ( figure 4b ). our results showed that individuals perceived the health behaviors to increase mi max among child, and teenage and adult, age groups ( figure 4a and b, respectively). our results also revealed that individuals perceived the preventive behavior to improve risk perception figure 4b) , and the elderly age group ( figure 4c ), but not in the child age group. our results indicated that there was 50% probability for exceeding the infected fraction of population (i); 0.73, 0.23, and 0.34 for child ( figure 5a ), teenage and adult ( figure 5b ), and elderly ( figure 5c ) age groups, respectively, in the condition of without perceived health behaviors. however, there was a 50% probability for reducing the infected fraction of population within the ranges of 0.004-0.20 for preventive behavior and 0.007-0.10 for protective behavior ( figure 5 ). the age-specific ∆mi with respect to with/without health behaviors was estimated based on equations 7 and 10. we found that, for instance, without any control information released, the median percentages of decrease in infection risk with ∆mis = 1 and 2 for elderly were 30 (1.5-83) and 57 (5.1-97), respectively, whereas the child age group had the lowest estimates of 5 (0.3-14) and 7 (0.3-79), respectively ( figure 6a ). on the other hand, ∆mi estimates at incremental mi changes with perceived health behaviors were 2%-3%, 10%-12%, and 26%-59% for child, teenage and adult, and elderly age groups, respectively ( figure 6b and c). the population with perceived health behaviors could not effectively decrease the percentage of infection risk in the child group, whereas for the elderly age group, the percentage of infection risk decreased more significantly with a 97.5th percentile estimate of 97% ( figure 6b and c). our results indicated that children may be preferable to adopt the protective behaviors. allison et al 7 indicated that the use of hand gel for hygiene was a feasible strategy in elementary schools to prevent influenza spread. our results implicate that children could use the accurate knowledge about the protective behavior to prevent influenza infection effectively. health-seeking behavior in the control of influenza infection our results found that the perceived protective behaviors enhanced the mi max in adults, whereas the perceived vaccination behavior might not. a meta-analysis of eligible studies also confirmed that raising risk perception from low to high would have a potential effect on vaccination behavior of adults. 30 we suggest that future studies should detect the differences among the health behaviors in adults. schneeberg et al 31 indicated that the vaccination rate for seasonal influenza was consistently low among the elderly population in canada. walter et al 32 indicated that the elderly population failed to obtain information about vaccine perception from the internet directly. it was also found that face mask wearing was easily performed by older adults in hong kong. 25 elderly people also appeared to be more active in conducting preventive measures. 33 in this article, we incorporated the probability-based hbm with regard to specific health behaviors into an sirbased epidemiological model. the hbm was used to examine individual's perceptual dimensions such as perceived susceptibility, severity, benefits, and barriers. however, the hbm has led to somewhat controversial issues in exploring the health behaviors such as for vaccination programs. 34, 35 the hbm presents a rational point of view that assumes the perceiver to be uninfluenced by the emotion, on describing the human you et al response to an epidemic. 9, 26 our study, however, establishes a more robust mechanistic framework on modeling the influence of network-driven risk perception on influenza infection. to our knowledge, we have conducted the first step on exploring the effects of risk perception in a population, on the spread of epidemics. we believe that our present methodology provides an innovative approach that integrates an epidemiology model with the information theory. we examined three scenarios for describing different agespecific populations to overcome susceptibility risk due to less accurate knowledge of influenza. we found that noise effect, which reflects as overlapping percentages about the uncertainty of accurate knowledge of influenza, can reduce risk perception information transfer on the network through the epidemic transmission. for example, previous studies found that participants had misconceptions between seasonal vaccine and pandemic strain. 36, 37 the effect of overlapping response may have resulted from the public health campaigns. for example, people were recommended to acquire the seasonal vaccine in pandemics. this may lead to a feedback mechanism between behavior change and disease dynamics. future work should carefully consider the effects of this noise on specific age groups. moreover, each intervention should be carefully investigated to the extent possible during an epidemic. this study has several limitations. the estimation of information flow of risk perception in age groups depended on the ili data. indeed, the human response to influenza varied with time and hence is not possible to detect in realtime situations. moreover, perceptual states in specific age groups may be affected by the severity levels of disease, the amount of accurate information about influenza, and other health-related leaflets. therefore, we suggest that the health authorities could reinforce health monitoring by using information technology and then linking it to the real-time epidemiological surveillance systems. a further limitation of our study is that we did not consider the influential factors on risk perception in an epidemic model. hence, future research should explicitly consider a number of additional influential factors on risk perception within an epidemic modeling, including disease prevalence, network effects, and government and media health messages. the findings of our study have an implication for public health. risk communication might be more effective if health authorities focus on a variety of information communication channels for conveying health behavior messages. moreover, our findings concerning perception of different health behaviors show substantial differences among age groups. we found that perceived protective behaviors (e.g., covering mouth, coughing hand washing) could reduce the infection risk for all age groups. this suggests that such crucial information for control measures would allow for targeting resources to designing and implementing the education plans concerning perception of healthy behaviors that are least perceived in the health behaviors. 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(virazole) in experimental influenza a virus infection in volunteers dose response of a/alaska/6/77 (h3n2) cold-adapted reassortant vaccine virus in adult volunteers: role of local antibody in resistance to infection with vaccine virus efficacy and safety of low dosage amantadine hydrochloride as prophylaxis for influenza a cold recombinant influenza b/texas/1/84 vaccine virus (crb 87): attenuation, immunogenicity, and efficacy against homotypic challenge evaluation of the infectivity, immunogenicity, and efficacy of live cold-adapted influenza b/ann arbor/1/86 reassortant virus vaccine in adult volunteers effects of the neuraminidase inhibitor zanamivir on otologic manifestations of experimental human influenza oral oseltamivir in human experimental influenza b infection the authors acknowledge the financial support of the ministry of science and technology, republic of china, under grant most 104-2221-e-002-030-my3. all authors contributed toward data analysis, drafting, and critically revising the paper and agree to be accountable for all aspects of the work. the authors report no conflicts of interest in this work. infection and drug resistance is an international, peer-reviewed openaccess journal that focuses on the optimal treatment of infection (bacterial, fungal and viral) and the development and institution of preventive strategies to minimize the development and spread of resistance. the journal is specifically concerned with the epidemiology of antibiotic resistance and the mechanisms of resistance development and diffusion in both hospitals and the community. the manuscript management system is completely online and includes a very quick and fair peerreview system, which is all easy to use. visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors. health-seeking behavior in the control of influenza infection key: cord-022130-jckfzaf0 authors: walsh, patrick f. title: intelligence and stakeholders date: 2018-09-19 journal: intelligence, biosecurity and bioterrorism doi: 10.1057/978-1-137-51700-5_7 sha: doc_id: 22130 cord_uid: jckfzaf0 this chapter underscores the need for more explicit and strategic engagement of stakeholders (scientists, clinicians, first responders, amongst others) by the intelligence community. the chapter argues that the intelligence community will increasingly rely on their expertise to build more valid and reliable assessments of emerging bio-threats and risks. however, the discussion also identifies some of the limitations and challenges stakeholders themselves have to understanding complex threats and risks. agricultural scientists and veterinarians) can all be critical stakeholders for intelligence communities. without them it would be almost impossible to see how the ic alone can fulfil its mission to identify, prevent, disrupt and treat potential and emerging bio-threats and risks. indeed as seen in chapter 4 'the scientific community' brings a lot of expertise to the intelligence community about how to assess bio-threats and risks in a number of different ways and contexts. these include understanding potential risks through gof experiments, the development of biosensors and knowledge about weaponisation, pathogenicity and transmissibility of various bio-agents. chapter 4 also surveyed briefly the role of scientists working in epidemiology and forensics as providing central roles in the prevention, disruption and treatment of bio-threats and risks. additionally, chapter 5, highlighted the critical role the scientific community plays in helping the intelligence community better frame their understanding of potential threats and risks emerging from the fast paced changing biotechnology and synthetic biology sectors. this chapter provides a thematic analysis of how important stakeholders can contribute to reducing current and emerging bio-threats and risks. in contrast to chapter 6, which focused on what internally the intelligence community can do to better equip itself to manage bio-threats and risks, this chapter surveys what important external stakeholders can bring to the table to improve intelligence capability and to reduce bio-threats and risks themselves. paraphrasing research impact scholar mark reed's definition, i define a stakeholder of the intelligence community as any person, organisation or group that is affected by or can affect a decision, action or issue relevant to preventing, disrupting or treating bio-threats and risks (reed 2016: 41) . specifically, i am referring to stakeholders in the scientific, research, clinical, policy, first responder and private sectors that can provide capability, expertise to the intelligence community and/ or contribute to biosecurity through their own actions. in particular, the thematic analysis of the role of stakeholders in this chapter is organised around three sub-headings: prevention, disruption and treatment. traversing the literature and interviews with a select number of stakeholders shows there that there is a large and diverse number of individuals and organisations that could potentially play a role in either preventing, disrupting or treating future bio-threats and in the biological context, surveillance is the ongoing collection, analysis, and interpretation of data to help monitor for pathogens in plants, animals, and humans; food; and the environment. the general aim of surveillance is to help develop policy, guide mission priorities, and provide assurance of the prevention and control of disease. in recent years, as concerns about consequences of a catastrophic biological attack or emerging infectious diseases grew, the term bio surveillance became more common in relation to an array of threats to our national security. bio surveillance is concerned with two things: (1) reducing, as much as possible, the time it takes to recognize and characterize biological events with potentially catastrophic consequences and (2) providing situational awareness-that is, information that signals an event might be occurring, information about what those signals mean, and information about how events will likely unfold in the near future (gao 2011: 9). this definition highlights how the functions and roles of biosurveillance has changed from a more narrow concern of mapping disease in the public health sector to represent a diverse array of knowledge and capabilities that are vital in understanding bio-threats in the national security context. the definition also underscores the ongoing multiple challenges in improving bio-surveillance capabilities and their utility in the national security context. three key challenges in particular remain for improving national bio-surveillance capabilities and they are: methodological, information sharing and integration issues. the information sharing and integration issues have already been discussed in chapter 6 so this section will focus on the bio-surveillance methodology issues. by methodological issues, i am referring to both the technical methods (biosensors) and the broader different disciplinary approaches to biosurveillance that now inform debates amongst stakeholders on how to improve bio-surveillance capabilities. from a technical perspective, there has been a range of bio-sensor research from inside and outside the ic to detect the release of dangerous pathogens into the environment. perhaps the most well-known of these initiatives-biowatch was developed by dhs in 2003 with the aim to detect aerolised bio attacks for high risk bioagents in major us cities. the program however, has had mixed success relating to the reliability of results and the delay in the publication of these once samples were collected from the field (gao 2016 (gao , 2017 . the dhs tried to speed up the detection times from the first generation manual systems to gen 3 acquisitions, which promised speedier autonomous systems though testing difficulties remained. further analysis, however, of alternatives by the dhs as showing any advantages of an autonomous system over the current manual system were insufficient to justify the cost of a fully technology switch (gao 2016: 7) . in the us, research continues to improve the robustness, sensitivity, specificity, timeliness and cost of biosensor equipment. while conventional pcr based methods and immunoassay are still being used other biochemical, microbiological and genetic solutions are being trialled such as the incorporation of antibodies and peptide molecules, which may greatly reduce detection times to minutes instead of several hours (kim et al. 2015) . leaving aside efforts to improve aerolised biosensors, the expected rapid growth of synthetic biology and biotechnology and the potential (however unknown) that bioengineered material may be used maliciously in a way that threatens public safety or national security may shift the focus into other scientific research that can detect signals of bio-engineering including types of changes, location and possibly in the future where changes were made. in july 2017, iarpa commissioned a new program-finding engineering linked indicators (felix) to meet such objectives. iarpa is seeking interest from a range of scientists (synthetic biologists, micro biologist, immunologist, statisticians and computer scientists) to carry out 3-5 research projects addressing the two main focus points of felix (eaves 2017) . if this research can produce reliable results, it will provide another useful collection and analysis point for the ic by allowing the detection of previously undetectable signatures of bio-engineered material in bio-criminal and terrorism cases. in addition to the various technical innovations in biosensors, a range of other bio-surveillance methods have been deployed. in the late 1990s, the us cdc pioneered syndromic surveillance systems, which were initially aimed at improving the early warning of infectious diseases and bio-terrorism and have now evolved to include situational awareness (buehler et al. 2004) . similar syndromic surveillance systems have developed in other 'five eyes' countries such as the uk's real-time syndromic surveillance team (resst), which collects four national syndromic surveillance systems from several sources. additionally and more recently, the robert koch institute is creating an early warning system based on machine learning and natural language processing that will include 'appealing' interactive web applications and be linked to the german electronic reporting and information system demis (robert koch institute 2018). syndromic surveillance systems are a critical adjunct to traditional public health lab surveillance as they strive to provide real time or near real time collection, analysis and dissemination of health data to enable early identification and management of public health threats as they are not based on lab confirmed diagnoses-and assess a wider set of health related data including: clinical signs, absenteeism, pharmacy sales or animal health production collapse (buehler 2004) . a clear benefit of syndromic surveillance is it can be cheaper, faster and potentially more transparent then a state's public health lab surveillance system. however, as with the use of big volumes of data more broadly in the ic, data quantity, quality and structural variation all impact on the utility, accuracy and timeliness of some rapid epidemic intelligence from internet based surveillance methods (yan et al. 2017) . increasingly these syndromic surveillance systems rely on the use of big data, machine learning and analytics. additionally, web based epidemic detection systems like biocaster portal developed by the national institute of informatics in tokyo (collier 2015) and canada's global public health intelligence network (gphin) an event based surveillance system which looks at news feeds globally have also contributed to syndromic surveillance systems (mawudeku et al. 2015) . several event based internet surveillance systems have grown in number in the last decade. using pubmed, scopus and google scholar data bases, o'shea's study found 50 based internet systems all using different technology and data sources to gather data, process and disseminate it to detect infectious disease outbreaks (o'shea 2017). in line with the broader ic development of exploiting social media analytics discussed in chapter 4, in 2013 dhs piloted another approach to bio-surveillance. the pilot involved dhs trialling various social media analytics from self-reported information on facebook and twitter to determine pandemics and acts of terrorism given social media feeds can provide close to real time reporting of symptoms, sickness access to hospital or pharmaceuticals (insinna 2013) . additionally, other private companies have entered the biosurveillance space-providing novel methods for capturing bio-surveillance data. wilson's discussion of how a private company (veratect corporation) assessed signal recognition in global media reports to provide warning on the emergence of the 2009 h1n1 influenza pandemic shows how the ic warning culture methodology can be employed usefully along with what he described as the 'risk adverse forensically oriented response culture favoured by traditional public health practitioners' (wilson 2017: 1) . the veratect case shows that the private sector has a role in developing better bio-surveillance capability as well. as can be seen from the brief discussion above about different methodological approaches to bio-surveillance. there are also different views amongst bio-surveillance scholars and practitioners about the merits of each, particularly in their abilities to predict the 'next pandemic'. can for example, a national bio-surveillance system informed by one or more methods discussed above predict the emergence of the next pandemic or outbreak, particularly novel new viruses? some scientists argue that the prediction of a micro-evolutionary process of some biological agents such as a virus (i.e. a short term emergence or cross species transition) is incredibly difficult given evolutionary and epidemiological timescales are fundamentally different. geoghegan and holmes argue that instead it would be better to build surveillance capability that 'assesses the fault line of disease emergence at the human-animal interface, particularly those shaped by ecological disturbances' (2017: 7). others have argued differently. scientists working on the usaid funded predict and the global virome project examine disease hotspots globally in order to sequence (rather ambitiously) almost all the viruses in birds and mammals that could potentially spill over into humans. in particular, researchers working on the global virome project believe that prediction of which viruses might spill over from animal to human health is possible. geoghegan and holmes in response argue focusing on disease hotspots relies on very small amounts of data that can be unreliable given they are rare events. they give the example of saudi arabia which has not classically been a hotspot, yet mers recently jumped into humans from camels there. sequencing these viruses may provide useful evolutionary information, but geoghegan and holmes argue it won't necessarily provide early warning of what is going to affect us (geoghegan and holmes 2017) . other scientists are trying to change the ecology of disease, which presumably in some cases would make the early warning of some pandemics easier. in recent years, the scientific community has increasingly exploited crispr gene editing techniques to change the genetic makeup of malaria mosquitoes. additionally, advances in gene drives have recently been shown to change the ecological parameters of disease. gene drives are artificial 'selfish' genes that can force itself into 99% of an organism's offspring instead of the usual 50%. currently there is a global research effort funded by the gates foundation to cause female mosquitoes to become sterile within 11 generations or 1 year. the objective would be to release the genetically altered mosquitoes into malarial areas by 2029 (regalado 2016) . there are concerns by the fbi however that gene drives could be misused to create a 'designer plague' (ibid.). in addition to the 'predictability' challenges presented by various bio-surveillance methods, there are also differences in opinion amongst members of the bio-surveillance community about what an effective bio-surveillance system looks like. on what metrics can an 'effective bio-surveillance' system be evaluated given the multiple methodological approaches and systems that have developed for bio-surveillance? clinician and public health security specialist jim wilson has argued that the development of an effective global surveillance and response system is probably at least a decade or more away (wilson 2017: 222) . in the interim, we are left with multiple approaches of varying validity and reliability. so based on the current fragmented bio-surveillance efforts how do we learn the lessons that need to be learnt that will enable the implementation of the long awaited national bio-surveillance capabilities? how do we know if progress is being made to that goal? importantly, beyond national efforts, how do we assess the current capability of state, local agencies to contribute to a national bio-surveillance capabilities? where are the gaps and vulnerabilities in the current sub-national bio-surveillance and detection systems? (gao 2011) . compounding the current challenge of evaluating bio-surveillance capabilities in order to construct a viable national approach is that different bio-surveillance systems have been created for different end users (e.g. animal and human). the blue ribbon project report into animal health detailed information sharing challenges in animal health bio-surveillance and its integration with other bio-surveillance data including in human health (blue ribbon report 2017: 25) . this lack of integration makes it difficult to assess how information collected for animal or agricultural bio-surveillance could improve national approaches to bio-surveillance, particularly in scenarios where the emergence of disease could be an intentional or a malevolent act. different approaches to bio-surveillance have been informed by multi-disciplinary perspectives, which can be both a strength and weakness to developing a national perspective. current efforts across the 'five eyes' to develop fully national and integrated bio-surveillance capabilities remain works in progress and the political will to steward them into being seems insufficient. for example, in the us a program designed to provide a national bio-surveillance and integration system was eliminated in the president's budget request for fy 2018 (blue ribbon report 2017: 41). any evaluation of the effectiveness of various methods and approaches for building a national bio-surveillance capability also needs to consider how national efforts can both enhance and lever off global bio-surveillance capabilities. gaps and impediments in global biosurveillance have become increasingly evident to the world in the wake of the largest ebola epidemic ever-in which these challenges impacted the ability to prevent, detect, and respond. under the looming threat of mers-cov, leishmaniasis, influenza, multidrug-resistant tuberculosis, and plague, the global public health community now realizes the urgent need to address shortcomings in global bio-surveillance and the broader public health security system. properly preparing for the next major outbreak hinges on our willingness to transform global health surveillance systems and those of countries with fragile health infrastructures (shaikh et al. 2015: 183-186) . in some respects, similar challenges in developing national bio-surveillance capabilities exist in those at the global level including: siloed systems, inadequate training and technical expertise, different information and communication technology (ict) standards, concerns over data sharing and confidentiality, poor interoperability, and inadequate analytical approaches and tools. there is likely not one bio-surveillance method, technique or tool that is going to detect in real time disease outbreaks, particularly unusual ones which might imply malicious intent. a fully integrated approach to bio-surveillance may rely on more than one method or capability which together can provide reliable and valid bio-surveillance data and early warning at the national and global level. it may mean investigating ways that older legacy systems can be integrated or at least made interoperable with newer more mobile platforms such as mobile or wireless health technologies particularly in the developing world (shaikh et al. 2015) . it should be clear by now that improving bio-surveillance capabilities is essential to improving the prevention of natural and suspicious outbreaks of disease. it is important for the 'five eyes' intelligence and law enforcement communities to understand broadly the theoretical and practical developments in bio-surveillance so that they are able to more effectively lever relevant knowledge on bio-threats and risks. a second cluster of stakeholders that are useful in the prevention of bio-threats and risks (both natural and malicious) are those working in national, regional and global health. the ebola epidemic (2014) (2015) was a recent reminder of the consequences of weak public health capability and infrastructure in failing to prevent, identify and respond quickly to infectious disease. the ebola epidemic also had a catalytic effect on many public health authorities, practitioners and researcher's views about the capability of the traditional un response to global health crisis mainly coordinated through the who. many public health watchers are now arguing the need for a broader more effective focus-not just on prevention and response to infectious disease, but one that also included reframing the focus as a human security issue. adherents to this view make a compelling point when seen through the ebola case that continues to have significant impact on the economic and social stability of countries impacted (sparrow 2016; marston et al. 2017; who 2015; mmwr 2016) . beyond west africa, similar vulnerabilities in capabilities such as diseases surveillance, detection, contract tracing, clinical care, community engagement and communications exist globally as was also seen with the proliferation of zika in latin american/caribbean and mers in the middle east. in 2016, the commission on a global health risk framework for the future that met after the ebola crisis estimated 4.5 billion per year investment would be needed for better detection and response tools. the same commission report also estimated that the economic cost for global pandemics per year was $60 billion (schnirring 2016; dzau and sands 2016) . effective national bio-surveillance relies on not only what 'five eyes' countries can do to improve the scientific and technical capability of bio-surveillance, but also how they can improve bio-surveillance globally particularly in at risk areas. beyond effective bio-surveillance, effective prevention of pandemics whether natural, accidental or malicious relies on good global (multilateral), regional and national public health responses. there are several multilateral instruments, institutions and initiatives that are relevant, but i will focus here on what have become the key ones rather than attempting to traverse in detail all major international health initiatives struck since 9/11. they include who international health regulations (ihr), un security resolution 1540, the global health security agenda (ghsa), the biological weapons convention (bwc) and the australia group. the who international health regulations (2005) entered into force in june 2007 to prevent, protect against, control and provide a public health response to the international spread of diseases (detect, assess, notify events has a biosafety and biosecurity function) and includes all 192 members of the un. the ihr 2005 has improved accountability of countries about progress towards building national core public health capability targets in several areas including, but not limited to: surveillance systems, creating rapid response teams, border management. however, the ihr annual reporting process has been by self-assessment of core capacities to the world health assembly (wha) by all state parties, which has resulted in incomplete or not credible reporting for some member states. the commission on global health risk framework for the future also expressed concerns over the self-assessment monitoring tool of the ihr, because questions are binary (yes/no) answers and recommended that who devise a regular independent mechanism to evaluate country performance against benchmarks (ghrf commission 2015: 33). for example, a country can 'tick yes' for having a national public health legislation, but other dependent legislation (biosecurity, food safety, environmental health) may not be in place-thereby reducing overall the country's ability to manage health crisis or for the global community to understand and respond to capability and information gaps in that country (ibid.). some countries continue to be slow or uneven in their reporting of ihr (2005) attributes. in 2013, one study showed that the african region was well below global averages across all attributes measures with no african state reporting full implementation (kasolo et al. 2013: 11-13) . the second multilateral instrument relevant to our discussion here is the un security council resolution 1540 (2004 , which calls on all 192 states to prohibit non-state actors from developing, acquiring, manufacturing, possessing, transporting, transferring or using nuclear, chemical or biological weapons and their delivery systems. more importantly and specific to bio-threats only, the bwc has historically played the most significant role in preventing the weaponisation of biology. the bwc was established in 1972 and seeks to prohibit the development, production, acquisition, transfer, stockpiling and use of biological and toxin weapons (gerstein 2013; chevrier and spelling 2016: 331-356) . in 2001, there was an attempt by some member states to introduce a verification process, but this was vetoed by the us following inspection of soviet sites under the tripartite agreement between the soviet union, usa and the uk. the us arguing it could be difficult to certify that a state's biological program was merely defensive rather than offensive. the us also had concerns that inspection to labs could be disruptive or provide opportunity for industrial espionage against legitimately operating biotechnology companies (gerstein 2013: 137) . historically there has been a mixed record by some 'five eyes' intelligence countries in assessing verification and therefore noncompliance of the bwc. koblentz surveyed the role of intelligence (particularly humint) in assessing the former soviet union's offensive bio-weapons program between 1971 and 1990 which resulted in an incomplete picture of moscow's program (koblentz 2009: 157) . additionally, as discussed in chapter 2, in 2002 several 'five eyes' intelligence communities (us, uk and australia) incorrectly assessed that iraq had a mobile offensive bio-weapon capability. intelligence collection on its own can either over or under-estimate such capabilities. between 5 yearly review conferences, several initiatives and activities have been introduced (confidence building measure, meetings of experts, information exchanges) to improve the effectiveness and the implementation of the convention. however, state parties are only encouraged to implement relevant national legislation and other measures to prohibit prevent the development, production, stockpiling or transfer or use of bio weapons. how they precisely undertake measures is at the discretion of individual state parties. the bwc has been criticised for several reasons over the years. some of this is warranted, while other criticisms seem to not take into account that the bwc is different from its chemical and nuclear counter proliferation counterparts. as gerstein argues, 'material is the centre of gravity for nuclear discussions and intent being the center of gravity for biological issues' (gerstein 2013: 176) . developing nuclear weapons leaves a large recognizable footprint, whereas the development of an offensive biological weapon requires virtually no specialised equipment (ibid.). the first major criticism of the bwc is that it has no verification mechanism or any other mandatory provisions for monitoring compliance. a second complaint is that for many years (until 2006) , it lacked an implementation capability to help states fulfil their obligations. since 2006, the convention has had a small three team implementation support unit (isu) based in the united nations office for disarmament affairs in geneva which aims to 'assist, coordinate, and magnify the implementation efforts of the states parties to help states parties help themselves' (lennane 2011: 85) . in reality though, the isu does not have 'capacity for analysis and coordination other than for the collection of the annually submitted confidence building measures, posting them to the website and organising and attending conferences' (gerstein 2013: 173) . historically there has also been a low number of party states submitting their annual confidence building measures. although the bwc isu was able to report that a record number (81) annual confidence building measures were submitted in 2016, this only represented 45.5% of all 179 state parties submitting that year. though the trend line seems to be going up from a low in 2014 of 19 (bwc newsletter 2017: 3). a third criticism of the bwc is that it has moved slowly since inception and further questions remain about its relevance strategically and operationally in preventing bio-threats and risks into the future. such questions are likely fundamental to its long term viability. however despite shortcomings, the bwc has nonetheless created a normative institution for reducing the risk of biological or toxin weapons being used or developed by state and non-state actors (lennane 2011: 85) . more importantly, as developments in biotechnology continue at a pace, the bwc does provide a venue, where the security implications of dual-use technology can be assessed which will be critical in 'mitigating these emerging threats' (gerstein 2013: 175) . the bwc still does have an important role in reducing weaponisation of biology in the future, though its poor funding particularly of the isu means that other multi-lateral measures are needed to amplify the work of the convention. in addition to the above historic/traditional proliferation arrangements of the bwc, other international regimes have been implemented such as the australia group (established in 1985) and the proliferation security initiative (established in 2003). both have a broader counter proliferation objectives beyond biological weapons to chemical and nuclear. the australia group 41 member countries have collaborated on the development of lists of technologies and materials that could be used in the development of chemical and biological weapons. member countries then commit to monitor the export or transfer of these materials. the australia group maintains common control lists for dual use bio-equipment, technology, software, bio agents and plant and animal pathogens as the basis for promoting common standards and regulations (australia group common control list handbook 2015). the australia group works in concert with the bwc. the psi was a bush administration initiative that sought to supplement existing non-proliferation regimes, but seeks to enforce these by interdicting and seizing illegal weapons or missile technology in planes or ships carrying cargo. the psi also includes intelligence sharing and joint operational activity (national institute for public policy 2009). turning the focus slightly away from multi-lateral counter proliferation measures, other multilateral initiatives have focused on improving global health security. in some respects the ghsa provides a bridge between traditional, narrow security approaches to biological weapons and a wider securitisation of global health. the ghsa was established in 2014 by the obama administration and is a multi-sectoral approach to global health security seeking to include governments, international organisations and non-government organisations. ghsa was set up in part to 'advance further the ihr implementation through focused activities to strengthen core capacities and to ensure a world safe and secure from global health threats posed by infectious disease; where we can prevent or mitigate the impact of naturally occurring outbreak and intentional or accidental releases of dangerous pathogens' (heymann et al. 2015 (heymann et al. : 1889 . ghsa is a refreshing approach not only because it seeks to establish a global framework and capacity to assess, measure and sustain advances in global preparedness for epidemic threats, but it also addresses biosecurity as a public health priority-thereby linking public health and health security, development, defense and agricultural sector (cameron 2017) . the underlining logic of ghsa suggests that the same attributes needed to prevent, detect and respond to deliberate use of a bio agent are those required to manage a natural or accidental outbreak of a biological agent. ghsa also includes 12 technical targets aligned to three areas: prevention, detection and response (heymann et al. 2015 (heymann et al. : 1889 . like earlier initiatives, such as the us sponsored global health initiative (ghi), which was discontinued by the obama administration in 2012 due a lack of financial and technical authority to leverage and coordinate multiple us agencies-the ghsa will need to secure ongoing funding beyond 2019 from major donors including the us. at a november 2017 ghsa ministerial meeting in uganda, assembled governments signed onto an extension of the ghsa for another five years. us secretary tillerson had issued public support for continuing it, but at the time of writing no commitment by the us for future financial support (beyond fy 2019) has been made. ghsa holds promise, but in addition to ongoing funding challenges, those member states signed up to it will need to ensure effective governance is in place to align funding to global health priorities articulated by the who, world bank, imf and other donors in order to avoid duplication and promote an effective approach to international health security capabilities (paranjape and franz 2015; . in summary, this discussion of multilateral security and global health initiatives demonstrates that there is a diverse number of stakeholders working in these sectors, which can play a role in preventing biothreats and risks-whether they are natural pandemics or a malicious attack from a biological weapon. it's clear that the 'five eyes' intelligence communities have worked extensively with other member states in counter-proliferation institutions such as the bwc and the australia group for several decades, but what remains still under developed is how global health security stakeholders and intelligence communities can work more collaboratively for the mutual goal of global health security regardless of whether the risks are natural pandemics or result from a bio-terror attack or theft of a dangerous select agent from a lab. more trusting and formalised contact between both global health security stakeholders and those working in the security and intelligence communities can only be mutually beneficial to preventing major bio-threats and risks. the final cluster of stakeholders that can help prevent bio-threats and risks are of course those that specialise in biosafety and its promotion in their research institutes, biotechnology companies, universities and medical facilities. promoting biosafety in environments that work with select agents and other facilities that work with less dangerous material which can still cause harm relies on consistently high risk management practices. in all 'five eyes' countries there has historically been in place biosafety risk management procedures and practices to prevent accidental infection, accidental release, or intentional misuse of biological substances. however, as noted in chapter 2 in the last two decades the expansion in synthetic biology, biotechnology and biological science research has meant there are now more people working in more locations on dangerous pathogens-not just in well-regulated liberal democracies such as those in the 'five eyes' countries, but also in developing countries; where biosafety and biosecurity capabilities and practice may be less established such as parts of africa, the middle east, pakistan and former soviet states (gronvall et al. 2016; shinwari et al. 2014) . just in terms of the scale of this expansion of facilities working with dangerous pathogens-in the us alone, there is thought to be thousands of bsl 3 labs and in china the number of such labs is increasing too (nature editorial 2014: 443). the us and other 'five eyes' countries such as canada have invested in cooperative engagement programs since 9/11 in several former soviet union states. the us defense threat reduction agency (dtra) has lead efforts in georgia to reduce bio-risk by securing/consolidating pathogens, training scientists in biosafety and biosecurity technology, regulation and detection. likewise, the cdc has been involved in building public health capacity there as well as in armenia and azerbaijan (bakanidze et al. 2010: 7) . as important as building biosafety capacity is in developing countries, it is clear that much more still needs to be done to build biosafety capacity in 'five eyes' countries-including finding better ways to understand and manage comprehensively threats and risks in the biosciences environment. biosafety experts such as salerno and gaudioso argue for more comprehensive risk management systems across the global bioscience community 'to avoid an accident that jeopardizes the entire bioscience enterprise' (salerno and gaudioso 2015: xv) . their argument is that such a system would supplement existing national and international biosafety regulations by risk managing fully at an organisational and unit level every single potential incident rather than by generic risk hazard assessments that are currently done by most facilities today (ibid.: 201). others have also called for more systematic tools and approaches for managing biosafety incidents in labs dealing with particular dangerous pathogens such as marburg virus (dickmann et al. 2015) . still others have argued that while 'security awareness is high among employees who work with biological select agents and toxins, it is not pervasive across the entire life research community' (grphyon scientific 2016 : 1014 . such a statement does not seem to be hyperbole if one looks at some of the cases of biosafety and security lapses since 9/11 (gao 2009 (gao , 2013 . there have been several lapses at cdc between 2014 and 2016. in june 2014, dozens of workers in cdc could have been potentially exposed to live anthrax that hadn't been killed before being shipped from cdc's bioterrorism rapid response and advanced technology (brrat) bsl 3 to a bsl 2 lab in its bacterial special pathogens branch. cdc investigations determined that at least 67 cdc staff members may have been exposed to viable anthrax cells or spores though no illness or deaths occurred (cdc 2014). the same report found several breaches of biosafety process and procedure including failures of policy, training, supervision, judgement and even scientific knowledge (ibid.). similarly, biosafety lapses cases involving cdc labs occurred in january 2014 when an unintentional cross contamination strain of low pathogenic avian influenza a (h9n2) with a strain of highly pathogenic avian influenza a (h5n1) was shipped from cdc to the usda (schnirring 2014) . further biosafety breaches were detected in july 2014-this time at the national institute of health campus in bethesda maryland; where 6 viable smallpox vials were discovered improperly stored (dennis and sun 2014a ). an additional five improperly stored vials were also found at the nih-three were select agents (burkholderia pseudmomallei, francisella tularensis and yersinia pestis ) (dennis and sun 2014b). in the nih cases despite their age, they were still viable organisms which could have caused illness. their theft could have also posed a bio-threat and risk to the community. then after a hiatus where biological material was suspended being sent between bsl 3 and bsl 2 labs live transfers commenced again. after a further internal cdc review (cdc 2015a, b) some additional safety measures were put into place, however there was a subsequent lapse when a specimen of chikungunya virus was shipped from a high secure lab in fort collins to a lower level one which had not been killed (young 2015) . similarly, in 2015 the pentagon shipped live anthrax spores from the dugway proving ground in utah to 9 states and one international location that were also meant to have been killed (burns 2015) . it was later found that dugway and the us dod had been shipping nationally and internationally live anthrax for more than 10 years-often without adequate safeguards. other reports suggested that some samples were sent by federal express (sisk 2016) . similarly in november 2016, the us hhs discovered that a private lab had 'inadvertently sent a toxic form of ricin to one of its training centres multiple times since 2011 putting training staff at risk' (gao 2017: 1). similar biosafety lapses have occurred in the uk resulting in 75 investigations since 2010 of government, university and hospital labs (sample 2014) . as noted in chapter 2, one possible bio-threat and risk pathway could be the theft of biological substances or information from a biosciences institution. lapses in biosafety arrangements demonstrate, at least in some cases, biosecurity vulnerabilities that could make the theft or even infiltration of a threat actor into high containment lab easier. thefts from labs have occurred in the past by an insider, and a motivated insider can compromise biosafety for a range of reasons. bunn and sagan's edited book insider threats provides a useful taxonomy for thinking about 'insider threats' (bunn and sagan 2016). they can be: self-motivated insiders, who at some point decide to become a spy or thief. insiders can also be recruited insiders, who are already inside an organisation, but become convinced to become part of a plot. finally, an infiltrated insider might be associated with some adversary of the organisation and join it with the purpose of carrying out a malicious act against it. bunn and sagan also refer to inadvertent or non-malicious actors, who pose a threat by making mistakes without really intending to do so-such as leaving a password lying around. finally, the authors refer to a 'coerced insider', who remains loyal in intent, but knowingly assists in theft or sabotage to prevent hostile acts against themselves or their loved ones (ibid.: 4). the insider threat that was posed by bruce ivins' activities in a high containment lab (that resulted in amerithrax in 2001) demonstrates the potentially high threat and risks associated with an insider. the ivins case provides a useful case study in how an organisation's security procedures and other organisational and cognitive biases can miss for several years risks posed by an insider threat actor (stern and schouten 2016: 74-102) . since the amerithrax incident, significant investment has been made to close the biosafety vulnerabilities revealed by it. increasingly since 9/11 and amerithrax, a number of policies, procedures and normative behaviour have developed in the scientific community to promote biosafety and biosecurity. these have ranged from safety regulation codes such as the us biosafety in microbiological and biomedical laboratories (bmbl ) to more formal legislative and oversight regulations. the latter will be addressed in chapter 8. there are also technical and policy improvements that can be made in securing both physical and remote access to labs including computer systems that house data, which are at risk of theft or being hacked (gryphon scientific 2016 : 1014 berger 2013: 113-127; slayton et al. 2013: 51-70) . leaving aside discussion of some of the formal legislative and regulatory instruments for promoting biosafety, the development and maintenance of effective risk management across the biosciences also relies on an organisational culture that treats biosafety and biosafety as an equal priority to other deliverables. a culture of accountability at all levels must also exist if effective risk management can prevent, identify and treat bio-threats and risks promptly. a rogue insider threat, who may have been assessed as appropriate to work with select agents and seems initially to follow all the relevant biosafety regulations and procedures could still pose a risk if they have not embraced the organisation's normative cultural biosafety values. it is critical then in order to stop opportunities for insider threats, that the organisation promote relevant biosafety cultural values as much as and perhaps more than adherence to formal biosafety regulations. risk management measures must of course be measured against the ability of scientists to carry out its functions. effective engagement with local law enforcement and relevant domestic security intelligence organisations in each 'five eyes' country to help scientists build viable biosafety cultures will likely remain important in addition to internal organisation biosafety initiatives. stern and schouten provide a number of useful suggestions for improving policies and procedures that may help improve biosafety cultures across the biosciences enterprise (2016: 101-102). two that i think would be helpful are, one: developing standard operating procedures for proactively identifying vulnerabilities including using 'red team' exercises to explore how systems could become exploited. in other words, what motivators (financial, psychological, religious, and political) might drive an insider threat and are there ways to assess the signs of such an evolving threat? the other is to 'ensure personnel reliability programs incorporate ongoing assessments of counterintelligence vulnerabilities, including vulnerabilities to self-ascribed whistle-blowers or attention seekers' (ibid.: 101). effective biosafety and biosecurity training is also crucial as the number of labs working with select agents or other dual use bio-agents proliferate globally, particularly in locations with fragile states. more consistent approaches to training will also be important so nations can be confident that as many scientists as possible regardless of the country or the context in which they work understand what bio-risks and threats may emerge and how to prevent or mitigate against them (sture et al. 2012 ). as discussed above there are multiple stakeholders in the scientific community, global health security and biosafety fields that can play a critical role themselves in preventing bio-threats and risks as well as supporting the operational efforts of the intelligence community to prevent these. while prevention of bio-threats and risks is one critical dimension that stakeholders can play central roles another is disruption. although the intelligence community can use a range of knowledge, technologies and methodologies from stakeholders in the scientific community, to prevent bio-threats and risks, we have to accept that it will not be possible to detect every criminal or terrorist act. nonetheless, some of the techniques, practices, technologies and knowledge available from stakeholders in the scientific community will still be useful to disrupting bio-threats and risks. in other words prevention may not always be possible yet measures can be put into placewhich can detect threats early enough to reduce their impact. similar to preventing bio-threats and risks, disrupting them will also rely on seeking advice from stakeholders involved in bio-surveillance, public health and biosafety research, amongst others on disrupting them as well. for example, as discussed earlier iarpa's commissioning of research into detecting signals of bioengineering changes (felix) may result in better capability for the intelligence community in not only preventing bioengineering changes that make it easier for terrorists to carry out attacks on populations, critical infrastructure or biotechnology companies, it could also help detect and disrupt the planning stages for such attacks. additionally as noted earlier, if a high containment lab has a strong biosafety culture it is more likely that disruption of a biothreat may be possible just by colleagues speaking up about suspicious activities in their working environment rather than any elaborate disruption knowledge and techniques, procedures the intelligence community might have in place to disrupt such threats. but knowledge, technologies, techniques and practice for disruption of bio-threats and risks cannot just come from scientific stakeholders in the biosciences, it should also come from other fields and practitioners working in other areas where successful disruption operations has taken place. these areas include criminology, policing, engineering, legislation, cyber, counter-intelligence amongst others. in this section, we examine briefly what other stakeholders and discipline perspectives might the intelligence community learn from that can provide better capabilities for the disruption of bio-threats and risks. are there lessons to be learnt from other stakeholders, disciplines or even other threat contexts that might be relevant to disrupting biothreats that might not have been initially detected? since 9/11, there are three stakeholder and discipline groups, which are investigating and applying disruption strategies to threats and risks and their knowledge might be relevant in disrupting threats and risks in the bio context. these are criminology, counter-terrorism and cyber. we will explore each briefly to see how stakeholders (researchers and practitioners) have developed disruption strategies in each and how they might be employed against bio-threats and risks. insights from criminology and the practical application of disruption for crime prevention has provided a supplementary approach to traditional law enforcement approaches of prosecution against certain crimes through the courts. disruption is not a new concept in criminology and law enforcement practice, though it can be difficult to define in all law enforcement contexts (ratcliffe 2008: 204) . its meaning at least in the criminology/policing/law enforcement contexts can partly be traced back to broader desires-initially by uk law enforcement followed later by other 'five eyes' countries in the late 1990s and early 2000s to move law enforcement away from its traditional reactive mode to offending to one driven by intelligence. this concept of law enforcement or policing being intelligence driven or led gained significant traction in the criminology and policing literature (walsh 2011; ratcliffe 2016; innes and sheptycki 2004) . it was driven initially in the uk by the desire for governments to maximise efficiencies and reducing costs by increasing the use of intelligence to drive strategic and operational decision-making. the implementation of intelligence led policing models into operational policing across 'five eyes' countries has had mixed results partly due to cultural, financial and leadership issues in agencies that have attempted to put intelligence at the centre of strategic and operational decision making in policing (walsh 2011; ratcliffe 2016) . nonetheless, despite historical challenges in adopting intelligence led approaches, increasing fiscal constraints and the ever increasing demands on law enforcement in managing both high volume crimes and complex operating environments in counter-terrorism, cyber and organised crime meant, at least in many national law enforcement agencies; a greater demand for an intelligence driven approach (walsh 2011) . this intelligence driven approach, which promulgated proactive disruption of crime strategies was in part an admission that not all crime could be prevented or the offenders prosecuted. additionally, in many law enforcement agencies such as the australian federal police (afp), the growing volumes of information collected have given intelligence a more central role in triaging the significance of information, value adding to it and guiding investigators to targets and operations that are high priority; or have the greater likelihood of successful prosecution outcomes. in complex organised crime cases such as transnational drug trafficking, people smuggling and even terrorism and cyber threats, which we discuss shortly-intelligence driven disruption strategies have become increasingly popular for many 'five eyes' law enforcement agencies. this has particularly been the case where it can be difficult to dismantle completely the organised crime group-or to even know the full extent of the group's network. disruption operations that attempt to take down threat actors with key roles (e.g. facilitator, financier, and logistics) may nonetheless reduce the threat posed by the organised crime network even if the network continues to exist. additionally, with some organised crime networks, it may be difficult to secure sufficient evidence for prosecution against a more serious offence such as drug importation, but there may be sufficient intelligence that can be used to make the criminal environment more hostile for the group's illicit enterprise by arresting key group members for lesser offenses such as unexplained wealth or migration irregularities. while disruption of crime does seem like a useful tool in preventing or reducing the impact of offenders, the criminology literature demonstrates it has been difficult to evaluate the effectiveness of intelligence driven disruption strategies. ratcliffe cited an rcmp disruption attributes tool, which attempts to examine where the disruption activity is aimed at (core business, financial, personnel) and whether the kind of disruption for one or more of these attributes is high, medium or low in impact (ratcliffe 2008: 207) . however, such tools are largely subjective and qualitative-making it difficult to accurately measure the impact of intelligence driven disruption measures. the other concern about disruption strategies is that they may just cause displacement, where other criminal enterprises take the place of those removed by law enforcement or as innes suggest, 'disrupting a network may just provide a vacuum for more dangerous offenders to step in' (innes and sheptycki 2004: 14) . finally, the literature suggest that employing effective disruption strategies rely on proactive collection and valid analysis that can led to both timely strategic and operational outcomes that in turn result in threat mitigation and harm minimisation. so are there benefits for the intelligence community working on bio-threats and risks to investigating research and practice for disrupting threats in the organised crime context? the answer is a qualified 'yes'. much of course depends on the nature of the threat and risk posed. clearly as with any crime, it is hard to disrupt a bio-threat, when it's still in the head of the offender. however, we do know that criminal and terrorist acts don't just happen spontaneously. there usually involve predicate steps taken by the offender. some of these might happen in very compressed periods while in other offences planning may take years. either way, and regardless of whether these can be detected by the intelligence community, there is likely to be some signs in the predicate planning stages of an impending threat/risk that can provide the intelligence community opportunities for disruption. it is difficult to say in which bio-threat cases disruption strategies will be most successful. much will depend on how quickly the intelligence community can collect and analyse information that may be indicative of an evolving bio-threat and risk. as discussed previously, good collection and analysis is contingent on having robust core intelligence processes in place and more importantly effective intelligence governance. both are needed to ensure intelligence efforts are coordinated across multiple internal intelligence community stakeholders, with relevant knowledge-as well as ensuring information and expertise from external stakeholders (the scientific community) is available to provide earlier warning signs of an emerging bio-threat. while it is important not to over-play the potential for success of the kind of disruption strategies used against traditional organised crime groups, there are likely bio-threat scenarios where disruption strategies may make a difference. arguably, disruption of bio-threats could be on a continuum with the individual threat actor on one end and a sophisticated organised group on the other. at the individual level one could have the scenario of a lone terrorist actor or a mad/bad scientist. while it may seem difficult to get early warning of the malicious act of mad/bad scientist, we saw in the earlier discussion on 'insider threats' that it may be possible to disrupt their activity before you reach an amerithrax style attack. twenty/twenty is hindsight with the bruce ivins amerithrax case, but the lessons learnt from this incident do provide guidance on the sources of collection and analysis required from within the intelligence and scientific communities to aid the disruption of this kind of bio-threat. it does not mean that all similar cases of 'insider threats' will be detected, prevented or disrupted, but a more careful collection and analysis of 'odd' behaviour or unusual security lapses by a scientist working in a high containment lab could reveal areas of vulnerabilities. detection both of abnormal changes to an individual's psychological profile and/or in their working environment can provide opportunities for those vulnerabilities to be disrupted. at the other end of the bio-threat scale, a more organised bio-criminal or terrorist planned event may resemble in some respects other illicit criminal markets and networks (drugs, identity fraud, money laundering) and thereby present opportunities for disruption. again this is not to suggest that disruption of organised bio-threat scenarios will be always be possible. as discussed in earlier chapters, since 9/11, even with state based wmd programs the intelligence community has had a mixed record in detecting them and uncovering the intention and capability of non-state actors to exploit dual use technology for malicious end remains difficult. however, disruption could be useful in some bio-crimes where there is a bigger network of actors involved in the illicit business. for example, in crime scenarios where food suppliers are not registered legally to import food into a 'five eyes' country because it poses a biosecurity risk, there may be opportunities for parts of the intelligence community (particularly national law enforcement agencies) to work with agriculture, animal health, food regulatory agencies and relevant scientific stakeholders to disrupt illicit food suppliers from a country of concern. equally there may be opportunities for disruption of activity from non-compliant biotechnology providers in a 'five eyes' country, who provide dual use equipment to a company overseas with a questionable profile that resides in a country vulnerable for terrorist infiltration. in addition to useful knowledge that can be gained from criminology and law enforcement practice there are also perspectives on disruption from contemporary counter terrorism studies that may have utility in the bio-threat and risk context. as noted above, since 9/11 law enforcement agencies across the 'five eyes' countries have been increasingly deploying disruption strategies in countering terrorism given the preservation of life demands an earlier interception of attacks preferably at the planning stage. as innes suggest in the case of counter terrorism operations, one aim is to overtly disrupt planned attacks, which has many effects including sending a message to other terrorist groups that they may be next, reassuring the community and if possible deploying countering violent extremism (cve) strategies in communities where future attacks may arise (innes et al. 2017: 253) . in the uk in particular, a key plank in its counter terrorism strategy has been disruption both at the strategic and tactical level. at the strategic level, disruption has involved a number of initiatives from arresting persons of interest, legislative action and enhanced surveillance (innes et al. 2017: 265) . in addition to global influence of groups such as al qaeda and islamic state, the growth in lone actor attacks-some 198 across the us and european countries from 1970s to late 2000s (danzell and montanez 2016: 136) has also been a significant catalyst for enacting further stringent legislative measures such as detention without trial and control orders (walsh 2016 ). all 'five eyes' countries have also adopted further legislative changes that allow disruption of terrorist attacks by reducing thresholds law enforcement and intelligence agencies need for reasonable suspicion in order to access both electronic and human intelligence (humint). governments desire to do something to reduce the threat and risks posed by terrorists by creating increasingly proactive, flexible and permissive legislative environments has also raised concerns about the role of intelligence, secrecy and privacy. these issues will be discussed as they relate to the bio-threat and risk context in chapter 8. but legislation is only one plank in effective counter terrorism and the scale and pace of actual and potential terrorist attacks suggest other disruption strategies are required at the tactical level. innes et al. suggest such strategies might include: 'prosecution against an individual or a network for offences other than those they were principally being investigated for and/or interfering with the operations of the criminal enterprise in cases where there is insufficient evidence to secure prosecution ' (2017: 265) . they add that, at the tactical level, disruption strategies can 'interfere with the ability of suspected adversaries to operate effectively and efficiently' (ibid.). innes et al. suggests that tactical disruption functions at 'near event interdiction', which can mitigate or minimise harms associated with the actual or planned terrorism attack (ibid.). other counter-terrorism disruption strategies in 'five eyes' countries have included the creation of cve policies and interventions as well as the disruption or take down of social media venues advocating politically motivated violence or recruitment to jihadist groups. regardless of the complexity of post 9/11 terrorist attacks-such as the multi-site attacks in paris 2015 orchestrated by a group; or the knife attack against two police officers in australia in 2014 by one individual-disruption strategies employed by law enforcement and national security intelligence agencies are also likely to be usefully employed in the bio-threat and risk context. just how useful strategic and tactical disruption strategies used in conventional counter-terrorism will be in the bio-threat context depends on the nature of the intent and capability of individual threat actor(s) and the risks posed by their actions. the effectiveness of disruption strategies in the bio-threat context like conventional terrorist attacks are contingent on a range of variables that are unique to that event. in the bio-threat context, leaving aside large levels of uncertainty about the future threat trajectory for bio-terrorism, effective disruption will rely on law enforcement and intelligence agencies understanding how the intention, capability and opportunities of threat actors operating in a particular environment-make an attack possible. intention, capability and opportunities will differ along the threat continuum from individual to group and from state to non-state actor. for example, in the research facility, hospital or high containment laboratory environment, intention, capabilities and opportunities may be shaped by actors that are internal, external or an indirectly involved in the facility (perman et al. 2013: 95) . threats can also be as perman suggest overt or clandestine (ibid.). in some cases, if a scientist is motivated politically (for religious, environmental or political reasons) to commit an act of violence by using a biological agent it may be easier to disrupt their activities if they are public about their agenda. however, in the case of a clandestine plan it could be very difficult to disrupt an attack launched externally or internally in a contained lab. nonetheless, as we saw with historical cases of lone actor threats such as the bruce ivins amerithrax incident there are likely predicate steps in the process to carrying out an attack which are revealable. similarly, in the lesser known case of dr. larry ford, who was suspected of murdering his business partner in a biotech company-the police subsequently found a cache of weapons, white supremacist writings and allegations that he attempted to infect six mistresses with biological agents (perman et al. 2013: 94) . again even in cases of lone actors such as this whose attack planning is more clandestine; there may well be an abundance of 'warning intelligence' that if collected and assessed in time might be useful in disrupting a lone actor planned attack. while it can be difficult to disrupt a lone actor plot, more elaborate ones by a group of conspirators could in some circumstances provide greater opportunities for interception and disruption by law enforcement and intelligence agencies. this is because in plots involving multiple actors there are more stages before the attack can be carried out. some stages such as communications, procuring supplies and transport also provide points of vulnerability, where threat actors can be exposed to authorities and disrupted. so an external threat such as a terrorist attack against a high containment laboratory might involve communications amongst group members, financing of the plan, purchasing of explosives and surveillance of the facility's perimeters. each stage presents opportunities for disruption providing intelligence and information is available to law enforcement and intelligence agencies. similarly a theft of intellectual property or biological material from a private sector biotechnology company might result from either an external criminal group; or state actor pressuring or paying an employee to steal information on their behalf. again, intelligence may exist already about the criminal group or the compromised employee that provides opportunities for disruption. in an ideal world of course, it would be desirable if all potential biothreat and risk scenarios could be prevented early in the intent stage, where they are mainly an idea in a perpetrator's head. pre-employment screening, including criminal checks and select agent risk assessments will show up some individuals, who are not suitable to access and work with dangerous biological agents. this will have an early disruptive effect but it is not fool proof. people can lie about their circumstances in security suitability checks allowing them the ability to access and plan malevolent acts in a secure biological facility rather than just thinking about them. once operating inside a facility-depending on the nature of the planned attack it can be very difficult for law enforcement and the intelligence community to respond quickly enough to disrupt the attack before its fully implemented. in all threat scenarios (simple to complex) in addition to the mandatory background checks for workers, each scientific institution needs to develop a full suite of threat assessments that can be updated regularly on different threat actors, including but not limited to: visitors, criminals, lone actor attacks (internal and external), terrorist and issued motived groups, international terrorists groups and foreign powers (perman et al. 2013: 94) . these threat assessments should be developed by an institution's internal security department in collaboration with local law enforcement. the relatively low number of threat scenarios that have taken place involving bio-agents since 9/11 will likely mean that there will be many intelligence gaps in assessing the intent, ability and opportunity of different threat types. however, providing baseline threat assessments will begin to build pictures of threats scenarios that should help promote better biosafety measures as well as opportunities to disrupt threats earlier should they begin to emerge. in summary, law enforcement and intelligence agencies working on bio-threats and risks of the future can learn a lot from their counter terrorism colleagues. since 9/11, countering terrorism continues to produce lessons for the law enforcement and intelligence communities on how more effectively to disrupt emerging terror plots before they are implemented. the knowledge gained from investigating conventional terrorism attacks that don't involve biology can help those working on future bio-threats and risks by seeing how to optimise the legislative, intelligence, investigative and community response to terrorism while also learning lessons from contemporary counter terrorism efforts. in particular, the increase in lone actor terrorist attacks in the westoften with short notice underscores that either an insufficient amount of intelligence or types of intelligence that cannot be revealed in court often exists. in these cases, other tactical disruption strategies are gaining traction amongst 'five eyes' countries to mitigate the threat and harm posed by terrorists. similarly, given the complexity of threat scenarios that could arise from the exploitation of dual use biotechnology, it may be difficult in some cases to collect sufficient solid 'evidence' or use bio-forensics to attribute confidently for a conviction on bioterrorism or bio-criminal activity. nonetheless, the various counter terrorism strategies discussed above point to ways threat actors may be disrupted on lesser offences while also providing a greater intelligence dividend on other individuals involved. the final knowledge area and stakeholder group that intelligence agencies and investigators working with bio-threat and risks may learn more from is cyber security. as koblentz and mazanec (2013) suggest there are a lot of common characteristics between biological and cyber weapons including but not limited to: difficulty of attribution and how multiple technologies can be used for offensive, defensive and civilian applications (421-425). both authors argue because of these similarities there is likely a lot cyber can learn from how bio-threats have been managed historically. this is undoubtedly true, though in this section the focus will be the opposite-i.e. what can intelligence and investigative agencies working on bio-threats learn from the cyber threat and capability landscape? even a cursory review of the literature suggest that there are a number of areas where current cyber research and practice could inform the 'five eyes' intelligence communities understanding of current and emerging bio-threats and risks. space does not allow an exhaustive discussion on all of them, but there are three cyber areas in particular; where i believe those working with bio-threats and risks could benefit greatly from knowing more about in order to learn the lessons from the cyber context as well as identifying good intelligence and investigative practice. these areas are: the dark web, cyber terrorism and cyber espionage. i will discuss each briefly in turn. turning to the dark web environment first here we are referring to the content on the internet that is 'not indexed by standard search engines' (weimann 2016: 196) . much of the dark web is hidden or blocked and can only be accessed by specialised browsers. given the relative anonymity it provides, the dark web has seen the proliferation of child pornography, credit card fraud, identify theft, drugs and arms trafficking amongst other illicit offences. the dark web only emerged in recent years though law enforcement and intelligence agencies have made some in roads into its penetration and disruption. the fbi's shut down of the dark web site silk road, which operated between february 2011 and october 2013 was to that point the largest and most sophisticated anonymous online market place for illicit drugs (zajã¡cz 2017) . new technological solutions are also being developed to better identify, collect and analyse illicit activity on the dark web, including darpa's memex software, which helps catalogue dark web sites (weimann 2016: 203) . nonetheless, all 'five eyes' intelligence communities will need to continue to develop their collection, analytical and investigative capabilities in the dark web content to profile more accurately various illicit market places in order to orchestrate impactful disruption activity across multiple markets. although it is unknown, at least in an unclassified sense the extent to which illicit markets exist that could benefit bio-threat actors (criminals or terrorists), undoubtedly law enforcement and intelligence agencies, who are given a watching brief on emerging bio-threats and risk should be exploiting the dark web more for opportunities for disruption. a first step might be first to map the bio-terrorism literature and identify researchers, who have access to bioterrorism agents/disease research, domain, institutions, countries and emerging topics and trends in bioterrorism agents/disease research. chen shows how by using informatics research it might be possible to use knowledge mapping techniques, to analyse productivity status, collaboration status and emerging topics in the bio-terrorism domain (chen 2011: 335-367) . additionally, other intelligence and investigative teams that are working on non-bio threats such as conventional terrorist attacks, terrorism financing, drug trafficking or even child sexual exploitation may come across offenders, who have links to others interested in exploiting dual use biological agents for malevolent objectives. so the work currently going on by intelligence agencies working on broader cyber security issues such as cybercrime or cyber terrorism is directly relevant to improving collection and analysis against emerging bio-threats and risks. developments in the second area cyber-terrorism provides another opportunity for bio-threat intelligence and investigative teams to learn off their colleagues working on cyber threats. in the past we often think about the classical 'bio-terrorism' attack involving the aerolising and dispersal of a dangerous pathogen like anthrax into a crowded place. this mode of attack may still be chosen in the future by a terrorist group (leaving aside for a minute the technical difficulties of such an attack). though committed acts through cyber opens up other choices for a bio-attack. cyber security specialist's knowledge of cyber terrorism is still developing. we have seen for example groups like the taliban and is increasingly use computers for recruitment, propaganda and communications, but it remains difficult to know empirically how many of the current virtual attacks such as ransomware can be attributed to terrorist or led to deaths or impacted critical infrastructure in significant ways. such attacks could just as easily be attributed to cyber hackers (criminals) or state sponsored espionage both issues we will return to shortly (riglietti 2017; bernard 2017; heicker㶠2014) . nonetheless, it is clear that terrorism groups are increasing their use of computers including the dark web given they know that intelligence communities are monitoring the surface internet and social media. in august 2014, al-aan tv reported a laptop belonging to a tunisian member of is captured in syria contained thousands of documents from the dark web including 19 pages about making biological weapons in a way to impact the biggest number of people (weimann 2016: 200) . there have also been cases where is has carried out a series of cyber-attacks, 'exclusively computer based, which in one instance even led to the disclosure of private information regarding us government officials, from private conversations to work and email addresses' (riglietti 2017: 19) . the final area of cyber security that is useful for bio-threat intelligence and investigative teams to reflect on relates to cyber hacks and espionage. putting hacks and espionage together is not meant to suggest that both are always linked-though we have seen in the russian interference in the 2016 us presidential election they can be. china too is playing an increasingly sophisticated and aggressive cyber espionage strategy aimed at political interference and stealing intellectual property (inkster 2015) . there seems little doubt that the extent of hacking (unauthorised access to a computer or network) being perpetrated by state and non-state actors is on the rise and network vulnerabilities across the civil and military space remain. in a recent article, fbi assistant special agent in charge (chicago), todd carroll said the average time between an unauthorised user getting inside a network and the user being detected is 150 days-'a lifetime in cyber means'. todd went on to say that 57% of business owners don't have a dedicated employee or vendor monitoring for cyber-attacks (stone 2017) . we have also seen in recent years the growth in malware and ransomware attacks across the globe. for example, in 2017 the wannacry ransomware attack caused 230,000 infections across 124 countries (locking down banking, energy and manufacturing systems) (schilling 2017) . the dark web also provides terrorist and criminal groups opportunities to operate botnet campaigns in anonymity that can remotely operate networks of computers to commit attacks on other systems including critical infrastructure. again there is insufficient space to provide a full survey of all the cyber hacking and espionage threats, and indeed what to do about them is beyond the scope of this chapter (clarke and knake 2010: 257-280) . nonetheless the hacking attacks-whether they are state sponsored (espionage) or non-state actors (terrorists or criminals) provide another rich source of knowledge to be collected and assessed that can be used by those working on emerging bio-threats and risks. for example, it would seem unwise for bio-threat intelligence and investigative teams to not learn from the fast changing angles of cyber-attack from hackers given how the physical security of biological institutions, their intellectual property and the kinds of biological products produced in such facilities is reliant on secure cyber systems. we have seen in recent years the take down of government websites involving ransomware attacks on both government and private sector networks. increasingly more information is being shared and stored via the cloud. what would be the impact of a major ransomware attack that locks down the entire bio-surveillance capability of a public health authority such as cdc do to maintaining national health security? could a cybercriminal group infiltrate the network of a major biodefense company steal ip and sell it to a terrorist group on the dark web? could research stored via the cloud on non-secure networks relating to the genetic sequences of pathogens be stolen by a terrorist group or state actor to engineer bio-weapons? (blue ribbon project 2015: 44-46) . in all the three areas discussed above, a fuller development of links between those working in the cyber intelligence collection and analysis streams, and those who might examine emerging bio-threats and risks is a necessary first step in bringing relevant knowledge and practice from cyber security to bio-threat stakeholders. in this final section the attention is turned to what kind of stakeholders play a role in treating bio-threats and risk? second, in performing these roles, how can they help the 'five eyes' intelligence communities build better capability (knowledge, practice and technology) about treating actual or emerging bio-threats and risks? as we have seen so far the management of bio-threats and risks is potentially a crowded enterprise with many stakeholders (beyond the intelligence communities) playing critical roles. in this section, i have grouped them into three 'types of stakeholder': first responders, science and technology stakeholders and security stakeholders. these are not three distinct clusters of unique stakeholders that do not interact with each other. depending on the nature of the bio-incident that has occurred, one would expect to see a close interaction amongst the various knowledge brokers and practitioners from each group. for example, a release of a synthetically manufactured select agent in an airport should result in the combined strategic and tactical contributions from first responders, engineers and security personnel rather each being delivered in isolation. an uncoordinated delivery of knowledge, practice and expertise to treat an unfolding bio-threat/risk from multiple stakeholders will not result in the best outcome for mitigating the risk or disrupting future potential of similar threats occurring. again as with previous sections, the focus here is not a deep exploration of the specific knowledge, practice or technology of all stakeholders involved potentially in the treatment of bio-risks. this would be an impossible task. instead this section will explain briefly what each of the three broad stakeholder categories (first responders, science and technology and security) can do broadly to treat bio-risks (current or potential), what intelligence communities can learn from this in ways that extend their capabilities to manage bio-threats and risks. the label 'first responders' is a descriptor for a much broader range of stakeholders including: fire/hazmat, paramedics, emergency responders, health and hospital service providers. each would play a different role in both responding to and treating a bio-incident depending on the type of biological hazard, their jurisdictional and legislative responsibilities and fiscal capacity. in all 'five eyes' countries with perhaps the exception of new zealand (with a smaller population and only one national government) the complexity of response will be particularly governed by the overlapping roles that various local, state and federal first responders might play. obviously in the us with multiple federal, state and local agencies, the coordination of first responder efforts to a bio-incident presents more challenges than other 'five eyes' countries such as australia and the uk with less agencies and jurisdictions. there is not an abundance of academic literature on the role of first responders in treating bio-threats and risks. this lack of evidence makes it difficult to assess accurately what first responders can do to treat bio-threats and risks, what the challenges are and what the intelligence community can learn from these important stakeholders. there is however, some research available that can increase the intelligence communities' understanding of first responder capabilities to treat bio-threats and risks as well as illuminate some of the challenges in doing so. this research should provide at least a start to what the intelligence community can learn from first responders as they deploy their knowledge and practice to disrupt and treat bio-threats and risks. 9/11 and the amerithrax incident provided a catalyst for law enforcement and public health agencies to work closer together to respond to an unfolding threat. since amerithrax, across the 'five eyes' countries further work has been done to better coordinate the work of law enforcement and public health agencies on treating bio-threats and risks. but such efforts have not involved routinely the broader spectrum of national security intelligence agencies, who have tended to play a more strategic and adhoc role compared to their law enforcement counterparts. overall, policy, coordination and legislative efforts to bring first responders and members of the intelligence and law enforcement community together have had only mixed success for a number of reasons. in 2007, a study of how law enforcement and public health agencies in the us, canada, uk and ireland work together on bio-threat incidents identified several common barriers to improving multi-agency responses (strom and eyerman 2007) . these included cultural, legal, structural, communication and leadership barriers (ibid.: 135). ten years on from strom and eyerman's research, other researchers have made similar observations about the ability of first responders to manage effectively a bio-threat incident and to work with law enforcement and intelligence community on such tasks. but it's not just the capability issues raised above, other research points to other technical challenges to treating the impact of bio-threats and risks in the physical environment. for example, research by chemists and environmental engineers show that given the varying nature and strains of the bacteria-the science for assessing risk of exposure may not be able to provide a fully accurate risk assessment of a building's vulnerability or resilience to a bio-attack nor-in some cases whether first responders have effectively 'cleaned the environment up after exposure' (canter 2007; taylor et al. 2013) . a lack of effectiveness in responding to a biothreat incident in a local area obviously can have broader public sector implications in both treatment and preparedness of bio-risks. for example, gerstein (2017: 86) citing a study by advocacy group trust for america's health reported that 26 states and dc scored 6/10 or lower on a scale for preparedness. additionally, since 9/11 major disease outbreaks such as sars and ebola have also demonstrated fragility in parts of the world, including some 'five eyes' country's public health response capability, which remains a concern if there was a major bio-terrorist event. the blue ribbon study project report raised similar concerns about the capability of certain responders including those local, state and federal agencies that might be involved in decontaminating sites following a bio-incident. in the us, the report raised similar coordination issues between federal, state and local agencies in which first responder agency would take the lead in decontaminating and remediating environments and how other agencies would get involved to ensure the attack site was deemed safe for people to return (blue ribbon study project 2015: 26). one underlying theme arising from the studies mentioned on first responder's roles in treating bio-threats and risks is that the intelligence community must share more information with emergency services on the nature of the threat they are meant to respond to. this is not to suggest that in all the 'five eyes' countries that no sharing is going on. my selected interviews with law enforcement and intelligence officials in each country did not give the impression that no sharing was going on with first responders. however it is clear if the local fire officers or emergency staff in a hospital are meant to better respond to a bio-incident they will need regular, consistent, reliable, real-time information and intelligence. this is vital to them safely securing the scene, or rapidly diagnosing and treating infected patients while also keeping themselves safe. importantly too, the more intelligence they receive will likely be helpful in first responders preserving any relevant evidence from the scene that might be needed by the either the law enforcement and intelligence communities. gerstein makes a valuable point when referring to improving bio-preparedness and response activities, when he suggests that first responders need to be seen as part of a complex system rather than each representing a series of programs (gerstein 2017: 88) . in addition to the range of knowledge and practice the intelligence community can learn from first responders, arguably the biggest lesson they can learn is to seek to better understand the 'linkages among disparate disciplines (biodefense, public health, emergency management), government, industry, the scientific community and themselves to better support first responders' (ibid.). if the 'five eyes' intelligence communities were able to create the necessary national health security coordination arrangements suggested in chapter 6 such as the health security coordination council and the national health security strategy, then through these institutions further intelligence sharing mechanisms could be established to improve information flow between the intelligence communities and first responders at federal, state and local levels. however, first further research is required to investigate how law enforcement and intelligence communities work currently with first responders to identify and as much as possible ameliorate the cultural, legal, communication and leadership barriers that persist. a second cluster of knowledge and stakeholders for treating bio-threats and risks could be loosely described as 'science and technology' stakeholders. in earlier sections, under the relevant headings (prevention and disruption), significant space was devoted to how our intelligence communities can learn from a range of stakeholders working across a diverse array of disciplines (including bio-surveillance, public health, biosafety, criminology, counter terrorism and cyber). in each of these disciplines, discussion included exploration of relevant science, technology and knowledge useful for the intelligence community in preventing and disrupting bio-threats and risks. some of that discussion, for example bio-surveillance, biosafety and strengthening global health is also relevant to our focus here in treating bio-incidents. however, in this section the focus is not what the intelligence community can learn from stakeholders working in the above disciplines, but rather what they can learn from disciplines more removed from the biological sciences or relevant social sciences (e.g. engineering or security studies). what can the intelligence community learn from physical, mechanical or environmental engineering? there are multiple roles engineering specialties could play and are playing in preventing, disrupting and treating bio-threats and risks. for one and historically, the us dod has relied on engineers, microbiologists to provide advice on weaponisation of biological agents under a range of scenarios and conditions (state actor and terrorists threats). for example, even pre 9/11, between 1999 and 2000 dtra funded project bacchus to see if a team of scientists and engineers, who allegedly did not have extensive experience in bio-weapons could make bio-weapon facility using just commercially available items. the objective was to see if the team could make anthrax successfully without the detection of the intelligence community, though it was later revealed that this team did have substantive technical knowledge and support throughout this project (vogel 2013: 41-43) . engineers have also long been engaged in studying aerolisation dynamics, which has become increasingly a multi-disciplinary collaboration of environmental engineers, biomedical engineers, microbiologists, chemists and epidemiologists (xu et al. 2011) . related to aerolisation studies has been the work of hardware and software engineers-many of whom came from the aerospace and automotive industries that have brought their skills into modelling bio-terrorism attacks to help first responders predict how airborne particles might move through sections of a city under certain weather and windflow conditions (thilmany 2005) . other engineering studies, sometimes referred to bio-protection studies have been important in the design of the heating ventilation and air conditioning (hvac) systems used to resist biological contaminants. much of this research became activated after the amerithrax incident, and is designed at reducing the health consequences from airborne contaminants by augmenting heating and air conditioning systems (ginsberg and bui 2015) . another focus of engineering led research relates to improving the portability, speed and reliability of bio aerosol monitors for pathogens. one recent study has been working on a device that would be fully portable and automated-capable of detection of selected air-borne microorganisms on the spot-within 30 to 8 minutes depending on the genome and particular strain of the organism (agranovski et al. 2017 ). in this last sub-section in our exploration of what other stakeholders may be useful in treating bio-threats and risks we turn our attention to the role of security officers. i am conscious in the discussion above regarding prevention and biosafety much was said about the role of security officers and managers in promoting biosecurity and biosafety across all sectors of the bio-sciences enterprise (e.g. research centres, hospitals, biotechnology companies, public and private labs). in this section, we focus instead on the role of security officers and managers across the broader economy-beyond biosciences. as argued in previous chapters, in addition to taking a one health perspective to bio-threats and risk, 'five eyes' intelligence communities and their law enforcement colleagues need to also understand the potential development of biothreats and risks beyond the technical world of biotechnology and labs to include also in their wider social, economic and community contexts. hence in this section, we are referring to the role of security officers and companies that work across the international, national, state and local economies in each 'five eyes' country. given the trajectory of most (if not all) future bio-threats is unknown, our intelligence communities need to be forging more formalised (less adhoc) relationships with security officers in a range of non-biotechnology industries (banking, mining, food supply, agriculture, critical infrastructure). as nalla and wakefield (2014) argue several factors have increased the role of private security since the second world war. increased economic wealth, enhanced security technology (alarms, access control and cctv), in addition to an increase in the control by a number of private sector companies of publicly accessible places have, amongst other factors all contributed to the growth in private sector security (ibid.: 727). while it is difficult to generalise 'as the functions of security officers/agencies are as varied as the organisations that employ them' (ibid.: 731), their functions and roles cut across many facets of each 'five eyes' nation to include office buildings, warehouses, shopping malls, education establishments, residential complexes and critical infrastructure. one often thinks of the classic scenario of a security guard standing in front of a physical gate, which is one role of many others which might also, depending on their functions include traffic control, surveillance, responding to emergencies, security vetting. in the security role of complex large companies, airports and electricity plants, it is likely that the security officers will have a deep understanding of their physical and virtual security environments and this kind of expert knowledge would be integral for them and the intelligence community gaining threat awareness, prevention, surveillance, disruption, treatment and recovery to bio threats and risks which may manifest in their operating environment. historically however, the relationship between intelligence communities (including law enforcement) and private sector security has not been optimal partially because a lack of trust between both (ibid.: 739). however, several studies on private and public sector security do show several areas of improvement across each 'five eyes' country. some of these improvements have been initiated by governments such as in the uk making significant cuts to policing in the late 1990s and mid-2000s and seeking the private sector security sector to pick up more cheaply what were considered less core policing such as offender management and transfers of prisoners. in other cases, governments were interested in engaging with the private sector to extend their own security and intelligence collection capabilities with terrorism. connors et al. (2000) , wakefield (2003) , and rigakos (2002) provide more detailed analysis of a range of factors that have been involved in building partnerships with private sector security companies in the us, uk and canada respectively. 9/11 and of course subsequent terrorist attacks in many western countries has seen a more focused attempt by 'five eyes' countries to reach out to the private sector-including private sector security given many attacks occur in public places owned or managed by the private sector. threats as well to public and privately owned critical infrastructure (aviation, power, water, and telecommunication) have also influenced 'five eyes' government's closer liaison with the private sector. for example in the us, dhs has established a private sector office to provide government advice on relevant security issues to the private sector as well as promoting public-private partnerships. in australia, since 9/11 parts of the australian intelligence community, particularly asio has developed closer links with the private sector. in 2004 australia's attorney general's department created the business-government advisory group on national security to provide a vehicle for the government to discuss a range of national security issues and initiative with ceos and senior business leaders (dpm &c 2015: 6). the group later (2014) evolved into the australian governments industry consultation on national security (ibid.). more recently (2017) the australian government released its strategy for protecting crowded places from terrorism. this significant policy document was developed in close partnerships with federal, state and local governments, the intelligence community and the private sector. the key objective being to assist owners and operators to increase the safety, protection and resilience of crowded places across australia (anzctc 2017). an interesting aspect of this strategy is that it places the primary responsibility for protecting sites and people on private sector businesses. similar policy articulations have been declared in the uk's counter-terrorism strategy (hmg 2011) and canada's approach to counter-terrorism (canadian government 2011). in summary, it's clear that various agencies of the 'five eyes' intelligence communities and their broader law enforcement counterparts have increased their liaison and implemented various initiatives with private sector industry. what is less clear is the nature and extent of these as they relate to the prevention, disruption and treatment of potential bio-threats and risks. much is unknown, for example, about whether intelligence and law enforcement communities are actively working in partnership with the private sector beyond the classical threat typologies of basic terrorist's tactics, improvised explosive devices or vehicle born attacks. given the low probability high impact nature of the evolving bio-threat environment, it is likely that many private sector companies (banking, shopping malls, mining, hotels) see little need to include bio-threats in their security risk management plans or indeed consult with intelligence and law enforcement communities on them. while it is important not to be alarmist on low probability threats that are more likely on balance to effect the biosciences community rather than the broader private sector economy, it seems unwise for the latter not to consider the impact of such bio-threats on their operations and to at least have formalised dialogues on these with the intelligence community. but such a dialogue will in the future rely on several factors identified already by researchers coming together to develop more effective public-private crime prevention strategies. prenzler and sarre list several factors including: a common interest in reducing a specific crime, leadership, mutual respect, information sharing based on high levels of trust in confidentiality and formalised mechanisms for consultation and communications (prenzler and sarre 2014: 783) . this chapter surveyed the role of external stakeholders external (to the 'five eyes' intelligence communities) in preventing, disrupting and treating bio-threats and risks. depending on the particular bio-threat a diverse array of stakeholders could provide knowledge, skills and capabilities to the intelligence community. the large number of disciplines and stakeholders with relevant technical knowledge suggest that they will continue to play a critical role in the prevention, disruption and treatment of bio-threats and risks. in many cases, such as in biosurveillance, forensics and even engineering the scientific and technical stakeholders discussed here may play a greater role than the traditional intelligence and investigative response to managing bio-threats and risks. the chapter also highlighted that although each 'five eye's intelligence community has a wealth of knowledge to tap into from stakeholders, however in most cases all stakeholder groups are faced 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dark: terrorism on the dark web ebola virus disease in west africa-the first nine months of the epidemic and forward projections signal recognition during the emergence of pandemic influenza type a/h1n1: a commercial disease intelligence unit's perspective. intelligence and national security utility and potential of rapid epidemic intelligence from internet-based sources labs cited for 'serious' security failures in research with bioterror germs silk road: the market beyond the reach of the state key: cord-012503-8rv2xof7 authors: levintow, sara n.; pence, brian w.; powers, kimberly a.; sripaipan, teerada; ha, tran viet; chu, viet anh; quan, vu minh; latkin, carl a.; go, vivian f. title: estimating the effect of depression on hiv transmission risk behaviors among people who inject drugs in vietnam: a causal approach date: 2020-08-24 journal: aids behav doi: 10.1007/s10461-020-03007-9 sha: doc_id: 12503 cord_uid: 8rv2xof7 the burden of depression and hiv is high among people who inject drugs (pwid), yet the effect of depression on transmission risk behaviors is not well understood in this population. using causal inference methods, we analyzed data from 455 pwid living with hiv in vietnam 2009–2013. study visits every 6 months over 2 years measured depressive symptoms in the past week and injecting and sexual behaviors in the prior 3 months. severe depressive symptoms (vs. mild/no symptoms) increased injection equipment sharing (risk difference [rd] = 3.9 percentage points, 95% ci −1.7, 9.6) but not condomless sex (rd = −1.8, 95% ci −6.4, 2.8) as reported 6 months later. the cross-sectional association with injection equipment sharing at the same visit (rd = 6.2, 95% ci 1.4, 11.0) was stronger than the longitudinal effect. interventions on depression among pwid may decrease sharing of injection equipment and the corresponding risk of hiv transmission. clinical trial registration clinicaltrials.gov nct01689545. electronic supplementary material: the online version of this article (10.1007/s10461-020-03007-9) contains supplementary material, which is available to authorized users. despite global progress in combating the hiv epidemic, people who inject drugs (pwid) remain disproportionately at risk of hiv infection in southeast and central asia and eastern europe [1] [2] [3] [4] [5] . sharing injection equipment is one of the most efficient means of hiv transmission [6, 7] , and in these regions, pwid have limited access to and suboptimal use of harm reduction services and antiretroviral therapy (art) [8, 9] . the persistence of injection drug use and viremia, without adequate preventive services, results in a high risk of hiv transmission to injecting or sexual partners [10] . the burden of depression is high among pwid and may further interfere with hiv prevention efforts. up to 50% of pwid suffer from severe depressive symptoms [11] [12] [13] [14] [15] , and the presence and severity of depressive symptoms are closely linked to frequency of injection and risk of relapse, suggesting a bidirectional relationship between depression and injection drug use [16] [17] [18] . comorbid depression consistently results in poor hiv treatment outcomes, such as lowering art use and viral suppression [19] [20] [21] [22] [23] [24] . the online version of this article (https ://doi.org/10.1007/s1046 1-020-03007 -9) contains supplementary material, which is available to authorized users. depression may be an important driver of continued hiv transmission among pwid if symptoms increase transmission risk behaviors (e.g., sharing injection drug use equipment, engaging in condomless sex) in the absence of viral suppression. however, while the deleterious effect of depression on hiv treatment outcomes is well established across populations, its effect on the injecting and sexual behaviors that can facilitate hiv transmission or acquisition is not well understood among pwid. although there is substantial evidence that depression increases sexual risk behaviors among men who have sex with men (msm) [25] [26] [27] [28] [29] , few studies have focused on pwid and assessed injecting behaviors. specifically, in vietnam, the focus of this study and a setting where the hiv epidemic is concentrated among men who inject drugs [30, 31] , there have been no prior studies of the relationship of depression with injecting and sexual behaviors. existing studies on depression and hiv transmission risk behaviors among pwid have suffered from several methodological limitations. to our knowledge, all previous studies that include pwid populations have assessed only correlations between depression and transmission risk behaviors, without inferring causality [32] [33] [34] [35] [36] [37] [38] [39] [40] . in these studies, depression and risk behaviors have typically been evaluated for the same time period (e.g., self-report covering the last month), without the ability to infer whether depression preceded risk behaviors or vice versa [35-37, 39, 40] . potential confounders of the relationship between depression and risk behaviors were also measured for the same retrospectively assessed time period. studies that used traditional statistical adjustment for these contemporaneous covariates [34, 38] may have induced bias if these variables acted as causal mediators rather than confounders [41] . in addition, although depression is known to be episodic [42] , prior analyses have primarily relied on a single assessment rather than accounting for changes in both depressive symptoms and time-varying confounders [33, 34, 38, 40] . possibly stemming from these methodological issues, existing evidence for an association between depression and transmission risk behaviors in pwid is inconsistent. while an early meta-analysis (that included studies among pwid) found little evidence for an association between depression and sexual risk behaviors [32] , more recent studies in pwid and msm populations have found higher sexual risk associated with depression [34, 35, 40] or a non-linear association [36] in which mild symptoms are most predictive of sexual risk. the few studies that have evaluated the association of depression with injecting risk behaviors among pwid have suggested that depressive symptoms were associated with greater injecting risk behaviors [35, [37] [38] [39] . we sought to overcome past methodological issues by using a causal approach to estimate the effect of depressive symptoms on hiv transmission risk behaviors among pwid. we used marginal structural models, a tool for causal inference that accounts for time-varying exposures and confounders [43] [44] [45] , with longitudinal data from male pwid living with hiv in vietnam. we hypothesized that depression would increase behaviors associated with risk of hiv transmission to injecting partners (sharing injection equipment) and sexual partners (condomless sex). by examining depression as a potential underlying cause of hiv transmission through these behavioral mechanisms, we sought to provide clearer evidence about the potential for interventions against depression to avert future hiv infections among pwid. we used longitudinal data from a randomized controlled trial of an hiv stigma and risk reduction intervention among pwid living with hiv in thai nguyen, vietnam from 2009 through 2013 [46] . thai nguyen is a province in northeastern vietnam with an estimated hiv prevalence of 34% among its approximately 6000 pwid [47] [48] [49] . participants were recruited via snowball sampling from the 32 thai nguyen sub-districts (of 180 total) with the most pwid. recruiters (former and current pwid) approached members of drug networks in private places to discuss study enrollment and then accompanied or referred interested participants to the study site for screening. at screening, all participants were tested for hiv using two rapid enzyme immunoassay tests run simultaneously (determine: abbot laboratories, abbott park, il and bioline: sd, toronto canada), with discordant results resolved with a third rapid assay (hiv rapid test: acon, san diego, ca). the trial enrolled 455 participants who met the following eligibility criteria: 1) hiv-positive according to study test results, 2) male (given that 97% of pwid in thai nguyen are male), 3) age ≥ 18 years, 4) had sex in the past 6 months, 5) injected drugs in the previous six months, and 6) planned to live in thai nguyen for the next 24 months (the duration of the trial). questionnaire and laboratory data were collected at study visits every 6 months during 24 months of follow-up. the questionnaire collected information on demographics, injection drug use and other substance use, sexual behavior, depressive symptoms, quality of life, pre-study hiv diagnoses (baseline only), and art use. blood specimens were collected to confirm hiv infection at baseline and measure cd4 cell count at baseline and over follow-up. the exposure of interest was depressive symptoms over the past week, as assessed by the 20-item center for epidemiologic studies depression scale (ces-d), which has been validated as a reliable measure of depressive symptoms in vietnam [50, 51] . consistent with past work, we defined severe depressive symptoms as ces-d scores ≥ 23, mild depressive symptoms as scores [16] [17] [18] [19] [20] [21] [22] , and no symptoms as scores < 16 [15, [50] [51] [52] . the transmission risk behavior outcomes were any sharing of injection equipment (needles, syringes, solutions, or distilled water) and any condomless sex with a female partner, reported for the prior 3 months. we also descriptively examined the numbers of injection equipment sharing and condomless sex acts in the prior 3 months reported at each visit. questionnaire and laboratory data included potential confounders of the depression-risk behavior relationship. time-fixed covariates, which were reported at baseline and assumed to be stable throughout the study period, were marital status, age, employment status, intervention arm, history of overdose, alcohol use, hiv diagnosis prior to enrollment, and previous art use. employment and alcohol use could, in theory, vary over time, but these variables remained fairly constant in our population, motivating our decision to treat them as time-fixed. time-varying covariates measured at one time point may affect subsequent depression and risk behaviors; they may also be influenced by depression and risk behaviors from a previous time point. thus, time-varying covariates may act as either confounders or mediators, depending on the time point assessed [41, 43] . for this analysis, time-varying covariates were cd4 cell count category (< 200, 200-499, ≥ 500 cells/μl), depressive symptoms at the visit prior to exposure measurement, and transmission risk behaviors at the visit prior to exposure measurement. in the main analysis, we used marginal structural models to estimate the average causal effect of severe depressive symptoms on the risks of any injection equipment sharing or any condomless sex (separately) in the period three to 6 months later, controlling for time-fixed and time-varying confounders. we evaluated each risk behavior outcome (reported with respect to the prior 3-month period) at the next 6-month visit in order to temporally separate it from the exposure of depressive symptoms (hereafter referred to as the "longitudinal effect"). in a second analysis, to facilitate comparison with prior research, we used marginal structural models to estimate the association between depressive symptoms and risk behaviors reported at the same visit, where temporal ordering could not be differentiated ("cross-sectional association"). we repeated both analyses using three levels of depressive symptoms (severe, mild, none) in addition to the binary categorization (severe, not severe). we used inverse probability weighted estimation of marginal structural models [43, 53] . weights were estimated from a propensity score model for the probability of severe depressive symptoms as a function of time-fixed and time-varying confounders. time-fixed confounders had a constant (baseline) value over all visits; time-varying confounders used the value from the visit immediately preceding the visit at which depressive symptoms were assessed. in the main analysis, the propensity score model was estimated using logistic regression to model the probability of severe (vs. mild or no) depressive symptoms. in a second set of analyses, we used ordinal logistic regression to separately model the three levels of depressive symptoms (severe vs. mild vs. none). propensity score model diagnostics assessed positivity for all confounderdefined subsets of the study population. the denominator of the weights was the predicted probability of depressive symptoms from the propensity score model, and weights were stabilized using the marginal probability of depressive symptoms in the numerator. application of the weights to the study population removes the association between depressive symptoms and potential confounding variables included in the propensity score model, permitting estimation of a causal effect under key assumptions [53, 54] (see discussion). in the weighted study population, we estimated the risk difference (rd) for the risk behavior outcomes using generalized estimating equations (binomial regression models with an identity link) to account for repeated observations on participants [55] [56] [57] . for the longitudinal analysis, this weighted rd can be interpreted as the causal effect of depressive symptoms on the risk behavior outcome: that is, the difference in risk of the behavior in the period three to 6 months later if all participants had depressive symptoms compared with the risk if they all did not have depressive symptoms. to account for missing data due to missed study visits, we used multiple imputation by chained equations (mice) [58, 59] , imputing and analyzing 50 datasets. we included participants who were incarcerated or died during the study period in the main analysis up until the start of the 6-month follow-up interval during which incarceration or death occurred, censoring them after their final visit preceding death or incarceration. in sensitivity analyses, we instead used the imputed risk behavior outcome for that 6-month interval (and censored them at the start of the following interval), given the possibility of engaging in unmeasured risk behaviors prior to incarceration or death. for all estimates, our interpretation focuses on the point estimate and confidence interval, rather than statistical significance [60] . analyses were conducted using r version 3.4.3 [61] . this study was approved by the ethical review committees at all participating institutions. written informed consent was obtained from all participants. as required by inclusion criteria, all 455 participants were male, hiv-positive, and reported being sexually active and using injection drugs at baseline. the median age of participants was 35 years (interquartile range [iqr]: 30, 39), and half were married or cohabitating (47%) ( table 1 ). onethird had a high school education (34%), and the majority were employed full-time (69%). most participants were newly hiv-diagnosed at baseline (74%), while 15% had been previously diagnosed and were not taking art, and 11% reported being previously diagnosed and currently using art. the median cd4 cell count was 241 cells/µl (iqr: 126, 370). general health was rated as poor by 30%. nearly half reported injecting heroin daily (45%), 18% had a history of overdose, and 67% reported current alcohol use. participants completed between zero and four follow-up study visits (median = 4, iqr: 2, 4) at 6-month intervals over 24 months, with 87% completing at least one follow-up visit. at baseline, 44% of participants reported severe depressive symptoms (ces-d ≥ 23), 25% had mild symptoms (16 ≤ ces-d ≤ 22), and 30% had no symptoms (ces-d < 16). one quarter of participants reported sex without a condom in the prior 3 months (24%), with a median of 10 condomless sex acts reported for that period (iqr: 5, 20) . most participants reported sharing injection drug use equipment with injecting partners over the past 3 months (73%); these participants reported a median of 21 sharing acts during that period (iqr: 7, 52). after the baseline visit-when all participants received risk reduction counseling and the majority became newly hiv-diagnosed-sharing injection equipment and condomless sex decreased across trial arms (previously reported in [46] ). however, among the 397 participants attending ≥ 1 follow-up visit, 21% reported sharing injection equipment at ≥ 1 visit, and 7% reported condomless sex at ≥ 1 visit. the severity of depressive symptoms varied over time (supplemental fig. 1 ) with 59% of those attending ≥ 1 follow-up visit reporting severe depressive symptoms at least once. the percentage of participants experiencing competing events increased over time, with 8% incarcerated and 23% deceased at 24 months. in our main analysis, we estimated that severe depressive symptoms (compared to no or mild symptoms) increased the risk of sharing injection equipment by 3.9 percentage points (rd = 3.9%, 95% ci −1.7%, 9.6%) and decreased the risk of condomless sex by 1.8 percentage points (rd = −1.8%, 95% ci −6.4%, 2.8%) in the period three to 6 months later (table 2, fig. 1 ). in the crosssectional analyses, the association between severe depressive symptoms and contemporaneous injection equipment sharing (rd = 6.2%, 95% ci 1.4%, 11.0%) was stronger than the estimated longitudinal effect, while the association with condomless sex was attenuated (rd = −0.7%, 95% ci −4.5%, 3.0%). in analyses using three levels of depressive symptoms, there were small decreases in the risk of condomless sex as depressive symptoms increased, although all confidence intervals overlapped substantially ( table 2 , fig. 2 ). for injection equipment sharing, patterns of risk corresponding to the three levels of depressive symptoms differed between the longitudinal effect and the cross-sectional association. in longitudinal analyses, we observed a u-shaped relationship in which the risk of injection equipment sharing in the period three to 6 months later was 12.8% (95% ci 8.1%, 17.6%) among those with no depressive symptoms, 9.2% (95% ci 5.3%, 13.2%) among those with mild symptoms, and 13.8% (95% ci 9.1%, 18.5%) among those with severe symptoms. in contrast, in the cross-sectional analysis, we observed a monotonic increasing relationship in which those with no depressive symptoms had the lowest risk of 8.5% (95% ci 5.3%, 11.8%) while those with mild symptoms had a risk of 15.5% (95% ci 11.1%, 20.0%) and those with severe symptoms had a risk of 17.4% (95% ci 13.1%, 21.8%). we did not find appreciable differences in sensitivity analyses that varied censoring time for participants who were incarcerated or deceased (supplemental fig. 2 ). using longitudinal data and methods for causal inference, we found that severe depressive symptoms increased the risk of sharing injection equipment but not the risk of condomless sex among pwid. to overcome past methodological issues, we used marginal structural models to capture the episodic nature of depression, enforce temporal ordering of depression and transmission risk behaviors, and control time-varying confounding in the analysis. by focusing on pwid living with hiv in vietnam, a population at high risk of ongoing hiv transmission, we aimed to better understand depression as an underlying cause of behaviors associated with transmission. in our main analysis of injection equipment sharing in the period three to 6 months after assessment of depression, we found a rd of 3.9% (95% ci −1.7%, 9.6%), comparing participants with severe depressive symptoms to those with mild or no depressive symptoms. this longitudinal effect was only slightly weaker than the corresponding cross-sectional association (rd = 6.2%, 95% ci 1.4%, 11.0%) found in the analysis that did not enforce temporality. the 95% ci of the longitudinal effect (−1.7%, 9.6%) shows that a risk difference ranging from a 1.7 percentage point decrease, a small negative association, to a 9.6 percentage point increase, a substantial positive association, is compatible with the data. given that the overall risk of injection equipment sharing was 10% across follow-up visits, the point estimate of a 3.9% point increase is substantively meaningful. previous research has suggested a possible non-linear relationship between the severity of depressive symptoms and occurrence of sexual risk behaviors, although this literature has focused on msm, not pwid, and findings have been mixed. some studies have found that mild depressive symptoms are associated with higher levels of sexual risk behavior but decreasing risk with severe depressive symptoms [25, 36] ; others have observed increasing risk with increasing severity of depressive symptoms [26] [27] [28] . in contrast, our analysis of condomless sex according to three levels of depressive symptoms suggested slight decreases in condomless sex with increasing severity of depressive symptoms, consistent with our main analysis. participants with depressive symptoms -regardless of severity -may be experiencing fatigue, social isolation, and loss of interest in sex, thereby reducing the risk of engaging in this behavior [62] . although all participants reported sex in the 6 months prior to baseline (due to trial eligibility criteria), a loss of interest in sex over 24 months of follow-up, particularly among participants with depressive symptoms, may have contributed to our findings. in contrast to condomless sex, we observed possible nonlinearities in the relationship between depressive symptom severity and risk of sharing injection equipment, which have not been observed previously. prior studies have found an increasing risk of injecting risk behavior with increasing depressive symptom severity [38] or have not differentiated between mild and severe symptoms [35, 37, 39] . we found monotonically increasing risk with increasing depressive symptoms in our cross-sectional analysis, and a u-shaped risk in our longitudinal analysis, where those with mild depressive symptoms had the lowest risk. interestingly, the u-shaped relationship we observed for longitudinal injecting risk is the inverse of some previous findings on sexual risk among msm (where those with mild depressive symptoms had the highest risk) [36] . this may be due to mild depressive symptoms manifesting differently for injecting behavior compared to sexual behavior and inherent differences between pwid and msm populations. depressive symptoms could lead to cognitive distortions, maladaptive coping, and loss of risk aversion [63] [64] [65] , and such symptoms may need to become severe in order to be expressed behaviorally as increased frequency of injection drug use (to treat severe symptoms) and consequently, greater sharing of equipment. although various relationships between depression and hiv transmission risk behaviors have been studied previously, the unique contributions of this study are its focus on pwid living with hiv, a population for whom there is limited data on depression and risk behaviors, and its methodological rigor in inferring causality rather than correlation. our modeling approach controlled time-varying confounding and incorporated the episodic nature of depressive symptoms by using longitudinal data from five study visits over 2 years. given that the longitudinal effect enforced temporal ordering of depressive symptoms prior to risk behaviors, we believe that it more closely reflects the causal effect than does the cross-sectional association. however, it is important to consider the trade-off between temporal ordering and etiologic relevance in the context of data limitations particular to this study. separating the measurement of depressive symptoms and risk behaviors by 6 months (with a 3-month "blackout period" in between) was necessitated by the parent trial's data structure. this incomplete interval coverage could have attenuated effect estimates relative to what they might have been if the entire interval were included (that is, if depressive symptoms were more likely to influence risk behaviors in the first 3 months of the follow-up interval). a shorter time interval with more complete data coverage may allow better capture of the effect of episodic depressive symptoms on subsequent risk behavior. inferring causality relies on several key assumptions, which must be evaluated carefully in light of the limitations of this observational study [53, 54] . the assumption of no unmeasured confounding holds that there are no systematic differences between participants with and without depression beyond any differences in variables controlled for in the analysis. although we controlled for a variety of confounders, it is possible that unmeasured confounding biased estimates of the effect of depression on risk behaviors. we also assumed positivity (i.e., participants with and without depressive symptoms were in all confounder-defined subsets of the population) and that models were correctly specified without measurement error for covariates. importantly, this study's ascertainment of depression relied on ces-d score categories, and the ces-d is not diagnostic of clinical depression. however, we used a conservative cut-point for severe depressive symptoms with high reliability and validity [50, 51] . there may also have been under-ascertainment of risk behaviors due to social desirability and recall bias. however, participants reported high levels of drug use and had been recruited by former drug users (aware of their injection drug use), indicating a willingness to disclose sensitive behaviors. finally, the consistency assumption holds that there is no meaningful variability in treatment relevant to its effect on the outcome. here, we did not model a specific treatment on depression, and results should only be interpreted as the hypothetical effect of eliminating severe depressive symptoms without specifying the treatment used for elimination. our conclusions are specific to this study population, which was not randomly sampled and may not be representative of all pwid living with hiv. while men who inject drugs drive the hiv epidemic in vietnam, our findings may not be applicable to other groups, such as women or pwid in other regions. however, our findings may be broadly generalizable to other asian and european countries where the hiv epidemic is concentrated among similar groups. we also note that the sample size of this hard-to-reach population was relatively small, which limited our statistical power to detect small differences in risk between depression groups. importantly, the risk behavior outcome in our study does not allow direct prediction of forward hiv transmission risk, as we did not take into account viral suppression status, the frequency of risk acts, or partner susceptibility to hiv. these determinants of transmission will be incorporated into a future mathematical modeling analysis that will explicitly estimate forward transmission events from this study population. we found that severe depressive symptoms may perpetuate the risk of sharing injection equipment among pwid living with hiv in vietnam. during the study period (2009) (2010) (2011) (2012) (2013) , there was very limited access to mental health services for people living with depression in vietnam [66] . however, in recent years, mental health services have become a national health priority, and there is growing attention and funding for increasing local services and availability of depression treatment [66, 67] . screening and treating depressive symptoms among pwid presents an opportunity not only to improve mental health and drug abuse outcomes but also to reduce behaviors associated with hiv transmission risk. funding doctoral training support for sara n. levintow was provided by nida (r36 da045569), niaid (t32 ai070114-10), and viiv healthcare (pre-doctoral fellowship). the parent trial for this study was funded by nida (r01 da022962-01). the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. this content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. conflicts of interest none. ethical approval this research was approved by the ethical review committees at the thai nguyen center for preventive medicine, the johns hopkins bloomberg school of public health, and the university of north carolina at chapel hill gillings school of global public health. all procedures performed were in accordance with the 1964 helsinki 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results from the hiv/sti integrated biological and behavioral surveillance (ibbs) in vietnam, round ii socialist republic of viet nam. vietnam aids response progress report 2014, following up the 2011 political declaration on hiv/ aids, reporting period thai nguyen provincial aids center and the division of social evils control and prevention, department of labor a self-report depression scale for research in the general population screening value of the center for epidemiologic studies-depression scale among people living with hiv/aids in ho chi minh city, vietnam: a validation study changes in depressive symptoms and correlates in hiv people at an hoa clinic in ho chi minh city vietnam constructing inverse probability weights for marginal structural models estimating causal effects from epidemiological data the r package geepack for generalized estimating equations estimating equations for association structures yet another package for generalized estimating equations. r-news multiple imputation for nonresponse in surveys mice: multivariate imputation by chained equations in r scientists rise up against statistical significance r: a language and environment for statistical computing depressive symptoms, social support, and personal health behaviors in young men and women sex, drugs and escape: a psychological model of hiv-risk sexual behaviours co-occurrence of treatment nonadherence and continued hiv transmission risk behaviors: implications for positive prevention interventions testing a social-cognitive model of hiv transmission risk behaviors in hiv-infected msm with and without depression mental health in vietnam: burden of disease and availability of services barriers and facilitators to the integration of depression services in primary care in vietnam: a mixed methods study key: cord-012932-alxtoaq9 authors: smerecnik, chris m. r.; mesters, ilse; verweij, eline; de vries, nanne k.; de vries, hein title: a systematic review of the impact of genetic counseling on risk perception accuracy date: 2009-06-01 journal: j genet couns doi: 10.1007/s10897-008-9210-z sha: doc_id: 12932 cord_uid: alxtoaq9 this review presents an overview of the impact of genetic counseling on risk perception accuracy in papers published between january 2000 and february 2007. the results suggest that genetic counseling may have a positive impact on risk perception accuracy, though some studies observed no impact at all, or only for low-risk participants. several implications for future research can be deduced. first, future researchers should link risk perception changes to objective risk estimates, define risk perception accuracy as the correct counseled risk estimate, and report both the proportion of individuals who correctly estimate their risk and the average overestimation of the risk. second, as the descriptions of the counseling sessions were generally poor, future research should include more detailed description of these sessions and link their content to risk perception outcomes to allow interpretation of the results. finally, the effect of genetic counseling should be examined for a wider variety of hereditary conditions. genetic counselors should provide the necessary context in which counselees can understand risk information, use both verbal and numerical risk estimates to communicate personal risk information, and use visual aids when communicating numerical risk information. recent advances in genetic research have enabled us to identify individuals at risk for a wide variety of medical conditions due to their genetic makeup (collins et al. 2003) . at the same time, these advances have created the need to educate and guide these individuals (lerman et al. 2002) . informing them of their hereditary risk and of the options for how to deal with this risk is the primary aim of genetic services (wang et al. 2004) . genetic services involve both genetic counseling and genetic testing; of these, genetic counseling in particular aims to enable at-risk individuals to accurately identify, understand and adaptively cope with their genetic risk (biesecker 2001; pilnick & dingwall 2001) . the national society of genetic counselors' (nsgc) task force defines genetic counseling as "the process of helping people understand and adapt to medical, psychological, and familial applications of genetic contributions to disease" (resta et al. 2006, p. 79) . as such, genetic counselors are faced with three important tasks: (1) to interpret family and medical histories to enable risk assessment, (2) to educate counselees about issues related to heredity, preventive options (e.g., genetic testing), and personal risk, and (3) to facilitate informed decisions and adaptation to personal risk (cf. trepanier et al. 2004) . the latter task may be considered the "core" (i.e., the desired outcome) of genetic counseling, with the former tasks in service of its fulfillment. informed decision making and adaptation to personal risk, however, are abstract concepts that cannot easily be assessed. as such, several measures have been developed to assess the efficacy of genetic counseling. kasparian, wakefield and meiser (2007) summarized 23 available measurement scales which include satisfaction, knowledge, psychological adjustment, and risk perception measures. although each of these measures significantly contributes to our understanding of the effect of genetic counseling, risk perception measures (and especially risk perception accuracy) may be regarded as one central concept. indeed, several influential models of health behavior, such as the health belief model (janz & becker 1984) , the protection motivation theory (rogers 1983) , and the extended parallel process model (witte 1992) , posit that adequate risk perception acts as a motivator to take (preventive) action and, as such, is a prerequisite of preventive behavior. moreover, risk perception and risk perception accuracy have been shown to be related to several other important outcomes of genetic counseling, such as coping (nordin et al. 2002) , worry (hopwood et al. 2001) , and anxiety . the effect of genetic counseling on risk perception has been heavily examined during the past two decades, from early research into reproductive genetic counseling (e.g., humphreys & berkeley 1987) to recent studies into genetic predispositions to cancer (e.g., bjorvatn et al. 2007) . while these studies are valuable in their own right, few have investigated the effect of genetic counseling on risk perception accuracy. indeed, to facilitate informed decision making and adaptation to personal risk, counselees must have accurate risk perceptions. in their 2002 meta-analysis, meiser and halliday (2002) identified only six studies that assessed the effects of genetic counseling on risk perception accuracy. their meta-analysis showed that individuals at risk for breast cancer significantly perceive their own risk more accurately after genetic counseling. in particular, they observed an average increase of 24.3% of the participants who accurately estimated their personal risk after counseling. a systematic review by butow and colleagues (2003) 1 year later confirmed the positive impact of genetic counseling in breast cancer risk perception accuracy, although 22-50% continued to overestimate their risk even after counseling. research thus suggests that genetic counseling may indeed improve risk perception accuracy in some individuals. however, meiser and halliday (2002) and butow et al. (2003) only included studies examining breast cancer risk. to date, there is no systematic review or metaanalysis which examines the effect of genetic counseling on perception of genetic risks in general. thus, the purpose of the present review is twofold: (1) to provide an updated overview of the impact of genetic counseling on risk perception accuracy in papers published between january 2000 and february 2007, and (2) to extend the results of meiser and halliday's (2002) meta-analysis and butow et al.'s (2003) systematic review to other genetic conditions. we searched the pubmed, embase, web of science, eric and psycinfo databases. we also used the search engine google scholar to find papers and grey literature (literature not published in a journal-e.g., in press or under review-but nevertheless available on the internet) on risk perception accuracy and genetic counseling on the internet. to this end, we used the search term "(risk perception or perceived risk or perceived susceptibility or susceptibility estimate or risk estimate) and (genetic counsel* or genetic risk or familial risk or genetic predisposition)." if available in the databases, we used the standardized, subject-related indexing terms of the concepts in the search term. we also searched the following journals manually: journal of genetic the selection procedure was performed independently by two reviewers. the review process then consisted of three phases. during the first phase, papers were reviewed based on title only. in the second phase, the reviewers examined the abstracts of papers that could not be definitively included or excluded based on their title. papers thought to be relevant to the review based on their abstracts were included; those judged irrelevant were excluded. in the third phase, the reviewers examined the papers included during the previous two phases for content. as recommended by the cochrane guidelines (higgins & green 2006) , we erred on the safe side during the whole selection process; if in doubt, we included the paper for more extensive review in the subsequent phase. the following inclusion and exclusion criteria were used to determine whether papers were eligible for the review. 1. studies should be published after 2000 (i.e., upper limit of the 2002 meiser and halliday meta-analysis, since one goal of this review was to provide an update of that analysis); studies published before 2000 were excluded (n=8; e.g., evans et al. 1994 ). 2. studies should focus on genetic risk perception; studies which did not (n=9; e.g., clementi et al. 2006) or which discussed the effect of genetic mutations, prevalence, incidence, morbidity, or mortality only were excluded (n=0). 3. studies should examine the effect of genetic counseling on risk perception accuracy; that is, should explicitly link perceived risk to objective risk estimates to examine whether they more closely align after (rather than before) counseling. studies were excluded if they examined changes in risk perception without linking them to some objective risk estimate (n=19; e.g., burke et al. 2000) , if they investigated risk perception as a determinant of genetic counseling participation (n=6; e.g., collins et al. 2000) , or if they focused on the effectiveness of decision aids as compared to standard genetic counseling (n=3; e.g., warner et al. 2003) . 4. to accurately assess whether genetic counseling affected risk perception accuracy, studies should employ either a prospective or a randomized control trial design. studies using other designs were excluded (n=12; e.g., cull et al. 2001 ). 5. risk perception accuracy should be assessed as a quantitative outcome measure; studies were excluded if they assessed risk perception as a qualitative outcome measure (n=0). 6. studies should focus on at-risk individuals; those focusing on intermediaries (e.g., genetic counselors, nurses) would be excluded (n=0). 7. studies should describe original research published in peer-reviewed journal in english. studies describing secondary data or reviewing other studies, editorials, commentaries, book reviews, bibliographies, resources or policy documents were excluded (n=5; e.g., palmero et al. 2004 ) as they provided too little detail. risk perception outcomes were abstracted by two authors independently, using standardized extraction forms. in the event of disagreement, the authors discussed the particular paper until they reached consensus. we abstracted the characteristics of the study, the participants and the genetic counseling session, as well as the results and quality of the study (cf. higgins & green 2006) . figure 1 presents the flowchart of the study selection process. from the initial sample of 3,798 eligible papers from the database searches and the 62 unique papers from the google scholar, journal, reference list and key author searches, a total of 82 papers were eligible for extensive review. of these, 19 papers were included in the review. table 1 lists the included papers and information about the study design, genetic counseling session content, criteria for risk perception accuracy, measurement time points, and finally the risk perception outcomes. given the heterogeneity in the studies, we decided against pooling the studies in a meta-analysis. concerning the content and quality of the genetic counseling sessions, four studies mentioned using a genetic counseling protocol (bjorvatn et al. 2007; bowen et al. 2006; kaiser et al. 2004; van dijk et al. 2003) . two mentioned using a standardized counseling script (codori et al. 2005; tercyak et al. 2001 ). an additional three used audiotapes as a content check of the counseling session (hopwood et al. 2003; kelly et al. 2003; , while the remaining twelve did not mention the use of any protocol, standardized script or audio-or videotapes as a content check. in-depth analyses of the content (see table 1 ) revealed that a majority of the studies described counseling sessions with similar content. however, four studies did not provide a description of the counseling session at all (hopwood et al. 2004; huiart et al. 2002; lidén et al. 2003; nordin et al. 2002) . comparing the descriptions of the counseling sessions of the remaining fifteen studies to the recommendations of the nsgc task force, we observed that only six of these mentioned the first task, "interpretation of family and medical histories to enable risk assessment" (bjorvatn et al. 2007; bowen et al. 2006; hopwood et al. 2003; kelly et al. 2003; pieterse et al. 2006; tercyak et al. 2001; van dijk et al. 2003) . likewise, only five studies explicitly mentioned performing the second task, "educate counselees about issues related to heredity and treatment and preventive options" (bjorvatn et al. 2007; codori et al. 2005; kelly et al. 2003; van dijk et al. 2003) . although judging whether counselors "facilitated decision making an adaptation to personal risk" is difficult, we did observe six studies claiming to advise counselees on surveillance (bjorvatn et al. 2007; kaiser et al. 2004; rimes et al. 2006; rothemund et al. 2001; tercyak et al. 2001) , which may be regarded as facilitating informed decisions. the included studies used two different types of measures to determine the effect of genetic counseling on risk perception accuracy: several studies reported changes in the proportion of individuals who accurately perceive their risk, while others reported the degree of overestimation or underestimation as a measure of risk perception accuracy. where available, we report both types of measures (see table 1 ). overall, the studies indicate that genetic counseling has a positive impact on risk perception accuracy (cf . table 1) . however, some studies observed no effect on risk perception accuracy at all, or only for low-risk individuals (cf. table 1 ). the studies assessing the proportion of individuals who accurately estimated their risk (see table 1 , subsection i) showed an average increase of approximately 25% (range: 2-55%) of counselees who correctly estimated their risk after counseling; from an average of 42% pre-counseling to an average of 58% post-counseling. however, on average 25% (range: 5-76%) continued to overestimate and 19.5% (range: 7-55%) continued to underestimate their risk even after counseling. 1 other studies which assessed changes in the average overestimation of participants' perceived risk (see table 1 , subsection ii) still observed an average overestimation of approximately 18% (range: 6-40%) after counseling, in comparison with 25% (range: 11.5-42%) before counseling. across the studies, the average decrease in overestimation was approximately 8%. 2 linking the outcome (i.e., risk perception accuracy) to the content of the counseling session (i.e., whether counselors performed the tasks as recommended by the nsgc task force), we observed that the studies in which the counselor gave information about family history and heredity as well as personal risk estimates positively influenced risk perception accuracy (bjorvatn et al. 2007; bowen et al. 2006; hopwood et al. 2003; kelly et al. 2003; tercyak et al. 2001) , although this improvement was not significant in two studies (pieterse et al. 2006; van dijk et al. 2003) . in contrast, the studies that did not mention giving counselees this information observed no significant improvement of risk perception accuracy as a result of genetic counseling (codori et al. 2005; kent et al. 2000; rothemund et al. 2001) , with the exception of one study (kaiser et al. 2004) . the results for the other two tasks were mixed. while some studies that educated counselees about heredity observed a positive impact on risk perception accuracy (bjorvatn et al. 2007; kelly et al. 2003; van dijk et al. 2003) , others did not (codori et al. 2005; . similar results were observed for the third task of facilitating informed decision making and adaptation to personal risk. three out of the six studies identified as performing this task observed a positive impact of genetic counseling on risk perception accuracy (bjorvatn et al. 2007; rimes et al. 2006; tercyak et al. 2001) , while the other three did not (kaiser et al. 2004; rothemund et al. 2001 ). the purposes of this review were (1) to provide an updated overview of the impact of genetic counseling on risk perception accuracy from january 2000 until february 2007, and (2) to extend the meiser and halliday (2002) meta-analysis and the butow et al. (2003) systematic review to other genetic conditions. overall, the studies showed that an increased proportion of individuals correctly perceived their risk after counseling rather than before, and those who did not had smaller deviations from their objective risk than before counseling. these positive effects were sustained even at follow-up 1 year later. some studies, however, observed no positive effect of genetic counseling, or only for low-risk individuals. these results are in line with those reported in the 2002 meiser and halliday metaanalysis and the 2003 systematic review conducted by butow and colleagues. the research in the present review may shed some light on why some studies observe positive effects of genetic counseling on risk perception accuracy and others do not. first, one study (codori et al. 2005 ) that observed no effect explicitly mentioned that personal risk information was not communicated during the relevant counseling session. second, the provision of information about the role of family history, as recommended by the nsgc task force, may provide an appropriate context in which counselees can make sense of the risk information (cf. codori et al. 2005) , resulting in accurate risk perceptions. third, some counselors may go to great lengths to explain risk information in terms the counselees can understand (cf. kent et al. 2000) . unfortunately, research has shown that verbal and numerical risk estimates often do not coincide. that is, verbal risk information results in more variability in risk perception than does numerical information (gurmankin et al. 2004b ). bjorvatn et al. (2007) , for example, observed incongruence between numerical and verbal measures of risk perception. similarly, hopwood et al. (2003) observed that counselees included a wide range of numerical risk estimates within the same verbal category. the significance of this is discussed below, where we present the implications of our study for clinical practice. finally, several studies (pieterse et al. 2006; rothemund et al. 2001 ) that observed no effect of genetic counseling on risk perception accuracy had small sample sizes, and thus may not have observed a significant effect due to power limitations. the present review has several important implications for future research. first, we selected a large number of studies assessing risk perception changes as a result of genetic counseling. however, we had to exclude 19 of these studies because they did not explicitly link risk perception to an objective risk figure. assuming that researchers are aware of these objective risk figures, future studies should link risk perception changes to objective risk figures to assess changes in risk perception accuracy. a second implication concerns the definition of risk perception accuracy, which differs between studies. for instance, in several studies accurate risk perception is defined as falling within a certain category (e.g., bjorvatn et al. 2007; kelly et al. 2003; lidén et al. 2003) or within 50% of the counseled risk (e.g., pieterse et al. 2006; rothemund et al. 2001) , while the majority define it as the correct counseled risk estimate (e.g., bowen et al. 2006; hopwood et al. 2003; tercyak et al. 2001 ). additionally, the reviewed studies based the counseled risk estimate on different methods, such as family history assessment (huiart et al. 2002) , gail's score (bowen et al. 2006) , or the brcapro procedure (kelly et al. 2003) . these issues reduce our ability to compare the results of the studies, thereby lessening their value. future researchers should define risk perception accuracy as correct counseled risk, and base their risk estimate on generally accepted and applied methods to allow for better interpretation of the results and comparison between studies. a third, related issue concerns the type of outcome measure used: several studies report changes in the proportion of individuals who correctly perceive their risk, while others report the degree of overestimation or underestimation as a measure of risk perception accuracy. researchers are advised to include both measures in their studies, as both provide valuable information about the effect of genetic counseling on risk perception accuracy. further, we observed that the quality of the genetic counseling descriptions (in those descriptions that were present) was poor. although the counseling sessions were labeled as standardized, they were described in general terms, such as "discussion about the risk" and "information was given about how hereditary factors contribute to disease." these general descriptions leave room for substantial differences between counseling sessions. this is especially problematic given that perceptions of genetic risks before genetic counseling can determine the content of the counseling session (julian reynier et al. 1995) , which tends to alter patient outcomes . differences in the quality of the counseling session content may well explain the fact that not all studies in the present review observed a positive effect on risk perception accuracy. future studies should therefore try to link the content of the counseling session to risk perception to determine which feature of the session actually contributes to improved risk perception accuracy (cf. pieterse et al. 2006 , or shiloh et al. 2006 . the present review provides some insight into how the content of the counseling session relates to risk perception accuracy. indeed, the provision of information on the role of family history was observed to positively impact risk perception accuracy, perhaps because it creates a context in which the counselee can understand the information. additionally, forcing numerical risk estimates to fit lay terms to aid counselees' understanding may lead to inaccurate risk perceptions (kent et al., 2000) . a possible avenue for further research may be to link effectiveness to certain sociodemographic variables. we could then examine the influence of known psychological differences between certain groups, which is a more complex process and should thus occur later in time. by associating these psychological differences to the effectiveness of genetic counseling, we may be able to identify the processes responsible for the positive effect of genetic counseling on risk perception accuracy. knowledge of such processes will enable us to match the session's content to these processes and thus to increase the session's effectiveness. finally, we observed a relative lack of diversity in research on genetic counseling and genetic test result disclosure in terms of the genetic disorder under consideration. although genetic counseling and testing can be effective for a variety of disorders (biesecker 2001; lerman et al. 2002; pilnick & dingwall 2001) , most recent studies focus on their impact on cancer risk perception, particularly breast cancer. although genetic counseling on cancer has been shown to positively affect risk perception accuracy, this does not guarantee it will do the same for other genetic conditions. extensive research is needed to assess whether genetic counseling also effectively enhances risk perceptions for other genetic predispositions. based on the results, we have formulated some implications for practice. first, in accordance with the recommendations of the nsgc task force, we again strongly urge genetic counselors to discuss the role of family history and perform a family history assessment. we suggest that this information is an important factor in accurate risk perception because it may provide the necessary context in which counselees can understand the risk information. indeed, the results seem to suggest that the provision of such information is positively related to risk perception accuracy. while this implication may seem redundant as it repeats the earlier recommendations by the nsgc task force, we nonetheless repeat it here since several studies in this review did not mention communicating this information to the counselee (codori et al. 2005; kaiser et al. 2004; kent et al. 2000; rothemund et al. 2001) . second, while explaining risk information in lay terms seems to be a useful strategy to help counselees to better understand their risk (cf. trepanier et al. 2004) , the one study that explicitly mentioned doing so did not observe a significant effect on risk perception accuracy (kent et al. 2000) . moreover, there appears to be incongruency between verbal and numerical risk estimates (e.g., bjorvatn et al. 2007; hopwood et al. 2003) . both types of risk estimates, however, possess qualities that would make them especially suited for counseling. compared to verbal risk estimates, numerical risk estimates have been shown to increase trust in (gurmankin et al. 2004a ) and satisfaction with (berry et al. 2004 ) the information. on the other hand, individuals have been shown to more readily use verbal information when describing their risk to others (erev & cohen 1990) and when deciding on treatment (teigen & brun 2003) . we therefore advise genetic counselors to present numerical risk estimates first, as they are accurate, objective information. the patient may then be asked what that risk estimate means to him or her. the patient's verbal response will provide an opportunity for further discussion of the meaning and impact of the risk information. genetic counselors should, however, be aware of the disadvantages of verbal information in accurately communicating risk information. a third, related implication concerns the presentation of numerical risk information. research has shown that visual presentation of risk information (e.g., odds or percentages) may be better understood than written presentation formats. indeed, there seems to be general agreement that graphical formats, in comparison with textual information, are better able to accurately communicate risk information (schapira et al. 2001; timmermans et al. 2004 ) although contradictory evidence has also been published (parrot et al. 2005 ). furthermore, graphical information seems to have a larger impact on risk-avoiding behavior than textual information (chua et al. 2006) . we therefore advise genetic counselors to use visual aids when communicating numerical risk information (cf. tercyak et al. 2001) . overall, this review suggests that genetic counseling may have a positive impact on risk perception accuracy. it has also resulted in several implications for future research. first, future researchers should link risk perception changes to objective risk estimates to assess the effect of genetic counseling on risk perception accuracy. researchers are advised to define risk perception accuracy as the correct counseled risk estimate instead of falling within a certain percentage of the counseled risk. additionally, they should report both the proportion of individuals who correctly estimate their risk and the average overestimation of risk. second, as the descriptions of the counseling sessions were generally poor, future research should include more detailed descriptions of these sessions, and link their content to risk perception outcomes to enable interpretation of the results. finally, the effect of genetic counseling should be examined for a wider variety of hereditary conditions. genetic counselors are advised to discuss the role of family history and perform a family history assessment to provide the necessary context in which counselees can understand the risk information. they should also use both verbal and numerical risk estimates to communicate personal risk information, and use visual aids when communicating numerical risk information. over the counter medicines and 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force report applying cognitive-behavioral models of health anxiety in a cancer genetics service cognitive and physiological processes in fear appeals and attitude change: a revised theory of protection motivation perception of risk, anxiety, and health behaviors in women at high risk for breast cancer frequency or probability? a qualitative study of risk communication formats used in health care the facilitating role of information provided in genetic counseling for counselees' decisions verbal probabilities: a question of frame psychological response to prenatal genetic counseling and amniocentesis different formats for communicating surgical risks to patients and the effect on choice of treatment genetic counselling and the intention to undergo prophylactic mastectomy: effects of a breast cancer risk assessment assessment of genetic testing and related counseling services: current research and future directions educating women about breast cancer. an intervention for women with a family history of breast cancer putting the fear back into fear appeals: the extended parallel process model (eppm) acknowledgements this study was financially supported by maastricht university and performed at the school for public health and primary care (caphri). caphri participates in the netherlands school of primary care research (care), recognized by the royal dutch academy of science (knaw) in 1995.open access this article is distributed under the terms of the creative commons attribution noncommercial license (https:// doi.org/creativecommons.org/licenses/by-nc/2.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. key: cord-035287-l6trtvil authors: kanno, takeshi; moayyedi, paul title: who needs gastroprotection in 2020? date: 2020-11-11 journal: curr treat options gastroenterol doi: 10.1007/s11938-020-00316-9 sha: doc_id: 35287 cord_uid: l6trtvil purpose of review: peptic ulcer disease (pud) is a recognized complication of non-steroidal anti-inflammatory drugs (nsaids). stress ulcers are a concern for intensive care unit (icu) patients; pud is also an issue for patients taking anticoagulation. helicobacter pylori test and treat is an option for patients starting nsaid therapy, and proton pump inhibitors (ppis) may reduce pud in nsaid patients and other high-risk groups. recent findings: there are a large number of trials that demonstrate that helicobacter pylori eradication reduces pud in nsaid patients. ppi is also effective at reducing pud in this group and is also effective in icu patients and those on anticoagulants. the effect is too modest for ppi to be recommended in everyone, and more research is needed as to which groups would benefit the most. increasing age, past history of pud, and comorbidity are the most important risk factors. summary: h. pylori test and treat should be offered to older patients starting nsaids, while ppis should be prescribed to patients that are at high risk of developing pud and at risk of dying from pud complications. upper gastrointestinal (gi) bleeding is a major health problem, and mortality from this problem has remained relatively unchanged for the last 50 years [1] [2] [3] . the apparent stability of a 5-12% in-patient 30-day mortality rate hides significant changes in the epidemiology and management of the condition. major advances have been made in the management of upper gastrointestinal bleeding including the routine use of proton pump inhibitor therapy after a peptic ulcer bleed which improves outcomes and probably reduces mortality [4] . endoscopic therapy also improves the outcomes of peptic ulcer and variceal bleeding [5] . the age-adjusted rates of peptic ulcer (pu) bleeding have fallen globally over the last 20 years largely due to the falling prevalence of helicobacter pylori (h. pylori) [6, 7] , but a modest contribution may relate to the increasing use of acid suppression in the community [8] . these positive factors have been balanced by the fluctuating use of non-steroidal anti-inflammatory drug (nsaid) [9] and by the increased use of antiplatelet [10] and anticoagulant therapy [11] over time. furthermore, the absolute numbers of patients with peptic ulcer bleeding are not falling as dramatically as might be expected due to populations living longer with more comorbidities, which are a major risk factor for both pu bleeding incidence [12] and death [13] . given that pu bleeding remains an important problem, it is helpful to develop strategies that will prevent this complication particularly as antiplatelet and anticoagulation therapy continue to rise [14] . there have been recent guidelines [15, 16] on nonvariceal upper gastrointestinal bleeding, but these have predominantly focused on management of the problem when it occurs rather than preventing the complication from happening in the first place. the main approaches to prevent peptic ulcer bleeding are h. pylori screening and treating those that are positive, long-term proton pump inhibitor (ppi), or h 2 receptor antagonists (h2ra) therapy. h2ra therapy is less effective than ppi [17] and will not be considered further in this review. in those taking nsaids, there are the additional approaches of replacing them with cyclooxygenase-2 (cox-2) inhibitors or adding prostaglandin analogues. none of these strategies will be cost-effective if used in the general population, and most guidelines would recommend that these interventions should only be used in highrisk groups [18] . this article will therefore evaluate risk factors for pu complications such as age, nsaid use, concomitant antiplatelet therapy, anticoagulant therapy, patients admitted to intensive care, and those with severe comorbidities [19] . we will then summarize the evidence for the efficacy of h. pylori eradication, ppi therapy, cox-2 inhibition, and prostaglandin analogues in preventing peptic ulcer bleeding and focus on which high-risk groups these approaches could be recommended. the most important determinant of pu complication population attributable to risk is increasing age. the risk of pu complication is 10-fold higher than those over the age of 60 years compared to younger age groups [20] . the vast majority of deaths from pu complications also occur in older age groups with a 50-fold increase in mortality in those over 60 compared to those less than 60 years old [20] . while mortality from pu complications in those under that age of 60 years is very rare, this cut off is somewhat arbitrary. the risk of pu complications is still modest in a 60-year-old but steadily increases with advancing age with a roughly two-fold increase in incidence with every decade [21] . many risk factors increase with age, and it is difficult to evaluate age separate from other risk factors such as increasing prevalence of h. pylori, polypharmacy, and comorbidity. nevertheless, it is likely that age is an important independent risk factor for pu complications. the message for the clinician is that gastroprotection is unlikely to be cost-effective in younger age groups and should mainly be considered in those over the age of 60 years. in those over the age of 60, the threshold to offer gastroprotection should decrease as age increases with a particular consideration given to those over the age of 80 years [21] . the potential for nsaids to cause peptic ulcer disease is well known. the analgesic effect of nsaids is mediated through reducing prostaglandin synthesis by inhibiting cyclooxygenase (cox) enzymes. there are two cox isoenzymes; cox-1 is present in most cells whereas cox-2 is present in only a few tissues and is induced by inflammation [22] . the gastrointestinal toxicity of nsaids is mediated by cox-1, and the reduction in gi prostaglandin caused by this isoform leads to loss of cytoprotection and increased risk of peptic ulceration. all traditional nsaids have a mixture of cox-1 and cox-2 inhibitor activity, but the proportions differ, and this is the main reason their gastrointestinal toxicity also varies [23] . the least toxics are ibuprofen and diclofenac with relative risks (rr) of around two followed by naproxen with rr of four, and the most toxics are piroxicam and ketoprofen with rr of 8 for the development of peptic ulcer disease [24, 25] . low-dose acetylsalicylic acid (asa) also has an increased risk of peptic ulcer complications with a rr of approximately 1.5 [26] . a modeling study [27] from rct and cohort study data suggested that 1:1200 to 1:2000 chronic nsaid users will die from peptic ulcer complications attributable to the drug. adenosine diphosphate-receptor inhibitors such as clopidogrel are typically used after acute coronary syndromes and following percutaneous coronary stenting as they reduce the risk of future coronary events at least over the next year [28] . the seminal study [28] that reported the benefit of dual antiplatelet therapy with clopidogrel and asa in acute coronary syndromes also found that 1.3% developed gi bleeding over the next 9 months. the pathways that asa causes gastrointestinal mucosal damage are well described, as with all nsaids, but the mechanism by which antiplatelet therapy leads to peptic ulcer bleeding is less clear. inhibition of platelet activity in a peptic ulcer that is already hemorrhaging will aggravate the problem and may lead to more peptic ulcers presenting with bleeding that would otherwise have remained "silent." plateletderived growth factors promote angiogenesis, and this is important in ulcer healing [29] . disruption of these growth factors by clopidogrel may impair peptic ulcer healing and lead to more complications. a population-based cohort [30] estimated the number needed to harm ranged between 30 and 60 for a gastrointestinal hemorrhage within the first 12 months of clopidogrel compared to those not taking this drug. this excess could be related to bias and confounding factors inherent with database studies, but a systematic review [26] of rcts supported this finding, and patients on dual antiplatelet therapy had almost twice the rate of gastrointestinal bleeding compared to those taking asa alone. anticoagulants are commonly used to prevent thromboembolic events in patients with venous thromboembolism, atrial fibrillation, or mechanical heart valves. clinicians and patients are well aware of the risk of bleeding from vitamin k antagonist anticoagulants such as warfarin. the risk of peptic ulcer bleeding is remarkably difficult to quantify as there are no rcts evaluating the risks of warfarin compared to placebo and there are remarkably few robust epidemiological studies. most older studies follow cohorts of patients taking warfarin with no comparator group [31] and suggest a large risk. it is generally believed that traditional views of the gi bleeding risks of warfarin are overestimated [32] and more contemporary assessments of risk support a more modest increased risk [33] . a systematic review [34] of randomized trials comparing anticoagulation with asa in atrial fibrillation found that major bleeding adverse events were more common in the anticoagulation group (or = 1.45; 95% ci = 0.93 to 2.27). this was all bleeding events and was not limited to peptic ulcer bleeding, but if we assume that this also reflects upper gi bleeding and factor in that asa alone also causes an increased risk of bleeding [26] , the overall risk from vitamin k antagonists is approximately increased three-fold. more recently the non-vitamin k antagonist oral anticoagulants (noacs) have been developed and shown to be more efficacious than warfarin in many settings, particularly related to atrial fibrillation [35] . as a result, noacs have overtaken the prescription of vitamin k antagonists for atrial fibrillation and deep vein thrombosis in the usa and several other countries [36] . noacs also cause less intracranial bleeding than vitamin k antagonist but are associated with greater risk of gi bleeding [35] . this meta-analysis of rcts [35] is considering all noacs together, and there are significant differences in risk of gi bleeding between drugs in this class. one database study [37] suggested that apixaban was associated with less gi bleeding than dabigatran or rivaroxaban although another found dabigatran was associated with less upper gi bleeding [38] . interestingly these database studies found similar rates of gi bleeding with noacs compared to vitamin k antagonists. this is in contrast to rct data, and this may relate to confounding factors or may relate to patients outside of rcts having their coagulation less rigorously monitored. the development of noacs has lowered the threshold at which anticoagulation is considered, and they are being used for ever wider indications [39] . this emphasizes the need to offer gastroprotection in patients taking anticoagulation if they are at a high risk of pu bleeding. defining high-risk groups is a challenge but there is rct evidence [39] that adding a naoc to asa doubles the risk compared to asa alone. there is also cohort evidence [40] that adding warfarin to clopidogrel triples the bleeding risk. corticosteroids have a wide range of actions including profound immunomodulatory effects. they are used in a wide range of inflammatory and autoimmune conditions [41] , and their adverse event profiles such as osteoporosis, obesity, mood disorder, diabetes mellitus, and risk of infection are well known. corticosteroids also delay wound healing, so it is logical that they may also inhibit peptic ulcer healing and be associated with increased risk of ulcer complications. clinicians are well aware of this putative risk and often provide patients with ulcer prophylaxis [42] . the rct evidence that they cause peptic ulcer complications is however less clear. a systematic review of rcts [43] did find an approximately 40% increase in risk peptic ulcer bleeding or perforation in those taking corticosteroids. however, the statistically significant effect was only seen in hospitalized patients and with events only occurring in 0.1% of ambulatory patients. these data suggest that the main risk is in patients with other risk factors for peptic ulcer complications, particularly those admitted to hospital, and there is no need to routinely provide gastroprotection to those in the community. the main focus should be on limiting the duration of therapy given the other adverse events related to corticosteroids rather than focusing on gastroprotection. selective serotonin reuptake inhibitors (ssris) are the most commonly prescribed antidepressant [44] and have been advocated for a variety of psychiatric and medical conditions [45] . they have a favorable adverse event profile compared to more traditional antidepressants [46] , but concerns have been raised regarding the risk of gi bleeding [47] . ssris decrease platelet serotonin, and this can result in reduced platelet aggregation [48] . ssris also increase gastric acid production, which could lead to a greater propensity to develop peptic ulceration [49] . an initial uk database study [50] did suggest a threefold increase in gi bleeding in those taking an ssri compared to controls, and this was supported by another cohort study [51] . there have been no rcts evaluating gi bleeding as an outcome, but further observational data has accrued. a systematic review [52] identified 15 case-control studies involving almost 4000 participants and found an increased risk of upper gi bleeding with ssri therapy compared to controls with an odds ratio (or) of 1.66 (95% confidence intervals (ci) = 1.44 to 1.92). the systematic review [52] also identified four cohort studies, and the increased risk was similar (or = 1.68; 95% ci = 1.13 to 2.50). the number needed to harm over 1 year varied between 3177 in a lowrisk dutch population and 881 in a higher risk us population [42] . the systematic review [52] also evaluated the impact of nsaids on the risk of upper gi bleed and found at least an additive effect. the risk of upper gi bleeding in patients taking ssris alone was 1.66, in those taking nsaid alone it was 2.8, and in those taking both drugs the or was 4.25. the number needed to harm for those taking both nsaids and ssris was 645 for a low-risk population and 179 for a higher risk us population [52] . these results could be due to bias or residual confounding as they relate to observational data, but these findings are supported by a hong kong study that attempted to reduce this concern [53] . this study evaluated 3358 ssri users and 57,906 non-users and only included patients that had h. pylori eradication therapy. this approach makes the population more homogeneous, and they further reduced the possibility of confounding by conducting a propensity match analysis. the propensity-matched analysis found patients taking ssri had a hazard ratio of 1.95 (95% ci = 1.41 to 2.71) for developing upper gi bleed compared to non-users [53] . h. pylori is the leading cause of peptic ulcer disease worldwide [54, 55] , and a proportion of both gastric and duodenal ulcers caused by this infection will go on to develop complications. a systematic review of observational studies suggested h. pylori is associated with a two-fold increase in peptic ulcer bleeding [56] . there also appears to be an interaction between nsaids and h. pylori as the same systematic review [56] found an approximately four-fold increased risk of developing peptic ulcer bleeding in those taking nsaids and a 6-fold increase in patients where both factors were present. a further systematic review [57] also found a two-fold increase in upper gastrointestinal bleeding in asa users infected with h. pylori compared to those that were not infected. the number needed to treat varied between 100 and 1000 depending on the underlying risk of peptic ulcer disease in the population [57] . serious comorbidity is associated with peptic ulcer bleeding although definitions of comorbidity vary between studies [7] . patients admitted to the intensive care unit (icu) exemplify the risk facing patients with severe stress and comorbidity with around 3% developing significant gi bleeding [58] , and this is associated with length of stay severity of underlying illness [59] . various scoring systems [60, 61] that evaluate risk of mortality from upper gi bleeding include comorbidity as part of the calculations. a systematic review of death from peptic ulcer bleeding [62] found that mortality was significantly higher in those with comorbidity than those without. in particular those with malignancy had a 6-fold, those with renal disease a 5-fold, and those with hepatic disease a 4-fold increased risk of mortality [62] . respiratory and cardiac disease were each associated with a two-fold risk of dying from peptic ulcer bleed and diabetes mellitus a relative risk of 1.6 [62] . it is important to note that only three of the 16 studies identified in this review were low risk of bias so the quality of the evidence is low, but nevertheless the impact of comorbidity seems to be important, and there is less research on this than many other risk factors for peptic ulcer bleeding. past history of peptic ulcer disease is a strong risk factor for future peptic ulcer although the impact is less strong after successful h. pylori eradication [63] . there is a paucity of data on the risk of developing complicated peptic ulcer in comparison with population-based controls. systematic review data [64] suggest that in patients taking nsaids, a previous history of peptic ulcer increases the risk of future peptic ulcer two to three-fold, and this increases for 4-6 fold for a past history of bleeding peptic ulcer. this is also supported by subgroup analyses of randomized controlled trials [65] . patients with a previous history of peptic ulcer prescribed oral anticoagulants have a doubling of their risk of having a gi bleed over a 10-year follow-up [66] . there are a number of risk factors for developing peptic ulcer disease complications, but the main focus of research has related to preventing nsaid-related peptic ulcer complications. this is understandable as this causes one of the highest increases in risk. the strategies that reduce nsaid-related bleeding are adding ppi therapy, substituting for a cox-2 inhibitor, or adding a prostaglandin analogue. the other approach is screening and treating for h. pylori, and this is the only approach that could be considered for patients other than those taking nsaids. seven days of eradication therapy can heal most patients with h. pylori-positive pud [67] , and treating the infection also dramatically reduces future ulcer recurrence [63] . this also applies to bleeding peptic ulcer as a systematic review of 7 rcts involving 578 infected bleeding patients reported that h. pylori eradication was more effective than anti-secretory therapy in preventing future bleeding recurrence [68] . the recurrence rate was 20% in the anti-secretory group and 3% in the h. pylori eradication group with a number needed to treat of seven. most guidelines [15, 16] therefore recommend testing for h. pylori in those with bleeding pud and treating those infected. randomized controlled trials have shown that population h. pylori screening and treatment reduces the incidence of peptic ulceration in the community [69, 70] . the impact on peptic ulcer complications in the general population is less certain, however, as these events are too rare for randomized trials to be powered to detect an impact on this outcome. the rare events observed in these trials highlight that testing for h. pylori is unlikely to be cost-effective in all groups and any population strategy to screen and treat cannot be instituted on the basis of reduced peptic ulcer complications. population h. pylori screening and treatment is advocated in countries that have a high incidence of gastric adenocarcinoma [71, 72] as systematic reviews of randomized controlled trials have shown that this reduced risk of gastric adenocarcinoma [73, 74] . population h. pylori screening and treatment could increase both the length and quality of life, and it has been estimated that almost 9 million disability-adjusted life years could be gained globally [74, 75] . this estimate just focuses on reduction in gastric cancer, and if prevention of peptic ulcer complications was considered, then the disability life years gained could be even higher. furthermore, a randomized controlled trial has suggested that h. pylori population test and treat could be cost neutral due to the reduction in dyspepsia in the population [76] [77] [78] . guidelines do not support population h. pylori screening and treatment in north america [79] , but the other benefits that could accrue from this approach suggest the clinician should have a low threshold for instituting this strategy when considering patients that may be at risk of developing pu complications. for example, patient taking only low-dose asa who are h. pylori positive may benefit from eradication therapy as one study reported that infected patients who had an asa-related pu bleed given eradication therapy had a similar risk for future bleeding as patients who were asa naã¯ve that had not had a bleed [80] . similarly, a systematic review of rcts [81] reported that patients allocated to h. pylori eradication had an almost 60% reduction in incidence of pud compared to infected nsaid patients in the control group. as this involves one of course of antibiotics for 2 weeks rather than long-term treatment with acid suppressive agents, this could be a very cost-effective approach [82] at preventing nsaid-related ulceration, and guidelines are now recommending this strategy [79, 83] . however, h. pylori eradication is not as effective as ppi therapy in patients on long-term nsaid therapy [81] , so this strategy is not sufficient for some patient groups. nsaids reduce gastric prostaglandin production and loss of mucosal defenses leading to an increased risk of pud [84] . the main reason that mucosal protection is necessary is the highly acid environment of the stomach. blocking acid production should reduce the risk of pud even if there is nsaid-mediated loss of mucosal protection. clinical data support this hypothesis with a systematic review [85] of 18 rcts involving over 10,000 participants demonstrating that ppis reduced pud bleeds by approximately 80% compared to controls although the effect was less marked in patients who were already taking nsaid therapy long term. overall the number needed to treat (nnt) was around 100 in these trials although this was heavily dependent on the underlying risk of the population. ppis also prevented symptomatic and endoscopic ulcers in patients taking nsaids with an nnt of 20 and 5, respectively [85, 86] . a systematic review [87, 88] of 5 rcts involving over 5000 participants also reported that ppis are effective in reducing pu bleeding related to clopidogrel-based antithrombotic therapy. there was a 66% reduction in pu bleed in patients allocated to ppi compared to placebo or famotidine with an nnt of 60 [88] . research on the gastroprotective role of ppi therapy has focused on patients taking nsaid and/or asa. there are a growing number of patients on anticoagulation therapy [36] , and these patients are at increased risk of pu bleed [37] . this was evaluated as part of the cardiovascular outcomes for people using anticoagulant strategies (compass) trial [39] . participants were randomized to rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg once daily alone to evaluate cardiovascular death, stroke, or myocardial infarction in these groups [39] .this is a 3-by-2 partial factorial rct as those that were not on a ppi were also randomized to pantoprazole 40 mg or placebo [89â�¢â�¢] . a total of 17,598 patients were randomized to the ppi or placebo, and there was no statistically significant difference in the primary outcome of the trial, which was clinically significant upper gi events [89â�¢â�¢] . there was a 50% reduction in the gastroduodenal bleeding in the ppi arm, but events were low and the nnt = 1770 after 3 years of ppi use. the definitions of pud and pu bleeding were very stringent, and this may have resulted in the nnt being so high. a post hoc analysis was therefore conducted relaxing definitions, and this did result in a 50% reduction in bleeding pud bleed, and a similar reduction in uncomplicated pud as well as a 66% reduction in gastric erosions in the ppi group. even when these outcomes were combined, the nnt was still around 500 [89â�¢â�¢] . furthermore, the main benefit of ppi therapy was seen in the asa alone group emphasizing ppis have little impact in patients taking anticoagulants alone. evidence therefore suggests that any benefit of ppis relates to patients taking nsaid or asa. the final group to consider are patients admitted to the icu as these patients are at increased risk of bleeding from upper gastrointestinal stress ulceration [58, 59] . systematic reviews [90, 91] of 19 rcts involving over 2000 icu patients found that ppi therapy reduced overt gi bleeding by 50% with no impact on length of stay, pneumonia, or mortality. ppis were superior to h2ra in these reviews although this is disputed by a network meta-analysis [92â�¢â�¢] of 43 rcts involving over 10,000 patients evaluating clinically important upper gi bleeding as an outcome. this review concluded both ppis and h2ras reduced gi bleeding, and ppis were possibly superior, but the 95% ci were wide (or = 0.58; 95% ci 0.29 to 1.17). this review highlighted that either ppi or h2ra were probably not beneficial in low-risk patients and this intervention should be reserved for those at high risk. the benefits of ppi therapy in preventing pu bleeding should be weighed against the harm of this approach. patients need to take ppi therapy for the duration of risk which may be life-long in the case of asa users. previously this would have been a significant expense, but as most ppis are now available generically in most countries, the costs have reduced significantly. ppi therapy is also very safe in the short term [93] , but concerns have been raised around the long-term adverse effects associated with these drugs [94] . ppis have been associated with pneumonia [95] , bone fracture [96] , enteric infections [97] , cardiovascular events [98] , chronic kidney disease [99] , dementia [100] , gastric cancer [101] , and even all-cause mortality [102] . the list of concerns increases with each passing year, and the latest harms that have been highlighted are an increased risk of renal calculi [103, 104] and risk of covid-19 [105] . the problem with all of these associations is that they are based on observational data, usually related to administrative databases. all of these studies have shown that sicker patients tend to be prescribed ppi therapy and comorbidities are a strong risk factor for developing other diseases [106] . it is possible that being prescribed ppi therapy is a good marker for comorbidity and all of these harms relate to residual confounding [106] . to evaluate this possibility, the rct evaluating ppi in patients taking anticoagulation and/or asa [89â�¢â�¢] described above also prospectively collected information on adverse events [107â�¢] . in over 53,000 patient years of follow up, there was no difference in risk of pneumonia, fracture, chronic kidney disease, dementia, myocardial infarction, gastrointestinal cancers, and all-cause mortality between the ppi and placebo groups [107â�¢ ]. the ppi group had slightly more enteric infections than those taking placebo, but the number needed to harm was over 900 for each year of ppi therapy. this trial followed patient for 3 years, and it is possible that adverse events may take longer to accrue, but there was no divergence on the curves over time in the rct [107â�¢] . furthermore, an rct also found no adverse events in ppi arm compared to surgery in reflux patients over 12 years [108] although this trial was underpowered. finally, there was actually a reduction in mortality in the high-dose ppi arm of a barrett's esophagus trial comparing esomeprazole 20 mg versus 40 mg bid given over a mean of 9 years in over 2500 patients [109] . there are also concerns that ppi may interact with clopidogrel reducing efficacy [110â�¢ ] and this could not be addressed in the compass trial as patients had to discontinue this drug. a systematic review of rcts [87, 88] did not find any difference in cardiovascular events in the ppi arm compared to the placebo/famotidine arms in patients taking clopidogrel suggesting that the results of observational data probably relate to residual confounding. these data suggest that the benefits of ppi therapy outweigh any putative risk provided the appropriate patients are selected for gastroprotection. the gastrointestinal adverse effects of nsaids largely relate to the cox-1 activity of the drug, while the analgesic effects of nsaids relate to cox-2 inhibition. cox-2 selective inhibitors were therefore developed on the principle that these drugs could provide similar analgesic properties to traditional nsaids without the gastrointestinal events [111] . systematic reviews of rcts confirmed this hypothesis with cox-2 inhibitors having a similar efficacy profile [112] but with a 70% reduction in endoscopic ulcers [113] and a 60% reduction in pu bleed and pu complications [113] . cox-2 inhibitors were initially used widely to protect against nsaid-related gi injury, but enthusiasm for this approach waned once it became apparent from rcts [114, 115] that the risk of cardiovascular events was increased from these drugs. a systematic review [116] of 280 rcts comparing nsaids/cox-2 inhibitor with placebo and 474 rcts comparing nsaids with another nsaid/cox-2 inhibitor confirmed that cox-2 inhibitors increased the risk of cardiovascular events by about 33% and this outweighed any benefits in terms of reduction of pu complications. an increase in cardiovascular event risk was also seen with nsaids such as diclofenac and ibuprofen, and the impact seemed as great as with cox-2 inhibitors [116] . in contrast, naproxen was not associated with an increased risk of cardiovascular events, suggesting this was a safer nsaid to use [116] . these data raise the question of whether any nsaid other than naproxen is safe to use in the long term as a 33% increase in cardiovascular disease will outweigh any improvement in quality of life for most patients. furthermore, another systematic review of rcts [117] suggested cox-2 inhibitors were associated with an increased risk of dementia, highlighting there may be other risks to taking these drugs long-term. another approach to gastroprotection is to replace the upper gastrointestinal deficiency in prostaglandin caused by nsaids with a prostaglandin analogue. misoprostol, a synthetic prostaglandin e1 analogue, dramatically reduces endoscopic ulcers in a systematic review of 22 rcts involving almost 6000 patients taking nsaids with an nnt of 10 [85] . there was early promise [65] that this would translate into a reduction in pu complications, but this was not supported by a systematic review of three rcts involving almost 9000 patients, where there was no statistically significant reduction in pu bleeding [85] . the use of misoprostol is also limited by adverse events such as diarrhea with up to 20% patients withdrawing because of adverse events [118] . this can be mitigated by lowering the dose [118] , but it remains a significant problem when used for long-term prophylaxis. prostaglandin analogues therefore cannot be recommended for gastroprotection routinely in patients taking nsaids. there may be selected patients where this might be the appropriate drug. for example, rct data suggest that misoprostol may reduce nsaid-related small bowel ulcers detected by video capsule endoscopy [119] . whether this translates to improvement in clinical outcomes remains to be determined, but this may be an option for patients with predominantly small bowel ulcer problems that cannot discontinue nsaids. the above evidence provides a framework to selecting which patients should receive gastroprotection. in general, these should be reserved for patients over the age of 60 years taking nsaids or those being admitted to icu. even in these groups, the risk is not sufficiently high to warrant gastroprotection to everyone [92â�¢â�¢] . ideally what is required is a validated risk calculator that gives the absolute risk of developing peptic ulcer disease over a given period of time similar to those used to determine risk of cardiovascular disease [120] . patients starting long-term nsaid or low-dose asa therapy should all routinely be screened for h. pylori, and those infected should receive eradication therapy with regimens that follow latest guidelines [79, 121] . this will reduce pu complications but will also have added benefits in reducing future dyspepsia and future gastric cancer risk. as this is a one-off treatment, this is likely to be cost-effective. for those over 60 years of age taking long term nsaids, naproxen should be the drug of choice due to the favorable cardiovascular risk profile. additional risk factors should be ascertained according to the scoring system outlined in table 1 . those that have 6 points or more for naproxen or 8 points for lowdose asa (as the underlying risk of developing pu complication is lower than for naproxen) should be offered long-term ppi therapy with careful discussion of the risks and benefits. for patients admitted to icu, additional risk factor should also be ascertained as determined by a systematic review [122] that identified 8 observational studies involving over 116,000 icu patients. patients with chronic liver disease and/or coagulopathy should be given prophylaxis with ppi therapy during their hospital admission [122] . similarly, those that need mechanical ventilation and are also in shock may benefit from ppi therapy [122] . those that are discharged should have their ppi discontinued if there is no indication for continued therapy [123] . there is a wealth of rct evidence on the benefits of h. pylori eradication and ppi therapy to prevent pu complications in patients taking nsaid. there is also rct evidence on the benefits of ppi therapy in patients taking anticoagulation and for icu patients. it is clear from these trials that these interventions are effective, but high-risk groups need to be identified, and this should be the focus of future research. conflict of interest takeshi kanno declares that he has no conflict of interest. paul moayyedi declares that he has no conflict of interest. papers of particular interest, published recently, have been highlighted as: of major importance trends for incidence of hospitalization and death due to gi complications in the united states from acute upper gi bleeding: did anything change? time trend analysis of incidence and outcome of acute upper gi bleeding between 1993 trends and outcomes of hospitalizations for peptic ulcer disease in the united states systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding epinephrine injection versus epinephrine injection and a second endoscopic method in high-risk bleeding ulcers systematic review: the global incidence and prevalence of peptic ulcer disease systematic review of the epidemiology of complicated peptic ulcer disease: incidence, recurrence, risk factors and mortality burden and cost of gastrointestinal, liver, and pancreatic diseases in the united states: update trends in opioid and nonsteroidal anti-inflammatory use and adverse events trends in ambulatory prescribing of antiplatelet therapy among us ischemic stroke patients trends in anticoagulant prescribing: a review of local policies in english primary care peptic ulcer disease mortality from peptic ulcer bleeding: the impact of comorbidity and the use of drugs that promote bleeding gastrointestinal bleeding with oral anticoagulation: understanding the scope of the problem management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the international consensus group asia-pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update ppi versus histamine h2 receptor antagonists for prevention of upper gastrointestinal injury associated with low-dose aspirin: systematic review and meta-analysis canadian association of gastroenterology consensus group. canadian consensus guidelines on long-term nonsteroidal antiinflammatory drug therapy and the need for gastroprotection: benefits versus risks the relative efficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs epidemiology of perforated peptic ulcer: age-and gender-adjusted analysis of incidence and mortality comparison of mortality from peptic ulcer bleed between patients with or without peptic ulcer antecedents peptic ulcer disease and non-steroidal antiinflammatory drugs new insights into the use of currently available non-steroidal anti-inflammatory drugs risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal antiinflammatory drugs, aspirin and combinations individual nsaids and upper gastrointestinal complications low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic nsaid use effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without st-segment elevation platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release gastrointestinal events with clopidogrel: a nationwide population-based cohort study age-related risks of long term oral anticoagulant therapy bleeding risks of antithrombotic therapy population-based cohort study of warfarin-treated patients with atrial fibrillation: incidence of cardiovascular and bleeding outcomes systematic review of long term anticoagulation or antiplatelet treatment in patients with non-rheumatic atrial fibrillation comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials trends and variation in oral anticoagulant choice in patients with atrial fibrillation gastrointestinal safety of direct oral anticoagulants: a large population-based study risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care rivaroxaban with or without aspirin in stable cardiovascular disease risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin k antagonists in denmark: a retrospective analysis of nationwide registry data corticosteroidmechanisms of action in health and disease a surviving myth"-corticosteroids are still considered ulcerogenic by a majority of physicians corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis increased use of antidepressants in canada effect of antidepressants and psychological therapies in irritable bowel syndrome: an updated systematic review and meta-analysis efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis risks of hospitalization for upper gastrointestinal bleeding in users of selective serotonin reuptake inhibitors after helicobacter pylori eradication therapy: a propensity score matching analysis global prevalence of helicobacter pylori infection: systematic review and meta-analysis role of helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients the attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients risk assessment after acute upper gastrointestinal haemorrhage a risk score to predict need for treatment for upper-gastrointestinal haemorrhage effect of comorbidity on mortality in patients with peptic ulcer bleeding: systematic review and metaanalysis eradication therapy for peptic ulcer disease in helicobacter pylori-positive people risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. a meta-analysis misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs bleeding risk and major adverse events in patients with previous ulcer on oral anticoagulation therapy systematic review and metaanalysis: is 1-week proton pump inhibitor-based triple therapy sufficient to heal peptic ulcer? helicobacter pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer effect of population screening and treatment for helicobacter pylori on dyspepsia and quality of life in the community: a randomised controlled trial impact of helicobacter pylori eradication on dyspepsia, health resource use, and quality of life in the bristol helicobacter project: randomised controlled trial helicobacter pylori eradication as a strategy for preventing gastric cancer second asian-pacific consensus guidelines for helicobacter pylori eradication helicobacter pylori eradication for the prevention of gastric neoplasia helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis the global, regional, and national burden of stomach cancer in 195 countries, 1990-2017: a systematic analysis for the global burden of disease study a community screening program for helicobacter pylori saves money: 10-year follow-up of a randomised controlled trial the cost-effectiveness of population helicobacter pylori screening and treatment: a markov model using economic data from a randomised controlled trial clinical trial: prolonged beneficial effect of helicobacter pylori eradication on dyspepsia consultations -the bristol helicobacter project acg clinical guideline: treatment of helicobacter pylori infection effects of helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users meta-analysis: role of helicobacter pylori eradication in the prevention of peptic ulcer in nsaid users systematic reviews of the clinical effectiveness and costeffectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding guidelines for prevention of nsaid-related ulcer complications gastric mucosal defense and cytoprotection: bench to bedside effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: meta-analysis of randomised trials prevention of nsaid-induced gastroduodenal ulcers proton-pump inhibitors for the prevention of upper gastrointestinal bleeding in adults receiving antithrombotic therapy clopidogrel-based antithrombotic therapy for cardiovascular prevention: a systematic review and meta-analysis of randomized controlled trials safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin this trial suggested that ppi therapy reduced the risk of peptic ulcer and peptic ulcer bleeding, but the event rate was too low for this to be cost-effective in all patients taking anticoagulation proton pump inhibitors versus histamine 2 recpetor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and metaanalysis efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis comprehensive network meta-analysis of all treatment options to prevent stress ulcer bleeding in intensive care patients. acid suppressive therapy was effective but probably not beneficial in low risk patients medical treatments in the short term management of reflux oesophagitis complications of proton pump inhibitor therapy risk of community-acquired pneumonia and use of gastric acid suppressive drugs long-term proton pump inhibitor therapy and risk of hip fracture omeprazole as a risk factor for campylobacter gastroenteritis: casecontrol study proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patient with first time myocardial infarction: a nationwide propensity score matched analysis proton pump inhibitor use and risk of chronic kidney disease association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis long-term proton pump inhibitors and risk of gastric cancer development after treatment for helicobacter pylori: a population-based study risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of united states veterans use of proton pump inhibitors increases risk of incident kidney stones leaving no stone unturned in the search for adverse events associated with the use of proton pump inhibitors increased risk of covid-19 among users of proton pump inhibitors the risks of ppi therapy safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin this trial evaluated the safety of ppis with over 53,000 patients years of follow-up. there was no evidence of harm of ppis apart from risk of enteric infections and the data suggested that the various harms of ppi described in observational studies are likely to be overestimated long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the sopran and lotus studies esomeprazole and aspirin in barrett's oesophagus (aspect): a randomised factorial trial the first randomized trial evaluating ppi and aspirin to prevent progression of barrett's esophagus to neoplasia. if this trial started today there would be objection to such high doses of ppi being used for an average of 9 years, but mortality was reduced in the twice daily ppi group. the gi bleeding rate was very low in this trial giving nsaid induced gastrointestinal damage and designing gisparing nsaids efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials gastrointestinal safety of cyclooxygenase-2 inhibitors: a cochrane collaboration systematic review cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention cnt) collaboration. vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: metaanalyses of individual participant data from randomised trials aspirin and other nonsteroidal anti-inflammatory drugs for the prevention of dementia misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (masters): a randomised, double-blind, placebo-controlled, phase 3 trial framinghambased tools to calculate the global risk of coronary heart disease the toronto helicobacter pylori consensus in context reply predictors of gastrointestinal bleeding in adult icu patients: a systematic review and meta-analysis prevalence and predictors of inappropriate prescribing according to the screening tool of older people's prescriptions and screening tool to alert to right treatment version 2 criteria in older patients discharged from geriatric and internal medicine wards: a prospective observational multicenter study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-010884-g4gesvzt authors: heitzer, andrew m.; piercy, jamie c.; peters, brittany n.; mattes, allyssa m.; klarr, judith m.; batton, beau; ofen, noa; raz, sarah title: cumulative antenatal risk and kindergarten readiness in preterm-born preschoolers date: 2019-08-16 journal: j abnorm child psychol doi: 10.1007/s10802-019-00577-8 sha: doc_id: 10884 cord_uid: g4gesvzt a suboptimal intrauterine environment is thought to increase the probability of deviation from the typical neurodevelopmental trajectory, potentially contributing to the etiology of learning disorders. yet the cumulative influence of individual antenatal risk factors on emergent learning skills has not been sufficiently examined. we sought to determine whether antenatal complications, in aggregate, are a source of variability in preschoolers’ kindergarten readiness, and whether specific classes of antenatal risk play a prominent role. we recruited 160 preschoolers (85 girls; ages 3–4 years), born ≤33(6)/(7) weeks’ gestation, and reviewed their hospitalization records. kindergarten readiness skills were assessed with standardized intellectual, oral-language, prewriting, and prenumeracy tasks. cumulative antenatal risk was operationalized as the sum of complications identified out of nine common risks. these were also grouped into four classes in follow-up analyses: complications associated with intra-amniotic infection, placental insufficiency, endocrine dysfunction, and uteroplacental bleeding. linear mixed model analyses, adjusting for sociodemographic and medical background characteristics (socioeconomic status, sex, gestational age, and sum of perinatal complications) revealed an inverse relationship between the sum of antenatal complications and performance in three domains: intelligence, language, and prenumeracy (p = 0.003, 0.002, 0.005, respectively). each of the four classes of antenatal risk accounted for little variance, yet together they explained 10.5%, 9.8%, and 8.4% of the variance in the cognitive, literacy, and numeracy readiness domains, respectively. we conclude that an increase in the co-occurrence of antenatal complications is moderately linked to poorer kindergarten readiness skills even after statistical adjustment for perinatal risk. electronic supplementary material: the online version of this article (10.1007/s10802-019-00577-8) contains supplementary material, which is available to authorized users. born preschoolers and their term-born peers yielded poorer scores in the former group, regardless of gestational age. group differences have been documented in expressive and receptive language abilities as well as in visuomotor or graphomotor (preprinting) skills in both very preterm (foster-cohen et al. 2010; caravale et al. 2005; torrioli et al. 2000) and late-preterm (baron et al. 2009 ; baron et al. 2011) cohorts. establishing the nature of early biomedical risk factors that forecast deficits in critical academic precursor skills is essential for identification of preschoolers at risk for deviation from the typical neurodevelopmental trajectory. findings from a recent quantitative integration of the literature suggest that both preterm birth and adverse antenatal factors are important antecedents of intellectual disability diagnosed between 1 and 17 years of age (huang et al. 2016 ). yet few preschool outcome studies included within-group examination of the links between complications associated with preterm-birth and performance on neuropsychological tasks that tap domain-specific, literacy or numeracy, precursor skills. fostercohen et al. (2010) , focusing on the impact of peri-, and neonatal, but not antenatal, complications, reported no significant associations between several early risk factors (including the sum of perinatal complications) and language delay within a cohort of four-year-old preschoolers born very preterm. in a similar sample of preschoolers born <34 weeks gestation torrioli et al. (2000) were able to document a significant relationship between a single major antenatal complication, intrauterine growth restriction, and intelligence (but not visual-motor integration). consistent with the prevailing fetal programming framework (barker 1998) , conditions or risks originating in-utero have the unique capacity to modify long-term physical health and behavioral outcome. though the exact mechanisms leading to disease or cognitive-behavioral deficits have yet to be specified, it has been suggested that fetal adaptation to environmental stress may involve vascular, metabolic or endocrine changes that permanently alter bodily structure or function (hocher et al. 2001) . antenatal perturbations are likely transmitted to the infant through their effects on placental function. the latter, in turn, adversely influences fetal and postnatal brain development and cognitive-behavioral outcome (zeltser and leibel 2011; buss et al. 2012; davis and sandman 2012) . within the high-risk group of preterm-born children, both the variability in the base-rates of various antenatal complications associated with prematurity and the sheer number of medical risk factors that require consideration often impede exploration of developmental outcome effects of early biological adversity. additionally, the developmental impact of discrete medical complications is probably cumulative (shalev et al. 2014) . cumulative risk indices may show increased stability across developmental periods, accounting for more outcome variability between individuals than specific complications (wade et al. 2015) . aggregate scores that reflect cumulative risk associated with a distinct early risk epoch may be increasingly sensitive compared to discrete complications that are likely linked to small effects that are difficult to detect (whitehouse et al. 2014) . although the influence of cumulative perinatal risk on developmental outcome of preterm children has received some consideration (e.g., carmody et al. 2006; foster-cohen et al. 2010) , the effects of cumulative antenatal risk in this vulnerable group remain essentially unexplored. hence, our chief objective was to examine the combined contribution of common antenatal complications to explaining individual differences in academic (kindergarten) readiness within a preterm-born cohort. in addition to gauging intellectual abilities, we evaluated language skills as precursors of reading attainment, visual-motor integration skills as antecedents of writing-skill development, and early number concepts as the preschool forerunners of math achievement. we predicted that degree of antenatal risk in preterm-born preschoolers will be inversely related to both general cognitive, and domain-specific, neuropsychological skills that provide the basis for scholastic achievement. preterm-born children (< 34 weeks' gestation) were recruited for the study between 3 and 4 years of age and evaluated between may 2011-july 2016. the children were born at william beaumont hospital (wbh), royal oak, mi, in 2007 mi, in -2012 , and treated in the neonatal intensive care unit (nicu). at wbh-nicu resuscitation is attempted for all infants with an estimated gestational age ≥ 23 0 / 7 weeks (batton et al. 2011) . children with congenital anomalies, or who required mechanical ventilation after discharge, were excluded from the retrospectively identified nicu cohort matching our inclusion criteria. the families of 41.63% of 860 cases could still be reached for recruitment attempt based on contact information provided at the time of birth (see online resource 1). of these, families of 38.27% cases were not interested, for multiple reasons. in accord with wbh human investigation committee guidelines nonparticipating families were not specifically queried, yet amongst common reasons spontaneously provided by families for nonparticipation were being "too busy", residing too far away or not wanting to travel from suburban areas to the city. families of 51 additional cases (14.24% of those successfully contacted) "no-showed" for the schedule assessment twice and were not rescheduled. the 170 available participants constituted 51.20% of the pool of cases whose families could be contacted between 3 and 4 years of age. of 170 evaluated cases ten were excluded from data analyses, five with suspected antenatal substance exposure and five with missing background medical information pertinent to this investigation. altogether 160 cases were available for this study (see table 1 for sociodemographic characteristics). as the table shows, our sample included participants from a very broad socioeconomic range. nonetheless, the relatively high mean ses (48.6 of 66 possible points; sd = 10.00) reflects the composition of the catchment area of wbh. this region includes primarily middle social strata, thereby minimizing the possibility of confounding the effects of antenatal risk with other adverse environmental factors associated with socioeconomic status. correspondingly, about 85% of nicu admissions were covered by private medical insurance and only 15% by medicaid. additionally, 78.1% of the mothers and 62.3% of the fathers attained a college degree. the final sample included 75 (46.9%) boys and 28 (17.5%) participants of african-american descent. the proportion of males to females in our sample (46.9%: 53.1%) was not significantly different from the proportion observed in the remaining portion of the total relevant nicu cohort from which we attempted to recruit (53.14%: 46.86%; χ 2 [1] = 2.05, p = 0.15). the proportion of singletons to multiples in our sample (56.3%: 43.8%) was also not significantly different from the proportion observed in the remainder of the total cohort (60.71%: 39.29%; χ 2 [1] = 1.08, p = 0.30). information about racial distribution was available for two thirds of the total relevant cohort. as noted above, our sample included 17.5% african americans, a somewhat smaller proportion than that observed in the remainder of the relevant nicu cohort (24.16%;χ 2 [1] = 3.01, p = .08). the mean gestational age (30.4 ± 2.6 weeks) and birth weight (1,424 ± 457 g) in our sample approximated the mean gestational age (29.8 ± 2.8 weeks) and birth weight (1,434.3 ± 513 g) available for the total relevant cohort. likewise, the length of stay was also similar for our sample (43.42 ± 34.17 days) and the total cohort (42.9 ± 34.5 days), and the proportion of children requiring ventilation in our sample was not statistically different from that observed in the remaining portion of the total cohort (36.5% vs. 38.57%; χ 2 [1] = 0.29, p = 0.585). according to parental report, none of the children had sustained a severe head injury with loss of consciousness. postnatal seizure history was reported for 11 cases, yet only three required anticonvulsant medications. whereas the intellectual abilities of two of these three children fell well within the average range, the remaining case manifested severe intellectual deficits. as table 1 shows, ninety participants were singletons and seventy were products of multiple pregnancy. sixty-four multiples were co-members of twinships or triplets and therefore shared antenatal risk. descriptive statistics regarding pregnancy and perinatal risk in our sample were based on data obtained retrospectively from hospital records ( table 2 ). additional information regarding intervention procedures is provided in online resource 2. gestational age in our sample ranged from 23 4 / 7 -33 6 / 7 weeks and was determined by maternal dates and confirmed by early prenatal ultrasound in >95% of cases. three children with cp diagnosis (spastic diplegia) were included in the sample. additionally, there were three cases with perinatal diagnoses of grade iii intraventricular hemorrhage, one with grade iv, one with periventricular leukomalacia (pvl), one with both pvl and subsequent cerebral palsy (spastic diplegia), and one with grade iv hemorrhage coupled with hydrocephalus (requiring reservoir placement). adding the aforementioned single seizure case with severe intellectual impairment, the "significant brain injury" subgroup included 11 cases. importantly, statistical analyses were performed both with and without these cases. general assessment considerations evaluations were conducted between 2011 and 2016 by clinical psychology graduate students who had been extensively trained in developmental neuropsychological assessment. they were kept uninformed about participants' medical background data, with the single exception of being aware that the children were nicu graduates. all testing and other data collection procedures were conducted in compliance with ethical standards of the helsinki 1964 declaration and its later amendments, as well kramer et al. (2001) i summary score for the nine above listed antenatal complications with sample frequency > 5% j includes any atypical presentations (breech, transverse lie, footling, etc.) k arterial cord ph examined for 130 participants, arterial ph below 7.1 was recorded (n = 3). when only venous cord ph was available (n = 21), venous ph below 7.2 was recorded (n = 1). for four cases, initial capillary blood below 7.2 was recorded (n = 1), whereas acid-base information was unavailable for five cases l as determined by obstetrician; > 95% of cases were corroborated by antenatal ultrasound. distribution: 33 cases ≤28 0 / 7 weeks (20.62%) + 31 cases ≤30 0 / 7 weeks (19.37%) + 62 cases <32 6 / 7 weeks (38.75%), + 34 cases ≤33 6 / 7 weeks (21.25%) m initial hematocrit <40% n established by positive blood culture o chronic lung disease: supplemental oxygen required at 36 weeks gestation or discharge for infants <32 weeks gestation. no cases were observed in this sample with gestational age ≥ 32 weeks p based on a chest roentgenogram and clinical evaluation q peak bilirubin ≥12 mg/dl r diagnosed at least once during nicu stay s documented on the basis of cranial ultrasound. (mild = bleed grade 1&2; severe = grade 3&4 using grading criteria by volpe, 2001) . routine cranial ultrasound given to all infants with gestational age ≤ 32 weeks, and when clinically indicated to infants with gestational age > 32 weeks. there were twenty cases (12.5%) with mild brain bleeds (sixteen grade i and four grade ii) and seven (4.4%) with severe intracranial pathology, including three grade iii intraventricular hemorrhage, two grade iv (one requiring shunt), and two cases with periventricular leukomalacia t infants discharged on the ventilator were not included in the current study u diagnosed by clinical manifestations and echocardiographic information v summary score for the nine above listed perinatal complications with sample frequency > 5% w the rate of severe retinopathy of prematurity (> stage 2) in the total sample was 4.11%, below our inclusion cutoff (one cases with stage iii, four cases with stage iii+, and two cases with stage iv) and there were no cases with grade iv rop after exclusion of eleven cases with significant neurological background. all cases with stage iii+ and stage iv had received laser treatment (wechsler 2002) . prereading skills language skills were assessed using the core language (cl) score from the clinical evaluation of language fundamentals-preschool (celf-p2; wiig et al. 2004 ). the cl stability coefficient for ages 3:0-3:11 is high (r 12 = 0.87), whereas internal consistency and split-half reliability are excellent (r xx = 0.91 and 0.92, respectively). the cl scale is comprised of three subtests: sentence structure, word structure, and expressive vocabulary. prenumeracy skills quantitative knowledge and reasoning were measured using the applied problems (ap) subtest from the woodcock johnson (wj-iii) tests of achievement (woodcock et al. 2001) . at the prekindergarten level, ap assesses emergent counting, addition, and subtraction skills. the split-half reliability for ages 3 and 4 is excellent (r 11 = 0.92 and 0.94, respectively), and test-retest correlations range from r 12 = 0.85-.90 for ages 2-7 (woodcock et al. 2001) . quantitative concepts (qc), another wj-iii task that may be administered at three years of age does not possess an adequate floor (alfonso and flanagan 2002) , and was therefore not included. preprinting skills eye-hand coordination skills were assessed using the visual-motor integration (vmi) subtest from the peabody developmental motor scales (pdms-2; folio and fewell 2000) . the vmi includes items that require reaching and grasping, building with blocks, or copying designs. internal consistency reliability for 36-47 months of age is excellent (r 11 = 0.94), whereas the overall test-retest (r 12 = 0.92) and inter-scorer (r 11 = 0.98) reliability coefficients are also exceptionally high (folio and fewell 2000) . descriptive information for performance measures the mean fsiq, cl, and vmi scores (±sd) of our participants fell well within the average range on three of the four readiness measures (107.83 ± 17.62, 106.43 ± 13.60, and 10.73 ± 2.91, respectively), whereas mean ap score fell above average (116.71 ± 13.55). these favorable results are likely attributable to the preponderantly middle-class background of our sample. notably, participants' scores spanned a broad range (with similar ranges and sd's for ap and cl) and it was our goal to explore the contribution of antenatal risk to explaining this variability. all standard scores were corrected for prematurity. the recalculation of the preterm preschooler's age-at-testing as time elapsed since the expected date of delivery allows one to derive standard scores based on age-reference norms of typical children who are similar in biological maturity. additional descriptive data for the total-, and subsample without significant brain injury may be found in online resource 3. cumulative antenatal risk consistent with the fetal programming hypothesis, our chief variable of interest was cumulative antenatal risk, operationalized as an index comprised of equally weighted complications. we included nine major complications with sample frequency > 5% (see table 2 ) and with well documented relationships to unfavorable neonatal outcome or neurobehavioral sequelae. hence, for each participant we summed the identified complications, out of the nine relatively common antenatal risks, with the following sample distribution: 0 (15%), 1 (40.62%), 2 (27.50%), 3 (13.75%) and 4 (3.10%). no cases were observed with frequency ≥ 5 complications. the correlations between pairs of antenatal complications were moderate at best, suggesting that the information provided by discrete complications was not redundant. the strongest relationship was observed between diagnosis of histological chorioamnionitis and pprom latency duration (time between membrane rupture and birth) > 12 h (r = 0.489; p < 0.001). cumulative perinatal risk a cumulative perinatal risk score was also computed and was included as a covariate. nine major perinatal complications with sample frequency > 5% provided the basis for the perinatal summary score (see table 2 ). abnormal presentation was not included because this complication is thought to exert little influence on longterm outcome (eide et al. 2005) and since the potentially unfavorable outcome effects are believed to be the result of confounding with the effects of prematurity or gestational age (ismail et al. 1999 ). the latter variable was taken into account as a separate risk factor in this study. background medical information was obtained retrospectively from the mother's labor and delivery hospitalization as well as the nicu records. intra-class correlations (icc-2; shrout and fleiss 1979) for the antenatal and the perinatal complications composite scores were excellent, owing in part to the ease and efficiency of searching electronic records. based on two independent and trained medical records reviewers, icc equaled or approached unity for ten cases (icc [9] = 1.00, and 0.98, for antenatal and perinatal composites, respectively). construct validity of the two summary scores was established in the singletons subsample (n = 90) by examination of the associations between the cumulative antenatal risk score and birth weight, an index of fetal growth and well-being, and between the cumulative perinatal risk score and both length of nicu stay and days on the ventilator, two indexes of need for medical intervention. in addition to the 90 singletons and seven single-members of twin pairs, our sample included 27 sets of co-twins and three sets of co-triplets. to capture the correlation between participants within sets of multiples, we used spss 24.0 mixed (maximum likelihood) to fit separate linear mixed effects models for each outcome variable, with multiplicity (cases from the same birth mother) as a random effect. thus, the individual multiples nested within each set were conceptualized as replications and were given a random block number that was unique, but identical for set members. in contrast, singleton children or multiples without an evaluated co-multiple had no replicates and were considered random block with size 1. this model enabled both co-multiples and singletons to be used in the same analysis without either violating independence assumptions or, alternatively, discarding important information by including only a single member of each set. the variable of interest, antenatal risk (the sum of antenatal complications), was entered together with sociodemographic covariates, sex and ses (hollingshead 1975 ), into the model. the hollingshead index is a composite score reflecting family social status. the score is based on four factors: parental marital status, employment status, educational attainment and occupational prestige. two additional covariates were entered to capture the influence of perinatal risk: gestational age and the perinatal complications summary score (see table 2 ). birth weight was highly correlated with gestational age and was therefore not included (r = 0.82; p < 0.001). hence, the effect of antenatal risk on readiness was statistically adjusted for influence of four covariates, with all five predictors entered simultaneously into the model. information about bivariate correlations among the five predictors may be found in online resource 4. one should note here that a fifth covariate, iq test edition, was used in analyses of cognitive outcome. the predicted variables were the cognitive (prorated fsiq) and pre-academic (celf-p2 cl score, wj-iii ap subtest score, and pdms-2 vmi score) measures of kindergarten readiness corrected for degree of prematurity. information about the correlations between the five predictors and four outcome measures is presented in online resource 5. three (1.9%) of the 160 participants were unable to complete any of the tasks included in this evaluation (two cases with cp and a single case without significant neurological findings who required >4.5 months on the respirator at birth). of the 148 children without significant brain injury who completed at least one task, a minority of cases failed to complete the tasks needed to obtain a score on one or more of the four preacademic performance indices (n = 1 [0.6%], 8 [5.4%], 14 [9.4%], and 6 [4.0%] cases for fsiq, cl, ap, and vmi, respectively). due to the children's young age, it was difficult, if not impossible, to ascertain the causes of failure to attempt or follow instructions for specific subtests. examination of the correlates of the sum of incomplete subtests per participant r e v e a l e d s i g n i f i c a n t a s s o c i a t i o n s n e i t h e r w i t h sociodemographic variables (r[158] = −.102 and − .100 for ses and sex; p = .199 and .207, respectively) nor with preschool attendance (r[155] = 0.084; p = 0.296). in contrast, a significant inverse relationship between the number of incomplete subtests and the fsiq was observed (r[156] = −.48, p < 0.001). to avoid bias resulting from potential influence of the missing subtest scores, we applied multiple imputation to replace these performance data. the results of data analyses are reported both before and after exclusion of cases with significant brain injury. prior to data analyses, interactions between sex and the remaining predictors were examined for all outcome measures. as none of the interactions were significant (all p values > .15), the reduced models were used. follow-up analyses were conducted to explore whether any observed associations between antenatal risk and kindergarten readiness were attributable to a particular class of complications. hence we grouped the nine antenatal complications comprising the summary score (table 2 ) into four categories. these four groupings were based on shared etiological pathways, or shared antepartum symptoms coupled with at least some shared antecedents. specifically, complications associated with either (1). intra-amniotic infection and inflammation (histologic chorioamnionitis and membranes ruptured >12 h; e.g., stock et al. 2015); (2). placental insufficiency (hypertension in pregnancy, hellp syndrome, and iugr; e.g., stepan et al. 2005) ; (3). maternal endocrine dysfunction (hypothyroid and diabetes; e.g., haddow et al. 2016) or (4). uteroplacental bleeding (abruption and previa; e.g., berhan 2014; getahun et al. 2006) . category scores were then assigned to participants based on the sum of complications accumulated within each class of antenatal risk. the data were then reanalyzed using the same sociodemographic and medical variables as covariates; however, we substituted the four sums of risk scores for the single composite sum of nine antenatal complications. table 3 shows analyses of performance for the total sample and for the subsample without significant brain injury cases. as shown, the antenatal complications score was inversely related to the fsiq, both before (p = 0.002) and after (p = 0.003) exclusion of brain injury cases. analyses of preacademic performance revealed similar associations between antenatal risk and both cl and ap scores, before (p = 0.001 and p = 0.001, respectively) and after (p = .002 and p = 0.005, respectively) excluding brain injury cases. no significant relationships were observed between cumulative antenatal risk and the vmi, yet the vmi was linked to gestational age (p = 0.042 and 0.012). added variable plots, depicting relationships between residualized antenatal risk scores and outcome of the remaining 157 cases, two failed to obtain a score on the fsiq (one with brain injury), nine on cl (3 with brain injury), seventeen on ap (three with brain injury), six on the vmi. f of the 148 "non-neurological" cases completing tasks required for a score on at least one of the four outcome measures, one (.06%) could not obtain a score on the fsiq, six (4.05%) on cl, fourteen (9.45%) on ap, six (4.05%) on the vmi. g computation of δr 2 based on snijders and bosker (1999, pp. 102-103) . h antenatal complications score is a composite of presence (=1) vs. absence (=0) of nine complications: placental abruption, placenta previa, chorioamnionitis, diabetes, hypertension in pregnancy, hellp syndrome (hemolysis, elevated liver enzymes, low platelet count), hypothyroidism, preterm premature rupture of the membranes (pprom) > 12 h, and intrauterine growth restriction. i due to the paucity of cases with four antenatal complications, analyses were repeated with three and four complications combined into a single category ( table 4 shows the relative contribution of each of the four categories of antenatal risk to the four performance measures; the proportion of variance explained (δr 2 ) is provided for statistical effects with p < 0.10. as the table reveals, intraamniotic infection risk was significantly related to the fsiq (p = 0.016), cl (p =0. 043), and ap (p =0. 012), whereas conditions associated with placental insufficiency were significantly related to cl (p = 0.047), with trends for associations with the fsiq and ap (p = 0.071 and 0.064, respectively). maternal endocrine dysfunction was associated with cl (p = 0.040), and disorders associated with uteroplacental bleeding were significantly related to the fsiq (p = 0.048). following statistical adjustment for sociodemographic and perinatal confounds, the sum of nine, relatively common, antenatal complications remained a significant source of variability in preterm-born preschoolers' cognitive and academic performance. exploration of the relative outcome contribution of four classes of antenatal risk revealed that complications associated with intra-amniotic infection, placental insufficiency and uteroplacental bleeding accounted for 4.8%, 2.3% and 3.4% of iq variance, respectively, altogether 10.5% of variability in kindergarten cognitive readiness. similarly, complications associated with maternal endocrine dysfunction, intraamniotic infection, and placental insufficiency accounted for 3.8%, 3.3% and 2.7%, of the variance in language skills, respectively, altogether 9.8% of variability in literacy readiness. complications associated with intra-amniotic infection risk and placental insufficiency contributed 5.9% and 2.5% of the variance in early number concepts, respectively, a combined share of 8.4% to variability in numeracy readiness. hence, when considered separately, each of the four risk categories accounts for a small slice of outcome variance in one or more preacademic domains (except visual-motor integration). yet in aggregate they accounted for 8.4-10.5% of the variance in kindergarten readiness of preschoolers free of major handicaps, consistent with effect sizes of moderate magnitude (cohen 1992) . interestingly, amongst the four categories of antenatal risk examined here, intra-amniotic infection was the most consistent contributor to kindergarten readiness. these findings are compatible with recent evidence that inflammation, including chorioamnionitis, contributes to preterm cns injury and is also an independent risk factor for brain injury in the term infant (yellowhair et al. 2018) . these results are also consistent with reports of marked increase in the probability of unexplained cerebral palsy in the presence of antenatal inflammation-infection (horvath et al. 2012) . in this context, one should note that a sizeable proportion of the mothers in our sample received antibiotics prophylaxis for prevention of early onset neonatal infection (see online resource 2). in a recent integrative review of the literature, braye et al. (2018) highlighted the observed decrease in incidence of early onset infection since the introduction of intrapartum antibiotic prophylaxis, as well as findings of randomized controlled studies documenting effectiveness. at the same time, however, braye and colleagues emphasized that the longer-term health implications of prophylaxis for early onset infection are unknown. it is difficult, therefore, if not impossible, to draw conclusions regarding the potential implications of antibiotic prophylaxis on kindergarten readiness until such data become available. nonetheless, our findings revealed that each of the four classes of antenatal risk studied here contributed significantly to explaining performance variance on one or more kindergarten readiness domains. the putative influence of each antenatal risk category on brain maturation trajectory and cognitivebehavioral development may be conceptualized within the broad framework of fetal programming of disease (buss et al. 2012; zeltser and leibel 2011; myatt 2006; andersen et al. 2014; miller et al. 2016; godfrey 2002) . however, the biological mechanisms mediating the relationship between cumulative antenatal risk and kindergarten readiness require specification. antenatal stressors lead to placental adaptive responses to the variations in the maternal-fetal environment (myatt 2006) . these responses, in turn, are followed by fetal adaptations expressed via vascular, metabolic or endocrine changes that permanently modify bodily structure or function (hocher et al. 2001 ). the precise nature and sequence of the biological changes mediating deficits in cognitive-behavioral functioning have yet to be elucidated. to accomplish this goal, future investigations should incorporate measures of potential sequential mediators, including indexes of placental size or function, intrauterine cerebral development, and postnatal brain structure or function. our findings are consistent with zeltser and leibel's (2011) observations that dissimilar intrauterine stress factors may nonetheless lead to similar fetal outcomes because they activate related mechanisms of placental adaptation (fowden et al. 2009 ) which, in turn, shape the trajectory of fetal brain development (buss et al. 2012) . the thesis that diverse insults converge on similar unfavorable outcomes (a relationship mediated by fetal brain programming) is compatible with the notion that the amalgamation of antenatal complications into a single index or several classes of risk may offer an important tool for the study of individual differences among pretermborn children in the severity of neurocognitive deficits. antenatal complications contributed less than ses to explaining outcome variance, although effect magnitude was typically moderate for both variables. girls outperformed boys on all measures, consistent with other reports of female outcome advantage following preterm birth (lauterbach et al. 2001 ). similar to fostercohen et al. (2010) , we did not find significant associations between the sum of perinatal complications and kindergarten readiness in this young age group. however, gestational age, often considered a proxy for perinatal risk, was found to be linked to development of visualmotor integration skills even after we excluded cases with evidence of significant brain injury from the analyses. additionally, there was a weak trend (p < 0.15; table 3 ) for a relationship between gestational age and global intellectual skills. the absence of the oft-reported significant relationships between the degree of prematurity and the remaining outcome measures (e.g., heuvelman et al. 2018 ; a recent epidemiological investigation) was somewhat unexpected. it is possible that within a restricted gestational age range, where values ≥34 weeks were truncated, the relationships between gestational age and preschool performance are more difficult to demonstrate whereas the adverse influence of other risk scales-2. f perinatal complications score is a composite score reflecting presence (=1) vs. absence (=0) of nine complications: anemia, bronchopulmonary dysplasia, bacterial infection, hyaline membrane disease, hyperbilirubinemia, hypoglycemia, intracranial pathology, patent ductus arteriosus, and supplemental oxygen requirement following discharge. g intra-amniotic infection risk score is a composite of two complications believed to share etiological pathways: preterm premature rupture of membranes (pprom) > 12 h and histological chorioamnionitis. h placental insufficiency score is a composite of three complications thought to share etiological pathways: maternal hypertension, hellp syndrome (hemolysis, elevated liver enzymes, low platelet count), and intrauterine growth restriction. i maternal endocrine dysfunction score is a composite of two complications found to share some etiological pathways: maternal diabetes and hypothyroidism. j uteroplacental bleeding risk score is a composite of two complications sharing antenatal symptomatology: placental abruption and placenta previa factors (e.g., antenatal complications) becomes more apparent. interestingly, the absence of gestational age effects on several performance measures employed here seems consistent with findings from a recent meta-analysis of the long-term cognitive and academic performance of children born with various degrees of prematurity (allotey et al. 2018 ). the quantitative integration revealed a miniscule, if any, effect of lower gestational age. children born between 28 and 34 weeks performed almost as poorly as those born <28 weeks. as noted earlier, our findings of an association between cumulative antenatal risk and kindergarten readiness are consistent with the fetal programming hypothesis. researchers of fetal programming have typically studied the role of the prenatal environment without taking into consideration the perinatal, or postnatal environment (grant et al. 2015 ). in the current study, however, we statistically adjusted cumulative antenatal risk for perinatal complications and for socioeconomic status in effort to account for confounding influences occurring after birth. limitations of this study include the retrospective nature of the participant identification and recruitment component. medical data were also collected retrospectively, yet interrater reliability for information obtained from medical records was excellent. the difficulty of a small number of participants to complete various tasks is not surprising, given the combination of young age and increased biomedical risk in our sample. the percentage of missing outcome data for the 148 children without significant neurological injury completing ≥ one task ranged from negligible (0.06%) for cognitive readiness (fsiq) to moderate (9.45%) for numerical readiness (ap). the amount of missing data for three of the four outcome measures was nonetheless small (< 5.0%). although our sample included children with a wide range of socioeconomic circumstances, the mean ses and educational characteristics of the sample revealed a greater representation of middle-class strata, thereby reducing the potentially confounding effects of socioeconomic adversity on kindergarten readiness. nonetheless, because to some extent generalizability to lower strata was traded-off for improved internal validity, our findings may have underestimated statistical effects in samples with greater representation of the lower end of the socioeconomic scale. the cross-sectional nature of this investigation precluded examination of the generalizability of the findings to elementary school readiness and beyond. in the current investigation antenatal risk accounted for up to 10.5% of the variance in kindergarten readiness. antenatal risk estimation was based on a simple frequency count of common complications. a more sensitive measure of risk may be developed to take the severity of discrete complications within each of the four antenatal risk categories examined here into account. increased sensitivity, in turn, may serve to enhance the magnitude of the statistical effects observed here between antenatal risk and emergent academic skills. as noted above, we statistically adjusted for degree of gestational maturity and for the presence of nine common perinatal risk factors (table 2 ) in order to estimate the unique portion of outcome variance that is attributable to cumulative antenatal risk. we further examined the data with and without 'neurological' cases, based on both ultrasound evidence obtained in the nicu and subsequent evidence of cerebral palsy. nonetheless, one may argue that the full effect of confounding perinatal risk factors such as chronic lung disease or germinal matrix hemorrhage may become evident in the longer term only, when academic performance demands are increased. a longitudinal study of educational attainment is best suited to address this issue. the significance of early academic skills as the foundation of scholastic achievement has been established in multiple follow-up investigations of typical kindergartners to the early school years (e.g., pagani et al. 2010; romano et al. 2010; grissmer et al. 2010) . moreover, developmental continuity has been demonstrated between preschool quantitative and oral-language skills and elementary school attainment in math and reading, in a variety of student populations (e.g., davison et al. 2011; manfra et al. 2014; manfra et al. 2017; nguyen et al. 2016) . the existence of robust developmental continuity between pre-academic and academic skill levels supports the notion that the same factors that explain variability in emergent academic skills also account for variability in mastery of both the reading process and basic arithmetic in the early elementary-school years. based on our findings, it is therefore likely that differences in scholastic achievement among graduates of the nicu are partly explained by cumulative 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corporation the effect of placenta previa on fetal growth and pregnancy outcome, in correlation with placental pathology prenatal, perinatal, and neonatal risk factors for specific language impairment: a prospective pregnancy cohort study clinical evaluation of language fundamentals: preschool-2 woodcock-johnson tests of achievement preclinical chorioamnionitis dysregulates cxcl1/cxcr2 signaling throughout the placentalfetal-brain axis roles of the placenta in fetal brain development acknowledgements the authors thank beth kring and tammy swails for their help in data collection. evaluations and testing materials were funded in part by the merrill-palmer skillman institute. none of the authors has a known conflict of interest concerning this manuscript.funding this work was supported in part by funding from the merrill palmer skillman institute, wayne state university, 71 east ferry, detroit, mi 48202. key: cord-025366-haf542y0 authors: offit, paul a.; destefano, frank title: vaccine safety date: 2012-11-07 journal: vaccines doi: 10.1016/b978-1-4557-0090-5.00076-8 sha: doc_id: 25366 cord_uid: haf542y0 nan during the past 100 years, pharmaceutical companies have made vaccines against pertussis, polio, measles, rubella, and haemophilus influenzae type b (hib), among others ( table 76-1 ) . as a consequence, the number of children in the united states killed by pertussis decreased from 8,000 each year in the early 20th century to fewer than 20; the number paralyzed by polio from 15,000 to 0; the number killed by measles from 3,000 to 0; the number with severe birth defects caused by rubella from 20,000 to 0; and the number with meningitis and bloodstream infections caused by hib from 20,000 to fewer than 300. vaccines have been among the most powerful forces in determining how long we live. 1 but the landscape of vaccines is also littered with tragedy: in the late 1800s, starting with louis pasteur, scientists made rabies vaccines using cells from nervous tissue (such as animal brains and spinal cords); the vaccine prevented a uniformly fatal infection, but the rabies vaccine also caused seizures, paralysis, and coma in as many as 1 of every 230 people who used it. [2] [3] [4] [5] in 1942, the military injected hundreds of thousands of american servicemen with a yellow fever vaccine. to stabilize the vaccine virus, scientists added human serum. unfortunately, some of the serum came from people unknowingly infected with hepatitis b virus. as a consequence, 330,000 soldiers were infected, severe hepatitis developed in 50,000, and 62 died. [6] [7] [8] [9] in 1955, five companies made jonas salk's new formaldehydeinactivated polio vaccine. however, one company, cutter laboratories of berkeley, california, failed to completely inactivate poliovirus with formaldehyde. because of this problem, 120,000 children were inadvertently injected with live, dangerous poliovirus; in 40,000, mild polio developed, 200 were permanently paralyzed, and 10 were killed. it was one of the worst biological disasters in american history. 10 vaccines have also caused uncommon but severe adverse events not associated with production errors. for example, acute encephalopathy after whole-cell pertussis vaccine, 11, 12 acute arthropathy following rubella vaccine, 13-17 thrombocytopenia following measles-containing vaccine, 18, 19 guillain-barré syndrome (gbs) after swine flu vaccine, 20 paralytic polio following live attenuated oral polio vaccine, 21 anaphylaxis following receipt of vaccines containing egg proteins (ie, influenza and yellow fever vaccines), 22, 23 severe or fatal viscerotropic disease following yellow fever vaccine, 24 possible narcolepsy following a squalene-adjuvanted influenza vaccine, 25 and severe allergic reactions associated with gelatin contained in the measles-mumps-rubella vaccine 26 are problems associated with the use of vaccines, albeit rarely. as vaccine use increases and the incidence of vaccine-preventable diseases is reduced, vaccine-related adverse events become more prominent in vaccination decisions ( figure 76-1 ) . even unfounded safety concerns can lead to decreased vaccine acceptance and resurgence of vaccine-preventable diseases, as occurred in the 1970s and 1980s as a public reaction to allegations that the wholecell pertussis vaccine caused encephalopathy and brain damage ( figure 76 -1 ). recent outbreaks of measles, mumps, and pertussis in the united states are important reminders of how immunization delays and refusals can result in resurgences of vaccine-preventable diseases. 27-30 because vaccines are given to healthy children and adults, a higher standard of safety is generally expected of immunizations compared with other medical interventions. tolerance of adverse reactions to pharmaceutical products (eg, vaccines, contraceptives) given to healthy people-especially healthy infants and toddlers-to prevent certain conditions is substantially lower than to products (eg, antibiotics, insulin) used to treat people who are sick. 31 this lower tolerance for risks from vaccines translates into a need to investigate the possible causes of much rarer adverse events after vaccinations than would be acceptable for other pharmaceutical products. for example, side effects are essentially universal for cancer chemotherapy, and 10% to 30% of people receiving high-dose aspirin therapy experience gastrointestinal symptoms. 32 safety monitoring can be done before and after vaccine licensure, with slightly different goals based on the methodological strengths and weaknesses of each step. 33-36 although the general principles are similar irrespective of country, the specific approaches may differ because of factors such as how immunization services are organized and the level of resources available. 37 vaccines, similar to other pharmaceutical products, undergo extensive safety and efficacy evaluations in the laboratory, in animals, and in phased human clinical trials before licensure. 38, 39 phase 1 trials usually include fewer than 20 participants and can detect only extremely common adverse events. phase 2 trials generally enroll 50 to several hundred people. when carefully coordinated, as in the comparative infant diphtheria and tetanus toxoids and acellular pertussis (dtap) vaccine trials, 40 important insight into the relationship between concentration of antigen, number of vaccine components, formulation, effect of successive doses, and profile of common reactions can be drawn and can affect the choice of the candidate vaccines for phase 3 trials. 41, 42 sample sizes for phase 3 vaccine trials are based principally on efficacy considerations, with safety inferences drawn to the extent possible based on the sample size (approximately 10 3 to 10 5 ) and the duration of observation (often < 30 days). 41 typically only observations of common local and systemic reactions (eg, injection site swelling, fever, fussiness) have been feasible. the experimental design of most phase 1 to 3 clinical trials includes a control group (a placebo or an alternative vaccine) and detection of adverse events by researchers in a consistent manner "blinded" to which vaccine the patient received. this allows relatively straightforward inferences on the causal relationship between most adverse events and vaccination. 43 several ways of enhancing prelicensure safety assessment of vaccines have been developed. one of these ways includes the brighton collaboration ( www.brightoncollaboration.org ), established to develop and implement globally accepted standard case definitions for assessing adverse events following immunizations in prelicensure and postlicensure settings. 44 without such standards, it was difficult if not impossible to compare and collate safety data across trials in a valid manner. for example, in the large multisite phase 3 infant dtap trials, definitions of high fever across trials varied by temperature (39.5°c vs 40.5°c), measurement (oral vs rectal), and time (measured at 48 vs 72 hours). 45 this was unfortunate because standardized case definitions had been developed in these trials for efficacy but not for safety, even though the safety concerns provided the original impetus for the development of dtap. 46, 47 the brighton case definitions for each adverse event are further arrayed by the level of evidence provided (insufficient, low, intermediate, and highest); therefore, they also can be used in settings with fewer resources (eg, studies in less developed settings or postlicensure surveillance). another of the recent advances to prelicensure safety assessments of vaccines has stemmed from the recognition of the need for much larger safety and efficacy trials before licensure. because of pragmatic limits on the sample sizes of prelicensure studies, there are inherent limitations to the extent to which they can detect very rare, yet real, adverse events related to vaccination. even if no adverse event has been observed in a trial of 10,000 vaccinees, one can only be reasonably certain that the real incidence of the adverse event is no higher than 1 in 3,333 vaccinees. 48 thus, to be able to detect an attributable risk of 1 per 10,000 vaccinees (eg, such as the approximate risk found for intussusception in the postlicensure evaluation of rotashield vaccine), a prelicensure trial of at least 30,000 vaccinees and 30,000 control subjects is needed. both second-generation rotavirus vaccines (rotateq and rotarix) were subjected to phase 3 trials that included at least 60,000 infants. 49, 50 while these trials were adequately powered to detect the problem with intussusception found following rotashield, in general, the cost of such large trials might limit the number of vaccine candidates that go through this process in the future. 51 because rare reactions, reactions with delayed onset, or reactions in subpopulations may not be detected before vaccines are licensed, postlicensure evaluation of vaccine safety is critical. historically, this evaluation has relied on passive surveillance and ad hoc epidemiologic studies, but, more recently, phase 4 trials and preestablished large linked databases have improved the methodological capabilities to study rare risks of specific immunizations. 43 such systems may detect variation in rates of adverse events by manufacturer 52,53 or specific lot. 54 more recently, clinical centers for the study of immunization safety have emerged as another useful infrastructure to advance our knowledge about safety. 55 in contrast with the methodological strengths of prelicensure randomized trials, however, postlicensure observational studies of vaccine safety pose a formidable set of methodological difficulties. 56 confounding by contraindication is especially problematic for nonexperimental designs. specifically, persons who do not receive vaccine (eg, because of a chronic or transient medical contraindication or low socioeconomic group) may have a different risk for an adverse event than vaccinated persons (eg, background rates of seizures or sudden infant death syndrome (sids) may be higher in unvaccinated people). therefore, direct comparisons of vaccinated and unvaccinated children are often inherently confounded, and teasing this issue out requires understanding of the complex interactions of multiple, poorly quantified factors. informal or formal passive surveillance or spontaneous reporting systems (srss) have been the cornerstone of most postlicensure safety monitoring systems because of their relative low cost of operations. 57-59 the national reporting of adverse events following immunizations can be done through the same reporting channels as those used for other adverse drug reactions, 59 as is the practice in france, 60 76 vaccine manufacturers also maintain srss for their products, which are usually forwarded subsequently to appropriate national regulatory authorities. 38, 73 in the united states, the national childhood vaccine injury act of 1986 mandated that health care providers report certain adverse events after immunizations. 77 the vaccine adverse events reporting system (vaers) was implemented jointly by the centers for disease control and prevention (cdc) and the us food and drug administration (fda) in 1990 to provide a unified national focus for collection of all reports of clinically significant adverse events, including, but not limited to, those mandated for reporting. 76 the vaers form permits narrative descriptions of adverse events. patients and their parents-not just health care professionals-are permitted to report to vaers, and there is no restriction on the interval between vaccination and symptoms that can be reported. report forms, assistance in completing the form, and answers to other questions about vaers are available on the vaers web site (vaers.hhs.gov). web-based reporting and simple data analyses are also available. a contractor, under cdc and fda supervision, distributes, collects, codes (currently using the medical dictionary for regulatory activities (www.meddramsso.com/index.asp), and enters vaers reports in a database. reporters of selected serious events are contacted by trained clinical staff on report receipt and are sent letters at 1 year after report receipt to provide additional information about the vaers report, including the patient's recovery. approximately 30,000 vaers reports are now received annually, and these data (without personal identifiers) are also available to the public (at vaers.hhs.gov and at wonder.cdc.gov/vaers.html). several other countries also have substantial experience with passive surveillance for immunization safety. in 1987, canada developed the vaccine associated adverse event (vaae) reporting system, 67,78 which is supplemented by an active, pediatric hospital-based surveillance system that searches all admissions for possible relationships to immunizations (immunization monitoring program-active, or impact). 79 serious vaae reports are reviewed by the advisory committee on causality assessment consisting of a panel of experts. 80 the netherlands also convenes an annual panel to categorize reports, which are then published. 74 the united kingdom and most members of the former commonwealth use the yellow card system, whereby a reporting form is attached to officially issued prescription pads. 58,63 data on adverse drug (including vaccine) events from several countries are compiled by the world health organization (who) collaborating center for international drug monitoring in uppsala. 81 with so many different passive surveillance systems that collect information on various medical events following vaccination, standardized definitions of vaccine-related adverse events are necessary. in the past, different definitions were developed in brazil, 75 canada, 67 india, 70 and the netherlands. 74 however, implementation of similar standards across national boundaries has been advanced by the international conference on harmonization 82 and the brighton collaboration. 44 vaers often first identifies potential new vaccine safety problems because of clusters of cases in time or space, often with unusual clinical features. for example, in 1999, passive reports to vaers of intussusception among children vaccinated with rotashield was the first postlicensure signal of a problem, 83 leading to epidemiologic studies that verified these findings. 84, 85 similarly, initial reports to vaers of a previously unrecognized serious yellow fever vaccine-associated neurotropic disease 86 and viscerotropic disease 87,88 have since been confirmed elsewhere. 89 because of the success in detecting these signals, there have been various attempts to automate screening for signals using srss reports. new tools developed for pattern recognition in extremely large databases are beginning to be applied. 90 these include empirical bayesian data mining to identify unexpectedly frequent vaccine-event combinations. 91 vaers has provided some of the first safety data after the introduction of a number of vaccines. 92-95 vaers has also successfully served as a source of cases for further investigation of idiopathic thrombocytopenic purpura after measles-mumpsrubella (mmr) vaccine, 96 encephalopathy after mmr, 67,97 and syncope after immunization. 98 when denominator data on vaccine doses distributed or administered are available from other sources, vaers can be used to evaluate changes in reporting rates over time or when new vaccines replace old vaccines. for example, vaers showed that after millions of doses had been distributed, reporting rates for serious events such as hospitalization and seizures after dtap in toddlers were one third of those after diphtheria and tetanus toxoids and whole-cell pertussis (dtp). 99 because vaers is the only surveillance system covering the entire us population with data available on a relatively timely basis, it is the major means available currently to detect possible new, unusual, or extremely rare adverse events. despite the aforementioned uses, srss for drug and vaccine safety have a number of major methodological weaknesses. underreporting, biased reporting, and incomplete reporting are inherent to all such systems, and potential safety concerns may be missed. 100-102 aseptic meningitis associated with the urabe mumps vaccine strain, for example, was not detected by srss in most countries. 103,104 some increases in adverse events detected by vaers may not be true increases, but instead may be due to increases in reporting efficiency or vaccine coverage. for example, an increase in gbs reports after influenza vaccination during the 1993 to 1994 season was found to be largely due to improvements in vaccine coverage and increases in gbs independent of vaccination. 105 an increased reporting rate of an adverse event after one hepatitis b vaccine compared with a second brand was likely due to differential distribution of brands in the public vs private sectors, which have differential vaers reporting rates (higher in the public sector). 106 finally, pending litigation resulted in the filing of a large number of vaers reports claiming that vaccines caused autism. 107 perhaps the most important methodological weakness of vaers, however, is that it does not contain the information necessary for formal epidemiologic analyses. such analyses require calculation of the rate of the adverse event after vaccination and a comparison rate among unvaccinated persons. the vaers database, however, provides data only for the number of persons who may have experienced an adverse event following immunization and, even then, only in a biased and underreported manner. vaers lacks data on the denominator of total number of people vaccinated and the corresponding data on number of cases and denominator population of unvaccinated people. sometimes reporting rates can be calculated by using vaers case reports for the numerator and, if available, doses of vaccines administered (or, if unavailable, data on vaccine doses distributed or vaccine coverage survey data) for the denominator. these rates can then be compared with the background rate of the same adverse event in the absence of vaccination, if available. because of underreporting, however, vaers reporting rates will usually be lower than the actual rates of adverse events following immunization. a higher proportion of serious events, such as seizures, that follow vaccinations are likely to be reported to vaers than milder events, such as rash, or delayed events requiring laboratory assessment, such as thrombocytopenic purpura after mmr vaccination. 100 the reporting efficiency or sensitivity of srss can sometimes be estimated if an independent source of cases of specific adverse events following immunization is available to conduct capture-recapture analyses. such an analysis was conducted to estimate that vaers reporting completeness for intussusception following rotashield vaccine was 47%. 108 formal evaluation has been limited by the quality of diagnostic information on vaers reports, especially the probability that a serious event reported to vaers has been diagnosed accurately. of 26 cases reported to vaers in which gbs developed after influenza vaccination during the 1990 to 1991 season, and for which hospital charts were reviewed by an independent panel of neurologists blinded to immunization status, the diagnosis of gbs was confirmed in 22 (85%). 109 intussusception was verified in 88% of vaers reports filed after rotashield vaccination. 83 clinical reviews of vaers reports submitted following 2009 h1n1 influenza vaccine were able to verify 56% of possible gbs reports and 42% of reports of possible anaphylaxis. 110 clinical review verification rates were similar for vaers reports following human papillomavirus vaccination: 57% for gbs and 38% for anaphylaxis. 95 these studies highlight the often crude nature of signals generated by vaers and the difficulty in ascertaining which potential vaccine safety concerns warrant further investigation. the problems with reporting efficiency and potentially biased reporting and the inherent lack of an adequate control group limit the certainty with which conclusions can be drawn. recognition of these limitations in large part has helped stimulate the creation of more population-based methods of assessing vaccine safety. vaccines may undergo clinical trials after licensure to assess the effects of changes in vaccine formulation, 111 vaccine strain, 112 age at vaccination, 113 number and timing of vaccine doses, 114 simultaneous administration, 115 and interchangeability of vaccines from different manufacturers on vaccine safety and immunogenicity. 116 unanticipated differential mortality among recipients of high-and regular-titered measles vaccine in developing countries (albeit lower than among unvaccinated children) 117 led to a change in recommendations by the who for the use of such vaccines. 118 to improve the ability to detect adverse events that are not detected during prelicensure trials, some recently licensed vaccines in developed countries have undergone formal phase 4 surveillance studies on populations with sample sizes that have included as many as 100,000 people. these studies usually have used cohorts in managed care organizations (mcos) supplemented by diary or phone interviews. these methods were first used extensively after the licensure of polysaccharide and conjugated hib vaccines. 119-121 large postlicensure studies on safety and efficacy have also been conducted for several other vaccines, including those for dtap, 46 varicella, and herpes zoster. 122, 123 requirements for phase 4 evaluation have even been extended to less frequently used vaccines, such as japanese encephalitis vaccine. 124 historically, ad hoc epidemiologic studies have been used to assess signals of potential adverse events detected by srss, the medical literature, or other mechanisms. some examples of such studies include the investigations of poliomyelitis after inactivated 10, 125 and oral 126 polio vaccines, sids after dtp vaccination, 127-130 encephalopathy after dtp vaccination, 131, 132 meningoencephalitis after mumps vaccination, 133 injection site abscesses after vaccination, 134 and gbs after influenza vaccination. 20, 105, 109 the institute of medicine (iom) has compiled and reviewed many of these studies. 11, 135 unfortunately, such ad hoc studies are often costly, timeconsuming, and limited to assessment of a single event or a few events or outcomes. given these drawbacks and the methodological limitations of passive surveillance systems (such as described for vaers), pharmacoepidemiologists began to turn to large databases linking computerized pharmacy prescription (and later immunization records) and medical outcome records. 102 these databases derive from defined populations such as members of mcos, single-provider health care systems, and medicaid programs. such databases cover enrollee populations numbering from thousands to millions, and, because the data are generated from the routine administration of the full range of medical care, underreporting and recall bias are reduced. with denominator data on doses administered and the ready availability of appropriate comparison (ie, unvaccinated) groups, these large databases provide an economical and rapid means of conducting postlicensure studies of safety of drugs and vaccines. 103, [136] [137] [138] [139] the cdc initiated the vaccine safety datalink (vsd) project in 1990 136 to conduct postmarketing evaluations of vaccine safety and to establish an infrastructure allowing for highquality research and surveillance. selection of staff-model prepaid health plans minimized potential biases for more severe outcomes resulting from data generated from fee-for-service claims. currently, eight mcos in the united states participate in the vsd. the eight participating mcos comprise a population of more than 9 million members. each mco prepares computerized data files using a standardized data dictionary containing demographic and medical information on their members, such as age and sex, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. other information sources, such as medical chart review; member surveys; and pharmacy, laboratory and radiology data are often used in vsd studies to validate outcomes and vaccination data. there is rigorous attention to the maintenance of patient confidentiality, and each study undergoes institutional review board review. the vsd project's main priorities include evaluating new vaccine safety concerns that may arise from the medical literature, 11,135 from vaers, 85,106 from changes in immunization schedules, 140 or from introduction of new vaccines. 120,121 the creation of near real-time data files has enabled the development of near real-time postmarketing surveillance for newly licensed vaccines and changes in vaccine recommendations. the size of the vsd population also permits separation of the risks associated with individual vaccines from those associated with vaccine combinations, whether given in the same syringe or simultaneously at different body sites. for example, vsd safety monitoring found that the combined mmrv vaccine carried an increased risk of febrile seizures compared with giving mmr and varicella vaccines simultaneously as separate injections. 141 such studies are especially valuable in view of combined pediatric vaccines. 142 more than 130 studies have been or are being performed within the vsd project, 139 including general screening studies of the safety of inactivated influenza vaccines among children and of thimerosal-containing vaccines. disease-or syndrome-specific investigations have been or are being performed, including studies investigating autism, multiple sclerosis, thyroid disease, acute ataxia, alopecia, rheumatoid arthritis, asthma, diabetes, and idiopathic thrombocytopenic purpura following vaccination. amid these promises, a few caveats are appropriate. although diverse, the population in the mcos currently in the vsd project is not wholly representative of the united states in terms of geography or socioeconomic status. more important, because of the high coverage attained in the mcos for most vaccines, few nonvaccinated control subjects are available. therefore, vsd studies often rely on risk-interval analyses (eg, to study the question of whether outcome "x" is more common in period "y" following vaccination compared with other periods) (table 76 -2). 143 this approach, although powerful for evaluating acute adverse events, has limited ability to assess associations between vaccination and adverse events with delayed or insidious onset (eg, autism). the vsd project also cannot easily assess mild adverse events (such as fever) that do not always come to medical attention. 136 finally, because vac-cines are not delivered in the context of randomized, controlled trials, the vsd project may not be able to successfully control for confounding and bias in each analysis, 144 and inferences on causality may be limited. 145 despite these potential shortcomings, the vsd project provides an essential, powerful, and cost-effective complement to ongoing evaluations of vaccine safety in the united states. 139, 139 in view of the methodological and logistic advantages offered by large linked databases, the united kingdom and canada also have developed systems linking immunization registries with medical files. 79,103 because of the relatively limited number of vaccines used worldwide and the costs associated with establishing and operating these large databases, it is unlikely that all countries will be able to or need to establish their own. these countries should be able to draw on the scientific base established by the existing large linked databases for vaccine safety and, if the need arises, conduct ad hoc epidemiologic studies. more recently, there has been an increasing awareness that the usefulness of srss as potential disease registries and the immunization safety infrastructure can be usefully augmented by tertiary clinical centers. well-organized, well-identified clinical infrastructures for the study of rare vaccine safety outcomes were first developed in certain regions in italy 146 and australia. 147, 148 in the united states, the cdc established the clinical immunization safety assessment (cisa) network in 2001 with the following primary goals: (1) to develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (aefi); (2) to improve the understanding of aefi at the individual level, including determining possible genetic and other risk factors for predisposed persons and high-risk subpopulations; (3) to develop evidence-based algorithms for vaccination of persons at risk of serious adverse events following immunization; and (4) to provide a resource of subject matter experts for clinical vaccine safety inquiries. 36 the cisa investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of adverse 1. define biologically plausible risk interval for adverse event after vaccination (eg, 30 days after each dose). 2. partition observation time for each child in the study into periods within and outside of risk intervals, and sum respectively (eg, for a child observed for 365 days during which three doses of vaccine were received, total risk interval time = 3 × 30 person-days = 90 persondays; total nonrisk interval time = 365 − 90 = 275 person-days). birth dose 1 dose 2 dose 3 365 days 3. add (a) total risk interval and nonrisk interval observation times for each child in the study (person-time observed; for mathematical convenience, the following example uses 100 and 1,000 person-months of observation) and (b) adverse events occurring in each period to complete a 2 × 2 table (for illustration, the example uses 3 and 10 cases): events following vaccinations. the cisa investigators have published a standardized algorithm for evaluating and managing persons who have suspected or definite immediate hypersensitivity reactions such as urticaria, angioedema, and anaphylaxis following vaccines. 149 some of the studies undertaken by cisa include an assessment of extensive limb swelling after dtap, 150 a study of the usefulness of irritant skin test reactions for managing hypersensitivity to vaccines, 151 the clinical evaluation of patients with serious adverse events following yellow fever vaccine administration, 152 and evaluation of vaccine safety among children with inborn errors of metabolism. 153 new understanding of the human genome, pharmacogenomics, and immunology hold promise for future cisa studies and may make it possible to elucidate the biological mechanisms of vaccine adverse reactions, which in turn could lead to the development of safer vaccines and safer vaccination practices, including revaccination when indicated. 154 in mass immunization campaigns during which many people are vaccinated in a short time, it is critical to have a vaccine safety monitoring system in place that can detect potential safety problems early so that corrective actions can be taken as soon as possible. mass immunization campaigns pose specific safety challenges precisely because large populations are vaccinated during a short time and often they are conducted outside the usual health care setting. 155 mass immunization campaigns are often conducted in developing countries, which poses a particular challenge of ensuring injection safety. 156 in any setting in which large numbers of immunizations are being administered, more adverse events will coincidentally occur following immunization. thus, it is important to have background rates available of expected adverse events to allow rapid evaluation of whether reported adverse events are occurring at a rate following immunization that is higher than would be expected by chance alone. the resources devoted to mass vaccination campaigns also provide opportunities to enhance existing immunization safety monitoring systems or to establish a system if none exists, and these may lead to long-term improvements in immunization safety monitoring beyond the specific mass immunization campaign. the response to the 2009 h1n1 influenza pandemic involved probably the largest and most intense immunization safety monitoring effort ever undertaken in the united states and internationally. the emergence of a novel influenza a (h1n1) virus prompted the development of 2009 influenza a (h1n1) monovalent vaccines. the fda licensed the first 2009-h1n1vaccines in september 2009. with potentially hundreds of millions of people expected to be vaccinated, adverse events were anticipated to occur in some recently vaccinated people. to address the question of whether the vaccine could be causing the adverse events, background rates for several adverse events were developed. 157 to rapidly detect any unforeseen safety problems, the federal government implemented enhanced postlicensure 2009-h1n1 vaccine safety monitoring. 158 first, vaers undertook special outreach efforts to encourage providers to report, and daily reviews and followup of submitted reports were conducted by medical personnel to rapidly evaluate the reports and obtain any needed additional clinical or other information. second, a new web-based active surveillance system was implemented to prospectively follow tens of thousands of vaccinees for medically attended adverse events. third, large population-based systems that link computerized vaccination data with health care encounter codes were used to conduct rapid ongoing analyses to evaluate possible associations of h1n1 vaccination with selected adverse events, including potential associations suggested by vaers or other sources. such systems included the existing vsd project; a new collaboration involving additional large health plans covering several million people that also performed rapid ongoing analyses similar to vsd; and the databases of the department of defense, medicare, and the veterans administration. fourth, active case finding for gbs was conducted in 10 areas of the united states with a combined population of about 50 million. the findings from the various safety monitoring activities were regularly reviewed by government and other scientists and an independent vaccine safety review panel convened by the department of health and human services. initial safety data were provided by vaers, which found that the adverse event profile after 2009-h1n1 vaccine in vaers ( > 10,000 reports) was consistent with that of seasonal influenza vaccines, although the reporting rate was higher after 2009-h1n1 than seasonal influenza vaccines, which may be, at least in part, a reflection of stimulated reporting; death, gbs, and anaphylaxis reports after 2009-h1n1 vaccination were rare (each < 2 per million doses administered). 110, 158 preliminary results from the large special study of gbs found 0.8 excess cases of gbs per 1 million vaccinations, which is similar to the increased risk found with some seasonal influenza vaccines. 159 similar efforts to intensely monitor the safety of influenza a (h1n1) 2009 vaccines occurred in other countries, primarily in north america, europe, and australia, but also included the development of new immunization safety monitoring systems in countries such as taiwan. 160 these countries collaborated in their activities and routinely shared information among themselves and with other countries that have limited vaccine safety monitoring capabilities. these extensive international safety monitoring activities and collaborations represented an unprecedented commitment to ensuring the safety of influenza a (h1n1) 2009 vaccines, as well as a model for how we might improve tracking of safety for all vaccines going forward. unfortunately, vaccine safety issues have increasingly taken on a life of their own outside of the scientific arena-arguably to society's overall detriment. liability concerns, for example, have severely limited development of maternal immunizations to protect their newborn infants against diseases such as from group b streptococcus . 161 more worrisome, however, are various chronic diseases (and their advocates) in search of a simple cause, for which immunizations-as a relatively universal exposuremake all too convenient a hypothesized link. case studies of some of these fears are discussed in the following sections. in 1974, kulenkampff and coworkers 162 reported a series of 22 cases of children with mental retardation and epilepsy following receipt of the whole-cell pertussis vaccine. during the next several years, fear of the pertussis vaccine generated by media coverage of this report caused a decrease in pertussis immunization rates in british children from 81% to 31% and resulted in more than 100,000 cases and 36 deaths due to pertussis. 163 media coverage of the kulenkampff report also caused decreased immunization rates and increased pertussis deaths in japan, sweden, and wales. 163 however, many subsequent excellent well-controlled studies found that the incidence of mental retardation and epilepsy following whole-cell pertussis vaccine was similar in vaccinated children compared with children who did not receive the vaccine and that many of these children actually suffered from dravet's syndrome (a neuronal sodium channel transport defect caused by an scn1a mutation). 166-171,171a in the mid-1980s, the antivaccine group called dissatisfied parents together raised the notion that the whole-cell pertussis vaccine could cause sids. subsequent study of children who did or did not receive dtp vaccine showed that the incidence of sids was not greater in the vaccinated group. 143 in the early 1990s, when the hepatitis b vaccine was recommended for routine use in newborns, a program on abc's 20/20 raised the question of whether vaccines could cause sids. again, studies failed to find any association between hepatitis b vaccine and sids. 130,170,171 two recent reviews have confirmed the notion that vaccines do not cause sids. 172, 173 vaccines cause mad-cow disease by july 2000, at least 73 people in the united kingdom developed a progressive neurological disease termed variant creutzfeldt-jakob disease that likely resulted from eating meat prepared from cows with "mad-cow" disease, a disease caused by proteinaceous infectious particles (prions). some vaccines were made with serum or gelatin obtained from cows in england or from countries at risk for mad-cow disease. two products obtained from cows may be present in vaccines: trace quantities of fetal bovine serum used to provide growth factors for cell culture and gelatin used to stabilize vaccines. however, the bovine-derived products used in vaccines are not likely to contain prions for several reasons. 174 first, fetal bovine serum and gelatin are obtained from blood and connective tissue respectively; neither are sources that have been found to contain prions. second, fetal bovine serum is highly diluted and eventually removed from cells during the growth of vaccine viruses. third, prions are not propagated in cell cultures used to make vaccines. fourth, transmission of prions occurs from eating meat contaminated with nervous tissue obtained from infected animals or, in experimental studies, from directly inoculating preparations of brains from infected animals into the brains of experimental animals. transmission of prions has not been documented after inoculation into the muscles or under the skin (routes used to vaccinate). taken together, the chance that currently licensed vaccines contain prions is essentially zero. the notion that the origin of aids could be traced to poliovirus vaccines that were administered in the belgian congo between 1957 and 1960 was the subject of a popular magazine article 175 and book. 176 the logic behind this assertion was as follows: (1) the polio vaccine used in the belgian congo was grown in chimpanzee kidney cells. (2) the chimpanzee kidney cells used at that time contained simian immunodeficiency virus (siv). (3) siv is very closely related to human immunodeficiency virus (hiv). (4) people were inadvertently inoculated with siv that then mutated to hiv and caused the aids epidemic. this reasoning is problematic and based on several false assumptions. 177-180 first, siv most closely related to hiv has been demonstrated in chimps in the cameroon, far from the chimps near stanleyville that were used to make the vaccine. second, siv and hiv are not very close genetically; mutation to hiv from siv would likely require decades, not years. third, polymerase chain reaction (pcr) analysis showed that the cell substrate used to make the vaccine was monkey, not chimp. fourth, siv and hiv are enveloped viruses that are easily disrupted by extremes in ph. if given by mouth (in a manner similar to the oral polio vaccine), both of these viruses would likely be destroyed in the acid environment of the stomach. last, and most important, original lots of the polio vaccine (including those used in africa for the polio vaccine trials) did not contain hiv or siv genomes as determined by the very sensitive reverse-transcription pcr assay. unfortunately, the notion that live attenuated polio vaccine could cause aids remains an obstacle to eliminating polio in some countries in africa. simian virus 40 (sv40) was present in monkey kidney cells used to make the inactivated polio vaccine, live attenuated polio vaccine, and inactivated adenovirus vaccines in the late 1950s and early 1960s. recently, investigators found sv40 dna in biopsy specimens obtained from patients with certain unusual cancers (ie, mesothelioma, osteosarcoma, and non-hodgkin lymphoma), leading some to hypothesize a link between vaccination and the subsequent development of cancer. 181 however, genetic remnants of sv40 were present in cancers of people who had or had not received contaminated polio vaccines; people with cancers who never received sv40-contaminated vaccines were found to have evidence for sv40 in their cancerous cells; and epidemiologic studies did not show an increased risk of cancers in people who received polio vaccine between 1955 and 1963 and people who did not receive these vaccines. 181 taken together, these findings do not support the hypothesis that the sv40 contained in polio vaccines administered before 1963 caused cancers. one hundred years ago, children received one vaccinesmallpox. today, young children receive 14 vaccines routinely. although some vaccines are given in combination, infants and young children could receive more than 20 shots and three oral doses by 2 years of age, including as many as five shots at one time. the increase in the number of vaccines, and the consequent decline in vaccine-preventable illnesses, has focused attention by parents and health care professionals on vaccine safety. specific concerns include whether vaccines weaken, overwhelm, 182,183 or in some way alter the normal balance of the immune system, paving the way for chronic diseases such as diabetes, asthma, multiple sclerosis, and allergies. although we have witnessed a dramatic increase in the number of vaccines routinely recommended for infants and young children, the number of immunogenic proteins and polysaccharides contained in vaccines has declined (table 76 -3). the decrease in the number of immunogenic proteins and polysaccharides contained in vaccines is attributable to discontinuation of the smallpox vaccine and advances in the field of protein purification that allowed for a switch from whole-cell to acellular pertussis vaccine. a practical way to determine the capacity of the immune system to respond to vaccines would be to consider the number of b and t cells required to generate adequate levels of binding antibodies per milliliter of blood. 184 calculations are based on the following assumptions: -approximately 10 ng/ml is likely to be an effective concentration of antibody directed against a specific epitope. -approximately 10 3 b cells/ml are required to generate 10 ng of antibody/ml. -given a doubling time of about 0.75 days for b cells, it would take about 7 days to generate 10 3 b cells/ml from a single b-cell clone. -because vaccine-specific humoral immune responses are first detected about 7 days after immunization, those responses could initially be generated from a single b-cell clone per milliliter. -one vaccine contains about 10 immunogenic proteins or polysaccharides ( table 76 -3 ). -each immunogenic protein or polysaccharide contains about 10 epitopes (ie, 10 2 epitopes per vaccine). -approximately 10 7 b cells are present per milliliter of blood. given these assumptions, the number of vaccines to which a person could respond would be determined by dividing the number of circulating b cells (approximately 10 7 /ml) by the average number of epitopes per vaccine (10 2 ). therefore, a person could theoretically respond to about 10 5 vaccines at one time. the analysis used to determine the theoretical capacity of a person to respond to as many as 10 5 vaccines at one time, although consistent with the biology and kinetics of vaccine-specific immune responses, is limited by lack of consideration of several factors. first, only vaccine-specific b-cell responses are considered. however, protection against disease by vaccines may also be mediated by vaccine-specific cytotoxic t lymphocytes (ctls). for example, virus-specific ctls are important in the regulation and control of varicella infections. 185 second, in part because of differences in the capacity of various class i or class ii glycoproteins (encoded by the mhc) to present viral or bacterial peptides to the immune system, some people are not capable of responding to certain virus-specific proteins (eg, hepatitis b surface antigen). 186 third, some proteins are more likely to evoke an immune response than others (ie, immunodominance). fourth, although most circulating b cells in a neonate are naïve, the child very quickly develops memory b cells that are not available for response to new antigens and, therefore, should not be considered as part of the circulating naïve b-cell pool. fifth, the immune system is not static. a study of t-cell population dynamics in hiv-infected persons found that adults have the capacity to generate about 2 × 10 9 new t lymphocytes each day. 187 although the quantity of new b and t cells generated each day in healthy people is unknown, studies of hiv-infected persons demonstrate the enormous capacity of the immune system to generate lymphocytes when needed. primarily because of this fifth reason, the assessment that people can respond to at least 10 5 vaccines at one time might be low. within hours of birth, cells of the innate and adaptive immune systems are actively engaged in responding to challenges in the environment (eg, colonizing bacterial flora). 188, 189 similarly, newborn and young infants are quite capable of generating protective immune responses to single and multiple vaccines. for example, children born to mothers infected with hepatitis b virus are protected against infection after inoculation with hepatitis b vaccine (given at birth and 1 month of age). [190] [191] [192] similarly, newborns inoculated with bacille calmette-guérin (bcg) vaccine are protected against severe forms of tuberculosis presumably by activation of bacteria-specific t cells. [193] [194] [195] in addition, about 90% to 95% of infants inoculated in the first 6 months of life with multiple vaccines, including diphtheria-tetanus-pertussis, pneumococcus, hib, hepatitis b and polio, develop protective, vaccine-specific immune responses. 196 conjugation of bacterial polysaccharides (such as streptococcus pneumoniae and hib) to carrier molecules that elicit helper t cells circumvents the poor immunogenicity of unconjugated polysaccharide vaccines in infants and young children. 197, 198 vaccines weaken the immune system infection with wild-type viruses can cause a suppression of specific immunologic functions. for example, infection with wild-type measles virus causes a reduction in the number of circulating b and t cells during the viremic phase of infection and a delay in the development of cell-mediated immunity. 199, 200 downregulation of cell-mediated immunity by wild-type measles virus probably results from downregulation of the production of interleukin-12 by measles-infected macrophages and dendritic cells. 199 taken together, the immunosuppressive effects of wild-type measles virus account, in part, for the increase in morbidity and mortality from measles infection. similarly, the immunosuppressive effects of infections with wild-type varicella virus 201 or wild-type influenza virus 202 cause an increase in the incidence of severe invasive bacterial infections. live viral vaccines replicate (albeit far less efficiently than wild-type viruses) in the host and, therefore, can weakly mimic events that occur after natural infection. for example, measles, mumps, or rubella vaccines can significantly depress reactivity to the tuberculin skin test, 203 can cause a decrease in protective immune responses to varicella vaccine, 210 and high-titered measles vaccine (edmonston-zagreb strain) can cause an excess of cases of invasive bacterial infections in developing countries. 211 all of these phenomena are explained by the likely immunosuppressive effects of measles vaccine viruses. however, current vaccines (including the highly attenuated moraten strain of measles vaccine) do not seem to cause clinically relevant immunosuppression in healthy children. studies have found that the incidence of invasive bacterial infections following immunization with diphtheria, pertussis, tetanus, bcg, measles, mumps, rubella, or live attenuated poliovirus vaccines was not greater than that found in unimmunized children. [212] [213] [214] [215] [216] vaccines cause autoimmunity mechanisms are present at birth to prevent the development of immune responses directed against self-antigens (autoimmunity). t-and b-cell receptors of the fetus and newborn develop with a random repertoire of specificities. in the thymus, t cells that bind strongly to self-peptide-mhc complexes die, while those that bind with a lesser affinity survive to populate the body. this central selection process eliminates strongly selfreactive t cells, while selecting for t cells that recognize antigens in the context of self-mhc. in the fetal liver, and later in the bone marrow, b-cell receptors (ie, immunoglobulins) that bind self-antigens strongly are also eliminated. therefore, the thymus and bone marrow, by expressing antigens from many tissues of the body, enable the removal of the majority of potentially dangerous autoreactive t and b cells before they maturea process termed central tolerance. 217 however, it is not simply the presence of autoreactive t and b cells that result in autoimmune disease. autoreactive t and b cells are present in all people because it is not possible for every antigen from every tissue of the body to participate in the elimination of all potentially autoreactive cells. a process termed peripheral tolerance further limits the activation of autoreactive cells. 218,219 mechanisms of peripheral tolerance include the following: (1) antigen sequestration (antigens of the central nervous system, eyes, and testes are not regularly exposed to the immune system unless injury or infection occurs.); (2) anergy (lymphocytes partially triggered by antigen but without costimulatory signals are unable to respond to subsequent antigen exposure.); (3) activation-induced cell death (a self-limiting mechanism involved in terminating immune responses after antigen is cleared); and (4) inhibition of immune responses by specific regulatory cells. [220] [221] [222] [223] therefore, the immune system anticipates that self-reactive t cells will be present and has mechanisms to control them. any theory of vaccine causation of autoimmune diseases must take into account how these controls are circumvented. as discussed subsequently, epidemiologic studies have not supported the hypothesis that vaccines cause autoimmune diseases. this is consistent with the fact that no mechanisms have been advanced to explain how vaccines could account for all of the prerequisites that would be required for the development of autoimmune disease. at least four key conditions must be met for development of autoimmune disease. first, self-antigen-specific t cells or selfantigen-specific b cells must be present. second, self-antigens must be presented in sufficient amounts to trigger autoreactive cells. third, costimulatory signals, cytokines, and other activation signals produced by antigen-presenting cells (such as dendritic cells) must be present during activation of self-reactive t cells. fourth, peripheral tolerance mechanisms must fail to control destructive autoimmune responses. if all of these conditions are not met, the activation of self-reactive lymphocytes and progression to autoimmune disease are not likely. 224 evidence that vaccines do not cause autoimmunity rigorous epidemiologic studies of infant vaccines and type 1 diabetes found that measles vaccine was not associated with an increased risk for diabetes; other investigations found no association between bcg, smallpox, tetanus, pertussis, rubella, or mumps vaccine and diabetes. 225 a study in canada found no increase in risk for diabetes as a result of receipt of bcg vaccine. 226 in a large 10 year follow-up study among finnish children enrolled in an hib vaccination trial, no differences in risk for diabetes were found among children vaccinated at 3 months of age (followed later with a booster vaccine) and children vaccinated at 2 years only or with children born before the vaccine trial. the weight of currently available epidemiologic evidence does not support a causal association between currently recommended vaccines and type 1 diabetes in humans. [227] [228] [229] the hypothesis that vaccines might cause multiple sclerosis was fueled by anecdotal reports of multiple sclerosis following hepatitis b immunization and two case-control studies showing a small increase in the incidence of multiple sclerosis in vaccinated persons that was not statistically significant. 230-232 however, the capacity of vaccines to cause or exacerbate multiple sclerosis has been evaluated in several excellent epidemiologic studies. 233-237 two large case-control studies showed no association between hepatitis b vaccine and multiple sclerosis 234 and found no evidence that hepatitis b, tetanus, or influenza vaccines exacerbated symptoms of multiple sclerosis. 235 other well-controlled studies also found that influenza vaccine did not exacerbate symptoms of multiple sclerosis. 236-238 indeed, in a retrospective study of 180 patients with relapsing multiple sclerosis, infection with influenza virus was more likely than immunization with influenza vaccine to cause an exacerbation of symptoms. 238 a recent review also showed that the novel h1n1 2009 vaccine had an attributable risk for guillain-barré syndrome of 1-2 cases per million doses administered, not higher than that found following the 2009-2010 seasonal influenza vaccine. 239 allergic symptoms are caused by soluble factors (eg, ige) that mediate immediate-type hypersensitivity; production of ige by b cells is dependent on release of cytokines such as interleukin-4 by th2 cells. two theories have been advanced to explain how vaccines could enhance ige-mediated, th2-dependent allergic responses. first, vaccines could shift immune responses to potential allergens from th1-like to th2-like. 240 second, by preventing common prevalent infections (the "hygiene hypothesis"), vaccines could prolong the length or increase the frequency of th2-type responses. 241, 242 although all factors that cause changes in the balance of th1 and th2 responses are not fully known, 243 it is clear that dendritic cells have a critical role. for example, adjuvants (eg, aluminum hydroxide or aluminum phosphate ["alum"] contained in some vaccines) promote dendritic cells to stimulate th2type responses. 244,245 adjuvants could cause allergies or asthma by stimulating bystander, allergen-specific th2 cells. however, vaccine surveillance data show no evidence for environmental allergen priming by vaccination. 246 furthermore, local inoculation of adjuvant does not cause a global shift of immune responses to th1 or th2 type. 247, 248 the other hypothesis advanced to explain how vaccines could promote allergies is that by preventing several childhood infections (the hygiene hypothesis), stimuli that evolution has relied on to cause a shift from the neonatal th2-type immune response to the balanced th1-th2 response patterns of adults have been eliminated. 241,242 however, the diseases that are prevented by vaccines constitute only a small fraction of the total number of illnesses to which a child is exposed, and it is unlikely that the immune system would rely on only a few infections for the development of a normal balance between th1 and th2 responses. for example, a study of 25,000 illnesses performed in cleveland, ohio, in the 1960s found that children experienced six to eight infections per year in the first 6 years of life; most of these infections were caused by viruses such as coronaviruses, rhinoviruses, paramyxoviruses, and myxovirusesdiseases for which children are not routinely immunized. 249 also at variance with the hygiene hypothesis is the fact that children in developing countries have lower rates of allergies and asthma than children in developed countries despite the fact that they are commonly infected with helminths and worms-organisms that induce strong th2-type responses. 250 finally, the incidence of diseases that are mediated by th1-type responses, such as multiple sclerosis and type 1 diabetes, have increased in the same populations as those that experienced an increase in allergies and asthma. although some relatively small early observational studies supported the association between whole-cell pertussis vaccine and development of asthma, 251 more recent studies have suggested otherwise. a large clinical trial performed in sweden found no increased risk, 252 and a very large longitudinal study in the united kingdom found no association between pertussis vaccination and early-or late-onset wheezing or recurrent or intermittent wheezing. 253 two studies from the vsd project have also lent data to this controversy. in one study of 1,366 infants with wheezing during infancy, vaccination with dtp and other vaccines was not related to the risk of wheezing in full-term infants, 254 and, in another study of more than 165,000 children, childhood vaccinations were not associated with an increased risk for developing asthma. 255 finally, a study from finland also suggested that children with a history of natural measles were at increased risk for atopic illness. such findings would run contrary to the hypothesis that the increase in atopic illnesses seen in several countries is due to the reduction in wild measles resulting from immunizations. 256 another separate concern is whether inactivated influenza vaccination may induce asthma exacerbations in children with preexisting asthma. results of studies examining the potential associations between administration of inactivated influenza vaccine and various surrogate measures of asthma exacerbation, including decreased peak expiratory flow rate, increased use of bronchodilating drugs, and increase in asthma symptoms, have yielded mixed results. most studies, however, have not supported such an association. 257 in fact, after controlling for asthma severity, acute asthma exacerbations were less common after inactivated influenza vaccination than before, 258 and inactivated influenza vaccination seems to be associated with a decreased risk for asthma exacerbations throughout influenza seasons. 259 several more recent studies have also shown a lack of correlation between receipt of vaccines and the development of asthma. 260-263 autism is a chronic developmental disorder characterized by problems in social interaction, communication, and responsiveness and by repetitive interests and activities. although the causes of autism are largely unknown, family and twin studies suggest that genetics has a fundamental role. 264 in addition, overexpression of neuropeptides and neurotrophins has been found in the immediate perinatal period among children later diagnosed with autism, suggesting that prenatal or perinatal influences or both have a more important role than postnatal insults. 265 however, because autistic symptoms generally first become apparent in the second year of life, some scientists and parents have focused on the role of mmr vaccine because it is first administered around this time. concern about the role of mmr vaccine was heightened in 1998 when a study based on 12 children proposed an association between the vaccine and the development of ileonodular hyperplasia, nonspecific colitis, and regressive developmental disorders (later termed by some as "autistic enterocolitis"). 266 among the proposed mechanisms was that mmr vaccine caused bowel problems, leading to the malabsorption of essential vitamins and other nutrients and eventually to autism or other developmental disorders. concern about this issue led to a decline in measles vaccine coverage in the united kingdom and elsewhere. 267 significant concerns about the validity of the study included the lack of an adequate control or comparison group, inconsistent timing to support causality (several of the children had autistic symptoms preceding bowel symptoms), and the lack of an accepted definition of the syndrome. 268 subsequently, population-based studies of autistic children in the united kingdom found no association between receipt of mmr vaccine and autism onset or developmental regression. 269, 270 a study in the united states in the vsd project investigated whether measlescontaining vaccine was associated with inflammatory bowel disease and found no relationship between receiving mmr vaccine and inflammatory bowel disease or between the timing of the vaccine and risk for disease. 271 soon after the lancet published the article that ignited the controversy, 266 two ecologic analyses found no evidence that mmr vaccination was the cause of apparent increased trends in autism over time, 272, 273 while two other studies found no evidence of a new variant form of autism associated with bowel disorders secondary to vaccination. 274, 275 several more recent studies have also refuted the notion that mmr vaccine caused autism. [276] [277] [278] [279] [280] [281] in february 2010, the lancet retracted the original article claiming an association. because of the level of concern surrounding this issue, the cdc and the national institutes of health requested an independent review by the iom. 282 the immunization safety review committee appointed by the iom to review this issue was unable to find evidence supporting a causal relationship at the population level between autistic spectrum disorders and mmr vaccination, nor did the committee find any good evidence of biological mechanisms that would support or explain such a link. the fda modernization act of 1997 called for the fda to review and assess the risk of all mercury-containing food and drugs. this led to an examination of mercury content in vaccines. public health officials found that infants up to 6 months old could receive as much as 187.5 µ g of ethylmercury (thimerosal) from vaccines, a level that exceeded recommended safety guidelines for methylmercury from the environmental protection agency, but not levels recommended by the fda or the agency for toxic substance disease registry. 283 consequently, the routine neonatal dose of hepatitis b vaccine in infants born to hepatitis b surface antigen-negative mothers was suspended in the united states until preservative-free vaccines became available, and transitioning to a vaccine schedule free of thimerosal began as a precautionary measure. 284 currently, some multidose influenza vaccines contain preservative quantities (ie, 25 µ g per dose) of thimerosal although thimerosal-free vaccines are available. mercury is a naturally occurring element found in the earth's crust, air, soil, and water. since the earth's formation, volcanic eruptions, weathering of rocks, and burning of coal have caused mercury to be released into the environment. once released, certain types of bacteria in the environment can change inorganic mercury to organic (methylmercury). methylmercury makes its way through the food chain in fish, animals, and humans. at high levels, it can be neurotoxic. thimerosal contains ethylmercury, not methylmercury. studies comparing ethylmercury and methylmercury suggest that they are processed differently; ethylmercury is broken down and excreted much more rapidly than methylmercury. therefore, ethylmercury is much less likely than methylmercury to accumulate in the body and cause harm. 284a several pieces of biological and epidemiologic evidence support the notion that thimerosal does not cause autism. first, in 1971 iraq imported grain that had been fumigated with methylmercury. 285 farmers ate bread made from this grain. the result was one of the worst, single-source, mercury poisonings in history. methylmercury in the grain caused the hospitalization of 6,500 iraqis and killed 450. pregnant women also ate the bread and delivered infants with epilepsy and mental retardation. however, there was no evidence that these infants had an increased incidence of autism. second, several large studies have now compared the risk of autism in children who received vaccines containing thimerosal with children who received vaccines without thimerosal or vaccines with lesser quantities of thimerosal; the incidence of autism was similar in all groups. 286-291 the iom has reviewed these studies and concluded that evidence favored rejection of a causal association between vaccines and autism and that autism research should shift away from vaccines. 292 denmark, a country that abandoned thimerosal as a preservative in 1991, actually saw an increase in the disease beginning several years later. third, studies of the head size, speech patterns, vision, coordination, and sensation of children poisoned by mercury show that the symptoms of mercury poisoning are distinguishable from the symptoms of autism. 293 fourth, methylmercury is found in low levels in water, infant formula, and breast milk. 294 although it is clear that large quantities of mercury can damage the nervous system, there is no evidence that the small quantities contained in water, infant formula, and breast milk do. an infant who is exclusively breastfed for 6 months will ingest more than twice the quantity of mercury that was ever contained in vaccines and 15 times the quantity of mercury contained in the influenza vaccine. one known and unfortunate sequela from the uncertainty surrounding the safety of thimerosal was confusion surrounding administration of the birth dose of hepatitis b vaccine. following the suspension of the routine use of hepatitis b vaccine for low-risk newborns in 1999, there was a marked increase in the number of hospitals that no longer routinely vaccinated all infants at high risk of hepatitis b. 295 as a result, there have been cases of neonatal hepatitis b that could have been prevented but were not because of many hospitals suspending their routine neonatal hepatitis b vaccination program. 296 the hypothesis for why vaccines might cause autism has continued to shift. in 1998, the concern was that the mmr vaccine caused autism. the following year, the concern shifted to include the fear that thimerosal in vaccines caused autism. as data continued to be generated showing that both of these concerns were ill founded, the hypothesis shifted again-this time to include the fear that too many vaccines given too soon caused autism. to address this concern, michael smith and charles woods mined data from a previous study that had been performed by cdc researchers to determine whether thimerosal in vaccines was associated with an increased risk of autism or neurodevelopmental delays. 297 smith and woods compared children who had received vaccines according to the cdc/american academy of pediatrics schedule with children for whom a decision was made to delay, withhold, separate, or space out vaccines, noting no difference between the two groups in neurodevelopmental outcomes. 298 aluminum salts have safely been used to adjuvant vaccines since the 1930s. however, by the mid-2000s, parents became concerned that aluminum in vaccines might be harmful. indeed, high levels of aluminum can cause local inflammatory reactions, osteomalacia, anemia, or encephalopathy, typically in preterm infants or infants with absent or severely compromised renal function who are also receiving high doses of aluminum from other sources (eg, antacids). 299 studies have shown that children who receive aluminum-containing vaccines have serum levels of aluminum that are well below the toxic range. [300] [301] [302] formaldehyde in vaccines is harmful formaldehyde has been used in vaccines to detoxify bacterial toxins (ie, diphtheria toxin, tetanus toxin, pertussis toxins) and to inactivate viruses (ie, poliovirus). because formaldehyde at high concentrations can cause mutational changes in cellular dna in vitro, 303 some parents have become concerned that formaldehyde in vaccines might be dangerous. however, because formaldehyde is a product of single-carbon metabolism, everyone has formaldehyde detectable in serum. 304 indeed, the level of formaldehyde in the circulation is about 10-fold more than would be contained in any vaccine. 305 also, people exposed to high levels of formaldehyde in the workplace (eg, morticians) are not at greater risk of cancer than people who are not exposed to formaldehyde. 306 finally, the quantity of formaldehyde present in vaccines is at least 600-fold lower than that necessary to induce toxicity in experimental animals. 307 two cell lines, mrc-5 and wi-38, both derived from elective abortions performed in europe in the early 1960s, have been used as cell substrates in vaccine manufacture. four vaccines continue to require the use of these cell lines: varicella, rubella, hepatitis a, and one of the rabies vaccines. human fetal cells were valuable in vaccine research because they support the growth of many human viruses and are sterile; they were first used at around the time that researchers found that primary monkey kidney cells were contaminated with sv40 virus. some religious groups have become concerned about the use of cells originally obtained from elective abortions. however, the pontifical academy of life of the catholic church has deemed vaccines made using these cells worthy of continued use, despite their origins. 308 disease prevention, especially if it requires continuous nearuniversal compliance, is a formidable task. in the preimmunization era, vaccine-preventable diseases such as measles and pertussis were so prevalent that the risks and benefits of disease vs vaccination were readily evident. as immunization programs successfully reduced the incidence of vaccine-preventable diseases, however, an increasing proportion of health care providers and parents have little or no personal experience with vaccine-preventable diseases. for their risk-benefit analysis, they are forced to rely on historical and other more distant descriptions of vaccine-preventable diseases in textbooks or educational brochures. in contrast, some degree of personal discomfort, pain, and worry is generally associated with each immunization. in addition, parents searching for information about vaccines on the world wide web are likely to encounter web sites that encourage vaccine refusal or emphasize the dangers of vaccines. 309, 310 similarly, the media may sensationalize vaccine safety issues or, in an effort to present "both sides" of an argument, fail to provide perspective. 311, 312 for reasons discussed earlier, there may be uncertainty if vaccines are associated with rare or delayed adverse reactions if only because the scientific method does not allow for acceptance of the null hypothesis. therefore, one cannot prove that a vaccine never causes a particular adverse event, only that an adverse event is unlikely to occur by a certain statistical probability. the combination of these factors may have an impact on parental beliefs about immunizations. a national survey found that although the majority of parents support immunizations, 20% to 25% have misconceptions that could erode their confidence in vaccines. 182 within this context, the art of addressing vaccine safety concerns through effective risk communication has emerged as an increasingly important skill for managers of mature immunization programs and health care providers who administer vaccines. the science of risk perceptions and risk communications, developed initially for technology and environmental arenas, 313 has only recently been formally applied to immunizations. 314 for scientists and other experts, risk tends to be synonymous with the objective probability of morbidity and mortality resulting from exposure to a particular hazard. 315 in contrast, research has shown that laypersons may have subjective, multidimensional, and value-laden conceptualizations of risk. 316 among the key principles and lessons learned about public perceptions of risk are the following: -individual people differ in their perceptions of risk depending on their personality, education, life experience, and personal values; 317, 318 educational materials tiered for different needs are therefore likely to be more effective than a single tier. -perceptions of risk may differ dramatically among various stakeholders, such as members of government agencies, industry, or activist groups. 319 the level of trust between stakeholders has an impact on all other aspects of risk communication. 320 trust is generally reinforced by open communication about what is known and unknown about risks and by providing candid accounts of the evidence and how it was used in the decisionmaking process. 321 -certain hazard characteristics, including involuntariness, uncertainty, lack of control, high level of dread, and low level of equity, lead to higher perceived risk; 316 only risks with similar characteristics should be compared in risk communication efforts. 322 -for quantitatively equivalent risk that is due to action (eg, vaccination reaction) vs inaction (eg, vaccinepreventable disease caused by nonvaccination), many people prefer the consequences of inaction to action. 323 -when there is uncertainty about risks, patients frequently rely on the advice of their physician or other health care professionals; continuing education of health care professionals on vaccine risk issues is key. 182 -finally, different ways of presenting, or framing, the same risk information (eg, using survival rates vs mortality rates) can lead to different risk perceptions, decisions, and behaviors. 324, 325 risk communication can be used for the purposes of advocacy, public education, or decision-making partnership. 313 people care not only about the magnitude of risks, but also how risks are managed and whether they participate in the risk-management process, especially in a democratic society. 326 in medical decision making, this has resulted in a transition from more paternalistic models to increasing degrees of informed consent. 327 some have argued that a similar transition to informed consent also should occur with immunizations. 328 however, immunization is unlike most other medical procedures (eg, surgery) in that the consequences of the decision affect not only the individual person, but also others in the society. because of this important distinction, many countries have enacted public health (eg, immunization) laws that severely limit an individual person's right to infect others. without such mandates, persons may attempt to avoid the risks of vaccination while being protected by the herd immunity resulting from others being vaccinated. 329 unfortunately, the protection provided by herd immunity may disappear if too many people avoid vaccination, resulting in outbreaks of vaccine-preventable diseases. 330, 331 debates in the united states have focused on whether philosophical (in addition to medical and religious) exemptions to mandatory immunizations should be allowed more universally and, if so, what standards for claim of exemption are needed. 328, 332, 333 thus, vaccine risk communications should not only describe the risks and benefits of vaccines for individual people, but also should include discussion of the impact of individual immunization decisions on the larger community. empathy, patience, scientific curiosity, and substantial resources are needed to address concerns about vaccine safety. although each evaluation of a vaccine safety concern is in some ways unique, some general principles may apply to most cases. as with all investigations, the first step is objective and comprehensive data gathering. 51 it is also important to gather and weigh evidence for causes other than vaccination. for individual cases or clusters of cases, a field investigation to gather data firsthand may be necessary. 134, 334 advice and review from a panel of independent experts also may be needed. 109, 335, 336 causality assessment at the individual level is difficult at best; further evaluation via epidemiologic or laboratory studies may be required. 337 even if the investigation is inconclusive, such studies can often help to maintain public trust in immunization programs. 338 scientific investigations are only the beginning of addressing vaccine safety concerns. in many countries, people who believe they or their children have been injured by vaccines have organized and produced information highlighting the risks of and alternatives to immunizations. from the consumer activist perspective, even if vaccine risks are rare, this low risk does not reassure the person who experiences the reaction. 339 such groups have been increasingly successful in airing their views in electronic and print media, frequently with poignant individual stories. 309, 310 because the media frequently raise controversies without resolution and choose "balance" over perspective, one challenge is to establish credibility and trust with the audience. 340, 341 factors that aid in enhancing credibility include demonstrating scientific expertise, establishing relationships with members of the media, expressing empathy, and distilling scientific facts and figures down to simple lay concepts. however, statistics and facts compete poorly with dramatic pictures and stories of disabled children. emotional reactions to messages are often dominant, influencing subsequent cognitive processing. 342 therefore, equally compelling firsthand accounts of people with vaccine-preventable diseases may be needed to communicate the risks associated with not vaccinating. clarifying the distinction between perceived and real risk for the concerned public is critical. if further research is needed, the degree of uncertainty (eg, whether such rare vaccine reactions exist at all) should be acknowledged, but what is certain also should be noted (eg, millions of people have received vaccine x and have not developed syndrome y; even if the vaccine causes y, it is likely to be of magnitude z, compared with the magnitude of known risks associated with vaccine-preventable diseases). in the united states, written information about the risks and benefits of immunizations developed by the cdc has been required to be provided to all people vaccinated in the public sector since 1978. 343 the national childhood vaccine injury act requires every health care provider, public or private, who administers a vaccine that is covered by the act to provide a copy of the most current cdc vaccine information statement (vis) to the adult vaccinee or, in the case of a minor, to the parent or legal representative each time a dose of vaccine is administered. 344 health care providers must note in each patient's permanent medical record the date printed on the vis and the date the vis was given to the vaccine recipient or his or her legal representative. viss are the cornerstone of provider-patient vaccine risk-benefit communication. each vis contains information on the disease(s) that the vaccine prevents, who should receive the vaccine and when, contraindications, vaccine risks, what to do if a side effect occurs, and where to go for more information. current viss can be obtained from the cdc's national center for immunization and respiratory diseases at www.cdc.gov/vaccines and are available in more than 20 languages from the immunization action coalition at www.immunize.org. an increasing number of resources that address vaccine safety misconceptions and allegations also have become available, including web sites, brochures, resource kits, and videos (table 76-4) . some studies have been conducted to assess the use and effectiveness of such materials; 345-349 however, more research in this area is needed. immunization programs and health care providers should anticipate that some members of the public may have deep concerns about the need for and safety of vaccines. a few may refuse certain vaccines or even reject all vaccinations. an understanding of vaccine risk perceptions and effective vaccine risk communication are essential in responding to misinformation and concerns. toward this end, cdc's vaccine safety website (http://www.cdc. gov/vaccinesafety/index.html) provides basic information on the safety of routinely administered vaccines, as well as responses to frequently asked questions. the website also provides more detailed information on how vaccines are tested and monitored for safety; cdc's specific projects for monitoring, evaluation, and research on vaccine safety (vaers, vsd, and cisa); detailed sections addressing common concerns (eg, autism, thimerosal); and a resource library with articles, fact sheets, and other related materials on immunization safety. parental vaccine acceptance in a new era: the role of health care providers and public health professionals one consequence of the success of vaccines is that an increasing number of parents and clinicians have little or no personal experience with or knowledge of many of the diseases that vaccines prevent. thus, vaccine-preventable diseases often are not perceived as a real threat by parents. 350,351 moreover, increasingly parents want to be fully informed about their children's medical care, 352 thus merely recommending vaccination may not be sufficient. also in this new era, stories in the media highlighting adverse events (real or perceived) may cause some parents to question the safety of vaccines. apart from the media attention on vaccine safety issues, a confluence of factors has an influence on parents' vaccine attitudes in the present environment of a low incidence of vaccinepreventable diseases. these factors would be relatively unimportant in an environment where diseases such as polio and measles were common and people lived in fear of their children contracting disease; however, they have become predominant in the current climate for some parents. some of these factors are: (1) lack of appropriately tailored information about the benefits of vaccines and contrary information from alternative health practitioners, (2) mistrust of the source of the information, (3) perceived serious side effects, (4) not perceiving the risks of vaccines accurately, and (5) insufficient biomedical literacy. addressing these issues is a challenge for medical and public health professionals because the typical arrangement for providing medical care does not allow full reimbursement of health care providers for educating patients and parents. 353 nevertheless, it is important for us to try to meet the challenge because an understanding of the aforementioned factors and a proactive approach to vaccine education may prevent future concerns from escalating into widespread refusal of vaccines, with a consequent increased incidence of vaccine-preventable diseases. most people today want to be thoroughly informed about their health care. 352 the desire for more information also applies to parents with regard to medical issues for their children. parents want to be part of the decision-making process when it comes to immunizations for their children. 354 providing the appropriate information at the appropriate time is especially important now with the increased questioning of vaccines and with 20 states allowing philosophical exemptions in 2011. there is an association between information and vaccine acceptance. a recent study found that while 67% of parents agreed that they had access to enough information to make a good decision about immunizing their children, 33% of parents disagreed or were neutral. 355 parents who disagreed they had enough vaccine information had negative attitudes about immunizations, health care providers, immunization requirements and exemptions, and trust in people responsible for immunization policy. moreover, a larger percentage of parents who reported they did not have access to enough information about vaccines also had several specific vaccine concerns compared with parents who were neutral or agreed they had access to enough information. 355 it may be that when there is a void of accurate, trusted information, doubts about vaccines arise and misinformation is more readily accepted. other studies have demonstrated the effect of providing information on the well-being of patients. for example, information is one factor that has been shown to positively influence a sense of control in patients with rheumatoid arthritis, 356 and perceived lack of information among mothers was one reason contributing to nonimmunization of children in india. 357 by using the principle of audience segmentation (partitioning a population into segments with shared characteristics), a survey study identified five parent groups that varied on health and immunization attitudes and beliefs. 358 the two audience segments identified as most concerned about immunizations ("worrieds" and "fencesitters") were chosen as the focus of a follow-up study to obtain the input of mothers in these segments in the development of evidence-based, tailored educational materials. the purpose of these materials would be to assist health care providers in busy office settings to address questions from these two groups of parents. presentation of these tailored brochures by children's health care providers to parents in an empathetic and respectful manner could aid in improving the health care provider-parent relationship, increasing vaccine acceptance, and ultimately preventing vaccine-preventable diseases. the viss are typically given to parents the day the child is scheduled for immunization. 345, 348, 359 this often places the parent in a conflict situation of attending to the vis or attending to a frightened or upset child. not surprisingly, studies have shown that parents would rather receive the information in advance of the first vaccination visit. 345, [359] [360] [361] suggested earlier times for vaccine education include prenatal clinic visits and just after delivery in a hospital. 362 a national survey indicated that 80% of providers said that a preimmunization booklet for parents would be useful for communicating risks and benefits to parents. 348 the use of complementary and alternative medicine (cam) has been increasing during the past 50 years in the united states. 363 part of this increase is due to mcos providing coverage for some cam therapies. 364 chiropractic care is among the top 10 most commonly used cam therapies. 365 it is of note that some chiropractic colleges teach a negative view of immunizations. 366 in one study, one third of chiropractors agreed that there is no scientific proof that immunizations prevent disease. 366 the basis for the negative views of vaccine effectiveness may lie in the chiropractic doctrine that disease is the result of spinal nerve dysfunction caused by subluxation coupled with the rejection of the germ theory of disease. 366, 367 it may be that some chiropractors who adhere to this belief influence parents against immunizing their children. in one study, parents who requested immunization exemptions for their children were more likely to report cam use in their families than parents who did not request these exemptions. 368 this emphasizes the importance of a trusting physician-patient relationship and providing parents with tailored information in advance of their child's immunizations; in this manner their questions are answered and they are prepared with the facts when they encounter contrary information from other sources. reaching out to chiropractic organizations to foster a better understanding of the benefits of immunizations may be advantageous to medical and public health professionals. parental concern about immunizations has been associated with a lack of trust. for example, one of the factors influencing parents who choose not to vaccinate their children for pertussis is doubt about the reliability of the vaccine information. 369 in another study, compared with parents of vaccinated children, parents of children with an immunization exemption were more likely to express a low level of trust in the government, in addition to other factors such as low perceived susceptibility to and severity of vaccine-preventable diseases and low perceived efficacy and safety. these parents were less likely to believe that medical and public health professionals are good or excellent sources of immunization information. 368 the majority of parents (84%), however, report receiving immunization information from a physician. 182 thus, having a physician who engenders trust providing immunization information and who is available to listen and answer questions is the optimal situation from the public health perspective. if trust in a child's physician is low, parents may be drawn to other, less credible sources of information. when a child experiences an adverse event following receipt of a vaccine, it often raises the question "was this vaccine necessary"? to the parent, it may seem that the risks of the vaccine are greater than the risks of not getting the vaccine. parents who sought medical attention for any of their children owing to an apparent adverse event following immunizations (6.9%) not only expressed more concern about immunizations, but also were more likely to have a child who lacked one or more doses of three high profile vaccines compared with parents who reported that none of their children had experienced an adverse event following immunization. 370 two scenarios were seen as plausible. it may be that parents who were already concerned about vaccines before their child began the vaccination schedule were more reactive and thus sought medical attention for minor side effects (eg, fever) or nonrelated problems. it is also possible that an apparent adverse event following immunization that resulted in parents seeking medical attention for their child caused the parents' perception of vaccines to become more negative. both possibilities may result in parents declining future vaccines for their children. negative attitudes could be addressed by improving communication between clinician and parent. benefit-cost analysis research has shown that physician advice can produce benefits for health issues (eg, problem drinking). 371 moreover, positive communication behaviors such as humor and soliciting questions are associated with lowered physician's risk of a malpractice suit. 372 it may be that in this era of low vaccine-preventable disease incidence and increased public questioning of immunizations, improved provider communication can produce a positive net benefit for parents (reduced anxiety), a cost benefit to the health care system (reduced calls and medical visits for nonserious adverse events following immunization), and an improved physician-patient relationship (more trust and fewer malpractice suits). individual people can vary in their perception of the magnitude of vaccine risks. studies have shown that various factors such as sex, race, political worldviews, emotional affect, and trust are associated with risk perception. 373 in addition, risk perception factors such as involuntariness, uncertainty, lack of control, and high level of dread can lead to a heightened perception of risks. 374 all of these can be seen as associated with childhood immunizations. moreover, these factors have been referred to as "outrage" factors in the risk communication literature. outrage can lead to a person responding emotionally and can increase further the level of perceived risk. 374 it can be difficult to communicate the risk of many vaccinepreventable diseases given their low prevalence in the united states and difficult to communicate the risks of serious vaccine adverse events because they affect such a small proportion of vaccine recipients. 375,376 several factors have been studied that might help people to better understand risk; the first are comparisons. comparisons that are similar (apples to apples) are reported to be better accepted, 377 and, thus, comparisons for vaccines should focus on things that generally prevent harm in children but could pose a small risk (such as bicycle helmets, car seats). the second are visual presentations that help people understand numerical risk, including risk ladders, 378 stick figures, line graphs, dots, pie charts, and histograms. 379 unfortunately, there has been little research done in either of these areas. trust in the source of the risk information is an important factor in its ability to influence people 380 and, as discussed, is developed through listening and ongoing communications. 381 in 1999, american adults had an average score of 51.2 on an index of biomedical literacy designed to measure understanding of biomedical terms and constructs. people with scores less than 50 would likely find it difficult to understand medical stories about why antibiotics are not effective in combating the common cold and the relationship between certain genes and health. 382 the main factors associated with biomedical literacy are the following: (1) level of formal education, (2) number of college-level science courses, and (3) age. some characteristics of scientific literacy include the following abilities: (1) distinguishing experts from the uninformed; (2) recognizing gaps, risks, limits, and probabilities in making decisions involving a knowledge of science or technology; (3) recognizing when a cause-and-effect relationship cannot be drawn; and (4) distinguishing evidence from propaganda, fact from fiction, sense from nonsense, and knowledge from opinion. unfortunately, parental characteristics of those least motivated to obtain timely immunizations for their children are often characterized by low educational level of either parent. 383 there is a wide gap in the level of biomedical understanding across the us population, and this gap emphasizes the need for tailored information. the need for tailored information applies to all areas of health, including childhood immunizations. immunization educational materials aimed at a middle level or a "one size fits all" are not likely to satisfy all parents' needs. 382 the importance of educating parents concerned about vaccines why should we care about a small number of parents who are worried about vaccines for their children? we should care because it is not only ethically the right thing to do, it is also the right thing to do from a practical viewpoint. vaccine acceptability refers to the factors that go into parents' decisions to have their children immunized. it is important not to assume that just because most parents are having their children immunized that they will continue to do so. 384 while the host of factors contributing to parents' decisions to have their children immunized (eg, need for information, experience with adverse events) might remain stable for some time, it is possible that one or more of the factors may change so that some parents perceive the risks of vaccines to be greater than the risk of disease. this would then push the parents above a theoretical "unacceptability threshold" in which they would choose not to have their children immunized with one or more vaccines. this is especially possible as more vaccines are added to the immunization schedule. an increasing number of parents have a choice, through religious or philosophical immunization exemption laws or schooling their children at home. 385 averting the future possibility of outbreaks of vaccine-preventable diseases will take a concerted effort by health care and public health professionals to educate and better communicate with parents concerned about immunizations. in guidance for clinicians, the american academy of pediatrics suggests that pediatricians should listen carefully and respectfully to parents' immunization concerns, factually communicate the risks and benefits of vaccines, and work with parents who may be concerned about a specific vaccine or having their child receive multiple vaccines in one visit. 386 providers can make a huge impact on vaccine acceptance, resulting in a cascading effect in which providing information can increase trust and increasing trust can lead to greater acceptance of and confidence in vaccines. for health care providers to be able to optimally fill this important role, however, two related issues should be addressed. the first is the need for quality communication courses and training in medical schools and residencies and training programs for medical and public health professionals. 387,388 the second is for mcos and medical insurance companies to adequately reimburse physicians for health education. lack of reimbursement to physicians has been noted as a barrier to implementation of behavioral treatments for health issues such as heart disease 353 and smoking. 389 it is important to note that studies have shown education programs can be a cost savings to health care systems. 390, 391 we live in a world already benefiting from vaccines that exist, and there is the promise of more vaccines to come. the challenge we have now is to make sure that the promise is not lost because we did not present the benefits and risks of vaccines in a meaningful way acceptable to the public. an optimal immunization safety system requires rigorous attention to safety during prelicensure research and development; active monitoring for potential safety problems after licensure; and clinical research and risk management activities, including risk communication, focused on minimizing potential vaccine adverse reactions. prelicensure activities form the foundation of vaccine safety. rapid advances in biotechnology are leading to the development of new vaccines, 392 and novel delivery technologies, such as dna vaccines and new adjuvants, are being developed to permit more antigens to be combined, reducing the number of injections. 142,393 new technologies can also be expected to be used to detect potential safety problems throughout the research and development process (eg, adventitial agents). a challenge will be determining the proper role and interpretation of new technologies. for example, a recent study used powerful new metagenomics and panmicrobial microarray technologies to screen for adventitious viral nucleic acid sequences in a number of vaccines. 394 the study identified the presence of dna from porcine circovirus type 1 (pcv1) in rotarix. this finding led to a temporary suspension of the use of the vaccine while the fda evaluated the study and its implications. ultimately, it was determined that the presence of the pcv1 nucleic acid sequences did not represent a health concern, and use of the vaccine was allowed to resume. 395 in the prelicensure evaluation of new vaccines, the trend is likely to continue to conduct larger phase 3 trials enrolling tens of thousands of participants. while such larger trials are helpful in identifying more rare adverse events, even these larger trials may not be large enough to detect increased risks of rare events. for example, the rotarix preclinical trial identified no increased risk of intussusception in a study that enrolled more than 60,000 infants. 49 the manufacturer nevertheless committed to conduct a large postlicensure safety monitoring study. a preliminary analysis of postlicensure monitoring data from mexico identified a statistically significant increased risk within 30 days of vaccination with an attributable risk of approximately 1 per 100,000. 396 the attributable risk was much less than that found for rotashield (approximately 1 per 10,000), and no changes were made to the vaccine recommendations. although technological advances and more thorough evaluation of safety before vaccines are licensed should lead to the development of safer vaccines, there will continue to be a need for comprehensive postlicensure safety monitoring systems. combined with the difficulties associated with identifying rare, delayed, or insidious vaccine safety problems in prelicensure studies, 43 the well-organized consumer activist organizations, 339 internet information of questionable accuracy, 309, 310 media eagerness for controversy, 311, 340 and relatively rare individual encounters with vaccine-preventable diseases virtually ensure that vaccine safety concerns are unlikely to go away. the existence of a robust vaccine safety monitoring system is essential for providing assurance of the safety of currently marketed vaccines and for rapidly identifying and responding to potential safety problems. currently, srss, such as vaers, serve as the frontline systems for the early identification of vaccine safety problems. such systems could be improved if reporting were more complete. application of web-based and text messaging technologies could make reporting easier and more accurate and also enable more active follow-up of vaccinated persons. alerts built into electronic medical record systems could also improve reporting to vaers, as could linkages with immunization registries. some of these advances will be particularly important to enable monitoring vaccine safety in mass vaccination campaigns during which vaccinations may be administered primarily outside of the traditional health care system. an optimal vaccine safety monitoring system must also include a mechanism or infrastructure to rapidly conduct formal epidemiologic evaluations of potential safety problems identified from srss or other sources. in the united states, this function is primarily served by the vsd project. the diffusion of electronic health records and the capability to link records across data systems (such as large health insurance claims databases and immunization registries) may allow the expansion of the population that could be included in postlicensure epidemiologic evaluations of vaccine safety. for example, the fda sentinel initiative has a goal to develop a national electronic system covering 100 million people for monitoring the postmarket safety of drugs and other medical products, including vaccines. 397 for adverse reactions that are established to be caused by vaccines, clinical and laboratory research is essential for determining the biological mechanisms of the adverse reaction, which in turn could lead to the development of safer vaccines. clinical research is also essential for the development of protocols for safer vaccination, including revaccination of persons who have previously experienced an adverse reaction. advances in genomics and immunology hold particular promise for elucidating biological mechanisms of vaccine adverse reactions and the development of possible screening strategies for persons who may be at high risk for an adverse reaction. a challenge for such research will be identifying sufficient numbers of people who may have rare vaccine adverse reactions and enrolling them into studies in which appropriate biological samples can be collected, stored, and analyzed under a standardized protocol. scientific data are essential in the monitoring and evaluation of vaccine safety, but scientific evidence alone often is not sufficient for providing reassurance about the safety of a vaccine. although immunization levels of us children are high, a sizable fraction of parents do not have their children fully immunized, and concern about vaccine safety is the leading reason for underimmunization. these concerns persist despite the scientific evidence that vaccines do not cause autism or a host of other conditions that have been alleged to be caused by vaccines, such as asthma, diabetes, and autoimmune diseases. thus, it is critically important that public health agencies, medical organizations, and other influential authorities continue to focus on the safety of vaccines and assure public confidence by providing clear, consistent messages on vaccine safety concerns; supporting effective and transparent vaccine safety monitoring systems and research activities; providing review and recommendations by respected independent expert groups on vaccine safety controversies; and engaging advocacy groups in constructive and open dialogue about their vaccine safety concerns. although the efforts of government, medical, and other authorities are important, it is health care providers who have the greatest influence in determining the acceptance of vaccines by individual people. even among parents who believe that vaccines may not be safe, most will have their children vaccinated if they have a trusting relationship with an influential health care provider. thus, development of tools and strategies that can assist health care providers in effectively communicating with their patients on the risks and benefits of vaccines will continue to be important. vaccine safety has also become an important concern in developing countries. 398 the high-titer measles vaccine mortality experience highlighted the importance of improving the quality control and evaluating the safety of vaccines used in developing countries. 112 plans to eliminate neonatal tetanus and measles via national immunization days, during which millions of people receive parenteral immunizations over a period of days, 399 pose substantial challenges to ensuring injection safety, 400 especially given concerns about inadequate sterilization of reusable syringes and needles, recycling of disposable syringes and needles, and cross-contamination resulting from the current generation of jet injectors. 401 the who has promoted the use of safer auto-disposable syringes and disposal boxes. 402 these and other new, safer administration technologies are urgently needed. 403 in addition, there is a need to establish minimal vaccine safety monitoring capabilities, such as srss, and the capability to rapidly investigate vaccine safety problems and effectively communicate the findings of the investigations. vaccines are among the most successful and cost-effective public health tools for preventing disease and death. vaccines, however, are not completely without risk of side effects or other adverse outcomes. a timely, credible, and effective monitoring system, coupled with prompt action in response to identified safety problems, is essential to preventing adverse effects of vaccination and to maintaining public confidence in immunizations. since immunizations are typically administered to healthy people and are often recommended or mandated to provide societal and individual protection, vaccines must be held to a very high standard of safety. vaccine safety monitoring and research should optimally be able to detect potentially very small levels of increased risk, especially for adverse events that can result in death or permanent disability from vaccines that are universally recommended or mandated. the ultimate goal of such research, including the application of new developments in biotechnology, is to develop safer vaccines and vaccination practices. access the complete reference deadly choices: how the anti-vaccine movement threatens us all ensuring the optimal safety of licensed vaccines: a prospective of the vaccine research, development, and manufacturing companies active surveillance for adverse events: the experience of the vaccine safety datalink project understanding the role of human variation in vaccine adverse events: the clinical immunization safety assessment network addressing parents' concerns: do multiple vaccines overwhelm or weaken the infant's immune system? addressing parents' concerns: do vaccines cause allergic or autoimmune diseases? measles-mumps-rubella vaccine and autism thimerosal in vaccines: a joint statement of the american academy of pediatrics and the public health service autism's false prophets: bad science, risky medicine, and the search for a cure addressing parents' concerns: do vaccines contain harmful preservatives, adjuvants, or residuals we are grateful to robert davis, deborah gust, robert chen, and charles hackett who contributed sections of this chapter in previous editions of this book and for the excellent assistance on this chapter rendered by the following persons: dan salmon, john iskander, susan scheinman, christine korhonen, allison kennedy, michele russell, tamara murphy, penina haber, and gina mootrey. key: cord-030116-ucmzbezx authors: hardell, lennart; carlberg, michael title: health risks from radiofrequency radiation, including 5g, should be assessed by experts with no conflicts of interest date: 2020-07-15 journal: oncol lett doi: 10.3892/ol.2020.11876 sha: doc_id: 30116 cord_uid: ucmzbezx the fifth generation, 5g, of radiofrequency (rf) radiation is about to be implemented globally without investigating the risks to human health and the environment. this has created debate among concerned individuals in numerous countries. in an appeal to the european union (eu) in september 2017, currently endorsed by >390 scientists and medical doctors, a moratorium on 5g deployment was requested until proper scientific evaluation of potential negative consequences has been conducted. this request has not been acknowledged by the eu. the evaluation of rf radiation health risks from 5g technology is ignored in a report by a government expert group in switzerland and a recent publication from the international commission on non-ionizing radiation protection. conflicts of interest and ties to the industry seem to have contributed to the biased reports. the lack of proper unbiased risk evaluation of the 5g technology places populations at risk. furthermore, there seems to be a cartel of individuals monopolizing evaluation committees, thus reinforcing the no-risk paradigm. we believe that this activity should qualify as scientific misconduct. most politicians and other decision-makers using guidelines for exposure to radiofrequency (rf) radiation seem to ignore the risks to human health and the environment. the fact that the international agency for research on cancer (iarc) at the world health organization (who) in may 2011 classified rf radiation in the frequency range of 30 khz to 300 ghz to be a 'possible' human carcinogen, group 2b (1, 2) , is being ignored. this has been recently exemplified in a hearing at the tallinn parliament in estonia (3) . an important factor may be the influence on politicians by individuals and organizations with inborn conflicts of interests (cois) and their own agenda in supporting the no-risk paradigm (4, 5) . the international commission on non-ionizing radiation protection (icnirp) has repeatedly ignored scientific evidence on adverse effects of rf radiation to humans and the environment. their guidelines for exposure are based solely on the thermal (heating) paradigm and were first published in icnirp 1998 (6) , updated in icnirp 2009 (7) and have now been newly published in icnirp 2020 (8) , with no change of concept, only relying on thermal effects from rf radiation on humans. the large amount of peer-reviewed science on non-thermal effects has been ignored in all icnirp evaluations (9, 10) . additionally, icnirp has successfully maintained their obsolete guidelines worldwide. cois can be detrimental, and it is necessary to be as unbiased as possible when assessing health risks. there are three points that should be emphasized. firstly, the evidence regarding health risks from environmental factors may not be unambiguous, and therefore informed judgements must be made. furthermore, there are gaps in knowledge that call for experienced evaluations, and no conclusion can be reached without value judgements. secondly, paradigms are defended against the evidence and against external assessments by social networks in the scientific community. thirdly, the stronger the impact of decisions about health risks on economic, military and political interests, the stronger will stakeholders try to influence these decision processes. since the iarc evaluation in 2011 (1, 2) , the evidence on human cancer risks from rf radiation has been strengthened based on human cancer epidemiology reports (9) (10) (11) , animal carcinogenicity studies (12) (13) (14) and experimental findings on oxidative mechanisms (15) and genotoxicity (16) . therefore, the iarc category should be upgraded from group 2b to group 1, a human carcinogen (17) . the deployment of the fifth generation, 5g, of rf radiation is a major concern in numerous countries, with groups of citizens trying to implement a moratorium until thorough research on adverse effects on human health and the environment has been performed. an appeal for a moratorium, currently signed by >390 international scientists and medical doctors, was sent to the european union (eu) in september 2017 (18) , currently with no eu response (19) . several regions have implemented a moratorium on the deployment of 5g motivated by the lack of studies on health effects, for instance geneva (20) . in the present article, the current situation in switzerland is discussed as an example (21) . additionally, the icnirp 2020 evaluation is discussed (8) . several swiss citizens have brought to our attention that associate professor martin röösli is the chair of two important government expert groups in switzerland (directeur), despite possible cois and a history of misrepresentation of science (22, 23) . these groups are beratende expertengruppe nis (berenis; the swiss advisory expert group on electromagnetic fields and non-ionizing radiation) (24) , and the subgroup 3, the mobile communications and radiation working group of the department of the environment, transport, energy and communications/eidgenössisches departement für umwelt, verkehr, energie und kommunikation, evaluating rf-radiation health risks from 5g technology (25, 26) . the conclusions made in the recent swiss government 5g report are biased and can be found here (27, 28) . this 5g report concluded that there is an absence of short-term health impacts and an absence or insufficient evidence of long-term effects [see table 17 (tableau 17) on page 69 in the french version (27) and table 17 (tabelle 17) on page 67 in the german version (28) ]. furthermore, it was reported that there is limited evidence for glioma, neurilemmoma (schwannoma) and co-carcinogenic effects, and insufficient evidence for effects on children from prenatal exposure or from their own mobile phone use. regarding cognitive effects, fetal development and fertility (sperm quality), the judgement was that the evidence on harmful effects is insufficient. these evaluations were strikingly similar to those of the icnirp (see appendix b in icnirp 2020; 8). other important endpoints, such as effects on blood-brain barrier, cell proliferation, apoptosis (programmed cell death), oxidative stress (reactive oxygen species) and gene and protein expression, were not evaluated. according this swiss evaluation is scientifically inaccurate and is in opposition to the opinion of numerous scientists in this field (18) . in addition, 252 electromagnetic field (emf) scientists from 43 countries, all with published peer-reviewed research on the biologic and health effects of nonionizing electromagnetic fields (rf-emf) have stated that: 'numerous recent scientific publications have shown that rf-emf affects living organisms at levels well below most international and national guidelines. effects include increased cancer risk, cellular stress, increase in harmful free radicals, genetic damages, structural and functional changes of the reproductive system, learning and memory deficits, neurological disorders, and negative impacts on general wellbeing in humans. damage goes well beyond the human race, as there is growing evidence of harmful effects to both plant and animal life' (30) . we are concerned that the swiss 5g report may be influenced by ties to mobile phone companies (cois) by one or several members of the evaluating group. funding from telecom companies is an obvious coi. martin röösli has been a member of the board of the telecom funded swiss research foundation for electricity and mobile communication (fsm) organization and he has received funding from the same organization (31) (32) (33) . it should be noted that the fsm is a foundation that serves formally as an intermediate between industry and researchers. according to their website, among the five founders of fsm who 'provided the initial capital of the foundation' four are telecommunications companies: swisscom, salt, sunrise, 3g mobile (liquidated in 2011). the fifth founder is eth zurich (technology and engineering university). there are only two sponsors, swisscom (telecommunications) and swissgrid (energy), who 'support the fsm with annual donations that allow for both the management of the foundation and research funding' (34) . the same situation applies to being a member of icnirp (table i) (35) . in 2008, the ethical council at karolinska institute in stockholm stated that being a member of icnirp is a potential coi. such membership should always be declared. this verdict was based on activities by anders ahlbom in sweden, at that time a member of icnirp, but is a general statement (2008-09-09; dnr, 3753-2008-609). in summary: 'it is required that all parties clearly declare ties and other circumstances that may influence statements, so that decision makers and the public may be able to make solid conclusions and interpretations. aa [anders ahlbom] should thus declare his tie to icnirp whenever he makes statements on behalf of authorities and in other circumstances' (translated into english). cois with links to industry are of great importance; these links may be direct or indirect funding for research, payment of travel expenses, participation in conferences and meetings, presentation of research, etc. such circumstances are not always declared as exemplified above. a detailed description was recently presented for icnirp members (22) . icnirp is a non-governmental organization (ngo) based in germany. members are selected via an internal process, and the organization lacks transparency and does not represent the opinion of the majority of the scientific community involved in research on health effects from rf radiation. independent international emf scientists in this research area have declared that: 'in 2009, the icnirp released a statement saying that it was reaffirming its 1998 guidelines, as in their opinion, the scientific literature published since that time has provided no evidence of any adverse effects below the basic restrictions and does not necessitate an immediate revision of its guidance on limiting exposure to high frequency electromagnetic fields. icnirp continues to the present day to make these assertions, in spite of growing scientific evidence to the contrary. it is our opinion that, because the icnirp guidelines do not cover long-term exposure and low-intensity effects, they are insufficient to protect public health' (30) . icnirp only acknowledges thermal effects from rf radiation. therefore, the large body of research on detrimental non-thermal effects is ignored. this was further discussed in a peer-reviewed scientific comment article (3) . in 2018, icnirp published 'icnirp note: critical evaluation of two radiofrequency electromagnetic field animal carcinogenicity studies published in 2018' (36). it is surprising that this note claims that the histopathological evaluation in the us national toxicology program (ntp) study on animals exposed to rf radiation was not blinded (12, 13) . in fact, unfounded critique of the ntp study had already been rebutted (37); however, this seems to have had little or no impact on this icnirp note casting doubt on the findings of the animal study: 'this commentary addresses several unfounded criticisms about the design and results of the ntp study that have been promoted to minimize the utility of the experimental data on rfr [radiofrequency radiation] for assessing human health risks. in contrast to those criticisms, an expert peerreview panel recently concluded that the ntp studies were well designed, and that the results demonstrated that both gsm-and cdma-modulated rfr were carcinogenic to the heart (schwannomas) and brain (gliomas) of male rats' (37) . in contrast to the opinion of the 13 icnirp commission members, the iarc advisory group of 29 scientists from 18 countries has recently stated that the cancer bioassay in experimental animals and mechanistic evidence warrants high priority re-evaluation of the rf radiation-induced carcinogenesis (38) . (39) . surprisingly, the iarc classification of rf-emf exposure as group 2b ('possibly' carcinogenic to humans) from 2011 was concealed in the background material to the new icnirp draft on guidelines. notably, one of the icnirp commission members, martin röösli (40), was also one of the iarc experts evaluating the scientific rf carcinogenicity in may 2011 (41) . he should be well aware of the iarc classification. the iarc classification contradicts the scientific basis for the icnirp guidelines, making novel guidelines necessary and providing a basis to halt the rollout of 5g technology. therefore, the icnirp provides scientifically inaccurate reviews for various governments. one issue is that only thermal (heating) effects from rf radiation are considered, and all non-thermal effects are dismissed. an analysis from the uk demonstrates these inaccuracies (4), also discussed in another article (5) . all members of the icnirp commission are responsible for these biased statements that are not based on solid scientific evidence. icnirp release of novel guidelines for rf radiation. on march 11, 2020, icnirp published their novel guidelines for exposure to emfs in the range of 100 khz to 300 ghz, thus including 5g (8). the experimental studies demonstrating a variety of non-thermal biological/health effects (9,10) are not considered, as in their previous guidelines (6, 7) . additionally, the icnirp increased the reference levels for the general public averaged over 6 min for rf frequencies >2-6 ghz (those that will be used for 5g in this frequency range), from 10 w/m 2 (tables 5 and 7 in ref. no. 6) to 40 w/m 2 ( table 6 in ref. no. 8), which paves the way for even higher exposure levels to 5g than the already extremely high ones. background dosimetry is discussed in appendix a of the icnirp 2020 guidelines (8) . the discussion on 'relevant biophysical mechanisms' should be criticized. the only mechanism considered by icnirp is temperature rise, which may also occur with 5g exposure, apart from the established non-thermal biological/health effects (42, 43) . it is well known among experts in the emf-bioeffects field that the recorded cellular effects, such as dna damage, protein damage, chromosome damage and reproductive declines, and the vast majority of biological/health effects are not accompanied by any significant temperature rise in tissues (44) (45) (46) (47) . the ion forced-oscillation mechanism (48) should be referred to as a plausible non-thermal mechanism of irregular gating of electrosensitive ion channels on cell membranes, resulting in disruption of the cell electrochemical balance and initiating free radical release and oxidative stress in the cells, which in turn causes genetic damage (15, 49) . the irregular gating of ion channels on cell membranes is associated with changes in permeability of the cell membranes, which icnirp admits in its summary (8) . health risks are discussed in appendix b of the icnirp 2020 guidelines (8) . again, only thermal effects are considered, whereas literature on non-thermal health consequences is disregarded (9, 10, 50) . in spite of public consultations on the draft, the final published version on health effects is virtually identical to the draft version, and comments seem to have been neglected (19) . in the following section, appendix b on health effects (8) (scenihr 2015) , and the swedish radiation safety authority (ssm) have produced several international reports regarding this issue (ssm 2015 (ssm , 2016 (ssm , 2018 . accordingly, the present guidelines have used these literature reviews as the basis for the health risk assessment associated with exposure to radiofrequency emfs rather than providing another review of the individual studies'. in the last 11 years since its previous icnirp 2009 statement (7), icnirp has not managed to conduct a novel evaluation of health effects from rf radiation. however, as shown in table i , several of the present icnirp members are also members of other committees, such as the eu scientific committee on emerging and newly identified health risks (scenihr), the swedish radiation safety authority (ssm) and the who, thus creating a cartel of individuals known to propagate the icnirp paradigm on rf radiation (4, 5, 22, 51) . in fact, six of the seven expert members of the who, including emelie van deventer, were also included in icnirp (5, 7) . therefore, emilie van deventer, the team leader of the radiation programme at who (the international emf project), is an observer on the main icnirp commission, and ssm seems to be influenced by icnirp. among the current seven external experts (danker-hopfe, dasenbrock, huss, harbo polusen, van rongen, röösli and scarfi), five are also members of icnirp, and van deventer used to be part of ssm. as discussed elsewhere (5), it is unlikely that a person's evaluation of health risks associated with exposure to rf radiation would differ depending on what group the person belongs to. therefore, by selecting group members, the final outcome of the evaluation may already be predicted (no-risk paradigm). additionally, we believe that this may compromise sound scientific code of conduct. the scenihr report from 2015 (52) has been used to legitimate the further expansion of the wireless technology and has been the basis for its deployment in a number of countries. one method, applied in the scenihr report, to dismiss cancer risks involves the selective inclusion of studies, excluding studies reporting cancer risks and including some investigations with inferior epidemiological quality. the report has been heavily criticized by researchers with no coi (53) regarding the ssm, only yearly updates are available and no overall evaluations are made. therefore, no thorough review is presented. over the years, the icnirp has dominated this committee (table i) . therefore, it is unlikely that the opinion of the ssm will differ from that of the icnirp. in 2014, the who launched a draft of a monograph on rf fields and health for public comments (54) . it should be noted that the who issued the following statement: 'this is a draft document for public consultation. please do not quote or cite'. icnirp completely ignored that request and used the aforementioned document. the public consultations on the draft document were dismissed and never published. in addition to van deventer, five of the six members (mann, feychting, oftedal, van rongen, and scarfi) of the core group in charge of the who draft were also affiliated with icnirp, which constitutes a coi (table i) . scarfi is a former member of icnirp (5) . several individuals and groups sent critical comments to the who on the numerous shortcomings in the draft of the monograph on rf radiation. in general, the who never responded to these comments and it is unclear to what extent, if any, they were even considered. nevertheless, the final version of the who 'in-depth review' has never been published. the authors of the present article were part of a team that applied to review sr1-human cancer. on december 20, 2019, the following reply was received from the who radiation programme: 'after careful review, we have decided to choose another team for this systematic review'. transparency is of importance for the whole process. therefore, a query was sent to the who requesting informa-tion regarding the following points: 'who did the evaluation of the groups that answered the call? what criteria were applied? how many groups had submitted and who were these? which groups were finally chosen for the different packages?'. in spite of sending the request four times, january 2, january 3, april 7 and april 30, 2020, there has been no reply from who. this appears to be a secret process behind closed doors. these circumstances have also been reported in microwave news (55) . it is important to comment on the current icnirp evaluation. notably, on february 27, 2020, two weeks before the icnirp publication, the who team on public health, environmental and social determinants of health issued a statement on 5g mobile networks and health: 'to date, and after much research performed, no adverse health effect has been causally linked with exposure to wireless technologies' (56) . this statement is not correct based on current knowledge (4, 5, (9) (10) (11) 17, 19) and was without a personal signature. the lack of research on 5g safety has been previously discussed (19) . furthermore, there is no evidence that can 'causally link' an adverse effect to an exposure. causality is no empirical fact, it is an interpretation. in the following section, only one (cancer) of the eight different end points in the icnirp publication (8) is discussed, since it deals with our main research area. viii) cancer. 'in summary, no effects of radiofrequency emfs on the induction or development of cancer have been substantiated. the only substantiated adverse health effects caused by exposure to radiofrequency emfs are nerve stimulation, changes in the permeability of cell membranes, and effects due to temperature elevation. there is no evidence of adverse health effects at exposure levels below the restriction levels in the icnirp (1998) guidelines and no evidence of an interaction mechanism that would predict that adverse health effects could occur due to radiofrequency emf exposure below those restriction levels'. the icnirp draft (39) has been previously described to some extent (19) . the published final version on health effects is virtually similar to the draft. it cannot be taken at face value as scientific evidence of no risk from rf radiation. one example is the following statement (p. 41): '…a set of case-control studies from the hardell group in sweden report significantly increased risks of both acoustic neuroma and malignant brain tumors already after less than five years since the start of mobile phone use, and at quite low levels of cumulative call time'. this allegation is not correct according to our publication for glioma (11) . in the shortest latency group >1-5 years, the risk of glioma was not increased (odds ratio (or), 1.1; 95% ci, 0.9-1.4) for use of wireless phones (mobile phone and/or cordless phone). there was a statistically significant increased risk of glioma per 100 h of cumulative use (or, 1.011; 95% ci, 1.008-1.014) and per year of latency (or, 1.032; 95% ci, 1.019-1.046) (11) . these published results are in contrast to the icnirp claims. regarding acoustic neuroma, the corresponding detailed results are reported in our previous study (57) . the shortest latency period >1-5 years yielded an or of 1.2 (95% ci, 0.8-1.6) for use of wireless phones; the risk increased per 100 h of cumulative use (or, 1.008; 95% ci, 1.002-1.014) and per year of latency (or, 1.056; 95% ci, 1.029-1.085) (57) . therefore, the allegation by icnirp is false. it is remarkable that icnirp is uninformed and that their writing is based on a misunderstanding of the peer-reviewed published articles as exemplified above. additionally, our studies (11, 57) and another study by coureau et al (58) , as well as the iarc evaluation from 2011 (1,2), are not included among the references. several statements by icnirp are made without any scientific references. on the other hand, the danish cohort study on mobile phone use (59) is included, in spite of the fact that it was judged by iarc (1,2), as well as in our review (60) , to be uninformative. a biased article written by authors including icnirp members, used to 'prove' the no-risk paradigm for rf radiation carcinogenesis (23) , is cited by icnirp. notably, the article has not undergone relevant peer-review and we believe that it should not have been published in its current version. the shortcomings in the aforementioned article are discussed in the following sections. as discussed below, another claim (23) is incorrect regarding increased risk of brain tumors associated with use of wireless phones: 'however, they are not consistent with trends in brain cancer incidence rates from a large number of countries or regions, which have not found any increase in the incidence since mobile phones were introduced'. the criticism of the icnirp draft guidelines from 2018 by the emf call (61) can also be applied to the current icnirp publication. the call has been signed by 164 scientists and medical doctors, as well as 95 ngos: 'the international commission on non-ionizing radiation protection (icnirp) issued draft guidelines on 11th july 2018 for limiting exposure to electric, magnetic and electromagnetic fields (100 khz to 300 ghz).1 these guidelines are unscientific, obsolete and do not represent an objective evaluation of the available science on effects from this form of radiation. they ignore the vast amount of scientific findings that clearly and convincingly show harmful effects at intensities well below icnirp guidelines. 2 we ask the united nations, the world health organization, and all governments to support the development and consideration of medical guidelines16, that are independent of conflict of interests in terms of direct or indirect ties to industry, that represent the state of medical science, and that are truly protective'. in the recent report on icnirp published by two members of the european parliament it is concluded: 'that is the most important conclusion of this report: for really independent scientific advice we cannot rely on icnirp. the european commission and national governments, from countries like germany, should stop funding icnirp. it is high time that the european commission creates a new, public and fully independent advisory council on non-ionizing radiation' (22) . published article. this section discusses an article with conclusions not substantiated by scientific evidence, representing a biased evaluation of cancer risks from mobile phone use and is an example of lack of objectivity and impartiality (23). the aforementioned report was used by icnirp 2020 (8) to validate that no risks have been found for brain and head tumors. therefore, the article should be discussed in further detail. the aforementioned article has numerous severe scientific deficiencies. one is that the results on use of cordless phones as a risk factor for brain tumors are not discussed. in fact, detailed results on cordless phones in studies by hardell et al (11, 57) are omitted. when discussing glioma risk, all results on cumulative use of mobile phones, as well as ipsilateral or contralateral use associated with tumor localization in the brain, are omitted from the figures in the main text. some results in the article by röösli et al (23) , such as cumulative use, can be found in the supplementary material, although the increased risk among heavy users is disregarded (11, 57, 58, 62) . in supplementary figure 4 , all odds ratios regarding long-term (≥10 years) use of mobile phones are above unity (>1.0) for glioma and neuroma (23) . no results are provided for ipsilateral mobile phone use (same side of tumor localization and mobile phone use), which is of large biological importance. results on cumulative use, latency and ipsilateral use are especially important for risk assessment and have shown a consistent pattern of increased risk for brain and head tumors (11, 57) . in the aforementioned article, recall bias is discussed as the reason for increased risk (23) . the studies by hardell et al (11, 57) included all types of brain tumors. in one analysis, meningioma cases in the same study were used as the 'control' entity (11) , and still a statistically significant increased risk of glioma was identified for mobile phone use (ipsilateral or, 1.4; 95% ci, 1.1-1.8; contralateral or, 1.0; 95% ci, 0.7-1.4) and for cordless phone use (ipsilateral or, 1.4; 95% ci, 1.1-1.9; contralateral or, 1.1; 95% ci, 0.8-1.6). if the results were 'explained' by recall bias, similar results would have been obtained for both glioma and meningioma. thus, this type of analyses would not have yielded an increased glioma risk. also, for acoustic neuroma a statistically significant increased risk was found using meningioma cases as 'controls' (57) . therefore, the results in the studies by hardell et al (11, 57) cannot be explained by a systematic difference in assessment of exposure between cases and controls. these important methodological findings were disregarded by röösli et al (23) . in the analyses of long-term use of mobile phones, a danish cohort study on mobile phone use is included (59) , which was concluded to be uninformative in the 2011 iarc evaluation (1, 2) . a methodological shortcoming of the aforementioned study was that only private mobile phone subscribers in denmark between 1982 and 1995 were included in the exposure group (59) . the most exposed group, comprising 200,507 corporate users of mobile phones, were excluded and instead included in the unexposed control group consisting of the rest of the danish population. users with mobile phone subscription after 1995 were not included in the exposed group and were thus treated as unexposed at the time of cut-off of the follow up. no analysis of laterality of mobile phone use in relation to tumor localization was performed. notably, this cohort study is now included in the risk calculations, although martin röösli was a member of the iarc evaluation group and should have been aware of the iarc decision. the numerous shortcomings in the danish cohort study, discussed in detail in a peer-reviewed article (60) , are omitted in the article by röösli et al (23) . regarding animal studies, a study by falcioni et al (14) at the ramazzini institute on rf radiation carcinogenesis is only mentioned as a reference, but the results are not discussed. in fact, these findings (14) provide supportive evidence on the risk found in human epidemiology studies (3), as well as the results in the ntp study (12, 13) . furthermore, for incidence studies on brain tumors, the results are not presented in an adequate way. there is a lot of emphasis on the swedish cancer register data (63, 64) , but the numerous shortcomings in the reporting of brain tumor cases to the register are not discussed. these shortcomings have been presented in detail in a previous study (63) , but are disregarded by röösli et al (23) . there is clear evidence from several countries regarding increasing numbers of patients with brain tumors, such as in sweden (63, 64) , england (65), denmark (66) and france (67) . the article by röösli et al (23) , does not represent an objective scientific evaluation of brain and head tumor risk associated with the use of wireless phones, and should thus be disregarded. by omitting results of biological relevance and including studies that have been judged to be uninformative, the authors come to the conclusion that there are no risks: 'in summary, current evidence from all available studies including in vitro, in vivo, and epidemiological studies does not indicate an association between mp [mobile phone] use and tumors developing from the most exposed organs and tissues'. röösli et al (23) , disregard the concordance of increased cancer risk in human epidemiology studies (11, 57, 58, 62) animal studies (12) (13) (14) 68, 69) and laboratory studies (15, 16, 37) . it is unfortunate that the review process of the aforementioned article has not been of adequate quality. finally, there is no statement in the article of specific funding of this particular work, which is not acceptable. only a limited number of comments on general funding are provided. it is not plausible that there was no funding for the study. we believe that, due to its numerous limitations, the aforementioned article should not have been published. cefalo. in 2011, a case-control study on mobile phone use and brain tumor risk among children and adolescents termed cefalo was published (70) . the study appears to have been designed to misrepresent the true risk, since the following question regarding cordless phone use was asked: 'how often did [child] speak on the cordless phone in the first 3 years he/she used it regularly?'. there are no scientific valid reasons to limit the investigation to the first 3 years. the result is a misrepresentation and a wrong exposure classification, since aydin et al (70) willingly omitted any increase in the child's use of and exposure from cordless phone radiation after the first 3 years of use. this unscientific treatment of cordless phone exposure was not mentioned in the article other than in a footnote of a table and in the methods section (70) ; however, no explanation was provided: 'specifically, we analyzed whether subjects ever used baby monitors near the head, ever used cordless phones, and the cumulative duration and number of calls with cordless phones in the first 3 years of use'. since previous studies have demonstrated that these phone types, in addition to mobile phones, increase brain tumor risk (11, 57) , we believe that the exclusion of a complete exposure history on the use of cordless phones represents scientific misconduct. in a critical comment the authors of the present study wrote: 'further support of a true association was found in the results based on operator-recorded use for 62 cases and 101 controls, which for time since first subscription >2.8 years yielded or 2.15 (95% ci 1.07-4.29) with a statistically significant trend (p = 0.001). the results based on such records would be judged to be more objective than face-to-face interviews, as in the study that clearly disclosed to the interviewer who was a case or a control. the authors disregarded these results on the grounds that there was no significant trend for operator data for the other variables -cumulative duration of subscriptions, cumulative duration of calls and cumulative number of calls. however, the statistical power in all the latter groups was lower since data was missing for about half of the cases and controls with operator-recorded use, which could very well explain the difference in the results' (71) . our conclusion was that: 'we consider that the data contain several indications of increased risk, despite low exposure, short latency period, and limitations in the study design, analyses and interpretation. the information certainly cannot be used as reassuring evidence against an association, for reasons that we discuss in this commentary' (71) . this is in contrast to the authors that claimed that the study was reassuring of no risk in a press release from martin röösli, july (73) . considering the results and the numerous scientific shortcomings in the study (70) , the statements in these press releases are not correct. there is no doubt that several individuals included in table i are influential, being members, as well as having consulting assignments, in several organizations, such as icnirp, berenis, the ssm, the program electromagnetic fields and health from zonmw in the netherlands, and the rapid response group for the japan emf information center (74) . in fact, there appears to be a cartel of individuals working on this issue (75) . associate professor martin röösli has had the chance to provide his view on the content of the present article relating to him. the only message from him was in an e-mail dated january 16, 2020: 'just to be clear, all my research is funded by public money or not-for -profit fundations [foundations] . i think you will not help an important debate if you spread fake news'. obviously, as described in the present article, his comment is not correct considering his funding from the telecom industry (76, 77) . as shown in table i , few individuals, and mostly the same ones, are involved in different evaluations of health risks from rf radiation and will thus propagate the same views on the risks in agencies of different countries associated with the icnirp views (4, 5) . therefore, it is unlikely that they will change their opinions when participating in different organizations. furthermore, their competence in natural sciences, such as medicine, is often low or non-existent due to a lack of education in these disciplines (2) . therefore, any chance for solid evaluations of medical issues is hampered. additionally, it must be concluded that if the 'thermal only' dogma is dismissed, this will have wide consequences for the whole wireless community, including permissions for base stations, regulations of the wireless technology and marketing, plans to roll out 5g, and it would therefore have a large impact on the industry. this may explain the resistance to acknowledge the risk by icnirp, eu, who, ssm and other agencies. however, the most important aspects to consider are human wellbeing and a healthy environment. telecoms can make profit in a variety of ways, and wireless is just one of them. they have the capacity to maintain profits by using different techniques, such as optical fiber, that will provide more data with less rf radiation exposure. particularly when considering the liability, they are incurring in their misguided insistence of wireless expansion that may ultimately catch up to them in the form of lawsuits, such as those previously experienced by asbestos and tobacco companies (78, 79) . a recent book describes how deception is used to capture agencies and hijack science (80) . there are certain tools that can be used for this. one is to re-analyze existing data using methods that are biased towards predetermined results (23) . for example, this can be performed by hiring 'independent experts' to question scientific results and create doubt (81, 82) . as clearly discussed in a number of chapters of the books (80-82), front groups may be created to gain access to politicians and to influence the public with biased opinions. other methods may involve intimidating and harassing independent scientists that report health risks based on sound science, or removing all funding from scientists who do not adhere to the no-risk proindustry paradigm. another tool would be economic support and courting decision makers with special information sessions that mislead them on science and mask bribery (3,5,19,80-82 ). an industry with precise marketing goals has a big advantage over a loose scientific community with little funding. furthermore, access to regulatory agencies and overwhelming them with comments on proposed regulations is crucial (3) . to counteract all these actions is time consuming and not always successful (19) . nevertheless, it is important that these circumstances are explored and published in the peer-reviewed literature as historical notes for future use. based on the swiss and icnirp experiences, some recommendations can be made. one is to include only unbiased and experienced experts without cois for evaluation of health risks from rf radiation. all countries should declare a moratorium on 5g until independent research, performed by scientists without any ties to the industry, confirms its safety or not. 2g, 3g, 4g and wifi are also considered not to be safe, but 5g will be worse regarding harmful biological effects (42, 83, 84) . the authors of the present article recommend an educational campaign to educate the public about the health risks of rf radiation exposure, and safe use of the technology, such as the deployment of wired internet in schools (85) , as previously recommended by the european council resolution 1815 in 2011 (86) and the emf scientist appeal (87) . additionally, it is recommended that the government takes steps to markedly decrease the current exposure of the public to rf radiation, (88, 89) . notably, dna damage has been identified in peripheral blood lymphocytes using the comet assay technique, and in buccal cells using the micronucleus assay, in individuals exposed to rf radiation from base stations (90) . finally, an alternative approach to the flawed icnirp safety standards may be the comprehensive work of the european academy for environmental medicine (europaem) emf working group that has resulted in safety recommendations, which are free from the icnirp shortcomings (50) . recently, the international guidelines on non-ionising radiation (ignir) have accepted europaem safety recommendations (91). the bioinitiative group has recommended similar safety standards based on non-thermal emf effects (92) . who and all nations should adopt the europaem/bioinitiative/ignir safety recommendations, supported by the majority of the scientific community, instead of the obsolete icnirp standards. in conclusion, it is important that all experts evaluating scientific evidence and assessing health risks from rf radiation do 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glioblastoma multiforme incidence in england 1995-2015 suggests an adverse environmental or lifestyle factor microwave news: spike in 'aggressive' brain cancer in denmark brain cancers: 4 times more new cases of glioblastoma in 2018 according to public health france indication of cocarcinogenic potential of chronic umts-modulated radiofrequency exposure in an ethylnitrosourea mouse model tumor promotion by exposure to radiofrequency electromagnetic fields below exposure limits for humans mobile phone use and brain tumors in children and adolescents: a multicenter case-control study childhood brain tumour risk and its association with wireless phones: a commentary kein erhöhtes hirntumorrisiko bei kindern und jugendlichen wegen handys reassuring results from first study on young mobile users and cancer risk swedish radiation safety authority: declaration of disqualification, conflicts of interest and other ties for experts and specialists of the swedish radiation safety authority electromagnetic radiation safety: icnirp's exposure guidelines for radio frequency fields swiss research foundation for electricity and mobile communication: list of funded research projects swiss research foundation for electricity and mobile communication: sponsors and supporters secret ties in asbestos -downplaying and effacing the risks of a toxic mineral greenwashing: the swedish experience the triumph of doubt: dark money and the science of deception doubt is their product. how industry's assault on science threatens your health corporate ties that bind. an examination of corporate manipulation and vested interest in public health towards 5g communication systems: are there health implications? 5 g wireless telecommunications expansion: public health and environmental implications measurements of radiofrequency radiation with a body-borne exposimeter in swedish schools with wi-fi. front public health 5: 279 radiofrequency radiation from nearby mobile phone base stations-a case comparison of one low and one high exposure apartment compared with results on brain and heart tumour risks in rats exposed to 1.8 ghz base station environmental emissions international guidelines on non-ionising radiation: guidelines. ignir's latest independent guidelines on emf exposure are available now to download and use a rationale for biologicallybased exposure standards for low-intensity electromagnetic radiation swedish radiation safety authority: publications this work is licensed under a creative commons attribution-noncommercial the authors would like to thank mr. reza ganjavi for valuable comments. no funding was received. the authors declare that they have no competing interests. key: cord-017620-p65lijyu authors: rodriguez-proteau, rosita; grant, roberta l. title: toxicity evaluation and human health risk assessment of surface and ground water contaminated by recycled hazardous waste materials date: 2005-07-07 journal: water pollution doi: 10.1007/b11434 sha: doc_id: 17620 cord_uid: p65lijyu prior to the 1970s, principles involving the fate and transport of hazardous chemicals from either hazardous waste spills or landfills into ground water and/or surface water were not fully understood. in addition, national guidance on proper waste disposal techniques was not well developed. as a result, there were many instances where hazardous waste was not disposed of properly, such as the love canal environmental pollution incident. this incident led to the passage of the resource conservation and recovery act (rcra) of 1976. this act gave the united states environmental protection agency regulatory control of all stages of the hazardous waste management cycle. presently, numerous federal agencies provide guidance on methods and approaches used to evaluate potential health effects and assess risks from contaminated source media, i.e., soil, air, and water. these agencies also establish standards of exposure or health benchmark values in the different media, which are not expected to produce environmental or human health impacts. the risk assessment methodology is used by various regulatory agencies using the following steps: i) hazard identification; ii) dose-response (quantitative) assessment; iii) exposure assessment; iv) risk characterization. the overall objectives of risk assessment are to balance risks and benefits; to set target levels; to set priorities for program activities at regulatory agencies, industrial or commercial facilities, or environmental and consumer organizations; and to estimate residual risks and extent of risk reduction. the chapter will provide information on the concepts used in estimating risk and hazard due to exposure to ground and surface waters contaminated from the recycling of hazardous waste and/or hazardous waste materials for each of the steps in the risk assessment process. moreover, this chapter will provide examples of contaminated water exposure pathway calculations as well as provide information on current guidelines, databases, and resources such as current drinking water standards, health advisories, and ambient water quality criteria. finally, specific examples of contaminants released from recycled hazardous waste materials and case studies evaluating the human health effects due to contamination of ground and surface waters from recycled hazardous waste materials will be provided and discussed. after world war ii, industries began to produce a whole new generation of industrial and consumer goods made of synthetic organic chemicals such as plastics, solvents, detergents, and pesticides. industries profited enormously from the production and marketing of these products and consumers became accustomed to the convenience of synthetic products as well as cheap, convenient, throwaway packaging materials. as the industrial production of these products increased, so did the production, accumulation, and disposal of hazardous waste. prior to 1976, facilities that handled and/or disposed of hazardous waste were not provided with detailed regulations and/or guidance on proper waste handling/ disposal techniques and, as a result, there were many instances where hazardous waste was improperly disposed. when chemicals are improperly disposed in the environment, abandoned hazardous waste sites are created that potentially affect human health and cost our society billions of dollars due to the high cost of not only evaluating human health and environmental impacts but also to performing site clean-ups. an example of one of the most well known incidents of improper disposal of hazardous waste was the love canal environmental pollution incident [ 1] . this incident led to the passage of the resource conservation and recovery act (rcra) of 1976. this act gave the united states environmental protection agency (usepa) regulatory control of all stages of the hazardous waste management cycle from the "cradle-to-grave:' beginning in the 1970s, congress passed several other acts designed to protect human health and the environment ( table 1 ) . based on the legislative directives in these acts, the usepa has issued numerous rules, regulations, and guidance documents that ensure that the use, disposal, processing, and handling of hazardous waste do not result in impacts to human health or the environment. state governments are authorized to implement these rules/regulations promulgated by the usepa, to permit facilities that handle hazardous waste in their states, and to create additional state rules and state regulations that apply to the operations of facilities in their specific state. the emphasis in recent years is to prevent pollution by recycling hazardous waste followed by proper disposal practices. rcra defines recyclable materials as "hazardous waste that are reclaimed to recover a usable product:' recycling is a broad term that applies to those who use, reuse, or reclaim waste to use as an ingredient to make a product and to use as an effective substitute for a commercial product. a material is reclaimed if it is processed to recover a useful by-product or forms the starting material for the systematic scientific approach of evaluating potential adverse health effects resulting from human exposure to hazardous agents or situations occur by the following steps: i) hazard identification; ii) dose-response (quantitative) assessment; iii) exposure assessment; iv) risk characterization [ 4] . the overall objectives of risk assessment are to balance risks and benefits, to set target levels, to set priorities for program activities at regulatory agencies, industrial or commercial facilities, or environmental and consumer organizations, and to estimate residual risks and extent of risk reduction [ 5] . diversity of risk assessment methodology helps ensure that all possible risk models and outcomes have been considered and minimize the potential for error [ 4] . this section will provide information on the concepts used in estimating risk and hazard due to exposure to ground water and surface water contaminated from the recycling of hazardous waste and/or hazardous waste materials for each of the aforementioned steps. the first step in the risk assessment process is an evaluation of all human and animal data to determine what health effects occur after exposure to a chemical. well-conducted human studies are preferred, but occupational or accidental exposures to chemicals also provide useful information. however, in most cases, the results from animal studies are used as models to predict effects in humans since animal studies allow for controlled dose-response investigations and detailed, thorough toxicological analysis. some toxicants produce health effects immediately following exposure such as air pollutants that can produce eye irritation in individuals after a few minutes of exposure. other effects, such as organ damage due to metals and solvents, may not become manifested for months or years after first exposure. the time from the first exposure to the observation of a health effect is called the latent period. the length of this period is dependent on various factors such as the type of pathology induced by the compound/chemical of potential concern (copc), dose, dose rate as well as host characteristics such as age at first exposure, gender, race, species, and strain. other host factors that influence susceptibility to environmental exposures include genetic traits; preexisting diseases; behavioral traits such as smoking; coexisting exposures; and medication and vitamin supplementation [ 5] . genetic studies include investigations of the effects of chemicals on the genes and chromosomes (genetic toxicology) and ecogenetics, a relatively new field, describes a host's genetic variation in predisposition and resistance to copc exposure [5] . ecogenetics involves studies of specific exposures ranging from pharmaceuticals known as pharmacogenetics, pesticides, inhaled pollutants, foods, food additives, to allergic and sensitizing agents [ 6] . moreover, induction of a health effect at the molecular level may occur after a single exposure, after repeated exposures, or after long-term continuous exposure. the length of the induction period may be a function of the same variables as the latent period. effective exposure time refers to the exposure time that occurred up to the point of induction [ 4] . ineffective exposure is readily observed in dose-response curves as a saturation of response in the high dose range. an experimental study must follow the subjects beyond the length of the minimum latent period to observe all effects and cases associated with exposure. under ideal circumstances, a study will follow subjects for their lifetime. lifetime follow-up is common for animal studies but uncommon for epidemiology studies [ 4] . qualitative assessment of hazard information should include a consideration of the consistency and concordance of the findings. such assessments should include a determination of the consistency of the toxicological findings across species and target organs, an evaluation of consistency across duplicate experimental conditions, and the adequacy of the experiments to detect the adverse endpoints of interest [5] . for consideration of whether a copc is a carcinogen, qualitative assessment of animal or human evidence is done by many agencies, including the usepa and the international agency for research on cancer (iarc). similar evidence classifications are used for both animal and human evidence categories by both agencies. these evidence classifications are used for overall weight-of-evidence (woe) carcinogenicity classification schemes where the alphanumeric classification levels recommended by usepa [7] are shown in table 2 . usepa's woe carcinogenicity classification schemes were first recommended in the guidelines for carcinogen risk assessment (usepa, 1986 , hereafter "1986 cancer table 2 usepa's carcinogenicity classification scheme [7] alphanumeric code evidence of noncarcinogenicity for humans; no evidence of carcinogenicity in adequate studies in at least two species or in both epidemiological and animal studies table 3 weight-of-evidence classification scheme for qualitative assessment of chemical mixtures from mumtaz and durkin [9] mechanistic understanding: i, ii, and iii i. direct and unambiguous mechanistic data ii. mechanistic data on related compounds iii. inadequate or ambiguous mechanistic data toxicologic significance: a, b, and c a. direct evidence of toxicologic significance of interaction b. probable evidence of a toxicologic significance based on related compounds c. unclear evidence of a toxicologic significance exposure modifiers: 1 and 2 1. anticipated exposure duration and sequence 2. different exposure duration or sequence 2.a. in vivo data 2.b. in vitro data 2.b.i. anticipated route of exposure 2.b.ii. different route of exposure mixture is additive (=),greater than additive (> ), orless than additive ( <). guidelines") [7] . however, the guidelines for carcinogen risk assessment, review draft (usepa, 1999,hereafter"1999 draft cancer guidelines") [8] recommend a woe narrative describing a summary of the key evidence for carcinogenicity. the 1999 draft cancer guidelines will serve as interim guidance until usepa issues final cancer guidelines [ 43] . for evaluating chemical mixtures of noncarcinogens, mumtaz and durkin [9] suggest the interaction data (i.e., independent joint action, similar joint action and synergistic action) and the qualitative and quantitative interaction matrix be taken into consideration when determining the hazard index. a qualitative woe scheme for evaluating chemical mixtures is shown in table 3 . the woe takes into consideration the copc, data, reference doses/concentrations, and hazard index based on additivity [10] . figure 1 illustrates each of the chemical mixture's woe determination by a symbol indicating the direction of the interaction followed by the alphanumeric expression in table 3 . the first two components are the major factors for ranking the quality of the mechanistic data to support the risk assessment. because toxicity studies must be evaluated to determine the quantitative dose-response relationship between the magnitude of exposure and the extent and severity of the adverse effect, a brief description of various toxicity tests will be provided. different methodologies are used to characterize doseresponse relationships, depending on whether or not the chemical has been identified as a carcinogen or noncarcinogen. carcinogens are assumed to pose some risk at any exposure level [4] . four classes of toxicant-induced health effects include: i) cancer: genotoxic and nongenotoxic mechanisms; ii) hereditary effects: genotoxic mechanisms; iii) developmental effects: genatoxic or nongenotoxic mechanisms; iv) organ/tissue effects: nongenotoxic mechanisms [4] . the evaluation of chemicals for acute toxicity is necessary for the protection of public health and the environment. acute toxicity is generally performed by the probable route of exposure in order to provide information on health hazards likely to arise from short-term exposure by that route (table 4 ) [11] . as shown in table 4 , there are four categories ranging from i to iv based on increasing doses. generally, acute studies evaluate oral, dermal, inhalation, and eye and skin irritation as well as dermal sensitization. the acute inhalation studies are performed from one to seven days while the intermediate studies are performed from seven days to several months [12] .an evaluation of acute toxicity data includes the relationship of the exposure to the copc and the incidence and severity of all abnormalities, gross lesions, body weight changes, effects on mortality, and any other toxic effects. an acute exposure is considered to be a one-time or short-term exposure with a duration of less than or equal to 24 h. acute toxicity testing is conducted toxity evaluation and human health risk assessment of surface and ground water 143 up to 7 days of exposure and subacute testing for 7-30 days. testing periods for the evaluation of developmental effects is less than 15 days since developmental toxicity can occur after short periods of exposure. sub chronic testing is typically conducted for 90 days to 1 year since subchronic exposures are considered to be multiple or continuous exposures occurring for approximately 10% of an experimental species lifetime. chronic exposures are assumed to be multiple exposures occurring over an extended period of time, or a significant fraction of the animal's or the individual's lifetime. to minimize the number of animals used and to take full account of their welfare, usepa recommends the use of data from structurally related substances or mixtures [ 11] . review of existing toxicity information on chemical substances that are structurally related to the copc may provide enough information to make preliminary hazard evaluations that may reduce the need for testing. for example, if a chemical can be predicted to have corrosive potential based on structure-activity relationships (sars), dermal or eye irritation testing does not need to be performed in order to classify it as a corrosive agent. all the human carcinogens that have been identified have produced positive results in at least one animal model. in the absence of adequate human data, it is plausible to regard agents and/or mixtures for which sufficient evidence of carcinogenicity in animals exists to be a possible carcinogenic risk to humans [5] . therefore, chemicals that cause tumors in animals are presumed to cause tumors in humans. in general, the most appropriate rodent bioassays are those that test the exposure pathways most relevant to human exposure pathways, i.e., inhalation, oral, dermal, etc. because it is feasible to combine bioassays together, it is desirable to tie these bioassays with mechanistic studies, biomarker studies, and genetic studies to understand the mechanism(s) of toxicity and/or carcinogenicity [13] . a typical experimental design includes two different species, both genders, at least 50 subjects per experimental group using near lifetime exposures. for dose-response purposes, a minimum of three dose levels should be used. the highest dose, typically the maximum tolerated dose, mtd, is based on the findings from a 90-day study to ensure that the test dose is adequate for the assessment of chronic toxicity and carcinogenic potential. the lowest dose level should produce no evidence of toxicity. in the oral studies, the animals are dosed with the copc on a 7-day per week basis for a period of at least 18 months for mice and hamsters and 24 months for rats [14] . for dermal studies, animals are treated with the copc for at least 6 h per day on a 7 -day per week basis for a period. a minimum of 24 h should be allowed for the skin to recover before the next dosing. the copc is applied uniformly over a shaved area that is approximately 10% of the total body surface area [14] . the animals are evaluated for an increase in number of tumors, size of tumors, and number of rare tumors seen and/or expressed. even without toxicity, a high dose may trigger events different from those triggered by low-dose exposures. also, these bioassays can be evaluated for uncontrolled effects by comparing weight vs time and mortality vs time curves [4] . if there is a divergence between the control group and the experimental group in the weight vs time curve, this indicates that there is a disruption of normal homeostasis due to high-level dosing. if there is a divergence in the mortality vs time curves, this indicates that there is an uncontrollable effect [4] . the national toxicology program (ntp) criterion for classifying a chemical as a carcinogen is that it must be tumorigenic in at least one site in one sex of f344 rats or b 6 c 3 f 1 mice. validation and application of short-term tests (stt) are important in risk assessment because these assays can be designed to provide information about mechanisms of effects. short-term toxicity experiments includes in vitro or short-term in vivo tests ranging from bacterial mutation assays to more elaborate in vivo short-term tests such as skin-painting studies in mice and altered rat liver foci assays. these studies determine if copcs are mutagenic, indicating they have the potential to be carcinogens as well. in general, stt are fast and inexpensive compared with the lifetime rodent cancer bioassays [5] . positive results of stt have been used to predict potential carcinogenicity. common stt include the following: ames salmonella/microsome mutagenesis assay (sal); assays for chromosome aberration (abs); sister chromatid exchange induction (sce) in chinese hamster ovary cells; the mouse lymphoma l5178y cell mutagenesis assay (moly). there are several limitations to stt such as: stt cannot replace long-term rodent studies for the identification of carcinogens; the available tests do not detect all classes of copcs that are active in the carcinogenic process such as hormones; and negative results from stt cannot rule out carcinogenicity [ 4] . the most convincing evidence for human risk is a well-conducted epidemiological study where an association between exposure to copc and a disease has been observed. these studies compare copc-exposed individuals vs non-copc-exposed individuals [5] . the major types of epidemiology studies are cross-sectional studies, cohort studies, and case-control studies. cross-sectional studies survey groups of humans to identify risk factors and disease. these studies are not very useful for establishing a cause-and-effect relationship. cohort studies evaluate individuals on the basis of their exposure to the copc under investigation. these individuals are monitored for development of disease. prospective studies monitor individuals who initially are diseasefree to determine if they develop the disease over time. in case-control studies, subjects are selected on the basis of disease status and are matched accordingly. the exposure histories of the two groups are compared to determine key consistent features. thus, all case-control studies are retrospective studies [5] . epidemiological findings are evaluated by the strength of association, consistency of observations, specificity, appropriateness of temporal relationship, dose responsiveness, biological plausibility and coherence, verification, and biological analogy [s].a disadvantage of epidemiological studies is an accurate measure of concentration or dose that the copc-exposed individuals receives is not available, so estimates must be employed to quantify the relationship between exposure and adverse effects. moreover, the control group is a major determinant of whether or not a statistically significant adverse effect can be detected. the various types of control groups are: regional general population; general population of a state; local general population; and workers in the same or a similar industry who are exposed to lower or zero levels of the toxicant under study [ 4] . dose-response assessment is the fundamental basis of the quantitative relationship between exposure to an agent and the incidence of an adverse response. the procedures used to define the dose-response relationship for carcinogens and noncarcinogens differ. for carcinogens, a non-threshold, zero threshold, dose-response relationship is used when there are known or assumed risks of an adverse response at any dose above zero. non-threshold toxicants include hereditary disease toxicants, genotoxic carcinogens, and genotoxic developmental toxicants. for noncarcinogens, a threshold, nonzero threshold is used to evaluate toxicants that are known or assumed to produce no adverse effects below a certain dose or dose rate. threshold toxicants include nongenotoxic carcinogens, nongenotoxic developmental toxicants, and organ/ tissue toxicants [ 4] . the two different approaches will be discussed separately in this section. the toxicity factors used to evaluate oral exposure and inhalation exposure are expressed in different units to account for the unique differences between these two routes of exposure. cancer slope factors (csfs), in units of (mg/kg/day)-t, and reference doses (rids), in units of mg/kg/day, are used to quantify the relationship between dose and effect for oral exposure whereas unit risk factors (urfs), in units of (jlg/m 3 )-t, and reference concentrations (rfcs), in units of mg/m\ are used to describe the relationship between ambient air concentration and effect for inhalation exposure. the urf and rfc methodology accounts for the species-specific relationships of exposure concentration to deposited/delivered doses to the respiratory tract by employing animal-to-human dosimetric adjustments that are different than those employed for oral exposure. the interaction with the respiratory tract and ultimate disposition are considered as well as the physicochemical characteristics of the inhaled agent and whether the exposure is to particles or gases. most important is the type of toxicity observed since direct effects on the respiratory tract (i.e., portal of entry effects) must be considered as opposed to toxicity remote to the portal-of-entry [15] . based on the differences between oral and inhalation exposure, route to route extrapolation of oral toxicity values to inhalation toxicity values may not be appropriate. please refer to appendix b of the soil screening guidance [16] for a discussion of issues relating to route-to-route extrapolation. carcinogenic assessment assumes that exposure to any amount of a carcinogenic substance increases carcinogenic risk. thus, zero risk does not exist (a non-threshold response) because there is no carcinogen exposure concentration low enough that will not increase risk of cancer. a genotoxic carcinogen alters the information coded in dna; thus, it is reasonable to assume that these agents do not have a threshold so that a risk of cancer exists no matter how low the dose. there are three stages of genotoxic carcinogenesis: initiation, promotion, and progression. initiation refers to the induction of an irreversible change in dna caused by a mutagen. the initiator may be a direct-activating carcinogen or a carcinogenic metabolite. promotion refers to the possibly reversible replication of initiated cells to form a "benign" lesion. promoters are not genotoxic or carcinogenic but they enhance the tumorigenic response initiated by a primary or secondary carcinogen when administered at a later time. complete carcinogens have initiation and promotion properties [ 4] . nongenotoxic carcinogenesis does not involve direct interaction of a carcinogen with dna. mechanisms of nongenotoxic carcinogenesis include an accelerated replication that may increase the frequency of spontaneous mutations or increase the susceptibility of dna damage. cancer may be secondary to organ toxicity and may occur only at high dose rates. moreover, many nongenotoxic cancer mechanisms are species-specific where the results from certain rodent species may not apply to human [4] . several approaches and models are used to provide estimates of the upper limit on lifetime cancer risks per unit of dose or unit of ambient air concentration, i.e., the csf or the urf, respectively. the upper bound excess cancer risk estimates may be calculated using models such as the one-hit, weibull, logit, log-probit,or multistage models [5, 17] . the linearized multistage model is considered to be one of the more conservative models and is typically used because the mechanism of cancer is not well understood and one model may not be more predictive than another one [7, 17] . because the risk assessor generally needs to extrapolate beyond the region of the dose-response curve for which experimentally observed data are available, models derived from mechanistic assumptions involve the use of a mathematical equation to describe dose-response relationships that are consistent with biological mechanisms of response [ 5] . "hit models" for cancer modeling assume that i) an infinite number of targets exist, ii) after a minimum of targets have been modified, the host will elicit a toxic response, iii) a critical target is altered if a sufficient number of hits occurs, and iv) the probability of a hit in the lowdose range is proportional to the dose of copc [18] . the one-hit linear model is the simplest mechanistic model where only one hit or critical cellular interaction is required for cell function to be altered. multi-hit models describe hypothesized single-target multi-hit events as well as multi-target events in carcinogenesis. biologically based dose-response (bbdr) modeling reflects specific biological process [5] . because a large number of subjects would be required to detect small responses at very low doses, several theoretical mathematical extrapolation models have been proposed for relating dose and response in the subexperimental dose range: tolerance distribution models, mechanistic models, and enhanced models. these mathematical models generally extrapolate low-dose carcinogenic risks to humans based on effects observed at the high doses in experimental animal studies. the linear interpolation model interpolates between the response observed at the lowest experimental dose and the origin. linear interpolation is recommended due to its conservatism, simplicity, and reliance because it is unlikely to underestimate the true-low dose risk [ 4] . there is no universally agreed upon method for estimating an equivalent human dose from an animal study. however, several methods are currently being used to obtain an estimate of the equivalent human dose. the first method calculates an equivalent human dose from an animal study by scaling the animal dose rate for animal body weight. to derive an equivalent human dose from animal data, the 1999 draft cancer guidelines recommend adjusting the daily applied oral doses experienced over a lifetime in proportion to bw 314 [8] . for noncarcinogens, an uncertainty factor is employed to estimate the equivalent human dose from an animal study if pharmacokinetic data is not available. noncarcinogenic dose-response assessment utilizes a point of effects method which selects the highest dosage level tested in humans or animals at which no adverse effects were demonstrated and applies uncertainty factors or margins of safety to this dosage level to determine the level of exposure where no health effects will be observed, even for sensitive members of the population. also, benchmark dose modeling may be conducted if the experimental data are adequate. animal bioassay data are generally used for dose-response assessment; however, the risk assessor is normally interested in low environmental exposures of humans, which are generally below the experimentally observable range of responses seen in the animal assays. thus, low-dose extrapolation and animal-to-human risk extrapolation methods are required and constitute major aspects of dose-response assessment. human and animal dose rates are frequently reported in terms of the following abbreviations, which are defined below: loel lowest observed effect level in mglkgâ·day, which produces a statistically or biologically significant effect loael lowest observed adverse effect level in mg/kgâ·day, which produces a statistically or biologically significant adverse effect noel no observed effect level in mg/kgâ·day, which does not produce a statistically or biologically significant effect noael no observed adverse effect level in mg!kgâ·day, which does not produce a statistically or biologically significant adverse effect. key factors in determining which noael or loael to use in calculating a reference dose (rid) is exposure duration. as mentioned previously, acute animal studies are typically conducted for up to 7 days, subacute studies for 7 to 30 days, and subchronic studies for 90 days to 1 year. chronic studies are conducted for a significant portion of the lifetime of the animal. animals may experience health effects during short-term exposure which may differ from effects observed after long-term exposure, so short-term animal studies less than 90 days should not be used to develop chronic rids except for the development of interim rids or developmental rids. exceptionally high quality >90 day oral exposure studies may be used as a basis for developing an rid whereas the inhalation route is preferred for deriving a rfc [15] . please note that the same approaches used to develop the rid are used to develop the rfc, the only difference being the route of exposure, animal-to-human dosimetric adjustments, and the units, (i.e., mg/m 3 for the rfc vs mg/kg/day for the rid). the highest dose level that does not produce a significantly elevated increase in an adverse response is the noael. the noael from the critical study should be used for criteria development, i.e., the health effect that occurs at the lowest dose. however, if a noael is not available, then the loael can be used if a loael to noael uncertainty factor (uf) is applied. significance generally refers to both biological and statistical criteria and is dependent on the number of dose levels tested, the number of animals tested at each dose, and the background incidence of the adverse response in the control groups [5] . noaels can be used as a basis for risk assessment calculations such as rids and acceptable daily intake values (adi). adi and rid values should be viewed as a conservative estimate of levels below which adverse affects would not be expected; exposures at doses greater than the adi or rid are associated with an increase probability (but not certainty) of adverse effects [19] . who uses adi values for pesticides and food additives to define "the daily intake of chemical, which during an entire lifetime appears to be without appreciable risk on the basis of all known facts at that time" [ 5] . in order to remove the value judgments implied by the words "acceptable" and "safety", the adi and safety factor (sf) terms have been replaced with the terms rid and up/modifying factors (mf), respectively. usepa publishes rids and rfcs in either iris or in the usepa's health effects assessment summary tables (heast) . rids and adi values (eqs. 1 and 2, respectively) are typically calculated from noael values divided by the uf and/or mf: the uncertainty factor (uf) may range from 1 to 10,000 depending on the nature and quality of the data and is determined by multiplying different ufs together to account for five areas of scientific uncertainty [20] . the uf is primarily used to account for a potential difference between the animal's and human's sensitivity to a particular compound. the ufh and uf a accounts for possible intraand interspecies differences, respectively. as mentioned previously, an ufs is used to extrapolate from a subchronic duration study to a situation more relevant for chronic study and an ufl is used to extrapolate from a loael to a noael. an uf 0 is used to account for inadequate numbers of animals, incomplete databases, or other experimental limitations. a modifying factor (mf} can be used to account for additional scientific uncertainties. in general, the magnitude of the individual ufs is assigned a value of one, three, or ten, depending on the quality of the studies used in developing the rid or rfc. this uf is reduced whenever there is experimental evidence of concordance between animal and human pharmacokinetics and when the mechanism of toxicity has been established. recently, benchmark dose modeling has been recommended by usepa instead of the noael approach. criticism of the noael approach exists because of its limitations, which include the following: i) the noael must be one of the experimental doses tested; ii) once the dose is identified, the remaining doses are irrelevant; iii) larger noaels may occur in experiments with few animals thereby resulting in larger rids; iv) the noael approach does not identify the actual responses at the noael and will vary based on experimental design. these limitations of the noael approach resulted in the benchmark dose (bmd) method [21] . the dose-response is modeled and the lower confidence bound for a dose (bmdl) at a specified response level, benchmark response (bmr), is calculated [5] . the bmdlx (with x representing the x percent bmr) is used as an alternative to the noael value for the rid calculations. thus, the calculation of the rid is shown in eq. (3}: advantages of the bmd approach includes: i) the ability to account for the full dose-response curve; ii) the inclusion of a measure of variability; iii) the use of responses within the experimental range; iv) the use of a consistent benchmark response level for rid calculations across studies [5] . there are numerous informational databases or resources that provide risk assessors essential information. usepa publishes rids, rfcs, csfs, and urfs in the integrated risk information system (iris) or in the health effects assessment summary tables (heast). the information in iris followed by heast should be used preferentially before all other sources. a recent review of other available resources was published in a special volume of toxicology, vol157, 2001. articles by poore et al. [ 22] and brinkhuis [ 23] provide a thorough review of u.s. government databases such as usepa's iris at http://www.epa.gov/ iriswebp/iris/, national center for environmental assessment (ncea),atsdr's chemical-specific toxicology profiles and acute, subchronic, and chronic minimal risk levels (mrls ), and hazdat at http:/ /www.atsdr.cdc.gov/hazdat.html, among many other databases. the reviewers provide advise for effective search strategies as well as strategies for finding the appropriate toxicology information resources. exposure occurs when a human contacts a chemical or physical agent. exposure assessment examines a wide range of exposure parameters pertaining to the environmental scenarios of people who may be exposed to the agent under study. the information considered for the exposure assessment includes monitoring studies of chemical concentration in environmental media and/or food; modeling of environmental fate and transport of contaminants; and information on different activity patterns of different population subgroups. the principal pathways by which exposure occurs, the pattern of exposure, the determination of copc intake by each pathway, as well as the number of persons and whether there are sensitive subpopulations that need to be evaluated are also included in the evaluation. in this step, the assessor characterizes the exposure setting with respect to the general physical characteristics of the site, the site copcs, and the characteristics of the populations on or near the site. hazard identification/evaluation consists of sampling and analysis of soil, ground water, surface water, air, and other environmental media at contaminated sites. a common method used in screening substances at a site is by comparison with background levels in soil or ground/ surface water [ 19] , determining if a chemical is detected or not and whether the detection limit for that chemical is less than reference concentrations as well as frequency of detection [24] . once a list of copcs have been identified at the site, the availability of chemical characteristics such as struc-ture, solubility, stability, ph sensitivity, electrophilicity, and chemical reactivity and toxicity data are collected and evaluated to ascertain the nature of health effects associated with exposure to these chemicals. in many cases, toxicity information on chemicals is limited. knowing the copc's characteristics can represent important information for hazard identification [s] .also, sars are useful in assessing the relative toxicity of chemically related compounds. during this phase of exposure assessment, the major pathways by which the previously identified populations may be exposed are identified. therefore, locations of contaminated media, sources of release, fate and transport of copcs, pathways and exposure points, routes of exposure (i.e., ingestion of drinking water, dermal contact when showering) and location and activities of the potentially exposed population are explored. for example, the common on-site pathways evaluated when conducting a rcra remediation baseline risk assessment where unauthorized chemical releases have occurred includes direct contact with soil either by ingestion of soil and/ or inhalation of volatile chemicals or contaminated dust [ 19] . the migration of chemicals off-site can occur via wind-blown dust and vapor emissions from soil, leaching of chemicals to ground water with subsequent movement off-site, and run-off surface water. these off-site chemicals can eventually accumulate in other transport media such that the copc ends up in vegetation crops, meat, milk, and fish that will eventually be consumed by humans. therefore, pathways, sources of release, locations of contaminated media, fate and transport of copcs, and location and activities of the potentially exposed population are explored. exposure points and routes of exposure (ingestion, inhalation) are identified for each exposure pathway. it is necessary to identify populations likely to receive especially high exposure and populations likely to be unusually sensitive to the chemical's effects. an example of possible point of exposures and exposure routes due to exposure to ground water or surface water (i.e., source medium) used for drinking water is shown in table 5 . please note that all of these exposure pathvolatilization from water air inhalation into enclosed space ways are typically not evaluated when doing a risk assessment on contaminated drinking water since the techniques and exposure parameters for evaluating these routes of exposure are not well developed. additional pathways to consider for surface water may include recreational exposures (i.e., swimming, boating), ingestion of contaminated fish, shellfish, etc., and dermal exposure to contaminated sediment. finally, an attempt should be made to develop a number of exposure scenarios. exposure scenarios are a combination of"exposure pathways" to which a single "receptor" may be subjected [25] . for example, a residential adult or child receptor may be exposed to all the exposure routes in table 5 (i.e., drinking water, showering/bathing, washing/cooking food, and volatilization from ground water or drinking water into an enclosed space). an industrial receptor may only be exposed through the drinking water pathway and volatilization from ground water into an enclosed space and not be exposed through showering/bathing or washing/ cooking, because these activities are not allowed at an industrial site. exposure scenarios are generally conservative and not intended to be entirely representative of actual scenarios at all sites. the scenarios allow for standardized and reproducible evaluation of risks across most sites and land use areas [ 25] . conservatism allows for protection of potential receptors not directly evaluated such as special subpopulations and regionally specific land uses. the magnitude, frequency and duration of exposure for each pathway are next evaluated. for each potential exposure pathway, the chemical doses received by each exposure route needs to be calculated. because chemical concentrations can vary, many different studies might be required to get a complete picture of the chemical's distribution patterns within the environment. off-site sampling and analysis are preferred methods to determine the exposure concentrations in the environmental media at the point of exposure. because sampling data forms the foundation of a risk assessment, it is important that site investigation activities are designed and implemented with the overall goals of the risk assessment to be performed [19] . for example, it is essential that appropriate analytical methods with proper quality assurance/quality control documentation be employed and that the analytical methods are sensitive enough to detect the copc at concentrations that are below health protective reference concentrations. after the sampling data is collected and evaluated, then statistical techniques may be used to calculate the representative concentration of copcs that will be contacted over the exposure area. different statistical techniques may be required for the determination of representative concentrations in ground water vs surface water [24] . fate and transport models can be used to estimate current concentrations in media and/or at locations for which sampling was not conducted. in addition, an increase in future chemical concentrations in media that are currently contaminated or that may become contaminated can be predicted by fate and transport modeling. detailed discussions of these models are contained elsewhere in this book. each scenario described in the exposure assessment should be accompanied by an estimated exposure dose for each pathway. once the exposure pathway is determined, then the estimated risks and hazards from each exposure pathway can be characterized. exposure estimates for the oral pathway are expressed in terms of the mass of substance in contact with the body per unit body weight per unit time (i.e., intakes) whereas exposure estimates from inhalation pathways are expressed as mass of substance per unit volume (i.e., inhalation concentrations). the general equation for calculating intakes (mg/kg/day) is as follows [24] : intake, the amount of chemical at the exchange boundary (mg/kg body weight-day) c copc concentration, average concentration contacted over the exposure period cr contact rate, the amount of contaminated medium contacted per unit time or event ef exposure frequency (days/year) ed exposure duration (years) bw body weight, the average body weight over the exposure period (kg) at averaging time or period over which exposure is averaged (days). each exposure pathway has slightly different variations of the above basic equation. please refer to appendix a for examples of equations used to calculate intakes for the major exposure pathway from ground and surface waters as well as examples of exposure parameters employed to calculate intakes: appendices a-1 and a-2, ingestion of drinking water; appendices a-3 and a-4, ingestion of contaminated fish tissue; appendices a-5 and a-6, dermal contact with contaminated water; and appendix a-7 inhalation of volatiles from contaminated ground water or surface water. please refer to kasting and robinson [26] and exposure to contaminants in drinking water [27] for additional information on the various issues involved in the assessment of dermal exposure to water. the exposure parameters (e.g., cr, ef, ed, bw, and at) for each pathway are derived after an extensive literature review and statistical analysis [ 28] . for example, information on water ingestion rates, body weights, and fish ingestion rates for adults, children, and pregnant women used to develop the national ambient water quality criteria were obtained from the following documents: exposure factors handbook [28]; national health and nutrition examination survey (nhanes iii) [29] ; and united states department of agriculture (usda) 1994-1996 continuing survey of food intakes [30] . exposure parameters may represent central tendency or average values or maximum or near-maximum values [24] . science policy decisions that consider the best available data and risk management judgments regarding the population to be protected are both used to choose appropriate exposure parameters. usepa emphasizes that exposure assessments should strive to achieve an overall dose estimate that represents a "reasonable maximum exposure (rme):' the intent of the rme is to estimate a conservative exposure scenario that is within the range of possible exposures yet well above the average case (above the 90 1 h percentile of the actual distribution). however, estimates that are beyond the true distribution should be avoided. if near maximum or maximum values are chosen for each exposure parameter, then the combination of all maximum values for each exposure parameter would result in an unrealistic assessment of exposure. using probabilistic risk assessment, cullen demonstrated that if only two exposure parameters were chosen at maximum or near maximum values, and other parameters were chosen at medium values, than the risk and hazards estimates represented a rme (>99% percentile level) [31] . risk assessors should identify the most sensitive parameters and use maximum or near-maximum values for one or a few of those variables. central tendency or average values should be used for all other parameters [24] . when central tendency and/or maximum values are chosen for exposure parameters used to calculate intake for an exposure pathway, single point estimates of risk and hazard are calculated (i.e., a deterministic technique). however, probabilistic techniques like monte carlo analysis can be employed to provide different percentile estimates of risk and hazard (i.e., soth percentile or 95th percentile estimates) as well as to characterize variability and uncertainty in the risk assessment. monte carlo simulation is a statistical technique by which a quantity is calculated repeatedly, using randomly selected values from the entire frequency distribution for an exposure parameter or multiple exposure parameters for each calculation. usepa recommends using computerized monte carlo simulations to provide probability distributions for dose and risk estimates by incorporating ranges for individual assumptions rather than a single dose or risk estimate [19] . using better estimates for the distribution of contaminant levels is a major focus of recent risk assessment research. to obtain such estimates, several techniques, such as generating subjective uncertainty distributions and monte carlo composite analyses of parameter uncertainty, have been applied [5] . these are approaches that can provide a reality check that is useful in generating more realistic exposure estimates [ 5] . also, high-end exposure estimates (heees) and theoretical upper-bound estimates (tubes) are now recommended for specified populations as well as calculation of exposure for highly exposed individuals [5] . heee represents an estimate of the exposure in the upper ninetieth percentile while tubes represent exposure levels that exceed exposures experienced by all individuals in the exposure distribution and assume limits for all exposure variables [5] . please refer to the policy for use of probabilistic analysis in risk assessment at the usepa and guiding principles for monte carlo analysis at http:/ /www.epa.gov/ ncea/mcpolicy.htm [32] . risk characterization, the last step in the risk assessment process, links the toxicity evaluation (hazard identification and dose-response assessment) to the exposure assessment. estimates of the upper-bound excess lifetime cancer risk and noncarcinogenic hazard for each pathway, each copc, and each receptor identified during the exposure assessment are calculated. another important component of risk characterization is the clear, transparent communication of risk and hazard estimates as well as an uncertainty analysis of those estimates to the risk manager. cancer risk is usually expressed as an estimated rate of excess cancers in a population exposed to a copc for a lifetime or portion of a lifetime [33] . oral intakes are multiplied by the csf (eq. 5), dermal intakes are multiplied by the csf adjusted for gi absorption (eq. 6), and lifetime average inhalation concentrations are multiplied by the urf (eq. 7) to obtain risk estimates. for evaluating the risk from oral exposure, the intakes from all ingestion pathways can be summed (i.e., ingestion of drinking water, ingestion of fish, etc.), then the total intake is multiplied by the csf, as follows: (5) intakeoral the combined amount of copc from all oral pathways at the exchange boundary (mg/kg/day) (appendices a-1 to a-4) csf cancer slope factor (mg/kg/day)-1 â�¢ for evaluating dermal exposure, the dermally absorbed dose (dad) is calculated (appendices a-5 and a-6) and multiplied by an adjusted csf, csf dermalâ· the csf is typically derived based on oral dose-response relationships that are based on administered dose, whereas the dermal intake estimates are based on absorbed dose. therefore, if the csf is based on an administered dose, it should be adjusted for gastrointestinal absorption, if gastrointestinal absorption is significantly less than 100% (e.g., <50%) [34] . therefore, if an estimate of the gastrointestinal absorption fraction (absgi) is available for the compound and absgi is less than 50% [34, 35] , then the oral dose-response factor, based on an administered dose, can be converted to an absorbed dose basis by dividing the csf by the absgr to form a csf derma!: where dad dermally absorbed dose (mg/kg/day) (appendices a-5 and a-6) (6) csfdermal dermal cancer slope factor (mg/kg/day)-1 ; csfdermat=(csf/absg1). when absgr values are not available from bast and borges [35] for a compound, then usepa region 4 [36] recommends the following defaults for absg 1 : 80% for volatile organics; 50% for semi-volatile organics and nonvolatile organics; and 20% for inorganics. for evaluation of inhalation exposure, the lifetime average inhalation concentration is multiplied by the urf: where cinh concentration of copc at the exchange boundary (mg/m 3 ) (appendix a-7) urf unit risk factor (jlg/m 3 )-1 â�¢ to obtain a conservative total risk estimate, the risks for an individual copc from each pathway is summed and then the risks from all copcs are summed (eq. 8): where (8) rtotal sum of all risk estimates from all i 1 h copcs from all pathways. however, usepa is still developing approaches to deal with the uncertainties associated with combining risk estimates of chemical mixtures across different routes of exposure (i.e., inhalation, oral, and dermal) since differences in the properties of the cells that line the surfaces of the air pathways and the lungs, the gastrointestinal tract and the skin may result in different intake patterns of chemical mixtures components depending on the route of exposure. another consideration in dealing with chemical mixtures is the chemicals in a mixture may partition to contact media differently [37] .a risk estimate of 1x10 6 , 1x10 5 , or 1 x 10 4 is interpreted to mean that an individual has not more than, and likely less than, a 1 in 1 ,000,000, 1 in 100,000, or 1 in 10,000 chance, respectively, of developing cancer from the exposure being evaluated. the range of carcinogenic risks acceptable by the usepa is iq-6 to iq-4 â�¢ for chronic exposures to noncarcinogens, the intake of a copc is compared to the appropriate rid (i.e., oral rid or rid dermal) or rfc to form the hazard quotient (hq) [33] . oral intakes are compared to the rid (eq. 9), dermally absorbed doses (dads) are compared to the rid dermal (i.e., rid adjusted for gi absorption refer to the previous section for a discussion of procedures for adjusting toxicity factors for gi absorption) (eq. 10), and inhalation intakes are compared to the rfc (eq. 11) to obtained hazard quotients for each route of exposure: l intakeoral hqoral = rjd (9) where intakeoral the combined amount of copc from all oral pathways at the exchange boundary (mg/kg/day) (appendices a-1 to a-4) rid oral reference dose (mg/kg/day) the total hazard index (hi) for an individual copc from all routes of exposure is the sum of the hqs from all applicable pathways (oral, dermal, or inhalation) (eq.12): hi; = l hq; (12) where hii the sum of the hazard quotients from all relevant pathway for the i 1 h co pc. in order to be conservative, a total hi can be calculated by summing the his from each individual copc. "if the overall hi value is less than one, public health risk is considered to be very low"; however, "if the hi value is equal to or greater than one, then the exposure assessment and hazard characterization should be investigated more thoroughly:' if the hi exceeds one, then the hazard estimates may be refined by grouping the copcs that affect the same target organ or have the same mechanism of action and adding only the his from similar-acting copcs [37, 38] . ideally, chemicals would be grouped according to effect-specific toxicity criteria, information on chemicals exhibiting multiple effects would be available, and their exact mechanism of action would be known. instead, rids and rfcs are available for just one of the several possible endpoints of toxicity for a chemical and data are often limited to gross toxicological effects in an organ or an entire organ system. the list of these specific endpoints of toxicity is limited so it is best to consult a toxicologist during this step of the hazard evaluation [16] . each copc and exposure pathway needs to be calculated to determine the actual risk. the hi provides a rough estimate of possible toxicity and requires careful interpretation [38] . the hi does not account for the number of individuals who might be affected by exposure or the severity of the effects. usepa recommends that a hi of 1.0 be used for noncancer health effects. in the "real world", exposures generally involve complex mixtures of copcs. there are three basic actions for mixtures: i) independent joint action, which describes copcs that act independently and have different modes of action and are not expected to affect the toxicity of one another; ii) similar joint action or "dose addition;' which describes a mixture where the copcs produce similar but independent effects; iii) synergistic action, which the effective mixture cannot be assessed from the individual ingredients but depends on knowledge of their combined toxicity [39] (table 3 and fig. 1 ). the total hi can exceed the target hazard level as a result of the presence of either one or more copcs with an hq exceeding the target hazard level or the summation of several copc-specific hqs that are each less than the target hazard level. it is important to mention that the numbers generated by risk assessors should not be viewed as either accurate measures or even predictors of rates of adverse health effects in human populations [33] . the calculated estimates are routinely based on assumptions recognized as being conservative. thus, these numbers should be used as tools open to interpretation on a site-by-site basis. it is important for the risk manager to be informed of the uncertainties during the risk assessment process. significant limitations and uncertainties can exist throughout the entire risk assessment process; thus, it is important that a discussion of uncertainty accompanies risk assessment analysis so that the limitations of the quantitative results are taken into consideration. both qualitative and quantitative methods have been developed to analyze the uncertainty associated with risk assessment. a quantitative analysis may be conducted using either a sensitivity analysis or a probability analysis. listed below are the various reasons why uncertainty exists in a risk assessment analysis [ 4, 19] : -deficient control groups -difference in smoking habits between an epidemiology study group and a risk group -differences or lack of consideration of pharmacokinetics and/or mechanism of toxicity between species -failure to diagnose or misdiagnosis the cause of mortality -inappropriate experimental study design -lack of knowledge regarding combined biological effects of exposure to multiple toxicants -limitation in data regarding nature and magnitude of levels in the environment -low-dose extrapolation from high-dose experimental conditions -reliance on mathematical models -toxicant interaction with another agent -use of animal studies in the determination of risk for humans 3 it is important to make clear the distinction between risk assessors and risk management. risk assessors generate risk estimates but a risk manager considers these risk estimates, other scientific information, and integrates it into societal decisions [ 40 ] . for example, risk managers consider data analysis, technical concerns, economic concerns, and social/political concerns in addition to comparing the risk estimates to an acceptable level set by federal or state health agencies [ 40 ] . generally, trade-offs or compromises are made for the lowest possible risk and society's demand for jobs and economic growth. examples of questions that may be asked by risk managers are: "is a particularly deadly type of cancer in a narrow population worse or better than widespread effects of a non-lethal nature? can this decision be successfully defended in court?" in general, risk management decisions may be based more on political and economic factors than risk factors [ 40 ] . risk assessment and risk management are an integral part of the contemporary regulatory scene. risk management refers to the selections and implementation of the most appropriate regulatory action based on: i) goals; ii) social and political factors; iii) available control technology; iv) costs and benefits; v) results of risk assessment; vi) acceptable risk; vii) acceptable number of cases [4] . another aspect to consider is cumulative risk in either the risk assessment or risk management phase. cumulative risk evaluation considers all "involuntary" risk to which a receptor may be exposed by a variety of environmental risks such as: i) automobile exhaust emissions; ii) leaking underground storage tanks; iii) untreated sewage; iv) agricultural land runoff; v) industrial process air emissions; vi) conventional combustion-related air emissions [ 41] . however, at the present time, definite guidance from usepa regarding the evaluation of cumulative risk is not available. a refined site-specific risk assessment takes into account the specific characteristics concerning the site, all relevant pathways a receptor is exposed to, and other site-specific information. this represents a "forward" calculation method where risk and hazard estimates are calculated. however, each state or usepa regional office may utilize slightly different exposure factors, exposure scenarios, target risk and hazard levels or different procedures to account for childhood exposure, cumulative risk, etc. it is a very time-and resource-intensive process, which involves numerous scientific policy decisions. however, risk and hazard estimates from a refined site-specific risk assessment typically provide more realistic estimates than a generic screening level risk assessment. in contrast, media-specific comparison values can be calculated based on a "backward" calculation method based on standardized equations, usepa toxicity values, standard exposure pathways or scenarios, default exposure factors, and conservative risk and hazard levels. usepa office of water has derived drinking water standards and health advisories to evaluate levels of contaminants in public drinking water supplies. to evaluate levels of contaminants in surface water, usepa publishes guidance documents [42] as well as national recommended water quality criteria. state and tribal agencies then develop water quality standards for each water body in the state based on usepa guidance and the use designation for the individual water body. usepa must review the proposed state water quality standards before they become legally enforceable standards. if drinking water standards and/ or state and tribal water quality standards are available for the copcs present at the site, these standards generally must be used to evaluate human health impacts to groundwater and/or surface water, respectively. water quality standards apply to surface waters of the united states, including rivers, streams, lakes, oceans, estuaries, and wetlands. water quality standards consist, at a minimum, of three elements: 1) the "designated beneficial use" or "uses" of a water body or segment of a water body; 2) the water quality "criteria" necessary to protect the uses of that particular water body; 3) an antidegradation policy. typical designated beneficial uses of water bodies include public water supply, propagation of fish and wildlife, recreation, agricultural water use, industrial water use and navigation. if information concerning copcs is not present in the drinking water and/or state and tribal water standards databases, or additional exposure pathways need to be included during the site assessment, then media-specific comparison values are available from the soil screening guidance [16] , several usepa regional offices, and individual state governments (table 6 ). these benchmark values may be used as a tool to perform initial site screenings or as initial cleanup goals, if applicable. the different media-specific comparison values are generic, but can be recalculated using more site-specific information and guidance provided on the applicable web addresses (table 6 ). however, they usually do not consider all potential human health exposure pathways or consider ecological concerns. many of the databases listed in table 6 also provide copc concentration in soil calculated with fate and transport models that are protective of ground water and surface water. if information concerning copcs is not present in these databases, or additional exposure pathways need to be included during the site assessment, then a detailed toxicity evaluation and risk assessment may need to be conducted based on state or other regulatory agency guidelines. usepa was granted authority to set drinking water standards by the safe drinking water act (sdwa) of 1974. the sdwa has since been amended in 1986 and 1996. the responsibility for implementing drinking water standards is delegated to states and tribes. usepa is responsible for identifying contaminants to regulate, establishing priorities for contaminants that are of the greatest concern, and then deriving national primary drinking water regulations. the sdwa is applicable to public water systems that provide water for human consumption through at least 15 service connections or regularly serve at least 25 individuals. the standards apply to the water delivered to any user of a public water system. the standards are not applicable to private wells, although state and local governments do set rules to protect users of these wells. owners are urged to test their wells annually for nitrate and coliform bacteria, to test their wells for other compounds if a problem is suspected, and to take precautions to ensure the protection and maintenance of their drinking water supplies. even though these drinking water standards do not apply to private wells, many states adopt them as ground water standards or use them to evaluate whether concentrations of contaminants in ground water are above a level of concern. the office of water establishes national primary drinking water standards, secondary drinking water regulations, as well as health advisories. the derivation of these standards, regulations, and health advisories are discussed below. the drinking water standards and health advisories tables may be reached from the office of science and technology ( ost) home page at http://www.epa.gov/ost. the tables are accessed under the ost programs heading on the ost home page. national primary drinking water standards are regulations the usepa sets to control the level of contaminants in the nation's drinking water. maximum contaminant level goals (mclgs) are the maximum level of a contaminant in drinking water at which no known or anticipated chronic adverse effect on the health of persons would occur, and which allows an adequate margin of safety. mclgs are non-enforceable public health goals. maximum contaminant levels (mcls) are enforceable standards that are set as close to mclgs as possible but take into consideration the availability of technology treatments and techniques as well as whether reliable analytical methods capable of detecting low concentrations of contaminants are available. the derivation of mclgs and mcls are discussed in the following sections. for noncarcinogens (not including microbial contaminants), the mclg is based on the rid. the definition and derivation of the rid has been discussed previously. the rid is first adjusted for an adult with body weight assumed to be 70 kg and consuming 2 l of water per day to produce the drinking water equivalent level (dwel): the dwel represents the concentration of a substance in drinking water that is not expected to cause any adverse noncarcinogenic health effects in humans over a lifetime of exposure and assumes the only exposure to the chemical comes from drinking water. however, exposure to the chemical can also occur through other pathways and routes of exposure. therefore, the mclg is calculated by reducing the dwel in proportion to the amount of exposure from drinking water relative to other sources (e.g., food, air). in the absence of actual exposure data, this relative source contribution (rsc) is generally assumed to be 20%. the final value is in mg/l and is generally rounded to one significant figure: mclg(mg!l) = dwel â· rsc (14) if the chemical is considered to be a class a orb carcinogen, then it is assumed that there is not a dose below which the chemical is considered safe. therefore, the mclg is set at zero. if a chemical is a class c carcinogen and scientific data provides information that there is a threshold below which carcinogenesis does not occur, then the mclg is set at a level above zero that is safe. prior to 1996, the mclg for class c carcinogens was based on an rid approach that applied an additional uncertainty factor of 10 to account for possible carcinogenic potential of the chemical. if there weren't any reported noncancer effects, then the mclg was based on a nominal lifetime excess cancer risk of 10-6 to 10-5 , if data were adequate. the office of water is now moving toward guidance contained in the 1999 draft cancer guidelines [8, 43] which allows standards for nonlin-ear carcinogens to be derived based on low dose extrapolation and a mode of action approach. for microbial contaminants that may present public health risk, the mclg is set at zero because ingesting one protozoa, virus, or bacterium may cause adverse health effects. usepa is conducting studies to determine whether there is a safe level above zero for some microbial contaminants. so far, however, this has not been established. as mentioned previously, maximum contaminant levels (mcls) are enforceable standards that are set as close to mclgs as possible but take into consideration the availability of technology treatments and techniques as well as whether reliable analytical methods capable of detecting low concentrations of contaminants are available. if there is not a reliable analytical method, than a treatment technique (tt) is set rather than an mcl. a tt is an enforceable procedure or level of technological performance, which public water systems must follow to ensure control of a contaminant. in addition, mcls take into account an economic analysis to determine whether the benefits of enforcing the standard justify the costs. for group a and group b carcinogens, mcls are usually promulgated at the 1 o-6 to 1 o-4 risk level. secondary drinking water regulations are non-enforceable federal guidelines that take into account whether a chemical produces cosmetic effects such as tooth or skin discoloration or aesthetic effects such as affecting the taste, odor, or color of drinking water. because there are at least 15 different contaminates (i.e., aluminum, chloride, copper, and fluoride) in drinking water that are not considered to be health threatening, secondary maximum contaminant levels (smcls) guidelines have been established for public water systems that voluntarily test the water. these secondary standards give the public water systems guidance on removing the contaminants. in most cases, the state health agencies and public water systems often monitor and treat their drinking water for secondary contaminants. in order to provide information and guidance concerning drinking water contaminants for which national regulations currently do not exist, the usepa health and ecological criteria division, office of water, in cooperation with the office of research and development prepares health advisories (ha). these detailed has are used to "estimate concentrations of the contaminant in drinking water that are not anticipated to cause any adverse noncarcinogenic health effects over specific exposure durations" [ 17] . they include a margin of safety to protect sensitive members of the population (e.g., children, the elderly, and pregnant women). has are not legally enforceable in the united states, are only used for guidance by federal, state and local officials, and are subject to change as new information becomes available. included in the has is information on analytical and treatment technologies. has are provided for acute or shortterm effects as well as chronic effects. the one-day ha, the ten-day ha and the longer-term ha are based on the assumption that all exposures to the contaminant comes from drinking water whereas the lifetime ha takes into account other sources such as food, air, etc. the following types of has have been developed [17] . one-day ha -the concentration of a chemical in drinking water that is not expected to cause any adverse noncarcinogenic effects for up to one day of exposure. a one-day ha is generally based on data from acute human or animal studies involving up to 7 days of exposure. the protected individual is assumed to be a 10-kg child with an assumed volume of drinking water (di) of 1 lingested/day. ten-day ha-the concentration of a chemical in drinking water that is not expected to cause any adverse noncarcinogenic effects for up to ten days of exposure. a ten -day ha is generally based on subacute animal studies involving 7-30 days of exposure. similarly to the one-day ha, the protected individual for the ten-day ha is assumed to be a 10-kg child with an assumed di of l l ingested/ day. longer-term ha-the concentration of a chemical in drinking water that is not expected to cause any adverse noncarcinogenic effects for up to approximately seven years (10% of an individual's lifetime) of exposure, with a margin of safety. a longer-term ha is generally based on subchronic animal studies involving 90 days to 1 year of exposure. the protected individual is assumed to be a 10-kg child with an assumed di of 1 l ingested/day and a 70-kg adult with an assumed di of 21 ingested/day. lifetime ha -the concentration of a chemical in drinking water that is not expected to cause any adverse noncarcinogenic effects for a lifetime of exposure. a lifetime ha is generally based on chronic or subchronic animal studies. the protected individual is assumed to be a 70-kg adult with an assumed di of 2 l ingested/day. a dwel is calculated and multiplied by a rsc of 20% to account for exposure to drinking water as well as other sources (food, air, etc.). therefore, the lifetime ha is derived similarly to the mclg. the following general formula is used to derive the one-day, ten-day, and the longer-term has and the dwel: health advisories for the assessment of carcinogenic risk (15) if a contaminant is recognized as a human or probable human carcinogen (groups a or b), a carcinogenic slope factor (csf) is derived based on techniques discussed above. the slope factor is then used to determine the concentrations of the chemical in drinking water that are associated with theoretical upper-bound excess lifetime cancer risks of w-4 , w-s, or w-6 â�¢ the following formula is used to calculate the concentration predicted to contribute an incremental risk level (rl) of 10-4 , w-5 , or 10-6 : cvw(mg.il) = ___ : : : . . _ where cow concentration in drinking water at desired rl (mg/l) rl desired risk level (lo-4 , 10-5 , or 70 assumed body weight of adult human (kg) csf carcinogenic potency factor for humans (mg/kglday}1 2 assumed water consumption of an adult human (l!day). (16) if a dwel was calculated for a class a, b, or c carcinogen based on an rid study, (i.e., noncarcinogen), then the carcinogenic risk associated with lifetime exposure to the dwel can be calculated to assist the risk manager for comparison in assessing the overall risks. the theoretical upper-bound cancer risk associated with lifetime exposure to the dwel is calculated as follows: 2lidâ· csf risk = dwel â· ----70 kg (17) toxity evaluation and human health risk assessment of surface and ground water 167 6 usepa is required by the clean water act of 1972 to develop, publish, and revise ambient water quality criteria (awqc). the awqc "involves the calculation of the maximum water concentration for a pollutant that ensures drinking water and/or fish ingestion exposures will not result in human intake of that pollutant (i.e., the water quality criteria level) in amounts that exceed a specified level based upon the toxicological endpoint of concern" [20] . in october 2000, usepa issued new guidelines [20] that replaced the 1980 awqc national guidelines [44] . the 2000 awqs guidelines incorporated significant scientific advances in the following key areas: cancer risk assessment (1986 cancer guidelines [7] vs the 1999 draft cancer guidelines) [ 8, 43] ; risk assessments for class c carcinogens using nonlinear low-dose extrapolation; non-cancer risk assessments (benchmark dose approach and categorical regression); exposure assessments (consideration of non-water sources of exposures); bioaccumulation in fish (bioaccumulation factors, bafs, are recommended for all compounds to calculate concentration in fish tissue). in addition, the procedures for deriving awqc under the cwa were made more consistent to the procedures for deriving mclg by the sdwa. this section will discuss guidelines from the methodology for deriving ambient water quality criteria for the protection of human health, hereafter referred to as the awqc methodology guidance [20] , accessible at http:/ /www.epa.gov/ost/ humanhealth/method/index.html. state and tribal environmental agencies are responsible for developing ambient water quality standards (awqs) for each water body in the state based on guidance provided by usepa [20] and the uses that water bodies have been designated for (i.e., drinking water supply, recreation, or fish protection, etc.). these designated uses are a part of the water quality standards, provide a regulatory goal for the water body and define the level of protection assigned to it. the watershed assessment, tracking&environmental results database (waters), accessible at http:/ /www.epa.gov/waters/ provides information on the water body designation for each individual state and tribe. the exposure pathways typically evaluated for awqc are direct ingestion of drinking water obtained from that water body and the consumption of fish/ shellfish obtained from that water body. when an awqc is set, anticipated exposures from other sources of exposure (e.g., food, air) are taken into account for noncarcinogenic effects, or carcinogenic effects evaluated by the margin of exposure (moe) approach (i.e., class c carcinogens, using the 1986 woe cancer guideline terminology). the amount of exposure attributed to each source compared to total exposure is called the relative source contribution (rsc) for that source. the rsc is typically set at 20% but if a site-specific assessment is conducted for a particular water body and it can be demonstrated that other sources of exposures are not likely to occur, then the rsc can be set as high as 80%. an exposure decision tree approach is described in the methodology guidance to assist in calculating a site-specific rsc for a water body [20] . the allowable dose (typically, the rid) is then allocated via the rsc approach to ensure that the criterion is protective enough, given the other anticipated sources of exposure: where awqc ambient water quality criterion (mg/l) rid reference dose for non-cancer effects (mg/kg-day) rsc relative source contribution factor to account for non-water sources of exposure -may be either a percentage (multiplied) or amount subtracted, depending on whether multiple criteria are relevant to the chemical bw human body weight ( default=70 kg for adults) di drinking water intake (default=2 l/day for adults) fli fish intake at trophic level (tl) i (i=2, 3, and 4) (defaults for total in-take=0.0175 kg/day for general adult population and sport anglers, and 0.1424 kg/day for subsistence fishers). trophic level breakouts for the general adult population and sport anglers are: tl2=0.0038 kg/day; tl3=0.0080 kg/day; and tl4=0.0057 kg/day bafi bioaccumulation factor at trophic level i (i=2, 3, and 4), lipid normalized (l/kg). the following equation is used for deriving awqc for chemicals evaluated with a nonlinear low-dose extrapolation (margin of exposure) based on guidance in the 1999 draft cancer guidelines: where pod point of departure for carcinogens based on a nonlinear low-dose extrapolation (mg/kglday), usually a loael, noael, or ledlo uf uncertainty factor for carcinogens based on a nonlinear low-dose extrapolation (unitless). for carcinogens, only two water sources (i.e., drinking water and fish ingestion) are considered when awqc are derived. awqc for carcinogens are determined with respect to the incremental lifetime risk posed by a substance's presence in water, and is not being set with regard to an individual's total risk from all sources of exposure [20] . the 1986 cancer guidelines are the basis for iris risk numbers that were used to derive the current awqc, except for a few compounds developed using the revised cancer guidelines [14, 45] . each new assessment applying the principles of the 1999 draft cancer guidelines [ 8, 43] will be subject to peer review before being used as the basis of revised, updated awqc. the cancer-based awqc was calculated using the risk specific dose (rsd) and other input parameters listed below. the rsd and awqc for carcinogens was calculated for the specific targeted lifetime cancer risk (i.e., iq-6 , iq-5 , iq-4 ), using the following two equations: where rsd risk specific dose (mg/kg/day) target cancer risk iq-6 , iq-5 , iq-4 (lifetime incremental risk) csf cancer slope factor (mg/kg-day)-1 (20) (21) exposure parameters based on a site-specific or regional basis can be substituted to reflect regional or local conditions and/or specific populations of concern. these include the relative source contribution, fish consumption rate, baf (including factors used to derive bafs such as concentration of particulate organic carbon applicable to the awqc (kg/l) or concentration of dissolved organic carbon applicable to the awqc (kg/l), percent lipid of fish consumed by target population, and species representative of given trophic levels. states and tribes are encouraged to make adjustments using the information and instructions provided in the awqc methodology guidance [20] . the national water quality standards database (wqsdb) at the web address, http:/ /www.epa.gov/wqsdatabase/, provides access to several wqs reports that provide information about designated uses, water body names, state numeric water quality standards, and epa recommended numeric water quality crite-ria. the wqsdb allows users the ability to compare wqs information across the nation using standard reports. some states and tribes use an incidental ingestion value (ii) instead of di value when the water body is used for recreational purposes and not as a source of drinking water. however, an ii value is not used to develop national awqc. the default value for ii is 0.01 l!day and is assumed to occur from swimming and other activities. the fish intake value is assumed to remain the same. besides protection of human health, awqc are developed based on other criteria such as organoleptic effects; aquatic life protection, sediment quality protection, nutrient criteria, microbial pathogens, biocriteria, excessive sedimentation, flow alterations, and wildlife criteria. for example, the national recommended water quality criteria table (http:/ /www.epa.gov/ost/standards/wqcriteria.html) lists freshwater or saltwater criteria maximum concentration (cmc) criteria values that are the acute limits for the priority pollutant for the protection of aquatic life in freshwater or saltwater. the freshwater or saltwater criterion continuous concentration (ccc) criteria value is the chronic limit for the priority pollutant for the protection of aquatic life in freshwater or saltwater, respectively. the table also includes criteria for organoleptic effects for 23 pollutants developed to prevent undesirable taste and/or odor imparted by them to ambient water. in some cases, a water quality criterion based on organoleptic effects or aquatic life protection would be more stringent than a criterion based on toxicologic endpoints. information and links to guidance documents relating to these subjects may be reached from the office of water, water quality criteria and standards program page at http://www.epa.gov/waterscience/standards/. as more knowledge is gained about the waste generated and disposed in landfllls by our society, there is great concern about the toxic effects that this waste has on our environment as well as animal and human health. over the past decade, there have been numerous attempts to recycle various waste products generated by our society. this section will review some of the recent literature on recycled hazardous waste materials. recycled concrete pavement as aggregate for the construction of highways can produce effluent with a high ph that can enter the underwater drains [46] . when portland cement is recycled, the concrete consists of limestones and minerals where 60-65% is lime ( cao ), silica (si0 2 }, alumina (al 2 0 3 }, and iron oxide (fe 2 0 3 ). ca(oh} 2 is formed sparingly in water and the saturated solution has a ph of 12.45 at 25 oc. the ph of the water effluent in underdrains is approximately 11-12. at this ph, the cac0 3 precipitates out and forms deposits on the screen [ 46] . the deposition on the screens produces clogging and scales to form in the underdrain; thereby, causing vegetative kill around the outlet. in addition to recycled concrete, rubber is recycled for asphalt pavements. recycling of rubber allows a means of disposal of scrap tires and reduces the quantity of construction materials for the asphalt. asphalt pavement contains hot mix asphalt with and without crumb rubber modifier. the use of rubber tires reduces the weight of the asphalt and provides good drainage media as well as extending the life of the asphalt [47] . while there is an apparent benefit for recycling rubber, it has been found by the minnesota pollution control agency that leaching can occur from the use of waste tires in sub grade roadbeds into the run -off water. in acidic conditions, leaching of barium, cadmium, lead, chromium, selenium, and zinc occurred from the asphalt while in basic conditions, there was leaching of polynuclear aromatic hydrocarbons. thus, the recommended allowable levels (rals) may be exceeded for drinking water standards in areas where there is recycled rubber in the asphalt. paper or wood itself does not contain any hazardous chemicals unless the paper undergoes recycling. the recycling process requires de-inking of waste paper prior to recovery of the fiber generating a sludge that contains particles of ink and fibers too short to be converted to a finished paper product [ 48] . the de-inking chemicals such as sulfur, chlorine, cadmium, and fluorine are present in the sludge generated. a sludge is any solid, semi-solid, or liquid waste generated from a municipal, commercial, or industrial wastewater treatment plant, water supply treatment plant, or air pollution control facility exclusive of treated effluent from a wastewater treatment plant [ 48] . thus, hazardous waste can be generated from the recycling paper process. a commodity used by numerous industries is plastic. because of the enormous amount of plastic disposed by consumers on a daily basis, it has become a common recycled item at many facilities. some metal sites will recycle the plastic insulation generated by their facility. the recycled plastic from such a facility generally includes metals such as lead, copper, manganese, and zinc, as well as dioxins, polychlorinated naphthalene, and polychlorinated biphenols. a leachate, contaminated run -off water, from the plastic "fluff" is formed during the recycling process. the leachate runs off into the water drains carrying hazardous chemical residue into soil and ground water. the plastic fluff is generally recycled on site into tiles, cushions, traffic cones, fenders, and highway barriers. the non-recyclable material and contaminated soil is generally taken to an off-site landfill. another common way to recycle plastic is to use the "sink-float" process where paper, fiber, and metal can be separated from the plastics and then recycled. the "sink-float" process uses water where the heavy items sink and the light items float [49] . it has been demonstrated that recycled plastics can be used as construction material as an alternative to lumber. this product is made from used bottles collected at curbside for recycling. the recycled plastics undergo sorting to remove unpigmented polyethylene milk/water jugs and polyethylene terephthalate carbonated beverage bottles. the leftover plastic material is referred to as curbside tailings (ct). ct consists of approximately 80% polyolefin (polyethylene and polypropylene) with the remaining percentages made of polyethylene terephthalate, polystyrene, polyvinyl chloride, and other plastics [50] . the ct product has reasonable strength compared to wood. we is et al. ( 1992) evaluated three ct recycled plastic formulations in fiddler crabs, snail, and algae [50] . it was found that limb regeneration of the fiddler crabs was accelerated with all three formulations but had no effect on fertilized eggs or larval developments formulations. there was a significant reduction in the sperm fertilization success rate [50] . furthermore, all three ct plastic formulation did not have an affect on the survival rate of snails or other algal species. the presence of metals in sludge and wastewater is a current problem. for instance, the use of sludge as a fertilizer of agricultural land generally receives cadmium (cd++) from aerial deposition and phosphatic fertilizers. cd++ is considered a hazardous chemical and has been shown to produce toxicity of the lung and kidney and to be carcinogenic in rats [51] . the highest concentration of cd++ is found in tobacco, lettuce, spinach, and other leafy products/vegetables. using crop uptake data from field trials, it is possible to relate potential human dietary intake of cd++ on which hazard depends, to soil concentrations of cadmium [52] . transfer via farm animals to meat and dairy products for human consumption is thought to be minimal even allowing for some direct ingestion of sludge-treated soil by the animals. background soil contains 0.1 to 1.0 mg cd++ /kg where 90% of cadmium is found in raw sewage that is converted to sludge. after the formation of sludge, 70% of the 90% cd++ is removed primarily by sedimentation. in order for cd++ uptake in roots to occur, cd++ must be in its soluble form adjacent to the root membrane for some finite period [52] . generally, a decrease in ph in soil will enhance the solubility of cd++, which will increase the crop uptake of cd++. in 1984, who/usepa agreed that the maximum acceptable daily uptake of cd++ was 70 f.lg/day. where 200 1-lg cd++jday over a 50-year period would be necessary to produce toxicity to the kidney. farm animals fed fodder crops grown on sludge-treated soil will absorb ~5% of the cd++ ingested [52] . in addition to recycling cd++, lead (pb )-edta wastewater also undergoes recycling. edta a chelating agent used in the soil washing process for the decontamination of pb contaminated soil. kim et al. [53] outlines a method to recycle pb-edta wastewater by substituting the pb-edta complex with feh ions at a low ph followed by precipitation of pb ions with phosphate or sulfate ions. feh ions-edta will precipitate at a high ph with naoh. the recycled edta solution can be recycled several times without losing its extractive power [53] . recycling computers can be extremely hazardous if not properly disposed. there are many parts of the computer that are toxic. to begin with, the cathode ray tube (crt) glass may be classified as a hazardous waste due to its high pb concentration. the liquid crystal display (lcd), which contains benzene material for the liquid crystal, is also considered hazardous. in addition, the mercury switch, mercury relay, lithium battery, ni-h battery, ni-cd battery, and polychlorinated biphenyl (pcb) capacitor are all hazardous materials. because of this, taiwan has recently established guidelines for the proper disposal of computer and/or computer parts [54] . the nine guidelines are: i) landfill or incineration of scrap computers shall be avoided; ii) the phosphorescent coatings which have been applied to the glass panel of crt must be removed; iii) all the batteries (li, ni-cd,ni-h) must be removed by non-destructive means; iv) all the pcb capacitors which have a diameter greater than 1 em and a height larger than 2 em must be removed; v) all the mercury containing parts must be removed; vi) crt must be ventilated before stored inside a building; vii) the high-ph content funnel glass of the crt must be properly treated; viii) the lcd of notebook computer must be removed by non-destructive means; and lastly, ix) plastic that contains the flameretardant, bromine, shall be treated properly. hopefully, this model can be used in other countries where computer waste is becoming a major issue of environmental concern. organic solvents have many applications in the industry such as formulation of products, thinning of products prior to use or cleaning of materials by removal of contaminants. during this application, solvent emission and waste solvent generation occur. most organic solvents are known to have adverse effects on both human health and the environment. solvents may affect the body through inhalation and skin contact and lead to either acute or chronic poisoning [55] . the effects of acute poisoning include narcosis, irritation of throat, eyes, or skin, dermatitis, and even death and the effects of chronic poisoning include damage to blood, lung, kidney, and gastrointestinal system and/or nervous system. in addition, many solvents are inflammable in nature. waste management of organic solvents includes: source reduction, recycling, treatment, and disposal [55] . case studies indicate that dry cleaning facilities use perchloroethylene (perc) in which workers around the cleaning machines are subject to high health risks; thus, vapor recovery systems are used to reduce the perc emissions especially from older machines [55] . riess et al. [56] evaluated the recyclability of flame-retarded polymers that contain brominated flame-retardants from 108 televisions (tv) and 78 personal computers (pcs) obtained from a recycling company. the flame-retardants identified in the tv were: 54% high-impact polystyrene, 24% acrylonitrile butadiene styrene, 15% polystyrene, and 7% polyphenyleneoxide polystyrene. the flame retardants found in pcs were: 43% acrylonitrile butadiene styrene, 35% polyphenyleneoxide polystyrene, 18% high-impact polystyrene, 3% polystyrene, and 1% polyvinyl chloride. recycling may be practical if 75% new material is added to mixture [56] . the denver potable reuse pilot project began in 1968 to recycle wastewater effluent to achieve potable water quality as well as being economically competitive with conventional technology. moreover, this project sponsored the first large-scale risk assessment studies using experimental animals [57] . after ten years, this pilot project was converted to a demonstration treatment plant to address many of the technical and non-technical issues. the objectives of the "reuse demonstration project were (i) to establish end product safety, (ii) to demonstrate the reliability of the process, (iii) to generate public awareness, (iv) to generate regulatory agency acceptance, and (v) to provide data for a largescale implementation" [57] . however, insuring end-product water safety proved to be difficult to demonstrate because the health standards established for drinking water were not intended to apply to treated waters. thus, additional criteria were used to prove that the effluent was suitable for human consumption. below were the criteria used in this project: -the product was compared with the national primary and secondary drinking water regulations values -the product was compared with federal or state regulated parameters -effluent levels were compared with the levels suggested to be hazardous -concentrations of product in the water were compared to denver's current drinking water criteria or other "acceptable" water supplies in the u.s. and/or worldwide -whole-animal studies (i.e., chronic toxicity, oncogenicity, and reproductive tests) were conducted using denver's current drinking water as a comparison standard the denver project used two dosage groups per water sample: reclaimed water from the demonstration plant with reverse osmosis treatment (rot) and denver drinking water from the foothills water treatment plant (dwt). ro and dw were administered to fischer 344 rats and b 6 c 3 f 1 mice at dosages at least 500 times the amount found in the original water samples. ultrafiltration water treatment samples (uft) were only administered to rats at the high dose (soox) and distilled water was used as the control in both the rats and mice studies. in addition to the chronic toxicity studies, reproductive toxicity studies were performed to identify potential adverse effects on reproductive performance, intrauterine development, and growth and development of the offspring. the teratology phase will identify potential embryotoxicity and teratogenicity. administration of ro, uft, and dw water at 500 times the amount found in the original water samples for 104 weeks in rats did not result in any toxicologic or carcinogenic toxicity [57] . the survival rate was slightly higher among the female rats (64%-84%) compared to the male rats (52%-70%). there were a variety of neoplasms seen in all treatment groups ( table 7) . the "c" cell tumors in the thyroids were not considered treatment related because these neoplasms were within the anticipated ranges for the age and strain of the rat. similar results were seen with the mouse chronic studies where there was no toxicity or carcinogenicity seen after 104 weeks of high dose treatment and the survival rate was identical to the rats. the organs most affected by the treatment were the hematopoietic system, liver, lung, and pituitary gland [57] . the remarkable finding of the reproductive studies was "the absence of treatmentrelated effects on reproductive performance, growth, mating capacity, survival of offspring, or fetal development in any of the treatment groups" [57] . the denver project met the outlined objectives at the start of the project and all three of the toxicity studies demonstrated that concentrations 500 times the original amount seen in sample water did not cause any notable toxicity. thus, secondary wastewater can be recycled into safe drinking water for human consumption. chemical mixtures have always been an issue of concern to address/assess the toxicity to the environment and to humans. an interagency agreement between atsdr and the ntp resulted in participation in a public health service (phs) activity related to the superfund act (cercla comprehensive environmental response, compensation and liability act) [58] . yang was the lead scientist at the national institute of environmental health sciences (niehs)/ntp for the development of the "superfund toxicology program". particular focus centered on chemical mixtures of environmental concern, especially groundwater contaminants derived from hazardous waste disposal and agricultural activities. yang states that obtaining a "representative" sample is practically impossible [58] . a core sample from one location of a site will definitely be different from a core sample from a different location of a site. also, a core sample taken from the exact location at different times of day and/or different days will be different because weather, activity at the site, and composition of the waste can change and degrade or synthesize new compounds. thus, yang proposed a strategy to study chemical mixtures [58] : 1. study chemical mixtures between binary and complex mixtures to avoid duplication of earlier studies that evaluated the two extremes 2. study chemically defined mixtures to make determination and mechanistic studies manageable 3. study chemical mixtures related to groundwater contamination because groundwater contamination is among the most critical environmental issue 4. study chemical mixtures at environmentally realistic concentrations to access the potential health effects of environmental pollution of long-term, low-level exposure 5. study chemical mixtures with potential for life-time exposure. a chemical mixture of groundwater contaminants from hazardous waste sites and agricultural activities were created. this formulation mixture contained 25-chemicals that simulated groundwater contamination as shown in table 8 . the concentrations selected represent the average survey values of 180 hazardous waste disposal sites representing all 10 usepa regions. even though such a mixture may never exist in reality, new insights may be gained to elucidate potential health effects from laboratory animals to human. for most of the end-points examined in this study, the results were negative. the negative results of this study were significant because various mixtures were tested at 10-to 100-fold or several orders of magnitude higher than potential human exposure levels [58] . insights gained from yang's project were: i) the effects will be subtle and marginal; ii) toxicologic interactions are possible at the environmentally realistic levels of exposure; iii) toxic responses may be from unconventional toxicologic end-point (immunosuppression, myelotoxicity); iv) possibility of subclinical residual effects may become more interactive with subsequent insults from chemical, physical, and/or biological agents; and v) negative results do not in-toxity evaluation and human health risk assessment of surface and ground water 179 dicate safety for humans because the studies were done on rodents. subsequent work on this mixture at low doses increased the acute toxicity of high doses of known hepatic and renal toxicants [59] . recently, niehs has begun to focus on simpler mixtures of chemicals that share common mechanisms of action rather than complex mixtures. over the past several decades, much effort has been made to establish national guidance on proper waste handling disposal techniques such that there are many local, state, national and federal agencies that provide guidelines to protect the surface and ground waters for humans. these guidelines also provide methods and approaches used to evaluate potential health effects and assess risks from contaminated source media, (i.e., soil, air, and water) as well as establish standards of exposure or health benchmark values in the different media, which are not expected to produce environmental or human health impacts. the use of the risk assessment methodology by various regulatory agencies using the following steps: i) hazard identification; ii) dose-response assessment; iii) exposure assessment; and iv) risk characterization balances the risks and benefits and sets the "acceptable" target levels of exposure to ground water and surface water. â�¢ for noncarcinogenic effects at=ed; for carcinogenic effects at=70 years. b exhibit 3-2 of the interim dermal guidance document [34) . different regulatory or state agencies may recommend different exposure parameters based on scientific policy or risk management decisions. waste management guide. the bureau of national affairs industrial waste recycling in: jessup dh (ed) waste management guide. laws, issues, and solutions. the bureau of national affairs revised rcra inspection manual oswer directive 9938 quantitative risk assessment for environmental and occupational health casarett and doull's toxicology: the basic science of poisons the emerging field of ecogenetics guidelines for carcinogen risk assessment 51 fr 33992 guidelines for carcinogen risk assessment. review draft. office of research and development a weight -of-evidence scheme for assessing interactions in chemical mixtures approaches and challenges in risk assessments of chemical mixtures. in: yang rsh (ed) toxicology of chemical mixtures health effect test guidelines: acute toxicity testing. us epa, office of prevention, pesticides, and toxic substances chlorethoxyfos-review of a repeated exposure inhalation study and evaluation of that study by the hazard identification assessment review committee. us epa, office of prevention, pesticides, and toxic substances biologic markers in risk assessment for environmental carcinogens health effect test guidelines: combined chronic toxicity/carcinogencity. us epa, office of prevention, pesticides, and toxic substances methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. us epa, office of research and development soil screening guidance: technical background document. us epa, office of waste and emergency response health advisories of drinking water contaminants. us epa, office of water and health advisories assessment and management of chemical risks, vol1 risk assessment in the remediation of hazardous waste sites methodology for deriving ambient water quality criteria for the protection of human health issues in qualitative and quantitative risk analysis for developmental toxicology toxicology information resources at the environmental protection agency risk assessment guidance for superfund, voll. human health evaluation manual (part a) assessment protocol for hazardous waste combustion facilities can we assign an upper limit to skin permeability? international life science institute (ilsi) (1999) exposure to contaminants in drinking water, estimating uptake through the skin and by inhalation memorandum on body weight estimates based on nhanes iii data, including data tables and graphs. analysis conducted and prepared by westat, under epa contract number 68-c-99-242 usda ( 1998) 1994-1996 continuing survey of food intakes by individuals and 1994-1996 diet and health knowledge survey measures of compounding conservatism in probabilistic risk assessment guiding principles for monte carlo analysis epa/630/r-97/001 risk assessment forum chemical risk assessment numbers: what should they mean to engineers? risk assessment guidance for superfund, voll. human health evaluation manual (parte, supplemental guidance for dermal risk assessment derivation of toxicity values for dermal exposure supplemental guidance to ragss. region iv bulletins. human health risk assessment waste management division supplementary guidance for conducting health risk assessment of chemical mixtures guidelines for the health risk assessment of chemical mixtures the toxicity of poisons applied jointly a practical guide to understanding, managing, and reviewing environmental risk assessment reports addendum:region 6 risk management -draft human health risk assessment protocol for hazardous waste combustion facilities epa year 2000 guidance document. contract number 68-w1-0055 guidelines and methodology used in the preparation of health effect assessment chapters of the consent decree water criteria documents implementing the food quality protection act. us epa, office of prevention, pesticides, and toxic substance remediation of hazardous effluent emitted from beneath newly constructed road systems and clogging of underdrain systems assessment of water pollutants from asphalt pavement containing recycled rubber in rhode island the rhode island department of transportation waste-to-energy plant for paper industry sludges disposal: technical-economic study superfund at work: hazardous waste cleanup efforts nationwide. us epa, solid waste and emergency response toxicity of construction materials in the marine environment: a comparison of chromated-copper-arenate-treated wood and recycled plastic the control of the heavy metals health hazard in the reclamation of wastewater sludge as agricultural fertilizer cadmium -a complex environmental problem. part ii recycling of lead-contaminated edta wastewater management of scrap computer recycling in taiwan management, disposal and recycling of waste industrial organic solvents in hong kong analysis of flame retarded polymers and recycling materials chemosphere health effect studies on recycled drinking water from secondary wastewater. in: yang rsh ( ed) toxicology of chemical mixtures toxicology of chemical mixtures derived from hazardous waste sites or application of pesticides and fertilizers. in: yang rsh (ed) toxicology of chemical mixtures toxicology studies of a chemical mixture of 25 groundwater contaminants: hepatic and renal assessment, response to carbon tetrachloride challenge, and influence of treatment-induced water restriction texas natural resource conservation commission (1999) texas risk reduction program rule review draft addendum to the methodology for assessing health risks associated with indirect exposure to combustor emissions estimating exposure to dioxin-like compounds review draft development of human health-based and ecologically-based exit criteria for the hazardous waste identification project. office of solid waste i and ii cw â· ir â· ef â· ed intake=--------bw a a number of studies has shown that an age-adjusted approach should be used to calculate intakes for children for carcinogens to take into account the difference in ingestion rates, body weights, and exposure duration for children from 1 to 6 years old and others from 7 to 31 years [16] . b the exposure parameters were taken from the texas risk reduction program rule [60] and are provided as examples only. different regulatory or state agencies may recommend different exposure parameters based on scientific policy or risk management decisions. [20] . ' use only when a rid is based on health effects in children [20] . d the office of water is in the process of preparing an exposure assessment technical support document in which an age-adjusted approach will be used to calculate fish intakes for children for carcinogens to take into account the difference in ingestion rates, body weights, and exposure duration for children from 1 to 6 years old and others from 7 to 31 years [20] . for copcs whose log k0w<4.0 for copcs whose log kow>4.0 cf = cw â· baf for dioxins, furans, and polychlorinated biphenyls cf = csed â· bsaf cf =chemical concentration in fish (mg/kg), fresh weight (fw) cw =chemical concentration in water (mg/l) bcf =bioconcentration factor (l/kg fw)h baf =bioaccumulation factor (l/kg fw)b c,ed =chemical concentration in sediment (mg/kg) bsaf =biota-sediment accumulation factor (unitless)<â�¢ please refer to reference [25] for a detailed discussion of procedures used to calculate chemical concentration in fish. different regulatory or state agencies may recommend different procedures based on scientific policy or risk management decisions [20, 44] . b please refer to appendix a-3 of reference [25] for bcf, baf, and bsaf values and procedures for calculating these values. also, please refer to [20, 44] . c bsafs are used to account for the transfer of copcs from the bottom sediment to the lipid in fish [25, [61] [62] [63] . organic compounds non-steady state" not applicable for inorganics cinh =the concentration of copc at the exchange boundary (mglm 3 ) cw =chemical concentration in water (mg/l) vf =volatilization factor [(mglm 3 )/(mg!l-h20)]â�¢ ef =exposure frequency (days/year)h ed =exposure duration (years)h at =averaging time in years (period over which exposure is averaged)h a specific fate and transport models are used to derive volatilization factors to quantify the transfer of volatile copcs from ground water into an enclosed space, from ground and surface waters into ambient air, etc. these fate and transport models are discussed elsewhere in this book. b the exposure parameters for ef, ed, and at from appendix a -1 can be used for the residential adult, residential child, and commercial/industrial worker for some pathways, but site-specific exposure parameters may need to be developed for other pathways. key: cord-023747-mvq6353a authors: ascherio, alberto; munger, kassandra l. title: epidemiology of multiple sclerosis: environmental factors date: 2009-12-25 journal: nan doi: 10.1016/b978-1-4160-6068-0.00004-8 sha: doc_id: 23747 cord_uid: mvq6353a this chapter discusses the environmental factors associated to epidemiology of multiple sclerosis. the epidemiologic evidence points to three environ­mental risk factors—infection with the epstein-barr virus (ebv), low levels of vitamin d, and cigarette smoking—whose association with multiple sclerosis (ms) seems to satisfy in varying degrees most of the criteria that support causality, including temporality, strength, consis­tency, biologic gradient, and plausibility. none of these associations, however, has been tested experimentally in humans and only one––vitamin d deficiency is presently amenable to experimental interventions. the evidence, albeit more sparse and inconsistent, linking other environmental factors to ms risk are summarized. epidemiologic clues to the hypothetical role of infection in ms are com­plex and often seem to point in opposite directions. the ecological studies, database/linkage analyses, and longitudinal studies of sunlight exposure and vitamin d are reviewed. biologic mechanisms for smoking and increased risk of ms could be neuro­toxic, immunomodulatory, vascular, or they could involve increased frequency and duration of respiratory infections. some other possible risk factors include––diet and hepatitis b vaccine. data. such has been the case, for example, with interventions to reduce lung cancer incidence by reducing exposure to tobacco smoke. as discussed in this chapter, epidemiologic evidence points to three environmental risk factors-infection with the epstein-barr virus (ebv), low levels of vitamin d, and cigarette smoking-whose association with multiple sclerosis (ms) seems to satisfy in varying degrees most of the criteria that support causality, including temporality (i.e., the cause must precede the effect), strength, consistency, biologic gradient, and plausibility. none of these associations, however, has been tested experimentally in humans, and only one (vitamin d deficiency) is presently amenable to experimental interventions. this chapter also summarizes the evidence, albeit more sparse and inconsistent, linking other environmental factors to ms risk. for many years, it appeared that the "who, where, and when" of ms epidemiology was well understood. however, some aspects of ms epidemiology may be changing, notably the observations of an attenuation of the latitude gradient 3, 4 and the increasing female-to-male ratio. 5 in this section, we discuss the "classic" view of ms epidemiology, some of which has been known for more than 50 years, and then some recent developments that may provide new clues to the etiology of ms. ms is the most common neurologic disease in young adults. incidence rates are low in childhood and adolescence (<6/100,000/year) high in the middle to late twenties and early thirties (11 to 18/100,000/year in high-risk populations), and gradually decline thereafter, with rates less than 9/100,000/year among those older than 45 years of age. 3, 6 women are approximately twice as likely as men to develop ms, 7, 8 and the lifetime risk among white women is about 1 in 200. 3, 9 ms exhibits a worldwide latitude gradient, with high prevalence and incidence in northern europe, 7 canada, 10,11 the northern united states, 3, 12, 13 and southern australia 14 and decreasing prevalence and incidence in regions closer to the equator. 15 exceptions to the latitude gradient exist and include a lower than expected prevalence in japan 16 and higher than expected prevalence and incidence in the mediterranean islands of sardinia and sicily. 7 kurtzke 17 summarized the early descriptive studies by depicting areas of high (≥30/100,000), medium (5 to 29/100,000), and low (<5/100,000) prevalence of ms; we have updated his figures with more recent prevalence estimates 7, 16, [18] [19] [20] [21] [22] [23] [24] (fig. 4-1) . a more comprehensive review of ms incidence and prevalence worldwide was published in 2005. 18 it is important to note that differences in estimated incidence across countries or time periods can result from differences in study design, case ascertainment, or diagnostic criteria, rather than from real changes in disease occurrence. differences in prevalence are even more difficult to interpret, because they may reflect increased survival or earlier diagnosis, both of which can occur even if the incidence is the same. 25 in spite of these limitations, the collective data do support a higher risk of ms at higher latitudes, both north and south of the equator. the existence of the latitude gradient alone is not enough to support an environmental component, because it could be explained by genetic differences. 18, 26 however, studies of ms incidence and prevalence among migrant populations also support a role for environmental factors. these studies have limitations, in that migrants may be different from nonmigrants in socioeconomic and health status, may not utilize local health care resources, and therefore they may be less likely to be diagnosed; in addition, enumeration of the immigrant population for disease statistics may be difficult or impossible. 25, 27 nevertheless, migrant studies on ms collectively support a decreased prevalence of ms among those who migrate from high-to low-risk areas, particularly if the migration occurs before 15 years of age. 27 moreover, one study found a decreased prevalence of ms in all age groups among immigrants from europe to australia, suggesting that the protective effect may extend into adulthood as well. 28 studies within the united states have also supported a decreased risk of ms among migrants from northern (>41° to 42° n), australia and new zealand europe figure 4-1 worldwide prevalence estimates of multiple sclerosis. blue, more than 90 cases per 100,000 population; purple, 60 to 89/100,000; green, 30 to 59/100,000; orange, 5 to 29/100,000; yellow, fewer than 5/100,000; white, insufficient data. an asterisk indicates that data for that region or country are older and should be interpreted cautiously. high-risk parts of the country to southern (<37° n), low-risk regions. 29, 30 the study of u.s. veterans 30 is particularly compelling because of its large sample size and rigorous design. in this study, kurtzke observed that individuals who were born in the northern united states but migrated to the southern part of the country before joining the military had a 50% reduced risk of ms compared with those who did not migrate ( fig. 4-2) . fewer studies have been conducted among migrants from low-to high-risk areas. in general, these studies have found that a low risk of ms is retained after migration, but that the offspring of migrants have a higher risk of ms, similar to that in the host country. 27, [31] [32] [33] [34] [35] in the u.s. veterans study, 30 individuals who were born in the southern part of the country and migrated to northern states before entering the military had a 20% increased risk of ms, and those migrating from the middle tier of states to northern regions had a 31% increased risk (see fig. 4 -2). more recently, in a study conducted in the french west indies (a low-risk area), an increased risk of ms was found among individuals who had moved to france (a high-risk area) and then returned to the west indies. the increase in risk was greatest among those who migrated to france before the age of 15 years. 36 the incidence of ms appears to have been relatively stable over the past 50 years in several high-risk areas, including denmark 6 and the northern united states, 37 but there is some evidence that ms may be increasing in japan 16 and in parts of southern europe, most notably in sardinia. 38 interestingly, the island of malta has continued to experience low, stable rates of ms 39 despite its proximity to sardinia and sicily and a high frequency of the ms-associated hla-drb1*1501 allele. 40 there is also evidence of an increased female-to-male ratio in ms incidence. in canada, the female-to-male ratio apparently has increased from approximately 2:1 among individuals born in the 1930s and 1940s to approximately 3:1 among those born in the 1970s. 5 this change is strongly correlated with, and could be at least in part explained by, a sharp increase in the female-to-male ratio in smoking behavior (unpublished data), because smoking is a strong risk factor for ms (see later discussion). an attenuation of the latitude gradient was observed independently in a population of u.s. nurses 3 and in u.s. military veterans. 4 among nurses born between 1920 and 1946 and among veterans of world war ii or the korean conflict, those living in the northern tier of states (>41° to 42° n) had a greater than threefold increased risk of ms compared to those in the southern tier (<37° n). among vietnam and gulf war veterans, however, this gradient was attenuated to less than twofold, and among nurses born between 1947 and 1964 it completely disappeared ( fig. 4-3) . because the methods used to determine rates of ms in the early and later cohorts were the same, and because the individuals in the cohorts had similar socioeconomic status 3 or access to health care, 4 this attenuation was unlikely to be due to artifact. a change of this magnitude over such a short period of time argues for an environmental, rather than a genetic, explanation of the latitude gradient; as discussed later, this environmental factor may involve changes in patterns of infection or sun exposure, or both. further, the attenuation was probably caused by an increase in ms incidence in the southern united states, because incidence rates in the northern states, based at least on data from the longitudinal study in olmsted county, minnesota, seem to have remained relatively stable. 37 an attenuation of the latitude gradient in europe has also been observed; however, no systematic studies have assessed this gradient within the same population over time, and the attenuation therefore may be due to improved study methodology and case ascertainment, particularly within the united kingdom. 18 the possibility of an infectious cause was considered early in ms history, and numerous viruses and bacteria were, at different times, implicated as likely etiologic agents. the results of early studies, based on microscopic examination of pathologic material and attempts to transmit the disease to animals, often were null or spuriously positive because of contamination and could not be replicated. later, numerous serologic studies were conducted, often demonstrating significantly elevated antibody titers against several viruses in ms patients compared with healthy controls, but these differences were probably an epiphenomenon of the immune activation rather than being of etiologic significance. 41 in part as a consequence of these investigations, many researchers became skeptical about the existence of an infectious agent causing ms, and this skepticism persists today. epidemiologic clues to the hypothetical role of infection in ms are complex and often seem to point in opposite directions. on the one hand, results of family studies, including investigations of half-siblings, adopted children, and spouses of individuals with ms, support a strong genetic component as the leading explanation of ms clustering within families and provide little evidence of person-to-person transmission. 42 on the other, there are well-documented, albeit controversial, 43 reports of epidemics of ms, most notably in the faroe islands, 44 that are most easily explained by the introduction and transmission of an infectious agent. to reconcile these findings, it has been postulated that ms is a rare complication of a common infection, with the disease occurring in genetically or otherwise predisposed individuals. in this scenario, the epidemics would be a consequence of the introduction of the ms-causing agent for the first time in remote, previously naïve populations. 45 two hypotheses as to the nature of this infection have been proposed: (1) the responsible microorganism is more common in areas of high ms prevalence (the "prevalence" hypothesis), and (2) the ms-causing agent is ubiquitous and more easily transmitted in areas of low ms prevalence, where infection occurs predominantly in infancy, when it would be less harmful and more likely to confer protective immunity. the latter proposal is called the "poliomyelitis" hypothesis, by analogy with the epidemiology of poliomyelitis before vaccination. 46 the poliomyelitis hypothesis is also consistent with the higher prevalence of ms in communities with better hygiene, 47 in individuals with higher education, 48, 49 and in those with late age at infection with common viruses, 50 as well as the general lack of increase in ms incidence among individuals migrating from low-to high-prevalence areas. 27 however, the poliomyelitis hypothesis cannot explain the reduced risk of ms among migrants from high-to low-risk areas and, in fact, would predict an increase in ms risk in this circumstance, whereas the prevalence hypothesis is consistent with the observations. failure to identify a specific microbe as the cause of ms, despite evidence that is consistent with some role for infection in at least modulating ms risk, has strengthened support for a third, more general, "hygiene" hypothesis, according to which exposure to multiple infections in childhood primes the immune responses later in life toward a less inflammatory and a less autoimmunogenic profile. 51 the hygiene hypothesis can explain all the features of ms epidemiology that are explained by the original formulation of the poliomyelitis hypothesis. in addition, the protective effect of migration from high-to low-ms areas, which is paradoxical under the poliomyelitis hypothesis, could be beneficial because of increased exposure of migrants to parasitic and other infections in the low-risk area. at the population level, prevalence of ms is positively correlated with high levels of hygiene, as measured, for example, by prevalence of intestinal parasites. 52 the improving hygienic conditions in southern europe in the last few decades could explain the increased prevalence of ms reported in multiple surveys (although whether there was a true increase in ms incidence remains unsettled). 7 it is also interesting that infection with intestinal helminths, which is highly prevalent in developing countries, had been reported to cause an immune deviation with attenuation of helper t-cell 1 cellular immune responses and remission of ms. 53 finally, the hygiene hypothesis provides a convincing explanation for the observations that infectious mononucleosis (im) is associated with an increased risk of ms (relative risk [rr] = 2.3; p < .00000001) 54 and that the epidemiology of im is strikingly similar to that of ms (table 4 -1). 55 because im is common in individuals who are first infected with ebv in adolescence or adulthood 56 but rare when ebv infection occurs in childhood, it is a strong marker of age at ebv infection, which is itself strongly correlated with socioeconomic development across populations and with socioeconomic status within populations. 57 an exception to this pattern is seen in asia, where ebv infection occurs uniformly early in life and im is thus rare. it is noteworthy that the incidence of ms remains relatively low in asian countries, including japan, despite the fast industrialization and reduction of infectious diseases, 58 although there is evidence that the incidence may be increasing in japan. 16 according to the hygiene hypothesis, the association between im and ms risk does not reflect a causal effect of ebv but rather the indirect manifestation of a common cause; that is, both ms and im are the result of high hygiene and a resulting low burden of infection during childhood. an important prediction of this hypothesis is that ms risk will be high among individuals reared in a highly hygienic environment, even if they do not happen to be infected with ebv later in life, whereas, if ebv has a causal role in ms, individuals who are not infected with ebv would have a low risk of ms. 59 the data on this point are unequivocal: individuals who are not infected with ebv, even though they have the same hygienic upbringing as those with im, have an extremely low risk of ms (odds ratio [or] from metaanalysis = 0.06; p < .00000001) ( table 4 -2). the contrast could not be sharper or more consistent: ms risk among individuals who are not infected with ebv is at least 10-fold lower than that of individuals who are ebv-positive, and 20-fold lower than that of individuals with a history of im. 59 because studies in pediatric ms 60,61 rule out a common genetic resistance to ms and ebv infection, 59 we can conclude either that ebv itself or some other factor closely related to ebv is a strong causal risk factor for ms or that ms itself strongly predisposes to ebv infection. temporality is the only truly necessary criteria for causality. the association between ebv infection and ms is strong and consistent across multiple studies in different populations, and there is to some extent a biologic gradient (higher risk associated with severity of infection, as indicated by history of im). until recently, all studies on ms and infection used a cross-sectional design and could not completely rule out the possibility that ebv infection was a consequence rather than a cause of ms. however, the results of four longitudinal serologic studies have now been published (table 4-3) . [62] [63] [64] [65] the most consistent finding across these studies is that, among individuals who will develop ms, there is an elevation of serum antibodies against the ebv nuclear antigen 1 (ebna1) that precedes the onset of ms symptoms by many years. the presence of anti-ebna1 antibodies is a marker of past infection with ebv, because titers typically rise only weeks after the acute infection. further, there is no evidence in clinical studies of acute primary ebv infection in individuals with ms. 66 taken together, these results indicate that ms is a consequence rather than a cause of ebv infection. until recently, ebv had not been found in ms lesions, 67, 68 and therefore the link between ebv and ms was postulated to be mediated by indirect mechanisms. the leading hypothesis was that the immune response to ebv infection in genetically susceptible individuals cross-reacts with myelin antigens (molecular mimicry). the discovery that ms patients have an increased frequency and broadened specificity of cd4-positive t cells recognizing ebna1 69 and the identification of two ebv peptides (one of which is from ebna1) as targets of the immune response in the cerebrospinal fluid of ms patients 70 provided support to the molecular mimicry theory. other proposed hypotheses included the activation of superantigens, 71 an increased expression of alpha b-crystallin, 72 and infection of autoreactive b lymphocytes. 73 however, in a recent, rigorous pathologic study, 74 large numbers of ebvinfected b cells were found in the brain of most of ms patients. these cells were more numerous in areas with active inflammatory infiltrates, where cytotoxic cd8-positive t cells displaying an activated phenotype were seen contiguous to the ebv-infected cells. alone, these pathologic findings provide only suggestive evidence for a causal role of ebv in ms, because the infiltration of ebv-infected b cells could be secondary to the inflammatory process that is the hallmark of ms, but their convergence with the epidemiologic evidence described earlier 59 is so striking that noncausal explanations become improbable. however, independent replication of these findings is needed before any conclusion can be drawn. the strong increase in ms risk after ebv infection and (if confirmed) the presence of ebv in ms lesions suggest that antiviral drugs or a vaccine against ebv could contribute to ms treatment and prevention. although antiviral drugs have been tried in the past for ms treatment with borderline results, 75-77 none of the treatment regimens used was sufficiently effective against latent ebv infection. several aspects of ms epidemiology cannot be explained by ebv infection, indicating that other factors must contribute. 59 genes are clearly important, and it is of interest that the association between anti-ebna1 titers and ms risk has been found in both hla-drb1*1501-positive and hla-drb1*1501-negative individuals. 78 variations in ebv strains could also play a role, although evidence in support of this hypothesis remains limited. 79, 80 many other infectious agents have been hypothesized to be related to ms, mostly because of pathologic studies or their role in animal models. recent candidates include chlamydia pneumoniae, 81-84 human herpesvirus 6, 85-87 retroviruses, 88, 89 and coronaviruses, 90 but there are no convincing epidemiologic studies linking these infections to ms risk. noninfectious factors may also be important, and prominent among them are vitamin d and cigarette smoking. one of the strongest correlates of latitude is the duration and intensity of sunlight, which in ecologic studies is inversely correlated with ms prevalence. [92] [93] [94] because exposure to sunlight is for most people the major source of vitamin d, 95 average levels of vitamin d also display a strong latitude gradient. ultraviolet b (uv-b) radiation (290 to 320 nm) converts cutaneous 7-dehydrocholesterol to previtamin d 3 . previtamin d 3 spontaneously isomerizes to vitamin d 3 , which is then hydroxylated to 25(oh)d 3 (25-hydroxyvitamin d 3 ), the main circulating form of the vitamin, and then to 1,25(oh) 2 d 3 (1,25-dihydroxyvitamin d 3 ), the biologically active hormone. 95 however, during the winter months at latitudes greater than 42° n (e.g., boston, ma), even prolonged sun exposure is insufficient to generate vitamin d, 96 and levels decline. 97, 98 use of supplements or high consumption of fatty fish (a good source of vitamin d) or vitamin d-fortified foods (mostly milk in the united states) may partially compensate for this decline, but few people consume large enough amounts of vitamin d, and seasonal deficiency is common. a link between vitamin d deficiency and ms was proposed more than 30 years ago as a possible explanation of the latitude gradient and of the lower prevalence of ms in fishing communities with high levels of fish intake 99 ; however, the immunomodulatory effects of vitamin d were not known, and the hypothesis did not generate much interest at the time. after the discovery that the vitamin d receptor is expressed in several cells in the immune system and is a potent immunomodulator, 100 a series of experiments revealed a protective role of 1,25(oh) 2 d 3 in several autoimmune conditions and in transplant rejection. 100 the effects in experimental autoimmune encephalomyelitis, an animal model of ms, were particularly striking: injection of 1,25(oh) 2 d 3 was found to completely prevent the clinical and pathologic signs of disease, 101,102 whereas vitamin d deficiency accelerated the disease onset. 102, 103 with vitamin d deficiency becoming a biologically plausible risk factor for ms, several epidemiologic studies were conducted to determine whether exposure to sunlight or vitamin d intake is associated with ms risk. the main results of these studies are shown in table 4 -4, and their strengths and limitations are discussed in the following paragraphs. as mentioned earlier, the results of ecologic studies support an inverse association between sunlight exposure and ms risk. however, because people living in the same area share many characteristics other than the level of sunlight, the consensus is that evidence from these studies is weak. in an exploratory investigation based on death certificates, working outdoors was associated with a significantly lower ms mortality in areas of high, but not low, sunlight. 104 in a separate study in the united kingdom, the skin cancer rate, a marker of sunlight exposure, was found to be about 50% lower than expected among individuals with ms (p = .03). 106 although the results of these investigations are consistent with a protective effect of uv light exposure, they could also represent "reverse causation" (i.e., individuals with ms could reduce their exposure to sunlight after disease onset). the results of case-control studies comparing history of sun exposure in childhood (presumed to be a critical period, mostly from the results of studies in migrants) between ms cases and controls have been conflicting. the results of one study were contrary to a protective effect of vitamin d, 106 and no association between sun exposure in childhood and ms risk was found in another. 107 in contrast, results consistent with a protective effect of sun exposure were reported in a study in tasmania in which information on time spent in the sun was complemented by measurement of skin actinic damage, a biomarker of uv light exposure, 108 as well as an investigation in norway 109 and a study of monozygotic twins in the united states. 110 in the norway study, an inverse association was also found between consumption of fish and ms risk. selection and recall biases are potential problems in case-control studies, but recall bias cannot explain the inverse association observed in tasmania with actinic damage, 108 and selection bias is unlikely in the twin study. the strongest evidence relating vitamin d levels to ms risk has been provided by two longitudinal studies, one based on assessment of dietary vitamin d intake, and one on serum levels of 25(oh)d. the relation between vitamin d intake and ms risk was studied in more than 200,000 women in the nurses' health study and nurses' health study ii cohorts. 111 dietary vitamin d intake was assessed from comprehensive and previously validated semiquantitative food frequency questionnaires administered every 4 years during the follow-up of the cohorts. 112, 113 total vitamin d intake at baseline was inversely associated with risk of ms: the age-adjusted pooled relative risk (rr) comparing the highest with the lowest quintile of consumption was 0.67 (95% confidence interval [ci], 0.40 to 1.12; p for trend = .03). intake of 400 iu/day of vitamin d from supplements only was associated with a 40% lower risk of ms. these rrs did not materially change after further adjustment for pack-years of smoking and latitude at birth. confounding by other micronutrients cannot be excluded, but adjustments for them in the analyses did not change the results. because dietary vitamin d is only one component contributing to total vitamin d status (the other being sun exposure), a determination of whether serum levels of vitamin d are associated with ms risk in healthy individuals would strengthen the evidence in favor of a causal role for vitamin d. the serum level of 25(oh)d is a marker of vitamin d status and bioavailability; therefore, if vitamin d is protective, high serum levels of 25(oh)d would be expected to predict a lower risk of ms in healthy individuals. this question was recently addressed in a collaborative, prospective case-control study using the department of defense serum repository (dodsr). 114 the study included 257 military personnel with confirmed ms and at least two serum samples collected before the onset of ms symptoms. risk of ms was 51% lower among white individuals with 25(oh)d levels of 100 nmol/l or higher, compared with those levels lower than 75 nmol/l, and the reduction in ms risk associated with 25(oh)d levels � 100 nmol/l compared with those levels < 100nmol/l was considerably stronger before the age of 20 years (16 to 19 years) than at ages 20 or older. an important question concerning vitamin d and ms is the age intervals during which vitamin d may be important. the results of migration studies suggest that more pronounced changes in ms risk are likely to occur among individuals who migrate in childhood. the age of 15 years, chosen as an arbitrary cutoff point in early studies, is usually quoted in the literature, but the reality is that data are insufficient to identify a meaningful threshold above which migration would not alter ms risk, 27 and in at least one study a reduction in risk was also observed among individuals who migrated as adults. 115 the results of the casecontrol study in tasmania suggest that exposure to sunlight is mostly protective in childhood. 108 further, vitamin d exposure in utero has been proposed as a possible explanation for the peak in ms incidence among individuals born in may (whose mothers were not pregnant during the summer, when uv light levels are higher) and the dip among those born in november, according to recent data from canada and sweden. 116 on the other hand, the results of the longitudinal studies support a protective effect of vitamin d also later in life. both the lower risk of ms among women taking vitamin d supplements 111 and the lower risk among men and women with higher levels of 25(oh)d 114 would be difficult to explain by a protective effect of vitamin d solely in utero or during childhood. therefore, it seems likely that, if vitamin d effectively protects against ms, levels during early adult life are also important. overall, the epidemiologic evidence of a causal association between vitamin d and ms is strong but not compelling, mainly because there are few studies based on prospective measurement of levels of exposure to sunlight, vitamin d intake, or serum 25(oh)d concentration. however, the public health implications of a possible causal association are enormous. if vitamin d reduces the risk of ms, supplementation in adolescents and young adults could be used effectively for prevention. based on studies among individuals with low sun exposure, supplements providing between 1000 and 4000 iu/day of vitamin d would increase serum 25(oh)d to the optimal levels. [117] [118] [119] [120] there is an urgent need to conduct further longitudinal studies, preferably in a large, randomized controlled clinical trial assessing whether vitamin d supplementation in the general population prevents ms. the trial would have to be very large, because ms is a rare disease, but the sample size could be reduced by oversampling individuals who are at high risk, such as those with first-degree relatives who have ms. alternative study designs might include national or multinational studies based on randomization of school districts or other suitable units. cigarette smoking was found to increase the risk of ms in some 121, 122 but not all 123, 124 case-control studies. a cross-sectional survey of the general population in hordaland county, norway, found an increased risk of ms in ever-smokers compared with never-smokers (rr = 1.8; 95% ci, 1.1 to 2.9). 125 four prospective studies on smoking and ms have been conducted. among 17,000 british women in the oxford family planning association study, those who smoked 15 or more cigarettes per day were compared with never-smokers and had an 80% increased risk of ms (rr = 1.8; 95% ci, 0.8 to 3.6). 126 a total of 46,000 women from across the united kingdom were enrolled in the royal college of general practitioners' oral contraception study, which found that women smoking 15 or more cigarettes per day had a 40% increased risk of ms (rr = 1.4; 95% ci, 0.9 to 2.2), compared with never-smokers. 127 the nurses' health study and nurses' health study ii cohorts included more than 200,000 u.s. women; those who smoked 25 or more pack-years had a 70% increased risk (rr = 1.7; 95% ci, 1.2 to 2.4; p < .01) compared with never-smokers. 128 in a prospective case-control study in the general practice research database, which included both men and women, ever-smokers had a 30% increased risk of ms, compared with never-smokers (rr = 1.3; 95% ci, 1.0 to 1.7). 129 the suggestion of an increased risk of ms among smokers was consistent across all four studies, and pooled estimates of the relative risk were highly statistically significant when never-smokers were compared with past and current smokers (fig. 4 -4a) or with moderate and heavy smokers (see fig. 4 -4b). additional support for a role of smoking includes a twofold increase in risk of pediatric ms among children exposed to parental smoking 130 and an increased risk of transition to secondary progressive ms among individuals with relapsing-remitting ms 129 ; however, the latter finding was not confirmed in a recent investigation. 131 biologic mechanisms for smoking and increased risk of ms could be neurotoxic, 132 immunomodulatory, 133, 134 or vascular (i.e., increased permeability of the blood-brain barrier), or they could involve increased frequency and duration of respiratory infections, 135 which may then contribute to increased ms risk. smoking also appears to increase the risk of other autoimmune diseases, including rheumatoid arthritis [136] [137] [138] [139] [140] and systemic lupus erythematosus, 141 arguing for a more general effect of cigarette smoking on autoimmunity. although several foods or nutrients were found to be related to be ms risk in ecologic or case-control studies, the results overall were inconsistent and unconvincing. in ecologic studies, positive correlations were found between ms and intake of animal fat [142] [143] [144] and saturated fat, 144 as well as consumption of meat, 145 milk, and butter, 143, 146 and inverse correlations were found with intake of fat from fish 143, 145 and nuts 143 (sources of polyunsaturated fat). an increased risk of ms with increasing animal or saturated fat intake and a protective effect of increasing polyunsaturated fat intake were also reported in a case-control study, 147 but otherwise the results of case-control studies have largely not supported an association between increased ms risk and milk or meat consumption, 121, [147] [148] [149] [150] or decreased risk and consumption of sources of polyunsaturated fat such as fish or nuts. 121, 147 however, in a recent study in norway, 109 fish consumption 3 or more times per week among individuals living at latitudes between 66° and 71° n was inversely related to ms risk. other results have included an inverse association of risk with intake of vitamin c and juice, 147 but no association with other antioxidant vitamins 147 or with fruits and vegetables 121, 123, 147, 151 has been reported. it is important to note that ecologic studies are prone to be confounding and in general provide only very weak evidence of the potential effects of diet on disease risk. retrospective case-control studies are also prone to bias due to both control selection and differential recall. the latter effect is particularly problematic, because even a modest difference in diet recall between cases and controls can cause a large bias in relative risk estimates. 152 this problem is compounded in ms by changes in diet that may occur in the early clinical or preclinical phases of the disease. therefore, although these studies have been important in drawing attention to several aspects of diet as potentially important risk factors for ms, their results, whether in favor or against an hypothetical association, should be interpreted extremely cautiously. understanding of the relation between diet and ms will require the conduct of large longitudinal investigations, with repeated assessment of diet using rigorous and validated methods and possibly measurements of biomarkers of nutrient intakes. so far, the only prospective studies of diet and ms were those conducted among women in the two nurses' health study cohorts. in this population, neither animal fat nor saturated fat was associated with ms risk, but there was a suggestion of an inverse association with intake of the n-3 polyunsaturated fat linolenic acid. 153 there were also no significant associations between intakes of dairy products, fish, meat, 153 vitamins c or e, carotenoids, or fruits and vegetables and ms risk. 154 however, participants in these studies were already 25 to 55 years of age at time of recruitment, and therefore they shed little light on the possible effect of diet earlier in life and ms risk. studies have also examined whether intake of polyunsaturated fats affects ms progression. n-3 polyunsaturated fat supplementation in doses ranging from 2.85 to 3.90 g/day administered for periods of 6 to 24 months did not have significant effects on disability levels in two randomized controlled trials that included a total of 339 patients with relapsing-remitting ms, 155, 156 although trends were in favor of the supplemented groups in both studies. results of three randomized controlled trials examining the effects of n-6 polyunsaturated fat supplementation (17 to 20 g/day for 24 to 30 months) on ms progression, including a total of 279 patients with relapsing-remitting ms, [157] [158] [159] and a meta-analysis of these studies 160 suggested that supplementation may reduce the severity and duration of relapses. in summary, there is no compelling evidence that dietary factors other than vitamin d play a causal role in ms, but neither can such a role be excluded, particularly for diet during adolescence or childhood, which may be important periods in the etiology of ms. estrogen has been hypothesized to protect against ms, because in high levels it appears to promote the non-inflammatory type 2 immune response, rather than the pro-inflammatory type 1 response predominately seen in ms, and because during pregnancy, when estrogen levels are high, women with ms experience fewer relapses than during the puerperium. 161 in prospective studies, 126, 127, 162, 163 neither oral contraceptive use, parity, nor age at first birth 162 was associated with ms risk. a decreased risk of ms during pregnancy followed by an increased risk during the first 6 months after delivery was shown in a study based on a general practice database in the united kingdom. 163 in the same study, recent use of oral contraceptives was also associated with a reduced risk. 163 collectively, these studies suggest that short-term exposure to estrogen may be protective against ms, but that this protection is transient. concerns that the hepatitis b vaccine may increase the risk of ms were raised after widespread administration of the vaccine in france, 164 but the results of most studies have not supported a causal association. studies in the united states conducted among subjects included in a health care database, 165 among nurses, 166 and among participants in three health maintenance organizations 167 found no association between hepatitis b vaccination and risk of ms. further, in studies of children and adolescents, no association was found between hepatitis b vaccination and ms risk 168 or risk of conversion to ms among children with a first demyelinating event. 170 however, a case-control study conducted in the general practice research database in the united kingdom did find a threefold increased risk associated with receipt of the vaccine within 3 years before ms onset, 170 and a french case-control study reported a nonsignificant increased risk of ms among individuals with clinically isolated syndrome after vaccination. 171 among individuals with ms, the vaccine does not appear to increase the risk of relapses. 172 overall, there is no convincing evidence that hepatitis b vaccination increases ms risk. other environmental factors have been associated with ms, but the available evidence is sparse, and the relevance of these factors to ms etiology remains uncertain. an increased risk of ms has been reported in relation to exposure to organic solvents, [173] [174] [175] [176] [177] physical trauma, 178 and psychological stress from the loss of a child (bereavement), 179 whereas a decreased risk has been observed for use of penicillin 180 and antihistamines, 181 high levels of 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a review altered antibody pattern to epstein-barr virus but not to other herpesviruses in multiple sclerosis: a population based case-control study from western norway altered prevalence and reactivity of anti-epstein-barr virus antibodies in patients with multiple sclerosis a role of late epstein-barr virus infection in multiple sclerosis exposure to infant siblings during early life and risk of multiple sclerosis key: cord-027950-4xwcb5j7 authors: bachman, thomas e.; iyer, narayan p.; newth, christopher j. l.; ross, patrick a.; khemani, robinder g. title: thresholds for oximetry alarms and target range in the nicu: an observational assessment based on likely oxygen tension and maturity date: 2020-06-27 journal: bmc pediatr doi: 10.1186/s12887-020-02225-3 sha: doc_id: 27950 cord_uid: 4xwcb5j7 background: continuous monitoring of spo(2) in the neonatal icu is the standard of care. changes in spo(2) exposure have been shown to markedly impact outcome, but limiting extreme episodes is an arduous task. much more complicated than setting alarm policy, it is fraught with balancing alarm fatigue and compliance. information on optimum strategies is limited. methods: this is a retrospective observational study intended to describe the relative chance of normoxemia, and risks of hypoxemia and hyperoxemia at relevant spo(2) levels in the neonatal icu. the data, paired spo(2)-pao(2) and post-menstrual age, are from a single tertiary care unit. they reflect all infants receiving supplemental oxygen and mechanical ventilation during a 3-year period. the primary measures were the chance of normoxemia (pao(2) 50–80 mmhg), risks of severe hypoxemia (pao(2) ≤ 40 mmhg), and of severe hyperoxemia (pao(2) ≥ 100 mmhg) at relevant spo(2) levels. results: neonates were categorized by postmenstrual age: < 33 (n = 155), 33–36 (n = 192) and > 36 (n = 1031) weeks. from these infants, 26,162 spo(2)-pao(2) pairs were evaluated. the post-menstrual weeks (median and iqr) of the three groups were: 26 (24–28) n = 2603; 34 (33–35) n = 2501; and 38 (37–39) n = 21,058. the chance of normoxemia (65, 95%-ci 64–67%) was similar across the spo(2) range of 88–95%, and independent of pma. the increasing risk of severe hypoxemia became marked at a spo(2) of 85% (25, 95%-ci 21–29%), and was independent of pma. the risk of severe hyperoxemia was dependent on pma. for infants < 33 weeks it was marked at 98% spo(2) (25, 95%-ci 18–33%), for infants 33–36 weeks at 97% spo(2) (24, 95%-ci 14–25%) and for those > 36 weeks at 96% spo(2) (20, 95%-ci 17–22%). conclusions: the risk of hyperoxemia and hypoxemia increases exponentially as spo(2) moves towards extremes. postmenstrual age influences the threshold at which the risk of hyperoxemia became pronounced, but not the thresholds of hypoxemia or normoxemia. the thresholds at which a marked change in the risk of hyperoxemia and hypoxemia occur can be used to guide the setting of alarm thresholds. optimal management of neonatal oxygen saturation must take into account concerns of alarm fatigue, staffing levels, and fio(2) titration practices. shifts in spo 2 exposure have a profound impact on neonatal outcomes. control of exposure is associated with the selection of a desired target range, selection of alarm limits as well as nursing compliance with good practices. manual titration of fio 2 to address unstable spo 2 is an arduous task. infants in the nicu typically spend only about half the time in the desired range, and there is significant variation among centers [1] . nursing intervention is driven by high and low spo 2 alarms, probably more than the prescribed target range. oximeter alarms are notorious for false positives and are associated with alarm fatigue [2] [3] [4] . a persistent low alarm necessitates the need for increased supplemental oxygen to minimize the impact of transient hypoxemia, usually a result of respiratory instability. in contrast, high alarms usually signal the need to titrate the oxygen down following recovery from a marked desaturation. if the alarm limits are too narrow or the response to aggressive, troublesome swings between hypoxemia and hyperoxemia can occur. further there is little evidence supporting guidelines and general practice with regard to selection of spo 2 alarm limits. even consensus international guidelines for extremely preterm infants are not consistent. european guidelines report there is weak evidence to support setting the alarms close to the desired target range [5] . clearly doing so increases the frequency of false alarms and the potential for alarm fatigue [3, 6] . the most recent guidelines from the american academy of pediatrics, in contrast, suggest looser low alarms are more appropriate [7] . they further suggest that spo 2 alarm limits and target range should not only be decoupled, but also take into account the infant's maturity. neither guideline integrates the possible impact of differences in averaging period, alarm delay or differences in devices. in the last two decades studies have focused on the intended spo 2 target ranges for the extremely premature with a resulting evolution of the standard of practice [1, 8] . the most recent very large studies suggest a higher, narrower target range might be preferred for extremely preterm infants [5, 9] . this perspective is, however, far from a consensus [8, [10] [11] [12] [13] . evaluations of the optimal spo 2 exposure for more mature infants are lacking. the risks associated with hypoxemia in near term infants are appreciated; however concerns about hyperoxemia have until recently been limited, at least compared to the extremely preterm. we have developed an extensive spo 2 -pao 2 database from our nicu and previously reported on the magnitude of the change of risk of severe hypoxemia and hyperoxemia across different spo 2 ranges [14] . the aim of this analysis was to see if specific spo 2 levels for selection of high and low alarms and target ranges could be identified based on the difference in the risk of hypoxemia and hyperoxemia and further to determine to what degree these thresholds might change depending on infant maturity. this is a prospectively defined analysis with the aim of describing arterial oxygenation levels (pao 2 ) associated with various possible spo 2 alarm limits and target ranges. the study is based on the paradigm that high and low spo 2 alarm limits should consider the risk of hypoxemia and hyperoxemia independent of the desired spo 2 target range and further consider infant maturity [7] . this study reflects infants in the neonatal and infant critical care unit (niccu) of children's hospital los angeles. it is a tertiary care referral center affiliated with the keck school of medicine of the university of southern california. the 58-bed niccu receives transfers from the greater southern california area. the bioethics review organization at children's hospital los angeles (chla-17-00236) has waived the need for informed consent for aggregate data analysis studies and specifically approved this project. in a previous publication we described the development of a spo 2 -pao 2 database of infants receiving mechanical ventilator support with supplemental oxygen between august 2012 and july 2015 [14] . the database links arterial blood gas measurements in laboratory records with simultaneous spo 2 data from the patient monitor system. the spo 2 level is the mean of four 30-s readings coincident with the arterial sample. the gestational age from medical records for each infant, along with the date of measurement permitted calculation of post-menstrual age for each sample. the oximeter in the patient monitoring system used masimo set technology (masimo corporation irvine, california), with 10 s averaging. continuous monitoring of spo 2 is by practice post-ductal, pre-ductal assessments are conducted with another oximeter. arterial samples were collected when clinically indicated. umbilical catheters are used in most infants in their first week of life. as a matter of practice after that right radial lines are preferred, but when not possible left radial or posterior tibial lines are placed. these study parameters were prospectively defined. normoxemia was defined as pao 2 between 50 and 80 mmhg. other oxemic levels were defined as severe hypoxemia (pao 2 ≤ 40 mmhg) and severe hyperoxemia (pao 2 ≥ 100 mmhg), we also evaluated levels below and above normoxemia (pao 2 < 50, > 80 mmhg). the selection of the severe thresholds was consistent with our previous publication. also a consensus of the investigators, the potential ranges of spo 2 alarm limits were 85-89% and 95-98% and spo 2 target ranges within the envelop of 88-95%. the endpoints were the chance of normoxemia, and the risk of the 4 oxemic levels. based on our previous work, we hypothesized that infant maturity would significantly impact the chance of normoxemia and risk of severe hyperoxemia and but not of severe hypoxemia. we used post-menstrual age (pma) as the metric of maturity. pma values were categorized into three groups. these were < 33 weeks, 33-36 weeks and > 36 weeks pma. we felt that categories would be of more use clinically than a continuous effect. on a post hoc basis we also explored the impact of postnatal age. our primary measure was the risk or chance of each of these oxemic categories within the relevant spo 2 range. for the power analysis we assumed a baseline of relevant risk or chance of 25%, and considered sample sizes of pao 2 values for both 150 and 300 in an adjacent spo 2 bins. the range of 150-300 was selected as this was consistent with the numbers of observations in the smaller maturity categories at the spo 2 extremes. based on this, we determined that there would be an 80% chance, at the p < 0.05 level, that we could detect a reduction to 12% with 150 observations and to 15% with 300 observations. we treated each spo 2 -pao 2 pair as an independent observation. we deemed consideration of within patient effects as not only impractical because of the large number of patients, but also inappropriate because of intrapatient sample variability of temperature, ph, paco 2 and transfusion timing. descriptive presentations of continuous data are shown as median and iqr, and of proportions as percent. the primary variables are presented as percentage along with their 95% confidence intervals of the proportion. comparison of continuous variables used the kruskal-wallis test with dunn's procedure for pairwise comparisons. comparisons of proportions were evaluated using the chi-square test, with maracuilo's procedure for pairwise comparisons. the impact of maturity on each of the three oxemic category parameters was tested by including maturity-category with spo 2 , as independent variables, in a logistic regression equation with oxemic risk or chance as the dependent variable. for the exploratory analysis of the effect of postnatal age, we added age to this logistic regression model. a two-tailed p < 0.05 was considered statistically significant for all comparisons. statistical tests were conducted with xlstat v19.02 (addinsoft, paris, france). our data included 26,162 spo 2 -pao 2 observations of infants receiving supplemental oxygen and respiratory support over a 3-year period. figure 1 provides a graphic overview of the risk of hypoxemia and hyperoxemia across spo 2 levels between 75 and 100%. the risk of each rises dramatically as spo 2 moves from a nominal target range. even when moving within the latter the trade off between hypoxemia and hyperoxemia is obvious. it is also of note that the difference in risk of severe hypoxemia and a pao 2 < 50 mmhg, is much larger than the difference between severe hyperoxemia and a pao 2 > 80 mmhg. for analysis these observations were divided into three groups according to post-menstrual age (pma). details characterizing the 3 groups are shown in table 1 . there were 2603 observations from 155 infants less than 33 weeks pma, 2501 observations from 192 infants between 33 and 36 weeks pma and 21,058 observations from 1031 infants greater than 36 weeks pma. the number of observations per infant was similar among the three groups. the gestational age and postmenstrual age were consistent with the 3 maturity categories. the median spo 2 and pao 2 levels were lower in the group less than 33 weeks pma. this group also included a higher share of measurements in normoxemia and less in severe hyperoxemia. the chance of normoxemia was dependent on spo 2 (p < 0.001) but not pma. the chance of normoxemia across the range of 88-95% spo 2 was 65% (64-67 95% ci). the actual chance of normoxemia for 4 different overlapping spo 2 target ranges are shown in table 2 , and were different, specifically slightly lower in the lower ranges (p < 0.001). the pao 2 levels for each are also shown in the table and the differences between them are statistically significant (p < 0.001). higher target ranges increase the possibility of higher the risk of hypoxemia (pao 2 < 50 and < 41 mmhg) was independent of pma but not spo 2 (p < 0.001). the risks at different potential alarm levels are shown in table 3 . the risks are not different at settings of 89, 88, and 87% spo 2 for either pao 2 < 50 mmhg or < 41 mmhg. they were both markedly higher at 86 and 85% spo 2 . (p < 0.01) at these levels the risk of severe hypoxemia (< 41 mmhg) was marked; at 86% spo 2 (risk: 20% (16-24, 95% ci)) and at 85% spo 2 (risk: 25% (21-29, 95% ci)). the changes in risks are consistent with the changes in the pao 2 also shown in the table. the variation (interquartile range) of pao 2 levels is similar. the risk of hyperoxemia (pao 2 > 80 and > 99 mmhg) was significantly different among the 3 pma categories (p < 0.001) and within each category among the spo 2 levels (p < 0.001). the actual risks at different potential alarm levels are shown in table 4 for each maturity category. the potential point of marked increase in the risk of a pao 2 > 80 and > 99 mmhg were different for the three maturity categories. with regard to severe hyperoxemia, for those < 33 weeks it was a reading of 98% spo 2 (risk: 25% (18-33, 95% ci)), which was significantly higher than at 95 and 96% spo 2 (p < 0.05). it was a spo 2 reading of 97% for those 33-36 weeks (risk: 20% (14-25%, 95% ci)), which was not significantly higher than 95 and 96%. a reading of 96% for those > 36 weeks (20% risk: (17-22, 95% ci)), and the difference between all pairs was statistically significant (p < 0.001). a point of demarcation for the risks of pao 2 > 80 mmhg is 1 spo2 level lower for each of the 3 pma categories. the changes in risks are consistent with the changes in the pao 2 levels also shown in the table. the variation (interquartile range) of pao 2 levels is similar except at 98% spo 2 , which is wider. our exploratory analysis determined that postnatal age was an independent predictor of chance of normoxemia (p < 0.001) and risk of severe hyperoxemia (p < 0.001), but not severe hypoxemia. with increasing age the chance of normoxemia increased while the risk of hyperoxemia decreased. however the size of the effect predicted by the regression equation was quite small; that is changes of + 0.7% (normoxemia) and − 0.6% (severe hyperoxemia) for each week of age. we evaluated a large database of neonatal spo 2 -pao 2 observations paired with infant postmenstrual age. our aim was to provide additional guidance to support the selection of spo 2 alarm levels and target ranges for neonates receiving supplemental oxygen. we identified a spo 2 range consistent with normoxemia, and showed how a target range could shift depending on a preference for avoiding higher or lower levels of pao 2 . we showed that the risk of hyperoxemia and hypoxemia increases exponentially as spo 2 moves toward extremes. we found that the risk of severe hypoxemia does not become marked until a level well below common low alarm settings. finally we found that the risk of severe hyperoxemia becomes marked at different levels depending on postmenstrual age and importantly at thresholds not consistent with standard practices. this report is, to our knowledge, the first to document these perspectives. we evaluated four overlapping target ranges, each 4 wide with mid points of 90, 91, 92, and 93% spo 2 . our data showed that there was a similar chance of normoxemia across these potential target ranges, but slightly favoring the higher target ranges. this consistency also suggests that a wider target range, even 88-95% spo 2 , would maintain a similar chance of normoxemia, but could be easier to maintain. a wider range at the low end has been suggested for extremely preterm infants [10, 11] , in contrast to the european guidelines that recommend a higher target range [5] . two recent reports of practices in europe and the us reported that most target ranges were within this wider envelop, though more often narrower than seven but rarely 4 or less [1, 8] . our analysis did not identify an effect related to maturity associated with normoxemia as we had expected. however our hypothesis was based on risk data of extreme pao 2 levels (< 41 and > 99 mmhg) at spo 2 levels between 90 and 95%, which is different from our normoxemia criteria (pao 2 50-80 mmhg). further the information about likely pao 2 values, consideration of which might align with maturity, ought to be useful in selecting a target range within these boundaries [11] . a clinical aversion to higher or lower pao 2 levels is reasonable. the consideration of a trade off of high and low oxygen exposure is supported by a landmark evaluation comparing the long term outcomes of nearly 5000 extremely preterm infants randomized to one of two spo 2 target ranges (85-89% or 91-95%) [9] . it found the high range was associated with increases in severe retinopathy of prematurity and more likely need for supplemental oxygen at 36 weeks pma, but lower levels of necrotizing enterocolitis and death. alarm fatigue in the nicu is a serious problem. pulse oximetry, while an essential tool, generates the most false alarms and is the alarm least likely to be associated with an actionable nursing intervention [2, 3, 15] . it is not uncommon with unstable infants to experience a spo 2 alarm every few minutes, while an intervention is often only warranted every 5-10 min. faced with this dilemma nurses have been shown to disregard alarm policy [1] . attention to selection of reasonable alarm settings (delay, and level) as well as sensor/probe integrity, can impact the frequency of alarms not needing intervention [16, 17] . however setting alarms, whether by policy or practice, to avoid excessive frequency must also consider the risk of missing or delaying response to important events. policy and practice must balance the need to find an acceptable medium to balance the risks associated with each. our data provide spo 2 thresholds that are associated with marked hyperoxemia and hypoxemia. it is reasonable to consider a buffer zone between the alarm setting and the level of spo 2 concern. in addition, many events are short and it is standard practice to set the alarm delay to avoid these transient events not needing intervention. correspondingly it seems appropriate to set a longer alarm delay when the buffer zone is wider. our data indicate that the risk of hypoxemia is not related to maturity and is not marked until the spo 2 is at 86% or 85%, at which point the risk is increasing exponentially. in contrast we found no relevant difference in risk at levels between 87 and 89%. setting the low alarm between 87 and 89% spo 2 would create a buffer but at the expense of increased false alarms and alarm fatigue, without a compensating longer alarm delay. a recent analysis has determined that episodes that are significantly lower (< 80% spo 2 ) and prolonged (> 60 s) are related to bad outcomes [18] . however, we speculate that episodes of spo 2 with a nadir between 87 and 89% even if prolonged, would not have a clinical impact, because of the low risk of severe hypoxemia. finally, based on an audit of extremely preterm infants in 83 nicus, hagadorn et al. reported good compliance with low spo 2 alarm unit guidelines, but provided no related details on the actual settings [1] . in preterm infants we found the risk of hyperoxemia did not become marked until spo 2 reached 97-98% in those < 33 weeks pma and those 33-36 weeks pma. this is higher than the most recent recommendations for setting the high spo 2 alarm around 95% in extremely preterm infants [5, 7, 10] . such a lower setting could be appropriate with two difference rationales. it could be considered an appropriate buffer zone. but it certainly would increase false positive alarms, without a compensating longer alarm delay. it might also be appropriate if the goal was to avoid pao 2 levels approaching 80 mmhg, in alignment with a lower target range. consistent with this likely excessive false positive rate from tighter high alarms, hagadorn reported only 63% compliance with high spo 2 alarm unit guidelines [1] . in contrast to preterm infants, we found that the risk of hyperoxemia, pao 2 > 80 and > 99 mmhg, in infants > 36 weeks pma was marked at a spo 2 of 96%. while reports of guidelines are sparse [19, 20] , it is our impression that upper alarms for near term populations are often set much higher than 96%. this practice provides no buffer zone and certainly increases false negatives that could increase clinical risk of hyperoxemia. the concern about the risks associated with hyperoxemia in near term infants is less prevalent than in preterms. nevertheless, hyperoxemia in children and adults has been associated with morbidity and mortality [21, 22] and it is reasonable to project these risks to near term infants. the shift of the oxy-hemoglobin dissociation curve with increasing maturity that one would anticipate, was evident in high levels of spo 2 but not at moderate and low levels. while the predicted shift in the sao 2 -pao 2 relationship is characterized in a shift of p50, it is understandable that the smaller predicted shifts in spo 2 at lower levels would be muted. the lack of precision and bias of the pulse oximeter, especially in these ranges, as well as other factors such as local perfusion are documented [23] . the transition from fetal to adult hemoglobin is quite predicable over a couple months of life in healthy neonates, but we did not identify a meaningful impact associated with postnatal age. however the transition from fetal hemoglobin is affected by treatment and disease severity. transfusions have a marked effect [24] [25] [26] . our study population, all transferred for a higher level of care, commonly were transfused. accordingly, transfusion naive infants would be shifted more to the left [14] . such a shift would reduce the risk of hyperoxemia. this study's design has several limitations. first the pao 2 thresholds we used for hypoxemia, normoxemia and hyperoxemia, while generally accepted, have not been validated with regard to outcome risk. it is unlikely they ever will be. there is a need for and a growing body of data correlating spo 2 exposure and outcomes. of particular interest is a pending analysis of the impact of the actual, rather than assigned, spo 2 exposure in the neoprom population [9] . we speculate that these interpretations will be easier with a better understanding of the relationship between pao 2 and spo 2 . other factors such as small for gestational age and hemoglobin level as well as cerebral and intestinal oxygenation are also relevant. second, the study is observational. the location of the spo 2 sensor and site of arterial sampling were not controlled. it is likely that some of the paired comparisons do not reflect pre-ductal assessment. this could increase the variance, but we do not think this would have a relevant effect on the bias of the risk (median values). third, we categorized the hyperoxemic risk into three pma groups. these are reasonable groupings, but it is probable that the effect is somewhat continuous with increasing maturity, but certainly not strictly categorical. whether using these results to design research or to evaluate unit guidelines, several generalizability issues should be considered. the first is comparabilty to our study population. our unit is referral based, with all infants transferred in for tertiary care. after intervention and recovery infants are often returned when they only need low levels of inspired oxygen and minimal pressure support. as reported their supplemental oxygen requirements are quite high. also previously noted, as a result of transfusions, their oxy-hemoglobin relationship is shifted to right. illustrative of this, in our least mature cohort we identified an incidence of severe hyperoxemia more than 10 times higher than that reported in a more traditional inborn population during the first week of life [27] . another important consideration is the averaging and alarm delay settings on the oximeter. one large study confirmed the clinical relevance of these settings [28] . they documented a marked decrease in the incidence of severe hypoxemic events with increasing averaging time, and also demonstrated that it was associated with increased duration of episodes. they recommended using shorter averaging times and longer delays. finally the oximeter measurement itself must be considered. our data reflect a good bit of scatter in the pao 2 at each spo 2 level. sources of the scatter seen with spo 2 monitoring are well described [13, 29] . .consideration of differences in oximeter brands, and models should be considered as well. our group previously reported no difference in bias between the massimo and nellcor devices across the range of saturations in the picu, but did identify a problem with the use of inappropriate sensors [23] . of more potential relevance, a difference between the massimo and nellcor oximeters has been reported in the spo 2 range of 87-90% [30] . while this difference is within the device's 3% accuracy specifications, it might well effect a decision about selecting a lower target range, or the low spo 2 alarm setting. we provide quantification of the rate at which the risk of hyperoxemia and hypoxemia increase exponentially as spo 2 moves towards extremes, and how it is affected by maturity. postmenstrual age influences the threshold at which the risk of hyperoxemia became pronounced, but pma did not alter the threshold for hypoxemia or normoxemia. the thresholds at which a marked change in the risk of hyperoxemia and hypoxemia occur can be used to guide the setting of alarm thresholds. these findings support reconsideration of common alarm treshold practices. in extreme preterm infants, but not in more mature infants, high spo 2 alarms may be set higher than 96%. likewise low spo 2 alarms may be set lower than 89%. spo 2 targeting ranges may be selected within the range of 88-95% spo 2 . optimal management of neonatal oxygen saturation must take into account concerns of alarm fatigue, staffing levels, and fio 2 titration practices. integration of these factors should be evaluated in quality improvement programs. fio 2 : fraction of inspired oxygen; spo 2 : arterial oxygen saturation measured noninvasively; nicu: neonatal intensive care unit; pao 2 : arterial partial pressure of oxygen (mmhg); paco 2 : arterial partial pressure of carbon dioxide (mmhg); pma: post-menstrual age (weeks) alarm safety and oxygen saturation targets in the vermont oxford network inicq 2015 collaborative nurses' reactions to alarms in a neonatal intensive care unit balancing the tension between hyperoxia prevention and alarm fatigue in the nicu alarm safety and alarm fatigue european consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants-2019 update retrospective analysis of pulse oximeter alarm settings in an intensive care unit patient population committee on fetus and newborn. oxygen targeting in extremely low birth weight infants pulse oximetry saturation target for preterm infants: a survey among european neonatal intensive care units association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration safe oxygen saturation targeting and monitoring in preterm infants: can we avoid hypoxia and hyperoxia? graded oxygen saturation targets and retinopathy of prematurity in extremely preterm infants pulse oximetry targets in extremely premature infants and associated mortality: one-size may not fit all oxygen saturation targeting by pulse oximetry in the extremely low gestational age neonate: a quixotic quest hypoxemia and hyperoxemic likelihood in pulse oximetery ranges: nicu observational study video analysis of factors associated with response time to physiologic monitor alarms in a children's hospital evaluation of two spo2 alarm strategies during automated fio2 control in the nicu: a randomized crossover study reducing alarm fatigue in two neonatal intensive care units through a quality improvement collaboration association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants practical recommendations for oxygen saturation targets for newborns cared for in neonatal units. new zealand: newborn clinical network clinical reference group monitoring of oxygen saturation levels in the newborn in midwifery setting admission hyperoxia is a risk factor for mortality in pediatric intensive care oxygen exposure resulting in arterial oxygen tensions above the protocol goal was associated with worse clinical outcomes in acute respiratory distress syndrome accuracy of pulse oximetry in children the reactivation of fetal hemoglobin synthesis during anemia of prematurity the effect of blood transfusion on the hemoglobin oxygen dissociation curve of very early preterm infants during the first week of life effects of fetal hemoglobin on accurate measurements of oxygen saturation in neonates arterial oxygen tension (pao2) values in infants <29 weeks of gestation at currently targeted saturations alarms, oxygen saturations, and spo2 averaging time in the nicu oxygen targeting in preterm infants: a physiological interpretation oxygen targeting in preterm infants using the masimo set radical pulse oximeter publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions tb was responsible for the conception of the study, the data analysis and initial draft of the manuscript. cn and ni collected the data. the authors (tb, ni, cn, pr, rk) critically reviewed and approved the manuscript and agree to be accountable for all aspects of the project. there was no funding provided to support the planning, implementation, analysis or manuscript development. the data sets generated and analyzed during this study are not currently publically available, but are available from the corresponding author on reasonable request. the bioethics review organization at children's hospital los angeles (chla-17-00236) has waived the need for informed consent for aggregate data analysis studies and specifically approved this project. not applicable. key: cord-021492-z2bjkl9g authors: brossman, charles title: planning for known and unknown risks date: 2016-04-15 journal: building a travel risk management program doi: 10.1016/b978-0-12-801925-2.00001-1 sha: doc_id: 21492 cord_uid: z2bjkl9g this chapter covers standard definitions of duty of care, example case law where employer duty of care was applicable, a variety of sample risks and concerns that employers and travelers should be aware of, in context with a travel risk management program. legal duty of care-definition 1 "duty of care" stands for the principle that directors and officers of a corporation in making all decisions in their capacities as corporate fiduciaries, must act in the same manner as would a reasonably prudent person in their position. courts will generally adjudge lawsuits against director and officer actions to meet the duty of care, under the business judgment rule. the business judgment rule stands for the principle that courts will not second guess the business judgment of corporate managers and will find the duty of care has been met so long as the fiduciary executed a reasonably informed, good faith, rational judgment without the presence of a conflict of interest. the burden of proof lies with the plaintiff to prove that this standard has not been met. if the plaintiff meets the burden, the defendant fiduciary can still meet the duty of care by showing entire fairness, meaning that both a fair process was used to reach the decision and that the decision produced a substantively fair outcome for the corporation's shareholders. ijet international defines "duty of care" specific to trm as follows: 2 duty of care: this is the legal responsibility of an organization to do everything "reasonably practical" to protect the health and safety of employees. though interpretation of this language will likely vary with the degree of risk, this obligation exposes an organization to liability if a traveler suffers harm. some of the specific elements encompassed by duty of care include: • a safe working environment-this extends to hotels, airlines, rental cars, etc. • providing information and instruction on potential hazards and supervision in safe work (in this case, travel) • monitoring the health and safety of employees and keeping good records • employment of qualified persons to provide health and safety advice • relative to "duty of care" is the "standard of care" that companies are compared to in defending what is "reasonable best efforts" or "reasonably practical," based upon what resources and programs are put into place by an organization's peers to keep travelers safe. prior to 2001, business travelers thought nothing of being able to walk into an airport and meet their loved ones at their arrival gate. no security barriers, no cause for concern because air travel was something that at the time, our collective psyche felt generally safe, with the exception of a hijacking upon occasion. fast forward to a post-9/11 world, and consider what the world's airports look like now and how the processes surrounding airport security have changed the way that we travel, whether for business or pleasure. why would any of us believe that the need for added security, particularly around those traveling for business, begins and ends at the airport? for companies who have been paying attention since 9/11, the ones who, outside of the public eye, have had to deal with critical incidents that had the potential for loss of lives, corporate liability, and damage to their company's reputation, having a structured trm program not only reduced the potential for risk, but heightened the awareness of risk to their travelers. their definition of "travelers" extended beyond employees (transient travelers to expatriates) to contractors, subcontractors, and dependents. keeping travelers aware of imminent dangers takes effort and planning, and isn't something that employers can any longer react to after the fact. in some countries, lack of planning or resources to support business travelers has the potential to be grounds for claims of negligence in a company's duty of care responsibilities, and can lead to a criminal offense, such as with the united kingdom's (uk) corporate manslaughter and corporate homicide act of 2007. what the "business judgment rule" in the above duty of care definition means in layman's terms is that a company must be able to prove that it put forth reasonable best efforts to keep its travelers safe. how this applies in different circumstances, jurisdictions and countries will vary. most countries' duty of care requirements fall under their occupational safety and health laws. for a comprehensive list of occupational health and safety legislation by country, an updated global database is maintained by the international labour organization (www.ilo.org 3 ). simply put, companies cannot afford to no longer have a proactive trm program and just react after an incident takes place. the end result could reflect negligence on behalf of the company. for extensive detail on the uk's definition of duty of care in relation to the corporate manslaughter and corporate homicide act of 2007, visit http://www.legislation.gov.uk/ukpga/2007/19. because each of the 50 u.s. states is a separate sovereign free to develop its own tort law under the tenth amendment, there are several tests to consider for finding a duty of care under u.s. tort law, in the absence of a federal law. tests include: • foreseeability-in some states, the only test is whether the harm to the plaintiff that resulted from the defendant's actions was foreseeable. • multifactor test-california has developed a complex balancing test consisting of multiple factors that must be carefully weighed against one another to determine whether a duty of care exists in a negligence action. california civil code section 1714 imposes a general duty of ordinary care, which by default requires all persons to take "reasonable measures" to prevent harm to others. in the 1968 case of rowland v. christian (after and based on this case, the majority of states adopted this or similar standards), the court held that judicial exceptions to this general duty of care should only be created if clearly justified based on the following public-policy factors: • the foreseeability of harm to the injured party; • the degree of certainty that he or she suffered injury; • the closeness of the connection between the defendant's conduct and the injury suffered; • the moral blame attached to the defendant's conduct; • the policy of preventing future harm; • the extent of the burden to the defendant and the consequences to the community of imposing a duty of care with resulting liability for breach; and the availability, cost, and prevalence of insurance for the risk involved; • the social utility of the defendant's conduct from which the injury arose. pioneering companies (often in the energy services sector or government contractors) who were some of the first to adopt and implement forward-thinking programs, recognized early on that a critical incident or "crisis," isn't usually defined as an event impacting large numbers of people. they found that the largest percentages of incidents that required support, involved individual travelers or small groups. so while policies, plans, and readiness exercises are good to have in place for those highly visible incidents impacting large numbers of people, if handled improperly, the smaller incidents can cost companies considerably in damages and litigation costs, should their travelers or their travelers' surviving families prove that the companies in question weren't properly prepared to handle such incidents as they arise. case study-u.s. workers compensation and arbitration khan v. parsons global services, ltd united states court of appeals, district of columbia circuit-decided april 11, 2008 (https://www.cadc.uscourts.gov/internet/opinions.nsf/8dd6474d9dd 96bce85257800004f879d/$file/07-7059-1110404.pdf) • during the course of employment in the philippines, on a day off, mr. khan was kidnapped and subsequently tortured. • employment contract included a broadly worded arbitration clause, and a separate clause specifying "workers compensation insurance" as "full and exclusive compensation for any compensable bodily injury" should damages be sought. • allegations that employer's disregard for mr. khan's safety in favor of minimizing future corporate kidnappings considering the way parsons handled the situation provoked mr. khan's kidnappers to torture him, cutting of a piece of his ear, sending a video tape of the incident to the employer, causing the khans severe mental distress. • mrs. khan alleged efforts by the employer to prevent her from privately paying the ransom, despite threats of torture, may have exposed mrs. khan to guilt of knowing that she could have prevented mr. khan's suffering if the employer had not withheld the ransom details from her. • mr. and mrs. khan filed a lawsuit for parsons' alleged mishandling of ransom demands by the kidnappers, and also alleging negligence and intentional infliction of emotional distress in d.c. superior court in 2003. the employer removed the case to the federal district court, arguing on the merits of the new york convention for the recognition and enforcement of foreign arbitral awards, and then filed a single motion to dismiss or, as an alternative, to obtain summary judgment to compel arbitration. the employer initially received a summary judgment to compel arbitration. • upon appeal, this judgment was reversed. the court found that the recovery of the khans' tort claims were not limited by mr. khan's contract to workers' compensation insurance. • an additional appeal contended that the initial summary judgment granted by the court denied the khan's discovery requests, and dismissed mrs. khan's claim for intentional infliction of emotional distress • through the appeals process, the court found that the employer had in effect waived their right to arbitration. this case study calls into question legal jurisdiction, u.s. workers' compensation liability limitations for employers, and the value of being prepared for such an incident as kidnapping. this chapter outlines at a high level general categories that all companies must take into consideration when developing a trm program. very often the question is asked, "do i really need to do any of this, because our company hasn't been sued to date?" if you have employees or contractors traveling on your behalf (especially internationally), whereby your company is paying for their time and/or expenses, then the answer is absolutely yes. the level of investment and complexity may vary between companies, but in general, all companies must have a plan for how to address the issues provided herein and others. duty of care is never finite in its definition because companies must consider how laws from one country to the next will apply to travelers, contractors, potential subcontractors, and expatriates and their dependents, as well as any potential for conflict of law. also, as shown in the khan v. parsons global services, ltd. case study listed earlier in this chapter, employer remedies such as worker's compensation insurance in the u.s. aren't absolute; and therefore, warrants additional efforts and protections. consider the following incident types or risk exposures, which in some instances can impact large numbers of travelers, but more commonly impact only one person. according to the u.s. department of commerce international trade administration, only 10 percent of international business travelers receive pretravel health care. pretravel health care can include, but is not limited to things like new or updates to vaccinations or inoculations, general health exams, medical treatment or procedures for a condition that may be risky to travel with, or prescription medicine planning for travel lasting for extended periods (longer than 30 days). the chief operating officer at ijet, john rose, comments that, "a percentage of calls into our crisis response center are for minor, individual medical issues." however, callers may not always know that the situation is minor until they reach someone for support, which is why having an easy-to-identify, easy-to-access, single contact number or hotline for medical and security support is so important to all companies. a contracted crisis support service will know based upon predetermined protocols, which providers will support the traveler in the part of the world where they are traveling for medical issues, and ensure that the traveler gets the immediate advice that they need from a vetted medical professional. sometimes with a brief conversation with a nurse, the parties can determine a minor treatment that the traveler can facilitate, and in other circumstances a referral to a more senior medical official or emergency medical resource may be necessary based upon the initial consultation by the first-level medical support personnel contracted by the traveler's company. as discussed later in the book, who provides the crisis response case management and who provides the medical or security services specific to the traveler in question are not necessarily mutually exclusive. there could be different providers in different parts of the world, used for different reasons that are outlined in company policies and protocols. the consequences of mistakes as a result of a lack of preparation or resources can be costly, from financial loss and traveler productivity loss to the company, to a serious health issue for the traveler, or simply a ruined trip. while clarity via training and policies on who supports traveler medical issues should be very clear to everyone within an organization, the following common medical mistakes should be avoided where possible, as recommended by dr. sarah kohl, md of travelreadymd (http://www.travelreadymd.com): statistically, most medical problems you are likely to experience while traveling overseas cannot be prevented with a vaccine. for example, there are no vaccines for jet lag, diarrhea, blood clots, malaria, or viral infections such as dengue. before you travel overseas, make sure you are educated about these potential problems. most can be prevented with simple measures. information from different sources on the internet can be conflicting and can lead you to believe you need more interventions than actually necessary. as travelers prepare to depart, employers should provide them with access to resources that can advise on medical concerns relative to your destinations. of course, travelers should also discuss any personal medical condition concerns with their own or qualified medical professionals in addition to receiving employer provided risk intelligence regarding their trip. unfortunately, travelers regularly suffer needless medical complications because they fail to take simple steps to avoid predictable issues. simple precautions can save you a lot of discomfort and make your trip safer and more enjoyable. here are some examples: medical compression stockings, if properly fitted, can protect you from a life-threatening blood clot. knowing the right insect spray to choose, from the multitude of choices available, can protect you from insect-borne disease. avoiding seemingly harmless activities in certain locations (ones that a hotel concierge might even recommend) can protect you from parasites, respiratory illness or malaria. travelers often fail to recognize how a common illness such as diarrhea or a respiratory infection can cause a flare-up of an underlying condition. travelers who are good at managing food allergies, asthma, and diabetes at home may experience difficulty finding the resources they need overseas. in addition, these individuals may find themselves looking to a non-english-speaking doctor for help. measles, tuberculosis, and other infections are gaining a foothold in some european countries. low immunization rates within these communities are thought to be the root cause. don't risk becoming ill or bringing an infection home. check with your health care provider before you travel to discuss preventive measures. if you have a chronic health problem that is well under control, you will want to be prepared to self-treat under certain conditions. you may also want to be prepared to access a network of doctors who speak your native language, if needed. lastly, travelers should never assume that a pre-existing condition is covered by corporate-or consumer-based travel insurance or medical membership programs. when in doubt, always ask your human resources department or trm program administrator. companies commonly expect that corporate insurance policies or business travel accident (bta) policies provide enough coverage for travelers, when sometimes they may not. this is why protocols and regular training exercises for internal risk program stakeholders take place, to understand what is covered and what is not, as well as how to handle each situation. whether insured or not, consider the value and cost savings of prevention based treatment as shown in the examples provided below. consider the possibility that anything that an employee or representative comes in contact with during the course of a business trip (during or after hours) that can potentially make them ill or kill them is a liability to the employer. biological hazards or biohazards are pathogens that pose a threat to the health of a living organism, which can include medical waste, microorganisms, viruses, or toxins. toxicity is the degree to which a substance can damage an organism (not exclusively biological, as it could be chemical). brett vollus, a former qantas airline employee of 27 years, filed suit against the airline claiming that his spraying of government-mandated insecticides on planes to prevent the spread of insect-related diseases like malaria, caused him to develop parkinson disease after 17 years of administering the chemicals in the flight cabins. it was also discovered from a brain scan after a tripping incident that vollus had a malignant brain tumor. considering this was a government mandate, it will be interesting to see if the question becomes: what did the government know about the risks of these chemicals? if a precedent is set in this suit, will liability extend to other airlines using or who have used such chemicals for extended periods, against repeat business travelers who regularly flew or fly in markets where such spraying was or is common practice over a long period of time? epidemics are outbreaks of disease that far exceed expected population exposures during a defined period of time. epidemics are usually restricted to a specific area, as opposed to pandemics that cover multiple countries or continents. mature trm programs monitor these more visible outbreaks and recommend vaccinations for travelers going to impacted areas; they also provide access to emergency medical resources when necessary, but also have a large focus on education, training, and prevention. however, employers should always be mindful of other environmental factors in the traveler's workplace both at home or abroad, such as urban or rural environmental factors. examples may include prolonged exposure to pollution, lack of sanitation (particularly when it comes to their expat communities). employers should work towards limiting those exposures or changing the environment through continuous process improvement reviews. according to major medical and security evacuations suppliers, corporate-sponsored evacuations involving one or more travelers happen almost every day when you include both medical and security-related evacuations. it is a mistake to think that just because a case study or example is slightly dated, the instances they represent occur infrequently. it's quite the opposite. however, most incidents are not publicly documented to the degree that they can be reported upon. the five primary things that companies must be concerned with when facing a pandemic situation are: 1. the potential impact on personnel. 2. the pandemic, crisis response plan. 3. the potential impact on business operations. 4. the potential impact on business supply chain. 5. the potential impact to share value or price. what many companies don't consider is the potential for shareholder lawsuits against executives for business losses resulting from a lack of planning for situations such as pandemics. from shared sick time policies to work-at-home policies during is your organization pandemic ready? harvard's school of public health recently released survey data showing how deeply concerned u.s. businesses are about the possibility of widespread employee absenteeism that might follow an outbreak of the swine flu (h1n1). researchers from the school questioned more than 1000 businesses across the country. two-thirds of companies said they couldn't operate normally if more than half of their workers were out for 2 weeks. and four of five organizations predicted severe operating problems if half of their workers missed a month of work. a crisis, being able to quickly communicate a position or a plan, and to answer questions in the event of such an emergency, can not only save money and productivity, but garner employee confidence and calm nerves. chapter 9 elaborates on the relationship between travel risk management (trm) and other aspects of risk management across the enterprise (erm-enterprise risk management). according to the new zealand herald, 4 the country's largest company, fonterra, could lose $150 million because of the ebola epidemic. fonterra ceo, theo spierings, noted that when african countries lock down their borders to control the disease, demand dropped for fonterra's products. he commented, "so…movements in west africa become more and more difficult, so that limits movement of food as well, movement of people-people going to the market, doing their groceries-so you see demand really dropping pretty fast." "if the market in west africa slowed down or dropped off that would affect 100,000 tonnes of powder," mr. spierings said. "that's about 5 percent, 6 percent of our exports. so you talk…$150 million or something like that." these survey results should encourage all organizations to prepare for the worst by developing a crisis management plan. in addition to ample warning, senior management has ample reason to prepare, and no excuse not to. an organization's executives won't be blamed for the outbreak, but they do risk censure if they fail to prepare, respond, and communicate with internal and external stakeholders. this white paper tells how. to help organizations and their leaders prepare for a possible h1n1 pandemic, certain key issues must be addressed to keep operations running as smoothly as possible: • human resource (hr) issues that drive pandemic planning. • planning for steps necessary to keep an organization operating during the pandemic period. • implementing steps needed to create an enterprise-wide crisis management plan. • internal and external issues that crisis communications must address. why bother planning for the h1n1 pandemic? to put it simply, companies and organizations that plan for any type of crisis demonstrate the behavior of responsible citizens. formulating a detailed crisis management plan specifically for h1n1 achieves four things: 1. protects employees' health and safety. 2. lessens the chance of a major interruption of your daily business. 3. protects your company's or your brand's reputation. 4. allows daily business activity to continue with minimal disruption if you are affected. companies must establish open lines of communication with all audiences while dealing with the effects of the pandemic or other significant events. should one occur, these stakeholders will want to know what you are doing to manage the situation and minimize their risks. if you communicate with these stakeholders openly and promptly, you send four valuable messages: • you are taking charge of the situation. • you take it seriously. • you have the best interests of your staff and customers at heart. • you run a responsible company with nothing to hide. pandemics have a disastrous effect on a company's optimal functioning because they prevent large numbers of critical employees from showing up for work. the resulting interruption to normal operations can have a disastrous cascading effect, affecting nearly every corner of the organization at considerable cost. employees unable to work or prevented from working become anxious and insecure. when they start asking management questions that aren't answered sufficiently or quickly, it exposes the fact that management hasn't developed contingency plans or that management failed to consider what employees need to know. part of the cost of failing to prepare can be measured by the resultant loss of trust in management's capability, judgment, and credibility. we know from experience there are certain predictable questions that employees will ask and hr departments must be prepared to answer. for example: hr departments should, as a matter of urgency, review attendance and sickday policies to ensure they have made allowances for managing the largerthan-normal issues h1n1 creates. some of the policies that will need to be considered for implementing or addressing include: 1. how/when to start monitoring/screening employees at the workplace to determine if they are sick or pose a risk. how/when sick employees should be sent home to protect colleagues at work or be stopped/prevented from coming to work where they could infect colleagues. 3. how/when the company should be temporarily closed due to the number of sick employees. 4. how/when to implement steps to minimize face-to-face contact at work. 5. how/when to allow certain employees, including senior management, to work remotely from home or another branch/office. 6. how/when employees should be allowed to stay at home to look after sick family members. 7. how/when the company's travel policies should be changed/suspended. 8. how/when to stop employees from coming into contact with suppliers and customers. 9. how/when to implement and enforce a "wash your hands" and "cover your mouth and nose when coughing and sneezing" policy; this must include making face masks and the use of hand sanitizers mandatory across the company. how/when to change the company payroll policy so that all employees receive electronic payments into their accounts; consider establishing an emergency "employee help" fund. 11. any and all extensions/additions to your existing payroll and work hours' policies. at the core of your h1n1 crisis plan, your hr department must be fully prepared to explain and communicate any new policies or changes to employees on an ongoing basis in all offices. this includes offices and employees that may not be affected by the pandemic at all. international and regional offices must also be briefed as they, too, could be directly impacted if there is an h1n1 outbreak. employees should also be asked for input and ideas. this may help to highlight potential management or operating aspects that have not been considered. it will also make employees feel part of the pandemic planning process and thus, more accepting of and cooperative with the final plan. if appropriate to your workplace and organizational culture, additional steps can be taken to protect employees by putting up educational posters, using training materials, and even arranging for annual flu shots (under doctor's supervision) to be provided in the workplace for convenience. employees should also be encouraged to learn and do more on their own and away from work. all of these actions send a message to employees that you are looking out for them, their jobs, and the company's well-being. in return, employees are much more likely to "go the extra mile" in order to lessen the business impact of widespread absences. communicating during a crisis is important, but what businesses do is always more important than what they say. making good decisions and providing straightforward, honest and factual information to all employees with frequent updates is one of the most critical actions management can take. ideally, all companies and organizations would have enterprise-wide crisis plans in place before a crisis breaks. but realistically, we know from multiple surveys that at least half don't. too many companies assume an "it can't happen to me" mentality or, in tough business or competitive conditions, they decide not to invest in "insurance" activities. unfortunately, some find out the hard way that you cannot choose your crisis; it chooses you-and almost always at the most inconvenient time. if yours is an organization that hasn't taken the steps necessary to implement crisis preparedness, here are some interim steps that you can take quickly to address h1n1. remember, the most effective and least costly way to manage a crisis is to prevent it from happening in the first place. you cannot stop h1n1, but you can take steps to keep it from damaging your operations, your reputation, and your bottom line. here's a quick checklist of things an organization can do, even at this late date: 1. appoint a pandemic coordinator or team. this individual or team will lead the organization through various steps to become pandemic-ready. have them first conduct a vulnerability and risk assessment. that means identifying areas in which you are at heightened risk of infection or in which your responses or ability to compensate will probably be weak. armed with this knowledge, you should be able to prepare for worst-case scenarios and begin planning accordingly. 3. get your crisis management team up to speed. a crisis management team consists of senior employees who will deal full time with a crisis while the rest of the organization runs as normally as possible. the most effective crisis teams typically consist of no more than five members who serve as its decision-making leadership. crises are not situations for committees or consensus building. they demand swift and certain decisions and actions be made under "battlefield conditions." we strongly recommend that you have a "five-star general" heading up your team. 4. a crisis management team must possess sufficient inherent or delegated power to command unrestricted access to a full cross-section of corporate disciplines, including hr, sales, customer service, information technology (it), security, operations, facilities management, communications, department/business unit headsfrom every corner of your organization. the crisis managers must know who from these disciplines are to be brought on to support the crisis management team on an as-needed "on-demand" basis. note that these disciplines are for advice and support, not crisis decision making. give them full authority to carry them out. 6. the team should also include someone who will be company spokesperson throughout the crisis. ideally, the spokesperson should be a senior company executive. he or she should have received formal media training, and should have the stamina, self-discipline, and inner strength to be able to convey trust and believability when speaking during a time when bad news may need to be delivered to various audiences. 7. think about including external experts on your team. these could include public health consultants, doctors, hr consultants, and business continuity experts. no organization can hope to be crisis-ready unless it is prepared with messaging ready to be disseminated to audiences on short notice and under pressure. crisis messaging typically consists of fully or partially (fill-in-the-blanks type) prepared statements addressing a range of potential situations anticipated in advance. prepared organizations keep them in a template format. then, as a crisis develops and the actual facts of the situation become known, the relevant template can be rapidly updated with all pertinent information. in a crisis, you simply do not have time to agonize for long over "what are we supposed to say?" remember, it is only during the first 60 minutes of a crisis that you have your one chance to take control of the situation via proactive communication. in that time, messages must be disseminated internally to staff and externally to the relevant audiences, such as customers, stockholders, suppliers, and partners, and possibly the media. businesses that conduct vulnerability and risk assessments will have a better idea of the templates and draft messaging they will need for a flu outbreak. these situations range from temporarily closing a site to announcing an interruption of service. the tone of all messaging must demonstrate that management is taking the situation seriously. employees are your first priority and must receive crisis-related messaging before anyone else. the media and relevant external stakeholders can then receive the same or similar messaging soon after. department heads in your company can be used to communicate directly with employees. employees should also be provided with messaging that they can share with others outside the organization. in today's "always-on" instantaneous online world, whatever employees are told invariably becomes public knowledge within minutes. from time to time, someone will ask a question that cannot be answered using prepared messaging. the crisis team must be prepared to reply "i don't know," and then either explain why, honestly and plainly, or commit to providing the answer at a given time in the future. nothing destroys trust and creates anger more than speculating or guessing at answers that may be proven wrong at a later stage. while you must respond quickly to all questions, you may not be able to answer them all. the crisis team must understand the difference. stakeholders want reassurance you are doing everything possible to manage the situation and communicating without a hidden agenda. if you intend to keep your business open and running during a significant event, say so. for credibility, communicate the steps that you are taking to ensure it is kept open. if you are asked questions and are uncertain about what will take place, acknowledge this honestly. make every effort to find the answer quickly and, when you have it, follow up as soon as possible. plan to work with third parties. adopting a go-it-alone attitude in dealing with a pandemic is needlessly dangerous. organizations are wise to be working with key third-party consultants to make crisis preparedness as robust as possible. key third parties could include: don't overlook your supply chains. companies providing each other with operations-critical products, goods, or services become inextricably linked. a problem in another company may cascade to yours, affecting your ability to meet contractual obligations. steps they take to stay in business may be beneficial or disruptive to you. knowing ahead of time will help you make appropriate arrangements or establish alternatives. cooperating with customers, partners, suppliers, and local governments helps you become pandemic-resilient. expert legal opinion must be obtained on how to address contractual obligations should a full scale pandemic break out. if you're prevented from delivering products or services and thus break legally binding contracts, customers/ partners could hold you liable for failing to plan adequately. such legal action could expand or precipitate a second crisis, when the media reports the legal action and you are forced to deal with a reputational crisis. during a pandemic, organizations must communicate effectively with all internal and external audiences. being ready to communicate proactively and at a moment's notice requires advance preparations. in all cases, employees are the most important communications targets during a crisis. friends and family will contact them along with many of their external business relationships (including the media) to ask "what's really going on?" and we know from experience that poorly briefed employees tend to speculate in the absence of solid information. this could easily precipitate a secondary crisis, forcing you to deal with rumor-mongering by employees and potentially false reporting by the media. either could cause serious damage. thus, you must designate in advance your primary or "official" internal communication channels, and let everyone in your organization know what they are. while face-to-face verbal communication is the best medium for internal audiences during a crisis, it may not be possible if h1n1 strikes. depending on your specific situation, one of the following channels should be considered in order to communicate companywide: remember: what is written and given to employees can be passed on to the media and other parties. communication with all external stakeholders must be timely and accurate, with messages consistent with what is being communicated internally. messaging differences should be determined by relevance to the receiver. but be safe: when in doubt, overcommunicate. in a crisis, everyone wants more information, not less. if you had to communicate with 100% of your customers within 60 minutes, could you? do you have up-to-date accurate contact information housed in databases that can support mass messaging such as blast e-mail or recorded voice messages with outbound autodialing? blast-fax? cell phone information for texting? nobody has time to build these contact databases once a crisis strikes. assemble them now. the best time to start communicating is when there is no crisis. a proactive information campaign could spearhead the opening of new channels of communication with your various external audiences prior to a crisis. the following external communication channels can be used proactively or reactively depending on the situation: while social media tools such as twitter, facebook, youtube, and blogs can play a role in crisis communication, at this time we believe they are not the tools best suited to be your primary or "official" communication channel to the outside world. especially for business organizations, social media are not yet universally accessible. but more importantly, they are not within your complete control. you must be extremely careful about what you say via social media, as it is very difficult to change anything after it has been sent out. it's the very nature of most crises that the situations and facts change, and change often. social media messages containing old information can too easily recirculate, causing misunderstandings and conflicts precisely at a time when they can do the most damage. a major h1n1 breakout could devastate supply-and-value chains, and possibly close down entire industry sectors. this will prevent companies from providing or delivering much needed services. customers, partners, suppliers, and employees will feel a significant impact. there will also be financial repercussions. in short, a business could be forced to close down if it is not ready for all eventualities. to be truly resilient in a crisis, the organization must have an up-to-date business continuity plan detailing how it will restore its operating functions, either totally or partially, within a certain period of time. to achieve this, key decision makers must: • have an in-depth look at their company to identify essential functions needed to keep doors open. nonessential ones can be temporarily discontinued without impacting day-to-day operations. people with key skills that are important to the business during the pandemic must be identified and protected whenever possible. those with nonessential skills may be told not to report for work during the pandemic. • consider contingency plans to switch operations to other sites, if possible. • identify alternative suppliers that you can switch to at a moment's notice. your primary suppliers of utilities, goods, products and services may suddenly shut down because of poor planning. you should ask current suppliers to disclose what contingency plans they have in place to ensure the provision of uninterrupted service to you. put backup plans in place to switch to other/competing suppliers and contractors if you're the least bit unsure of their preparedness. • determine if their it systems are sufficiently robust so critical technology-dependent business processes would still function. even though more than one billion people travel via commercial aircraft every year, illness as a direct result of air transportation isn't common; however, there are risk exposures associated with air travel that both employers and travelers should be cognizant of in order to mitigate the risks when possible. most modern aircraft are equipped with hepa (high efficiency particulate air) filters, which, according to the european air filter efficiency classification, can be any filter element that has between 85% and 99.9995% removal efficiency. according to pall corporation, for aircraft cabin recirculation systems, the definition has been tightened by the aerospace industry to a standard of 99.99% minimum removal efficiency. 5 most modern aircraft provide a total change of aircraft cabin air 20 to 30 times per hour, passing through these hepa filters, which trap dust particles, bacteria, fungi, and viruses. many airlines have an airflow mix of approximately 50% outside air, and 50% recirculated, filtered air whereby the environmental control systems circulate the air in a compartmentalized fashion by pushing air into the cabin from the ceiling area, and taking it in at the floor level from side to side, versus air movement from the front to back of the aircraft. however, most viral respiratory, infectious diseases, such as influenza and the common cold, are transmitted via droplets that are most commonly transmitted between passengers by sneezing or coughing. these droplets can typically only travel only a few feet this way. however, it is their survival rate once they land on seats, seatbelts, tray tables, and other parts of the passenger cabin that can provide additional exposure, which is why sanitation of your personal seating area when traveling, particularly your hands with an alcohol-based sanitizer before eating, is important. surgical masks have been shown to reduce the spread of influenza in combination with hand sanitization, particularly when worn and practiced by the infected individual. viral outbreaks in recent years of concern to business travelers have included middle east respiratory syndrome (mers), severe acute respiratory syndrome (sars), and ebola, h1n1 (swine flu), among others. the international air transport association (iata) has developed an "emergency response plan template" for air carriers during a public health emergency, which can be found at the following link: http://www.iata.org/whatwedo/safety/health/ documents/airlines-erp-checklist.pdf disinsection is the use of chemical insecticides on international flights for insect and disease control. international law allows disinsection and the world health organization (who) and the international civil aviation organization suggest methods for aircraft disinsection, which include spraying the aircraft cabin with an aerosolized insecticide while passengers are on board, or by treating aircraft interior surfaces with a residual insecticide when passengers are not on board. two countries, panama and american samoa, have adopted a third method for spraying aerosolized insecticide without passengers on board. not specific to just air travel, blood clots or dvt (deep vein thrombosis) can be a serious and potentially deadly health risk for any traveler with restricted mobility in an aircraft, car, bus, or train. anyone traveling for more than 4 hours without sufficient movement can be at risk. many blood clots are not necessarily visible and can go away on their own, but when a part of one breaks off, there is the possibility of it traveling to your lungs, creating a pulmonary embolism, which could be deadly. in addition to traveler training on prevention of dvt, companies should take this threat into consideration with regards to international class of service policies or reimbursement consideration for upgrades. according to the u.s. centers for disease control (cdc), the level of dvt risk depends on whether you have any other risks of blood clots in addition to immobility, as well as the length or duration of travel. the cdc also states that most people who develop blood clots have one or more other risks for them, such as: 6 • older age (risk increases after age 40 years) civil unrest generally takes place when a group of people in a specific location is angry, resulting in protests and violence. around the world, there are countless incidents of civil unrest that erupt, which can not only cause inconvenience and safety concerns for business travelers, but can also cause mental and emotional stress for which the employer is ultimately responsible to try to limit the effects of whenever possible, and to treat as early as possible after the incident is over. within the first 6 months of 2014, the world saw civil unrest and protests in turkey, brazil, ukraine, thailand, venezuela, malaysia, cambodia, india, egypt, hong kong, russia, china, and the united states (excluding military acts of war or civil war). in january of 2011, governments and private organizations from around the world began evacuating people from egypt due to civil unrest. approximately 50,000 americans lived and worked throughout egypt at the time, and approximately 2400 requested evacuation assistance from the u.s. government. such an exercise requires massive planning and resource availability, even for much smaller groups of people. consider the number of other companies competing for the same resources to evacuate their people, as well as the general public trying to leave. companies without a plan in place, along with proper strategic crisis response resources, would have been last in line to evacuate their impacted travelers and at greater risk for someone getting hurt or killed. at one time, civil unrest may have been considered primarily politically motivated, but today, there are many factors that lead to the spark that starts the fires of violence. things such as overpopulation, lack of food and resources, poverty versus wealth (income inequality), crime, lack of jobs and religious persecution, while sometimes related to political causes, are all reasons for the increased violence we see today. with the advent of mobile technology being increasingly available to the middle and lower classes of the world, it doesn't take much or long time-wise, to incite anger or hatred in others who can assemble quickly, sometimes before one has a chance to react. throughout the text of this book, readers should see a common theme about the importance of quality risk intelligence. the previous statement about violence breaking out before one can react, is a perfect example of how real, risk intelligence (not simply recycled news) can often predict these events as they are starting to come together and warn people in advance, so that companies and individuals can take steps to mitigate their exposure. in such examples, would employers and travelers want "cheap information" from a provider that primarily scrapes news wires on the internet, or qualified, vetted security analysts with thousands of sources? if a life depended on it, i'm confident that people would choose vetted intelligence. another way to understand the value of news versus intelligence is that "intelligence" is in effect "analysis + news + context + advice." experienced security analysts specializing in specific geographic areas and subject matter produce quality intelligence. climate change can also drive civil unrest with sea-level risings, damage to property, water shortages, and increased costs associated with lost productivity or infrastructure collapse. people simply go where the goods and the work are provided. when that is lost for various reasons over a large area, there can be mass migrations that sometimes see the intervention of military units to prevent border crossings and an unanticipated drain on other population's resources. property damage and serious violence in vietnam in may 2014, as a result of anti-chinese protests, was experienced not only by chinese businesses, but by other assets owned by companies from additional countries. some manufacturing experienced an interruption to production, causing between 4 percent and 16 percent decreases in company share prices. these figures and insight are intended to support business cases for companies to invest in not just products and programs to avoid business disruptions caused by civil unrest and other factors, but the time required to simply have plans in place to mitigate the risk. imagine being in a foreign country on business and getting pulled over on the road in your rental car by a local police officer. unaware of any laws that you may have broken, after a quick discussion with the officer, you realize that they are extorting you for a bribe and you simply don't have the cash or the training to respond to the situation properly. alternatively, a traveler arrives in foreign country via a commercial flight, carrying marketing collateral and merchandise to give away at a conference that they are attending. the local customs authorities misinterpret part of your merchandise, because the conference is being held in a deeply religious country with harsh laws regarding morality. not only does the traveler fear for their safety, the company doesn't want to cause an international incident, which can be difficult to clean up. does your company provide resources and training to travelers regarding how to handle themselves in such situations? women from western countries may still find it hard to believe how many places in the world where their personal safety, and possibly their lives, can depend upon the length of their skirt and sleeves, or the time of day that they are out and about, particularly without a male escort. in 2013, a woman from new york was found dead in turkey; a turkish man confessed to killing her after allegedly trying to kiss her. according to news reports, she was a first-time international traveler, an avid social media user, and was in constant contact with friends and family. it is reported that she wasn't off the beaten path or doing anything risky, simply taking photographs. sometimes just having some awareness training about your destination can save female travelers the potential for conflict or incident, such as holding one's purse in her lap or at her feet with a thick strap around her leg to secure it, or ensuring that luggage tags do not openly display addresses and have a cover that must be opened to reveal the information. according to joni morgan, director of analytic personnel at ijet international, "in some cultures, for instance, it's not appropriate for a woman to initiate a handshake." "in afghanistan, it's considered an insult to show the bottom of your shoe, so when crossing your legs, you want to be aware of that." 7 female road warriors are learning important skills that are notably helpful in all destinations, but in some more than others, additional care should be taken. indications of when to take additional care is an important part of pretrip travel intelligence provided by an employer's trm program, supported by a vetted travel risk intelligence provider. some considerations for female business travelers while traveling alone or even with peers on business include the following: 1. always plan your route before going anywhere. never leave your hotel or office without understanding where you are going and appropriate routes. travelers do not want to look lost in the street looking at maps or their mobile devices for directions. 2. use vetted taxis or ground transportation providers. make an attempt to prebook all transportation with providers that your company has preapproved, and have appropriate security policies and procedures in place, such as identifiable car numbers, driver identification, tracking, and electronic order confirmation. removing the potential for unfamiliar, unvetted ground transportation providers can drastically reduce the potential for assault or abduction. can purchase a device to block the outside view of the inside of their hotel room by assailants who have devices that enable broad visibility inside hotel rooms from the outside via peepholes. in the absence of such a device, place tape or a sticker over the inside peephole opening. 4. choose your hotels carefully. make it clear to your employer that you take safety seriously and that you expect safety considerations to have been taken into account when designating preferred hotels for employees to stay at. employers should be able to articulate what kinds of safety standards go into their preferred hotel selections, which form the basis for how different incidents can be mitigated or handled should an incident occur. 5. never stay at hotels or motels where the room door is exposed to the open air (outside). 6. try to not accept hotel rooms on the ground floor. being on a higher floor makes it more difficult for an assailant to get away or not be seen on surveillance cameras. 7. never tell anyone your room number verbally. if a hotel employee asks for it, provide them with it in writing and personally hand it to them. do not write it on a check and leave it unattended. you don't want someone in the area to overhear you providing this information verbally or to view it on your check. 8. alcohol consumption-never leave your drink unattended or out of your sight. a momentary distraction is an opportunity for someone to place drugs into your drink. also, never drink until intoxicated while on business and be mindful of locations where drinking alcohol may even be illegal. 9. emergency phone numbers-know the equivalent of 911 or the local emergency services phone number and your local consulate or embassy phone numbers and preprogram them into your mobile phone, in addition to your company's provided crisis response hotline. whichever number you are instructed to call first according to your company's policies (if your company provides a crisis hotline), having those numbers handy can save your life when moments count. 10. never tell anyone that you are traveling alone. avoid solitary situations. try to remain in social situations where plenty of people are around. if you feel uncomfortable, leave. 11. leave a tv or radio on when you leave your hotel room to provide the perception that someone is in the room. 12. never hesitate to ask security or someone to escort you to your room, and avoid exiting an elevator on your hotel room's floor when sharing the elevator with a man. if necessary, go back to the lobby level until more people get on the elevator or you can ride it alone. use valet parking. self-parking can often put individuals at risk of assault in unsupervised car parks or garages. 14. upon arrival at your hotel, take a hotel business card or postcard and keep it with you at all times. if ever you are away and need to return, and you either don't remember the address, or your driver doesn't know where it is, or you don't have a signal on your mobile device, you can use the card to provide address details (usually in the local language). 15. do not use door-hanging room service order forms (typically for breakfast), as they often note how many guests you are ordering for. 16. make sure you have adequate insurance. just because you are on a business trip, doesn't mean that your employer has obtained enough insurance or services to support you in the event that a crisis occurs. hopefully, employer-provided insurance and support services are adequate and have been effectively communicated, but don't travel for business without a thorough understanding of what kind of coverage and support you have. in particular, any medical coverage should guarantee advance payment to local service providers and not require travelers to pay for services and file for reimbursement upon their return home. most people don't have access to the many thousands of dollars that might be necessary to procure sufficient treatment and support. 17. travel with smart travel accessories. travel with a small, high-powered flashlight and one or more rubber door stops for the inside of your hotel room (be aware of the downside of using in case of a fire). 18. leave copies of your passport with someone at home who can easily get a copy to you if you need it. having a copy can expedite the replacement of a lost or stolen passport if needed. an honor killing is a homicide of a family member, typically by another family member, based upon the premise that the victim has brought dishonor or shame to the family, in such a way that violates religious and/or cultural beliefs. again, as with religious or cultural restrictions on modest clothing, honor killings are not exclusive to women, but within the cultures and countries where honor killings are more generally accepted, men are more commonly the sources or perpetrators of the revenge or honor killings, very often charged by the family to watch over and police female family member behavior, restricting or prohibiting things such as adultery, refusal to accept an arranged marriage, drinking alcohol, or homosexuality. honor killings are not exclusive to any one country or religious faith, because they are found in a broad scope of cultures, religions, and countries. although more common in places such as the middle east and asia, there have been documented cases of honor killings in the united states and europe. if honor killings were based largely on the premise of family honor, why would nonfamily members or business travelers need to be concerned? honor killings have been known to happen to nonfamily members in strict, culturally conservative countries. perceived inappropriate behavior, typically with a female member of a conservative family, could result in the killing of the female family member and the nonfamily suspect. such killings can even take place in broad daylight. in lahore, pakistan in 2014, one such incident occurred involving multiple participants while the police looked on. the victim killed for marrying a man that she loved without family consent. 8 often these crimes are hard to document or record because they are disguised as suicides or, in some latin american countries, as "crimes of passion." the united nations fund for population activities (unfpa) estimates that as many as 5000 women fall victim to honor killings each year. 9 article 57 of qatar's constitution states that it is a "duty of all" who resides in or enters the country to "abide by public order and morality, observe national traditions and established customs." this means that wearing clothing considered indecent or engaging in public behavior that is considered obscene is prohibited to all, including visitors. in qatar, the punishment could be a fine and up to 6 months in prison. with kissing or any kind of physical intimacy in public, as well as homosexuality, being outlawed under sharia law, all travelers to or via the middle east for business or tourism purposes (e.g., to attend the 2022 world cup), should take heed. the qatar islamic cultural centre has launched the "reflect your respect" social media campaign to promote and preserve qatar's culture and values. posters and leaflets advise visitors, "if you are in qatar, you are one of us. help preserve qatar's culture and values, please dress modestly in public places." while research finds no definition in qatar's article 57 for modest clothing, campaigns such as this suggest that people cover up from their shoulders to their knees and avoid wearing leggings. they are not considered pants or modest dress. an example of the campaign leaflet can be found in "qatar launches campaign for 'modest' dress code for tourists" published by the independent (uk newspaper). 10 modest dress applies to both men and women. of course, strict laws, preferences or rules regarding dress expectations for women are not exclusive to any one country. http://www.pewresearch.org/fact-tank/2014/01/08/ what-is-appropriate-attire-for-women-in-muslim-countries/. while each employer may have specific approaches to handling an incident such as sexual assault, there must be a defined process for reporting such an event that involves crisis response resources that can intervene and provide advice on how to handle the situation with local authorities, perhaps first by contacting diplomatic contacts before contacting the police. facing local authorities alone in a foreign country for such a sensitive issue as sexual assault can be daunting and intimidating 8 nbc news, "family stones pakistani woman to death in 'honor killing' outside court," may 27, 2014, http://www.nbcnews.com/news/world/family-stones-pakistani-woman-death-honor-killing-outsidecourt-n115336. 9 united nations, resources for speakers on global issues, "violence against women and girls: ending violence against women and girls," http://www.un.org/en/globalissues/briefingpapers/endviol/. 10 lizzie dearden, "qatar launches campaign for 'modest' dress code for tourists," independent, may 27, 2014, http://www.independent.co.uk/news/world/middle-east/qatar-launches-campaign-for-modest-dresscode-for-tourists-9438452.html. without a company or diplomatic representative being there to assist. crisis response suppliers should be equipped with necessary contacts, recommended protocols, and resources to help the victim and employer to address the situation and get help as soon as possible. this is another good example of why employers should have a single global crisis response hotline for any crisis that a traveler may encounter while on business travel. sexual harassment can happen anywhere. what happens if you require a traveler to use a supplier per the company's travel policy, and a representative of that supplier sexually harasses the traveler? in addition to standard protocols within the workplace, considerations must be given to business travel, which from many perspectives today is an extension of the workplace. a hate crime is a criminal act of violence targeting people or property that is motivated by hatred or prejudice toward victims, typically as part of a group, based upon creed, race, gender, or sexual orientation. a critical component of any trm program is disclosure of potential risks to the traveler prior to taking a trip to a destination. in consideration of laws and cultural beliefs in select countries or regions that sanction the persecution, imprisonment or killing of members of the lgbt (lesbian, gay, bisexual, and transgender) community, specific races, religions, or sex (mainly women), travelers must be prepared a female business traveler, over the course of several months on a project, travels during the week, returning home on weekends. over time, a car rental clerk at the location she rented from weekly, began making comments to her about her appearance each time she checked-in or returned a car. eventually, the rental clerk began calling her mobile phone to share how he liked what she was wearing and began sending her text messages while she was in town, using the mobile number she provided at check-in. not responding and scared, the traveler canceled all future reservations and books rental cars with another provider. shortly thereafter, the clerk began calling and texting her, asking why she canceled and when she would be coming back. a concerned colleague of the traveler brought the situation to the company's travel manager, who intervened with their human resources and legal departments to proactively address the situation with the authorities and the supplier, and to provide appropriate support for the traveler as best they could. the end result, after much investigation, was the issuance of restraining orders against the clerk and termination of his employment. it turned out that the supplier hadn't done sufficient background checks on its employees and the clerk in question had a history of similar behavior. with information and training on acceptable behavior when traveling to these destinations and understand how to get help should they find themselves in a difficult position or a potential victim of a hate crime. saying the wrong thing, at the wrong time, in the wrong place, or wearing something inappropriate, or acting a certain way that isn't culturally acceptable in some parts of the world, can put travelers in real danger. how does your company prepare your travelers for facing these challenges as they travel? while some laws that promote discrimination that can lead to hate crimes are more notable in the press, such as the antigay propaganda law put into place in russia prior to the sochi olympics, some are less obvious to the average business traveler, such as up to 14 years in prison in nigeria for simply being gay, or india's supreme court ban on gay sex, or the execution of homosexuals in saudi arabia. in april 2013, an 82-year-old man wearing islamic dress was attacked and killed while walking home from his mosque in birmingham, uk, by a 25-year-old ukrainian student who told police that he murdered the victim because he hated "nonwhites." 11 according to "one in six gay or bisexual people has suffered hate crimes, poll reveals," a 2013 article in the the guardian (uk), some 630,000 gay and bisexual people in the uk have been victims of hate crimes in the previous 3 years, prompting police to take the problem more seriously. 12 such examples continue to support the notion that a crisis doesn't need to be an incident that impacts large numbers of people at once. quite often they involve one person at a time, and they don't need to take place in a high-risk destination, thus discounting the argument by some companies that trm isn't necessary for those who don't travel to high-risk destinations. a crisis can happen anywhere for many different reasons, affecting as few as one person at a time. although privacy laws generally prohibit companies from asking employees about sexual orientation, making sure that all employees (of any sexual orientation) understand the dangers that face lgbt travelers, can help to mitigate risks for themselves (if lgbt, traveling with an lgbt person, or if perceived as lgbt) or their fellow travelers, considering that there are many countries still in the world where homosexuality is a crime. • in mauritania, sudan, northern nigeria, and southern somalia, individuals found guilty of "homosexuality" face the death penalty. the last five years have witnessed attempts to further criminalize homosexuality in uganda, south sudan, burundi, liberia, and nigeria. • south africa has also seen at least seven people murdered between june and november 2012 in what appears to be targeted violence related to their sexual orientation or gender identity. five of them lesbian women and the other two were non gender-conforming gay men. • in cameroon, jean-claude roger mbede was sentenced to three years in prison for 'homosexuality' on the basis of a text message he sent to a male acquaintance. • in cameroon, people arrested on suspicion of being gay can be subjected to forced anal exams in an attempt to obtain 'proof' of same-sex sexual conduct. • in most countries, laws criminalizing same-sex conduct are a legacy of colonialism, but this has not stopped some national leaders from framing homosexuality as alien to african culture. • a cave painting in zimbabwe depicting male-male sex is over 2000 years old. • historically, woman-woman marriages have been documented in more than 40 ethnic groups in africa, including in nigeria, kenya, and south sudan. • in some african countries, conservative leaders openly and falsely accuse lgbti (lesbian, gay, bisexual, transgender, and intersex) individuals of spreading human immunodeficiency virus (hiv)/acquired immune deficiency syndrome (aids) and of "converting" children to homosexuality and thus increasing levels of hatred and hostility towards lgbti people within the broader population. lgbti individuals are more likely to experience discrimination when accessing health services. this makes them less likely to seek medical care when needed, making it harder to undertake hiv prevention work for, and to deliver treatment where it is available. in many government programs they are not identified as an "at risk" same-sex marriage 1 laws restricting freedom of expression and association kidnapping and ransom activities targeting military enemies and employees of multinational companies who are from countries considered to be enemies to terrorist causes, are the primary fundraising strategies of organized terrorist groups. even for companies that do not routinely visit high-risk locations, having some sort of policy in place for proof of life, which is the means for verifying that a captive is in fact who the captors say they are and that the captive is still alive, such as by providing information that only the alleged victim would know, can save valuable time in a sensitive situation and perhaps someone's life. additionally, a kidnap and ransom insurance policy is something for all companies to consider, with an understanding that kidnappings happen at anytime around the world, and largely go unreported. according to the guardian news and media (uk), approximately 75% of fortune 500 companies have kidnap and ransom (k&r) insurance. k&r insurance originates from 1932, when it was first offered by insurance provider lloyd's of london, after the kidnapping and murder of american aviator charles lindbergh's infant son. in 2015, the uk's home secretary, theresa may, supported and passed the uk's "counter-terrorism and security act of 2015," which prohibits insurers from paying claims used to finance payments to terrorist groups. the uk is where many of the world's k&r insurers operate. many insurers insist that it shouldn't matter because they claim to not pay or finance ransoms, but instead pay claims for services and expenses related to negotiating the release of the captives in question, medical and counseling treatment, along with things such as employee salaries while in captivity. it's difficult to obtain information from clients who hold such policies, because most policies have strict cancelation provisions to prevent a company from disclosing the fact that it has such a policy. details specific to restrictions on insurance related payments associated with terrorist related ransoms in the uk's counter-terrorism act of 2015 can be found at http://www.legislation.gov.uk/ukpga/2015/6/section/42/enacted. companies with any travel to high-risk destinations have a responsibility to provide some kind of survival training for those travelers, in addition to access to resources and provision of current intelligence before, during, and sometimes after their travel is complete. to complicate matters, based upon a 2013 g8 summit, an agreement was made to not pay ransoms to kidnappers for fear that the money was directly funding terrorist organizations; therefore, some countries, such as the uk, are enacting laws to prohibit the transfer of funds for hostages in certain circumstances or locations. senior foreign and commonwealth office (fco) officials in the uk estimate over $60 million has been paid in ransoms to terrorists during the 5 years leading up to the 2013 report. it isn't safe to assume that your government will help bankroll your hostages' release if you find yourself in such a situation, and you may face criminal prosecution if you offer a ransom to specific groups. people who commit kidnappings do so for a variety of reasons, including political or religious views, but most often they are purely financially motivated. perception is everything, so identifying traveling employees of large or multinational companies, makes them an easy target, thus the reason for using code names for arriving ground transportation signs. of course, how one dresses and where one goes, also have an impact on how victims are targeted (i.e., wearing expensive jewelry, standing out from the crowd in expensive clothing or making it clear that you work for a large multinational company [clothing with logos or meeting drivers with company names on greeting placards]). later in this book, kidnappings are explored in greater detail. some statistics will be presented that both companies and travelers should find serious enough to change their perception about the possibility of kidnapping happening to them. kidnapping incidents should be accounted for in all corporate crisis response plans. while some medical emergencies may require the need for evacuation, it is more common to receive calls for assistance involving acute or preexisting conditions that can be diagnosed and treated locally. lost or stolen medication, allergic reactions to food or the environment, and unexpected illnesses, are common occurrences when calling a corporate crisis response hotline. however, in some instances, individuals must be quickly assessed to determine if adequate medical care can be obtained locally, and if not, a decision must be made to evacuate that person to the closest logical facility capable of treating the individual. many domestic health insurance plans do not provide coverage for individuals traveling abroad, and often when they do, they require out of pocket expenditures for services; in other words upfront payment by the patient, leaving the patient to file for reimbursement upon the patient's return. more often than not, in these circumstances, this equates to thousands of dollars that most people do not have immediate access to, especially on short notice. the cdc recommends that if domestic u.s. coverage applies, and supplemental coverage is being considered, the following characteristics should be considered when examining coverage for planned trips: • exclusions for treating exacerbations of preexisting medical conditions. the company's policy for "out of network" services. • coverage for complications of pregnancy (or for a neonate, especially if the newborn requires intensive care). • exclusions for high-risk activities such as skydiving, scuba diving, and mountain climbing. • exclusions regarding psychiatric emergencies or injuries related to terrorist attacks or acts of war. • whether preauthorization is needed for treatment, hospital admission, or other services. • whether a second opinion is required before obtaining emergency treatment. • whether there is a 24-hour physician-backed support center. additionally, one should have coverage for repatriation of mortal remains, should someone covered unfortunately die while away from their home country. because so many domestic healthcare plans do not provide for international coverage and evacuations services, companies must provide comprehensive coverage for their employees globally and employees should be fully aware of what is included in said coverage. employees may decide that what the company offers is not enough by their personal standards and consider purchasing additional coverage to supplement what the company provides. when purchasing different types of travel-related insurance, it's important to understand the differences between the different products offered in the marketplace, especially the differences between consumer and business travel products. options can include: 1. travel insurance, which provides trip cancellation coverage for the cost of the trip, delays or interruptions, and lost luggage coverage. it can and often does provide some amount of emergency medical and evacuation coverage, but often requires payment of medical expenses by the insured in the country where services are rendered (versus direct payment by the insurer), and the filing of paperwork for reimbursement upon the insured's return home. buyers should be mindful of whether or not the policy provides guaranteed payment directly to the suppliers in question. 2. generally, some consumer based travel health insurance pays for specified or covered emergency medical expenses while abroad; however, such insurance (and others) may require that the individual pay any medical expenses in the country where services are rendered and file for reimbursement upon the individual's return home. insured parties should always check whether guaranteed payment to providers is included in coverage, as with some consumer-based travel insurance. medical evacuation coverage is for medical transport to either the closest available treatment facility or the insured's home country for medical attention, depending upon the policy and the situation or medical condition. considering the cost of medical evacuations, depending upon the distance and the services required for the transport, expenses can vary greatly, but can be very costly. it is recommended that policies have greater than us$100,000 in coverage (some provide up to us$500,000 or more), and include transportation support for an accompanying loved one or family member. policies with less than us$100,000 in coverage should be reconsidered for possibly not providing enough coverage. buyers should note that these products cover primarily just the evacuation and not medical services or treatments. 4. medical membership programs can cater to individual travelers on a per-trip or annual basis or on a companywide basis. these programs can vary widely by provider and membership type, but can potentially provide access to network services resources with separate liability for payment, or network access with some coverage for payment of specified services rendered based upon premiums and policy guidelines. the lii at cornell university law school provides a third-party overview of workers' compensation. 13 variable forms of this type of coverage are provided at both the state and federal levels in the united states, with similar forms of workers' compensation laws also in place in select countries around the world. these laws are typically intended to provide some form of medical benefits and wage replacement for employees who are injured on the job. this coverage is often provided to employees in exchange for releasing their right to sue their employer for negligence, sometimes with fixed limits on payment of damages. employers need to understand whether the workers' compensation coverage that is applicable and in place for their and their employees' protection, covers international travel. in some cases, additional policies or riders will be required to provide coverage for travel outside of the traveler's home country or state. additional considerations to this kind of coverage should be as to "when" and "where" the coverage is in effect outside of a company office or facility (e.g., business travel). in some cases this may limit employer liability, but whether it does varies by jurisdiction and circumstance. considering how workers' compensation benefits have been reduced in recent years, especially in the united states, 14 much consideration needs to be given to assessing what coverage is needed for traveling employees above and beyond workers' compensation, and coordinated with crisis response protocols and risk management support providers for efficient case management, claims, and documentation. all of these considerations provide a strong business case for why employers should have unique and specific programs in place for medical services and evacuations for employees and contractors traveling abroad in addition to their standard domestic health care plans and workers' compensation plans. no traveler should embark on a business trip without the complete confidence that medical coverage and resources not requiring their personal, out-of-pocket expenditure is being provided by their employer. a 2014 study that included disclosures from 767 institutional investors, representing us$92 trillion in assets, provided by sustainable-economy nonprofit gross domestic product (gdp), stated that in addition to increased physical risks that are being caused by climate change, climate change is already impacting their bottom line. one major uk retailer has stated that 95 percent of its global fresh produce is already at risk from global warming. according to the french foreign minister, commenting at a 2015 un conference in japan, two-thirds of disasters stem from climate change. comments were made days after the 4-year anniversary of the fukushima nuclear disaster that killed approximately 19,000 people in 2011 from an earthquake and tsunami. margareta wahlstrom, the head of the un disaster risk reduction agency, stated that preventative measures provided a very good return as compared to reconstruction. un secretary general ban ki-moon asked world nations to spend us$6 billion dollars a year on prevention. an important aspect of both a company's trm and business continuity plan is to determine what are the unique dangers or risks associated with where your offices or facilities are located, as well as where you travel to on a regular basis, making emergency evacuation and safety plans in the event that a unique incident occurs, such as the following case study related to the 2011 japanese earthquake and tsunami. it is important to know what local governments have made available in close proximity to your travelers' or expats' locations in terms of resources, or something that your company itself may provide, such as "vertical evacuation points" to escape rising tsunami flood waters. these vertical evacuation points may be in a building that is tall enough to support large numbers of the local population at a high water level, with ample support systems and supplies. not understanding and communicating these plans to your people when appropriate could exact a cost in lives, money, and corporate reputation. * american red cross, "japan earthquake and tsunami: one year update, march 2012," http:// www.redcross.org/images/media_customproductcatalog/m6340390_japanearthquaketsunami_ oneyear.pdf. on march 11, 2011, a 9.0 magnitude earthquake created a 124-foot tsunami. more than 19,000 people died or were presumed dead, with more than 400,000 people evacuated and more than 12.5 million people impacted across the country.* for the first time in more than 190 years, iceland's eyjafjallajökull volcano erupted on march 20, 2010, with massive lava flows and ash clouds that closed most of europe's commercial air space for several days, but then the ashcloud spread to other parts of the world, stranding millions of air travel passengers. based upon the composite map from the london volcanic ash advisory centre for the period april 14 to 25, 2010, one can clearly see the massive geographic scale of this incident, and why almost all commercial and private air transportation was prohibited and severe shortages of lodging and emergency shelters occurred. whether or not you believe in climate change and the reasons behind it, the statistics demonstrating the depletion of the world's ice sheets and glaciers, warmer ocean waters, and consistent year-over-year sea-level increases, will touch most multinational companies profoundly in the 21 st century. the new york times states that sea levels worldwide are expected to rise 2 to 3 feet by the year 2100, but rates are not occurring evenly worldwide. the times' referenced study states that the atlantic seaboard could rise by up to 6 feet, with boston, new york, and norfolk, virginia, named as the three most vulnerable areas. 15 if current warming trends and rising sea levels continue, cities such as london, bangkok, new york, shanghai and mumbai could eventually end up under water according to greenpeace, displacing millions of people and causing massive economic damage. 16 consider a weather event the size of 2012's hurricane sandy, which tips the scales of expected water levels in a low-lying urban city, and results in the displacement of thousands or millions of people, with your travelers or expatriates stuck in the middle of it. when evacuation is not an immediate option, questions regarding the availability of safe accommodation, power, food, and water become priorities as demand far outweighs supply under such circumstances. these occurrences are much more common now than in our recent past. whether working in their local office or manufacturing facility, or traveling for business, many companies have employees with disabilities. although building or facility laws and rules may require designated escape routes, ramps, and elevators/lifts in the event of an emergency such as a fire, what about plans for when a disabled traveler is in transit or at a hotel? special considerations need to be made for disabled travelers in the event of a medical or security-related evacuation, such as: the need to relocate travelers can be caused by any number of factors, but before the decision to evacuate is made (usually at considerably more expense than traditional commercial air travel), someone with access to quality intelligence has to make the call as to whether to "shelter in place," assuming safe shelter is available, or to evacuate to the closest safe location. nonmedical causes for evacuation could be biohazards (e.g., the fukushima nuclear facility damage in japan), or civil unrest, or incoming natural disasters. to evacuate or not to evacuate requires thoughtful planning and resources, in order to insure that companies aren't competing with the rest of the world in a reactive situation where many others were caught off guard as well. ijet case study-ijet and the south sudan evacuations in december 2013, ijet international provided continuous monitoring, intelligence, and analysis of the situation involving heavy ethnic fighting in south sudan to existing clients with operations in the country. support included providing real-time situational updates, establishing direct lines of communications with client personnel, and arranging for safe havens and security evacuations. on december 18, 2013, the situation worsened to include the closure of the juba international airport. during the first 2 days of fighting, prior to the airport closure, more than 500 people were killed and more than 800 wounded in the violence. during this time, several client personnel traveled across the country's borders to safe havens, but soon after the airport closure, with mounting concerns about large numbers of refugees, those borders quickly closed. ijet successfully evacuated its clients within the first 3 hours of the airport's reopening, bringing in a 15-seat light-passenger aircraft from nairobi, kenya, performing some of the first successful group evacuations from this incident without injury. the ijet case study excerpt is an example of why a company's trm program cannot consist of technology alone, and discounted news being marketed as intelligence. in situations like these, quality intelligence is what saves people's lives. in this instance, quality intelligence was critical to the coordination of ijet's incident management team's on-the-ground services and support, which lead to not only evacuating its clients, but knowing when was the right time to move its clients to the airport and into the air. some medical evacuation services do not provide security-based evacuations, while some can offer both. companies should consider that one provider for both medical and security services and support, intelligence and insurance, might not always be the best solution. some companies select one provider for their terms and coverage for medical services, support, and evacuations, but another provider for security-related intelligence, services, and evacuations. there are even those companies with multiple providers for each medical and security service in different parts of the world, working with completely separate insurance providers to pay for the services rendered. each company must consider the coverage and resources currently available to them via their existing insurance relationship, and then solicit proposals for coverage based upon a clear outline of what the company needs are based upon claims history. ultimately, companies need a program that can coordinate with all contracted services and insurers, providing a seamless experience for travelers and administrators, and consolidated documentation. the term "open booking" refers to a booking made by a traveler that was made outside of their managed corporate travel program, avoiding usage of any contracted travel management company (tmc). technical advances have found ways to incorporate reservations data from multiple websites or suppliers for a traveler's trips into one place for reporting and calendar population. however, to properly capture this data, there are two primary methods available. the first is to allow the applications the ability to scan our inbox for travel-related e-mails and import the data accordingly. the second method is having travelers or independent suppliers e-mail reservation confirmations to an application or "parser," which can parse the data into a standardized database. with some major travel suppliers (such as airlines, for example) there are "direct connections" from their websites to some of these applications. however, in the absence of a direct connection, if you cannot get beyond the security concerns of a third-party application scanning your inbox, one cannot guarantee the automatic capture of 100 percent of open booking data because of human error. for that reason and many others relative to policy and program management, and because of the high probability of human error, for effective trm, open booking should not be promoted as a primary booking method within a managed travel program. however, there is a place for open booking technology within a managed travel program: to help capture data from travel data normally considered "leakage," which is often not collected for reporting. such data can originate from conference-or meeting-based bookings made via housing authorities or meeting planners, or perhaps for travel that is booked and paid for by a client. companies who allow open booking for all travel struggle to effectively locate travelers in a crisis, disclose any potential risks or alerts, or provide services to some travelers in the event of a crisis. outside of suppliers with direct connections to open booking applications or parsers, even when your travelers are trained to e-mail those open booking itineraries to the required application for data capture, employers have no control over when they do this. within a managed program (via most tmcs), all new bookings, modifications and cancelations are usually updated in the database in real time or close to it, providing employers with ample opportunities to mitigate risk in a number of ways when time is of the essence. some well-known companies, offering travel-related solutions, claim that open bookings equate to more traveler choice and that their solutions can bridge the gap for any potentially missing data. when using an open booking application's itinerary data for security purposes, changes and cancelations can be a major issue. some applications require user intervention to manually delete trips that have been canceled, or to resubmit trips for changes unless an update can be e-mailed or picked up by an e-mail scan. consider a situation where a trip is booked and ticketed via an airline website, the itinerary is e-mailed to the traveler, who either allows their inbox to be scanned or they forward the e-mail to the open booking application. days later, the traveler needs to cancel that booking and rebook with another airline to travel with someone else from the company. the arrangements are made with the new airline, but the traveler forgets to delete the original trip in the open booking application. now there are two trips in the system for the traveler. imagine the confusion this could cause with employers if similar circumstances impacted multiple employees at the same time? a good managed travel program can still provide a variety of options, including easy methods of making reservations, yet still capture critical reservations data needed to effectively manage risk for business travelers. trying to manage risk with a completely unmanaged booking process for the sake of open booking, even if it did offer more traveler choice, is not worth the risk, considering that in a crisis you have a higher likelihood of inaccurate data unlike if the traveler had booked via your managed program (via a contracted tmc working in conjunction with your trm provider). does that mean that managed program data is perfect? no, but if implemented properly, reservations data can be more tightly controlled. on january 15, 2009, when us airways flight 1529 went down in the hudson river in new york city, a regional office for an employer received a phone call from an employee's relative who was hysterical, insisting that his family member was on that plane. the office in question contacted their tmc, but was unable to obtain any information on the traveler, so they then turned to the travel manager. by this time, the inquiring family member had intentions of coming into the office because he wanted "some answers," for which there were none at the time. human resources suggested that the relative contact the crisis response hotline, while dispatching security to the office in question to protect the facility and its personnel. human resources also advised the person to stay home for any communications, and for their safety, considering the person was so upset. it turns out that the traveler in question was on a legitimate business trip, but that the traveler had purchased the trip online (outside of the employer's managed program), with the traveler's personal credit card, and without using an open booking application for itinerary data capture. because of this situation, it was difficult or nearly impossible to get helpful intelligence to the traveler or the traveler's family or to provide adequate resources and support, and had there been a death or severe bodily injury involved, the traveler wouldn't have been eligible for their corporate credit card's accidental death and dismemberment (ad&d) coverage. consider the personal losses of a business traveler whose hotel room was just broken into. what if as a result of such a theft, the traveler's identity was stolen? will your company support the needs of the traveler to ensure that the traveler's assets and identity are preserved? the traveler wouldn't have been where the traveler was if it weren't for the business trip! identity theft has reached epidemic proportions globally, with plenty of statistics published by consumer advocacy groups and government agencies, such as the u.s. federal trade commission. the u.s. federal trade commission's 2014 consumer sentinel network data book listed identity theft as the top reported complaint by consumers for the 15th year in a row, with approximately 332,646 complaints. the act of traveling for business presents many opportunities for a traveler to be exposed to scam artists looking to steal the traveler's identity. while taking precautions may be inconvenient and time consuming, there are many things that business travelers can do to reduce their chances of having their personal information stolen, such as: • keep a copy of all account numbers and relative account information in a safe place that is separate from where debit and credit cards are kept. • put mail and newspaper delivery on hold. this can prevent mail theft or an indication that the person is away, which can lead to the person's home being robbed. • don't travel with a checkbook; use only credit cards and cash. • don't use debit cards as pins (personal identification numbers) can be stored in some card reader devices and if the information is stolen, criminals could steal all of the cash available in the account(s) linked to the debit card. • notify credit card issuers prior to travel, especially if traveling internationally, so that they can authorize legitimate charges and notify the card holder promptly if activity on the account doesn't match their records. • use vpns (virtual private networks) when using the internet. if the traveler's company doesn't provide one, the traveler should purchase their own annual subscription. what if your employee had prescription medicine that may have black market value and it got taken as well? now, a theft has turned into a potential medical issue. ask yourself the following: • some medicines cannot be refilled before their due date, and other medicines are not easily refilled before their due dates. do you have the resources and support available globally (24 × 7 × 365) to get those medicines replaced? • do you have the means to get the traveler replacement medicine before the traveler experiences any serious medical issues? • what kind of medical support do you have available, particularly outside of the traveler's home country, should the traveler need immediate medical attention? having someone steal property from your hotel room or safe is bad enough, but when theft has happened, the event itself ends quickly. but if your computer is hacked, the problem could linger in many ways. hotels are ideal places for business travelers to fall victim to hackers who not only may want access to some of your intellectual property, but to your identity as well. referenced in subsequent chapters, there are tips about using hotel and public access wi-fi, if you must use them. however, by whatever means you access the internet while on business travel (e.g., personal hotspot, or wi-fi with vpn, or other tools), try to not conduct any financial transactions or to log into financial-related websites while traveling. losing personal passwords to e-mail accounts or other personal use websites can not only be financially damaging to the individual, but can occasionally be humiliating when private information is made public. the most important thing to remember when faced with a mugging or pickpocketing incident is to not resist in the event of any confrontation and do not pursue assailants. things can be replaced, but not your life or well-being. your first priority should be to get away to a safe place, typically a business or well-lit public place with lots of people, where you can contact the authorities. according to the united states cdc (centers for disease control and prevention), the percentage of adults aged 55-64, during the years 2009 to 2012: • percent of persons using 1-4 prescription drugs in the past 30 days: 55.6% • percent of persons using five or more prescription drugs in the past 30 days: 20.3% source: http://www.cdc.gov/nchs/data/hus/hus14.pdf#085 according to a 2013 report by cbs news atlanta, approximately 7 in 10 americans use prescription drugs. 17 consider that with such a large percentage of the working population taking prescription medications regularly, people taking medications need a basic understanding and awareness to always do their research prior to international travel about bringing the drugs with them into another country. in general, most countries allow up to a 30-day supply of legitimately prescribed medications, in their original bottle. more than 30 days of prescription medication on a traveler can be considered a violation of many country's laws, particularly when it comes to controlled substances, such as narcotic pain medication or psychotropic drugs. in some cases, it simply isn't enough to carry the original prescription bottles with medication in them; travelers may be required to carry additional documentation along with having filed advance approval forms to be in compliance with the jurisdiction in question. in particular, narcotics or psychotropic drugs must have extensive paperwork prepared by your doctor and submitted to the government of the country that you are visiting well in advance of travel, in order to process your paperwork for approval. employers must consider providing this kind of information to travelers with their pretrip briefings or risk reports, where applicable. the possibility of medicine being confiscated and/or criminal charges filed against someone for lack of approval to transport controlled substances into some countries is very real, and could cost someone their life if stranded on international travel without their medicine. tclara, a travel data analytics firm, has developed a scoring system to track how much wear and tear each traveler accumulates from his or her travels. the goal is to predict which road warriors are at the highest risk of burnout, so that management can intervene in a timely manner. the system uses a company's managed travel data to score a dozen factors found in each traveler's itineraries. trip friction 18 points are assigned to factors such as the length of the flight, the cabin, the number of connections and time zones crossed, the time and day of week of each flight, etc. this allows for traveler-specific and companyspecific benchmarking, which in turn helps senior executives to influence travel policy, procurement strategy, and traveler behavior to optimize a managed travel program. push travelers through too many pain points, and the traveler may soon find reasons to not take the next trip. for example, think about flying coach from chicago to singapore, or taking a short haul connection for a lower fare. tighten the travel policy too much, and you could have recruiting and retention problems, which could have serious cost or business implications. companies shouldn't focus solely on minimizing the transaction cost of their trips; instead, they should focus on minimizing the total cost of traveling. that's the sum of the trip's transaction cost plus the cost of traveler friction (the black curve in the figure below) or the "total cost paradigm." to put trip friction into perspective, tclara provides two trip examples (refer to the figure below) showing a low level of trip friction in "trip a" versus a higher level in "trip b." according to tclara (refer to the figure below), their data shows a correlation between trip friction and higher numbers of road warrior or frequent traveler turnover. trip friction is clearly correlated with higher road warrior turnover. while strong travel policies under managed corporate travel programs are critical to successful trm (versus unmanaged, open booking allowances), there is a delicate balance between cost savings, safety, traveler satisfaction, and, very importantly, business continuity. trip friction and traveler friction are good examples of the link between trm and operational risk management (see chapter 9), which shows how losses of productivity or employees managed under the guise of trm can impact company production and/or success. personal well-being of travelers might be the most surprising of topics for consideration, but it certainly is relevant in context with trm programs today. believe it or not, employers must be as cognizant of their employees' or contractor's mental wellbeing as of their physical safety. stressed out, tired, or even unhappy employees can represent lower productivity and a higher threat of risk. from something as simple as knowingly requiring someone to work in a stressful environment without trying to make it better, or just working them to excess, can cause an employee to suffer various forms of posttraumatic stress or depression. however, it can also be as extreme as requiring employees to work in a stressful situation without being properly trained or counseled, as was the case with some flight attendants who may have been forced to immediately fly again out of new york after witnessing the 9/11 attacks, when the commercial flights began operating again, without consideration of stress or trauma, proper treatment, and counseling. to the extent that employers monitor and evaluate the physical safety of employees or contractors in the workplace, they must now take notice of the level of employee/contractor stress and contribute to overall happiness. it turns out that employees with high states of well-being have lower health care costs. 19 it's unfortunate that employers must usually see a financial benefit associated with such things before implementing them, but in addition to health care costs, if people are happier and healthier, it stands to reason that they are also more productive. the cwt solutions group conducted a study to shed light on the hidden costs of business travel caused by travel-related stress. their aim was to understand and measure how and to what extent traveler stress accumulates during regular business trips. they defined a methodology and a set of key performance indicators (kpis) to estimate the impact that this travel-induced stress has on an organization (see "the carlson wagonlit travel solutions group study"). the scope of the study includes data from 15 million business trips booked and recorded by carlson wagonlit travel (cwt) over a 1-year period. they followed a divide-and-conquer approach: each trip was conceptually broken down into 22 potentially stressful activities covering pretrip, during trip (transportation-and destination-related elements), and posttrip. associated stress was measured based on the duration and the perceived stress intensity for each activity. in essence, each of the 22 steps of the trip was viewed as having two components: stress-free time and lost time. to quantify the effects of stress, we introduced the following kpis [key performance indicators]: the travel stress index (tsi) across all trips booked through cwt is 39%. our results show that the actual lost time is 6.9 hours per trip, on average. the largest contributions to this lost time arise from flying economy class on medium and long-haul flights (2.1 hours) and getting to the airport/train station (1.1 hours). the financial equivalent of this 6.9 hours is us$ 662. the lost time greatly depends on the type of trip taken: an increase in the transportation time typically generates an increase in the lost time. the average actual lost time values by trip type are: finally, the study indicates that the impact of stress can be reduced, but not entirely eliminated. they analyzed the tsi on a client-by-client basis and found out that companies can expect to control, on average, 32 percent of the actual lost time. in a previous publication [ref . 1] , cwt solutions group presented the perceived stress reported for 33 activities related to a typical business trip. the current study incorporates 22 of these factors (table 1 .1), including nine of the be provided directly to suppliers for services as needed, or will prepayment be required by the family or loved ones, only to request reimbursement later? if it can be avoided, such understanding can reduce stress associated with paperwork, authorizations, and payment. according to the cornell university law school, in general terms, intellectual property is any product of the human intellect that the law protects from unauthorized use by others. the ownership of intellectual property inherently creates a limited monopoly in the protected property. intellectual property is traditionally comprised of four categories: patent, copyright, trademark, and trade secrets. in summary, if you are in business, you likely have some intellectual property to protect. it could be an idea, or simply a process that you use, which gives you a competitive edge. most people think of a stolen laptop or mobile phone when they think of vehicles for stolen intellectual property, but a far more common vehicle is a flash drive, which most business travelers carry with them today on business trips and aren't monitored or regulated in the same manner as phones, computers, or tablets. companies should either limit the use of flash drives to those drives that have some level of fips (u.s. federal information processing standard) to encrypt the data and/or destroy the data should the drive be tampered with physically in an attempt to access its contents. information on current fips standards (fips 140-2) and announcements regarding the upcoming fips 140-4 standard, can be found by visiting http://csrc.nist.gov/ groups/stm/cmvp/standards.html#05. many companies have policies specific to certain countries whereby, when travelers intend to visit the countries in question, the travelers either cannot take laptops or standard mobile devices with them, or the travelers must take "clean machines" or hardware designed for travel specifically to countries with high numbers of intellectual property theft. some of this hardware may have special configuration or software to add layers of protection, in addition to not storing important files locally (i.e., cloud computing), or transportation of valuable files is done via one-time-use usb flash drives. because there are times when identifying intellectual property thieves can be nearly impossible, one might not have the opportunity to take advantage of any legislation or treaties. however, it is good to know that programs are developing and in place to try and protect intellectual property owners, such as the trips (trade related aspects of intellectual property rights) agreement from the wto (world trade organization). trips was designed to set some standards for how intellectual property rights are protected around the world under common international rules. these trade rules are seen as a way to provide more predictability and order, and a system for dispute resolution, providing a minimum level of protection for all wto member governments. for more details on the trips agreement, see https://www.wto.org/english/ thewto_e/whatis_e/tif_e/agrm7_e.htm. as of may 2015, 36 countries place various forms of restrictions for the entry, stay, and/or residence of people who are hiv-positive. 21 in 2009, the united states removed its entry restrictions for people living with hiv, which received considerable media coverage and is believed to have had an influence on many another country's legislation on the matter, as the number of countries with such restrictions has declined from 59 in 2008 to 36 in 2015. restrictions vary from country to country, but are broken down into the following categories: 22 reminder: although this text provides various reference materials found on the internet, there is no substitute for or comparison to the quality of medical and security intelligence created, monitored, and provided by qualified risk intelligence providers, which are at the core of employer-managed trm programs. one specific reason for the importance of risk intelligence providers is because guidelines, laws and requirements regularly change. what is surprising to realize is that some of the countries from which an hivpositive traveler could be deported if the traveler's hiv status were known, are countries that are common destinations for many business travelers today. imagine a security check that uncovers prescription hiv treatment medication in a country where there are entry restrictions? this is a difficult position for employers because of the privacy concerns of employees or travelers and their medical records, which are not typically the kinds of records or information that a person shares with employers. however, just as with prescription medications that people can travel with, employers need to provide appropriate training and information to travelers going to places where hiv concerns may be an issue. while adding this kind of information on top of standard risk and policy disclosures may be an extensive and painfully large amount of information to read and understand prior to travel, employers have a duty to provide it, and travelers have a duty to understand it and act accordingly if one or more of any disclosed travel restrictions apply to them. in some of the more strict countries with legislation that allows deportation of hiv-positive travelers, deportation often doesn't apply to travelers connecting or in transit only. however, employers and travelers have to decide whether or not they want to take such a chance. some countries require medical exams for those who intend to stay longer than 30 days, and if hiv is discovered, doctors are required to report it to the government, and the law will be administered relative to the country in question. exploding the myths: pandemic influenza center for infectious disease research and policy (cidrap) 10-point framework for pandemic influenza business preparedness pandemic planning and your supply chain four-fifths of businesses foresee severe problems maintaining operations if significant h1n1 flu outbreak pandemic influenza planning: a guide for individuals and families at the time of this publishing, the following countries maintain strict regulations for travelers with restricted medications (see full list in the incb "yellow list measuring traveler wear and tear too much travel can burn many a road warrior out. the costs of this burnout are well known: lost productivity, increased safety risks, poor health, increased stress at work and home, unwillingness to travel, and, ultimately, increased attrition. top 12-those with scores above 60/100. the remaining 11 factors are either challenging to quantify (e.g., "eating healthily at destination") or require certain data that was not available at this time. several stress factors, such as flight delays, mishandled baggage, and traveling to a high-risk destination, require the usage of external data stress triggers for business travel is a leading publisher of flight information to travelers and businesses around the world sita (www.sita.aero) com) is an intelligence-driven provider of operational risk management solutions, working with more than 500 multinational corporations and government organizations 2. having adequate medical supplies available during and after evacuation transportation.3. an accessible method of handicap transport. 4. addressing any additional criteria needed to determine whether the disabled traveler should be transported or be sheltered in place. a. deciding who makes the call about whether it is safer to "stand by for assistance." 5. determining whether the transport destination is handicap accessible. 6. determining whether the transport destination has adequate food, shelter, and supplies for any special needs. 7. determining whether employers prepared to incur any additional costs relative to evacuating disabled travelers. a. determining whether adequate resources are available. b. identifying the risks or costs for lack of planning.the adoption of this convention is regarded as a milestone in the history of international drug control. the single convention codified all existing multilateral treaties on drug control and extended the existing control systems to include the cultivation of plants that were grown as the raw material of narcotic drugs. the principal objectives of the convention are to limit the possession, use, trade in, distribution, import, export, manufacture, and production of drugs exclusively to medical and scientific purposes and to address drug trafficking through international cooperation to deter and discourage drug traffickers. the convention also established the international narcotics control board, merging the permanent central board and the drug supervisory board. article 36, penal provisions of single convention on narcotic drugs, 1961, as amended by the 1972 protocol amending the single convention on narcotic drugs, 1961, provides:1. a. subject to its constitutional limitations, each party shall adopt such measures as will ensure that cultivation, production, manufacture, extraction, preparation, possession, offering, offering for sale, distribution, purchase, sale, delivery on any terms whatsoever, brokerage, dispatch, dispatch in transit, transport, importation and exportation of drugs contrary to the provisions of this convention, and any other action which in the opinion of such party may be contrary to the provisions of this convention, shall be punishable offences when committed intentionally, and that serious offences shall be liable to adequate punishment particularly by imprisonment or other penalties of deprivation of liberty. b. notwithstanding the preceding subparagraph, when abusers of drugs have committed such offences, the parties may provide, either as an alternative to conviction or punishment or in addition to conviction or punishment, that such abusers shall undergo measures of treatment, education, after-care, rehabilitation and social reintegration in conformity with paragraph 1 of article 38. unfortunately, people sometimes die while away from home on business. making arrangements to transport their remains across international borders can be complicated and expensive, as legislation and protocols vary greatly from country to country, as do suppliers who will provide such services. don't assume that your tmc will or can handle this for you. usually these situations are handled by medical emergency or insurance providers. the following items should be covered in repatriation of mortal remains insurance:• if passing takes place outside of a medical facility, adequate transportation (ambulance, airplane, or helicopter) equipped with proper storage and handling capabilities for the body during transport to the closest appropriate medical facility prior to international transport.• treatment costs incurred (including embalming).• legally approved container for shipment of the remains.• transportation costs for the deceased and an accompanying adult to the country of residence.• cremation if legally required (conditional).other coverage may be included for things such as hotel accommodations preor posttreatment prior to the passing of the insured, but coverage will vary widely between providers. under such stressful circumstances, it is very important for the insured's family to understand the claims process and coverage, such as will payment key: cord-022367-xpzx22qg authors: murphy, peter e. title: risk management date: 2009-11-16 journal: the business of resort management doi: 10.1016/b978-0-7506-6661-9.50014-0 sha: doc_id: 22367 cord_uid: xpzx22qg nan risk management has been placed at the end of this book in affirmation of its crucial and central role in resort management, and as a prime example of pulling together the external and internal elements of parts b and c. while some may think risk management is a recent phenomenon, a result of global warming and terrorism, it has been associated with resort management for a long time and in a variety of ways. in normal business, financial risk is a regular occurrence that should be recognized and managed like other factors of demand and supply. however, with the taking-in of guests comes an extra responsibility, known as 'duty of care', where management is obliged to protect their guests from harm to the best of their ability. on the demand side guests are often looking for excitement and the spectacular, which can put them at risk. those who seek excitement in adventure tourism, when they challenge themselves or look for an adrenalin rush, purposely place themselves at risk and it is up to resorts to ensure the real risk is minimalized by managing the situation. even those who have not come to a resort to exert or excite themselves regularly demand spectacular views and sunsets that often require building on risky sites and in nonconformist style. the sounds of the sea and uninterrupted tropical sunsets attract resorts to the water's edge in areas where hurricanes and cyclones occur with regularity. in the mountains, similar demands for spectacular views place buildings at crests or on steep slopes where local climatic conditions are at their extreme and avalanches can occur. on the supply side risk is present at the very start, requiring a correct interpretation of market research and feasibility studies over the 30-50year life span of many resort investments. risk is present in the location of many resorts on the 'edge of civilization', well removed from regular infrastructure and services that are the basis of quality service experiences. it is present in the operation of resorts where guests come to participate in challenging activities, regular sports or simply to unwind, a process that inevitably leads some of them to leave natural caution and common sense behind at home. it is not surprising that 'risk management is not just good for business, but is absolutely necessary in order for tourism and related organizations to remain competitive, to be sustainable, and to be responsible for their collective future' (cunliffe, 2006: 35) . resort management risk not only involves both demand and supply considerations, it can range in scale from minor yet important internal issues like a lack of staff in crucial situations and places to overwhelming natural disasters or human external interventions like terrorism or financial crises. whatever form it takes the element of risk is ever present for resort management and some type of management structure needs to be in place to minimize its impact on the business. if no event or business decision within resort management is risk free, a risk management framework needs to take on a statistical probability structure. tarlow (2006) has suggested a useful framework would be one that considers the probability of an event and its likely consequences. figure 11 .1 provides some examples, using tarlow's suggested framework, but it should be noted that the consequences will vary according to each incident's severity and relevance to the resort product offerings. food poisoning is a serious occurrence for a resort because it means one duty of care has failed, ruining the visit of some guests and possibly closing a restaurant; but in the overall scheme of things, it has a low probability of occurrence and low consequences in a well-run establishment. the consequences are generally limited to some temporary bad publicity, financial compensation, a revision of safety procedures and possibly new equipment. this level of risk is discussed under the heading of 'security' within this chapter. accidents are presented in the form of personal injury, where the probability of occurrence can be high when a resort is associated with adventure tourism or dangerous locations. duty of care is still a major consideration, but if a guest chooses to undertake a risky activity they are expected to assume some of that risk. under these circumstances resorts are expected to minimize the level of risk by preparing the site properly, instructing the guest where appropriate, and providing warning signs or professional help where warranted. this level of risk has been assigned a low consequences ranking in that it usually applies to individuals or small groups and through the implementation of 'risk management' these consequences can be minimized, but not eliminated. natural disasters have been a fact of life for the resort industry since its inception, with one of the earliest recorded disasters being the tarlow, 2006.) destruction of pompeii by the mount vesuvius volcano in ad79. natural disasters have high consequences because they cause severe damage and can destroy a resort or close it down for a long period. fortunately, their probability of occurrence is generally low. this form of risk is more difficult to anticipate so 'crisis management' is presented more as contingency planning, preparing for the worst in order to minimize its impact, especially on the loss of life. the weather had been classified as a high probability and consequence risk, because so many resorts are dependent on this feature yet it is something beyond their control. bad weather or even the threat of it can reduce visits and sales, but in this era of global warming the signs of severe weather stress are starting to have an impact. the increasing number of force 5 hurricanes is raising the insurance rates of all tropical resorts and not just those affected directly. the long-term drought in australia's alpine areas is creating poor snow seasons and raising questions about the ski industry's viability in these areas. such events do not have the sudden impact of a site-specific natural disaster, but they can have a major say on the long-term viability of a resort business. in this regard such risks are incorporated into the overall framework of 'sustainable management', where the evolving weather patterns are integrated into the long-term resource planning for a resort. at the basic level a resort's 'duty of care' requires it to ensure the safety of its guests within reasonable limits. possible threats to a guest's safety can arise from internal and external sources. internally, the design of facilities should include safety considerations along with their functional role, whether that involves a ski lift or a hotel balcony. staff should be trained to undertake their tasks safely, to keep an eye on guests and the general situation, and to note any external threats. these threats can include vandalism, theft or terrorism. the level of security will be determined by the perceived degree of threat in the local area, but some attention to this matter is necessary everywhere, for insurance and legal purposes alone. security of a resort involves three basic steps: 1. analyze and identify vulnerable areas/processes. resorts offer extensive and varied terrain with open and friendly access to welcome guests. they need to reduce the vulnerability of property and guests by identifying the weakest and most exposed elements of the property, and the riskiest regular activities of the guests. 2. establish security priorities. as figure 11 .1 indicates not all risks warrant equal attention because their probabilities of occurrence and levels of impact on the operation will vary. in terms of basic security a differentiation should be made between public areas and private accommodation which ensures the privacy and security of guest accommodation can be maintained. in the restaurants and food outlets the storing, cooking and presentation of food must be undertaken with respect to health and safety regulations. in the most popular recreational areas like swimming pools and play areas, there must be qualified supervision. in guest rooms there should be a smoke alarm and sprinkler system to protect guests and the resort investment. 3. organization of a security system. the combination of guest enjoyment and security often requires a delicate touch in a resort environment, so as not to spoil the vacation experience. this means security should be present, but as invisible as possible. in a casino resort the presence of occasional guards can be re-assuring, but most of the security surveillance is conducted by closed circuit television (cctv). in other resorts there may be patrols for the grounds, especially at night, alarms in sensitive areas and instructions to staff and guests about possible dangers. in-room security is aided by instructions via notices or local hotel channel on the television, and an in-room safe. when resorts are exclusive in terms of being up-market, providing extensive facilities and attracting wealthy guests they need to be particularly concerned with security because they can become a magnet for criminal activity and litigious activity. for example, the jalousie plantation resort and spa in the island of st lucia would offer a tempting target according to the description offered by pattullo (1996: a security system is only as good as its staff and cannot operate effectively in isolation from general staff and guests. resorts can either hire their own security staff or outsource the responsibility to a professional company. regardless of the approach used it must be integrated into the daily operations in such a way as to be effective yet undetected. 'management should view the cost of developing a security training program as an investment. a resort in which all employees are attuned to the safety and security concerns can create a safer environment for guests and employees and a more profitable operation in the long run' (gee, 1996: 415) . there are several aspects to security planning: in major resorts it is now common to hire a professional security company to provide coverage for key areas and assets. in addition to being skilled in their task the individuals selected for resorts need to be presentable and able to interact with guests. just like disney theme park street sweepers are trained to know about their theme park and emergency procedures, resort security will find themselves called upon for directions and advice by the guests. ■ staff training. even if a resort has a professional security arm it needs to include general staff in its security planning. they should be knowledgeable about basic procedures and able to advise guests. they should learn to keep their ears and eyes open for trouble. ■ records and reports. recording what happens is vital because it can help identify danger spots and become invaluable evidence for insurance and litigation purposes. there are several types of reporting mechanisms; daily activity report, general incident report, loss report, accident report, monthly statistical report. failure to fulfil the 'duty of care' responsibility may result in a security related liability law suit. in a suit alleging negligence, the plaintiff (the accuser) must show the defendant (the resort) failed to provide 'reasonable care' regarding 'foreseeable' acts or situations. judges often apportion blame for an accident. that is a certain percentage of the blame is seen as the responsibility of the operator and the remainder the responsibility of the guest. damages associated with negligence can be of two types: 1. compensatory damages: to compensate for loss of income, for pain and suffering. 2. punitive damages: to inflict punishment for outrageous conduct and to act as a lesson for others (setting precedence). examples of the legal consequences from insufficient attention paid to 'duty of care' abound, but in many cases involving private companies the cases are settled out-of-court with minimum publicity. to illustrate what can happen with regard to apportioned blame and the challenges in safeguarding tourists, the following two published accounts of australian cases are presented. the first involves a young man, who like many before him went to swim at a local waterhole in the murray river. he dived from a log in the waterhole and struck the riverbed, suffered permanent spinal injuries and sued the berrigan shire council and forestry commission of nsw for a$8 million in damages.'both defendants denied liability, but agreed that damages should be assessed at a$8.2 million' (gregory and hewitt, 2005: 6) . in the original judgement the presiding judge reduced the assessment by 32 per cent to take account of the plaintiff's share of responsibility, through contributory negligence. for the remaining a$5.6 million he ordered the council to pay 80 per cent and the commission 20 per cent. as often happens in such cases involving large sums this 2004 judgement was appealed. in 2005 a new judge upheld the decision but placed all the blame and financial responsibility on the council. in his summary the new judge said: council employees were aware of people diving from the log, and the changes to the riverbed that floods could cause. he said the council has means and opportunity to put up warning signs, and in the longer term, to remove the log. justice nettle said the council owed (the plaintiff) a specific duty (of care) to take reasonable steps to guard against the risk of harm resulting from the use of the log for diving. but he said the commission had a very different charter and purpose (responsible for managing the forest alongside the river), and arguably no actual knowledge of the use of the log (as a diving platform). (gregory and hewitt, 2005: 6) the second case involves a man who on a warm day in 1997 went to sydney's bondi beach for a swim and like a responsible australian risk management waded into the sea 'between the red-and-yellow "safe swimming" flags, (where) he dived under a foaming wave and collided with a sand bar' (feizkhah, 2002: 46) . by 2005, the plaintiff who is now a quadriplegic as a result of this incident, claimed: waverley council's life-guards should have put the flags in a different spot or installed warning signs. perhaps 'a fellow diving and a cross through it or some words saying "sand banks"'. last week a jury agreed, ordering the council to pay (the plaintiff) a$3.75 million. (feizkhah, 2002: 46) this judgement not only cost a local council a great deal of money, it sent shock waves through the industry because it meant standard procedures had failed to demonstrate sufficient 'duty of care' in the eyes of the law. the wider implication of this case and others like it has been an increase in claims for negligence and a rise in public liability insurance. feizkhah (2002: 46) reports: between 1998 and 2000, the number of public liability claims australiawide rose by 60% to 88 000: total payouts rose by 52% to a$724 million. most claims are settled out of court for less than a$20 000. but, 'there is a jackpot mentality, where people with minor injuries see reports of big payouts and see if they can get something too'. one of the most affected tourism activities in this regard has been adventure tourism, an activity closely associated with resorts whose owners, such as international chains and public companies, are often viewed as possessing deep pockets. claims in these activities and areas have been increasing over a long period and have been associated with rising public liability insurance costs to cover not just recorded claims; but to help cover the broader costs of global insurance increases. given its importance as a major attraction for many resorts and as a prime source of risk and insurance claims, adventure tourism deserves special attention. depending on the level of risk and size of insurance claims, it can vary from a general security issue to a risk management issue. as can be seen in table 11 .1 representing the insurance claims for a whole state, the number and amounts are relatively minor, although they can be crippling for small businesses with limited resources. when accidents and claims involve major incidents, with extensive pain and suffering, loss of the business of resort management income and possibly life there is a need for more extensive risk management and control as will be discussed in the next section. adventure tourism is a very general term and hence a very inclusive subset of tourism, including a large array of activities. the term implies excitement and a change from normal daily life by pursuing an activity in a different environment. adventure tourism can take many forms because three dimensions have been linked to its structure (page et al., 2005) . these dimensions involve the following characteristics, with an indication in the brackets of who is the major player: the amount of physical effort a person is prepared to put into the activity is a major feature of adventure tourism. in terms of an active situation the guest is an active participant who, with or without the help of a guide or instructor, is looking for excitement and an adrenalin rush. in a passive situation the guest is a spectator or observer, one who wishes to learn more about the world around them rather than about themselves and their personal limits. ■ hard-soft dimension (business). these are the categories applied by the industry and relate more to the degree of preparation and pampering the guest requires for the activity. a 'soft' activity is one where the guest is able to view the scenery or wildlife from a safe vantage point with low risk of injury. a 'hard' activity is more risky because the guest participates directly in the activity in order to obtain that adrenalin rush and requires more individual attention, before (preparation) and during (guidance) the activity. ■ high risk-low risk dimension (business-guest). this is where guest perception and business management create the preferred and real tourism experience. beedie (2003: 206) notes correctly that a paradox has been created, 'whereby the more detailed, planned and logistically smooth an adventure tourist itinerary becomes, the more removed the experience is from the notion of adventure'. this helps to explain why 'injury rates do not necessarily conform to the notion of perceived risk', with some soft activities having substantial injury and death rates while some hard activities have far fewer than commonly expected. in bringing the guest's desires and expectations together with the resort's prepared and staged offerings, adventure tourism has been seen as a natural business opportunity by some (cloutier, 2003) and a commodifiction of the human spirit by others (beedie, 2003) . regardless of which interpretation is correct, for resorts it provides a varied and profitable business mix (figure 11 .2). many of the references quoted in this section have extensive lists of activities cited as adventure tourism, but most shy away from classifying them because whatever groups are selected cannot be mutually exclusive given the three dimensional characteristics and the varying conditions under which they operate. for example, skiings' rating would be influenced by its location, whether it be in mountain areas with steep slopes and tricky runs or on the gentler beginner slopes attached to some resorts and urban centres. it would also depend on whether we are considering downhill or cross-country skiing, and of course on the skill and experience of the individual skier. when resorts present hard adventure tourism products they face the challenge of providing an exciting adrenalin provoking experience in the safest way possible. in many tropical resorts scuba diving is one of the key attractions, and although not physically demanding does require a reasonable level of health and fitness. wilks and davis (2000: 596) observe, however, that a review of 100 consecutive scuba diving deaths found 'that in 25% of the fatalities there was a pre-existing medical contraindication to scuba diving' and those people should not have risked a dive. in this respect most dive companies rely heavily on personal honesty when guests fill in preliminary medical questionnaires, and at times this trust is abused through bravado and peer pressure. at other times the bravado and peer pressure can be laid at the door of the adventure tourism company. this was one accusation and explanation offered in relation to the canyoning tragedy in switzerland that claimed 21 lives in 1999 (head, 1999: 3) . according to morgan and fluker (2000: 2) : clearly the risks associated with this incident were beyond the capabilities of participants. importantly, newspaper reports of the interlaken tragedy speculated that early warning signs of danger had been ignored by the activity's guides. expert opinions of experienced river guides were also reported. these reports expressed serious concerns that the interlaken river guides employed by the adventure company may have been under pressure to put profits before safety, this being compounded by their lack of knowledge of local conditions. the judge apparently agreed, stating the 'safety measures taken by the now defunct adventure world were totally inadequate -with no proper safety training for the employees' (bbc news, 2001) . something that should have been undertaken before hand, as part of a risk management process. risk management is a way in which to prepare for the security risk and crisis issues outlined above. it is becoming a significant aspect of resort risk management management given the adventurous nature of many of their activities, their exciting locations, the growing litigious nature of customers, and the growing threat of terrorism. risk management should incorporate the following, which involves considerable overlap with the previous security planning. the difference being that risk management is more comprehensive, including environmental concerns and financial considerations as well as human safety. the unique characteristic of adventure tourism, and those resorts offering that type of product, is that 'participants are deliberately seeking and/or accepting the chance of sustaining physical injury' (morgan and fluker, 2000: 4) . this means that for adventure clients perceived risk becomes an important part of the adventure experience, while for the commercial operator the actual and managed level of risk is the real risk as shown in figure 11 .2. when guests pay money for the specialized knowledge, skills and equipment of the commercial provider, 'they reduce their need for risk awareness and responsibility. this transfer of risk responsibility to an activity operator, arising from the tourist's financial consideration (contract), raises a number of legal and ethical issues' (morgan and fluker, 2000: 3) . the legal issues revolve around duty of care and individual responsibility, the ethical issues include the paradox that 'accidents can add to the allure of the adventure experience through providing a valid testimony of the risk' (morgan and fluker, 2000: 9) . risk management is a rational approach to deal with real risk. it is about managing risk rather than eliminating it because as we have seen some degree of perceived risk is inherent in adventure tourism and many resort locations. but 'it is important to grasp the concept that the level of risk management applied is relative to the tolerance of a specific business and its guests for risk, which can vary substantially from one operator to another' (cloutier, 2000: 96) . gee (1996: 437-440) has identified a general process, that can assist resorts in their management of risk for both adventure tourism and general operations which consists of four steps. risk is associated with all aspects of business, and like the adventure tourist that is part of the thrill for many entrepreneurs and business people. adventure tourism operations must be identified in terms of their real risk, and even when they are outsourced to separate organizations with their own liability insurance, their professionalism and record will still impact on a resort's reputation and business. asset risks involve the major investment in property and facilities that need to be protected. identifying areas of particular danger and hazard is an important first step, such as the buildup of under growth and leaf-litter in woodland areas; the presence of currents or steeply shelving beaches along the beach-front; the physical dangers associated with wastewater treatment plants and with electrical substations; and the ever present danger of fire when people are relaxed and having fun. income risks are a major concern for resorts, which have a high dependence on external conditions often beyond their immediate control. anderson (2006 anderson ( : 1290 in the introduction to her article on crisis management in the australian tourism industry lays out a catalogue of disasters that have befallen that country's tourism over the past 20 years: ■ 1989 -pilot's strike ■ 1991 -gulf war ■ 1997 -asian economic crisis ■ 2000 -dot com crash ■ 2001 -collapse of hih insurance company (which was the major public liability insurer in australia and with its demise there were major increases in insurance premiums for everyone). -world trade centre attacks -demise of ansett airlines (which had a 35 per cent market share of the domestic airline business at the time). ■ 2002 -bali bombings which killed 202 people ■ 2003 -iraq war -outbreak of severe acute respiratory syndrome (sars) as if this is not enough some countries could add the outbreak of foot and mouth disease, avian flu epidemics, further terrorists attacks and unreliable weather. although in australia and most countries tourism has recovered from such experiences, the industry has learned valuable lessons along the way. one has been to recognize the potential loss of business that can occur through interruption or damage, and to prepare for it through contingency planning and market diversification. legal liability risks are increasing as society becomes more litigious. resorts as businesses are responsible to their guests, employees and shareholders, all of whom are better educated regarding their rights and are more prepared and able to exercise those rights in court if need be. now liability insurance is a major cost factor that all businesses must consider, including resorts. loss of key personnel risks are often under-appreciated until such a situation occurs and the resort discovers how much a certain individual contributed to the business' overall attraction. a key person like a chef, an entertainer or instructor whose skills and special qualities are hard to replace can leave a big hole in a resort's reputation. these people should be identified and retained wherever possible, and if they are lost to illness or poaching then succession plans should be in place. to control the frequency and magnitude of losses due to risk it is essential to develop recording procedures and to create a repository of past records. detailed record keeping is a key to identifying where and when risks are occurring, and the staff who were or should be involved. if personal injury is involved it is particularly important to obtain independent witnesses to the incident, in case there are later legal or insurance claims. such data should be recorded in a central registry on a daily and weekly basis to be deposited in an appropriate computer database.this will provide important information regarding the safety record, or otherwise, of individual operations and the total resort. such data will prove useful when negotiating liability insurance or to demonstrate the resort's actual duty of care record. 3. risk reduction. business, like life, is never risk free so in designing and operating a resort one important emphasis is safety -for guests and staff. many of the common dangers like food, health and safety and fire are regulated and controlled by local by-laws or ordinances. however, such statutes often involve the 'minimum acceptable' precautions, so a resort may choose to follow the walt disney world lead and select higher standards. this will mean higher initial building costs, however it should reduce both the associated risks and annual insurance premiums. 'one of the most rewarding loss-control projects is training personnel to think in terms of accident and loss avoidance' according to gee (1996: 439) . this becomes particularly important in the operations phase and needs to be emphasized as part of the resort's duty of care. when accidents occur they become significant 'moments of truth' for the guests and if they are handled in an empathetic and professional manner many later difficulties can be avoided. most businesses, including resorts can absorb small and infrequent losses brought on by seasonal fluctuations or occasional accidents, but will need to transfer the risk of large business interruptions or liability claims to outside suppliers of such coverage, such as insurance companies or brokers. small losses and claims will still be a matter for management's discretion even when they have insurance coverage, due to the deduction or excess clause associated with their insurance premium. most personal injury and damage claims can be accommodated within these parameters and involve negotiation with the affected parties rather than court cases, but if it becomes a major contentious court case insurance providers will become involved. resort owners can also transfer risk to other parties via non-insurance responsibility. in terms of major recreation equipment, like ski lifts or spas, the supplier can be encouraged to guarantee the safety of its equipment if it is properly installed and operated. this often involves the supplier installing the equipment and certifying the operators. in terms of more hazardous adventure tourism activities the resort can sub-contract these activities to specialist operators who carry their own and independent insurance policies. cloutier (2000: 104-105) provides some insights into actual risk management, as seen through the eyes of will leverette, who offers simple guidelines based on the real experience of lawsuits and consultations with adventure tourism companies. according to leverette there are six basic rules to follow: 1. develop a means to prove that guests were adequately warned and informed. 2. any guarantee of safety made in a business' literature or marketing materials is an open invitation to be sued. 3. all field staff must have current training in basic first aid. 4. the business should develop a written emergency/evacuation plan for all areas and activities to be used. 5. one good witness statement will shut down a frivolous lawsuit faster, more cheaply and less painfully than will anything else. 6. the business must use a properly drafted liability-release form. (this author's emphases) such personal experiences are a guide as to how today's risk management is evolving into a legal discourse over duty of care, but when there is a major disruption to business through some form of disaster the emphasis changes from prevention to the rescue and recovery of crisis management. 'crisis management is an extension of risk management' according to the pacific asia travel association (pata, 2003: 3) . risk management can be viewed as management initiatives designed to minimize loss through poor decision-making; but it can also be viewed as an important proactive step in reducing the dangers of catastrophic business collapse due to crisis or disaster. the pata booklet presents a 'four r' step process to crisis management: 1. reduction -detecting early warning signs; 2. readiness -preparing plans and running exercises; 3. response -executing operational and communication plans in a crisis situation; 4. recovery -returning the organization to normal after a crisis; where risk management practices would dominate the first two steps. risk management procedures that help to identify safety and security weaknesses in an operation will not only help to minimize danger and loss, they will expose the weak points in case a crisis occurs. crisis in a literate sense represents a moment of acute danger or difficulty, which in terms of the tourism industry has been defined as: an unwanted, unusual situation for an organization, which, due to the seriousness of the event, demands an immediate entrepreneurial response. (glaesser, 2003: 8) this approach places the emphasis of crisis management on the response and recovery phases of a crisis and brings it into line with disaster planning which has its own four-stage process of: assessment-warningimpact-recovery (foster, 1980) . it is natural disasters which often trigger crisis within the tourism industry be they earthquakes (kyoto -1995) , volcanic eruptions (mount st helens -1980), forest fires (yellowstone national park -1988), tsunami (phuket -2004) or hurricanes (new orleans -2005) . one should not forget that human beings can and do create their own crises for tourism and the resort industry. wars, terrorism and political decisions can bring about dramatic declines in visitation due to the prospect of danger or the removal of access. king and berno (2002) provide a good example of this in their analysis of the impact of fiji's two coups in 1987 and 2000 on the local tourist trade, which is heavily resort oriented. they note that: like many other tropical island nations, fiji has long established procedures in place to deal with emergencies such as cyclones. this meant that the overall preparedness in 1987 was relatively good with provision to contact hotels across the country with advice on how to react (king and berno, 2002: 49) such an experience demonstrates strong synergistic links can exist between natural disaster and human crisis management. from past crisis experiences ritchie (2004) sets out a strategic framework for the planning and management of crises by public or private organizations. his model outlines three main stages in managing such incidents -prevention and planning, implementation, evaluation and feedback. ritchie's three strategic management stages, along with faulkner's earlier crisis stages and their ingredients, has been combined with more resort oriented issues and actions in table 11 .2. if the process is divided into the three phases of pre-, actual and post-crisis it is possible to determine a clear pattern of events and responsibilities for resorts. pre-crisis for most resorts will be some form of preparation for a future possible disaster. whether that be an 'inevitable' physical disaster like an earthquake in certain regions or a possible negative political change, such major 'unthinkable' events need to be considered and prepared for. the recommended and common approach at this phase is to develop contingency plans -plans for actions that will mitigate the disaster's effects. this involves recognizing the potential scale and frequency of the expected disaster, and planning accordingly. in terms of the guests, all staff must be trained in emergency procedures and have a role to fulfil. in most cases there will be an obvious overlap with regular security measures such as fire drills, but in terms of major disaster preparation additional factors will need to be considered and plans prepared. for human created crises the degree of notice may be shorter than for natural disasters but there will usually be a warning period of political unrest. in this case the experts will be political commentators and the global news services, and it will be up to owners and managers to keep abreast with their regional situations. more governments are becoming involved in this scanning process on behalf of their travelling citizens, and are offering travel advisories. for many resort destinations these advisories have both positive and negative features. on the positive side they provide up-to-date and comparable risk assessments for tourists; on the negative side they are susceptible to political influence and may not be as objective as one would hope; plus they paint the risk picture with broad strokes, so that relatively safe enclaves become included in the national summary. glaesser (2003: 131-132) provides an example of how one crisis, the bali bombing of 12 october 2002, produced various levels of advisory notice in europe, ranging from a low level general security advice to warnings against travel under any circumstances. during the actual crisis there is going to be chaos and confusion and it is the prepared and cool-headed who will prevail. hence the key management task at this stage is to have staff able to implement the contingency plan and to be empowered to show initiative when conditions do not exactly follow the predicted pattern of events. a major disaster or crisis is likely to affect more than one resort or destination, so collaboration with other tourism organizations and government agencies will be essential. hopefully in the imminent stage all or most guests would have been evacuated with the help of public agencies and industry partners to safer areas, but generally a skeleton staff of key personnel will be required to stay on site as long as possible to ensure the safety of assets. one of the biggest challenges during this period will be media relations, for in today's global village a disaster or crisis attracts the attention of the world and a media frenzy erupts. glaesser (2003: 223) in his discussion of communications policy with respect to a crisis states 'the principle (sic) task is to convey information with the aim of influencing and guiding consumer behaviour, opinions and expectations'. to achieve this he advocates the affected organization creates a quick understanding of the situation and a transparency in its preparation and response, to build the credibility of the business. he recommends (glaesser, 2003: 230-231) a communication process that follows the sequence of: 1. portray the dismay and responsibility of the organization. 2. describe decisions and measures introduced to cope with the crisis. 3. indicate, based on the current experience, what further measures will be introduced to avoid future repetitions. in the case of major disasters and crises resort destinations and businesses will need to collaborate with central and regional governments, for it is they alone who can mobilize the resources needed to handle major catastrophes.the evacuation of guests to other areas will require bus and truck transportation and possibly air evacuation. the chaos and confusion of a crisis provides the opportunity for crime and lawlessness, so governments will need to bolster regular police forces with federal police and possibly troops. in the case of the new orleans hurricane of 2005 such a government response was widely criticized for its slowness and inadequacy. since much of the world's resort business occurs in the developing world when a major disaster or crisis occurs the host communities often need international assistance. it is at such times that the international community has revealed its better nature, ignoring old differences to come to the aid of fellow humans suffering from the ravages of nature or the actions of a few. unfortunately, the generosity of individuals, charities and nations is not generally put to the best use. partly this is because many receiving nations have neither their own contingency plans for such disasters nor the organization and infrastructure to handle a major in-pouring of generosity; and partly because some of the recovering nations have been susceptible to pilfering and corruption, which results in funds and materials not reaching the designated destinations and sufferers. given the occurrence of irregularities and disappointments with various international aid programs, it is not surprising that their recovery period is often much longer and more difficult than many expect. the post-crisis phase occurs when the actual crisis has abated and is out of the international news headlines, and represents the business and community efforts to return to pre-crisis conditions. as many students of disaster/crisis management indicate this is not only the time to get back to business as quickly as possible, it is an opportunity to redevelop and learn from the mistakes of the past. an immediate concern is to take advantage of the media attention that will have placed the resort destination in the world headlines, by demonstrating that the crisis has passed and life is returning to normal. it is quite likely that the global public has been presented an inaccurate and exaggerated picture of local devastation, which needs to be remedied as quickly as possible. for example, when hurricane iwa struck the hawaiian island of kauai in november 1982 some international news media were reporting that part of the island had sunk and thousands of people had died, which was far from the truth, although the hurricane caused a lot of physical damage (murphy and bayley, 1989: 38) . such stories need to be refuted, and information about the undamaged areas and recovery put in their place wherever possible. when it comes to repairing the damage an opportunity is presented to upgrade a resort's infrastructure and facilities. there will always be improvements (real or imagined) that the consumer society has developed since the original building of a resort destination which can and should be integrated into the new resort. there will be lessons learned from the disaster or crisis that can be incorporated into the design of the new resort which will make it more disaster-proof in the future. one example of how a disaster can be turned into a positive for tourism occurred with the mount st helens eruption. prior to the eruption mount st helens was a relatively quite tourist attraction, appealing mostly to outdoor recreationists and offering mainly basic facilities. the publicity of the 1980 eruption, including dramatic television coverage, increased interest in the volcano to the extent that 'a national monument was created by setting off 110 000 acres from the existing national forest to commemorate the eruption . . . a new visitor center was opened in december 1986, with illustrations and other graphics that depict the events and the subsequent natural regeneration of the devastated areas' (murphy and bayley, 1989: 42) . this new visitor centre has good access to the local interstate freeway and now many more visitors are drawn to the area, incorporating a wider range of tourist types and market segments than before. as has been mentioned, life is a risk and as we modify the earth's environment we are creating new and uncharted conditions that will bring increased risk. signs that business conditions are changing come in various guises. nature seems to be going through a period of instability, with evidence of climate change beginning to take on more significance as scientific evidence points more to a global shift in weather patterns rather than normal climatic cycles. climate change is a serious and urgent issue. while climate change and climate modeling are subject to inherent uncertainties, it is clear that human activities have a powerful role in influencing the climate and the risks and scale of impacts in the future. all science implies a strong likelihood that, if emissions continue unabated, the world will experience a radical transformation of its climate. (stern, 2006: 17) even the conservative periodical the economist has come to the conclusion that 'the chances of serious consequences are high enough to make it worth spending the 'not exorbitant' sums needed to try to mitigate climate change' (the economist, 2006b: 5). resort tourism is particularly vulnerable to climatic change given that many resorts are located in high risk areas like mountains and tropical beaches, and it uses high levels of energy drawing in its guests and on-site water to keep them happy. war has been joined by global terrorism as a major disruption and deterrent to travel, with tourists seen as 'soft targets' bringing maximum exposure to the terrorist cause. an evercrowded world with over-stretched medical systems appears to be waiting for the next pandemic, with the recent outbreaks of sars (2003) and avian flu (2006) revealing a certain lack of control and openness in dealing with global health crises. under these circumstances one of the most direct business signs of change has been the dramatic increase in insurance premiums that everyone seems to have faced in this new millennium. increased liability insurance has put some single owner peripheral tourism operations out of business, regular security insurance as well as liability insurance has risen dramatically for resorts, and resort destinations in vulnerable locations are facing either dramatic increases in premiums or the loss of direct insurance. after a disastrous 2005, with insured losses of $55 billion in the us, of which $38 billion was caused by hurricane katrina,american insurers 'are cutting back their exposure in coastal areas . . . home owners who can get insurance coverage face sharply higher rates. some premiums have risen by as much as 200% . . . many residents cannot get private coverage at all. as a result, state -backed insurance plans, meant to provide coverage as a last resort, are being inundated' (the economist, 2006a: 74) . this is only the tip of the iceberg according to figures provided by winn and kirchgeorg (2005: 245) who quote table 11 .3 from the topics geo 2003 report, which shows 'the number of natural catastrophes rose nearly five fold (and) economic losses nearly 16 fold over the last five decades'. winn and kirchgeorg use such information to suggest business in general needs to rethink its strategic approach to the environment and the business of resort management sustainable development. they view past and present management interest in environmental management and sustainable development as an 'inside-out' approach, 'one in which the primary perspective is to look from the firm out at the external environment' (winn and kirchgeorg, 2005: 240) that includes ecological and social considerations. but given the dramatic external forces in nature, politics and health which are leading to new levels of uncertainty in the ecological and societal realms, they see the need for 'a radical departure from the inside-out perspective of environmental management and its more systems theory-informed cousin from sustainability management' to one where sustainability management should be 'expanded and complemented, and may even need to be substituted by conceptual frameworks fairly new to organization theories, such as "resilience management" or "discontinuity management"' (winn and kirchgeorg, 2005: 250) . this is because if we are facing significant shifts in environmental and political conditions, the balancing nature of sustainable development will no longer apply in an unstable world. rather, business will need to take on board the possibility or probability of structural shifts and the prospect of facing several global emergencies during their lifetime. 'since ecological global systems cannot be affected significantly by actors in the short-term (the inside-out approach), broader adaptive behaviors that secure the survivability of the economy and society become increasingly relevant. crisis management, risk management, and emergency responses need to be supplemented with long term management for survival' (winn and kirchgeorg, 2005: 252) . to put such thoughts into practice will require guidelines that incorporate all the knowledge that has been accumulated to date on risk and crisis management to be supplemented by a broader and more collaborative decade 1950 -1960 -1970 -1980 -1990 -last 10 1959 1969 1979 1989 1999 approach to business survival and sustainability. given the noted exposure of tourism to the environmental, political and medical forces that seem to be in flux, it is not surprising to find some are already thinking along these lines. santana (2003: 304) considers that if decision-makers acknowledge that in these complex and unpredictable times in which we live and operate, anything is possible, including a major crisis that may prove devastating to their organizations, management will be in the 'right frame of mind' to accept the contention that forms the basic foundation of crisis management; proper advanced planning. as santana points out, with the increasing impact of external forces on tourism operations, crisis should be looked upon as an evolving process in itself, one that develops its own logic and consequences, rather than be treated as an isolated event. 'it is the degree to which management heeds the warning signals and prepares the organization (that) will determine how well it responds to the impending crisis' (santana, 2003: 310) . likewise, hall et al. (2003: 2) note that tourism and destinations are 'deeply affected by the perceptions of security and the management of safety, security and risk'. they think the concept of security has broadened significantly since the end of the cold war, with a dominant single political enemy being replaced by terrorism, wars of independence, indigenous rights, and religious differences. 'security ideas now tend to stress more global and peoplecentered perspectives with greater emphasis on the multilateral frameworks of security management' (hall et al., 2003: 12) . one of the few at this point to provide practical guidelines for sustainable crisis management in tourism is de sausmarez (2004) . de sausmarez maintains that many future crises will require careful detection and collaborative efforts to minimize their impact, and she has outlined a six step approach to tackle such major external threats. we, as students of tourism, know tourism and resorts are important socio-economic functions for many people, communities and nations, but we cannot assume others give tourism the same degree of importance in the bigger picture and more comprehensive view of events, including crises. hence, the first step in the establishment of a national or regional crisis management policy is to determine and demonstrate the relative importance of the tourism and resort sectors. until this has been done, it is impossible to prepare any sound strategy for the response to a crisis. this was well illustrated by sharpley the business of resort management and craven (2001) who show that even though tourism contributes substantially more to the british economy than agriculture does, the british government's response to the foot and mouth crisis in 2001 was to slaughter rather than vaccinated animals and to close the countryside to visitors, moves which favoured the agricultural sector rather than the tourism sector and cost the taxpayer substantially more than was necessary. (de sausmarez, 2004: 4) it is only when tourism in general and the resort component in particular are shown to be significant local and regional socioeconomic activities that governments and planners will consider them seriously and integrate their needs into macro-crisis management planning. if resorts and tourism are to integrate crisis management with their sustainable development philosophy they will need to identify the anticipated areas of greatest risk. in the literature and this chapter the emphasis has been on natural disasters, which are essentially supply side characteristics as they change or eliminate the attractiveness of a destination. however, just as important are demand side characteristics such as international political relations affecting visa requirements, economic conditions affecting the ability to travel, world health and safety, and competition from other destinations and leisure activities. although none of these supply and demand risks will fall under the direct control of resort management, knowledge of their existence and development will be essential for future strategic planning, and should be used to lobby government. while it is important to scan the environment continuously it is important to be able to measure trends in a relevant and timely manner. the evidence of global warming is building momentum, but it is often sending out confusing and at times conflicting information, little of which has any bearing on a single location or site. managers and owners of resort properties need to know what this impending crisis means for them specifically. de sausmarez (2004: 7) maintains tour operators and travel agents, along with government agencies, are in a 'strong strategic position to monitor and assess changes in the tourism status quo as they have access to data on both supply and demand'. she notes that the world tourism organisation's (1999) recommendation after the asian financial crisis of 1997 was that destinations should develop three categories of indicators, to warn of impending crises. i. short-term indicators of up to three months, that include advance bookings from key markets, or an increase in the usual length of time needed to settle accounts. ii. medium-term indicators, with a lead time of 3-12 months such as that needed for tour operator allocations and take-up to be recorded. iii. long-term indicators, with a lead time of a year or more that include planned capacity developments, international currency valuations and trends in gdp, interest rates and inflation in key markets. to which sustainability crisis management would add a fourth category: iv. future indicators, with a lead time of 10-50 years which covers the life of most mortgages and leases and provides sufficient time to determine whether the current climatic experiences are long-term phenomena or cyclical aberrations. these indicators would subjectively convert the environmental, political, business and health trends into local and more useful indices. they would be subjective because it would depend on local knowledge to disaggregate the global information meaningfully, and that process would be influenced by the outlook of the assessor -be they an optimist or pessimist. the type of global crises that tourism may be facing will be sufficiently large scale and evolving that they will require collaboration to implement an effective management strategy. this means that responsibilities and coordination plans need to be drawn up at an early stage and should cover three essential areas: a speedy response, appropriate measures in terms of the local needs of impacted areas and communication and coordination between different levels of jurisdiction and different sectors. 5. the development of a crisis plan. the development of a national crisis management plan is itself an example of macro-level proactive crisis management (de sausmarez, 2004: 9) , and a considerable achievement in itself. such plans need to be flexible as we can expect a series of different crises in the future, with varying local and regional impacts within national jurisdictions. an important part of any large scale crisis management plan will be media relations, relying on the various forms of media to distribute the relevant information as quickly and effectively as possible and being transparent about the severity of the crisis and remedies being undertaken. in some countries there may already be plans in place to cope with anticipated natural crisis such as cyclones (fiji) or earthquakes (pacific north west of america) that can be extended to include other forms of possible crisis. such plans would need regular re-assessment by government departments and the private sector, but can build an invaluable data bank and procedural map. in an asian context de sausmarez (2004: 11) feels communication and inter-agency cooperation needs to overcome the perceptual association between a crisis and 'loss of face', as is claimed to have occurred with the sars outbreak in east asia in 2003. in terms of global warming and its associated crisis no single country or person is to blame, we all need to take joint responsibility. 6. the potential for regional cooperation. although de sausmarez focusses on the creation of national crisis management she recognizes that global issues like climate change require an even larger operational scale. no single country can be isolated from its neighbors, as 'was clearly illustrated by the decline in tourism to southeast asia following the bali bombings in october 2002' (de sausmarez, 2004: 12) . she points out that the combined effort of the association of southeast asian nations (asean) was able to effectively contain the sars epidemic through regional preventative action in 2003, and that success has been repeated with the later outbreak of avian flu in east asia. the six steps outlined by de sausmarez do not follow a natural linear sequence, but should be viewed more as a continuous dynamic process which has been divided up to permit closer examination and appreciation of its component parts. the whole process depends on continual learning and adjustment, so as to be responsive and flexible in the face of future crises. for resorts which have survived as a separate form of tourism since the early days it becomes imperative to embrace risk and crisis management as a central part of their business strategy. this chapter has discussed the growing importance of risk management to resorts as our business and natural environments have changed. although financial risk has been a constant within business it is only in recent times, with the rise of a litigious society and a less stable natural environment, that it has become a more general and important issue for management. its increased prominence in business and society now means resorts should make it a key feature of their strategic management, and possibly their central concern. risk management does make a logical central theme for resort management in that it provides a focussed context for its past, present and future directions. the past experiences and business literature (part a) provide a guide as to what management may expect today, and the general level of risk associated with most options. present management must consider both external factors (part b) and internal strategies (part c) to create the most viable and sustainable options for today's resorts. the future can be extrapolated from the present if global business conditions change slowly and in a familiar manner, as predicted in the forecast for a growing senior's market for resorts. but what if we are experiencing major changes to the physical well-being of our planet and in human behaviour to one another? the risk factors that we have calculated from the past and present may no longer work so well or even apply, and we will need to enlarge our risk management process to incorporate more fluid business and environmental situations (part d). the purpose of this chapter and book is to encourage the reader to think about the wonderful legacy that has been provided by resorts; how we should strive to ensure resorts continue to delight our senses and educate us about our planet and its various cultures; and how we can achieve this through appropriate business management, even in this era of global change. a risk management focus would not only assist with the general sustainability objectives of a resort business, it can help position resorts at the forefront of monitoring and adjusting to the predicted changes in our natural and human environments. the chapter and book closes with an examination of one recent global crisis, which had a direct impact on resorts throughout a large area of the world, and one resort which learned a great deal from one hurricane season. the indian ocean tsunami of 2004 illustrates how we can still be caught unawares by a natural disaster, how such disasters can become international in scale, and thanks to rising sea levels may have even more significance in the future. walt disney world resort received its first hurricane direct hit in more than 40 years in mid-august 2004, only to have it followed by three others in the space of six weeks. in the process it learned some invaluable lessons. the indian ocean tsunami, also known in some quarters as the boxing day tsunami, occurred on 26 december 26 2004.this tsunami was generated by an earthquake under the indian ocean near the west coast of the indonesian island of sumatra, and is estimated to have released the energy of 23 000 hiroshima-type atomic bombs. by the end of that day 'more than 150 000 people were dead or missing and millions more were homeless in 11 countries, making it perhaps the most destructive tsunami in history' (national geographic news, 2005: 1). these figures were subsequently revised upward, so that now the indian ocean tsunami is estimated to have 'left 216 000 people dead or missing' (guardian unlimited, 2006: 1) . if this terrible natural disaster is examined using the threefold strategic action template of table 11 .2 certain key crisis management lessons emerge. at the pre-crisis stage little formal preparation had been undertaken at either government or resort levels of responsibility. this is understandable because there had been little history of major tsunamis in the indian ocean, the last being associated with krakatoa's eruption in 1868, but unforgivable for tsunamis are still a risk in oceans with volcanic and tectonic activity. what was missing was both an early warning system of seismic buoys and a way to convey that information to potentially threatened areas, so they could instigate evacuation plans. while the 'pacific tsunami warning centre in hawaii had sent an alert to 26 countries, including thailand and indonesia, (it) struggled to reach the right people.television and radio alerts were not issued in thailand until 9 a.m. local time -nearly an hour after the waves had hit' (global security, 2006: 3) . in this case there had been no regional forecasting or risk analysis and there was no internationally coordinated contingency plan to deal with such a situation. the result was that even if a coastal resort had its own evacuation plan there was nothing to trigger it until the arrival of the first wave, and by then it was too late. the actual crisis stage was viewed by millions of us around the globe, as we were able to view tourists' video camera images of this spectacular and unusual sunday morning feature on our television screens. the world press immediately brought us these graphic images to go along with the rising death and damage statistics, so that once again the selective reporting of a natural disaster convinced many that the whole region had been devastated. this was particularly the case with phuket island, where the images of destruction at patong beach on the west coast were transformed to represent the whole island in the minds of many, even case studies though phuket is a large island with many separate resort enclaves scattered around its varied shoreline and many of them were untouched by the tragedy. this confirms the need for control over communications, to ensure reporting remains factual and in proportion, rather than sensational and exploitive. the post-crisis stage represents an opportunity to learn from the crisis and to rebuild. this is certainly the case with the indian ocean tsunami. the biggest weakness was the lack of information and warning, which prevented the implementation of effective contingency planning. this is now being addressed with the building of the indian ocean tsunami warning system in 2006.this system has been coordinated by the united nations' educational, scientific and cultural organization (unesco) and consists of 25 new seismographic stations, supplemented by three deep-ocean sensors to provide the required early warning. but this is just the start, for the information needs to get to the areas around the indian ocean that are likely to be affected and the people in those areas who need to know what actions to take. therefore, unesco is continuing to work on international coordination and with governments to provide grassroots preparedness (terra daily, 2006) . unesco is providing expertise to assist with the redevelopment of mangrove, sea grass and coral reef rehabilitation; it is strengthening disaster preparation for cultural and heritage sites and integrating this into its reconstruction processes; and it is teaching tsunami awareness in schools, training decision-makers and broadcasters and staging local practice drills. the recovery is well underway around much of the indian ocean. in phuket where the damage was highly localized, patong beach showed no outward sign of the tsunami by october 2005, when the author paid a visit. the local tourism industry and english newspaper reported that while business had been slow in the months immediately following the tsunami, things had started to pick up around june and 'we expect it will be 80 per cent to 90 per cent from new year (2006) to the end of march (high season)' (phuket gazette, 2005: 3c) . another example of crisis recovery is provided in the maldives. like all low-lying islands the maldives are particularly susceptible to this form of disaster; thousands of local inhabitants lost their homes and 82 were killed in the tragedy. however, only two tourists lost their lives and although most resorts were damaged their 'higher construction standards (meant they) withstood the waves much better than local housing did' (travel wire news, 2005: 2) . consequently, it did not take most resorts long to rebuild and re-open, but in the process local businesses and government wanted to be better prepared for the future. five months after the tsunami swept across these islands in the indian ocean, the tourism sector and government agencies are cooperating to ensure that low-lying resorts and the nation's airport are better equipped to handle any type of emergency. (travel wire news, 2005: 2) among the changes proposed are improving communications through the installation of satellite telephones on each island and a centralized emergency information command. new resort regulations will require evacuation plans and emergency supplies. a higher seawall around the airport and safeguards for electrical power supplies are also being considered. these and other accounts of the indian ocean tsunami indicate the challenges facing the resort sector with today's concerns over global warming and the negative impact of news coverage for such disasters. major tsunamis are fortunately rare events, but this case has demonstrated the need for some international warning system, so that regional and local contingency plans can be put into operation to minimize the impact. this will clearly require coordination at government levels and the will to maintain vigilance and training over long time periods between natural disaster events -something that will test human nature to the full. one also has to ask, if future tsunamis are associated with the rising sea levels of global warming will such improvements be enough? this is the type of question that some academics and researchers are asking us to consider, and should certainly be examined in terms of the sustainability and risk management of many resorts and their relevance in an era of possible climatic shifts. this case is based on an article by barbara higgins (2005) who was director of operations integration for walt disney world resort when four hurricanes impacted the resort's operations in 2004, providing an invaluable learning opportunity for them and other resort operations. walt disney world's hurricane plans, as part of its general emergency planning, had definite priorities and procedures. priorities included (higgins, 2005: 41) : ■ keep guests safe; ■ keep employees safe; ■ have a thoughtful plan for tie-down, ride-out and recovery; and ■ provide the ability to get our parks open and operating as soon as possible after the storm. the procedures were designed to account for varying hurricane strengths, and whether the hurricane involved a direct hit or a near miss in terms of its path across central florida. to prepare for this walt disney world has instituted a five-phase approach to its hurricane preparedness, with each phase being selected in consultation with the national hurricane centre and local authorities. reviewing hurricane plans and verifying contact numbers for employees. further review of plans and beginning of preparation for possible shutdown of long-lead-time operations. predetermined emergency supplies are delivered, the site is cleared of loose materials and where relevant lightweight equipment and buildings are anchored to the ground, and managers evaluate moving to next phase. guests and essential staff take shelter in hurricane-proofed buildings or begin evacuation. all activities closed down, with only essential ride-out crews remaining in designated shelters. despite these plans and the thoroughness of preparation the sequence of four very different hurricanes revealed some additional factors and priorities. one major lesson from that summer's hurricane experience is that no two hurricanes are alike, so a resort can only prepare for hurricanes in general and not the specific one(s) that come its way.'the first lesson we learned was that our rigorous plans were only guidelines that needed to be flexible enough to adjust to changes dictated by our circumstances' (higgins, 2005: 42) . the most important elements in the general emergency plans turned out to be: ■ maintaining guest and employee communication, letting them know about the impending storm and providing the relevant information regarding each phase's action plan; ■ operating the food service, with the provision of hot meals being the biggest priority; ■ offering in-resort entertainment to guests who were room-bound for many hours; ■ preparing guests for confinement in their rooms over long periods, which is not what they came to the resort to do; ■ arranging for the ability to use news media to give (information on park closures and re-openings) and to get (weather details and various local government announcements regarding schools, police and emergency services). one 'important lesson to be learned in the face of a crisis is to show compassion for your employees and the toll the situation has had upon them, their families and their loved ones' (higgins, 2005: 45) . it is important to release unessential staff from their duties as soon as possible so they can attend to the safety of their family and homes as the hurricane approaches. likewise, in the aftermath it is likely some employees will require shelter and hot meals due to the hurricane damage. 'one lesson many floridians learned in the wake of these storms was the high deductible (excess) associated with hurricane insurance claims . . . (as a consequence) we anticipate providing more than $8 million to as many as ninety-five hundred employees who desperately need the funds to recover from the damage to their homes' (higgins, 2005: 45) . thus, in the end we have a reaffirmation that the business of resort management is 'to think globally but act locally'. although the driver is business and financial concerns, there needs to be an appreciation of the importance of the local environment and community to the long-term success of a resort. furthermore, if resorts are to continue to survive by adjusting to changing social and technical circumstances, they will need to become more proactive with regard to the current climate and cultural changes that face us all. crisis management in the australian tourism industry: preparedness, personnel and postscript six guilty in swiss canyoning trial adventure tourism legal liability and risk management in adventure tourism the business of adventure tourism risk management for tourism: origins and needs crisis management for the tourism sector: issues in policy development towards a framework for tourism disaster management disaster planning: the preservation of life and property resort development and management the business of resort management glaesser asian tsunami/tiger waves dive quadriplegic keeps his millions, plans to buy a house. the age asian nations stage tsunami drill security and tourism: towards a new understanding profit drive blamed for swiss canyon tragedy the storms of summer: lessons learned in the aftermath of the hurricanes of '04 tourism and civil disturbances: an evaluation of recovery strategies in fiji accidents in the adventure tourism industry: causes consequences and crisis management topics geo -annual review, national catastrophes tourism and disaster planning the deadliest tsunami in history tourist safety in new zealand and scotland crisis: it won't happen to last resorts: the cost of tourism in the caribbean chaos, crises and disasters: a strategic approach to crisis management in the tourism industry crisis management and tourism: beyond the rhetoric the 2001 foot and mouth crises -rural economy and tourism policy implications: a comment stern review on the economics of climate change. london: h.m. treasury.www.hmtreasury.gov.uk/independent_reviews/stern_review_ economics_climate disaster management: exploring ways to mitigate disasters before they occur indian ocean tsunami warning system up and running the price of sunshine: hurricanes and insurance. the economist the heat is on: a survey of climate change maldives takes steps to improve crisis response risk management for scuba diving operators on australia's great barrier reef the siesta is over: a rude awakening from sustainability myopia impacts of the financial crisis on asia's tourism sector. madrid: world tourism organisation key: cord-016405-86kghmzf authors: lai, allen yu-hung; tan, seck l. title: impact of disasters and disaster risk management in singapore: a case study of singapore’s experience in fighting the sars epidemic date: 2014-06-13 journal: resilience and recovery in asian disasters doi: 10.1007/978-4-431-55022-8_15 sha: doc_id: 16405 cord_uid: 86kghmzf singapore is vulnerable to both natural and man-made disasters alongside its remarkable economic growth. one of the most significant disasters in recent history was the severe acute respiratory syndrome (sars) epidemic in 2003. the sars outbreak was eventually contained through a series of risk mitigating measures introduced by the singapore government. this would not be possible without the engagement and responsiveness of the general public. this chapter begins with a description of singapore’s historical disaster profiles, the policy and legal framework in the all-hazard management approach. we use a case study to highlight the disaster impacts and insights drawn from singapore’s risk management experience with specific references to the sars epidemic. the implications from the sars focus on four areas: staying vigilant at the community level, remaining flexible in a national command structure, the demand for surge capacity, and collaborative governance at regional level. this chapter concludes with a presence of the flexible command structure on both the way and the extent it was utilized. situated in southeast asia yet outside the pacific rim of fire, singapore is fortunate enough to have been spared from major natural disasters such as typhoons, floods, volcanic eruptions, and earthquakes. however, this does not imply that singapore is safe, or immune from being affected by disasters. singapore houses a population of 5.2 million, a ranking of the third highest population density in the world. about 80 % of singapore's population resides in high-rise buildings (asian disaster reduction center 2005) . a major disaster of any sort could inflict mass casualties and extensive destruction to properties in singapore. clearly, like its neighboring countries, singapore is also vulnerable to both natural and man-made disasters alongside its remarkable economic growth. the potential risks may result from its dense population, intricate transportation network, or a transnational communicable disease. moreover, singapore can be affected by the situations in surrounding countries. for example, flooding in thailand and vietnam may affect the price of rice sold in singapore. indeed, singapore in her short history of 47 years has experienced a small number of disasters. chief among these, the severe acute respiratory syndrome (sars) epidemic in 2003 was the most devastating. the sars outbreak brought about far-reaching public health and economic consequences for the country as a whole. fortunately, the outbreak was eventually contained through a series of risk mitigating measures introduced by the singapore government and the responsiveness of all singaporeans. it is important to point out that these risk mitigating measures, along with the public's compliance, were swiftly adjusted to address the volatile conditions-such as when more epidemiological cases were uncovered. in this chapter, we introduce singapore's all-hazard management framework as well as the insights drawn from singapore's risk management experience with specific references to the sars epidemic. to achieve our research objective, we utilized a triangulation strategy of various research methodologies. to understand the principles and practices of singapore's approach to disaster risk management, we carry out an historical analysis of official documents obtained from the relevant singapore government agencies as well as international organizations, literature reviews, quantitative analysis of economic impacts, qualitative interviews with key informants (e.g. public health professionals and decision-makers), and email communications with frontline managers from the public sector (e.g. the singapore civil defense force, the communicable disease centre) and non-governmental organizations. the authors also employed the 'cultural insider' approach by participating in epidemic control procedures against sars. 1 in particular, we use the method of case study to illuminate singapore's approach to disaster risk management. the rationale of doing a case study of sars along with singapore's all-hazard approach is that the case study can best showcase the contextual differences, those being political, economic, and social. this case study aims to highlight the lessons drawn from past experiences in a specific context and timeframe, through which we are able to focus more on the nature of the risks, and the processes and the impacts of the disaster risk management and policy intervention. we also examined relevant literature on risk mitigating measures against communicable diseases in order to establish our conclusions. we evaluated oral accounts provided by key health policy decision-makers and experts for valuable insights. this chapter offers empirical evidence on the role of the whole-of-government approach to risk mitigation of the sars epidemic. applying the approach to a case study, our research enriches the vocabulary of risk management, adding to the body of knowledge on disaster management specific to the region of southeast asia. indeed, the dominant perspective in this field holds that the state must be able to exercise brute force and impose its will on the population (lai and tan 2012) . however, as shown in our paper, this dominant perspective is incomplete as the exercise of authority and power from the government is not necessarily sufficient to contain the transmission of transnational communicable diseases. success in fighting epidemics, as most would agree, is also contingent on a concerted effort of partnership between governmental authorities and the population at large. as discussed in the first section of this volume, community and family ties along with government responses can mitigate disasters. this chapter has four main sections. following this introduction, we provide an overview of singapore's historical disaster profiles. second, we introduce the policy and legal framework, and budgetary allocations for risk mitigation in singapore. third, we detail a case study of singapore's experience in fighting sars, as well as the impact of sars on singapore in its economic, healthcare, and psychosocial aspects. in the fourth section, we discuss the implications for practice and future research in disaster risk management, followed by conclusions. singapore has experienced a small number of disasters since it was founded in 1965. in this section, we briefly provide an historical account of singapore's disaster risk profiles including earthquakes, floods, epidemics, civil emergencies, and haze. singapore has a low risk of earthquakes and tsunamis. geographically, singapore is located in a low seismic-hazard region. however, the high-rise buildings that are built on soft-soil in singapore are still vulnerable to earthquakes from far afield (asian disaster reduction center 2005) . this is because singapore is at a distance (nearest) of 600 km from the sumatran subduction zone and 400 km away from the sumatra fault both of which have the potential of generating large magnitude earthquakes. this geographic vicinity may produce a resonance like situation within high-rise buildings on soft-soil. recent tremors from the september 2009 sumatra offshore earthquake were experienced in 234 buildings located mainly in the central, northern and western parts of singapore. on the front of potential tsunamis, singapore has developed a national tsunami response plan which is a multiagency government effort comprising of an early warning system, tsunami mitigation and emergency response plans, and public education. though singapore does not suffer from flood disasters due to the continuous drainage improvement works by the local authorities, the country has a risk of local flooding in some low-lying parts. the floods take place due to heavy rainfall that aggregates over short periods of time. the worst floods in singapore's history took place on 2 december 1978. the floods claimed seven lives, forced more than 1,000 people to be evacuated, and the total damages reached sgd10 million (tan 1978) . the swift and sudden floods in 1978 were caused by a combination of factors including torrential monsoon rains, drainage problems, and high incoming tides. over the following years, singapore saw a series of flash floods hit various parts of the city-state. for example, 2006 for example, -2007 southeast asian floods hit singapore on 18 december 2006 as a result of 366 mm rainfall in 24 h. from 2010 onwards, singapore has experienced a series of flash floods due to the higher-than-average rainfall. one severe episode occurred on16 june 2010 that flooded shopping malls and basement car parks in its most famous shopping area-orchard road. as per the reported historical disaster data from the cred international disaster database, singapore has suffered only two disaster events caused by epidemics. in 2000, singapore experienced its largest known outbreak of hand-foot-mouth disease (hfmd) which affected more than 3,000 young children, causing three deaths. later in 2003, sars hit singapore and it was singapore's most devastating disaster to date. the sars virus infected around 8,500 people worldwide and caused around 800 deaths. in singapore, sars infected 238 people, 33 of whom died of this contagious communicable disease. in 2009, novel avian influenza h1n1 struck singapore, which affected 1,348 people with 18 deaths. civil emergencies are defined as sudden incidents involving the loss of lives or damage to property on a large scale. they include (1) civil incidents such as bomb explosions, aircraft hijacks, terrorist hostage-taking, chemical, biological, radiological and explosive (cbre) agents and the release of radioactive materials by warships, and (2) civil emergencies, for example major fires, structural collapses, air crashes outside the airport boundary, and hazardous material incidents. in singapore, the singapore civil defense force (scdf) is responsible for civil emergencies. since 1965, singapore has experienced several episodes of civil emergencies. for example, the greek tanker spyros explosion at the jurong shipyard in 1978 was singapore's worst industrial disaster in terms of lives lost (ministry of labor, singapore 1979) . in 1986, the six-storey hotel new world collapse was singapore's deadliest civil disaster claiming 33 lives. the collapse was due to structural faults. the scdf, together with other rescue forces, spent 7 days on the whole relief operation. after the collapse, the government introduced more stringent regulations on construction building codes, and the scdf went through a series of upgrades in training and equipment (goh 2004 ). singapore experienced its first haze in the period of the end of august to the first week of november 1997 as a result of prevailing winds. the haze in 1997, called the southeast asian haze, was caused by slash and burn techniques adopted by farmers in indonesia. the smoke haze carried particulate matter that caused an increase of acute health effects including increased hospital visits due to respiratory distress such as asthma, pulmonary infection, as well as eye and skin irritation. the haze also severely affected visibility in addition to increasing health problems. as a result, singapore's health surveillance showed a 30 % increase in outpatient attendance for haze-related conditions (emmanuel 2000) . apart from healthcare costs, other costs associated with the haze included short-term tourism and production losses. a study by environmental economists of the 1997 southeast asian haze indicated a total of usd$74.1 million in economic losses in singapore alone. singapore is actively involved in various regional meetings to deal with transboundary smoke haze pollution in order to reduce the risk (singapore institute of international affairs 2006). the singapore government adopts a cross-ministerial policy framework-a wholeof-government integrated risk management (wog-irm), for disaster risk mitigation and disaster management (asia pacific economic cooperation 2011). this is a framework that aims to improve the risk awareness of all government agencies and the public, and helps to identify the full range of risks systematically. in addition, the framework identifies cross-agency risks that may have fallen through gaps in the system. this framework also includes medical response systems during emergencies, mass casualty management, risk reduction legislation for fire safety and hazardous materials, police operations, information and media management during crises and public-private partnerships in emergency preparedness. the wog-irm policy frame work in singapore functions in peacetime and in times of crisis. it refers to an approach that all relevant agencies work together in an established framework, with seamless communication and coordination to manage the risk (pereira 2008) . in peacetime, the home team comprises of four core agencies at central government level. these four agencies are the strategic planning office, the home front crisis ministerial committee (hcmc), the national security coordination secretariat, and the ministry of finance at the policy layer. among them, the strategic planning office provides oversight and guidance as the main platform to steer and review the overall progress of the wog-irm framework. during peacetime, the strategic planning office convenes meetings quarterly for the permanent secretaries from the various ministries across government. in a crisis, the home front crisis management system provides a "ministerial committee" responsible for all crisis situations in singapore. in the wog-irm structure, the hcmc is led by the ministry of home affairs (mha). in peacetime, mha is the principal policy-making governmental body for safety and security in singapore. in the event of a national disaster, the mha leads at the strategic level of incident management. the incident management system in singapore is known as the home front crisis management system (hcms). under the hcms, the scdf is appointed as the incident manager, taking charge of managing the consequences of disasters and civil emergencies. reporting to the hcmc is an executive group known as the home front crisis executive group (hceg), which is chaired by the permanent secretary for mha. the hceg is in charge of planning and managing all types of disasters in singapore. within the operation allayer, there are various functional inter-agency crisis management groups with specific responsibilities, integrated by the various governmental crisis-management units. at the tactical layer, there are the crisis and incident managers who supervise service delivery and coordination. the singapore government holds relevant ministries accountable in accordance to the nature and scope of the disaster. among those ministries and government agencies, the scdf is the major player in risk mitigation and management for civil emergencies. now, let us look into the scdf in more detail. for civil security and civil incidents, the singapore civil defense force (scdf) 2 is singapore's leading operational authority-the incident manager for the management of civil emergencies. the scdf is responsible for leading and coordinating the multi-agency response under the home front crisis management committee. the scdf operates a three-tier command structure, with headquarters (hq) scdf at the apex commanding four land divisions. these divisions are supported by a network of fire stations and fire posts strategically located around the island. the scdf also serves the following pivotal functions. the scdf provides effective 24-h fire fighting, rescue and emergency ambulance services. the scdf developed the operations civil emergency (ops ce) plan-a national contingency plan. when ops ce is activated, the scdf is vested with the authority to direct all response forces under a unified command structure, thus enabling all required resources to be pooled. however, the wog-irm policy framework only came to existence when singapore encountered sars. the sars epidemic in 2003 was an institutional watershed for singapore's approach to risk mitigation and disaster management (pereira 2008) . prior to the sars epidemic, singapore's executive group 3 mainly focused on crises or disasters that were civil defense in nature. these emergencies were merely conceived to be well managed by a solitary incident manager, supported by other relevant agencies. a specific multi-sectoral governance structure was not considered necessary to handle the crisis. the sars epidemic challenged the prevailing home front crisis management structure as the epidemic transcended just managing civil defense incidents. the policymakers realized the necessity to adopt a comprehensive disaster management framework, an all-hazard approach that includes a mechanism for seamless integration at both the strategic and operational levels among various government agencies. to this end, singapore revamped its home front crisis management framework to produce the current inter-agency structure. the main legislation supporting emergency preparedness and disaster management activities in singapore are the civil defense act of 1986, the fire safety act of 1993, and the civil defense shelter act of 1997. the civil defense act provides the legal framework for, amongst other things, the declaration of a state of emergency and the mobilization and deployment of operationally-ready national service rescuers. provides the legal framework to impose fire safety requirements on commercial and industrial premises, as well as the involvement of the management and owners of such premises in emergency preparedness against fires; and the civil defense shelter act provides the legal framework for buildings to be provided with civil defense shelters for use by persons to take refuge during a state of emergency. to tackle disease outbreak, singapore had earlier promulgated the infectious disease act in 1977. this legislation is jointly administered by the moh and the national environment agency (nea). unlike most governments that make regular national budgetary provision for potential disaster relief and early recovery purposes, the government of singapore makes no annual budgetary allocations for disaster response because the risks of a disaster are low (global facility for disaster reduction and recovery 2011, p.24). however, the singapore government can swiftly activate the budgetary mechanisms or funding lines in the event of a disaster and ensure these lines are sufficiently resourced with adequate financial capacity. to illuminate singapore's approach to disaster management, we now use a case study of singapore's fight against sars to highlight policy learning and lessondrawing in a specific context and timeframe. this case study has three sections. we first introduce the epidemiology of sars in singapore. in the second section, we describe the impact caused by sars epidemics on singapore in the economic, healthcare, and psychosocial aspects. in the third section, we demonstrate singapore's risk mitigating management, and detail the government's risk mitigating measures to contain the epidemic. singapore is a small open economy. external shocks can result in high levels of volatility resonating across the domestic economy. these shocks in turn would bring about higher levels of risk and uncertainty in singapore. at the beginning of 2003, singapore's economic outlook was clouded by the iraq war and its impact on oil prices (attorney-general's chambers 2003). the unexpected outbreak of sars led to greater uncertainty in the singapore economy. singapore's financial markets were severely affected due to the loss of public confidence and reduced floor trading. the impact of sars on the stock market reflected in the straits times index (sti) (see fig. 15 .1). the market did not react well to the sars epidemic. in the first fortnight of the epidemic, the sti closed down 76 points. even though more cases were reported, the sti climbed progressively up 86 points over the next fortnight, eclipsing the earlier falls. this could be attributed to the strict measures which the singapore government introduced. the sti remained relatively stable over the immediate fortnight as new cases were reported. however, it started a downward plunge over the following fortnight as the number of cases peaked once more. the sti plunged 96 points. however, the resilience of the sti was shown when it climbed back up, surpassing the level reported at the beginning of the sars period. the volatility of the sti demonstrates the vulnerability of a small open economy from exogenous forces-in this case, the sars epidemic. sars was the one single activity which contributed to the volatility of singapore's gross domestic product (gdp) in 2003. the ministry of trade and industry (mti) revised the forecast for singapore's annual gdp growth down from 3 to 0.5 %. this forecast was later revised upwards to 2.5 %. there were a number of channels by which the sars epidemic affected the economy. the economic impacts will be discussed from the positions of demand and supply shocks. the main economic impact of the sars outbreak was on the demand side, as consumption and the demand for services declined (henderson 2003) . the economic consequence caused fear and anxiety among singaporeans and potential tourists to singapore. the hardest and most directly hit were the tourism, retail, hospitality and transportrelated industries, for example airline, cruise, hotel, restaurant, travel agent, retail and taxi services, and their auxiliary industries (see fig. 15 .3 and this had a direct impact on hotel occupancy rates, which declined sharply to 30 % in late april 2003. cancellation or postponement of tourism events increased by about 30-40 %. revenues of restaurants dropped by 50 % while revenues of the travel agents decreased by 70 %. sars had an uneven impact on various sectors of the economy. a four-tiered framework to assess the impact on the respective sectors showed that tier 1 industries, such as the tourism and travel-related industries were most severely hit. tier 1 industries account for 3.5 % of gdp. the tier 2 industries, such as restaurants, retail and land transport industries were significantly hit, which account for 7.5 % of gdp. the next two tiers were less directly affected by the sars outbreak. tier 3 industries include real estate and stock broking, which account for close to 19 % of gdp. the remaining 70 % of the domestic economy in tier 4 includes manufacturing, construction and communications. these industries were not directly impacted by the outbreak of sars. all in all, the estimated decline in gdp directly from sars was 1 %, equaling sgd875 million. singapore experienced a significant drop in tourist arrivals where visitors usually stay for up to 3 days and transit onto their next destination. the trend for visitor inflow is that visitor inflows fall sharply. this is especially true in the case of singapore, when visitor stays tend to be shorter and the high-end visitors stayed away. as a result, tourism and other related industries were nearly crippled due to a significant reduction in both leisure and business travel. visitors from around the world cancelled or postponed their trips to singapore, causing a drastic decrease of total expenditure from visitors. (see table 15 .2) plummeting visitor arrivals directly impacted hotel occupancy rates, which declined sharply to 30 % in late april (see table 15 .3). the hotel occupancy rate plummeted from 72 to 42 %, compared to the normal level of 70 % or above. the annual averages for hotel occupancy rates were 74.4 % in 2002, 67.3 % in 2003, and 80.6 % in 2004 . singapore's national carrier, singapore airlines (sia), faced a record-breaking low passenger capacity of 29 % in april and may 2003. sia cancelled approximately 30 % of its weekly schedules (henderson 2003) . sia laid off 414 employees, of which 129 were ground staff, as a consequence of a usd200 million loss in june 2003. the hospitality industry had to resort to cutting budgets, which led to a steep plunge in the number of employed in the service sector. out of a total of 12,100 made unemployed, hotels and restaurants went through the biggest cut, that being 5,800 employees. the breakdown of total job losses showed 47 % in the service sector, 28 % in construction, and 25 % in manufacturing. additionally, transactions in the retail sector were dropped by 50 %. the private property volume transactions for condominiums and private property price index are also good proxies on the impact of the economy from sars. based on quarterly figures between 2002 and 2004, the volume transactions dipped to a low in the first quarter of 2003. also, there was a corresponding decline in the price index. transactions recovered steadily by the third quarter boosted by confidence in market sentiments (see fig. 15.3) . the sti and private property price index seemed to display fairly similar trends, albeit with some observed lag. note also that there is a lagged effect of consumer's deferred purchases after the outbreak of sars in singapore. demand creates its own supply. therefore, a fall in demand of goods and services is likely to bring about a fall in the supply of such goods and services. also, the loss of consumer and business confidence would reduce the level of aggregate demand. these effects were observed as the manufacturing industry experienced supply chain disruptions as the singaporean economy and employment market continued to weaken. singapore was taken off the who's list of sars affected countries on 31st may 2003-one of the first countries to be removed from the list. with the "fear-factor" managed, normal daily activities slowly resumed. sars affected industries and sectors started to show signs of recovery towards the end of the second quarter in 2003. a more comprehensive analysis of the economic costs of sars will need to consider the direct impact on consumer spending and indirect repercussions of the shock on trade and investment (asian development bank outlook 2003). the economic costs from a global disease, such as sars, go beyond the immediate impacts incurred in the affected sectors of disease-inflicted countries. this is not just because the disease spreads quickly across countries through networks related to global travel, but also because any economic shocks to one country spread quickly to other countries through the increased trade and financial linkages associated with globalization. however, just calculating the number of cancelled tourist trips, the declines in retail trade, and some of the factors discussed earlier do not provide a complete picture of the impact of sars. this is because there are close linkages within economies, across sectors, and across economies in both international trade and international capital flows. thus, analyzing the tourism sector alone may not be sufficient in analyzing the overall financial impact of sars. sars inflicted a heavy toll on businesses and immediately impacted severely the viability of business. businesses lost employees for long periods of time due to factors such as illness, the need to care for family members and fear of infection at work, or retrenchment. as the workforce shrunk due to absenteeism, business operations, for example supply chain, flow of goods worldwide and provision of services, were all affected both locally and internationally. in terms of retrenchment, the job prospects of employees in affected companies appeared miserable. a survey performed during the sars period showed that the jobless rate increased more than 5.5 %, the highest for the last decade in singapore (ministry of manpower, singapore 2003) . in absolute numbers, overall employment diminished by 25,963 in the second quarter of 2003, the largest quarterly decline since the mid-1980s recession. unlike previous retrenchment that affected mainly blue-collar labor, sars also affected whitecollar employees too. the implementation of workplace sars control measures added to operational and administrative costs. for example, the policy of temperature taking was implemented at workplaces in the private sector. numerous private establishments installed thermal-scanners in their entrances from day one. however, such precautionary measures were necessary to contain the disease. this helped to restore business confidence and investment potential (a lower level of investments will lead to slower capital growth). but the reduction in an economy's capacity may linger on for a few quarters before it is restored to pre-sars levels. the loss of productive working days from quarantine, and implementation costs incurred to monitor movements of employees contributed to the reduction in the aggregate supply front. some of these economic effects may have worsened the public health situation if strategic planning was not in place. sars reduced levels of service and care in singapore's healthcare system as the system mobilized its medical resources to deal with the sars epidemic. the influx of influenza patients to hospitals and clinics crowded out many other patients with less urgent medical problems for treatment. this particularly affected those seeking elective operations that had to be postponed until the epidemic ended in singapore. sars also severely impacted singapore's healthcare manpower. during the peak of sars from mid-march 2003 to early april 2003, there was a shortage of medical and nursing professionals because (1) the demand for care of influenza patients substantially increased, and (2) the supply of healthcare manpower decreased as some were also affected by the epidemic. like other business sectors, hospitals, clinics and other public health providers also faced a high staff-absenteeism rate and encountered difficulties in maintaining normal operations. this resulted in a further reduction in the level of service capacity. psychosocial impact from sars was mainly caused by limited medical knowledge of sars when it began its insidious spread in singapore. such uncertainty of contracting a highly contagious disease actually deteriorated the fear of security breaches, and the panic of overexposure (tan 2006) . responding to the uncertainty of disease transmission, the singapore government instituted many draconian public policies, such as social distancing, quarantine and isolation, as risk mitigating measures. all of these control measures created an instinctive withdrawal from society for the general population. this brought about a behavior which resulted in the public avoiding crowds and public places with human interaction. on 24 march 2003, the moh invoked the infectious disease act (ida) to isolate all those who had been exposed to sars patients. after ida was invoked, on 25 march 2003, schools and non-essential public places were closed. public events were cancelled to prevent close contact in crowds. singaporeans with contact history were asked to stay home for a period of time to prevent transmission. harsh penalties, such as hefty fines of more than usd4,000 or imprisonment, were imposed on those who defied quarantine orders. in a drastic move reminiscent of a police state, closedcircuit cameras were installed in the houses of those ordered to stay home to monitor their compliance with the quarantine order (abc news online 2003). at the height of sars, 12,194 suspected cases were ordered to stay home, all of whom were monitored either by cameras or in less severe cases, by telephone calls. quarantine, regardless of its effectiveness, received strong criticism from the general public during the outbreak of sars due to the invasive nature of that measure (duncanson 2003) . impact of social distancing remains unclear, but who has recommended such control measures depending on the severity of the epidemic, risk groups affected and epidemiology of transmission (world health organization 2005). singapore's moh advocated the practice of social distancing during the outbreak of sars. the sole intention of social distancing was to limit physical interactions and close contact in public areas to slow the rate of disease transmission. additionally, social distancing measures in particular have a psychological impact. the practice of social distancing led to a social setback in businesses that suffered economic losses as a result (duncanson 2003) . the psychological impact of sars is longer lasting. the most immediate and tragic impact was the loss of loved ones. in this section, we detail singapore's command structure, legal framework in fighting sars, as well as risk mitigating measures in economic, healthcare, and psychosocial perspectives. one of the most important lessons the singapore government learned from the sars epidemic was the crucial role played by the bureaucracy in disaster management. the bureaucratic structure in place then was severely inadequate in terms of handling a situation that was both fluid and unprecedented; indeed, fighting sars required more than a medical approach because resources had to be drawn from agencies other than the moh. accordingly, a three-tiered national control structure was created in response to sars-these tiers were individually represented by the inter-ministerial committee (imc), the core executive group (ceg) and the inter-ministry sars operations committee (imoc) (tay and mui 2004) . the nine-member imc was chaired by the minister of home affairs (mha) and it fulfilled three major functions: (1) to develop strategic decisions, (2) to approve these major decisions, and (3) to implement control measures. 4 notably, the imc also played the role of an interagency coordinator overseeing the activities of other ministries and their subsidiaries. on 7 april 2003 (5 weeks after the first case of sars was reported), the ceg and a ministerial committee was formed. the ceg was chaired by the permanent secretary of home affairs and consisted of elements from three other ministries: the moh, the ministry of defense (mod) and the ministry of foreign affairs (mfa). in particular, the role of the ceg was to manage the sars epidemic by directing valuable resources to key areas. the imoc, meanwhile, was seminal in carrying out health control measures issued by the imc (see fig. 15 .4 below). the moh, at the operational layer, formed an operations group responsible for the planning and coordination of health services, and operation in peacetime. during sars, it commanded and controlled all medical resources and served as the main operational linkage between the moh and all the healthcare providers. on 15 march 2003, when the epidemiological nature of sars was still unclear, the moh initiated a sars taskforce to look into the mysterious strain. only 2 days later, after more sars cases were reported and a better epidemiological understanding of the strain was developed, the singapore government swiftly declared sars a notifiable disease under the infectious disease act (ida) (ministry of health, singapore 2003a) . in the case of a broad outbreak, ida made it legally permissible to enforce mandatory health examination and treatment, exchange of medical information and cooperation between healthcare providers and the moh, and the quarantine and isolation of sars patients (infectious disease act 2003). in particular, the government amended the ida on 24 april 2003 requiring all those who had come into contact with sars patients to remain indoors or report immediately to designated medical institutions for quarantine (ministry of health, singapore 2003b) . asa legacy of singapore's british colonial past, the singapore legislature is unique and well-known for passing laws in a swift and efficient manner. the uniqueness in singapore's legal framework allows singapore to tan (2006) swiftly amend the ida during health crises to suit volatile conditions, for instance when more epidemiological cases were uncovered and the virus was better understood. all in all, the ida played an adaptive role in terms of facilitating a swift response to the outbreak of this particular epidemic. on 22 march 2003, the ceg designated the restructured public hospital-tan tock seng hospital (ttsh) as the sars hospital (james et al. 2006; tan 2006) . that is, once a suspected sars patient was detected at a local clinic or emergency department, he or she would then be transferred to ttsh immediately for further evaluation and monitoring. the national healthcare system prioritized life-saving resources such as medicine and medical equipment to allocate manpower and protective equipment to the ttsh. to ease the flu-like patient influx into the ttsh, the government diverted non-flu patients away from ttsh so that the sudden surge in the number of flu cases at ttsh did not paralyze its service delivery. the full impact of sars on the economy by and large depended on how quickly sars was contained, as well as the course of the sars outbreak in the region and beyond. to mitigate sars impact on singapore's economy, the government took every precaution and spared no effort to contain the sars outbreak in singapore. two aspects of sars warranted government intervention to mitigate economic impact. first, the information that needs to be collected and disseminated to effectively assess sars displays the characteristics of public good. second, there are negative externalities related to contagious diseases in the sense that they affect third parties in market transactions. public good and negative externalities are typical areas where government action is needed (fan 2003) . there are three major factors which can explain why some economies are more vulnerable and susceptible to the effect of sars than others (asian development bank outlook 2003) . these factors are structural issues (e.g. shares of tourism in gdp and the composition of consumer spending), initial consumer sentiments, and government responses. as the research shows, the singapore government implemented a usd 132 million (sgd 231 million in 2003) sars relief package to reduce the costs for tourism operators and its auxiliary services. on the other hand, an economic relief package worth usd 131m (sgd 230m) was created to aid businesses hit by sars. 5 in addition, the government incurred usd$109m (sgd 192m) in direct operating expenditure related to sars, and committed another usd 60m (sgd105m) development expenditure of hospitals for additional isolation rooms and medical facilities to treat sars and other infectious diseases. the government's economic incentives worked when seeking cooperation of other healthcare providers (such as public hospitals and local clinics) so that they would absorb additional cases of non-flu illnesses. to help sars affected firms tide over the plight and minimize job losses, singapore's national wage council widely consulted the private sector, and recommended sars-struck companies adopt temporary cost-cutting measures to save jobs. 6 the measures adopted by the private sector included the implementation of a shorter working-week, temporary lay-offs and the arrangement for workers to take leave or undergo skills training and upgrading provided by the ministry of manpower and associated agencies. when these measures failed to preserve jobs, the last resort was temporary wage cuts. surveillance and reporting is critical in combating pandemics because it serves to provide early warning and even detection of impending outbreaks. the surveillance process involves looking out for possible virulent strains and disease patterns within a country's borders as well as at major border-crossings (jebara 2004; ansell et al. 2010; narain and bhatia 2010) . when sars first surfaced, the nature of this virus was largely unknown. as a consequence, health authorities worldwide were mostly unable to detect and monitor suspected cases. health authorities in singapore encountered this same problem. but with the aid of who technical advisors, singapore managed to establish in a timely manner identification and reporting procedures. furthermore, the moh also expanded the who's definitions for suspected cases of sars (to include any healthcare workers with fever and/or respiratory symptoms) in order to widen the surveillance net (goh et al. 2006) . as the pace of sars transmission quickened, the singapore parliament amended the ida on 25 april 2003 requiring all suspected sars cases to be reported to the moh within 24 h from the time of diagnosis. although these control measures were laudable, sars also exposed the weaknesses of singapore's fragmented epidemiological surveillance and reporting systems (goh et al. 2006) . as a major part of lesson-drawing in the post-sars era, a number of novel surveillance measures were introduced to integrate epidemiological data and to identify the emergence of a new virulent strain faster. one of the most notable was the establishment of an infectious disease alert and clinical database system to integrate critical clinical, laboratory and contact tracing information. today, the surveillance system has four major operational components that include community surveillance, laboratory surveillance, veterinary surveillance, external surveillance, and hospital surveillance. to limit the risk of transmission in healthcare institutions once the sars epidemic had broken out, the moh implemented a series of stringent infection-control measures that all healthcare workers (hcws) and visitors to hospitals visitors had to adhere to. the use of personal protective equipment (ppe) 7 was made compulsory. visitors to public hospitals were barred from those areas where transmission and contraction were most likely. the movements of hcws in public hospitals were also heavily proscribed. unfortunately, except for ttsh, these critical measures were not enforced in all healthcare sectors until 8 april 2003, and this oversight resulted in a number of intra-hospital infections (goh et al. 2006 ). in addition, the policy of restricting the movements of hcws and visitors to hospitals was taken further. more specifically, their movements between hospitals were now restricted. patient movement between hospitals, meanwhile, was strictly restricted to medical transfers. the number of visitors to hospitals was also limited and their particulars recorded during each visit. it is also important to point out that these somewhat draconian control measures required strong public support and cooperation. indeed, their implementation would not have been successful had these two elements been missing. public education and communication are two indispensable components in health crisis management (reynolds and seeger 2005; reddy et al. 2009 ). communication difficulties are prone to complicate the challenge, especially when there is no established, high-status organization that can act as a hub for information collation and dissemination. therefore, it is necessary to disseminate essential information to the targeted population in a transparent manner. during the sars outbreak, the moh practiced a high degree of transparency when it shared information with the public. indeed, the clear and distinct messages from the moh contributed significantly to lowering the risk of public panic. the moh worked closely with the media to provide regular, timely updates and health advisories. this information was communicated to the public through every possible medium. in addition to the media (e.g. tv and radio), information pamphlets were distributed to every household and the moh website provided constant updates and health advisories to the general public. notably, a government information channel dedicated to providing timely updates was created on the same day-13 march 2003-when the who issued a global alert. a dedicated tv channel called the sars channel was launched to broadcast information on the symptoms and transmission mechanisms of the virus (james et al. 2006) . the importance of social responsibility and personal hygiene was a frequent message heard throughout the sars epidemic. as an example, when tan tock seng hospital was designated as the sars hospital at the peak of sars epidemics, the government undertook many efforts in public communication and education to seek cooperation and support from other healthcare providers, such as public hospitals and local clinics, so that they would absorb the additional cases of non-flu illnesses. many organizations displayed prominent signs in front of their building entrances that reminded their staff as well as visitors to be socially responsible. school children were instructed to wash their hands and take their body temperature regularly. the public was told to wear masks and postpone non-essential travel to other countries. the moh advocated the practice of social distancing during the outbreak of sars. the sole intention of social distancing was of course to limit physical interactions and close contact in public areas thereby slowing the rate of transmission. as a result, all pre-school centers, after-school centers, primary and secondary schools, and junior colleges were closed from 27 march to 6 april 2003. school children who had stricken siblings were advised to stay home for at least 10 days. moreover, students who showed flu-like symptoms or had travelled to other affected countries were automatically granted a 7-day leave of absence and home-based learning program were instituted for those affected. extracurricular activities were also scaled down to minimize social contact. meanwhile, the moh also advised businesses to adopt social distancing measures such as allowing staff to work from home and using split-team arrangements. those who were most at higher risk of developing complications if stricken were moved and removed from frontline work to other areas where they were less likely to contract the virus. as mentioned earlier, the practice of social distancing also drew strong criticisms from those businesses that suffered economic losses as a result. apart from providing economic compensation, measures to mitigate psychosocial impacts are also important. the government's measures of public health control, as mentioned above, drew strong criticisms from businesses and the public during the outbreak of sars due to the invasive nature of those actions. besides these, the economic slowdown affected overall employment and personal income. some households required financial assistance. in response to the public complaints, authorities in singapore provided economic assistance to those individuals and businesses who had been affected by home quarantine orders through a "home quarantine order allowance scheme" (tay and mui 2004; teo et al. 2005) . at the same time, the moh worked together with various ministerial authorities to provide essential social services to those affected by the quarantine order. for example, housing was offered to those who were unable to stay in their own homes (because of the presence of family members) during their quarantine, ambulance services were freely provided by the singapore civil defense force to those undergoing quarantine at home to visit their doctors, as well as high-tech communication gadgets such as webcams, for those undergoing quarantine to stay in touch with relatives and friends. impacts on social welfare in large part relate to economic outlook, especially in the area of consumption patterns. all these risk mitigating measures were not only effective in containing the epidemic, but also valid for implications in disaster risk management. in this section, we draw on the lesson-learning from singapore's experience in fighting the sars epidemic, and discuss implications for future practice and research in disaster risk management. the implications are explained in four aspects: staying vigilant at the community level, remaining flexible in a national command structure, demand for surge capacity, and collaborative governance at regional level. it remains questionable that singapore's draconian health control measures may not be applicable or replicable in other countries, for example setting a camera to monitor the public's compliance during home quarantine. the evidence suggests that draconian government measures, such as quarantine and travel restrictions, are less effective than voluntary measures (such as good personal hygiene and voluntarily wearing of respiratory masks), especially over the long term. however, reminding the public to maintain a high level of vigilance and advocate individual social responsibility can be a persuasion tactic by an authority to influence and pressure, but not to force individuals or groups into complicity with a policy. therefore, promoting social responsibility is crucial in terms of slowing the pace of infection through good personal hygiene and respiratory etiquette in all settings. to achieve this goal, public education and risk communication are two indispensable components in health crisis management (reddy et al. 2009; reynolds and seeger 2005) . the community must be aware of the nature and scope of disasters. they have to be educated on the importance of emergency preparedness and involvement in exercises, training and physical preparations. at the community level, institutions and capacities are developed and strengthened which in turn systematically contribute to vigilance against potential risks. this is best illustrated in the singapore government's communication strategy to manage public fear and panic during the outbreak of sars (menon and goh 2005) . throughout the epidemic, the singapore government relentlessly raised the level of vigilance of personal hygiene and awareness of social responsibility. this, in large part, has to rely on public education and risk communication. to effectively disseminate the idea of vigilance across the public, political leaders were seen as doing and initiating a series of countermeasures to reassure the public. by showing the people that government leaders practiced what they preached, the examples served to naturalize and legitimize the public discourse of social responsibility for all singaporean citizens (lai 2010) . the need to stay vigilant is never overemphasized, but being vigilant does not equate to a panacea that ensures all government agencies work together. to be well prepared for the unexpected, we need a clear and swift national command structure that can flexibly respond to, and even more promptly than in the case of disease transmission, the changing situation. all local agencies responding to an emergency must work within a unified national command structure to coordinate multi-agency efforts in emergency response and management of disasters. on top of facilitating close inter-agency coordination, the strength of this flexible structure is in its ability to ensure a swift response to an epidemic outbreak by implementing risk mitigating measures more effectively and efficiently. structural flexibility involves swift deployment of forces to mitigate the incident at the tactical level, and to provide expert advice at the operational level, in order to minimize damage to lives and property. among other things, the flexibility endemic to this command structure facilitates the building of trust between the state and its people (lai 2009 ). this in turn ensures that government measures are quickly accepted by the general public. as shown in this chapter, the moh has been entrusted by the singapore government and pre-designated to be the incident manager for public health emergencies. when a sudden incident involves public health or the loss of lives on a large scale, the moh is responsible for planning, coordinating and implementing an assortment of disease control programs and activities. during the outbreak of sars, the singapore government established a national command and control structure that was able to adapt to rapidly changing circumstances that stemmed from the outbreak. specifically, the moh set up a taskforce within that ministry even when the definition of sars remained unclear. as more sars cases were uncovered and better epidemiological information became available, the government quickly created the inter-ministerial committee (imc) and core executive group (ceg)-both of which were instrumental in the design and implementation of all risk mitigating measures-to coordinate the operation to combat the outbreak (pereira 2008) . while this overarching governance structure is more or less standard worldwide ('t hart et al. 1993; laporte 2007) , the case of singapore is unique in that the city-state was able to overcome bureaucratic inertia and adapt this governance structure. from singapore's experiences during the sars crisis, we have learnt that the strength of a national command structure lies in its flexibility to link relevant ministries on the same platform. these linkages ensure a timely, coordinated response and service delivery. having a flexible structure was not the only reason behind the successful defeat of sars. in singapore's case, we also notice the success of containing an uncertain, high-impact disaster has to rely on surge capacity. in the context of this paper, surge capacity refers to the ability to mobilize resources (such as ppes, vaccines and hcws) to combat the outbreak of a pandemic. singapore's response to sars in 2003 illustrates the importance of being able to increase surge capacity swiftly to deal with an infectious disease outbreak. in the asia pacific region, this problem continues to hamper many countries' ability to combat infectious diseases (putthasri et al. 2009 ). for many public health organizations in asia, it is a matter of fact that they are unable to deal with pandemics because the resources to do so are simply absent (balkhy 2008; hanvoravongchai et al. 2010; lai 2012b; oshitani et al. 2008) . meanwhile, there are evidences which suggest that surge capacity alone is not the full answer. for example, during the sars outbreak, abundant resources contribute an important but not all-encompassing element in the fight against these pandemics. as it turned out, when different stakeholders brought to the task-at-hand their unique skill sets and resources, they actually complicated the fight due to their lack of synergy. in fact, abundant resources without synergy might even undermine collaborative efforts. therefore, it is essential that the ability to link up various stakeholders must be complemented by some type of synergy between them. such ability can be enhanced through close collaboration. this brings us to the third implication for disaster management: collaborative governance at regional level. the trans-boundary nature of the disasters calls for a planned and coordinated approach towards disaster response for efficient rescue and relief operations lai 2012a) . combating epidemics requires multiple states and government agencies to work together in close (webby and webster 2003) . therefore, it is clear that collaborative capacity of various stakeholders is central to the fight against transboundary communicable diseases (lai 2011; lai 2012b; leung and nicoll 2010; voo and capps 2010) . while member states that are of advanced economic development typically lead such efforts, the inclusion of other developing countries, non-traditional agencies, and organizations (including non-governmental ones) is necessary and ultimately, inevitable. indeed, major countermeasures such as border control and surveillance are often made possible with the aid of regional collaboration. take the association of southeast asian nations (asean) as an example. asean countries take regional, national and sub-national approaches to disaster risk management ). the asean committee on disaster risk management (acdm) was established in 2003 and tasked with the coordination and implementation of regional activities on disaster management. the committee has cooperated with united nations bodies such as the united nations international strategy for disaster reduction (unisdr) and the united nations office for the coordination of humanitarian affairs (unocha). the asean agreement on disaster management and emergency response (aadmer) provides a comprehensive regional framework to strengthen preventive, monitoring and mitigation measures to reduce disaster losses in the region. in recent years, singapore has been active in providing training and education for disaster managers from neighboring countries. singapore has an ongoing exchange program with a number of asia pacific nations and europe. for example, to partner with apec to increase emergency preparedness in the asia-pacific region, singapore's scdf provides shortterm courses on disaster management in the civil defense academy (asia pacific economic cooperation 2011). the world today is far more inter-connected than ever before. international travel, transnational trade, and cross-border migration have drastically increased as a consequence of globalization. no country is spared from being influenced directly or indirectly by disasters. singapore is no exception. singapore is vulnerable to both natural and man-made disasters alongside its remarkable economic growth. in response, the singapore government adopts an approach of whole-of-government integrated risk management, a concerted, coordinated effort based on a total national response. we have witnessed in the case study singapore's all-hazard management framework with specific references to the sars epidemic. in fighting sars, singapore's health authority was responsive enough to swing into action when they realized that the existing bureaucratic structure was inadequate in terms of facilitating close cooperation between various key government agencies to tackle the health crisis on hand. therefore, a command structure was swiftly established. the presence of a flexible command structure, the way and the extent it was utilized, explains how well an epidemic was successfully contained. flexibility actually enhanced organizational capacities by making organizations more efficient under certain conditions. epidemic control measures such as surveillance, social distancing, and quarantine require widespread support from the general public for them to be effective. singapore's experiences with sars strongly suggest that risk mitigating measures can be effective only when a range of partners and stakeholders (such as government ministries, non-profit organizations, and grass-roots communities) become adequately involved. this is also critical to disaster risk management. whether all of these aspects are transferrable elsewhere needs to be assessed in future research. nonetheless, this unique discipline certainly has helped singapore come out of public health crises on a regular basis. singapore's response to the outbreak of sars offers valuable insights into the kinds approaches needed to combat future pandemics, especially in southeast asia. singapore imposes quarantine to stop sars spreading. abc news managing transboundary crises: identifying the 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to coordinate emergency medical services and emergency department teams crisis and emergency risk communication as an integrative model collaboration in the fight against infectious diseases economic survey of singapore singapore's efforts in transboundary haze prevention singapore real estate, and property price annual report on tourism statistics annual report on tourism statistics annual report on tourism statistics singapore floods sars in singapore -key lessons from an epidemic an architecture for network centric operations in unconventional crisis: lessons learnt from singapore's sars experience. california: thesis of naval postgraduate school sars in singapore: surveillance strategies in a globalizing city influenza pandemic and the duties of healthcare professionals are we ready for pandemic influenza who guidelines on the use of vaccines and antivirals during influenza pandemics. geneva: word health organization acknowledgement the authors would like to thank the economic research institute for asean and east asia (eria) to initiate this meaningful research project, and four commentators-professor yasuyuki sawada (tokyo university), professor chan ngaiweng (university sains malaysia), dr. sothea oum (eria), mr. zhou yansheng (scdf) and all participants in eria's two workshops, for their insightful comments for an earlier draft of this chapter. key: cord-257467-b8o5ghvi authors: smith, barbara a. title: anesthesia as a risk for health care acquired infections date: 2010-12-31 journal: perioperative nursing clinics doi: 10.1016/j.cpen.2010.07.005 sha: doc_id: 257467 cord_uid: b8o5ghvi anesthesia is delivered in a variety of modalities including general, regional, or local. patients are most vulnerable when receiving anesthesia, as they must depend on the anesthesia team to provide this care without untoward effects. it is expected that patients will be protected from health care acquired infections (hais) by appropriate use of infection prevention measures. in addition, the anesthesia team may be at risk of hais because of their intimate contact with the patient's blood and respiratory system. adequate adherence to infection prevention methods should reduce the risk of occupation exposure and infection to the anesthesia team members. health care associated infections involving anesthesia have been transmitted from health care worker to patient, patient to patient, and patient to the anesthesia provider. this article further discusses the risks for hais apparent in intravascular cannulation, endotracheal intubation, and the development of surgical site infections, and examines occupational measures to prevent infections in the health care worker. regardless of the health care setting or the level of provider, the standard of care for infection prevention and managerial oversight of this care should remain the same. of provider, the standard of care for infection prevention and managerial oversight of this care should remain the same. the anesthesia team has direct and indirect responsibility for the prevention of infections, which may manifest most commonly as bloodstream infections, local injection site infections, abscesses, meningitis, respiratory tract infections, and surgical site infections (ssis). bacterial and viral infections may also be attributed to anesthetic care. because anesthesia care interrupts two of the body's significant defense mechanisms, there is the potential for risk of infection to the patient. first, the body's intact skin functions as a barrier to pathogenic organisms. however, intravascular cannulation for conscious sedation disrupts the skin integrity and permits a local or systemic infection to occur. these risks also apply to central venous vascular catheters inserted by the anesthesiologist, whether in the operating room or as part of a critical care team. insertion of a needle, cannula, or implantable device into the spinal column for anesthesia or analgesia disrupts the skin integrity and provides a direct portal of entry for organisms. second, surgery will often be performed with general anesthesia that involves the insertion of an endotracheal tube to maintain an open airway and permit artificial ventilation during the procedure. although endotracheal intubation during surgery is generally a controlled safe procedure, this artificial airway predisposes the body to exposure to respiratory pathogens whether from the health care provider, the environment, or equipment. the same risk arises when intubation is performed during an emergency situation such as cardiopulmonary resuscitation. measures to prevent this exposure, including the role of the environment and equipment, are discussed in this article. third, although not physically involved at the sterile operative field, the anesthesia team can have influence over the development of ssis by their collaboration with the surgical team in achieving normothermia, glycemic control, and appropriate antibiotic prophylaxis for the patient. 6 finally, the author examines occupational measures to prevent infections in the health care worker. access to the spinal column is used to provide regional anesthesia, for example with epidural anesthesia, or to deliver medication such as analgesics or steroids. other examples of procedures that enter the spinal column include diagnostic procedures such as lumbar puncture and myelography. the overall risk of infection from these procedures appears to be low. miller 7 cites a rate of less than 1 per 10,000 cases of serious infection (ie, meningitis or spinal abscess). he notes 2 factors that had a relation to infection: the duration of epidural anesthesia and the patient's medical conditions. in a review conducted through 2005, schulz-stü bner and colleagues 8 noted rates of 3.7 to 7.2 spinal abscesses per 100,000 cases and 0.2 to 83 epidural abscesses per 100,000 procedures. baer 9 lists 179 cases of postdural meningitis occurring after spinal or epidural anesthesia and other types of instrumentation. spinal or epidural anesthesia accounted for 65% of the cases ( table 1) . some investigators have argued that the true incidence is unknown because there is no uniform reporting mechanism in the united states. nonetheless, ruppen and colleagues 10 attempt to define the risk in obstetric epidural anesthesia and cite a rate of 1 deep epidural infection per 145,000 procedures; an admittedly low smith incidence. nonetheless, in an american society of anesthesiology newsletter, hughes 11 urges his obstetric colleagues that they can lower the risk to their patients. evidence of infection transmission is also documented in the descriptions of outbreaks. five women in two separate states (new york and ohio) developed bacterial meningitis after intrapartum anesthesia ( table 2) . 1 the article reveals that the causative organism was recovered from a nasal swab of one of the anesthesiologists linked to the 2 cases in ohio. in each outbreak, unmasked personnel (including the anesthesiologist delivering the spinal anesthesia in ohio) were present in the room during the procedures. eight cases of meningitis following myelography were reported by the centers for disease control and prevention (cdc) that appear related to contamination from mouth flora from the clinicians who performed the procedure. 12 as part of the investigation, the cdc eliminated equipment and fluids as a potential source for these infections, and confirmed that adequate aseptic technique had been followed. as described by baer, 9 the mechanism of infection in these cases occurs through: droplet transmission of aerosolized mouth organisms, contamination from skin bacteria or hematogenous or direct spread from an endogenous site of infection. regarding this first method of transmission, the likelihood is that some of these infections are related to the clinician who performed the procedure. this assumption is supported by arguments that several cases were related to clusters among specific operators, or were linked by dna testing of nasal swabs from the operator and positive cerebrospinal fluid cultures, as in the ohio case cited. these data suggest that the clinician can implement preventive practices related to anesthesia or analgesia given through the spinal cord to reduce the likelihood of infection. these practices include skin disinfection with an appropriate antiseptic, sterile gloves and sterile drapes, and aseptic technique. because of the growing evidence for droplet transmission of oropharyngeal flora during the procedures that puncture the spinal column, the cdc's guidelines for isolation precautions recommend the use of a surgical mask by personnel placing a catheter or injecting material into the spinal canal or subdural space. 12 a recent practice advisory prepared by the american society of anesthesiologists (asa) concurs with the implementation of aseptic technique when handling neuraxial needles and catheters, and states it should include "hand washing, wearing of sterile gloves, wearing of caps, wearing of masks covering both the mouth and nose, use of individual packets of skin preparation, and sterile draping of the patient." the same advisory does not make a specific recommendation regarding the type of skin antisepsis to use. 13 intravascular catheters, including central and peripheral venous catheters and arterial catheters, play an integral part in the delivery of anesthesia or analgesia. once again, these devices provide an opportunity for organisms to enter the normally sterile vasculature. the insertion and care of these catheters should remain the same regardless of whether they are inserted in an operating room, a critical care unit or a free-standing practice. there are 2 key mechanisms by which a catheter can lead to an infection. 14 the first occurs with colonization of the device and is referred to as catheter-associated infection. the pathogenesis of these types of infections is: skin organisms gain entry via the puncture site at time of insertion or shortly thereafter, the catheter hub can become contaminated during use or organisms spread hematogenously from another site of infection in the body. catheter-associated infections can lead to local site infections or systemic infections including bacteremia, sepsis, or endocarditis. the second mechanism occurs with contamination of the medication or substance being injected, which is referred to as infusate-associated infection. although intrinsic contamination of intravenous fluids or medications from the manufacturer is rare in the united states, improper procedures by the anesthetist or technician during medication preparation and administration can led to infusate-associated infections. in this situation the bacteria, virus, or fungus is directly infused into the patient's bloodstream. the rate of catheter-associated infections varies by the type of device used. for peripherally inserted, short-term catheters the risk is low. lee and colleagues 15 report a local site infection rate of 2.1% to 2.6% among 3165 patients with short peripheral intravenous catheters. no patients in this group developed a bloodstream infection. rates of arterial line catheter infections are similarly low, with lucet and colleagues 16 and koh and colleagues 17 reporting rates of 1.0 and 0.92 bacteremias per 1000 catheter days, respectively. these investigators report low rates of bacteremias related to central venous lines as well. the risk of central line-associated bloodstream infections in critical care patients ranges from 1.3 infections per 1000 catheter days in pediatric medical units to 5.5 in burn units. 18 table 3 lists the central line-associated bloodstream infection rates in a sample of units in which the anesthetist may have involvement. although it is possible for individual solutions to become contaminated and subsequently infused into patients, it is difficult to attribute an individual infection to a specific medication, vial, or infusion bag without direct causal evidence. hence, data related to infusate-related infections derives mainly from experiences with outbreaks. for example, blossom and colleagues 19 describe an outbreak of 162 serratia marcescens bacteremias in 9 states related to manufacturer's contamination of prefilled heparin and saline syringes. these circumstances are clearly beyond the control of the anesthesia team, although the team must respond promptly to alerts regarding potential contamination. there are, however, reports of medication contamination occurring under the control of the anesthesia personnel. in 2003, morbidity and mortality weekly report reported hepatitis b and c virus transmission occurring in 3 separate locations. 3 in each of these practices, reuse of needles and syringes and contamination of multidose medication vials led to patient-to-patient transmission of viral infections. as depicted in table 4 , more than 200 people were affected. despite this significant number of patient-to-patient transmissions, practitioners have continued to demonstrate unsafe medication practice. as recently as 2008, 6 patients were infected with hepatitis c due to unsafe injection practice used during sedation for endoscopic procedures. 2 the investigation revealed that the anesthesia provider contaminated vials of propofol by repeated aspiration into the vial with a syringe contaminated with hepatitis c from backflow of the index patient's blood. although the vial was labeled for single-patient use, the practitioner used the vial on the next patients. a graphical example is shown in fig. 1 . the cdc has published extensive guidelines for the prevention of intravascular infections. 20 key elements intended to reduce catheter-associated infections that apply to peripheral, central, or arterial catheters handled by the anesthesia team include: skin disinfection of the intravenous insertion site with an appropriate disinfection (a chlorhexidine-based preparation is preferred), aseptic technique during insertion and care and decontamination of ports and stopcocks with a disinfectant such as 70% alcohol before accessing the device. the cdc guidelines and the asa recommend additional specifications for the insertion and maintenance of central venous catheters because of their higher risk of infection. 21 many facilities have adopted a bundle approach to the insertion of central line catheters both in the operating room and elsewhere. the elements of the bundle are: 1. hand hygiene before insertion 2. full barrier precautions: sterile gown, gloves, masks, and large sterile drapes 3. skin antisepsis with chlorhexidine 4. subclavian vein as preferred anatomic site versus internal jugular or femoral 5. daily review of line necessity. from the anesthetist's perspective, the elimination of infusate-related infections demands preventing contamination of medications and infusions. most practitioners presumably would report adherence to safe medication handling. yet a survey conducted by the american association of nurse anesthetists (aana) revealed that 1% to 3% of clinicians reuse needles or syringes on multiple patients. 22 the aana has joined with the cdc, two state medical societies, the association for practitioners in infection control, and other advocacy groups in the safe injection practices and awareness campaign to further educate health care providers and the public about the importance of these practices. the campaign poster is displayed in fig. 2 . 23 because of the aforementioned outbreaks of hepatitis transmission, the cdc's 2007 guidelines for isolation precautions 12 highlights safe injection practices that are outlined in fig. 3 . the asa supports these practices 21 and makes further recommendations: cleanse rubber septum of vials and the neck of glass ampoules with a disinfectant. medications should be drawn up as close as possible to the time of use. medications in a syringe should be discarded within 24 hours unless specified by the manufacturer or pharmacy. expiration times for medications must be followed, especially the time limits for the use of lipid formulations such as propofol. according to the national health care safety network, the range of postprocedure pneumonias varies greatly by procedure. 18 for example, among those procedures reporting more than 1000 cases, patients undergoing knee prosthesis had a rate of 0.06 postoperative pneumonias per 100 procedures compared with cardiac surgery patients who had a rate of 1.19 pneumonias per 100 procedures. some additional information is gleaned from examining rates of ventilator-associated pneumonias (vap). among surgical type critical care units, the pooled mean rate per 1000 ventilator days was a low of 0.6 in pediatric cardiothoracic units to a high of 8.1 in trauma units. however, it is difficult to distinguish how much of a direct impact intubation and anesthesia had on the development of these pneumonias. one study by rello and colleagues 24 examined the development of pneumonia within the first 48 hours of intubation. eighteen of 250 intensive care unit (icu) patients developed pneumonia within the first 24 hours. there were 65 surgical patients included in this study. the 2 most important risk factors for pneumonia in patients were undergoing cardiopulmonary resuscitation and receiving conscious sedation. the investigators conclude that variables directly related to the intubation had less of an impact on the occurrence of pneumonia. nonetheless, intubation places the patient at risk of infection for several reasons. because intubation interrupts the defense mechanisms of the upper airway, it increases the risk of aspiration. aspiration of oral pharyngeal secretions is a prime cause of health care acquired pneumonia. this condition may be further aggravated by mechanical damage to the larynx or trachea from the endotracheal tube or stylet. 7 furthermore, mechanical ventilation increases the risk of infection. measures to reduce infection risk associated with intubation and mechanical ventilation deal with technique and equipment. cheung and colleagues 25 reviewed the literature to determine the impact of sterile handing of the endotracheal tube and the incidence of pneumonia. of note, the investigators found very few data on the topic yet noted that intubations performed under unsterile conditions do occur, although they do not provide a recommendation. it is prudent for intubation to be performed as aseptically as possible, with personal protective equipment worn for the safety of the health care worker. oral intubation is preferred over nasal intubation because the latter is more likely to lead to sinusitis, thereby increasing the risk of aspiration of infected secretions. 26 care should be taken to drain condensate in the ventilator tubing away from the patient. although there are other measures to reduce vap such as mouth care and semirecumbent position of the patient, these apply after the intraoperative period. equipment utilized by the anesthesia team includes endotracheal tubes, laryngoscope handles and blades, fiberoptic endoscopes, and anesthesia circuits, machines, and carts. there are also ancillary devices used by the team such as pulse oximetry, invasive temperature probes, and airways. this equipment may become contaminated from contact with the patient's skin, blood, secretions, splashes from the operative field, or contact with contaminated hands of the health care worker. the cdc, asa, and aana each have comparable standards for cleaning and disinfection of these items. these standards are based on the spaulding classification method 27 that stratifies items based on their likely contact with a sterile body site, mucus membrane, or intact skin, as noted in table 5 . neither the cdc 12 nor the asa 21 recommends the routine use of a bacterial filter for the breathing circuits or anesthesia ventilators. conversely, the aana states "protective anesthesia as a risk for hai use of bacterial filters is recommended," although they do acknowledge its use is controversial. 28 each of these organizations supports the use of a bacterial filter when caring for an infectious tuberculosis patient. another debated topic is the disinfection of laryngoscope handles. because they do not enter sterile tissue or touch mucous membranes, the spaulding classification would indicate cleaning and low-level disinfection. there is, however, the risk of contamination with body fluids. call and colleagues 29 challenged a common practice of wiping blades with low-level disinfectant between operative cases. after culturing 40 handles that had been cleaned according to the facilities' standard practice, they found 75% had positive bacterial cultures. most importantly, standard protocols should be developed that outline the correct cleaning, disinfection, or sterilization process for each item used by the anesthesia team. the manufacturer of the equipment should be consulted for their recommendations. an oversight mechanism should be included in the policy to ensure adherence with the correct practice. adequate training must be provided. overall, the documented transmission of infection from anesthesia equipment appears to be low. yet loftus and colleagues 30 raise the issue of transmission of bacteria in the anesthesia work area. these investigators cultured 2 specific areas of the anesthesia machine and the sterile stopcock just before the beginning of the case and again at the end of the case. their results showed that 32% of the stopcocks were contaminated by the end of the case. the work area showed a significant increase in bacterial contamination as well. two cases of methicillin-resistant staphylococcus aureus (mrsa) were transmitted to the work area intraoperatively. one case of vancomycin-resistant enterococcus transmission was documented between the anesthesia work are and the stopcock. the investigators also noted a trend toward increased hais among patients with contaminated stopcocks. the machine and stopcocks appear to have become contaminated by contact with providers' hands or lapses in aseptic technique. these results reinforce the need for rigorous attention to hand hygiene not only before the start of surgery but also intraoperatively. most studies indicate that adherence to hand hygiene by health care workers needs to be improved. mcguckin and colleagues 31 report only modest improvement to 51% compliance among non-icu staff after a year-long program of observation and feedback. a 2004 report by pittet and colleagues 32 found a 23% compliance rate among anesthesiologists. hand hygiene is clearly a challenge in the operating room because of the multiple functions being performed. limited access to hand hygiene products within the operating room undoubtedly contributes to poor compliance in the room. koff and colleagues 33 address this latter challenge through a study utilizing a portable device that dispenses alcohol-based hand rub. the device has the added benefit of tracking the frequency of use and providing a reminder if too long a time has elapsed between hand hygiene events. the introduction of the device was considered the study phase. during the study phase, hand hygiene events increased among attending anesthesiologists and other caregivers by 6.9 and 8.3 times per hour, respectively. the investigators also monitored the frequency of stopcock contamination and the occurrence of hais, and demonstrated decreases in both of these indicators as noted in table 6 . while the reduction in hais is promising, koff and colleagues caution that additional research is needed to confirm these results. ssis are the second most frequent hai. 34 control measures for the prevention of ssis include preoperative preparation of the patient, sterile attire and draping, surgical hand preparation, skin antisepsis, air handling, and sterile surgical instrumentation. there are additional conditions that can influence the occurrence of ssis when the anesthesiologist may be involved. one measure aimed at reducing bacteria at the surgical site is the delivery of antibiotic prophylaxis. the national surgical infection prevention project (sip) proposes a 25% reduction in national surgical complication rates by adherence to 3 indicators 35 : 1. administration of an appropriate antibiotic as described by the sip. the antibiotic is selected based on the organisms most likely to cause infection and varies by the type of surgery. 2. timely administration of the antibiotic. to reach adequate blood and tissue concentrations, the antibiotic should be administered within the 60 minutes prior to the surgical incision. (vancomycin may be given up to 120 minutes prior.) 3. discontinuation of prophylactic antibiotics with 24 hours (48 hours for cardiac surgery). a second intervention to reduce ssis is the maintenance of normothermia. hypothermia is thought to contribute to infection because of a decrease in subcutaneous tissue perfusion. 6 lastly, glycemic control has been shown to reduce the rate of infections. anesthesia providers are at risk of occupational infections from direct contact with blood and respiratory secretions. in addition, they may be exposed to microorganisms via the airborne or droplet route. diseases transmitted through the airborne route include tuberculosis, measles, and varicella. most clinicians should be immune to measles and varicella because of effective vaccines. surgery should be delayed for patients with these active infections. if the case cannot be postponed, the air handling in the operating room should ideally have negative pressure relative to the corridor. as previously mentioned, a bacterial filter should be placed on the anesthesia breathing circuit for patients with active tuberculosis. the health care provider should wear an n95 respirator approved by the national institute for occupational safety and health. when called to intubate patients on airborne isolation, again the n95 respirator is indicated. a large number of sars cases in canada were occupationally acquired. fowler and colleagues 5 determined in one small series that physicians and nurses involved in intubation had a relative risk of 3.82 and 13.29, respectively, of developing sars. this result stresses adequate respiratory protection. infections spread through the droplet route include pertussis, mumps, and influenza. as most of these cases are unlikely to undergo elective surgery or procedures while symptomatic, the exposure may occur from undiagnosed cases or from people who are shedding organisms in the few days prior to symptoms. respiratory protection is indicated for known or suspect cases. immunization is strongly encouraged. (for the 2009-2010 influenza season, the cdc recommended use of an n95 for contact with patients with influenza-like symptoms. current recommendations can be found at http://www.cdc.gov/flu/professionals.) hand hygiene is indicated. because of their contact with blood and other body fluids, anesthesia providers may be exposed to viral pathogens such as hepatitis b or c and human immunodeficiency virus (hiv). it is difficult to determine the actual number of occupationally acquired blood-borne infections in the discipline. in a 1998 study among anesthesia personnel, the estimated average 30-year risks of hiv or hepatitis c virus infection per full-time equivalent was 0.049% and 0.45%, respectively. 36 in addition, there may be exposure to bacterial pathogens such as mrsa and clostridium difficile. the aana supports the cdc's recommendations to use standard precautions in the care of all patients. 28 in summary, standard precautions entail: consider all blood and body fluid as potentially infectious. use of personal protective equipment (ppe) (gloves, gowns, protective eye wear, and masks) when anticipating contact with blood or body. the ppe worn will depend on the task being performed and the possibility that splash or aerosolization can occur. handle and dispose of all needles and syringes properly. the practitioner should be aware of his or her facility's protocol for managing occupational exposure to blood and body fluid. body fluid exposures should be evaluated promptly to determine the need for antiviral or other prophylaxis. transmission-based precautions may be added for particular diseases that are highly transmissible or of epidemiologic importance. there are 3 categories: airborne isolation, droplet precautions, and contact precautions. the documented risk of infection related to anesthesia is low, yet the potential exists for serious infectious outcomes including death. the risk of infection can be minimized by adherence to hand hygiene, aseptic technique, safe infection practices, equipment decontamination, and use of ppe by all members of the anesthesia team. bacterial meningitis after intrapartum spinal anesthesia-new york and ohio acute hepatitis c virus infections attributed to unsafe injection practices at an endoscopic clinic-nevada transmission of hepatitis b and c viruses in outpatient settings clinical anesthesia. philadelphia: lippincott, williams and wilkins treatment of severe acute respiratory syndrome during intubation and mechanical ventilation the anesthesiologist's role in the prevention of surgical sire infection nosocomial infections and infection control in regional anesthesia post dural puncture meningitis incidence of epidural hematoma, infection and neurologic injury in obstetric patients with epidural analgesia/anesthesia neuraxial blockade in obstetrics and complications related to infection: can we lower the risk? park ridge (il): american society of anesthesiology newsletter guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the american society of anesthesiologists task force on infectious complications associated with neuraxial techniques intravascular device infection risk factors for peripheral intravenous catheter infection in hospitalized patients: a prospective study of 3165 patients infectious risk associated with arterial catheters compared to central venous catheters prospective study of peripheral arterial catheter infection and comparison with concurrently sited central venous catheters national healthcare safety network report (nhsn): data summary for multistate outbreak of serratia marcescens bloodstream infections caused by contamination of prefilled heparin and isotonic sodium chloride solution syringes guidelines for prevention of intravascular catheter-related infections american society of anesthesiologists. recommendations for infection control for the practice of anesthesiology aana condemns unsafe injection practice. press release risk factors for developing pneumonia within 48 hours of intubation endotracheal intubation: the role of sterility apic text of infection control and epidemiology guideline for disinfection and sterilization in healthcare facilities american association of nurse anesthetists. aana infection control guide for certified nurse anesthetists. park ridge (il): aana nosocomial contamination of laryngoscope handles: challenging current guidelines transmission of pathogenic bacterial organisms in the anesthesia work area hand hygiene compliance rates in the united states-a one year multicenter collaboration using product/volume usage measurement and feedback hand hygiene among physicians: performance, beliefs and perceptions reduction in intraoperative bacterial contamination of peripheral intravenous tubing through the use of a novel device apic text of infection control and epidemiology multicenter study of contaminated percutaneous injuries in anesthesia personnel key: cord-265595-55s19mr1 authors: brug, johannes; aro, arja r.; richardus, jan hendrik title: risk perceptions and behaviour: towards pandemic control of emerging infectious diseases: international research on risk perception in the control of emerging infectious diseases date: 2009-01-06 journal: int j behav med doi: 10.1007/s12529-008-9000-x sha: doc_id: 265595 cord_uid: 55s19mr1 nan in the beginning of 2003, the world was alarmed by the emergence of a new and apparently fatal infectious disease. the disease was labelled sars. thanks to enormous efforts made by national and international organisations, the epidemic was brought under control by the summer of that year. in recent years, the world has also been confronted with outbreaks or threats of outbreaks of other emerging infectious diseases such as avian influenza. to control new infectious diseases, the identification of the organisms, the infectivity, development of vaccines and therapies, contact tracing, isolation and screening may all be important. many of these issues are partly dependent on human behaviours. for example, the success of prevention of infectivity (e.g. engaging in precautionary behaviours such as wearing masks, hand hygiene, isolation etc.), vaccination, contact tracing and population screening are all more or less dependent on whether people at risk comply with behavioural recommendations. especially in the early phases of a possible epidemic, compliance to precautionary behaviours among the populations at risk is often the only means of prevention of a further spread of the disease. however, very little research has been conducted to explore the determinants of behavioural responses to infectious disease outbreaks [1, 2] . the present special series of the international journal of behavioral medicine is dedicated to such research. one of the six papers, i.e. by vartti et al. [3] , in this special series originated from international collaboration of behavioural scientists to study risk perceptions around sars during the sars outbreak. the aro et al. [4] paper represents early work related to risk perceptions among travellers during the avian influenza outbreak. three papers [5] [6] [7] were the result of a european commission funded project, called sars-control that was partly dedicated to exploring risk perceptions and risk communications related to sars and other emerging infectious diseases. severe acute respiratory syndrome (sars) was a new infectious disease due to an infection with a novel coronavirus, which was provisionally termed sars-associated coronavirus (sars-cov) [8] [9] [10] . the earliest cases of sars are known to have occurred in mid-november 2002 in guangdong province, china. sars was first recognised in late february 2003, when cases of an atypical pneumonia of unknown cause began appearing among staff at hospitals in guangdong, china and hanoi, vietnam [11] . within 2 weeks, similar outbreaks occurred in various hospitals in hong kong, singapore and toronto, and the number of worldwide cases exceeded 4,000 within 2 months, and 7,000 a few weeks later, with cases being reported from 30 countries. during the peak of the global outbreak, near the start of may 2003, more than 200 new cases were being reported each day. more than 900 people died from sars [12] . china was hit hardest, with over 5,000 patients and approximately 350 deaths. after july, sars appeared to be under control. although sars did not have the disastrous health impact that many at first feared, the panic caused by sars had an enormous economic impact in many countries because of the health fears and related control measures. the global travel, tourism and related industries in particular faced a significant downturn in income, although mostly temporary. the global macroeconomic impact has been estimated at 30 to 100 billion us dollars. although the european union was not afflicted heavily by the sars epidemic in terms of patient numbers, there was a large public concern related to the disease. while the dissemination of sars has been prevented in europe and controlled in all affected areas within a few months, this may not be the case for other emerging infectious diseases. for instance, the west nile virus was introduced in north america in 1999 and has been widely diffused since then despite very aggressive control efforts. in the usa in 2002, 4,156 cases were notified among whom 284 died [13] . severe infection can emerge in europe too. the h7n7 influenza episode among workers of the dutch poultry industry in 2003 [14] has shown that the potential for pandemic influenza to start within europe is there. circulation of a human strain at the same time as the zoonotic strains (h7n7) were circulating in the poultry worker population could have precipitated the emergence of a new strain adapted to humans with fast secondary diffusion. already in april 2003, an international psychosocial sars research consortium was formed initiated by professor george bishop at singapore university, which developed a survey instrument in several languages to probe awareness, knowledge, risk perceptions and precautionary behaviours related to sars. in 2004, a european union sponsored 3year research programme sarscontrol was started with collaborators from europe and china (partly building on the methods of the psychosocial sars research consortium) with the title "effective and acceptable strategies for the control of sars and new emerging infections in china and europe"; sarscontrol. risk perception and risk communication were themes in two out of nine work packages of the sarscontrol project. effective management of new epidemic infectious disease risks in the phase that no treatment or vaccination is yet possible is largely dependent on precautionary behaviour of the population. implementation of precautionary behaviour is largely dependent on effective risk communication, i.e. communication that induces realistic risk perceptions, correct knowledge and skills to promote and enable precautionary practices. scientific knowledge about these topics in the area of infectious disease control is scarce. neither is there knowledge if the theories and measures developed for risk perception research on, for example chronic diseases, can be applied in the area of infectious diseases. however, such knowledge is vital for effective control of newly emerging infectious diseases, because our ability to promote health protective behavioural change depends on our knowledge of important determinants of such behaviour [15] . for people to voluntarily engage in precautionary actions, they first of all need to be aware of the risk. risk perception is a central feature in many health behaviour theories. according to the protection motivation theory, for example [16] , protection motivation is the result of the threat appraisal and coping appraisal. threat appraisal consists of estimates of the chance of contracting a disease (perceived vulnerability or susceptibility) and estimates of seriousness of a disease (perceived severity). risk perceptions thus are important for precautionary actions, but risk perceptions are often biased [17] . unrealistic optimism about health risks is often observed related to familiar risks that are perceived to be largely under volitional control. such optimism may result in lack of precautions and false feelings of security. a pessimistic bias is more likely for new, unfamiliar risks that are perceived as uncontrollable. such unwarranted high-risk perceptions may lead to unnecessary mass scares, and are often combined with stigmatisation of specific risk groups. perceptions of risk are a necessary but often not sufficient condition for engagement is such behaviours. therefore, higher risk perceptions may only predict protective behaviour when people believe that effective protective actions are available (response efficacy) and when they are confident that they have the abilities to engage in such protective actions (self-efficacy). preliminary research on sars as well as avian influenza risk perceptions support these theorised associations and show inverse associations between risk perceptions and efficacy beliefs [2, 18] . furthermore, risk perceptions as well as efficacy beliefs in the early stages of a possible pandemic are dependent on communications with and between the members of the groups at risk. risk communication messages that are not comprehended by the public at risk, or communication of conflicting risk messages will result in lack of precaution-ary actions. communications that are perceived as coming from a non-trustworthy source may have the same results. however, risk communication messages are sometimes very quickly adopted by the media, possibly leading to an 'amplification' of risk information that may lead to unnecessary mass scares and unnecessary or ineffective precautionary actions. in the first paper of this special series, leppin and aro [19] provide an overview of the theoretical frameworks on which risk perception and infectious disease research is founded. leppin and aro first of all make a distinction between a more sociological and a primarily psychological approach to risk perception research. they conclude that the current risk perception research in infectious disease epidemics is seldom theory based or conceptually clear. this is understandable when doing first surveys in the early phases of new emerging epidemics, but there certainly is a need to do consolidate the theoretical and methodological research base. we also need to find out empirically if the theories and methods developed mostly for chronic diseases under volitional control of individuals can be directly applied in emerging epidemics. four of the papers present empirical mostly explorative original research on risk perceptions, knowledge, beliefs and other issues related to sars during or after the sars outbreak in 2003. de zwart and colleagues, in their eightcountry survey in 2005, almost 2 years after the sars outbreak, found out that perceived threat of sars in case of an outbreak in the country was higher than that of other diseases [7] . perceived vulnerability of sars was at an intermediate level compared to other diseases while perceived severity was high. perceived threat for sars varied between countries in europe and asia, but these differences did not appear to be associated with the proximity of the sars 2003 outbreak. vartti et al. [3] in their study during the sars outbreak found that despite the fact that both finland and the netherlands were unaffected by the outbreak the finns were more likely to be knowledgeable and worried about sars as well as to have low perceived comparative sars risk and poor personal efficacy beliefs to prevent sars. the finns were also more likely to have high confidence in physicians in the sars issues and less likely to have received information from the internet and have confidence in the internet information than the dutch. voeten et al. [5] and jiang et al. [6] studied the chinese communities in the netherlands and the uk because of their close communication and travel contacts with china, where the outbreak was the most severe. jiang and colleagues, in their qualitative study, revealed that information from affected asia influenced the perceived threat form sars and protective behaviour among the chinese in europe when more relevant local information was absent. when a high perceived threat was combined with low efficacy regarding precautionary measures, avoidance-based precautionary action appeared to dominate responses to sars. these actions may have contributed to the adverse impact of sars on the community. the voeten et al. [5] study results indicate that the chinese community members relied more on information from friends and chinese media and had less confidence in their doctor, government agencies and consumer interest groups. while their knowledge of sars was high, they reported a lower perceived threat and higher self-efficacy than general populations with regard to sars and avian flu, due to a lower perceived severity. the aro et al. [4] study, from the early phase of the avian influenza outbreak, found out that younger travellers and those on holidays are willing to take more health risks than those older or on business trips. the overall results indicate that people across europe and east asia do regard recently emerging infectious diseases as serious potential health threats, based on information they receive from a range of different sources, with clear differences between countries and regions. these differences appear not to be necessarily associated with proximity of an outbreak. it remains unclear if cultural differences or experience with an outbreak may explain these differences in risk perceptions and beliefs. given the clear and present danger of newly emerging infectious disease outbreaks in the near future and the importance of the public response and precautionary actions to control the spread, additional research on risk perceptions and other behavioural determinants is warranted. the present series of papers present a first qualitative and social-epidemiological exploration. more theory-driven and stronger designed longitudinal and experimental studies are needed to test some of the hypotheses touched upon in this issue. responding to global infectious disease outbreaks: lessons from sars on the role of risk perception, communication and management sars risk perception, knowledge, precautions, and information sources, the netherlands sars knowledge, perceptions and behaviors: a comparison between finns and the dutch during the sars outbreak in 2003 willingness to take travel-related health risks: a study among finnish tourists in asia during the avian influenza outbreak sources of information and health beliefs related to sars and avian influenza among chinese communities in the united kingdom and the netherlands, as compared to the general population in these countries the perceived threat of sars and its impact on precautionary actions and adverse consequences: a qualitative study among chinese communities in the united kingdom and the netherlands perceived threat, risk perception and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey coronavirus as a possible cause of severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome cumulative number of reported cases of severe acute respiratory syndrome (sars) comparative susceptibility of selected avian and mammalian species to a hong kong-origin h5n1 highpathogenicity avian influenza virus transmission of avian influenza viruses to and between humans theory, evidence and intervention mapping to improve behavior nutrition and physical activity interventions cognitive and physiological processes in fear appeals and attitude change: a revised theory of protection motivation the precaution adoption process avian flu risk perception: europe and asia risk perception related to sars and avian influenza: theoretical foundations of current behavioral research key: cord-102776-2upbx2lp authors: niu, zhibin; cheng, dawei; zhang, liqing; zhang, jiawan title: visual analytics for networked-guarantee loans risk management date: 2017-04-06 journal: nan doi: 10.1109/pacificvis.2018.00028 sha: doc_id: 102776 cord_uid: 2upbx2lp groups of enterprises guarantee each other and form complex guarantee networks when they try to obtain loans from banks. such secured loan can enhance the solvency and promote the rapid growth in the economic upturn period. however, potential systemic risk may happen within the risk binding community. especially, during the economic down period, the crisis may spread in the guarantee network like a domino. monitoring the financial status, preventing or reducing systematic risk when crisis happens is highly concerned by the regulatory commission and banks. we propose visual analytics approach for loan guarantee network risk management, and consolidate the five analysis tasks with financial experts: i) visual analytics for enterprises default risk, whereby a hybrid representation is devised to predict the default risk and developed an interface to visualize key indicators; ii) visual analytics for high default groups, whereby a community detection based interactive approach is presented; iii) visual analytics for high defaults pattern, whereby a motif detection based interactive approach is described, and we adopt a shneiderman mantra strategy to reduce the computation complexity. iv) visual analytics for evolving guarantee network, whereby animation is used to help understanding the guarantee dynamic; v) visual analytics approach and interface for default diffusion path. the temporal diffusion path analysis can be useful for the government and bank to monitor the default spread status. it also provides insight for taking precautionary measures to prevent and dissolve systemic financial risk. we implement the system with case studies on a real-world guarantee network. two financial experts are consulted with endorsement on the developed tool. to the best of our knowledge, this is the first visual analytics tool to explore the guarantee network risks in a systematic manner. financial safety is a main concern of the government and banks. the majority of small and medium enterprises (smes) are difficult to get loan from the banks for their limited credit qualification, thus they often need to seek loan guarantees. in fact, guaranteed loan is already an important way to raise money in addition with seeking listed. in some developed economy like in us and uk, special government backed banks are established to provide guarantee credit [22, 27, 30, 40, 55] ; while in emerging economies like korea [19] and china [31] , it is more common that the corporations guarantee each other when they are trying to secure loans from lending institutions. it is reported that a quarter of the $13 trillion in total outstanding loans in china are guaranteed loans in 2014 [40] and there is an 18% year-to-year increase [36] . this has led to a noticeable new phenomenon: a large amount of corporations back each other and form complex guarantee networks. appropriate guarantee union may reduce the default risk but contagious damages over the networked enterprises may happen in practice. with the economic down period, large -scale breach of contract would hazard the banking asset quality deteriorated seriously and cause systematic crisis. although the loan guarantee network appeared for less than twenty years and it is still not well understood. the current financial academic community published some qualitative analysis works on small guarantee networks and there is few quantitative analysis research. in banking industry, the credit assessors evaluate an enterprise basically on the basis of classic credit rating approach. such a approach is not well suited for the complex benefit relationships. the risk management for the loan guarantee network is challenging: firstly, the loan guarantee network may consist of thousands of enterprises with complex guarantee relationships and intertwined risk factors, making it very difficult to analysis. fig. 1 illustrates a real guarantee network we constructed using ten years of bank loan records and it consists of more than 1000 enterprises, each of which has more than 3000 financial entries. monitoring the financial status is so difficult that usually only after capital chain rupture, can the regulators study the case in-depth. secondly, the fact that small and medium enterprise business operations (for example, the loan officers do not access to the enterprise net assets information) have inadequate transparency makes the loan risk evaluation more difficult. some borrowers fraudulently obtain loans using the faultiness of bank lending risk managements. the cognition to risk loan guarantee especially malicious guarantee is still relatively limited. thirdly, thousands of guarantee networks of different complexities coexist for a long period and evolve over time, this requires adaptive strategy to prevent, identification and dismantling systematic crisis. in the complex background of the growth period, the structural adjustment of the pain period and the early stage of the stimulus period, the structural and deep-level contradictions emerged in the economic development, all kinds of risk factors along the guarantee network accelerate the risk transmission and amplification, the guarantee network may be alienated from "mutual aid group" as "breach of contract". in this paper, we propose visual analytics approach for loan guarantee network risk management. it includes visual analytics for i) enterprises default risk; ii) high default groups; iii) high default pattern; iv) evolving guarantee network; and v) default diffusion path. in a nutshell, the main contributions are: 1. we consolidate with financial experts and identify five key research problems for loan guarantee network risk management, which is driven by emerging finance industry demands, and we believe this is an important research problem to the visual analytics science and technology community; 2. we propose intuitive visual analytics approaches for the tasks of i) enterprises default risk; ii) high default groups; iii) high default pattern; iv) evolving guarantee network; and v) default diffusion path. 3. we construct real loan guarantee network and perform empirical study on ten years of bank loan records. we highlight three high default patterns which are difficult to be discovered without visual analytic approach. we conduct interviews with two banking loan experts and got endorsed. the rest of the paper is organized as following: section 2 describes works involving different aspects related to our problem; section 3 details the five visual analytic tasks and our approaches; section 4 describe the data, case study; and we report user study results in section 5. conclusions and future works are described in section 6. to our best knowledge, this is the first work of visual analysis for the loan guarantee network risk management. we thus introduce several relevant work on network analytics in the financial domain; anomalous and significant subgraph detection in attributed networks; and works on financial security visualization. credit risk evaluation consumer credit risk evaluation is often technically addressed in a data-driven fashion and has been extensively investigated [5, 24] . since the seminal "partial credit" model [39] , numerous statistical approaches are introduced for credit scoring, including logistic regression [60] , k-nn [26] , neural network [18] , support vector machine [28] . more recently, [4] presents an in-depth analysis on how to interpret and visualize the learned knowledge embedded in the neural networks using explanatory rules. the authors in [32] combine debt-to-income ratio with consumer banking transactions, and use a linear regression model with timewindowed data set to predict the default rates in a short future. they claim a 85% default prediction accuracy and can save cost between 6% and 25%. financial network analytics financial crises and systemic risk have always been a major concern [9, 21] . networks or graph is a natural representation of the financial systems as they often bear complex interdependence and connections inside [2] . the relationship between network structure and financial system risk are carefully studied and several insights have been drawn: network structure has few impact for system welfare but plays an important role in determining systemic risk and welfare in short-term debt [3] . after the 2008 global financial crisis, network theory attracts more attention: the crisis brought by lehman brothers spreads on connected corporations in a similar infectious way as the epidemic of severe acute respiratory syndrome (sars) in 2002 -both are small damage that hits a networked system and causes serious events [8, 13] . the journal of nature physics organizes a special on how to understand some fundamental economic issues using network theory [1] . these publications suggest the applicability of network based financial model. for example, the dynamic network produced by bank overnight funds loan may be an alert of the crisis [13] . contrary to the conventional stereotype that large institutions are "too big to fail", the truth is the position of the institution in the network is equally and sometimes more important than its size [6] . more central the vertex is to the graph, more influential it is to the whole economic network when default occurs [13] . moreover, the research that aims to understand individual behavior and interactions in the social network, has also attracted extensive attention [7, 20, 46, 47, 61, 62, 67] . although preliminary efforts have been made using network theory to understand fundamental problems in financial systems [12, 17, 64] , there is little work on the system risk analysis in the loan guarantee network except for the preliminary work [41] . among them, may be the most important work is using k-shell decomposition to predict the default rate; positive correlation between the k-shell decomposition value of the network and default rates was reported [41] . anomalous and significant subgraph detection in network anomalous and significant subgraphs have been applied in many domains such as societal events in social media, new business discovery, auction fraud, fake reviews, email spams, false advertising [42, 54] . classic anomalous and significant subgraphs refer to subgraphs, in which the behaviors (attributes) of the nodes or edges are significantly different from the behaviors of those outside the subgraphs [48] . anomalous and significant subgraphs in social network can be used for early detection of emerging events such as civil unrest prediction, rare disease outbreak detection, and early detection of human rights events. the heterogeneous social network is modeled as a sensor network in which each node senses its local neighborhood, computes multiple features, and reports the overall degree of anomalousness. p-values of the subgraphs are used to represent the significance, and iterative subgraph expansion are used for the scaling problem [15] . emerging events such as crimes or disease cases are detected from spatial networks [34, 44] . a common challenge for the subgraph detection is the complexity. as many of the algorithms are turned into subgraph isomorphism problem which is n-p complete problem, it is computationally infeasible for naive search. algorithms are designed to optimize the performance. readers are referred to [43, 58, 59, 68] for more details. visualization in financial systems financial risk is a major concern of the government and the banks. visual analysis can enhance the understanding and communication of risk, help to analysis risks and prevent systemic risks. this is done by developing interpretable models, and and couple them with visual, interactive interfaces. in modern banking industry the business becomes more and more complex, the risk assessment and risk loan pattern detection have attracted a major concern. animation is used to visually analysis large amounts of time-dependent data [63] . in [29] , 3d tree map are introduced to monitor the real-time stock market performance and to identify a particular stock that produced an unusual trading patterns. interactive exploratory tool is designed to help the casual decision-maker quickly choose between various financial portfolios [50] . coordinated specific keywords visualization within wire transactions are used to detect suspicious behaviors [14] . the self-organizing map (som), a neural network based visualization tool is often used in financial risk visualization analysis, for monitoring the sovereign defaults occurrence in less developed countries [52] , visual analysis of the evolution of currency crises by comparing the clusters of crises between decades [51] , and discovering imbalances in financial networks [53] . self-organizing time map (sotm) are used to decompose and identify temporal structural changes in macro financial data around the global financial crisis in 2007 and 2009. readers are referred to [37] for more references on financial visualization. we consult with financial experts and consolidate five analysis tasks. in this section, we give an brief introduction in the first place before describing detailed algorithm, strategy and interactions. fig. 2 gives the overview of the system and tasks. we first construct the real loan guarantee networks from bank record, perform statistical analysis and employ machine learning based approach to predicate enterprise default risk. all these data are fit into the interface to finish the tasks proposed by financial experts. specifically, the tasks include: t1: visual analytics for enterprise default risk. the current internal loan credit rating system is based on the pure financial status of the individual borrower. credit assessor can usually access to the first layer of guarantee chain, and could not trustfully evaluate the entire guarantee network. in order to avoid inadequate risk assessment, it is necessary to carry out a systematic analysis of the enterprise. t2: visual analytics for high default group. identifying the high default groups helps the banking experts single out and tackle the principal default problem. visual analytics tools should be developed for thoroughly analyzing of the network, and recognize high defaults enterprises. t3: visual analytics for high default pattern. some known guarantee patterns may lead to default and diffusion, but there may exist more complex patterns which is difficult to be discovered. this task requires visualize the known risk guarantee pattern and able to explore other more complex risk guarantee patterns. t4: visual analytics for evolving guarantee network. like many other real networks, there are competitive decision making taking place in the guarantee network. understanding the network dynamic helps financial experts understand how the firms are connected together temporally. this task requires visualizing the guarantee network evolution based on history data. t5: visual analytics for default propagation path. before the crisis, forecasting the default diffusion path and monitoring the default spread status helps the government and bank take precautionary measures, conduct research, and take effective measures to prevent and dissolve risks, such that no regional or systemic financial risk occur. default risk predication the loan records reveal that the guarantee network and default rates are both increasing, and the network structures show strong correlation with the defaults. we construct feature vector consisting of hybrid information and employ supervised learning approach to train the prediction model. in what follows, we discuss the hybrid features used in our model. in order to build a highly representative feature which can reliably reflect the statistical relationships between the customers information and their repayment ability, we clean the data and construct the features as: basic profile, the essential company registration information, which reflects the character, capital, collateral, capability, condition and stability [41] . we use business nature, registered capital, enterprise scale, employee number and others as corporation's basic profile. most banks require company to update the basic information when the enterprise makes a loan application, and we choose to use the latest information as the basic profile features of the loan. credit behavior, historical behavior e.g. credit history, default records, default amount, total loan amount and loan count, total loan frequency (if any), total default rates. they are calculated by all the loan records before the active loan contract. active loan, the loan contract in its execution period. it contains active loan amount, active loan times, type of capital return and interest return etc. network structure, network features such as centralities are extracted as ns. note that as discussed above, the basic profile may be not completely trustworthy as the smes may provide out of date or even fake information to the bank. however, the guarantee network is trustable information as the bank can build it from its own record systems. the prediction of default for a customer's loan guarantee can be modeled as a supervised learning problem. we use logistic regression based on gradient boosting tree [23] for the predication. the tree ensemble model using k additive function to prediction output can be represented as: in eq. 1, f k is the k th decision tree, x i is the training feature andå· i is predication results.finding parameters of the tree model is turned into minimize the objective function problem and it can be trained in an additive manner [16] . where where â�� i l(å· i , y i ) is a training loss function measures the difference between the prediction and the target; â�¦( f ) is a smoothing regularization term to avoid over fitting. specifically, we use three-month window for training, observation, predication, and evaluation. as fig. 3 shows, in the training stage, for all customers who obtain bank loans from 2013 q1(first quarter 1. prediction shall be adapted to a dynamic setting with a regularly updated forecasting results. in fact, using sliding window is a typical way for rolling prediction as commonly adopted in event prediction practices such as [65, 66] . 2. the business often runs on a quarterly basis. thus from a business demand perspective, it would be helpful to know the borrowers who may be default on a quarterly basis. default risk visualization. we design and implemented visual interface enable to view the network with various multiple measurements. fig. 4 gives the interface, by which users can adjust the node size by the predicted default risk and by the following network centrality measurements: hub score and authority score, k-shell decomposition score, pagerank, eigenvector centrality scores, betweenness centrality, closeness centrality. fig. 5 gives a part visualization of a real guarantee network. in the graph, all defaulted enterprises are highlighted by red circles. node size proportional to predicted risk (a), k-shell value (b), and authority score (c). through the interface, users can also observe the rolling prediction risk of an enterprise over month and highlight it on the whole network by choosing it on the heatmap. recognizing high default groups narrow down the risk guarantee relationship search scope and enable financial experts focus on firms with high-default crowd. usually, community detection divides the guarantee network into groups (communities) based on how the nodes are connected together. theoretically, community structure in graph is defined as the node set internally interacts with each other more frequently than with those outside it. identifying such sub-structures provides insight into understanding the structure of complex networks (both functions and topology affect each other) [57] . based on the conjecture that defaults occur in clusters, we first divide the whole network into several disjoint sets by community detection. fig. 6 (a) shows the results on a typical independent subgraph we constructed from the bank loan records. the communities are marked using separate color background and average default rates are labeled. there are 30 communities, but the default occurs on four of them with average 38% to 8.6% defaults rates, all other 9 communities have no default during the guarantee network existence. similar phenomenon are observed on random walks, edge betweenness, and spinglass community. in practice, we first use random walk algorithm [45, 49] to divide the whole guarantee networks into groups. we use a revised treemap interface to visualize the community detection results. the community label and default rates are displayed on the flat colored blocks.the treemap chart used for navigation here, thus the sum of area does not necessarily to be one. the larger blocks reveal the high default communities saliently. however, the evaluation of community detection is still an open question [35] , and the community detection algorithm only considers the link information and neglect node attribute information, the partition may not be consonant to the actual conditions. the basic rule for community detection is to minimize the number of links between communities and this uses pure network structure information. in financial practice, each node in the network comes with rich information such as enterprise sectors, changes in deposits, assets, loan amount, etc,. it would be unreliable discarding such attributes when dividing the network. by interaction, we enable the users to edit the communities into coherent ones by referring to relevant financial matric. we allow users to interactively perform the following manipulation actions. interactive community editing. we enable users to explore the financial information and interactively edit the communities by merging strong associated communities, reassign the community labels for the structural hole spanners, a key role in the information diffusion [11] or split a community into several disjoin smaller groups. the generated subgraph are noted as group of interest (goi), the high risk guarantee pattern are often hidden in the goi. reassign. the reassign operation allow to the change the community labels of the structure hole spanner. structure hole spanner is the bridge node which connect different communities in a network. fig. 7 is reproduced from [25] , and it illustrates a network with three communities and six structural hole spanners. empirical study suggests that individuals would benefit from filling the "holes" (called as structural hole spanners) between people or groups that are otherwise disconnected [10] . principled methodology to detect structural hole spanners from a given social network are still not clear [38] . in fact, we observed high default on structure hole spanners with their neighbouring internal nodes. we enable the users can investigate the financial matric and reassign the community labels of the structure hole spanners. specially, when the user wish to merge two adjacent communities, he/she firstly double clicks one block on the tree map, all the other connected commonties are highlighted. single clicking the structure hole spanner node can reassign it into the opposite community. for example, when community c 1 and c 2 are chosen, single click node a, both communities will be merged as c 1 , and vice versa. merge. neighbouring communities can be merged. as the community detection divides a graph purely based on links in the graph, algorithm may generate too many communities where some of them share common sector category or similar network structures. merging the communities referring the financial matric can produce medium size and more tractable subgraphs. specifically, when the user wish to merge two adjacent communities; he firstly double click one "tile" on the tree map, all other the connected commonties are highlighted. double click the structure hole spanner node can merge the two commonties together and labeled as the clicked community. split. sometimes, we need to split the community into several parts. this happen when there exists when the default unevenly distributed. we can cut off the stable parts and this may reduce the moi computation complexity. specifically, when the user wish to split the community; he firstly double click one "tile" on the tree map, all other the connected commonties are highlighted. double click the edge, the two opposite parts of the subgraph will be split into two communities. financial information is useful. we use a financial radar chart to encode the key financial status under the tree map. specially, the key indices include: defaults, historic default behavior; la/rc the ratio of loan amount to registered capital. it would more insightful using the ratio of loan amount to enterprise net assets, however, as the latter one is not always available. we use registered capital instead. deposit loss the percentage of deposit loosing. the shorting of money and rapid decrease of deposit should not be ignored. sector the enterprise sector is also important clue when editing communities. ga/rc the ratio of guarantee amounts to registered capital. as the loan guarantee is an obligation of a borrower if that borrower defaults, the ratio of guarantee amount to enterprise net assets is a crucial factor for the financial systematic stability. similarly, we use registered capital instead. credit rating it is the review rating of bank expert, which is also a key clue when editing communities. usually, high default pattern discovery is not possible by observation as a practical loan guarantee network may consist of several tens of thousands nodes; nor does it via algorithms -naive subgraph mining from the network led to isomorphism problem which is proved to be np-complete problem. we adopt a shneiderman mantra strategy to reduce the computation complexity. guarantee circle visualization. the small and medium firms improve their borrowing capacity by a third party guarantor. empirical studies by bank risk control specialist suggest the guarantee circle is a source of default risk. the most frequently used guarantee circle patterns include mutual guarantee, joint liability guarantee, star shape guarantee loan,and revolving guarantee (see fig. 8 ). such interactions are legal in china currently. they can enhance the solvency level to some extent but may induce occurrence of risks and transmission of risk pointed by financial regulatory documents. often the specialists in the bank risk control department have only sql query capability to find relative simple guarantee pattern. in this work, we enable automatically guarantee circle detection and visualization -the common recognized risk loan patterns including mutual guarantee, co-guarantee, and revolving guarantee are highlighted on the network. fig. 9 gives an example of revolving loan guarantee detected from a real-world loan guarantee network. users are able to focus on the relevant firms and explore more details. besides, there are five firms default among the eleven firms in the three revolving structure, informing the banking experts to pay more attention on the firms involved in such patterns. new risk pattern discovery. as mentioned above, guarantee circles are relatively clearly understood by banking experts. however, they still can not quite understand does there exist more complicated guarantee patterns that may have implicit connections with high default phenomenon. we develop a visual analytics tool to help the experts discover and understand what have happened. the task is challenging: arbitrary guarantee pattern which has high default rate can be underneath the complex network structures. it is impossible to exhaustively compare all network patterns to determine whether it is in high default. based on the conjecture that defaults occur in clusters, we propose an interactive shneiderman mantra strategy [56] to narrow down the risk guarantee pattern searching space. fig. 2 gives the processing flow. because the goi are groups with high default rates, there may exist guarantee patterns which are prone to default. usually, the motifs are the most basic building blocks for a network and the number of structures are limited. motifs may reflect functional properties and provide a deep insight into the networks. a complex guarantee network is always connected by several smaller subgraphs bridged by the structural hole spanners. the sub-graphs inside the communities may reveal certain risk even fraud pattern. in this work, we obtain a set of motifs by first detecting motifs from the goi. the motifs are ranked by their default rates (eq. (4) ). among them, high default rate motifs are noted as pattern of interest (poi) and they may need be investigated by banking experts in priority. where m is a motif. all motifs are possible risk loan guarantee patterns. however, it is still computationally challenging to obtain all pois by the approach above for the following reasons. firstly, motif structures increases with the node number increase rapidly, for example, 4 node motif has over 3000 possibilities. it is impossible to enumerate all motif structures. secondly, motif matching is exhaustively searched from the query graph into the large network, and it is essences subgraph isomorphism problem. it still takes too much time for motifs with more nodes to be matched on the network. in this work, we propose an interactive motif editing approach. users can further explore the financial information of adjacent nodes and add them to the motifs and generate poi. network evolution over time is observed from the guarantee network. the topology of the network keeps changing -some nodes are connected to the network or removed from it, some communities are connected together through the guarantee of the structural hole spanner. like many other real networks, there are competitive decision making taking place in the guarantee network: when a firm lack security to obtain a loan from the bank, it may resort to a guarantee corporation or thirty party firms. to some extent, the new guarantors may improve the overall system rationality but also may induce unstable factor as the network becomes even more complex. understanding the network dynamic helps to financial experts understand how the firms are connected together temporal. in this work, we use animation to visualize the evolving of guarantee network. users can drag the time bar to backtrack how the network evolve over time. they are allowed to hover mouse cursor over the node to view the company's financial information. this will help the financial experts understand what has happened historically. fig. 10 gives an example how a real network evolve from july 2013 to april 2014. combining enterprises financial status of different time, financial experts would be able to make analysis. financial systematic risks is a top concern for the government and banks, however, as a new phenomenon, the understanding to the systematic risk of the loan guarantee network is still not sufficient. sophisticated guarantee relationships tend to cause credit granted by multiple lenders and excessive credit. in the loan guarantee, a guarantor has the debt obligation if the borrower defaults, if the guarantee could not payback to the back, it may resort to its guarantors. in this case, the default may propagate like virus.the default contagious increases the possibility of occurrence of risks and transmission of risks. especially in the economic downturn, some enterprises face operation difficulties and the financial crisis will have a domino effect: the default phenomenon may spread rapidly in the network, and this will make a large number of enterprises fall into unfavorable situation. the government and the banks always wish to monitor the default spread status and understand the complexity of the current issue of risks before they can take precautionary measures, conduct research, and take effective measures to prevent and dissolve risks, to ensure that no regional or systemic financial risk occur. based on the relevant knowledge and experience, we develop the visual analytics tool to aid the default path discovery by visualization. a principle of the default diffusion can be described as the vulnerable nodes are the guarantors. fig. 11 gives a diffusion path illustration. (a) is a guarantee network with eight nodes, where node e provides guarantee to five adjacent nodes and c, d provide guarantee to b and then to a; (b) is the possible diffusion path, the default of node a may lead to the b, c, d even e default. it is noted that node g, f, h are not connected with node e, as the default of e will not affect the repayment status of g,f, and h. in practice, there may be multiple possible propagation path as each node can serve as guarantor or get guaranteed. it is difficult to outline the main propagation path from the entire. we make the following assumption: the node on multiple propagation pathes is the key to prevent large scale default diffusion and thus should be highlighted. we compute all the propagation pathes, count occurrences and highlight the node on the network. we use the color to illustrate the propagation risk importance. we design the visual analytics tool which enables financial experts take into account of several factors on the judgment of defaults. the factors include the financial information of the corporation and guarantee contract amount information. the former information is plain listed when the user hovers the mouse pointer on the node, while a sankey diagram is used to represent the guarantee flow. the widths of the sankey diagram bands are directly proportional to the guarantee amount. fig. 12 (a) gives results on a real guarantee network, when we choose one node, for example, node 32, the whole potential propagation path is highlighted in (b), and (c) is the corresponding sankey diagram. it can be seen that upstream companies usually provides more guarantee than they received. for example, node 18 provides much more guarantee than it receives. the imbalance of guarantee amount and collateral amount provide clue for the credit line assessment. the real situation is even much more complex. the default may be diffused like a virus infection and the virion must identify and bind to its receptor (guarantor). as mentioned earlier, each enterprises has more than 3000 financial entries, it is difficult to quantify anti-infective ability for each enterprises. we enable users to look up multiple financial status and cut off the propagation path. we also note that the propagation model provides more insights to end users and we plan to perform in-depth study for the topic and provide simulation interface in the future. we collect loan records spanning ten years from a major commercial bank in china. the names of the customers in the records are encrypted and replaced by an id; we can access the basic profile like the enterprise scale, the loan information like the guarantee id and loan credit. we first introduce the loan process, and then explain how the information are extracted and cleaned. the banks need to collect as much fine-grained information as possible, concerning the repayment ability of the enterprise. the information falls into four categories: transaction information, customer information, asset information such as mortgage status, history loan approval bank side record, etc. the most relevant to the loan guarantees are eight data tables: customer profile, loan account information, repayment status, guarantee profile, customer credit, loan contract, guarantee relationship, guarantee contract, default status. there are often more than one guarantors for one loan transaction, and there may be several loan transactions for a single guarantor in a period. once the loan is approved, the smes usually can obtain the full size of loan immediately, and start to repay to the bank regularly by an installment plan until the end of the loan contract. in the record preprocess phase, by joining the nine tables, we obtain records related to the corporation id and loan contracts. we then construct the guarantee network and compute the network related measurements. we now report the observations derived from the data. overall statistics there are 11,000 loan customers, which span 60,948 mutual guarantee relationships derived from 36,618 loan contracts. there are 5,911 defaults during the past ten years, out of the total 87,307 repayments. the overall default rate to the number of contracts is 6.77%. centrality indicators are helpful to identify the relative importance of nodes in the network. fig. 13 gives the histogram of several most complex subgraphs on how the defaults distributed with different centrality indicator values. it is noted defaults happen more on nodes with large authority value and small hub values. this is consistent with intuition -the enterprise works as the hub ones back a large number of other corporations and it is supposed to be relatively stable and operates in good condition. in contrast, the enterprise works as the authority ones and accepts guarantee from many other corporations and this means they lack funds security and have higher risk in trouble. the statistics indicate the lender to watch the status of the "authority" high nodes in the guarantee network. although the underlying assumption of pagerank is quite alike authority score, we did not observe similar correlation between the values and default rates (see fig. 13 ). it is observed that the larger the centrality the higher default rates. the tasks were as follows: (1) visual analytics for high default groups; and (2) visual analytics for high default pattern. the first case study is to find high default groups. the random walk community detection algorithm divides the guarantee network into 36 communities. the statistics are given in table 1 . we edit the community following basic guidelines: (1) consider default status, loan amount and other financial statistics comprehensively; (2) mall communities can be either merged with its neighbouring large communities or pruned. for example, community 35,34 both have 4 nodes and these firms never default. there is low possibility they will become high default groups in the future; while the community 23 be merged with the neighbouring communities. (3) structural hole spanner nodes should be paid special attention. usually, there are defaults happen on the structural hole spanners, the adjacent communities can be merged. finally, we obtain ten communities and seven of them has relative high default rates as table 2 . the seven medium sized groups of subgraphs which can be efficiently processed for further tasks. it is noted that the merge and reassign operation are based on the user expertise. as the user may choose various criteria, the final tree map can demonstrate different combinations and default rates. in this subsection, we explore high default patterns beyond guarantee circles. it includes (1) automatic motif detection from high default groups. specifically, we employ the gtriescanner (http://www.dcc.fc.up.pt/gtries/) approach. (2) matching the motifs with the entire network and calculate the ratio for default firms. (3) ranking the motifs in descending defaults order, and they are high default patterns. (4) the user interactively edits the high default patterns by adding more nodes, and the system will automatically match the new subgraph with the entire network and produce the ratio for default firms. theoretically, there are 199 and 9,364 possibility combinations for 4-and 5-vertex-motifs [33] for a directed network, respectively. matching all those motifs on the whole network would be time-consuming. the user interactively editing motifs helps more efficient to explore new patterns. in practice, we choose to analyze community 3, which consists of 103 enterprises; 36% of them default the 85% loans from the bank, as table 2 shows. fig. 15 gives the twenty 4-vertex-motifs automatic algorithm detected from community 3, and table 3 shows the statistical information. although there are nearly 200 kinds of 4 vertex node motif shapes, there are only 20 existing in the high default group. we thus perform analysis on the 20 motifs instead of every shape. the detailed motif shapes are given in fig. 15 . most of the them have rather complex structures, however, some of them are known to banking experts, for example, motif 6 is joint liability loan. some others can be understood by a combinations of smaller guarantee patterns. for example, motif 5 is a combination of joint liability with a single guarantee. three of the motifs, motif 15, 16, and 17 attracted our attention. (1) high default rates for the patterns (ranging from 61% to 90% in ratio for default firm and 55% to 100% in ratio for default amount); (2) relative small number of instances (4 or 5) are detected from the whole network. besides, (3) the top five risk motifs show single input, single output, feed forward structures. fig. 16 gives all the pattern 15 instances detected from the entire network. some of motif instances coincide together. these three patterns are interesting, for example, pattern 15 recurrent for five times in a group, the bank lost all the money lend to the enterprises with such guarantee structures(see table 3 ). there is high possibility that fraud loan guarantee may happen for several times; and local bank failed to recognize the fraud pattern. similar analysis implies pattern 16 and 17 may be also guarantee patterns with high default. we then conduct interviews with two banking loan experts. the first one comes from the financial regulator. the expert has more than five years of guarantee network research experience and has published several important investigation reports and books on the chinese loan guarantee network status. the second one comes from a major commercial bank credit department; who has ten years of loan approval experience. both experts are attracted by and understand the visualization guarantee relationships immediately. the first expert is rather interested with the community editing. he said they try to resolve the financial risks in guarantee network, a major operation is to split the loan guarantee network into smaller ones with risks isolated. in this case, health enterprises will not be affected by financially risk enterprises. the editing function of our tool provides them a powerful weapon to achieve their target. besides, the expert also has interest in the risk guarantee pattern discovery module, and he agrees the significant value provided by the finding of such risk patterns. there might exist illegally convey benefits under the suggested high default patterns. the expert will also dive into the financial disclo-sures of the risk guarantee enterprises and examine whether fraud guarantees are happening. the second expert expressed that he has never grasp the whole intercalations between enterprises so clear when assessing a loan. the expert claims the tree map gives an intuitive understanding about the guarantee groups. we present visual analytics approach for loan guarantee network risk management in this paper. to our best knowledge, this is the first work using visualization analysis approaches to address the guarantee network default risk issue. we design and implement interactive interface to analysis the individual enterprises default risk, high default groups, patterns in the group, network evolution and default diffusion path. the analysis can help the government and bank monitoring default spread status and provides insight for taking precautionary measures to prevent and dissolve 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for personal loans relational learning via latent social dimensions community detection and mining in social media applying animation to the visual analysis of financial time-dependent data using social network knowledge for detecting spider constructions in social security fraud sales pipeline win propensity prediction: a regression approach towards effective prioritizing water pipe replacement and rehabilitation evaluation without ground truth in social media research graph-structured sparse optimization for connected subgraph detection figure 14 : high default groups after interactive editing. motif key: cord-204125-fvd6d44c authors: chowdhury, muhammad e. h.; rahman, tawsifur; khandakar, amith; al-madeed, somaya; zughaier, susu m.; doi, suhail a. r.; hassen, hanadi; islam, mohammad t. title: an early warning tool for predicting mortality risk of covid-19 patients using machine learning date: 2020-07-29 journal: nan doi: nan sha: doc_id: 204125 cord_uid: fvd6d44c covid-19 pandemic has created an extreme pressure on the global healthcare services. fast, reliable and early clinical assessment of the severity of the disease can help in allocating and prioritizing resources to reduce mortality. in order to study the important blood biomarkers for predicting disease mortality, a retrospective study was conducted on 375 covid-19 positive patients admitted to tongji hospital (china) from january 10 to february 18, 2020. demographic and clinical characteristics, and patient outcomes were investigated using machine learning tools to identify key biomarkers to predict the mortality of individual patient. a nomogram was developed for predicting the mortality risk among covid-19 patients. lactate dehydrogenase, neutrophils (%), lymphocyte (%), high sensitive c-reactive protein, and age acquired at hospital admission were identified as key predictors of death by multi-tree xgboost model. the area under curve (auc) of the nomogram for the derivation and validation cohort were 0.961 and 0.991, respectively. an integrated score (lnlca) was calculated with the corresponding death probability. covid-19 patients were divided into three subgroups: low-, moderateand high-risk groups using lnlca cut-off values of 10.4 and 12.65 with the death probability less than 5%, 5% to 50%, and above 50%, respectively. the prognostic model, nomogram and lnlca score can help in early detection of high mortality risk of covid-19 patients, which will help doctors to improve the management of patient stratification. the novel coronavirus disease (covid-19) spread rapidly throughout the world from wuhan (hubei, china) since december 2019 [1] [2] [3] [4] [5] . since the outbreak, the number of reported cases has surpassed 12 million with more than 550 thousand deaths worldwide as of 12 july 2020 [6] . the covid-19 disease is caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which is a member of the coronavirus family. on 11 march 2020, covid-19 was declared as a pandemic by the world health organization (who) [7] . due to the pandemic, hospital capacity is being exceeded in many places and face issues in terms of limited medical staff, personal protective equipment, life-support equipment and others [8, 9] . symptoms of covid-19 are nonspecific, and infected individuals may develop fever (83-99%), cough (59-82%), loss of appetite (40-84%), fatigue (44-70%), shortness of breath (31-40%), coughing up sputum (28-33%) or muscle aches (11-35%) [10]. the disease can further progress into a severe pneumonia, acute respiratory distress syndrome (ards), myocardial injury, sepsis, septic shock, and even death [11] . though most covid-19 patients have a mild illness, there are some patients who show rapid deterioration (particularly within 7-14 days) from the onset of symptoms into severe covid-19 with or without ards [12, 13] . current epidemiological data suggest that the mortality rate of patients with severe covid-19 is higher than that of patients with non-severe covid-19 [14, 15] . it has been reported that 26.1-32.0% of patient infected with are prone to progressing critical illness [16] . recent studies have confirmed a high fatality rate of 61.5% for patients in critical cases, which increases with age and other medical comorbidities [16] . a large cohort study from 2449 patients has reported that during this pandemic healthcare system can be overwhelmed by hospitalization (20-31%) and intensive care unit (icu) admission rates (4.9-11.5%) [17] . this can be avoided by prioritizing hospital treatment for patients at high risk of deterioration and death, and treating low-risk patients in ambulatory environments, or by home-based self-quarantine. an effective tool is required to predict the disease trajectory to allocate resources efficiently and also improve the patient's condition. understanding the great potential of this approach, it is important to identify key patient variables that can help to predict the course of the disease at diagnosis. in other words, early identification of patients at high risk for progression to severe covid-19 will help in efficient utilization of healthcare resources via patient prioritization to reduce the mortality rate. several researches indicate that biomarkers can help to classify covid-19 patients with elevated risk of serious disease and mortality by providing crucial information regarding the patients' health status. al youha et al. [18] proposed a prognostic model called the kuwait progression indicator (kpi) score for predicting progression of severity in covid-19. the kpi model was based on quantifiable laboratory readings unlike other self-reported symptoms and other subjective parameters based scoring systems. the kpi score categorizes patients to low risk if the score goes below -7 and high risk if the score goes above 16, however, the progression risk in the intermediate group (for patients scores within -6 to 15) deemed by the authors as uncertain. this intermediate category however exists with many prognostic systems. weng et al. [19] reported an early prediction score called andc to predict mortality risk for covid-19 patients using 301 adult patients' data. lasso regression has identified age, neutrophil-to-lymphocyte ratio (nlr), ddimer, and c-reactive protein recorded during admission as mortality predictors for covid-19 patients [19] . they have developed a nomogram demonstrating good performance and also derived an integrated score, andc, with its corresponding death probability. they have also developed cutoff andc values to classify covid-19 patients into three groups: low, moderate and high-risk groups. the death probability were 5%, 5% to 50% and more than 50% in the low-, moderate-and high-risk group, respectively. using a cohort of 444 patients, xie et al. [20] proposed a prognostic model using lactate dehydrogenase, lymphocyte count, age, and spo2 as key-predictors of covid-19 related death. the model showed good discrimination for internal and external validation with c-statistics of 0.89 and 0.98 respectively. (c=0ꞏ98) validation. even though the model shows promising performance for internal calibration, however, external validation showed over and under-prediction for low-risk and high-risk patients respectively. yan et al. [21] reported a machine learning approach to select three biomarkers (lactic dehydrogenase (ldh), lymphocyte and high-sensitivity c-reactive protein (hs-crp)) and using them to predict individual patients mortality, 10 days ahead with more than 90 percent accuracy. in particular, high levels of ldh alone have been found to play a crucial role in identifying the vast majority of cases, which require immediate medical attention. however, there is no scoring system reported in this work, which can help the clinicians to identify the patients under risk quantitatively. another clinical study on 82 covid-19 patients showed that respiratory, cardiac, hemorrhage, hepatic, and renal injury had caused the death of 100%, 89%, 80.5%, 78.0%, and 31.7% patients respectively. most of the patients had increased crp (100%) and d-dimer (97.1%) [22] . the value of d-dimer as a prognostic factor was also shown to significantly increase odds of death if the amount is greater than 1 μg ml −1 upon admission [23, 24] . although several predictive prognostic models are proposed for the early detection of individuals at high risk of covid-19 mortality, a major gap remains in the design of state-of-the-art interpretable machine learning based algorithms and high performance quantitative scoring system to classify the most selective predictive biomarkers of patient death. identifying and prioritizing those at severe risks is important for both resource planning and treatment therapy. moreover, the high risk patients should be possible to continuously monitored using a reliable scoring tool during their hospital stay-time. likewise, reducing patient admission with very low risk of complications that can be handled safely by self-quarantine will help to minimize the pressure on healthcare facilities. therefore, using state-of-the-art machine learning algorithm, an early prediction scoring system was developed and also implemented to classify the most discriminatory biomarkers of patient mortality. the problem was initially introduced as a classification problem for determining the most appropriate biomarkers at the end of the test period with the aid of corresponding survival or death outcomes. the top ranked features with the best classification performance were used to develop a multivariable logistic regression-based nomogram and validated for the prognosis of death and survival. the findings obtained through this study provides a simple, easy-to-use and reliable algorithm for the prognosis of high-risk individuals and possess potential for clinical application. blood samples collected between 10 january and 18 february, 2020 from 375 patients in wuhan, china were retrospectively analyzed to identify reliable and relevant markers of mortality risk. medical records were collected using standard case report forms, which included information on epidemiological, demographic, clinical, laboratory and mortality outcomes. yan et al. [21] has published the dataset along with the article and the original study was approved by the tongji hospital ethics committee. patients' exclusion criteria for the study were: age (<18 years), pregnant, breastfeeding and missing data (>20%). out of 375 patients, 187 (49.9%) had fever while cough, fatigue, dyspnea, chest distress and muscular soreness were present in 52 (13.9%), 14 even though multiple blood sample data of the patients were available, only the data from the first sample were used as inputs for model training and validation to identify the key predictors of the disease severity. the model also helps in distinguishing patients that require immediate medical assistance. research using clinically captured data often suffers from missing data challenge leading to either bias introduction or negative impact on analytical outcomes. simple approach to handle this challenge is deleting the respective rows of data from further analysis. this simple approach is not very useful as it leads to loss of valuable information that would have been beneficial in the analysis and also can lead to biased estimates [25] . (1) where ℎ. a diagnosis nomogram was constructed by alexander zlotnik's nomolog [29] , based on multivariate logistic was carried out to identify the threshold values in which nomograms were clinically useful, using stata software. the parameters were drawn as a numerated horizontal axis scale and the values for the patient are put on the numerated scale. a vertical line was drawn down from the different parameter numerated arranged scales downward to a score axis. all five scores on the score axis were added to make a total score and this was linked to a death probability. it can be noted that according to the nomogram, higher score corresponds to a higher death probability. the model was designed using the initial blood sample of the patients. however, it can be applied to the biomarkers collected in later during the hospital stay period of the patients to predict death probability longitudinally using the lnlca score. of the 375 patients, 174 (46.4%) died, while 201 (53.6%) patients recovered from covid-19 and were discharged from hospital. figure 1 to determine the independent variables associated with death, univariate logistic regression analysis was performed with top-1, top-2, and up to top-10 features identified using two different techniques. it is clear from the figure 3 that top ranked 5 features produced highest auc of 0.97 for data imputed using mice algorithm while top-ranked 3 features produced highest auc of 0.95 for the data imputed using -1 ( figure 3 ). table 2 shows the overall accuracies and weighted average performance for other matrices for different models using top 1 to 10 features for 5-fold cross-validation using the logistic regression classifier along with the confusion matrices for each case. a multivariate logistic regression based nomogram for predicting early covid-19 mortality was built using topranked five biomarkers that were found important both statistically and using ml based classifier (as shown in table 1 , 2 and figure 3 ). the relationship between linear prediction of death and these biomarkers was evaluated using multivariable logistic regression which was reported in table 3 . regression coefficient, z-value, standard error and its statistical significance along with 95% confidence interval were shown in table 3 . z-value is the ratio of regression coefficient and its standard error. typically z-value indicates the strong and weak contributors in logistic regression. the the corresponding probability of death for a given lnlca score was determined from the model and is listed in figure 7 shows an example nomogram based scoring system for a covid-19 patient with the variable values at admission. individual score for each predictors were calculated and added to produce total score and death probability was calculated to 80%. this can be done as early as 9 days before the death of the patient. furthermore, we have categorized the patients from training and testing subgroups into three subgroups (low, moderate and high-risk) by associating actual outcome with the predicted outcome using the lnlca score. for training set ( table 4 and prioritize the moderate and high risk group patients. there were 52 patients in the test set who had an outcome of death after different duration of hospital stay. some patients were hospitalized in very late stages while some other patients were admitted in the early stages. the minimum, maximum, 262 (100.0%) p-value among three group is less than 0.001 p-value of low-risk group vs moderate-risk group is less than 0.001. p-value of low-risk group vs high-risk group is less than 0.001. p-value of moderate-risk group vs high-risk group is less than 0.001. 113 (100.0%) p-value among three group is less than 0.001 p-value of low-risk group vs moderate-risk group is 0.0037. p-value of low-risk group vs high-risk group is less than 0.001. p-value of moderate-risk group vs high-risk group is less than 0.001. age was identified as a key predictor of mortality in previous studies on coronavirus family such as sars [30] , middle east respiratory syndrome (mers) [31] and covid-19 [32] . this study has also concluded similar findings and this is because with the older age the immunosenescence and/or multiple medical conditions tend to make patients more prone to critical covid-19 illness [19] . yan et al. [16] showed that in patients with severe pulmonary interstitial disease, there is a significant increase of ldh and can be associated with indications for lung injury or idiopathic pulmonary fibrosis [33] . consistent results from the previous research were also found in this study, in which critically ill patients with covid-19 had elevated levels of ldh suggesting an increase in activity and severity of lung injury. ldh is an intracellular enzyme that leaks from damaged cells due to infection and viral replication leading to elevated levels in circulation. recently, liu et al. [34] proposed that increased neutrophil-to-lymphocyte ratio (nlr) can aid in the early prediction of the severity of covid-19 illness. both neutrophils and lymphocytes are critical components of the immune system and play very important role in host defense and clearing infections. lymphopenia, medical condition due to lower number of lymphocytes in the blood, is a typical feature in covid-19 patients, and may be a key factor in disease severity and mortality [35] . in this study, we have used neutrophils and lymphocytes percentage and similar to the previous studies have found that lower percentage of these two quantities were associated with severe covid-19 patients. according to previous research, patients with communityacquired pneumonia have significant immune system activation and/or immune dysfunction leading to changes in these quantities [35] . in addition, on the event of immunosuppression and apoptosis of lymphocytes caused by specific anti-inflammatory cytokines, bone marrow circulates neutrophils [36] , resulting in an increased nlr. however, in contrast to other models, it was observed in this study, both the parameters were small for high-risk patients. lu et al. [37] stated that crp tested upon admission may assist in predicting confirmed or suspected short-term mortality associated with covid-19. crp is an acute phase protein formed by hepatocytes caused by leukocyte-derived cytokines induced by infection, inflammation or tissue damage [38] [39] [40] . similar findings were found in this study where increased crp rates were measured at admission for the high mortality risk covid-19 patients. this indicated that these patients developed a serious lung inflammation or possibly a secondary bacterial infection, and clinical antibiotic treatment might be appropriate for those patients [21] . non-survivors in our study had low lymphocyte and neutrophil percentages, higher age, hscrp and ldh than those of survivors. in addition to the dysregulation of the coagulation system and/ immune system, it can be seen that covid-19 severity was significantly linked to the inflammatory response to the infection. this could lead to other worse medical consequences like ards, septic shock and coagulopathy etc. therefore, this kind of prognostic model will aid in the development of a rational and personalized therapeutic plan for the patients with critical illness. weng et al. [19] recently suggested that age, nlr, ddimer and crp were individual key predictors correlated with death probability. these key-predictors were used to create a nomogram for death prediction due to covid-19. in our research, the five key predictors recorded at admission were chosen by the xgboost feature selection to create a nomogram based prognostic model that exhibits excellent calibration and discrimination in predicting death probability of covid-19 patients. it was also validated by an unseen validation cohort. moreover, it was verified with multiple blood sample data collected from the patients during their hospital stay and the model holds valid for those cases as well. the auc values for development and validation cohort showed a strong distinction of 0.961 and 0.991 respectively using the proposed nomogram, which is, to the best of our knowledge, outperforms any other nomogram based models for covid-19 mortality prediction. in addition, this nomogram-derived lnlca score offered a simple, easy-to-understand and interpretable early detection tool for stratifying the high-risk covid-19 patients at admission and thereby assist their clinical management. covid-19 patients were categorized into three risk groups with varying risk of death using lnlca score measured and calculated at admission. low-risk group cases could be isolated and treated in an isolation center while the moderaterisk patients could be treated isolation ward in a specialized hospital. on the other hand, patients in high-risk group could be under close monitoring and should be moved to critical medical services or icu for urgent treatment if required. this study has scope for further improvement, which will be carried out in the future work. firstly, the study motivates the possibility of research on covid-19 clinical data helping in early mortality prediction but the proposed machine learning method is purely data-driven and may vary if starting from different datasets. the model can be further improved with the help of a larger dataset. secondly, the modelling principle adopted here is to have a minimal number of features for accurate predictions to avoid overfitting, which can be revised with several other models to identify any other sets of best features on a multi-center and multi-country data to produce a generalized model. in summary, based on multiple risk factors (lactate dehydrogenase, neutrophils (%), lymphocytes (%), high sensitive c-reactive protein, and age), our developed nomogram can predict the prognosis of patients with covid-19 with good discrimination and calibration. the model can predict the patient's outcome far ahead of the day of primary clinical outcome with very high accuracy. therefore, the application of lnlca would help clinicians make an efficient and optimized patient stratification management plan without overloading the healthcare resources and also reduce the death with improved and planned response. the authors also plan to further improve the performance of the model with the help of larger dataset with multi-center and multi-country data. the authors declare that they have no conflict of interest. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. the lancet clinical characteristics of coronavirus disease 2019 in china clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention coronavirus disease 2019 (covid-19): situation report-107 coronavirus disease 2019 (covid-19) situation report -68 critical care utilization for the covid-19 outbreak in lombardy, italy: early experience and forecast during an emergency response projecting hospital utilization during the covid-19 outbreaks in the united states estimating the 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for hospitalized patients with covid-19 an interpretable mortality prediction model for covid-19 patients clinical characteristics of 82 death cases with covid-19 clinical decision support tool and rapid point-of-care platform for determining disease severity in patients with covid-19 d-dimer levels on admission to predict in-hospital mortality in patients with covid-19 mice vs ppca: missing data imputation in healthcare xgboost: extreme gradient boosting. r package version 04-2 ridge estimators in logistic regression a general-purpose nomogram generator for predictive logistic regression models prognostication in severe acute respiratory syndrome: a retrospective time-course analysis of 1312 laboratoryconfirmed patients in hong kong epidemiological, demographic, and clinical characteristics of 47 cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study. the lancet infectious diseases risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in china staging of acute exacerbation in patients with idiopathic pulmonary fibrosis neutrophil-to-lymphocyte ratio predicts severe illness patients with 2019 novel coronavirus in the early stage lymphopenia in severe coronavirus disease-2019 (covid-19): systematic review and meta-analysis an increased alveolar cd4+ cd25+ foxp3+ t-regulatory cell ratio in acute respiratory distress syndrome is associated with increased 30-day mortality acp risk grade: a simple mortality index for patients with confirmed or suspected severe acute respiratory syndrome coronavirus 2 disease (covid-19) during the early stage of outbreak in wuhan predictive factors for pneumonia development and progression to respiratory failure in mers-cov infected patients dynamic changes and diagnostic and prognostic significance of serum pct, hs-crp and s-100 protein in central nervous system infection. experimental and therapeutic medicine high sensitive c-reactive protein: a new marker for urinary tract infection, vur and renal scar ethical approval: this article uses the clinical data which was made publicly available by yan et al. [21] . therefore, the authors of this study were not involved with human participants or animals. however, the original retrospective study carried out by yan et al. [21] was approved by the tongji hospital ethics committee. key: cord-011407-4cjlolp6 authors: cotton‐barratt, owen; daniel, max; sandberg, anders title: defence in depth against human extinction: prevention, response, resilience, and why they all matter date: 2020-01-24 journal: glob policy doi: 10.1111/1758-5899.12786 sha: doc_id: 11407 cord_uid: 4cjlolp6 we look at classifying extinction risks in three different ways, which affect how we can intervene to reduce risk. first, how does it start causing damage? second, how does it reach the scale of a global catastrophe? third, how does it reach everyone? in all of these three phases there is a defence layer that blocks most risks: first, we can prevent catastrophes from occurring. second, we can respond to catastrophes before they reach a global scale. third, humanity is resilient against extinction even in the face of global catastrophes. the largest probability of extinction is posed when all of these defences are weak, that is, by risks we are unlikely to prevent, unlikely to successfully respond to, and unlikely to be resilient against. we find that it’s usually best to invest significantly into strengthening all three defence layers. we also suggest ways to do so tailored to the classes of risk we identify. lastly, we discuss the importance of underlying risk factors – events or structural conditions that may weaken the defence layers even without posing a risk of immediate extinction themselves. • future research should identify synergies between reducing extinction and other risks. for example, research on climate change adaptation and mitigation should assess how we can best preserve our ability to prevent, respond to, and be resilient against extinction risks. our framework for discussing extinction risks human extinction would be a tragedy. for many moral views it would be far worse than merely the deaths entailed, because it would curtail our potential by wiping out all future generations and all value they could have produced (bostrom, 2013; parfit, 1984; rees, 2003 rees, , 2018 . human extinction is also possible, even this century. both the total risk of extinction by 2100 and the probabilities of specific potential causes have been estimated using a variety of methods including trend extrapolation, mathematical modelling, and expert elicitation; see rowe and beard (2018) for a review, as well as tonn and stiefel (2013) for methodological recommendations. for example, pamlin and armstrong (2015) give probabilities between 0.00003% and 5% for different scenarios that could eventually cause irreversible civilisational collapse. to guide research and policymaking in these areas, it may be important to understand what kind of processes could lead to our premature extinction. people have considered and studied possibilities such as asteroid impacts (matheny, 2007) , nuclear war (turco et al., 1983) , and engineered pandemics (millett and snyder-beattie, 2017) . in this article we will consider three different ways of classifying such risks. the motivating question behind the classifications we present is 'how might this affect policy towards these risks? ' we proceed by identifying three phases in an extinction process at which people may intervene. for each phase, we ask how people could stop the process, because the different failure modes may be best addressed in different ways. for this reason we do not try to classify risks by the kind of natural process they represent, or which life support system they undermine (unlike e.g. avin et al., 2018) . an event causing human extinction would be unprecedented, so is likely to have some feature or combination of features that is without precedent in human history. now, we see events with some unprecedented property all of the timewhether they are natural, accidental, or deliberateand many of these will be bad for people. however, a large majority of those pose essentially zero risk of causing our extinction. why is it that some damaging processes pose risks of extinction, but many do not? by understanding the key differences we may be better placed to identify new risks and to form risk management strategies that attack their causes as well as other factors behind their destructive potential. we suggest that much of the difference can usefully be explained by three broad defence layers ( figure 1 ): 1. first layer: prevention. processesnatural or humanwhich help people are liable to be recognised and scaled up (barring defeaters such as coordination problems). in contrast processes which harm people tend to be avoided and dissuaded. in order to be bad for significant numbers of people, a process must either require minimal assistance from people, or otherwise bypass this avoidance mechanism. 2. second layer: response. 1 if a process is recognised to be causing great harm (and perhaps pose a risk of extinction), people may cooperate to reduce or mitigate its impact. in order to cause large global damage, it must impede this response, or have enough momentum that there is nothing people can do. 3. third layer: resilience. people are scattered widely over the planet. some are isolated from external contact for months at a time, or have several years' worth of stored food. even if a process manages to kill most of humanity, a surviving few might be able to rebuild. in order to cause human extinction, a catastrophe must kill everybody, or prevent a long-term recovery. the boundaries between these different types of risk-reducing activity aren't crisp, and one activity may help at multiple stages. but it seems that often activities will help primarily at one stage. we characterise prevention as reducing the likelihood that catastrophe strikes at all; it is necessarily done in advance. we characterise response as reducing the likelihood that a catastrophe becomes a severe global catastrophe (at the level which might threaten the future of civilisation). this includes reducing the impact of the catastrophe after it is causing obvious and significant damage, but the response layer might also be bolstered by mitigation work which is done in advance. finally, we characterise resilience as reducing the likelihood that a severe global catastrophe eventually causes human extinction. 2 successfully avoiding extinction could happen at each of these defence layers. in the rest of the article we explore two consequences of this. first, we can classify damaging processes by the way in which we could stop them at the defence layers. in section 2, we'll look at a classification of risks by their origin: understanding different ways in which we could succeed at the prevention layer. in section 3, we'll look at the features which may allow us to block them at the response layer. in section 4, we'll classify risks by the way in which we could stop them from finishing everybody. we conclude each section by policy implications. each risk will thus belong to three classesone per defence layer. for example, consider a terrorist group releasing an engineered virus that grows into a pandemic and eventually kills everyone. in our classification, we'll call this prospect a malicious risk with respect to its origin; a cascading risk with respect to its scaling mechanism of becoming a global catastrophe; and a vector risk in the last phase we've called endgame. we'll present more examples at the end of section 4 and in table 1 . second, we present implications of our framework distinguishing three layers. in section 5, we discuss how to allocate resources between the three defence layers, concluding that in most cases all of prevention, response, and resilience should receive substantial funding and attention. in section 6, we highlight that risk management, in addition to monitoring specific hazards, must protect its defence layers by fostering favourable structural conditions such as good global governance. avin et al. (2018) have recently presented a classification of risks to the lives of a significant proportion of the human population. they classify such risks based on 'critical systems affected, global spread mechanism, and prevention and mitigation failure'. our framework differs from theirs in two major ways. first, with extinction risks we focus on a more narrow type of risk. this allows us, in section 4, to discuss what might stop global catastrophes from causing extinction, a question specific to extinction risks. second, even where the classifications cover the same temporal phase of a global catastrophe, they are motivated by different questions. avin et al. attempt a comprehensive survey of the natural, technological, and social systems that may be affected by a disaster, for example listing 45 critical systems in their second section. by contrast, we ask why a risk might break through a defence layer, and look for answers that abstract away from the specific system affected. for instance, in section 2, we'll distinguish between unforeseen, expected but unintended, and intended harms. we believe the two classifications complement each other well. avin and colleagues' (2018) discussion of prevention and response failures is congenial to our section 6 on underlying risk factors. their extensive catalogues of critical systems, spread mechanisms and prevention failures highlight the wide range of relevant scientific disciplines and stakeholders, and can help identify fault points relevant to particularly many risks. conversely, we hope that our coarser typology can guide the search for additional critical systems and spread mechanisms. we believe that our classification also usefully highlights different ways of protecting the same systems. for example, the risks from natural and engineered pandemics might best be reduced by different policy levers even if both affected the same critical systems and spread by the same mechanisms. lastly, our classification can help identify risk management strategies that would reduce whole clusters of risks. for example, restricting access to dangerous information may prevent many risks from malicious groups, irrespective of the critical system that would be targeted. our classification also overlaps with the one by liu et al. (2018) , for example when they distinguish intended from other vulnerabilities or emphasise the importance of resilience. while the classifications otherwise differ, we believe ours contributes to their goal to dig 'beyond hazards' and surface a variety of intervention points. both the risks discussed by avin et al. (2018) and extinction risks by definition involve risks of a massive loss of lives. this sets them apart from other risks where the adverse outcome would also have global scale but could be limited to less severe damage such as economic losses. such risks are being studied by a growing literature on 'global systemic risk' (centeno et al., 2015) . rather than reviewing that literature here, we'll point out throughout the article where we believe it contains useful lessons for the study of extinction risks. finally, it's worth keeping in mind that extinction is not the only outcome that would permanently curtail humanity's potential; see bostrom (2013) for other ways in which this could happen. a classification of these other existential risks is beyond the scope of this article, as is a more comprehensive survey of the large literature on global risks (e.g. baum and barrett, 2018; baum and handoh, 2014; bostrom and cirkovi c 2008; posner, 2004) . avoiding catastrophe altogether is the most desirable outcome. the origin of a risk determines how it passes through the prevention layer, and hence the kind of steps society can take to strengthen prevention ( figure 2 ). the simplest explanation for a risk to bypass our background prevention of harm-creating activities is if the origin is outside of human control: a natural risk. examples include a large enough asteroid striking the earth, or a naturally occurring but particularly deadly pandemic. we sometimes can take steps to avoid natural risks. for example, we may be able to develop methods for deflecting asteroids. preventing natural risks generally requires proactive understanding and perhaps detection, for instance scanning for asteroids on earth-intersecting orbits. such risks share important properties with anthropogenic risks, as any explanation for how they might materialise must include an explanation of why the human-controlled prevention layer failed. all non-natural risks are in some sense anthropogenic, but we can classify them further. some may have a localised origin, needing relatively small numbers of people to trigger them. others require large-scale and widespread activity. in each case there are at least a couple of ways that it could get through the prevention layer. note that there is a spectrum in terms of the number of people who are needed to produce different risks, so the division between 'few people' and 'many people' is not crisp. we might think of the boundary as being around one hundred thousand or one million people, and things close to this boundary will have properties of both classes. however, it appears to us that for many of the plausible risks the number required is either much smaller (e.g., an individual or a cohesive group of people such as a company or military unit) or much larger than this (e.g., the population of a major power or even the whole world), so the qualitative distinction between 'few people' and 'many people' (and the different implications of these for responding) seems to us a useful one. also potentially relevant are the knowledge and intentions of the people conducting the risky activity. they may anthropogenic risks from small groups the case of a risk where relatively few people are involved in triggering and they are unaware of the potential harm is an unseen risk. 4 this is likely to involve a new kind of activity; it is most plausible with the development of unprecedented technologies (gpp, 2015) , such as perhaps advanced artificial intelligence (bostrom, 2014) , nanotechnology (auplat, 2012 (auplat, , 2013 umbrello and baum, 2018) , or high-energy physics experiments (ord et al., 2010) . the case of a localised unintentional trigger which was foreseen as a possibility (and the dynamics somewhat understood) is an accident risk. this could include a nuclear war starting because of a fault in a system or human error, or the escape of an engineered pathogen from an experiment despite safety precautions. if the harm was known and intended, we have a malicious risk. this is a scenario where a small group of people wants to do widespread damage; 5 see torres (2016 torres ( , 2018b for a typology and examples. malicious risks tend to be extreme forms of terrorism, where there is a threat which could cause global damage. turning to scenarios where many people are involved, we ask why so many would pursue an activity which causes global damage. perhaps they do not know about the damage. this is a latent risk. for them to remain ignorant for long enough, it is likely that the damage is caused in an indirect or delayed manner. we have seen latent risks realised before, but not ones that threatened extinction. for example, asbestos was used in a widespread manner before it was realised that it caused health problems. and it was many decades after we scaled up the burning of fossil fuels that we realised this contributed to climate change. if our climate turns out to be more sensitive than expected (nordhaus, 2011; wagner and weitzman, 2015; weitzman, 2009) , and continued fossil fuel use triggers a truly catastrophic shift in climate, then this could be a latent risk today. in some cases people may be aware of the damage and engage in the activity anyway. this failure to internalise negative externalities is typified by 'tragedy of the commons' scenarios, so we can call this a commons risk. for example, failure to act together to tackle global warming may be a commons risk (but lack of understanding of the dynamics causes a blur with latent risk). in general, commons risks require some coordination failure. they are therefore more likely if features of the risk inhibit coordination; see for example barrett (2016) and sandler (2016) for a game-theoretic analysis of such features. finally, there are cases where a large number of people engage in an activity to cause deliberate harm: conflict risk. this could include wars and genocides. wars share some features with commons risk: there are solutions which are better for everybody but are not reached. in most conflicts, actors are intentionally causing harm, but only as an instrumental goal. in the above we classify risks according to who creates the risk and their state of knowledge. we have done this because if we want to prevent risk it will often be most effective to go to the source. but we could also ask who is in a position to take actions to avoid the risk. in many cases those creating it have most leverage, but in principle almost any actor could take steps to reduce the occurrence rate. if risk prevention is underprovided, this is likely to be a tragedy of the commons scenario, and share characteristics with commons risk. from a moral and legal standpoint intentionality often matters. the possibility of being found culpable is an important incentive for avoiding risk-causing activities and part of risk management in most societies. if creating or hiding potential catastrophic risks is made more blameworthy, prevention will likely be more effective. unfortunately it also often motivates concealment that can create or aggravate risk; see chernov and sornette (2015) for case studies of how this misincentive can weaken prevention and response. this shows the importance of making accountability effectively enforceable. • to be able to prevent natural risks, we need research aimed at identifying potential hazards, understanding their dynamics, and eventually develop ways to reduce their rate of occurrence. • to avoid unseen and latent risks, we can promote norms such as appropriate risk management principles at institutions that engage in plausibly risky activities; note that there is an extensive literature on rivalling risk management principles (e.g. foster et al., 2000; o'riordan and cameron, 1994; sandin, 1999; sunstein, 2005; wiener, 2011) , especially in the face of catastrophic risks (baum, 2015; bostrom, 2013; buchholz and schymura, 2012; sunstein, 2007 sunstein, , 2009 tonn, 2009; tonn and stiefel, 2014 )advocating for any particular principle is beyond the scope of this article. see also jebari (2015) for a discussion of how heuristics from engineering safety may help prevent unseen, latent, and accident risks. regular horizon scanning may identify previously unknown risks, enabling us to develop targeted prevention measures. organisations must be set up in such a way that warnings of newly discovered risks reach decision-makers (see clarke and eddy, 2017 , for case studies where this failed). • accidents may be prevented by general safety norms that also help reduce unseen risk. in addition, building on our understanding of specific accident scenarios, we can design failsafe systems or follow operational routines that minimise accident risk. in some cases, we may want to eschew an accident-prone technology altogether in favour of safer alternatives. accident prevention may benefit from research on high reliability organisations (roberts and bea, 2001 ) and lessons learnt from historical accidents. where effective prevention measures have been identified, it may be beneficial to codify them through norms and law at the national and international levels. alternatively, if we can internalise the expected damages of accidents through mechanisms such as insurance, we can leverage market incentives. 6 • solving the coordination problems at the heart of commons and conflict risks is sometimes possible by fostering national or international cooperation, be it through building dedicated institutions or through establishing beneficial customs. 7 one idea is to give a stronger political voice to future generations (jones et al., 2018; tonn, 1991 tonn, , 2018 . • lastly, we can prevent malicious risks by combating extremism. technical (trask, 2017) as well as institutional (lewis, 2018) innovations may help with governance challenges in this area, a survey of which is beyond the scope of this article. • note that our classification by origin is aimed at identifying policies that wouldif successfully implementedreduce a broad class of risks. developing policy solutions is, however, just one step toward effective prevention. we must then also actually implement themwhich may not happen due to, for example, free-riding incentives. our classification does not speak to this implementation step. avin et al. (2018) congenially address just this challenge in their classification of prevention and mitigation failures. classification by scaling mechanism: types of response failure for a catastrophe to become a global catastrophe, it must eventually have large effects despite our response aimed at stopping it. to understand how this can happen, it's useful to look at the time when we could first react. effects must then either already be large or scale up by a large factor afterwards ( figure 3 ). if the initial effects are large, we will simply say that the risk is large. if not, we can look at the scaling process. if massive scaling happens in a small number of steps, we say there is leverage in play. if scaling in all steps is moderate, there must be quite a lot of such stepsin this case we say that the risk is cascading. paradigm examples of catastrophes of an immediately global scale are large sudden-onset natural disasters such as asteroid strikes. since we cannot respond to them at a smaller-scale stage, mitigation measures we can take in advance (part of the second defence layer as they would reduce damage after it has started) and the other defence layers of prevention and resilience are particularly important to reduce such risks. prevention and mitigation may benefit from detecting a threatsay, an asteroidearly, but in our classification this is different from responding after there has been some actual small-scale damage. leverage points for rapid one-step scaling can be located in natural systems, for example if the extinction of a key species caused an ecosystem to collapse. however, it seems to us that leverage points are more common in technological or social systems that were designed to concentrate power or control. risks of both natural and anthropogenic origin may interact with such systems. for instance, a tsunami triggered the 2011 disaster at the fukushima daiichi nuclear power plant. anthropogenic examples include nuclear war (possible to trigger by a few individuals linked to a larger chain of command and control) or attacks on weak points in key global infrastructure. responding to leverage risks is challenging because there are only few opportunities to intervene. on the other hand, blocking even one step of leveraged growth would be highly impactful. this suggests that response measures may be worthwhile if they can be targeted at the leverage points. with the major exception of escalating conflicts, cascading risks normally cascade in a way which does not rely on humans deciding to further the effects. a typical example is the self-propagating growth of an epidemic. as automation becomes more widespread, there will be larger systems without humans in the loop, and thus perhaps more opportunities for different kinds of cascading risk. since cascading risks are those which have a substantial amount of growing effects after we're able to interact with defence in depth them, it seems likely that they will typically give us more opportunities to respond, and that response will therefore be an important component of risk reduction. for risks which cascade exponentially (such as epidemics), an earlier response may be much more effective than a later one. reducing the rate of propagation is also effective if there exist other interventions that can eventually stop or revert the damage. however, there are a few secondary risk-enabling properties that can weaken the response layer and therefore help damage cascade to a global catastrophe which we could have stopped. for example, a cascading risk may: • impede cooperation: by preventing a coordinated response, the likelihood of a global catastrophe is increased. cooperation is harder when communication is limited, when it is hard to observe defection, or when there is decreased trust. • not obviously present a risk: the longer a cascading risk is under-recognised, the more it can develop before any real response. for example, long-incubation pathogens can spread further before their hazard becomes apparent. • be on extreme timescales: if the risk presents and cascades very fast, there is little opportunity for any response. johnson et al. (2012) analyse such 'ultrafast' events, using rapid changes in stock prices driven by trading algorithms as an example (braun et al., 2018 , however find that most of these 'mini flash crashes' are dominated by a single large order rather than being the result of a cascade). note, however, that which timescales count as relevantly 'fast' depends on our response capabilitiestechnological and institutional progress may result in faster-cascading threats but also in opportunities to respond faster. on the other hand people may be bad at addressing problems that won't manifest for generations, as is the case for some impacts of global warming. policy implications for responding to extinction risk • by their nature, we cannot respond to large risks before they become a global catastrophe. of particular importance for such risks are therefore: mitigation that can be done in advance, and the defence layers of prevention and resilience. • leverage risks provide us with the opportunity of a leveraged response: we can identify leverage points in advance and target our responses at them. • while the details of responses to cascading risks must be tailored to each specific case, we can highlight three general recommendations. first, detect damage early, when a catastrophe is still easy to contain. second, reduce the time lag between detection and response, for example, by continuously maintaining response capabilities and having rapidly executable contingency plans in place. third, ensure that planned responses won't be stymied by the cascading process itselffor example, don't store contingency plans for how to respond to a power outage on computers. 8 for a global catastrophe to cause human extinction, it must in the end stop the continued survival of the species. this could be direct: killing everyone; 9 or indirect: removing our ability to continue flourishing over a longer period (figure 4 ). in order to kill everyone, the catastrophe must reach everyone. we can further classify direct risks by how they reach everyone. the simplest way this could happen is if it is everywhere that people are or could plausibly be: a ubiquity risk. if the entire planet is struck by a deadly gamma ray burst, or enough of a deadly toxin is dispersed through the atmosphere, this could plausibly kill everyone. if it doesn't reach everywhere people might be, a direct risk must at least reach everywhere that people in fact are. this might occur when people have carried it along with them: a vector risk. this includes risk from pandemics (if they are sufficiently deadly and have a long enough incubation period that it is spread everywhere) or perhaps risks which are spread by memes (dawkins, 1976) , or which come from some technological artefacts which we carry everywhere. note that to directly cause extinction, a vector would need to impact hard-to-reach populations including 'disaster shelters, people working on submarines, and isolated peoples' (beckstead, 2015a, p. 36) . if not ubiquitous and not carried with the people, we would have to be extraordinarily unlucky for it to reach everyone by chance. setting this aside as too unlikely, we are left with agency risk: deliberate actors trying to reach everybody. the actors could be humans or nonhuman global policy (2020) intelligence (perhaps machine intelligence or even aliens). agency risk probably means someone deliberately trying to ensure nobody survives, which may make it easier to get through the resilience layer by allowing anticipation of and response to possible survival plans. in principle agency risk includes cases where someone is deliberately trying to reach everyone, and only by accident does so in a way that kills them. if the risk threatens extinction without killing everyone, it must reduce our long-term ability to survive as a species. this could include a very broad range of effects, but we can break them up according to the kind of ability it impedes. habitat risks make long-term survival impossible by altering or destroying the environment we live in so that it cannot easily support human life. for example a large enough asteroid impact might throw up dust which could prevent us from growing food for many yearsif this was long enough, it could lead to human extinction. alternatively an environmental change which lowered the average number of viable offspring to below replacement rates could pose a habitat risk. capability risks knock us back in a way that permanently remove an important societal capability, leading in the long run to extinction. one example might be moving to a social structure which precluded the ability to adapt to new circumstances. we are gesturing towards a distinction between habitat risks and capability risks, rather than drawing a sharp line. habitat risks work through damage to an external environment, where capability risks work through damage to more internal social systems (or even biological or psychological factors). capability risks are also even less direct than habitat risks, perhaps taking hundreds or thousands of years to lead to extinction. indeed there is not a clear line between capability risks and events which damage our capabilities but are not extinction risks (cf. section 6). nonetheless when considering risks of human extinction it may be important to account for events which could cause the loss of fragile but important capabilities. an important type of capability risk may be civilisational collapse. it is possible that killing enough people and destroying enough infrastructure could lead to a collapse of civilisation without causing immediate extinction. if this happens, it is then plausible that it might never recover, or recover in a less robust form, and be wiped out by some subsequent risk. it is an open and important question how likely this permanent loss of capability is (beckstead, 2015b) . if it is likely, the resilience layer may therefore be particularly important to reinforce, perhaps along the lines proposed by maher and baum (2013) . on the other hand, if even large amounts of destruction have only small effects on the chances of eventual extinction, it becomes more important to focus on risks which can otherwise get past the resilience layer. we finally illustrate our completed classification scheme by applying it to examples, which we summarise in table 1 . throughout the text, we've repeatedly referred to an asteroid strike that might cause extinction due to an ensuing impact winter. we've called this a natural risk regarding its origin; a large risk regarding scale, with no opportunity to intervene between the asteroid impact and its damage affecting the whole globe; and, if we assume that humanity dies out because climatic changes remove the ability to grow crops, a habitat risk in the endgame phase. our next pair of examples illustrates that risks with the same salient central mechanismin this case nuclear warmay well differ during other phases. consider first a nuclear war precipitated by a malfunctioning early warning system that is, a nuclear power launching what turns out to be a first strike because it falsely believed that its nuclear destruction was imminent. suppose further that this causes a nuclear winter, leading to human extinction. this would be an accident that scales via leverage, and finally manifests as a habitat risk. contrast this with the intentional use of nuclear weapons in an escalating conventional war, and assume further that this either doesn't cause a nuclear winter or that some humans are able to survive despite adverse climatic conditions. instead, humanity never recovers from widespread destruction, and is eventually wiped out by some other catastrophe that could have easily been avoided by a technologically advanced civilisation. this second scenario would be a conflict that again scaled via the leverage associated with nuclear weapons, but then finished off humanity by removing a crucial capability rather than via damage to its habitat. we close by applying our classification to a more speculative risk we might face this century. some scholars (e.g. bostrom, 2014) have warned that progress in artificial intelligence (ai) could at some point allow unforeseen rapid self-improvement in some ai system, perhaps one that uses machine learning and can autonomously acquire additional training data via sensors or simulation. the concern is that this could result in a powerful ai agent that deliberately wipes out humanity to pre-empt interference with its objectives (see omohundro, 2008 , for an argument why such preemption might be plausible). to the extent that we currently don't know of any machine learning algorithms that could exhibit such behaviour, this would be an unseen risk; the scaling would be via leverage if we assume a discrete algorithmic improvement as trigger, or alternatively the risk could be rapidly cascading; in the endgame, this scenario would present an agency risk. • to guard against what today would be ubiquity risks, we may in the future be able to establish human settlements on other planets (armstrong and sandberg, 2013) . 10 • vector risks may not reach people in isolated and self-sufficient communities. establishing disaster shelters may hence be an attractive option. self-sufficient shelters can also reduce habitat risk. jebari (2015) discusses how to maximise the resilience benefits from shelters, while beckstead (2015a) has argued that their marginal effect would be limited due to the presence of isolated peoples, submarine crews, and existing shelters. • resilience against vector and agency risks may be increased by late-stage response measures that work even in the event of widespread damage to infrastructure and the breakdown of social structure. an example might be the 'isolated, self-sufficient, and continuously manned underground refuges' suggested by jebari (2015, p. 541 ). in this section we will use our guiding idea of three defence layers to present a way of calculating the extinction probability posed by a given risk. we'll draw three high-level conclusions: first, the most severe risks are those which have a high probability of breaking through all three defence layers. second, when allocating resources between the defence layers, rather than comparing absolute changes in these probabilities we should assess how often we can halve the probability of a risk getting through each layer. third, it's best to distribute a sufficiently large budget across all three defence layers. we are interested in the probability p that a given risk r will cause human extinction in a specific timeframe, say by 2100. whichever three classes r belongs to, in order to cause extinction it needs to get past all three defence layers; its associated extinction probability p is therefore equal to the product of three factors: 1. the probability c for r getting past the first barrier and causing a catastrophe; 2. the conditional probability g that r gets past the second barrier to cause a global catastrophe, given that it has passed the first barrier; and 3. the conditional probability e that r gets past the third barrier to cause human extinction, given that it has passed the second barrier. in short: p = cágáe. each of c, g, and e can get extremely small for some risks. but the extinction probability p will be highest when all three terms are non-negligible. hence we get our (somewhat obvious) first conclusion that the most concerning risks are those which can plausibly get past all three defence layers. however, most concerning doesn't necessarily translate into the most valuable to act on. suppose we'd like to invest additional resources into reducing risk r. we could use them to strengthen either of the three defences, which would make it less likely that r passes that defence. we should then compare relative rather than absolute changes to these probabilities, which is our second conclusion. that is, to minimise the extinction probability p we should ask which of c, g, and e we can halve most often. this is because the same relative change of each probability will have the same effect on the extinction probability phalving either of c, g, or e will halve p. by contrast, the effect of the same absolute change will vary depending on the other two probabilities; for instance, reducing c by 0.1 reduces p by 0.1ágáe. in particular, a given absolute change will be more valuable if the other two probabilities are large. when one of c, g, or e is close to 100%, it may be much harder to reduce it to 50% than it would be to halve a smaller probability. the principle of comparing how often we can halve c, g, and e then implies that we're better off reducing probabilities not close to 100%. for example, consider a large asteroid striking the earth. we could take steps to avoid it (for example by scanning and deflecting), and we could take steps to increase our resilience (for example by securing food production). but if a large asteroid does cause a catastrophe, it seems very likely to cause a global catastrophe, and it is unclear that there is much to be done in reducing the risk at the scaling stage. in other words, the probability g is close to 1 and prohibitively hard to substantially reduce. we therefore shouldn't invest resources into futile responses, but instead use them to strengthen both prevention and resilience. what if each defence layer has a decent chance of stopping a risk? we'll then be best off by allocating a non-zero chunk of funding to all three of thema strategy of defence in depth, our third conclusion. the reason just is the familiar phenomenon of diminishing marginal returns of resources. it may initially be best to strengthen a particular layerbut once we've taken the low-hanging fruit there, investing in another layer (or in reducing another risk) will become equally cost-effective. of course, our budget might be exhausted earlier. defending in depth therefore tends to be optimal if and only if we can spend relatively much in total. we close by discussing some limitations of our analysis. first, we remain silent on the optimal allocation of resources between different risks (rather than between different layers for a fixed risk or basket of risks); indeed, as we'll argue in section 6, comprehensively answering the question of how to optimally allocate resources intended for extinction risk reduction requires us to look beyond even the full set of extinction risks. we do hope that our work could prove foundational for further research that investigates both the allocation between risks and between defence layers simultaneously. indeed, it would be straightforward to consider several risks p i = c i ág i áe i , i = 1, . . ., n; assuming specific functional forms for how the probabilities c i , g i , and e i change in response to invested resources could then yield valuable insights. second, we have not considered interactions between different defence layers or different risks (graham et al., 1995; baum, 2019; baum and barrett, 2017; martin and pindyck, 2015) . these can present both as tradeoffs or synergies. for example, traffic restrictions in response to a pandemic might slow down research on a treatment that would render the disease non-fatal, thus harming the resilience layer; on the other hand, they may inadvertently help with preventing malicious risk or being resilient against agency risk. • the most important extinction risks to act on are those that have a non-negligible chance of breaking through all three defence layersrisks where we have a realistic chance of failing to prevent, a realistic chance of failing to successfully respond to, and a realistic chance of failing to be resilient against. • due to diminishing marginal returns, when budgets are high enough it will often be best to maintain a portfolio of significant investment into each of prevention, response, and resilience. in sections 2-4 we have considered ways of classifying threats that may cause human extinction and the pathways through which they may do so. our classification was based on the three defence layers of prevention, response, and resilience. giving centre stage to the defence layers provides the following useful lens for extinction risk management. if our main goal is to reduce the likelihood of extinction, we can equivalently express this by saying that we should aim to strengthen the defence layers. indeed, extinction can only become less likely if at least one particular extinction risk is made less likely; in turn this requires that it has a smaller chance of making it past at least one of the defence layers. this is significant because there is a spectrum of ways to improve our defences depending on how narrowly our measures are tailored to specific risks. at one extreme, we can increase our capacity to prevent, respond to, or be resilient against one risk; for example, we can research methods to deflect asteroids. in between are measures to defend against a particular class of risk, as we've highlighted in our policy recommendations. at the other extreme is the reduction of underlying risk factors that weaken our capacity to defend against many classes of risks. risk factors need not be associated with any potential proximate cause of extinction. for example, consider regional wars; even when they don't escalate to a global catastrophe, they could hinder global cooperation and thus impede many defences. global catastrophes constitute one important type of risk factor. we already discussed the possibility of them making earth uninhabitable or removing a capability that would be crucial for long-term survival. but even if they do neither of these, they can severely damage our defence layers. in particular, getting hit by a global catastrophe followed in short succession by another might be enough to cause extinction when neither alone would have done so. there are significant historic examples of such compound risks below the extinction level. for instance, the deadliest accident in aviation history occurred when two planes collided on an airport runway; this was only possible because a previous terrorist attack on another airport had caused congestion due to rerouted planes, which disabled the prevention measure of using separate routes for taxiing and takeoff (weick, 1990) . when considering catastrophes we should therefore pay particular attention to negative impacts they may have on the defence layers. our capacity to defend also depends on various structural properties that can change in gradual ways even in the absence of particularly conspicuous events. for example, the resilience layer may be weakened by continuous increases in specialisation and global interdependence. this can be compared with the model of synchronous failure suggested by homer-dixon et al. (2015) . they describe how the slow accumulation of multiple simultaneous stresses makes a system vulnerable to a cascading failure. it is beyond the scope of this article to attempt a complete survey of risk factors; we merely emphasise that they should be considered. we do hope that our classifications in sections 2-4 may be helpful in identifying risk factors. for example, thinking about preventing conflict and common risks may point us to global governance, while having identified vector and agency risks may highlight the importance of interdependence (even though, upon further scrutiny, these risk factors turn out to be relevant for many other classes of risk as well). we conclude that the allocation of resources between layers defending against specific risks, which we investigated in section 2, is not necessarily the most central task of extinction risk management. it is an open and important question whether reducing specific risks, clusters of risks, or underlying risk factors is most effective on the margin. the study and management of extinction risks are challenging for several reasons. cognitive biases make it hard to appreciate the scale and probability of human extinction (wiener, 2016; yudkowsky, 2008) . most potential people affected are in future generations, whose interests aren't well represented in our political systems. hazards can arise and scale in many different ways, requiring a variety of disciplines and stakeholders to understand and stop them. and since there is no precedent for human extinction, we struggle with a lack of data. faced with such difficult terrain, we have considered the problem from a reasonably high level of abstraction; we hope thereby to focus attention on the most crucial aspects. if this work is useful, it will be as a foundation for future work or decisions. in some cases our classification might provoke thoughts that are helpful directly for decision-makers that engage with specific risks. however, we anticipate that our work will be most useful in informing the design of systems for analysing and prioritising between several extinction risks, or in informing the direction of future research. data sharing is not applicable to this article as no new data were created or analysed. notes 1 we are particularly indebted to toby ord for several very helpful comments and conversations. we also thank scott janzwood, sebastian farquhar, martina kunz, huw price, se an o h eigeartaigh, shahar avin, the audience at a seminar at cambridge's centre for the study of existential risk (cser), and two anonymous reviewers for helpful comments on earlier drafts of this article. we're also grateful to eva-maria nag for comments on our policy suggestions. the contributions of owen cotton-barratt and anders sandberg to this article are part of a project that has received funding from the european research council (erc) under the european union's horizon 2020 research and innovation programme (grant agreement no 669751). 1. in the terminology of the united nations office for disaster risk reduction (undrr, 2016), response denotes the provision of emergency services and public assistance during and immediately after a disaster. in our usage, we include any steps which may prevent a catastrophe scaling to a global catastrophe. this could include work traditionally referred to as mitigation. 2. the concept of resilience, originally coined in ecology (holling, 1973) , today is widely used in the analysis of risks of many types (e.g. folke et al., 2010) . in undrr (2016) terminology, resilience refers to '[t]he ability of a system, community or society exposed to hazards to resist, absorb, accommodate, adapt to, transform and recover from the effects of a hazard in a timely and efficient manner, including through the preservation and restoration of its essential basic structures and functions through risk management.' in this article, we usually use resilience to specifically denote the ability of humanity as a whole to recover from a global catastrophe in a way that enables its long-term survival. this ability may in turn depend on the resilience of many smaller natural, technical, and socio-ecological systems. 3. strictly knowledge and intentionality are two separate dimensions; however it is essentially impossible to intend the harm without being aware of the possibility, so we treat it as a spectrum with ignorance at one end, intent at the other end, and knowledge without intent in the middle. again, there is some blur between these: there are degrees of awareness about a risk, and an intention of harm may be more or less central to an action. 4. there are degrees of lack of foresight of the risk. cases where the people performing the activity are substantially unaware of the risks have many of the relevant features of this category, even if they have suspicions about the risks, or other people are aware of the risks. 5. they may not intend for that damage to cause human extinctionfor the purposes of acting on this classification it's more useful to know whether they were trying to cause harm. 6. we thank an anonymous reviewer for suggesting the policy responses of avoiding dangerous technologies and mandating insurance. 7. global coordination more broadly may however be a double edged tool, since increased interdependency if not well managed can also increase the chance of systemic risks (goldin & mariathasan, 2014) . 8. we thank an anonymous reviewer for suggesting both the third general recommendation and the example. 9. what about a risk that directly kills, say, 99.9999% of people? technically this poses only an indirect risk, since to cause extinction it needs to remove the capability of the survivors to recover. however, if the proportion threatened is high enough then we can reason that it must also have a way of reaching essentially everyone, so the analysis of direct risks will also be relevant. 10. some scholars have argued that humanity expanding into space would increase other risks; see for example an interview (deudney, n.d.) and an upcoming book (deudney, forthcoming) by political scientist daniel deudney and torres (2018a) . assessing the overall desirability of space colonisation is beyond the scope of this article. eternity in six hours: intergalactic spreading of intelligent life and sharpening the fermi paradox the challenges of nanotechnology policy making part 1. discussing mandatory frameworks the challenges of nanotechnology policy making part 2. discussing voluntary frameworks and options classifying global catastrophic risks collective action to avoid catastrophe: when countries succeed, when they fail, and why risk and resilience for unknown, unquantifiable, systemic, and unlikely/catastrophic threats risk-risk tradeoff analysis of nuclear explosives for asteroid deflection', risk analysis towards an integrated assessment of global catastrophic risk global catastrophes: the most extreme risks 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precautionary principle global challenges: 12 risks that threaten human civilization reasons and persons catastrophe: risk and response our final hour: a scientist's warning: how terror, error, and environmental disaster threaten humankind's future in this century -on earth and beyond on the future: prospects for humanity must accidents happen? lessons from high-reliability organizations probabilities, methodologies and the evidence base in existential risk assessments. working paper, centre for the study of existential risk dimensions of the precautionary principle strategic aspects of difficult global challenges global policy (2020) © 2020 the authors laws of fear: beyond the precautionary principle the catastrophic harm precautionary principle', issues in legal scholarship worst-case scenarios the court of generations: a proposed amendment to the us constitution obligations to future generations and acceptable risks of human extinction philosophical, institutional, and decision making frameworks for meeting obligations to future generations evaluating methods for estimating existential risks human extinction risk and uncertainty: assessing conditions for action agential risks: a comprehensive introduction space colonization and suffering risks: reassessing the "maxipok rule agential risks and information hazards: an unavoidable but dangerous topic?', futures, 95 safe crime prediction: homomorphic encryption and deep learning for more effective nuclear winter: global consequences of multiple nuclear explosions evaluating future nanotechnology: the net societal impacts of atomically precise manufacturing report of the open-ended intergovernmental expert working group on indicators and terminology relating to disaster risk reduction climate shock: the economic consequences of a hotter planet the vulnerable system: an analysis of the tenerife air disaster on modeling and interpreting the economics of catastrophic climate change the rhetoric of precaution the tragedy of the uncommons: on the politics of apocalypse cognitive biases potentially affecting judgment of global risks owen cotton-barratt is a mathematician at the future of humanity institute, university of oxford. his research concerns high-stakes decision-making in cases of deep uncertainty, including normative uncertainty, future technological developments, unprecedented accidents, and untested social responses.max daniel is a senior research scholar at the future of humanity institute, university of oxford. his research interests include existential risks, the governance of risks from transformative artificial intelligence, and foundational questions regarding our obligations and abilities to help future generations.anders sandberg is a senior research fellow at the future of humanity institute, university of oxford. his research deals with the management of low-probability high-impact risks, societal and ethical issues surrounding human enhancement, estimating the capabilities of future technologies, and very long-range futures. key: cord-023473-ofwdzu5t authors: tan, wei‐jiat; enderwick, peter title: managing threats in the global era: the impact and response to sars date: 2006-06-26 journal: nan doi: 10.1002/tie.20107 sha: doc_id: 23473 cord_uid: ofwdzu5t in early 2003, the sars virus brought disruption of public and business activities in many areas of the world, particularly asia. as a result of its impact, sars quickly established itself as a new kind of global uncertainty and posed challenges for traditional methods of risk management. this article examines the impact that sars has had through means of a case study and builds on this to provide recommendations for how uncertainty may be managed in an increasingly globalized world. reconsideration of strategic and risk‐management approaches have become necessary. supply‐chain management and corporate strategy require a fundamental rethink to balance the pursuit of efficiency with increased responsiveness and flexibility. unpredictability and turbulence in the international business environment suggest that traditional planning approaches that assume linear growth may give way to more scenario‐based planning. this will encourage firms to contemplate a variety of possible futures and better prepare them for unanticipated events. similarly, contingent‐based continuity plans help businesses continue running even during a crisis. © 2006 wiley periodicals, inc. managing threats in the global era: the impact and response to sars wei-jiat tan ■ peter enderwick in early 2003, the sars virus brought disruption of public and business activities in many areas of the world, particularly asia. as a result of its impact, sars quickly established itself as a new kind of global uncertainty and posed challenges for traditional methods of risk management. this article examines the impact that sars has had through means of a case study and builds on this to provide recommendations for how uncertainty may be managed in an increasingly globalized world. reconsideration of strategic and risk-management approaches have become necessary. supply-chain management and corporate strategy require a fundamental rethink to balance the pursuit of efficiency with increased responsiveness and flexibility. unpredictability and turbulence in the international business environment suggest that traditional planning approaches that assume linear growth may give way to more scenario-based planning. this will encourage firms to contemplate a variety of possible futures and better prepare them for unanticipated events. similarly, contingent-based continuity plans help businesses continue running even during a crisis. © 2006 wiley periodicals, inc. province in november 2002 (horstman, 2003) . largely due to the failure of the chinese authorities to recognize the seriousness of the problem or provide international notification, sars quickly spread throughout china (enderwick, 2003 ) and, in february 2003 kong was to provide the global accelerant from which sars quickly spread, particularly to neighboring asian countries, including vietnam, singapore, and taiwan. the high incidence of travel between toronto and asia also saw the outbreak of sars in canada (enderwick, 2003) . over the course of the outbreak, sars infected more than 8,000 people and left more than 900 dead in 32 countries, with 349 of those fatalities recorded in mainland china. while infectious epidemics are by no means a new phenomenon, there is little doubt that sars had a greater impact on the international business environment than its predecessors. this is largely due to the fact that countries and economies are now more interconnected than before, allowing for easy transmission of a virus like sars. while literature does exist on the management of risk, sars is indicative of a new kind of uncertainty, the impact and management of which must be analyzed in the context of a world that has become increasingly globalized. this article examines the impact of sars on the international business environment and considers how managers can incorporate events such as sars into an ongoing riskmanagement framework. the discussion comprises four substantive sections. the first section provides a contextual background of the international business environment at the time of the sars outbreak. the second section provides a case-study discussion of the impact of sars on international business operations. drawing on this case study, the third section examines some strategic implications for firms seeking to cope with the new types of uncertainty such as that created by sars. concluding thoughts are provided in the final section. there is little doubt that businesses and firms operate in an increasingly globalized and integrated environment. globalization manifests itself as an increase in cross-border movements of goods and services, capital and technology flows, tourist and business travel, and the migration of people (craig & douglas, 1999) . this integration has been made possible by declining trade and investment barriers, the growth of free trade agreements, and regional integration. another driver of globalization has been technological advancements in communications and transportation. the use of satellite links, company intranets, and the internet has improved communication networks and linkages across borders, thereby lowering the costs of coordinating and controlling a global organization. modern communication systems have also enabled the rapid dissemination of information, leading to some convergence of consumer tastes and preferences. in addition, developments in transportation have allowed the rapid supply of people, goods, and services from distant locations. globalization has provided significant opportunities for firms to reconfigure their supply chains and globalize their production processes, thereby reaping economies of scale and taking advantage of national differences in the cost and quality of factors of production. however, globalization also presents some very real challenges. the interconnectedness that is characteristic of globalization also means that local conditions are no longer the result of purely domestic influence (thomas, 2002) . indeed, crises in one country now have the ability to affect other countries around the world. this was evident from the 1997 asian financial crisis, september 11, and sars, where such crises had a "ripple effect" so that their direct and residual impacts were felt far from their epicenters (enderwick, 2001) . the international business environment has never been predictable or certain. however, the scale of investments in today's globalized world, coupled with rapid technological change, shortening product life cycles, and the increasing aggressiveness of competitors (volberda, 1996) , has increased the uncertainty and complexity of operating in such an environment. indeed, it has been stated that: globalisation and technology are sweeping away the market and industry structures that have historically defined the nature of competition. the variables that can profoundly influence success and failure are too numerous to count. that makes it impossible to predict, with any confidence, which markets a company will be serving or how its industry will be structured, even a few years hence. (bryan, 2002. p. 18) accordingly, unlike past decades that exhibited long, stable periods in which firms could achieve sustainable competitive advantage, competition is increasingly characterized by short periods of advantage, the interconnectedness that is characteristic of globalization also means that local conditions are no longer the result of purely domestic influence. marked by frequent disruptions (volberda, 1996) . in such hypercompetitive environments, risk is not so much predicted as it is responded to. accordingly, strategies that focus solely on efficiency and pay close attention to cost structures must now be reassessed in light of the inflexibilities they exude in a changing and uncertain environment. further, exploitation of core competencies that were once seen as a precondition to success are now viewed as presenting the risk of core rigidities (volberda, 1996) . accordingly, a higher premium is now being placed on considerations such as flexibility, responsiveness, and adaptiveness. one area in which this need for flexibility has been recently espoused is that of supply-chain management. until recently, companies focused on developing tightly controlled supply chains, with the emphasis on efficiencies in operations and distribution. while tightly controlled supply chains work well in stable environments with minimal disruptions, we are now experiencing an environment of increasing unpredictability, where disruptions are more common. accordingly, the ability to respond to the resulting fluctuations in demand is paramount, and considerations such as flexibility and responsiveness are now considered as important as efficiency (morton, 2003) . globalization has also seen the emergence of a new type of risk, with a nature quite different to what was traditionally regarded as risk in international business. in the 1970s, 1980s, and even 1990s, risk was generally equated to financial, exchange rate, and inflationary risks and, in particular, "political risk," which was reflective of host-government hostility toward foreign investment during much of this time. political risk was country-specific and could be summed up as the likelihood that a multinational enterprise's foreign operations could be constrained by host-government policies through measures such as forced divestment, unwelcome regulation, and interference with operations. accordingly, risk management was also country-specific and involved assessing the riskiness of a particular country through a variety of predictive approaches. where a country was deemed too risky, the firm would avoid investing or withdraw its current investment. other risk-management devices also involved responding to risk that largely emanated from host governments. indeed, defensive political risk-management strategies involved locating crucial aspects of the company's operations beyond the reach of the host, while integrative strategies aimed to make the firm an integral part of the host society, thereby minimizing the risk of government intervention. however, as the world economy has become increasingly global, political risk, while still present, is arguably not as pressing as before. this is largely because of a change in attitude toward trade and investment, with most countries now encouraging foreign direct investment (fdi). indeed, between 1991 and 2003, more than 165 countries made 1,885 changes in legislation governing fdi, with 95 percent of these changes involving the liberalization of fdi regulations. this has also been supported by a dramatic increase in the number of bilateral investment treaties, as well as regional and global free-trade agreements (united nations conference on trade and development [unctad], 2003) . at the same time, we have witnessed the emergence of a new type of environmental business threat that has manifested itself in incidents such as global terrorism, sars, financial crises, and computer viruses, all of which have the ability to disrupt a firm's operations. enderwick (2003) describes such threats as being sudden, unexpected, and unpredictable, with the ability to spread quickly through global processes and forces, thus having a widespread impact but with a disproportionate impact on regions, sectors, and industries. clearly, risk is no longer country-specific, nor is it limited to threats from host-government actions. instead, it is global and systemic, and capable of being perpetrated by individuals or small groups. further, such threats do not simply affect a firm's operating conditions, but also its overall viability, as they can cause severe disruptions, threatening the very survival of the firm. accordingly, new strategies for managing this type of threat are required, and they cannot be avoided by simply deciding not to invest in a particular country, or by using strategies centered on host governments. however, while in the past risk was largely seen as negative, it should be noted that these environmental uncertainties provide both challenges as well as opportunities for those businesses that have the ability to respond quickly and effectively (enderwick, 2003) . it is useful to clarify the exact nature of a disruption such as sars in terms of risk and uncertainty. while these terms are often used interchangeably, they have distinct meanings (knight, 1921) . according to knight's analysis, risk is considered as the variation in potential outcomes to which an associated probability can be assigned. in statistical terms, while the distribution of the variable is known, the particular value that will be realized is not. uncertainty exists when there is no understanding of even the distribution of the variable. for decision making, uncertainty is a greater problem than risk. because probabilities can be attached to risk, options to mitigate risks through clearly, risk is no longer countryspecific, nor is it limited to threats from host-government actions. insurance or hedging are possible. because probability cannot be assigned to uncertainty, instruments to reduce uncertainty are not available. we suggest that sars (and similar recent environmental disruptions such as global terrorism, computer viruses, and avian bird flu) are uncertainties, not risks. these types of disruptions share a number of characteristics. first, they can be considered as "jolts" (meyer, 1982 ) that occur randomly. no one anticipated the emergence of sars, or any similar virus. because such events are not continuous or even regular, it is not possible to assign probabilities to them. second, the nature of these jolts is such that they evolve, changing their forms, and do not simply recur. for example, viruses such as sars and avian bird flu are capable of mutating and assuming different forms with differing impacts. in the case of avian bird flu, there have been recent reports of the first full case of human-to-human transmission, and a recurring fear is that it could mutate into a human pandemic with devastating effects. similarly, global terrorism assumes a variety of forms including car bombs, suicide bombers, aircraft as weapons of destruction, and chemical attacks. this makes it difficult to use historical experience as a predictor of future occurrences and impacts. third, the impact of these uncertainties tends to be concentrated, either by sector or by geographical location. as the next section makes clear, the primary effects of sars were experienced in asia and disproportionately affected the transport, tourism, and medical industries. the impacts of natural disasters such as extreme weather events or financial and political problems appear to be more widely and randomly distributed. this is not to suggest that sars did not become a global issue; however, its global spread was clearly traceable to well-established patterns of personal and business contact. to understand the impact that sars had, it is useful to employ a "concentric band" framework (enderwick, 2001) , which sees a crisis like sars as having a "ripple effect," as illustrated in figure 1 . the band closest to the center represents the primary or immediate impacts of sars. moving outward, the next band represents secondary impacts that are likely to develop over the short to medium term, followed by those impacts that result from the various responses to sars. finally, the outermost band represents the longer-term issues that are likely to arise out of the sars crisis. we suggest that sars (and similar recent environmental disruptions such as global terrorism, computer viruses, and avian bird flu) are uncertainties, not risks. the sectors that were immediately and significantly affected by sars were those that involved regular human contact (enderwick, 2003) . accordingly, asian tourism and transport were hit especially hard. flights to asia were cancelled, with sars hot zones like singapore and hong kong suffering the most (lemonick & park, 2003) . the hotel business in asia also suffered and plummeted 25% between february and march (lemonick & park, 2003) , with hong kong five-star hotels at occupancy rates of 10% and singapore occupancies falling from a norm of 70% to 20% to 30%. as fewer tourists arrived and locals chose to stay home to avoid public places, stores and restaurants in singapore and hong kong were almost empty at peak hours (engardio, shari, weintraub, arnst, & roberts, 2003) . sars also had a significant impact on medical facilities and staff. rapid increases in the number of cases quickly exposed inadequate surge capacities in hospitals and public health systems and a lack of protective gear, with the problem exacerbated by health workers falling victim to the disease (world health organization [who], 2003) . in beijing, a shortage of bed space in hospitals meant suspected sars cases could not be hospitalized and quarantined quickly, contributing to the spread of the illness (hutzler, 2003) . to reduce this heavy burden on existing hospitals, governments invested sub(who, 2003) . indeed, hong kong spent hk$400 million to create 1,280 hospital beds and a further hk$100 million to train medical staff (fowler & dolven, 2003) . food industry. sars also led to secondary impacts in the food industry. food prices in asia plummeted as restaurants cut down on purchase orders, thereby affecting the region's farmers and fishing fleets (carmichael, mcginn, & theil, 2003) . supermarket sales in key markets such as singapore, taiwan, japan, and china also fell due to a loss in consumer confidence (tso, 2003) , although increased food preparation at home-and, in some cases, panic buying-had a positive impact on supermarkets. manufacturing. there was widespread belief that a major disruption like sars could paralyze just-in-time supply chains by holding up production and the flow of goods and services between countries due to port closures, travel restrictions, and forced closures of manufacturing plants if employees got infected. despite such media hysteria, the impact on the manufacturing sector was not that pronounced. this was largely because asian companies took preemptive steps as soon as the epidemic became known and increased production in the anticipation that there could be a problem, building up their buffer levels in inventory and safety stock. the result was very few plant shutdowns in the far east (morton, 2003) . investment. investment in asia was also affected, as international firms postponed plans to begin or expand operations in asia. real estate sales fell drastically as buyers refused to travel to hong kong or china to look at building sites (bodamer, 2003) . similarly, the cancellation of trade fairs affected manufacturers, particularly in china, who rely on such fairs to sell their goods (ben-ami, 2003) . the capital markets did not emerge unscathed, and it is estimated that overall fundraising in asia fell 10-20% in 2003 due to sars (hamlin, smith, meyer, kirk, & horn, 2003) . stock prices of those companies with extensive operations in asia also fell (bolger, 2003) . unemployment. given that the tourism and hospitality industries that were hit hardest by sars were labor-intensive, there was also a corresponding rise in unemployment in sars-affected countries, mainly concentrated in these industries. in the worst-hit countries like china, hong kong, singapore, taiwan, and vietnam, the tourist industry faced losses of 30% of travel and tourism employment. the global impact of sars was also expected to bring a 15% loss in the tourism workforce in indonesia and oceania, and 5% in the rest of the world (bita, 2003) . economy and growth. the impact of sars on regional economies and projected economic growth was also substantial. indeed, economists estimate that china and south korea have each suffered $2 billion in losses in tourism, retail sales, and productivity due to sars, with japan, hong kong, taiwan, and singapore estimated to lose approximately $1 billion each. toronto, severely affected by sars, was losing $30 million a day at the height of the crisis. in terms of the global cost of sars, this is estimated to have reached $30 billion. positive effects. while negatively affecting a number of industries, others were able to capitalize on the opportunities that sars provided. the outbreak of sars saw a worldwide surge in demand for facemasks, given that sars is largely transmitted by coughing and sneezing. this saw demand outstripping supply, forcing large manufacturers like 3m to switch to 24-hour production (hopkins, 2003) . video conferencing was another industry to benefit, as asian employers sent their workers home and cancelled overseas conferences, meetings, and visits. while no industrywide traffic figures are available, many video-conferencing services reported spikes in usage in asia since the sars epidemic began. indeed, intercall, a hong kong teleconferencing company, doubled its business in march and april 2003 and saw a 200% increase in users signing up for the service in hong kong in april and a 30% rise in new customers worldwide (flynn, 2003) . individual firms. in response to the sars crisis, businesses undertook a number of measures to minimize the impacts of sars. business travel bans to sars-affected areas were a common risk-management device, as were temporary quarantine measures for those who had recently traveled to such areas (e.g., working from home, segregating them from other employees). less common was the repatriation of employees, and according to one survey, less than 7% of firms had brought employees home from sars-affected regions or placed them in another country (minihan, 2003) . many firms implemented business continuity plans, with some firms setting up operations at parallel sites or shifting operations altogether to other office complexes (hamlin et al., 2003) . it played a major role in all continuity plans, with firms issuing notebooks capable of accessing the firm's intranet so employees could work from home and employing technology such as video conferencing to ensure business continued as usual (lim, 2003) . government spending. in response to sars, governments in asia also took action and increased government spending to sarsaffected industries. in china, the central government launched the largest-ever tax relief package to help the aviation, tourism, and retail sectors recover from the sars epidemic, estimated to cost several billion yuan (pun, 2003) . the hong kong government similarly offered a $1.5 billion relief package for local businesses (carmichael et al., 2003) and has invested $80 million to revitalize the tourism industry, with part of this money to be spent on a worldwide campaign to reassure visitors (coulter, 2003) . domestic measures. the outbreak of sars prompted governments to take decisive and often drastic action to curb the spread of sars. the singapore government authorized measures such as closure of schools and universities, temperature checks twice daily (at home and in the workplace), home quarantine for those exposed to sars, and triage centers at the entrances of hospitals to identify and separate sars patients (yew, 2003) . in taiwan, remote video monitors were installed in quarantine households to ensure against any quarantine violations (chinese government information office, 2003). in china, far more draconian measures were taken, arguably to compensate for the government's previous lack of responsiveness and reluctance to report the seriousness of the sars crisis in china. public entertainment spots in beijing were closed down, as were public schools and universities (kaufman & chen, 2003) . stricter border control. governments also responded to the rapid spread of sars by implementing stricter border control measures and the collection of detailed health and contact information. at one extreme, several countries, such as taiwan, banned individuals who had traveled to sars-affected regions (kaufman & chen, 2003) . other strict measures included requirements that travelers from sars-affected areas wear facemasks for two weeks after arrival and special powers of quarantines. greater international cooperation. in recognition of the fact that sars is a global problem, governments have also been more willing the outbreak of sars prompted governments to take decisive and often drastic action to curb the spread of sars. to cooperate to prevent its further spread. one such example was the "special asean-china leaders meeting on sars" held on april 29, 2003, in bangkok, where ten association of southeast asian nations leaders and the chinese premier held crisis talks on how to fight the virus. this was consistent with the way the international community rallied together to understand and treat the sars virus. indeed, the global response was unprecedented and saw 11 laboratories around the world that were previously strong competitors sharing information freely. importance of the state. as illustrated by the response-generated impacts, it is clear that the role of the state in international business is still important, as the sars crisis saw the state take on a major crisis management role. governments were responsible for mobilizing resources such as hospitals and other medical facilities, as well as coordinating public health care. quarantine measures also had to be introduced, monitored, and enforced, coupled with surveillance capacity to monitor and report quickly on disease outbreaks and their progress. finally, governments were responsible for handling the economic slowdown caused by sars and providing assistance to severely affected industry sectors through increased public spending. these tasks are not amenable to market forces and highlight the unlikelihood of globalization leading to the elimination of the nation-state (enderwick, 2003) . open and transparent government. connected to the idea of the growing importance of the state is the need for open and transparent government. the reasons for this are twofold. first, the need for transparency is paramount if a crisis is to be contained. china's initial understating of the number of confirmed cases, refusal to give daily reports, and blocking of who specialists from visiting guangdong (the origin of sars) allowed sars to spread rapidly (lavella, 2003) . it was only after china began reporting the true seriousness of the situation and allowed who officials to investigate that the sars crisis slowly came under control. in contrast, vietnam was able to contain the virus relatively quickly through prompt and open reporting, the early request for who assistance, and rapid case detection, isolation, infection control, and vigorous contact tracing (who, 2003) . accordingly, any attempt to conceal a crisis such as sars for fear of the social and economic consequences can only be regarded as a short-term measure that ultimately risks the situation spiraling out of control (who, 2003) . second, it is in the interests of government to be open and transparent, as in today's turbulent and unpredictable environment, investors are now placing a premium on governments that can be trusted. indeed, china's behavior during the sars crisis has resulted in a loss of credibility in the international community (who, 2003) and created fears among foreign investors about doing business in china. fear. another long-term issue is how to handle the fear and panic that accompanied sars, given it was fear that spread faster and had a greater impact than the disease itself. indeed, as far as infectious diseases go, sars is relatively mild; it is harder to catch than the flu, with a fatality rate of only 6% to 8%. despite this, sars had a devastating effect on the tourism industry, as people became unwilling to fly to sars-affected regions. business was also affected, as foreigners cancelled conferences and meetings in countries in asia, such as south korea, that had not reported a single sars case. this was largely because asia is viewed as "one place" (hamlin et al., 2003) , and therefore the crisis in one part of asia was extrapolated to the whole. personal behavior. sars is also likely to have a longer-term impact with regard to personal behavior and cultures. in singapore, through massive public-education efforts to promote public-health practices, there has been a noticeable change in personal habits. people wash their hands more, and public and restaurant toilets are much cleaner. similarly, people are using serving spoons for shared dishes when eating, and sick people are more likely to see a doctor when they become ill rather than do nothing (borsuk & prystay, 2003) . sars could also see a change in the way that business is done in asia. as mentioned earlier, many businesses turned to video conferencing at the height of the outbreak. video conferencing was found to be an effective tool to maintain communication during the crisis-and without the associated travel/hotel costs and jet lag (hamlin et al., 2003) . however, tensions remain in that asian businesspeople place a high value on personal contact and prefer to meet clients and customers face-to-face (minihan, 2003) . the reality of globalization-the need for openness and trust. the sars crisis has illustrated the consequences of living in an interconnected world and has further clarified the nature of globalization. technology, such as e-mail, instant telephone communication, and the internet, has united people and increased enormously the number of contacts that people have. these contacts are eventually purthe sars crisis has illustrated the consequences of living in an interconnected world and has further clarified the nature of globalization. sued through personal visits or through business meetings, conferences, and plant tours. further, advancements in air travel mean any place in the world is accessible within 24 hours, and coupled with the movement of commerce, this has brought china and other developing nations out of relative isolation (engardio et al., 2003) . the result has been a global network within which an infectious disease like sars can spread, and while diseases in the past have taken weeks or months to spread, sars was literally transmitted within days, setting a record for the speed of continent-to-continent transmission (borenstein, 2003) . accordingly, while globalization has provided the world with many benefits, it also brings risks, and increased connectedness also means that threats have a greater global impact. this implies that countries must understand that they can no longer insulate themselves from threats such as sars given the open borders of a globalized world, and there must be an increasing recognition that crises like sars are not simply a regional problem, but a global one. the case study illustrates that sars represents a new kind of threat and has implications for the way uncertainty is managed in the future. risk-management strategies that were largely country-focused are no longer adequate in themselves, given that this new type of threat is global and systemic. despite the high levels of uncertainty associated with events such as sars, this should be incorporated into decision making. a lack of precise knowledge does not preclude decision makers from further information gathering or from making decisions about likely probabilities of events occurring. as has been recognized, traditional strategic management approaches encourage perceptions of uncertainty in a binary fashion (courtney, kirkland, & viguerie, 1997) . the world is seen either as sufficiently certain that precise, and usually single, predictions of the future can be made, or that uncertainty renders such an approach totally ineffective. in the latter case, there may be a temptation to abandon analytical approaches and to rely wholly on gut instinct. courtney et al. (1997) argue that in many cases uncertainty can be significantly reduced through careful search for additional information; in effect, much that is unknown can be made knowable. the uncertainty that remains after the most thorough analysis they term residual uncertainty. there are a number of approaches that offer insights into how to manage uncertainty. the simplest approach is to ignore it. this can be done by developing a "most likely prediction" often based on "expert input" or by assigning a margin of error to key variables. each of these approaches yields a single unequivocal strategic option by either ignoring uncertainty or assigning it a probability. neither approach is satisfactory. ignoring an uncertain environmental event is clearly dangerous. assigning probabilities to unique events is invalid. even subjective probability derived from expert analysis is untestable and arbitrary. miller (1992) highlights a useful distinction between financial riskmanagement and firm-strategy approaches to managing environmental uncertainties. financial risk-management techniques such as insurance and futures contracts reduce the firm's exposure to specific risks without changing the underlying strategy. but, as noted earlier, such techniques only apply to risks, not uncertainties. in the case of an event such as sars, strategic responses, which attempt to mitigate the firm's exposure to uncertainties, are likely to be more useful. miller (1992) identifies five generic strategic responses to environmental uncertainties: avoidance, control, cooperation, imitation, and flexibility. avoiding an event such as sars through divestment, delayed entry, or a focus on low uncertainty markets is difficult. the irregular occurrence and variable impact of such events is unlikely to justify divestment. similarly, their unpredictable and evolving nature makes postponement or niching very difficult. uncertainty control strategies based on political lobbying, vertical integration, or enhanced market power are not an effective counter to sars. in the same way a cooperative strategy deals primarily with behavioral risk and is not likely to be effective, neither is an imitative strategy that addresses competitive rivalry. of more value is the management of uncertainty through organizational flexibility. flexibility focuses on the ability of the organization to respond and adapt to significant environmental changes. high levels of flexibility imply lower costs of organizational adaptation to uncertainty. in contrast to approaches that try to increase the predictability of uncertain events, flexibility strategies emphasize internal responsiveness, irrespective of the predictability of contingencies. a widely used strategy for increasing flexibility is diversification, whether of products, markets, or sources of supply. with regard to sars, the key strategic responses are likely to occur in the areas of supply-chain management, diversification, scenario planning, and ensuring business continuity. we consider these in more detail. in contrast to approaches that try to increase the predictability of uncertain events, flexibility strategies emphasize internal responsiveness, irrespective of the predictability of contingencies. the need for flexibility and responsiveness is no more evident than in the area of supply-chain management. while the manufacturing sector did not suffer severe disruptions given the relatively quick manner in which sars was contained, had the crisis persisted and impeded the flow of goods and services and/or caused plant shutdowns, major disruptions to manufacturing and distribution would have occurred. indeed, potential disruptions quickly became apparent as firms contemplated the possible effects of travel bans. firms recognized that problems could arise if a factory needed repair help to continue manufacturing but engineers could not be sent due to travel bans (wonacott, chang, & dolven, 2003) . in combination, these issues highlight the need for flexible supply chains that can respond quickly to changes in demand and cope with major disruptions. to develop this responsiveness, firms can do a number of things. first, in handling a crisis like sars, every moment of delay is critical, and the earlier you can get the supply-chain network to respond, the easier it is to manage (mcclenahen, 2003) . accordingly, to ensure prompt action, firms must ensure quicker access to and action on information, preferably at the source, that may provide timely warnings. this certainly reiterates the importance of management basics such as environmental scanning and monitoring, and the need for it to be an ongoing activity. however, such environmental scanning will no longer simply involve monitoring the local political environment, as often happened in the past. instead, it will need to encompass the larger regional and global environment. further, while host-country managers previously played a vital role in conveying information about the political environment back to higher management, what will become increasingly important is the ability to channel this information to the firm's affiliates in other parts of the world and to share any lessons learned from the crisis so that these affiliates may benefit from them. this further reinforces the value of establishing an integrated global network and facilitating intracompany learning. the need to be responsive also has implications when choosing manufacturing locations. china's initial unresponsive and surreptitious approach to the sars crisis illustrates that while cost of production and a low-cost labor force have been, and will still remain, dominant considerations in the investment decision, stability, reliability, and predictability are likely to be given a higher premium. given the unexpected and sudden nature of threats such as sars, management is also likely to add to its investment criteria how well various parts of the world are equipped to deal with crises (mcclenahen, 2003) . in handling a crisis like sars, every moment of delay is critical, and the earlier you can get the supply-chain network to respond, the easier it is to manage. firms may also opt to switch from large production sites in a single location like china to smaller, but multiple facilities around the world, thereby creating a global network of manufacturing facilities. this allows increased flexibility so that if disruptions to manufacturing or the supply chain occur in one country, the firm has the ability to vary plant loadings and increase production elsewhere (maccormack, newman, & rosenfield, 1994) . such a manufacturing network will considerably increase the complexity of coordinating the global supply chain. however, this may simply be a necessary trade-off for firms wishing to balance cost-efficiency and responsiveness in managing their global supply network. alternatively, firms may find that establishing their own manufacturing operations is too risky an investment and may instead choose to outsource, thereby continuing a trend that has been taking place over the last ten to fifteen years. however, sars has highlighted the value of diversifying the supply base and sourcing from multiple locations (mcclenahen, 2003) , thereby reducing a firm's dependence on a single supply location (maccormack et al., 1994) . indeed, outsourcing offers the flexibility to switch sourcing to another country if a crisis like sars should disrupt supply-chain operations in a particular country. accordingly, many global firms are considering back-up suppliers outside of asia, with latin america and eastern europe likely locations. the way in which outsourcing is conducted may also change as events such as sars have increased the reluctance and inability to travel. indeed, rather than establishing their own network of suppliers, firms may increasingly turn to third-party logistics providers such as bchinab, who have offices on u.s. soil but manage a sprawling network of 1,500 factories, tool and die shops, materials suppliers, and plastic molders in china. by using such a provider to manage their logistics operations abroad, firms can reduce the requirement of traveling overseas to negotiate price quotations and samples and having to deal with chinese manufacturers directly (marshall, 2003) . the move toward responsiveness may also necessitate less of a focus on cost-efficiency and a loosening of the tight control that is currently held over supply chains. after sars, firms may have to reexamine their supply chains to identify potential problems and bottlenecks and allow for enough slack to accommodate delays and potential problems that can arise. such readjustments may include keeping buffer inventory and safety stock to hedge against uncertainties. while such measures incur costs, the costs of disruptions to an unresponsive supply chain may prove more severe-these being extended lead times, lost service contracts, and higher emergency logistics costs. another lesson from the sars crisis may be to illustrate the risks of having too focused a corporate strategy and the potential benefits of diversification. in the same way that financiers diversify their investment portfolios to decrease variability in their rate of return, a portfolio approach to corporate strategy ensures that even if some of the firm's corporate initiatives fail, the success of other initiatives achieves an overall favorable outcome for the firm (bryan, 2002) . this is especially so where the impacts of events like sars and terrorism are disproportionately borne by certain sectors or locations (enderwick, 2003) . accordingly, corporate strategies may now require this "portfolio approach" so that a firm is not overly focused on one sector or location. for example, the sars crisis, coupled with a more global world market, is likely to see exporters increase diversification in both products and geographical markets. on a larger scale, economies may also look to become more diversified, as sars revealed that many asian countries were heavily dependent on the services sector (shanmugaratnam, 2003) . for businesses, related diversification appears to be superior to unrelated diversification (rumelt, 1974) . as noted earlier, the nature of environmental threats is changing and is increasingly difficult to anticipate. indeed, sars illustrated the difficulty of trying to predict where the next threat will come from and has called into question traditional linear planning and forecasting. such planning techniques work on the assumption that the environment in the future will be very much like today, and that extrapolation is meaningful. however, in today's turbulent and disruptive environment, this assumption is no longer valid and what are needed are plans that are flexible enough to adapt to the circumstances (pritchard, 2003) . accordingly, the sars crisis is likely to accelerate the current trend toward the adoption of scenario planning. rather than forecasting a specific future or "most likely outcome," scenario planning builds on existing knowledge to develop several plausible future scenarios and then necessitates constructing robust strategies that will provide competitive advantage no matter what specific events unfold. as such, it encourages firms to think about "worstcase" scenarios, which may include technological, economic, political, or environmental calamities. schnaars (1986) discusses a number of different approaches that can be adopted when designing strategy for multiple scenarios. accordingly, scenario planning forces firms to pay closer attention to internal, external, and the broader global environmental factors that may influence the firm's future. this process challenges firms to avoid complacency in their strategy formulation and encourages managers to think more broadly and unconventionally and view events with a new perspective (lohr, 2003) , an essential requirement in trying to prepare for unknowable shocks and crises (kennedy, perrottet, & thomas, 2003) . arguably, sars will "shake things up" and encourage strategists to further consider more diverse and unexpected scenarios, as prior to sars, many strategic-planning scenarios had not been done with a disease in mind (hamlin et al., 2003) . the federal emergency management agency estimated that the costs of disasters are 15 times greater than the costs of preparing for them (read, 2003) . indeed, events such as september 11 and sars illustrated the value of business continuity planning, which essentially involves strategies, services, and technologies that enable firms to prevent, cope with, and recover from disasters, while at the same time ensuring the continued running of the business (read, 2003) . while the sars crisis certainly reinforced the need for such planning, it also provided implications for the content of such continuity plans in the future. while some continuity plans actioned during the sars crisis saw the establishment of parallel operations or the shifting of work to safer regions/locations so as to create back-up locations (minihan, 2003) , it is apparent that cost and time factors can mitigate against this being a feasible option for many firms (read, 2003) . however, what sars did demonstrate, and what has been suggested by business continuity writers, is that technology may be the key and that "telecommuting" or "teleworking" should be a part of any company's business continuity plan (jimenez, 2003) . accordingly, firms need to ensure they have the technological infrastructure to support the ability to work from home or from remote locations, in case an event like sars forces offices to close. at a basic level, this requires employees to have access to the firm's information/data or intranet from home, and such access must be secure. to reduce reliance on a single data source, firms are also beginning to employ "network storage" or "data mirroring" technologies so that key transactional data is copied in almost real time to other locations, thus creating a back-up (newing, 2003) . the sars crisis also highlighted the usefulness of video-conferencing and teleconferencing technology, particularly given that higher bandwidth speed now makes such conferencing a more viable option. while travel bans and the reluctance to travel persisted, conferencing technology allowed continued contact with clients and overseas partners, and allowed important meetings to take place. while such technologies may not immediately become the industry norm, given that personal contact in asian countries is highly valued, their introduction as a riskmanagement device may secure their gradual acceptance as their longterm benefits become more obvious. indeed, anecdotal evidence suggests that firms who invested in such technology during the sars crisis will continue to use this technology in the future (neuman, 2003) . while technology is important, it alone may not be sufficient, and the human element in continuity plans is also important. key workers must be identified and must have access to the right it equipment and training to enable them to carry on working if the office has to be shut down. key staff should also be spread among different sites, as one organization learned the hard way, when it lost its entire it recovery team located in the world trade center during september 11 (newing, 2003) . finally, firms must also realize that telecommuting has a human element, as workers stuck at home often experience feelings of isolation, anxiety, and depression (wayne, 2003) . accordingly, planning must incorporate how such psychological problems can be addressed. as mentioned in the case study, the impact from the fear of sars was greater than sars itself, and has implications for how a crisis such as sars is managed in the future. what is glaringly obvious is the need for full disclosure of information, given that the panic about sars was fueled when information was concealed or only partially disclosed, leading to rumors and exaggeration (who, 2003) . employees need facts from, and questions answered by, reliable and credible sources. responses that have proved effective include establishing 24hour hotlines to communicate with staff and directing staff to other information sites, such as the who web site (aldred, 2003) . the sars crisis occurred against the backdrop of a highly interconnected and integrated world economy and has established itself as a new kind of global threat, along with other unpredictable events such as the asian financial crisis and global terrorism. rather than having a localized impact, the impact of sars has been far-reaching, even if this was largely from the fear of the virus rather than the virus itself. the impact from the fear of sars was greater than sars itself, and has implications for how a crisis such as sars is managed in the future. in table 1 , we summarize some of the key differences between the traditional and new forms of risk. for governments, the message is clear-even in a world without borders, the state will still have a role, given that unsupported market processes are insufficient by themselves to solve the problems created by sars. however, with this responsibility comes the requirement that governments act in an open and transparent manner, something that is arguably a precondition for the effective handling of a crisis such as sars. global phenomena such as sars also emphasize the need for a collective response and more openness and cooperation among nations. for businesses, the ability of sars to significantly disrupt international business and the speed in which the disease was transmitted suggests that the nature of this new kind of event is global and systemic, and accordingly warrants a broad and encompassing risk-management approach. the implication is that firms must put a higher premium on strategies that emphasize flexibility and responsiveness. indeed, firms will find value in increasing diversification, whether this is in sourcing or in corporate strategy. planning must also become less linear and more contingent-based, and in considering a range of possible future scenarios, firms will be in a better position to handle disruptions that increasingly cannot be predicted. technology also appears to offer a possible solution as a risk-management device, and we are likely to see technologies such as video conferencing become a commonplace feature in offices of the future. further research on the role that strategies, structures, and resources play in anticipating, responding, and adjusting to environmental disruptions is necessary (meyer, 1982) . in sum, while an event like sars produces considerable challenges, it also offers insights into how firms can better equip themselves to manage within an increasingly turbulent and unpredictable environment. virus challenges efficacy of risk management plans the cost of sars virus threat to 227,000 tourism jobs. the australian sars fears continue to weigh on investors. the times sars is the latest in explosion of new infectious diseases how singapore beat the virus-and still awaits it the mckinsey quarterly: 2002 special edition-risk and resilience chinese taipei to brief on its measure in response to the sars epidemic hong kong spends pounds 80m on recovery. travel trade gazette strategy under uncertainty configural advantage in global markets terrorism and the international business environment. aib newsletter, fourth quarter responding to new environmental uncertainties: terrorism and sars in the global business environment deadly virus-the economic toll: delayed deliveries, closed factories, and the spectre of recession teleconference business up as sars fuels demand our future with sars sars test. institutional investor sales of masks, air filters soar as sars spreads; manufacturers get busier as fliers try to protect themselves the outbreak: the virus factories of southern china the sars outbreak: beijing confronts crucial test in its struggle against sars-mayor cites big shortages of beds hong kong cases relapse technology key factor in business continuity the sars outbreak: beijing imposes new sars curbs city's theatres and cafes are shut down as china lists another 161 cases scenario planning after 9/11: managing the impact of a catastrophic event risk, uncertainty and profit is the panic worse than the disease? the truth about sars. time technology keeps asia running despite sars scenario planning" explores the many routes chaos could take for business in these very uncertain days the new dynamics of global manufacturing site location many unhappy gains. crain's get ready for the next sars adapting to environmental jolts a framework for integrated risk management in international business work goes on despite dangers asia, sars and the supply chain sars leaves a silver lining: companies save by videoconferencing flexible models to face up to the unexpected: disaster recovery: business continuity has to fight it out with other areas for funding. financial times strategy, structure and economic performance how to develop business strategies from multiple scenarios dealing with sars-rebuilding confidence and taking opportunities essentials of international management: a cross-cultural perspective seafood prices affected by sars world investment report 2003: fdi policies for development. national and international perspectives united nations toward the flexible form: how to remain vital in hypercompetitive environments executives in singapore chafe at sars-related travel bans china's handling of sars virus concerns investors-new leadership's image suffers amid signs beijing failed in crisis management key: cord-273175-bao8xxe2 authors: tran, viet-thi; ravaud, philippe title: covid-19–related perceptions, context and attitudes of adults with chronic conditions: results from a cross-sectional survey nested in the compare e-cohort date: 2020-08-06 journal: plos one doi: 10.1371/journal.pone.0237296 sha: doc_id: 273175 cord_uid: bao8xxe2 background: to avoid a surge of demand on the healthcare system due to the covid-19 pandemic, we must reduce transmission to individuals with chronic conditions who are at risk of severe illness with covid-19. we aimed at understanding the perceptions, context and attitudes of individuals with chronic conditions during the covid-19 pandemic to clarify their potential risk of infection. methods: a cross-sectional survey was nested in compare, an e-cohort of adults with chronic conditions, in france. it assessed participants’ perception of their risk of severe illness with covid-19; their context (i.e., work, household, contacts with external people); and their attitudes in situations involving frequent or occasional contacts with symptomatic or asymptomatic people. data were collected from march 23 to april 2, 2020, during the lockdown in france. analyses were weighted to represent the demographic characteristics of french patients with chronic conditions. the subgroup of participants at high risk according to the recommendations of the french high council for public health was examined. results: among the 7169 recruited participants, 63% patients felt at risk because of severe illness. about one quarter (23.7%) were at risk of infection because they worked outside home, had a household member working outside home or had regular visits from external contacts. less than 20% participants refused contact with symptomatic people and <20% used masks when in contact with asymptomatic people. among patients considered at high risk according to the recommendations of the french high council for public health, 20% did not feel at risk, which led to incautious attitudes. conclusion: individuals with chronic conditions have distorted perceptions of their risk of severe illness with covid-19. in addition, they are exposed to covid-19 due to their context or attitudes. the novel coronavirus disease 2019 (covid-19) pandemic threatens to saturate healthcare systems all around the world [1] . on april 7 th of july 2020, 6,416,828 cases were confirmed in 213 countries, with 382,867 deaths [2] . in france, 152,444 cases were confirmed, with 29,065 deaths [3] . severe acute respiratory distress develops in about 16% to 26% of patients hospitalized with covid-19, thus requiring oxygen supplementation and/or intensive care [4] . as the number of cases grows worldwide, in order to avoid a surge of demand on the healthcare system and shortages of equipment such as ventilators needed to care for critically ill patients [5] [6] [7] , many countries have imposed quarantine and recommended physical distancing to reduce transmission to people likely to have a severe illness (i.e., older patients and those with chronic comorbidities). those individuals with chronic comorbidities should also, in return, avoid contacts and/or use appropriate measures to prevent potential infection. yet, in france and around the world, specific advice for individuals with chronic conditions and their households is scarce with most information is intended for the general public. for example, information from the european centre for disease prevention and control refer to only "people with chronic diseases" without specifying specific groups of individuals. this was confirmed by a recent study showing that adults with comorbid conditions lacked critical knowledge about covid-19 [8] . in this study, we aimed to understand the perceptions, context and attitudes toward covid-19 of individuals with chronic conditions in order to clarify their potential risk of infection. this study was a cross-sectional survey nested in compare, a nationwide e-cohort of patients with chronic conditions in france [9] . participants were adults with chronic conditions recruited from the community of patients for research (compare, http://compare.aphp.fr), a nationwide e-cohort of patients with chronic conditions in france. participants of compare are adults (>18 years old) who reported having at least one chronic condition (defined as a condition requiring healthcare for at least 6 months) and who joined the project to donate time to accelerate research of their conditions by answering regular patient-reported outcomes and experience measures online [9] . all participants provide electronic informed consent before participating in the ecohort. compare was approved by the comité de protection des personnes ile de france 1 (irb: 0008367). all methods were performed in accordance with the relevant guidelines and regulations. data from this study were collected between march 23 and april 2, 2020 at the peak of the french epidemic. during that time, 27 475 new cases of covid-19 were confirmed, with a total of 56 261 cases on april 2, 2020. this time period includes the maximum number of daily cases in france (april 1, 2020) [10] . since march 17, france had been under lockdown (movement restrictions and closure of non-essential businesses), and people with chronic conditions were encouraged to stay at home [11] . during this time, knowledge of covid-19 was still limited and information for the public was imprecise. for example, information available on the website of the french ministry of health referred to "people at risk", mixing older people and patients with chronic conditions [12] . of note, at the time of the study, benefits of using face masks were debated in france and in europe. participants' demographic and clinical data were collected as part of their participation in the compare e-cohort. all variables are updated yearly. conditions and medications are selfreported by patients by using the international classification of primary care-version 2 [13] and the thesorimed database of medications (french database of medications developed by the national health insurance) [14] . in addition, participants answered a dedicated survey designed by vtt and pr by use of the literature and their own expertise [8] . it was then face-validated by two other researchers (ip and cr) with expertise in questionnaire development before dissemination. the questionnaire was not tested with patients; however, the first respondents provided comments in a dedicated open-ended question at the end of the questionnaire, which led to minor reformulations. final survey questions are available in s1 and s2 data. this survey covered 3 topics. • for perception of risk of severe illness with covid-19, we asked participants whether they felt at high risk of severe illness with covid-19 with the question: "do you feel at increased risk of severe illness with covid-19 as compared to people of the same age as you but without chronic disease?" (yes/no). • for their context. participants described their activity (e.g., whether they continued working outside of the home); their household (i.e., whether any member of their household worked outside of the home and were in contact with the public); and their recent physical visits to healthcare professionals. • for their attitudes to prevent infection, participants were presented four theoretical situations involving different types of contacts: frequent (e.g., family member frequently visiting, child care, etc.) or occasional (e.g., during shopping) and discerning whether these contacts showed symptoms or not. in each situation, participants reported whether they would refuse contact, enact physical distancing or wear personal protective equipment (mask, gloves, etc.). results of the survey were described globally and for the subgroup of patients considered at high risk of a severe illness according to the french high council for public health (box 1). these patients were those with a severe cardiac or vascular disease (high blood pressure with complications, history of stroke or ischemic heart disease, cardiac surgery, heart failure), insulin-dependent diabetes, chronic lung disease or lung disease likely to be exacerbated by a viral infection, chronic kidney disease under dialysis, cancer under treatment, immunodeficiency (due to a drug [cancer chemotherapy, immunosuppressive medications, biotherapy and/or corticosteroids], an uncontrolled hiv infection, transplantation, or cancer), liver cirrhosis, or severe obesity (body mass index [bmi] >40 kg/m 2 ), or pregnant in the third trimester [15] . to operationalize these criteria with the data available in compare, one physician (vtt) matched the conditions and treatments reported by patients in compare with the list of high-risk conditions and treatments presented above. cancer chemotherapy immunosuppressive medications, biotherapy and corticosteroids were those classified as such in manufacturers' prescribing information, by using the vidal dictionary (https://www.vidal.fr/classifications/vidal/). descriptive statistics (mean with sd and frequency with percentage) were calculated for all patient characteristics and survey responses. associations between participant characteristics and responses to the survey items were then examined in bivariate analyses by chi-square or t test, as appropriate. in addition, we fitted two logistic regressions aimed at exploring the association between participants' characteristics and 1) their perception of their risk for severe infection and 2) their attitudes to prevent infection with occasional contacts with asymptomatic people. variables included in the model were sex, age (as a continuous variable), household with > 1 person (including the patient), low educational level, smoking status (current smoker vs. others), treatment considered at risk according to the french high council for public health, bmi �40 kg/m 2 , high blood pressure, diabetes (under insulin treatment or not), history of stroke or cardiac ischemic disease, heart failure (any new york heart association stage), asthma, chronic obstructive pulmonary disease, thyroid disease, chronic kidney failure (under dialysis or not), cancer (under treatment or not) and osteoarthritis. analyses were performed on complete cases only. p < 0.05 was considered statistically significant. no corrections for multiple testing were performed. • third trimester of pregnancy analyses involved using a weighted dataset obtained by calibration on margins with weights for age categories (<24, 25-34, 35-44, 45-54, 55-64, 65-74, >75 years), sex and educational level (low, middle school or equivalent, high school or equivalent, associate's degree, higher education). weights were derived from national census data describing the french population reporting chronic conditions [16, 17] . analyses involved use of r v3.6.1 (http://www.r-project.org, the r foundation for statistical computing, vienna, austria). between march 23 and april 2, 2020, we invited 18,651 patients from compare to complete our survey and 7169 (38.4%) answered (s1 fig). participants were mostly female (5616 [78.3%]) with mean (sd) age 46.1 (14.7) years. in the non-weighted data, diseases most frequently reported were high blood pressure (11.6%), diabetes (7.1%), asthma (6.2%) and cancer (5.2%); 3684 (51.4%) participants reported �2 chronic conditions. differences between respondents and non-respondents are shown in s1 table. in the weighted sample, 39.4% were at high risk for a severe illness according to the french recommendations: 33.0% because of their conditions, 8.8% because of their treatments, 1.9% with bmi > 40 kg/m 2 , and 0.5% in their third trimester of pregnancy. patients' characteristics before and after weighting are presented in table 1 . in the weighted sample, 63% of participants felt at risk of severe illness with covid-19, of whom 51% (32% of the whole sample) reported a high-risk situation according to the french high council for public health. conversely, 37% participants did not feel at risk of severe covid-19, of whom 20% (7.4% of the whole sample) reported a high-risk situation according to the french high council for public health (fig 1) . patients' characteristics associated with a perceived risk of severe covid-19 identified in the logistic regressions are presented in table 2 . in total, 7041 (98%) participants answered the survey section regarding their risk of infection due to their context. risk of infection involved working outside of the home (8.8% of participants, of whom 29% were care professionals), visits to health facilities for a consultation or test (54.7% of participants) or to a pharmacy (82% of participants); their household (74.9% of participants lived with at least on other person, of whom 18% worked outside of the home and 13% were children < 15 years old), or regular contacts with people outside of their home (e.g., family, friends, housekeeping, child care, etc.) (5% of participants). in all, 23.7% were exposed to some risks because of their work, their household members working outside of the home, or regular visits from external contacts. among patients at high risk of a severe illness according to the french high council for public health, 5% continued working, 15% had a household member working outside of the home and 7% reported regular contacts with people outside of their home. in all, 21.1% were exposed to some risks because of their work, their household members working outside of the home, or regular visits from external contacts. in total, 6940 (97%) participants answered the survey section regarding their attitudes to prevent infections. independent of the type of contact, participants reported that they would enact physical distancing under all situations presented to them. about one quarter of patients would refuse any contact with symptomatic people (17.8% and 23.4% for occasional and covid-19-related perceptions, context and attitudes of adults with chronic conditions frequent contacts, respectively). concerning the use of personal protective equipment, use of masks ranged from 19% (for occasional contacts with asymptomatic people) to 65% (for frequent contacts with symptomatic people). similarly, use of gloves ranged from 19% (for occasional contacts with asymptomatic people) to 50% (for frequent contacts with symptomatic people) (fig 2) . we found similar results in the subgroup of patients at high risk of a severe illness according to the french high council for public health. only 18.2% and 23.2% patients would refuse contact with symptomatic people for occasional and frequent contacts, respectively. concerning the use of personal protective equipment, use of masks ranged from 30% (for occasional contacts with asymptomatic people) to 63% (for frequent contacts with symptomatic people). similarly, use of gloves ranged from 21% (for occasional contacts with asymptomatic people) to 44% (for frequent contacts with symptomatic people). patients' characteristics associated with a perceived risk of severe illness with covid-19 identified on logistic regression are presented in table 3 . the only variable found associated with use of face masks with asymptomatic people (or refusal to see these people) was patients' perception of high risk of severe infection by covid-19 (odds ratio 1.93, 95% confidence interval 1.53-2.43). table 2 . association between participant characteristics and their perceived risk of severe covid-19. results of logistic regression analysis of complete cases, accounting for weights obtained after calibration on margins for sex, age categories and educational level by using data from a national census describing the french population self-reporting at least one chronic condition. odds ratio (95% confidence interval) we involved 7169 individuals with chronic conditions in a nationwide survey nested in an existing cohort and described their perception of risk of severe covid-19 and their potential risk of infection due to context and attitudes. first, our study highlighted that patients with chronic conditions have distorted perceptions of their risk of severe covid-19. among patients with criteria for high risk of severe covid-19 by the french high council for public health (40% of our sample), about 20% did not feel at risk and could therefore adopt incautious attitudes. this figure may even be conservative in light of recent works suggesting that all patients with hypertension, diabetes, cardiovascular disease, or chronic lung disease are at risk, not just those with complicated diseases [18] [19] [20] . data from the he chinese center for disease control and prevention showed increased case fatality rate among patients with preexisting comorbid conditions-10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [20] . especially, our findings highlight that patients with a bmi � 40 kg/m 2 or who smoked did not feel at risk nor took extra precautions when in contact with other people despite these two factors being associated with risk of severe complications and mortality from covid-19 [21, 22] . these results are of importance because of the confluence of two elements. first, preventing infection for people at risk of severe disease is difficult. in our study, 21.2% of patients at high risk of a severe illness according to french recommendations were in frequent contact with "the outside world" during the quarantine because of their work, their household members working outside of the home, or regular visits from external contacts. second, feeling at risk seems to be the major factor for using face masks with asymptomatic people. at the time of the table 3 . association between participant characteristics and the use of face masks for occasional contacts with asymptomatic people (or the refusal to see these people). results of logistic regression analysis of complete cases, accounting for weights obtained after calibration on margins for sex, age categories and educational level by using data from a national census describing the french population self-reporting at least one chronic condition. odds ratio (95% confidence interval) covid-19-related perceptions, context and attitudes of adults with chronic conditions study, it was still unknown that 40% to 80% of transmission events could occur from people who are presymptomatic or asymptomatic [23] . therefore, specific communication clearly identifying patients at risk for severe illness by covid-19 is mandatory. communication should also target the household of these patients because the rate of secondary transmission among household contacts of patients with sars-cov-2 infection was estimated at 30% [24] . our results are important given the cumulative amount of evidence showing that patients with chronic conditions, about 20 million individuals in france, are at increased risk of severe covid and death. in a small case series conducted at the beginning of the epidemic in china, among 102 patients hospitalized for covid-19, those with comorbidities (especially hypertension, diabetes, cardiovascular and respiratory diseases) were more likely to be hospitalized in intensive care units [25, 26] . similar findings were observed in europe. in a large case series of 4000 patients hospitalized in icus in italy, the highest risk of death was for patients with chronic obstructive pulmonary disease (adjusted hr [ahr] 1.68, 95% ci 1. 28-2.19 ) and type 2 diabetes (ahr 1.18, 95% ci 1.01-1.39) [27] . reasons underlying these findings are still unclear, with hypotheses related to meta-inflammation or use of angiotensin-converting enzyme inhibitors (aceis)/angiotensin receptor blockers (arbs) in these populations, despite recent controversial findings about this latter point [28, 29] . our study complements the literature on the awareness and attitudes of patients with chronic conditions related to covid-19. to date, most works have focused on the general public [30, 31] . knowledge and attitudes of patients with chronic conditions is unknown, apart from a study of 600 patients with chronic conditions in the united states that showed gaps in awareness and knowledge of covid-19 among patients with chronic conditions [8] . our findings confirm these results and provide details on individuals' risks associated with their context and their attitudes to prevent infection. this study has several limitations. first, all data were self-reported, with risk of desirability bias regarding their attitudes. second, individuals at high risk of severe illness with covid19 are not yet well known; recommendations from the french high council for public health are mostly based on case reports in china and precaution measures [15] . third, the response rate was relatively low (38%) owing to the short duration of data collection (10 days) and the sole use of e-mails for the invitation and reminders. yet, such response rate is consistent with the literature of online surveys for the general public [32, 33] . non-respondents were younger, less multimorbid and had fewer conditions considered at high risk according to recommendations than respondents. despite statistical weighting, results should be generalized with caution. in conclusion, we found that individuals with chronic conditions may have distorted perceptions of their risk of severe illness with covid-19. targeted communication may increase the use of personal protective equipment and prevent infection, which is fundamental because 20% of these individuals are exposed to infection because of their work, their household or regular visits from external contacts, despite quarantine. table. demographic characteristics of respondents and non-respondents to the survey (raw data). (docx) preventing a covid-19 pandemic world health organization. novel coronavirus (covid-19) situation 2020 clinical infectious diseases: an official publication of the infectious diseases society of america critical supply shortages-the need for ventilators and personal protective equipment during the covid-19 pandemic. the new england journal of medicine the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study. the lancet public factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease awareness, attitudes, and actions related to covid-19 among adults with chronic conditions at the onset of the u.s. outbreak: a cross-sectional survey. annals of internal medicine collaborative open platform e-cohorts for research acceleration in trials and epidemiology (cooperate) european centre for disease prevention and control. data on the geographic distribution of covid-19 cases worldwide: european centre for disease prevention and control emmanuel macron annonce une série de mesures 2020 page du ministère de la santé international classification of primary care avis provisoire: patients à risque de formes sé vères de covid-19 et priorisation du recours aux tests de diagnostic virologique institut national de la statistique et des etudes économiques. la macro sas calmar: institut national de la statistique et des etudes é conomiques direction de la recherche dé, de l'évaluation et des statistiques. l'é tat de santé de la population en france-rapport 2017. paris: ministère des solidarité s et de la santé covid-19: risk factors for severe disease and death clinical research ed). 2020; 368:m1091. epub 2020/03/29. pmid: 32217556 www.icmje.org/coi_disclosure.pdf and declare: support from the tongji hospital for pilot scheme project and the chinese national thirteenth five years project in science and technology, national commission of health, people's republic of china, for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention severity and mortality associated with copd and smoking in patients with covid-19: a rapid systematic review and meta-analysis www.icmje.org/coi_disclosure.pdf and declare: support from the kenneth c griffin charitable fund for submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov2) household transmission of sars-cov-2 clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit clinical infectious diseases: an official publication of the infectious diseases society of america risk factors associated with mortality among patients with covid-19 in intensive care units in lombardy, italy obesity, and metabolic inflammation create the perfect storm for covid-19 dr torp-pedersen reported receiving grants from bayer and novo nordisk. dr køber reported receiving speaker honoraria from novartis us public concerns about the covid-19 pandemic from results of a survey given via social media adoption of personal protective measures by ordinary citizens during the covid-19 outbreak in japan response rate and completeness of questionnaires: a randomized study of internet versus paper-and-pencil versions challenges using online surveys in a danish population of people with type 2 diabetes the authors thank isabelle pane and carolina riveros for their help in the survey development and isabelle pane for data management. key: cord-125330-jyppul4o authors: crokidakis, nuno; sigaud, lucas title: modeling the evolution of drinking behavior: a statistical physics perspective date: 2020-08-24 journal: nan doi: nan sha: doc_id: 125330 cord_uid: jyppul4o in this work we study a simple compartmental model for drinking behavior evolution. the population is divided in 3 compartments regarding their alcohol consumption, namely susceptible individuals s (nonconsumers), moderated drinkers m and risk drinkers r. the transitions among those states are rules by probabilities. despite the simplicity of the model, we observed the occurrence of two distinct nonequilibrium phase transitions to absorbing states. one of these states is composed only by susceptible individuals s, with no drinkers ($m=r=0$). on the other hand, the other absorbing state is composed only by risk drinkers r ($s=m=0$). between these two steady states, we have the coexistence of the three subpopulations s, m and r. comparison with abusive alcohol consumption data for brazil shows a good agreement between the model's results and the database. epidemic models have been widely used to study contagion processes such as the spread of infectious diseases [1] and rumors [2] . this kind of model has also been used for the spread of social habits, such as the smoking habit [3] , cocaine [4] and alcohol consumption [5] , obesity [6] , corruption [7] , cooperation [8] , ideological conflicts [9] , and also to other problems like rise/fall of ancient empires [10] , dynamics of tax evasion [11] and radicalization phenomena [12] . the main reason such social behaviors can be modelled by contagion processes is the response by elements of the ensemble to the social context of the studied subject. both social or peer pressure and positive reinforcement from other agents, regardless if the behavior brings positive or negative consequences to the individual, can influence each one's way of life. therefore, models for the epidemics of infectious diseases are also able to describe the spread of such tendencies, like alcoholism [13, 14] . the standard medical way of categorizing alcohol consumption [15] is in three groups -nonconsumers, moderate (or social) consumers and risk (or excessive) consumers; thus, modeling of the interactions and consequent changes of an individual from one group to another is governed by interaction parameters. one interesting aspect that should be taken into consideration when modeling alcohol consumption is the tendency on some individuals to gradually increase their consumption rate, not due to social susceptibility, but when under stressful or depressing circumstances, since alcohol plays a major role both as cause and consequence of depression, for instance [16] . this means that one can attach a probability of a moderate drinker to become an excessive drinker that is dependent only on the actual moderate drinkers population size, instead of the two population groups involved in the change. if one considers the current world situation with the recent coronavirus disease 2019 outbreak (covid-19), this self-induced increase in alcohol consumption is not only realistic, but also becomes more prominent -this has been observed in a myriad of studies this year detailing the consequences and dangers of both alcohol withdrawal (in places where it has become harder to legally acquire alcohol during the pandemic) and alcohol consumption increase [17, 18, 19, 20] . this work is organized as follows. in section 2, we present the model and define the microscopic rules that lead to its dynamics. the analytical and numerical results are presented in section 3, including comparisons with brazil's alcohol consumption data for a range of eleven years, used as a case study in order to evaluate the present model. finally, our conclusions are presented in section 4. our model is based on the proposal of references [5, 13, 14, 21, 22, 23, 24, 25] that treat alcohol consumption as a disease that spreads by social interactions. in such case, we consider an epidemic-like model where the transitions among the compartments are governed by probabilities. in this work we consider population homogeneous mixing, i.e., a fully-connected population of n individuals. this population is divided in 3 compartments, namely: • s: nonconsumer individuals, individuals that have never consumed alcohol or have consumed in the past and quit. in this case, we will call them susceptible individuals, i.e., susceptible to become drinkers, either again or for the first time; • m: nonrisk consumers, individuals with regular low consumption. we will call them moderated drinkers; • r: risk consumers, individuals with regular high consumption. we will call them risk drinkers; to be precise, a moderated drinker is a man who consumes less than 50 cc of alcohol every day or a woman who consumes less than 30 cc of alcohol every day. on the other hand, a risk drinker is a man who consumes more than 50 cc of alcohol every day or a woman who consumes more than 30 cc of alcohol every day [5] 1 . since we are considering a contagion model, the probabilities related to changes in agents' compartments represent the possible contagions. the transitions among compartments are as following: in the above rules, β represents an "infection" probability, i.e., the probability that a consumer (m or r) individual turns a nonconsumer one into drinker. the risk drinkers r can also "infect" the moderated m agents and turn them into risk drinkers r, which occurs with probability δ. these two infections occur by contagion, in our model, where individuals belonging to a group with a higher degree of consumption can influence others to drink more via social contact. this transition m → r can also occur spontaneously, with probability α, if a given agent increase his/her alcohol consumption -this is the only migration pathway from one group to another, in this model, that does not depend on the population of the receiving compartment, since it corresponds to a self-induced progression from moderate (m) to risk (r) drinking. as stated in the introduction, above, the increase of alcohol consumption has been documented to occur under stressful circumstances (like the covid-19 pandemic) or clinical depression, regardless of social interaction with risk drinkers. finally, the probability γ represents the infection probability that turn risk drinkers r into susceptible agents s. in this case, it can represent the pressure of social contacts (family, friends, etc) over individuals that drink excessively. we did not take into account transitions from risk (r) to moderate (m), assuming that, as a rule, once an individual reaches a behavior of excessive consumption of alcohol, contact with moderate drinkers does not imply on a tendency to lower one's consumption -meanwhile, it is assumed that contacts that do not drink at all are able to exert a higher pressure on them to quit drinking. it is not that the from risk to moderate transition cannot occur -it is just that for our model this probability, when comparing it with the overall picture, is negligible. for simplicity, we consider a fixed population, i.e., at each time step t we have the normalization condition s(t) + m(t) + r(t) = 1, where we defined the population densities s(t) = s(t)/n, m(t) = m(t)/n and r(t) = r(t)/n. since we will only deal with the relative proportions among the three different groups in relation to the total population n, i.e. the population densities, we will not take into account birth-mortality relations and populational increase/decrease effects. so, even if n is not a constant number, for all mod-elling purposes it will not matter due to the fact that we will deal only with the s(t), m(t) and r(t) subpopulations in relation to the total population. one other way of looking at this approximation is to consider only the adult population as relevant to our modelling, and assume that new individuals coming of age correspond to the number of deaths [24, 25] . based on the microscopic rules defined in the previous subsection, one can write the master equations that describe the time evolution of the densities s(t), m(t) and r(t) as follows, and we also have the normalization condition valid at each time step t. first of all, one can analyze the early evolution of the population, for small times. considering the initial conditions s(0) ≈ 1, m(0) ≈ 1/n and r(0) = 0, one can linearize eq. (2) to obtain that can be directly integrated to obtain m(t) = m 0 e α(r 0 −1) t , where m 0 = m(t = 0) and one can obtain the expression for the basic reproduction number as it is usual in epidemic models [1, 27] , the disease (alcoholism) will persist in the population if r 0 > 1, i.e., for β > α. one can start analyzing the time evolution of the three classes of individuals. we numerically integrated eqs. (1), (2) and (3) the effects of the variation of the model's parameters. as initial conditions, we considered s(0) = 0.99, m(0) = 0.01 and r(0) = 0, and for simplicity we fixed α = 0.03 and δ = 0.07, varying the parameters β and γ. in fig. 1 (a) , (b) and (c) we exhibit results for fixed β = 0.07 and typical values of γ. one can see that the increase of γ causes the increase of s and the decrease of m and r. remembering that γ models the persuasion of nonconsumers s in the social interactions with risk drinkers r, i.e., the social pressure of individuals that do not consume alcohol over their contacts (friends, relatives, etc) that consume too much alcohol. on the other hand, in fig. 1 (d) we considered γ = 0.15 and β = 0.07. for this case, where we have β > γ, we see that the densities evolve in time, and in the steady states we observe the survival of only the risk drinkers, i.e., for t → ∞ we have s = m = 0 and r = 1. this last result will be discussed in more details analytically in the following. as we observed in fig. 1 , the densities s(t), m(t) and r(t) evolve in time, and after some time they stabilize. in such steady states, the time derivatives of eqs. (1) -(3) are zero. in the t → ∞ limit, eq. (1) gives us (−β m − β r + γ r) s = 0, where we denoted the stationary values as s = s(t → ∞), m = m(t → ∞) and r = r(t → ∞). this last equation has two solutions, one of them is s = 0 and from the other solution we can obtain a relation between r and m, considering now the limit t → ∞ in eq. (2), one obtains β s r = (α + δ r − β s) m . if the obtained solution s = 0 is valid, this relation gives us m = 0 and consequently from (4) we have r = 1. this solution represents an absorbing state [28, 29] , since the dynamics becomes frozen due to the absence of s and m agents. we will discuss this solution in more details in the following. considering now the relation (7) and the normalization condition (4), one can obtain substituting (9) and (7) in (8) considering this result (10) in eqs. (9) and (7) we obtain, respectively the obtained eqs. (10) -(12) represent a second possible steady state solution of the model, that is a realistic solution since the three fractions s, m and r coexist in the population. we can look to eq. (10) in more details. it can be rewritten in the critical phenomena perspective as [30, 31] where the critical points are given by the competition among the contagions cause the occurrence of such three regions in the model. from one side we have drinkers (moderated and risk) influencing nonconsumers to consume alcohol, with probability β. on the other hand, we have the social pressure of nonconsumers over risk drinkers, with probability γ, in order to make such alcoholics to begin treatment and stop drinking. finally, it is important to mention the parameter α, that drives the only transition of the model that does not depend on a direct social interaction. that parameter models the spontaneous increase of alcohol consumption, and it is also responsible for the first phase transition (together with γ), since we have β (1) c = 0 for α = 0. it means that the alcohol consumption (the "disease") cannot be eliminated of the population after a long time if there is a spontaneous increase of alcohol consumption from individuals that drink moderately, which is a realistic feature of the model. for clarity, we exhibit in fig. 3 the phase diagram of the model in the plane β versus γ, separating the three above discussed regions. in fig. 3 , the absorbing phase with s = 1 and m = r = 0 is located in region i for β < β (1) c , the coexistence phase is denoted by ii for β (where the three densities coexist) and the other absorbing phase where s = m = 0 and r = 1 is located in region iii. from this figure we see the mentioned competition among the contagions. indeed, if β is sufficiently high, many nonconsumers become moderated drinkers. such moderated drinkers will become risk drinkers (via probabilities α and δ), and in the case of small γ we will observe after a long time the disappearance of nonconsumers and moderated drinkers (region iii). in the opposite case, i.e., for high γ and small β, the flux into the compartment s is intense, and in the long-time limit the other two subpopulations m and r disappears (region i). finally, for intermediate values of β and γ the competition among the social interactions lead to the coexistence of the three subpopulations in the stationary states (region ii). it is worthwhile to mention that the sizes of regions i and ii are directly dependent on probability α, while region iii is always fixed due to eq. (18) . this means that, if parameter α is increased, region i will become gradually larger, which is an indication that the spontaneous evolution from moderate to risk drinking behavior increases the latter's absorbing state. in consequence, since probability α represents a percentage of moderate drinkers that become risk drinkers without the need for social interaction, it is a crucial factor not only to implement the theoretical model but also to identify a possible percentage of the population that has a natural tendency to present excessive alcohol consumption behavior, regardless of their social interaction network. for fig. 3 , for instance, this value is 3%. larger values of α narrow the set of parameters that can be chosen in order to realistically describe a real system. finally, we compare the model's results with data of drinking abusive consumption in brazil [26] . data were collected from 2009 to 2019, thus in fig. 4 the initial time t = 0 represents the fraction of abusive drinkers for 2009, t = 1 represents the fraction for 2010, and so on. since the data is for the fraction of people that consume alcohol abusively, we plot the density of risk drinkers r(t) together with the data. in order to compare them with the model, we considered for the initial density of risk drinkers r(0) = 0.185 and numerically integrated eqs. (1) -(3). the value 0.185 was chosen since it is the fraction of abusive drinkers for 2009 obtained from the database [26] . in addition, we rescaled the time of the simulation results to match the time of real data: such simulation time was multiplied by 0.12 for a better comparison. we find that the simulated drinking trajectories qualitatively correspond to the data. for the numerical results, we considered the parameters β = 0.06, γ = 0.11, α = 0.047 and δ = 0.2, which indicate that the probability of finding an individual that will spontaneously become a risk drinker in brazil during the last decade is around 4,7%. furthermore, looking at eqs. (17) and (18) , it is easy to see that in order to model brazil's c < β < β (2) c , showing that the model describes the available data in its most realistic spectrum (region ii of figure 3 ). naturally, in comparison with actual data, models should always present the three different phases, i.e. coexistence between the three different population groups, since descriptions with only nonconsumers or risk drinkers are unrealistic. this qualitative agreement with brazil's database in the realistic spectrum of the model points to a good, albeit simplistic, modelling. in this work, we have studied a compartmental model that aims to describe the evolution of drinking behavior in an adult population. we considered a fully-connected population that is divided in three compartments, namely susceptible individuals s (nonconsumers), moderated drinkers m and risk drinkers r. the transitions among the compartments are ruled by probabilities, representing the social interactions among individuals, as well as spontaneous decisions, in particular from moderate evolving into risk drinkers, and we studied the model through analytical and numerical calculations. from the theoretical point of view, the model is of interest of statistical physics since we observed the occurrence of two distinct nonequilibrium phase transitions. these transitions separate the model in three regions: (i) existence of nonconsumers only; (ii) coexistence of the three compartments and (iii) existence of risk drinkers only. regions i and iii represent two distinct absorbing phases, since the system becomes frozen due to the existence of only one subpopulation for each case -this means that, in order to describe real populational systems, the parameters must be chosen so that the model falls in region ii, since populations consisting solely of nonconsumers or risk drinkers do not represent a realistic entity. the critical points of such transitions were obtained analytically. a comparison with available data for brazil's extreme alcohol consumption for the past decade shows a good qualitative agreement with the model, with the chosen parameters framed within its realistic boundaries. it will be important in a couple of years time to re-evaluate these results in the light of new data comprising years 2020 and 2021, in order to verify the direct effects of the covid-19 pandemic in the brazilian population's alcohol consumption. an hypothesis to be tested is a possible increase in parameter α combined with a corresponding decrease in the other parameters, corresponding to social interactions. the phase transitions observed in the model are active-absorbing phase transitions, and the predicted critical exponent for the order parameter is 1 (m ∼ (β−β c ) 1 ) as in the mean-field directed percolation, that is the prototype of a phase transition to an absorbing state [30, 31] . it would be interesting to estimate numerically other critical exponents of the model, as well as to simulate it in regular d-dimensional lattices (e.g. square and cubic) in order to obtain all the critical exponents. this is important to define precisely the universality class of the model, as well as its upper critical dimension. this extension is left for a future work. furthermore, it can also be considered the inclusion of heterogeneities in the population, like agents' conviction [32] , time-dependent transition rates [33] , inflexibility [34] , etc. the mathematical theory of infectious diseases and its applications, charles griffin & company ltd, 5a crendon street, high wycombe, bucks hp13 6le epidemics and rumours analysing the spanish smoke-free legislation of 2006: a new method to quantify its impact using a dynamic model predicting cocaine consumption in spain: a mathematical modelling approach alcohol consumption in spain and its economic cost: a mathematical modeling approach modeling the obesity epidemic: social contagion and its implications for control can honesty survive in a corrupt parliament? evolution of tag-based cooperation on erdős-rényi random graphs encouraging moderation: clues from a simple model of ideological conflict the dynamics of the rise and fall of empires dynamics of tax evasion through an epidemic-like model modeling radicalization phenomena in heterogeneous populations social epidemiology and complex system dynamic modelling as applied to health behaviour and drug use research agent-based modeling of drinking behavior: a preliminary model and potential applications to theory and practice world health statistics 2018: monitoring health for the sdgs, sustainable development goals the prevalence and impact of alcohol problems in major depression: a systematic review bilinski, alcohol consumption reported during the covid-19 pandemic: the initial stage alcohol use and misuse during the covid-19 pandemic: a potential public health crisis? complicated alcohol withdrawalan unintended consequence of covid-19 lockdown alcohol use in times of the covid 19: implications for monitoring and policy modelling alcohol problems: total recovery mohyud-din, a conformable mathematical model for alcohol consumption in spain dynamics of an alcoholism model on complex networks with community structure and voluntary drinking modeling binge drinking drinking as an epidemica simple mathematical model with recovery and relapse, in: therapist's guide to evidence-based relapse prevention vigitel brasil 2019 : vigilncia de fatores de risco e proteo para doenas crnicas por inqurito telefnico : estimativas sobre frequncia e distribuio sociodemogrfica de fatores de risco e proteo para doenas crnicas nas capitais dos 26 estados brasileiros e no distrito federal em 2019 covid-19 spreading in rio de janeiro, brazil: do the policies of social isolation really work? survival of the scarcer in space symbiotic two-species contact process nonequilibrium phase transitions in lattice models non-equilibrium critical phenomena and phase transitions into absorbing states competition among reputations in the 2d sznajd model: spontaneous emergence of democratic states critical behavior of the sis epidemic model with time-dependent infection rate inflexibility and independence: phase transitions in the majority-rule model the authors thank ronald dickman for some suggestions. financial support from the brazilian scientific funding agencies cnpq (grants 303025/2017key: cord-017351-73hlwwdh authors: quarantelli, e. l.; boin, arjen; lagadec, patrick title: studying future disasters and crises: a heuristic approach date: 2017-09-12 journal: handbook of disaster research doi: 10.1007/978-3-319-63254-4_4 sha: doc_id: 17351 cord_uid: 73hlwwdh over time, new types of crises and disasters have emerged. we argue that new types of adversity will continue to emerge. in this chapter, we offer a framework to study and interpret new forms of crises and disasters. this framework is informed by historical insights on societal interpretations of crises and disasters. we are particularly focused here on the rise of transboundary crises – those crises that traverse boundaries between countries and policy systems. we identify the characteristics of these transboundary disruptions, sketch a few scenarios and explore the societal vulnerabilities to this type of threat. we end by discussing some possible implications for planning and preparation practices. disasters and crises are as old as when human beings started to live in groups. through the centuries, new types have emerged. for instance, the development of synthetic chemicals in the 19th century and nuclear power in the 20th century created the possibility of toxic chemical disasters and crises from radioactive fallouts. older crisis types did not disappear: ancient types such as floods and earthquakes remain with us. the newer disasters and crises are additions to older forms; they recombine elements of old threats and new vulnerabilities. the literature on crisis and disaster research suggests that we are at another important historical juncture with the emergence of a new distinctive class of disasters and crises not often seen before (ansell, boin, & keller, 2010; helsloot, boin, jacobs, & comfort, 2012; tierney, 2014) . in this chapter, we discuss the rise of transboundary crises and disasters. we seek to offer a heuristic approach to studying these new crises and disasters. we offer a heuristic approach to understanding the disasters and crises of the future. it is presented primarily as an aid or guide to looking further into the matter, hopefully stimulating more investigation on conceptions of disasters and crises in the past, the present, and the future. unlike in some areas of scientific inquiry, where seemingly final conclusions can be reached (e.g., about the speed of light), the basic nature of the phenomenon we are discussing is of a dynamic nature and subject to change through time. the answer to the question of what is a disaster or crisis has evolved and will continue to do so (see perry' s chapter in this handbook). human societies have always been faced with risks and hazards. earthquakes, hostile inter-and intra-group relationships, massive floods, sudden epidemics, threats to take multiple hostages or massacre large number of persons, avalanches, fires and tsunamis have marked human history for centuries if not eons. disasters and crises requiring a group reaction are as old as when human beings started to live in stable communities. 1 the earliest happenings are attested to in legends and myths, oral traditions and folk songs, religious accounts and archeological evidence from many different cultures and subcultures around the world. for example, a "great flood" story has long existed in many places (lang, 1985) . as human societies evolved, new threats and hazards emerged. to the old there have been added new dangers and perils that increasingly have become potentially dangerous to human groups. risky technological agents have been added to natural hazards. these involve chemical, nuclear and biological threats that can accidentally materialize as disasters. intentional conflict situations have become more damaging at least in the sense of involving more and more victims. the last 90 years have seen two world wars, massive air and missile attacks by the military on civilians distant from battle areas, many terrorist attacks, and widespread ethnic strife. genocide killed one million persons in rwanda; millions have become refugees and tens of thousands have died in darfur in the sudan in africa. while terrorism is not a new phenomenon, its targets have considerably expanded. some scholars and academics have argued that the very attempt to cope with increasing risks, especially of a technological nature, is indirectly generating new hazards. as the human race has increasingly been able to cope with such basic needs as food and shelter, some of the very coping mechanisms involved (such as the double edged consequences of agricultural pesticides), have generated new risks for human societies (beck, 1999; perrow, 1999) . for example, in 2004, toxic chemicals were successfully used to eradicate massive locust infestations affecting ten western and northern african countries. those very chemicals had other widespread negative effects on humans, animals and crops (irin, 2004) . implicit in this line of thinking is the argument that double-edged consequences from new innovations (such as the use of chemicals, nuclear power and genetic engineering) will continue to appear (tenner, 1996) . we cannot say that the future will bring more disasters, as we have no reliable statistics on prior happenings as a base line to use in counting (quarantelli, 2001) . at present, it would seem safer to argue that some future events are qualitatively different, and not necessarily that there will be more of them in total (although we would argue the last is a viable hypothesis that requires a good statistical analysis). societies for the most part have not been passive in the face of these dangers to human life and well-being. this is somewhat contrary to what is implicit in much of the social science literature especially about disasters. in fact, some of these writings directly or indirectly state that a fatalistic attitude prevailed in the early stages of societal development (e.g., quarantelli, 2000) . this was thought because religious beliefs attributed negative societal happenings to punishments or tests 1 this seems to have occurred about five to six thousand years ago (see lenski, lenski, & nolan, 1991) . however, recent archeological studies suggest that humans started to abandon nomadic wanderings and settled into permanent sites around 9,500 years ago (balter, 2005) so community recognized disasters and crises might have an even longer history. by supernatural entities (the "acts of god" notion, although this particular phrase became a common usage mostly because it served the interests of insurance companies). but prayers, offerings and rituals are widely seen as means to influence the supernatural. so passivity is not an automatic response to disasters and crises even by religious believers, an observation sometimes unnoticed by secular researchers. in fact, historical studies strongly indicate that societal interpretations have been more differentiated than once believed and have shifted through the centuries, at least in the western world. in ancient greece, aristotle categorized disasters as the result of natural phenomena and not manifestations of supernatural interventions (aristotle, 1952) . the spread of christianity about 2,000 years ago helped foster the belief that disasters were "special providences sent directly" from "god to punish sinners" (mulcahy, 2002, p. 110) . in the middle ages, even scholars and educated elites "no longer questioned the holy origins of natural disasters" (massard-guilbaud, platt, & schott, 2002, p. 19) . starting in the 17th century, however, explanations started to be replaced by "ones that viewed disasters as accidental or natural events" (mulcahy, 2002, p. 110) . this, of course, also reflected a strong secularization trend in western societies. perhaps this reached a climax with the 1755 lisbon earthquake which dynes notes can be seen as the "first modern disaster" (2000, p. 10). so far our discussion has been mostly from the perspective of the educated elites in western societies. little scholarly attention seems to have been given to what developed in non-western social systems. one passing observation about the ottoman empire and fire disasters suggests that the pattern just discussed might not be universal. thus, while fire prevention measures were encouraged in cities, they were not mandated "since calamities were considered" as expressions of the will of god (yerolympos, 2002, p. 224) . even as late as 1826 an ottoman urban building code stated that according to religious writing "the will of the almighty will be done" and nothing can and should be done about that. at the same time, this code advances the idea that nevertheless there were protective measures that could be taken against fires that are "the will of allah" (quoted in yerolympos, 2002, p. 226) . of course, incompatibility between natural and supernatural views about the world are not unique to disaster and crisis phenomena, but that still leaves the distinction important. 2 even recently, an australian disaster researcher asserted that in the 2004 southwestern asian tsunami most of the population seemed to believe that the disaster was "sent either as a test of faith or punishment" (mcaneney, 2005, p. 3). or as another writer noted, following the tsunami, religiously oriented views surfaced. some were by: "fundamentalist christians" who tend to view all disasters "as a harbinger of the apocalypse". others were by "radical islamists" who are inclined to see any disaster that "washes the beaches clear of half-nude tourists to be divine" (neiman, 2005, p. 16) . after hurricane katrina, some leaders of evangelical groups spoke of the disaster as punishment imposed by god for "national sins" (cooperman, 2005) . in the absence of systematic studies, probably the best hypothesis that should be researched is that at present religious interpretations about disasters and crisis still appear to be widely held, but relative to the past probably have eroded among people in general. the orientation is almost certainly affected by sharp cross-societal difference in the importance attributed to religion as can be noted in the religious belief systems and practices as currently exist in the united states and many islamic countries, compared to japan or a highly secular western europe. apart from the varying interpretations of the phenomena, how have societies behaviorally reacted to existing and ever-changing threats and risks? as a whole, human groups have evolved a 2 for an interesting attempt to deal with these two perspectives see the paper entitled disaster: a reality or a construct? perspective from the east, written by jigyasu (2005) an indian scholar. variety of formal and informal mechanisms to prevent and to deal with crises and disasters. but societies have followed different directions depending on the perceived sources of disasters and crises. responses tend to differ with the perception of the primary origin (the supernatural, the natural or the human sphere). for example, floods were seen long ago as a continuing problem that required a collective response involving engineering measures. stories that a chinese emperor, 23 centuries before christ, deepened the ever-flooding yellow river by massive dredging and the building of diversion canals may be more legend than fact (waterbury, 1979, p. 35) . however, there is clear evidence that in egypt in the 20th century bc, the 12th dynasty pharaoh, amenemher ii completed southwest of cairo what was probably history's first substantial river control project (an irrigation canal and dam with sluice gates). other documentary evidence indicates that dams for flood control purposes were built as far back as 1260 b c in greece (schnitter, 1994, p. 1, 8-9) . such mitigatory efforts indicate both the belief that there was a long-term natural risk as well as one that could be coped with by physically altering structural dimensions. later, particular in europe, there were many recurrent efforts to institute mitigation measures. for example, earthquake resistant building techniques were developed in ancient rome, although "they had been forgotten by the middle ages" (massard-guilbaud et al., 2002, p. 31) . the threats from floods and fires spurred mitigation efforts in greece. starting in the 15th century, developing urban areas devised many safeguards against fires, varying from regulations regarding inflammable items to storage of water for firefighting purposes. in many towns in medieval poland, dams, dikes and piles along riverbanks were built (sowina, 2002) . of course, actions taken were not always successful. but, if nothing else, these examples show that organized mitigation efforts have been undertaken for a long time in human history. there have been two other major behavioral trends of long duration that are really preventive in intent if not always in reality. one has been the routinization of responses by emergency oriented groups so as to prevent emergencies from escalating into disasters or crises. for example, in ancient rome, the first groups informally set up to fight fires were composed of untrained slaves. but when a fire in 6 a.d. burned almost a quarter of rome, a corps of vigiles was created that had full-time personnel and specialized equipment. in more recent times, there are good examples of this routinization in the planning of public utilities that have standardized operating procedures to deal with everyday emergencies so as to prevent them from materializing into disasters. in the conflict area, there are various un and other international organizations, such as the international atomic energy agency and the european union (eu), that also try to head off the development of crises. in short, societies have continually evolved groups and procedures to try to prevent old and new risks and threats from escalating into disasters and crises. a second more recent major trend has been the development of specific organizations to deal first with wartime crises and then with peacetime disasters. societies for about a century have been creating specific organizations to deal first with new risks for civilians created by changes in warfare, and then improving on these new groups as they have been extended to peacetime situations. rooted in civil defense groups created for air raid situations, there has since been the evolvement of civilian emergency management agencies (blanchard, 2004) . accompanying this has been the start of the professionalization of disaster planners and crisis managers. there has been a notable shift from the involvement of amateurs to educated professionals. human societies adjusted not only to the early risks and hazards, but also to the newer ones that appeared up to the last century. the very existence of the human race is testimony to the social coping mechanisms of humans as they face such threats. here and there a few communities and groups have not been able to cope with the manifestations of contemporary risks and hazards (diamond, 2005) . but these have been very rare cases. neither disasters nor crises involving conflict have had that much effect on the continuing existence of cities anywhere in the world. throughout history, many cities have been destroyed. they have been: "sacked, shaken, burned, bombed, flooded, starved, irradiated and poisoned", but in almost every case they have phoenix-like been reestablished (vale & campanella, 2004, p. 1) . around the world, from the 12th to the 19th century, only 42 cities were "permanently abandoned following destruction" (vale & campanella, 2004, p. 1) . the same analysis notes that large cities such as baghdad, moscow, aleppo, mexico city, budapest, dresden, tokyo, hiroshima and nagasaki all suffered massive physical destruction and lost huge numbers of their populations due to disasters and wartime attacks. all were rebuilt and rebounded. at the start of the 19th century, "such resilience became a nearly universal fact" about urban settlements around the world (vale & campanella, 2004, p. 1) . looking at these cities today as well as warsaw, berlin, hamburg and new orleans, it seems this recuperative tendency is very strong (see also schneider & susser, 2003) . in the hiroshima museum that now exists at the exact point where the bomb fell, there is a 360-degree photograph of the zone around that point, taken a few days after the attack. except for a few piles of ruins, there is nothing but rubble as far as the eye can see in every direction. there were statements made that this would be the scene at that location for decades. but a visitor to the museum today can see in the windows behind the circular photograph, many signs of a bustling city and its population (for a description of the museum see webb, 2006) . hiroshima did receive much help and aid to rebuild. but the city came back in ways that observers at the time of impact did not foresee. early efforts to understand and to cope with disasters and crises were generally of an ad hoc nature. with the strong development of science in the 19th century, there was the start of understanding the physical aspects of natural disasters, and these had some influence on structural mitigation measures that were undertaken. however, the systematic social science study of crises and disasters is about a half-century-old (fritz, 1961; kreps, 1984; quarantelli, 1988 quarantelli, , 2000 schorr, 1987; wright & rossi, 1981) . in short, there is currently a solid body of research-generated knowledge developed over the last half century of continuing and ever increasing studies around the world in different social science disciplines. to be sure, such accounts and reports are somewhat selective and not complete. there are now case studies and analytical reports on natural and technological disaster (and to some extent on other crises) numbering in the four figures. in addition, there are numerous impressions of specific behavioral dimensions that have been derived from field research (for summaries and inventories see alexander, 2000; cutter, 1994; dynes, demarchi, & pelanda, 1987; dynes & tierney, 1994; farazmand, 2001; helsloot, boin, jacobs, & comfort, 2012; mileti, 1999; oliver-smith, 1999; perry, lindell, & prater, 2005; rosenthal, boin, & comfort, 2001; rosenthal, charles, & 't hart, 1989; tierney, lindell, & perry, 2001; turner, 1978) . what are the distinctive aspects of the newer disasters and crises that are not seen in traditional ones? to answer this question, we considered what social science studies and reports had found about behavior in disasters and crises up to the present time. we then implicitly compared those observations and findings with the distinctive behavioral aspects of the newer disasters and crises. one issue that has always interested researchers and scholars is how to conceptualize disasters and crises. there is far from full agreement that all disasters and crises can be categorized together as being relatively homogeneous phenomena (quarantelli, 1998; perry & quarantelli, 2005) . this is despite the fact that there have been a number of attempts to distinguish between, among and within different kinds of disasters and crises. however, no one overall view has won anywhere near general acceptance among self-designated disaster and crisis researchers. to illustrate we will briefly note some of the major formulations advanced. for example, one attempt has been to distinguish between natural and technological disasters (erikson, 1994; picou & gill, 1996) . the basic assumption was that the inherent nature of the agent involved made a difference. implicit was the idea that technological dangers or threats present a different and more varying kind of challenge to human societies than do natural hazards or risks. most researchers have since dropped the distinction as hazards have come to be seen as less important than the social setting in which they appear. in recent major volumes on what is a disaster (quarantelli, 1998; perry & quarantelli, 2005) , the distinction was not even mentioned by most of the two dozen scholars who addressed the basic question. other scholars have struggled with the notion that there may be some important differences between what can be called "disasters" and "crises". the assumption here is that different community level social phenomena are involved, depending on the referent. thus, some scholars distinguish between consensus and conflict types of crises (stallings, 1988 tries to reconcile the two perspectives). in some research circles, almost all natural and most technological disasters are viewed as consensus types of crises (quarantelli, 1998) . these are contrasted with crises involving conflict such as are exemplified by riots, terrorist attacks, and ethnic cleansings and intergroup clashes. in the latter type, at least one major party is either trying to make it worse or to extend the duration of the crisis. in natural and technological disasters, no one deliberately wants to make the situation worse or create more damage or fatalities. now, there can be disputes or serious disagreements in natural or technological disasters. it is almost inevitable that there will be some personal, organizational and community conflicts as, for example, in the recovery phase of disasters, where scapegoating is common (bucher, 1957; drabek & quarantelli, 1967 cf. boin, mcconnell, & 't hart, 2008) . in some crises, the overall intent of major social actors is to deliberately attempt to generate conflict. in contrast to the unfolding sequential process of natural disasters, terrorist groups or protesting rioters not only intentionally seek to disrupt social life, they modify or delay their attacks depending on perceived countermeasures. apart from a simple observable logical distinction between consensus and conflict types of crises, empirical studies have also established behavioral differences. for example, looting behavior is distinctively different in the two types. in the typical disaster in western societies, almost always looting is rare, covert and socially condemned, done by individuals, and involves targets of opportunity. in contrast, in many conflict crises looting is very common, overt and socially supported, undertaken by established groups of relatives or friends, and involves deliberately targeted locations (quarantelli & dynes, 1969) . likewise, there are major differences in hospital activities in the two kinds of crises, with more variation in conflict situations. there are differences also in the extent to which both organizational and community-level changes occur as a result of consensus and conflict crises, with more changes resulting from conflict occasions (quarantelli, 1993) . finally, it has been suggested that the mass media system operates differently in terrorism situations and in natural and technological disasters (project for excellence in journalism, 1999 journalism, , 2001 . 3 both the oklahoma city bombing and the 9-11 world trade center attack led to sharp clashes between different groups of initial organizational responders. there were those who saw these happenings primarily as criminal attacks necessitating closure of the location as a crime 3 for a contrary view that sees terrorist occasions as more or less being the same as what behaviorally appears in natural and technological disasters (fischer, 2003) . scene, and those who saw them primarily as situations where priority ought to be on rescuing survivors. in the 9-11 situation, the clash continued later into the issues of the handling of dead bodies and debris clearance. all this goes to show that crises and disasters are socially constructed. whether it is by theorists, researchers, operational personnel, politicians or citizens, any designation comes from the construction process and is not inherent in the phenomena itself. this is well illustrated in an article by cunningham (2005) where he shows that a major cyanide spill into the danube river was differently defined as an incident, an accident, or a catastrophe, depending on how culpability was perceived and who was doing the defining. still other distinctions have been made. some advocate "crisis" as the central concept in description and analysis (see the chapter of boin, kuipers and 't hart in this handbook). in this line of thinking, a crisis involves an urgent threat to the core functions of a social system. a disaster is seen as "a crisis with a bad ending" (boin, 2005) . this is consistent with the earlier expressed idea that while there are many hazards and risks, only a few actually manifest themselves. but the crisis idea does not differentiate among the manifestations themselves as the consensus and conflict distinction does. this is not the place to try and settle conceptual disagreements and we will not attempt to do so. anyone in these areas of study should acknowledge that there are different views and different proponents should try to make their positions as explicit as possible so people do not continue to talk past one another. it is perhaps not amiss here to note that the very words or terms used to designate the core nature of the phenomena are etymologically very complex with major shifts in meaning through time. 4 we are far from having standardized terms and similar connotations and denotations for them. a conceptual question that has come increasingly to the fore in the last decade or so is the question: have new kinds of crises and disasters began to appear? we think it is fair to say that there are new types of risks and hazards. there are also structural changes in social settings. together, they raise the prospect of new types of disasters and crises. for example, we have seen the breakdown of modern transportation systems (think of the volcanic ash crisis that paralyzed air traffic in 2010; kuipers & boin, 2015) . there have been massive information system failures either through sabotage or as a result of technical breakdowns in linked systems. there have been terrorist attacks of a magnitude and scale not seen before. we are living with the prospect of widespread illnesses and health-related difficulties that appear to be qualitatively different from traditional medical problems. we have just lived through financial and economic collapses that cut across different social systems around the world. many of these "new" disruptions have both traditional and non-traditional features: think of the heat waves in paris (lagadec, 2004) and chicago (klinenberg, 2002) , the ice storms in canada (scanlon, 1998) , but also the genocide-like violence in africa and the former yugoslavia. the chernobyl radiation fallout (1986) led some scholars and researchers to start asking if there was not something distinctively new about that disaster. the fallout was first openly measured in sweden. officials were mystified in that they could not locate any possible radiation source in their own country. later radiation effects on vegetation eaten by reindeer past the arctic circle in northern sweden were linked to the nuclear plant accident in the soviet union. the mysterious origins, crossing of national boundaries, and the emergent involvement of 4 see safire (2005) who struggles with past and present etymological meanings of "disaster", "catastrophe", "calamity" and "cataclysm"; also see murria (2004) who looking outside the english language found a bewildering set of words used, many of which had no equivalent meanings in other languages. many european and transnational groups was not something researchers had typically seen together in other prior disasters. looking back, it is clear that certain other disasters also should have alerted all of us to the probability that new forms of adversity were emerging. in november 1986, water used to put out fire in a plant involving agricultural chemicals spilled into the river rhine. the highly polluted river went through switzerland, germany, france, luxembourg and the netherlands. a series of massive fire smog episodes plagued indonesia in 1997 and 1998. land speculations led to fire-clearing efforts that, partly because of drought conditions, resulted in forest fires that produced thick smog hazes that spread over much of southeast asia (barber & schweithelm, 2000) . these disrupted travel, which in turn affected tourism as well as creating respiratory health problems, and led to political criticism of indonesia by other countries as multi-nation efforts to cope with the problem were not very successful. both of these occasions had characteristics that were not typically seen in traditional disasters. in the original version of this chapter, we spoke about "trans-system social ruptures". this term was an extension of the earlier label of "social ruptures" advanced by lagadec (2000 lagadec ( , 2004 . the term "transboundary" has since become the more conventional way to describe crises and disasters that jump across different societal boundaries disrupting the social fabric of different social systems (ansell et al., 2010) . the two prime and initial examples we used in the original chapter were the severe acute respiratory syndrome (sars) and the sobig computer f virus spread, both of which appeared in 2003. the first involved a "natural" phenomenon, whereas the second was intentionally created. since there is much descriptive literature available on both, we here provide only very brief statements about these phenomena. the new infectious disease sars appeared in the winter of 2003. apparently jumping from animals to humans it originated in southern rural china, near the city of guangzhou. from there it moved through hong kong and southeast asia. it spread quickly around the world because international plane flights were shorter than its incubation period. at least 774 infected persons died. it hit canada with outbreaks in vancouver in the west and toronto far away in the east. in time, 44 persons died of the several hundred that got ill, and thousands of others were quarantined. the city's healthcare system virtually closed down except for the most urgent of cases with countless procedures being delayed or cancelled. the result was that there was widespread anxiety in the area resulting in the closing of schools, the cancellation of many meetings and, because visitors and tourists stayed away, a considerable negative effect on the economy (commission report, 2004, p. 28) . the commission report notes a lack of coordination among the multitude of private and public sector organizations involved, a lack of consistent information on what was really happening, and jurisdictional squabbling on who should be doing what. although sars vanished worldwide after june 2003, to this day it is still not clear why it became so virulent in the initial outbreak and why it has disappeared (yardley, 2005) . the sobig computer f virus spread in august 2003 (schwartz, 2003) . it affected many computer systems and threatened almost all computers connected to the internet. the damage was very costly. a variety of organizations around the world, public and private, attempted to deal with the problem. initially uncoordinated, there eventually emerged in an informal way a degree of informational networking on how to cope with what was happening (koerner, 2003) . 5 what can we generalize from not only these two cases, but also others that we looked at later 5 in may 2017, the so-called wannacry virus affected millions of computers across the world with ransomware. many hospitals were affected. (ansell et al., 2010) ? the characteristics we depict are stated in ideal-typical terms; that is, from a social science perspective, what the phenomena would be if they existed in pure or perfect form. first, the threat jumps across many international and national/political governmental boundaries. it crosses functional boundaries, jumping from one sector to another, and crossing from the private into public sectors (and sometimes back). there was, for example, the huge spatial leap of sars from a rural area in china to metropolitan toronto, canada. second, a transboundary threat can spread very fast. cases of sars went around the world in less than 24 hours with a person who had been in china flying to canada quickly infecting persons in toronto. the spread of the sobig f virus was called the fastest ever (thompson, 2004) . this quick spread is accompanied by a very quick if not almost simultaneous global awareness of the risk because of mass media attention. third, there is no known central or clear point of origin, at least initially, along with the fact that the possible negative effects at first are far from clear. this stood out when sars first appeared in canada. there is much ambiguity as to what might happen. ambiguity is of course a major hallmark of disasters and crises (turner, 1978) . it is more pervasive in transboundary crises as information about causes, characteristics and consequences is distributed across the system. fourth, there are potentially if not actual large number of victims, directly or indirectly. the sobig computer virus infected 30% of email users in china, that is about 20 million people and about three fourths of email messages around the world were infected by this virus (koerner, 2003) . in contrast to the geographic limits of most past disasters, the potential number of victims is often open ended in disruptions that span across boundaries. fifth, traditional "solutions" or approachesembedded in local and/or professional institutions will not always work. this is rather contrary to the current emphasis in emergency management philosophy. the prime and first locus of planning and managing cannot be the local community as it is presently understood. international and transnational organizations must typically be involved very early in the initial response (boin, ekengren, & rhinard, 2013) . the nation state may not even be a prime actor in the situation. sixth, although responding organizations and groups are major players, there is an exceptional amount of emergent behavior and the development of many informal ephemeral linkages. in some respects, the informal social networks generated, involving much information networking, are not always easily identifiable from the outside, even though they are often the crucial actors at the height of the crisis. in this section, we sketch several future scenarios that most likely would create transboundary disasters. even though some of the scenarios discussed might seem to be science fiction in nature, the possibilities we discuss are well within the realm of realistic scientific possibilities. the most obvious scenario revolves around asteroids or comets hitting planet earth (di justo, 2005) . this has, of course, happened in the past, but even more recent impacts found no or relatively few human beings around. there are two major possibilities with respect to impact (mcguire, 2000; wisner, 2004) . a landing in the ocean would trigger a tsunami-like impact in coastal areas. just the thinking of the possibility of how, when and where ahead of time coastal population evacuations might have to be undertaken, is a daunting thought. statistically less likely is a landing in a heavily populated area. but a terrestrial impact anywhere on land would generate very high quantities of dust in the atmosphere, which will affect food production as well as creating economic disruption. this would be akin to the tambora volcanic eruption in 1813, which led to very cold summers and crop failures (post, 1977) . the planning and management problems for handling something like this would be enormous. the explosion of space shuttle columbia scattered debris over a large part of the united states. this relatively small disastercompared to a comet or asteroid impactinvolved massive crossing of boundaries, a large number of potential victims, and could not be managed by local community institutions. the response required that an unplanned effort coordinating organizations that had not previously worked with one another and other unfamiliar groups, public and private (ranging from the us forest service to local red cross volunteers to regional medical groups), be informally instituted over a great part of the united states (beck & plowman, 2013; donahue, 2003) . a second scenario is the inadvertent or deliberate creation of biotechnological disasters. genetic engineering of humans or food products is currently in its infancy. the possible good outcomes and products from such activity are tremendous (morton, 2005) and are spreading around the world (pollack, 2005) . but the double-edged possibilities mentioned earlier are also present. there is dispute over genetically modified crops, with many european countries resisting and preventing their use and spread in their countries. while no major disaster or crisis from this biotechnology has yet occurred, there have been many accidents and incidents that suggest that this will be only a matter of time. for example, in 2000, starlink corn, approved only for animal feed is found in the food supply, such as taco shells and other groceries. the same year farmers in europe learned that that they had unknowingly been growing modified canola using mixed seed from canada. in 2001, modified corn was found in mexico even though it was illegal to plant in that country. that same year, experimental corn that had been engineered to produce a pharmaceutical that was found in soybeans in the state of nebraska. in several places, organic farmers found that it was impossible for them to keep their fields uncontaminated (for further details about all these incidents and other examples, see pollack, 2004) . noticeable is the leaping of boundaries and uncertainty about the route of spreading. it does not take much imagination to see that a modified gene intended for restricted use, could escape and create a contamination that could wreak ecological and other havoc. perhaps even more disturbing to some is genetic engineering involving human beings. the worldwide dispute over cloning, while currently perhaps more a philosophical and moral issue, does also partly involve the concern over creating flawed human-like creatures. it is possible to visualize not far-fetched worst-case scenarios that could be rather disastrous. it should be noted that even when there is some prior knowledge of a very serious potential threat, what might happen is still likely to be as ambiguous and complex as when sars first surfaced. this can be seen in the continuing major concern expressed in 2004 to mid-2005 about the possible pandemic spread of avian influenza, the so called "bird flu" (nuzzo, 2004; thorson & ekdahl, 2005) . knowledge of the evolution and spread of new pandemics, their effects and whether presently available protective measures would work, may well be very limited. knowledge that it might occur provides very little guidance on what might actually happen. it is possible to imagine the destruction of all food supplies for human beings either through the inadvertent or deliberate proliferation of very toxic biotechnological innovations for which no known barriers to spreading exists. these potential kinds of global disasters are of relatively recent origins and we may expect more such possibilities in the future. the human race is opening up potentially very catastrophic possibilities by innovations in nanotechnology, genetic engineering and robotics (barrat, 2013; joy, 2000; makridakis, 2017) . a potential is not an actuality. but it would be foolish from both a research as well as a planning and managing viewpoint to simply ignore these and other doomsday possibilities. the question might be asked if there is a built-in professional bias among disaster and crisis researchers and emergency planners to look for and to expect the worst (see mueller, 2004 for numerous examples). in the disaster and crisis area, this orientation is reinforced by the strong tendency of social critics and intellectuals to stress the negative. 6 it would pay to look at the past, see what was projected at a particular time, and then to look at what actually happened. the worldwide expectations about what would happen at the turn of the century to computers are now simply remembered as the y2k fiasco. it would be a worthy study to take projections by researchers about the future of ongoing crises and disasters, and then to look at what actually happened. in the 1960s, in the united states, scholars made rough analyses about the immediate future course of racial and university riots in the country. their initial appearances had not been forecasted. moreover, there was a dismal record in predicting how such events would unfold (no one seemed to have foreseen that the riots would go from ghetto areas to university campuses), as well as that they rather abruptly stopped. we should be able to do a better job than we have so far in making projections about the future. but perhaps that is asking more of disaster and crisis researchers than is reasonable. after all, social scientists with expertise in certain areas, to take recent examples, failed completely to predict or forecast the non-violent demise of the soviet union, the peaceful transition in south africa, or the development of a market economy in communist china (cf. tetlock, 2005) . a disaster or crisis always occurs in some kind of social setting. by social setting we mean social systems. these systems can and do differ in social structures and cultural frameworks. there has been a bias in disaster and crisis research towards focusing on specific agents and specific events. thus, there is the inclination of social science researchers to say they studied this or that earthquake, flood, explosion and/or radioactive fallout. at one level that is nonsense. these terms refer to geophysical, climatological or physical happenings, which are hardly the province of social scientists. instead, those focused on the social in the broad sense of the term should be studying social phenomena. our view is that what should be looked at more is not the possible agent that might be involved, but the social setting of the happening. this becomes obvious when researchers have to look at such happenings as the 2004 southeast asia tsunami or locust infestations in africa. both of these occasions impacted a variety of social systems as well as involving social actors from outside those systems. this led in the tsunami disaster to sharp cultural clashes regarding on how to handle the dead between western european organizations who came into look mostly for bodies of their tourist citizens, and local groups who had different beliefs and values with respect to dead bodies (scanlon, personal communication with first author). the residents of the andaman islands lived at a level many would consider "primitive". at the time of the 2004 tsunami in southeast asia, they had no access to modern warning systems. but prior to the tsunami, members of the tribal communities saw signs of disturbed marine life and heard unusual agitated cries of sea birds. this was interpreted as a sign of impending danger, so that part of the population got off the beaches and retreated inland to the woods and survived intact (icpac report, 2006) . there is a need to look at both the current social settings as well as certain social trends that influence disasters and crises. in no way are we going to address all aspects of social systems and cultural frameworks or their social evolution, either past or prospective. instead, we will selectively discuss and illustrate a few dimensions that would seem to be particularly important with respect to crises and disasters. what might these be? let us first look at existing social structures around the world. what differences are there in authority relationships, social institutions and social diversity? as examples, we might note that australia and the united states are far more governmentally decentralized than france or japan (bosner, 6 for example, rees (2004) , a cosmologist at cambridge university, gives civilization as we know it only a 50-50 chance of surviving the 21st century. schoff, 2004) . this affects what might or might not happen at times of disasters (it is often accepted that top-down systems have more problems in responding to crises and disasters). but what does it mean for the management of transboundary disruptions, which require increased cooperation between and across systems? will decentralized systems be able to produce "emergent" transboundary cooperation? as another example, mass media systems operate in rather different ways in china compared with western europe. this is important because to a considerable extent the mass communication system (including social media) is by far the major source of "information" about a disaster or a crisis. they play a major role in the social construction of disasters and crises. for a long time in the former soviet union, even major disasters and overt internal conflicts by way of riots were simply not openly reported (berg, 1988) . and only late in 2005 did chinese authorities announce that henceforth death tolls in natural disasters would be made public, but not for other kinds of crises (kahn, 2005) . another social structural dimension has to do with the range of social diversity in different systems (bolin & stanford, 2006) . social groupings and categories can be markedly different in their homogeneity or heterogeneity. the variation, for instance, can be in terms of life styles, class differences or demographic composition. the aging population in western europe and japan is in sharp contrast to the very young populations in most developing countries. this is important because the very young and the very old incur disproportionately the greatest number of fatalities in disasters. human societies also differ in terms of their cultural frameworks. as anthropologists have pointed out, they can have very different patterns of beliefs, norms, and values. as one example, there can be widely held different conceptions of what occasions disasters and crises. the source can be attributed to supernatural, natural, or human factors as indicated earlier. this can markedly affect everything from what mitigation measures might be considered to how recovery and reconstruction will be undertaken. norms indicating what course of action should be followed in different situations can vary tremendously. for example, the norm of helping others outside of one's own immediate group at times of disasters and crises ranges from full help to none. thus, although the kobe earthquake was an exception, any extensive volunteering in disasters was very rare in japan (for a comparison of the us and japan, see hayashi, 2004) . in societies with extreme cross-cultural ethnic or racial differences, volunteering to help others outside of one's own group at times of disasters or crisis is almost unknown. social structures and cultural frameworks of course are always changing. to understand future disasters and crises, it is necessary to identify and understand trends that may be operative with respect to both social structures and cultural frameworks. in particular, for our purposes, it is important to note trends that might be cutting across structural and cultural boundaries. globalization has been an ongoing force. leaving aside the substantive disputes about the meaning of the term, what is involved is at least the increasing appearance of new social actors at the global level. with respect to disaster relief and recovery, there is the continuing rise of transnational or international organizations such as un entities, the european union, religiously oriented groupings, and the world bank (boin et al., 2013) . with the decline of the importance of the nation state (guéhenno, 1995; mann, 1997) , more and new social actors, especially of an ngo nature, are to be anticipated. the rise of the information society has enabled the development of informal social networks that globally cut across political boundaries. this trend will likely increase in the future. such networks are creating social capital (in the social science sense) that will be increasingly important in dealing with disasters and crises. at the cultural level, we can note the greater insistence of citizens that they ought to be actively protected against disasters and crises (beck, 1999) . this is part of a democratic ideology that has spread around the world. that same ideology carries an inherent paradox: the global citizen may not appreciate government interference in everyday life, but expects government to show up immediately when acute adversity hits. finally, there has been the impact of the 9/11 attacks especially on official thinking not just in the united states but elsewhere also. this happening has clearly been a "focusing event" (as birkland, 1997 uses the term) and changed along some lines, certain values, beliefs and norms (smelser, 2004; tierney, 2005) . there is a tendency, at least in the us after 9/11, to think that all future crises and disasters will be new forms of terrorism. one can see this in the creation of the us department of homeland security, which repeated errors in approach and thinking that over 50 years of research have shown to be incorrect (e.g., an imposition of a command and control model, assuming that citizens will react inappropriately to warnings, seeing organizational improvisation as bad managing, see dynes, 2003) . these changes were accompanied by the downgrading of fema and its emphasis on mitigation (cohn, 2005) . valid or not, such ideas influence thinking about transboundary disasters and crises (and not just in the united states). the ideas expressed above and the examples used were intended to make several simple points. they suggest, for instance, that an earthquake of the same magnitude in france to one in iran will probably be reacted to differently. a riot in sweden will be a different phenomenon than one in myanmar. to understand and analyze such happenings requires taking into account the aspects just discussed. it is hard to believe that countries that currently have no functioning national government, such as somalia and the democratic republic of the congo or marginally operatives ones such as afghanistan, will have the same reaction to disasters and crises as societies with fully functional national governments. different kinds of disasters and crises will occur in rather different social settings. in fact, events that today are considered disasters or crises were not necessarily so viewed in the past. in noting these cross-societal and cross-cultural differences, we are not saying that there are no universal principles of disaster and crisis behavior. there is considerable research evidence supportive of this notion. we would argue, for example, that many aspects of effective warning systems, problems of bureaucracies in responding, the crucial importance of the family/household unit are roughly the same in all societies. to suggest the importance of cross-societal and cross-cultural differences is simply to suggest that good social science research needs to take differences into account while at the same time searching for universal principles about disasters and crises. this is consistent with those disaster researchers and scholars (e.g., oliver-smith, 1994) who have argued that studies in these areas have badly neglected the historical context of such happenings. of course, this neglect of the larger and particularly historical context has characterized much social science research of any kind (wallerstein, 1995) ; it is not peculiar to disaster and crisis studies. one trend that affects the character of modern crises and disasters is what we call the social amplifications of crises and disasters. pidgeon, kasperson, and slovic (2003) described a social augmentation process with respect to risk. to them, risk not only depends on the character of the dangerous agent itself but how it was seen in the larger context in which it appeared. the idea that there can be social amplification of risk rests on the assumption that aspects relevant to hazards interact with processes of a psychological, social, institutional, and cultural nature in such a manner that they can increase or decrease perceptions of risk (kasperson & kasperson, 2005) . it is important to note that the perceived risk could be raised or be diminished depending on the factors in the larger context, which makes it different from the vulnerability paradigm which tends to assume the factors involved will be primarily negative ones. we have taken this idea and extended it to the behaviors that appear in disasters and crises. extreme heat waves and massive blizzards are hardly new weather phenomena (burt, 2004) . there have recently been two heat waves, however, that have new elements in them. in 2003, a long lasting and very intensive heat wave battered france. nearly 15,000 persons died (and perhaps 22,000-35,000 in all of europe). particularly noticeable was that the victims were primarily socially isolated older persons. another characteristic was that officials were very slow in accepting the fact that there was a problem and so there was very little initial response (lagadec, 2004) . there was a similar earlier happening 1995 in chicago not much noticed until reported in a study seven years later (see klinenberg, 2002) . it exhibited the same features, that is, older isolated victims, bureaucratic indifference, and mass media uncertainty. at the other temperature extreme, in 1998, canada experienced an accumulation of snow and ice that went considerably beyond the typical. the ice storm heavily impacted electric and transport systems, especially around montreal. the critical infrastructures being affected created chain reactions that reached into banks and refineries. at least 66 municipalities declared a state of emergency. such a very large geographic area was involved that many police were baffled that "there was no scene", no "ground zero" that could be the focus of attention (scanlon, 1998) . there were also many emergent groups and informal network linkages (scanlon, 1999) . in some ways, this was similar to what happened in august 2003, when the highly interconnected eastern north american power grid started to fail when three transmission lines in the state of ohio came into contact with trees and short circuited (townsend & moss, 2005) . this created a cascade of power failures that resulted in blackouts in cities from new york to toronto and eventually left around 50 million persons without power, which, in turn, disrupted everyday community and social routines (ballman, 2003) . it took months of investigation to establish the exact path of failure propagation through a huge, complex network. telecommunication and electrical infrastructures entwined in complex interconnected and network systems spread over a large geographic area with multiple end users. therefore, localized disruptions can cascade into large-scale failures (for more details, see townsend & moss, 2005) . such power blackouts have occurred among others in auckland, new zealand in 1998 (newlove, stern, & svedin, 2002) ; in buenos aires in 1999 (ullberg, 2004); in stockholm in 2001 and in siberian cities in 2001 (humphrey, 2003 ; in moscow in 2005 (arvedlund, 2005 ; in brazil in 2009 (brooks, 2009); in bangladesh in 2014 (al-mahmood, 2014 , and in sri lanka in 2016 (lbo, 2016). all of these cases initially involved accidents or software and hardware failures in complex technical systems that generate severe consequences creating a crisis with major economic and often political effects. these kinds of crises should have been expected. a national research council report (1989) forecast the almost certain probability of these kinds of risks in future network linkages. blackouts can also be deliberately created either for good or malevolent reasons having nothing to with problems in network linkages. employees of the now notorious enron energy company, in order to exploit western energy markets, indirectly but deliberately took off line a perfectly functioning las vegas power plant so that rolling blackouts hit plant-dependent northern and central california with about a million residences and businesses losing power (egan, 2005) . in the earliest days of electricity in new york city, the mayor ordered the power cut off when poor maintenance of exposed and open wires resulted in a number of electrocutions of citizens and electrical workers (jonnes, 2004) . one should not think of blackouts as solely the result of mechanical or physical failures creating chain-like cascades. most disasters are still traditional ones. for example, four major hurricanes hit the state of florida in 2004. we saw very little in what we found that required thinking of them in some major new ways, or even in planning for or managing them. the problems, individual or organizational, that surfaced were the usual ones, and how to successfully handle them is fairly well known. more important, emergent difficulties were actually somewhat better handled than in the past, perhaps reflecting that officials may have had exposure to earlier studies and reports. thus, the warnings issued and the evacuations that took place were better than in the past. looting concerns were almost non-existent and less than ten percent indicated possible mental health effects. the pre-impact organizational mobilization and placement of resources beyond the community level was also better. the efficiency and effectiveness of local emergency management offices were markedly higher than in the past. not everything was done well. long known problematical aspects and failures to implement measures that research had suggested a long time ago were found. there were major difficulties in interorganizational coordination. the recovery period was plagued by the usual problems. even the failures that showed up in pre-impact mitigation efforts were known. the majority of contemporary disasters in the united states are still rather similar to most of the earlier ones. what could be seen in the 2004 hurricanes in florida was rather similar to what the disaster research center (drc) had studied there in the 1960s and the 1970s. as the electronic age goes beyond its birth and as other social trends continue, new elements may appear creating new problems that will necessitate new planning. if and when that happens, we may have rather new kinds of hurricane disasters, but movement in that direction will be slow. as the famous sociologist herbert blumer used to say in his class lectures a long time ago, it is sometimes useful to check whatever is theoretically proposed against personal experience. in 2005, an extensive snowstorm led to the closing of almost all schools and government offices in the state of delaware. this was accompanied by the widespread cancellations of religious and sport events. there was across the board disruption of air, road and train services. all of this resulted in major economic losses in the millions of dollars. there were scattered interruptions of critical life systems. the governor issued a state of emergency declaration and the state as well as local emergency management offices fully mobilized. to be sure, what happened did not fully rival what surfaced in the canadian blizzard discussed earlier. but it would be difficult to argue that it did not meet criteria often used by many to categorize disasters. what happened was not that different from what others and we had experienced in the past. in short, it was a traditional disaster. finally, at the same time we were thinking about the florida hurricanes and the delaware snowstorm, we also observed other events that many would consider disasters or crises. certainly, a bp texas plant explosion in 2005 would qualify. it involved the third largest refinery in the country. more than a hundred were injured and 15 persons died. in addition, there was major physical destruction of refinery equipment and nearby buildings were leveled. there was full mobilization of local emergency management personnel (franks, 2005) . at about the same time, there were landslides in the state of utah and california; a stampede with hundreds of deaths in a bombay, india temple, train and plane crashes in different places around the world, as well as large bus accidents; a dam rupture which swept away five villages, bridges and roads in pakistan; recurrent coal mine accidents and collapses in china; recurrent false reports in asia about tsunamis that greatly disrupted local routines; sinking of ferries with many deaths, and localized riots and hostage takings. at least based on press reports, it does not seem that there was anything distinctively new about these occasions. they seem to greatly resemble many such prior happenings. unless current social trends change very quickly in hypothetical directions (e.g., marked changes as a result of biotechnological advances), for the foreseeable future there will continue to be many traditional local community disasters and crises (such as localized floods and tornadoes, hostage takings or mass shootings, exploding tanker trucks or overturned trains, circumscribed landslides, disturbances if not riots at local sport venues, large plant fires, sudden discoveries of previously unknown very toxic local waste sites, most airplane crashes, stampedes and panic flights in buildings, etc.). mega-disasters and global crises will be rare in a numerical and relative sense, although they may generate much mass media attention. for example, the terrorist attacks in european cities (madrid in 2004; london in 2005; paris in 2015; brussels, nice, munich berlin in 2016; stockholm and manchester in 2017) were certainly major crises and symbolically very important, but numerically there are far more local train wrecks and car collisions everyday in many countries in the world. the more localized crises and disasters will continue to be the most numerous, despite the rise of transboundary crises and disasters. what are some of the implications for planning and managing that result from taking the perspective we have suggested about crises and disasters? if our descriptions and analyses of such happenings are valid, there would seem to be the need for new kinds of planning and preparation for the management of future crises and disasters (ansell et al., 2010) . non-traditional disasters and crises require some non-conventional processes and social arrangements. they demand innovative thinking "outside of the box" (boin & lagadec, 2000; lagadec, 2005) . this does not mean that everything has to be new. as said earlier, all disasters and crises share certain common dimensions or elements. for example, if early warning is possible at all, research has consistently shown that acceptable warnings have to come from a legitimately recognized source, have to be consistent, and have to indicate that the threat or risk is fairly immediate. these principles certainly pertain to the management of transboundary disruptions. actually, if traditional risks and hazards and their occasional manifestations were all we needed to be worried about, we would be in rather good shape. as already said several times, few threats actually manifest themselves in disasters. for example, in the 14,600 plus tornadoes appearing in the united states between 1952 and 1973, there were casualties in only 497 of them, and 26 of these occasions accounted for almost half of the fatalities (noji, 2000) . similarly, it was noted in 1993 that while about 1.3 million people had been killed in earthquakes since 1900, over 70% of them had died in only 12 occurrences (jones, noji, smith, & wagner, 1993, p. 19) . we can say that risks and hazards and their relatively rare manifestations in crises and disasters are being coped with much better than they ever were even just a half-century ago. for example, there has been a remarkable reduction in certain societies of fatalities and even property destruction in some natural disaster occasions associated with hurricanes, floods and earthquakes (see scanlon, 2004 for data on north america). in the conflict area, the outcomes have been much more uneven, but even here, for example, the recurrence of world wars seems very unlikely. but transboundary crises and disasters require some type of transboundary cooperation. for example, let us assume that a health risk is involved. if international cooperation is needed, who talks with whom about what? at what time is action initiated? who takes the lead in organizing a response? what legal issues are involved (e.g., if health is the issue, can health authorities close airports?)? there might be many experts and much technical information around; if so, and they are not consistent, whose voice and ideas should be followed? what should be given priority? how could a forced quarantine be enforced? what of ethical issues? who should get limited vaccines? what should the mass media be told and by who and when? at a more general level of planning and managing, we can briefly indicate, almost in outline form, a half dozen principles that ought to be taken into account by disaster planners and crisis managers. first, a clear connection should be made between local planning and transboundary managing processes. there usually is a low correlation between planning and managing, even for traditional crises and disasters. but in newer kinds of disasters and crises, there are likely to be far more contingencies. planning processes need to be rethought and enhanced to help policymakers work across boundaries. second, the appearance of new emergent social phenomena (including groups and behaviors) needs to be taken into account. there are always new or emergent groups at times of major disasters and crises, but in transboundary events they appear at a much higher rate. networks and network links have to be particularly taken into account. third, there is the need to be imaginative and creative. the response to hurricane katrina suggests how hard it can be to meet transboundary challenges. but improvisation can go a long way. a good example is found in the immediate aftermath of 9/11 in new york. in spite the total loss of the new york city office of emergency management and its eoc facility, a completely new eoc was established elsewhere and started to operate very effectively within 72 h after the attack. there had been no planning for such an event, yet around 750,000 persons were evacuated by water transportation from lower manhattan (kendra & wachtendorf, 2016; kendra, wachtendorf, & quarantelli, 2003) . fourth, exercises and simulations of disasters and crises must take into account transboundary contingencies. most such training and educational efforts along such lines are designed to be like scripts for plays. that is a very poor model to use. realistic contingencies, unknown to most of the players in the scenarios, force the thinking through of unconventional options. even more important, policymakers need to be explicitly trained in the management of transboundary crises and disasters. fifth, planning should be with citizens and their social groups, and not for them. there is no such thing as the "public" in the sense of some homogenous entity (blumer, 1948) . there are only individual citizens and the groups of which they are members. the perspective from the bottom up is crucial to getting things done. this has nothing to do with democratic ideologies; it has instead to do with getting effective and efficient planning and managing of disasters and crises. related to this is that openness with information rather than secrecy is mandatory. this runs against the norms of most bureaucracies and other organizations. the more information the mass media and citizens have, the better they will be able to react and respond. however, all this is easier said than done. finally, there is a need to start thinking of local communities in ways different than they have been traditionally viewed. up to now, communities have been seen as occupying some geographical space and existing in some chronological time. instead, we should visualize the kinds of communities that exist today are in cyberspace. these newer communities must be thought of as existing in social space and social time. viewed this way, the newer kinds of communities can be seen as very important in planning for and managing disasters and crises that cut across national boundaries. to think this way requires a moving away from the traditional view of communities in the past. this will not be easy given that the traditional community focus is strongly entrenched in most places around the world (see united nations, 2005) . but "virtual reality communities" will be the social realities in the future. assuming that what we have written has some validity, what new research should be undertaken in the future on the topic of future disasters and crises? in previous pages, we suggested some future studies on specific topics that would be worthwhile doing. however, in this section we want to outline research of a more general nature. for one, practically everything we discussed ought to be looked at in different cultures and societies. as mentioned earlier, there is a bias in our perspective that reflects our greater familiarity with and awareness of examples from the west (and even more narrowly western europe, the united states and canada). in particular, there is a need to undertake research in developing rather than only developed countries. and that includes at least some of these studies being undertaken by researchers and scholars from the very social systems that are being studied. the different cultural perspectives that would be brought to bear might be very enlightening, and enable us to see things that presently we do not see, being somewhat a prisoner of our own culture. second, here and there in this chapter, we have suggested that it is important to study the conditions that generate disasters and crises. but there has to be at least some understanding of the nature of x before there can be a serious turn to ascertaining the conditions that generate x. we have taken this first step in this chapter. future work should focus more on the generating conditions. a general model would involve the following ideas. the first is to look at social systems (societal, community and/or organizational ones), and to analyze how they have become more complex and tightly coupled. the last statement would be treated as a working hypothesis. if that turns out to be true, it could then be hypothesized that systems can break down in more ways than ever before. a secondary research thrust would be to see if systems also have developed ways to deal with or cope with threatening breakdowns. as such, it might be argued that what ensues is an uneven balance between resiliency and vulnerability. in studying contemporary trends, particular attention might be given to demographic ones. it would be difficult to find any country today where the population composition is not changing in some way. the increasing population density in high risk areas seems particularly important. another value in doing research on this topic is that much demographic data are of a quantitative nature. we mentioned financial and economic collapses cutting across different systems. how can financial collapse conceivably be thought of as comparable in any way to natural disasters and crises involving conflict? one simple answer is that for nearly a hundred years, one subfield of sociology has categorized, for example, panic flight in theater fires and financial panics as generic subtypes within the field of collective behavior (blumer, 1939; smelser, 1963) . both happenings involve new, emergent behaviors of a non-traditional nature. in this respect, scholars long ago put both types of behavior into the same category. although disaster and crisis researchers have not looked at financial collapses, maybe it is time that they did so. these kinds of happenings seem to occur very quickly, are ambiguous as to their consequences, cut across political and sector boundaries, involve a great deal of emergent behavior and cannot be handled at the community level. in short, what has to be looked for are genotypic characteristics not phenotypic ones (perry, 2004) . if whales, human beings, and bats can all be usefully categorized as mammals for scientific research purposes, maybe students of disasters should also pay less attention to phenotypic features. if so, should other disruptive phenomena like aids also be approached as disasters? our overall point, is that new research along the lines indicated might lead researchers to seeing phenomena in ways different than they had previously seen. finally, we have said little at all about the research methodologies that might be necessary to study transboundary ruptures. up to now, disaster and crisis researchers have argued that the methods they use in their research are indistinguishable from those used throughout the social sciences. the methods are simply applied under circumstances that are relatively unique (stallings, 2002) . in general, we agree with that position. but two questions can be raised. first, if social scientists venture into such areas as genetic engineering, cyberspace, robotics and complex infectious diseases, do they need to have knowledge of these phenomena to a degree that they presently do not have? this suggests the need for actual interdisciplinary research. social scientists ought to expand their knowledge base before venturing to study certain disasters and crises, especially the newer ones. there is something here that needs attention. in the sociology of science there have already been studies of how researchers from rather different disciplines studying one research question, interact with one another and what problems they have. researchers in the disaster and crisis area should look at these studies. our view is that the area of disasters and crises is changing. this might seem to 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disasters letter from the president. international sociological association newsletter 2 hydropolitics of the nile valley the popular culture of disaster: exploring a new dimension of disaster research handbook of disaster research the societal implications of a comet/asteroid impact on earth: a perspective from international development studies social science and natural hazards after its epidemic arrival, sars vanishes urban space as "field" aspects of late ottoman town planning after fire cities and catastrophes: coping with emergency in european history key: cord-015255-1qhgeirb authors: busby, j s; onggo, s title: managing the social amplification of risk: a simulation of interacting actors date: 2012-07-11 journal: j oper res soc doi: 10.1057/jors.2012.80 sha: doc_id: 15255 cord_uid: 1qhgeirb a central problem in managing risk is dealing with social processes that either exaggerate or understate it. a longstanding approach to understanding such processes has been the social amplification of risk framework. but this implies that some true level of risk becomes distorted in social actors’ perceptions. many risk events are characterised by such uncertainties, disagreements and changes in scientific knowledge that it becomes unreasonable to speak of a true level of risk. the most we can often say in such cases is that different groups believe each other to be either amplifying or attenuating a risk. this inherent subjectivity raises the question as to whether risk managers can expect any particular kinds of outcome to emerge. this question is the basis for a case study of zoonotic disease outbreaks using systems dynamics as a modelling medium. the model shows that processes suggested in the social amplification of risk framework produce polarised risk responses among different actors, but that the subjectivity magnifies this polarisation considerably. as this subjectivity takes more complex forms it leaves problematic residues at the end of a disease outbreak, such as an indefinite drop in economic activity and an indefinite increase in anxiety. recent events such as the outbreaks in the uk of highly pathogenic avian influenza illustrate the increasing importance of managing not just the physical development of a hazard but also the social response. the management of hazard becomes the management of 'issues', where public anxiety is regarded less as a peripheral nuisance and more as a legitimate and consequential element of the problem (leiss, 2001) . it therefore becomes as important to model the public perception of risk as it does to model the physical hazard-to understand the spread of concern as much as the spread of a disease, for example. in many cases the perception of risk becomes intimately combined with the physical development of a risk, as beliefs about what is risky behaviour come to influence levels of that behaviour and thereby levels of exposure. one of the main theoretical tools we have had to explain and predict public risk perception is the social amplification of risk framework due to kasperson et al (1988) . as we explain below, this framework claims that social processes often combine to either exaggerate or underplay the risk events experienced by a society. this results in unreasonable and disproportionate reactions to risks, not only among the lay public but also among legislators and others responsible for managing risk. but since its inception the idea of a 'real', objective process of social risk amplification has been questioned (rayner, 1988; rip, 1988 ) and, although work in risk studies and risk management continues to use the concept, it has remained problematic. the question is whether, if we lose the notion of some true risk being distorted by a social process, we lose all ability to anticipate and explain perplexing social responses to a risk event in a way that is informative to policymakers. we explore this question in the context of risks surrounding the outbreaks of zoonotic diseases-that is, diseases that cross the species barrier to humans from other animals. recent cases of zoonotic disease, such as bse, sars, west nile virus and highly pathogenic avian influenza (hpai), have been some of the most highly publicised and controversial risk issues encountered in recent times. many human diseases are zoonotic in origin but in cases such as bse and hpai the disease reservoirs remain in the animal population. this means that a public health risk is bound up with risk to animal welfare, and often risk to the agricultural economy, to food supply chains and to wildlife. this in turn produces difficult problems for risk managers and policymakers, who typically want to avoid a general public amplifying the risk and boycotting an industry and its products, but also want to avoid an industry underestimating a risk and failing to practice adequate biosecurity. the bse case in particular has been associated with ideas about risk amplification (eg, eldridge and reilly, 2003) and continues to appear in the literature (lewis and tyshenko, 2009) . other zoonoses, such as chronic wasting disease in deer herds, have also been seen as recent objects of risk amplification (heberlein and stedman, 2009) . in terms of the social reaction, not all zoonoses are alike. endemic zoonoses like e. coli 157 do periodically receive public attention-for example following outbreaks at open farms and in food supply chains. but it is the more exotic zoonoses like bse and hpai that are more clearly associated with undue anxiety and ideas about social risk amplification. yet these cases also showed how uncertain the best, expertly assessed, supposedly objective risk level can be, and this makes it very problematic to retain the idea of an objective process of social risk amplification. such cases are therefore an important and promising setting for exploring the idea that amplification is only in the heads of social actors, and for exploring the notion that this might nonetheless produce observable, and potentially highly consequential, outcomes in a way that risk managers need to understand. our study involved two main elements, the second of which is the main subject of this article: 1. exploratory fieldwork to examine how various groups perceived risks and risk amplification in connection with zoonoses like the avian influenza outbreaks in 2007; 2. a systems dynamics simulation to work out what outcomes would emerge in a system of social actors who attributed amplification to other actors. in the remainder of the paper we first outline the fieldwork and its outcomes, and then describe the model and simulation. although the article concentrates on the latter, the two parts provide complementary elements of a process of theorising (kopainsky and luna-reyes, 2008) : the fieldwork, subjected to grounded analysis, produces a small number of propositions that are built into the systems dynamics model, and the model both operationalises these propositions and explores their consequences when operationalised in this way. the modelling is a basis for developing theory that is relevant to policy and decision making, rather than supporting a specific decision directly. a discussion and conclusion follow. traditionally, the most problematic aspect of public risk perception has been seen as its sometimes dramatic divergence from expert assessments-and the way in which this divergence has been seen as an obstacle both to managing risks specifically and to introducing new technology more generally. this has produced a longstanding interest in the individual perception of risk (eg, slovic, 1987) and in the way that culture selects particular risks for our attention (eg, douglas and wildavsky, 1982) . it has led to a strong interest in risk communication (eg, otway and wynne, 1989) . and it has been a central theme in the social amplification of risk framework (or sarf) that emerged in the late 1980s (kasperson et al, 1988) . the notion behind social risk amplification, developed in a series of articles (kasperson et al, 1988; renn, 1991; burns et al, 1993; kasperson and kasperson, 1996) , is that a risk event produces signals that are processed and sometimes amplified by a succession of social actors behaving as communication 'stations'. they interact and observe each other's responses, sometimes producing considerable amplification of the original signal. a consequence is that there are often several secondary effects, such as product boycotts or losses of institutional trust, that compound the effect of the original risk event. a substantial amount of empirical work has been conducted on or around the idea of social amplification, for example showing that the largest influence on amplification is typically organisational misconduct (freudenberg, 2003) . it continues to be an important topic in the risk literature, not least in connection with zoonosis risks (eg, heberlein and stedman, 2009; lewis and tyshenko, 2009 ). there has always been a substantial critique of the basic idea of social risk amplification. its implication that there is some true or accurate level that becomes amplified is hard to accept in many controversial and contested cases where expertise is lacking or where there is no expert consensus (rayner, 1988) . the phenomenon of 'dueling experts' is common in conflicts over environmental health, for instance (nelkin, 1995) . more generally, the concept of risk amplification seems to suggest that there is a risk 'signal' that is outside the social system and is somehow amplified by it (rayner, 1988) . this seems misconceived when we take the view that ultimately risk itself is a social construction (hilgartner, 1992) or overlay on the world (jasanoff, 1993) . and it naturally leads to the view that contributors to the amplification, such as the media (bakir, 2005) , need to be managed more effectively, and that risk managers should concentrate on fixing the mistake in the public mind (rip, 1988) , when often it may be the expert assessment that is mistaken. it thus becomes hard to sustain the idea that there is a social process by which true levels of risk get distorted. and this appears to undermine the possibility that risk managers can have a way of anticipating very high or very low levels of social anxiety in any particular case. once risk amplification becomes no more than a subjective judgment by one group on another social group's risk responses, it is hard to see how risk issues can be dealt with on an analytical basis. however, subjective beliefs about risk can produce objective behaviours, and behaviours can interact to produce particular outcomes. and large discrepancies in risk beliefs between different groups are still of considerable interest, whether or not we can know which beliefs are going to turn out to be more correct. in the remainder of this article we therefore explore the consequences of the idea that social risk amplification is nothing more than an attribution, or judgment that one social actor makes of another, and try to see what implications this might have for risk managers based on a systems dynamics model. before this, however, we describe the fieldwork whose principal findings were meant to provide the main structural properties of the model. the aim of the fieldwork was to explore how social actors reason about the risks of recent zoonotic disease outbreaks, and in particular how they make judgments of other actors systematically amplifying or attenuating such risks. this involved a grounded, qualitative study of what a number of groups said in the course of a number of unstructured interviews and focus groups. it follows the general principle of using qualitative empirical work as a basis for systems dynamics modelling (luna-reyes and andersen, 2003) . focus groups were used where possible, for both lay and professional or expert actors; individual interviews were used where access could only be gained to relevant groups (such as journalists) as individuals. the participants were selected from a range of groups having a stake in zoonotic outbreaks such as avian influenza incidents and are listed in table 1 . the focus groups followed a topic guide that was initially used in a pilot focus group and continually refined throughout the programme. they started with a short briefing on the specific topic of zoonotic diseases, with recent, well-publicised examples. the professional and expert groups were also asked to explain their roles in relation to the management of zoonotic diseases. participants were then invited to consider recent cases and other examples they knew of, discuss their reactions to the risks they presented, and discuss the way the risks had been, or were being, managed. their discussions were recorded and the recordings transcribed except in two cases where it was only feasible to record researcher notes. the individual interviews followed the same format. analysis of the transcripts followed a typical process of grounded theorising (glaser and strauss, 1967) , in which the aim was to find a way of categorising participants' responses that gave some theoretical insight into the principle of risk amplification as a subjective attribution. the categories were arrived at in a process of 'constant comparison' of the data and emerging, tentative categories until all responses have been satisfactorily categorised in relation to each other (glaser, 2002) . in glaser's words, 'validity is achieved, after much fitting of words, when the chosen one best represents the pattern. it is as valid as it is grounded'. our approach also drew on template analysis (king, 1998) in that we started with the basic categories of attributing risk amplification and risk attenuation, not a blank sheet. a fuller account of the analysis process and findings is given in a parallel publication (busby and duckett, 2012) . the first main theme to emerge from the data was the way in which actors privilege their own views, and construct reasons to hold on to them by finding explanations for other views as being systematically exaggerated or underplayed. it is surprising in a sense that this was relatively symmetrical. we expected expert groups to characterise lay groups as exaggerating or underplaying risk, but we also expected lay groups to use authoritative risk statements from expert groups and organisations of various kinds as ways of correcting their own initial and tentative beliefs. but there was no evidence for this kind of corrective process. the reasons that informants gave for why other actors systematically amplify or attenuate risk were categorised under five main headings: cognition, or the way they formed their beliefs; disposition, or their inherent natures; situation, or the particular circumstances; strategy, or deliberate, instrumental action; and structure, or basic patterns in the social or physical world. for example, one group saw the highly pathogenic avian influenza (hpai) outbreak at holton in the uk in 2007 as presenting a serious risk and explained the official advice that it presented only a very small risk as arising from a conspiracy between industry and government that the dispositions of the two naturally created. this second main theme was that some groups of informants often lacked specific and direct knowledge about relevant risks, and resorted to reasoning about other actors' responses to those risks. this reasoning involved moderating those observations with beliefs about whether other actors are inclined to amplify or attenuate risk. lay groups received information through the media but they had definite, and somewhat cliche´d, beliefs about the accuracy of risk portrayals in the media, for example. thus some informants saw the media treatment of hpai outbreaks as risk amplifying and portrayed the media as having an incentive to sensationalise coverage, but others (particularly virologists) saw media coverage as risk attenuating out of scientific ignorance. a third theme was that risk perceptions often came from the specific associations that arose in particular cases. for example, the holton hpai outbreak involved a large food processing firm that had earlier been involved in dietary and nutritional controversies. the firm employed intensive poultry rearing practices and was also importing partial products from a processor abroad. this particular case therefore bound together issues of intensive rearing, global sourcing, zoonotic outbreaks and lifestyle risks-incidental associations that enabled some informants to perceive high levels of risk and indignation, and portray others as attenuating this risk. the fourth theme was that some actors have specific reasons to overcome what they see as other actors' amplifications or attenuations. they do not just discount another actor's distortions but seek to change them. for example, staff in one government agency believed they had to correct farmers who were underplaying risk and not practicing sufficient bio-security, and also correct consumers who were exaggerating risk and boycotting important agricultural products. such actors do not simply observe other actors' expressed risk levels but try to communicate in such a way as to influence these expressed levels-for example through awareness-raising campaigns. the fieldwork therefore pointed to a model in which actors like members of the public based their risk evaluations on what they were told by others, corrected in some way for what they expected to be others' amplifications or attenuations; discrepancies between their current evaluations and those of others would be regarded as evidence of such amplifications, rather than being used to correct their own evaluations. the findings also indicated a model in which risk managers would communicate risk levels in a way that was intended to overcome the misconceptions of actors like the public. these are the underpinning elements of the models we describe below. systems dynamics was a natural choice for this modelling on several grounds. first, there is an inherent stress on endogeneity in the basic idea of social risk amplification, and in particular in the notion that it is an attribution. risk responses first and foremost reflect the way people think about risks and think about the responses of other people to those risks. second, the explicit and intuitive representation of feedback loops was important to show the reflective nature of social behaviour: how actors see the impact of their risk responses on other actors and modify their responses accordingly. third, memory plays an important part in this, since the idea that some actor is a risk amplifier will be based on remembering their past responses, and the accumulative capacity of stocks in systems dynamics provides an obvious way of representing social memory. developing a systems dynamics model on the grounded theory therefore followed naturally, and helped to add a deductive capability to the essentially inductive process of grounded theory (kopainsky and luna-reyes, 2008) . kopainsky and luna-reyes (2008) also point out that grounded theory can produce large and rich sets of evidence and overly complex theory, making it important to have a rigorous approach to concentrating on small numbers of variables and relationships. thus, in the modelling we describe in the next section, the aim was to try to represent risk amplification with as little elaboration as possible, so that it would be clear what the consequences of the basic structural commitments might be. this meant reduction to the simplest possible system of two actors, interacting repeatedly over time during the period of an otherwise static risk event (such as a zoonosis outbreak). applications of systems dynamics have been wide-ranging, addressing issues in domains ranging from business (morecroft and van der heijden, 1992) to military (minami and madnick, 2009) , from epidemiology (dangerfield et al, 2001) to diffusion models in marketing (morecroft, 1984) , from modelling physical state such as demography (meadows et al, 2004) to mental state such as trust martinez-moyano and samsa, 2008) . applications to issues of risk, particularly risk perception, are much more limited. there has been some application of system dynamics to the diffusion of fear and sarf, specifically (burns and slovic, 2007; sundrani, 2007) , but not to the idea of social amplification as an attribution. probably the closest examples to our work in the system dynamics literature deal with trust. luna-reyes et al (2008), for example, applied system dynamics to investigate the role of knowledge sharing in building trust in complex projects. to make modelling tractable, the authors make several simplifying assumptions including the aggregation of various government agencies as a single actor and various service providers as another actor. each actor accumulates the knowledge of the other actor's work, and the authors explore the dynamics that emerge from their interaction. greer et al (2006) modelled similar interactions-this time between client and contractor-each having its own, accumulated understandings of a common or global quantity (in this case the 'baseline' of work a project). martinez-moyano and samsa (2008) developed a system dynamics model to support a feedback theory of trust and confidence. this represented the mutual interaction between two actors (government and public) in a social system where each actor assesses the trustworthiness of the other actor over time, with both actors maintaining memories of the actions and outcomes of the other actor. our approach draws from all these studies, modelling a system in which actors interact on the basis of remembered, past interactions as they make assessments of some common object. the actors are in fact groups of individuals who are presumed to be acting in some concerted way. although this may seem questionable there are several justifications for doing so: (1) the aim is not to represent the diversity of the social world but to explore the consequences of specific ideas about phenomena like social risk amplification; (2) in some circumstances a 'risk manager' such as a private corporation or a government agency may act very much like a unit actor, especially when it is trying to coordinate its communications in the course of risk events; (3) equally in some circumstances it may be quite realistic to see a 'public' as acting in a relatively consensual way whose net, aggregate or average response is of more interest than the variance of response. in the following sections we develop a model in three stages. in the first, we represent the conventional view of social risk amplification; in the second, we add our subjective, attributional approach in a basic form; and in the third we make the attributional elements more realistically complex. the aim is to explore the implications of the principal findings of the fieldwork, and our basic theoretical commitments to social risk amplification as an attribution, with as little further adornment as possible, while also incorporating elements shown in the literature to be important aspects of risk amplification. in the first model, shown in figure 1 , we represent in a simple way the basic notion of social risk amplification. the fundamental idea is that risk responses are socially developed, not simply the sum of the isolated reactions of unconnected individuals. the model represents a population as being in one of two states of worry. this is simpler than the three-state model of burns and slovic (2007) particularly adds to the model. there is also no need for a recovering or removal state, as in sir (susceptible infectious recovered) models (sterman, 2004, p 303) , since there is no concept of immunity and it seems certain that people can be worried by the same thing all over again. the flow from an unworried state to a worried state is a function of how far the proportion in the worried state exceeds that normally expected in regard to a risk event such as a zoonotic disease outbreak. members of the public expect some of their number to become anxious in connection with any risk issue: when, through communication or observation, they realise this number exceeds expectation, this in itself becomes a reason for others to become anxious. this observation of fellow citizens is not medium-specific, so it is a combination of observation by word-of-mouth, social networks and broadcast media. in terms of how this influences perception, various processes are suggested in the literature. for example, there is a variety of 'social contagion' effects (levy and nail, 1993; scherer and cho, 2003) relevant to such situations. social learning (bandura, 1977) or 'learning by proxy' (gardner et al, 2000) may also well be important. we do not model specific mechanisms but only an aggregate process by which the observation of worry influences the flow into a state of being worried. the flow out of the worried state is a natural relaxation process. it is hard to stay worried about a specific issue for any length of time, and the atrophy of vigilance is reported in the literature (freudenberg, 2003) . there is also a base flow between the states, reflecting the way in which-in the context of any public risk event-there will be some small proportion of the population that becomes worried, irrespective of peers and public information. this base flow also has the function of dealing with the 'startup problem' in which zero flow is a potential equilibrium for the model (sterman, 2004, p 322) . the public risk perception in this model stands in relation to an expert, supposedly authoritative assessment of the risk. people worry when seeing others worry, but moderate this response when exposed to exogenous information-the expert or managerial risk assessment. what ultimately regulates worry is some combination of these two elements and it is this regulatory variable that we call a resultant 'risk perception'. unlike burns and slovic (2007) we do not represent this as a stock because it is not anyone's belief, and so need not have inertia. the fact that various members of the public are in different states of worry means that there is no belief that all share, as such. instead, risk perception is an emergent construct on which flows between unworried and worried states depend (and which also determines how demand for risky goods changes, as we explain below). in the simplest model we simply take this resultant risk perception as a weighted geometric mean of the risk implied by the proportion of the population worried and the publically known expert risk assessment. the expert assessment grows from zero toward a finite level, for a certain period, before decaying again to zero. this reflects a time profile for typical risk events-for example zoonotic outbreaks such as sars-where numbers of reported cases climb progressively and rapidly to a peak before declining (eg, leung et al, 2004) . the units for risk perception and the expert assessment are arbitrary, but for exposition are taken as probabilities of individual fatality during a specific risk event. numerical values of the exogenous risk-related variables are based on an outbreak in which the highest fatality probability is 10 à3 . but risks in a modern society tend to vary over several orders of magnitude. typically, individual fatality probabilities of 10 à6 are regarded as 'a very low level of risk', whereas risks of 10 à3 are seen as very high and at the limit of tolerability for risks at work (hse, 2001) . because both assessed and perceived risks are likely to vary widely, discrepancies between risk levels are represented as ratios. the way in which the expert assessment is communicated to the public is via some homogenous channel we have simply referred to as the 'media'. in our basic model we represent in very crude terms the way in which this media might exaggerate the difference between expert assessment and public perception. but the sarf literature suggests there is no consistent relationship between media coverage and either levels of public concern or frequencies of fatalities (breakwell and barnett, 2003; finkel, 2008) , so the extent of this exaggeration is likely to be highly case specific. it is also possible that the media have an effect on responses by exaggerating to a given actor its own responses. the public, for example, could have an inflated idea of how worried they are because newspapers or blogs portray it to be so. but we do not represent this because it is so speculative and may be indeterminable empirically. finally, the base model also represents the way in which risk perception influences behaviour, in particular the consumption of the goods or services that expose people to the risk in question. the 2005 holton uk outbreak of hpai, for example, occurred at a turkey meat processing plant and affected demand for its products; the sars outbreak affected demand for travel, particularly aviation services. brahmbhatt and dutta (2008) even refer to the economic disruption caused by 'panicky' public responses as 'sars type' effects. there are many complications here, not least that reducing consumption of one amenity as a result of heightened risk perception may increase consumption of a riskier amenity. air travel in the us fell after 9/11 but travel by car increased and aggregate risk levels were said to have risen in consequence (gigerenzer, 2006) . a further complication is that in certain situations, such as bank runs (diamond and dybvig, 1983 ), risk perceptions are directly self-fulfilling rather than self-correcting. the most common effect is probably that heightened risk perceptions will lead to reduced demand for the amenity that causes exposure, leading to reductions in exposure and reductions in the expert risk assessment, but it is worth noting that the effect is case-specific. the expert risk assessment is therefore not exogenous, and there is a negative feedback loop that operates to counteract rising risk perceptions. as we show later from the simulation outcomes, the base model shows a public risk perception that can be considerably larger than the expert risk assessment. it therefore seems to show 'risk amplification'. but there is no variable that stands for risk in the model: there are only beliefs about risk (called either assessments or perceptions). the idea that social risk amplification is a subjective attribution, not an objective phenomenon, means that this divergence of risk perception and expert assessment does not amount to risk amplification. and it says that actors see others as being risk amplifiers, or attenuators, and develop their responses accordingly. this means that we need to add to sarf, and the basic model of the previous section, the processes by which actors observe, diagnose and deal with other actors' risk assessments or perceptions. what our fieldwork revealed was that the social system did not correct 'mistaken' risk perceptions in some simpleminded fashion. in other words, it was not the case that people formed risk perceptions, received information about expert assessment, and then corrected their perceptions in the correct direction. instead, as we explained earlier, they found reasons why expert assessments, and in fact the risk views of any other group, might be subject to systematic amplification or attenuation. they then corrected for that amplification. risk managers, on the other hand, had the task of overcoming what they saw as mistaken risk responses in other groups, not simply correcting for them. therefore in the second model, shown in figure 2 , we now have a subsystem in which a risk manager (a government agency or an industrial undertaking in the case of zoonotic disease outbreaks) observes the public risk perception in relation to the expert risk assessment, and communicates a risk level that is designed to compensate for any discrepancy between the two. commercial risk managers will naturally want to counteract risk amplification that leads to revenue losses from product and service boycotts, and governmental risk managers will want to counteract the risk amplification that produces panic and disorder. as beck et al (2005) report, the uk bse inquiry found that risk managers' approach to communicating risk 'was shaped by a consuming fear of provoking an irrational public scare'. the effect is symmetrical to the extent that the public in turn observes discrepancies between managerial communications and its own risk perceptions, and attributes amplification or attenuation accordingly. attributions are based on simple memory of past observations. this historical memory of another actor's apparent distortions is sometimes mentioned in the sarf literature (kasperson et al, 1988; poumadere and mays, 2003) . this memory is represented as stocks of observed discrepancies, reaching a level m i (t)for actor i at time t. the managerial memory, for example, is r public ðtþ r expert ðtþ dt m i (t)40 implies that actor i sees the other actor as exaggerating risk, while m i (t)o0 implies perceived attenuation. the specific deposits in an actor's memory are not retrievable, and equal weight is given to every observation that contributes to it. the perceived scale of amplification is the time average of memory content, and the confidence the actor has in this perceived amplification is 1àe à|m(t)| where confidence grows logarithmically towards unity as the magnitude of the memory increases. the managerial actor modifies the risk level it communicates by the perceived scale of public amplification raised to the power of its confidence, while the public adjusts the communicated risk level it takes account of by the perceived scale of managerial attenuation raised to the power of its confidence in this. in the third model, in figure 3 , we add three elements found in the risk amplification literature that become especially relevant to the idea of risk amplification as a subjective attribution: confusion, distrust and differing perceptions about the significance of behavioural change. the confusion issue reflects the way an otherwise authoritative actor's view tends to be discounted if it shows evidence of confusion, uncertainty or inexplicable change. two articles in the recent literature on zoonosis risk (bergeron and sanchez, 2005; heberlein and stedman, 2009 ) specifically describe the risk amplifying effect of the authorities seeming confused or uncertain. the distrust issue reflects the observation that 'distrust acts to heighten risk perception . . . ' (kasperson et al, 2003) , and that it is 'associated with perceptions of deliberate distortion of information, being biased, and having been proven wrong in the past' (frewer, 2003, p 126) . a distinguishing aspect of trust and distrust is the basic asymmetry such that trust is quick to be lost and slow to be gained (slovic, 1993) . in figure 3 , the confusion function is based on the rate of change of attributed amplification, not rate of change communication itself, since some change in communication might appear justified if correlated with a change in public perception: g ¼ 1 à e àg c g ðtþ j j ; where c g (t) is the change in managerial amplification in unit time. the distrust function is based on the extent of remembered attributed amplification: f ¼ 1 à e àf m g ðtþ j j ; where m g (t) is the memory of managerial risk amplification at time t and f is the distrust parameter. there is no obvious finding in the literature that would help us set the value of such a parameter. the combination of the confusion and distrust factors is a combination of an integrator and a differentiator. it is used to determine how much weight is given to managerial risk communications in the formation of the resultant risk perception. it is defined such that as distrust and confusion both approach unity, this weight w tends to zero: w ¼ w max (1àg)(1àf). this weight was exogenous in the previous model, so the effect of introducing confusion and distrust is also to endogenise the way observation of worry is combined with authoritative risk communication. the third addition in this model is an important disproportionality effect. the previous models assume that risk managers base their view of the public risk perception on some kind of direct observation-for example, through clamour, media activity, surveys and so on. in practice, the managerial view is at least partly based on the public's consumption of the amenity that is risk, for example the consumption of beef during the bse crisis, or flight bookings and hotel reservations during the sars outbreak. the problem is that when a foodstuff like beef becomes a risk object it may be easy for many people to stop consuming it, and such a response from the consumer's perspective can be proportionate to even a mild risk assessment. reducing beef consumption is an easy precaution for most of the population to take (frewer, 2003) , so rational even when there is little empirical evidence that there is a risk at all (rip, 2006) . yet this easy response of boycotting beef may be disastrous for the beef industry, and therefore seem highly disproportionate to the industry, to related industries and to government agencies supporting the industry. unfortunately there is considerable difficulty in quantifying this effect in general terms. recent work (mehers, 2011) looking at the effect of heightened risk perceptions around the avian influenza outbreak at a meat processing plant suggests that the influence on the demand for the associated meat products was very mixed. different regions and different demographic groups showed quite different reactions, for example, and the effect was confounded by actions (particularly price changes) taken by manufacturer and retailers. our approach is to represent the disproportionality effect with a single exogenous factorthe relative substitutability of the amenity for similar amenities on the supply and demand side. the risk manager interprets any change in public demand for the amenity multiplied by this factor as being the change in public risk perception. if the change in this inferred public risk perception exceeds that observed directly (for example by opinion survey), then it becomes the determinant of how risk managers think the public are viewing the risk in question. this relative substitutability is entirely a function of the specific industry (and so risk manager) in question: there is no 'societal' value for such a parameter, and the effects of a given risk perception on amenity demand will always be case specific. for example, brahmbhatt and dutta (2008) reported that the sars outbreak led to revenue losses in beijing of 80% in tourist attractions, exhibitions and hotels, but of 10-50% in travel agencies, airlines, railways and so on. the effects are substantial but a long way from being constant. in this section we briefly present the outcomes of simulation with two aims: first to show how the successive models produce differences in behaviour, if at all, and thereby to assess how much value there is in the models for policymakers; second to assess how much uncertainty in figure 3 model of a more complex attributional view of risk amplification. outcomes such as public risk perception is produced by uncertainty in the exogenous parameters. figure 4 shows the behaviour of the three successive models in terms of public risk perception and expert risk assessment. for the three models, the exogenous variables are set at their modal values and when variables are shared between models they have the same values. the expert risk assessment is thus very similar for each model, as shown in the figure, rising towards its target level, falling as public risk perception reduces exposure, and then ceasing as the crisis ends around day 40. in the base model, the public risk perception is eight times higher than the expert assessment at its peak, which occurs some 20 days after that in the expert assessment. but once the attributional view of risk amplification is modelled, this disparity becomes much greater, and it occurs earlier. in the simple attributional system the peak discrepancy is over 40 times, and in the complex attributional system nearly 400 times, both occurring within 8 days of the expert assessment peak. thus the effect of seeing risk amplification as the subjective judgment of one actor about another is, given the assumptions in our models, to polarise risk beliefs much more strongly and somewhat more rapidly. we can no longer call the outcome a 'risk amplification' since, by assumption, there is no longer an objective risk level exogenous to the social system. but there is evidently strong polarisation. there is some qualitative difference in the time profile of risk perception between the three models, as shown in the previous figure where the peak risk perception occurs earlier in the later models. there are also important qualitative differences in the time profiles of stock variables amenity demand and worried population, as shown in figure 5 . when the attributional view is taken, both demand and worry take longer to recover to initial levels, and when the more complex attributional elements are modelled (the effects of mistrust, confusion and different perceptions of the meaning of changes in demand), the model indicates that little recovery takes place at all. the scale of the recovery depends on the value of the exogenous parameters, and some of these (as we discuss below) are case specific. but of primary importance is the way the weighting given to managerial communications or expert assessment is dragged down by public attributions. this result indicates the importance of a complex, attributional view of risk amplification. unlike the base model, in the attributional model it is much more likely there will be an indefinite residue from a crisis-even when the expert assessment of risk falls to near zero. figures 6 and 7 show the time development of risk perception in the third model in terms of the mean outcome with (a) 95% confidence intervals on the mean and (b) tolerance intervals for 95% confidence in 90% coverage over 1000 runs, with triangular distributions assigned to the exogenous parameters and plausible ranges based solely on the author's subjective estimates. the exogenous parameters fall into two main groups. the first group is of case-specific factors and would be expected to vary between risk events. this includes, for example, the relative substitutability of the amenity that is the carrier of the risk, and the latency before changes in demand for this amenity change the level of risk exposure. the remaining parameters are better seen as social constants, since there is no theoretical reason to think that they will vary from one risk event to another. these include factors like the natural vigilance period among the population, the normal flow of people into a state of worry, the latency before people become aware of a discrepancy between emergent risk perception and the proportion of the population that is in a state of worry. figure 6 shows the confidence and tolerance intervals with the social constants varying within their plausible ranges and the case-specific factors fixed at their modal values, and figure 7 vice versa. thus figure 6 shows the effect of our uncertainty about the character of society, figure 4 outcomes of the three models. whereas figure 7 shows the effect of the variability we would expect among risk events. the substantial difference between the means in risk perception between the two figures reflects large differences between means and modes in the distributions attributed to the parameters, which arises because plausible ranges sometimes cover multiple orders of magnitude (eg, the confusion and distrust constants both range from 1 to 100 with modes of 10, and the memory constant from 10 to 1000 with a mode of 100). these figures do not give a complete understanding, not least because interactions between the two sets of parameters are possible, but they show a reasonably robust qualitative profile. figure 8 shows the 'simple' correlation coefficients between resultant risk perception and the policy-relevant exogenous parameters over time, as recommended by ford and flynn (2005) as an indication of the relative importance of model inputs. at each day of the simulation, the sample correlation coefficient is calculated for each parameter over the 1000 runs. no attempt has been made to inspect whether the most important inputs are correlated, and to refine the model in the light of this. nonetheless the figure gives some indication of how influential are the most prominent parameters: the expert initial assessment level (ie, the original scale of the risk according to expert assessment), the expert assessment adjustment time (ie, the delay in the official estimate reflecting the latest information), the base flow (the flow of people between states of non-worry and worry in relation to a risk irrespective of the specific social influences being modelled) and the normal risk perception (the baseline against which the resultant risk perception is gauged, reflecting a level of risk that would be unsurprising and lead to no increase in the numbers of the worried). the first of these is case-specific, but the other three would evidently be worth empirical investigation given their influence in the model. it is extremely difficult to test such outcomes against empirical data because cases differ so widely and it is unusual to find data on simultaneous expert assessments and public perceptions over short-run risk events like disease outbreaks, particularly outbreaks of zoonotic disease. but a world bank paper of 2008, on the economic effects of infectious disease outbreaks (primarily sars, a zoonotic disease), collected together data gathered on the 2003 sars outbreak, and some-primarily that of lau et al (2003) -showed the day-by-day development of risk perception alongside reported cases. figure 9 is based on lau et al's data (2003) , and shows the number of reported cases of sars as a proportion of the hong kong population at the time, together with the percentage of people in a survey expressing a perception that they had a large or very large chance of infection from sars. the two lines can be regarded as reasonably good proxies for the risk perception and expert assessment outcomes in figure 4 and they show a rough correspondence: a growth in both perception and expertly assessed or measured 'reality', followed by a decay, in which the perception appears strongly exaggerated from the standpoint of the expert assessment. the perceptual gap is about four orders of magnitude-greater than even the more complex attributional system in our modelling. moreover, the risk perception peak occurs early, and in fact leads the reported cases peak. it is our models 2 and especially 3 in which the perception peak occurs early (although it never leads the expert assessment peak). the implications of the work the social amplification of risk framework has always been presented as an 'integrative framework' (kasperson et al, 1988) , rather than a specific theory, so there has always been a need for more specific modelling to make its basic concepts precise enough to be properly explored. at the same time, as suggested earlier, its implication that there is some true level of risk that becomes distorted in social responses has been criticised for a long time. we therefore set out to explore whether it is possible to retain some concept of social risk amplification in cases where even expert opinion tends to be divided, the science is often very incomplete, and past expert assessment has been discredited. zoonotic disease outbreaks provide a context in which such conditions appear to hold. our fieldwork broadly pointed to a social system in which social actors of all kinds privilege their own risk views, in which they nonetheless have to rely on other actor's responses in the absence of direct knowledge or experience of the risks in question, in which they attribute risk amplification or attenuation to other actors, and in which they have reasons to correct for or overcome this amplification. to explore how we can model such processes has been the main purpose of the work we have described. and the resulting model provides specific indications of what policymakers need to deal with-a much greater polarisation of risk beliefs, and potentially a residue of worry and loss of demand after the end of a risk crisis. it also has the important implication that risk managers' perspectives should shift, from correcting a public's mistakes about risk to thinking about how their own responses and communications contribute to the public's views about a risk. our approach helps to endogenise the risk perception problem, recognising that it is not simply a flaw in the world 'out there'. it is thus an important step in becoming a more sophisticated risk manager or manager of risk issues (leiss, 2001) . it is instructive to compare this model with models like that of luna-reyes et al (2008) which essentially involve a convergent process arise from knowledge sharing, and the subsequent development of trust. we demonstrate a process in which there is knowledge sharing, but a sharing that is undermined by expectations of social risk amplification. observing discrepancies in risk beliefs leads not to correction and consensus but to self-confirmation and polarisation. our findings in some respects are similar to greer et al (2006) , who were concerned with discrepancies in the perceptions of workload in the eyes of two actors involved in a common project. such discrepancies arose not from exogenous causes but from unclear communication and delay inherent in the social system. all this reinforces the long-held view in the risk community, and of risk communication researchers in particular, that authentic risk communication should involve sustained relationships, and the open recognition of uncertainties and difficulties that would normally be regarded as threats to credibility (otway and wynne, 1989) . the reason is not just the moral requirement to avoid the perpetuation of powerful actors' views, and not just the efficiency requirement to maximise the knowledge base that contributes to managing a risk issue. the reason is also that the structure of interactions can be unstable, producing a polarisation of view that none of the actors intended. actors engaged with each other can realise this and overcome it. a basic limitation to the use of the models to support specific risk management decisions, rather than give more general insight into social phenomena, is that there are very few sources of plausible data for some important variables in the model, such as the relaxation delay defining how long people tend to stay worried about a specific risk event before fatigue, boredom or replacement by worry about a new crisis leads them to stop worrying. it is particularly difficult to see where values of the case-specific parameters are going to come from. other sd work on risk amplification at least partly avoids the calibration problem by using unit-less normalised scales and subjective judgments (burns and slovic, 2007) . and one of the benefits of this exploratory modelling is to suggest that such variables are worthwhile subjects for empirical research. but at present the modelling does not support prediction and does not help determine best courses of action at particular points in particular crises. in terms of its more structural limitations, the model is a small one that concentrates specifically on the risk amplification phenomenon to the exclusion of the many other processes that, in any real situation, risk amplification is connected with. as such, it barely forms a 'microworld' (morecroft, 1988) . it contrasts with related work such as that of martinez-moyano and samsa's (2008) modelling of trust in government, which similarly analyses a continuing interaction between two aggregate actors but draws extensively on cognitive science. however, incorporating a lot more empirical science does not avoid having to make many assumptions and selections that potentially stand in the way of seeing through to how a system produces its outcomes. the more elaborate the model the more there is to dispute and undermine the starkness of an interesting phenomenon. we have had to make few assumptions about the world, about psychology and about sociology before concluding that social risk amplification as little more than a subjective attribution has a strongly destabilising potential. this parsimony reflects towill's (1993) notion that we start the modelling process by looking for the boundary that 'encompasses the smallest number of components within which the dynamic behaviour under study is generated'. the model attempts to introduce nothing that is unnecessary to working out the consequences of risk amplification as an attribution. as ghaffarzadegan et al (2011) point out in their paper on small models applied to problems of public policy, and echoing forrester's (2007) argument for 'powerful small models', the point is to gain accessibility and insight. having only 'a few significant stocks and at most seven or eight major feedback loops', small models can convey the counterintuitive endogenous complexity of situations in a way that policymakers can still follow. they are small enough to show systems in aggregate, to stress the endogeneity of influences on the system's behaviour, and to clearly illustrate how policy resistance comes about (ghaffarzadegan et al, 2011) . as a result they are more promising as tools for developing correct intuitions, and for helping actors who may be trapped in a systemic interaction to overcome this and reach a certain degree of self-awareness (lane, 1999) . the intended contribution of this study has been to show how to model a long-established, qualitative framework for reasoning about risk perception and risk communication, and in the process deal with one of the main criticisms of this framework. the idea that in a society the perception of a risk becomes exaggerated to the point where it bears no relation to our best expert assessments of the risk is an attractive one for policymakers having to deal with what seem to be grossly inflated or grossly under-played public reactions to major events. but this idea has always been vulnerable to the criticism that we cannot know objectively if a risk is being exaggerated, and that expert assessments are as much a product of social processes as lay opinion. the question we posed at the start of the paper was whether, in dropping a commitment to the idea of an objective risk amplification, there is anything left to model and anything left to say to policymakers. our work suggests that there is, and that modelling risk amplification as something that one social actor thinks another is doing is a useful thing to do. there were some simple policy implications emerging from this modelling. for example, once you accept that there is no objective standard to indicate when risk amplification is occurring, actors are likely to correct for other actors' apparent risk amplifications and attenuation, instead of simple-mindedly correcting their own risk beliefs. this can have a strongly polarising effect on risk beliefs, and can produce residual worry and loss of demand for associated products and services after a crisis has passed. the limitations of the work point to further developments in several directions. first, there is a need to explore various aspects of how risk managers experience risk amplification. for example, the modelling, as it stands, concentrates on the interactions of actors in the context of a single event or issue-such as a specific zoonotic outbreak. in reality, actors generally have a long history of interaction around earlier events. we take account of history within an event, but not between events. a future step should therefore be to expand the timescale, moving from intra-event interaction to inter-event interaction. the superposition of a longer term process is likely to produce a model in which processes acting over different timescales interact and cannot simply be treated additively (forrester, 1987) . it also introduces the strong possibility of discontinuities, particularly when modelling organisational or institutional actors like governments whose doctrines can change radically following elections-rather like the discontinuities that have to be modelled to represent personnel changes and consequences like scapegoating (howick and eden, 2004) . another important direction of work would be a modelling of politics and power. it is a common observation in risk controversies that risk is a highly political construction-being used by different groups to gain resources and influence. as powell and coyle (2005) point out, the systems dynamics literature makes little reference to power, raising questions about the appropriateness of our modelling approach to a risk amplification subject-both in its lack of power as an object for modelling, and its inattention to issues of power surrounding the use of the model and its apparent implications. powell and coyle's (2005) politicised influence diagrams might provide a useful medium for representing issues 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the oil producers: capturing oil industry knowledge in a behavioural simulation model. modelling for learning, a special issue of the science controversies: the dynamics of public disputes in the united states risk communication: paradigm and paradox (guest editorial) the dynamics of risk amplification and attenuation in context: a french case study identifying strategic action in highly politicized contexts using agent-based qualitative system dynamics muddling through metaphors to maturity: a commentary on kasperson et al. 'the social amplification of risk' risk communication and the social amplification of risk should social amplification of risk be counteracted folk theories of nanotechnologists a social network contagion theory of risk perception perception of risk perceived risk, trust and democracy business dynamics: systems thinking and modelling for a complex world understanding social amplification of risk: possible impact of an avian flu pandemic. masters dissertation, sloan school of management and engineering systems division acknowledgements-many thanks are due to the participants in the fieldwork that underpinned the modelling, and to dominic duckett who carried out the fieldwork. we would also like to thank the anonymous reviewers of an earlier draft of this article for insights and suggestions that have considerably strengthened it. the work was partly funded by a grant from the uk epsrc. key: cord-030984-2mqn4ihm authors: davies, anna; hooks, gregory; knox-hayes, janelle; liévanos, raoul s title: riskscapes and the socio-spatial challenges of climate change date: 2020-08-20 journal: nan doi: 10.1093/cjres/rsaa016 sha: doc_id: 30984 cord_uid: 2mqn4ihm anthropogenic climate change is increasing the frequency and severity of the physical threats to human and planetary wellbeing. however, climate change risks, and their interaction with other “riskscapes”, remain understudied. riskscapes encompass different viewpoints on the threat of loss across space, time, individuals and collectives. this special issue of the cambridge journal of regions, economy, and society enhances our understanding of the multifaceted and interlocking dimensions of climate change and riskscapes. it brings together rigorous and critical international scholarship across diverse realms on inquiry under two, interlinked, themes: (i) governance and institutional responses and (ii) vulnerabilities and inequalities. the contributors offer a forceful reminder that when considering climate change, social justice principles cannot be appended after the fact. climate change adaptation and mitigation pose complex and interdependent social and ethical dilemmas that will need to be explicitly confronted in any activation of “green new deal” strategies currently being developed internationally. such critical insights about the layered, unequal and institutional dimensions of risks are of paramount import when considering other riskscapes pertaining to conflict and war, displaced people and pandemics like the 2019–2020 global covid-19 pandemic. this special issue of the cambridge journal of regions, economy, and society expands and enhances our understanding of the spatial, temporal, economic and sociological dimensions of climate change and riskscapes. riskscapes "play out in time and space" (müller-mahn and everts, 2018, 87) , encompassing different points of view on risk that highlight the "real-andimagined geographies based on individual and collective experience, tradition and knowledge" (müller-mahn et al., 2013 , 2025 . these articulations of riskscapes were preceded by theorists examining the social forces giving rise to diffuse risk distribution and contestation in modernity (see rosa et al., 2014) . by 2001, empirically inclined social scientists in the usa argued "social, economic, and political forces inevitably create myriad [environmental] riskscapes in which overlapping air pollution plumes emitted by [various sources]…lead to cumulative exposures that pose health risks to diverse communities" (morello-frosch et al., 2001, 572 ; see also fitzpatrick and lagory, 2003) . the 'riskscape' concept has subsequently been applied in a range of other contexts beyond air quality (müller-mahn and everts, 2018) . however, explicit examinations of climate change riskscapes and their interaction with other riskscapes remain comparatively understudied (cf. gebreyes and theodory, 2018) . this is surprising, given the attention to climate change risks and their configuration by leading international agencies, including the intergovernmental panel on climate change (ipcc). in its 2012 special report 'managing the risks of extreme events and disasters to advance climate change adaptation' (ipcc, 2012) , for example, the ipcc acknowledges the challenges of understanding and managing the risks related to climate change. in particular, they emphasise that climate change impacts have social and economic as well as physical dimensions. so, while changes in the frequency and severity of the physical events generated by climate change will affect risk, the spatially diverse and temporally dynamic patterns of exposure and vulnerability also need to be considered. indeed, they recognise that differences in vulnerability and exposure can arise from non-climatic factors and from multidimensional inequalities that are produced by uneven development processes. alongside this, the ipcc conclude, with a high degree of confidence, that climate-related hazards can exacerbate other stressors, often with negative outcomes for livelihoods, especially for those living in poverty. contemporary events, like the 2019-2020 global covid-19 pandemic, underscore the importance of understanding the layered dimensions of risks. as with climate vulnerabilities and public and environmental health (faber, 2015; gebreyes and theodory, 2018; klinenberg, 2002; solomon et al., 2016) , emerging accounts of the covid-19 pandemic indicate that communities facing elevated threats to their lives and livelihoods are those who are elderly, experience chronic medical conditions, and are socially, politically and economically marginalised (cdc, 2020; manderson and levine, 2020; raffaetà, 2020) . this special issue demonstrates how analysing riskscapes can advance our understanding of climate change dynamics. these insights can be extended to anticipate dynamics at work on the covid-19 pandemic. physically, climate change will have greatest effect on communities with high population density. these communities are often near coastlines and in flood plains where they may face vulnerabilities of exposure to rising sea levels and other threats (see liévanos, 2020) , or have overbuilt environments to a degree that greater meteorological variability has outsized effect (for example, superstorm sandy in new york) (faber, 2015 ; see also taylor and weinkle, 2020) . the high density of people in such spaces also make these communities more vulnerable to pandemics like covid-19. indeed, as of 1 may 2020, confirmed 478) and associated deaths (18,069) within the usa were concentrated in the major population centre of new york city (dong et al., 2020) . in both the case of climate and covid-19 vulnerability, the local overbearance of human settlements on the environment makes adaptation and mitigation still more difficult. overlap in terms of community economic risk and resilience between covid-19 and climate change is also substantial, highlighting the kind of 'double exposure' risks initially flagged by o'brien and leichenko (2000) and elaborated in leichenko and o'brien (2008) . cascading economic effects from covid-19 (lockdowns) and climate change have the greatest effect on the poorest and socially marginalised communities. similar to the realm of climate-related inequalities in the usa (faber, 2015; klinenberg, 2002) , the disparate impact of covid-19 on low income and under-represented minority communities has been extreme, with some states in the us reporting up to a third of deaths being among racial and ethnic minorities, and projections that the economic implications of the pandemic will also hit minority communities the hardest (cdc, 2020; hale, 2020) . the disparate outcomes from underlying inequalities are projected to extend across the global south (wood, 2020) . in separate realms of inquiry (for example, environmental studies, health disparities, economic geography, criminology, security and terrorism, disasters and spatial inequality), scholars have already documented that place matters when considering risk. exposure to risk and its consequences varies by where a social actor lives, works and the multiplicity of other contexts in which they engage in social interaction. too often, however, these risks have been studied in isolation, for example, heightened environmental exposure studied in isolation of elevated exposure to crime, elevated exposure to health risks without concern for heightened economic risks and so forth (muller et al., 2018) . the ramifications of this approach have been laid bare and not least during the covid-19 crisis, which has had substantial interwoven health, economic, political and social implications. in the reshaped world responding to this crisis, considering the complexities, nuances and place-specificities of riskscapes and climate change is now more important than ever. using the concept of riskscapes highlights the social, temporal and spatial texture of risk (neisser and müller-mahn, 2018) and calls attention to interactions among risks and their "cumulative impact" across several dimensions of human life and the biophysical environment (renn, 2008; solomon et al., 2016) . entire nations-concentrated in the global south-are at heightened risk of repeated cycles of war (collier, 2008) . these conflicts scar the environment in profound and enduring ways (smith et al., 2014) ; these wars are often precipitated by environmental dislocation, with climate change playing an increasingly prominent role (dunlap and brulle, 2015) . whether internally displaced or migrating across national borders, those forced to flee violence live with multiple risks and face an uncertain future (hooks, 2020; united nations high commissioner for refugees, 2017) . these communities are also at risk of comparable long-term impacts (stalled economies, overtaxed medical systems and nutritional shortages) of pandemics like covid-19. the origins of these risks and the forces that sustain them often operate on and across multiple spatial scales-from the local to the global. by studying climate change and riskscapes, it becomes possible to understand the "interdependencies and spillovers between risk clusters" (renn, 2008, 5 ; see also beck, 2009; neisser and müller-mahn, 2018) . prominent social theorists-most notably beck ([1986] 2005) and giddens (2015)have drawn attention to the pervasive and growing importance of risk in contemporary societies. this concern extends beyond the academy-it is of concern to the general public and policy makers. the growing reflexivity of late-modernity-made possible by an unprecedented capacity to gather, analyse and share information-not only creates unprecedented opportunities, it also creates unprecedented threats to individuals and entire societies. moreover, this capacity to compile and analyse information allows for a discourse centred on identifying, mapping and managing risks (beck, [1986 (beck, [ ] 2005 (beck, [ , 2009 giddens, 2015) . efforts to identify, avoid, mitigate and manage risks are transforming political and social institutions. building on his earlier work (beck, [1986] 2005), beck's (2009) "world risk society" thesis highlights the growing prominence of large-scale technological and industrial processes in modernity that has given rise to unstable global financial markets and climate change and associated threats for the broader public. extant social and political institutions are not equipped to manage such risks. these trends pose threats to the legitimacy of science and of political institutions because accurate risk analysis is often hindered by the indeterminable and uninsurable nature of human "manufactured" risks. because the "dangers posed by global warming aren't tangible, immediate or visible in the course of day-to-day life" , our collective response will be halting and insufficient (giddens, 2009, 2) . furthermore, the physical, social, political and economic risks are fundamentally interwoven together. communities with lower social resilience-for example, those divided by substantial class, racial, ethnic, gender or cultural cleavages that undermine shared trust-lack the cohesion to effectively understand and respond to crisis (gotham and greenberg, 2014) . the identification and response to risk occurs in an institutional context. experts and political economic elites are often entrusted with the authority to classify and organise risk for the broader public (beck, [1986 (beck, [ ] 2005 (beck, [ , 2009 clarke, 1989; freudenburg et al., 2009; perrow, [1984 perrow, [ ] 1999 . in the context of environmental risk, it has been shown that scientific, corporate and state actors are tightly coupled in decision-making processes that are predicated on the dynamics of maintaining the prestige and objectivity of scientific inquiry, capital accumulation and state legitimacy (beck, 2009) . furthermore, the institutional context of government policy and professional associations "incubate" the expert and elite organisation of risk in taken-for-granted norms of safety and "acceptable" codes of conduct-all of which are monitored and enforced by experts and elites (beamish, 2002; clarke, 1989; perrow, [1984 perrow, [ ] 1999 turner, 1978) . for example, political and economic actors and institutions across the world are refashioning previous capital accumulation strategies and their spatial and ecological "fixes" through financial instruments and market-based mechanisms that seek to mitigate against and adapt people and places to environmental disasters, terrorist threats and the climate crisis (castree and christophers, 2015; gotham and greenberg, 2014; knox-hayes, 2013; ouma et al., 2018) . these dynamics-that is, elite domination and the downplaying, normalising and obscuring of environmental risks-extends to military organisations and warfare (bonds, 2011) . risk is culturally embedded. research into this aspect of risk illustrates the importance of attending to the local "historical legacy and interpretive contexts to perceptions of risk" (beamish, 2001, 11) . auyero and swistun's (2009) ethnographic and historical study of flammable, a poor and heavily contaminated argentine shantytown, is instructive for understanding how the normalisation of risk can shape how it is subsequently understood and responded to. in this case, the normalisation of exposure to environmental health risk was associated with an institutionally organised confusion over the cause of environmental contamination and how to motivate and articulate collective solutions to that contamination. alternatively, as norgaard (2011) illustrates in the context of local responses to climate change, normative modes of thought and practice normalise risk-perpetuating practices even in the face of mounting evidence of the dangers of climate change. similarly, in her work, knox-hayes (2014 demonstrates that cultural knowledge and practice shape the adoption of universalistic solutions to climate mitigation, even in economic domains such as with the creation of emissions markets. in order to be more effective, policy makers must consider the way different communities and societies make value judgements, assess risks and devise strategies to respond (knox-hayes, 2016) . this special issue brings together international scholars at the forefront of empirical and conceptual thinking about riskscapes. their research refines and sharpens our understanding of climate change risk and riskscapes, integrating understandings of risk from across diverse realms on inquiry under two, interlinked, themes: governance and institutional responses and vulnerabilities and inequalities. this also acknowledges how governance and state in/action can exacerbate risks, a theme that is addressed by several of the articles in this issue. it is no surprise to find a strong focus across the articles in this special issue on how different locations and communities attempt to manage the sum of complex combinations of risks. understanding the form, dynamics and impacts of governing riskscapes lies at the heart of much intellectual inquiry and practical action. ravi raman's tightly contextualised article is focussed on the rebuilding of post-flood kerala, india (raman, 2020). the physical scars of flood events are visible reminders of not only risks and their spatiality, but also of how institutions respond to that spatiality. raman documents how various agencies, including local people and state and non-state actors, influence each phase of rescue, relief and rebuilding. local fisher-folk communities, for example, draw on their cultural knowledge of climate change and risk to rescue flood victims just as others have done elsewhere (see knox-hayes, 2016) . in addition to these local governing alliances, raman also flags the role of international institutional alliances-for example with the un agencies-in supporting humanitarian interventions. he argues these diverse but coordinated responses create a state-society synergy sensitised to the "ecospatiality" of riskscapes in kerala. the ecospatiality concept recognises that building resilience in the aftermath of an extreme event requires new consideration of the arrangement and assemblage of spaces that make dwelling and habitation more attuned to the specific geographical features and potential risks of a region. rather than relying on rehabilitation and restoration to previous conditions, the goal of the ecospatiality state-society synergy is to redevelop while laying the foundation for a more resilient, egalitarian and ethical society. raman's article has broader implications, as its findings align with the broader suggestion that the covid-19 pandemic, for example, presents societies with the opportunity to move forward with new technologies for enhanced energy efficiency and resilience (invest away from fossil fuels where markets have experienced collapse) rather than to return to the old normal (worldand, 2020) . meanwhile, iain white and judy lawrence explicitly focus on the governance challenges posed by climate change in new zealand (white and lawrence, 2020) . they emphasise that as climate change impacts are dynamic, uncertain and contested, they pose significant challenges to the ways in which policy actors imagine and manage risks across space and time. identifying and applauding major efforts to reflect the latest insights from risk research in national policy in new zealand, they nonetheless find significant challenges remain to be resolved if appropriate governance and implementation strategies are to be successfully designed and implemented. white and lawrence demonstrate how tensions emerge between the theory of riskscapes, which emphasises that risks are always in a state of becoming, and the practices of risk management which seek to periodically "fix" risks, through plans, for example, in order to address them. while this process is a familiar feature of public policy design and implementation in many arenas, time lags between establishing scientific consensus for a particular course of action, developing policy and implementing that policy tend to be extensive with respect to climate change. positively, white and lawrence's historically situated paper identifies a greater impetus for policy development, more extensive political consensus on action and widespread use of the language of contingency, uncertainty and dynamism in new zealand now than ever before. while this is narrowing the gap between riskscape theory and climate change policy practice, issues remain with regard to connecting complex climate change riskscape imaginaries-comprised of an assemblage of biophysical, social, economic or political forces-to governance arrangements that are able to address them. there have long been academic calls for anticipatory risk governance (see fuerth, 2009; rosa et al., 2014; quay, 2010 ) that can recognise and address the dynamism and uncertainty of climate change riskscapes. however, the means and mechanisms for operationalising anticipatory governance remain unclear. nowhere is the art of anticipation more foregrounded than within the realm of re/insurance. in their paper examining the riskscapes of re/ insurance in florida, zac taylor and jessica weinkle use riskscapes theory to draw critical insights from existing re/insurance debates (taylor and weinkle, 2020) . they extend müller-mahn et al.'s (2018) argument that riskscape thinking must directly contend with machinations of power, working to reveal the asymmetrical, ongoing and always-political nature of re/ insurance. ultimately, taylor and weinkle argue against the expansion of re/insurance markets to govern climate risks precisely because the riskscapes approach demonstrates the importance of geographical contingencies and the limits to marketisation given the contested and shifting nature of "extra-market" considerations. jonathon everts and katja müller reveal the pivotal role that extra-market considerations played in the dynamic german coal industry (everts and müller, 2020) while building on recent calls to bridge conceptualisations of riskscapes and scale (aalders, 2018; müller-mahn et al., 2018) . climate change appears more and more like a "boundary object" (star and griesemer, 1989) , a common reference point for conflicting parties who invoke different meanings about climate change for different reasons. in this article, the authors examine the intertwined scales of riskscapes of coal mining, regional economic development and climate change in germany. the authors bring brenner's (2001) notion of "politics of scaling" into the analysis of riskscapes and look at the ways in which coal mining structures and embeds deep socio-ecological vulnerabilities across time. they argue that understanding the intricate relationship within and between different riskscapes and practices of scaling (from the local to the global) provides us with an analytical handle for deciphering the complexities of economic and environmental politics. further, they argue that doing so points us toward the transformative potential that lies within rescaling risks. risk has temporal implications through the politics of scaling. detlef müller-mahn, mar moure and million gebreyes also take on the themes of multiscalar politics and anticipation within governance in their study of riskscapes and climate change in the african cases of ethiopia and côte d'ivoire (müller-mahn et al., 2020) . they argue for greater scrutiny of how space is structured by multiscalar connections and uneven power relations. in particular, they urge practitioners and scholars to give increased consideration to how the future is made present through risk management. this includes taking into account how futures are envisioned differently by diverse actors both substantially and in terms of time horizons, the extent to which different visions incorporate risk (or not), and ultimately, how visions and risk assessments translate into agency. comparing and contrasting the politics of anticipation with a riskscapes framing, müller-mahn and colleagues conclude that thinking in terms of riskscapes with its focus on the nested and contested nature of the future, better acknowledges the diversity of material conditions, discourses and practices. the work is particularly trenchant for efforts to address climate change. to succeed, communities will need to adapt governance frameworks and social policies to address present conditions. the structure, distribution and flexibility of governance have a profound impact on the capacity of communities to conduct successful climate change mitigation and adaption. governance must be attentive to the social, political, economic and environmental dimensions of crises like climate change to assess the risks that these bring and to generate integrated responses. the capacity of governing institutions to think systematically and holistically in rapidly evolving situations and to do so across a range of socially and politically constructed temporal and spatial scales is also critical. the successes and failures of governing structures are addressed throughout the above articles in this special issue. however, the efficacy of various responses must be evaluated holistically and across different dimensions of risk, and for different groups given their relation to a given risk. here the human and social dynamics of riskscapes come to the fore. prior research debates the nature and durability of vulnerable social and spatial positions within climate change riskscapes and other socio-spatial manifestations of risk. models of the "world risk society" (beck, 2009) or analogous "urban risk societies" (elliott and frickel, 2013; romero-lankao et al., 2013) posit and observe a "social boomerang" dynamic of diffuse risk distribution in the post-war era. in contrast, five contributions to this special issue illuminate the significance of local and regional "risk settings" (müller-mahn and everts, 2013) or "contextual environments" (leichenko and o'brien, 2008 ) that structure and interlock multiple exposures to climate change-related risks and other risks over time. these articles highlight the stark inequalities and differentiated vulnerabilities that individuals and communities face from climate change riskscapes. ann tickamyer and siti kusujiarti interrogate three disasters experienced in indonesia to identify how socio-spatial risks are differentiated within particular contexts (tickamyer and kusujiarti, 2020) . power and gender roles, relations and practices are shown to be significant in mapping the socio-spatial relations of the resulting riskscapes. tickamyer and kusujiarti use their empirical analysis to demonstrate how such insights might inform plans for climate resilience in indonesia. using three case studies from indonesia, the 2004 aceh tsunami, the 2006 bantul earthquake and the 2010 merapi eruption, the authors illustrate how spatial, social, cultural, religious and political structures affect the experience of disaster. across the cases, gender relations, social capital and community resources are intertwined as drivers of risk and resilience across varying riskscapes. in particular, where women are empowered, have greater equality and participation in public spheres as well as opportunities to develop social capital and leadership, their families and communities have greater response and resilience to hazards. building resilience therefore requires great social and gender equality. from the standpoint of governance, it also requires a shift from market-based policies with hierarchical and predatory political systems to systems immersed in civic engagement and community cohesion. in a similarly nuanced fashion, jesse divalli and tracy perkins analyse neighbourhoods in southwest washington, dc, usa as sites of disparate expert and lay risk identification and mitigation practice (divalli and perkins, 2020). they find that this context results in what müller-mahn and everts (2013) describe as a "space of tension" . highlighting the disproportionate power held by the city, which has resulted in development plans that rarely account for residents' visions for their homes, divalli and perkins argue that the neoliberal growth strategy is being resolved largely in favour of the district and developers the district favours. while this effort is likely to produce a more resilient city in some ways, according to certain metrics they may also displace many current residents in the process; perhaps illustrating the birth of a new form of climateproofed gentrification. as documented widely within climate change policy (see hügel and davies, 2020) , divalli and perkins find tensions between the rhetoric of planning strategies that claim to speak for all residents and the reality of limited public participation and engagement within them. this is particularly the case for low income, residents of colour who have long experienced disadvantage in other contexts. a false picture of increased resilience will be generated as people become displaced through the district's strategies, pushing vulnerable residents beyond their administrative borders through what divalli and perkins call "resilience through attrition" . conceptualising resilience-related redevelopment as a risk to vulnerable populations in this way pushes considerations of climate change and riskscapes into social interactions at the neighbourhood scale. policy and design professionals are increasingly urged to consider and mitigate these risks within resilience planning as is seen in the metro vancouver region in canada examined by lily yumagulova in this special issue (yumagulova, 2020) . this article uncovers barriers and enablers for resilience planning across canada's multiscalar governance systems. in particular, yumagulova uses empirical material to unpack the underlying mechanisms for producing, reproducing and disrupting unequal patterns of risk across the region in british columbia. she does this by examining the role of the historic and existing flood management regimes in enabling and constraining collaborative planning capacities to address future climate risks such as sea-level rise. yumagulova finds clear evidence of historically differentiated treatment of indigenous communities in terms of flood risk transfer in the area. in particular, the analysis shows that the flood management regime favoured investments in structural flood protection (such as dykes) for colonial settlements, while leaving indigenous communities exposed to flood risk. these historical decisions left a legacy of underdevelopment for contemporary indigenous residents that led to further inequalities. yumagulova makes a strong call for a greater presence of indigenous voices in future risk and resilience planning in the region if these inequalities are to be addressed. raoul liévanos's case study of stockton, california, usa offers three main contributions to the climate change and riskscape literature (liévanos, 2020) . first, it synthesises a conceptual framework from prior research that attends to how elites' use of racial categories and racist real estate investment and development patterns structure the spatial concentration of separate and interlocking climate, environmental and economic risk exposures over time in what he calls "high-risk neighbourhoods" . the study conceptualises climate, environmental and economic riskscapes, respectively, "as spatially varying vulnerabilities of exposure to sea-level rise, flooding, and adverse housing market incorporation and displacement" . liévanos draws on archival sources spanning 1930-2010 and an innovative coupling of geographic information systems and qualitative comparative analysis. he uncovers how different "configurations" or "recipes of risk" (grant et al., 2010, 480) involve the devaluation of particular racial groups and racially classified spaces, threatening housing market positions, unequal flood protections and elevated risk of exposure to climate-related sea-level rise in stockton's high-risk neighbourhoods. moving continents, but staying with the theme of vulnerability and inequalities, yvonne braun draws on the concepts of riskscapes and "syndemics" (de waal and whiteside, 2003; singer, 2011) to explore the (un)intended consequences of development, which can exacerbate existing vulnerabilities for communities in the southern african country of lesotho (braun, 2020) . braun finds that poverty, food security, inequality and health risks co-occur, particularly in relation to regional climate stressors and to the impacts of large-scale infrastructural development such as the lesotho highlands water project (lhwp), one of the five largest transnational construction projects active in the world. in lesotho, it was largely small-scale farming families who absorbed the most direct losses and stresses to their livelihoods from the lhwp project, and yet it is these same people who experience the greatest risk from current and future climate changes (twomlow et al., 2008) . braun argues that it is international and national development agendas which have created a series of displacements to increase rather than reduce vulnerability and risks. instead she urges those who govern to adopt a more holistic approach to their work; an approach that deliberately seeks to anticipate and mitigate interactive, syndemic relationships and their consequences. even as we applaud the contributions of this special issue, we recognise gaps and challenges. some of the most daunting challenges and disruptive changes that are being set in motion by climate change and the arc of human history have received too little attention. while climate change is a central theme throughout this special issue, several topics associated with it are not fully addressed. in this section, we consider connections between climate change riskscapes and three of these: conflict and warfare; migration and displacement; and pandemics. in the first decades of the 21st century, wars have been fought by and in middle income countries (for example, iraq, colombia and syria) and among the world's least developed countries (for example, central and eastern africa) (collier, 2008; hooks, 2020; kaldor, 2012; mann, 2018) . there is a growing body of literature which identifies the risks of climate change as a threat multiplier, linking the onset and dissemination of warfare and conflict with rapid environmental change (barnett and adger, 2007; gleick, 2014; kelley et al., 2015) . beyond the human suffering and infrastructural damage, wars degrade the social capital and institutional integrity needed to secure the peace. as a result, cycles of violence bring repeated bouts of conflict to people and places who can least afford it (collier, 2008; hooks, 2016) . multi-sided wars and conflict among irregular armed forces create overlapping risks, including (but not limited to) environmental degradation, predatory commandeering of the economy, gender and age-related coerced labour and enslavement, and systematic degradation of the infrastructure (health, transportation and communication). these threats intersect with existing riskscapes, amplifying risks, heightening inequality and crippling efforts to mitigate risks. to be sure, the risk society literature has focussed on the social, political and economic dynamics of war, militaristic, and terrorist threats and risk management strategies (for example, amoore and de goede, 2008; beck, 2009; heng, 2006; rasmussen, 2006; rosa et al., 2012; williams, 2008) . in addition, recent riskscape literature has begun to illuminate the reproduction of social vulnerabilities and ensuing uneven redevelopment trajectories following terrorist attacks (gotham and greenberg, 2014) , and it features propositions about the salience of war games and analogous performative exercises and simulations for making future riskscapes present and the target of anticipatory action (neisser and runkel, 2017 ). yet the riskscape literature has not explicitly addressed war and conflict. because riskscapes highlight the temporal and spatial texture of risk and because they shed light on the multiplicity of perceptions and meaning assigned to these risks, adapting the riskscape framework to the study of war and conflict offers great potential. this is particularly the case in the context of climate change, as there is widespread concern and mounting evidence that climate change stresses will exacerbate distributional and political tensions, making wars more likely still (see dunlap and brulle, 2015) . a second gap centres on the issues of displacement and migration. people are on the move. in sympathetic accounts of globalisation, this mobility allows migrants to seek out economic opportunities and more hospitable political contexts to pursue their aspirations. but this geographic mobility reveals the darker side of globalisation. in the first decades of the 21st century, many migrants have been forced to migrate, are fleeing intolerable oppression and are escaping dangerous war zones (hooks, 2020) . the united nations high commissioner for refugees (unhcr) reports an alarming increase in the total number and a rapid increase of "people of concern" . from 1993 to 2003, there were approximately 20 million persons of concern, but this number more than tripled by 2017. as of 2018, there were more than 71 million persons of concern (united nations high commissioner for refugees, 2017). the rate of growth is not only striking but the total now represents a significant share of the world's population. if displaced persons constituted a country, it would rank as the 20th most populous in the world. for both scholarly and substantive reasons, it is unfortunate that the riskscape literature has not been deployed to understand this humanitarian challenge. these mass migrations pose conceptual challenges that the concept of riskscape is well-suited to address. in the riskscapes literature-including the contributions to this special issue-there is a strong tendency to focus on a specific geographic area, the people who reside there, and/or institutional dynamics that contribute to the displacement of people from those areas. displaced people (internal and external) and migrants are moving across riskscapes at a variety of scales across the globe. what risks do they perceive? how do they (attempt to) cope with them? what voice do they have in identifying risks and institutionalising mitigation? how and why do elites, experts and risk management institutions respond to such migrants? taking full advantage of the fluidity and flexibility of the riskscape concept, and its attention to multiple and interlocking risks, would help us better understand this startling increase in displacement and forced migration on their own terms and in relation to climate-induced displacement and migration. indeed, sea-level rise is displacing vulnerable social groups and coastal settlements (hardy et al., 2017; maldonado et al., 2013; shearer, 2012) . further, overtly and covertly racist and nativist state policies, organisations and narratives threaten the lives and livelihoods of climate-change migrants, particularly from the global south, sometimes under the guise of resilience-based climate change adaptation and mitigation (baldwin, 2016; methmann, 2014) . because it is likely that the number of climate refugees will continue to grow in coming decades, these contributions will be all the more valuable in coming years. for example, the amazon rainforest is a riskscape. the indigenous peoples who have long lived in the rainforest are being displaced. these encroachments impose multiple layers of vulnerabilities, threatening their culture, their livelihood and the health. the risks are perceived and can be examined-as the contributors to this special issue have done in a range of settings. but the amazon rainforest is a riskscape with global implications. in the riskscape literature, including several contributors to this special issue, emphasis is placed on the varied meanings and perceptions of risk. in the case of climate change and pandemics, these differences can have global implications. in the amazon rainforest, cutting a tree or clear-cutting a hectare of forest may seem insignificant in the context of a vast-seemingly endless-rainforest. on the grounds that it is emblematic of and a requisite for progress, brazil's president, jair bolsonaro, aggressively promotes and defends this clear-cutting. this clear-cutting may push the deforestation to a tipping point that changes regional weather patterns and the global climate (piotrowski, 2019). furthermore, in the anthropocene epoch, just as climate change can be attributed to human activities, so human activity accounts for the increasing rate of zoonotic spillover (wood et al., 2012) . and, if these practices lead to zoonotic spillover, they could set in motion one or more global pandemics. current risk management organisations and institutions cannot see viruses and cannot detect the spillover from one host to the next. nor can these organisations and institutions immediately perceive the connection between individual acts and the global climate. for both climate change and pandemics, we are at risk of calamity. by the time that the effects are sufficiently "visible and acute" to spur concerted action, "it will, by definition, be too late" (giddens, 2009, 2) . the events of spring 2020 bring to the fore the dynamics and disruption of pandemics. the emergence, impact and aftermath of pandemics intersect with and transform existing riskscapes and the people who navigate them. in her contribution to this special issue, braun (2020) discusses syndemics (a concept emerging from the public health literature) and explores implications for riskscapes. syndemics draws attention to the multiple and overlapping factors that shape health disparities. by weaving in the concept of riskscape, she highlights spatial and temporal processes that reinforce and exacerbate syndemics. while braun's focus was on a megadevelopment project, the theoretical synthesis that she advances provides guidance for understanding the origins, context and aftermath of the covid-19 pandemic. the spillover of viruses from animal to human populations is and has been a threat to human health. before the covid-19 pandemic, this threat was accelerating. over the many millennia that the human species has existed, there were 219 viruses known to infect humans, as of 2012 (woolhouse et al., 2012) . given this modest total, the rate of novel infections in recent years is striking. as reported by the world health organization (2020) there is every reason to believe that this alarming rate of novel disease emergence will continue and may well accelerate. it is estimated that there are over 1.5 million unknown viruses in animal reservoirs; it is believed that over 600,000 (perhaps as many as 850,000) of these viruses have the potential to infect humans (carroll et al., 2018) . various social, political and economic activities are encroaching on and destroying fragile ecologies around the globe, and in so doing, they are at the same time, (i) stressing mammalian and bird populations that are host to hundreds of thousands of viruses, (ii) dramatically increasing interactions between domesticated animals and these mammalian and bird populations and (iii) increasing direct human interactions with these animals and the viruses they host (carroll et al., 2018) . consider the dynamics underway in the amazon basin. vast tracts of the amazon forest are being cleared (often burnt) to make way for large agricultural operations-ranching prominent among them. the amazon rainforest is an ecological hotspot, thousands of species are found in this forest-and only in this forest. as their unique ecosystem shrinks or disappears altogether, animals will be stressed (many will go extinct) and they (and the tens of thousands of viruses they host) will come into sustained contact with livestock and with people. since so few of these viruses have been identified and studied, it is impossible to predict the potential for zoonotic spillover and the emergence of a dangerous pandemic (carroll et al., 2018 )-but it is certain that the risk of spillover is heightened by the destruction of the rainforests and other such biodiverse habitats. moreover, these encroachments and destructive practices-and the associated risks-are taking place around the globe. as with climate change, pandemics such as covid-19 tend to bring less attention to the destructive practices and behavioural changes needed to shift course, and instead draw attention towards technological solutions. managing covid-19, including the closure and reopening of communities, depends on the rate and capacity to develop, manufacture and disseminate technologies including testing capabilities and vaccines. shortages in critical medical equipment like personal protective equipment including n95 masks and respirators exacerbated the medical crisis in countries like italy, and these shortages forced reconsideration of the operation of global supply chains (raffaetà, 2020; zhou, 2020) . while in some instances, political, economic and social institutions may be adequate, the covid-19 pandemic has shed light on the areas where social, political and economic institutions need improvement. further, the covid-19 pandemic may illuminate how communities with low levels of trust and social solidarity may not sustain lockdowns, allowing the virus to spread or rebound (manderson and levine, 2020; raffaetà, 2020) . in the case of climate change, low levels of trust and an inability to commit to and implement shared sacrifice will impede or delay the painful physical (energy transition, re-zoning) and economic measures necessary for mitigation and adaptation. the poor and socially marginalised also have least capacity to work remotely or relocate. further, they have limited financial reserves to overcome the effects of covid-19 (for example, purchase staple goods at inflated prices) and climate change (repair buildings after harsh storms). these concerns are particularly daunting for the communities around the globe that are, (i) currently locked down in response to the covid-19 crisis and (ii) also exposed to overlapping climate-related environmental risks such as flooding, fires, hurricanes and extreme heat events. these events will require considerable institutional flexibility and rapid political response. from the political standpoint, resilience is not an attribute possessed by a community in isolation. in the context of these multiple challenges, resilience will likely depend on communities gaining access to state resources and their needs being anticipated and addressed in state policies. community resilience is of decisive importance. where the challenge is of a global scale-as is the case with covid-19 and climate change-community resilience can be magnified or undermined by the larger state. in the case of covid-19, hard-hit communities cannot secure the inflow of needed medical equipment on their own. in some instances, national-level responses have exacerbated these shortages. in other instances, the national response has procured needed supplies and bolstered local efforts, thereby strengthening community resilience. as effective countermeasure (testing regimes, lockdowns and contact tracing) must be organised at higher levels (state/ province or national), community resilience will be amplified or undermined by the larger political context. in a similar fashion, those communities experiencing the worst effects of climate change may well lack the ability to secure the inflow of resources needed for mitigation (energy reduction and shifts to renewables) and adaptation (anti-flood measures, increased water storage capacity). community resilience can minimise these shortfalls. but, once again, community-level options will be limited or augmented by the larger political context and the state's commitment to systematically address climate effects. as such, the concern for risk goes well beyond the realms of environmental issues and climate change, issues of crime, terrorism, economic (in)security and health equity are increasingly framed in terms of risk, and efforts to mitigate risk. in the immediate context of the covid-19 pandemic, the biomedical impact of the pandemic is transforming riskscapes around the globe. the facility of contagion, the severity of illness and likelihood of death vary by where one lives, who one is, and one's socioeconomic resources. writing in the spring of 2020, it is impossible to predict the long-term impacts of the pandemic (assuming optimistically that a vaccine successfully tamps down infection in 2021 and thereafter). businesses will fail, unemployment has soared and may remain extremely high, the food supply and household-level food security are at risk, and global trade and travel may fall precipitously. each of these developments will play out unevenly across human societies; each will heighten vulnerabilities for many people. together this collection demonstrates, both empirically and conceptually, the relevance of adopting a riskscapes frame when considering climate change risks and their governance. it extends our understanding of riskscapes with respect to territorial coverage, with articles focussing on case studies drawn from diverse territories including india, new zealand, usa, indonesia, canada, germany and lesthoto. conceptually, in several respects, contributors have critically engaged with and have extended the riskscape concept. first, contributors have developed explicit connections between the temporality and spatiality of riskscapes (everts and müller, muller-mann, moure and gebreyes, and white and lawrence) . second, they have displayed a concern with social inequalities and pushed the riskscape literature to come to terms with gender (tickamyer and kusujiarti), race (divalli and perkins, liévanos), indigeneity (yumagulova) and class (divalli and perkins, liévanos, braun) . third, in different ways, each contributor to this special issue displayed a concern for power differences, highlighting the manner in which some individuals, social groups and organisations exert disproportionate influence in the definition of risk and characterisation of risk in time and space. fourth, they have drawn out the linkages between and among understandings of riskscapes, imagining alternatives and social justice. these insights include envisioning a more equitable and more inclusive planning of: (re)insurance markets in florida (taylor and weinkle), megadevelopment projects in africa (braun; muller-mann, moure and gebreyes), climate change mitigation in british columbia (yumagulova) , efforts to anticipate and "fix" climate change risks in new zealand (white and lawrence), urban renewal and gentrification in washington, dc (divalli and perkins), understanding the layers of risks in stockton (california) (liévanos) , coming to terms with climate change risks for small-scale agriculture (braun; müller-mann et al.; tickamyer and kusujiarti) and energy transition challenges (everts and müller) . these insights into social justice further enrich and add texture to the concept of riskscapes. the riskscape literature in general-and contributors to this issue specifically-have emphasised social justice. it is not simply the case that there are distinct, at times incompatible, interpretations of risks and riskscapes. social justice focuses on the institutionalised recognition of risks, steps taken (if any) to mitigate risks and imposition of costs for these mitigation efforts. the articles in the issue draw together lessons from cases around the globe. although riskscapes highlight the unique characteristics and the context of specific places, they also draw together important lessons of governance, planning and socio-ecological engagement that are critical to building resilience at the local, regional, national and global scales. communities need governance structures that are adaptive, inclusive and forward thinking to build resilient systems. they also require economies that empower different segments of society and build long-term value across multiple domains. these systems are essential for crises arising from issues such as climate change, war, displacement and migration or the current covid-19 pandemic. they bring to bear considerations of risk and resilience not only across space, but also layered through time. the contributors offer a forceful reminder that social justice principles cannot be appended after the fact. the covid-19 pandemic is creating and will leave multiple, profound and overlapping scars. recovering from this pandemic will require biomedical reforms, health care enhancements, job creation and economic renewal. as this special issue has emphasised, the recovery from this pandemic will play out across time and space-amplifying or dampening vulnerabilities of extant riskscapes. if these efforts are inclusive and infused with social justice, the post-pandemic social world could be marked by greater resiliency and enhanced social wellbeing. in a similar vein, climate change adaptation and mitigation pose complex and interdependent social and ethical dilemmas. if megadevelopment projects create winners and losers-and they do-global climate change mitigation and adaptation will do likewise, on a much larger scale. calls for "green new deal" resonate because the term references both the environmental (green) and the social justice dimensions (new deal). examining and advocating a calls for a "green new deal" through the lens of riskscapes offers a reminder and a tool to consider the interplay between environmental and social justice interventions across space and time, and from the individual to the national and global scales. the scale of risk: conceptualising and analysing the politics of sacrifice scales in the case of informal settlements at urban rivers in nairobi risk and the war on terror flammable: environmental suffering in an argentine shantytown premeditation and white affect: climate change and migration in critical perspective climate change, human security and violent conflict environmental hazard and institutional betrayal: lay-public perceptions of risk in the san luis obispo county oil spill silent spill: the organization of an industrial crisis risk society: towards a new modernity. thousand oaks world at risk the knowledge-shaping process: elite mobilization and environmental policy environmental change, risk and vulnerability: poverty, food insecurity and hiv/ aids amid infrastructural development and climate change in southern africa the limits to scale? methodological reflections on scalar structuration the global virome project: expanded viral discovery can improve mitigation banking spatially on the future: capital switching, infrastructure, and the ecological fix coronavirus disease 2019: racial and ethnic minority groups. center for disease control and prevention acceptable risk? making decisions in a toxic environment the bottom billion: why the poorest countries are failing and what can be done about it new variant famine: aids and food crisis in southern africa they know they're not coming back": resilience through displacement in the riskscape of southwest an interactive web-based dashboard to track covid-19 in real time climate change and society: sociological perspectives the historical nature of cities: a study of urbanization and hazardous waste accumulation riskscapes, politics 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systemic risk: sea level rise and high-risk neighbourhoods in the impact of climate change on tribal communities in the us: displacement, relocation, and human rights covid-19, risk, fear, and fallout have wars and violence declined? visualizing climate-refugees: race, vulnerability, and resilience in global liberal politics environmental justice and southern california's 'riskscape': the distribution of air toxics exposures and health risks among diverse communities environmental inequality: the social causes and consequences of lead exposure the risk society at war: terror, technology and strategy in the twenty-first century risk governance: coping with uncertainty in a complex world exploration of health risks related to air pollution and temperature in three latin american cities managing the risks of climate change and terrorism the risk society revisited: social theory and governance the social construction of alaska native vulnerability to climate change toward a critical 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three. ideas, the atlantic a framework for the study of zoonotic disease emergence and its drivers: spillover of bat pathogens as a case study human viruses: discovery and emergence world health topics what coronavirus means for the possibility of a carbon-free economy disrupting the riskscapes of inequities: a case study of planning for resilience in canada's metro vancouver region the global effort to tackle the coronavirus face mask shortage. the conversation key: cord-149069-gpnaldjk authors: gomes, m. gabriela m. title: a pragmatic approach to account for individual risks to optimise health policy date: 2020-09-02 journal: nan doi: nan sha: doc_id: 149069 cord_uid: gpnaldjk developing feasible strategies and setting realistic targets for disease prevention and control depends on representative models, whether conceptual, experimental, logistical or mathematical. mathematical modelling was established in infectious diseases over a century ago, with the seminal works of ross and others. propelled by the discovery of etiological agents for infectious diseases, and koch's postulates, models have focused on the complexities of pathogen transmission and evolution to understand and predict disease trends in greater depth. this has led to their adoption by policy makers; however, as model-informed policies are being implemented, the inaccuracies of some predictions are increasingly apparent, most notably their tendency to overestimate the impact of control interventions. here, we discuss how these discrepancies could be explained by methodological limitations in capturing the effects of heterogeneity in real-world systems. we suggest that improvements could derive from theory developed in demography to study variation in life-expectancy and ageing. using simulations, we illustrate the problem and its impact, and formulate a pragmatic way forward. since the detection of aids in the early 1980s, it has been evident that heterogeneity in individual sexual behaviours needed to be considered in mathematical models for the transmission of the causative agent -the human immunodeficiency virus (hiv) 8 . much research has been devoted to measuring contact networks in diverse settings and by different methods, to attempt to reproduce transmission dynamics accurately [9] [10] [11] . meanwhile other equally important sources of inter-individual variation were overlooked. for example, unmodelled heterogeneity in infectiousness and susceptibility led to over-attribution of hiv infectivity to the acute phase 12 and, consequently, to concerns that interventions relying on treatment as prevention might be compromised. the problem of unaccounted heterogeneity in predictive models can be illustrated with the simplest mathematical description of infectious disease transmission in a host population. figure 1 shows the prevalence of infection over time under three alternative scenarios: all individuals are at equal risk of acquiring infection (black trajectories [notice unrealistic time scale]); individual risk is affected by a factor that modifies either their susceptibility to infection (blue) or exposure through connectivity with other individuals (green). risk modifying factors are drawn from a distribution with mean one (blue and green density plots on the left) while the homogeneous scenario is sketched by assigning a factor one to all individuals (black frequency plot). as the virus spreads in the human population, individuals at higher risk are predominantly infected as indicated at endemic equilibrium (figure 1 a, b , c, density plots on the right, coloured red) and after 100 years of control (figure 1 d, e, f). the control strategy applied to endemic equilibrium in the figure is the 90-90-90 treatment as prevention target advocated by the joint united nations programme on hiv/aids 4 whereby 90% of infected individuals should be detected, with 90% of these receiving antiretroviral therapy, and 90% of these should achieve viral suppression (becoming effectively non-infectious). ; distributed susceptibility to infection with variance 10 (b, e); distributed connectivity with variance 10 (c, f). in disease-free equilibrium, individuals differ in potential risk in scenarios b and c, but not in scenario a (risk panels on the left). the vertical lines mark the mean risk values (1 in all cases). at endemic equilibrium, individuals with higher risk are predominantly infected (risk panels on the right, where red vertical lines mark mean baseline risk among individuals who eventually became infected), resulting in reduced mean risk among those who remain uninfected (black vertical lines). to compensate for this selection effect, heterogeneous models require a higher ! to attain the same endemic prevalence (a, b, c). interventions that reduce infection also reduce selection pressure, which unintendedly increases mean risk in the uninfected poll and in heterogeneous models, ( ) is a probability density function with mean 1 and variance 10, and 〈 # 〉 denotes the th -moment of the distribution. gamma distributions were used for concreteness. figure 1 shows that heterogeneous models that account for wide biological and social variation require higher basic reproduction numbers ( ! ) to reach a given endemic level and predict less impact for control efforts when compared with the homogeneous counterpart model. this holds true regardless of whether heterogeneity affects susceptibility or connectivity. at endemic equilibrium, individuals at higher risk are predominantly infected (red distributions have mean greater than one as marked by the red vertical lines), and hence those who remain uninfected are individuals with lower risk (blue and green distributions have mean lower than one as marked by the black vertical lines). thus, the mean risk in the uninfected but susceptible subpopulation decreases, and the epidemic decelerates (thin blue and green curves); higher values of ! are consequently required if the heterogeneous models are to attain the same endemic level as the homogeneous formulation (heavy blue and green curves). finally, interventions are less impactful under heterogeneity because ! is implicitly higher. indeed, these biases could help explain trends in hiv incidence data which lag substantially behind targets informed by model predictions, even in settings that have reached the 90-90-90 implementation targets 3,4 . a novel severe acute respiratory syndrome coronavirus (sars-cov-2) isolated at the end of 2019 from a patient in china has spread worldwide causing the covid-19 pandemic, despite intensive measures to contain the outbreak at the source. countrywide epidemics have been extensively analysed and modelled throughout the world. initial studies projected attack rates of around 90% if transmission had been left unmitigated 13 , while subsequent reports noted that individual variation in susceptibility or exposure to infection might reduce these estimates substantially 14 risk distributions are simulated in three scenarios: homogeneous (black); distributed susceptibility to infection with variance 10 (blue); distributed connectivity with variance 10 (green). left panels represent distributions of potential individual risk prior to the outbreak, with vertical lines marking mean risk values (1 in all cases). as the epidemic progresses, individuals with higher risk are predominantly infected, depleting the susceptible pool in a selective manner and decelerating the epidemic. the inset overlays the three epidemic curves scaled to the same height to facilitate shape comparison. right panels show in red the risk distributions among individuals who have been infected over 4 months of epidemic spread (mean greater than one when risk is heterogeneous, as marked by red vertical lines) and the reduced mean in heterogeneous models, ( ) is a probability density function with mean 1 and variance 10, and 〈 # 〉 denotes the thmoment of the distribution. gamma distributions were used for concreteness. as models inform policies, we cannot but stress the importance of representing individual variation pragmatically. while much is being discovered about sars-cov-2 and its interaction with human hosts, epidemic curves are widely available from locations where the virus has been circulating. models can be constructed with inbuilt risk distributions whose shape can be inferred by assessing their ability to mould simulated trajectories to observed epidemics while accounting for realistic social distancing interventions 6 . variation in infectiousness was critical to attribute the scarce and explosive outbreaks to superspreaders when the first sars emerged in 2002 16 , but what we are discussing here is different. infectiousness does not respond to selection as susceptibility or connectivity do, i.e. models with and without variation in infectiousness perform equivalently when implemented deterministically and only differ through stochastic processes. the need to account for heterogeneity in risk to acquire infections is not restricted to aids and covid-19 but is generally applicable across infectious disease epidemiology models. moreover, similar issues arise in methods intended to evaluate the efficacy interventions from experimental studies as illustrated for vaccines in the sequel. individual variation in susceptibility to infection induces biases in cohort studies and clinical trials. vaccine efficacy trials offer a useful illustration of the problem and give insight into the potential solution. in a vaccine trial, two groups of individuals are randomised to receive a vaccine or placebo and disease occurrences are recorded in each group. as disease affects predominantly higher-risk individuals, the mean risk among those who remain unaffected decreases and disease incidence declines. in the vaccine group the same trend will occur at a slower pace (presuming that the vaccine protects to some degree). as a result, the two randomised groups become different over time with more highly susceptible individuals remaining in the vaccine group. the vaccine efficacy, described as a ratio of cases in vaccinated compared to control group, therefore appears to wane (figure 3) 17, 18 . this effect will be stronger in settings where transmission intensity is higher, inducing a trend of seemingly declining efficacy with disease burden 19 . the concept is illustrated in figure 3 by simulating a vaccine trial with heterogeneous and homogeneous models analogous to those utilised in figures 1 and 2 . selection on individual variation in disease susceptibility thus offers an explanation for vaccine efficacy trends that is entirely based on population level heterogeneity, in contrast with waning vaccine-induced immunity, an individual-level effect 20 . as both processes may occur concurrently in a trial, it is important to disentangle their roles, as they lead to different interpretations of the same incidence trend. for example, vaccine efficacy might wane in all individuals, or it might be constant for each individual but decline at the population level due to selection on individual variation. to capture this in a timely manner requires multicentre trial designs with sites carefully selected over a gradient of transmission intensities (e.g. optimally spaced along the incidence axis in figure c, f) , and analyses performed by fitting curves generated by models that incorporate individual heterogeneity. an alternative and more tightly controlled approach would be to use experimental designs in human infection challenge studies where these are available 21 to generate dose-response curves and apply similar models. these approaches have recently been successfully tested in animal systems 22 . heterogeneities in predispositions to infection depend on the mode of transmission but play a role in all high-burden infectious diseases. in respiratory infections, heterogeneity may arise from a variation in exposure of the susceptible host to the pathogen, or the competence of host immune systems to control pathogenic viruses or bacteria. these two processes have multiple the mechanisms underpinning single factors for infection and their interactions determine individual propensities to acquire disease. these are potentially so numerous that to attain a full mechanistic description may be unfeasible. even in the unlikely scenario that a list of all putative factors may be available, the measurement of effect sizes would be subject to selection within cohorts resulting in underestimated variances 23 . to contribute constructively to the development of health policies, model building involves compromises between leaving factors out (reductionism) or adopting a broader but coarse description (holism). holistic descriptions of heterogeneity are currently underutilised in infectious diseases. recently, measures of statistical dispersion commonly used in economics have been adapted to describe risk inequality in cancer 24 , tuberculosis 25 and malaria 26 , offering a holistic approach to improve the predictive capacity of disease models. essentially, this involves stratifying the population into groups of individuals with similar risk, which may be as granular as individual level for frequent diseases, such as malaria or influenza. for infectious diseases which cluster by proximity, such as tuberculosis, stratification can use geographical units. familial relatedness pertains when there is a clear genetic contribution to risk, such as cancer. by recording disease events in each group, specific incidence rates can be calculated and ranked. unknown distributions of individual risk are then embedded in dynamic models and estimated by fitting the models to the stratified data. because they incorporate explicit distributions of individual risk, these models automatically adjust average risks in susceptible pools to changes in transmission intensity, occurring naturally or in response to interventions. not subject to the selection biases described above, this model approach inherently enables more accurate impact predictions for use in policy development. there is compelling evidence that epidemiologists could use indicators that account for the whole variation in disease risk. heterogeneity is unlimited in real-world systems and cannot be completely reconstructed mechanistically. inspired by established practices in demography and economics and supported by successful applications in both infectious and non-communicable diseases, the use and further development of these approaches offers a powerful route to build disease models that enable more accurate estimates of intervention efficacy and more accurate predictions of the impact of control programmes. an application of the theory of probabilities to the study of a priori pathometry, part i modeling infectious disease dynamics in the complex landscape of global health is the unaids target sufficient for hiv control in botswana? joint united nations programme on hiv/aids (unaids), global aids update elimination of lymphatic filariasis in south east asia herd immunity thresholds for sars-cov-2 estimated from unfolding epidemics impact of heterogeneity in individual frailty on the dynamics of mortality a preliminary study of the transmission dynamics of the human immunodeficiency virus (hiv), the causative agent of aids heterogeneities in the transmission of infectious agents: implications for the design of controls programs networks and epidemic models transmission network parameters estimated from hiv sequences for a nationwide epidemic reassessment of hiv-1 acute phase infectivity: accounting for heterogeneity and study design with simulated cohorts impact of non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand (imperial college covid-19 response team individual variation in susceptibility or exposure to sars-cov-2 lowers the herd immunity threshold a mathematical model reveals the influence of population heterogeneity on herd immunity to sars-cov-2 superspreading and the effect of individual variation on disease emergence estimability and interpretability of vaccine efficacy using frailty mixing models apparent declining efficacy in randomized trials: examples of the thai rv144 hiv vaccine and caprisa 004 microbicide trials clinical trials: the mathematics of falling vaccine efficacy with rising disease incidence seven-year efficacy of rts,s/as01 malaria vaccine among young african children design, recruitment, and microbiological considerations in human challenge studies vaccine effects on heterogeneity in susceptibility and implications for population health management understanding variation in disease risk: the elusive concept of frailty inequality in genetic cancer risk suggests bad genes rather than bad luck introducing risk inequality metrics in tuberculosis policy development modelling the epidemiology of residual plasmodium vivax malaria in a heterogeneous host population: a case study in the amazon basin key: cord-252182-v0cveegl authors: déportes, isabelle; benoit-guyod, jean-louis; zmirou, denis title: hazard to man and the environment posed by the use of urban waste compost: a review date: 1995-11-30 journal: science of the total environment doi: 10.1016/0048-9697(95)04808-1 sha: doc_id: 252182 cord_uid: v0cveegl abstract this review presents the current state of knowledge on the relationship between the environment and the use of municipal waste compost in terms of health risk assessment. the hazards stem from chemical and microbiological agents whose nature and magnitude depend heavily on the degree of sorting and on the composting methods. three main routes of exposure can be determined and are quantified in the literature: (i) the ingestion of soil/compost mixtures by children, mostly in cases of pica, can be a threat because of the amount of lead, chromium, cadmium, pcdd f and fecal streptococci that can be absorbed. (ii) though concern about contamination through the food chain is weak when compost is used in agriculture, some authors anticipate accumulation of pollutants after several years of disposal, which might lead to future hazards. (iii) exposure is also associated with atmospheric dispersion of compost organic dust that convey microorganisms and toxicants. data on hazard posed by organic dust from municipal composts to the farmer or the private user is scarce. to date, microorganisms are only measured at composting plants, thus raising the issue of extrapolation to environmental situations. lung damage and allergies may occur because of organic dust, gram negative bacteria, actinomycetes and fungi. further research is needed on the risk related to inhalation of chemical compounds. in the management of household wastes, the sorting-composting approach presents many advantages: (i) sorting not only provides for the selection of recyclable and compostable materials, it also reduces the volume of waste to be treated by incineration. hence, the putrefiable part represents 50-70% of the weight of the entire municipal solid waste (msw) [1, 2] . (ii) the volume of the putrefiable portion will be reduced during the composting process. (iii) compost is widely utilized in agriculture, especially in europe [3] and its use is also strongly encouraged in the usa [4-61. depending on its degree of maturity and quality, it can be used in vine yards, for mushroom farming (fresh compost), in horticulture (hot-beds with fresh compost), sylviculture, country-side planning (flower beds), preparation of sports fields, or golf courses, maintenance of public or private parks, maintenance of motor-way embankments to cover waste discharge systems, or in the rehabilitation of sites such as mines and sand pits [7-121. the chemical components play important roles in the physical and chemical properties of the soil f13,14]. amendment is more interesting for the improvement of soil characteristics than for the fertilizer value of the compost [15] . indeed, the use of municipal solid waste (msw) influences the water retention capacity, resistance to erosion, density, ph, conductivity and the nutrient content of the soil [15,161. there are three main methods for cornposting: gathering of waste in windrows that are turned at regular intervals, static piles of waste that are aerated by deliberate passage of air within the mass (aerated static piles), and finally by gathering waste materials in a totally enclosed and controlled environment, that is, in a reactor [2,17-201. many organic waste products are used for compost: yard wastes (yw), sewage sludge (ss), municipal solid wastes (msw), industrial and agricultural (wood, animal droppings, etc.) [211. in the present work, we have only studied domestic waste in single composts or accompanied with ss or yw. the compost is not a harmless product; msw may contain a number of contaminants with health or environmental risks. these chemical or biological contaminants may expose different populations to health hazards, ranging from the composting plant workers to the consumer of vegetable products treated with compost fertilizers. for example, the humus part of composts consists of numerous ligands, some of which are more or less irreversibly bound to metallic elements [22] . the metals may be released in the soil, when a change in environmental conditions such as ph occurs during application of the compost [23] ; released metals then become bioavailable for plants. among the toxic elements found in composts, arsenic, asbestos, hexavalent chromium, nickel or pcb have been classified as carcinogens or potential carcinogens [241. finally, composts could be potentially hazardous through the presence of microorganisms [25] . in france, out of 20500000 tons of msw per year, 7% (1435000 t) are treated and transformed into 640000 tons of compost [261. due to the diversity of the populations exposed to the use of compost, the huge mass of products involved, and the potential risk of contamination, it is interesting to evaluate the public health and environmental risks arising from the utilization of compost originating from msw. based on literature surveys, the state of present knowledge with regard to the type and the quantity of contaminants is discussed. the different populations at risk through various routes of contamination are also discussed. in the preparation of this review, various comparable literature data on msw from europe, north america and japan were collected [27, 28] . all the articles were selected on composts of msw origin. on account of the similarity of the problems encountered, our literature review also covered compost made from sediment wastes from water treatment stations and green wastes (gardens, parks, forests, etc.) . for the same reasons, some articles that treated non-composted ss were considered. the quality of a compost determines its sales [29] and a hazard-free utilization, which may be viewed from two points: the agronomic value and the absence of contaminants. many authors have written on the agronomic quality of composts t1,30-347. the contamination of the finished product may come from the primary material, that is, essentially from the content of our garbage bins as well as other composted wastes (yw or ss). metals, for example, are provided by plastics (pigments and stabilizers), batteries (torch and radio), car batteries, electronic components, electric bulbs and their sockets, leather materials, glassware or ceramics [28, 35, 36] . asbestos is found in household refuse because of insulation materials [37] . a number of organic compounds (solvents, grease, pesticides, etc.) find their way into our garbage bins as residues. these are also found in yw (lindane, pcb, pcdd, pcdf), and in ss (pah, pesticides, halogenated hydrocarbons, phthalates, esters, pcb) 138-431. sorting of msw is increasingly used and has proved to be very effective in reducing the contamination of the finished product. mercury, lead, chromium, cadmium, zinc and copper are mostly derived from batteries, glassware, plastics and ferrous materials. elimination of these recyclable components before making the compost leaves not more than 50% of lead and copper, 25-30% of zinc and nickel, which persists in papers/cardboards and is more or less strongly bound to organic materials [27] . sorting may be carried out at the source by the producer or at the waste disposal plant, implemented manually or automatically by special machines, especially in the case of small amounts of plastics and metals, or after cornposting [18, 31, . early sorting ensures lower contamination with organic and inorganic pollutants [28, 44, 47] . biological contamination is also encountered in msw. pathogenic microorganisms are likely to come from dirty discarded cloth, faeces of domestic animals, sanitary tissue papers or putrefying foods [25, 48] . as a result of their origin, contamination exists in ss where one can easily find many strains of bacteria, viruses, fungi and other parasites (table 1) the cornposting procedure is very important. the parameters that must be controlled during this process are: the composition of the mass, aeration, temperature, humidity, carbon/nitrogen (c/n) ratio and ph. some components such as keratinous wastes, papers and cardboards are not easily composted [50] . depending on the method of compost formation that is chosen, the parameters may be controlled to a reasonable extent [50-521. anaerobic conditions may provoke an increase in the duration of cornposting and, more table 1 pathogens that may be found in sewage sludge and in municipal solid wastes (49, 80, 110, 122, 124) importantly, an adverse sanitary condition if the temperature conditions are not fulfilled. a hygienic compost is free of the pathogens that it might have contained. there is an inherent risk in the use of unhygienic composts [8,53-561. it is possible to disinfect them by monitoring the temperature during composting. as can be seen in table 2 , the destruction of the pathogens depends on the temperature reached and the duration of the oxidation process. temperatures of about 55-60°c for at least 3 days are recommended [50, 57, 58] . this has proved effective against salmonella spp. and other parasites [59, 60] . unfortunately, these conditions are table 2 '\ level of temperature and length of time necessary to destroy some pathogens present in primary products of composts (180). lethal temperature not always fulfilled because temperature is dependent upon the degree of oxidation of the entire mass of compost. control of temperature and aeration is not possible for the entire mass of wastes windrow cornposting. the compost is therefore not always disinfected by this method. the use of windrow presents, in addition, the risk of contaminating clean areas with unclean wastes from other parts of the heap infected during turning [31, 51, 61, 62] . it should be noted however that these pathogens are not in their natural environment, that is, in their hosts. this does not favor their survival. if fungi and bacteria strains have the possibility to multiply, viruses and other parasites can at best acquire a form of resistance. the pathogens are forced to compete with other microorganisms which are in their natural environment. these are mostly bacterial strains at the beginning of the composting process, but turn to fungi and actinomycetes by the end, as a result of selection pressure due to increased temperature [61, 63] . the method of composting permits both improvement of the hygienic conditions of the compost and promotes chemical decontamination. during the degradation of the primary wastes, the chemical contaminants are often implicated in the process of transformation. this is supported by laboratory results which show that chlorpyrifos, isofenphos, diazinon (insecticides) and pendimethalin (herbicide) found in plant wastes are totally degraded by composting [64] . other studies have reported a degradation of 6% of chlorinated pesticides and 45% of pcb [38] . the phenomenon is widespread and it has been tried for the rehabilitation of soils by composting [65] . only pollution by organic wastes can be treated by this approach. by contrast, mineral contaminants tend to concentrate during composting by reduction in volume. the process used must encourage a good maturity of compost. maturity refers to the degree of biological, chemical and physical stability of the compost. it can be measured in several ways [l&66-74] . there is a meeting point between the two terms maturity and stability. while maturity defines such aspects of the compost like color, friability and odor, stability on the other hand is based on all the physical, chemical and biological evaluations [74] . the use of an immature compost may present an agronomic problem since it may become toxic to plants [11,631. the degradation of the wastes continues in the soil after application of the compost, with several toxic intermediate metabolites being present, such as phenols, ammonia, acetic, propionic, butyric and isobutyric acids [32, 75] . on the other hand, when immature composts are used, the risks inherent in increasing soil temperature, the competition between plants and microorganisms for available soil nitrogen and a reduction in the level of soil oxygen are equally important unfavorable factors for plant growth. the maturity of compost is also important because of its ability to create nuisance when used. the decomposition of immature compost is completed in the soil under anaerobic conditions, resulting in odor [63] . furthermore, the bioavailability of heavy metals is a function of the degree of maturity of the compost, since the humic material is capable of binding them. experiments have shown that metals become less bioavailable with increasing maturity. this condition, in turn, limits the risk of spreading and hence contamination of the food chain (via plants) and the entire environment [72,76-791. the parameters discussed above are controlled and described differently in laboratory experiments or when field measurements are taken, making a summary of such diverse data difficult. the quantitative data that have been considered in this review are the highest and the lowest values encountered in composts and not averages, since there is a wide variability between data from each article. in addition, the values of the parameters that determine the level of contamination in each compost are not always described in each article. man and his environment are exposed to contaminants from composts during processing, storage and utilization. fig. 1 summarises the different means of contamination and their risk implication. there is limited literature data on storage of compost. oral contamination through contaminated hands is possible for biological and chemical contaminants. this risk is particularly pronounced for children. studies have shown that a child may ingest as much as 100 mg/day of dust from the soil, and when the child suffers from geophagy -or pica -(pathologic exaggeration of the hand-mouth behaviour) this may increase up to 5 g [82, 83] . environmental contamination may result from open air storage of compost or under bad or inadequate protection which exposes it to rain. pollutants are then washed by rain and carried along by water run-off or spread by percolation into the soil. wind may also disperse inadequately stored composts. the storage of immature compost also provokes the emanation of a nauseating odor. application. the applicator may be wounded if sharp objects are left in the compost. compost generates dusts and many particles are suspended in the air during spreading. their inhalation may be dangerous to health since they adsorb both biological and chemical contaminants. dispersion of these dusts and their components in the ecosystem may also constitute an environmental risk. spread compost. composts add chemical or biological pollutants to the soil. these pollutants exist either in a free state or are bound to humus components of the soil. the free chemical contaminants are said to be bioavailable and may be assimilated by plants. there is therefore a potential risk of contamination of the food chain through plants cultivated on such soils and to animals which are fed with these plants as well as to their predators. the external parts of plants are in contact with treated soil. a consumer who does not wash or peel edible materials is thus exposed to the risk of either chemical or biological contamination. the consumption of animals fed with such plants might lead to hazard. under this condition, meat transmits essentially chemical contaminants and parasites. from a different point of view, the free chemi-203 cal and biological contaminants may be washed along by flowing water or rain and may percolate down to groundwaters. this is a means of dispersion in the environment and a threat to man if these infiltrations reach groundwater used as drinking water. the concentration of contaminants in composts, their bioavailability, the recovery rate in plants cultivated on compost-treated soils and in compost sewage systems will now be described. bioavailability of contaminants may be evaluated in different ways using different agents for extraction or binders. bioavailability is calculated from the ratio of the weight of the extract and the quantity of the compound in the compost or treated soil. this knowledge helps in the estimation of the free fraction of metals that may be assimilated by plants or capable of contaminating water bodies or soils. odor resulting from soil treatment with immature compost will not be dealt with here because of the very limited amount of research done in this area [63,84]. only a certain number of compounds selected according to their known toxicity will be discussed in the following section. their general characteristics as well as those of other contaminants are presented in table 3 . cadmium. the amount in compost ranges from 0.26 ppm to 11.7 ppm (fig. 2 , graph a) (unless otherwise stated, all data are in dry weights), although the minimum level is much lower, since about 10 observations did not reach the detection level with the analytical method used [85, 86] . although there is no statistical difference in the quantity of cadmium in compost of diverse origins (p = 0.57), uncomposted sewage sludge contains higher levels (s-2450 ppm) [87-891. bioavailability varies from about 0 to 52% (fig. 2, . for the record, the acceptable maximum concentration of cd in potable water in france is 5 i*,g/l. one does not detect it in leachates originating from compost constituted from plant materials [86] . several authors have considered the assimilation of cd by plants as a result of treatment of soils with compost [88,93-951; cd content of 1.75 ppm was therefore found in beetroot [93] . a cd range from 0.5 ppm to 1.7 ppm was found in beetroot cultivated on soils treated with ss composts or yw. table 4 indicates that assimilation depends on the plant and the level of metals in the soils. similar results have been obtained in other studies carried out in fields treated with uncomposted ss. one month after planting, tobacco plants assimilated 7-10% of cd present in the soil while maize took in only 5% [88] . the effects are long lasting. for example, on a soil treated for 7 years, 0.9-32 ppm cd was observed in beetroot several years after treatment was stopped [95] . a concentration of 50-70 ppm was found in the leaves of maize 14 years after a treatment with ss was stopped [88] . lead. the levels of lead in compost of msw range from 10.6 ppm to 13 212 ppm (fig. 2 , graph b) with a statistically significant difference between composts made partially or completely of msw and those without msw (p = 10m5). the latter contains much lower levels of pb. this may attain 200-20000 ppm in non-composted sewage sludge [28,87-891. its bioavailability is from 4.1% to 75.4% (fig. 2, graph b ). these two extreme values have been measured in two mixtures of soil/compost of urban wastes. the methods of extraction were similar but the ph of both soils was very different. the lowest bioavailability was measured in a soil of ph 8.1 [77] while that of ph 5.2 [941 gave a very high bioavailability value. the release of pb in ss is known to be low [96] . experiments carried out with lysimeters gave contable 3 literature dealing with 14 compounds present in urban compost. . nickel. the usually observed level of nickel in composts, 0.8-1220 ppm, is only slightly dependent on the original primary materials from which the composts were formed (p = 0.17), though the highest values are obtained in composts containing ss (fig. 2 , graph c). the extreme values of bioavailability range from 1.4% to 58.6% (fig. 2, mercury. the only available information deals with the mercury content of composts. no author, to the best of our knowledge, has been interested in its bioavailability and its presence in plants as a result of the application of composts or in leachates. the quantity found in a compost depends on the origin of the compost and there is a significant difference between composts of different origins (p = 0.05). composts of msw have the highest level of mercury which range from 0.9 ppm to 20.3 ppm (fig. 2 , graph e). selenium. the selenium content of composts varies from 0.1 ppm to 8.8 ppm with a difference as a function of their origins (p = 0.01) which may be explained by a high contamination with ss (fig. 2, graph f) . yw and msw composts have similar concentrations of selenium but data are scarce. beetroot grown on soils treated with a msw compost may contain about 0.04 ppm to 0.17 ppm of selenium depending on the origin of the compost [93] . we have no information on selenium in leachates of composts. arsenic. very little information on the measurements of arsenic in compost has been found in the course of this research. the values range from 7 ppm to 9 ppm. the application of msw compost for more than 30 years did not increase the arsenic content of plants cultivated in sites [27, 102] . asbestos. the presence of asbestos has been studied in different experiments [10, 37] . in eight samples of msw composts, fibres were found in all, while 13 observations were positive out of 22 carried out with non-msw composts. in contrast to metals, organic contaminants may be metabolized by microorganisms during the process of composting [38] . only the very stable compounds may persist in the composts because of the length of time of compost formation, the presence of microorganisms and the high temperature. hence, pesticides such as diazinon which has a life span of 12 weeks were not found in compost [64] , while pentachlorophenol which may persist for 5 years in the soil is found in compost [103] . few studies have been made on pollution with organic contaminants, but many compounds have been measured (table 5 ). for the sake of a summary, these substances will be examined in groups, adding also specific examples. the major families treated have been chosen based on their relative resistance to biological degradation, or their toxicity to man, animals and plants, and on their tendency to accumulate in the food chain [104] . unlike the inorganic compounds, organic compounds may be transmitted to plants in two ways: by classical routes through the roots, and through the air into the leaves during vaporization of some of the compounds [104]. pah. their half-life in the soil is long and they are stable even when metabolized in the plants. total pah content in composts ranges from 1 ppm to 250 ppm. for each element, the values range from 0.0006 ppm to 49.3 ppm (table 5) . pesticides. though many organochlorinated pesticides have been banned, they are often found in the environment. composts made of wastes that are sorted early contain very little organochlorinated pesticides [38] . pesticides detected are in the range of 0.007 ppm to 2.2 ppm (table 5 ). chlorinated hydrocarbons. the different substances gathered in this family of compounds range from 0.02 to 1.1 ppm. volatile solvents are among the most important since they are found at a concentration as high as 0.1 ppm. pcdd /f. they are lower in composts of msw that have been sorted early and range from 0.1 to 7 ppm. very small quantities are found in ss (in the order of ppb) [104] . pcb. the quantity of pcb found in composts is about 0.5-5 ppm (table 5 ). in ss, this may vary from 0.5 to 5 ppm. natural substances. in contrast to pollutants (exogenous compounds), natural substances (endogenous compounds) are derived from the compost itself. for example, microorganisms produce fatty acids and methylated esters, but in quantities that do not add more than 0.025-0.05 ppm to the soils during application. these quantities are considered not to be dangerous [105] . the excess soluble organic materials from composts may constitute a nuisance, particularly for flowing water. successive leachates might introduce organic matter into water and may pose a risk of ecological disequilibrium. in a study over 3 years [1061, a decrease of cod (chemical oxygen demand) from 5000 mg/l to 200 mg/l (corresponding to 600 mm of leachates) was observed after 2 years, and bod (biological oxygen demand) represented 10% of cod. given the diversity of the references as to the type of microorganisms and the method of composting, it is difficult to summarize the literature. the aim of this work, therefore, is simply to find a base from which the microbiological risks associated with composting can be evaluated. those who wish more details may go through the original papers. two types of microorganisms are envisaged. first, the pathogens present in raw materials meant for composting and liable to disappear during the composting process (tables 1,2) . these agents are representative of the microorganisms present in the digestive tract. secondly, there are microorganisms which develop during the process of compost formation and which play a role in the degradation of organic matter. these are fungi and mesophilic and thermophilic bacteria. there are several obligatory and facultative pathogens [61] . the organism as well as its spore or toxin (endotoxins of gram negative bacteria), may be implicated in the pathogenicity. hazard essentially occurs through the respiratory system and these germs constitute a potential risk for workers at the composting site and for users of composts, whether workers or private users. table 6 summarises the concentrations of these germs found in the literature, according to their route of penetration (ingestion or inhalation). air measurements have been carried out in tunnels of a mushroom culture house or in composting sites, near mounds of mature compost. the latter will be used, in this review, as an index for the risk resulting from the use of composts because no other data on atmospheric measurements during compost disposal are available. microorganisms which constitute a potential respiratory hazard are more frequent than those which follow the digestive route. these are gram positive (including actinomycetes) and gram negative bacteria and fungi. the microorganisms are essentially bound to dusts produced by composts, especially during turning [117] . about 50-85% of particles in suspension in the atmosphere about composts can be inspired because of their small diameter (< 5 pm), and can therefore reach pulmonary alveoli [12, 116, 126] . in parallel to the microbiological hazard through inhalation, there is also a physical risk due to the deposition of dust in the lungs. in a study among workers, concentrations of 10.6-80 mg/m3 of dust (n = 4) were measured in the atmosphere at a composting site [12, 116, 117] . these values are higher than the occupational standard of 10 mg/m3 [12] . very few studies have been done on organic dusts from composts. total colifonns: 1.5 x lo6 to 5.6 x lo6 cfu/g (n = 31, from 79 to organisms/g (n = 3) (107,110) fecal coliforms: 4.1 x 10' to 4 x lo6 cfu/g (n = 3),9.1 x lo'-2.5 x lo2 organisms/g (n = 8) (61, 107). fecal streptococcus: (n = 12) lo2 to 1.9 x 10' organisms/g, (n = 4). lo2 to 4.7 x lo6 cfu/g (61,62,107,111) (118) 'on two occasions, the authors suggested a sampling error. the two assays, depending on the method used (most probable nu only give a qualitative identification, i.e., < 0.2 organism/g. this review deals with a limited number of contaminants because not all have been studied in compost. the risk associated with ingestion of dust from an amended soil depends on its use. for farming, especially for vegetables and potted farm crops, 50 t/ha of compost is used while 300 t/ha is spread in public places (gardens and green playgrounds). composts are usually mixed with a depth of soil of approximately 30 cm [127] . if the density of soil and compost are comparable, the dilution of the compost in the soil is, depending on the quantities that are disposed, in a fraction of one-hundredth or one-tenth. the level of exposure of an individual depends on the quantity of soil ingested. the best estimate of ingestion of telluric dust by a normal child is about 100 mg and about 60 mg for an adult while a child suffering from geophagy may absorb up to 5 g/day [82, 83] . this route of exposure is, however, modest because the use of compost for soil treatment by private owners or for public gardens and parks currently represents only 2-5% of the total compost production [127] . the hypothesis that an individual is in permanent contact with an amended soil is theoretically possible, but this is not very likely to occur. the maximum quantity of contaminants that are absorbed daily may thus be estimated as: q absorbed ( pg) = maximum concentration of toxicant observed in composts (c, ppm) x dilution of compost in ground x amount soil ingested (g) + amount compost dust in the air x c x amount air inspired (1). as a first approach, aerial contamination may be ignored due to relatively low exposure. compost is dispersed in the air essentially during manipulation. this is a minor route of exposure for the general population. on the other hand, however, this route is not negligible for the workers of the compost production and manipulation sites. the ingested fraction (eda: estimated daily absorption) will hereafter be the main route of exposure considered in this review. its intake will be compared with the acceptable daily intake (adi) for each substance. exposure by ingestion may occur through contamination of the food chain from plants and animals raised on soils treated with composts (animals bred on open fields may ingest soil up to 6% of their daily food ration) [128] . the contamination of underground water by products from amended soils may equally present a human health hazard or an environmental nuisance when the ground water is not used for potable water. 5.1. chemical hazard table 7 summarizes results which help comparisons for inorganic compounds' adis and estimation of the maximum potential exposure associated with compost. the contribution of the ingestion of a mixture of soil and composts to the adis of an adult is shown to range from 1.5 x 10e3 to 4%. it is therefore negligible for all metals. for a normal child, the risk is higher for chromium and lead in the case of direct contact with treated public gardens and parks. the contribution of this type of soil may rise up to l-4%. in the case of pica, four contaminants may be dangerous. for cd, eda may amount to 23% of the adi, 40% for cr and 73% for pb. these are extreme values estimated from the most contaminated composts, and are unusual (fig. 2) . the us-epa assessed the risk associated with the use of ss and considered all the possible routes of contamination. it estimated a corresponding noael (no observed adverse effect level) for some pollutants [3] . according to the data in the literature, only pb occurs in composts at quantities that are frequently higher than the noael (59% of samples described in the literature) (fig. 2, graph b ). in view of the possible dilution in the environment, the concentration of metals encountered in leachates does not suggest a significant risk of contamination of the environment or of drinking water. the nuisances that concern soil, fauna and flora after treatment with composts are not well known, but they are unlikely to yield important risks. only pb is suggested to have an impact on invertebrate fauna in the soil through which the food chain of wild life may be contaminated [98, 129] . though the risks indicated in this review seem to be of little importance, it must be remembered that composts persist in the soil for several years [16, 130] and that repeated applications may lead to an accumulation of pollutants [88, 102] . the table 7 potential contribution of composts to the contamination of the soil (based on the estimation of l/10 for the compost/soii volume ratio). as na: information non available *maximum quantity: concentrations in the most polluted soil after treatment with the most contaminated compost excess relative to the highest %: percentage increase in the concentration of contaminants after soil amendment = (concentration in the least contaminated soil + the most contaminated compost)/(concentration in the least contaminated soil) **the risk associated with the absorption of argricultural soil is not considered ***acceptable daily intake ****no observed adverse effect level. fate of pollutants in treated agricultural soil was studied bi-annually in holland for 30 years, showing an increase in the quantity of cd (3.4 times the baseline level), of as and of cr (x 1.5), ni (x 3.7), hg and pb (x 4). in spite of this, no increases were observed in the levels of cd and ni in cultivated crops. rather, a decrease in the quantity of as was observed while cr and pb increased only by 15% in carrots, beetroot, turnip, pears and beans. however, in another s-year study of the fate of cd and ni in soils amended annually with ss and of their transfer to the leaves of maize plants, a strong increase in the quantities of both metals were observed (50-105%) for cd and 40% for ni in comparison with the levels measured after the first application [88] . the food chain is a potential route of human exposure because most of the composts produced are used in agriculture [127] , but it is difficult to make a global assessment of the risk to the gen-era1 population since the overall agricultural land area where composts are applied is not well known. some hypotheses will be made in order to set the risk scenario. it will be estimated that the dilution of compost in targe and vegetable farm soils is about one-hundredth burden. under this assumption, each inorganic pollutants will be reviewed. cadmium. the body burden of cd comes essentially from food, except among smokers [3, 131] . cd is very persistent in the human body, since its half-life is about 17-30 years [132, 133] . the consequence of an intoxication with cd is primarily renal and hepatic; the bones are also a target after very high contamination (the 'itai-itd episode in japan) [3, 131, 134, 135] . cd found in compost may strongly contaminate food because the relationship between the quantity of cd in the soil and that in plants is linear without threshold [131, 132] . a steeper gradient is found in lettuce (60%) than in irish potatoes (3%) [131, 136] , showing that cd accumulates differently according to the organ of the plants (leaves > roots > fruits and grains) [3, 128] . the quantity of cd in food also depends upon the use of the food. for instance, when wheat is transformed into flour, the quantity of cd is reduced by about 46% due to elimination from the chaff [128] . contamination of the food chain may also come through animals. grass grown on soils with high concentrations of metals may contaminate animal feed. this hazard is apparently minimal for cd because the quantities present in composts are not sufficient to yield high amounts in plants that might accumulate in the muscles of animals. with increasing daily intake, accumulation in the body is minor. a 40-fold increase in cd daily intake in pig does not yield a significant increase in the quantity in the muscle [128,1371. cd normally accumulates in the offal which represents only a small fraction of our food regime (0.3-0.5%). only populations that abundantly eat liver or kidney are seriously exposed [1281. however, there is a direct potential risk for animals grazing on grounds treated with composts. during grazing, animals ingest 3-6% of soil with grass. an increase has been observed in muscular tissues for animals grazing in fields amended with ss containing 8.8 ppm of cd [128] . the concentration observed in compost is much lower (maximum 12 ppm) and the risk is therefore less than when ss is used, even after application for several decades [102] . the case of lettuce is interesting because its cd content depends very strongly on the quantity in the soil [3] . the normal level of cd in lettuce grown in normal agricultural land ranges between 50 and 60 pg/kg (fresh wt.). hence, lettuces cultivated on pure compost (a very unfavorable situation and very unlikely, except for experiments) may contain only 68 pg/kg (fresh wt.) [135] , which is very close to the normal value. risks associated with food also depend on the frequency at which that food is consumed. a low contamination of a food item that is consumed frequently may be more deleterious than high contamination of food that is rarely eaten. unfortunately, though there are data on the average food intakes and on the natural content of metals in food items [135] , data from cd contaminated zones are scarce [138] . lead. pb quantities in composts are apparently not high enough to represent a risk to animals through grazing. furthermore, the risk of contamination to man through the consumption of such animals is low, since, as in the case of cd, pb does not accumulate in meat but in offal 11371. pb is assimilated in small fractions by plants. its penetration in grapes is poor but higher in maize and wheat. the risk of contamination of products made from these crops is reduced by the biological barriers in plants which prevent the penetration of pb in the grains [98, 139] . nickel. ni is found mainly in green vegetable 11401. there are poor data on the transfer of ni to man through plants, and the existing data does not suggest any risk. some studies seem to indicate that at the levels recovered, ni may not pose any phytotoxicity problem [98] . however, this metal is toxic to crops before attaining the toxic dose for man [3] . chromium. data on the risk of cr via food is also scarce; 60% of cr in the food chain is found in plants and an increase in consumption might be dangerous [lo] . cr accumulates mostly in the roots of some vegetables 110,981. mercury. hg is only slightly assimilated from the soil by higher plants (mineral mercury even less than methylated mercury) [98, 141] ; on the other hand, mushrooms accumulate hg very easily [98, 142] . in france, the use of urban compost in mushroom farms has decreased from 60 to 10% in 5 years, and an afnor standard has targeted a reduction from 10 to 5% which will further reduce the risk associated with such practice [127]. it has not been proved if hg accumulates in animals fed on plants grown on compost amended soils [3] . selenium. fruits and vegetables contain on average 0.1-0.6 ppm se [143] . one study on the assimilation of se by plants cultivated on msw compost amended soil did not indicate an increase compared to the normal level 1931. paradoxically, a study on amendment of ss has shown in several species of fruits, vegetables and cereals, that the levels obtained are well below those measured in normal food (4.8-46 ppb) [141] . the maximum concentration observed in soil does not exceed the standard values for agricultural or residential areas (table 7 ) [144] . arsenic. there is only a limited amount of studies on the absorption of as by plants. however, available results suggest that assimilation takes place in the leaves and not through the roots [145] . as to the risk from arsenic, there is no adverse indication regarding the use of compost in agriculture. the potential risks associated with organic compounds have been assessed to a lesser degree. pah. the international reference values for total pahs range l-50 ppm for gardens or residential areas [144] . quantities found in compost may reach 200 ppm which, for a one-tenth dilution, give a non-negligible surplus; this increase is lower in the case of a one-hundredth dilution. these results are due to the high content of certain contaminants (phenanthrene, naphthalene, anthracene, pyrene, acenaphthalene and fluorene) but these compounds are not very toxic. out of the seven pahs that are well known carcinogens (table 5 ) none was found above the standard in the soil after compost was applied. agricultural use of ss (at levels comparable to those of composts) gives only low concentrations of pah in plants, even after a very long trial [104] . while pahs penetrate into plants, they concentrate mainly in the underground teguments and only very little in the aerial parts. peeling and washing before cooking helps to avoid contamination through the food chain [104] . however, the risks might increase during repeated applications. no accumulation of pahs in agricultural soil was noticed after treatment with msw composts for 3 years but the authors of the study admit the inadequacies of the data and the necessity to carry out experiments of longer duration [146] . as regards the risks associated with leachates of composts, 10% of pahs are free in ss (and many thus percolate) [147] . if this fraction holds true in compost and taking into account future dilution, the chances of contamination of water is minute [147] . pcdd / f. though who has recommended an adi of 10 pg/day/kg for 2,3,7,8 tcdd [148] , the ad1 for complex mixtures of compounds is not known. the us-epa has calculated an acceptable exposure dose to pcdd/f for a general population as 6 x 10d9 rig/kg/day [149] . this exposure should not provoke the occurrence of more than one cancer in a population of one million persons. if one considers the least contaminated compost (0.1 ppm) and depending on what the soil is used for, the daily absorbed doses by an adult, a normal child and a child with pica are 40-100000 times the recommended dose. however, this result should be considered with care because there are only a very small amount of measurements on dioxins and furans in composts and it is not possible to assess whether the samples were representative. these compounds are sparingly soluble in water and are strongly adsorbed onto dust and soils. therefore, they accumulate but have low availability 11041. yet, a literature review shows that several surveys reported leaf assimilation of pcdd/f by plants due to their dispersion in air [150] . the transfer of pcdd/f by animals has been reported when grazing animals ingest dispersed contaminated ss [150] . finally, pcdd/fs are not easily bioavailable and, therefore, are not likely to concentrate in leachates. pcb. the maximum quantities recommended in the soil range from 0.05 ppm to 0.5 ppm [144] . the concentrations observed in composts (0.0007-5 ppm), with a dilution of one-tenth, might lead to an increase of the amounts in the soil above standard values and represent a potential qk in the case of ingestion of soil, especially to chrldren. risks through crops are weaker. after dispersion of ss with a pcb level of 52 ppm in a trial including several crop species, it was recovered only from carrot [104] . on the other hand, fields amended with ss containing an average of 292 ppm pcb might represent a risk to farm animals by accumulation of the chemical [151] . it should be noted that pcbs are very persistent products and measures should be taken to control long-term uses. pesticides. the maximum acceptable quantities for pesticides such as aldrin, dieldrin or ddt for agriculture purposes without risk are 0.1 ppm for the first two and 0.75 ppm for ddt [104] . these values are higher than those found in composts. the contaminants often concentrate in the external teguments and peeling might reduce risk 11041. plants possess metabolic pathways which, over a certain length of time, eliminate pesticides from the tissues [104] . diazinon, isofenphos, chlopyrifos and pendimethalin (non organochlorinated) are less persistent and disappear during composting [64] . ch. the non-volatile ch accumulates only slightly in crops grown on compost amended soil, which eliminates the danger inherent in the consumption of these crops [152, 153] . by contrast, the volatile ones (trichloromethane, chloroethylene) may pose a risk since marked cl4 indicated a non-negligible foliar assimilation 11041. unfortunately, these works concern ss and there is no information on the volatilization of volatile organic compounds (voc) in msw compost during use [431. it should be lower than during the application of ss since there are many occasions for loss during the process of composting (heat, turning of the windrow, duration of cornposting). authors have shown that at the composting site, the highest levels of vocs are found near fresh wastes [43] . there are two routes of exposure for pathogens or toxins: ingestion of a mixture of soil/compost and inhalation of microorganisms dispersed in the air during manipulation of composts. microorganisms present in composts do not seem to compete with those in the soil. therefore, spreading of composts is apparently without biological risk to the environment [119]. x2.1. risks associated with ingestion of microoqanisms different authors and institutions have proposed standards for the microbial quality of composts using indicators of contamination as an index. this issue still provokes scientific controversy in terms of relevance [61, 111] . the following have been proposed as limiting values: 5 x lo3 faecal streptococci/g, 5 x 10' enterobacteria/g, absence of salmonella in 100 g, and absence of eggs of parasites [61] . salmonella strains are rarely present in msw compost but more often in compost of ss [125] while eggs of ascaris are absent. with regards to faecal streptococcus (table 6) , seven studies out of 16 which were screened in the literature showed higher concentrations than the recommended values. however, these results are inconsistent and these observations were made under different processes of composting. the slow methods of composting (such as turning of compost in windrow) are less efficient in sanitization of composts [61, 62] . during storage or after application of composts, pathogens may disappear more or less rapidly. survival of viruses depends on humidity, temperature and on the type of strain [122, 154] . they do not seem to concentrate in leachates [122] . some authors reported that it is possible for viruses to penetrate into the plant through the roots and to migrate into the stem [1221. the survival of enteric bacteria is also influenced by humidity and temperature. in the soil, they survive longer in the saturated zone. in an experiment, though no bacterial indicator was detected in the soil before amendment with ss, it took 7 months to eliminate the effect of 6 x lo8 strepto-coccus/g, 1.3 x lo8 total coliforms/g and 0.37 x 10' faecal coliforms/g [80, 122] . during this time span, the paradoxical phenomenon of recolonization of mixtures of soil and compost may take place especially after rain. hence, a compost with a normal rate of indicators may undergo a sudden increase in their concentration (and reach values above the proposed norms) following changes in environmental conditions [1551. the survival of parasites is the longest. eggs of ascaris may persist 3 years during storage of mud and up to 78-107 days in the soil [122, 59] . however, the us-epa has shown that after 5 years of soil amendment with ss that were contaminated by parasites, toxocaru were isolated in 13% of the samples but no ascaris was found [bo] . pathogens may be ingested by children through hand-mouth contact, which is an important route of exposure in cases of geophagy. the composts observed in this review did not contain adequate levels of salmonella as to represent a risk, and parasites were rarely found. the infective dose of e. coli is about lo6 [25] which should not be reached after ingesting a mixture of soil and compost. the infective dose of streptococcus (lo'), however, may be attained in case of pica. atlatoxin is produced mainly by aspergillus jravus and a. parasiticus. this carcinogenic toxin is hazardous when ingested [156, 157] . the impact of aflatoxin is difficult to evaluate because there is only qualitative information on its presence in composts. this route of contamination may be found during utilization of composts which cause air dispersal of microorganisms responsible of the process of cornposting. these are different from the faecal microorganisms which come from a contamination related to the nature of the composted material. apparently, respiratory infection caused by enteric pathogens during air dispersion of composts is negligible. studies on workers at sewage treatment plants (a highly exposed zone) have never shown evidence of disea.se due to faecal pathogens through the inhalation route [108, 158] . among the most frequently studied organisms, aspergillus fimigutus remains a controversial subject. the amounts measured in the air are often high but serological studies carried out on exposed workers did not indicate the presence of circulating antigens [156, 159] . the infective dose of this fungus has not been assessed but was shown to be hazardous only to susceptible persons who are hypersensitive or immunodepressed [57, 112, 113, 117, 157] . by contrast, evidence of higher risks has been shown after exposure to dust containing gram negative bacteria. epidemiological studies carried out among workers in a msw sorting factory, or in wastewater treatment plants, in farms, mushroom farms or in a cornposting plant have shown that symptoms of headache, diarrhea or eye problems are more frequent during massive exposure to factory dust [126,159-1611. gram negative bacteria are pathogenic because of the endotoxin they produce. the activity of the endotoxin does not depend on the integrity of the bacterial cell because it relates to the lipopolysaccharides present in their wall. a fragment of the wall is as dangerous as the whole bacterial cell [115, 162] . a security level of 1000/m3 has been proposed for gram negative bacteria [12] , though some authors claimed that this concentration could provoke an allergic reaction [118] . when endotoxins are measured, several air measurements around composts (lo-14 ng/m3) were comparable to the limit proposed by several authors as levels without effect [115, 162] . the risk associated with actinomycetes is well known to workers in mushroom farms and is referred to as 'mushroom farmers lung' [114, 159] . those germs also cause the 'farmers lung' disease [1631. a massive (108/m3) and sudden exposure to these bacteria during utilization of composts may initiate a sensitization and an allergic reaction [163, 118] with circulating antibodies being measurable 11591. it is therefore plausible that sensitized individuals develop allergic reactions to actinomycetes following exposure to mature compost. some atmospheric measurements during mature compost handling at composting plant gave results similar to those where allergic reactions were observed among exposed workers [126] . as an example, a 52-year-old urban planner was reported to have developed a pulmonary problem 12 h after he had manipulated farmyard waste composts. retrospective reconstitution of his exposure provided the following data in the air: 1.4 x 106-4.7 x 10' cfu/m3 of fungi, 6.3 x 105-7.7 x lo8 &t/m3 of bacteria (with gram negative bacteria in the majority) and 1.3 x lo*-3.7 x 10' spores/m3 [164] . no hazardous yeast strain was found in this review. one of the most studied yeast, cundiuh albicans, was never encountered. extrapolation of these results obtained in the context of professional exposure to the general population using compost should be done with caution. measurements taken at the composting sites are the only data available. hence, the concentrations of the organisms are not necessarily representative of those obtained in natural conditions of use. the amounts that are measured at the plant site represent a mixture of emanations from the different stages of composting. at the beginning of composting, one essentially observes bacterial populations [165] , which are subsequently replaced by fungal populations [53] . a study comparing just mature compost with composts at the salting point, has shown a big decline in gram negative bacteria between the two locations. by contrast, the populations of actinomycetes remained constant [12] . to our knowledge, air measurements during application of composts were not made. therefore, other studies should be made in order to assess this risk more precisely. the hazard associated with chemical contamination of the food chain during agricultural use of composts seems very low. however, application of compost by individuals or during the amendment of public fields (parks, playgrounds) might pose a risk to health and these applications are likely to develop in the future. the risks that were discussed in this review have been assessed using extreme concentrations of contaminants in composts -levels that were found in rare circumstances. the most prominent risks are associated with hand-mouth contact and ingestion by children. a child with geophagy might ingest, under such hypotheses, 730% of the total admissible daily intake (adi) of lead, 400% and 23% for chromium and cadmium, respectively. for a normal child, the intake of lead through ingestion of compost poses a risk for lead, and to a lesser extent, for chromium. the same route of exposure might incur a significant hazard with pcdd/f and pcb but the data are too scarce to make conclusions. repeated application of composts may cause accumulation of contaminants in the soil. this can be prevented by appropriate msw management policies and by the extension of selective collection of msw that should contribute to a reasonable reduction in the contamination of composts, hence reducing the risks. the microbiological hazard arising from fecal contamination is apparently modest, although direct intake of soil contaminated by faecal streptococcus present in the compost might represent a potential danger. exposure to organisms responsible for the composting are difficult to control. some of the fungi and bacteria are direct pathogens or can act through their toxins. the manipulation of composts triggers their aerial dispersion that can induce their inhalation, as shown among workers in composting plants or in mushrooms farms (fresh compost). it is presently difficult to extrapolate these results to populations that do not produce but use msw composts. future studies aimed at assessing the risk associated with inhalation of compost dust should also take into account the chemical hazard caused by molecules adsorbed on dusts. such hazard has never been described to date. the high dilution of composts and of their pollutants throughout the environment (water, air, soil) and the discontinuous exposure of the population create a low risk for use of msw composts by the public. the health risk associated with cornposting seems to be occupational. this work was supported by the ademe (agence de l'environnement et de la maitrise de l'energie), the french environment agency and has been developed by the gridec (groupe de recherche interdisciplinaire sur les d&hets, grenoble, france). eur 14254 en model for humus in soil and sediments chemical properties of soils amended with compost of urban waste physical and chemical properties of soil as affected by municipal solid waste compost application plant quality and soil residual fertility six 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the various composting processes criteria of quality of city refuse compost based on the stability of its organic fraction assuring compost quality: suggestions for facility managers, regulators and researchers some environmental problems connected with the use of town refuse compost sources and fates of lead and cadmium in municipal solid waste plastics from household waste as a source of heavy metal pollution. an inventory study using inaa as the analytical technique asbestos in yard or sludge composts from the same community as a function of time-of-waste-collection organic chemicals in compost: how revelant are they for the use of it? in composting and compost quality assurance criteria. commission of the european communities publisher, eur 14254 en fate of organic contaminants during sewage sludge composting clean compost production organische schandstoffe in siedlungsabfallen: herkunft, gehalt und umsetzung in bidden und pflanzen. toxic organic compounds in municipal waste material: origin, contents and turnover in soils and plants level and source of pcdds, pcdfs, cps, and cbzs in compost from a municipal yard waste composting facility potential emissions of synthetic vocs from msw composting recycling at msw composting parameters for sorting/composting of municipal solid wastes, in composting and compost quality assurance criteria. commission of the european communities publisher, eur 14254 en sorting/composting of domestic waste technical brochure on administration of water resources pollution and risk prevention separate collection of compostables diaper industry workshop identifies research needs to minimize environmental impacts the composting process: susceptible feedstock, temperature, microbiology, sanitisation and decomposing technological aspects of composting including modeling and microbiology composting process design criteria. part i: feed conditioning definition of compost-quality: a need of environmental protection compost processes in waste management, commission of the european communities publisher composting process design criteria kinetik der inaktivierung von salmonellen bei der thermischen desinfektion von fliissigmist survival of plant pathogens and weed seeds during anaerobic digestion principle of compostmg leading to maximization of decomposition rate, odor control, and cost effectiveness, in composting of agricultural and other wastes relationship amongst organic matter content heavy metal concentrations, earthworm activity, and soil microfabric on sewage sludge disposal site microbiological specification of disinfected compost comparative survival of pathogenic indicators in windrow and static pile phytotoxins during the stabilization of organic matter degradation of diazinon, chlorpyrifos, isofenphos and pendimethalin in grass and compost humidification index (hi) as an evaluation of the stabilization degree during cornposting organic fertilizer and humification in soil characterization of humified substances in organic fertilizers by means of analytical electrofocusing (ef): a first approach change in organic matter during stabilization of compost from municipal solid waste experimentation of three curing and maturing processes of fine urban fresh compost on open air areas. a study carried out and financed on the initiative of the county council of cotes du nord -france evaluating garbage compost. part ii chemical properties of municipal solid waste composts parasitological study of waste-water sludge compost stability phytotoxicity suppression in urban organic wastes evaluation of heavy metals during stabilization of organic matter in compost produced with municipal solid wastes the influence of composting and maturation processes on the heavy metal extractability from some organic wastes how composting affects heavy metal content hazards from pathogenic microorganisms in land-disposed sewage sludge a methodology for establishing phytotoxicity criteria for chromium, copper, nickel and zinc in agricultural land application for municipal sewage sludge how much soil do young children ingest: an epidemiologic study the development of assessment and remediation guidelines for contaminated soils, a review of the science factor affecting ammonia volatization from sewage sludge applied to soil in a laboratory study survey of toxicants and nutrients in composted waste materials environmental impact of yard waste compost mobility and extraction of heavy metals from sewage sludge effet de l'utilisation de boues urbaines en essai de longue duree: accumuiation des metaux par les v6getaux superieurs incidence de l'bpandage des boues urbaines sur l'apport de chrome alimentaire speciation of heavy metals in sewage sludge and sludge-amended soil chemical characteristics of leachate from refuse-sludge compost leaching of heavy metals from composted sewage sludge as a function of ph cadmium and selenium absorption by swiss chard grown in potted composted materials fate of trace metal in sewage sludge compost cd and zn phytoavailability of a field-stabilized sludgetreated soil study of the organic matter and leaching process from municipal treatment sludge compost: brown gold or toxic trouble? trace element in municipal solid waste composts: a review of potential detrimental effects on plants, soil biota and water quality chemical fractionation and plant uptake of heavy metals in soils amended with co-composted sewage sludge evaluation of heavy metals bioavailability in compost treated soils effect of using urban composts as manure on soil contents of some nutrients and heavy metals results of municipal waste compost research over more than fifty years at the institute for soil fertility at haren/groningen, the netherlands guide for identifying cleanup alternatives at hazardous waste sites and spills: biological treatment bioavailability to plants of sludge-borne toxic organics identification of free organic chemicals in composted municipal refuse leaching from land disposed compost municipal compost: 1. organic matter bacterial and fungal atmospheric contamination at refuse composting plants: a preliminary study health and safety aspects of compost preparation and use occurrence, growth and suppression of salmonellae in composted sewage sludge hygienic quality of sewage sludge compost survival of fecal indicator micro-organisms in refuse/sludge composting using the aerated static pile system the aspergillus fumigatw debate: potential human health concerns levels of aspergillusfumigatus in air and in compost at a sewage sludge composting site mushroom worker's lung: serologic reactions to thermophilic actinomycetes present in the air of compost tunnels airborne endotoxins: an association with occupational lung disease levels of gram-negative bacteria, aspergillus jkmigatus, dust and endotoxin at compost plants dispersal of aspergillusfimigats from sewage sludge compost piles subjected to mechanical agitation in open air airborne microorganisms associated with domestic waste composting microbiological characterization of four composted urban refuses yeast microflora evolution during anaerobic digestion and cornposting of urban waste quantitative assessment of factors affecting the recovery of indigenous and released thermophilic bacteria from compost survival of pathogenic micro-organism and parasites in excreta, manure and sewage sludge identification of thermophilic bacteria in solid-waste composting umweltrevelante schastoffe in miillkomposten determination of pathogen levels in sludge products clinical and immunological findings in workers exposed to sewage dust gestion de la matiere organique, f. dubosc cadmium: a complex environmental problem. part ii: cadmium in sludge used as fertilizer effect of cadmium on the biota: influence of environmental factor long-term effects of quality-compost treatment on soil controlling cadmium in the human food chain: a review and rationale based on health effects toxicologic et s&mite des al.iments. technique et documentation occupational and community exposure to toxic metals: lead, cadmium, mercury and arsenic cadmium in the environment and human health: an overview plomb cadmium et mercure. rapport du conseil superieur d'hygi8ne publique de france, section alimentation cadmium uptake and distribution in three cultivars of lactuca sp translocation of lead and cadmium from feed to edible tissues of swine table de compositions des aliments biochemistry and measurement of environmental lead intoxication toxicologic et hygiene industrielles, ii: les derives mincraux. techniques et documentation mercury and selenium content and chemical form in vegetable crops grown on sludgeamended soil bioaccumulation of hg in the mushroom pleutorus ostreatus selenium in the environment premiere approche pour l'kaluation de la pollution dun site d'ancienne usine b gaz: utilisation de valeurs guides de differents pays atmospheric deposition of trace elements around point sources and human health risk assessment ii: uptake of arsenic and chromium by vegetables grown near a wood preservation factory determination of polynuclear aromatic compounds in composted municipal refuse and compost-amended soils by simple clean-up procedure estimation of the environmental hazard of organochlorines in pulp mill biosludge used as soil fertilizer assessment of health hazards associated with exposure to dioxins. chemosphere environmental toxicology of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans the influence of sewage sludge applications to agricultural land on human exposure to polychrorinated dibenzo-p-dioxins (pcdds) and -furans (pcdfs) polychlorinated biphenyls in digested uk sewage sludge sorption and degradation of pentachlorophenol in sludge amended soils plant uptake of pentachlorophenol from sludge-amended soils f-specific coliphages in disposables diapers and landfill leachates survival of indicator organisms in sonoran desert soil amended with sewage sludge biological health risks associated with the cornposting of wastewater treatment plant sludge health risks of cornposting: a critique of the article 'biological health risks associated with the cornposting of wastewater treatment plant sludge coliforms in aerosols generated by a municipal solid waste recovery system circulating antibodies against thermophilic actinomycetes in farmers and mushroom workers occupational symptoms among compost workers respiratory impairment among workers in garbage-handling plant biological health risk associated with resource recovery, sorting of recycle waste and composting un risque respiratoire nouveau: les stations d'bpuration et les installations de compostage organic dust exposures from compost handling: case presentation and respiratory exposure assessment actinomycetes as agents of biodegradation in the environment -a review produ$o de fertilizante organic0 por compostagem do lodo gerado por estacoes de tratamento de esgotos chemical toxicity of metals and metalloids composition of toxicants and other constituents in yard or sludge composts from the same community as a function of time of waste collection leaching from land disposed compost municipal compost: 3 inorganic ions fertilizing value and heavy metal load of some composts from urban refuse heavy metal levels and their toxicity in composts from athens household refuse chemical and physico-chemical characterization of vermicomposts and their humic acid fractions effect of the application of municipal refuse compost on the physical and chemical properties of a soil the llip side of compost: what's in it, where to use it and why changes in atp content, enzyme activity and inorganic nitrogen species during cornposting of organic wastes hygienische untersuchungen an einzelbetriebmlichen anlangen sowie einer grobtechnischen anlagen zur entseuchung von flissigmist durch aerob-thermophile behandlung. forum stldte-hygiene anaerobic cornposting saves waste from landtill sludge cornposting maintains growth comment on: 'acid digestion for sediments, sludge, soils and solid wastes. a proposed alternative to epa sw 846 method 3050 when is compost 'safe evaluation de certains additifs ahmentaires et contaminants, 41""' rapport du comite mixte fao/oms d'experts des additifs aliientaires copper and zinc concentrations in edible vegetables grown in tarragona province key: cord-009417-458rrhcm authors: luce, judith a. title: use of blood components in the intensive care unit date: 2009-05-15 journal: critical care medicine doi: 10.1016/b978-032304841-5.50082-0 sha: doc_id: 9417 cord_uid: 458rrhcm nan most patients admitted to an intensive care unit (icu) require the administration of one or more blood components during their stay. such patients exhibit great diversity in conditions necessitating care in the icu, age, underlying medical problems, and integrity of physiologic compensatory mechanisms. all these patients, however, share the need for optimized oxygen-carrying capacity and tissue perfusion. ongoing blood loss resulting from injuries, surgical wounds, invasive monitoring equipment, and blood sampling requirements, coupled with inadequate marrow function and, in some, red cell destruction, makes red cell transfusion a necessity for many icu patients. additionally, many patients are susceptible to the development of hemostatic disorders requiring the administration of such blood components as plasma, cryoprecipitate, or platelet concentrates. blood components should be considered drugs because they exert potent therapeutic responses yet are also capable of causing signifi cant adverse effects. the food and drug administration (fda) regulates blood component preparation, testing, and administration. 1 unlike pharmaceutical agents, however, blood components have fewer objective indications for use and no therapeutic index relating dose to safety. it is not as simple to monitor the effi cacy and continuing need for a blood component as it is to determine the blood level of a drug. in addition, the risks associated with transfusion cannot be known in advance and may be lethal; such risks include medical errors, as well as infectious and immunologic hazards. unlike pharmaceutical agents, these prescribed products require documentation of patient consent and indication for use. although the american blood supply is now safer than ever before, zero-risk transfusion is not achievable, even if blood components could be sterilized. the process of donor selection and screening has become increasingly stringent, an evolution that began in response to the welldefi ned risks of transfusion-transmitted hepatitis and human immunodefi ciency virus (hiv) infection. although the value of maximizing recipient safety is unarguable, increasing donor selectivity has its price. as more tests are added and more conditions placed on the donor, the number of usable donations has declined. this trend has led to occasional regional and seasonal blood shortages and, rarely, outright inability to provide certain blood components. clinicians who prescribe blood components must be aware of these uncertainties in availability and contribute by using blood products appropriately while the national blood banking system seeks strategies to ensure an adequate, safe blood supply. donor screening strategies to ensure recipient safety take several forms. 1, 2 american blood donors are voluntary donors; cash payment was eliminated in the 1970s after studies linked professional donors with transmission of hepatitis. confi dential questionnaires were initiated to limit transmission of hiv and hepatitis and to allow voluntary self-exclusion and involuntary exclusion of donors who pose an increased risk of transmitting infectious agents. multiple specifi c serologic and biochemical tests are performed to detect the potential for transmission of hiv and other retroviruses, hepatitis, and syphilis. any donor who indicates high-risk behavior or who tests repeatedly positive is placed on a permanent deferral list. some patients may insist on blood obtained from relatives or friends. this practice is termed directed or designated donation. these selected donors must undergo the same rigorous questioning and testing as volunteer donors. some studies have found an increased frequency of hepatitis markers in the blood of directed donors when compared with blood drawn from unselected volunteers, but others suggest that designated donors may be no different from new volunteers. 3, 4 there continues to be no consensus about whether directed donors are, as a group, as safe as volunteer donors. 5, 6 institutional policies about the acceptability and processing of directed donations vary widely. in any case, supporting icu patients who require large-volume transfusion with directed donations is unlikely to be advantageous or practical. the basic principle of blood component therapy is prescription of the specifi c blood product needed to meet the patient's requirement. a single whole blood (wb) donation can be separated into its composite parts, or components, which can be distributed to several recipients with differing physiologic needs. component therapy thus meets the clinical requirements of increased safety, efficacy, and conservation of limited resources. as the variety of blood product components increases, however, the complexity of transfusion medicine also increases. a wb donation is typically separated into red blood cells (rbcs), a platelet concentrate, and fresh frozen plasma (ffp) within hours of its collection. the plasma may be further processed into cryoprecipitate and supernatant (cryopoor) plasma. one unit of wb measures approximately 500 ml, including 63 ml of citrate anticoagulant/preservative solution. each unit of wb supplies about 200 ml of rbcs and 300 ml of plasma for volume replacement. wb is refrigerated for 21 to 35 days, depending on the preservative used. after less than 24 hours of refrigerated storage in this preservative and bag system, platelet and granulocyte function is lost. with further storage, levels of the "labile" coagulation factors v and viii decrease. 7 some blood centers offer modifi ed wb, which is produced by removal of the platelet or cryoprecipitate fraction and return of the supernatant plasma to the red cells. this permits provision of the more labile components to patients with specifi c needs, with the remainder forming a product having a composition essentially the same as cold-stored wb. however, the growing need for specialized blood components has resulted in processing the majority of blood donations into components, thus limiting the availability of wb and modifi ed wb. rbcs, or in common usage, "packed" red cells (prbcs), are the blood component most commonly transfused to increase red cell mass. prbcs are derived from the centrifugation or sedimentation of wb and removal of most of the plasma/anticoagulant solution. if collected into citrate-phosphate-dextrose-adenine solution, the volume is approximately 250 ml, the hematocrit (hct) is 70% to 80%, and the storage life is 35 days. extended additive solutions permit storage up to 42 days but increase the volume to 300 ml and decrease the hct to 60%. these extended storage units are commonly used and easier to transfuse because of lower viscosity, but they may pose a problem because of their larger volume. the transfusion of leukocyte-reduced rbcs may benefi t certain patients. transfusion of blood components containing leukocytes may lead to febrile reactions, a greater propensity for alloimmunization, platelet alloimmunization, and transmission of pathogens carried by leukocytes, such as cytomegalovirus (cmv). leukocyte reduction, as defi ned by the fda, requires fi ltration of the blood component by a special fi lter. 1 filtration may be performed either at the time of blood donation and processing or later at the time of transfusion ("bedside fi ltration"). filtration before storage conveys the benefi t of removing white blood cells (wbcs) before they can deteriorate and elaborate cytokines and other unwanted substances during storage. 8 because of proven and theoretical benefi ts of leukocyte reduction of blood components (discussed later in the section covering the adverse effects of transfusion), many european countries and canada require that all transfusions be leukocyte reduced, a process called universal leukoreduction (ulr). some institutions in the united states have also made that decision, but either method of leukocyte reduction adds signifi cantly to the cost of each transfusion ($25 to $30), and the benefi ts of this measure when applied globally have yet to be quantifi ed. 9 washing prbcs involves recentrifuging to remove the plasma/preservative solution from the unit. however, washing may take an hour or more, limits subsequent storage time, and causes some loss of rbcs. washing is also not an effective method of leukoreduction. there are very few indications for the use of washed rbcs, although some recipients with plasma reactions may benefi t. prbcs can be frozen in cryoprotective solution and stored for extended periods. frozen rbcs are generally limited to units of special value, such as those with a rare rbc antigen profi le or autologous blood donations that need to be stored for future use. a rare-donor registry of frozen prbcs exists to assist in providing blood to patients with complex or multiple alloantibodies to red cell antigens. signifi cant advanced planning is necessary to acquire and thaw frozen prbcs for transfusion, thus limiting their use in acute situations. wb and prbcs suffer some cell loss during storage. the current technology of bag and preservative solutions attempts to optimize cell quality and quantity by using strict criteria to determine the length of allowable storage time. nonetheless, as red cell metabolism decreases progressively, a "storage lesion" results, 10 with accumulation of a variety of undesirable substances and loss of cellular function. over time in storage, a slow rise in the concentration of potassium, lactate, aspartate aminotransferase, lactate dehydrogenase, ammonia, phosphate, and free hemoglobin and a slow decrease in ph and bicarbonate concentration occur. cytokines and infl ammatory mediators such as interleukin-1, interleukin-6 and tumor necrosis factor also accumulate. the ph of freshly stored blood in citrate solution is 7.16, which declines to approximately 6.73 at the end of the unit's shelf life. as potassium leaks from red cells during storage, levels as high as 25 meq/l may result. however, each unit transfused supplies at most 7 meq of potassium, which is well tolerated under most circumstances. during the storage period there is also a progressive decrease in rbc-associated 2,3-diphosphoglycerate (2,3-dpg) and adenosine triphosphate (atp). 10 a decrease in 2,3-dpg increases the affi nity of hemoglobin for oxygen, which shifts the oxygen dissociation curve to the left and decreases oxygen delivery to tissues. there is little evidence, however, that this transient increase in oxygen affi nity has clinical importance. after infusion, 2,3-dpg gradually increases as the transfused red cells circulate, with 25% recovery in 8 hours and full replacement by 24 hours. 11 decreased atp during storage diminishes the viability of red cells after transfusion and is one of the chief factors limiting storage time. there is no currently available storage or rejuvenation solution that optimizes these cellular constituents. the majority of blood transfusions are in the form of prbcs, the component indicated for normovolemic patients or those for whom intravascular volume constraints are necessary. the use of wb may be desirable for patients who require both increased oxygen-carrying capacity and volume resuscitation because of a large and ongoing hemorrhage; however, the availability of wb is generally limited. resuscitation is effectively achieved with the use of prbcs and crystalloid solutions. each unit of prbcs or wb is expected to raise the hemoglobin level by 1 g/dl and the hct by 3% in stable, nonbleeding, average-sized adults. although some studies have demonstrated a slight superiority of fresh wb over components when used during cardiac surgery in selected patients, 12 the benefi ts of fresh blood remain controversial, and current testing and processing requirements limit general availability. despite a long tradition of transfusion of rbcs in critically ill patients, the precise indications for transfusion remain a source of controversy, and specifi c transfusion practices may vary widely among clinicians. before the major randomized studies of rbc transfusion policies, a survey of transfusion practice showed that about half of icu patients were receiving red cell transfusions, 13 and another showed that if the icu stay was longer than a week, the rate of transfusion was 85%. 14 the total number of transfusions was high, and icu practice was characterized by high rates of transfusion. 15 the reasons for the controversies are clear: rbcs should be transfused only to enhance tissue oxygen delivery, but the underlying physiology of anemia, the complex adaptations to anemia, and the potential advantages and disadvantages to particular groups of patients are not as well understood. compensatory mechanisms for acute and chronic anemia are diverse and complex. 16, 17 all work in concert to maintain oxygenation within the microcirculation. cardiovascular adjustments leading to increased cardiac output include decreased afterload and increased preload resulting from changes in vascular tone, increased myocardial contractility, and elevated heart rate. lowered blood viscosity permits improved fl ow of erythrocytes within capillaries. blood fl ow is redistributed to favor critical organs with higher oxygen extraction. pulmonary mechanisms, though contributing relatively little to shortterm oxygenation demands, exert potent effects on related metabolic variables. finally, the hemoglobin molecule can undergo biochemical and conformational changes to enhance unloading of oxygen at the capillary level. all these mechanisms contribute to an "oxygen reserve" capacity that exceeds baseline requirements by approximately fourfold. 16 no experimental model exists that encompasses the diversity of physiologic compensations for hypoxia. experiments carried out in animals and case reports in patients refusing transfusion indicate that an extremely low hct is tolerated if tissue perfusion is adequate. [18] [19] [20] certain objective, though indirect, measurements of tissue oxygenation exist and are available to clinicians caring for patients monitored invasively in the icu. mixed venous oxygen content (pv o 2 ) and cardiac output can be measured in patients undergoing pulmonary artery catheterization; arterial oxygen content can also be measured directly. the oxygen extraction ratio (er) can be calculated directly, and in the presence of normal or high cardiac output it is a measure of tissue oxygen extraction and, indirectly, the adequacy of tissue oxygen delivery. the total body er at baseline is about 25%. a falling pv o 2 and an er increasing to greater than 50% have been proposed as indicators of the need for red cell transfusion. 21 there have been only 10 randomized trials of transfusion policy in the icu, and only 1 of them was large enough to draw specifi c, statistically signifi cant conclusions. 22 the canadian critical care trials group compared a liberal (target hemoglobin, 10 to 12 g/dl) with a restrictive (target hemoglobin, 7 to 9 g/dl) red cell transfusion policy in patients stratifi ed for disease severity. at 30 days from randomization, the restrictive strategy was at least as good as, if not better than (p = .11) the liberal strategy, and overall hospital mortality was signifi cantly lower in the restrictive strategy group (p = .05). for patients younger than 55 years and for patients with lower (<20) apache (acute physiology, age, and chronic health evaluation) ii scores, the restrictive strategy was clearly superior. in addition, liberal transfusion was not associated with shorter icu stays, less organ failure, or shorter hospital stays; longer mechanical ventilation times and cardiac events were more frequent in the liberal strategy group. a later subgroup analysis of patients with cardiovascular disease, though small enough to have statistical doubt, suggested that a more liberal transfusion strategy was probably appropriate for patients with severe ischemic coronary disease. 23 this observation has some support in experimental studies of the effects of anemia in laboratory animals with coronary occlusion. 24 the canadian study has highlighted the many and complex issues involved in transfusion decision making in the icu. since publication of the canadian study, several large reports have examined the use of red cell transfusions in critical care units. vincent and colleagues 25 surveyed european icus and found that the transfusion rate in 3534 patients was 37% during the icu stay and 12.7% after the stay. the mean pretransfusion hemoglobin level was 8.4 g/ dl. corwin and colleagues 26 studied 284 icus in the united states a year later and found great similarity: nearly 50% of patients received transfusions, and the mean threshold hemoglobin level was 8.6 g/dl. a single large scottish teaching hospital reported a more parsimonious practice: the rate of transfusion was still 52% in its icu patients, but the total volume of blood used was slightly smaller and the mean pretransfusion hemoglobin level was only 7.8 g/dl. 27 all these authors have concluded that icu practice has not fully embraced the guidelines of the canadian clinical trial. in contrast, 18 hospitals in australia and new zealand have reported on transfusion in 1808 consecutive icu admissions, and although the authors found a median pretransfusion hemoglobin concentration of 8.2 g/dl, the rate of transfusion was lower, at only 19.7% of patients, 60% of whom were bleeding. 28 the "inappropriate" transfusion rate was 3%. the authors speculate that the practitioners may have been infl uenced by publication of the canadian study and their own regional survey of transfusion practices. nonetheless, they agree that full implementation of the canadian guidelines in their clinical setting might be controversial. the literature on rbc transfusion in the setting of surgery, particularly surgery with the use of blood products, is growing. a mounting body of data illustrate the human tolerance of a low hct during and after surgery. a recent randomized trial of rbc transfusion strategy in orthopedic surgery demonstrated no signifi cant differences in outcome between a restrictive (8 g/dl) and a liberal (10 g/dl) transfusion threshold and included monitoring for silent myocardial ischemia preoperatively and postoperatively. 29 provided that adequate perfusion of the microcirculation is maintained, purposeful maintenance of a low hct during surgery, a technique called normovolemic hemodilution, 30 can be a powerful tool in minimizing blood loss and the attendant need for red cell transfusion. table 80 -1 summarizes guidelines proposed by the national institutes of health, 31 the american society of anesthesiologists, 32 and the american college of physicians 33 relative to the transfusion of rbcs. these guidelines have been provided with the intent of establishing parameters, not with the intent of substituting for the individual clinician's judgment. the art of medical decision making in transfusion, as in other areas of medicine, lies in determination of the appropriate treatment for the individual patient. a platelet concentrate (random-donor platelets) is obtained by centrifugation from a unit of donated wb. each unit contains a minimum of 55 ã� 10 10 platelets suspended in about 50 ml of plasma. platelets are stored at room temperature to avoid loss of function from refrigeration and are constantly agitated to maximize gas exchange. the length of storage varies with the container used, but most systems permit 5-day storage. because of this limited storage time and the increasing demand for this component, platelets are often subject to supply shortages. some loss of viability and platelet numbers occurs during storage, but 5-day-old platelets still effect hemostasis. once the bags are entered for pooling before transfusion, the platelets must be administered within 4 hours. each unit of platelets is expected to increase the platelet count by 10 ã� 10 9 /l in a typical 70-kg adult. the usual dose is 6 units, or 1 u/10 kg of body weight. a 1-hour post-transfusion platelet count should be obtained to determine the adequacy of response. the following equation, which relates platelet number and body size to the post-transfusion increment, can be used to assess the effectiveness of the transfusion: abo-compatible platelets are desirable but not essential. when abo-mismatched platelets are given, removal of some of the incompatible plasma can be carried out at the time of pooling for transfusion. likewise, volume reduction may be necessary for patients at risk for fl uid overload from the 300 to 500 ml of plasma present in 6 to 10 units of platelets. nonetheless, the remaining plasma is a good source of stable coagulation factors and contains diminished but still potentially benefi cial amounts of factors v and viii. there is no contraindication to the use of rh-positive platelets in rh-negative patients; if given to women with future childbearing potential, rh immune globulin (rhig) may be used prophylactically against the small risk of rh alloimmunization from red cells that may be contained in the platelet concentrate. plateletpheresis (common terms: single-donor platelets, apheresis platelets) involves separating and removing platelets from one donor by cytapheresis during a 1 1 / 2 -to 2-hour procedure on an automated device and then retransfusing the remainder of the blood back into the donor. each collection contains an equivalent of 6 to 10 units of platelet concentrates. single-donor platelets are suspended in about 300 ml of plasma, so the same abo and volume considerations discussed earlier pertain. single-donor platelets offer the clear benefi t of reducing the risk of multiple-donor exposure to the recipient. single-donor platelets may also be the only available alternative for recipients who have been alloimmunized by previous platelet transfusions because they may be human leukocyte antigen (hla) or platelet antigen matched to the recipient. the use of apheresis platelets now exceeds the use of pooled random-donor platelets; however, use of this product in emergency situations is limited by the availability of volunteer donors. 35 platelet transfusions are indicated for patients bleeding because of thrombocytopenia or functional platelet defects. 36 guidelines for transfusion continue to evolve, and the current guidelines merely provide a desirable range for platelet counts, assuming normal platelet func-tion (table 80 -2). there is ample evidence that bleeding medical or surgical patients with platelet counts of 50 ã� 10 9 /l or above will not benefi t from transfusion if thrombocytopenia is the only abnormality. for critical invasive procedures in which even a small amount of bleeding could lead to loss of vital organ function or death, maintaining the platelet count at 50 ã� 10 9 /l or greater is typically preferred. the presence of other factors that diminish platelet function, such as certain drugs, foreign intravascular devices (e.g., intra-aortic balloon pump or membrane oxygenator), infection, or uremia, may alter this requirement upward. patients at risk for small but strategically important hemorrhage, such as neurosurgical patients, may need to be maintained at counts of 80 to 100 ã� 10 9 /l. patients without hemorrhage who have platelet counts of 5 ã� 10 9 /l or lower appear to be at increased risk for signifi cant hemorrhage. indications for transfusion to patients with counts above 10 ã� 10 9 /l are less well established; thus, the majority of guidelines propose prophylactic platelet transfusion to prevent hemorrhage at a threshold of 10 ã� 10 9 /l. the bleeding time is not a useful procedure in this situation because it is usually prolonged at counts below 80 ã� 10 9 /l, may be insuffi ciently reproducible, and correlates poorly with the risk for bleeding. 37 patients undergoing cardiac bypass surgery experience a drop in platelet count and often acquire a transient platelet functional defect from damage associated with the bypass apparatus. 38 most patients do not experience platelet-associated bleeding, however, so prophylactic transfusion in the absence of bleeding is not warranted. in a patient who continues to bleed postoperatively, more likely causes are a localized, surgically correctable lesion or failure to reverse heparinization. if these conditions are excluded, empiric transfusion of platelets may be justifi ed. patients thrombocytopenic by virtue of immunologic destructive processes such as idiopathic thrombocytopenic purpura (itp) receive little benefi t from platelet transfusions because the transfused platelets are rapidly removed from the circulation. in the event of life-threatening hemorrhage or an extensive surgical procedure, transfusion may prove benefi cial for its short-term effect. transfusion may be accomplished effectively by pretreatment with high-dose immunoglobulin or high-dose anti-d antiserum (rhig). 39, 40 platelet transfusion has been reported to be deleterious in thrombotic thrombocytopenic purpura (ttp), 41 in the related hemolytic-uremic syndrome, and in heparin-induced thrombocytopenia. cautious administration, in cases of life-threatening thrombocytopenic bleeding only, is prudent. prophylactic platelet transfusion for thrombocytopenia secondary to underproduction remains controversial. the common practice of transfusion to maintain the platelet count above 20 ã� 10 9 /l derives from data published in 1962, which demonstrated an increase in spontaneous bleeding in leukemic patients at that level. 42 however, critical evaluation of the data reveals that serious hemorrhage was not greatly increased until counts fell to 5 ã� 10 9 /l or lower and that these patients received aspirin for fever, which might have compromised platelet function and enhanced the bleeding. a somewhat more recent study quantitating stool blood loss in aplastic anemia patients defi ned a bleeding threshold at platelet counts of 5 to 10 ã� 10 9 /l. 43 a prospective study of a more conservative transfusion protocol found that major bleeding episodes occurred on 1.9% of days with counts of less than 10 ã� 10 9 /l and on only 0.07% of days with counts of 10 to 20 ã� 10 9 /l. 44 the trigger for prophylactic platelet transfusion in the 5 to 10 ã� 10 9 /l range, however, applies primarily to stable thrombocytopenic patients. factors such as fever, use of anticoagulant or antiplatelet drugs, and invasive procedures must be considered when generating a treatment plan for individual patients. patients experiencing rapid drops in platelet count may be at greater risk than those at steady state and thus may benefi t from transfusion at higher counts. benefi ts to the patient with more judicious use of platelet transfusion include decreased donor exposure, which lessens the risk of transfusion-transmitted disease; fewer febrile and allergic reactions that may complicate the hospital course; and the potential delay or prevention of alloimmunization to hla and platelet antigens. 45 the development of refractoriness to platelet transfusions is a serious event heralded by a falling cci. poor response to platelet transfusions can be seen in patients with other reasons for platelet consumption, including splenomegaly, fever, trauma and crush injury, burns, disseminated intravascular coagulation (dic), concomitant drugs, or transfusion of platelets of substandard quality. 46 these factors should be sought and corrected if possible. alloimmunization is characterized by the development of anti-hla or platelet-specifi c antibodies, with resultant immune platelet destruction. as many as 70% of patients receiving multiple red cell or platelet transfusions become immunized. 45 leukocyte depletion of transfused components can prevent or delay this phenomenon, but it is important to use leukoreduced components early in the course of transfusion therapy. 45, 47 when patients fail to achieve expected increments after platelet transfusion, provision of abo-specifi c platelet concentrates that are less than 48 hours old may improve the response. if no improvement is seen and the aforementioned medical conditions are excluded, the patient should be screened for hla antibodies or be hla typed and provided with hla-compatible single-donor platelets. alternatively, platelet crossmatching with the patient's serum can be carried out. there is no advantage to unmatched singledonor platelets in this situation. standard ffp is prepared by centrifugation of wb and is frozen within 8 hours of blood donation. 1,2 ffp may be stored frozen for 1 year. the usual volume is about 250 ml, depending on the donor's hct. the most common method of thawing before transfusion is soaking in a 37â° c water bath, which requires about 30 to 45 minutes. once thawed, ffp can be stored refrigerated for a maximum of 24 hours. when prepared and stored in this manner, ffp supplies all the constituents in the amounts normally present in circulating plasma, including stable and labile coagulation factors, complement, albumin, and globulins. by convention, the coagulation factors are present in concentrations of 1 u/ml. crossmatching to the recipient is not performed, but ffp must be abo compatible. standard ffp is as likely to transmit hepatitis, hiv, and most other transfusion-related infections as cellular components are. new ffp products have recently been introduced in response to concern about the transmission of infectious diseases. one such product is solventdetergent-treated ffp. 48 solvent-detergent treatment is a means of viral inactivation that removes the infectivity of lipid-enveloped viruses, such as hepatitis b and c and hiv. because the product is derived from pooled plasma, with as many as 2500 donors in each lot, it has the potential to actually increase recipient exposure to pathogens not inactivated by the solvent-detergent method, such as hepatitis a and parvovirus b19, and be more vulnerable to any newly emerging non-lipid-enveloped agent. a variety of other techniques for reducing pathogen exposure in ffp have been developed, including exposure to low ph or vapor heating and treatment with ultraviolet irradiation, gamma irradiation, or psoralens and light to inactivate pathogens by inducing dna damage. 49 because none of the ffp products is entirely free from the risk of disease transmission or other adverse effects and because infection-reducing modifi cations add significantly to the cost of the components, ffp should be used judiciously. 50 it should be administered only to provide coagulation factors or plasma proteins that cannot be obtained from safer sources. ffp is commonly used to treat bleeding patients with acquired defi ciency of multiple coagulation factors, as in liver disease, dic, or dilutional coagulopathy, or to treat patients with congenital defi ciency of a coagulation factor or other protein for which concentrates or safer sources do not exist. ffp may be indicated for emergency reversal of the coagulopathy induced by warfarin anticoagulants when more concentrated products are not available or for the provision of protein c or s in patients who are defi cient and suffering acute thrombosis. ffp should be administered as boluses as rapidly as feasible so that the resulting factor levels allow hemostasis. the use of ffp infusions without adequate bolus administration is not helpful. ffp should not be used for volume expansion or wound healing or as a nutritional source of protein. ffp does not reverse anticoagulation induced by heparin and in theory might exacerbate bleeding by supplying more antithrombin, heparin's cofactor. prophylactic administration of ffp does not improve patient outcome in the setting of massive transfusion or cardiac surgery unless there is bleeding with an associated documented coagulation abnormality. 51, 52 patients do not usually bleed as a result of coagulation factor insuffi ciency when the international normalized ratio (inr) is less than about 2.0, and even then the results are not always predictable. 53 the partial thromboplastin time (ptt) is not useful in predicting procedural bleeding risk. 54 ffp is often requested prophylactically before an invasive procedure when the patient exhibits mild prolongation in coagulation studies. most of these procedures may be carried out safely without transfusing ffp. 53, 55 ffp is probably the most misused blood component, as illustrated by retrospective surveys. 56 coagulation factors are normally present in the blood far in excess of the minimum levels required for hemostasis. as little as 10% of the normal plasma concentration of several factors will effect hemostasis. conversely, ffp treatment of acquired multiple defi ciencies, as in hepatic failure, is often ineffective because many patients cannot tolerate the infusion volumes required to achieve hemostatic levels of coagulation factors, even transiently. 57 the plasma half-life of transfused factor vii is only 2 to 6 hours. it may be impossible to administer suffi cient ffp every few hours without encountering intravascular volume overload. finally, in some instances, transfusion of seemingly adequate volumes may still fail to correct the coagulopathy. 58 careful documentation of both the need for ffp and the adequacy and outcomes of therapy is essential. 59 cryoprecipitate is manufactured by thawing and centrifuging ffp below 6⺠c and resuspending the precipitated proteins in about 15 ml of supernatant plasma. 1,2 each bag is a concentrated source of factor viii (80 to 120 units), von willebrand factor (vwf) (50% of original plasma content), fi brinogen (250 mg), factor xiii (30% of original plasma content), and fi bronectin. cryoprecipitate offers the advantage of transfusing more specifi c protein and less total volume than the equivalent dose of ffp does. it has been used to treat patients with inherited coagulopathies, such as hemophilia a, von willebrand disease, or factor xiii defi ciency. in the critical care setting, it is more commonly used to replenish fi brinogen, especially in bleeding patients with hypofi brinogenemia caused by dilutional or consumptive coagulopathy. cryoprecipitate also reportedly improves hemostasis in uremic patients, presumably by reversing the functional platelet defect, 60 but desmopressin acetate (ddavp) 61 or conjugated estrogens exert similar effects and should be used preferentially to avoid potential transfusion-transmitted disease. the usual dose of cryoprecipitate to treat hypofi brinogenemia is 10 bags/units to start, then 6 to 10 bags/units every 8 hours or as necessary to keep the fi brinogen level above 100 mg/dl. each bag/unit of cryoprecipitate carries a risk of disease transmission equivalent to that of 1 unit of blood. for this reason, commercial factor viii concentrates, recombinant or treated to inactivate viruses, are preferred over cryoprecipitate for treating hemophilia a patients. immune serum globulin (ig), rhig, and hyperimmune globulins for diseases such as hepatitis b and varicella zoster are obtained by fractionation of pooled plasma, followed by chromatography, delipidation, and other steps to remove aggregates and infectious agents. intravenous ig (ivig) is available in solution or lyophilized form, with protein content varying by mode of preparation. the available products vary slightly in the amounts of iga and igm contained in them, which are mostly present in only trace quantities. ig preparations can be used to provide passive antibody prophylaxis or to supply ig in certain immunodeficiency states. hyperimmune globulins may be used to treat active infections in immunosuppressed hosts. recent applications have exploited ig's immunomodulatory effects in treating a wide variety of disorders with an immune basis. the specifi c mechanism of action of ivig in such conditions has not yet been identifi ed, but possibilities include interference with macrophage fc receptor function, neutralization of anti-idiotypic antibodies, and interference with the incorporation of activated complement fragments into immune complexes. a recent review more completely discusses the effects of ivig on the immune system and its potential uses. 62 rhig is prepared from pools of plasma obtained from donors sensitized to the red cell antigen d from the rh group. the standard-dose vial contains primarily igg anti-d, with a protein content of 300 âµg in 1 ml. this dose will protect against 15 ml of d + red cells or 30 ml of wb. 63 rhig carries no risk of virus transmission. although rhig is used primarily in obstetrics, it may also be indicated to prevent alloimmunization in rh-negative patients receiving small amounts of rh-positive red cells, as in platelet concentrates. routine prophylaxis against large numbers of red cells, as in a unit of rh-positive wb or prbcs given by accident to an rh-negative recipient, is not reliable and usually involves the administration of large amounts, but instances of its effective use in these circumstances have been reported. higher doses of intravenous rhig have been used in the treatment of itp. plasma-derived colloids include human serum albumin (hsa), available in 5% and 25% solutions, and plasma protein fraction (ppf), available in a 5% solution. both are derived from pooled donor plasma but are essentially pathogen-free. hsa is composed of at least 96% albumin, whereas ppf is subjected to fewer purifi cation steps and contains at least 83% albumin, with correspondingly more globulins. the 5% solutions are iso-oncotic, whereas the 25% solution of hsa is hyperoncotic and requires infusion with crystalloid solutions. potential clinical indications for colloid solutions include hypovolemic shock, hypotension associated with hypoproteinemia in patients with liver failure or protein-losing conditions, as a replacement solution in plasma exchange or exchange transfusion, and to facilitate diuresis in fl uidoverloaded hypoproteinemic patients. albumin solutions are not indicated as a nutritional source to raise serum albumin. their use in some indications, particularly for resuscitation, has become controversial, and pulmonary edema has been reported in association with their infusion. 64 although albumin solutions are reasonably safe products to administer, expense and limited availability restrict their use. anaphylactic reactions have been reported in less than 0.1% of recipients. the use of ppf has been associated with severe hypotensive episodes, with hageman factor fragments or prekallikrein activator being demonstrated, 65 thus making ppf a less desirable resuscitation fl uid and contraindicated in cardiac surgery. granulocyte concentrates for transfusion are obtained from a single donor by cytapheresis methods, which generally involve the administration of hydroxyethyl starch and corticosteroids to the donor to improve granulocyte yield. granulocyte colony-stimulating factor (g-csf) has been added to some collection regimens and increases both cell counts and granulocyte survival substantially. each collection should contain at least 10 10 granulocytes 1,2 and is suspended in approximately 200 ml of plasma. a signifi cant number of red cells are present, so crossmatching for the recipient is required. because of the potential risk for graft-versus-host disease (gvhd), granulocytes are usually collected from hla-matched donors. granulocytes are stored at room temperature and must be transfused within 24 hours of collection, although sooner is better because of rapid deterioration of the cells. patients who may benefi t from granulocyte transfusions include those who are neutropenic (absolute neutrophil count of less than 0.5 ã� 10 9 /l) and those who are unresponsive to appropriate antibiotic treatment but in whom bone marrow recovery is expected to occur. a course of therapy generally involves daily infusion for 4 to 7 days. granulocytes have been used for progressive fungal infections in immunosuppressed granulocytopenic patients, in patients with defective leukocytes (e.g., chronic granulomatous disease), and in the neonatal icu for neonatal sepsis. randomized trials had suggested that granulocyte transfusions under these circumstances can reduce mortality, but such trials have not been conducted for more than 2 decades. 66 effective antibiotic regimens and the signifi cant adverse effects associated with the use of granulocyte concentrates, including pulmonary insuffi ciency related to alloimmunization and cmv infection, have limited their use in recent years. the decision to transfuse blood components, like any therapeutic maneuver, must be made with full awareness of the potential risk to the recipient, as well as the expected benefi ts. public expectations of a zero-risk blood supply help raise the acuity of physicians' decisions. for some patients, the benefi t from transfusion is so obvious that the associated risks pale in comparison to the consequences of withholding transfusion. however, the clinician's knowledge of the incidence and management of adverse reactions to transfusion is vital, not only to ensure the best patient care but also to provide appropriate patient education and true informed consent. almost every patient who receives an allogeneic blood transfusion will experience some adverse reaction if such universal effects as immunomodulation and bone marrow suppression are considered. measurable reactions to transfusion occur in about 20% of patients; more serious adverse responses may be expected in only 1% to 2% of transfusions. 67 the nature of these adverse reactions ranges from those that are common but clinically unimportant to those that may cause signifi cant morbidity or death (table 80-3) . transfusion in the icu is a common and often lightly regarded event. however, because the signs and symptoms of severe, life-threatening reactions are frequently indistinguishable from those of troublesome, but less signifi cant reactions, every transfused patient who experiences a signifi cant change in condition, such as an elevation in temperature, change in pulse or blood pressure, dyspnea, or pain, must be promptly and fully evaluated to identify the cause of the reaction and to institute treatment when necessary. the basic approach to all acute reactions should be to maintain a high index of suspicion for acute hemolytic reactions by stopping the transfusion immediately, maintaining venous access with intravenous fl uids, and informing the blood bank laboratory immediately so that the appropriate transfusion reaction protocol can be in stituted and post-transfusion specimens obtained. early recognition of severe transfusion reactions may be lifesaving. the most feared reaction to blood transfusion is intravascular hemolysis, caused by the recipient's complementfi xing antibodies attaching to donor rbcs with resultant rbc lysis. abo incompatibility is most often implicated in these incidents. intravascular hemolysis is still the single most common acute cause of fatalities associated with the transfusion episode. 68 in addition to hemolysis, complement activation stimulates the release of infl ammatory mediators and cytokines and thereby leads to hypotension and vascular collapse. activation of the coagulation system may result in dic. acute renal failure may also occur, presumably on the basis of immune complex interactions. morbidity and mortality are directly related to the quantity of incompatible blood transfused, which is why prompt recognition and cessation of transfusion cannot be overemphasized. misidentifi cation of the patient, or "clerical error," at any time beginning with the process of specimen acquisition through release of the unit and initiation of infusion is the major cause of acute intravascular hemolysis. 69, 70 this reaction is more likely to occur in critical care settings, such as the icu, operating room, and emergency department, than anywhere else in the hospital. it is far preferable to transfuse uncrossmatched group o red cells than to chance abo incompatibility caused by improper patient and specimen identifi cation procedures. the most common clinical sign of hemolysis is fever, with or without chills. 71 other common signs and symptoms include back or fl ank pain, anxiety, nausea, lightheadedness, dyspnea, and hemodynamic instability. in a comatose or anesthetized patient, many of these symptoms will not be evident; therefore, signs such as hypotension, hemoglobinuria, and diffuse oozing from puncture sites or incisions may be the only notable features. immediate management of hemolytic transfusion reactions must include cessation of the transfusion; the remainder of care is supportive. rapid verifi cation of patient and unit identifi cation must be made, not only to confi rm the suspected reaction but also to prevent a second patient from receiving a reciprocally incompatible unit if a clerical error has been made. desired end points of supportive care include maintenance of blood pressure, high urine output, and support of coagulopathy or further blood loss. steroids, heparin, or other specifi c pharmacologic interventions have no role in treatment. anaphylactic reactions to blood transfusions are fortunately rare but may be life-threatening. the usual cause is recipient antibody to a component of plasma that the patient lacks, most commonly antibody to iga in igadefi cient individuals. 72 signs and symptoms include severe malaise and anxiety, fl ushing, dizziness, dyspnea, bronchospasm, abdominal pain, vomiting, diarrhea, hypotension, and eventually shock. fever and hemolysis do not occur. management includes immediate cessation of transfusion and standard therapy for anaphylaxis. if anti-iga antibodies are determined to be the cause of this reaction, the patient must receive blood components donated by iga-defi cient individuals or, if unavailable, specially prepared washed rbcs and platelet concentrates. plasmaderived preparations, such as albumin, and ig contain varying amounts of iga and pose a substantial risk in these patients. febrile nonhemolytic reactions (fnhrs) are the most commonly occurring immediate transfusion reaction. these reactions are annoying to the clinician, patient, and transfusion service alike in that they can cause signifi cant discomfort and, because they share certain manifestations with acute hemolytic reactions, must be investigated in every instance. fnhrs occur in approximately 0.5% to 1.0% of transfusion episodes. 73 the etiologic factors are probably complex and multiple, but many reactions are caused by the release of cytokines and pyrogens, either within the transfused unit of blood or as a result of recipient antibodies to donor leukocytes. clinical signs include fever, with or without chills, usually beginning 1 to 2 hours after the start of the transfusion but occasionally delayed up to 4 to 6 hours. multiparous women and patients who are multiply transfused are particularly prone to fnhrs. the transfusion must be stopped and the appropriate transfusion reaction evaluation instituted. antipyretics such as acetaminophen may be administered. though commonly used, antihistamines such as diphenhydramine are neither preventive nor therapeutic. once acute hemolysis is excluded, transfusion of a new unit may be instituted. most patients will not experience a second such reaction. 73 if repeated reactions become problematic, leukocyte-depleted blood components may be supplied. the implementation of ulr results in a reduction in the frequency of all fevers seen after transfusion by only about 12%. 74 hives and pruritus are relatively common adverse effects of transfusion. 68 they are a hypersensitivity reaction localized to the skin, and their cause is unknown but may include both donor and recipient characteristics. these reactions consist of localized or generalized urticaria beginning shortly after the start of transfusion without other signs or symptoms of anaphylaxis or hemolysis. the transfusion should be temporarily stopped, and antihistamines may be administered. if the hives resolve in a short time, the same unit of blood may be cautiously restarted. if repeated urticarial reactions occur, premedication with antihistamines may be effective, or blood components washed to remove plasma may be required. intravascular volume overexpansion is particularly likely to occur in critical care patients with limited cardiac reserve. aside from the inherent volume of the blood components, the intravenous normal saline concurrently administered adds to the volume load. unfortunately, normal saline solution is the only intravenous fl uid that may be administered with blood components. with careful attention to transfusion requirements and the use of volume reduction maneuvers available to the transfusion service, volume overload can be minimized in most instances. the frequency of this complication of transfusion is not reported. delayed hemolysis is an uncommon but probably underrecognized reaction to transfusion that results from the stimulation of a primary or secondary (anamnestic) recipient antibody response to foreign rbc antigens. these antibodies are undetected at the time of transfusion but increase after transfusion in a manner analogous to the vaccination "booster" effect. these reactions typically occur 3 to 14 days after transfusion but are unrecognized because of the lack of a clear temporal association with transfusion. fever, chills, and an unexplained decline in hct are the usual signs. 75 transient elevation in bilirubin and lactate dehydrogenase may also occur. the diagnosis is established by a positive direct antiglobulin (coombs) test resulting from recipient antibody coating donor rbcs. the antibody may be identifi ed by eluting it from the rbcs or by demonstrating it within the recipient's serum. the specifi city of the antibody is often against such rbc antigens as the rh family, kidd, duffy, or kell systems. hemolysis may not occur, but if it does, it is likely to be extravascular and only rarely causes renal failure or dic. prevention of these reactions is diffi cult. alloimmunization to foreign rbc antigens occurs in approximately 1% of transfusions. 67 detection of delayed antibodies is the purpose for requiring a new blood bank specimen every 72 hours if the patient has recently been transfused. permanent transfusion records should record the occurrence of delayed antibodies, even though they may not be apparent at a later crossmatch. access to transfusion databases is critical for the care of patients with a past history of transfusion. transfusion-related acute lung injury (trali) is an uncommon (0.02%) 76 but serious adverse effect of transfusion that has only recently been gaining recognition. similar reactions have been called pulmonary leukoagglutinin reaction or noncardiogenic pulmonary edema. these reactions consist of acute respiratory distress syndrome (ards), which develops 1 to 6 hours after transfusion. signs and symptoms include bilateral pulmonary infi ltrates, hypoxemia, fever, and occasionally hypotension. monitored patients are found to have normal or low pulmonary wedge pressure and central venous pressure, as contrasted with patients experiencing volume overload. if adequate respiratory support and oxygenation are established promptly, spontaneous resolution generally occurs within 1 to 4 days. deaths have nonetheless occurred, particularly with a delay in diagnosis. 77, 78 episodes of trali appear to have several possible causative mechanisms. some cases may be caused by donor antibodies reacting with recipient neutrophil or hla antigens. 79 plasma factors related to blood storage have also been implicated, such as lipid substances from deterioration of donor cell membranes that prime recipient neu-trophils, which then damage the pulmonary vasculature and lead to increased capillary permeability and an ardslike syndrome. 80 other clinical factors may contribute to increased risk, such as cardiac bypass surgery or other procedures. in the antibody model at least, the implicated antibody is unique to the donor and the affl icted recipient will probably not experience another such reaction, provided that the recipient is not exposed to the same donor. trali is undoubtedly under-recognized in the critical care setting and may frequently be confused with fl uid overload or cardiogenic pulmonary edema. transfusion-associated gvhd (ta-gvhd) is a welldocumented, but probably under-recognized, highly lethal immunologic complication of blood transfusion. 81 immunocompromised patients infused with blood components containing viable donor lymphocytes are at risk for engraftment of the allogeneic lymphocytes and ensuing rejection of recipient (host) tissues. transfusion recipients who are at highest risk include neonates, especially the very premature, bone marrow and organ transplant recipients, and leukemia and lymphoma patients. ta-gvhd has also been reported in patients after cardiac surgery who received designated donor blood from relatives; presumably, the hla antigenic differences between donor and recipient were insuffi cient to stimulate a recipient immune response but suffi cient to elicit a donor immune response. 82 the onset of ta-gvhd is usually within 8 to 30 days after transfusion, and it is manifested as fever and rash, followed by diarrhea and evidence of liver and bone marrow injury. ta-gvhd differs from that seen in bone marrow transplantation (bmt) by its involvement of the marrow and by far greater mortality. treatment is largely ineffective, and mortality exceeds 90%. irradiation of blood components at 25 gy prevents ta-gvhd by eliminating the donor lymphocyte mitogenic response. all cellular blood components should be irradiated before transfusion to high-risk patients. the functions of the cellular components of blood are unaffected, although damage to rbc membranes limits postirradiation storage of prbcs. 83 blood donated by a relative for any patient should be irradiated, as should hla-matched or crossmatched platelet products. allogeneic blood transfusion has been shown to modulate and suppress the recipient's immune response, an effect fi rst noted with kidney transplantation. 84 immunosuppression in a critical care setting is generally undesirable, but whether transfusion has a signifi cant impact is debated. ongoing clinical issues center around two areas of controversy: the putative association between blood transfusion and increased numbers of postoperative infections and increased and more rapid rates of tumor recurrence in surgical oncology patients with certain malignancies. there has been no resolution of either issue despite a few prospective trials having been performed. the largest pro-spective trial of colorectal cancer resection, for example, is negative, 85 but a meta-analysis of the extant data suggests that an adverse effect on recurrence does exist. 86 similarly, most of the randomized trials of postoperative or critical care unit infections are too small to indicate an effect of transfusion, but all point in the direction of an adverse effect. 87, 88 controversy will continue until larger randomized trials are conducted. the precise mechanism of the immunosuppression induced by allogeneic transfusion has not yet been delineated, and several mechanisms may be involved. 89 alterations identifi ed in laboratory and clinical transfusion recipients have included depression of the t-helper/tsuppressor lymphocyte ratio, decreased natural killer cell activity, diminished interleukin-2 generation, formation of anti-idiotype antibodies, impairment of phagocytic cell function, and chronic persistence of donor lymphocytes (microchimerism), suggestive of low-level gvhd. difficulties in analysis of human data arise because patients requiring blood transfusions have conditions that themselves induce immune changes. there is some evidence, bolstered by the results of two large clinical trials, to suggest that leukocyte reduction of blood components reduces or eliminates this immunosuppressive effect. 90 proponents of this viewpoint argue that for this reason, ulr would benefi t most patients receiving blood transfusions and lead to fewer infections, tumor recurrences, and other related putative risks of transfusion, all potentially resulting in saving lives and cost. prospective trials will be extremely important. 91 public awareness of transfusion-associated acquired immunodefi ciency syndrome (aids) has done more to revolutionize transfusion practice than any other transfusion risk by resulting in more conservative blood use, more stringent donor selection criteria, and improved screening tests. the result is that viral transmission rates are now diffi cult to measure, and the risk of transfusionrelated infectious diseases is lower than ever. 92 the current best estimate is that 3 to 4 units per 10,000 will transmit some kind of infection 93 if agents such as cmv or epstein-barr virus are included. bacterial infection has become the most common infectious risk thanks to increasingly sensitive donor screening tests, including nucleic acid testing (nat) to detect viral dna or rna, which has shortened the infectious period and reduced the risk for post-transfusion hepatitis (pth) and other viral infections. several fatalities are reported yearly from the transfusion of blood components contaminated with viable, proliferating bacteria, with or without the accumulation of endotoxin. 94 platelet concentrates, because they must be stored at room temperature, are particularly prone to bacterial growth, with a reported incidence of 6 in 10,000 transfusions. 95 organisms isolated from platelets and implicated in fatal transfusion reactions include staphylococcus and streptococcus species and gram-negative bacilli. fatalities resulting from bacterial contamination of refrigerated rbcs have occurred as well and more often involve cryophilic bacteria. rbc transfusions contaminated by yersinia enterocolitica have been consistently reported for a decade. 96 transfusion reactions caused by bacterial or endotoxin contamination are fortunately quite rare, but mortality exceeds 60%. signs and symptoms of reactions caused by microbial contamination overlap those of hemolytic transfusion reactions and consist primarily of fever and hypotension, along with other signs of endotoxic shock. if recognized promptly, a gram stain of the implicated unit can be prepared immediately and, if positive, appropriate antibiotic and supportive therapy instituted. autologous blood components may also be contaminated at the time of collection; therefore, reactions occurring in patients who are receiving their own blood should not be dismissed but instead should be evaluated as fully as though the patients had received allogeneic blood. the success of viral screening measures is most clearly illustrated by the fall in the risk for pth over the past 2 decades. although pth continues to be a signifi cant cause of morbidity and mortality, the nature of pth has changed through the years with the stepwise institution of various donor screening measures. the elimination of paid donors in 1972 and the successive introduction of immunologic tests for hepatitis b have resulted in a steady reduction in the rates of pth caused by hepatitis b virus (hbv) to approximately 17 per million units of transfused blood products. although about 30% to 40% of hbv transmissions will result in acute hepatitis, chronic hbv infection develops in less than 10% of such patients. in contrast, the risk for chronic hepatitis c virus (hcv) infection after transfusion is higher, nearly 50%, and the long-term risk for cirrhosis-or hepatocellular carcinoma-related mortality is about 15% over more than 20 years after pth secondary to hcv. 97, 98 the clinical course of hepatitis a is generally milder, and the lack of a chronic carrier state means that with donor screening for symptoms of the acute illness, the risk of transmission is much lower, estimated at less than one in a million units. 99 the prevalence of hepatitis b surface antigenemia among fi rst-time blood donors is 0.7%, and the prevalence of hepatitis c antibodies in donors is approximately 0.1% to 0.5%. at this time, given the sensitivity of current screening assays, including the latest generation of enzyme immunoassays (eias) and nat, the current risk of pth resulting from hcv is believed to be about 1 in 150,000 or less. 100 although hbv is still implicated in pth (attributable to the seronegative "window" period in newly infected donors), the risk of transfusion-associated hepatitis b is about 1 in 200,000 units. 100 retroviruses, rna-based viruses characterized by their reverse transcriptase and integration into the host genome, and lentiviruses, a subset of retroviruses, are ubiquitous in animals and were initially identifi ed in humans in the early 1980s. those known to be capable of transmission by transfusion are hiv-1, hiv-2, and human t-cell leukemia/lymphoma virus (htlv) i and ii. transfusion-associated aids was initially reported in late 1982. 101 the fi rst report of an associated viral agent did not appear until late in 1983, and in march 1985 the screening enzyme-linked immunosorbent assay (elisa) to detect antibody to hiv-1 was licensed and immediately incorporated into the blood-screening process. improved confi dential donor screening appeared to decrease the risk of infectious units appearing in the donor pool. 102, 103 the discovery that heat treatment reduced transmission resulted in a reduction in transmission by plasma products, especially to persons with hemophilia. clinical aids developed in more than 90% of recipients of infected blood products, and the vast majority succumbed to the disease. removal of donor units with seropositivity by elisa was insuffi cient to prevent transmission of hiv-1; several hundred cases were reported annually after introduction of the elisa test. subsequent development of an assay for the p24 antigen and then nat has lowered the risk of transfusion-associated hiv-1 infection to less than one in a million (see table 80 -3). despite donor screening and sensitive assays, including eia, nat, and p24 antigen, an extremely small, but fi nite risk of hiv-1 transmission by screened blood transfusions remains. this risk is largely due to the seronegative "window" period experienced by newly infected donors, which is estimated to be an average of 16 days. 100 a second retrovirus, hiv-2, fi rst described in residents of countries in west africa and subsequently detected in migrants to western europe, causes an immunodeficiency syndrome similar to that caused by hiv-1. although very few cases of hiv-2 have been reported in the united states 104, 105 and there have been no reported transfusion-transmitted cases, experience with other retroviruses suggests that screening may prevent the majority of potential transmission. therefore, donated blood is now screened by an assay for the presence of antibody to hiv-2. the retrovirus htlv-i is the causative agent of adult t-cell leukemia (atl) and is strongly implicated in the chronic, progressive neurologic disorder termed tropical spastic paraparesis or htlv-i-associated myelopathy (tsp/ham). htlv-ii has been linked to hairy cell leukemia, but no transfusion-transmitted cases have been reported. the virus exhibits strong serologic crossreactivity with htlv-i such that screening assays fail to distinguish between antibodies to either virus. transfusion-transmitted htlv-i has been demonstrated. 106 tsp/ham has developed in a small percentage of infected transfusion recipients, but no transfusionassociated cases of atl have been seen. approximately 0.025% of donors in the united states are seropositive for htlv-i and htlv-ii 107 ; further testing reveals the majority of them to be htlv-ii. donated blood is currently screened for antibodies to htlv-i and htlv-ii. the estimated risk of htlv transmission by screened negative blood is believed to be 1 in 250,000 to 2 million. cmv is a human herpesvirus that establishes latent infection in the host's tissues, particularly leukocytes, and is transmitted by all cellular blood components. 108 seropositivity, or the presence of antibody, denotes previous exposure to the virus but does not confer protective immunity. secondary reinfection or reactivation of latent infection can occur. antibodies to cmv persist for life and serve as a marker indicating the potential for transmission of live virus. immunocompetent recipients of transfused cmvpositive blood experience minimal morbidity and mortality. the majority are asymptomatic, whereas a heterophile-negative mononucleosis syndrome may develop in a few. immunocompromised patients, however, may suffer life-threatening manifestations such as severe interstitial pneumonitis, gastroenteritis, hepatitis, or disseminated disease. several groups of patients are at particular risk (box 80-1), 109 and these patients should receive blood incapable of transmitting the virus. other patients may benefi t from cmv-negative blood as well, such as seronegative solid organ transplant recipients or autologous bmt patients. screening of donated blood for cmv is not routinely done but can be performed quickly if necessary. because the prevalence of donor seropositivity is quite high in some regions (50% to 70%), cmvseronegative blood may not be readily available. blood that is leukocyte depleted ("cmv safe") may be as effective as seronegative blood in the prevention of cmv transmission, although a recent meta-analysis of clinical trials comparing the two methods suggests that cmvnegative blood products might have a slight advantage over leukocyte-depleted products. 110 many blood-borne parasites may be transmitted by transfusion, although this is a rare occurrence in the united states because of donor screening questions and the low endemicity of implicated agents. 111 changing immigration patterns and worldwide travel, however, make transfusion-transmitted parasites an increasing concern. on a worldwide basis, malaria is the most important transfusion-transmitted infective organism, although only about three cases occur in the united states each year. such infections are manifested by delayed fever, chills, seronegative pregnant women seronegative premature infants weighing less than 1200 g seronegative allogeneic or autologous bone marrow transplant recipients seronegative transplant recipients of seronegative organs diaphoresis, and hemolysis, often masked by underlying medical conditions. fatalities have occurred. babesiosis, a tick-borne disease, is endemic in regions of the united states, especially the northeast, with a seroprevalence of about 4%. transfusion-transmitted cases have been reported, with asplenic or immunocompromised patients being particularly susceptible. with increases in the number of latin american immigrants to the united states, american trypanosomiasis (chagas' disease), which is endemic in latin american countries, has emerged as a potential pathogen. other parasitic diseases that have been transmitted by transfusion include toxoplasmosis, leishmaniasis, and lyme disease. parvovirus b19 has now been recognized as a pathogen capable of transmission by transfusion, with typical clinical fi ndings and the potential for severe hematologic complications. cases of epstein-barr virus infection with a typical mononucleosis-like illness have been reported after transfusion. west nile virus has also been transmitted by transfusion. h2n1 infl uenza, severe acute respiratory syndrome (sars), and other new viral infections should be capable of transmission by transfusion, although cases have not been reported and the prevalence of asymptomatic disease is unknown. a rising area of concern is the transmission of prion disease, either jacob-creutzfeldt disease or bovine spongiform encephalopathy (bse). donor referral criteria were implemented in 1987 for these diseases, and transmission of bse has been reported in the united kingdom. massive transfusion is defi ned as the administration of blood components in excess of one blood volume within a 24-hour period. in an average adult (70 kg), this represents approximately 10 units of wb or equivalent prbcs, crystalloid solution, and other components. massive transfusion, especially in the range of 20 or more units of blood products, causes complications not generally seen in usual transfusion practice: accumulation of undesirable substances present within banked blood and dilutional depletion of normal blood constituents that are lacking in stored units. trauma victims, surgical patients undergoing extensive procedures, and patients with vascular or coagulation disorders may be massively transfused in the critical care setting. survival of the massive transfusion episode is determined more by the nature and degree of the patient's injuries or medical conditions than by the transfusions themselves, but the presence of adverse effects of massive transfusion can complicate patients' courses in the icu. transfusion of large quantities of stored blood defi cient in functional platelets often results in hemostatic defects or outright thrombocytopenia. circulating platelets consistently decrease in inverse proportion to the amount of blood administered, with the hemostatically signifi cant level of 50 ã� 10 9 /l reached after 20 u. 112, 113 functional defects have also been noted, and the bleeding time is prolonged. 114 despite these laboratory changes, severe diffuse bleeding develops in less than 20% of massively transfused patients, and no laboratory studies predict those who will. prophylactic platelet transfusion has not been shown to be of benefi t. 115 platelet counts may return to hemostatically effective levels quickly in patients with normal marrow function. currently, resuscitation of massively bleeding patients is most often accomplished with prbcs in combination with crystalloid solution. this should result in hemodilution to about 60% of normal plasma factor levels after the transfusion of about 10 units; this factor level can effect normal hemostasis. in reality, however, crystalloids may be given in excess of prbcs, so after 10 units is transfused, less plasma protein may remain. bleeding is unlikely until prothrombin time (pt)/inr and ptt prolongations exceed 1.5 to 1.8 times the midpoint normal range, the equivalent of an inr approaching 2.0. 113 as with platelets, prophylactic administration of ffp has not proved effective in preventing diffuse bleeding. 116 thus, the decision to transfuse should be made on an individual basis, as determined by the presence of bleeding or unacceptable risk in patients with documented abnormalities in coagulation. one new area of controversy in the treatment of patients with massive hemorrhage is the use of recombinant activated factor vii. this new agent was created for the treatment of hemophiliac patients with high titers of antibodies to factor viii, which makes them unable to benefi t from transfusion of recombinant factor viii. activated factor vii bypasses that problem by binding to tissue factor and directly activating thrombin and hence generating fi brin. 117 it is extremely expensive, has a short half-life, and carries a risk of inducing pathologic thrombosis, with potentially grave consequences. nevertheless, in numerous case reports, this new agent appears to potentially be benefi cial if used early in the resuscitation of massively injured patients. unfortunately, its unsupervised use has also resulted in thrombotic complications and relative lack of success, both of which suggest that carefully controlled clinical trials are appropriate. 118 blood preservative solutions contain excess citrate, which anticoagulates stored blood by binding ionized calcium. wb contains approximately 1.8 g of citrate/citric acid per unit in the plasma fraction. patients with normal liver function can metabolize the citrate load in 1 unit of wb in 5 minutes, but hepatic impairment may extend removal to 15 minutes or longer. toxicity may result when citrate is administered in excess of the metabolic rate, thereby causing a decrease in ionized calcium levels. 119 although paresthesias, cramps, and myoclonus accompany citrate excess, the chief danger of hypocalcemia is depression of myocardial contractility and potential prolongation of the qt interval. because the effects of citrate are transient and the use of prbcs containing little residual citrated plasma is far more common than massive transfusion with wb, routine administration of calcium is not indicated; clinically signifi cant rebound hypercalcemia may result. calcium infusion should be limited to hypoperfused patients with hepatic or cardiac failure who manifest citrate toxicity, and careful monitoring is essential. as potassium leaks from rbcs during storage, up to 7 meq of extracellular potassium may accumulate in each unit. however, dangerous levels of potassium rarely develop in adults from stored blood; the potassium level is more likely to be determined by the patient's acid-base status. 117 studies of massively transfused patients have demonstrated a wide range of potassium levels, with hypokalemia seen as frequently as hyperkalemia. because of the many physiologic mechanisms altered during resuscitation, including those of the respiratory, renal, cardiac, and hepatic systems, it is impossible to predict the net effect of massive transfusion on serum potassium levels. the ph of banked blood drops during storage, from 7.16 at the time of collection to as low as 6.73 after several weeks of storage. administration of large quantities of acidic blood, together with the metabolic acidosis common in these patients before resuscitation, would lead one to expect worsening acidosis as the outcome of massive transfusion. however, patients are more likely to exhibit metabolic alkalosis at the end of the transfusion episode, 120,121 partly because of improved tissue perfusion and the metabolism of citrate and lactate to bicarbonate. patients in renal failure may be unable to handle the bicarbonate load and require dialysis. acidosis persisting after transfusion suggests inadequate tissue perfusion. 119 empiric administration of bicarbonate to counter the acid load is not warranted and may contribute to the deleterious effects of hypercapnia in patients with impaired ventilation. as discussed previously, the level of rbc-associated 2,3-dpg in banked blood declines during storage, which increases the affi nity of hemoglobin for oxygen and thereby results in decreased oxygen off-loaded to tissues. even in massively transfused patients, it has been diffi cult to document a clinical impact of this shift, and no reliable method for restoring red cell 2,3-dpg has been developed. wb and prbcs are stored at approximately 4⺠c and require 30 to 45 minutes to warm to room temperature. elective transfusions at standard fl ow rates are tolerated without the need to warm the blood; however, core body temperature, measured by esophageal probe, can fall to 30⺠c or lower with the administration of large volumes of cold blood over a period of 1 to 2 hours. 122 adverse effects of hypothermia include a decreased heart rate and myocardial contractility, cardiac arrhythmias, increased affi nity of hemoglobin for oxygen resulting in decreased tissue oxygen delivery, dic, and impaired ability to metabolize the citrate load of stored blood. both blood warmers and patient warming may be instituted during massive transfusion, and patient core temperature should be monitored during such resuscitative efforts. whether massive transfusion in and of itself is a cause of ards is another source of controversy. there are certainly theoretical reasons why massive transfusion might precipitate ards: all cellular transfusions contain damaged or activated wbcs, cell membranes, aggregated platelets, and microthrombi, all of which are capable of lodging in and damaging pulmonary capillaries. despite this possibility, neither microfi ltration of transfusions nor routine leukocyte depletion has shown a signifi cant impact on the incidence of ards in massively transfused patients. 123 certainly, other causes of ards exist in patients who undergo massive transfusion, and the possibility of volume overload and trali should be considered in the evaluation of patients with hypoxia and diffuse pulmonary infi ltrates after massive transfusion. management of such patients is supportive, consistent with the overall management of massive transfusion. 124, 125 autoimmune hemolytic anemia patients with autoimmune hemolytic anemia (aiha) have an autoantibody, usually of broad specifi city, that fi xes itself to their rbcs and triggers extravascular immune-mediated destruction. patients with aiha have a positive direct antiglobulin test 126 (dat, commonly known as the coombs test) and varying degrees of he molysis, and their autoantibodies cause agglutination of rbcs from all donors during crossmatching. if the hemolysis is brisk, patients may require red cell transfusion to support oxygen needs before medical management of the aiha is effective. hence, transfusion is diffi cult because agglutination during crossmatching interferes with proper defi nition of compatible units of rbcs and because the transfused rbcs are themselves subject to the same immune hemolysis as the host rbcs. many blood banks have methods for depletion of autoantibodies from the recipient's plasma and elution of antibodies from rbcs to arrive at a proper crossmatch. 127 although such crossmatches are time consuming and not generally available on an emergency basis, they can be lifesaving. criteria for transfusion should remain the same as for other recipients. rbcs are crossmatched for red cell antigens in the abo and rh 0 (d) group and for other red cell antigens when antibodies are present. however, there are several hundred other red cell antigens in the human family, and with repeated transfusion recipients may become alloimmunized to other antigens. generally, alloimmunization occurs in approximately 1% of transfusions, 68 but the prevalence of alloantibodies is higher in chronically transfused, relatively immunocompetent patients, especially african americans, whose distribution of red cell antigens has signifi cant variation from the white population. alloimmunization rates of 30% or higher may be found in chronically transfused patients with hemoglobinopathies who have not received rbcs matched to potent minor antigens such as kell, duffy, and lewis. alloimmunization may present diffi culties in crossmatching of blood, to the point that compatible blood must be obtained from raredonor registries, if at all. other patients present unresolved serologic problems in that the alloantibody is never precisely identifi ed yet the majority of blood available for transfusion is incompatible. the delay engendered by working with multiple or unidentifi ed antibodies may be unacceptable in some critical care situations in which the need for oxygen-carrying capacity leaves no choice but to transfuse incompatible blood. the behavior of these antibodies in the laboratory may assist in predicting the clinical outcome of the incompatible transfusion. 128 special procedures such as clearance studies, 129 fl ow cytometry 130 and in vivo crossmatching (cautious administration of a small aliquot of blood, with subsequent observation of serum and urine for evidence of hemolysis) are useful if time permits. emergency transfusion of type o, rh-negative uncrossmatched blood is generally reserved for the resuscitation of trauma patients, for whom the delay in crossmatching may be life-threatening. the risks of alloimmunization are generally accepted as low. even rh-positive type o rbcs may be used because rates of alloimmunization to rh 0 (d) are low under the circumstances of emergency transfusion. 128, 131 dic can present the clinician with diffi cult therapeutic choices. this common disorder in critically ill patients may be manifested as severe hemorrhage or thrombosis. therapy is primarily directed at alleviating the cause and supporting the patient. supportive therapy includes the transfusion of components needed to correct the bleeding diathesis caused by the consumption of platelets and fi brinogen, in addition to prbcs to restore oxygencarrying capacity. platelets and fi brinogen (as cryoprecipitate) are the most useful components needed to repair the coagulopathy, but their use risks merely "fueling the fi re" and increasing the microthrombosis of dic. heparin anticoagulation is controversial 132, 133 and may increase the risk of bleeding, especially if depleted factors are not replenished. no defi nitive clinical trials have endorsed the routine use of heparin, and randomized trials of other components and coagulation inhibitors have uniformly been negative. in general, the use of heparin and antifi brinolytic agents has been confi ned to the most severe and protracted cases of dic. 134 cirrhotic patients or those with fulminant hepatic failure have a variety of hemostatic disorders that complicate transfusion management of a bleeding patient. 135 hepatic synthesis of coagulation factors may be markedly diminished, thereby necessitating replacement by ffp or cryoprecipitate. patterns of factor diminution may vary between acute hepatic necrosis and chronic cirrhosis. 136 associated hemodynamic alterations may make it impossible to administer the volumes required for effective hemostasis, however, and any effect is transient. the use of factor concentrates or antifi brinolytic agents may precipitate thrombosis. activation of fi brinolysis and decreased clearance of activated factors may produce or mimic chronic dic, thus further exacerbating the factor defi ciencies and impairing coagulation. abnormal platelet function and thrombocytopenia may contribute to the coagulopathy of liver disease, with concomitant splenomegaly reducing the effectiveness of platelet transfusions. bleeding in uremic patients is exacerbated by an acquired platelet defect, in part secondary to dialyzable circulating molecules soluble in platelet membranes. plateletassociated vwf and plasma high-molecular-weight vwf multimers have also been shown to be decreased, 137 which may explain the benefi t shown by ddavp 138 and cryoprecipitate in shortening the bleeding time and improving hemostasis in some uremic patients. raising the hct by red cell transfusion in anemic patients has also been shown to shorten the bleeding time, presumably as a result of blood vessel wall-laminar blood fl ow interaction. transfusion of platelets in the absence of thrombocytopenia is unlikely to be of benefi t because the transfused platelets rapidly become dysfunctional. more aggressive hemodialysis is the most widely accepted method of reducing platelet dysfunction. bmt patients are vulnerable to the severe infectious and toxic side effects of ablative treatment and hence may be cared for in critical care units. these patients may have intensive red cell and platelet transfusion requirements and need specialized products such as cmv-negative and irradiated blood components. a blood bank problem uniquely encountered in bmt is the need to switch the patient's abo group because of an abo-mismatched transplant, thus necessitating an exchange transfusion of red cells and plasma-containing products (i.e., platelet concentrates) of differing abo type to avoid hemolysis of donor and recipient cells. bmt patients may also manifest an increased rate of delayed hemolytic reactions 139 as donor "passenger" lymphocytes recognize recipient or transfused red cell antigens. patients should be monitored particularly closely between days 10 and 20 after a minormismatched allogeneic transplant, and aggressive transfusion should be undertaken if the hemoglobin level falls and the dat result becomes positive. the safest transfusion is one that is not given. therefore, alternatives to blood component therapy continue to be sought and are valuable adjuncts in some instances. it is possible to limit homologous blood exposure by the appropriate use of pharmacologic agents that promote hemostasis and the administration of recombinant hematopoietic growth factors or biologic growth modifi ers to stimulate marrow hematopoiesis. only one substitute for rbc transfusions has been approved in the united states, a polyfl uorocarbon oxygen carrier with signifi cant limitations as a blood substitute. 140 other preparations that have been explored in clinical trials are cell-free hemoglobin solutions cross-linked or polymerized by chemical manipulation to prevent rapid clearance from the circulation. they are intended to provide short-term oxygen-carrying capacity for acutely ill patients and have the advantage of not requiring crossmatching or infection control. although these proposed products may have a longer shelf-life and are easier to transport, their drawbacks are many. most have a circulatory half-life of only about 24 hours. the oxygen dissociation curve for these substitutes is also frequently not favorable: either a high fio 2 is required to "load" these molecules or they are less likely to deliver oxygen efficiently at lower po 2 levels. 141 because the hemoglobin source is reclaimed bovine or human red cells, it is unlikely that patients who do not accept blood components because of their religious beliefs (jehovah's witnesses) will accept these types of hemoglobin solutions. one product in development uses recombinant technology to generate hemoglobin, and it is hoped that this solution may be acceptable to these patients. the licensed perfl uorocarbon solutions have failed to demonstrate any utility as intravascular oxygen carriers because of their unfavorable p-50 (oxygen half-saturation pressure) and oxygen off-loading characteristics. they are fi nding limited application in regional oxygenation during angioplasty or stent placement procedures and a more novel use in "liquid ventilation." this involves the ventilation of intubated patients experiencing severe pulmonary compromise with superoxygenated perfl uorocarbon solutions in place of oxygen-enriched air. 142 the synthetic vasopressin analogue ddavp increases plasma factor viii : c and promotes the release of vwf from endothelial stores. 143 ddavp has provided effective hemostasis in bleeding patients with mild hemophilia a and type i von willebrand's disease and has been used as prophylaxis for patients undergoing surgery. ddavp reportedly improves platelet function in some patients with qualitative platelet disorders associated with uremia, 136 cirrhosis, and aspirin ingestion. studies of its effi cacy in cardiopulmonary bypass procedures are confl icting, but a subset of these patients may benefi t. the chief drawback to its use is tachyphylaxis, which develops in essentially all cases after short-term repeated administration. the lysine analogues îµ-aminocaproic acid and tranexamic acid inhibit fi brinolysis by blocking the binding of plasminogen and plasmin to fi brin. these antifi brinolytic agents may decrease bleeding and thus the need for homologous blood components in patients with hemophilia, thrombocytopenia, and systemic fi brinolysis. a novel and effective use of tranexamic acid involves administration as a mouthwash in preparation for oral surgery in patients with hemophilia or those receiving oral anticoagulant therapy. 144 the most serious side effect of these agents when systemically administered is thrombosis; thus, it is important to use them appropriately and monitor the patient carefully during their use. aprotinin is a naturally occurring bovine serine protease inhibitor that acts on plasma serine proteases such as plasmin, kallikrein, trypsin, and some coagulation proteins. aprotinin has been shown to reduce blood loss in patients undergoing cardiopulmonary bypass surgery 145 by inhibiting fi brinolysis and preventing platelet damage. however, more recent reports of renal injury and longterm mortality may mean an end to its use. 146 aprotinin has been used extensively in liver transplantation, which involves high blood loss. repeated administration poses the risk of anaphylaxis and renal dysfunction. when time permits, vitamin k is the preferred agent to reverse the coagulopathy induced by oral anticoagulants. normalization of the pt can be seen in as few as 6 to 12 hours. additionally, selected cirrhotic patients may exhibit improvement in the pt when treated with therapeutic doses of vitamin k. many patients in critical care units exhibit a prolonged pt, especially if dietary supplements are limited and broad-spectrum antibiotic therapy is given. vitamin k is a safe and effective agent for reversing this effect. recombinant erythropoietin (epo) has dramatically reduced the red cell transfusion requirements of patients in chronic renal failure. epo also has applications in the adjunctive treatment of the anemia of premature infants and the anemia of chronic disease, especially rheumatoid arthritis, cancer, and aids. studies of its effi cacy in reducing perioperative red cell transfusion requirements by increasing the yield of predeposited autologous blood or stimulating bone marrow synthesis after surgery have shown benefi t in reducing blood transfusion, although preoperative planning and autologous deposits are required. 147 in contrast and probably because the impact of epo is not immediate, the effi cacy of epo in the icu is unproven and awaits the results of large clinical trials. recombinant growth factors such as granulocytemacrophage colony-stimulating factor (gm-csf) and g-csf stimulate marrow production of leukocytes by enhancing several different granulocyte and macrophage functions. these agents are fi nding application in reducing the neutropenic period in bmt and cancer chemotherapy by increasing the leukocyte count in hypoproliferative marrow conditions. these myeloid growth factors are replacing granulocyte transfusions for their few remaining indications. cell salvage equipment has been in clinical use for several decades, and although cell salvage is clearly capable of rescuing otherwise "lost" red cells, its full impact on transfusions has been poorly documented. cell salvage generally consists of collection of shed blood from a clean, uncontaminated operating fi eld, followed by removal of the cellular elements and retransfusion into the patient. cell salvage has been used both intraoperatively and postoperatively, especially in cardiac surgery. although the clinical studies of cell salvage have many fl aws, the overall success of this therapy in reducing transfusion has resulted in its wide application. 148 risks include bacterial contamination, febrile reactions, triggering of dic, and coagulopathy as a result of dilution. when combined with acute intraoperative hemodilution, this technology is also potentially cost saving. 149 the word apheresis is derived from the greek aphairein, "to take away"; thus, therapeutic hemapheresis is performed to remove unwanted plasma constituents (plasmapheresis) or blood cells (cytapheresis). automated cell separators use centrifugation or membrane fi ltration to remove and concentrate the selected blood element. many of the same devices used to prepare apheresis blood components for transfusion are used to perform patient procedures, so therapeutic apheresis is often administered under the auspices of the transfusion medicine service. rapid removal of plasma or cells may fi nd several applications in intensive care practice (box 80-2). the goal of plasmapheresis, or plasma exchange (pe), is to remove or reduce the levels of an undesirable plasma constituent or, alternatively, by means of plasma replacement, to supply a missing substance. the agent to be removed by pe is thought to be an autoantibody in some of the neurologic, renal, or hematologic conditions treated in this manner. 150 immunomodulation by pe is another explanation for its effect, a theory indirectly supported by the equivalent effi cacy of ivig therapy for several of these disorders. 151 pe for the amelioration of hyperviscosity from either excess igm in waldenstrã¶m's macroglobulinemia or excess ig in multiple myeloma is an effective temporizing measure in the treatment of these conditions. 152 plasmapheresis with pe is the standard therapy for ttp. 153 unfortunately, few controlled trials of pe exist, although anecdotal reports abound. pe is seldom the defi nitive treatment of most of these conditions and is used most appropriately as a short-term adjunct to other medical modalities. the kinetics of pe predicts that a one-volume exchange removes 65% of a given plasma constituent if the blood volume does not change or additional synthesis or mobilization of the substance does not occur. two or three volume exchanges remove 87% and 95%, respectively. highly protein-bound, intravascularly concentrated substances are most effi ciently removed, whereas substances with a large volume of distribution such as igg, active synthesis, or large extravascular stores are removed at less than predicted rates. the usual short-term intense course of pe schedules fi ve one-volume exchanges (approximately 3 l in normal-sized adults) over a 7-day period. the appropriate replacement fl uid in most conditions is an albumin-saline mixture, which provides oncotic support without the risk of disease transmission borne by ffp. pe in patients with ttp uses replacement with ffp to supply the plasma protease that is consumed during the disease. side effects of pe are relatively common (10% to 30% of procedures) but generally minor and are related to vascular access, temporary discomfort, or vasomotor symptoms. 154 patient death is rarely due to the procedure itself but is largely of cardiopulmonary causes. plasma proteins such as coagulation factors, immunoglobulins, and complement will be removed by pe, and laboratory test results of coagulation and electrolytes may be deranged in the hours after pe. clinical bleeding is rarely observed. most coagulation factors do not fall below hemostatic levels and recover within hours, with the exception of fi brinogen, which may require several days for complete replenishment. leukapheresis may be required to urgently reduce the wbc count in patients with acute myeloid or lymphoblastic leukemia or chronic myelogenous leukemia with peripheral counts of 100 ã� 10 9 /l or greater. each procedure is expected to drop the count by a third, but the effect is short lived. leukapheresis should be reserved for use only as an adjunct to chemotherapy in patients with pulmonary or cerebral leukostasis or for cytoreduction before chemotherapy in patients at risk for severe tumor lysis syndrome. plateletpheresis may be benefi cial as short-term therapy in patients with symptomatic thrombocythemia manifested as cerebral or myocardial ischemia, pulmonary emboli, or gastrointestinal bleeding. each procedure should effect a 50% reduction in the platelet count. cytotoxic therapy should be started concomitantly as the defi nitive treatment. litigation related to blood transfusion has become prominent, particularly after the epidemic of transfusionassociated aids. 155 most states regulate blood banking and medical practice, but blood products are regarded as symptomatic hyperviscosity thrombotic thrombocytopenic purpura neurologic diseases: myasthenia gravis, guillain-barrã© syndrome uncontrolled systemic vasculitis with critical end-organ injury symptomatic leukocytosis symptomatic thrombocythemia sickle cell anemia crisis (pulmonary or central nervous system manifestations) a service, not as a commodity, so standard product liability does not pertain to blood components. 156 however, negligence in the course of preparing, testing, transferring, crossmatching, or administering blood products is still a potential cause for legal action. every clinician who orders transfusions must be aware that blood components, like drugs, are approved for specifi c uses and that the indications should be clearly documented in the medical record. the informed consent of the patient is an important area of potential liability. the joint commission on accreditation of healthcare organizations (jcaho) has required written patient consent for blood transfusions since 1996. what constitutes adequate informed consent and who is responsible for advising the patient are still in contention. elements of informed consent include an understanding of the need for transfusion, its risks and benefi ts, and the alternatives, including the risk of not undergoing transfusion, as well as the opportunity to ask questions. whether the clinician documents informed consent with an individual progress note in the patient record or with a standardized form is generally established as institutional policy. similarly, institutions vary with respect to policies for consenting adults who are temporarily incompetent, such as sedated patients in the icu. a competent adult patient may refuse blood transfusion, and jehovah's witnesses commonly do so for religious reasons. case law is clear in upholding this right of the patient, 157 which extends to care given at such time as the patient may become incompetent (i.e., comatose) after such refusal was expressed before becoming incompetent. courts will usually order a lifesaving transfusion for minors. exceptions have been made in the case of some "emancipated minors" who are at the age of reason. most states have evoked a "special interest" in the welfare of a fetus in ordering transfusions to pregnant women. the advent of sentinel event reviews and other quality management procedures for patient safety has had an impact on transfusion practice as well. procedures for patient identifi cation before surgical procedures, including devices such as bar code readers, have also been applied to transfusion practice. however, annual sentinel event reviews reporting transfusion errors have remained constant according to jcaho records. 158 â�  blood components should be prescribed like drugs. appropriate blood component therapy requires that the specifi c blood product needed for a clear indication be prescribed, with avoidance of a formulaic approach. â�  red blood cells should be transfused only to increase oxygen-carrying capacity. transfusion decisions should be based on individual patient physiology. the majority of patients with hemoglobin levels greater than 60 or 70 g/l will not require transfusion unless they have limited cardiopulmonary reserve or active bleeding. â�  platelet transfusions are indicated for patients who are bleeding because of thrombocytopenia or functional platelet defects. guidelines for platelet transfusion are also conservative. prophylactic platelet transfusion remains controversial and is not warranted in many situations. â�  fresh frozen plasma is indicated for the repletion of coagulation factors in bleeding patients defi cient in those factors or to provide specifi c plasma proteins that cannot be obtained from safer sources. â�  cryoprecipitate is a concentrated source of fi brinogen and selected coagulation factors. cryoprecipitate may be more helpful in correcting the hypofi brinogenemia of dilutional or consumptive coagulopathy than fresh frozen plasma. â�  adverse reactions to blood components occur in 1% to 2% of transfusion episodes. adherence to routine protocols for the evaluation of transfusion reactions may save lives. â�  acute hemolytic reactions are the leading cause of immediate transfusion fatalities. prevention of these reactions requires strict adherence to transfusion and patient identifi cation procedures. â�  transmission of infectious agents by transfusion has been markedly reduced, and bacterial infection is now the most common infectious complication of transfusion. â�  adverse effects unique to massive transfusion are likely to occur in the icu and complicate the management of critically ill or severely injured patients. component therapy for such patients should remain conservative. the emerging role of activated factor vii in the treatment of these patients requires further evaluation. â�  informed consent for blood transfusion is a standard of practice. a competent adult has the legal right to refuse blood transfusion. consent in 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plasmapheresis for neurological disorders correction of hyperviscosity by apheresis improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome therapeutic plasma exchange as a nephrological procedure: a singlecenter experience a review of transfusion-associated aids litigation: 1984 through 1993 legal, fi nancial, and public health consequences of hiv contamination of blood and blood products in the 1980s and 1990s legal aspects of transfusion of jehovah's witnesses joint commission on accreditation of hospitals and healthcare organizations: sentinel event statistics: available at key: cord-033328-ny011lj3 authors: vese, donato title: managing the pandemic: the italian strategy for fighting covid-19 and the challenge of sharing administrative powers date: 2020-09-03 journal: nan doi: 10.1017/err.2020.82 sha: doc_id: 33328 cord_uid: ny011lj3 this article analyses the administrative measures and, more specifically, the administrative strategy implemented in the immediacy of the emergency by the italian government in order to determine whether it was effective in managing the covid-19 pandemic throughout the country. in analysing the administrative strategy, the article emphasises the role that the current system of constitutional separation of powers plays in emergency management and how this system can impact health risk assessment. an explanation of the risk management system in italian and european union (eu) law is provided and the following key legal issues are addressed: (1) the notion and features of emergency risk regulation from a pandemic perspective, distinguishing between risk and emergency; (2) the potential and limits of the precautionary principle in eu law; and (3) the italian constitutional scenario with respect to the main provisions regulating central government, regional and local powers. specifically, this article argues that the administrative strategy for effectively implementing emergency risk regulation based on an adequate and correct risk assessment requires “power sharing” across the different levels of government with the participation of all of the institutional actors involved in the decision-making process: government, regions and local authorities. “and the flames of the tripods expired. and darkness and decay and the red death held illimitable dominion over all”. edgar allan poe, the mask of the red death, complete tales and poems (new york, vintage books 1975) p 273 international concern" (pheic). 2 in the light of its later levels of spread and severity worldwide, the who then assessed covid-19 as a "pandemic". 3 the pandemic has spread rapidly in several european union (eu) member states. italy, however, is a special case: here, the covid-19 outbreak spiralled upwards earlier and more severely than elsewhere in europe, reaching a high mortality rate and creating the conditions for the public healthcare system's collapse. in this scenario, the italian government (from now on the government) declared a nationwide state of emergency, 4 followed by increasingly restrictive measures aimed at slowing and containing the spread of the virus and mitigating the pandemic's effects under the by now well-known "flatten the curve" imperative. the last of these measures 5 established the national lockdown, extending the emergency rules to the entire country for six months 6 and, more generally, providing what has been called the "italian model to fight covid-19", namely "diminish viral contagions through quarantine; increase the capacity of medical facilities; and adopt social and financial recovery packages to address the pandemic-induced economic crisis". 7 in this article, starting from the main regulatory acts and considering recent scientific knowledge and epidemiological data on covid-19, we will examine the administrative measures the government has taken and the strategy it has implemented to deal with the pandemic in the immediacy of the emergency. after this initial analysis, we might legitimately wonder whether those measures and that strategy have proven effective in containing the pandemic. more generally, by analysing the administrative strategy, the article emphasises the role that the current system of constitutional separation of powers plays in emergency management and how this system can impact health risk assessment. an explanation of the risk-management system in italian and eu law will be provided and the following key legal issues will be analysed: (1) the notion and features of emergency risk regulation from a pandemic perspective, distinguishing between risk and emergency; (2) the potential and limits of the precautionary principle in eu law; 2 who, "statement on the second meeting of the international health regulations (2005) emergency committee regarding the outbreak of novel coronavirus (2019-ncov)", geneva, switzerland, 30 january 2020 <https://www. who.int/news-room/detail/30-01-2020-statement-on-the-second-meeting-of-the-international-health-regulations-(2005)emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov)>. pheic has been defined in the international health regulations (ihr) of 2005 as an extraordinary event which can: (1) constitute a public health risk to other states through the international spread of disease; and (2) potentially require a coordinated international response. furthermore, this definition implies a situation that is: (1) serious, unusual or unexpected; (2) carries implications for public health beyond the affected state's national borders; and (3) and may require immediate international action. 3 who, "director-general's opening remarks at the media briefing on covid-19", 11 march 2020 <https://www. who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19-11-march-2020>. 4 resolution of the council of ministers of 31 january 2020, adopted pursuant to legislative decree 1/2018 (civil protection code) <https://www.gazzettaufficiale.it/eli/id/2020/02/01/20a00737/sg>. on the declaration of emergency rule, see european commission for democracy through law (venice commission) <https://www.venice.coe.int/ webforms/documents/default.aspx?pdffile=cdl-std(1995)012-e>. 5 dpcm of 9 march 2020 <www.gazzettaufficiale.it/eli/gu/2020/03/09/62/sg/pdf>. 6 for the general framework of all measures adopted by the italian state during the covid-19 emergency, see <https://www.camera.it/temiap/documentazione/temi/pdf/1203754.pdf?_1588279335853>. 7 fg nicola, "exporting the italian model to fight covid-19" (the regulatory review, 23 april 2020) <https:// www.theregreview.org/2020/04/23/nicola-exporting-italian-model-fight-covid-19/>. and (3) the italian constitutional scenario with respect to the main provisions regulating central government, regional and local powers. specifically, the article argues that the administrative strategy for effectively implementing emergency risk regulation based on an adequate and correct risk assessment requires "power sharing" across the different levels of government with the participation of all of the institutional actors involved in the decision-making process: government, regions and local authorities. following the declaration of the state of emergency, the government approved decree-law no. 6 of 23 february 2020 vesting the president of the council of ministers with wide ordinance powers to handle the emergency by issuing his own administrative decrees. 8 in particular, decree-law 6/2020 gave the prime minister the power to issue typical emergency administrative measures in order to ensure social distancing, impose lockdown areas, close offices and public services and suspend economic activities. in addition, it allowed him to adopt atypical administrative powers whereby "further containment and emergency management measures" could be established. 9 in a matter of days, the government approved three important regulatory acts based on the implementation of decree-law 6/2020: 10 first with the decree of the president of the council of ministers (dpcm) of 8 march 2020, 11 second with the dpcm of 9 march 2020 12 and third with the dpcm of 11 march, 13 the government established stringent emergency administrative measures to curb the pandemic's spread throughout the country. 14 in the first instance, these measures were gradual and concerned specific municipalities, provinces or regionsespecially in northern italythat were hardest hit by the virus and therefore classified as "red zones" subject to government-imposed local lockdowns. later on, the government established the national lockdown, and emergency measures were extended to the entire country for six months. in particular, pursuant to article 1(1) of the dpcm of 8 march 2020, the government imposed a lockdown in lombardy and another fourteen provinces of northern italy. in doing so, the government introduced several legal prohibitions, such as the ban on people travelling to and from places in the red zones. with the subsequent national lockdown, the government imposed a travel ban in the entire country according to article 1(1), dpcm of 9 march 2020, and prevented all forms of social gathering in public places or places open to the public across the country, according to article 1(2), dpcm of 9 march 2020. furthermore, pursuant to articles 1(1), 1(2) and 1(3), dpcm of 11 march 2020, retail businesses and personal services were suspended. 15 as a consequence of the national lockdown, the ministry of health's order of 20 march 2020 provided several stringent measures that prohibited many activities, such as the ban on accessing all public places, on exercising in public places and on going to holiday homes. 16 in addition, with its order of 28 march 2020, the ministry of health, in agreement with the ministry of transport, established that people entering italy by plane, boat, rail or road must declare their reason for travel, the address where they plan to self-isolate, how they intend to travel there and their phone number so that authorities can contact them throughout an obligatory fourteen-day quarantine. 17 moreover, several administrative sanctions were gradually established in the various regulatory acts. the last of these acts introduced rigorous sanctions for people who leave home without valid reasons and for undertakings that do not comply with the order to close. 18 in the meantime, the regions and local authorities also adopted several ordinances establishing emergency administrative measures for the pandemic in their area. 19 lastly, the government issued decree-law no. 19 of 25 march 2020, with the aim of rationalising and coordinating emergency powers among the different levels of government. 20 *** in the following pages, emphasising the role that the current structure of constitutional separation of powers plays in risk assessment, i will argue that the main problems of the italian administrative strategy for the covid-19 pandemic are due to the lack of effective "sharing of powers", and more specifically to the failure to share administrative 15 20 in particular, art 2(3) of decree-law 19/2020 did not affect the effects produced and acts adopted on the basis of decrees and ordinances issued pursuant to decree-law 6/2020 or art 32 of law 833/1978, and established that the measures previously adopted by the dpcms of 8 march 2020, 9 march 2020, 11 march 2020 and 22 march 2020 as still in force on the date of entry into force of the said decree-law shall continue to apply within the original terms. regulatory powers among the different levels of government with the participation and cooperation of all institutional actors involved in the emergency decision-making process: the government, regions and local authorities. 21 from this point of view, as i will attempt to explain, the failure to share administrative regulatory powers can have a decisive impact on risk assessment at the national level in terms of the effectiveness/ineffectiveness of the strategies adopted by the various institutional actors called upon to manage the emergency in their own areas. here, by "sharing powers", i mean the idea that the institutional actors involved in the decision-making process cooperate in the exercise of their powers by adopting consistent measures in the public interest; that is to say, with the aim of maximising the rights of individuals as required by the italian constitution. 22 power sharing does not mean homologation. indeed, adopting different administrative strategies at different levels of government might increase the effectiveness of the response to a pandemic, but these measures must be shared among all of the actors involved in emergency management. sharing powers, measures and local strategies will be useful for an effective policy for containing the virus's nationwide spread based on an overall risk assessment. hence, the idea of shared powers emphasises the role of cooperation in specific institutional contexts, such as italy's, where competences are allocated across the different levels of government. the sense, more generally, is that sharing powers in multi-level systems enables states to perform better in terms of democracy, as powers are balanced between state and local levels. 23 as we will see, however, the absence of effective power sharing at all levels of government in a pandemic can produce serious problems in correctly assessing risk and consequently in the emergency management strategy. in particular, i will discuss the problem of the lack of effective power sharing in italian policies from two key points of view: the government's administrative strategy in addressing the virus's spread by means of an "incremental approach" (section iv.1.a); and the government's administrative strategy in implementing a national pandemic health plan (section iv.1.b). before doing so, i will outline some key legal issues for the topics examined in this article. in particular, to put the administrative strategy devised by the government in the covid-19 emergency into context, i will analyse: (1) the notion and features of emergency risk regulation from a pandemic perspective, distinguishing between risk and emergency; (2) the potential and limits of the precautionary principle in eu law; and (3) the italian constitutional scenario with respect to the main provisions governing government's, regions' and local authorities' powers. 21 this preliminary analysis of key legal issues is useful for understanding why the administrative strategy has proven ineffective in managing the pandemic (sections iv.1.a and iv.1.b). placing the notion and its main features in the context of a pandemic, we could define emergency risk regulation as the action undertaken in the immediacy of a pandemic in order to mitigate its impact. 24 from this perspective, we should bear in mind the distinction between risk and emergency. generally speaking, the traditional approach of administrative law refers to the notion of emergency and not also to the notion of risk, which legal doctrine touches on only marginally. 25 with regards to the emergency, as a safeguard clause to deal flexibly with pandemic risks, 26 governments and other public authorities may invoke the use of extraordinary powers to restore the normal course of legal relations. 27 what is more, regulators have used emergency tools to act in the expectation of a risk for many years, although there is no denying that a risk is a potential danger, whereas an emergency is an actual danger. indeed, it should be sufficiently clear that emergency power is ineffective when applied in a situation that is only potentially dangerous. in this connection, it has been argued 28 that the methods of exercising administrative powers can be better regulated by putting the administrative regulation in the category of risk rather than that of emergency. we might observe that if the notion of "risk" characterises a peculiar, intermediate state between security and destruction, 29 in "emergency risk" the balance between these two clearly tilts towards the latter. 30 in fact, as it is triggered by a pandemic, emergency risk regulation presupposes the existence, or the mere threat, of a pandemic. the pandemic, as 24 a alemanno (ed.), governing disasters: the challenges of emergency risk regulation (cheltenham, edward elgar 2011) p xix. 25 however, the notion of risk in italian administrative law is analysed by m simoncini, la regolazione del rischio e il sistema degli standard. elementi per una teoria dell'azione amministrativa attraverso i casi del terrorismo e dell'ambiente [risk regulation and the standards system. elements for a theory of administrative action through the cases of terrorism and the environment] (napoli, editoriale scientifica 2010) chs 2 and 4, where the author postulating the notion of risk argues and suggests, in an innovative approach, the transition from the "emergency" perspective to the "risk regulation" perspective. 26 . beck is responsible for analysing the sociopolitical dimension of risk management and in particular the problem of the relationship between science and society through the criticism of the monopoly that scientific rationality currently holds. 30 alemanno, supra, note 24, xxii. a possible cause of disaster for humans, is an event of substantial extent causing significant physical damage or destruction, loss of life or drastic change to the natural environment. 31 typically, one speaks of a pandemic when a threat to people's health is perceived that calls for urgent remedial action under conditions of uncertainty. 32 fundamentally, emergency risk regulation in a pandemic event, as in other disasters, finds its natural regulatory space in two stages: mitigation and emergency response. 33 in principle, mitigation efforts attempt to reduce the potential impact of a pandemic before it strikes, while a pandemic response tends to do so after the event. however, the distinction between emergency mitigation and emergency response is not always very sharp. when called upon to act under the menace of a pandemic, governments must both mitigate and respond to the threat in a situation characterised by suddenness (emergency) and significance. 34 in a pandemic, emergency risk regulation is clearly called on to operate in the initial phase of the disease's spread, when the mere threat overshadows the regulatory context by virtue of its status as an emergency. accordingly, the most cost-effective strategies for increasing pandemic preparedness with administrative regulation, especially in resource-constrained settings, may consist of: (1) investing to reinforce the main public health infrastructure; (2) increasing situational awareness; and (3) quickly containing further outbreaks that could extend the pandemic. in addition, especially once the pandemic has begun, a coordinated response should be implemented where the public regulator focuses on: (4) maintaining situational awareness; (5) public health messaging; (6) reducing disease transmission; and (7) care and treatment of the ill. successful contingency planning and an administrative strategy using the emergency risk regulation approach call for surge capacity, or in other words the ability to scale up the delivery of health interventions in proportion to the severity of the event, the pathogen and the population at risk. 35 the pandemic may produce significant impact on the regulatory context by justifying the partial or total suspension of the ordinary decision-making process. 36 departures from the rule of law, or simply from established procedures, are generally perceived as necessary if the event has met the significance threshold. however, the use of emergency administrative measures, such as temporary and exceptional measures, should be considered legitimate only for the period in which the pandemic 31 ibid, xxii-xxiii. see also dd caron, "addressing catastrophes: conflicting images of solidarity and self interest" in dd caron and ch leben (eds), lasts. 37 by contrast, prolonging exceptional order beyond the time of the pandemic means that any powers and measures designed to be temporary will be made permanent, intensifying the controlling authority's capacity, even though this might limit the enjoyment of individual rights. 38 in addition, if the general need to prevent a pandemic cannot be ignored, it should be well thought out as an opportunity for risk regulation to prevent not only the sudden impact of a pandemic situation, but also any distorting effects or mishandling of the necessary recourse to emergency powers. consequently, it might now be inferred that emergency risk regulation in the context of a pandemic is a relevant regulatory methodology that combines the risk approach with the possibility of resorting to extraordinary measures in case a pandemic occurs. this methodology is essential for an effective administrative strategy for dealing with a pandemic because it permits constant monitoring and management of risks that can have serious consequences for society. by assessing the risks and taking proportionate measures, the negative effects of the emergency can be reduced and the use of emergency powers can be limited. indeed, it should be pointed out that the principle of reasonableness, which is generally invoked in the exercise of emergency powers against immediate danger, does not operate in emergency risk regulation. instead, as i will claim later, it will be the precautionary principle that matters (section iii.2). furthermore, it must be said that emergency risk regulation entails an accurate assessment of the factual situation based on scientific evidence. 39 to apply this methodology correctly, a variety of factors must be consideredincluding the real level of the threat as well as how people perceive itin a step-by-step analysis based on the available scientific knowledge. in particular, as i will claim in analysing the italian policies (sections iv.1.a and iv.1.b), the administrative strategy for effectively implementing emergency risk regulation in a pandemic requires power sharing across the different levels of government with the participation of all of the institutional actors involved in the decision-making process in order to adopt consistent measures based on the constant monitoring and updating of the nationwide epidemiological risk assessment. hence, effective sharing of administrative powersand more specifically the administrative regulatory powers for emergenciesbetween the government, regions and local authorities would optimise the adoption of proportionate measures for controlling and containing the virus throughout the country, avoiding or at least delaying the application of stringent measures such as the lockdown of municipalities, provinces, regions or entire states. 37 g martinico and m simoncini, "emergency and risk in comparative public law" (verfassungsblog, 9 may 2020) <https://verfassungsblog.de/emergency-and-risk-in-comparative-public-law/>. according the authors, it is the facts and not the law that indicate the conclusion of an emergency. thus, the risks posed by the use of extraordinary administrative measures should be considered, especially at the end of the emergency when the government's powers should be subject to legal control in order to avoid departures from original objectives. in the same sense, see also simoncini, supra, note 27, 39. 38 on the state of exception, see c schmitt, die diktatur: von den anfängen des modernen souveränitätsgedankens bis zum proletarischen klassenkampf (berlin, duncker & humblot 1989). schmitt's jurisprudential thinking placed the state of exception at the very centre of analysis, beginning with his work on the roman dictatorship. 39 martinico and simoncini, supra, note 37. in managing the pandemic, the government's administrative strategy should take the emergency risk regulation methodology we have just outlined into account. in the eu legal system, the precautionary principle 40 is described in article 191(2) tfeu on environmental policy. 41 the jurisprudence of the european court of justice (ecj) played a prominent role in elevating the precautionary principle to the status of a general principle of eu law. some ecj judgments in health matters are seminal in this regard. 42 according to the ecj's jurisprudence, the precautionary principle requires that competent authorities adopt appropriate administrative measures to prevent specific potential health risks. the ecj's approach maintains that an appropriate application of the precautionary principle presupposes the identification of hypothetically harmful effects for health flowing from the contested administrative measure, combined with comprehensive assessment of the risks to health based on the most reliable scientific data available. 43 in like manner, the european commission (ec) has contributed significantly to outlining the features of the precautionary principle in the eu legal system. in the communication of 2000, the ec sought to establish a common understanding of the factors leading to recourse to the precautionary principle and its place in decisionmaking. 44 according to the ec communication, the principle covers those circumstances where scientific evidence is insufficient, inconclusive or uncertain, but where preliminary scientific evaluation provides reasonable grounds for concern that the potentially dangerous effects on human health might be inconsistent with the chosen level of protection. 45 various factors can trigger the adoption of precautionary measures. these factors inform the decision on whether to act or not, this being an eminently political decision, a function of the risk level that is "acceptable" to the society on which the risk is imposed. 46 the ec has also established guidelines for those situations where action based on the precautionary principle is deemed necessary in order to manage risk. in these situations, a cost-benefit analysis to compare the likely positive and negative effects of the envisaged action and of inaction is recommended, and it should also include non-economic considerations. 47 however, risk management in accordance with the precautionary principle should be proportionate, meaning that administrative measures should be proportional to the desired level of protection. in some cases, an administrative response that imposes a total ban may not be proportional to a potential risk; in others, it may be the only possible response. in any case, such measures should be reassessed in the light of recent scientific data and changed if necessary. in eu law, therefore, the precautionary principle has been widely recognised as a defining principle of risk regulation alongside the regulatory aim of a high level of protection. nevertheless, this principle might prove ineffective or even harmful if applied in a "strong" form. the strong form of the principle has been authoritatively criticised 48 on the grounds that it suggests that regulation is required whenever there is a potential risk to health, even if the supporting evidence is conjectural and the economic costs of administrative regulation are high. in particular, if governments adopt the strong form of the principle, it would always require regulating activitiesconsequently imposing a burden of proof each timeeven if it cannot be demonstrated that those activities are likely to cause harms. 49 in addition, as the need for selectivity of precautions is not simply an empirical fact but is a conceptual inevitability, no society can be highly precautionary with respect to all risks. 50 44 hence, in this strong form, the precautionary principle proves ineffective and even harmful by requiring stringent administrative measures that can be paralysing, in that they prohibit regulation and all courses of action, including inaction. thus conceived, this principle may not lead in any direction or provide precise guidance for governments and regulators. recently, the limits of the precautionary principle have been analysed in the field of administrative and constitutional law. an interesting recent work proposes that precautionary and optimising constitutionalism are a dichotomy. 51 in summary, the theory advances two distinct propositions. the first is that constitutions should be viewed as devices for regulating political risks. those political risks are referred to as "second-order risks", as opposed to "first-order risks" such as wars, diseases and other social ills. 52 many of these risks are described as "fat-tail risks" that are exceedingly unlikely to materialise, but more likely than in a normal distribution, and are exceedingly damaging if they do materialise, as in the case of a pandemic. 53 under "maximin constitutional" approaches, it is suggested that precautionary rules can overcompensate for these low-likelihood risks and even cause the very dangers that they seek to prevent. 54 hence, precautionary constitutionalism is myopic in focusing on certain risks, and the notion of unappreciated or unaccommodated risks is central. on the basis of this hypothesis, the best way to regulate risk is thus to avoid obsessive views on risk avoidance or precautions and instead to allow greater flexibility in addressing the full array of risks inherent in government. 55 what vermeule calls "optimising constitutionalism" is an answer to those who frame their understanding of the constitution along more rigid precautionary principles. 56 vermeule's approach has been criticised. 57 following these criticisms, i believe that this approach also reveals some critical points about the notion of risk. unless one adopts a more fungible notion of risk, i do not believe that "precautionary constitutionalism" is suboptimal for risk. it depends on how one weighs the risks involved in governing, even if one accepts risk analysis as the best measure for the success of a constitutional system. i claim, more generally, that correctly applying the precautionary principle, although it works better in a context of risk rather than one of emergency, is nonetheless important in managing a pandemic because it makes it possible to delay the implementation of stringent emergency measures. we have emphasised that administrative precautionary measures, unlike emergency ones, do not suspend the rule of law, since they activate soft government regulation that does not jeopardise fundamental rights concurrent with those threatened by imminent danger. hence, in my opinion, precautionary measures, where they are effectively shared across the different levels of government through appropriate risk assessment, would serve to avoid or at least delay governments' activation of a state of emergency. activating a state of emergency, consequently, would trigger hard government regulation through emergency measures that suspend the rule of law and therefore jeopardise fundamental rights. in a particular context such as the covid-19 pandemic, the precautionary principle could also be invokedand the implementation of precautionary administrative measures would be usefulin the presence of an emergency declaration issued by governments. in this sense, i argue that the declaration of a state of emergency for a pandemic is based on a technical risk assessment (ie technical discretion 58 ) by the administration (eg government). in a pandemic, then, the emergency relates essentially to the capacity of administrations (eg governments, health authorities) to manage cases requiring healthcare (eg intensive care for respiratory support, hospitalisations for advanced pharmacological treatments and so on). thus, the subject of the technical assessment of the fact (the pandemic) is be provided by the evaluation relating to the administration's capacity to fulfil the tasks established by the legal system to protect the right to health enshrined in article 32 of the italian constitution (section iv.2). furthermore, to be effective in emergencies such as a pandemic, the notion of the principle to which i refer should not entail the activation of precautionary measures typical of its strong version (which is exemplified in the well-known phrase "better safe than sorry"). in its strong version, in fact, the precautionary principle would be both paralysing and uneconomical, since it requires that any and all risks be prevented, even those that are least likely to occur or have been created artificially for 58 italian legal doctrine distinguishes between "administrative discretion" and "technical discretion" under the influence of ms giannini, il potere discrezionale della pubblica amministrazione political reasons (i am thinking here of george w. bush's preventative war doctrine) in order to justify stringent administrative measures issued by governments for purposes not necessarily related to the alleged risk. by contrast, balancing costs against benefits might provide the basis of a principled approach for making decisions in complex contexts, such as the italian legal system, where the current constitutional separation of powers can lead to an inadequate and incorrect assessment of risks and therefore to ineffective emergency management by the different levels of government. in any case, scientific evidence is an essential prerequisite for better regulation by acting on the precautionary principle. to be cost effective, governments should take precautionary administrative measures based on scientific knowledge and thus carefully assess the risks they intend to manage. taking the potential and limits of the precautionary principle from the perspective we have outlined above into account might have an impact on governments' ability to deal effectively with pandemic emergencies. this matters in the case of italy, where the current structure of the constitutional separation of powers between the government, regions and autonomous local authorities plays a crucial role in effectively managing the pandemic emergency. analysing the italian constitutional scenario can provide substantial guidance for understanding the legal structure of powers and competences of government, regions and local authorities and explain why assessing pandemic risk can be impacted by a given separation of powers. such an analysis can shed light on the administrative strategy implemented by the government in the pandemic and enable us to evaluate its effectiveness in managing covid-19 across the country. first of all, we should bear in mind that the italian constitution (from now on the constitution) does not explicitly refer to emergency power, except for a state of war (article 78). however, this power has traditionally been included in the typical powers that the constitution assigns to the government. in the constitutional system, the main rules governing the government's powers are established by articles 76 and 77. indeed, parliament does not have a monopoly on legislative power, and the government may also issue laws by two legal instruments that should be understood as extraordinary: legislative decree and decree-law. in particular, article 76 allows parliament to delegate its legislative power to the government, which in turn is given the power to issue legislative decrees. hence, the legislative decree is a form of delegated law-making power, where parliament may pass an enabling act entrusting the government to adopt one or more acts that have legal force. generally, the legislative decree is a legislative tool that is often deployed in all matters where a strong technical content is present. the second extraordinary instrument, the decree-law, is provided for by article 77. this is a form of law-making through emergency powers that the government may exercise in "exceptional cases of necessity and urgency" and under "its own responsibility". 59 the government can thus issuewithout an enabling act from parliament as required by the provisions of article 76administrative measures that have the force of ordinary laws. however, such administrative measures will lose their effects as of the date of issue if parliament does not transpose them into an ordinary law within sixty days of their publication. 60 with the major reform on "administrative federalism" enacted by law no. 3 of 18 october 2001, which amended title v of the constitution, italy rapidly devolved legislative and regulatory powers to the regions. 61 fundamentally, the constitutional amendment provided a new framework for the distribution of powers and competences between the national and local levels. 62 it established a new institutional structure by dividing legislative and administrative competences and powers across the different levels of government. 63 the amended articles of the constitution are the basis for the fundamental reform of administrative federalism. article 114 recognises local authorities (municipalities, provinces, metropolitan cities) and regions as autonomous entities of the state with their own statutes, powers and functions in accordance with the principles laid down in the constitution. article 117 establishes the role and legislative powers of the state and regions, indicating those matters for which the state has exclusive legislative power and those for which concurrent legislation of both the state and the regions is possible. the regions have exclusive power in all matters not expressly covered by state law. municipalities, provinces and metropolitan cities also have regulatory powers for the organisation and implementation of the functions attributed to them. specifically, article 117(3) establishes that the state and regions have concurrent power, and the regions have regulatory powers, in matters of public health. 64 in this connection, at the national level, parliament and government are called upon to: (1) adopt fundamental health principles by means of framework laws and guidelines; and (2) establish essential levels of healthcare. at the regional level, the regions implement: (1) general legislative and administrative activity; (2) the organisation of health facilities and services; and (3) the provision of healthcare based on specific local needs. article 118 provides for the subsidiarity principle, according to which all functions are exerted by municipalities, while the possibility remains to confer them to higher levels of government in order to guarantee the uniform implementation of spending functions across the country. article 120 guarantees national unity and the unitary nature of the constitutional system by providing for the government's substitution power. 65 according to article 120(2), the government can act for the regions and other local authorities if: (1) the latter fail to comply with international rules and treaties or eu legislation; (2) in the case of grave danger for public safety and security; or (3) whenever such action is necessary to preserve legal or economic unity and in particular to guarantee the basic level of benefits relating to civil and social entitlements, regardless of the geographical borders of local authorities. to this end, the law shall lay down the procedures to ensure that (4) subsidiary powers (ie the government's substitution power) are exercised in compliance with the principles of "subsidiarity" and "loyal cooperation". lastly, with regards to powers and competences in emergencies, it should be noted that in the italian legal system several authorities can introduce specific regulatory acts establishing administrative measures needed to deal with emergencies in accordance with the constitution. the power of ordinance has a particular role in managing emergencies, as it can be exercised in situations of necessity and urgency. in particular, the legal system provides for: (1) 66 as we will see, the structure of power just described highlights the problem of risk assessment among the institutional actors involved in the administrative decisionmaking process. though the current system of allocation of powers and competences to the regions and other local authorities might be an advantage in terms of correctly assessing and managing risk in their areas, at the national level, this system requires an effective sharing of powers and strategies between the centre and the periphery, where the measures of the regions and local authorities must be adopted in accordance with the measures advanced by the government, and vice versa. since correct risk assessment by an authority must take the characteristics of its area into accountdata on the epidemiological situation, for example, or on the average age of 65 the legal nature of the "state's substitution power" in italian legal doctrine has been extensively discussed. in particular, some scholars argue that art 120 provides a form of "administrative" substitution of the state over the regions, and that art 117(5) concerns "legislative" substitution. other scholars agree on the idea that art 120 provides the genus of substitution powers, whereas art 117(5) refers to one species of the genus, being a mere specification of art 120. however, the constitution seems clear on this point. as we have seen, the provisions of art 120 speak of the "government", while the provisions of art 117(5) speak of the "state". the population, and the capacity of the health system with regards especially to the availability of intensive care bedsit might be assumed that in the italian legal system's effective risk assessment could be facilitated by the specific competences established by the constitution for the regions and other local authorities in health matters. however, as i will argue, this is a theoretical advantage that works only if power is effectively shared between the different levels of government. in fact, in order to provide an adequate and correct risk assessment at the national level and take effective measures to contain and manage the pandemic, the current system needs powers and strategies to be shared between local authorities, regions and the government. sharing administrative powers at all levels of government is an important part of the task of states. 67 indeed, enhancing multi-level regulatory governance has become a priority in many eu states. for this reason, the eu supports sharing of administrative regulatory powers by encouraging better regulation at all levels of government, calling on the member states to improve coordination and avoid overlapping responsibilities among regulatory authorities. 68 in italy, until the adoption of constitutional law 3/2001, regulatory reform had been promoted, designed and implemented mainly at the national level. with the reform, as we have seen (section iii.3), such a centralised approach lost legal and political ground. at the same time, responsibilities for developing and implementing administrative regulation policies have not been explicitly allocated to either the state, the regions or the local authorities. hence, the responsibility for administrative regulation and regulatory reform lies with each of the levels of government in the matters where they exert legislative powers. in like manner, there is no overall competence at the central level to monitor and control regulatory reform programmes at the local level. accordingly, the new constitutional structure calls for effective sharing of administrative powers across the different levels of government. on the basis of the analysis carried out so far, i will now argue that the main problems of the italian administrative strategy for the covid-19 pandemic are due to the lack of effective sharing of administrative powers and, more specifically, to the failure to share regulatory powers across the different levels of government with the participation and cooperation of all institutional actors involved in the emergency decision-making process: the government, regions and local authorities. in particular, this problem 67 oecd, "the territorial impact of covid-19: managing the crisis across levels of government" (last updated 16 june 2020) <https://read.oecd-ilibrary.org/view/?ref=128_128287-5agkkojaaa&title=the-territorial-impact-of-covid-19managing-the-crisis-across-levels-of-government>. 68 the european committee of the regions (cor), "division of powers between the european union, the member states and regional and local authorities" (december 2012) <https://cor.europa.eu/en/engage/studies/documents/ study-division-powers/study-division-powers-en.pdf>. see also, oecd-puma, "managing across levels of government" (1997) <http://www.oecd.org/governance/budgeting/1902308.pdf>. has impacted the risk assessment of the various authorities called upon to manage the health emergency. as a result, the problem has impacted nationwide risk assessment and, consequently, the management of the emergency at the national level, leading to the adoption of inconsistent measures by the various institutional actors involved in the administrative decision-making process. in particular, i discuss this problem in italian policies from two key points of view: the government's administrative strategy for managing the virus's spread by means of the "incremental approach" (section iv.1.a) and the government's administrative strategy for implementing the nationwide pandemic health plan (section iv.1.b). in doing so, i shall take into account the considerations presented above concerning emergency risk regulation (section iii.1), the precautionary principle (section iii.2) and the rules governing powers in the constitutional scenario (section iii.3). one of italy's main problems in relation to the ineffective sharing of administrative powers for managing the pandemic is clearly displayed in what i will call the "incremental approach". 69 this approach is essentially based on the "progressive" application of emergency measures by the government in order to manage the "exponential" spread of the virus. the italian administrative strategy for the pandemic is fundamentally founded on such an approach. in fact, as we have seen (section ii), the government addressed the pandemic by enacting several decrees (dpcms) that "progressively increased" restrictions in lockdown areas (red zones), which were then extended from time to time until they finally applied to the entire country in the national lockdown. in my opinion, although the incremental approach may be a correct application of the principle of proportionality, given the government's proportionate use of emergency powers in dealing with the pandemic, it is the result of an ineffective sharing of administrative regulatory powers between the government, regions and local authorities. indeed, the progressive enforcement of lockdown areas, which from time to time increased the extent and severity of the emergency measures, demonstrates the difficulty of governing the spread of the virus in the red zones rather than the effective implementation of a proportionate administrative strategy. and this is mainly due to the lack of effective cooperation between the government and the regions in exercising their respective emergency powers. from a general point of view, the incremental approach reveals the limited effectiveness of the national and local measures and strategies for managing and containing the pandemic when those measures and strategies are not shared. i argue that even the stringent national lockdown 70 is essentially the result of the ineffective sharing and planning of administrative measures and strategies for managing the pandemic across the different levels of government and especially, in 69 on this approach, see g pisano, r sadum and m zanini, "lessons from italy's response to coronavirus" (harvard business law review, 27 march 2020) <https://hbr.org/2020/03/lessons-from-italys-response-to-coronavirus#comment-section>. 70 dpcm of 9 march 2020 <www.gazzettaufficiale.it/eli/gu/2020/03/09/62/sg/pdf>. this case, between the government and the regions. one can legitimately wonder whether the government can adopt an effective administrative strategy for managing the emergency without sharing and planning their measures with those of the regions. from this perspective, we can say that the government's incremental approach has proven ineffective in coping with the pandemic. i will now explain why in the following points. (1) regarding risk assessment for pandemics, the science 71 shows that the spread of covid-19 is rapid and exponential. consequently, the incremental approach does not work if it is not properly implemented with the effective participation of all institutional actors involved in managing the pandemic. scientific data 72 and statistics 73 on the spread of the virus were not predictive of what the situation would have been in the short and medium term. hence, a correct risk assessment of the virus's nationwide spread would have suggested that the administrative measures and, more generally, the strategies should have been shared among all players involved in the main strategy. very often, however, the government's strategy has not been in line with those of the regions, revealing an inadequate assessment of the risk that the virus would spread throughout the country, and thus the ineffective sharing of emergency powers. in fact, some important emergency measures implemented by the regions clearly contradict the government's main strategy. to take a few examples, 74 marche region ordinance no. 1 of 25 february 2020, issued pursuant to decree-law no. 6 of 2020, established measures that were more stringent than the government's, disregarding the latter's strategy. for this reason, the government contested the order before the court. 75 although a judgment in favour of the government was handed down and the challenged ordinance was suspended, the marche region legitimately adopted a new ordinance establishing emergency measures based on the same decree-law no. 6/2020, once again disregarding the government's strategy. another paradigmatic case is provided by a series of ordinances by the campania region aimed at imposing a more stringent lockdown at the local level than the lockdown established by the government at the national level. unlike the marche case, the ordinances of the campania region, although contested before the administrative judge, were not suspended, thus making the government's strategy ineffective. 76 consequently, in the absence of effective sharing and planning of the main strategy with the regions, the government had to 'increase' the emergency measures from time to time until finally imposing the stringent national lockdown. (2) in the absence of power sharing and strategies based on correct risk assessment at the national level, the government's incremental approach seems to have played a considerable role in people's behaviour, inducing them to make "bad choices". as the data show, 77 the government's incremental lockdown of municipalities, provinces and regions in northern italy induced masses of people to move towards the southern regions, spreading the virus to parts of italy that had not yet been affected. an emblematic case of this kind took place immediately after the dpcm of 8 march 2020 (see section ii) locked down lombardy and another fourteen provinces in northern italy, spurring thousands of people to flee to the south. such potential negative externalities, as well as other negative spill-overs or distortions, should have suggested that the government share its regulatory acts with those of the "target" regions (ie the northern regions), as well as with the other regions that could be indirectly jeopardised by the lockdown measures (ie the southern regions). alternatively, the government should have undertaken to coordinate the strategies of the regions and local authorities in order to enhance the adoption of effective control measures for people exiting the red zones and entering less affected regions. 78 more generally, in applying lockdown measures, the government should have shared and planned its strategy with the regions on the basis of a common risk assessment that took into account not only the regional territories, but the entire country. accordingly, the government should have established effective countermeasures together with all of the regions potentially involved in lockdown decisions to prevent the virus from spreading from high-risk to low-risk areas. an effective emergency response must be coordinated as a consistent system of actions taken simultaneously by the different actors involved in the decision-making process. (3) the government's incremental approach also revealed the problem of effectively sharing and planning precautionary measures (see section iii.2) across the different levels of government. the critical situation that arose because of the epidemic's severity called for effective testing of symptomatic and asymptomatic cases, as well as proactive tracing of potential positives across the country. on this point, these precautionary measures were supported by scientific data on the transmission of covid-19 by asymptomatic people. 79 the absence of a shared strategy for the adoption and implementation of precautionary measures proved particularly harmful in regions where the epidemic risk is higher. indeed, it is no coincidence that the outbreak spread so quickly in northern italy and especially in lombardy. in this region, the efficient public rail transport network 77 connecting urban areas, large numbers of commuters 80 and high levels of air pollution 81 are thought to have increased the incidence of infection. from this point of view, it is clear that risk assessment has been inadequate, and strategies have thus been ineffectively shared between lombardy and the government. the government should have promoted an effective precautionary strategy for health checks by sharing it with the strategies of the regions and ensuring efficient nationwide implementation on the basis of a global risk assessment. conversely, data on infections and deaths reveal that strategies were not shared effectively with the hardest-hit regions. (4) the incremental approach shows that most of the problems of administrative strategy are also motivated by political issues between parties governing regions and belonging to the coalition now governing the country. from the time when the virus began to spread, the multi-level management of the emergency has triggered competition and institutional division between the government and regions 82 due to policymakers' political differences. the management of the pandemic, in fact, has thrown light on the deep political division between the government, led by the coalition of left-wing parties such as the democratic party and the five star movement, and the hardest-hit regions -lombardy and venetoled by traditionally right-wing populist parties such as the league and brothers of italy. in particular, many of the administrative measures taken by the regions were in contrast with the government's strategy, largely for political reasons. from this standpoint, it can be seen that there has been an "institutional clash" between the regional governments and the national government on the political and administrative actions to be taken to effectively manage the emergency. it is no coincidence that the government's minister of health is a member of one of the opposition parties in lombardy and veneto, and that the governors of lombardy and veneto belong to the coalition opposing the government. to give a few specific examples, a bitter dispute has occurred between prime minister giuseppe conte and attilio fontana, governor of lombardy and member of the rightwing populist party league, with regards to the ineffective management of the emergency in the region most affected by the virus. similarly, as we have seen, luca ceriscioli, governor of the marche region and member of the centre-left party in the majority coalition, opposed the government's decision to declare a state of emergency only in the northern regions. 83 in essence, these strong political divisions have impacted effective power sharing among the different levels of government, causing problems for the government's incremental administrative strategy. (5) the incremental approach also shows the important role that scientific competence plays in emergency management. 84 in this regard, one of the main goals of scientific expertise is to inform and legitimise governments' decisions, especially in high-uncertainty situations relating to public health. during the covid-19 outbreak, scientific and technical experts have assisted central and regional governments by contributing to the content of decisions and, more generally, of administrative emergency management strategies. as scientific evidence is the basis for sound political choices, scientific and technical experts have become part of the rationale of governments' decisions and have been useful in reassuring the public with concrete solutions. 85 indeed, in the immediacy of a pandemic, as is logical to assume, the demand for scientific expertise increases as governments search for certainty in understanding problems and choosing effective measures for managing the emergency. especially in the most delicate phases of an emergency, scientific expertise is useful in informing, legitimising and justifying government evaluations and responses to problems, even as political and administrative considerations continue to govern such choices. the result is an increased reliance on scientific expertise and politicisation of scientific and technical information. 86 by invoking scientific expertise, policymakers create the need for what is perceived as evidence-based policymaking, which suggests to the public that political and administrative decisions are based on reasoned and informed judgments 87 aimed at ensuring the public interest and guaranteeing individual rights. however, a major problem is that scientific expertise might obscure the accountability of decisions. as scientific and technical experts serve to inform and legitimise political and administrative decisions, they may also obscure responsibility for policy responses and outcomes. 88 scientific expertise helps to establish the severity of a pandemic in a population, to understand the epidemiological trend over time and to evaluate the effects of political and administrative measures, from mitigation to suppression. nonetheless, undertaking policy actions is the responsibility of government leaders. as scientific expertise becomes more prominent in the policy process, who is accountable for policymaking becomes more obscure. 89 to work better in emergencies, scientific expertise also requires effective sharing of administrative powers based on accurate risk assessment, as i will now explain. in italy, since the beginning of the virus's spread, the various institutional actors, especially the government and the regions, have established their own scientific task forces to support administrative measures and strategies in managing the pandemic. the main problem is that, by doing so, risk assessment at the national level is fragmented. conflicts can also arise between institutional actors involved in the 84 decision-making process. in this scenario, indeed, the government and the regions have adopted administrative decisions and strategies based on the risk assessments provided by their own central and regional task forces. it should be noted that this situation, like others discussed here, derives from the current constitutional architecture of separation of powers where the decision-making process is assigned to the different levels of government. however, managing a pandemic requires a comprehensive risk assessment. italian policies matter, as they show how, at the beginning of the pandemic, some regions' task forces underestimated covid-19, while other regions gave it a certain importance. this behaviour on the part of policymakers was not led by the government, which, on the contrary, criticised the regional governments' solutions. the outcome, as i claimed for the incremental approach, is that the government's measures and strategies are not shared with those of the regions and vice versa, and policymakers' accountability is obscured by invoking scientific expertise for pandemic management decisions. b. implementing the national pandemic health plan there is no doubt that a pandemic affects the whole of society. no single organisation can effectively prepare for a pandemic in isolation, and uncoordinated preparedness of interdependent public organizations will reduce the ability of the health sector to respond. 90 a comprehensive, shared, coordinated, whole-of-government approach to pandemic preparedness is required. 91 the government's strategy, as we have seen in the incremental approach to dealing with the emergency, proved particularly ineffective due to the failure to share administrative powers with the other institutional actors involved in the pandemic decision-making process, particularly the regions. but this, as we shall see now, was not the only weak point. i will argue here that another of the major problems was the lack of effective implementation of the national pandemic health plan. in particular, we will see how and why the ineffective implementation of the plan by the government, regions and local authorities posed serious problems for containing the spread of the virus and, more specifically, for avoiding the collapse of the public healthcare system. on this point, one of the main problems for public health posed by the novel coronavirus is its ability to spread with exceptional ease and speed, 92 threatening to overwhelm the healthcare system. in particular, what should be especially clear from the data is the critical situation of the intensive care system in italy, 93 which has been severely weakened by the pandemic. 94 intensive care system at the national level, cooperating with the regions and local authorities to ensure that critical care bed availability is efficiently managed. in this case, effective actions shared among all institutional actors and based on an adequate and accurate risk assessment at the national level would avoid saturating the intensive care system in the medium and long term, while the government should be able to increase capacity in the short term. yet, the data on the intensive care system show that the situation was inefficiently managed in the regions hardest hit by covid-19, especially in lombardy, which paid a high price at the local level for the ineffective implementation of the pandemic health plan at the national level. more generally, it should be emphasised that this point also demonstrates the importance of sharing administrative powers between government, regions and local authorities to implement the pandemic management plan effectively throughout the country. in this connection, many elements based on scientific and epidemiological data demonstrate that the covid-19 pandemic called for effective cooperation and coordination across all levels of government. in addition, it must be borne in mind that fighting a pandemic hinges on many factors, most of which are time consuming or in any case cannot be accomplished quickly. preparing a candidate vaccine, for example, takes a long time in terms of both preclinical and clinical development. likewise, developing and testing an effective drug involves complex multi-stage clinical trials. such considerations might be sufficient on their own to justify taking effective actions to mitigate the pandemic emergency's impact on the public healthcare system. in this phase, as we have seen, emergency risk regulation requires that regulatory action be taken in the immediacy of an emergency in order to mitigate its impact (section iii.1). to avoid the collapse of the public health system, the government should thus have contained the spread of the virus by effectively implementing the nationwide pandemic management plan with the participation of all institutional actors. the who has recognised the importance of sharing administrative powers through the participation and cooperation of the various institutional actors involved in the strategy against pandemics. in this regard, the who has drawn up specific guidelines 95 for implementing a pandemic influenza preparedness plan 96 that states should apply in order to manage the spread of the virus throughout their territories. in particular, the who's guidelines encourage states to develop efficient plans, based on national risk assessments, with the effective participation of institutional actors at all levels of government. in italy, the most serious problem is that the government, although it had already developed its own national plan, 97 foster its effective adoption by the regions and local authorities, disregarding a crucial point of the who's guidelines. consequently, the failure to implement the national pandemic plan, as we have seen, created the conditions for the collapse of the public health system, with the overcrowding of intensive care units and the consequent loss of life. *** in conclusion, the italian policies regarding the covid-19 outbreak can demonstrate the importance of: (1) rethinking the incremental approach; and (2) implementing a national health plan for pandemics by sharing powers, and more specifically administrative regulatory powers for emergencies based on an adequate and accurate risk assessment at the national level, among the different levels of government with the participation, cooperation and coordination of all institutional actors involved in the pandemic decision-making process. as we have seen, sharing administrative powers at the different levels of government plays a particularly important role in managing emergencies in the constitutional scenario, where competences are distributed between government, regions and local authorities, and several institutional actors are allowed to adopt regulatory acts (see section iii.3). the major changes that the constitutional amendments have brought to policymaking in the italian legal system require that constant support be provided to the regions and local authorities, especially in emergencies. despite significant decentralisation, the government still has a fundamental role to play in sharing and coordinating administrative powers at the different levels of government and in ensuring loyal cooperation among all of the institutional actors involved in emergency decisionmaking processes. indeed, the government is tasked with promoting and coordinating "action with the regions" (article 5 of law 400/1988), as well as with advancing cooperation "between the state, regions and local authorities" (article 4 of legislative decree 303/1999). 99 similarly, the government must promote "the necessary actions for the development of relations between the state, regions and local authorities" and ensure the "consistent and coordinated exercise of the powers and remedies provided for cases of inaction and negligence" (article 4 of legislative decree 303/1999). looking at the constitutional perspective, some possible solutions might be proposed. (1) in the italian constitutional scenario, although concurrent power to legislate on matters of public health is vested in the state (ie the government) and the regions pursuant to article 117(3), the state (ie the government and the regions together), on the basis of the principle established by article 32(1), "safeguards health as a fundamental right of the individual and as a collective interest". i argue, more specifically, that safeguarding health is a task of the state based on the fundamental principle of the constitution referred to in article 3 (2) , where the duty of the state is to "remove those obstacles of an economic or social nature" that, by constraining 99 legislative decree 303/1999 <http://www.parlamento.it/parlam/leggi/deleghe/99303dl.htm>. the "freedom and equality of citizens", impede the "full development of the human person and the effective participation of all workers in the political, economic, and social organisation of the country". thus, i believe that under the joint interpretation of article 3 (2) and article 32 of the constitution, as well as the principle of loyal cooperation, the government and the regions must act by sharing administrative powers (and strategies) among them in order to protect the fundamental right to health. in so doing, the government can play an essential role in promoting institutional balance and cooperation between the national and local levels, maximising loyal cooperation and implementing vertical and horizontal subsidiarity. (2) sharing administrative powers for emergencies can also be encouraged and enhanced through the effective implementation of constitutional tools, such as the system of conferences based on the principle of loyal cooperation. (a) the conference on the relationships between government, the regions and the self-governing provinces is the key legal tool for multi-level political negotiation and collaboration. it serves in an advisory, normative and planning capacity and acts as a platform facilitating power sharing. (b) the conference on the relationships between government and the municipalities coordinates relations between the government and local authorities through studies, information and discussion of issues affecting local authorities. (c) the permanent conference on the relationships between government, the regions and the municipalities deals with areas of shared competence. 100 (3) in order to "safeguard health as a fundamental right of the individual and as a collective interest", article 120(2) of the constitution could be applied whenever it is necessary to guarantee "the national unity and the unitary nature of the constitutional system". i claim that this provision, which establishes the government's administrative substitution power, provides for the centralisation of administrative powers in specific cases contemplated by the constitution. in this sense, article 120(2) lays down that the government can act for the regions and/or local authorities in cases of "grave danger for public safety and security". in the light of this definition, the government's substitution for the regions and/or local authorities might be invoked as a result of the "grave danger for public safety", as well as in order to preserve "economic unity" and guarantee the "basic level of benefits relating to civil and social entitlements". in my view, however, the government should exercise its power of substitution as an extrema ratio whenever effective sharing among all of the institutional actors has not been implemented. article 120(2) is clear in this regard, requiring that the substitution power be exercised in compliance with the principles of "subsidiarity" and "loyal cooperation". 100 italy's national pandemic plan was adopted through the permanent conference on the relationships between central government, the regions, municipalities and other local authorities <http://www.regioni.it/sanita/2006/02/ 14/accordo-stato-regioni-9-2-06-su-pandemia-influenzale-97179/>. administrative powers"and more specifically the administrative regulatory powers for emergenciesbased on an adequate and accurate risk assessment, across the different levels of government with the participation, cooperation and coordination of all institutional actors involved in the emergency decision-making process: the government, regions and local authorities. fundamentally, i emphasised that the italian case reveals the importance of sharing administrative powers from two main points of view. first, i argued that the "incremental approach" to dealing with the emergency, although based on the proportionate use of powers, is largely ineffective or even harmful in the absence of cooperation among all actorsthe regions and local authoritiesinvolved in the main strategy implemented by the government (section iv.1.a) . second, i discussed the importance of cooperation between the government, regions and local authorities for the effective and efficient implementation of a nationwide pandemic health plan (section iv.1.b). i suggested that these points be viewed from a constitutional perspective in order to propose some possible solutions. from this perspective, the problems of effective sharing of administrative powers across the different levels of government could be resolved by systematically interpreting the constitution and implementing specific constitutional tools provided by the legal system (section iv.2). in conclusion, more generally, i argue thatand this is the main thrust of the articleadministrative powers should be shared across the different levels of government based on an adequate and accurate risk assessment with the participation and cooperation of all of the institutional actors involved in the emergency decision-making process in order to safeguard the fundamental rights enshrined in the constitution as well as in eu and international law. in pandemics, this aim must be achieved not only to guarantee the right to health, but also to safeguard all of the rights that might be jeopardised by the exercise of administrative powers and, more specifically, the exercise of emergency powers in dealing with the pandemic. the strong measure of "lockdown", for example, should be the extrema ratio of administrative powers because it suspends the rule of law and jeopardises rights. indeed, as i have claimed in analysing the italian policies, sharing powers with effective cooperation between government, regions and local authorities in managing the pandemic would optimise the adoption of nationwide virus containment measures, avoiding or at least delaying the application of stringent emergency measures such as the lockdown of municipalities, provinces, regions or even the entire country. taking into consideration the correct application of emergency risk regulation (section iii.1) and the precautionary principle (section iii.2), although lockdowns aim to contain specific areas that are most affected by the virus, they must be proportional to the risk that they intend to curtail. when such measures are adopted to protect the right to health, as is the case in a pandemic, this right must be balanced with other rights. yet, if administrative powers are not shared effectively across the different levels of government, the balancing principle might be disregarded by jeopardising one or more rights without legitimate justification (eg the right to freedom of movement enshrined in article 16 of the constitution). this is the problem that the italian policies bring to light: a problem that i believe that the government must take into account in the near future as it strives to manage covid-19 and other similar pandemics. perspectives on the precautionary principle les avatars du principe de precaution en droit public le principe de précaution en droit communautaire: stratégie de gestion des risques ou risque d'atteinte au marché intérieur? the legal origins of the precautionary principle are to be found in the vorsorgeprinzip established by german environmental legislation in the mid-1970s; see there is a close relationship between the two principles that has led some to argue that they may be used "interchangeably". however, other authors contend that the prevention principle applies in situations where the relevant risk is "quantifiable" or "known" and there is a certainty that damage will occur. in this sense, see, respectively, wt douma principio di prevenzione e novità normative in materia di rifiuti dal pericolo al rischio: l'anticipazione dell'intervento pubblico" [from danger to risk: the anticipation of public intervention] (2010) 2 diritto amministravio 355. 42 ecj case t-13/99 pfizer animal health sa v council in the same sense, see also case c-157/96 national farmers' union case c-180/96 united kingdom v. commission [1998], ecr i-2729 case c-236/01 monsanto agricoltura italia art 77 of the italian constitution <https italian constitutional justice in global context il sistema amministrativo dopo la riforma del titolo v della costituzione amministrazione e costituzione sussidiarietà e diritto alla salute substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov2) a novel coronavirus emerging in china, key questions for impact assessment mathematical biosciences and engineering 3062-87. for daily reports around the world, cf. who of the marche regional administrative court suspended the marche region ordinance issued on 25 the campania regional administrative court in particular, i maintain that this power would have been useful as a remedy for inaction or delay on the part of the regions and local authorities in implementing the national pandemic health plan or adopting emergency measures. in such cases, substitution powers may be granted to the central level of government (the appropriate ministry or the council of ministers), which intervenes instead of the local level (the regions and/or local authorities).the same considerations on the government's administrative substitution power can be applied to the following solutions as "ex post remedies" for the failure to share administrative powers effectively across the different levels of government.(4) the government has extraordinary administrative power to annul illegitimate measures (eg ordinances) issued by local authorities in order to "safeguard the unity of the national legal system" (article 138 of law 267/2000 101 and article 2 of law 400/1988). 102 the power, generally applied to measures issued by the municipalities, can be extended to regional measures on the basis of article 120(2) of the constitution. 103 (5) the government has the right of action to challenge illegitimate measures issued by the regions and other local authorities before the court, in accordance with the constitutional provisions governing judicial review in the italian administrative justice system (articles 24, 101, 103, 111, 113 and 125 of the constitution). in this article, starting from the main regulatory acts and considering scientific knowledge and epidemiological data on covid-19, i have analysed the administrative measures and strategies for fighting the pandemic implemented by the government in the immediacy of the emergency.specifically, i carried out this analysis to verify this strategy's effectiveness at managing the pandemic throughout the country.in analysing the administrative strategy, i emphasised the role that italy's current system of constitutional separation of powers plays in emergency management and how this system can impact health risk assessment.to do so, i first illustrated the risk management system in italian and eu law and discussed some key legal issues that are useful for clarifying the main points of the matter and for understanding the weaknesses of the administrative strategy with a view to proposing solutions that the government might take into account in adopting its strategy.in particular, i briefly examined the notion and features of emergency risk regulation (section iii.1), the potential and limits of the precautionary principle (section iii.2) and the rules governing powers and competences in the italian constitutional scenario (section iii.3).to summarise the main points of this analysis, i stressed that the italian policies for managing the pandemic demonstrate the importance of effective "sharing of key: cord-275496-ajlmvg1o authors: pasco, remy f.; fox, spencer j.; johnston, s. claiborne; pignone, michael; meyers, lauren ancel title: estimated association of construction work with risks of covid-19 infection and hospitalization in texas date: 2020-10-29 journal: jama netw open doi: 10.1001/jamanetworkopen.2020.26373 sha: doc_id: 275496 cord_uid: ajlmvg1o importance: policy makers have relaxed restrictions for certain nonessential industries, including construction, jeopardizing the effectiveness of social distancing measures and putting already at-risk populations at greater risk of coronavirus disease 2019 (covid-19) infection. in texas, latinx populations are overly represented among construction workers, and thus have elevated rates of exposure that are compounded by prevalent high-risk comorbidities and lack of access to health care. objective: to assess the association between construction work during the covid-19 pandemic and hospitalization rates for construction workers and the surrounding community. design, setting, and participants: this decision analytical model used a mathematical model of covid-19 transmission, stratified by age and risk group, with construction workers modeled explicitly. the model was based on residents of the austin–round rock metropolitan statistical area, with a population of 2.17 million. based on 500 stochastic simulations for each of 15 scenarios that varied the size of the construction workforce and level of worksite transmission risk, the association between continued construction work and hospitalizations was estimated and then compared with anonymized line-list hospitalization data from central texas through august 20, 2020. exposures: social distancing interventions, size of construction workforce, and level of disease transmission at construction worksites. main outcomes and measures: for each scenario, the total number of covid-19 hospitalizations and the relative risk of hospitalization among construction workers was projected and then compared with relative risks estimated from reported hospitalization data. results: allowing unrestricted construction work was associated with an increase of covid-19 hospitalization rates through mid-august 2020 from 0.38 per 1000 residents to 1.5 per 1000 residents and from 0.22 per 1000 construction workers to 9.3 per 1000 construction workers. this increased risk was estimated to be offset by safety measures (such as thorough cleaning of equipment between uses, wearing of protective equipment, limits on the number of workers at a worksite, and increased health surveillance) that were associated with a 50% decrease in transmission. the observed relative risk of hospitalization among construction workers compared with other occupational categories among adults aged 18 to 64 years was 4.9 (95% ci, 3.8-6.2). conclusions and relevance: the findings of this study suggest that unrestricted work in high-contact industries, such as construction, is associated with a higher level of community transmission, increased risks to at-risk workers, and larger health disparities among members of racial and ethnic minority groups. we first estimate the proportion of children having either asthma, diabetes, cancer or hiv (assuming no overlap in these conditions). we estimate city-level morbid obesity in children using the estimated morbid obesity in adults multiplied by a national constant ratio for each age group estimated from hales et al., 30 this ratio represents the prevalence in morbid obesity in children given the one observed in adults. from morgan et al., 7 we estimate that 25% of morbidly obese children have another high-risk condition and adjust our final estimates accordingly. resulting estimates. we compare our estimates for the austin-round rock metropolitan area to published national-level estimates 31 of the proportion of each age group with underlying high risk conditions (table s2 ). the biggest difference is observed in older adults, with austin having a lower proportion at risk for complications for covid-19 than the national average; for [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] year olds the high risk proportion is slightly higher than the national average. figure s1 . demographic and risk composition of the austin-round rock msa. bars indicate age-specific population sizes, separated by low risk, high risk, and pregnant. high risk is defined as individuals with cancer, chronic kidney disease, copd, heart disease, stroke, asthma, diabetes, hiv/aids, and morbid obesity, as estimated from the cdc 500 cities project, 5 reported hiv prevalence, 6 and reported morbid obesity prevalence, 7, 8 corrected for multiple conditions. the population of pregnant women is derived using the cdc's method combining fertility, abortion and fetal loss rates. [32] [33] [34] table s1. high-risk conditions for influenza and data sources for prevalence estimation data source cancer (except skin), chronic kidney disease, copd, coronary heart disease, stroke, asthma, diabetes cdc 500 cities 5 hiv/aids cdc hiv surveillance report 6 obesity cdc 500 cities, 5 sturm and hattori 8 morgan et al. 7 pregnancy national vital statistics reports 32 and abortion data 33 35 and hamer et al. 36 suggest that black race, lack of insurance, male sex, smoking, obesity, and physical inactivity increase risk. in order to assess the adequacy of our model, we measured the correlation between the prevalence of high risk conditions assumed by our model and the prevalence of other covid-19 high risk conditions, namely obesity, physical activity, insurance rates, and smoking rates across the cities included in the cdc 500 cities's dataset. 5 we find a high degree of overlap, with uninsured rates having the lowest correlation ( figure s2 ). figure s2 . correlation between high risk proportions assumed in the model (y-axis) and other covid-19 high-risk factors (x-axes): lack of health insurance, smoking, obesity, and physical inactivity prevalence. each point corresponds to a city included in the cdc's 500 cities project. numbers in plots are the pearson correlation coefficients. the model structure is diagrammed in figure s3 and described in the equations below. for each age and risk group, we build a separate set of compartments to model the transitions between the states: susceptible (s), exposed (e), pre-symptomatic infectious (p y ), pre-asymptomatic infectious (p a ), symptomatic infectious (i y ), asymptomatic infectious (i a ), symptomatic infectious that are hospitalized (i h ), recovered (r), and deceased (d). the symbols s, e, p y , p a ,i y , i a , i h , r, and d denote the number of people in that state in the given age/risk group and the total size of the age/risk group is . the model for individuals in age group and risk group is given by: where a and k are all possible age and risk groups, , , , are the relative infectiousness of the , , , compartments, respectively, is transmission rate, , is the mixing rate between age group , ∈ , , , are the recovery rates for the , , compartments, respectively, is the exposed rate, , are the pre-(a)symptomatic rates, is the symptomatic ratio, is the proportion of symptomatic individuals requiring hospitalization, is rate at which hospitalized cases enter the hospital following symptom onset, is mortality rate for hospitalized cases, and is rate at which terminal patients die. we model stochastic transitions between compartments using the -leap method 2,3 with key parameters given in table s3 . assuming that the events at each time-step are independent and do not impact the underlying transition rates, the numbers of each type of event should follow poisson distributions with means equal to the rate parameters. we thus simulate the model according to the following equations: with and where denotes the force of infection for individuals in age group and risk group and is given by: figure s3 . compartmental model of covid-19 transmission each subgroup (defined by age and risk) is modeled with a separate set of compartments. upon infection, susceptible individuals (s) progress to exposed (e) and then to either pre-symptomatic infectious ( ) or preasymptomatic infectious ( ) from which they move to symptomatic infectious (i y ) and asymptomatic infectious (i a ) respectively. all asymptomatic cases eventually progress to a recovered class where they remain protected from future infection (r); symptomatic cases are either hospitalized (i h ) or recover. mortality (d) varies by age group and risk group and is assumed to be preceded by hospitalization. individuals were initially separated into five age groups: 0-4, 5-7, 18-49, 50-64, and 65+ years old based on population data for the five-county austin-round rock metropolitan area from the 2017 american community survey. 4 each age group was divided into a low-risk and high-risk group, based on the prevalence of chronic conditions estimated for the austin population (fig. s2 ). 58 we also estimated the proportion of pregnant women in each age group as a special risk class. 9 all individuals were assumed to be susceptible to the disease. there are an estimated 50,000 construction workers in the austin metropolitan area representing over 4% of the labor force, 10 not accounting for undocumented workers. we assumed all construction workers to be in the 18-49 group for simplicity, with the same low/high-risk distribution, and we modeled them as a 6 th separate group with specific contacts, adding an extra row and an extra column to the contact matrices specifically for construction workers so as to be able to model their specific contact patterns as intended. all details on the construction of the adjusted contact matrices as well as the derived matrices are provided in sections 2.3-2.5. in order to keep the total population constant, we reduced the number of individuals in the 18-49 group according to the number of construction workers. infected individuals were modeled to enter an incubation period where they were symptom-free and not yet infectious. they then enter a pre-(a)symptomatic compartment where they do not present symptoms yet but they already transmit the disease, 11 with distinction between asymptomatic and symptomatic starting in this compartment. individuals then progressed accordingly to either a symptomatic or asymptomatic compartment. asymptomatic individuals were assumed to have the same pre-symptomatic and infectious period as symptomatic individuals but lower infectiousness. 12 the rates at which symptomatic cases were moved to a hospitalized compartment and died depended on both age and risk group. recovered individuals were considered fully immune. all model parameters are provided in tables s3-s5 and were based on published estimates from covid-19 studies as well as input from the us cdc and city of austin. age-specific contact rates were estimated using contact matrices published by prem et al. and are adjusted to model school closures and various levels of social distancing. 13 the pre-symptomatic period was sampled from a triangular distribution from 1.9 days to 3.9 days with mean of 2.9 days 11,14 and the infectious period was sampled from a triangular distribution from 3 days to 5 days with mean of 4 days, 11 with a mean generation interval estimated at 5.8 days. 14 we assumed the asymptomatic ratio to be 43% 15 with 44% of infections arising from pre-symptomatic transmission during the incubation period. 11 following the cdc's planning scenarios and observed data from the 2009 h1n1 pandemic in the united states, we assumed that the infection hospitalization rate and infection fatality rate was ten times higher in high-risk than low-risk individuals, within each age group. the average length of stay of 11 days in the hospital for people who survive and recover and 7.8 days for people who die is estimated using arrival and departure data from the seton system in austin. 16, 17 we estimate and simultaneously using a nonlinear least squares fitting procedure in the scipy/python package 18 for a given pair of and , we run a deterministic simulation of our model assuming central values for each parameter. using a trust region method, the algorithm finds values of and that minimize the sum of squared daily differences between the simulated ( ) and actual ( ) daily hospitalizations from march 13, 2020 through may 3, 2020: . we calculated 95% confidence intervals for the social distancing parameter indirectly by running 500 stochastic simulations for each of the following possible values of : 0.0, 0.05, ...., 0.95, 1.0. for each value of , we conducted the following analysis to determine if lies inside the 95% confidence interval for . • for all simulations, we calculate the day-to-day difference in hospitalizations (i.e., heads in beds) during the period following the stay home-work safe order: . we do the same for the actual data: . • we compute the 95% prediction interval for across all 500 stochastic simulations for for each day . • we then conduct a test of the null hypothesis . under this null hypothesis, we would expect roughly 95% of the observed data ( ) to fall within the 95% prediction band for that we constructed from our simulations. by analyzing the day-to-day difference in hospitalizations rather than daily hospitalizations, we can assume that the data are independent from one day to the next. then the expected number of observed values contained in the 95% prediction band is given by the binomial expression: where is the number of data points contained within the 95% prediction band and is the total number of data points (i.e., days). • if the binomial probability of is less than 0.05, we reject the null hypothesis . to construct a 95% confidence interval for we take the minimum and maximum for which we did not reject the null hypothesis . in order to obtain 95% confidence intervals for the basic reproductive number and the doubling time we calculated the 95% confidence interval for the transmission rate using the same methodology as that used for the social distancing parameter . we fixed the social distancing parameter at its best estimated value and ran 500 stochastic simulations for each of the possible values of : , , ... , with our best estimate for the transmission rate. we then conducted the same analysis as that described above and the 95% confidence interval for is obtained by taking the minimum and maximum for which we did not reject the null hypothesis . the confidence intervals for and the doubling time are then obtained by using the confidence interval bounds of as input to the system's next generation matrix. we assume there are currently 50,000 construction workers in the austin-round rock msa, all in the 18-49 yearold age group. the proportion of construction workers at high-risk of complications from covid-19 is the same as the overall 18-49y age group in the austin-round rock msa. we extended our us covid-19 pandemic model to include a separate population subgroup representing construction workers. we moved 50,000 individuals from the regular 18-49y low risk and high risk compartments into the corresponding construction compartments. we also extended the contact matrices 1 governing transmission between age groups to allow us to manipulate the number of construction workers and intensity of their contacts separately from the rest of the workforce. initially, we set their contact rates equal to those of the entire 18-49y population, except that we assume that all work contacts take place within the subgroup of construction workers. social distancing measures reduce home, work and other contacts for non-construction workers and home and other contacts for construction workers. tables s6-s9 give the original contact matrices and tables s10-s13 give the updated contact matrices assuming 50,000 construction workers. let ( ) , denote the average daily number of contacts that a person in group has with people in group at location . let denote the proportion of construction workers in the 18-49y group. age-specific contact rates were estimated by adjusting contact matrices published by prem et al. 13 we assume that, without construction work, the community-wide reproduction number is below one. basic epidemiology tells us that if the average number of secondary infections from infected construction workers to other construction workers exceeds one, then the community-wide reproduction number will also rise above one. we use this approach to determine the level of worksite transmission risk above which construction work undermines community mitigation (i.e., raises r0 above one). let denote the average number of secondary infections from an infected construction worker. we decompose this quantity into where and represent the number of infections occurring at work and other locations, respectively. our model assumes that construction workers only have contacts with other workers while at work, so that represents infections among workers. in general, indicates the proportional change in transmission risk on construction sites that would raise or lower to one. using our estimates for the population-wide reproduction number of covid-19 in austin (see eappendix 2.2) and published estimates for workplace and other contact patterns (see eappendix 2.4), we estimate for the austin area construction workforce, as follows. • we assume that, in the absence of covid-19 mitigation measures, the basic reproduction number for construction workers is the same as the population-wide basic reproduction number ( ) and that the average number of workplace secondary infections for construction workers ( ) is equal to the average number of secondary infections at the average workplace for the population as a whole. • let , , and denote the contact matrices governing interactions at home, work, school and other locations, provided in ref. 1 . we then estimate the typical weekday and weekend contact matrices as: and . and the average weekly contact matrix as: . let n be vector giving the population proportions for each age group and be the vector of ones of the same dimension as n. then the average number of weekly contacts in the population is given by . similarly the average number of weekly workplace contacts is given by . • let be a constant proportional to the transmission rate of the virus, such that and . this implies that . • given our estimate of for austin in march 2020 (table s4 ), we thereby estimate that the average number of workplace secondary infections for construction workers is . given that , we estimate that a 14% increase in workplace transmission risks relative to average workplace risk would enable sustained transmission among the construction workforce and undermine community wide social distancing efforts. in our main results, we assume that the high risk proportion among construction workers is the same as the general 18-49y population. thus, the estimated excess risk of hospitalizations among construction workers stems solely from increased exposure at work. given that the construction workforce may experience higher rates of high risk conditions 37,38 stemming from overlapping socioeconomic, racial, occupational and health vulnerabilities, we varied the high risk proportion for the construction workforce. specifically, we held the overall high risk proportion constant (for the population as a whole) and adjusted the ratio between the construction high risk proportion and the general 18-49y high risk proportion. we considered eight different ratios ranging from 0.8 (high risk proportion 20% lower in construction workers) to 2.0 (proportion double in construction workers). let and denote the proportion of high-risk individuals among construction workers and among 18-49y in the general population, respectively. we varied the number of high-risk construction workers and 18-49y such that: . the primary analysis presented in the manuscript assumes equal high risk proportions in the two groups and corresponds to . for each of these ratios, the corresponding numbers and proportions of high-risk construction workers and other adults in the 18-49 group are given in table s14. table s15. numbers and proportions of high-risk individuals among construction workers and nonconstruction workers in the 18-49y age group for the eight different risk scenarios. the ratio of high risk proportions, given as column headings, equals the proportion in the second row divided by the proportion in the fourth row. figure s5 compares the estimated relative risk of hospitalizations for construction workers through august 17, 2020 across the eight different scenarios. as in figure 3 , we calculated the ratio of hospitalization rate among construction workers and the hospitalization rate among other 18-49y. projecting social contact matrices in 152 countries using contact surveys and demographic data modeling infectious diseases in humans and animals approximate accelerated stochastic simulation of chemically reacting systems american community survey (acs) cities project: local data for better health | home page | cdc for disease control c, prevention, others. hiv surveillance report morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza a(h1n1) disease morbid obesity rates continue to rise rapidly in the united states estimating the number of pregnant women in a geographic area from cdc division of reproductive health temporal dynamics in viral shedding and transmissibility of covid-19 the relative transmissibility of asymptomatic covid-19 infections among close contacts projecting social contact matrices in 152 countries using contact surveys and demographic data evolving epidemiology and transmission dynamics of coronavirus disease 2019 outside hubei province, china: a descriptive and modelling study spread of sars-cov-2 in the icelandic population presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area incidence, clinical outcomes, and transmission dynamics of hospitalized 2019 coronavirus disease among 9,596,321 individuals residing in california and washington, united states: a prospective cohort study minimize(method='trust-constr') -scipy v1.4.1 reference guide estimates of the severity of coronavirus disease 2019: a model-based analysis people at high risk of flu multilevel regression and poststratification for small-area estimation of population health outcomes: a case study of chronic obstructive pulmonary disease prevalence using the behavioral risk factor surveillance system coronavirus disease 2019 case surveillance -united states transmission interval estimates suggest pre-symptomatic spread of covid-19 health outcomes | 500 cities who lives with chronic conditions. pew research center: internet, science & tech. published prevalence and costs of five chronic conditions in children cancer facts & figures trends in obesity and severe obesity prevalence in us youth and adults by sex and age prevalence of high-risk indications for influenza vaccine varies by age, race, and income births: final data for 2017 abortion surveillance -united states estimated pregnancy rates and rates of pregnancy outcomes for the united states characteristics associated with hospitalization among patients with covid-19 lifestyle risk factors, inflammatory mechanisms, and covid-19 hospitalization: a community-based cohort study of 387,109 adults in uk covid-19) health indicators and services -health risk factors and chronic illnesses among construction workers key: cord-147853-h9t7sp4z authors: stephany, fabian; stoehr, niklas; darius, philipp; neuhauser, leonie; teutloff, ole; braesemann, fabian title: the corisk-index: a data-mining approach to identify industry-specific risk assessments related to covid-19 in real-time date: 2020-03-27 journal: nan doi: nan sha: doc_id: 147853 cord_uid: h9t7sp4z while the coronavirus spreads, governments are attempting to reduce contagion rates at the expense of negative economic effects. market expectations plummeted, foreshadowing the risk of a global economic crisis and mass unemployment. governments provide huge financial aid programmes to mitigate the economic shocks. to achieve higher effectiveness with such policy measures, it is key to identify the industries that are most in need of support. in this study, we introduce a data-mining approach to measure industry-specific risks related to covid-19. we examine company risk reports filed to the u.s. securities and exchange commission (sec). this alternative data set can complement more traditional economic indicators in times of the fast-evolving crisis as it allows for a real-time analysis of risk assessments. preliminary findings suggest that the companies' awareness towards corona-related business risks is ahead of the overall stock market developments. our approach allows to distinguish the industries by their risk awareness towards covid-19. based on natural language processing, we identify corona-related risk topics and their perceived relevance for different industries. the preliminary findings are summarised as an up-to-date online index. the corisk-index tracks the industry-specific risk assessments related to the crisis, as it spreads through the economy. the tracking tool is updated weekly. it could provide relevant empirical data to inform models on the economic effects of the crisis. such complementary empirical information could ultimately help policymakers to effectively target financial support in order to mitigate the economic shocks of the crisis. with covid-19 ("coronavirus") reaching the level of a pandemic (see fig. 1a ), governments and companies around the world are also exposed to the resulting risks for the highly interconnected global economy. to slow down the spread of covid-19, governments in china, europe, the us, and beyond are taking drastic measures, such as travel warnings, border and store closures, regional lockdowns, and curfews. these measures are having drastic consequences for personal freedom and the economy. some sectors, such as airlines or hotels, are facing a nearly complete breakdown of demand. as a first reaction to the expected economic shocks, the global stock markets have collapsed (see fig. 1b ). in an attempt to mitigate the general economic downturn, governments all over the world are providing considerable financial support. the us government, for example, is preparing an aid package of 2.2$ trillion in response to the virus [1] . the german government plans to take up to 156 billion euros of additional debt (equivalent to half of the federal budget for 2020) to support the economy [2] . many of these immediate aid packages are not targeted to specific industries, but are meant to support businesses in all parts of the economy. while such general programmes can help to stabilise financial markets in the short term, it is paramount for their long-term effectiveness to concentrate the support to those areas of the economy that are most in need. for this reason, governments have to identify the industries that are most severely affected by the coronavirus pandemic. however, in the current situation, policy-makers lack reliable and up-to-date empirical data, which would allow to assess industry-specific economic risks in real-time. such information would be crucial to effectively target financial support as the crisis hits the economy and to mitigate the economic shocks. the study presented here investigates a potential data source that could provide an empirical basis to identify industry-specific economic risks related to covid-19 and to inform models on the economic effects of the current crisi. we examine company risk reports (10-k reports) filed to the u.s. securities and exchange commission (sec) and introduce a data-mining approach to measure firms' risk assessments. 1 in collecting all 1,750 reports published from 30th january 2020 -the day the term coronavirus first appeared in a 10-k report -to 29th march, we can assess and track the reported risk perceptions related to covid-19 for different industries. preliminary findings suggest that the company risk reports' show a forward-looking awareness of potential economic risks associated with the corona-crisis, which is leading stock market developments by weeks. moreover, the awareness towards covid-19 differs substantially between industries. for example, while 48 % of the firms in retail have mentioned the coronavirus as a potential economic risk, only 22 % of the businesses in financial services have done so. thirdly, based on natural language processing, we can identify specific corona-related risk topics and their perceived relevance for the different industries. lastly, our approach allows us distinguish the industries by their reported risk awareness towards covid-19. while not all sectors of the economy mention severe short-term risk factors due to the corona-crisis, the dense integration of business activities between all parts of the economy implies that adverse effects of the crisis could likely spread from currently affected industries to others over time. the empirical information provided could help to inform macro-economic models on the effects of the corona-crisis and, thus, help to inform policy-makers to better target current economic support programmes to industries that report most severe risks at the current phase of the crisis. the preliminary findings presented here are summarised in one compound index. the corisk-index 2 tracks industry-1 sec filings represent financial statements of publicly listed companies including a risk assessment. sec filings are imperative to comply with legal and insurance requirements and therefore should contain the most relevant risks. as a result, companies have a strong incentive to neither under-nor overestimate risks. moreover, analysing the most recent two-month period of sec filings represents a random sample of all companies since companies are obliged to report to the sec at a fixed, but randomly assigned date, independent of their industry. 2 http://oxford.berlin/corisk specific risk assessments related to covid-19 in real-time. it is available on an interactive online dashboard. this tool is constantly updated and the methodology will be refined. it allows researchers, policymakers, and the public to estimate potential risk factors of covid-19 in individual sectors of the economy. as the risk filings database is updated on a daily basis, the online tool will allow tracking the potential impact of the crisis as it unfolds and spreads through the economy. with more firms providing risk reports that describe the potential or real impacts of the crisis, the tool will be refined to allow for a more granular perspective on individual industries and sub-sectors. not all sectors of the economy are substantially affected in the early phase of the crisis, but dense inter-connections between all parts of the economy imply that the adverse business effects might spread to other industries over time. in this section, we review related work on the economic consequences of covid-19 and studies on previous epidemics. moreover, we discuss the assessment of economic risks via reports such as the 10-k reports required by the u. s. securities and exchange commission (sec). global pandemics of infectious diseases are not a new phenomenon. throughout the last century, the world experienced several global and regional outbreaks: most severely, millions died during the spread of the spanish flu in 1918-1920. regarding the economic impact by sector, gopinath [11] identifies manufacturing and the services sector as disproportionately affected in china, based on the purchasing managers' index. ramelli and wagner [12] uses google search intensity to measure attention paid to covid-19 and stock market data to reveal the economic impact by sector. their analysis shows that the energy, retail, and transportation sector experienced the largest losses in the united states and china, whereas health care gained considerably in both countries. the analysis by huang et al. [13] (also based on stock market data) confirms that the services sectors seem to be the most severely affected in china. in sum, baldwin and mauro [10] provides valuable context, insights and timely policy recommendations. however, none of the recent contributions provide an empirical database to analyse the economic risks of different industries based on up-to-date empirical evidence (beyond highly aggregated stock market signals). 3 at this point we want to highlight that it is not the aim of this study to present a model of risk forecasting that is competing with established macro-economic approaches. in contrast, the data-driven methodology presented here aims to explore an alternative data source that could help to inform such economic models. the advantage of the data we provide here is the high time resolution. more traditional sources of empirical information used to calibrate macro-economic model usually include, for example, unemployment rates. while the value of such statistics is undisputed, they are reported with a time-lag. we perceive the purpose of the index provided here to be a complementary data source that could be compared with official statistics on the economic effects of the crisis over time. while research on recent epidemics are limited to simulations [14, 15] , or specific sectors [16] , the study of historical pandemics might provide informative empirical assessments of pandemic-related economic effects. studies on the 1918 spanish flu confirm the primordial effectiveness of non-pharmaceutical (such as, for example, social distancing) interventions even if these come at the cost of economic slowdowns [17, 18] . moreover, based on the historical data, researchers find a correlation between mortality rates and declines in gdp, consumption and returns on stocks [19] and an increase in poverty [20] . however due to the global scope of the crisis for the highly inter-connected world economy of 2020, insights derived from past epidemics are of limited use in identifying the various industry-related risks during the covid-19 pandemic. both, the research on covid-19 and the historical pandemics rely on stock market information to quantify the economic effects of infectious diseases. however, stock market information comes with several drawbacks. most importantly, stock markets are prone to irrational herd behaviour and prices capture a variety of information signals into one aggregated index. examining current stock market dynamics reveals a general economic downturn, but it does not allow to isolate the sector-specific covid-19 risks. therefore, we propose to use sec reports which include risk statements. we argue that these reports represent a promising real-time measure of industry-specific business risks. furthermore, the analysis of report statements discussing 'coronavirus' allows to isolate the business risks exclusively associated with the covid-19 outbreak. since the great recession hit the world economy in 2008, risk has been a crucial topic in governance and finance. while risk assessments of the financial system led to diverse measures to make the world economy less vulnerable to economic shocks originating in the financial sector, a health crisis, such as the current pandemic, poses different risks to the economy. while government measures against the spread of the disease hinder the population from working and consuming, which results in businesses interrupting production, many economies face demand and supply shocks at the same time. in particular, as different industries rely on distinct input factor compositions and supply chains, the sectors of the economy react differently to shocks [21] . regarding the covid-19 crisis, we expect sectors whose operations are more connected to supply from manufacturers in china to publicly report corona-related risk earlier than others. these sectors are also highly connected and interdependent within the national economy and risk might spread between sectors [22, 23] . most risk assessment approaches focus on quantitative probability-based methods and financial data [24, 25] . the data published in such quantified risk assessments is often made available retrospectively, which makes a real-time evaluation of risks difficult. in contrast to such assessments, we investigate the annual 10-k reports filed to the u. s. securities and exchange commission (sec), which provide verbal corporate risk disclosure and financial statements. besides, sec filings are imperative for legal and insurance requirements and they need to contain the most relevant risks to protect the company from legal liabilities. depending on the volume of publicly traded stocks, companies with a public float of over 700 million usd are obliged to report within 60, while smaller companies have 75 or 90 days after the end of the fiscal year. furthermore, the reports inform investment decisions and risk governance at the same time and, thus, companies, as rational agents, are likely to communicate moderate risk assessments [26] . in fact, prior work has underlined the forward-looking nature of the reports, since they allowed a more effective prediction of volatility on stock market returns than the compared approaches [27] . correspondingly, we expect the 10-k reports to also provide forward-looking information on risk assessments during the observed time period and in particular on rising business risk in relation to the spread of covid-19. moreover, the filing companies are categorised into sectors using the "standard industry classifier", which allows a real-time analysis of industry-specific risk developments. in this study we apply natural language processing to extract corona-related risk information from the reports and analyse sector-specific differences in risk awareness and disclosure (details in section 3 and in the appendix a). based on the literature on the potential economic effects of pandemics and on the information available in business risks reports, we derive the working hypothesis 4 of this study: working hypothesis: sec 10-k reports contain corona-related information, which allow to track the industryspecific economic risk assessments in near real-time as the economic crisis unfolds. this working hypothesis is split into five operationalised hypotheses. a core assumption of the investigation of the risk reports is that they contain economic meaningful information. accordingly, the sentiment of the reports should reflect overall market conditions: h 1: 10-k risk reports contain economic relevant information on short-term market expectations, i. e. they are correlated with overall stock market trends in the current crisis. in contrast to stock indices, which are essentially a highly aggregated signal of all market expectations, risk reports provide a detailed outlook of individual risk factors and their potential influence on business outcomes. 5 as some of the potential economic effects of the corona-crisis could be already foreseen when the disease was still largely concentrated in china (in particular risks with respect to supply chain interruptions), we hypothesise that: industries are affected differently during the crisis, depending on their business model. as introduced in [28] , the economic crisis will unfold in several phases with different characteristics. those sectors of the economy that are more vulnerable to supply chain interruptions and short-term collapses of consumer demand should be more affected in the early phase of the crisis than other sectors: corona-related risk factors in 10-k reports differ between industries. 4 while the results provided in this working paper are largely descriptive, we present the research hypotheses, which have guided our data exploration. 5 this should not imply that the firms have a correct risk forecasting model in place or that they actually use all available information to provide a best-possible risk prediction. instead, we assume that the firms report risks that they perceive as relevant at the time of reporting (see also the methodological limitations section below). a presumption of our approach is that firms try to 'honestly' report relevant risks, not that they actually predict them. with more data becoming available over the next weeks (in particular first statistics on the macro-economic effects, such as unemployment rates), we will incorporate predictive models to get a better understanding in how far the reported risk factors indeed correlate with advers effects experienced. in the early phases of the crisis, as the market expectations adjust, all sectors suffer from restrictions to business activity, which manifest in collapsing stock market prices. however, one would assume that those firms that show most severe corona-related risks in the early phase of the crisis will see most stock market losses: h 4: stock prices of firms in industries that report high risks lose more value than other firms in the short term. while the crisis unfolds, adverse economic effects radiate through the highly inter-connected economic system. as some sectors that are severely affected already in the early phase of the crisis face increasing challenges, their problems transmit to other sectors, in form of less demand, reduced purchasing power or supply interruptions. consequently, we hypothesise that 6 : h 5: as the crisis unfolds, those sectors that are densely connected with industries that report high risks in the early phase of the crisis, are likely to report increasing risks sooner than other industries. to test the hypotheses, we use web-mining techniques to collect data from sec 10-k reports and conduct text mining to extract information relevant for the individual hypotheses, as outlined in the next section. section 4 presents the results of the analysis. the 10-k sec filings, as legal reports to publicly communicate corporate risks and financial statements, provide a valuable and innovative text data source for risk assessment. 7 we use a web scraper to collect all 10-k filings published between 30/01/2020 and 20/03/2020 from the sec's "electronic data gathering, analysis and retrieval system" (edgar) database. the filing documents contain the company names and central index keys (cik) as unique firm identifiers and the standard industry classifier (sic) that allow linking and comparing the filings data with individual business and industry data. each 10-k filing contains a risk factor section (item 1a) under which the reporting company is obliged to disclose all types of risks their business might be facing to adequately warn investors. companies are required to use "plain english" in describing these risk factors, avoiding overly technical jargon that would be difficult for a layperson to follow. the text of each risk factor section builds the document by which a company is represented in our analysis smaller reporting companies are hence not included in our analysis. the entire risk factor text is set to lower case for further analysis, before the occurrence of the main two keyword tokens, 'corona' and 'covid', is counted. any word containing one of the two main tokens is likewise counted. hereby the measure 'corona-keyword count per report' is created. similarly, each company that reports one of the keywords at least once is included in the 'share of corona-mentioning firms per industry' . after text pre-processing, we apply different natural language processing tools to analyse the risk factor section of the reports. different sectors are facing different challenges, therefore companies are reporting about different corona-related risks. we aim to capture these risk topics via a keyword search on predefined topics. in order to explore possible topics, we use latent dirichlet allocation (lda) for unsupervised topic modelling, similar to [29] . we only apply the topic model to corona-related paragraphs in the risk sections. we additionally examine the most frequent words 6 testing this hypothesis requires more time-series data and data on potential propagation mechanisms through the economy. we plan to include an analysis on this in a revised of the working paper. 7 the data source explored here is not meant to replace any established macro-economic statistics, but rather to provide a complementary alternative source of data to identify immediate industry-specific risk perceptions. and bi-grams in the documents. using this exploratory analysis, we define a set of topics by hand, which are specified by keywords. we then conduct a keyword search to count how much these terms are mentioned in the different industries in order to estimate the topic prevalence. moreover, we measure the sentiment of corona-related paragraphs via sentiment analysis. additionally, we build a sentiment-based risk indicator of the sentiment in sentences that mentioned the coronavirus and compare it to stock market movements during the observation period ( fig. 1b and 1d) . a more detailed description of the different methods can be found in the appendix a. the main results of our analysis are displayed in figure 1c and d as well as in figure 2 . 8 from the end of january 2020, an increasing number of 10-k reports refers to the coronavirus (fig. 1c) , indicating an increasing awareness of covid-19 as a potential economic risk. the overall sentiment of the 10-k reports decreased sharply (red line in fig. 1d ), following the collapsed stock markets after 15th february (red line in fig. 1b) . this timely correlation provides evidence in favour of research hypothesis h 1 -the 10-k reports provide economically relevant information. moreover, the sentiment of the text sections that discuss the corona-related business risk factors (blue line in fig.1d) decreases already a few weeks before the overall negative business outlooks manifested in falling stock prices. this observation supports hypothesis h 2: corona-related risk sentiments show a time lead compared with overall stock market dynamics. from this comparison, we conclude that the 10-k reports contain business relevant information that can be isolated -in contrast to the aggregated signal covered in stock indices alone. investigating the reports can, thus, provide additional information about the firm-and sector-specific risks associated with the pandemic. differences in corona-related risk assessment by industries are displayed in figure 2 . not all sectors of the economy show a similar awareness of the potential business impacts of the pandemic ( fig. 2a) , which provides evidence in favour the firms, moreover, differ substantially with regards to the intensity with which they discuss the potential impacts of the coronavirus to their businesses in the 10-k reports. as fig. 2b shows, some firms, in particular in retail and manufacturing, mention terms related to the pandemic ('corona', 'coronavirus', 'covid') substantially more often than other firms. the 10-k reports moreover provide information about specific types of risk perceptions. fig. 2c provides a heatmap with important topics per sector. the rows represent five relevant topics (demand, finance, production, supply, and travel), which have been derived from unsupervised topic modelling and subsequent uni-and bi-gram search. 10 the cells of the heatmap are coloured according to the topic relevance, i. e. the number of topic-specific keywords per industry. additionally, we have applied a hierarchical clustering algorithm on the data to identify related topics and sectors, which report about similar topics (tree-like dendrogram plots at the side of the heatmap). 8 at this point we want to highlight, again, that the results reported here are preliminary. with more data becoming available over the next weeks and, hence, with a refined methodology, we expect to be able to report more in-depth analyses and conclusive findings. these will be constantly updated on the online dashboard. moreover, we want to emphasise that all quantitative findings are build on data of u. s. firms. it remains to be seen in how far the findings could be extrapolated to other economies. 9 in some of the industries, only very few firms have provided risk reports in the current observation period. in particular in these groups, the results are likely to change as more data become available. 10 details of the text mining approach and the final keywords that define the topics are provided in the appendix. the figure reveals that most firms either report demand and financial risk factors (left branch of the top-dendrogram) or production and supply chain risks (middle branch of the top-dendrogram). for example, supply chain problems represent the biggest reproted risk component for firms in the retail industry, while manufacturing firms report both supply and production risks, as well as finance and potential demand risks. while reports of the mining industry consider demand-related issues as the biggest risk factor, other sectors, such as real estate or education, do not report extensively about any of the specific risk types. these findings support hypothesis h 3 -corona-related risk factors reported in 10-k reports differ between industries with regard to occurrence and topical context. the reports are, thus, a valid data source to identify sectors that face particular risk factors in the current early phase of the crisis. based on the quantifiable corona-related risk factors inferred from the 10-k reports (share of reports mentioning corona-risks per industry, average count of corona-keywords per report, sentiment of corona-related text sections), we could categorise the industries into three risk groups (details of the calculation of the risk ranking and the categorisation are provided in the appendix). 11 the clustering of sectors into the groups is displayed in fig. 2d . the lowest risk group 1 is dominated by infrastructure sectors, such as construction and power supply, but also includes financial services. several intermediate risks (group 2) are reported by different industries from the services sector, for example, admin services or information and communication. the highest risk group 3 contains manufacturing, retail, education, water supply, and hospitality. in contrast to hypothesis h 4, the different risk groups do not show substantial differences with regards to short-term stock losses. while this observation is not aligned with our initial hypothesis, it underlines that stock markets are less suited to differentiate industries by corona-related economic risk perceptions, as the deteriorating overall market expectation dominate in the stock price signal. other data sources, like the 10-k reports investigated here, provide a more granular perspective on covid-19 related perceived risks. while a one-dimensional categorisation of risk assessments tends to over-simplify the crisis firms are facing, it allows to compare the different industries and to identify those parts of the economy, which currently report more or less severe effecs due to the immediate economic consequences of the pandemic. the data-driven assessment reveals, in particular, that manufacturing and retail are among the industries that report to be most vulnerable to the changing economic environment. not only decreasing consumer demand but particularly problems along the supply chain mark substantial risk factors for those industries. on the other hand, it is mostly firms from the information and communication services sector, which are less dependent on the physical transport of goods, that are currently reporting fewer risks. moreover, with only 4 % of the 10-k reports mentioning the coronavirus as a potential risk factor, the construction sector seems largely unaffected by the short term economic shocks. the extent to which the industries are affected by corona-related business risks is likely to change over time. accordingly, the risk categorisation presented here is a static measure that needs constant updating and refinement as the crisis unfolds. to do this, the study is supplemented by an online dashboard, which tracks the main findings 11 please note that the ordinal categorisation into different risk groups will be replaced by a continuous risk index for all industries, as more reports are released over time. the simplyfing categorisation of industries into risk groups would most likely need considerable adjustments over time, as more reports will include corona-related risks. with substantially lower values. with more reports being released over time, we will update and refine the corisk-index to allow for more fine-grained industry-specific analyses, including breakdown by topics and sentiment. the index starts with zero, indicating no corona-related business risks in the reports. we will track the corisk-index over the course of the corona crisis until the index reaches zero again. as discussed in section 2, economies are characterised by dense flows of demand, supply, and capital between the industries. accordingly, we highlight this inter-connectedness in fig. 3b , displaying the top-two cross-industry capital flows per sector within the u. s. economy (based on 2015 the national input-output table provided by the oecd). as the figure reveals, specific parts of the economy are currently mentioning the most substantial risks, in particular manufacturing, retail, and hospitality. industries in the primary sector, infrastructure, and services are currently reporting fewer risks. while the short term nature of the investigation presented here does not allow for industry-specific time-series investigations, which would be necessary to provide final evidence in favour of hypothesis h 5, the dense interconnection between all parts of the economy indicates that it is only a matter of time until the risk factors from decreasing consumer demand and supply chain interruptions will transfer to the other parts of the economy. 12 as the covid-19 pandemic unfolds, governments are attempting to reduce contagion rates at the expense of personal freedom and negative economic effects. sizeable cyclical and fiscal policy packages are prepared in order to counterbalance the dooming global economic downturn. in order to ensure an effective usage of public crisis spending, it is paramount to understand in detail which industries are most affected by the pandemic and currently most in need of support. this study introduces a data-mining approach to measure the reported business risks induced by the current covid-19 pandemic. we examine company risk reports filed to the u.s. securities and exchange commission (sec). harnessing this data set enables a real-time analysis of potential risk factors. preliminary findings show that the companies' risk awareness is preempting stock market developments by weeks. while stock prices typically condense the market's multiple signals, the 10-k reports allow to isolates the company risk perceptions associated to the covid-19 outbreak. moreover, this risk awareness differs substantially between industries, both in magnitude as well as in nature. based on natural language processing techniques, we can identify specific corona-related risk-topics and their relevance for the different industries: supply chain-and production related issues seem to be mostly relevant for retail and manufacturing, while several industries have reported demand-or finance related risk factors. additionally, our approach allows to cluster the industries into three groups of reported risk factors, giving a better understanding of which industries are considering the most severe impacts at the current stage. we summarise the corona-related business risk perceptions per industry in a compound index published online. 13 the corisk-index, which will be updated constantly over the course of the crisis, provides an up-to-date database to identify the industries that report most substantial risk factors in the different phases of the unfolding economic crisis. the online dashboard can provide a data source to inform economic models and to provide empirical information that could help to assess potential policies, which aim to effectively target financial support and to mitigate the economic shocks of the current crisis. 12 in the current version of the working paper, fig. 2e represents a simple visualisation of some relevant economic flows within the u. s. economy, which imply likely propagation channels of adverse economic effects. in a revised version, we will include a more detaile network analysis to investigate potential risk propagation mechanisms. 13 http://oxford.berlin/corisk governments are eager to counterbalance the dooming global economic crisis induced by the covid-19 pandemic with cyclical and fiscal policy packages of enormous volumes. democratic accountability demands this public crisis stimulus to be spend as effectively as possible. our data-driven analysis of the 10-k sec filings provides an alternative data source, which could be used to help identifying industries that are most severely affected by covid-19. in particular the industries in risk group 3 are currently reporting most severe effects from the sharply decreasing consumer demand and interruptions of the supply chain, and might face substantial problems through the unfolding of the crisis. 14 other parts of the economy, in particular information-processing service industries and construction, are currently reporting less severe corona-related risks. however, as the shock will transmit throughout the tightly inter-connected economy over time, these industries are likely to face larger challenges at a later stage in time. nonetheless, at the current stage, their core businesses seem to be less directly affected by supply chain interruptions and collapsing consumer demand than other industries. our approach is based on the risk assessments in the u. s. securities and exchange commission (sec) filing reports. thus, the value of the approach relies crucially on company self-reporting. while the firms are unlikely to provide a risk prediction with a high forecasting accuracy, it might still be worth exploring the reports as alternative data source to measure risk perceptions. as the reports serve as legal and insurance requirements against financial risks, but also as a basis for investment decisions of investors, companies are implicitly encouraged to neither over-nor understate the risks they are facing. nevertheless, our results are limited to this self-assessment. as many of the implications of the corona crisis are still uncertain, our approach thus reflects a way to approximate potential implications on current estimations of experts in the different sectors, represented by the companies, and does not include risks that are unforeseeable for themselves at a given point in time. moreover, the data to assess the precision of these estimations does not exist yet, as there has not been a pandemic with comparable global economic consequences in recent time. in the future, we will evaluate our results by looking at employment data in different sectors. moreover, the pandemic continues to spread and will soon affect all industry sectors and all countries of the world. as more and more companies will report on related risks, the count of corona mentions alone will lose its information-value as a measure to differentiate between endangered industry sectors. then, more granular measures, such as the identified topic categories, will become more important to distinguish between different natures of risks. the exploration of alternative data sources that are meant to complement or now-cast established economic statistics always comes with uncertainty. for example, it is not yet clear how the short-term risks described by the different industries will translate into long-term economic outcomes, such as bankruptcies. nonetheless, we believe that the reports could be a reliable source of empirical information about the issues faced by different industries in the current situation, and they might be used to inform forecasting models on industry-specific economic effects of the crisis, as they help fill a data gap. models that incorporate alternative data sources such as the one presented here could then be beneficial for developing economic support packages that are currently provided by governments. all technical methods serve the higher purpose of providing timely and comprehensible insights into the industryspecific effects caused by the global outbreak of the coronavirus. to mitigate susceptibility to errors and increase 14 at this point, we want to emphasise again that the findings are preliminary and might change over time, as more data becomes available and as the research methodology is refined. moreover, the risk categorisation presented in this study is not meant as a direct policy recommendation. instead, the tool is meant to provide an empirical source of information for real-time tracking of industry-specific risk perceptions, which can help to inform policy makers in times of a fast-evolving economic crisis. reproducibility, we mostly draw from more basic technical methods. this can be seen in the discovery of corona-relevant keywords which is based on the matching of regular expressions to avoid error-prone text pre-processing. reduction of technical complexity, however, comes at the cost of diminished modelling fidelity and potential accuracy of results. for instance, the sentiment classifier has not been fine-tuned on text snippets discussing financial risks in particular. further, it may be questioned whether a generalist sentiment score yields a reliable measure for the assessment of risks. additionally, the lda-based topic modelling approach lacks in interpretability and robustness, and we therefore only use it for exploration until now. the topics and keywords we use for estimating topic prevalence are therefore hand-coded which limits the detection of topics to predefined terms. in general, the findings presented here should be considered as preliminary. sensitivity checks are needed to validate their robustness, and numerous extensions will help to better assess the potential value of the exploration of 10-k reports as a complementary data source to measure industry-specific risk factors. we expect some of these limitations to be mitigated with more reports to be analysed in the near future. adjusted results will be published on the online dashboard and in a refined version of the working paper. the following impetus for future work builds directly on the identified methodological limitations and caveats mentioned throughout the paper. rather than harnessing generalist sentiment analysis, future efforts should explore risk classifiers trained on labelled financial risk assessments and entity sentiment analysis [30] . the robustness of the results needs to be checked in more detail. in particular, we will compare historical stock market and unemployment data with risk measures extracted from 10-k reports to investigate the correlation between risk reports and overall economic trends. this also holds for the natural language processing methods applied. based on more data that is to be captured in the next weeks, we will explore in how far different text mining methods lead to similar results with respect to the topics that can be extracted, and what the effect of different keyword choices is on the results presented in the heatmap. to investigate the potential propagation of risk factors through the economy, we will include a network analysis based on input-output data to identify the most contagious areas of the economy. another promising direction is the extension of the inter-sectoral u. s.-centred trade network to more comprehensive data on international inter-and intra-sectoral trade. analysing inter-national cooperation networks [31] , mining industry-specific key technologies [32] and drawing from more advanced network analysis techniques such as dynamicity [33] or sentiment-based network clustering [34] will be highly beneficial. likewise, the content of other online platforms, such as wikipedia, as a source for risk assessment could be explored [35, 36] . this could allow an estimation of operational risk channels and risk spillovers propagating between industries and countries due to global supply chains and peer-tier co-operations. considering more financial data could include credit risks (financial exposures) of companies. besides the comparison with additional financial signals, we plan to include unemployment rates in our analysis as an exogenous variable to the sec risk assessment. we are grateful for comments made by andrew stephen, felix reed-tsochas, felipe thomasz, and slava jankin. their comments have helped to substantially improve the working paper. sentiment analysis on the sec filings serves the purpose of a more contextualised semantic understanding of the risk assessment concerning covid-19. we selected the paragraph of the risk report, with the highest number of coronavirus mentions and calculated the sentiment based on the textblob api [39] using the code developed in [30] , we use unsupervised learning techniques to identify the main topics that companies mention when describing coronavirus related risks. latent dirichlet allocation (lda) is a bayesian computational linguistic technique that identifies the latent topics in a corpus of documents [40] . this statistical model falls into the category of generative probabilistic modelling: a generative process which defines a joint probability distribution over the observed random variable, i.e. the words of the documents, and the hidden random variables, which is the topic structure. in other words, lda uses the probability of words that co-occur within documents to identify sets of topics and their associated words [29] . the number of topics has to be defined in advance. lda is a frequently used technique to identify main topics in a corpus. nevertheless, the interpretation of these topics can sometimes be difficult. we thus perform lda for explorative purposes in our research only. by additionally exploring the most common words and bi-grams we then define topics and the defining keywords by hand. we then detect how often companies mention these keywords in the corona related risk sections to estimate how important the topics are in different sectors. in particular, we perform the following steps: referring to section a.3, we filter all sentences from the risk sections that mention either "corona" and "covid", thereby also accounting for "coronavirus" and "covid-19". before we train the lda model we prepare the documents to achieve better performance of the method. we remove all common english stopwords, which are frequent words such as "is, " "the, " and "and" as well as those words which appear in at least 80% of the documents. these words are not useful in classifying topics as they are too frequent and therefore decrease performance. moreover, we delete all words that do not occur in at least 2 documents. we turn the documents into numerical feature vectors ("bag of words" representation). these vectors disregard word order and simply contain the number of times a word appears. we then use lda to extract the topic structure. like any unsupervised topic model, this requires setting the number of topics a priori. we selected this key parameter based on semantic coherence, evaluating a range of 2 to 8 topics, which leads to a final model of 4 topics. the top 10 terms of each topic are displayed in table 2 . the derived topics give a good insight into the general narratives of risks used in the documents. nevertheless, they are hard to interpret, as the early corona-related risk reports are still quite generic such that most of the companies cover a lot of risk factors. thus we make use of our insights from the topic modelling to define 5 main topics defined by keywords, displayed in table 1 . the choice of keywords is additionally informed by clustering the most frequently used words and bi-grams in the documents. we then measure the frequency of these keywords per topic per industry in all of the documents to get more insights into the nature of risks different sectors are facing due to the pandemic. production business operation, business disruption, product, work stoppage, labor disruption, labor, work, manufacturing operation, labor shortage, employee productivity, product development, business activity supply manufacturing facility, manufacture facility, contract manufacturer, service provider, logistic provider, supply disruption, party manufacturer, supply disruption, facility, supply, transportation delay, delivery delay, supplier, business partner, supply chain, material shortage house leaders 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safety some foundational issues related to risk governance and different types of risks sec adopts rules to modernize and simplify disclosure predicting risk from financial reports with regression covid-19: europe needs a catastrophe relief plan the evolution of 10-k textual disclosure: evidence from latent dirichlet allocation measuring proximity between newspapers and political parties: the sentiment political compass global networks in collaborative programming mining the automotive industry: a network analysis of corporate positioning and technological trends disentangling interpretable generative parameters of random and real-world graphs hashjacking" the debate: polarisation strategies of germany's political far-right on twitter an exploration of wikipedia data as a measure of regional knowledge distribution coding together-coding alone: the role of trust in collaborative programming rank and filed, sec filings for humans yahoo! finance market data downloader simplified text processing -textblob 0.15.2 documentation probabilistic topic models we use web crawlers and scrapers written in the general programming language python for finding and extracting the relevant risk section in the 10k reports. via the sec online interface 15 past sec filings are queried since the first emergence of 'coronavirus' in a report on january 30th 2020. a web crawler allows to find the relevant risk factor section in the 10-k reports and stores each paragraph for later text processing and analysis. the collection of stock market data follows the incentive to provide reference data for the company sec filings. in both, sec filings and financial markets, each company is assigned a unique central index key (cik) and a ticker number. based on the cik, we identified a list of 13,737 companies using the data registry provided by rank and filed [37] . this list was then filtered by the list of companies of which we obtained sec filings. using the yahoo finance api, we finally retrieved stock prices for all remaining companies in the list [38] . since this study examines the attention attributed to covid-19 in the sec filings, the discovery mechanism of relevant covid-19 mentions is of central importance. to mitigate susceptibility to errors due to word splitting, stemming and other text preprocessing, we decided for the most simple approach based on the matching of regular expressions. we scanned the reports for the two relatively unambiguous terms "corona" and "covid", also accounting for "coronavirus" and "covid-19" without duplication. key: cord-282982-dc5m81bx authors: rouillard, smita; liu, vincent x.; corley, douglas a. title: covid-19: long-term planning for procedure-based specialties during extended mitigation and suppression strategies date: 2020-05-18 journal: gastroenterology doi: 10.1053/j.gastro.2020.05.047 sha: doc_id: 282982 cord_uid: dc5m81bx nan the covid-19 pandemic has placed patients and their communities at tremendous risk from acute illness as well as economic uncertainty. 1 given varying degrees of mitigation and suppression may persist for 1-2 years, there is a critical need for pragmatic approaches for reopening procedural and surgical units, addressing backlogs, and establishing standards of care which balance patient risk and benefit, while maintaining the procedural volumes needed for patient care during this time of ongoing disease control measures. this commentary will: define mitigation/suppression; describe its effects on procedure-related health care backlogs; and discuss strategies for risk stratification and patient care. these will be supplemented by relevant examples from a large region of kaiser permanente, an integrated healthcare system that cares for approximately 1 of every 30 people in the united states. the successful management of epidemics from the world health organization 2 and the imperial college covid-19 response team 3 suggests several initial phases and recommended actions: • emergence of infection (recommended action of early detection); • localized transmission (recommended action of containment, using countermeasures such as isolation, contact tracing, and testing); • amplification and rapid spread (recommended action is control measures such as mitigation and suppression). mitigation permits a controlled outbreak; it slows viral spread to "flatten the curve" with the aim of maintaining levels of illness within existing healthcare system capacity, using measures such as quarantine of infected patients and their contacts and social distancing of those at increased risk of severe disease. suppression, a more aggressive control approach, seeks to minimize cases, even to reverse epidemic growth, using additional measures such as social distancing of the entire population, with closures of schools and businesses (including elective medical visits). 4 healthcare systems have radically restructured their operations to brace for surges in acute covid-19 hospital demand and in response to regional mitigation and suppression measures. these measures included deferrals of routine elective and semi-elective healthcare, including the majority of endoscopic and surgical interventions 5 for screening, diagnosis, and treatment. these actions may impact patients' health and, for many systems, modify revenues needed to sustain healthcare delivery during and after the pandemic. at kaiser permanente in northern california (kpnc), a kaiser permanente region serving 4.5 million members, early surges of covid-19 inpatients in two medical centers led to regional mitigation/suppression measures and the rapid cancellation of elective procedures/surgeries throughout our 21 hospital system in march 2020, aligned with recommendations from the centers for disease control and prevention (cdc), gastrointestinal specialty societies, and the american college of surgery. 6 , 7,8 the resulting number of deferred elective procedures across our system by may, 2020 is substantial, since we typically have approximately 10,000 gastrointestinal procedures and 30,000 elective surgeries per month. as communities begin relaxing covid-19 mitigation and suppression measures, healthcare systems are preparing to reinstate elective procedures and surgeries. addressing ongoing healthcare needs, ongoing mitigation/suppression, and procedure backlogs will require three primary components: telehealth to continue social distancing and maintain mitigation, risk stratification to maximize benefit of procedures being scheduled, risk stratification to minimize harm, and methods for optimizing healthcare capacity and safety to provide relevant services to the most people possible. multispecialty collaborations and virtual care platforms will continue to be essential during ongoing mitigation/suppression for maintaining specialty and peri-procedural care in almost all healthcare settings. telehealth (video or telephone) visits accounted for approximately 18% of specialty care visits prior to march 1, 2020 in kpnc; in contrast, by the week of april 19, they accounted for approximately 76% of visits (albeit at a decline in total specialty visits from approximately 300,000 per month to approximately 150,000 per month). between march 16, 2020 and april 17, 2020, at kpnc, gastroenterologists and surgeons received nearly 6,000 and 30,000 outpatient referrals respectively, and were able, using tele-and video-based consultations, to disposition >80% of referrals for procedures within 3 days of receipt, addressing urgent indications and deferring non-time sensitive cases. although elective procedural volume decreased markedly over this period, urgent or emergent procedural and surgical caseloads (typically accounting for 30-40% of our procedural/surgical volume) remained stable. this suggests that, even during high levels of mitigation/suppression, a combination of telehealth and highly selected office visits can allow the prompt evaluation and scheduling of critical procedures and surgeries (including cancer-related care) despite decreased procedural volumes. the likely benefit of procedures varies markedly by indication and includes both disease morbidity (e.g. amelioration of symptoms) and mortality (i.e. likelihood of earlier intervention decreasing the likelihood of disease progression). recent publications for gastrointestinal procedures provide important information regarding patient benefit for the most common indications for colonoscopy: screening, surveillance, and follow-up of fecal immunochemical test (fit) results. higher risk patients include fit positive patients who are approaching six months from their test (after which there is a significantly increased risk of disease progression) 9-12 ; symptomatic patients (e.g. dysphagia, weight loss, gastrointestinal bleeding, inflammatory bowel disease flare, etc.); laboratory abnormalities suggestive of acute disease (e.g. acute or progressive iron deficiency anemia, abnormal imaging, obstructive jaundice, etc.); and patients with large or incompletely resected polyps. 13 understanding disease risk around these factors can inform prioritization of covid-19 relative procedure backlogs during re-opening and ongoing mitigation/suppression control measures, which may include repeated partial closures during local increases of disease incidence (table 1 ). for example, a risk measurement process at kpnc to identify and schedule pending routine and high risk (fit +, post cancer, high risk adenoma follow up) patients awaiting colonoscopy across all 21 facilities in kpnc in late 2019 and in early 2020 resulted in a 33 percent reduction in such patients within 10 weeks, from approximately 11,000 to 8000. however, after california's shelter in place orders were implemented, the number of patients awaiting colonoscopy initially plateaued and then rapidly rose to over 12,000, exceeding the pre-covid numbers. these risk measurement methods can now be used to prioritize patients for early scheduling of high-risk patients (table 1) . procedure-related harm during a pandemic includes: 1) patient infection risk; 2) medical staff infection risk; and 3) procedure-related complications. while covid-19 hospitalizations began subsiding in parts of california in late april, new cases continue to arise, lending considerable uncertainty to estimates of community transmission risk. because patients presenting for procedures/surgery may also be at risk for covid-19-related complications, kpnc is using regional data to identify patient characteristics associated with covid-19 deterioration. among 2,168 kpnc patients with covid-19 positive tests in our system at the time of analysis, we corroborated external reports that younger age and lower comorbid disease burden are associated with lower rates of hospitalization, critical care, mechanical ventilation, and death. 14 these data assist our clinicians in stratifying patients based on their risk of covid-19 complications. given endoscopic procedures are generally low risk, even among persons with high comorbidities, risk is primarily related to identification of a disorder amenable to surgery. for relevant indications (e.g. evaluation of a colon mass seen on radiologic imaging), if such patients are unlikely to tolerate surgery, they are less likely to benefit from endoscopy. to assess surgical risk for all types of operations, we developed a risk score incorporating age, comorbid disease burden, and surgical venue for predicting post-surgical major morbidity or mortality using national surgical quality improvement program (nsqip) definitions. this model demonstrated good discrimination for identifying patients at risk for post-surgical complications (c-statistic of 0.77 in training and test sets including a total of 144,784 patients) and is now being automatically calculated in our surgical reopening electronic health record dashboards. detailed online tools from the nsqip risk calculator are available to quantify patient surgical risk. 15 applying such risk tools to our deferred surgical cases (all types of surgery), 39% of patients were at low covid-19-related-risk; for surgical risk 76% were low-risk, 23% medium-risk, and 1% high risk. these perioperative risk scores help contextualize discussions between surgeons and patients related to surgical timing during the reopening period. mitigation/suppression) with evolving decisions in many states to gradually ease mitigation and suppression restrictions, strategies are needed for optimizing procedure safety and throughput to complete new and deferred procedures. in california, for example, in response to a recent statewide declaration to resume elective procedures 16 , hospitals are preparing for surgical reopening. this requires a careful assessment of aggregate procedural/surgical capacity to ensure that local constraints can be addressed by conducting procedures at local or other hospitals with available capacity. ppe availability is an overarching consideration for procedural/surgical reopening given desires for the safety of the medical staff and the challenges of maintaining a stable supply chain in the covid-19 era. thus, it is important for facilities to use ppe forecasts that account for increasing usage with surgical reopening, the number of surgical team members per case, and the type of ppe needed (airborne or standard surgical) to balance resources while accounting for the ongoing risk of covid-19 surge. kpnc, using this type of forecasting, has successfully modulated procedure volume, continuing ppe conservation and stewardship efforts using cdc guidelines for extended use and reuse to protect patients and providers. increasing procedural capacity and safety will likely depend, in part, upon pre-procedural screening for infection. throughput for gastrointestinal procedures was challenged by the gi multi-society recommendations for airborne precautions for all patients, extending room dwell time for 45 minutes after each case to allow for adequate air exchanges. 17 thus, expansion of sars-cov-2 pre-procedure testing prior to bowel preparation can allow for more standard room turnaround times and use of standard ppe rather than airborne precautions for test negative patients. similarly, for surgical cases, as testing capacity increases, preoperative sars-cov-2 testing can clarify airborne ppe requirements for high-risk procedures (i.e., endotracheal intubation, airway procedures) and to ensure that those with an anticipated icu stay are at low risk for covid-19 complications during recovery. 18 there is a complex interaction between test performance characteristics, background prevalence, and the potential for false negative (or positive) tests. this may influence confidence in using lower levels of ppe in test-negative persons, for conservation of this vital resource, particularly in regions with a very high prevalence of active infections. performance characteristics depend, in part, on the test used (some rapid point of care tests may have lower sensitivity); adequacy of sample acquisition; and disease burden (a person with lower viral burden may be both less infectious and less likely to test positive). a disease prevalence of 3%, for example, would result in a negative predictive value of 99.7% for a test with 90% sensitivity (and 90% specificity) and 99.0% for a test with 70% sensitivity. after taking into account that patients with symptoms typical of infection can be treated as covid positive, as regards ppe precautions, however, the joint probability appears extremely low of: a person being infected; being asymptomatic; having a false negative test; and standard ppe usage in this patient leading to spread of disease within a healthcare setting. to minimize false negative testing, we recommend using higher sensitivity tests (and updating test type as methods improve), having testing performed by trained personnel for adequate sampling, and adjusting evaluations as needed if community prevalence surges (thereby potentially increasing the proportion of total people tested who have a false negative test). the current kpnc framework integrates all these factors for reopening procedural/surgical care (table 1) . because care in the covid-19 era engenders novel types of risks for patients and providers, this framework is designed to facilitate shared decision-making between procedurebased physician and patients for procedural timing. using the described evaluations of benefit and risk, 19 prior to rescheduling kpnc is currently having its procedure-based specialists, including gastroenterologists and surgeons, review each case, leverage expert internal guidance, and engage with their patients in shared decision making to assess whether a delay is in the patient's best interests. we will initially focus on prioritizing procedures among patients with high medical urgency/likely benefit (based on internal expert opinion, gastrointestinal society guidelines, and the acs "elective case triage guidelines for surgical care" 20 ) and low covid-19 and procedural-risk. together, our clinicians have also worked across specialties to identify medically urgent noncancer-related procedures needed for diagnosis or treatment for both gastrointestinal diseases (table 1 ) and general surgical procedures across multiple specialties (e.g. bucket handle tears, bilateral ureteral stones, and aortic aneurysms >6.5 cm). for patients with low medical urgency and high covid-19 or surgical risks, we will discuss the risks and benefits of non-surgical care pathways. older patients likely to proceed to surgery, who may be at higher risk of covid-19 complications, will be encouraged to await vaccine availability or will participate in the acs geriatric surgery verification program based on risk and frailty. special considerations will be given to those expected to need skilled nursing facility recovery given the emerging risks of covid-19 now recognized in these facilities. patients with high medical urgency and high procedural/surgical risk will continue to receive interventions to optimize their health -including for diabetes, hypertension, anemia, obesity, and smokingwhile awaiting their surgical date. discussions with patients who have low medical urgency and low risk will focus on nonprocedural treatment options given the potential for extended procedural/surgical waiting times. disagreements between surgeons and their patients about the timing and risks of surgery will be assessed by second opinion or through local multidisciplinary teams. alternative methods, for example, can be used for lower-risk patients needing screening and surveillance endoscopic examinations. patients originally scheduled for screening colonoscopy can instead utilize a fit testing approach while awaiting colonoscopy. this allows higher-risk patients to complete colonoscopies, while providing average-risk patients with guideline concordant care. fecal testing can particularly be recommended to patients whose risk of complications from covid -19 risk is high, such as those over age 60 and those 50-59 with at least one serious comorbidity. concordant with recent gastrointestinal society guidelines, patients with a history of 1-2 small adenomas scheduled for follow up five years after their initial exam can instead be recommended for testing at 7-10 years, given their long-term risk appears comparable to people without any adenomas. 21 covid-19 has resulted in tremendous disruptions to routine healthcare and elective procedures, challenging our existing approaches for optimal peri-procedural and procedural planning and care. in the setting of ongoing, albeit lower, rates of covid-19, reopening deferred procedures/surgeries requires a balanced and data-driven framework that prioritizes the timing of procedures based on medical urgency (patient likelihood of benefit), covid-19 risk, procedural risk, and the availability of ppe and preoperative sars-cov-2 testing. this framework may help minimize the potential impact of deferred care, and diminish additional waves of adverse outcomes among those impacted by the covid-19 pandemic, until the threat of recurrent viral infection surges abates. the uncertainty of this pandemic calls for healthcare systems to prepare for sustained mitigation/suppression and the commitment of physicians and patients to discuss critical peri-procedural and procedural decisions together. * the availability of personal protective equipment is a key overarching consideration for effective and sustainable procedure/surgical re-opening. additional factors for consideration include anesthetic approach, home versus inpatient recovery, local covid-19 case activity, public health agency guidance and regulations, and regional aggregate procedural-related care availability. ten weeks to crush the curve world health organization. managing epidemics: key facts about major deadly diseases impact of non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand suppression and mitigation strategies for control of covid-19 in new zealand. medrxiv the untold toll -the pandemic's effects on patients without covid-19 cdc's recommendations for 30 day mitigation strategies for santa clara county, california, based on current situation with covid-19 transmission covid-19: guidance for triage of non-emergent surgical procedures gastroenterology professional society guidance on endoscopic procedures during the covid-19 pandemic association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis long-term risk of colorectal cancer after removal of conventional adenomas and serrated polyps long-term risk of colorectal cancer and related death after adenoma removal in a large, community-based population colorectal cancer incidence and mortality after removal of adenomas during screening colonoscopies hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease american college of surgeons national surgery quality improvement program. surgical risk calculator resuming california's deferred and preventive health care aga institute rapid recommendations for gastrointestinal procedures during the covid-19 pandemic precautions for operating room team members during the covid-19 pandemic medically necessary, time-sensitive procedures: scoring system to ethically and efficiently manage resource scarcity and provider risk during the covid-19 pandemic covid-19: elective case triage guidelines for surgical care recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the us multi-society task force on colorectal cancer key: cord-255204-3qruat3s authors: osborne, vicki; davies, miranda; lane, samantha; evans, alison; denyer, jacqueline; dhanda, sandeep; roy, debabrata; shakir, saad title: lopinavir-ritonavir in the treatment of covid-19: a dynamic systematic benefit-risk assessment date: 2020-06-23 journal: drug saf doi: 10.1007/s40264-020-00966-9 sha: doc_id: 255204 cord_uid: 3qruat3s introduction and objective: covid-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. the benefit-risk balance for the use of lopinavir-ritonavir in covid-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. a key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. methods: a systematic benefit-risk assessment was conducted using the benefit-risk action team (brat) framework. the exposure of interest was lopinavir-ritonavir treatment in severe covid-19 compared to standard of care, placebo or other treatments. a literature search was conducted in pubmed and embase to identify peer-reviewed papers reporting clinical outcomes. two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. results: we screened 143 papers from pubmed and 264 papers from embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. in comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95–1.80). from one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). there also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). limited data were available for comparison of lopinavir-ritonavir to other treatments. conclusions: based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe covid-19. risk data suggested a possible decrease in serious adverse events. there was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. overall, the benefit-risk profile for lopinavir-ritonavir in severe covid-19 cannot be considered positive until further efficacy and effectiveness data become available. coronaviruses have circulated in human and animal populations for many years and in humans they are a cause of respiratory tract infections [1] . more recently, severe acute respiratory syndrome coronavirus 2 emerged in wuhan, china in december 2019 [2, 3] . severe acute respiratory syndrome coronavirus 2 causes coronavirus disease and this outbreak was declared a global pandemic by the world health organization in march 2020 [4] . fever, cough and shortness of breath are the main reported symptoms of covid-19 [5] but this disease also has a concerning case mortality rate among certain populations, such as older adults and those with underlying health conditions. in the current covid-19 pandemic, there is a need to identify effective safe treatments as rapidly as possible. lopinavir-ritonavir (lpvr) is a combination protease inhibitor and nucleoside analogue used for the treatment of human immunodeficiency virus (hiv) type 1 [6] . the use of lpvr in severe acute respiratory syndrome has been examined previously and indicated a favourable clinical response, with a decreased incidence of adverse clinical outcomes at day 21, reduced viral load at 48 h, decreased steroid use and reduced incidence of nosocomial infections [7] . for this reason, multiple trials in covid-19 are currently being conducted to determine if lpvr is an effective treatment, including the worldwide recovery trial and the world health organization's solidarity trial [8] [9] [10] . it is essential to examine the benefit-risk profile of all medications, but ongoing monitoring is especially important where treatments may be used with limited evidence in new indications. lopinavir-ritonavir is already being used as a standard treatment for covid-19 in some countries. systematic reviews have been conducted to examine the efficacy of lpvr in the treatment of covid-19, though not all of these have been peer reviewed to date [11] ; so far these have concluded that there is a lack of evidence of efficacy [11, 12] . however, a systematic benefit-risk assessment on the use of lpvr for covid-19 treatment, based on currently available evidence, has not yet been conducted. the benefit-risk action team (brat) uses a structured descriptive framework to outline the key benefits and risks of a medication within a defined disease context. if sufficient relevant data are available, an additional quantitative assessment can be used to further examine the benefit-risk profile [13] . the brat was also designed to assist communication with regulatory authorities [14] . the framework design allows for transparency in the decisionmaking process and assumptions can be explored further by sensitivity analyses using quantitative methods [15] . this dynamic approach to a benefit-risk assessment of potential treatments for covid-19 has been previously applied to the anti-viral agent remdesivir [16] . the systematic benefit-risk assessment for lpvr was conducted based on publicly available data to 13 may, 2020. because of continuous emerging data on the use of lpvr in covid-19, the framework can be subsequently used to repeat the assessment as further data arise, allowing for rapid and dynamic evidence-based decision making as more relevant data become available. this assessment was conducted to aid clinicians and public health and regulatory authorities in the decision-making process on treatments for covid-19. this study aimed to examine the benefit-risk profile of lpvr in patients with covid-19 compared to standard of care, placebo or other treatments. a key objective of this study was to provide a platform for a dynamic systematic benefitrisk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. importantly, it allows additional data to be incorporated as they become available, and reevaluation of the benefit-risk profile. the brat framework was used to assess the overall benefitrisk of using lpvr as a treatment for covid-19 compared to standard of care, placebo or other treatments. the brat uses a six-step iterative process to support the decision and communication of a benefit-risk assessment: define decision context, identify outcomes, identify data sources, customise framework, assess outcome importance, and display and interpret key benefit-risk metrics [17] . three settings of interest for use of covid-19 treatments were identified; treatment for severe disease, treatment of mild disease in the community and prevention in healthcare professionals exposed to the virus. this assessment focuses on lpvr for the treatment of severe covid-19 disease, which we defined as hospitalisation as a result of covid-19 infection. patients with covid-19 who were treated with lpvr were the population of interest, while patients receiving standard of care, placebo or other treatments were the comparators of interest. where standard of care was reported as the comparator group, this refers to no use of a specific pharmaceutical treatment for covid-19 but provision of standard supportive therapy within the hospital setting. all potential benefits and risks related to lpvr were initially identified, regardless of their importance. key benefits and risks were selected by clinician judgement, i.e. those considered to be of clinical importance or potentially serious, and included in the value tree, which provides a visual representation of these outcomes in the context of severe covid-19 disease. these benefits and risks displayed in the value tree were ranked according to perceived importance (benefits) and potential seriousness (risks). two clinicians performed this ranking after discussion of the importance of each benefit and risk. risks were categorised according to which system organ class (soc) they belonged to, and where multiple events were identified within the same soc, the ranking was based on the most serious event(s) within that soc, with the most serious event(s) in each soc presented first. a literature search was performed in pubmed and embase using the following search strategy: (lopinavir and ritonavir) and (covid* or sars-cov-2 or n?cov or coronavirus). two reviewers examined articles for eligibility and a third clinical reviewer made the final decision on inclusion. papers were included in the data extraction tables if they reported quantitative data on effectiveness and/or safety of lpvr in patients with severe covid-19. case reports and case series were excluded from the data extraction tables, but were considered for construction of the value tree. results were restricted to english language only (abstracts in english language were acceptable where sufficient data provided) and peer-reviewed publications from 2019 to 13 may, 2020. data were extracted for each benefit and risk, for lpvr and the comparator (standard of care, placebo or other treatments), where available. eudravigilance spontaneous reporting data (up to 8 may, 2020) for lpvr where used in covid-19 were also examined. eudravigilance data were examined because of the usefulness of identifying real-world reports of adverse events outside of the clinical trial setting and because the publicly available version of this specific data source is frequently updated. after data extraction, a second reviewer performed a quality-control check on the extracted data. key benefits and risks associated with the use of lpvr were identified for inclusion in the value tree from available data sources, including the product information, regulatory assessment reports and published literature. predicted key benefits (clinical endpoints) were derived from both the published literature and in the case of ongoing studies, available clinical trial protocols. these benefits and risks, as presented in the value tree, were derived from both qualitative and quantitative data. a summary benefit-risk table was created to allow visualisation of the magnitude of each benefit and risk. risk differences and corresponding 95% confidence intervals (cis) were calculated for each outcome where both numerator (number of events) and denominator (number of patients at risk) were available for both the treatment group (lpvr) and comparator group. no appropriate comparator groups were identified for lpvr within eudravigilance owing to the recent nature of the pandemic and the lack of treatments made available for covid-19 outside of the clinical trial setting. as such, adverse events reported for a comparison treatment in eudravigilance were not available. consequently, spontaneous reports are not included in the benefit-risk table and are presented in the text only. given the limited data at this point in time, further quantitative assessment was not considered appropriate. however, such methods can be used to account for both the importance of outcomes and the size of the study from which data were extracted by weighting outcomes. in anticipation of using further quantitative methods in the future when further data are made available, we have ranked the outcomes in the value tree by considered clinical importance. figure 1 displays the value tree of the key benefits and risks related to lpvr treatment in covid-19, which was constructed using a wide variety of data sources. key benefits have been listed in the value tree in descending order of perceived clinical importance. at the current time, only one clinical trial was identified that provided empirical data for any of the clinical endpoints listed in the value tree [18] . whilst the primary objective of this clinical trial was time to clinical improvement, additional data were provided for various endpoints including mortality risk, risk and duration of invasive mechanical ventilation, risk of non-invasive ventilation and oxygen requirement. key risks were identified for lpvr based on the current available evidence. it is acknowledged that this product is not licenced for use in the treatment of covid-19 disease, and whilst safety data are available for its licenced use in hiv type 1, its safety profile in the context of covid-19 is largely unknown. furthermore, for the limited safety data that are available for its use in covid-19, it is often unclear whether the reported adverse event is due to the use of lpvr, or attributable to the underlying disease. potentially serious risks that are likely to still pose a risk with the proposed short-term use of lpvr for covid-19 have been summarised in the value tree and ranked according to perceived seriousness. one of the most serious risks is prolongation of the qt interval, and the subsequent increased risk of sudden cardiac death [19] [20] [21] [22] . patients with covid-19 are already predisposed to the development of cardiac arrhythmia owing to the effect of the virus on metabolic dysfunction, myocardial inflammation and the sympathetic nervous system [20] . additionally, it is important to note that lpvr is an inhibitor of cytochrome p450 3a4, and therefore it cannot be used with other medicines that are substrates of this enzyme, such as chloroquine, which itself can cause qt prolongation [21] . in addition to the effects on qt prolongation, lpvr has also been shown to cause modest asymptomatic prolongation of the pr interval in some healthy adult subjects, with rare reports of second-or third-degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the pr interval (such as verapamil or atazanavir), and therefore lpvr should be used with caution [23] in such patients. lopinavir/ritonavir are both inhibitors of the cytochrome p450 3a isoform, and therefore treatment is likely to fig. 1 value tree of key benefits and risks identified for lopinavir/ ritonavir, ranked by order of clinical significance. superscript 1: both benefits and risks have been ranked according to perceived clinical significance. risks have been categorised according to system organ class. the system organ classes have been ranked based on the most serious events/events within each system, which have been presented first. alt alanine aminotransferase, ards acute respiratory distress syndrome, ast aspartate aminotransferase, cyp cytochrome p450, ecmo extracorporeal membrane oxygenation, ggt gamma-glutamyl transpeptidase, icu intensive care unit, mi myocardial infarction increase plasma concentrations of concomitant medicinal products that are primarily metabolised by cytochrome p450 3a [23] . clinically significant drug interactions have been observed with lpvr use during treatment for covid-19, including increased plasma concentrations of direct oral anticoagulants [24] , and increased plasma concentrations of immunosuppressants in organ transplant recipients [25] . certain risks factors and clinical characteristics have been associated with the development of acute respiratory distress syndrome (ards) amongst patients with covid-19 [26] . patients who developed covid-19-related ards were likely to require admission to the intensive care unit. in the study by cao et al., respiratory failure/ards was reported as a serious adverse event in both treatment groups [18] . whilst causality in these cases is not known, it would seem likely that these cases were attributable to progression of the underlying covid-19 disease. hypersensitivity reactions such as urticaria and angioedema are reported to occur commonly with the use of lpvr for the treatment of hiv, and rarely serious skin reactions such as stevens-johnson syndrome and erythema multiforme have been reported with its use in this treatment population [23] . gastrointestinal side effects of lpvr are well recognised, and diarrhoea and nausea are very common. serious gastrointestinal adverse effects included in the key risks for this assessment include pancreatitis, which has been associated with the use of lpvr [7, 23, 27] ; most patients who developed pancreatitis during treatment for hiv had a prior history of this condition. treatment with lpvr has been associated with an increase in triglycerides in patients treated for hiv [23] , and amongst patients treated for covid-19 [28] [29] [30] [31] , which is likely to be another contributory factor in the development of pancreatitis. in the context of treatment for hiv, lpvr has been uncommonly associated with certain adverse renal outcomes, including a reduction in creatine clearance, nephritis and haematuria [23] . cases of acute kidney injury have been reported in patients taking lpvr in covid-19; however, it is unclear whether there is any association, as this outcome was reported more frequently amongst patients in the standard of care comparator group [18] in addition to overall limited safety data availability. elevations of liver enzymes have also been commonly reported with the use of lpvr in the treatment of hiv [23] , and liver injury has been reported in patients treated with lpvr for covid-19 [32, 33] . blood dyscrasias have also been associated with the use of lpvr during hiv treatment [23] , with reports of severe anaemia amongst patients treated for covid-19 [18] . data for outcomes are presented in the data extraction table and key benefit-risk summary table (tables 1 and 2, respectively). from literature searching, we identified 143 papers from pubmed and 264 papers from embase for lpvr. all papers were reviewed for information on the benefits and risks relating to lpvr, including both quantitative and qualitative data. after initial review and removal of duplicates, 43 papers were identified with information on safety of lpvr and 15 papers with efficacy information for lpvr. these papers were reviewed further to determine whether they met all inclusion criteria; seven papers were included in the final benefit-risk assessment. in comparison to standard of care, data for several key benefits and risks for lpvr were identified. in the cao et al. trial [18] , the benefit of time to clinical improvement (intention-to-treat analysis) was not statistically significant after adjustment for other covariates in comparison to standard of care (16 vs 16 days, hazard ratio = 1.31, 95% ci 0.95-1.80). other non-significant benefit data were identified in this trial including median duration of mechanical ventilation (risk difference = − 1 day, 95% ci − 4 to 2) and death at 28 days (risk difference = − 0.06, 95% ci − 0.17 to 0.06). risk data were mainly available from the cao et al. trial, which reported fewer serious adverse events in patients taking lpvr (20%) compared to standard of care (32%). there were fewer cases of ards with lpvr compared to standard of care (13% vs 27%). the difference in the proportion of adverse events between groups was not tested statistically in the study and the study was also not powered to detect differences in adverse events. limited data were available for comparison of lpvr to other treatments. viral clearance at day 14 for lpvr was lower compared with arbidol (85% vs 91%), and there was minimal difference in mean time to viral clearance (10.20 days vs 10.11 days, respectively). data were only available for one risk in comparison to arbidol; a lower proportion of those patients treated with lpvr experienced increased alt compared with arbidol (9% vs 19%, respectively). in spontaneous reports from eudravigilance, for lpvr used in covid-19, there were 28 reports of hepatocellular injury, 15 reports of acute kidney injury, 17 reports of prolongation of the qt interval, six reports of ards and three reports of pancreatitis. information on case reports was only available from the publicly available dataset and thus was limited; however, these data are useful in identifying real-world reports of adverse events outside of the clinical trial setting. the study aim was to examine the benefit-risk profile of lpvr in covid-19 patients compared to standard of care, placebo or other treatments. a key objective of this study was to provide a platform for a dynamic systematic benefitrisk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. importantly, it allows additional data to be incorporated as they become available, and reevaluation of the benefit-risk profile. this paper provides a systematic benefit-risk assessment using the brat methodology and is inclusive of the available literature up to and including 13 may, 2020. therefore, this represents a snapshot of the data available to date and outlines a clear and transparent framework into which subsequent clinical trial and observational study data can be incorporated, and the benefit-risk profile re-assessed. at the current time, data relating to the benefits of lpvr are limited, with efficacy data for clinical endpoints available from only one published clinical trial. this trial found no statistically significant difference in the primary outcome of time to improvement (intention-to-treat analysis) between the two groups (lpvr treatment in addition to standard supportive care vs standard care alone); however, the sample size was small. there was some evidence (though not statistically significant) that lpvr reduced mortality at 28 days (95% ci 19.2% vs 25.0%), difference of -5.8% (95% ci -17.3 to 5.7). it is of note that the median time interval between symptom onset and randomisation was 13 days (interquartile range, 11-16 days), therefore it is unknown whether more favourable results may have been seen if drug treatment had been initiated earlier in the course of the disease. the safety profile of lpvr in the treatment of severe covid-19 disease is largely unknown. we identified key risks from its usage in the treatment of hiv, in addition to the limited safety data available from its use in covid-19. comparator safety data revealed a lower incidence of all serious adverse events amongst patients receiving lpvr compared with standard of care (risk difference − 123 events per 1000 patients). very small numbers of cases of some adverse events were reported in the study by cao et al., including severe anaemia, acute gastritis and lower gastrointestinal bleeding, all of which were only reported amongst patients taking lpvr. the incidence of acute kidney injury was lower in the cao et al. trial amongst patients taking lpvr compared with standard of care (3% vs 6%). the incidence of ards was also observed to be lower in patients using lpvr compared with standard of care (13% vs 27%). it is acknowledged that ards is a known outcome in covid-19 and thus a reduction in risk could potentially be considered a benefit of lpvr treatment. acute respiratory distress syndrome is included as a risk in the current value tree because it was considered an adverse event in all trials examined; however, the benefit-risk assessment may be updated if sufficient evidence becomes available to suggest it should be considered a benefit instead. consequently, the incidence of ards with lpvr in covid-19 should be intensively monitored as further data are made available to determine if this could potentially be a benefit of treatment. overall, there was a lack of efficacy data with no clear benefits identified for lpvr treatment compared with standard of care. risk data, although limited, suggested a possible decrease in adverse events for some serious outcomes compared to standard of care. further data are needed on the efficacy and effectiveness of lpvr for severe covid-19. an update to this dynamic benefit-risk assessment will be published when sufficient data are made available from further peer-reviewed studies that impact significantly on the benefit-risk of lpvr. a strength of this approach is the inclusion of all key benefits and risks in the same model and a transparent framework into which further data can be included as and when these become available. the method has a significant advantage compared with systematic reviews, which are equally comprehensive but focus only on efficacy or safety, rather than considering both together. when sufficient data are available, the methodology allows benefits and risks to be ranked, and weightings applied based on this ranking, with further quantitative analysis. the reproducibility of this assessment allows multiple treatments to be assessed using this approach, thereby allowing direct comparison between different treatments. this is of great significance during the current covid-19 crisis, in which several potential interventions currently under evaluation need to be assessed and evaluated in real time, and where new data need to be incorporated quickly. regulatory decision makers are also familiar with this framework, facilitating interpretation. a limitation of the benefit-risk assessment presented at this time is the relative paucity of data that has been included in the model, as many clinical trials assessing lpvr are still ongoing. in addition, trials for which data were available had very small sample sizes and were likely to be underpowered when examining non-primary outcomes. causality cannot be confirmed for many outcomes at this point in time but in general there is a need for further data regarding outcomes in covid-19. it is anticipated that such data will become available in due course and allow us to comment further on the causal association between lpvr and outcomes included in the value tree. the dynamic nature of this benefit-risk assessment allows further updates in the future if sufficient data are made available to significantly impact the conclusion of the benefit-risk assessment. study quality was not considered in the assessment, although we only included peer-reviewed articles. the importance of each benefit and risk was assessed by two physicians and ranked accordingly based on their clinical judgement. because of the dynamic nature of the benefit-risk assessment, other experts could be engaged in the future to reassess the importance of the benefits and risks and revise the value tree. outcomes displayed in the value tree were identified from a variety of sources and may therefore be related to different underlying diseases with different management including potentially different doses of lpvr. efficacy outcomes could also be dependent on the time of administration of lpvr. further, while we defined standard of care as no use of a specific pharmaceutical treatment for covid-19 but provision of standard supportive therapy within the hospital setting, we acknowledge that standard of care may vary by setting and country. based on currently available data, there was no clear benefit for use of lpvr compared to standard of care in severe covid-19. risk data suggested a possible decrease in serious adverse events. there was a reduction in ards with lpvr in one study. overall, the benefit-risk profile for lpvr in severe covid-19 cannot be considered positive until further efficacy and effectiveness data become available. author contributions vo assisted with the study design and data extraction and wrote the study proposal and the first draft of the manuscript. md assisted with study design, identified outcomes of interest, constructed the value tree and assisted with data extraction. sd assisted with the value tree and rankings. dr, sl, jd and ae assisted with the study design, literature searching and data extraction. saws assisted with the concept, study design and manuscript revisions. all authors reviewed the manuscript, contributed to revisions, and approved the manuscript and accept full responsibility for its overall content. funding the drug safety research unit (dsru) is an independent academic institution that works in association with the university of portsmouth. no funding was received for this project. data availability data used in this analysis are available from the references supplied. the dsru is an independent charity (no. 327206) that works in association with the university of portsmouth. it receives unconditional donations from pharmaceutical companies. the companies have no control on the conduct or the publication of the studies conducted by the dsru. abbvie, the marketing authorisation holder for lopinavir-ritonavir, has paid the dsru for consultancy services unrelated to lopinavir-ritonavir. abbvie is also providing support for an unrelated methodological project led by the dsru as a part of a large group of pharmaceutical companies, unrelated to lopinavir-ritonavir or any other abbvie product. saad shakir is a member of the data safety monitoring board for diurnal and biogen. miranda davies, vicki osborne, samantha lane, debabrata roy, sandeep dhanda, jacqueline denyer, alison evans and saad shakir have no other conflicts of interest to declare. this study was conducted in accordance with international ethical guidelines. ethics approval was not required for this study. consent to participate not applicable. code availability (software application or custom code) not applicable. open access this article is licensed under a creative commons attribution-noncommercial 4.0 international license, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by-nc/4.0/. origin and evolution of pathogenic coronaviruses a novel coronavirus outbreak of global health concern naming the coronavirus disease (covid-19) and the virus that causes it who. who announces covid-19 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engineering (beijing) treating covid-19 with chloroquine efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/ moderate covid-19: an exploratory randomized controlled trial clinical efficacy of lopinavir/ritonavir in the treatment of coronavirus disease 2019 arbidol monotherapy is superior to lopinavir/ritonavir in treating covid-19 realworld efficacy and safety of lopinavir/ritonavir and arbidol in treating with covid-19: an observational cohort study key: cord-019009-3ngfv96u authors: gea-banacloche, juan title: risks and epidemiology of infections after hematopoietic stem cell transplantation date: 2016-02-15 journal: transplant infections doi: 10.1007/978-3-319-28797-3_6 sha: doc_id: 19009 cord_uid: 3ngfv96u infections following hct are frequently related to risk factors caused by the procedure itself. neutropenia and mucositis predispose to bacterial infections. prolonged neutropenia increases the likelihood of invasive fungal infection. gvhd and its treatment create the most important easily identifiable risk period for a variety of infectious complications, particularly mold infections. profound, prolonged t cell immunodeficiency, present after t cell-depleted or cord blood transplants, is the main risk factor for viral problems like disseminated adenovirus disease or ebv-related posttransplant lymphoproliferative disorder. understanding the epidemiology of infections after allogeneic hematopoietic stem cell transplantation (hct) is important to implement appropriate preventive strategies as well as to effectively diagnose and treat individual patients. several groups of experts and professional organizations publish guidelines that provide specifi c recommendations for prophylaxis and management of infections after hct [ 1 -8 ] , including vaccinations [ 1 , 9 , 10 ] . many of these recommendations are necessarily based on low-quality evidence and rely heavily on expert opinion. guidelines should not be followed blindly, but understood as tools that may help to provide the best possible care. risk factors for infection include individual characteristics (e.g., indication for hct, prior infections, cmv serostatus, particular genetic traits) and type of transplant (based on conditioning regimen, stem cell source, degree of hla homology, and immunosuppression). the development of graft-versus-host disease (gvhd) is frequently the decisive contributor to infectious morbidity and mortality. different indications for hct are associated with their own infectious risks. primary immunodefi ciencies (pid), hemoglobinopathies, and hematologic malignancies present different challenges. even in hematologic malignancies, the risk may vary depending on the specifi c condition: patients with chronic myelogenous leukemia (cml), acute myeloid leukemia (aml), and chronic lymphocytic leukemia (cll) present different risks based on both the biology of the disease and prior treatment. these factors should be considered when assessing individual patients. prior infections must be considered. a history of infection or colonization with a multidrug-resistant organism (mdro) like carbapenem-resistant enterobacteria (cre), extended-spectrum beta-lactamase (esbl)-producing gram-negative bacteria, vancomycin-resistant enterococcus (vre), or methicillin-resistant staphylococcus aureus (mrsa) has implications regarding optimal management of fever during neutropenia [ 6 , 11 , 12 ] , which is a common complication of hct. transplant candidates are routinely screened for serologic evidence of latent infections that may reactivate (hsv, vzv, cmv, ebv, hepatitis b and c, toxoplasmosis); some of these will be discussed later in this chapter. some transplant centers will perform screening for tuberculosis with tuberculin skin test (tst) or interferon-gamma release assay (igra), at least for patients who are considered at signifi cant risk for the disease. prior invasive fungal infections may reactivate following transplant, and secondary prophylaxis is required [ 13 -15 ] . even active fungal infection has been reported to be controllable. there are, however, cases of progression of prior aspergillosis after transplant; myeloablative conditioning, prolonged neutropenia, cytomegalovirus (cmv) disease, and graft-versus-host disease (gvhd) are risk factors [ 15 , 16 ] . as the correlates of native and adaptive immunity are better understood, genetic associations are coming to light. there is evidence that some donor haplotypes of tlr4 , the gene that encodes the toll-like receptor protein 4 (tlr4) are associated with increased risk of invasive aspergillosis after hct [ 17 ] . recipient's mutations in mbl2 , the gene that encodes mannose-binding lectin (mbl), have been associated with increased risk of infection after neutrophil recovery following myeloablative transplant [ 18 ] . other polymorphisms of mbl2 may be important for infection through a direct infl uence on the risk of developing gvhd [ 19 , 20 ] . different genotypes of activated killer immunoglobulin-like receptors (akir) in the donor have been found to protect from cmv reactivation [ 21 ] . many of these associations are preliminary and require more data to be confi rmed, but they hold the promise of a more individualized approach to infectious prophylaxis. from a practical standpoint, it is helpful to consider three distinct periods during transplant: pre-engraftment (until neutrophil recovery), early post-engraftment (from engraftment until day 100) , and late post-engraftment (after day 100) . this framework originated with myeloablative transplants, and is eminently pragmatic. the pre-engraftment phase may be accompanied by profound neutropenia and signifi cant mucositis, which results in increased risk of bacterial infections from the resident gastrointestinal fl ora, candidiasis, aspergillosis (in cases of prolonged neutropenia) and herpes simplex virus reactivation. after engraftment, with neutropenia no longer being a factor, many infections are related to the profound defect in cellular immunity caused by the conditioning regimen and the immunosuppression administered to prevent gvhd. cmv reactivation and the development of acute gvhd and its treatment play a central role during this time. the day 100 landmark derives from the standard time at which immunosuppression (e.g., cyclosporine a or tacrolimus) is frequently tapered. infections after this point would be primarily related to lack of immune reconstitution and, in the absence of gvhd, become progressively less common. not all allogeneic stem cell transplantations are the same. several characteristics of the transplant infl uence the risk of infection: the conditioning preparative regimen, the source of stem cells, the degree of hla identity between donor and recipient, and the prophylactic strategy adopted to prevent gvhd (use of t cell depletion or immunosuppressive medications). table 6 -1 summarizes the impact of these factors on infections. matching for ucb transplants focuses on three loci (hla-a, hla-b, and hla-drb1). the majority of ucb transplants are mismatched by at least one locus (often two). among transplants mismatched at two loci, mismatching at hla-c and hla-drb1 was associated with the highest risk of mortality [ 24 ] . the degree of mismatch between the donor and the recipient affects the infectious risk mainly through the likelihood of gvhd. more gvhd usually results in more infections. to prevent gvhd in a mismatched transplant, more potent immunosuppression may be required, increasing the risk of infection. it is also possible that immune reconstitution proceeds more slowly (even with the same immunosuppressive regimen) after a urd hct. these factors may result in increased risk of infections associated with t cell immunodefi ciency, like cmv, pneumocystis jirovecii pneumonia (pcp), and epstein-barr virus (ebv)-related posttransplant lymphoproliferative disorder (ptld). however, provided the number of stem cells administered is the usual (>3 × 10 6 kg −1 ), neutrophil recovery proceeds at the standard pace and there is no increased risk of neutropeniarelated infections. the problems with ucb transplants include a markedly decreased stem cell dose (often <1 × 10 5 kg −1 ) which results in prolonged neutropenia (up to 6 weeks), with the attendant risk of bacterial and fungal infections [ 27 ] . in addition, the cord blood does not have antigen-specifi c memory t cells that can expand in a thymus-independent fashion to provide protection against viruses and opportunistic pathogens. this results in high frequency of late severe infections following cord transplantation, even when the neutropenic period is shortened by coadministration of stem cells from a thirdparty donor [ 28 ]. stem cells may be given using the bone marrow, g-csfmobilized peripheral blood stem cells (pbscs), or ucb. frequently bone marrow will result in more prolonged neutropenia compared with pbsc, and increased infections during neutropenia should be expected. however, a multicenter randomized trial comparing peripheral blood stem cells with the bone marrow from unrelated donors showed no difference in the relapse or infectious mortality between both groups, but confi rmed that chronic gvhd is more common with mobilized pbsc [ 29 ] . the particular features of ucd transplants were discussed on the preceding paragraph. manipulation of the stem cells, immunosuppressive drugs, or a combination gvhd may be prevented by decreasing the amount donor t cells or by limiting t cell function with immunosuppressive agents. the stem cells, whether from the bone marrow or the periphery, may be administered unmanipulated (sometimes called "t cell replete") or enriched by cd34 selection (also called "t cell depleted"). if unmanipulated bone marrow or pbscs are used, the dose of cd3+ t cells administered with the graft varies between 24 × 10 6 kg −1 when bone marrow is used and 300 × 10 6 kg −1 when pbscs are used [ 30 ] . reductions in the amount of t cells of 2-3 log 10 are possible, and in some haploidentical transplant regimens, as few as 12.5 × 10 3 cd3+ cells are given, which still results in detectable immune reconstitution starting 2-3 months after transplant [ 31 ] . t cell depletion may minimize or altogether prevent gvhd but may result in prolonged immunodeficiency, depending on the degree of depletion. if an unmanipulated product is used, t cell depletion may be attained in vivo by using alemtuzumab or atg. these agents produce a profound depletion of t cells in vivo, and their long halflife makes them still be present and active in the recipient when the stem cell product is administered. if no in vitro or in vivo t cell depletion is used, one of a variety of immunosuppressive regimens will be given to prevent gvhd (e.g., tacrolimus + methotrexate, tacrolimus plus mycophenolate mofetil, cyclosporine a, sirolimus, posttransplant cyclophosphamide). a randomized controlled trial documented more infections in patients randomized to (moderate) t cell depletion than in the group who received pharmacologic immunosuppression [ 32 ] . t cell depletion in vivo with alemtuzumab has been associated with increased risk of infection [ 33 ] . it is possible that different pharmacological regimens may result in different infectious risks, but this has not been adequately studied. preliminary evidence suggests that a sirolimus-based regimen may result in less cmv reactivation [ 34 ] and that posttransplant cyclophosphamide result in relatively decreased risk of ptld [ 35 ]. the above categories may combine in several ways, compounding the risk of infection. these variations should be considered both when designing a regimen of anti-infective prophylaxis and when considering an individual patient who may have an infection. gvhd is the most important cause of non-relapse mortality following hct, and it is frequently complicated by infection. gvhd is categorized as acute or chronic based on its time of onset. acute gvhd develops before day 100 and is characterized by gastrointestinal disease (secretory diarrhea, nausea, vomiting), liver dysfunction, and skin rash. stages of gvhd in the skin, gut, and liver combine to give a grade (i-iv) of the severity of the disease. acute gvhd grades iii-iv is associated with signifi cant mortality. the treatment of choice is high-dose systemic corticosteroids. gvhd is associated with signifi cant immune dysregulation [ 36 , 37 ] and is frequently accompanied by cmv reactivation [ 38 ] . the combination of disruption of the gi mucosa (and sometimes skin) and high-dose corticosteroids (in addition to the immunosuppressive agents concurrently given, like tacrolimus and mmf) constitute a high-risk setting for infection. bacterial, fungal, and viral infections are common under these circumstances. chronic graft-versus-host disease (cgvhd) has been traditionally defi ned chronologically: gvhd starting after day 100. it has been classifi ed based on its relation to prior gvhd (progressive when acute gvhd continues after day 100, quiescent when there is a period of time during which the patient is free of gvhd, or de novo when chronic gvhd is the fi rst manifestation of gvhd) and its extension (limited or extensive, reformulated as clinical limited, or clinical extensive). the clinical syndrome of typical chronic gvhd is quite distinct from the acute form, and a new classifi cation focusing on the clinical characteristics of the disease as well as on the timing is being increasingly used [ 39 ] . from the standpoint of infectious diseases, the important consideration is that the presence of chronic gvhd is associated with high risk of infection [ 40 , 41 ] . multiple immune defects have been described during chronic gvhd, involving humoral and cellular immunity [ 42 , 43 ] as well as functional hyposplenism [ 44 , 45 ] . besides these abnormalities, that result in delayed immune reconstitution and poor response to immunizations, the risk is of infection is increased by the treatment of extensive cgvhd [ 41 ], which typically includes systemic corticosteroids and a variety of steroid-sparing agents. notably, cgvhd is a well-documented risk for pneumococcal infections [ 45 , 46 ] , fungal infections, and late cmv disease. however, all types of infections are more common during cgvhd, particularly during the fi rst few months [ 47 ] . when gvhd is not controlled by corticosteroids, it is called " steroid refractory ," and there is currently no universally accepted standard treatment. this situation is important from the infectious disease standpoint because patients are usually treated with a variety of highly immunosuppressive regimens (e.g., atg, cyclophosphamide, mmf, infl iximab, daclizumab, alefacept, alemtuzumab, sirolimus, visilizumab, denileukin diftitox, and others) [ 48 ] that result in a wide array of infectious complications. reactivation of cmv is very common, as are fungal infections [ 49 , 50 ] , epstein-barr virus-related ptld [ 51 ] , as well as human herpesvirus 6 (hhv-6) [ 52 ] and adenovirus [ 53 ] . there are no controlled studies to support any particular infection prevention strategy during this period of increased immunosuppression, but some authors have emphasized that early use of prophylactic antibiotics and antifungals is an essential part of a successful approach to this problem [ 54 ] . unfortunately, this is a condition for which controlled trials are unlikely to be performed, and different centers will have to decide on a particular approach of close monitoring versus prophylaxis based on local experience and published case series. in the following sections, the epidemiology of bacterial, fungal, viral, and parasitic diseases will be discussed. the implications for prophylaxis and management will be mentioned. immunizations for transplant recipients, (as well as their caregivers and immediate contacts) are discussed in chap. 48 6.6 risks and epidemiology of bacterial infections after allogeneic hct 6.6.1 early bacterial infections: pre-engraftment approximately 20% of hct recipients will experience at least one episode of bacteremia during the fi rst few weeks, and a similar proportion after engraftment [ 55 ] . these infections are usually related to either neutropenia with subsequent bacterial translocation through the gi mucosa (mucosal barrier injury laboratory-confi rmed bloodstream infection or mbi-lcbi) or the intravascular catheter (central lineassociated bloodstream infections or clabsis) [ 56 ] . the relative frequency of gram-positive and gramnegative infections during neutropenia varies in different series and with the use of prophylactic antibiotics. in some centers, the most frequent gram-positive isolates are viridans group streptococcus [ 55 ] ; this may be a function of the conditioning regimen or the patient population. enterococcus faecium , frequently vre, is another gram-positive organism that tends to cause bloodstream infection relatively early, although this seems to be rather institution dependent [ 57 ] . the gram-negative bacteria are commonly enterobacteriaceae . these infections are generally related to the disruption of the gi mucosa due to the preparative regimen. the role of reduced diversity of the microbiota with subsequent bacterial domination and ultimately bacteremia is an area of intense study [ 58 ] . the risk of bacteremia during neutropenia may be decreased by the use of prophylactic antibiotics [ 59 , 60 ] . this had been shown in multiple studies over the years, but the recommendation of using antibiotics did not become part of practice guidelines until recently. it is not clear whether this recommendation will continue amidst the increasing concern over the role of antibiotic-induced decreased microbiome diversity on the outcome of hct [ 61 ] . in this regard it is of interest that fl uoroquinolones seem to have less detrimental effects on biodiversity of the fecal fl ora than beta-lactams. levofl oxacin at a dose of 500 mg/d for patients who are going to be profoundly neutropenic for longer than 1 week is the current recommendation of the idsa [ 11 ]. following engraftment in a large study from the sloan kettering cancer center, the risk factors for post-engraftment bacteremia included acute gvhd, renal dysfunction, hepatic dysfunction, and neutropenia [ 55 ] . enterococcus (vre) and coagulase-negative staphylococcus were the most common gram-positive isolates. enterobacteriaceae and non-fermentative gram-negative bacteria (including pseudomonas , stenotrophomonas , and acinetobacter , possibly related to the indwelling catheter) were the most common gramnegative isolates. bacteremia following engraftment often happens in the setting of patients with a complicated clinical course, acute gvhd, and multiple medical problems or else is catheter related. daily bathing with chlorhexidine-impregnated washcloths decreased the risk of acquisition of mdros and development of hospital-acquired bloodstream infections in transplant recipients in a randomized trial [ 62 ] , and this practice should be considered by every transplant program. the advantages and disadvantages of active screening for colonization by resistant pathogens have not been adequately studied in hct recipients. it is likely that local epidemiology determines whether screening is an effi cacious and costeffective approach to either prevent infection or improve outcomes. a retrospective study on vre bacteremia from the sloan kettering cancer center showed that vre carriage was predictive of subsequent vre bacteremia, but failed to detect the pathogen in many patients [ 63 ] . performing surveillance cultures for resistant organisms in vulnerable patient populations is part of the cdc recommendations "management of multidrug-resistant organisms in healthcare settings, 2006" [ 64 ] , and has been vigorously advocated by some experts [ [ 66 , 67 ] . both early and late (beyond day 100) pneumococcal disease has been reported, with late infections strongly associated with active cgvhd [ 46 ] . these have been attributed to inadequate antibody production and functional hyposplenism [ 44 , 67 ] . vaccination against s. pneumoniae should be given to all hct recipients, starting 3-6 months after transplant and using the 13-valent conjugate vaccine [ 9 ] (see chap. 48 for details). four doses of the vaccine result in enhanced antibody response and tolerable side effects [ 68 ] . antibiotic prophylaxis against s. pneumoniae prophylaxis for adults with active cgvhd has been recommended [ 69 ] , although there is only weak evidence supporting its effi cacy. penicillin v-k is safe and well tolerated, but the local patterns of penicillin resistance may make other antibiotics (e.g., trimethoprim, sulfamethoxazole, azithromycin, or levofl oxacin) preferable, although their long-term safety is not well established. late bacterial infections often involve the respiratory tract. pneumonia is the most common cause of fatal late infection [ 40 , 70 ] . chronic gvhd is the risk factor most commonly identifi ed. besides s. pneumoniae , multiple other pathogens have been reported. nocardia also tends to occur late and in patients with cgvhd [ 71 , 72 ] . mycobacterial infections are uncommon and diffi cult to diagnose [ 73 ] . risk factors for the development of active tb include gvhd, corticosteroid treatment, and total body irradiation (tbi) [ 74 ] . the need for universal testing for tuberculosis is controversial, given the unknown sensitivity and specifi city of the tests in this population and the fact that tuberculosis is a relatively uncommon complication after hct (albeit still approximately three times higher than in the general population) [ invasive candidiasis follows prior colonization and favorable conditions for the yeast: disruption of the gi mucosa during chemotherapy or acute gvhd, overgrowth in the presence of broad-spectrum antibiotics, and/or presence of indwelling catheters (the catheter seems to be the main risk factor in the case of c. parapsilosis ). early studies showed that fl uconazole during the pre-engraftment period could decrease the incidence of invasive candidiasis [ 76 , 77 ] . accordingly, fl uconazole is recommended as part of the standard prophylactic regimen during the pre-engraftment period. the prevalent use of fl uconazole has resulted in substantial decrease in the incidence of infections caused by c. albicans with relative increases in the incidence of other species of candida with decreased susceptibility to this agent (e.g., c. glabrata , c. krusei ) [ 78 ] . invasive aspergillosis occurs during specifi c "at risk" periods following hct, with a fi rst peak around the time of neutropenia pre-engraftment, a second peak between days 40 and 70 (the time of acute gvhd and its treatment), and a third peak late after transplant, usually in the midst of actively treated cgvhd [ 79 ] (figure 6-1 ) . a variety of risk factors for invasive aspergillosis have been identifi ed over the years, but the most consistently found to be signifi cant in multivariate analyses are acute gvhd, chronic extensive gvhd, and cmv disease [ 80 -82 ] . systemic corticosteroids are almost always present as part of the treatment of acute and chronic gvhd. non-aspergillus mold infections (e.g., fusariosis, mucormycosis, scedosporiosis), sometimes referred to as emerging mold infections, have been reported with increasing frequency [ 83 ] . the increased use of prophylaxis with activity against aspergillus would be expected to result in a relative increase of other opportunistic mycoses like mucormycosis [ 84 ] . considering the diversity of fungal infections after transplant and the current antifungal armamentarium, it is controversial which antifungal prophylaxis is appropriate at what point during transplant. for instance, although fl uconazole is a safe and well-established intervention during the preengraftment period of myeloablative transplants [ 76 , 77 ] , it is reasonable to question how necessary it is in transplants with conditioning regimens that result in shorter neutropenia. micafungin showed to be equivalent to fl uconazole in a randomized controlled trial [ 85 ] , and the same question (what kind of transplant patient would benefi t most) applies. regarding the duration of antifungal prophylaxis, fl uconazole up to day 75 posttransplant was associated with improved survival mainly due to decreased incidence of systemic candidiasis [ 86 ] , but it is uncertain whether this strategy should be used for all patients or should be received for some selected subgroups considered at higher risk. similarly, it is reasonable to question the indication for fl uconazole during periods when the main fungal infection is aspergillosis. several randomized controlled trials have compared fl uconazole with another azole with activity against molds (itraconazole [ 87 , 88 ] , voriconazole [ 89 ] , or posaconazole [ 90 ] ) either as standard posttransplant prophylaxis or during periods of increased risk. the general conclusion of these trials is that the aspergillus-active drugs are, indeed, more effective than fl uconazole in preventing ia, but the benefi t in survival in the context of a clinical trial with careful monitoring of galactomannan antigen is hard to demonstrate [ 91 ] . the 2009 asbmt/ebmt guidelines recommend posaconazole or voriconazole as antifungal prophylaxis in the setting of gvhd and micafungin in the setting of prolonged neutropenia [ 1 ] . of note, posaconazole prophylaxis was superior to fl uconazole or itraconazole and improved survival in prolonged neutropenia in non-transplant patients [ 92 ] . now, there are even more options of mold-active prophylaxis with posaconazole delayed-release tablets, intravenous posaconazole, and the new agent isavuconazole. infections after allogeneic hct viral infections remain a challenge because newer transplant modalities result in severe prolonged t cell immunodeficiency and because the current antiviral armamentarium is very limited. multiple latent viruses may reactivate following hct [ 93 ] . the role of monitoring by pcr is well defi ned mainly for cmv. latent viral reactivation is of particular concern in recipients of cord [ 94 ] or t cell-depleted transplants. table 6 -3 presents a summary of this section. members of the herpesvirus family that have caused significant disease after transplant include hsv-1, hsv-2, vzv, ebv, cmv, and hhv-6. posttransplant complications of hhv-7 are not well defi ned, although multiple associations have been described. hhv-8 infection and disease (primary effusion lymphoma and kaposi's sarcoma) occur only infrequently after hct. hsv-1 and hsv-2 may reactivate following the preparative regimen and complicate chemotherapy-induced mucositis, so it is customary to administer prophylaxis with acyclovir or valacyclovir at least until engraftment. in patients with common recurrences, long-term suppression may be appropriate. vzv predictably reactivates following transplant (approximately 25% in the fi rst year), either as shingles, multidermatomal, disseminated, or even without a rash ("zoster sine herpete"). in patients who are at risk for vzv reactivation, the use of long-term acyclovir safely prevents the occurrence of vzv disease [ 95 , 96 ] , and currently it is recommended for at least 1 year following hct. cmv remains latent in a variety of human cells. cmvseropositive hct recipients are at risk for cmv reactivation and disease after transplant. the term "cmv infection" is used to denote the presence of cmv in the blood detected by pcr or pp65 antigenemia [ 97 ] . following reactivation, cmv may cause disease typically in the form of pneumonia and/or gastrointestinal disease (most commonly colitis). other cmv diseases like retinitis or cns involvement are rare after hct but have been described: retinitis has been associated with high cmv viral load [ 98 ] sometimes in the context of chronic gvhd and cns disease (encephalitis and ventriculitis), sometimes with resistant virus in the cns [ 99 , 100 ] . the risk for reactivation may be related to the presence of cmv-specifi c immunity in the donor. the rate of cmv infection in the donor-recipient (d/r) pairs often follows the progression d r d r d r d r -+ + + + , suggesting that cmv-specifi c memory t cells administered with the stem cells may play a role in preventing reactivation and disease. cmv infection or disease in cmv-seronegative recipients of seronegative donors (r−/d−) is rare when leucodepleted or cmv-negative blood products are used [ 101 ] . every transplant program must decide on a strategy to monitor cmv and prevent disease. depending on a variety of factors, either universal prophylaxis with ganciclovir up to day 100 or a preemptive strategy of weekly monitoring and early therapy may be used. both approaches resulted in similar overall mortality when compared in a randomized controlled trial, but universal prophylaxis was followed by more cases of late cmv disease [ 97 , 102 ] . late cmv disease has emerged as a signifi cant problem, as it occurs when patients are not being under close monitoring by the transplant center. risk factors include lymphopenia and chronic gvhd [ 103 ] . preventing late cmv disease may be accomplished by either prophylaxis with valganciclovir or the preemptive approach with weekly cmv pcr monitoring [ 104 ] . the effect of cmv serostatus of donor and recipient on overall survival is complex (for a review, see [ 105 ] and chap. 24 ). ptld is a spectrum of lymphoid proliferations that may happen after solid organ or allogeneic stem cell transplantation, usually (but not always) driven by ebv [ 106 ] . pathologically the spectrum goes from polymorphic, polyclonal tissue infi ltration of lymphocytes to monomorphic involvement with high-grade b cell lymphoma. after allogeneic hct, the proliferating cells may be from donor (most commonly) or recipient origin. this disorder is typically related to insuffi cient or abnormal t cell responses against ebv [ 107 ] , and accordingly it is more common in the setting of hla-mismatched transplants, t cell depletion, or intense immunosuppression for the treatment of gvhd [ 108 -110 ] . some cases have followed the use of alemtuzumab for in vivo t cell depletion or gvhd prophylaxis [ 110 ] , despite the fact that anti-cd52 also results in depletion of b cells and earlier had been reported to be associated with relatively less risk. interestingly, the use of posttransplant cyclophosphamide to prevent gvhd seems to be associated with lower risk of ptld [ 35 ] . monitoring of ebv viral load by quantitative pcr is now recommended in those transplants considered at high risk. preemptive management of increasing ebv viral load in patients at risk has been associated with good outcomes [ 111 ] , although it is not clear when exactly this treatment should be given. a ct/pet may be useful to localize areas amenable to biopsy (figure 6 -2 ). hhv-6 is acquired early in life, when it may cause roseola infantum and nonspecifi c febrile illnesses. it frequently reactivates following hct. using quantitative pcr, hhv-6 can often be detected in peripheral blood 2-5 weeks after transplant. most of the time the reactivation seems to be asymptomatic [ 112 ] , but a number of associations (rash, delayed engraftment, gvhd, thrombocytopenia, increased overall mortality) as well as actual clinicopathological entities (hepatitis, pneumonitis, encephalitis) have been described [ 113 -115 ] . hhv-6 is possibly the most common cause of infectious encephalitis after hct [ 116 ] . it seems to be particularly frequent after cord blood transplant. cases of encephalitis tend to be accompanied by higher viral loads of hhv-6 in plasma [ 117 ] , but the role of systematic monitoring of hhv-6 in plasma is unknown at this time, as reactivation seems much more common than disease [ 118 ] and attempts to use a preemptive strategy using foscarnet have not been successful [ 119 ] . the european conference on infections in leukemia has proposed evidence-based guidelines to address the diagnostic and therapeutic uncertainties related to this infection [ 120 ] . respiratory viruses , a heterogeneous group of virus that is responsible for most upper acute respiratory infections in normal hosts, result in signifi cant morbidity and mortality after hct, particularly during the fi rst 3 months following transplant [ 121 ] . even asymptomatic carriage of respiratory viruses at the time of transplant has been reported to result in increased risk of unfavorable outcomes [ 122 ] . besides respiratory syncytial virus (rsv) [ 123 ] , infl uenza, parainfl uenza virus (piv) [ 124 ] , rhinovirus [ 125 ] , and adenovirus, newly identifi ed viruses including metapneumovirus [ 126 ] , coronavirus [ 127 ] , and bocavirus [ 128 ] have emerged as signifi cant pathogens. these infections present signifi cant risks both acutely and in the long term. during the acute infection, hct recipients are at risk of developing viral pneumonia that sometimes progresses to respiratory insuffi ciency, mechanical ventilation and death, and also at risk of concomitant or secondary bacterial or fungal infections that are associated with increased mortality [ 124 , 129 , 130 ] . longterm, there seems to be an association between early infection (pre-day 100) with some of these viruses (most notably piv and rsv) and later development of chronic airfl ow obstruction [ 131 ] . the most signifi cant risk factor overall for progression of these infections from the upper respiratory tract to the lungs seems to be lymphopenia [ 132 ] . corticosteroid use seems to contribute to progression to pneumonia in rsv and parainfl uenza infections but not so in infl uenza [ 129 , 130 ] (see table 6 -3 ). besides its role among the community-acquired respiratory virus, adenovirus may cause disease in transplant recipients following reactivation in the gastrointestinal tract followed by dissemination and end-organ damage [ 133 ] . de novo acquisition of adenovirus may also result in disseminated disease. there are more than 60 types of human adenovirus, with dif-ferent tropisms and possibly varying susceptibilities to antiviral agents. they can cause a variety of diseases, including upper and lower respiratory tract infection, colitis, hemorrhagic cystitis (hc), nephropathy, and cns disease. systemic adenovirus disease seems to be more common in children, particularly in recipients of cord blood or t cell-depleted transplants [ 134 -136 ] . patients with gvhd on treatment with high-dose corticosteroids are also at risk (figure 6-3 ) . some studies have documented that sustained high levels of adenoviremia are associated with disease [ 137 ] . it is not known yet whether a preemptive approach with cidofovir can successfully prevent disseminated disease and death [ 133 , 138 ] . bk virus infects 90% of humans by age 12. it predictably reactivates in most patients following hct and causes hemorrhagic cystitis (hc) in a minority of them [ 139 ] . detection of high levels of bk in the peripheral blood seems to correlate with the presence of bk-induced hc [ 140 , 141 ] . in a large study from the fred hutchinson cancer research center (fhcrc), no association was found between bk virus-associated hc and lymphopenia, corticosteroid use, and gvhd-the typical risk factors for viral infections after hct [ 140 ] . in contrast, other smaller studies have found an association with gvhd. the pathogenesis of this disease remains unexplained. bk-induced nephropathy, a common problem after kidney transplant, remains infrequent after hct and does seem to be related to profound immunosuppression [ 142 ] . bk pneumonitis has also been described, but it is distinctly rare [ 143 ] . jc virus is also acquired by most people during childhood. in immunocompromised hosts, it may cause encephalitis (jc encephalitis, previously called progressive multifocal leukoencephalopathy (pml)) with multiple areas of demyelin-ation without edema detectable by mri. some studies have suggested that detectable viral load after hct may be more common than currently thought [ 144 ] . ascertaining risk factors for this disease is diffi cult because some transplant recipients may have conditions known to be associated with it and also received medications like mmf, rituximab, or brentuximab, which have been associated with pml even in the absence of allo-hct. pcp is an opportunistic infection of patients with profound cellular immunodefi ciency, and prophylaxis is recommended after hct. it is now relatively uncommon: 1.3-2.4% of patients transplanted from several series [ 145 , 146 ] most cases seem to occur relatively late, after discontinuing prophylaxis or during periods of intensive immunosuppression for the treatment of gvhd [ 147 ] . hypoxemia is characteristic at presentation. atypical radiological manifestations, including nodular infi ltrates and pleural effusions (in contrast to typical interstitial pneumonitis), are described frequently, as is the presence of co-pathogens [ 148 ] . the preferred prophylaxis is trimethoprim/sulfamethoxazole (tmp/smx) , and several dosing regimens are effective (one single-strength tablet daily, one double-strength tablet daily, or one double-strength tablet three times/week) [ 149 ] . tmp/ smx may be poorly tolerated because of hematologic toxicity, skin rash and/or gastrointestinal toxicity [ 150 ] . it is unclear which is the prophylaxis of choice if tmp/ smx cannot be used. aerosolized pentamidine is convenient, obviates the problem of compliance, and is less toxic than dapsone and better tolerated than atovaquone. however, it has been reportedly associated with more failures than dapsone [ 150 ] . dapsone seemed to be effective and well tolerated in one study [ 151 ] but not in another when it was given only three times per week [ 152 ] . dapsone should not be given to patients with g6pd defi ciency. methemoglobinemia is a well-known complication of dapsone [ 153 ] that should be considered in the presence of unexplained shortness of breath. atovaquone suspension 1500 mg/d may be used, but published experience in hsct recipients is limited [ 154 , 155 ] . atovaquone is expensive and poor tolerance has made compliance for some patients diffi cult. absorption is better in the presence of signifi cant amount of fat, and breakthroughs are well documented ( figure 6-4 ) . pcp prophylaxis is recommended at least until all immunosuppression has been stopped but it is unclear how much longer to continue it [ 156 ] . most cases of toxoplasmosis after hct represent reactivation, although rare cases of transmission with bone marrow transplant have been suspected [ 157 ] . recipients should be tested for anti-toxoplasma igg antibody, and if they are found to be positive, prophylaxis is recommended. rare cases of toxoplasmosis after hct have occurred in seronegative recipients [ 158 , 159 ] . the disease tends to occur within the fi rst 6 months after transplant, but it can happen later in the presence of persistent immunosuppression [ 160 -162 ] . the risk of toxoplasmosis varies with the type of transplant and the immunosuppression: cord blood and use of atg were found to be risk factors for disease in a prospective study [ 162 ] ; most cases in another series occurred in urd or mismatched transplants [ 107 ] . tmp/smx as given for pcp prophylaxis is considered adequate to prevent toxoplasmosis, although there have been cases on hct recipients who were receiving it [ 162 ] . the best alternative for patients who are intolerant to tmp/smx is unknown. dapsone and atovaquone showed some effi cacy in hiv-infected patients and there is increasing experience after hct [ 163 ] , although failures have been reported. other regimens include clindamycin with pyrimethamine and leucovorin, pyrimethamine with sulfadiazine, or pyrimethamine and sulfadoxine and leucovorin [ 107 ] . if a reliable quantitative pcr assay is available, frequent monitoring and preemptive treatment may be appropriate, since pcrdetected reactivation seems to precede symptoms by 4-16 days [ 162 ] . retrospective data suggest this strategy may result in improved outcome [ 164 ] . in summary, infections following hct are frequently related to risk factors caused by the procedure itself. neutropenia and mucositis predispose to bacterial infections. prolonged neutropenia increases the likelihood of invasive fungal infection. gvhd and its treatment create the most important easily identifi able risk period for a variety of infectious complications, particularly mold infections. profound, prolonged t cell immunodefi ciency, present after t cell-depleted or cord blood transplants, is the main risk factor for 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review of the literature. bone marrow transplant team disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient toxoplasmosis after hematopoietic stem cell transplantation report of a 5-year survey from the infectious diseases working party of the european group for blood and marrow transplantation early detection of toxoplasma infection by molecular monitoring of toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation atovaquone for prophylaxis of toxoplasmosis after allogeneic hematopoietic stem cell transplantation molecular diagnosis of toxoplasmosis in immunocompromised patients: a three-year multicenter retrospective study risks and epidemiology of infections after hematopoietic stem cell transplantation key: cord-011701-toevn37u authors: venkatesan, sudhir; carias, cristina; biggerstaff, matthew; campbell, angela p; nguyen-van-tam, jonathan s; kahn, emily; myles, puja r; meltzer, martin i title: antiviral treatment for outpatient use during an influenza pandemic: a decision tree model of outcomes averted and cost-effectiveness date: 2018-06-28 journal: j public health (oxf) doi: 10.1093/pubmed/fdy108 sha: doc_id: 11701 cord_uid: toevn37u background: many countries have acquired antiviral stockpiles for pandemic influenza mitigation and a significant part of the stockpile may be focussed towards community-based treatment. methods: we developed a spreadsheet-based, decision tree model to assess outcomes averted and cost-effectiveness of antiviral treatment for outpatient use from the perspective of the healthcare payer in the uk. we defined five pandemic scenarios—one based on the 2009 a(h1n1) pandemic and four hypothetical scenarios varying in measures of transmissibility and severity. results: community-based antiviral treatment was estimated to avert 14–23% of hospitalizations in an overall population of 62.28 million. higher proportions of averted outcomes were seen in patients with high-risk conditions, when compared to non-high-risk patients. we found that antiviral treatment was cost-saving across pandemic scenarios for high-risk population groups, and cost-saving for the overall population in higher severity influenza pandemics. antiviral effectiveness had the greatest influence on both the number of hospitalizations averted and on cost-effectiveness. conclusions: this analysis shows that across pandemic scenarios, antiviral treatment can be cost-saving for population groups at high risk of influenza-related complications. influenza pandemics are rare, unpredictable events with potentially serious consequences. they are considered to be important public health emergencies by the world health organization, and a number of countries, with many having specific pandemic preparedness plans. [1] [2] [3] neuraminidase inhibitors (nai) often feature prominently in pandemic influenza preparedness plans 2 and several high-income countries have acquired nai stockpiles because pandemic specific vaccines may not be widely available for up to 6 months. 4 clinical trials show nai effectiveness in modestly reducing duration of symptomatic illness in patients with uncomplicated seasonal influenza. [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] however, these trials were under-powered to assess nai impact on secondary outcomes such as hospitalizations. [15] [16] [17] two meta-analyses of the extant clinical trial data, examining outcomes based on the intention-to-treat-influenza infected (itti) approach, found that early nai treatment (≤48 h of symptom onset) was associated with a risk reduction of 59 18 and 63% 19 for hospital admission in otherwise healthy patients with influenza. other meta-analyses of trial data that evaluated all outpatients with influenza-like-illness (ili) using the intention-to-treat (itt) approach did not find a reduction in hospitalizations in those treated with nais. 20, 21 if a future pandemic is severe, hospital capacity may be exhausted and therefore reserved for the severely ill who are most likely to benefit. 22 countries may decide to focus a significant part of their pandemic response plan towards community treatment aimed at averting hospitalizations. policy makers considering nai stockpiling for a future pandemic of unknown severity will have to consider both number of hospitalizations averted and the cost-effectiveness of such an intervention. nai treatment for pandemic influenza has generally been estimated to be cost-effective for higher-income countries. [23] [24] [25] however, a review identified that previous health economic evaluations often neglected pandemic uncertainty by only evaluating singular, fixed pandemic scenarios. 26 moreover, few models have incorporated the increased risks of adverse pandemic influenzarelated outcomes for patients with at-risk conditions. we present a spreadsheet-based decision tree model that evaluates the impact of community-based nai treatment in terms of the averted influenza-related hospitalizations and associated costeffectiveness in a range of pandemic scenarios. we built a decision tree model ( fig. 1) to calculate the impact of community-based nai treatment for five pandemic scenarios. the first scenario is based on the uk's a(h1n1) pdm09 experience, with a clinical attack rate (car) of 7% and a case hospitalization risk (chr) of 0.3 and 1.5% among non-high-risk and high-risk patients, respectively (table 1) . the other four scenarios were based on hypothetical pandemics that varied the car (20 and 30%) and the chr (1.05-4.0% for non-high-risk patients; 5-20% for high-risk patients) ( table 1 ). the hypothetical scenarios are based on a risk assessment framework developed by the cdc. 27,28 a standardized risk space was defined based on previous influenza pandemics, and hypothetical pandemic scenarios were identified from this risk space to allow easy comparisons to future economic evaluations. the chrs for the high-risk groups in these four hypothetical pandemics were assumed to be five times the chr for the non-high-risk group of patients based on estimates from the 2009 a(h1n1) pandemic. 29 we also assumed that the percentage of patients seeking outpatient/ambulatory care would increase with the chr of the pandemic, ranging from 40% among non-high-risk patients in a 2009-type pandemic to~81% among high-risk patients when the chr is 20% (table 1) . we estimated the number of deaths averted through averting hospitalizations by multiplying the number of hospitalizations averted with an inhospital mortality risk that was constant across the scenarios. we did not differentiate between oseltamivir and zanamivir in the definition of nais in our model; however, we based our cost and treatment effectiveness estimates on data specific for oseltamivir. we focus on community-based treatment and do not consider nai prophylaxis. we used nai effectiveness estimates from an individual participant data (ipd) meta-analysis of clinical trials data on otherwise healthy patients with seasonal influenza 19 based on itti analysis (relative risk: 0.37, 95% confidence interval: 0.17-0.81) since nais are not active against non-influenza respiratory infections. 30 to account for nai prescriptions to patients with non-influenza ili, we assumed a 'wastage factor' of 40%, i.e. patients with non-influenza ili would be prescribed 40% of the number of regimens that are prescribed to patients with influenza. 31 we assumed that all patients would start nai treatment ≤48 h of symptom onset in our main model and then performed a sensitivity analysis varying the promptness of care-seeking within 48 h of symptom onset from 25 to 75% (percentage of all care-seeking patients who do so ≤48 h of symptom onset). based on estimates from 2009, we also assumed that 64% of patients would be compliant with the prescribed regimen. 32 unit cost data for our model were obtained from secondary sources including the british national formulary and uk-based reports on the cost of health and social care (table 1) . briefly, we used a weighted average cost of physician-based consultation of £24.20. this cost was calculated as a weighted average cost of either a conventional primary care consultation or a phone-based consultation with the 2009 national pandemic flu service (npfs). 33 the weighting of the costs was done using the proportion of assessments routed through each consultation service in 2009. we used a cost of £16 for an nai prescription, which included the cost of delivery. costs of hospitalizations ranged from £436 for non-high-risk patients to £1727 for highrisk patients (table 1 ). all costs were inflated to the 2017 british pound sterling (£) using the hospital and community health services (hchs) index. 34 the overall population of 62.28 million was based on the 2009 uk population. 35 we performed the analyses from the perspective of the healthcare payer, the uk national health service (nhs). given that we did not undertake a full costutility analysis, we chose to measure our outcomes in natural units (deaths and hospitalizations) rather than in standardized units (qalys). 36 we considered a time horizon of less than one year (one pandemic event), therefore a discounting rate would not apply. in each pandemic scenario, we compared the number of outcomes averted (hospitalizations and deaths) and total costs associated with nai treatment compared to no nai treatment. we assessed cost-effectiveness of communitybased nai treatment by estimating the cost per averted hospitalization. our primary analysis was performed using the middle values of our input parameters using formulas provided in appendix 1. to account for uncertainty in parameter estimates, we performed sensitivity analyses by probabilistically varying input parameters along pre-defined probability distributions (table 1 ) and using monte carlo simulations (5000 iterations using latin hypercube sampling) to calculate mean output values and 95% confidence intervals for different combinations of input parameters. the sensitivity analyses were performed using the software @risk version 7.3 (palisade corporation). further, we also performed two-way sensitivity analysis to assess the impact of varying nai effectiveness and patient compliance on the outcome (hospitalizations averted). in a 2009-like pandemic scenario, we estimated that in our base-case model (no nai treatment) there would be 28 773 hospitalizations in the overall population. we estimated that 1.9 million regimens of nais would be dispensed for outpatient treatment. nai treatment would have averted 4034 (14%) hospitalizations in a population of 62.28 million (65 hospitalizations averted/million population) at a cost of £7110 per hospitalization averted ( table 2 ). the cost to avert one hospitalization was £2238 in high-risk populations and £20 473 in the non-high-risk population ( table 2 ). in the 20% car-severity 1 scenario (chr: non-high-risk = 1.05%; high-risk = 5.25%), we estimated that 287 734 hospitalizations would occur. the 8.07 million regimens of nais would be dispensed, averting 57 281 (19.9%) hospitalizations at a cost per averted hospitalization of £1008 in the overall population and £5497 in the non-high-risk population. nai treatment was seen to be cost-saving in the high-risk population. in the 20% car-severity 2 scenario (chr: non-high-risk = 4%; high-risk = 20%), we estimated that over 1.09 million hospitalizations would occur. the 9.34 million nai regimens would be dispensed, averting 250 478 (22.9%) hospitalizations in the total population at a cost per averted hospitalization of £1079 in the non-high-risk population. nai treatment was seen to be cost-saving in the overall population and in the high-risk population. in the 30% car-severity 1 scenario, (chr: non-highrisk = 1.05%; high-risk = 5.25%), we estimated that over 430 000 hospitalizations would occur. the 12.1 million nai regimens would be dispensed, averting 85 922 (19.9%) hospitalizations at a cost per averted hospitalization of £1 008 in the overall population and £5497 in the non-high-risk population. nai treatment was seen to be cost-saving in the high-risk population. in the fourth pandemic scenario, (chr: non-high-risk = 4%; high-risk = 20%), we estimated that over 1.6 million hospitalizations would occur. the 14.01 million nai regimens would be dispensed, averting 375 717 (22.9%) hospitalizations in the overall population at a cost per averted hospitalization of £1079 in the non-high-risk population. nai treatment was seen to be cost-saving in the overall population and in the high-risk population. we found that varying the proportion of care-seeking patients who do so within 48 h of symptom onset, while keeping all other variables constant, lowered the percentage of averted hospitalizations in the overall population from 14.0% (assuming 100%) to 3.5% (assuming 25%) in the 2009-like pandemic scenario ( table 2, supplemental table s1 ). our sensitivity analyses revealed that using just the middle values of input parameters in a simple multiplicative model without probability distributions was likely to overestimate the number of hospitalizations averted and underestimate the cost per averted hospitalization. for the 2009-like pandemic scenario, multiplying the middle values of input parameters (table 2 ) overestimated the overall number of averted hospitalizations by 28% and underestimated the overall cost peraverted hospitalization by 34% when compared to the mean estimated from the monte carlo simulation (supplemental table s2 ). similar differences in estimates were observed in the other scenarios as well. the sensitivity analyses, based on a 2009-like pandemic scenario, indicated that nai effectiveness had the greatest impact on both the total number of hospitalizations averted, as well as on the cost per hospitalization averted (see fig. 2 for 2009 scenario). when the nai effectiveness was varied from 19 to 83%, the resulting overall proportion of averted hospitalizations ranged between 6 and 15%, at a cost per averted hospitalization of £6936-£19 338. the percentage of care-seeking patients who were prescribed nai, the proportion of nai prescriptions to non-influenza patients, and nai treatment compliance were in the top three influential parameters for one or both outcomes (fig. 2) . in our two-way sensitivity analysis we varied the treatment compliance level along with nai effectiveness beyond the 95% confidence intervals of our input parameter (from 90% effectiveness to 10% effectiveness). increased compliance levels were consistently associated with an increased number of averted hospitalizations across nai effectiveness estimates (fig. 3) . the impact of prescribing nais to non-influenza ili patients had a considerable effect on the cost per averted hospitalization. for the 2009-like pandemic scenario, this ranged from £7983 per averted hospitalization (wastage factor = 30%) to £11 032 per averted hospitalization (wastage factor = 70%). main finding of this study we found that community-based nai treatment would avert a significant proportion of hospitalizations and deaths, particularly in high-risk patients, across the pandemic scenarios we explored in this analysis. however, a substantial number of hospitalizations and deaths would continue to occur even with community-based nai treatment. the proportion of hospitalizations averted by nais could be an important consideration while planning for conditions when hospital capacity could be exceeded. community-based nai treatment was seen to be cost-saving for the overall population in a pandemic with a high car and high severity, and costsaving for patients at high risk of complications from influenza across all the pandemic influenza scenarios tested. the value of nai treatment for population groups not at high risk and for milder pandemic scenarios will have to be determined by careful review under country-specific willingnessto-pay thresholds and the desire to reduce the number of hospitalizations and potential hospital capacity issues. what is already known on this topic nai treatment for pandemic influenza has generally been shown to be cost-effective, when compared to no nai treatment. [23] [24] [25] 37 previous studies have found that nai effectiveness is, by far, the most influential factor affecting the numbers of outcomes averted and the associated cost-effectiveness. 23, 31 results from our sensitivity analysis support this finding. a study based in the united states that used a similar model 31 showed slightly lower proportions of hospitalizations averted due to nai treatment when compared to ours, but the difference could be because of the lower level of treatment effectiveness assumed in the us study. the us study further found that while nai treatment averted many hospitalizations, large numbers of hospitalizations would remain, 31 which is similar to what we have found. we found that variations in nai prescription rate, treatment compliance and healthcare-seeking behaviour (to include the choice to seek care and the promptness in care-seeking) impacted considerably on the outcomes, suggesting that even with a drug of fixed effectiveness, factors relating to healthcare-seeking and healthcare delivery could significantly influence the total number of hospitalizations and deaths averted. these data indicate that a successful pandemic stockpiling strategy must be linked to operational procedures which optimize timely access to antivirals, widespread treatment implementation, and high levels of compliance in targeted groups. one recognized limitation of some previous economic analyses of nai treatment has been that entire populations have been modelled homogenously without accounting for the increase in the likelihood of influenza-related care-seeking and complications in patients with underlying at-risk conditions. 23, 24 in our model, we vary the propensity to seek care and chr by patients' at-risk status. the significance of this is that countries with limited resources could consider obtaining smaller antiviral stockpiles to target at-risk population groups and avert a higher number of hospitalizations and deaths for each antiviral course dispensed than if they adopted a treat-all approach. the car was an important factor in determining the number of nai regimens that would be needed for communitybased treatment. our model showed that a highly transmissible, but low severity pandemic would require a larger nai stockpile than a pandemic with lower transmissibility and higher severity. however, across all pandemic scenarios, the number of nai regimens dispensed for outpatient treatment was well below the uk's published national nai stockpile size of almost 40 million courses of the drug. 38 we have adopted a simple and transparent approach to model building in which we account for important epidemiological factors, population healthcare-seeking behaviour and service utilization rates in a range of pandemic scenarios. our analyses are uk-focussed, but the spreadsheet tool is easily adaptable to represent other healthcare systems. while the epidemiological parameters are unlikely to change drastically by country, input parameters relating to healthcare utilization and costs will need to be replaced with country-specific ones. we provide the simple version of the spreadsheet tool (without the sensitivity analysis) in appendix 2. we used updated nai effectiveness estimates from seasonal influenza data, although observational data from the 2009 a(h1n1) pandemic in a high-severity (high risk of hospitalization) population suggest similar estimates of nai effectiveness (≤48 h from symptom onset). 39 we assumed nai effectiveness is the same in patients with and without atrisk conditions. while there is some evidence to suggest that the level of effectiveness against hospitalization is similar for both groups, 39 there is also evidence that suggests a reduction in nai effectiveness in patients with at-risk conditions. 40 this study is subject to limitations. we used a decision tree model (not a transmission dynamic model) and assumed no effect of nai treatment on transmission. there is evidence to suggest that nai treatment, at a population level, is likely to have minimal impact on influenza transmission. 41 however, decision tree models are known to be limited, especially in their ability to describe the change in influenza attack rates in different risk groups over the course of a pandemic. 37 a comparison of static and dynamic models of nai treatment for pandemic influenza concluded nai treatment was seen to be costeffective with both modelling paradigms; although the associated cost-effectiveness ratios were seen to differ. 37 due to a lack of evidence specific to hospitalization, we did not consider benefits of nai treatment >48 h of symptom onset. nai treatment has, however, been shown be beneficial even when started beyond 48 h from symptom onset. 12 the use of nais may be associated with additional costs to the healthcare system due to possible adverse effects of nais 21 but we have not considered these costs in our model since most side effects are known to be minor. 19 finally, we have assumed that the multiplier for high-risk patients remains constant between severity scenarios resulting in a chr as high as 20%. chrs of 20%, even for high-risk patients, may be unlikely. our analyses show that nai treatment in outpatients can be cost-saving, particularly for population groups at high risk of influenza-related complications. model-based estimates like these of the potential hospitalizations, deaths and costs associated with different pandemic scenarios can help countries consider different treatment options and inform stockpiling decisions while developing pandemic preparedness plans. nai stockpiling decisions are also influenced by other costs to the healthcare system related to storage and maintenance of the nai stockpile. currently, the shelf-life for the 75 mg hard capsules of oseltamivir phosphate that comprise most of the nai stockpile is estimated to be 10 years if stored as per instructions. 42 however, influenza pandemics cannot be predicted, and nai stockpiles could remain unused at the end of their shelf-life, or they may be rendered ineffective or less relevant by the development of antiviral drug resistance or newer, more effective influenza antiviral therapies. additionally, evidence suggests that in-hospital nai treatment may also be associated with protective effects 43, 44 and nai treatment has been shown to be cost-effective if the benefits of nai usage are confined only to those treated in hospital. 45 if a pandemic treatment policy was pursued which combined community use of nais to prevent hospital admission and nai treatment of hospitalized patients to reduce mortality, then cost-effectiveness and stockpile strategies across both scenarios would need to be considered. future research in optimizing nai distribution to risk groups during a pandemic will further inform the costeffectiveness of stockpiling. supplementary data are available at the journal of public health online. dh pandemic influenza preparedness 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health. the national pandemic flu service: an evaluation uk population total health outcomes in economic evaluation: the qaly and utilities dynamic versus static models in cost-effectiveness analyses of anti-viral drug therapy to mitigate an influenza pandemic public accounts committee. 2 stockpiling tamiflu and the management of the stockpile in impact of outpatient neuraminidase inhibitor treatment in patients infected with influenza a(h1n1)pdm09 at high risk of hospitalization: an individual participant data metaanalysis effectiveness of neuraminidase inhibitors in preventing hospitalization during the h1n1 influenza pandemic in british columbia the early transmission dynamics of h1n1pdm influenza in the united kingdom electronic medicines compendium (emc). tamiflu 30, 45 and 75 mg hard capsules effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza a h1n1pdm09 virus infection: a metaanalysis of individual participant data impact of neuraminidase inhibitors on influenza a(h1n1)pdm09-related pneumonia: an individual participant data meta-analysis evidence synthesis and decision modelling to support complex decisions: stockpiling neuraminidase inhibitors for pandemic influenza usage scientific summary of pandemic influenza & its mitigation: scientific evidence base review using an online survey of healthcare-seeking behaviour to estimate the magnitude and severity of the 2009 h1n1v influenza epidemic in england influenza-like illness, the time to seek healthcare, and influenza antiviral receipt during the 2010-2011 influenza season-united states seasonal influenza vaccine uptake amongst gp patient groups in england: provisional monthly data for 1 influenza pandemic: an independent review of the uk response to the 2009 influenza pandemic predictors of clinical outcome in a national hospitalised cohort across both waves of the influenza a/h1n1 pandemic 2009-2010 in the uk unit costs of health and social care department of health. nhs reference costs vaccination against pandemic influenza a/h1n1v in england: a real-time economic evaluation we would like to thank anita patel from cdc, atlanta, for reviewing this manuscript and offering helpful comments. key: cord-030279-pv770doe authors: novossiolova, tatyana title: twenty-first century governance challenges in the life sciences date: 2016-11-29 journal: governance of biotechnology in post-soviet russia doi: 10.1007/978-3-319-51004-0_4 sha: doc_id: 30279 cord_uid: pv770doe the chapter explores the rapid advancement of biotechnology over the past few decades, outlining an array of factors that drive innovation and, at the same time, raise concerns about the extent to which the scope and pace of novel life science developments can be adequately governed. from ‘dual-use life science research of concern’ through the rise of amateur biology to the advent of personalised medicine, the chapter exposes the limitations of the existing governance mechanisms in accommodating the multifaceted ethical, social, security, and legal concerns arising from cutting-edge scientific and technological developments. so far as to suggest that the 'life sciences knowledge, materials and technologies are advancing worldwide with moore's law-like speed.' 3 and whilst some commentators have questioned the extent to which the ongoing progress of biotechnology has translated into practical applications and novel products, 4 there is some consensus that the biotechnology landscape has been fundamentally transformed over the recent decades with the possibilities now unlocked holding revolutionary potential. indeed, rapid advances in the field have produced a knowledge base and set of tools and techniques that enable biological processes to be understood, manipulated and controlled to an extent never possible before 5 ; they have found various applications in numerous spheres of life, generating enormous benefits and offering bright prospects for human betterment; and they have come to be regarded as a key driver of economic development with potential to close the gap between resource-rich and resource-poor countries. 6 the progress of biotechnology has been largely driven by three sets of forces, namely social, political and economic. 7 the social dynamics at work in this context are understood as the efforts to improve public health and overall wellbeing of individuals both in the global north and global south, boost agricultural yields and encourage environment-friendly practices to mitigate the adverse effects of climate change. several factors account for the significant value attached to the life sciences in the context of intense globalisation and continuous change. surging population numbers and extended life expectancy are augmenting the demand for developing effective and affordable medications, novel approaches for the treatment of chronic diseases and additional cost-effective sources of energy and food production. at the same time, rising global trade and travel, coupled with increased urbanisation, and an uneven distribution of wealth are creating optimal conditions for disease outbreaks, pandemics and environmental degradation. 8 against this backdrop, biotechnology appears full of promise and critical to tackling social and natural concerns; enhancing disease prevention, preparedness and surveillance; promoting development; and alleviating human suffering. 9 economic dynamics include national expenditure on research and development, purchasing power, trends in consumerism and market pressures and fluctuations. besides public funding for r&d which remains a key factor in the growth and flourishing of bioindustry in developed and emerging economies alike, private investment from venture capital firms, start-up companies and transnational corporations (tncs) have also played an indispensable role in capturing new markets and further facilitating the extension of bioeconomy on a global scale. dupont's significant footprint in india is indicative in this regard, not least because of the depth and diversity of the activity that the company has undertaken via its offshore r&d centres ranging from crop science to biofuels. 10 likewise, merck has outlined a 1.5 billion dollar commitment to expand r&d in china, as part of which it intends to establish an asia headquarters for innovative drug discovery in beijing. 11 political dynamics are triggered by states' increasing commitment to support the progress of biotechnology as a way of maximising their power and boosting their status in the international arena. 12 in the aftermath of 9/11 and the 'anthrax letters' attack of october 2001, substantial effort has been given to harnessing life science research for the purposes of national security. biodefence and bioterrorism preparedness are thus considered high-priority areas for national investment by government agencies and the military alike. an illustrative example of this two-tiered approach is the funding policy in the usa, where biodefence research is financed by the nih, department of homeland security (dhs) and defense advanced research projects agency (darpa), to name a few. under the synergistic influence of these three sets of forcessocial, economic and politicalbiotechnology has been transformed into a truly global fast-evolving enterprise encompassing a multitude of stakeholders, delivering considerable benefits and holding out still greater promise, with profound and far-reaching implications for virtually every aspect of human well-being and social life. the pharmaceutical industry is a case in point, for its steady expansion would hardly be possible were it not for the vast array of techniques and methods enabled by the progress of the life sciences. worth roughly 400 billion dollars, the global pharmaceutical market dominates the life sciences industry and arguably determines the trajectory of life sciencesrelated technological development and global spread. 13 gene cloning, dna sequencing and recombinant construction of cell lines, to name a few, are all deemed indispensable for the development of novel medicines and therapeutics. it suffices to mention that more than half of the top selling commercially available drugs in the usa would not exist without those methods. 14 agriculture, too, has been heavily influenced by the ongoing biotechnology revolution, as evidenced in the rapid growth and dispersion of commercialised transgenic crops (biotech crops) and the efforts to use gmos (both animals and plants) for the production of vaccine antigens and other biologically active proteins ('biopharming'). 15 indeed, the increase in the area of farmland planted with transgenic crops rose dramatically from 1.7 hectares in 1996 to about 60 million hectares in 2002 16 and is still growing. in addition, technological convergence 17 between biotechnology, nanotechnology, information technologies and cognitive science has unlocked a broad scope of opportunities for maximising public (and private) welfare, offering substantial benefits in wideranging areas such as medicine, pharmacy, crime investigation and national security by ensuring precision and reliability, while at the same time, reducing the amount of time previously required for the performance of certain tasks. four key features of biotechnology make it so appealing to the majority of stakeholders involved. first, biotechnology innovation is characterised by duality, whereby research yields results that simultaneously lead to advances in basic knowledge and stimulate product development. 18 second, the output that the life sciences generate in the form of new medicines, improved nutrition products, enhanced yields and novel materials, is 'strongly positive'. 19 the increasing utility of tools and strategies for human enhancement, whether in professional sport, for cosmetic and aesthetic purposes, or on the battlefield, vividly reflects the firm conviction that the transformative capacity of biotechnology, even at the most fundamental level, is something to be welcomed and vigorously embraced. what is more, biotechnology possesses proven economic viability, as illustrated in the burgeoning industries and new markets it has spurred. against this backdrop, the high rate of biotechnology expansion is anything but surprising, since every increment in biological capability pays back the researcher and the researcher's sponsors in short order. payback comes in the esteem of peers, in promotions, and in increases in the academic or corporate salaries of the researchers whose work generates knowledge and new therapies. payback comes in the form of profits for the manufacturers of kits to perform the manipulations, royalties for the writers of the methods manuals profits for the drug industry. payback comes for the public in the form of new drugs and therapies. 20 fourth, besides being cost-effective, many of the benefits that biotechnology offers are easy to obtain and disseminate. in other words, many of the various prospects for public (and private) betterment are not situated at some distant moment in the future but can be realised immediately, as a result of which pressing problems can be alleviated, if not fully resolved, and substantial revenue can be generated in the short term. last but not least, while there are some risks and concerns associated with the advancement of biotechnology, few of those are deemed urgent or significant enough to impact on the pace of innovation. as the actual manifestation of such risks is often contingent upon the interplay of a variety of factors, this renders the likelihood of a major crisis unfolding as a result of the progress of biotechnology low. moreover, there is a genuine belief that any challenges that may arise from the proliferation of novel technologies can either be foreseen or dealt with on a case-by-case basis. given the enormous potential of biotechnology for addressing societal, economic and environmental challenges, it is unsurprising that most states have readily endorsed scientific and technological innovation and embarked on largescale generously-funded r&d programmes in the life sciences. given the powerful multifaceted impetus for biotechnology advancement, it is possible to identify at least five key trends in the governance of biotechnology that are common for highly industrialised and developing countries alike. those include: high-level coordination, facilitation and funding; synergies within and between both the public and private sector; emphasis on strategic and competitive interests at the expense of precaution; regulations that seek to promote rather than restrict scientific and technological progress; and overreliance on technical solutions. at international level, the on-going expansion of biotechnology has been hailed not only as an inherently positive development but also as an essential prerequisite for enhancing human welfare and addressing various socio-economic, environmental and health concerns. in its 2013 world health report, the who called for: increased international and national investment and support in [life science] research aimed specifically at improving coverage of health services within and between countries. 21 the who has also strived to promote research on specific diseases, such as hiv/aids, cancer, pandemic influenza, tuberculosis and malaria, with the goal to improve methods for prevention and diagnostics and facilitate the development of effective therapeutics and vaccines. 22 in a similar fashion, the un food and agriculture organisation (fao) has highlighted the positive impact that biotechnology could have on the development of agriculture: . . . biotechnology could be a major tool in the fight against hunger and poverty, especially in developing countries. because it may deliver solutions where conventional breeding approaches have failed, it could greatly assist the development of crop varieties able to thrive in the difficult environments where many of the world's poor live and farm. 23 it is not difficult to see how those assertions have been translated into national policies and practical steps across the globe. the us nih that provide the bulk financial support for medical and health-oriented r&d in the us spent over 30.9 billion dollars during the fiscal year 2012, about a third of which was allocated for funding biotechnology and bioengineering projects. 24 within its sixth framework programme for research and technological development spanning the period 2002-2006 the european union (eu) distributed more than 2.5 billion euro for projects under the theme 'life sciences, genomics and biotechnology for health'. 25 developing countries, too, are increasingly investing in 'red' biotechnology as part of their efforts to address public health concerns. according to a recent who report, support for biotechnology and particularly, for cancer research, in cuba has soared over the past 20 years, amounting to over one billion dollars. 26 as a result, the cuban biotechnology industry is burgeoning, holding around 1200 international patents and exporting vaccines and pharmaceuticals to more than 50 countries. the prospect of climate change coupled with rising population numbers has compelled governments in the global north and south alike to explore 'green' biotechnology as a means of ensuring food security. the usa remains by far the largest commercial producer of gm crops. several eu member states (france, germany, spain, poland, romania, czech republic, portugal and slovakia), canada and australia further feature in the list of industrialised nations that have embarked on growing gm plant breeds. more and more emerging economies are striving to expand their agrobiotechnology sector, most notably brazil, india, argentina, south africa, mexico, burkina faso, myanmar and chile. 27 in 2008, the chinese government launched a major r&d initiative worth 4 billion dollars to develop new plant varieties by 2020 that will enhance yields, have improved nutritional value and be resistant to pests. 28 public-private partnerships underpinned by access to early-stage risk capital and strong linkages between business, universities and entrepreneurial support networks constitute an important vehicle for promoting innovation and fostering technology transfer and product development. for instance, the chinese government has launched a major initiative mobilising 2.5 billion dollars in venture capital to support start-ups in the immense zhangjiang science park outside shanghai 29 ; russia's rusnano has entered a 760 million dollar partnership with the us venture capital firm domain associates to fund 'emerging life science technology companies and establish manufacturing facilities in russia for production of advanced therapeutic products'; and cleveland's university hospital has allocated 250 million dollars for setting up a 'non-profit entity to fund and advise physician-scientists on transitional research and a related for-profit accelerator that will develop selected compounds to proof of concept.' 30 the kauffman foundation in the usa, a wealthy philanthropic establishment dedicated exclusively to the goal of entrepreneurship has been particularly zealous in its quest for promoting university-based entrepreneurial activities nationwide. its kauffman campuses initiative launched in early 2003 enjoyed so much popularity among universities that following the initial round of grants totalling 25 million dollars, the foundation announced its resolve to leverage a 100 million dollar investment for the creation of new interdisciplinary education programmes. 31 university-industry partnerships, while not a novel phenomenon in the area of biotechnology, have considerably intensified over the past several decades, thus facilitating the widespread commercialisation of life science research. indeed, 90 per cent of the companies in the us surveyed by blumenthal et al. in 1996 had relationships with an academic institution in that year and in more than half of those cases industry provided financial support for research in such institutions. 32 according to another study, the total industry investment in academic life science research in the usa tripled between 1985 and 1998 reaching almost 2 billion dollars and has been growing ever since. 33 against this backdrop, some commentators have put forward the 'triple helix' model, which serves both as a conceptual tool and a policy blueprint. in the former case, it is used to elucidate the academic-industry-government relationships that underpin the institutional arrangements and changing practices in the processes of production, transfer and application of knowledge in post-industrial societies; in the latter, it is promoted as a framework for economic development through state investment and knowledge sharing between academia and industry. 34 others, however, have remained sceptical of the close integration of universities and the private sector voicing concerns about the possible deleterious effects arising therefrom: as in other activities, when big money flows fast, temptations and opportunities arise for risky behaviour and stealthy or even brazen wrongdoing in pursuit of personal or institutional advantage. the new world of academiccommercial dealings is characterised by some grey areas and evolving rules for permissible and impermissible conduct. the people who manage and conduct research in scientific organisations are not immune to the weaknesses and foibles so plentiful elsewhere, despite the accolades for probity that science bestows upon itself. 35 with more and more universities joining the biotechnology 'gold rush' and corporate values and goals steadily penetrating the professional academic cultures, scholarship turns into a result-oriented activity subject to the priorities and interests of business partners and industrial sponsors. strategy and careful planning deemed essential to the pursuit of for-profit knowledge can have a restraining effect on the spontaneous vigour characteristic of academic research, limiting the range of problems that could be studied to those defined by the market. 36 at the same time, scientists often find themselves under tremendous pressure striving to satisfy the demands of their industrial clients without utterly neglecting their academic duties ranging from mentorship through filing grant applications to publishing. the extensive workload coupled with the bright prospects for securing long-term research funding and achieving some individual gain and prominence provide a favourable environment in which instances of dubious, sometimes fraudulent, behaviour, conflicts of interest and lack of transparency, unless too severe, are unlikely to encounter widespread opprobrium and may even go unnoticed. 37 in the race for patents and venture capital, the business mentality dulls scientific rigour and the ethics threshold appears not too difficult to cross. interests at the expense of precaution given the tremendous benefits that biotechnology is expected to generate in virtually any sphere of human activity, it is not difficult to understand why its progress is predominantly viewed through an explicitly positive lens by policy-makers. since the opportunities for achieving public betterment and enhancing state prestige and international standing are too tempting and too abundant, there is a powerful urge to dedicate both will and resources to promoting the large-scale expansion of the life sciences. for one thing, the prospect of conquering disease and maximising human wellbeing provides solid justification for a deliberate and sustained investment in fostering scientific and technological prowess. lack of commitment and reluctance to support r&d in the life sciences then becomes an unfavourable option in the political calculations of states regardless of their level of economic development and international status. within the context of political calculus pervaded by realist fears, competition and power, the perceived risks of inaction with regard to scientific and technological development justify vast expenditure, lower regulatory barriers to innovation and product development. political choices concerning biotechnology support are therefore frequently made at the expense of calls for caution and potential social, environmental and ethical concerns. the regulation of genetic engineering is a case in point. as discussed in the previous chapter, from the outset, the attempts of governments to impose strict controls on research involving rdna faced a severe backlash from academic scientists and business executives alike. by the 1980s, the various legislative initiatives put forward in the usa were abandoned in favour of the regime established by the nih guidelines, which virtually exempted the biotechnology industry from formal regulation. while the leading us-based companies pledged to 'voluntarily comply' with the guidelines, behind the scenes they craftily continued to push for a system that would insulate them from governmental and public scrutiny. 38 indeed, during the 1990s when the states parties to the btwc strived to strengthen the treaty by negotiating a binding verification mechanism corporate interests proved too big and too important to be ignored. both the pharmaceutical research and manufacturers of america (phrma) which represented the country's major research-based pharmaceutical and biotechnology companies, and the biotechnology industry organisation (bio) which at that time represented some 1400 biotechnology firms, became vocal opponents of any measures designed to promote international arms control which seemed to hinder in any way the protection of proprietary information and intellectual property. 39 in the period between 1994 and 2001 the associations invested considerable effort, time and ingenuity in lobbying the us government and influencing the diplomatic talks in geneva to secure an outcome that was in line with the demands of their constituencies. of course, it would be naive to ascribe the us resolve to reject in 2001 both the text of the protocol and its utility in general for providing adequate verification and enhancing confidence among states parties solely to the activity of the biotechnology industry; nevertheless, it would be equally naive to suppose that corporate interests played no significant role in the process. 40 besides economic priorities, national security and military calculations can also provide a compelling rationale for downplaying the potential risks associated with biotechnology expansion. following the 'anthrax letters' attack in october 2001, the us government embarked on a massive financial investment to boost its bioterrorism preparedness and enable the prevention, early detection, monitoring and emergency response to biological threats. as outlined in biodefense for the 21st century, a presidential directive that set out a comprehensive framework for national biodefence policy, between 2001 and 2005 the federal government provided roughly 6 billion dollars 'to state and local health systems to bolster their ability to respond to bioterrorism and major public health crises'. 41 along with the highly controversial vaccination programme that the government envisaged, 42 another important development designed to enhance america's biodefence preparedness and capability was the drastic increase both in the number of high-containment labs (bsl-3 and bsl-4) and the number of researchers with access to some of the most dangerous pathogens known to mankind, including the causative agents of ebola, plague and q fever. some commentators have questioned the logic behind this policy highlighting the heightened risk of accidental or deliberate release of pathogens. 43 far from being ill-founded or hypothetical, such fears stemmed from a range of high-profile cases that occurred after 2001 across the us in which the lack of proper training and professional negligence resulted in scientists being exposed to or infected with deadly microbes. 44 real-life horror stories about vials of plague being transported in the hand-luggage of researchers on passenger aircraft without the required authorisation, and deadly cultures gone missing from what appeared to be secure laboratories further fuelled the criticism toward the us biodefence policy raising difficult questions about its appropriateness and actual goals even before the 'anthrax letter' investigation revealed that the attack was 'insider's business'. 45 life science research, just as any other sphere of professional activity, is subject to a range of institutional, national and international regulations. along with the more general rules such as those related to occupational health and safety, fair pay and job competition, conflict of interests, labour rights, and professional liability, there are also specific ones addressing particular aspects of the research process including project clearing (e.g. review by local biosafety committees), safe laboratory practice and transport of pathogens (e.g. 2005 international health regulations), exchange of viral strains (e.g. pandemic influenza preparedness framework, 2011), handling of dangerous pathogens (e.g. us select agent programme) and ethical treatment of human subjects and samples obtained therefrom (e.g. the 2004 human tissue act in the uk). 46 while hardly exhaustive, this list suffices to convey the idea that the regulatory regime governing the practice of life science research is dense and comprehensive. with more than 30 international organisations overseeing biotechnology from various perspectives, 47 there is a prima facie reason to assume that the regime in its current form is sufficiently flexible to accommodate novel advances and hold any potential risks, which they may pose, at bay. yet in reality over the past decade the opposite trend has prevailed, that is, the existing governance mechanisms have struggled to respond adequately to the proliferation of new scientific developments with multiple adaptive uses and the multiplicity of cutting-edge developments posing profound ethical quandaries. how to account for this discrepancy? part of the problem stems from the fact that since at least the late 1970s the regulation of biotechnology has been streamlined so as to become compatible with and not a restriction on continued technological change and economic growth. 48 as such, it rests upon the barely questioned assumption that the progress of biotechnology is inherently good and needs to be harnessed and vigorously promoted. needless to say, any measures that seem to slow down or restrain its advancement are deemed undesirable and even detrimental to socio-economic development. hence, when developing regulations, policy-makers have generally pursued a twofold objective: first, to promote the safe practice of life science research by reducing any risks arising therefrom both to scientists and the general public; and second, to ensure that any issues that may hinder the expansion of biotechnology are not subject to restrictive legislation. a vivid manifestation of this approach is the way in which the ongoing debate on 'dual use research of concern'benignly-intended research that seeks to maximise human welfare by responding to health, societal and environmental ills but could also facilitate to the development of more sophisticated and potent biological weapons and enable bioterrorism 49has been handled. for more than a decade, researchers, journal editors, security experts and policy-makers have strived to devise oversight mechanisms and governance initiatives that could adequately tackle the challenge of dual use without stifling innovation. unfortunately, to date their efforts have met with little success, as a result of which virtually each experiment of dual use concern is dealt with separately on a case-by-case basis. this is not to say that there are no similarities across the studies of this kind. on the contrary, a few of the most notable examples follow a similar paradigm, including the creation of a vaccine-resistant strain of the mousepox virus, the artificial synthesis of the polio virus, the recreation of the 1918 spanish influenza virus and, most recently, the production of a mammalian-transmissible h5n1 avian influenza virus (see fig. 4 .1). 50 all four of them were performed in strict compliance with the rules and procedures in place for laboratory biosafety, biosecurity and biorisk management and under appropriate physical containment conditions; all had passed thorough review by the respective local biosafety and bioethics committees; and all of them were deemed essential in terms of public health benefits. above all, the ethical and security concerns that the studies have raised go far beyond the laboratory door, posing fundamental questions about how life science research is reviewed, conducted and communicated. yet none of the high-profile experiments of concern has proved critical enough to provoke a radical change in the way dual-use research is governed. 51 three points merit consideration in this regard. the first pertains to the manner in which the dominant discourse on dual use is framed, that is, in purely ethical terms as a dilemma. while bioethics undoubtedly has a role to play in the discussions on dual use, the language in early 2001, the journal of virology published a report of the creation of a highly virulent strain of the ectromelia virus, the causative agent of mousepox. the work described in the report was carried out by a group of australian scientists based in canberra. its original goal was the development of an infectious immunecontraceptive that could be used against wild mice for the purpose of pest control. to achieve this, the group drew upon previously published work. during the course of the experiment, the researchers unexpectedly discovered that the newly engineered strain of the mousepox virus, which they created, killed 60% more mice than the parent virus, including mice that had been vaccinated or that had natural immunity. when the research was published, concerns were raised that it could potentially be misapplied for hostile purposes, or even that the same technique could be utilised for creating a more virulent strain of the variola virus, which causes smallpox in humans. in 2002, a team of scientists led by dr eckard wimmer from the university of new york at stony brook announced that they had successfully created a polio virus 'from scratch'. to carry out the research, the scientists 'followed a recipe they downloaded from the internet and used gene sequences from a mail-order supplier'. a once the virus created, it was tested on mice, as a result of which the infected animals became paralysed and died. the study spurred a wide-ranging debate, not least because it drew attention to the possibility of using synthetic biology for constructing de novo viruses for the purposes of bioterrorism. in 2005, it was announced that cdc scientists, together with colleagues from several research institutions across the usa, had successfully recreated the influenza virus, that was responsible for the 1918 pandemic, which killed between 20 and 50 million people worldwide. using dna from a tissue of a flu victim buried in the permafrost in alaska, the researchers managed to reconstruct the influenza virus and thus study its pathogenesis and properties that contributed to its virulence. despite the scientific justification that was put forward, critics have argued that the study is 'a recipe for disaster', not least because the availability of the virus' full-genome sequence and detailed method for its reconstruction on the internet may facilitate its synthesis by a of 'dual-use dilemmas' is too abstract to offer appropriate analytical tools for dealing with the issues at play. as discussed above, the questions that dual-use research poses such as data sharing, research funding and project planning are far from hypothetical but they feature explicitly in everyday professional practice. however, the 'dilemma framework' automatically strips them of the complex socio-technical arenas in which they have actually presented themselves by laying an emphasis on what action should ideally be taken, rather than what is practically feasible given the circumstances. 52 moreover, such issues are typically structural in nature for they constitute fundamental elements of the life sciences professional culture, and as such, could hardly be adequately addressed solely at the level of individual researchers. yet framing social, legal and security concerns in terms of moral dilemmas allows for structural issues to be omitted from the discussion, rendering life scientists the chief, if not the only, moral agents expected to reach what is deemed to be the 'right' answer. 53 assigning abstract duties then comes to be regarded as an appropriate 'solution', even if those are virtually impossible to fulfil given the complexities of the working environment within which researchers operate. the second point is related to the reductionist view that dominates the discourse of what counts as a risk in life science research. perhaps one of the most significant legacies of the asilomar conference on rdna (see chapter 3) is the emphasis on laboratory risk that could be effectively managed by dint of physical containment and rules and procedures for safe laboratory practice. 54 it suffices to mention that the bulk of guidelines and formal regulations published by the who focus exclusively on promoting and refining measures that aim to maximise laboratory biosafety and prevent the accidental release of pathogens. hence, it is hardly surprising that the concept of dual use and the idea of risks beyond the laboratory door implicit in it seem alien to the majority of practising researchers. striking as it may appear, even though dual use research has been debated for more than a decade now, the level of awareness among life scientists of the broader social, security and legal implications of their work remains low. 55 the third point deals with the way in which risks in life science research are assessed and mitigated. given the narrow definition of risk encompassing technical particulars, physical containment and biosafety, risk assessment is considered an appropriate and reliable tool for ensuring research safety. the heavy reliance upon risk assessing tools is underpinned by two underlying assumptions. one is that it is possible to foresee and calculate most, if not all, things that could potentially go wrong both during the development phase of the project and after its completion. the other is that it is possible then to use the produced data as a basis for devising measures and strategies for eradicating, or at least, mitigating the risks likely to occur. attractive as it may seem, this 'new alchemy where body counting replaces social and cultural values' presupposes a clear distinction between the risk assessment 'experts' and the general public, whereby the former are granted a licence to make decisions about the risks that the latter cannot do without. 56 likewise, costbenefit analysis on the basis of which research proposals are screened for potentials risks and security concerns has attracted some serious criticism. in the view of some commentators, besides being sometimes deeply inaccurate, the cost-benefit analysis is 'ethically wrong' since 'applying narrow quantitative criteria to human health and human life' is unacceptable. 57 but there are other problems, too. as pointed out by dickson, the cost-benefit analysis distorts political decision-making by omitting any factors that cannot be quantified, thus obscuring questions of equity, justice, power, and social welfare behind a technocratic haze of numbers. 58 as a result, complex and politically charged decisions are reduced to a form that fits neatly into the technocratic ways of making regulatory decisions, whereby calculations and approximations made by the few substitute for the judgements of many. 59 the wide-ranging controversy that unraveled in late 2011 when two teams of scientists working independently in the netherlands and the usa managed to produce an air-borne strain of the h5n1 avian influenza virus, a highly pathogenic and lethal microbe with over 60 per cent mortality rate in humans arguably constituted the pinnacle of the deliberation on dual use research. both studies set alarm bells ringing for the security community who almost immediately jumped in the debate voicing concerns over the possibility of biological proliferation and bioterrorism. some commentators even argued that the experiments ran counter to the spirit if not to the letter of the 1975 btwc. 60 against this backdrop, the resultant controversy was deemed at least initially to offer a timely opportunity to evaluate the existing governance mechanisms, determine their gaps and weaknesses, and broaden the scope of deliberation inviting participation of a wide range of stakeholders. unfortunately, the outcome of the debate proved far more moderate, signalling preference for preserving the status quo without disrupting the established systems for governance and oversight. despite the extensive mass media coverage of the controversy, only few public consultations were held and none of those was designed as a platform for making policy proposals or developing action plans. moreover, the denselypacked agenda prepared duly in advance left very limited scope for posing 'tricky' questions which the participating 'experts' might have struggled to answer. needless to say, all consequential decisions were made behind closed doors away from public scrutiny and on some occasions the people with the greatest vested interest in the publication of the studies were also the ones with the greatest say in the process. 61 there were no significant changes in terms of governance initiatives, either. far from being ground-breaking developments, the us government policy for oversight of life sciences dual use research of concern 62 and the decision of the dutch government to invoke export control legislation before allowing the publication of the study conducted within its jurisdiction were little more than desperate moves that aimed to obscure the inadequacy and shortcomings of the measures already in place. 63 overall, the manner in which the h5n1 debate was handled could be treated as a missed opportunity, whereby those in charge of the decision-making process did little to address or even acknowledge the broader issues underpinning dual-use research of concern but simply 'kicked the can down the road to the next manuscript' waiting for the next controversy to erupt. 64 technology seems to play a significant role in the governance of life science research. high-containment laboratories, well-equipped biosafety cabinets, sophisticated waste management systems, enhanced personal protective equipment and secure containers for the safe storage and transportation of biohazard materials are just a few of the tools and systems in place that allow the safe handling of dangerous pathogens and toxins and, at the same time, protect both laboratory personnel and the general public from exposure to deadly microbes. that said, the effectiveness of technical solutions should not be overstated if only for the fact that 'problems' of governance are barely technical matters per se but rather constitute complex issues of human relatedness. nevertheless, the attractiveness of technological fixes as offering reliable risk mitigation and reassurance in the safety of biotechnology is ever growing. it suffices to mention that the h5n1 controversy discussed above was in part resolved after the lead researchers in the netherlands and the usa respectively agreed to add a detailed section on the technical specificities and laboratory biosafety and biosecurity measures taken during the experiments. 65 the strategy has proven effective in diverting attention from the rather inconvenient questions regarding the utility and significant potential for hostile misuse of the so called 'gain-of-function' (gof) research and concentrating it on more mundane issues dealing with in-house precautions and safety procedures. once the latter were deemed adequately resolved, the former were effectively forgotten. still, the value of technical means in ensuring reliable risk management should not be taken for granted. for one thing, laboratory biosafety precautions, however sophisticated, are far from perfect and accidents do occur. such is the case with the pirbright site in the uk which was at the centre of a major outbreak of foot-and-mouth disease in 2007, as a result of which over 2100 animals were slaughtered. 66 in 2012 the bioterrorism bsl-3 laboratory at the us cdc in atlanta suffered repeated problems with airflow systems designed to help prevent the release of infectious agents. 67 the faulty system could perhaps be regarded as an exception had it not been for the authoritative investigation report of the us government accountability office (gao) released in march 2013. according to the report, the cost of building and maintaining high-containment laboratories, coupled with the absence of national standards for their design, construction, operation, and maintenance 'exposes the nation to risk'. 68 far more critical is the situation in the developing world and emerging economies where lax regulations and technical failures have significantly heightened the risk of accidental release of pathogens, as demonstrated by the numerous 'escapes' of the severe acute respiratory syndrome (sars). 69 but even if technology functions impeccably, this hardly reduces the likelihood for a human error or inappropriate behaviour. unlocked doors in high-containment facilities hosting deadly pathogens, eating and drinking in laboratories and poor waste disposal practices are just a small part of the otherwise long list of mundane mishaps that may result in severe consequences. it is worth mentioning that the us cdc came under the spotlight after internal e-mail correspondence revealed that doors in the bsl-3 block where experiments involving the causative agenets of anthrax, sars and influenza were performed were left unlocked on numerous occasions, thus increasing the risk of unauthorised access or theft. 70 given the chance of technical flaw and the potential for human error, some life scientists have begun to question the reliability of existing laboratory precautions and demand thorough review and evaluation. in a recent letter to the european commission the foundation for vaccine research has asked for 'a rigorous, comprehensive risk-benefit assessment' of gof research that 'could help determine whether the unique risks posed by these sorts of experiments are balanced by unique public health benefits which could not be achieved by alternative, safe scientific approaches'. 71 engines that drive biotechnology momentum by and large, the ongoing progress of biotechnology is largely viewed and assessed through an explicitly positive lens which allows focusing almost exclusively on the benefits likely to be accrued notwithstanding the risks, actual and potential. the resultant distorted image is problematic, not least because it precludes any comprehensive discussion on the potential side effects and negative implications of novel life science advances. above all, it sustains the barely questioned assumption that the existing governance mechanisms are adequate and sufficient to cope with the stresses and strains of the rapidly evolving biotechnology landscape. yet given the complex and multifaceted dynamics shaping the life science enterprise, the rapid pace of innovation, and the limits to predicting the synergistic and cumulative effects of the proliferation of new technologies, the uncritical acceptance of such assumptions is at best naïve and at worst dangerous. arguably the advancement of the life sciences has greatly benefited from the fascinating breakthroughs made in other areas of study, such as chemistry, engineering, computing, informatics, robotics, mathematics and physics. some commentators even talk about a third revolution in biotechnology underpinned by scientific and technological convergence: convergence does not simply involve a transfer of tools sets from one science to another; fundamentally different conceptual approaches from physical science and engineering are imported into biological research, while life science's understanding of complex evolutionary systems is reciprocally influencing physical science and engineering. convergence is the result of true intellectual cross-pollination. 72 the resultant 'new biology' has opened up a range of marvellous possibilities enabling the manipulation of living matter at the full range of scales, as well as the application of biological systems principles for the development of novel materials, processes and devices. 73 as such, it has been largely hailed as possessing the 'capacity to tackle a broad range of scientific and societal problems.' 74 this is not an exaggeration. as noted by a recent report of the us nas, the precipitous decline in the cost of genome sequencing would not have been possible without a combination of engineering of equipment, robotics for automation, and chemistry and biochemistry to make the sequencing accurate. 75 likewise, it is the combination of expertise from fields as diverse as evolutionary biology, computer science, mathematics, and statistics that has allowed both the analysis of raw genomic data and the subsequent use of these data to other fields. 76 at the same time, advances in nanoscience and nanotechnology have considerably enhanced drug delivery making it more accurate by targeting specific parts of the body. 77 yet the transformative potential of scientific and technological convergence comes at a price, not least because parallel to the benefits it offers, there are risks the effects of which could be truly devastating. 78 take drug delivery, for instance. thanks to the technological breakthroughs over the past decade, doctors have gained unprecedented access to the human body which, in turn, has facilitated the treatment of previously incurable disease and conditions (e.g. some forms of cancer). nanoparticles and aerosols are now utilised for delivering a precise dose of therapeutics to tissues and cells via novel pathways circumventing body's natural defences and evading immune response. it is not difficult to imagine how such knowledge could be misapplied for malicious ends, including incapacitating and killing. research on bioregulators is a case in point. bioregulators are natural chemicals in the human body that play a vital role in the maintenance of the homeostasis but when administered in large quantities or in healthy individuals could be toxic and lead to serious disorders, even death. given their properties, bioregulators constitute the perfect bioweapon: efficient and virtually impossible to detect. and if in the past, security analysts discounted the risk of their weaponisation due to the instability of the compounds when released in the atmosphere, the emergence of novel drug delivery techniques has significantly altered the security calculus. 79 this is just but one example of the challenges that the increasing convergence between biology and chemistry poses to the integrity of the international biological and chemical non-proliferation regimes. 80 even though some effort has been made over the recent years to address those and other areas of concern and strengthen the international prohibition against biological and chemical warfare, in practical terms little has been achieved, as a result of which the risk of the hostile exploitation of novel scientific developments remains far from hypothetical. along with the risk of misuse of new knowledge, there is the risk posed by the lack of sufficient scientific knowledge. cross-disciplinary convergence opens a multitude of opportunities for manipulation and modification of living matter but, at the same time, it precludes almost any sensible assessment of the potential interactions likely to occur in the process. nano-based medicine is but one area that has attracted criticism in this regard. since some elements behave differently at nano-scale, it becomes extremely difficult to assess their level of toxicity or other negative side effects that they may exert. such is the case with long carbon nanotubes, which having been initially praised for their potential to improve implant development 81 were later blamed for exhibiting asbestos-like behaviour that could lead to cancer. 82 another area of converging science with far-reaching implications is synthetic biology, a cross-disciplinary field that draws upon strategies and techniques from molecular biology, chemistry, engineering, genomics, and nanotechnology and thus enables the design and modification of biological systems at a fundamental level. empowered by the tools of synthetic biology, in 2002 scientists managed to assemble a polio virus 'from scratch' in the absence of a natural template. and in 2010 craig venter and his team announced the construction of the first self-replicating synthetic cell which, in their view, was 'a proof of the principle that genomes can be designed in the computer, chemically made in the laboratory and transplanted into a recipient cell to produce a new self-replicating cell controlled only by the synthetic genome.' 83 the controversial work has attracted criticism on several grounds, including the potential negative effects of the accidental or deliberate release of the novel organism in the environment and the arrogance of scientists to 'play god'. 84 more broadly, both the polio and synthetic cell studies have exposed the obstacles to the regulation of synthetic biology. 85 while some commentators dismiss the risk of bioterrorism, underscoring the key role of tacit skills and knowledge and the difficulties that the lack thereof poses to the replication of the experiments, 86 other issues still merit attention. consider the question of access to commercially available genomic sequences. even though the oversight system for screening base pair orders has improved since the 2006 guardian report that exposed the lax regulations under which virtually anyone could order gene sequences, 87 gaps still remain leaving scope for abuse by those with malign intent. for example, schmidt and giersch have outlined at least three areas of emerging challenges that the existing governance regimes would struggle to accommodate, including 'split orders', 'outsourcing', and the potential for non-natural biological systems. 88 the human genome project completed in 2003 lasted over ten years and cost close to 3 billion dollars; by contrast, about a decade later, wholegenome sequencing can be performed within hours at a price of roughly 1000 dollars or less. 89 while still in its infancy, personalised medicine and individual genetic testing are steadily gaining popularity. indeed, 'up to 100 000 people in england are expected to have their entire genetic makeup mapped in the first stage of an ambitious public health programme' launched by the national health service in 2012 that aims to 'revolutionise the treatment and prevention of cancer and other disease.' 90 according to its proponents, genomic testing offers numerous advantages vis-à-vis traditional evidence-based medicine, including the possibility of early diagnostics of disease, of individually-tailored treatment and, perhaps most importantly, of disease prevention, as illustrated in the resolve of the hollywood actress angelina jolie to undergo double mastectomy after discovering she has an inherited genetic mutation that puts her at high risk of breast and ovarian cancer. 91 but this is just the beginning. in 2012 scientists managed to sequence a foetus's entire genome using a blood sample from the mother and a saliva specimen from the father, a development that could potentially allow for a range of genetic disease conditions to be detected prenatally. 92 and laboratory experiments have already demonstrated the efficacy of genetic therapy to cure mitochondrial disease by creating an embryo with genetic material from both parents and a third person acting as a donor. 93 while truly breathtaking, the advances outlined above raise a host of thorny issues of ethical, social, and legal concern that merit public scrutiny and extensive deliberation before decisions regarding their widespread application are made. at a very basic level, there is the question of whether and to what extent we as individuals are capable of assimilating the information that our own genetic makeup may reveal. are we sufficiently resilient to cope with the emotional distress, anxiety, shame, stigma and guilt that the awareness of severe medical conditions that we or our closed ones are suffering or likely to develop? far from hypothetical, this question has prompted the establishment of a novel profession, that of the genetics counsellor whose task is to help patients overcome any negative effects, stress, or psychological trauma that the disclosure of their genomic map may create. 94 this is just a partial solution though, for the crux of the matter lies in finding a way to deal effectively with risk and probabilities and we as humans are yet to demonstrate a capacity for understanding or relating them to our own lives. 95 individual emotional turmoil, however significant, constitutes only the tip of the iceberg. according to daniel kevles, the torrent of new genetic information has already begun to fundamentally reconfigure social practices and inter-personal relations: it has been rightly emphasised that employers and medical or life insurers may seek to learn the genetic profiles of, respectively, prospective employees or clients. employers might wish to identify workers likely to contract disorders that allegedly affect job performance while both employers and insurers might wish to identify people likely to fall victim to diseases that result in costly medical or disability payouts. whatever the purpose, such genetic identification would brand people with what an american union official has called a life-long 'genetic scarlet letter' or what some europeans term a 'genetic passport'. 96 linking genetic makeup with human identity would ultimately set the scene for the proliferation of technologies aimed at human enhancement: after all, if a gene therapy could allow one to stand a chance in a job competition, boosting one's capabilities would potentially make them a more desirable candidate. other issues of more immediate concern are also likely to arise. one is privacy. gene-sequencing companies usually hold the genetic data of their clients in digital format on online platforms, which automatically creates a risk that personal information may be leaked, hacked or stolen. 97 further, there is the question of ownership. consider, for instance, the controversial issue of human gene patenting, whereby patented genes are treated as research tools and, as such, are controlled by the patent holder who may restrict and charge for their use. 98 thus created, the system often operates to the detriment of patients by hindering research practice, elevating diagnostics prices and denying access to second and independent medical opinion. 99 gene identification alone has a potential 'dark side' too, for it could enable the development of weapons targeted at groupspecific gene markers (e.g. ethnicity). 100 pre-natal genetic testing is yet another significant bone of contention, not least because it evokes notions of state-mandated eugenic programmes and assaults on human rights and dignity. while a nazi-like campaign for a superior race seems improbable in the twentieth-first century, this is not to say that other forms of eugenics may not be encouraged. indeed, some commentators have highlighted the rise of 'homemade eugenics', 101 whereby individual families can make decisions on the attributes of their progeny: the lure of biologically improving the human race, having tantalised brilliant scientists in the past, could equally seduce them in the future, even though the expression of the imperatives may differ in language and sophistication. objective, socially unprejudiced knowledge is not ipso facto inconsistent with eugenic goals of some type. such knowledge may, indeed, assist in seeking them, especially in the consumer-oriented, commercially driven enterprise of contemporary biomedicine. 102 it is plausible to assume that when presented with the opportunity of having their future child tested for genetic disorders, many parents would barely hesitate to accept. such a resolve could have far-reaching implications though. for instance, some genetic therapies entail the use of donor dna different from that of the parents, whereby any genetic modifications in the embryo will pass down to future generations. 103 despite the government support for the 'three-parent babies' in the uk, local religious organisations have protested vociferously against the legalisation of the technique. 104 at the same time, there are certain genetic disorders that can be diagnosed at an early stage but, as of yet, cannot be cured, which inevitably poses the tough choice between raising an unhealthy child and abortion. to be sure, such questions constitute more than individual parents' dilemmas, for they touch upon established social and cultural values, something evident in the profound differences across national reproductive policies. more broadly, there are concerns that reproductive genomics may remain a prerogative of those affluent enough to afford it, thus further exacerbating the divide between the global rich and the global poor. 105 the growth of life science capacity over the past few decades across the globe has been truly astonishing, leading to the emergence of a vibrant research community that brings together researchers from various parts of the world. indeed, a 2011 nas report highlights the extension of both north-south and south-south partnerships, which has played a key role in synergising strengths and maximising competitiveness by improving the quality and effectiveness of research and facilitating data sharing. 106 at the same time, increasing collaboration in the realm of biotechnology industry has offered companies situated in emerging economies access to the global market, thus contributing to economic development and growth. 107 recent advances in technology and laboratory and experimental equipment have further impacted on the practice of life science research in profound ways. improvements in dna sequencing technology have significantly shortened the time required for the preparation of nucleic base-lines, thus relieving scientists of the burden of completing the task themselves and allowing them to focus on their actual project instead. studies and experiments once performed by senior researchers with extensive experience are now carried out by masters students. aided by specially designed genetic engineering toolkits, children as young as the age of ten start exploring the realm of biology in an interactive and engaging manner. needless to say, their notion of science and the world in general would differ significantly from that of their parents whose primary sources of knowledge used to be textbooks and encyclopaedias. indeed, the increasing commercialisation of synthetic biology offers anyone curious enough to fiddle with biological systems the chance of doing so in the comfort of their own home. 108 such modern gene hackers often lack formal background in biology and come from various walks of life. driven by an insatiable appetite for knowledge and the vision of a ground-breaking discovery that could be turned into a multimillion dollar profit, they take up the rather unusual hobby of biohacking which entails the redesign of existing and the creation of novel biological systems. for just few hundred dollars bio enthusiasts set up laboratories easily obtaining all essential requisites and equipment from online sales. and if to some biohacking equates to little more than an unusual hobby, others highlight its potential to generate substantial revenue and fuel economic development. 109 contrary to popular expectation, biohackers are not just eccentric individuals who work in solitude away from public attention. rather, they are members of a wide global movement dedicated to the ideal of do-it-yourself biology (diy), which has branches in 45 locations on four continents. 110 the movement has been partially institutionalised through the establishment of the biobricks 111 and international genetically engineered machine (igem) foundations, which seek to promote the open and ethical conduct of biological engineering and stimulate innovation and creativity. to this end, igem holds an annual competition open to high school students, university undergraduates and entrepreneurs from all over the world. with more than 200 participating teams, the competition constitutes the premiere forum at which biohackers can showcase their skills through project presentation. exciting as it may seem, the ongoing diffusion of life science expertise poses an array of governance conundrums. at the level of professional practice, the proliferation of research facilities around the world has exposed the urgent need for laboratory biosafety and biosecurity training, especially in developing states where a tradition of handling dangerous pathogens is lacking. the issue is further complicated, for such countries often lack the required legal and institutional infrastructure to ensure that professional practice is in compliance with relevant international regulations. foreign aid has gone some way in helping overcome those deficiencies but it has given rise to new problems, too. for instance, it is far from unlikely for a donor state to provide material support for the construction of a state-of-theart laboratory eventually leaving its maintenance to the local government, which can hardly afford the subsequent costs. a similar trend is observed in the area of capacity building and human resource development. most projects that aim to promote biorisk management and a biological security culture tend to be severely constrained in terms of time and funding and overly ambitious in terms of agenda and expected outcomes. lack of adequate mechanisms for quality assessment hinders progress evaluation and sometimes leads to duplication of effort and resources. the emergence of the diy biologists in the life science arena has further added to the challenge of ensuring that novel scientific and technological developments are utilised in a safe and ethical manner. even at the level of everyday practice, difficulties still persist. for instance, many amateur scientists have complained of the lack of manuals and guidelines regarding the safe operation and maintenance of home laboratories. issues such as waste disposal, safe handling and storage of biological material and prevention of contamination pervade the work of biohackers who unlike professional researchers conduct experiments in a much more volatile environment. 112 potential security concerns are also present. with more and more individuals gaining access to biological engineering technologies, ensuring appropriate oversight of what goes on in garage laboratories becomes increasingly difficult. the experience of the us fbi is a case in point. back in 2004 the fbi arrested steven kurtz, a professor at the university of buffalo under the suspicion of plotting a bioterrorist attack. 113 the subsequent investigation revealed that all laboratory and dna extraction equipment found in kurtz's house was legitimately obtained and used in his artwork. in an attempt to avoid mistakes of this kind, the fbi has drastically changed its approach to dealing with the diy movement launching a series of outreach activities that seek to raise awareness of the potential security implications of biohacking. 114 while undoubtedly necessary, such initiatives may well be seen as too little, too late in light of the wide spread of materials, tools and devices that could facilitate the malign misuse of the life sciences. indeed, it is worth noting that as early as the late 1990s the us defence threat reduction agency (dtra) managed to build a research facility that simulated the manufacture of weaponised anthrax using only commercially available materials and equipment. 115 the role of states: both a poacher and gamekeeper structural factors have an important bearing on the development and growth of biotechnology. economic considerations, power interests and realist fears generate potent dynamics that shape and influence and sometimes direct the life science trajectory. within this context, states assume a dual role. on the one hand, they are expected to act as gamekeepers and regulate, monitor and control the process of life science research and the dissemination of novel technologies. on the other hand, though, they also have powerful incentives to act as 'poachers', not least because of the fascinating opportunities for enhancing their prosperity, prestige and security that scientific and technological development open up. 116 the following passage effectively outlines states' dual function: government has an important role in setting long-term priorities and in making sure a national environment exists in which beneficial innovations will be developed. there must be a free and rational debate about the ethical and social aspects of potential uses of technology, and government must provide an arena for these debates that is most conducive to results that benefit humans. at the same time, government must ensure economic conditions that facilitate the rapid invention and deployment of beneficial technologies, thereby encouraging entrepreneurs and venture capitalists to promote innovation. 117 given that the agent (i.e. state governments) in charge of initiating ethical debates on the progress of biotechnology is also the one expected to provide the conditions that would allow this progress to generate outcomes likely to contribute to economic growth and political superiority, it is hardly surprising that any issues likely to slow down or otherwise hinder the enormous momentum of the life sciences are omitted from public discussion. this duality further informs how risks are perceived, framed and addressed. for instance, even though most of the developing countries lack capacity to manage dual use research of concern, they do not see this as an immediate priority and prefer to invest effort and resources in improving their laboratory biosafety and laboratory biosecurity infrastructure and capacity. 118 in the view of their governments, the dangers of naturally occurring and circulating diseases constitute a far greater worry than the potential for misuse of cutting-edge research. by contrast, some developed countries, most notably the usa, have embarked on building their biological defence systems highlighting the grave threat posed by the potential use of bioweapons by non-state actors. their activities have encountered severe opprobrium as some analysts see them as a contravention of the norms embedded in the btwc. 119 the evolution of the chemical and biological non-proliferation regime epitomises the attempts of states to avert the hostile exploitation of the life sciences whilst promoting their use for 'peaceful, prophylactic and protective purposes'. the entry into force of the btwc and the chemical weapons convention (cwc) in 1975 and 1997, respectively, is indicative both of states' renunciation of chemical, biological, and toxin weapons and of their commitment to the goals of arms control and disarmament. that said, the imperfections and shortcomings of these treaties signify the influence of realist fears and political calculations that pervade international negotiations. in the case of the btwc, two points merit attention. the first pertains to the lack of verification mechanism when the treaty was first agreed back in the early 1970s. subsequent revelations of secret state-led offensive biological programmes in the former soviet union, south africa and iraq up until the early 1990s have significantly undermined the convention. second, the failure to negotiate a binding protocol in 2001 has further dimmed the prospects for strengthening the regime and thus ensuring universal compliance with its prescriptions. less acute but just as worrying is the situation regarding the cwc. even though the convention is exemplary in many respects, not least because of its verification system, almost universal membership and implementing body -organisation for the prohibition of chemical weapons (opcw)it still faces serious challenges that need to be considered. for instance, while the treaty bans the development, production, acquisition, and retention of chemical weapons, the definition of 'purposes not prohibited under th[e] convention' entails 'law enforcement including domestic riot control purposes' (article ii.9d). some commentators have argued that given the lack of a universally agreed definition what kind of activities count as 'law enforcement', this text opens a major loophole in the convention. 120 several states parties of the convention have voiced concerns in this regard. australia has noted that: the weaponisation of [central nervous system] acting chemicals for law enforcement purposes is of concern to australia due to the health and safety risks and the possibility of their deliberate misuse, both of which have the potential to undermine the global norm against the use of toxic chemicals for purposes prohibited by the convention. [ . . . ] australia's position is that it is not possible for a state party to disseminate anaesthetics, sedatives or analgesics by aerial dispersion in an effective and safe manner for law enforcement purposes. 121 critics highlight the possibility for the deployment of novel chemical weapons for the purposes of countering terrorism, something evident in the 2002 moscow theatre siege (dubrovka) when the russian security forces used a fentanyl-derivative agent, as a result of which about a sixth of the hostages and all of the terrorists involved died. 122 in 2011 the european court of human rights ruled with regard to the dubrovka operation that: there had been no violation of article 2 (right to life) of the european convention on human rights concerning the decision to resolve the hostage crisis by force and use of gas. 123 the court, nonetheless, noted that: even if the gas had not been a 'lethal force' but rather a 'non-lethal incapacitating weapon', it had been dangerous and even potentially fatal for a weakened person [ . . . ]. 124 the court further confirmed some of the earlier criticisms that were levelled against the government, particularly in terms of preparedness and provision of medical assistance. 125 according to the ruling, russia had to pay damages to all the 64 applicantsrepresentatives of siege victims. to date, russian officials have withheld information concerning the exact formula of the gas, which was used during the dubrovka operation, on security grounds. 126 given the lack of an internationally agreed definition of what constitutes 'terrorism' on the one hand, and the rise of irregular/asymmetric warfare and sporadic conflicts, on the other, some commentators have warned against the possibility of a 'grey area' which may enable states to utilise non-traditional methods of war to gain advantage. 127 deliberative systems encompass a vast array of practices, processes and mechanisms, both formal and informal, whereby a polity considers the 'acceptability, appropriateness and control of novel developments in or impacting on, shared social and physical arenas'. 128 by design, they reflect and are informed by the values, beliefs and standards shared among the group, or in other words, by the prevalent culture. as such, deliberative systems vary across societies with their intensity, inclusiveness and structure depending on the established political and social norms. yet their chief purpose and function remain virtually the same, namely to help societies adapt to the changing circumstance of their milieu in a way that ensures stability, sustainability and safety. public deliberation requires time; and wide-ranging life science advances, current and planned, offer profound challenges to shared ideas and ideals about the foundations of human relatedness and of social coherence, justice, human dignity and many other norms, both formal and informal. 129 yet given the ruminative nature of deliberative processes, on the one hand, and the fast speed at which biotechnology innovation is evolving on the other, the danger of the former being steadily outpaced and overburdened by the latter is far from hypothetical. consider the following passage sketching the scale of social changes likely to arise from the increasing convergence between nanotechnology, biotechnology, cognitive neuroscience and information technology: in the foreseeable future, we will be inundated with new inventions, new discoveries, new start-ups, and new entrepreneurs. these will create new goods and new services. [ . . . ] as expectations change, the process of politics and government will change. people's lives will be more complex and inevitably overwhelming. keeping up with the changes that affect them and their loved ones exhausts most people. they focus most of their time and energy on tasks of everyday life. in the future, when they achieve success in their daily tasks, people will turn to the goods and services, the new job and investment opportunities, and the new ideas inherent in the entrepreneurial creativity of the age of transitions. no individual and no country will fully understand all of the changes as they occur or be able to adapt to them flawlessly during this time. 130 this vision of a 'brave new world' merits attention on two important grounds. first, it implies that the changes likely to occur in the not too distant future as a result of the rapid progress of science and technology are imminent and unavoidable in the sense that their advent hardly depends on or even requires extensive public deliberation. second, given that our capacity for adaptation to and grasp of those changes will be considerably impaired, the age of transitions leaves little space for public deliberation. to add to this gloomy picture, there is already some evidence that the progress in the life sciences is overwhelming the existing deliberative mechanisms. for instance, kelle et al. argue that the rapidity of biotechnology advancement coupled with the immensity and complexity of the knowledge accumulated therefrom complicates efforts to deal with potential risks, something evident in the regulatory gap that the convergence of chemistry and biology has created in the area of arms control. 131 this is problematic, for the reduced resilience of deliberative systems provides favourable conditions in which scientific and technological innovation can continue unabated. a vicious circle is thus created in which the inability of deliberative systems to cope with the strain exerted by biotechnology advancement fuels the latter turning it into a self-propelling force. the proliferation of contentious 'gain-of-function' research is a case in point. even though the h5n1 controversy discussed in the preceding sections exposed the limitations of existing governance mechanisms for addressing the potential security, ethical, and legal implications arising from such studies, it hardly precluded scientists from conducting similar experiments. indeed, less than four months after the moratorium on research involving contagious h5n1 virus was lifted, a team of chinese researchers announced the creation of a hybrid of the h5n1 strain and the h1n1 virus that caused the 2009 flu pandemic. 132 and it was not long until the newly-emerged h7n9 influenza virus became airborne, as well. 133 if anything, those examples indicate that in light of the rapid pace of life science progress, addressing governance concerns on a caseby-case basis is not only self-defeating but given the number and variety of conundrums, it is likely to become unsustainable in the long run. given the significant potential of biotechnology to bring about multifaceted changes in different spheres of life and generate considerable benefits in the form of new products, enhancement of public and private capital and alleviation of social ills, there is a powerful urge to allow the ongoing expansion of the life sciences to proceed largely unfettered. risks are carefully calculated and, where possible, downplayed as hypothetical at the expense of comprehensive deliberation. and even when proposals for risk mitigation measures are entertained, preference is usually given to those unlikely to hinder the progress of life sciences. by and large, there is a genuine belief that the existing governance mechanisms in the area of biotechnology can accommodate and cope with the wide-ranging pressures exerted by scientific innovation and the rapid diffusion of technologies with multiple uses, by offering 'solutions' and handling concerns on a case-by-case basis. in particular, the technology of safety is still 'celebrated as an unadulterated improvement for society as a whole'. 134 yet there are reasons for scepticism toward the adequacy and effectiveness of the governance approaches currently in place. much of the discussion in the preceding sections has focused on the ways in which the increasing pace, growth and global diffusion of biotechnology advances are beginning to expose the limits of the existing measures for control and risk management by challenging accepted values and beliefs and redefining established norms of practice. as the multifaceted dynamics driving the biotechnology momentum continue to intensify and multiply, it becomes more and more difficult to comprehend, let alone foresee, the various impacts that the large-scale deployment and proliferation of novel scientific and technological advances have both on our social systems and the environment. given the tight coupling between human-made and natural systems and their complex, often unanticipated interactions with catastrophic potential, the existing narrow definitions of risk are rendered inadequate. 135 at the same time, the advent of new technologies with multiple adaptive applications opens up an array of possibilities for hostile exploitation thus compelling governments to make tough decisions in an attempt to reconcile the benefits of biotechnology with the potential security concerns arising therefrom. while the advancement of biotechnology promises tremendous public health benefits, it also holds a considerable catastrophic potential, as the case of 'gain-of-function' experiments illustrate. as scientific capabilities and work involving dangerous pathogens proliferate globally, so do risks and the prospects of failures, whether technical or arising from human error. indeed, assessing the rapidly evolving life science landscape some security commentators argue that 'current genetic engineering technology and the practices of the community that sustains it have definitively displaced the potential threat of biological warfare beyond the risks posed by naturally occurring epidemics' 136 . laboratories, however well equipped, do not exist in isolation but are an integral part of a larger ecological system. as such, they constitute a 'buffer zone' between the activities carried out inside and the wider environment. and despite being technically advanced and designed to ensure safety, this 'buffer zone', just as other safety systems is far from infallible. for one thing, mechanical controls leave room for human error and personal judgement, both of which are factors that could be highly consequential but which could hardly be modelled or predicted with exact certainty. 137 the speed at which the transformation of the life sciences is taking place is yet another factor that adds to the complexity of life science governance. stability is a fundamental condition for the development and preservation of human and natural systems alike. in social systems, culture is the primary source of stability, for it determines what values, beliefs, practices and modes of behaviour are deemed acceptable and, as such, lays the foundations of order. all forms of governance therefore are cultural artefacts and manifestations of culture. culture also provides the tacit standards whereby change is assessed and treated as acceptable or unacceptable. hence, any state of affairs in which the rate of change precludes regulation disrupts the ordinary functioning of the system and jeopardises its preservation: the breakdown of human regulation does not extinguish regulation of a simpler sort. [ . . . ] the system formed by men and the rest of the natural world will continue to regulate itself after a fashion, even if human regulation wholly fails at all levels above the primary group. but the resulting 'order' would exclude all those levels of human order which man-made stability makes possible. 138 to be sure, a world characterised by a runaway biotechnology would be far different from the one we know. the main challenge to averting this prospect lies in ensuring that the systems of governance are in sync with the progress of life sciences. history has shown that even highly developed, long-standing systems of governance can fail for reasons as diverse as disasters; loss of authority/legitimacy of governing bodies; and pervasive corruption. one further source of failure includes the inability of a society to adapt to its changing milieu: men are adaptable; they can learn to live even in harsh and hostile environmentsso long as the environment remains constant enough to give them time to learn. [ . . . ] if they form the habit of adapting by constantly changing that to which they are trying to adapt, they build uncertainty into the very structure of their lives. they institutionalise cluelessness. 139 the process of adaptation is closely connected to cultural patterns and any serious disruptions in the latter could have detrimental effects and impair it severely. the extent to which change is taking place within the framework of the prevalent culture defines the borderline between system evolution and system disintegration. the governance mechanisms currently in place, both formal and informal, are all a function of historical, cultural, and sociopolitical contingencies. as such, their capacity for adaptation largely depends on our ability to comprehend and assimilate the complex changes that the progress of biotechnology brings about. they can only evolve as fast as our shared standards, values, routines and perceptions allow them to. and that is why governance can hardly be reduced to a technocratic exercise; on the contrary, to be effective, it requires extensive deliberation and full appreciation of the far-reaching implications of novel life science advances. trends and drivers of change in the biomedical healthcare sector in europe: mapping report (dublin: european foundation for the improvement of living and working conditions chemical synthesis of poliovirus cdna: generation of infectious virus in the absence of natural template the test-tube synthesis of a chemical called poliovirus: the simple synthesis of a virus has far-reaching societal implications craig venter creates synthetic life form', the guardian moore's law pertains to the rapid rate of technological development and advances in the semiconductor industry, specifically the doubling of the number of transistors on integrated circuits that occurs approximately every 18 months. although advances in the life sciences occur at more random intervals and are driven by new conceptual breakthroughs in understanding of biological processes, it is a useful metaphor for the exponential growth of knowledge related to biology. see committee on the advances in technology and the prevention of their application to next generation bioterrorism and biological warfare threats, an international perspective on advancing technologies and strategies for managing dual-use risks the myth of the biotech revolution: an assessment of technological, clinical and organisational change globalization, biosecurity and the future of the life sciences innovation in global industries: u. s. firms competing in a new world biotechnology and the un's millennium development goals top ten biotechnologies for improving health in developing countries rising to the challenge: u.s. innovation policy for global economy innovating in the new austerity, burrill & co's 26th annual report on the life sciences industry globalization and the future of the life sciences, op cit an international perspective on advancing strategies for managing dual-use risks the valley of the shadow of death', dspace@mit globalization and the future of the life sciences the biotechnology promise: capacity-building for participation of developing countries in the bioeconomy converging technologies for enhancing human performance: science and business perspectives converging technologies -shaping the future of european societies taking care of the symbolic order: how converging technologies challenge our concepts enhancement technologies and the modern self the ethics of nbic convergence bringing converging technologies closer to civil society: the role of precautionary principle', innovation: the innovation in global industries, op cit in the valley of the shadow of death see the 'infectious diseases' section of the who website for an overview of the nih budget for 2015, see david malakoff and jeffrey mervis, 'first look: us spending deal a mixed bag for science within nih's flat 2015 budget, a few favourites', scienceinsider for information on the eu sixth framework programme and the activity area of life sciences cuba -battling cancer with biotechnology global status of commercialised biotech/gm crops plant genetic engineering: china hesitates on the brink', gmo safety rising to the challenge, op cit government academic, and venture firms come together in march to fund translational and early-stage development', fiercebiotech science for sale: the perils, rewards and delusions of campus capitalism relationships between academic institutions and industry in the life sciences -an industry survey the expanding role of university patenting in the life sciences: assessing the importance of experience and connectivity university-industry relationships and the design of biotechnology research entrepreneurial science in the academy: a case of the transformation of norms the triple helix of university-industry-government relations the triple helix: university-industry-government innovation in action the dynamics of innovation: from national systems and "mode 2" to a triple helix of university-industry-government relations commercialisation of the university and the problem choice by academic biological scientists see also dina biscotti et al. 'the "independent investigator": how academic researchers construct their professional identity in university-industry agricultural biotechnology research collaborations toward more secrecy in science: comments on some structural changes in science -and on their implications for an ethics of science varieties of secrets and secret varieties: the case of biotechnology for a detailed analysis on the us decision to reject the draft btwc protocol, see malcolm dando the white house the pitfalls of bioterrorism preparedness: the anthrax and smallpox experiences bioterrorism and smallpox planning: information and voluntary vaccination taking biodefence too far new labs, more terror a plague of researchers mixing bugs and bombs lab loses trio of plague mice', nature news anthrax letters' attack and the controversy of the us biodefence programme see jeanne guillemin army suspends germ research at maryland lab back to bioweapons? international health regulations (who, 2005), specifically section 'laboratory pandemic influenza preparedness framework for the sharing of influenza viruses and access to vaccines and other benefits (who for further discussion on the implementation of biotechnology regulations, see bo sundqvist et al. 'harmonisation of european laboratory response networks by implementing cwa 15793: use of gap analysis and an "insider" exercise as tools on the development of health and safety regulations on the use of nanotechnology, see eileen kuempel et al. 'risk assessment and risk management of nanoparticles in the workplace: translating research into practice there is a debate on whether the 'american model' of science-policy making underpinned by neoliberal ideology is fully embraced in europe. see, for example, gabriele abels, 'the long and winding road from asilomar to brussels: science, policy and the public in biotechnology regulation further, a policy paper issued by a business taskforce appointed by the uk government issued a policy paper in late 2013 demanding the liberalization of the existing eu legislation which, in their view, 'places restrictions on products and technologies without adequate evidence of risk'. see department for business, innovation & skills and the prime minister's office, cut the eu red tape: report form the business task force proposed framework for the oversight of dual use life science research: strategies for minimising the potential misuse of research information biosecurity reconsidered: calibrating biological threats and responses some commentators have expressed scepticism toward the claim that scientific and technological advancement poses serious threats underscoring the importance of other factors, such as socio-economic and socio-technic contexts. see, for example, kathleen vogel, 'intelligent assessment: putting emerging biotechnology threats in context others, however, argue that advances in modern biology and medicine have implications for the evolution of biological weapon programmes. see malcolm dando, 'the impact of the development of modern biology and medicine on the evolution of offensive biological warfare programmes in the twentieth century expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox the efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4 disaster in the making creation of killer poxvirus could have been predicted chemical synthesis of poliovirus cdna: generation of infectious virus in the absence of natural template a tale of two studies: ethics, bioterrorism and the censorship of science first synthetic virus created', bbc news university of bradford, available at www.brad.ac.uk/ acad/sbtwc (accessed 8/03/2013). see also german ethics council, biosecurity -freedom and responsbility of research on the framing of risk in biotechnology, see geert van calster, 'risk regulation, eu law and emerging technologies: smother or smooth? ethics of risk analysis and regulatory review: from bio-to nanotechnology european biotechnology regulation: framing the risk assessment of a herbicide tolerant crop framing the uncertainty of risk: models of governance for genetically modified crops denmark's regulation of agri-biotechnology: co-existence bypassing risk issues a distorted regulatory landscape: genetically modified wheat and the influence of non-safety issues in canada on the shortcomings of the existing models for public deliberation on the risks of biotechnology, see les levidow, 'european public participation as risk governance: enhancing democratic accountability for agrobiotech policy for critique of cost-benefit analysis, see also brian rappert the creation of contagious h5n1 avian influenza virus: implications for the education of life scientists all meetings of the us national science advisory board for biosecurity (nsabb) convened to discuss the manuscripts were restricted to selected individuals and full proceedings were never published. moreover, the consequential consultation meeting organised by the world health organisation (who) in february 2012 which rejected the nsabb recommendation for a redacted publication of the manuscripts featured the lead scientists who conducted the experiments and representatives of the us national institutes of health flu experts -and one ethicist -debate controversial h5n1 papers', scienceinsider fight over dutch h5n1 paper enters endgame', scienceinsider fight over dutch h5n1 paper enters endgame', scienceinsider dutch appeals court dodges decision on hotly debated h5n1 papers', scienceinsider bias accusation rattles us biosecurity board experimental adaptation of an influenza h5 ha confers respiratory droplet transmission to a reassortant h5 ha/h1n1 virus in ferrets airborne transmission of influenza a/h5n1 virus between ferrets: materials/methods, supporting text, tables, figures, and/or refences safety incidents" at animal lab', bbc news notes 155 airflow problems plague cdc bioterror lab high-containment laboratories: assessment of the nation's need is missing the scientist lab infection blamed for singapore sars case between 2014 and 2015, several high-containment facilities in the us have experienced serious biosafety lapses. accidents involving dangerous pathogens such as the causative agents of anthrax and bird flu were reported biosafety in the balance' anthrax? that's not the real worry cdc closes anthrax and flu labs after accidents about the same time, there were also reports about smallpox vials being retrived after having been left unaccounted for over 50 years. see ap, 'forgotten vials of smallpox found in storage room gain-of-function' influenza research and proposal to organise a scientific briefing for the european commission and conduct comprehensive risk-benefit assessment the third revolution: the convergence of the life sciences see committee on biomocular materials and processes, national research council, inspired by biology: from molecules to materials to machines a new biology for the 21st century nanotechnology: what it can do for drug delivery facing the truth about nanotechnology in drug delivery carbon nanotubes -bullets in the fight against cancer on the governance challenges brought about by the convergence between biology and other fields of science, see francis fukuyama and caroline wagner, information and biological revolutions: global governance challenges -summary of a study group report of the first workshop the body's own bioweapons innovation, dual use, and security: managing the risks of emerging biological and chemical technologies life sciences and related fields: trends relevant to the biological weapons convention building better implants some nanotubes could cause cancer and breeding: panacea or pandora's box?', news release on the security implications of synthetic biology, see international council for the life sciences synthetic biology and biosecurity awareness in europe on the social and ethical aspects of synthetic biology, see presidential commission for the study of bioethical issues, new directions: the ethics of synthetic biology and emerging technologies synthetic biology: social and ethical challenges framing biosecurity: an alternative to the biotech revolution model vogel's view are contested in jonathan tucker 'could terrorists exploit synthetic biology lax laws, virus dna and potential for terror on the issue of commercial order screenings, see stephen maurer et al. making commercial biology safer: what the gene synthesis industry has learned about screening customers and orders on the governance of synthetic biology, see catherine lyall dna synthesis and biological security industry self-governance: a new way to manage dangerous technologies unpacking synthetic biology: identification of oversight policy problems and options synthetic biology, security and governance'¸biosocieties dna synthesis and security science enters $1,000 genome era', bbc news happened when i had my genome sequenced', the observer for information about commercial companies offering full-genome sequencing genome-based therapeutics: targeted drug discovery and development: workshop summary dna of 100,000 people to be mapped for nhs', the guardian systems cancer medicine: towards realisation of predictive, preventive, personalised and participatory (p4) medicine' grateful and moved" by reaction to her mastectomy decision', the guardian dna blueprint for fetus built using tests of parents cure for illness raises ethical fear', the guardian what happened when i had my genome sequenced another point that cadwalladr raises is the danger of a negative placebo effect whereby doubts about certain genetic disorder may lead to psychosomatic symptoms from eugenics to patents: genetics, law, and human rights unhidden traits: genomic data privacy debates heat up from eugenics to patents see also harriet washington, deadly monopolies: the shocking corporate takeover of life itself -and the consequences for your health and our medical future taking life: private rights in public nature benefits and threats of developments in biotechnology and genetic engineering' in sipri yearbook, armaments ethnic-affiliation estimation by use of population-specific dna markers racial differences in the response to drugs -pointers to genetic differences the achilles' helix from eugenics to patents three-person" embryos to combat genetic disease', the guardian innovative genetic treatment to prevent mitochondrial disease, press release three-parent embryos for mitochondrial disease? twelve reasons for caution february 2015, the uk passed legislation allowing the use of the technique. see james gallagher, 'uk approves three-person babies', bbc news building baby from the genes up one commentator distinguishes between 'big science' which was 'todown, hierarchical, vertical' and 'networked science' characterised by 'open systems, open software, open participation'. see diane rhoten biopunk: solving biotech's biggest problems in kitchens and garages life hackers biology is technology: the promise, peril, and new business of engineering life diffusion of synthetic biology: a challenge to biosafety do i understand what i can create: biosafety issues in synthetic biology charge dropped against artist in a terror case strategies to educate amateur biologists and scientists in non-life science disciplines about dual use research in the life sciences governing amateur biology: extending responsible research and innovation in synthetic biology to new actors, research report for the wellcome trust project 'building sustainable capacity in dual use bioethics secret project manufactured mock anthrax', the washington times biological weapons and america's secret war global governance and the twenty-first century technology converging technologies for improving human performance: nanotechnology, biotechnology, information technology and cognitive science report of the who informal consultation on dual use research of concern biological threat assessment: is the cure worse than the disease? dangerous ambiguities: regulation of riot control agents and incapacitants under the chemical weapons convention weaponisation of central nervous system acting chemicals for law enforcement purposes, xix session of the conference of the states parties moscow theatre siege: questions remain unanswered', bbc news press release: use of gas against terrorists during the moscow theatre siege was justified, but the rescue operation afterwards was poorly planned and implemented spasenie zalozhnikov ili unichtozhenie terroristov?', novaya gazeta the 2002 dubrovka and 2004 beslan hostage crises: a critique of russian counter-terrorism sekretov bol'she net', rossiskaya gazeta see also national research council, avoiding surprise in an era of global technology advances the challenge to deliberative systems of technological systems convergence converging technologies for improving human performance, op cit preventing a biochemical arms race, op cit bringing the bwc conventions closer together', the cbw conventions bulletin h5n1 hybrid viruses bearing 2009/h1n1 virus genes transmit in guinea pigs by respiratory droplet infectivity, transmission, and pathology of human-isolated h7n9 influenza virus in ferrets and pigs limited airborne transmission of h7n9 influenza a virus between ferrets shifting the blame: literature, law, and the theory of accidents in nineteenth-century america normal accidents, op cit building a bio world shifting the blame, op cit freedom in a rocking boat: changing values in an unstable society some commentators have critiqued the work of diamond on the grounds of simplicity. for a summary of some of the criticisms levelled at his work, see eric powell key: cord-269566-mgzal1th authors: carmody, sean; murray, andrew; borodina, mariya; gouttebarge, vincent; massey, andrew title: when can professional sport recommence safely during the covid-19 pandemic? risk assessment and factors to consider date: 2020-05-07 journal: br j sports med doi: 10.1136/bjsports-2020-102539 sha: doc_id: 269566 cord_uid: mgzal1th nan the covid-19 pandemic has had, and will have, profound effects on every person on earth. measures advocated by the who and put in place by national governments, businesses and individuals will save millions of lives, but current movement restrictions (ie, various degrees of lockdown) cannot continue indefinitely. the activity restrictions imposed by governments are designed to reduce human-to-human transmission; they buy time and allow international collaboration between governments and internally to build and allocate the resources and systems to 1. test: every suspected case where testing is merited and available while having effective prevention strategies in place. 2. trace: follow up all confirmed cases of covid-19 and contact trace every relevant contact to identify and cut off transmission. 3. treat: manage all cases effectively, with adequate intensive care unit capacity, ventilators and staff. rightly, professional sport has been placed on hold during the covid-19 pandemic. the who (#beactive) and many governments continue to promote certain types of moderate physical activity for the benefits it confers on the immune system and physical and mental health. [1] [2] [3] [4] sport has health, social and economic benefits for individuals and society, and when the covid-19 pandemic is better 'controlled', it may be appropriate to reintroduce community sport and professional editorial sport. in this editorial, we opine on what needs to be in place for professional sport to recommence. the relaxation of movement/activity/business restrictions is likely to happen over a gradual period, and time frames will differ across nations and even within nations. the following is expected 5 : ► lockdowns will be lifted strategically and in a stepwise fashion; the effects of easing will be carefully monitored, given the 2-week latency between actions (eg, allowing more social engagement) and outcomes (no change in infection rates or an increase in cases). ► countries and/or regions with lower community transmission of cases will begin easing restrictions before those with higher community transmission. ► physical distancing and enhanced standards of personal hygiene will continue longer term. some, like regular handwashing, should be part of routine behaviour forever. ► risk assessment (systematically looking at risk and potential consequence of covid-19) and control measures designed to eliminate, reduce or minimise the risks will be used. [6] [7] [8] mass gatherings such as a large number of participants and particularly crowds attending sporting events likely increase risk of transmission of covid-19. 9 additionally, there are some sports (eg, golf and time trial cycling) where social distancing is possible, and others (eg, football and rugby) where it is not practical. travel (use of airports and hotels) can also increase risk, although this may be no different from travel on other business. if professional sport is to return in the near future, event organisers must accept that assessment of risk must be undertaken and measures put in place to ensure any risks from the event are less than the benefits. the who highlights five key factors in determining risk 10 : ► will the event be held in a country that has documented active local transmission of covid-19 (community spread)? ► will the event be held in a single venue or multiple venues/cities/countries? ► will the event include international participants (athletes and spectators) from countries that have documented active local transmission of covid-19 (community spread)? ► will the event include a significant number of participants (athletes or spectators) at higher risk of severe covid-19 disease (eg, people over 65 years of age or people with underlying health conditions)? ► will the event include sports that are considered at higher risk of spread for covid-19 (eg, contact sports)? we illustrate in figure 1 that, for a nonclosed doors, english premier league football match, played in april, the risk is very high, and the match should not proceed regardless of government policies, which at present would also preclude it going ahead. once the risk assessment is conducted, event organisers should refer to mitigation measures to see where these considerations can be incorporated into the planning of the events to further decrease the risk of spread of covid-19. if, for example, a match was postponed to august, was played behind closed doors, substantial but achievable mitigations including enhanced hygiene, social distancing where practical, the ability to test and contact trace were put in place and transmission was (for illustration) present but significantly less editorial in the host country, then the risk from that event can be reduced to low. players would need to have time to gain fitness prior to matches resuming. discussion with government, local health authorities, event organisers and the participants could take place, regarding suitability to proceed and what other controls can further decrease risk ( figure 2) . if community transmission is low and adequate risk mitigation procedures are in place, the overall risk can be very low. this could apply to a local golf competition, where the sport is outdoors, social distancing is possible, and participants are <65 years old, fit and well. key measures to decrease risk of covid-19 at sporting events are illustrated in figure 3 . we suggest the following documents can serve as a guide to those undertaking risk assessments for events within their sports: ► who key planning recommendations for mass gatherings. 6 ► who considerations for sports federations/sports event organisers when planning mass gatherings in the context of covid-19. 7 ► who mass gathering sporting risk assessment. 8 if sporting events return, close liaison with the participants, local/national government and public health authorities is necessary. event organisers must 1. minimise risk of transmission for all groups of sporting event participants. 2. work to ensure readily available accurate testing while not taking these from health systems that need them most. 3. be able to accurately contact trace. further important steps include individual sporting bodies producing guidance regarding return to training postrestrictions, policies and procedures for testing, and management of players diagnosed with covid-19, recognising the science is fast evolving. professional sport, as well as its resumption, is a secondary concern in the context of the covid-19 pandemic globally. however, international collaboration has enabled major sporting events to proceed during who declared public health emergencies, including vancouver 2010 olympic games during the h1n1 pandemic, and rio 2016 olympic games during the zika outbreak. we should start planning to resume sporting events, given the health, social and economic benefits of professional sport and the substantial planning and work required prior to any resumptions. in this editorial, we build on who guidance and tools and discuss the factors and risk assessments which should be in place prior to sport returning. correction notice this article has been corrected since it published online first. the acknowledgement section has been updated. twitter andrew murray @docandrewmurray, vincent gouttebarge @vgouttebarge and andrew massey @andy_massey effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy exercise and the immune system be active during covid-19-press briefing. world health organisation covid-19): what you need to do prepare for a 'new normal' as lockdown restrictions ease. monday's who covid-19 briefing key planning recommendations for mass gatherings in the context of covid-19: interim guidance considerations for sports federations/sports eventorganizers when planning mass gatherings in the context of covid-19 mass gathering sporting risk assessment pandemic influenza: mass gatherings and mass infection mass gathering events and reducing further global spread of covid-19: a political and public health dilemma contributors amu and sc drafted the initial version of this manuscript. ama, mb and vg modified the subsequent versions. all authors approved the final version of the manuscript. the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.competing interests none declared. provenance and peer review not commissioned; internally peer reviewed.this article is made freely available for use in accordance with bmj's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by bmj. you may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. key: cord-266180-32gw2ug3 authors: haider, najmul; yavlinsky, alexei; simons, david; osman, abdinasir yusuf; ntoumi, francine; zumla, alimuddin; kock, richard title: passengers' destinations from china: low risk of novel coronavirus (2019-ncov) transmission into africa and south america date: 2020-02-26 journal: epidemiology and infection doi: 10.1017/s0950268820000424 sha: doc_id: 266180 cord_uid: 32gw2ug3 novel coronavirus (2019-ncov [sars-cov-2]) was detected in humans during the last week of december 2019 at wuhan city in china, and caused 24 554 cases in 27 countries and territories as of 5 february 2020. the objective of this study was to estimate the risk of transmission of 2019-ncov through human passenger air flight from four major cities of china (wuhan, beijing, shanghai and guangzhou) to the passengers' destination countries. we extracted the weekly simulated passengers' end destination data for the period of 1–31 january 2020 from flirt, an online air travel dataset that uses information from 800 airlines to show the direct flight and passengers' end destination. we estimated a risk index of 2019-ncov transmission based on the number of travellers to destination countries, weighted by the number of confirmed cases of the departed city reported by the world health organization (who). we ranked each country based on the risk index in four quantiles (4(th) quantile being the highest risk and 1(st) quantile being the lowest risk). during the period, 388 287 passengers were destined for 1297 airports in 168 countries or territories across the world. the risk index of 2019-ncov among the countries had a very high correlation with the who-reported confirmed cases (0.97). according to our risk score classification, of the countries that reported at least one coronavirus-infected pneumonia (covid-19) case as of 5 february 2020, 24 countries were in the 4(th) quantile of the risk index, two in the 3(rd) quantile, one in the 2(nd) quantile and none in the 1(st) quantile. outside china, countries with a higher risk of 2019-ncov transmission are thailand, cambodia, malaysia, canada and the usa, all of which reported at least one case. in pan-europe, uk, france, russia, germany and italy; in north america, usa and canada; in oceania, australia had high risk, all of them reported at least one case. in africa and south america, the risk of transmission is very low with ethiopia, south africa, egypt, mauritius and brazil showing a similar risk of transmission compared to the risk of any of the countries where at least one case is detected. the risk of transmission on 31 january 2020 was very high in neighbouring asian countries, followed by europe (uk, france, russia and germany), oceania (australia) and north america (usa and canada). increased public health response including early case recognition, isolation of identified case, contract tracing and targeted airport screening, public awareness and vigilance of health workers will help mitigate the force of further spread to naïve countries. on 31 december 2019, local hospitals in wuhan, china reported that they had detected a series of cases of novel coronavirus-infected pneumonia to the world health organization (who) [1] . on 7 january, the causative agent was identified by the chinese centre for disease control and prevention as a novel coronavirus and designated '2019-ncov' and finally as "sars-cov-2". epidemiological investigations identified the local huanan seafood wet market as the location of an initial exposure event [2] . the market was closed on 31 december 2019 [2, 3] and wildlife market activity was banned countrywide. despite travel restrictions to and from the city imposed by chinese authorities to limit the potential dispersion of the virus beyond the region [4, 5] , international cases continue to be reported. as of 5 february 2020, there were 24 554 confirmed novel coronavirus-infected pneumonia (covid-19) cases in 27 countries or territories, of which 24 363 (99.2%) were within mainland china [6] . the locations of internationally imported cases are consistent with risk models generated from flight data out of wuhan city. transmission from mildly symptomatic (i.e. cough, lethargy, myalgia) infected individuals was identified early in the course of this outbreak, with human-to-human transmission detected in international case series [7] . the timing of this outbreak around the lunar new year widely celebrated in china coincides with a period of highest annual human movement patterns in the region and between china and globally [8] , increasing the potential for rapid geographic dispersal of the infection. further, recent investment in the african continent by the chinese state and private investors has led to an increasing chinese diaspora [9] and a greater number of direct and indirect flight connections to the african continent from china [10] . there are few studies available on global risk of 2019-ncov spread [4, 5, 11] . bogoch et al. [5] and chinazzi et al. [11] estimated the risk of importation of 2019-ncov from major chinese cities to the most frequent international destinations. wu et al. estimated the risk of international spread compared to domestic outbound flights [4] . these articles do not model the cumulative risk of importation of 2019-ncov in a country and instead focus on specific points of entry. here, we considered all the end destinations of flights from four important cities of china involving 168 countries/territories around the world and calculated the total risk of transmission into a country by aggregating the risk associated with all the entry airports of the country. we further looked in more detail at the risk to africa where the health infrastructure would be challenged tracking a new epidemic across its 54 countries. the aim of the current study was to explore the effect of sustained transmission from the four chinese cities of wuhan, beijing, shanghai and guangzhou on international disease importation risk to 168 countries and territories, with a specific focus on africa where current levels of healthcare infrastructure could provide a significant challenge for managing this novel epidemic. we extracted modelled flight data for the final destination of passengers travelling from four chinese cities (including domestic and international destinations) from the flirt database [12, 13] . flirt was designed to predict the flow and likely destination of infected travellers through the air travel network. it uses a database of flight schedules from over 800 airlines and displays direct flight connections in addition to a modelled end destination (three-letter iata code for airports). flight connection data and passenger numbers are based on the data collected since october 2014 [12] . we extracted the simulated passenger's data for each week for the period of 1 january to 31 january 2020 from four major chinese cities: wuhan, beijing, shanghai and guangzhou. the simulation can process up to 20 000 passengers' information for a particular time frame from any city (including surrounding airports). we collected the reported 2019-ncov case data from the who's daily situation update website [14] . to estimate the relative risk of 2019-ncov transmission, we considered all infected passengers who travelled between 1 january and 31 january to possess a maximum risk of transmission 1 (and no infected passengers means no risk) and estimated the relative risk of each country based on the number of passengers who travelled from each of the four cities. thus countries with a higher number of passengers travelling from any of these cities had a higher risk of transmission. we then weighted the risk estimated for each city with the number of reported infected people in each city by 31 january 2020 [14] and estimated the mean average risk of transmission termed as 'risk index' which follows the equation below: where x is the destination country, risk index (x) is the risk of infection importation in country x, p(x) n is the number of passengers to country x from city n, p n is the total number of passengers who left city n, i n is the number of infected people in city n and c n is the population size of city n. the risk index denotes the risk of at least one case being imported into a country or territory where 1 means an absolute certainty and 0 means no risk at all. our model assumed that there is no case outside china and thus ignored if any country already had imported case(s). in countries where 2019-ncov is already detected, the risk index would explain the risk of importing additional infected individuals from china. we performed a pearson correlation coefficient test between the risk index of the country and the who's reported case number from the country. we grouped the countries in four quantiles based on the risk index where high-risk countries were grouped as the 4 th (>75 th percentiles) and the 3 rd (>50 th to ⩽75 th percentiles) quantiles and low-risk countries were grouped as the 2 nd (>25 th to ⩽50 th percentiles) and the 1 st (⩽25 th percentile) quantiles (table 1) . we modelled 388 287 passengers travelling to 1297 airports in 168 countries or territories. the risk index of 2019-ncov for these countries is presented in figure 1 . a regularly updated risk map is hosted on pandora's website ( https://ncovdata.io/import/). outside china, the countries with the highest risk of 2019-ncov transmission from our model were thailand, cambodia, malaysia, canada and the usa, all of which have reported at least one case. among the top 25 countries identified with the highest risk of 2019-ncov transmission (fig. 2) , all countries except four (indonesia, turkey, pakistan and qatar) have detected at least one case as of 5 february 2020 (table 1) . according to our risk score classification, of the countries that reported at least one 2019-ncov case as of 5 february 2020, 24 countries were in the 4 th quantile of the risk index, two (sweden and belgium) in the 3 rd quantile, one (nepal) in the 2 nd quantile and none in the 1 st quantile [14] . asian and european countries are dominant in the 3 rd and 4 th quantile (high-risk index) while african and south american countries are the majority in the 1 st and 2 nd quantiles (low-risk index) ( table 1) . out of 43 countries in the 4 th quantile, 22 were from asia and 13 from pan-europe, whereas in the 1 st quantile, 19 out of 42 countries were from africa ( table 1) . the overall risk of transmission of the virus into africa is low. however, ethiopia, south africa, egypt and mauritius have a the correlation coefficient between the estimated risk index of the countries and the who-reported confirmed cases was 0.97. our analysis showed a high risk of transmission of 2019-ncov through air flights from four chinese cities to neighbouring asian countries. the risk of 2019-ncov (sars-cov-2) transmission was relatively low in africa and south america. several countries in both north america and oceania showed high risk with these countries reporting at least one case of 2019-ncov. our risk index showed a very high correlation with the who's reported covid-19 cases. china has four times as many air passengers now than it had during sars outbreaks in 2003. a large number of workers now travel internationally where china is heavily investing in infrastructure development in africa, parts of asia and latin america. a significant and mobile chinese population live in europe and north america alongside an increasing amount of chinese tourism. this travel poses a high risk of 2019-ncov travelling across international borders. although acquiring a case is low for these countries, the consequences are likely to be higher because of the country's capacity to control such situations [15] . based on our model, the countries with the highest risk index but have not reported any case of 2019-ncov as yet are indonesia, pakistan, turkey, qatar and ethiopia. these countries are at risk and they should be the priorities for investment in case detection and airport screening. compared to the sars outbreak of 2003, the situation in 2020 differs due to the increased frequency and volume of international air travel. during these early stages of the epidemic, case numbers have doubled on average every 7.4 days with an estimated basic reproduction number (r 0 ) of 2.2 (1.4-3.9) [1] . although the data so far suggest that the disease is mild in most cases and that the case fatality rate is currently reported to be lower than sars or mers, the situation is likely to go on for months and could cause severe disruption in countries that are not well prepared. hence countries ranked as high risk in our model (4 th and 3 rd quantiles) should take all steps necessary to ensure prompt detection of cases and the capacity to manage these cases to prevent ongoing spread. international investment needs to be directed especially to countries with limited healthcare and public health surveillance capacity to enable the detection of cases and disease control [16, 17] our estimation showed a lower risk of transmission in africa and south america. nevertheless, low and middle countries on these continents are more likely to see the ongoing spread and major disruption from the introduction of a single case, even if the risk of importation is lower. direct flights between chinese cities and african countries are few which has contributed to a lower estimated risk of 2019-ncov transmission. as of 5 february 2020, five cases have been reported from the united arab emirates (uae) which acts as an important travel hub for onward journeys to the african continent. implementation of mildly symptomatic passenger screening in the uae may reduce the potential for 2019-ncov to enter africa. screening and diagnostic capacity in africa has been supported by a rapid grant from the bill and melinda gates foundation to the african cdc, mitigating the consequences of an importation. the current situation is extremely dynamic and since then some countries have instigated flight restrictions and closed borders (e.g. russia). these decisions were relevant for these locations but not based on probabilities. who has not recommended a cessation of transportation to free countries but suggested preventive measures. this would seem appropriate for africa and south america with the caveat that only one case is needed to initiate a local epidemic without proper biosecurity and quarantine measures, whilst other regions will need to decide on a case-by-case basis through appropriate risk assessment. our study has several limitations. we considered flights from four cities of china, three of which (beijing, shanghai and guangzhou) are ranked among top five busiest airports (based on the number of flights) in china and wuhan as the site of origin of outbreaks. while including further cities in our analysis would have added further information, beijing and shanghai cover most of the international destinations to which other airports are connected. further, we have adjusted for the number of reported cases in each departure. when developing the model, we initially explored using only wuhan as the departure airport, the rank of top 10 at-risk countries remained the same. thus our findings are still representative of the total risk posed by other airports or cities. we did not consider the risk associated with the travel route through water and land which might have an impact in the spread of 2019-ncov. another limitation is that the model does not account for travel patterns in other affected countries. for example, some cases have started acquiring the disease outside of china: the third case notified in the uk acquired the disease in singapore. however overall, the risk compared with the risk of acquisition in china is very low, therefore it probably would not change the order of countries. the risk of transmission of sars-cov-2 from china on 31 january 2020 was highest to neighbouring countries in asia (thailand, cambodia, malaysia), followed by europe (uk, france, russia and germany), oceania (australia and new zealand) and north america (usa and canada). the situation is dynamic and may have changed with the closure of flights and borders since this analysis was done. the higher correlation coefficient with travellers and case detection data indicate that 2019-ncov will remain a significant threat from the air-borne movement of people. the authors suggest an ongoing risk-based approach to the prioritisation of and investment by international and national agencies and authorities, in emergency interventions for the prevention of movement of 2019-ncov (sars-cov-2) through human travel. this is achieved by appropriate actions at high-risk points of departure and at highly used ports of entry from these infected zones. closure of certain routes, targeted airport screening, risk communication, public awareness and targeted training and vigilance of health workers associated with the portals of entry of visitors to their countries will help mitigate the force of further spread of 2019-ncov. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study undiagnosed pneumonia -china (hu) (01): wildlife sales, market closed nowcasting and forecasting the potential domestic and international spread of the 2019-ncov outbreak originating in wuhan, china: a modelling study. the lancet potential for global spread of a novel coronavirus from coronavirus covid-19 global cases by transmission of 2019-ncov infection from an asymptomatic contact in germany tracing the largest seasonal migration on earth what kinds of chinese 'geese' are flying to africa? evidence from chinese manufacturing firms the evolution of china's international aviation markets from a policy perspective on air passenger flows preliminary assessment of the international spreading risk associated with the 2019 novel coronavirus (2019-ncov) outbreak in wuhan city flirt-ing with zika: a web application to predict the movement of infected travelers validated against the current zika virus epidemic flirt: a product of ecohealth alliance who (2020) novel coronavirus(2019-ncov) situation report johns hopkins center for health security (2020) global health security index the continuing 2019-ncov epidemic threat of novel coronaviruses to global health -the latest 2019 novel coronavirus outbreak in wuhan sars to novel coronavirus -old lessons and new lessons acknowledgements. all authors are part of pandora-id-net consortium (edctp reg/grant ria2016e-1609) funded by the european and developing countries clinical trials partnership (edctp2) programme which is supported under horizon 2020, the european union's framework programme for research and innovation. az is in receipt of a national institutes of health research (nihr) senior investigator award and the pandora-id-net. fn and az acknowledge support from edctp (cantam2). we acknowledge the eco health alliance for making flirt data publicly available.conflict of interest. the authors declare that they have no conflict of interest. key: cord-265343-4wfsze80 authors: mhango, malizgani; dzobo, mathias; chitungo, itai; dzinamarira, tafadzwa title: covid-19 risk factors among health workers: a rapid review date: 2020-06-06 journal: saf health work doi: 10.1016/j.shaw.2020.06.001 sha: doc_id: 265343 cord_uid: 4wfsze80 coronavirus disease 2019 (covid-19) poses an important occupational health risk to health workers (hws) that has attracted global scrutiny. to date, several thousand hws globally have been reported as infected with the severe acute respiratory syndrome coronavirus 2 virus that causes the disease. it is therefore a public health priority for policymakers to understand risk factors for this vulnerable group to avert occupational transmission. a rapid review was carried out on 20 april 2020 on covid-19 risk factors among hws in pubmed, google scholar, and ebscohost web (academic search complete, cinahl complete, medline with full text, cinahl with full text, apa psycinfo, health source—consumer edition, health source: nursing/academic edition) and who global database. we also searched for preprints on the medrxiv database. we searched for reports, reviews, and primary observational studies (case control, case cross-over, cross-sectional, and cohort). the review included studies conducted among hws with covid-19 that reported risk factors irrespective of their sample size. eleven studies met the inclusion criteria. lack of personal protective equipment, exposure to infected patients, work overload, poor infection control, and preexisting medical conditions were identified as risk factors for covid-19 among hws. in the context of covid-19, hws face an unprecedented occupational risk of morbidity and mortality. there is need for rapid development of sustainable measures that protect hws from the pandemic. the coronavirus disease pandemic caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has challenged the health systems of countries it has affected. as of 30 april 2020, the pandemic has infected more than 3,2 million individuals with over 230,000 fatal cases in 187 countries [1] . the person-to-person transmission routes of include direct transmissions, such as cough, sneeze, droplet inhalation transmission, and contact transmission, such as the contact with oral, nasal, and eye mucous membranes [2] . health workers (hws) are at the forefront of the covid-19 outbreak response and as such are exposed to hazards that put them at risk of infection [3] . as early as february 2020, scholars had established that transmission of the disease among hws is associated with overcrowding, absence of isolation room facilities, and environmental contamination [4] . however, in the context of the rapidly evolving covid-19 pandemic, occupational health and safety policymakers need timely access to updated health information on the risk hws face. this evidence is best obtained through a systematic review; however, this review method requires vast resources, including time, to complete that do not suit the needs [5e7]. in this study, we aimed to map available evidence on covid-19 risk factors among hws to guide future research and policy. we searched pubmed, google scholar, and ebscohost web (academic search complete, cinahl complete, medline with full text, cinahl with full text, apa psycinfo, health sourcedconsumer edition, health source: nursing/academic edition) and who global database for relevant studies. we also searched for preprints on the medrxiv database. the search terms included "coronavirus," "covid-19," "2019-ncov," "sars-cov-2", "risk", "risk factor", "infection", "illness", "disease", "health care worker", "health care professional", and "occupational health". boolean terms, and and or, were used to separate the keywords. the reference lists of all full-text articles screened were searched for relevant studies. we searched for reports, reviews, and primary observational studies (case-control, case-cross-over, cross-sectional, and cohort). the review included studies conducted among hws that reported covid-19 risk factors irrespective of their sample size. we developed a screening criterion a priori for each of the three stages, title and abstract and full text. two researchers screened the articles independently. differences in screen results at full-text stage were resolved by discussion. a data abstraction form was developed, discussed, and revised a priori. the form extracted information on first author, title, sample size, reported risk factors, and other relevant findings. only one reviewer (td) abstracted data from the included studies. for collating, summarizing, and reporting of the findings, first, the reviewers familiarized themselves with the content of the articles. second, findings reported in the articles were grouped into categories based on the reported factors, and a narrative was provided. our initial keyword database search found 1,698 potentially eligible articles. results from each database search are presented in supplementary file 1. following title screening, 82 articles were eligible for inclusion in abstract screening. these articles were imported into endnote x9 and eight duplicates removed, leaving 74 articles included in abstract screening. following abstract screening, 38 studies were excluded, leaving 36 articles for full-text screening. twenty-five articles were excluded after full articles screening, leaving 11 articles for data extraction. table 1 shows characteristics of included articles. all included studies reported covid-19 risk factors among hws. of these, one was a short communication [8] , two were reports [9, 10] , four were reviews [11e14], one retrospective cohort [15] , one retrospective data analysis [16] , one prospective cohort [17] , and one casee control [18] . all included studies were published in 2020. the total number of hws reported in the studies was 1,619; however, five studies did not specify a sample size. one study was a preprint article pending peer review [16] . eleven articles were included for data extraction and narrative summary. the reported covid-19 risk factors among hws were grouped into five: lack of personal protective equipment (ppe), exposure to infected patients, work overload, poor infection control, and preexisting medical conditions. insufficient ppe [9, 10, 14, 16] or lack thereof [8] was reported as an important risk factor for . exposure to infected patients mainly through work in high-risk departments and contaminated fluid/aerosols were reported as another important covid-19 risk factor among hws. work overload resulted in lack of rest, long-time exposure to infected patients [8, 9] , and working under pressure [16] . longer duty hours were reported as covid-19 risk factor in a retrospective cohort conducted at a hospital in wuhan, china [15] . a review conducted by yu et al. revealed limited or absence of knowledge on infection control as a risk factor for covid-19 among hws in the radiology department [13] . similarly, a retrospective analysis by bai et al. [16] and a rapid review by viswanath et al. [11] revealed lack of established practices of infection control poor infection control and direct contact with contaminated surfaces as important risk factors. surprisingly, suboptimal hand hygiene was reported as a covid-19 risk factor among hws [15] . a review conducted by ing et al. [14] on physician deaths from covid-19 reported older age (physicians 57 years of age or older accounted for three-quarters of covid-19-related deaths), male gender (90% of deaths were male physicians), and preexisting conditions (hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, and immunocompromised individuals) as risk factors. this review has revealed that research on covid-19 risk factors for hws is still in its infancy. while this is to be expected given the pandemic only broke out in december of 2019, the available evidence shows active research interest on the subject. the review revealed lack of ppe, exposure to infected patients, work overload, poor infection control, and preexisting medical conditions as covid-19 risk factors among hws. the who released interim guidance on hws risk assessment and management in the context of covid-19 3 . the guidance is offered for both the hws and their facilities. while this blanket guidance is available, occupational health policymakers would need to contextualize the procedures based on available resources and information. our review revealed exposure to infected patients and work overload as two important covid-19 risk factors among hws. this corroborates a recent centers for disease control and prevention report that estimated that of the 9282 cases of covid-19 cases among hws in the united states of america, 55% had exposure in the healthcare setting [19] . further, a mathematical modeling study by temime et al. found that r0 for covid-19 was higher for hws as compared with that of the general public as they have prolonged contact with infected individuals [20] . hws at greatest risk are those who are exposed to the airways and the oral cavity of patients for prolonged periods such as dentists. our review found contact with contaminated fluid as a covid-19 risk factor. similarly, according to meng et al., dentists accounted for 5% of the fatalities among physicians exposed to covid-19 [21] . concerns on contamination through suction have also been reported elsewhere [2] . covid-19 has overwhelmed health systems globally resulting in longer working hours and increased workload for hws. italian physicians have suggested a community-centered or home care system for to not only lessen the workload on hws but also decrease the transmission of disease and hws exposure [22] . further, there is a need for social support services to help hws who are struggling emotionally and allow for periodic breaks from work. the protection of hws is essential despite the increased demand and global shortage of ppe. to ensure the availability of adequate ppe for all hws, governments need to expedite the procurement and devise strategic use of the available ppe. for example, in developing countries, the strategic use of ppe may include extended wear and reuse of certain ppe like gowns, especially in low-risk hospital departments. with the covid-19 pandemic, there is also the potential for panic among hws that may result in the irrational use of ppe. a balance will need to be struck between hws safety and strategic use of available resources. finally, hws should be trained on proper ways of wearing and taking off ppe to prevent contamination. the covid-19 pandemic has put a strain on the health system workforce because of the overwhelming infection rates in some countries. this has meant that older hws, mostly doctors and nurses, have had to join as frontline workers and some to come out of retirement to offer experience, expertise, leadership, and boost the morale of younger professionals. old age alongside preexisting health conditions such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, and immunosuppression were important covid-19 risk factors identified in this review. these have been touted as major risk factors for severe disease elsewhere [23, 24] . health facilities ought to assign duties for high covid-19 risk departments based on age and underlying conditions. this article has a number of strengths and weaknesses. while there are many existing papers dealing with occupational health issues related with the covid-19, identifying the risk factors for infection is an important first step to guide appropriate measures to reduce these risks. this article provided a concise review of available evidence on the subject as at 20 april 2020, a period when there was an upward trajectory in the number of cases among hws globally. rapid reviews by nature have multiple limitations [25] . in this study, important omissions were made on steps for a full systematic review. these include publication language restriction and risk of bias/quality appraisal. however, this review will serve as a precursor to a larger, thorough, and systematic review and metaanalysis the authors of this article are working on. secondly, the evidence on risk factors are likely to be underreported given the rapid evolution of the pandemic and lack of readily available data from other parts of the world like africa at the time of the review. third, owing to the heterogeneity among included articles, our review findings cannot be generalized or clinically implicated. however, we believe the review yielded important findings to inform occupational health policymakers on covid-19 risk factors among hws and researchers on gaps in scientific evidence. in the context of covid-19, hws face an unprecedented occupational risk of morbidity and mortality. lack of and/or inadequate ppe, exposure to infected patients, work overload, poor infection control, and preexisting medical conditions put hws at risk for nosocomial infection. further studies are needed to inform the development of efficacious infection control measures. there is a need for rapid development of sustainable measures that protect hws from the pandemic. no funding was received for this study. none declared. covid-19) situation report e 101 transmission routes of 2019-ncov and controls in dental practice health workers exposure risk assessment and management in the context of covid-19 virus (interim guidance) characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention a scoping review of rapid review methods evidence summaries: the evolution of a rapid review approach systematic reviews in the social sciences: a practical guide reasons for healthcare workers becoming infected with novel coronavirus disease 2019 (covid-19) in china protecting healthcare workers during the coronavirus disease 2019 (covid-19) outbreak: lessons from taiwan's severe acute respiratory syndrome response hospital experiences responding to the covid-19 pandemic: results of a national pulse survey working through the covid-19 outbreak: rapid review and recommendations for msk and allied heath personnel facing covid-19 in ophthalmology department infection control against covid-19 in departments of radiology physician deaths from corona virus disease (covid-19). medrxiv risk factors of healthcare workers with corona virus disease 2019: a retrospective cohort study in a designated hospital of wuhan in china sars-cov-2 infection in health care workers: a retrospective analysis and a model study. medrxiv prevalence of sars-cov-2 infection in previously undiagnosed health care workers at the onset of the u.s. covid-19 epidemic. medrxiv clinical characteristics of 30 medical workers infected with new coronavirus pneumonia characteristics of health care personnel with covid-19dunited states estimating r0 of sars-cov-2 in healthcare settings. medrxiv coronavirus disease 2019 (covid-19): emerging and future challenges for dental and oral medicine at the epicenter of the covid-19 pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation covid-19: risk factors for severe disease and death severe outcomes among patients with coronavirus disease 2019 (covid-19) -united states expediting systematic reviews: methods and implications of rapid reviews the authors acknowledge librarians dzingayi shangwa and nontobeko sikhosana for assistance with search criteria for multiple databases. supplementary data to this article can be found online at https://doi.org/10.1016/j.shaw.2020.06.001. key: cord-164666-ktrw377u authors: gupta, abhishek; lanteigne, camylle; institute, victoria heath montreal ai ethics; microsoft,; lab, algora title: report prepared by the montreal ai ethics institute (maiei) on publication norms for responsible ai date: 2020-09-15 journal: nan doi: nan sha: doc_id: 164666 cord_uid: ktrw377u the history of science and technology shows that seemingly innocuous developments in scientific theories and research have enabled real-world applications with significant negative consequences for humanity. in order to ensure that the science and technology of ai is developed in a humane manner, we must develop research publication norms that are informed by our growing understanding of ai's potential threats and use cases. unfortunately, it's difficult to create a set of publication norms for responsible ai because the field of ai is currently fragmented in terms of how this technology is researched, developed, funded, etc. to examine this challenge and find solutions, the montreal ai ethics institute (maiei) co-hosted two public consultations with the partnership on ai in may 2020. these meetups examined potential publication norms for responsible ai, with the goal of creating a clear set of recommendations and ways forward for publishers. in its submission, maiei provides six initial recommendations, these include: 1) create tools to navigate publication decisions, 2) offer a page number extension, 3) develop a network of peers, 4) require broad impact statements, 5) require the publication of expected results, and 6) revamp the peer-review process. after considering potential concerns regarding these recommendations, including constraining innovation and creating a"black market"for ai research, maiei outlines three ways forward for publishers, these include: 1) state clearly and consistently the need for established norms, 2) coordinate and build trust as a community, and 3) change the approach. • create tools to navigate publication decisions: the use of extrinsic measurements like benchmarks, or third-party expert panels could be a crucial step to navigating publication decisions in a fair way. such methods could set a certain standard in terms of the acceptable level of risk associated with a publication. in line with this suggestion, it would also be pertinent to keep a record of the papers that were rejected due to their inherent risk, as well as some metrics on these. • offer a page number extension: it may be beneficial to extend the page limit for published papers to allow researchers to include negative results (results that are insignificant or disprove researchers' hypotheses), which aren't traditionally printed. in addition to expanding the number of pages, there should also be a significant change in the culture surrounding the publication of negative results. • develop a network of peers: developing a network of peers to evaluate researchers' ai models in terms of potential risks and benefits may be an important tool towards better and safer publication norms. if such a mechanism were put in place, the evaluation could be fully or partly based on philosopher john rawls's "veil of ignorance." if this idea was applied to reviewing ai research, peer reviewers could be asked to consider the potential advantages and risks of a new ai research from different social perspectives. • require broad impact statements: the neurips conference requires that submitted papers include a statement of broader impact with respect to the research presented. this incentivizes researchers to think about potential risks and benefits by making reflection a requirement for one's work to be considered at neurips. similar measures at all conferences and publications would encourage researchers to critically assess their research in terms of its effects, positive and negative, on the world • require the publication of expected results: requiring that researchers write and publish the expected results of their research project (including but not limited to its broader social and ethical impacts) could help foster reflection around potential benefits and harms even before researchers undertake their project. • revamp the peer-review process: the well-established practice of peer review is a great opportunity for exchanges on the risks and benefits each reviewer sees in the paper they are revising. if a question or requirement were added to this effect when papers were reviewed, it may have a rapid and widespread impact in inciting researchers to consider what may follow from their research. an effective review process should promote limiting risks while also being clear, fair, and efficient. one way of doing this is to intensify the requirements for publication proportionally to how risky the research is deemed by peers reviewing the paper. the history of science and technology shows that seemingly innocuous developments in scientific theories and research have enabled real-world applications with significant negative consequences for humanity; from the eugenics movement in the late 19th and early 20th centuries to the cataclysmic nuclear destruction in japan in 1945 . this history reveals that the 1 2 real-world impacts of scientific research cannot be separated from the research itself, and it's important to look at the social, cultural, political, and economic realities that shape the way science is used and the norms that regulate it. it's also important to consider the impacts these developments may have on people across the world. often, researchers do not consult with or consider individuals that may be negatively affected by scientific developments, reflecting existing power imbalances in which a small group of privileged individuals make decisions or take risks that impact millions, if not billions, of lives. we need to be aware of these power imbalances and how they're rooted in existing inequalities-this is especially true in the field of artificial intelligence (ai). the pace and scale of impact from ai far exceed other technologies. thus, critical examination is necessary, especially as this technology becomes increasingly deployed throughout society. the aforementioned power imbalances and inequalities in scientific research are apparent in the general disconnect between the research priorities of funders (e.g. grant-making bodies, companies, governments, etc.) and the broader societal interest. the academic paradigm of " publish or perish" and the undue pressure it creates, overshadows more fundamental 3 questions that need to be asked. the most important of which is, "why is this research project being pursued in the first place?" this lack of critical reflection and external pressure has given rise to predatory journals with lax quality standards regarding what gets accepted for publication-this is especially an issue for researchers who are new to an academic field and are uncertain about publishing norms. for example, research in phrenology continues to be accepted in highly revered journals despite decades of precedent demonstrating that 4 phrenology is pseudoscience. the egregious inclusion of this type of research resulted in severe backlash from scholars that led to a retraction and apology from the journal. this example highlights how fallacious research can slip through the cracks, especially without critical reflection. in order to ensure that the science and technology of ai are developed in a humane manner, we must develop research publication norms that are informed by our growing understanding of ai's potential threats and use cases. unfortunately, there haven't been many efforts to create a set of publication norms for responsible ai because the field of ai is currently fragmented in terms of how this technology is researched, developed, funded, etc. thus, the norms around ai publications and ethical standards are not only fragmented, but also contradictory in many cases. a standardized approach to publication norms in ai across a large number of jurisdictions is essential. many subfields in ai are experiencing a boom in interest, with growing demands to produce novel research. thus, there is an elevated risk of a lack of awareness on what adequate and rigorous publishing norms are. additionally, there is a high degree of susceptibility to predatory journals that lure budding researchers through a "pay-to-play" model. 5 this amplifies the potential impacts of harmful research that must be critically reviewed before published for public consumption. most scientific and academic journals have particular guidelines for submissions, which are a form of publication norms. however, problematic research can still be published. for example, researchers exerted external pressure on springer to withdraw the publication of a paper in 6 which the researchers claimed to "predict criminality" using neural networks for facial recognition. this demonstrates that the publication ecosystem requires norms with multiple filters. as well as editorial boards that have sufficient demographic diversity and a range of expertise to be able to flag problematic research and prevent its publication, especially in cases where there is potential to render harm on marginalized peoples. however, the prevalent practice in peer-reviewed journals is to evaluate a work purely on its scientific merit, which overlooks the inherent interaction between fundamental research and the social context in which it's conducted. publication norms have a strong role to play in ensuring interdisciplinarity in review processes so that too narrow a focus does not allow potentially harmful work to pass as seemingly innocuous. beyond the social implications of research, it's also important to consider the technical implications. for example, in cryptography, it's important to find vulnerabilities in a system to improve robustness. cryptographers do this by looking at a system from an adversarial perspective, as well as by sharing their systems openly so they can be evaluated for undue risks by as many people as possible. for example, through this process decades ago, unnecessary risks arose from the use of substitution boxes (s-box) in data encryption standard 7 (des), which led to the subsequent discovery of differential cryptanalysis. this is also important type of vulnerability was seen in the jboss middleware, which shipped quietly with dozens of consumer grade softwares but often with an unpatched, or even unpatchable, version. 15 similarly, software which incorporates ai that relies on an unpatchable library will be vulnerable. to expose such vulnerabilities, as well as better understand the social implications of ai research, journal editors must be better equipped to identify all actors who may engage with ai research and make well-informed decisions around whether research should be published, and how. we believe developing a standardized approach to publication norms in ai across a large number of jurisdictions is the first step towards ensuring that the science and technology of ai are developed in a humane manner. the use of extrinsic measurements like benchmarks, or third-party expert panels could be a crucial step to navigating publication decisions in a fair way. such methods could set a certain standard in terms of the acceptable level of risk associated with a publication. in line with this suggestion, it would also be pertinent to keep a record of the papers that were rejected due to their inherent risk, as well as relevant metrics. for example, what subfield of ai was the paper part of? what institution or corporation was the authors affiliated with (if any)? demographic and identity metrics may also be pertinent to help ensure the review process is not discriminatory. to this end, mechanisms like retraction watch that are invested in by the scientific community and held to the highest academic standards will be a cornerstone to strategies combating spurious 16 research. awareness of such mechanisms and their integration into tools like google scholar, akin to covid-19 research warnings for non-peer-reviewed articles, is essential. it may be beneficial to extend the page limit for published papers to allow researchers to include negative results (results that are insignificant or disprove researchers' hypotheses), which aren't traditionally printed. there is a bias towards publishing papers with positive results. that is, results that confirm or partially confirm one's hypothesis. in addition to expanding the number 17 of pages, there should also be a significant change in the culture surrounding the publication of negative results. while a higher maximum of pages may help, it should be accompanied by other measures to encourage researchers to share their negative results and push the broader scientific community to consider negative results in their analysis. publishers could require the inclusion of all negative results that led the researchers to the positive results published and/or submitted. these could also be indexed through a standardized mechanism for retrieval by engines like google scholar so that downstream researchers are aware of what areas have already been explored. improving citations and value of such negative results work will also incentivize the ecosystem to invest in making negative results more public and elevate the quality of scientific publishing in the space. developing a network of peers to evaluate researchers' ai models in terms of potential risks and benefits may be an important tool towards better and safer publication norms. if such a mechanism were put in place, the evaluation could be fully or partly based on philosopher john rawls's "veil of ignorance," which asks individuals to create a new society and choose its governing principles without knowing their individual characteristics (e.g. gender, race, social class, etc.). the idea is that they'll choose principles that will benefit everyone in society since they're "ignorant" of their personal circumstances and social standing. if this idea was applied to reviewing ai research, peer reviewers could be asked to consider the potential advantages and risks of a new ai research from different social perspectives. specific details about fictional but realistic situations and personas may be used to help reviewers think more accurately and relevantly about privileges and disadvantages they might not have themselves. of course, this shouldn't replace important efforts to make the field of ai more diverse and inclusive-but the exercise of imagining how another person may be affected, positively or negatively, by an ai model is relevant for everyone. this practice has precedent in design thinking approaches and 19 has shown to create products and services that are ultimately more empathetic to the needs of the communities that they are meant to serve and encourage the construction of more inclusive work. an important method to incite researchers to reflect on the impacts of their work is to give them incentives to do so. for example, the neurips conference recently added a requirement for papers that are submitted: they must include a statement of broader impact with respect to the research presented. this incentivizes researchers to think about potential risks and benefits by 20 making reflection a requirement for one's work to be considered at neurips, one of the most prestigious conferences in the field of ai. therefore, similar measures at all conferences and publications may be a good way of encouraging researchers to critically assess their research in terms of its effects, positive and negative, on the world. iclr has followed suit and has included a code of ethics for their 2021 edition which is an important step in the proliferation of these 21 standards becoming mainstream, not just something that one gives a brief nod to. it's important to note that how the research community adopts the formulation of broader impact statements is of fundamental importance. if broader impact statements become yet another "ethics stamp" on poorly conceived research, then the entire endeavour becomes counterproductive. researchers need to critically evaluate the broader impacts of their research before starting a project and use these insights to guide a conscientious research methodology and not construct these perspectives after the fact. the point of writing a broader impact statement must be to introspect the ethics of one's work and not as a mechanism to avoid desk rejection. one way of doing so is to popularize the importance of these norms in the early stages of a researcher's journey into the publishing world. during the formative years in the field, early-career researchers might be naturally drawn to emulating the behaviour of the more experienced researchers in their labs and workplaces. an educational push for holding research ethics, norms, and standards as the paramount element of doing research and development in a consequential field like ai needs to be strongly encouraged. principal investigators (pis) and other senior researchers in both academic and industry labs should shepherd those who are still growing accustomed to the modes of operation of research in the domain. the widespread presence of such a requirement could also incite greater awareness among technical researchers in the field of ai regarding fields and areas like ethics, psychology, anthropology, sociology, and critical race theory. furthermore, making impact statements and other educational pushes necessary could spark interdisciplinary collaborations between researchers. requiring that researchers write and publish the expected results of their research project (including but not limited to its broader social and ethical impacts) could help foster reflection around potential benefits and harms even before researchers undertake their project. for example, a list of journalists who would be interested in hearing about the benefits of the author's thesis on the rest of society could be created, incentivizing the consideration of their project benefits (scientists will want their papers to be promoted in newspaper articles). this would not only encourage researchers to reflect on the impacts of their work, but perhaps guide them towards generally less risky and more beneficial research. this could be similar to how many psychologists now publish a preliminary report on how they will conduct their research, the variables they will be measuring, and their hypothesis, before they perform an experiment. this prevents data manipulation in attempts to find statistically significant results. in the 22 language of software engineering, it could create something akin to test-driven development (tdd) whereby the researchers can preemptively highlight what it is that they are aiming to achieve with their research and view negative results in a positive light as a way of showing ways that don't lead to results that were stated as the goals of the research nonetheless led to an understanding of some aspects of the field helping to improve the knowledge base for future researchers in the domain. of course, having much greater diversity of researchers in the field of ai-in terms of race, gender identity, sexual orientation, geography, language, lived experiences, and socioeconomic status-could also make a significant difference in how and how much researchers think about the impacts of their work. it seems reasonable that, in at least some cases (if not many), the potential benefits and pitfalls of researchers' work may be more pronounced for a certain demographic, and people who are part of that demographic are more likely to be attuned to how it may impact them. thus, having more diverse actors in the field of ai could help foster more comprehensive reflection on the potential impacts of a research project. additionally, a framing whereby the researchers take on the onus to surface these impacts rather than placing the burden on the people who might be impacted (often they might not have adequate knowledge, resources, or abilities) to defend themselves creates a more pro-social way forward for conducting research. the well-established practice of peer review is a great opportunity for exchanges on the risks and benefits each reviewer sees in the paper they are revising. if a question or requirement were added to this effect when papers were reviewed, it may have a rapid and widespread impact in inciting researchers to consider what may follow from their research. this could be done in a way that is similar to how the world health organization (who) highlights dual use research of concern (durc): research in the realm of the life sciences "that is intended for benefit, but which might easily be misapplied to do harm." to have a similar category for ai 23 research would be pertinent, and developing guidelines for this kind of research seems crucial, both to define it and to control it, especially given that ai squarely falls under the category of a dual-use and general-purpose technology. such guidelines might include needing special authorization to conduct this type of research, or it may be required that the research be reviewed more extensively before being published. further, it's obvious that an effective review process should promote limiting risks while also being clear, fair, and efficient. one way of doing this is to intensify the requirements for publication proportionally to how risky the research is deemed by peers reviewing the paper. one way to go about this could be to identify a list of specific risks that any ai model proposed in a research paper could have. these risks may have numerical weights assigned to them depending on how dangerous their consequences may become. each peer reviewer could identify the risks they deem relevant to the ai model they are examining, and assign a score between 0 and 5 to each risk in accordance with how likely it is that the risk will materialize. the risks' weights could then be multiplied by their corresponding likelihood score. each of these quotients can be compiled into a sum. the sums obtained by each reviewer for one paper can then be added up and made into an average. if this 'total risk average' is higher than a pre-established number, the paper could then be immediately rejected, require further reviewing and discussion by a third-party group of experts, or be published under much stricter requirements than other papers that are below the 'total risk average' threshold. such a threat modelling approach is already used extensively in the field of cybersecurity to prioritize risks and vulnerabilities to guide the efforts of researchers and practitioners in working to address them . 24 this process, or one with a similar structure, has the advantage of remaining somewhat efficient by not requiring that papers that are considered non-risky be subjected to more time-consuming reviewing or more stringent requirements unnecessarily. of course, a procedure like the one presented above risks potentially wrongly identifying a model as low risk, whereas a model that held all papers to higher standard regarding risk avoids this. however, it's unlikely that applying more stringent standards to all papers is necessary, efficient, or realistic considering the sheer volume of papers published. a more targeted approach seems better suited to the reality of publishing in the domain of ai. a consideration that publishers can adopt is to think about the rate of false positives and track them over the period of reviews and adjust as they go along to judge the efficacy of this mechanism. to the risk of this becoming repetitive, the cornerstone of an effective review process, as previously mentioned, will be a diverse body of reviewers from the point of view of race, gender, disability, socioeconomic status, geography, and more. risk assessment is unlikely to be fair and comprehensive if all reviewers have similar backgrounds and experiences. this will result in direct harm to those not represented among reviewers, which are often individuals who are already marginalized and most at risk. this is something that needs to be created proactively and will not necessarily emerge organically since reviewers are often sourced from a tightly knit network of people one is already familiar with; breaking free from that requires constant and conscious effort. one important area where there may be some pitfalls is innovation. if publishing norms are more stringent, then cutting-edge research may be ignored or underfunded. in some cases this may be because the potential risks outweigh the benefits. however, in other cases it may be the result of a lack of awareness from the researcher's part on what those publication norms are. this could have a particularly negative impact on emerging scholars in ai from regions and countries where ai research and development is in nascent stages, especially those which have a less than proportionate representation in the scientific publications at major conferences and journals (which are mostly concentrated in the western hemisphere). this could harm 25 scientific diversity in the field. one can undoubtedly see this as a missed opportunity, but it's better framed as an opportunity for better work and innovation. what if we could use this as an opportunity to build ai that did more good than harm? by erring on the side of caution, we may encourage researchers to better understand the consequences of developing and deploying a certain system or application. understanding the tail risks of innovation is critical. the insights from fields such as cryptography are that the risks are enormous from poor research, and given the nature of ai systems, a similar level of risk is to be expected. in light of this understanding of asymmetric returns, we need to raise our standards of what constitutes "innovation," and who gets to decide if a new technological application constitutes positive innovation; bringing more good than harm. from this perspective, constraining innovation is not a pitfall of changing publishing norms. instead, changing publishing norms may foster higher quality, more inclusive and positive innovation. it can be viewed as a mechanism to bend the field of research towards a prosocial direction, something that governments use frequently in the form of regulations to guide how innovation happens in the market. in a similar vein, like many other scientific disciplines, machine learning and artificial intelligence have been affected by their own reproducibility crisis, where a worrying number of algorithmic research results cannot be reproduced when other data scientists run the same experiments. 26 this is of particular concern in fields such as digital biomedicine, where faulty models for disease diagnosis and monitoring can place human lives at great risk. one key component of the problem is the absence of information about the training and evaluation code, the number of training runs required, and datasets used. another part of the issue is the environment in 27 which data scientists operate, where there is a pressure to publish quickly, a reluctance to report failed replications and a lack of computational and human resources to test every condition and fine-tune each hyperparameter. better publication norms will not only encourage 28 more rigour in scientific methodology, but also limit the number of cases where research is modelled on "false starts." the danger of this can ensure that future innovation in the field is based on a set of verifiable and veritable discoveries. in an inherently stochastic domain like ai, the degree of variability that can occur in experiments where one might possibly find an experimental run through sheer luck to get the results that showcase a correlation that they want is all the more reason for advocating for higher rigour; a focus on causation over correlation is going to be essential in addition to the points mentioned above. 29 with more stringent norms on what gets published in the field of ai, there is a possibility that research deemed too risky will be driven underground. meaning, researchers whose work is 26 rejected may publicize their research in other ways, circumventing the measures put in place. due to the stricter publishing norms, the rejected research may become even more dangerous as it's excluded from mainstream critique and necessary scrutiny. put simply, stringent publishing norms may actually increase the likelihood of harmful ai by creating a "black market" for research that has subversive aims. of course, there are counterarguments against this scenario. first, the field of ai/ml is heavily dominated by individuals who are affiliated with universities and companies. in both cases, getting research published by a reputable journal or presented at a recognized conference is key to advancing their career. simply putting out research without it being published or affiliated with their institution (whether academic or corporate) because it is too risky according to publishing norms is of limited use. hence it seems unlikely that someone with the knowledge and qualifications necessary to build innovative yet risky ai would have an incentive to share it using an alternative method. there may be a greater incentive for scientists to conduct research that is more likely to be published in accordance with the new, more stringent standards. it is highly unlikely that the risks for underground research are big enough to warrant not moving towards more stringent publishing standards in terms of security and risk in the field of ai. it's also important to note that the field's current exclusivity to those with affiliations to large and wealthy institutions is not in itself positive. we believe the field of ai should be more accessible than it currently is in that regard. 30 paradoxically, there are questions as to whether it's actually more dangerous if risky ai research goes "underground" than if it's publicized and sanctioned by highly regarded institutions and publications. if an ai research submission is rejected by a publication, then it's likely that it'll receive minimal attention. however, if risky ai research were to be published by these journals and publications then it's likely it may do significant harm because people (especially academics and fellow researchers) tend to refer to these sources for the latest relevant information about progress in the field; under the assumption that the information published has been peer-reviewed. it's this same research that often gets widespread media coverage as well. this follows from the principle of using "strategic silence" as a way of limiting the oxygen that is provided to mis-, dis-, and mal-information by not offering it a platform by way of discussion, time, and resources. furthermore, general audiences are less likely to scrutinize research sanctioned by a journal or an institution. in other words, when risky papers are published, we may not be able to count on public scrutiny to highlight its dangerous possibilities. there have been numerous instances of popular media coverage for dubious research stemming from low-quality journals, preprint servers, and other places that had a significant impact on the public's perception of ai. as an example, research that claimed to create a "gaydar" identifying a person's sexual orientation was thoroughly debunked by leading researchers in the field of ai, but the harmful and 32 offensive work still received significant media attention. we posit that this might be because 3334 of the highly technical nature of the field (not that this isn't the case in other domains, but there is a disproportionate attention paid to the advances in this field while the ability of the general public to parse the advances for what they truly are might not be sufficient) which leads to an overestimation in the capabilities of the systems. the fact that such research was published-and thus, endorsed by the publication or institution behind it-created a false sense of security and legitimacy for many people. papers that are published are usually revised and reviewed, and this process, along with the metaphorical seal of approval from the publication/institution, can obfuscate the overly risky nature of the results being published. it essentially shields the paper from any scrutiny because, at first glance, the paper has all the characteristics of an acceptable or even outstanding paper. thus, getting widespread public scrutiny, especially from individuals outside the ai community, is likely to be quite difficult as nothing seems particularly questionable. with this in mind, there is a responsibility on the part of the journal's editorial board to have experts outside of the field review papers in order to identify errors or risks with the research. homogenous editorial boards (i.e. dominant avatars of society), don't have the required perspective to ask essential, critical questions like that of a diverse board. in this sense, a diverse board will be able to provide additional points of failure for controversial scrutiny, before even requiring any public intervention. hence, stricter publication norms that include such a board would be desirable. in addition, one of the mechanisms trialled with neurips and icml over the last few months is the concept of ml retrospectives (co-organized by abhishek 35 gupta, one of the authors of this document) where researchers are asked to reflect on their prior work and identify shortcomings, improvements, changes, and any other comments that they have on those papers to highlight the need to revise understandings of discoveries over time as new evidence and knowledge comes to light. normalizing the "owning" of faults in prior publications can move accountability back to authors, no matter their prestige, leading to a healthier intellectual ecosystem. research progress may be slowed to allow for more thorough risk evaluation. this may affect the quick rate at which ai papers are currently published. nevertheless, pausing the influx of information on ai can provide more time to dissect, digest, and process research. furthermore, a stricter process to pass, and one that takes time, could discourage researchers against cutting corners, which could lead to having their paper rejected and making the process unnecessarily long. this can then help guard against unnecessary research being proposed. one of the trends of taking rejected submissions from one conference or journal and making quick, minor tweaks and pushing it out to the next conference is a particularly problematic scenario which encourages the behaviour whereby researchers attempt a "keep trying to till you win" mindset that has the potential to lower the quality of overall scholarship in the field. making explicit perhaps where this idea was submitted before and reasons for rejections, how those shortcomings were addressed can serve two purposes: improve allocation of scarce reviewing resources in the field and push higher standards of transparency in the field. cross-linking submissions on a platform like openreview (acknowledging though that there are many caveats on the platform) can help us move in that direction. some publishers may feel as if they have lost an element of control over what they publish if more stringent norms are put into place. they may also perceive these new norms as constricting what they traditionally viewed as "worthy" of scientific regard. whether true or not, many publications perceive themselves as being apolitical; taking an explicitly agnostic stance towards scientific developments. therefore, norms that have an arguably social and/or political bent could present a fundamental challenge and potentially give rise to an increase in the bifurcation of journals split on social, political, or other lines. there are a host of concerns that must be accounted for in the case that an external body-such as a journal, a norm-enforcement committee, an ethics board, etc.-oversees the release of research findings; one being the importance of equal opportunity and diverse representation in the technological sphere. this standard not only ensures that the domain of technological research remains democratic, but also prevents it from becoming an echo chamber or a site of informational homogeneity. in order to frame best publication practices for high-stake ai-related research, we must ensure that this set of practices is predicated upon a firm anti-oppression mandate, whether this oppression is related to socioeconomic status, race, gender, ethnicity, mental/physical disability, or any other characteristic that incites unjust discrimination. responsible publication norms, by their very nature, must not only strive to mitigate harms related to the exposure of certain research findings, but also to inhibit the epistemic threat of information suppression under the guise of best practices. in order for a novel set of publication practices to be truly responsible in nature, it must be acknowledged that while a regulatory framework for ai research has the potential to reduce threats to public safety, it may also inadvertently serve as a site of gatekeeping, suppression and other forms of exclusionary practice. such a framework therefore risks consolidating epistemic injustice within the academic, technological and political spheres of influence, the prevention of which will require a defined set of safeguarding measures. injustice can be mitigated through the use of radical transparency where the publisher maintains an open list of papers that were rejected and the reasons for rejection in a public repository that is subject to public scrutiny and analysis preventing biases against any groups. to ensure that reactive measures for harm mitigation (i.e. flagging papers post-publication) are not discriminatory in nature or grounded in any form of identity-based prejudice, a more robust set of flagging requirements must be established. in addition to allowing the user to select a general reason for flagging certain content, the process could be made less enticing and/or gameable to those with unfounded reasoning and discriminatory motives by requiring a more exhaustive and substantiated explanation as to why the content should be removed. to this end, making the process involved enough to prevent trolling behaviour can be one proposed approach. in the case of suspected discriminatory practice throughout the publication process, there ought to be an appeal protocol in place whereby subjects of discrimination can formalize a complaint against the relevant publication or platform and negotiate reconsideration of their research by a designated secondary screening committee. such a protocol may include an instrument of a similar nature to that of the checklist or dread-like (damage, reproducibility, exploitability, affected users, discoverability) scoring principles . rather than measuring security threats, this 36 instrument could assess and systematize the long-term personal impacts of discriminatory publication practices whether they be social, professional, or economic in nature. within a novel regulatory framework for responsible release norms, this impact checklist could be appealed to and taken up with a third party entity in instances of publication prejudice; this entity having authority over the reconsideration of initially rejected research, along with the pursuit of certain disciplinary measures if necessary. such an organizational framework could serve to encourage publisher accountability, caution against future discriminatory practices, and ultimately preserve epistemic justice in the domain of ai research. more staged or closed publication practices pose a threat to democratized exposure under the guise of responsible release norms, which may result in the omission of crucial information or gatekeeping. for instance, if research unveils potential risk of a given ai/ml model and there exists a conflict of interest between the publication platform and stakeholders invested in the model, the pretence of "alternative release strategies" could serve as something of a loophole for these stakeholders to suppress certain information and preserve their interests (whether financial, social, etc.) without being held liable for censorship. the malicious application of release norms not only entails self-interested nondisclosure, but also the suppression of projects carried out by actors who occupy marginalized identities, which could theoretically be falsely attributed to the overstated "harms" that their findings may yield, should they be disclosed publicly. such scenarios lend themselves to the risk of epistemic discrimination against marginalized groups. they can also have a chilling effect on the field of research and promote underground attempts at recreating the systems without proper controls in place because of this obfuscation of the real impacts of the system, thus potentially leading to more harm. it's clear that additional restrictions and/or guidelines in the field of ai are required because there are risks that need to be addressed without exception. unfortunately, however, there is no consensus on this in the field. therefore, more individual researchers, institutions, governments, etc. need to clearly and publicly communicate the potential societal impacts of ai research in order to convey the need for third party regulation. in addition, more researchers and institutions supporting and replicating efforts like the neurips impact statement requirement would make such considerations more standardized across the field. 37 forming alliances, making connections, and building relationships are the hallmarks of effective community collaboration. one way this can be enacted is through connecting with a publication standard-setting body, whereby concerned researchers and institutions would be able to lobby for greater action on the topic and witness first-hand how the publication norms are created. for example, a potential partnership with cope could prove fruitful. cope is an organization 38 committed to educating and supporting editors, publishers and those involved in publication ethics with the aim of moving the culture of publishing towards one where ethical practices become a normal part of the publishing culture. so far, it seems they haven't done any work related to the field of ai, but perhaps they would be interested in expanding their work to account for new ethical issues arising in the technology and computer science space. on a larger scale, a solid foundation for this collaboration within the community is the potential for an institution or process that is recognized worldwide and respected in terms of trust around technology. maiei's work on secure and green lighting ml are potential options. these 39 40 initiatives could provide a standardized comparative measure to evaluate the trust in ai systems across the broad range of topics and themes contained within the community, providing a much-needed lingua franca . as previously mentioned with cope, the field of ai must work towards a new publication culture that prioritizes ethical practices and de-prioritizes progress for the sake of progress. to create safe and responsible ai, the core values and culture of the field must be informed by ethical practices, principles, and guidelines. additionally, it may be important to place a greater emphasis on the application of the technology after it has been deployed, rather than simply the publishing of the information itself. for example, canada has developed national ai standards, which regulate the application of the technology rather than the published content about said technology. this isn't to say that ai publication norms shouldn't be created and followed, but 41 physiognomy's new clothes gaydar" study and the real dangers of big data the invention of ai 'gaydar' could be the start of something much worse . the verge that they should be done in parallel with other efforts necessary to ensure that the science and technology of ai are developed in a more humane manner committee on publication ethics (cope) secure: a social and environmental certificate for ai systems green lighting ml: confidentiality, integrity, and availability of machine learning systems in deployment canada's cio strategy council publishes national ai standards key: cord-271698-n9qd14oe authors: dy, louie florendo; rabajante, jomar fajardo title: a covid-19 infection risk model for frontline health care workers date: 2020-08-08 journal: netw model anal health inform bioinform doi: 10.1007/s13721-020-00258-3 sha: doc_id: 271698 cord_uid: n9qd14oe the number of confirmed covid-19 cases admitted in hospitals is continuously increasing in the philippines. frontline health care workers are faced with imminent risks of getting infected. in this study, we formulate a theoretical model to calculate the risk of being infected in health care facilities considering the following factors: the average number of encounters with a suspected covid-19 patient per hour; interaction time for each encounter; work shift duration or exposure time; crowd density, which may depend on the amount of space available in a given location; and availability and effectiveness of protective gears and facilities provided for the frontline health care workers. based on the simulation results, a set of risk assessment criteria is proposed to classify risks as ‘low’, ‘moderate’, or ‘high’. we recommend the following: (1) decrease the rate of patient encounter per frontline health care worker, e.g., maximum of three encounters per hour in a 12-h work shift duration; (2) decrease the interaction time between the frontline health care worker and the patients, e.g., less than 40 min for the whole day; (3) increase the clean and safe space for social distancing, e.g., maximum of 10% crowd density, and if possible, implement compartmentalization of patients; and/or (4) provide effective protective gears and facilities, e.g., 95% effective, that the frontline health care workers can use during their shift. moreover, the formulated model can be used for other similar scenarios, such as identifying infection risk in public transportation, school classroom settings, offices, and mass gatherings. as of march 20, 2020, coronavirus disease (covid-19) has infected 250,704 worldwide, resulting in 10,256 deaths, with italy surpassing china in the reported number of deaths on the same day (novel coronavirus 2020; italy coronavirus death toll overtakes china 2020). aggressive suppression strategies have been recommended (ferguson et al. 2020) , and countries across the world have implemented strategies to mitigate the damage caused by this pandemic (anderson et al. 2020) . health care workers work in the frontlines across the world unceasingly, running the greatest risk of getting infected and infecting others in their immediate environment-in the hospital, at home-or wherever they go. in the philippine context, health care system can be described as two tiered (dayrit et al. 2018 ). there is a huge disparity in the capacity between the public and private health sectors (dayrit et al. 2018) . as of 2016, there are a total of 101,688 hospital beds, with a ratio of 23 beds for 10,000 people in the national capital region, and more than half (53.4%) of these are in private hospitals (dayrit et al. 2018 ). the number of confirmed covid-19 cases admitted in hospitals is continuously increasing exponentially (panela 2020) . therefore, given that the health system is likely to be overwhelmed (dayrit et al. 2018; baticulon 2020) , these frontline health care workers (frontliners) are faced with unimaginable risks of getting infected. every doctor, nurse, medical technologist, radiation technologist, nursing assistant, hospital janitor and security guard will inevitably face the risk of covid-19 infection. here, we formulate a mathematical model to investigate how many frontliners are expected to be infected under certain scenarios (rabajante 2020) . we use this expected number of possible new infections as a measure of the risk. a set of risk assessment criteria has been formulated based on the theoretical results to determine if a frontliner has low, moderate or high risk of covid-19 infection. mathematical models can be used for predicting scenarios and in prescribing solutions to problems (rabajante 2020; choudhury et al. 2018; ferrett et al. 2020; cortez 2017) , such as addressing the covid-19 pandemic. based on the simulations and risk assessment, several recommendations are suggested to inhibit the spread of sars-cov-2, especially in health care facilities. tion to reduce exposure to aerosolized particles (e.g., for those tasked to do intubation either via direct or via video laryngoscopy, to do nasopharyngeal or oropharyngeal swabs). in the following discussion, the parameters will be discussed in terms of the frontliner setting, but the parameters can likewise be applied in other settings, such as in crowded places, classrooms, offices, public vehicles, and markets. the average number of encounters per hour can be defined as the average number of patients a frontliner has interacted in an hour given that an interaction is less than or equal to 30 s. we can convert number of patients per minute to number of encounters using the following formula: for example, a 10-15-min interview with a patient is equivalent to 20-30 encounters. a doctor doing brief rounds on 10 patients (where each patient is looked upon in at most 30 s) or the situation of having 5 patients per minute are equivalent to 10 encounters. according to our simulation results, the expected number of infected frontliners increases as the average number of encounters between the frontliner and covid-19 patients increases as well as when work shift duration or exposure time increases (fig. 1a, b) . if there is highly interacting population (e.g., the average number of encounters per hour is 120, which means that the frontliners and the patients are interacting every 30 s) or a series of long interactions (e.g., 4 patient interviews per hour where each interview takes 15 min), then there is a high chance that one person will be infected. if there is low interaction rate (e.g., seeing one patient only for less than or equal to 30 s once per hour), then the chance of getting infected is low but the risk is not zero. it should be noted that if the number of possible infected frontliners is greater than or equal to one, then there is high risk of infection; if the number of possible infected frontliners is less than one but not equal to zero, then there is still some level of risk (low or moderate risk of infection). in a 7-h work shift duration, there is high chance a frontliner will be infected if the interaction rate is around 12 encounters per hour (fig. 1b) . this can be imagined as a triage nurse seeing 1 patient for at most 30 s every 5 min during the duration of his or her 7-h work shift. average number of patients encountered per hour × average duration of interaction in minutes 0.5 minutes . the formulated risk model (see "appendix: methods") aims to examine the risk factors of virus transmission per day, quantify these risks, estimate the number of new infections, and suggest ways to minimize these risks. there are several factors that determine the risk of infection: • average number of covid-19 patients (or, in other settings, number of susceptible persons) entering a given location at a given time, whether they are confirmed to be positive or not; • average number of encounters with a patient (or, in other settings, any susceptible person) at a given time, whether covid-19 infected or not, where an encounter is defined to be less than or equal to 30 s; • duration of interaction of each of these encounters; • work shift duration of each frontliner (or, in other settings, can be equivalent to the exposure time for any person in public transportation, offices, classrooms, and mass gatherings); • crowd density, which may depend on the amount of space available in a given location, the presence of compartments or dividers in a room, and how frequent cleaning is done in the environment as the density of sars-cov-2 virus particles present on surfaces limits the safe space available; and • level of protection present (e.g., isolation booths, n95 masks, face and eye shields) including level of protecthe number of newly infected frontliners is directly proportional to the average number of encounters per hour ( table 1) . regardless of work shift duration, a hospital security guard or a triage nurse entertaining 120 persons per hour (1 patient every 30 s) is at least 12 times more likely to get infected than a medical or radiation technologist encountering 10 patients per hour. a doctor conducting long-duration interviews and examinations on patients (20-80 persons per hour) is 2-8 times more likely to get infected than, for example, a radiation technologist. regardless of the type of frontliner, a work shift duration of at least 10 h is at least 1.25 times more likely to be infected than that of 8 h. the longer the work shift duration or exposure time, the higher the infection risk (table 2 ). we define crowd density as the number of people in a room divided by the maximum capacity of the room. we can also define it as the average proportion of covid-19-infected entities present within a 2-m radius (minimum radius for social distancing) from the health care worker. the entity may be an infected patient (confirmed or not confirmed), or any object or surface in the immediate environment that contains sars-cov-2 virus particles. there is evidence that the virus particles stay as long as 3 h as aerosols and 72 h on plastic surfaces (van doremalen et al. 2020) . looking at the following figure (fig. 2) , crowd density acts as a fraction that modifies the risk of getting infected at all levels of encounter rates, from the laboratory (low encounter rate per hour) to the triage area (high encounter rate per hour). a crowded place where social distancing is not highly implemented can initiate transmission of the disease. having more space available for each patient, putting dividers between infected patients, and cleaning the workspaces more often lead to a lower crowd density. a lower crowd density implies that the frontliner is receiving a lesser fraction of the risk of infection. a higher crowd density increases the chance of being infected. the effect of crowd density is so important that, even if ten covid-19-infected patients enter the same room at the same time, the risk of the frontliner getting infected can be dramatically reduced by reducing the crowd density (fig. 3) . for example, a health care worker in a room with crowd density of 10% is at least 95% less likely to be infected than a health care worker in a room with crowd density of 100%. moreover, as expected, the number of newly infected patients in a room is directly proportional to the infection risk faced by the frontliners (fig. 3 ). protection level is defined as the fraction of the risk being removed or mitigated by measures done by the health care worker or any other person. it has a minimum value of 0 and a maximum value of 1. it can be observed in fig. 4 that a 95% or better protection level significantly reduces infection risk. we can assign values which may be additive as shown in table 3 . regardless of the number of covid-19 patients entering a given location at the same time, regardless of the average number of encounters per hour, and regardless of the work shift duration or exposure time, the protection level removes a substantial fraction of the risk faced by the health care worker (fig. 4) . in general, having ppes confers protection towards the health care worker, but certain procedures, especially doing an endotracheal intubation for critically ill covid-19 patients, exposes the health care worker to aerosolized particles. however, the number of covid-19 patients entering at the same time at a given place influences the level of protection needed (fig. 5) . for even an hour of exposure, when ten covid-19 patients enter at the same time in the same place, the risk of getting infected with 70% level of protection is the same as the risk of getting infected when there is no ppe worn in a room with at most three covid-19 patients. from the previous tables and figures, we, therefore, propose an overall risk score to be used by each frontliner (tables 4, 5) . we define the overall risk score as a function of the expected number of new infected persons. if the overall risk score is less than 1.0, then there is a low risk that a person will become infected. an increase in the risk score is proportional to the increase in the number of persons expected to be infected. for example, an overall risk score of 2.00 implies that there are two expected new infected persons. the maximum overall risk score is 10 (where points encounter rate = 10 , points duration = 10 , crowd density = 1 , and protection level = 0 ). the proposed formula is defined as: analogous to the "low" and "high" risk assessments for health care providers of the united states centers for disease control and prevention (us cdc) (united states centers for disease control and prevention 2020), we likewise propose a categorization of "low risk" and "high risk". if the overall risk score is greater than or equal to 1.0, then there is a high risk of a person getting infected. we can also add an intermediate category between "low" and "high" risks. a "moderate" risk category may be defined as those overall risk scores between 0.5 and 1. by doing a monte carlo sensitivity analysis (5 million simulation runs), assuming each input has 10% error, the overall risk score has 0.45 standard error. to account for this uncertainty, overall risk scores between 0.5 and 1 can be classified under the qualitative category of moderate risk. the overall risk score can be used to compare practices. moreover, as the number of days the health care worker is doing his or her regular job related to a covid-19 task, the risk of infection increases. the number of days can be scaled accordingly as exposure time. from the simulations, we have proposed risk assessment criteria and several recommendations. through these, governments and organizations can have insights on how to minimize or eliminate the transmission of sars-cov-2, especially in health care facilities. it is important to protect our health care workers as they are considered essential part of the health care capacity that can provide optimal care to the patients. to test the utility of our model, the model has overall risk score = points encounter rate + points duration 2 × crowd density × (1 − protection level). been used in the job risk profiling calculator (https ://datas tudio .googl e.com/s/icaey mt7al g) that is used by private and public institutions in the philippines. all in all, based on the simulations, the following recommendations can be made: • decreasing the rate of patient encounters per frontliner, such as having multiple frontline triage nurses, multiple queues, multiple entrances, and proper referral systems, mitigates the risk of infection. crowd density factor should always be considered. having many covid-19 patients in a room can render a protective measure relatively inadequate. it is recommended to have a quota on the number of covid-19 patient encounters per duration of work shift. telemedicine or online consultations can also be an effective control in reducing high risk frontliner-patient interaction (shaikh 2015; burton et al. 2012 ). • shorter work shift duration or exposure time reduces the risk faced by the frontliners, especially the security guard and the triage nurse. the protection level against sars-cov-2 transmission must be increased accordingly if shortening of work shift duration is not feasible. • increased spacing, frequent cleaning of work spaces, and compartmentalizing the rooms of patients in open space decrease the risk of infection not only for health care workers but also for the other patients who are covid-19 negative or non-person-under-investigation (pui) (nishiura et al. 2020 the most infectious), must be given extra protection, and hospital policies must minimize their duration of exposure and the number of patients they encounter or interact with per shift. • health care workers play a very important role in a community's battle against the medical effects of covid-19. decreasing the infection risks faced by each health care worker per day, coupled with superior health, well-being and welfare practices, will result in a robust health care wearing a full body biohazard suit ≈ 1.00 absolute protection; either being totally absent from the job or out of shift, or being in full and functional ppe (n95 masks, face and eye shields, gloves, biohazard suit); strict compliance with hand hygiene; having effective engineering controls table 4 proposed risk assessment based on overall risk score overall risk score risk assessment 0 to less than 0.5 low risk 0.5 to less than 1.0 moderate risk greater than or equal to 1.0 high risk table 5 sample scenarios of frontline health care workers and their corresponding risk score high risk in this study, we formulated a mathematical model to calculate the risk of being infected in health care facilities. we considered the following factors: (1) the average number of encounters with a suspected covid-19 patient per hour; (2) interaction time for each encounter; (3) work shift duration or exposure time; (4) crowd density, which may depend on the amount of space available in a given location; and (5) availability and effectiveness of protective gears and facilities provided for the frontline health care workers. a set of risk assessment criteria has been proposed based on the theoretical results to determine if a frontliner is facing low, moderate or high risk of infection. based on the simulations and risk assessment, several recommendations are suggested, namely (1) decrease the rate of patient encounter per frontline health care worker, e.g., maximum of three encounters per hour in a 12-h work shift duration; (2) decrease the interaction time between the frontline health care worker and the patients, e.g., less than 40 min for the whole day; (3) increase the clean and safe space for social distancing, e.g., maximum of 10% crowd density, and if possible, implement compartmentalization of patients; and/or (4) provide effective protective gears and facilities, e.g., 95% effective, that the frontline health care workers can use during their shift. acknowledgement jfr is supported by the abdus salam international centre for theoretical physics associate scheme, trieste italy. conflict of interest the author declares that there are no conflicts of interest. the estimated values for the number of possible newly infected patients are generated using the runge-kutta 4 (rk4) method of integration to solve the system of differential equations. we use the software (berkeley madonna for mac ver.9.1.19). the differential equations are based on an s-e-i compartment model of disease transmission (see fig. 6 ). the model is described by the following system of differential equations: where s, e, i are the number of susceptible, exposed, and infected persons (in this case, frontliners); f is the force of infection; is the rate of an exposed individual becoming not infected (e.g., through handwashing or other protective measures); and 1 − is the rate of getting infected. the force of infection f is defined as: where is the effective transmission rate, and i 0 is the initial number of infected persons (or "the inoculum"), where the effective transmission rate is defined as: where is the transmission risk or probability, and p is the total contact rate. we cannot express p as i/n, which is the ratio of the total number of infected persons to the total population in a given area because it assumes that everyone is homogenously distributed in a given place. instead, we note that p is in terms of the fraction of the initial number of susceptibles ( s 0 ) over the maximum number of susceptibles that a given area can accommodate ( s max ), multiplied by the encounter ratio ( ), where is the average number of encounters per hour and is the threshold number of encounters per hour. suppose = n per hour. if < 1 then we are sure that the frontliner has not yet encountered everyone in the room; if = 1 then there is a possibility that the frontliner already encountered everyone in the room; if > 1 then we are sure that the frontliner encountered a person in the room more than once (by pigeonhole principle). the ratio s 0 s max can also be interpreted as the crowd density. the case where s 0 = s max and = characterizes the usual wellmixed s-e-i model. the parameter (e.g., = 0.2 (ferretti et al. 2020) ) is assumed to be a function of the covid-19 basic reproductive number (e.g., r 0 = 3) divided by the infectious period (e.g., = 14 ). we can also interpret > 1 as increasing the average nature of the reproductive number. therefore: which results in the following: the goal of the study is to investigate the risk of individuals during one cycle of day job. the simulations should end before 48 h since the dynamics may already change as the newly infected person also becomes infectious. the exposed (e) class here, in contrast to the classical seir model, does not represent persons at the latency stage of the disease. simply, e class here includes people who have been exposed with the virus (e.g., from respiratory droplets) but the persons can be unexposed through protections (e.g., through washing hands and wearing of face masks). incubation period is not included because the goal of the study is only for short duration (less than 48 h). the i compartment is only for counting how many new individuals have been infected, and is not intended to reflect feedback loop leading to a community outbreak. the paper is for risk assessment and not intended to simulate epidemics in the whole community. ; the assumed r0=3 and tau=14 can be changed. the choice of this in the numerical example is based on studies that the force of infection beta=r0/tau is around 0.2 (min of beta=0.05 for asymptomatics, and max of beta=r0/tau=3/6 or 2.5/5=0.5 for symptomatics). how will country-based mitigation measures influence the course of the covid-19 epidemic? opinion: the philippine healthcare system was never ready for a pandemic leveraging social networks for anytime-anyplace health information social-network analysis in healthcare: analysing the effect of weighted influence in physician networks from epigenetic landscape to phenotypic fitness landscape: evolutionary effect of pathogens on host traits the philippines health system review. world health organization. regional office for south-east asia impact of non-pharmaceutical interventions (npis) to reduce covid19 mortality and healthcare demand quantifying sars-cov-2 transmission suggests epidemic control with digital contact tracing italy coronavirus death toll overtakes china closed environments facilitate secondary transmission of coronavirus disease 2019 (covid-19) world health organization (who) metro manila coronavirus cases could peak mid-april if not contained, math model shows insights from early mathematical models of 2019-ncov acute respiratory disease (covid-19) dynamics the impact of soa on a system design for a telemedicine healthcare system interim operational considerations for public health management of healthcare workers exposed to or with suspected or confirmed covid-19: non-u.s. healthcare settings. united states centers for disease control and prevention aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 key: cord-287129-g2zdv5dc authors: sowerby, leigh j.; patel, zara m. title: reply to: correspondence – international registry of otolaryngologist – head and neck surgeons with covid‐19 date: 2020-08-22 journal: int forum allergy rhinol doi: 10.1002/alr.22689 sha: doc_id: 287129 cord_uid: g2zdv5dc nan 19". 1 we completely agree with all the limitations raised, as we had already raised them in the discussion of our own paper. what we apparently disagree on is the idea that accumulating knowledge from verified cases with contact tracing is somehow detrimental to our knowledge base and specialty. there has been an increasing fear surfacing across all scientific journals that data coming out of studies that are less robust than a randomized clinical trial is dangerous to our global scientific endeavor. this article is protected by copyright. all rights reserved. as dr. turner points out, the risk our specialty faces can be reduced with appropriate mitigation and use of personal protective equipment (ppe). unfortunately, while access issues have abated in most developed countries, this continues to be a challenge on an international level. as we write this letter in reply, nineteen percent of all cases of covid-19 reported in mexico are in healthcare workers and our colleagues in otolaryngology have not been spared. the risk of death for healthcare workers in mexico is four times higher than in the united states and this is related and attributable to restricted access to ppe. 2 sadly, some other countries are actively supressing case data and information, making the situation is even more dire -this data could not be included in our registry for fear of repercussions to the local representatives. one of the main aspirations of our registry was to help quantify situational risk and empower advocacy for proper ppe for those that do not have it -or at least to increase awareness around cases with potential risk so that whatever risk mitigation can be performed is done (i.e. reverse draping the microscope during a mastoidectomy). dr. turner does an excellent job in summarizing the currently established risk for hcws. he did not include a prospective observational study from the uk looking at 9,800 employees found that those working in covid-facing areas had a higher rate than those elsewhere (21.2% vs. 8.2%). 3 the numbers reported for canada also demonstrate the pitfalls of broad surveys while studying covid-19. 4 while we agree that the disparate rates between hcws and non-hcws is mostly due to testing in the study by schwartz et al, the substantially higher mortality rate in non-hcws is because the vast majority of outbreaks were encountered in long-term care homes -80% of all canadian deaths have been in long-term care residents. 5 while we support and amplify the caution that should be used when reading this type of data, we reject the idea that simply because the media or public figures may jump to conclusions before gathering all the evidence, means that all other physicians and scientists will do the same. we have more faith in our fellow otolaryngologists' ability to take the data in the context with which it is presented and simply add it to the growing knowledge base we are accumulating about this disease process and how best to continue safely practicing and operating within a pandemic. sincerely, letter to the editor re: international registry of otolaryngologist -head and neck surgeons with covid-19. int forum all rhinol why the coronavirus is killing so many of mexico's healthcare workers. the guardian differential occupational risks to healthcare workers from sars-cov-2: a prospective observational study covid-19 infections among healthcare workers and transmission within households 81% of covid-19 deaths in canada were in long-term care -nearly double oecd average the authors have neither financial interests nor support to declare. key: cord-278418-i8cbrs7y authors: leitner, stephan title: on the dynamics emerging from pandemics and infodemics date: 2020-08-31 journal: mind soc doi: 10.1007/s11299-020-00256-y sha: doc_id: 278418 cord_uid: i8cbrs7y this position paper discusses emerging behavioral, social, and economic dynamics related to the covid-19 pandemic and puts particular emphasis on two emerging issues: first, delayed effects (or second strikes) of pandemics caused by dread risk effects are discussed whereby two factors which might influence the existence of such effects are identified, namely the accessibility of (mis-)information and the effects of policy decisions on adaptive behavior. second, the issue of individual preparedness to hazardous events is discussed. as events such as the covid-19 pandemic unfolds complex behavioral patterns which are hard to predict, sophisticated models which account for behavioral, social, and economic dynamics are required to assess the effectivity and efficiency of decision-making. the covid-19 pandemic poses extreme and severe challenges to the society: there is a dramatic loss of lives worldwide, we experience and also expect for the future a multiplicity of challenges for economic systems, individuals are confronted with new and often very demanding situations, and public and private institutions are challenged to decide upon draconian measures under high time-pressure (johns hopkins university of medicine 2020; atkeson 2020; xiang et al. 2020) . this paper discusses emergent issues which appear to become particularly relevant in the context of the covid-19 pandemic: sect. 2 focuses on delayed effects of pandemics and sect. 3 discusses adaptive societies and preparedness in the context of hazardous events. the understanding of the dynamics which unfold during and in the direct aftermath of a pandemic are key to effective and efficient management decisions. in additon, the insights into the dynamics of pandemics and infodemics can be employed for the good of the society in a long-term perspective as they might help minimize unwanted (and often delayed) effects. 1 the temporal profile of hazardous events significantly affects how the related risks are perceived: individuals are more averse to events in which a large number of people are harmed or killed in a short period in time, compared to events which have similar consequences but span over a longer time-period (slovic 1987; bodemer et al. 2013; ayton et al. 2019) . the covid-19 pandemic, a low-probability and high-consequence event, is of the former type; individuals are very likely to perceive it as a dread risk (gerhold 2020) . this perception is likely to affect individual behavior, which might unfold rather complex dynamics: gigerenzer (2004) , for example, shows that such dread risks affect individual decision-making behavior not just in the short but also in the long run. for the aftermath of the 9/11 attacks he finds that perception of the terrorist attack has caused a change in individual transport behavior and, in consequence, has led to an increase in traffic fatalities beyond what would have been expected without the change in individual behavior. it is likely that similar behavioral patterns will emerge in the aftermath of the covid-19 pandemic. these effects are likely to be shaped by two factors: the individual mind and structure of the environment (gaissmaier and gigerenzer 2012; simon 1990 ). the former is affected by the perception of the covid-19 pandemic as a dread risk with changes in behavioral patterns lurking (gigerenzer 2004) . the latter also affects individual behavior as it determines the boundaries for adaptivity (simon 1990 ). the structure of the environment is, amongst others, shaped by policy decisions. these two influencing factors are discussed in the following subsections. risks are made up of a multiplicity of qualitative and subjective attributes (jenkin 2006; slovic et al. 1981; xu et al. 2020 ). 2 however, risk-perception is also a sociocultural phenomenon: it is affected by the structure of networks between individuals (e.g., social networks, organizations) and the resulting world views (gore et al. 2009; sjöberg 2000; marris et al. 1998) . how individuals perceive risks is crucially affected by the information accessible to them (huurne and gutteling 2008) , whereby accessibility of information and resulting opinions about factors influencing risk-perception are often shaped by one's networks (burt 1987; scherer and cho 2003; grimm and mengel 2020) . 3 phenomena such as the infodemic, which accompanies the current pandemic, adds complexity to the the current situation: there is a chance that mis-information leads to unwanted effects in individual behavior so that the speed at which the virus spreads increases: cinelli et al. (2020) argue that rumors about lockdowns in northern italy led to overcrowded trains and airports, which, in consequence, increased the speed at which the virus spreads. besides direct effects on behavior there might be indirect and delayed effects of an infodemic, as the spread of mis-information might increase the perception of the covid-19 pandemic as a dread risk (zarocostas 2020). it is, thus, plausible to assume that there are non-trivial interactions among behavioral implications induced by the covid-19 pandemic and the accompanying infodemic which might result in complex dynamics: if not understood properly, mutually reinforcing dynamics with unprecedented consequences might unfold. these dynamics might be even reinforced by the algorithms employed by information platforms, which are usually designed to respond to the individual information-seeking behavior (budak et al. 2016) . it is, therefore, of ultimate importance to understand how people select information sources during hazardous events and how information dynamics interfere with risk perception and behavioral dynamics (cinelli et al. 2020 ; sharot and sunstein 2020). the structure of the environment is the second driving force behind delayed effects of the covid-19 pandemic which is discussed in this paper as, following simon (1990) , it defines the limits of the adaptation. gaissmaier and gigerenzer (2012) , for example, regard the availability of driving opportunities as a main factor that contributed to the change in behavioral patterns in the aftermath of the 9/11 attacks which led to more fatalities than would have been expected without the change in behavior (see also gigerenzer 2004) . 4 similarly, lópez-rousseau (2005) analyzed traffic patterns in the aftermath of terrorist train attacks in spain in 2011: they observed that train travel had decreased in the months following the attacks, the amount of other traffic, however, had not increased. 5 aside from cultural reasons, lópez-rousseau (2005) traces the differences back to political decisions and social factors: while the boundaries for individual adaptation after the 9/11 attacks were set by shutting down all flight traffic, social factors caused a significant increase in train traffic on the days after the attack in spain as demonstrations related to the attacks were organized across the country. thus, in the aftermath of hazardous events the environment appears to be a main factor to affect (and to set the boundaries for) the adaptation of individual behavior, whereby it appears to be shaped, amongst others, by policy decisions. 6 this is why policy-makers would be well advised to consider the dynamics resulting from the interaction of decisions related to the aftermath of the covid-19 pandemic with processes of individual adaptation in their policy decisions. currently, there is a multiplicity of (often draconic) measures taken by different governments which are decided upon under time pressure and under limited information: it is, therefore, likely that policy-makers are not fully aware of the impact of their decisions (elsenbroich and badham 2020). this might be explained by the fact that the models currently employed hardly consider the full range of social and behavioral complexity (squazzoni et al. 2020) : they are well-suited for short-term policy-making which aims at reducing the speed at which the virus spreads. in order to provide proper policy advice for long-term decisions, however, extended models need to be developed in order to avoid poorly conceived policies which strike back through delayed behavioral effects. the second emerging topic discussed in this position paper covers issues related to the preparedness of societies. 7 this is an issue of ultimate interest: oppenheim et al. (2019) , for example, highlight that despite significant investment, many countries are not able to manage virus outbreaks. preparedness, however, is not just a necessary feature at the macroscopic level but also needs to be analyzed at the level of the individual (käser et al. 2019 ). there exist strong interrelations between the two levels: lim et al. (2013) , for example, found that institutional preparedness to disasters is positively affected by the individual preparedness of supervisors, while individual preparedness, amongst others, appears to be driven by the a person's experience with similar situations, the preparedness of colleagues and the family, and training. in order to increase the preparedness of a society, a multiplicity of issues has to be considered, such as communication and coordination infrastructure, health-care infrastructure, logistics to name but a few (madad et al. 2020; oppenheim et al. 2019; gupta et al. 2018 ). however, soft factors which influence behavior at the individual level, such as strategies for information retrieval, also need to be taken into account (misuraca et al. 2018) . issues related to preparedness can be analyzed through the lens of complexity science: societies are regarded as adaptive systems which consist of multiple human decision-makers and self-organization refers to a process in which the society, for example, creates an order or a structure and assigns roles, tasks or capabilities to be acquired by their members (odum 1988; di marzo et al. 2005) . what appears to be particularly interesting in this context is how societies can be guided in their process of self-organization so that their resilience increases. there is enormous progress in the fields of engineering and information technology related to complex adaptive systems, when it comes to the consideration of systems composed of humans, their complexity increases significantly (karwowski 2012) . this might be due to a multiplicity of factors related to human behavior and interactions among them, such as culture, attitudes, and cognitive abilities. regarding preparedness with respect to hazardous events, the functioning of soft factors and their interrelations with human factors might be even more challenging to capture in models, as situations with less predictable and more complex patterns in individual behavior need to be covered (poletti et al. 2009; funk et al. 2009; reluga 2010; del valle et al. 2005) . the development of sophisticated models of adaptive human systems which capture the dynamics related to pandemics-with a particular focus on the soft-facts related to resilience-appears to be highly relevant. such models might prove to be particularly useful when used to evaluate means to guide societies toward selforganization in order to increase their resilience. this paper highlights some issues which emerge from pandemics and accompanying infodemics: delayed effects of pandemics and factors influencing these effects, and the preparedness of adaptive societies. understanding the dynamics related to pandemics and infodemics is an indisputable precondition for efficient and effective decision-making. the discussion provided in this paper hopefully gives an impulse to action towards research related to hazardous events that puts more emphasis on the emerging behavioral, social, and economic dynamics. funding open access funding provided by university of klagenfurt. conflict of interest the author declares that he has no conflict of interest. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. social and ecological resilience: are they related? what will be the economic impact of covid-19 in the us? rough estimates of disease scenarios terrorism, dread risk and bicycle accidents when dread risks are more dreadful than continuous risks: comparing cumulative population losses over time fair and balanced? quantifying media bias through crowdsourced content analysis social contagion and innovation: cohesion versus structural equivalence the covid-19 social media infodemic effects of behavioral changes in a smallpox attack model self-organization in multi-agent systems focussing on our strengths the spread of awareness and its impact on epidemic outbreaks act ii: a fine-grained analysis of regional variations in traffic fatalities in the aftermath of the terrorist attacks covid-19: risk perception and coping strategies dread risk, september 11, and fatal traffic accidents application of risk concepts to wildlife management: special issue introduction experiments on belief formation in networks analysis of results from the joint external evaluation: examining its strength and assessing for trends among participating countries information needs and risk perception as predictors of risk information seeking risk perception and terrorism: applying the psychometric paradigm covid-19 global cases a review of human factors challenges of complex adaptive systems: discovering and understanding chaos in human performance individual disaster preparedness: explaining disaster-related information seeking and preparedness behavior in switzerland avoiding the death risk of avoiding a dread risk: the aftermath of march 11 in spain ready or not, patients will present: improving urban pandemic preparedness. disaster medicine and public health preparedness a quantitative test of the cultural theory of risk perceptions: comparison with the psychometric paradigm trends in analyzing access to information. part i: cross-disciplinary conceptualizations of access trends in analyzing access to information. part ii. unique and integrating conceptualizations social innovation and resilience: exploring the dynamics and impacts on the digital transformation of governance and society theory of reasoned action, theory of planned behavior, and the integrated behavioral model self-organization, transformity, and information assessing global preparedness for the next pandemic: development and application of an epidemic preparedness index spontaneous behavioural changes in response to epidemics game theory of social distancing in response to an epidemic a social network contagion theory of risk perception how people decide what they want to know invariants of human behavior consequences of perceived risk: demand for mitigation risk perception by the public and by experts: a dilemma in risk management factors in risk perception perception of risk rating the risks. risk/benefit analysis in water resources planning and management computational models that matter during a global pandemic outbreak: a call to action infodemic and risk communication in the era of cov-19 timely mental health care for the 2019 novel coronavirus outbreak is urgently needed extending the theory of planned behavior to understand residents' coping behaviors for reducing the health risks posed by haze pollution how to fight an infodemic key: cord-257622-m6j0us2e authors: herman, joanna; patel, dipti title: advising the traveller date: 2017-12-07 journal: medicine (abingdon) doi: 10.1016/j.mpmed.2017.10.004 sha: doc_id: 257622 cord_uid: m6j0us2e global travel continues to increase, particularly to tropical destinations that have different health risks from those encountered closer to home. currently, over a billion people travel annually, with over 65 million visits made from the uk. seeking pre-travel advice should be an essential part of any trip for a traveller. the key elements of pre-travel advice are health risk assessment, health promotion and risk management; this involves advice on prevention of malaria, travellers' diarrhoea, sexually transmitted infections and accidents, as well as appropriate vaccinations. higher risk groups of travellers, such as those visiting friends and relatives, those with co-morbidities, pregnant women and very young or elderly individuals, particularly need to be targeted. international travel continues to increase, with >1 billion travellers worldwide now crossing international borders, and >65 million visits made from the uk each year. although many travellers from the uk visit europe and north america, there has been an increase in travel to tropical destinations. this places travellers at risk of a variety of travel-related conditions, such as malaria, dengue and other tropical or vaccine-preventable infections, many of which are rarely, if ever, encountered at home. travellers are therefore an important group to target owing to their movement, the risk of adverse health outcomes abroad and the possibility of importation or exportation of infectious diseases. however, estimation of disease risk in travellers has proved elusive, with difficulty ascertaining precise data on both numbers travelling to specific locations and incidence of illness in travellers. despite their limitations, frequently quoted studies estimate the overall risk of morbidity from illness or injury to be between 20% and 70%. 1 although most illnesses tend to be self-limiting, approximately 5% of travellers require a doctor's attention, 1% require hospitalization while abroad, and many travellers require medical care on returning home. however, the most likely causes of mortality in travellers are accidental injury (e.g. road traffic accident (rta), drowning) or a cardiovascular event, rather than an infectious disease, which accounts for only 1e2% of deaths. many travel-related illnesses are preventable by taking sensible precautionary measures, and, for some diseases, by having the appropriate vaccinations and taking chemoprophylactic medications. in the uk, pre-travel advice is given in the primary care setting or at specialized travel clinics, and is usually nurseled. access to pre-travel healthcare surveys of travellers visiting less-developed countries indicate that approximately 50% seek pre-travel health advice. use of pretravel healthcare is low because of a lack of concern about health issues related to travel; primary care and the internet were the most common sources of information. the likelihood of seeking pre-travel advice varies in different groups of travellers, with migrants who return to their country of origin to visit friends and relatives (vfrs) being the least likely to seek advice or take precautionary measures. this group has a disproportionately increased risk of acquiring the more common tropical infections compared with other travellers, and they should be targeted specifically for pre-travel advice. 2 the travel clinic consultation the key features of a pre-travel consultation are health risk assessment, and health promotion with risk management (table 1) . risk of infection varies according to the area to be visited, endemicity of diseases, nature of travel (holiday, business, backpacker, vfr), type of accommodation, anticipated activities and duration of trip. it also varies according to the health status key points c there has been an increase in travel to tropical destinations, with subsequent exposure of travellers to malaria, dengue and other tropical and vaccine-preventable infections c the most likely causes of mortality in travellers are accidental injury or a cardiovascular event, rather than an infectious disease c malaria is one of the most common and serious causes of fever in travellers the key features of a pre-travel consultation are health risk assessment, and health promotion with risk management c higher risk groups of travellers include those visiting friends and relatives, those with co-morbidities, pregnant women and very young or elderly travellers of the traveller: their medical conditions, current medications, allergies and immunization history. most (80e95%) travellers to the tropics undertake short-term visits (<1 month). the remaining 5e20% spend long periods abroad, either travelling or working (e.g. backpackers, missionaries, volunteer workers, placements with the armed forces), or on repeated short-term visits (e.g. businessmen, airline crews). these groups incur different risks and exposures, depending on both individual behaviour and environment, with the long-term traveller at greater risk of acquiring infections endemic in the local population they are visiting. there is also a risk difference between the sexes, with male travellers at greater risk of most disease acquisition, except for travellers' diarrhoea, which is more frequent in female travellers. risk also varies according to the geographical area visited. travellers to africa have the highest rate of all-cause morbidity and account for the greatest number of cases of plasmodium falciparum malaria. the highest risk of plasmodium vivax and diarrhoeal illness is in travellers to south asia, while cutaneous leishmaniasis is most common in visitors to latin america. furthermore, risk within a country can differ; for example, malaria risk is negligible in nairobi compared with a significant risk on the kenyan coast. travel medicine is dynamic, and both travellers and physicians should be aware of, and respond to, changes in epidemiology of potential infections, including the occurrence of outbreaks. recent outbreaks (e.g ebola, zika, yellow fever, middle east respiratory syndrome), and wide media coverage have alerted travellers to the potential risk of previously rarely encountered tropical infections. however, although the risk of acquiring these infections is low for most travellers, they can have a role in spread of disease, particularly vfrs. information about outbreaks can be found on various websites including those of the world health organization, the national travel health network and centre, and the centers for disease control and prevention ( table 2 ). these websites also offer valuable information for vaccine recommendations, although regional prevalence of specific disease can be difficult to obtain. finally, it is important to remember that non-tropical infections account more commonly for the infections that present in returned travellers. health promotion and risk management many travel consultations focus on vaccinations, but these can be among the least cost-effective preventive measures in travellers as vaccine-preventable diseases account for <5% of travelassociated morbidity. the main priorities should be given to health problems that are common, preventable, treatable and serious or potentially fatal. these include malaria, travellers' diarrhoea, sexually transmitted infections (stis) and rtas. health hazards that are rare (e.g. cholera, japanese encephalitis, parasitic infections) should be put into perspective and discussed, based on the individual traveller's risk profile. current best practice emphasizes the need for a patientcentred approach and shared decision-making. therefore, for each risk, the travel medicine practitioner must balance the need for prophylaxis against the realistic risk of infection, and the likelihood of adherence to preventive measures by the traveller. the latter depends on a number of factors including perception of risk, concerns about available preventive measures and treatments, and preferred risk management options. 3 travellers should know that no intervention is fully protective. malaria is one of the most common and serious causes of fever in travellers, occurring while abroad or on return (see malaria on pages 52e58 of this issue). the risk of malaria is greatest in sub-saharan africa (particularly west africa), intermediate in south asia (india), and lowest in central and south america and south-east asia. however, the risk for acquiring malaria can vary widely from traveller to traveller, from region to region and within countries. those at particular risk of disease acquisition are long-term vfr travellers, while those at risk of severe disease are pregnant women, travellers with complex co-morbidities and elderly individuals. prevention of infection involves understanding the disease process and the 'abcd' of malaria: awareness of risk bite prevention from nocturnal anopheles spp. mosquitoes chemoprophylaxis prompt diagnosis of infection. health risk assessment bite prevention measures include use of insect repellent such as deet, covering up during the highest risk time periods (dusk to dawn), and sleeping under an insecticide-impregnated mosquito net if enclosed and screened accommodation is not available. the choice of chemoprophylaxis depends on the type of malaria that is endemic in the region being visited, and whether drug resistance (usually chloroquine resistance of p. falciparum) is present. it also depends on individual factors and preferences for the different drug regimens, such as dosing frequency (e.g. weekly for mefloquine, daily for doxycycline or atovaquoneeproguanil), and affordability. for countries with a high prevalence of chloroquine-resistant p. falciparum, mefloquine, doxycycline or atovaquoneeproguanil can be taken. for the limited areas with little chloroquine resistance, chloroquine plus proguanil should be taken, and in areas without resistance, chloroquine alone can be used. practitioners should be aware of the adverse effects of and contraindications to all the antimalarials. for detailed information, including adverse effects and special situations such as pregnancy, see the 2017 uk malaria guidelines at: www.gov.uk/government/publications/malaria-prevention-guide lines-for-travellers-from-the-uk. travellers should be advised that although malaria prevention methods are highly effective, they do not provide 100% protection, and they should seek immediate medical attention if they have symptoms suggestive of infection. diarrhoea is the most common illness affecting travellers to developing countries, with 20e60% being affected (see diarrhoea in travellers on pages 24e29 of this issue). it can cause significant morbidity and can result in loss of travel time, amendment of itineraries and medical encounters, including hospitalization. travellers diarrhoea is usually non-bloody, watery, may be frequent and explosive, but has minimal or no fever. table 2 prevention of malaria (the 'abc' of malaria prevention) awareness of risk mefloquine https://www.gov.uk/government/publications/malaria-prevention-guidelines-for-travellers-from-the-uk a a 20e50% concentration is usually recommended and is safe for all travellers >2 months of age; manufacturer's guidelines for use should be followed. b before prescribing an antimalarial agent, the prevalence, species and potential resistance of malaria found in the travel destination must be determined, as should any medical contraindications. the most common causal organisms are bacteria, particularly enterotoxigenic escherichia coli, enteroaggregative e. coli, salmonella spp., campylobacter and shigella, but viruses (rotavirus, noroviruses) and protozoa (giardia lamblia, cryptosporidium spp.) can also be the cause. rarer, but more serious, are the enteric fevers (typhoid, paratyphoid), which have the same risk factors as other gastrointestinal infections. travellers can be concerned about the risk of cholera, but apart from a few specific circumstances (e.g. working in refugee camps), this poses little threat to most travellers. the travel health practitioner should discuss both prevention and self-treatment. prevention advice should focus on food and water hygiene, and it is useful to emphasize the 'boil it, cook it, peel it or forget it' approach to eating while abroad. the importance of hand hygiene (washing, sanitizer gels) should also be stressed; however it is not always easy to follow this advice, and illness can still occur despite adhering to it. prophylaxis with antibiotics is recommended in limited circumstances (see diarrhoea in travellers on pages 24e29 of this issue). guidelines on self-treatment should stress the importance of maintaining hydration and advise when to control symptoms with an antimotility agent, and when to treat illness with a short course of antibiotics. mild diarrhoea should only require increased hydration and possibly an antimotility agent (e.g. loperamide), but antibiotics may be advised for moderate diarrhoea and should be used if it is severe. 4 self-administered fluoroquinolone antibiotics (ciprofloxacin, levofloxacin) or a macrolide (e.g. azithromycin) significantly reduce the duration and severity of symptoms in acute watery diarrhoea. a single dose of ciprofloxacin or levofloxacin can be sufficient in many cases if taken soon after the onset of symptoms, but treatment can be continued for up to 3 days if diarrhoea persists. in areas where fluoroquinolone-resistant campylobacter is widespread (south and south-east asia), azithromycin is the drug of choice. however, owing to its proarrhythmogenic properties, it should be avoided in elderly travellers with cardiovascular disease. for moderate diarrhoea, the combination of antibiotic and loperamide is more effective in reducing both the duration and severity of symptoms compared with antibiotics alone. however, an antimotility agent is not advised if the diarrhoea is dysenteric (i.e. bloody stool with abdominal pain) or if the person is febrile. packaged oral rehydration salts (or a self-made simple rehydration solution) can be used to maintain hydration in infants, young children and the elderly. medical advice should be sought abroad if symptoms continue or if the diarrhoea is dysenteric. travellers with persistent diarrhoea on return from their trip should undergo further investigations, particularly looking for protozoan infection with giardia intestinalis or cryptosporidium. travellers and tourists often engage in risky behaviour when abroad, and may have unprotected sexual intercourse with other travellers or locals from high-risk populations. studies have found that 25e30% of people with a confirmed sti attending a genitourinary medicine clinic reported a new partner while away, with 60e70% not using or inconsistently using condoms. the risk of transmission of stis and hiv should be discussed with all travellers who seek pre-travel advice, as the risk can be virtually eliminated by practising safer sex. raising awareness of these sensitive issues is an important part of the travel health consultation, although some practitioners find them difficult to address. less common risk factors for hiv infection include invasive medical treatment and transfusion with contaminated blood, which are of particular importance in sub-saharan africa, where the seroprevalence of hiv can approach 30%. vaccinations (table 4 ) vaccine-preventable diseases are uncommon to rare in travellers (usually <1 case per 1000 overseas visits). the decision to vaccinate a traveller is based on the epidemiology and risk of the disease, the effectiveness of the vaccine, the risk of vaccineassociated adverse events, the individual's underlying health, the cost of vaccination and the ability to employ other diseasepreventing measures. the three main reasons for vaccinating travellers are: recommended as part of routine healthcare required by the destination country recommended because of travel-related risk. routine vaccinations: the pre-travel visit is an ideal time to make sure that travellers are up to date with routinely recommended vaccines, such as those against measles, mumps, rubella, tetanus, diphtheria, pertussis and polio. it also provides an opportunity to ensure that the traveller is up to date with any additional vaccines that might be recommended as a result of their work, lifestyle choice or underlying health problems. the recent increase in cases of measles in high-income countries emphasizes the need both to protect travellers and the destination and receiving countries. yellow fever vaccine is recommended for those travelling to areas where there is a risk of yellow fever transmission (tropical parts of africa, south america, eastern panama in central america, trinidad in the caribbean). however, as a condition of entry, some countries require an international certificate of vaccination or prophylaxis (icvp) against yellow fever as proof of vaccination against the infection. before administering yellow fever vaccine, consideration must be given to the viscerotropic and neurological severe adverse events associated with the vaccine, which have been recognized over the past decade. although these adverse events are rare (0.3e0.8 events per 100,000 doses), they are more common in those aged 60 years and older. the ihr (2005) have also recently been applied to poliovirus. in 2014, an emergency committee of the world health organization declared that, under ihr (2005), the international spread of poliovirus represented a public health emergency of international concern, and recommendations were made for countries reporting cases and/or exporting the virus to reduce the potential for spread. these measures included a requirement for an icvp for polio vaccine for some groups of travellers as a condition of exit from a country reporting and/or exporting cases of polio. there are occasionally specific vaccination requirements for entry into countries. for example, saudi arabia requires all pilgrims and seasonal workers travelling for the hajj or umrah to show proof of having been given the quadrivalent meningococcal vaccine as a condition for granting a visa. immunization for travel-related risk: once the practitioner has taken account of the disease epidemiology in the destination region, the mode of acquisition (e.g. food-, water-or vectorborne) and the non-vaccine preventive measures available, they can then determine the likely risk of significant disease, and the need for vaccination. most travellers can be safely vaccinated, although in some, vaccination can be contraindicated or should be deferred. caution is required for travellers who are severely immunosuppressed, for whom live vaccines are contraindicated and the efficacy of inactivated vaccines may be reduced. for travellers living with hiv, guidelines from the british hiv association (www.bhiva.org/vaccination-guidelines.aspx) should be consulted. live vaccines should generally be avoided, and must not be given to hiv-positive adults with cd4 cell counts <200 cells/ microlitre. however, when travel is unavoidable, and risk of infection outweighs risk of vaccination, some live vaccines can be given to those who are asymptomatic with a stable cd4 count >200 cells/microlitre and a suppressed viral load. all travellers should be informed that no vaccine is 100% effective and that appropriate precautionary measures should still be taken. vaccines administered in the uk for age-specific routine healthcare a accidents, safety and security approximately 18e24% of traveller deaths are to the result of injuries. unfamiliar environments, cultural and language differences, less stringent health and safety standards, increased risktaking behaviour and lack of accessibility or adequacy of emergency care all contribute. most injury deaths are caused by rtas, and travellers should be aware of the risks of being a pedestrian, passenger or driver in a foreign country, particularly when unfamiliar with local road systems. travellers should always use seatbelts and should never drive after alcohol consumption. other causes of injuries include watersports, adventure activities and crime. travellers can be perceived as wealthy, naive, inexperienced or unfamiliar with the environment and customs, and are therefore often targets for criminals. the need for moderation of alcohol consumption and avoidance of illicit drug use must be addressed because of its tendency to promote risk-taking behaviour, including unsafe sexual practices, in addition to accidents. travellers from the uk should consult the foreign and commonwealth office country page ( table 2) to determine if there are any safety or travel restrictions for their destination. travellers with co-morbidities travellers with underlying medical conditions can be at increased risk of adverse outcomes both during and after travel, and therefore require careful evaluation. 5 in addition to the standard travel-related risks, the stability of their condition(s) and the impact of travel, the overseas environment, endemic diseases, and vaccinations and other preventive measures on their underlying diseases or medication must be evaluated. the adequacy of local medical facilities and the availability of medication and medical equipment also need consideration. careful counselling on what to do in the event of illness abroad, medication management, use of self-treatment measures and when to seek medical assistance is key. giving the traveller a summary of their medical record, including a medication list, can also be helpful. in the case of medication, regulations on importing or transporting medicines at their destination may also need to be checked. although there are few absolute contraindications to travel, some airlines may refuse to transport individuals with unstable or acute medical conditions. therefore early preparation, liaison with their specialist and comprehensive travel insurance that will cover their underlying medical condition(s), in addition to their expected activities, is essential. disease-specific resources are available and provide additional guidance for travellers on healthcare facilities abroad and specialist travel insurance. in summary, most travel-related illness is avoidable if the necessary preventive measures are taken and the appropriate high-risk groups are targeted for pre-travel advice. however, some tropical infections can manifest only weeks to months after returning home. to test your knowledge based on the article you have just read, please complete the questions below. the answers can be found at the end of the issue or online here. a 40-year-old man attended for travel health advice. he planned to travel to brazil for work in 4 weeks' time. he would be travelling to the amazon starting in manaus for 2 weeks, and then he would spend 2 weeks in rio, although his plans were subject to change. he was well, but was hiv-positive, with a cd4 count of 350 cells/microlitre and a suppressed plasma hiv-1 rna load. he was on antiretroviral therapy. he was up to date with his childhood vaccinations, but was non-immune to measles. he had never had any travel vaccinations. what is the most appropriate vaccination advice for this traveller? a. travel vaccines are contraindicated b. replicating (live) vaccines are contraindicated c. oral typhoid vaccine is recommended d. measles/mumps/rubella vaccine is recommended e. yellow fever vaccine is contraindicated a 32-year-old woman was planning to take her 6-month-old baby boy to visit her parents in accra, ghana, in 3 weeks' time, staying for 4 weeks. both were fit and well, and the child was up to date with his vaccinations. the mother was 8 weeks' pregnant and was requesting advice about malaria. what advice is the most appropriate advice with regard to malaria prevention for mother and child? a. the mother should be advised 50% n,n-diethyl-metatoluamide (deet) is contraindicated for the child because of his age b. chloroquine plus proguanil is suitable for chemoprophylaxis for both mother and child c. the mother should be advised that bite prevention measures are particularly important during peak aedes mosquito biting times d. mefloquine is suitable for chemoprophylaxis for both mother and child e. the mother should be advised that picaridin is the insect repellent of choice for her in view of her pregnancy a 23-year-old student planned to travel to cambodia the following month to volunteer in a rural school, where he would be staying with a local family. following 6 weeks of work, he planned to travel around south-east asia for a further month. he had travelled to south america the previous year but had experienced repeated 'stomach problems' while abroad and was worried about having the same issues again. what advice should he be given with regard to prevention of gastrointestinal problems while abroad? a. given the problems he had last time, antibiotics should be taken as a preventive measure b. ciprofloxacin should be given as a 'standby treatment' if he develops moderate or severe symptoms c. hand, food and water hygiene advice should be an essential part of the consultation d. if he develops bloody diarrhoea with fever, he should start antibiotics e. antimotility agents are not generally recommended health risks among travellers e need for regular updates pre-travel health adviceseeking behavior among us international travelers departing from boston logan international airport travel clinic consultation and risk assessment guidelines for the prevention and treatment of travelers' diarrhea: a graded expert panel report 104e10. further reading lalloo dg, hill dr. preventing malaria in travellers adverse event reports following yellow fever vaccination safe travels? hiv transmission among britons travelling abroad enteropathogens and chronic illness in returning travelers epidemiology of travel-related hospitalization key: cord-277800-dtpsiaj9 authors: stefan, norbert title: metabolically healthy and unhealthy normal weight and obesity date: 2020-08-20 journal: endocrinol metab (seoul) doi: 10.3803/enm.2020.301 sha: doc_id: 277800 cord_uid: dtpsiaj9 increased fat mass is an established risk factor for the cardiometabolic diseases type 2 diabetes and cardiovascular disease (cvd) and is associated with increased risk of all-cause and cvd mortality. however, also very low fat mass associates with such an increased risk. whether impaired metabolic health, characterized by hypertension, dyslipidemia, hyperglycemia, insulin resistance, and subclinical inflammation, may explain part of the elevated risk of cardiometabolic diseases that is found in many subjects with very low fat mass, as it does in many obese subjects, is unknown. an important pathomechanism of impaired metabolic health is disproportionate fat distribution. in this article the risk of cardiometabolic diseases and mortality in subjects with metabolically healthy and unhealthy normal weight and obesity is summarized. furthermore, the change of metabolic health during a longer period of follow-up and its impact on cardiometabolic diseases is being discussed. finally, the implementation of the concept of metabolic health in daily clinical practice is being highlighted. worldwide there is an increase in the prevalence of overweight and obesity [1] . both, overweight and particularly obesity are associated with an increased risk of the cardiometabolic diseases type 2 diabetes and cardiovascular disease (cvd), certain types of cancer and mortality [2] [3] [4] [5] . in most studies that investigated the relationships of fat mass with all cause and cause-specific mortality, fat mass has been estimated by the calculation of the body mass index (bmi) [2] [3] [4] . in this respect the nadir of allcause mortality risk was found to be 23 kg/m 2 at age younger than 70 years, rising to 25 kg/m 2 at age 70 years and older, while a bmi in the range of 21 to 25 kg/m 2 was associated with the lowest risk of cancer, cardiovascular, and respiratory mortality [4] . in all of these studies a j-shaped relationship of bmi with all-cause and disease-specific mortality was found [2] [3] [4] . the increased mortality, that has been observed at a bmi <21 kg/m 2 , and particularly in the range of underweight (<18.5 kg/m 2 ), may be largely attributed to increased mortality from mental and behavioural, neurological, and external causes [4, 6] . however, as patients with lipodystrophy [7] or a lipodystrophy-like phenotype [8, 9] have an increased cardiometabolic risk, it cannot be excluded that particularly a low amount of fat mass in the subcutaneous region may also increase mortality in the general population with a low bmi. recent analyses from the women's health initiative study in postmenopausal women with normal copyright © 2020 korean endocrine society bmi (18.5 to <25 kg/m 2 ) showed that lower gluteofemoral fat mass, estimated using dual-energy x-ray absorptiometry (dexa), was associated with a higher incidence of cvd and that this increased risk was independent of increased trunk fat mass [10] . furthermore, there is emerging evidence from precise phenotyping studies and from genetic studies showing that increased gluteofemoral and leg fat mass is protective of cardiometabolic diseases [11] [12] [13] . because it is often not feasible to precisely measure fat distribution using dexa, computed tomography or magnetic resonance imaging, during the last decade estimation of the cardiometabolic risk using insulin resistance and/or parameters of the metabolic syndrome has been the focus of intense research. stefan et al. [14] found in 2008 that insulin sensitive obese subjects have a very characteristic body fat distribution that is characterized by a low amount of visceral fat and, more so, by a lower amount of liver fat content. in a back-to-back publication with our study, wildman et al. [15] found in the national health and nutrition examination surveys 1999 to 2004 a similar prevalence of metabolically healthy obese subjects, when using parameters of the metabolic syndrome, a high homeostasis model assessment of insulin resistance (homa-ir) and an elevated high-sensitivity c-reactive protein (hs-crp) level. importantly, assuming that subjects cannot be considered 'metabolically healthy' when setting the cut-off for 'health' <3 parameters of the metabolic syndrome, they considered individuals being metabolically healthy when <2 parameters of the metabolic syndrome, except waist circumference, and high homa-ir and hs-crp levels were present. thus, while currently there is no broad agreement among the researchers and clinicians on how to define metabolic health (mh) [16] [17] [18] [19] [20] [21] , the definition proposed by wildman et al. [15] appears to be most useful (table 1) . nevertheless, many studies having investigated the relationship of metabolic healthy obesity (mho) with cardiometabolic risk or cardiometabolic mortality used the definition of the metabolic syndrome. in meta-analyses of these studies subjects with mho were found to have a moderately increased (~30%) risk of cvd and cvd mortality, when compared to subjects with metabolically healthy normal weight (mhnw). however, for a comparable bmi, the same risk was much higher (~150%) in subjects with metabolically unhealthy obesity (muho) [22] [23] [24] [25] . while these studies mostly included caucasians, similar relationships were also found in asian populations. for example in an analysis of 323,175 adults from the large korean national health insurance system (nhis) database, who were followedup for a median of 96 months, subjects with mho even had a lower all-cause (-19%) and cardiovascular (-27%) mortality risk, when compared to non-obese and metabolically healthy subjects. of note, in that study the authors used a very strict definition of mh, in that subjects with mh were required to have none of three metabolic disease components (hypertension, diabetes, dyslipidemia) [26] . thus, in general, subjects with mho cannot be considered being truly healthy, but of having a much lower cardiometabolic risk, than most of the obese individuals. in the course of the investigation of the cardiometabolic risk of subjects with mho, for a long time the unexpected finding of very high risk (~120%) of cvd and cvd mortality of subjects with metabolically unhealthy normal weight (muhnw), compared to subjects with mhnw, was not well recognized [22] [23] [24] [25] . when investigating the body fat distribution phenotypes of subjects with muhnw stefan et al. [8] found that it somewhat differed from the one observed in subjects with muho. while subjects with muho mostly have a very high visceral fat mass and an elevated liver fat content, subjects with muhnw are predominantly characterized by a low amount of gluteofemoral fat mass [8] . recently data from the women's health initiative study support that a low gluteofemoral fat mass, measured by dexa, associates with a high risk of cvd in lean women, and www.e-enm.org 489 that this risk is independent of elevated trunk fat mass, which was also measured using dexa [10] . it is widely accepted that adipose tissue in the gluteofemoral region serves as a healthy sink to store excess fat. this is mostly due to the fact that under excess energy intake this fat compartment responds predominantly by hyperplasia, which is accompanied by lower lipolytic activity. thus, there is less spill-over of fatty acids into the circulation and less storage of fat ectopically in metabolic relevant organs, such as the liver and the pancreas [11] . genetic studies further suggest that while the muho phenotype is predominantly characterized by variability in genes regulating food intake, the muhnw phenotype is strongly characterized by variability in genes regulating adipocyte differentiation, lipogenesis and lipolysis. furthermore, genes regulating hepatic de novo lipogenesis and lipid release from the liver and lifestyle parameters of the individual and its parents, impact on the pathogenesis of fatty liver (fig. 1 ) [8, 27, 28] . during ageing there is body fat redistribution, predominantly from the gluteofemoral area to the upper body and, in most cases, a decrease in physical activity. this may result in a decline of the prevalence of mh. in agreement, in the whitehall ii study, about 50% of initially healthy obese individuals converted to an unhealthy phenotype over 20 years of follow-up [29] . in the largest study, also with the longest period of follow-up, that investigated the change of mh over time, the nurses' health study, among the initially metabolically healthy obese women only 16% remained metabolically healthy over 20 years of follow-up. this number decreased to 6% after 30 years of followup. however, also in initially metabolically healthy women with normal weight mh declined and after 30 years of follow-up only 15% of the women remained metabolically healthy [30] . copyright © 2020 korean endocrine society an important question is whether and to what extent the cardiometabolic risk differs in obese subjects who can retain mh over a longer period of follow-up. data from the north west adelaide health study suggest that risk of diabetes, cvd, or stroke is not increased in people with mho compared to people with mhnw, if the metabolically healthy obesity phenotype is maintained during a natural follow-up over 5.5 to 10.3 years [31] . in the nurses' health study, women who maintained the mho phenotype over 20 years still had a higher (34%) risk of cvd over the following 10 years of follow-up, when compared with normal weight women who were metabolically healthy over the same time period. however, this risk was much higher (120%) in obese women who could not retain mh (fig. 2 ) [30] . these relationships were found in studies that predominantly included caucasians. however, they may also be present in asian populations. for example in a community-based population in shanghai, china, 46.8% of individuals with mho developed a metabolically unhealthy status during a follow-up period of 4.4 years. while subjects with transient mho had an increased risk (152%) of a composite subclinical atherosclerosis endpoint, the risk was statistically not different (8%) in subjects with stable mho, when compared to subjects who were metabolically healthy and non-obese (mhno) [32] . of interest, persistent mh in obesity does not protect from heart failure as was most recently shown in an analysis of data from the korean nhis datasets from 2002 to 2017 [33] . when compared to stable mhno individuals, subjects who retained mho during a mean follow-up of 3.70 years, had a 17.3% increased hazard of hospitalization for heart failure (hhf). furthermore, individuals who shifted from mho to mhno had a 34.3% lower hazard of hhf [33] . this is in agreement with previous observations showing that subjects with mho may have no or only a moderately increased risk of myocardial infarction, but are not protected from heart failure [34] , which is also strongly driven by obesity [35, 36] . an important question related to the concept of mh is how can a metabolically healthy state be retained or achieved in subjects with impaired mh. in this respect weight loss that is brought about by a lifestyle intervention, may be very effective. in support of this hypothesis in the tübingen lifestyle intervention program, in subjects with muho, a median weight loss of 9.2 kg over a median period of 9 months was associated with the conversion to mh. furthermore, among several of the baseline fig. 2 . transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease (cvd) risk across body mass index categories in 90,257 women of the nurses' health study. risk of cvd in women with normal weight and obesity, stratified by metabolic health status. hazard ratios (hrs) are adjusted for age, race, highest degree, alcohol consumption, postmenopausal status, physical examinations for screening purposes, family history of myocardial infarction and diabetes, aspirin use, smoking status change, physical activity. the data are from eckel et al. [30] , with permission from elsevier. ci, confidence interval. www.e-enm.org 491 parameters tested (age, sex, bmi, waist circumference, systolic and diastolic blood pressure, fasting glucose, high density lipoprotein cholesterol and triglycerides, and mri-and 1 hmrspectroscopy-derived measurements of visceral fat mass and liver fat content), only bmi and liver fat content remained independent predictors of the conversion from muho to mh [37] . in agreement with an important role of fatty liver in the pathogenesis of cardiometabolic diseases, involving insulin resistance, subclinical inflammation, increased hepatic glucose production, dyslipidemia and dysregulated hepatokine production [38] [39] [40] [41] [42] [43] , fatty liver was also found to be a stronger determinant of subclinical atherosclerosis than visceral fat mass and hyperglycemia [44] . however, can such a beneficial effect also be observed with a lifestyle intervention that is not accompanied by weight loss? in this respect data from the prevención con dieta mediterránea (predimed) study show that even in the absence of a large amount of weight loss, adherence to a mediterranean diet can promote the transition to mh in subjects with muho and protect against deterioration of mh in subjects with mho [45] . similar results were also found in other studies involving healthy diets [18] . it is undisputed that all obese individuals, independent of the status of mh, should aim at achieving normal weight. for this several weight-loss programs have been recommended by the medical guidelines focusing on diet, exercise, pharmacological therapy and bariatric surgery [46] . however, based on the limited resources that are available for weight-loss programs, it may be reasonable to allocate resources predominantly to the muho people. in support of this assumption a study investigating the effect of phentermine/topiramate-induced weight loss compared to placebo on the prevention of diabetes in subjects who were stratified by the cardiometabolic disease staging (cmds) score in those with a high or a low cardiometabolic risk, provided interesting information. this score incorporates the parameters of the metabolic syndrome and, thus, is very similar to the mho/muho concept. in that study the baseline mean bmi ranged from 34.2 to 41.2 kg/m 2 among the subgroups and the percentage of weight loss was with around 10% almost identical in the verum groups. although the treatment reduced diabetes risk compared to placebo in the high-risk group, in the latter group a risk as low as baseline in the low-risk was not achieved. thus, substantially larger weight loss may be necessary to achieve a similarly low diabetes risk as the low-risk group. second, still, the numbers needed to treat to prevent one case of diabetes over about 1 year were 120 in the low-risk group but only 24 in the high risk group. thus, this study provided support that targeting high-risk patients for specific weight-loss strategies may improve the cost-benefit ratio of such interventions. furthermore, while during the covid-19 pandemic obesity emerged as an important and independent risk factor for a more severe course of the disease [47] [48] [49] , a metabolically unhealthy condition is still considered to substantially increase this risk [49, 50] . mh is not an entirely new concept. the parameters that are being used for its definition are well-known parameters of the metabolic syndrome [51] . however, there is agreement among the researchers and health care providers that a more stringent exclusion of risk parameters, such as is being done when defining mh, may improve the cardiometabolic risk prediction [11, 18, 20] . furthermore, while intense research was done to understand the risk of diseases in subjects with mho compared to people with muho, the widely neglected increased risk of cardiometabolic diseases in some of the lean people, became a major focus of recent cardiometabolic studies. finally, as for many overweight and obese people mh may be an interesting and easily reachable 'low hanging fruit' on the path of weight-loss [37] , implementation of the concept of mh in the communication of the health care providers with their patients may be of great motivational value. no potential conflict of interest relevant to this article was reported. trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents health effects of overweight and obesity in 195 countries over 25 years association of bmi with overall and cause-specific mortality: a population-based cohort study of 3·6 million adults in the uk overweight, obesity, and mortality from cancer in a prospectively studied cohort of u.s. adults the association between bmi and mortality: implications for obesity 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covid-19 and pre-existing type 2 diabetes the metabolic syndrome key: cord-017527-ylng1us2 authors: herman, philippe; pauwels, katia title: biosafety recommendations on the handling of animal cell cultures date: 2014-11-05 journal: animal cell culture doi: 10.1007/978-3-319-10320-4_22 sha: doc_id: 17527 cord_uid: ylng1us2 the first steps in tissue culture are dating back to the beginning of the nineteenth century when biosafety measures did not yet exist. later on, animal cell culture became essential for scientific research, diagnosis and biotechnological activities. along with this development, biosafety concerns have emerged pointing to the risks for human health and in a lesser extent for the environment associated to the handling of animal cell cultures. the management of these risks requires a thorough risk assessment of both the cell cultures and the type of manipulation prior the start of any activity. it involves a case-by-case evaluation of both the intrinsic properties of the cell culture genetically modified or not and the probability that it may inadvertently or intentionally become infected with pathogenic micro-organisms. the latter hazard is predominant when adventitious contaminants are pathogenic or have a better capacity to persist in unfavourable conditions. consequently, most of the containment measures primarily aim at protecting cells from adventitious contamination. cell cultures known to harbour an infectious etiologic agent should be manipulated in compliance with containment measures recommended for the etiologic agent itself. the manipulation of cell cultures from human or primate origin necessitates the use of a type ii biosafety cabinet. the scope of this chapter is to highlight aspects relevant for the risk assessment and to summarize the main biosafety recommendations and the recent technological advances allowing a mitigation of the risk for the handling of animal cell cultures. specified-pathogen-free tse transmissible spongiform encephalopathies biosafety is a concept that refers to the need to protect human health and the environment from the possible adverse effects of pathogenic and/or genetically modified organisms and micro-organisms used in basic research, research and development (r&d) and modern biotechnology. to this end, a case-by-case risk assessment is conducted which consists in the identification and characterisation of potential effects, which may be intended or unintended, together with an assessment of the likelihood and consequences should any effect occur. depending on the risks identified, risk management measures can be proposed. the use of cell cultures may fall within the scope of one or several regulatory provisions which consider an assessment of biological risks. for example in europe, tissue culture work will in many cases involve the use of genetically modified cell lines as well, in which case a risk assessment should be made in accordance with the provisions of the directive 2009/41/ec related to the contained use of genetically modified micro-organisms (european commission 2009). cell culturing activities aiming at manufacturing biopharmaceuticals are covered by the regulation (ec) no 726/2004 and its amending acts laying down procedures for the authorisation and supervision of medicinal products for human and veterinary use (european commission 2004a), whereas activities that involve the use of human cells and tissues for application to the human body falls within the scope of the directive 2004/23/ec and its amending acts (european commission 2004b) . the manipulation of animal cell cultures also exposes the worker to potential biological risks which are considered under the provision of the european directive 2000/54/ ec (european commission 2000) . it should be pointed out that guidelines aiming at mitigating the biological risks for the laboratory workers, public health and the environment have been issued by some scientific advisory bodies or competent authorities (world health organization 2004; centers for disease control and prevention 2009a; swiss expert committee for biosafety 2011). while biosafety recommendations (as outlined hereafter) are principally aimed at providing maximal protection of human health (including laboratory workers) and the environment, it is recognised that many of the precautionary measures will also directly benefit the quality of research activities involving animal cell cultures. indeed, cross-contamination (lucey et al. 2009; capes-davis et al. 2010; stürzl et al. 2013; jäger et al. 2013; johnen et al. 2013; macleod et al. 2013) or inadvertent contamination with infectious micro-organisms (bacteria, fungi, yeasts, virus, and prion) are plaguing many researchers, often leading to unproductive data, misinterpretation of results and a considerable waste of time and energy (mahy et al. 1991; drexler and uphoff 2000; mirjalili et al. 2005; cobo et al. 2007; pinheiro de oliveira et al. 2013) . it should also be emphasized that even if good manufacturing process (gmp) aim at protecting the product, some of the gmp measures are compatible with biosafety measures and reveal to be complementary. the objective of this chapter will be to address and review biorisk assessment and management considerations of diagnostic and research activities involving cell cultures. from an historical perspective, the assessment of biological risks has an empirical basis and has resulted from the awareness of the scientific community with regards the risks associated with the handling of pathogenic organisms, as demonstrated through many reported cases of laboratory-acquired infections, followed by the potential risks associated with experiments involving recombinant dna. in the 1970s, some initiatives for implementing measures guaranteeing the safe use of recombinant dna were linked to the safety measures which were at that time already successfully applied in microbiology for the containment of pathogenic organisms (national institute of health 1979). the conjunction of these two aspects constitutes two pillars of biosafety and has led to a classification system of organisms into risk classes or risk groups. so far, many risk assessments have been carried out among the scientific community on the use of pathogenic organisms (genetically modified or not), regardless of the scale or the purpose of the activity. the basis for this risk assessment methodology takes into account the most recent scientific, technical data and uses a scientifically sound approach. the methodology of biological risk assessment of contained use activities involving pathogenic and/or genetically modified organisms (gmo) identifies and takes into account the probability of occurrence and the severity of a potential negative effect on public health (including the exposed workers) and/or the environment. as a result of this methodology, a well characterised risk will lead to the choice of appropriate preventive measures encompassing the adoption of an appropriate containment level, the use of safety equipment including personal protective equipment, work practices and waste management. the risk assessment methodology is commonly used and its 4-step approach is described in fig. 22 .1. the first step (1) takes into account the characteristics of the organism(s) used and, in the case of genetic modification, the genetic material introduced and the resulting gmo. based on information relative to their harmful characteristics, natural pathogenic micro-organisms can be categorised in several classes of risk or risk groups. this classification takes into account the severity of the disease that pathogenic organisms may cause to human or animal health, their ability to spread amongst the population and the availability of prophylaxis or efficient treatment (world health organization 2004) . for zoopathogens, the classification system is mainly based on the definitions of the world organisation of animal health (oie), which categorises animal pathogens into four groups according to their risk to animal health, and since 2008, their risk to human health as well (world organisation for animal health 2009). micro-organisms that are unlikely to cause disease are classified into class of risk 1 while etiologic agents responsible for severe diseases with a high potential of transmissibility and for which no prophylaxis or treatment is available are assigned to class of risk 4. as such, pathogenic organisms will be categorised from class of risk 2 to class of risk 4. some periodically revised reference lists issued by international and national authorities or advisory committees classify natural biological agents (not genetically modified) into risk groups or assign the biosafety level under which these should be manipulated ( in the second step (2), the magnitude of the identified negative effects such as human diseases, including allergenic or toxic effects or the transfer of genetic material to other organisms are characterized. in a third step (3), an assessment is performed of the exposure of the laboratory worker, the population and/or the environment to the considered organism and the consequences of each negative effect should it occur. in the fourth step (4), a characterization of the risk is performed resulting in the assignment of the risk level associated with the contained use involving the use of the organism(s). on this basis, the containment measures and other protection measures (e.g. safe work practices, safety equipment and biological waste management) to be adopted are determined. there are four levels fig. 22 .1 flow diagram summarizing the biorisk assessment and management methodology of risk to which contained uses can be assigned, with level of risk increasing from 1 to 4. the final step consists in definitively classifying the contained use activity by conducting a re-assessment of the whole procedure before starting the research, diagnosis or production activity. in this chapter, the risk assessment methodology applied to animal cell cultures is developed and illustrated by examples. it is important to mention that such a risk assessment is always performed on a case by case basis by the scientist (s) responsible for the activity and the biosafety officer (or biosafety professional) in compliance with local guidance and regulatory requirements. the risk assessment applied to animal cell cultures relies on a thorough evaluation of both the intrinsic properties of the cell culture -including subsequent properties acquired as a result of genetic modification(s) -and the possibility that the cell culture may inadvertently be contaminated or deliberately infected with pathogenic micro-organisms. it also includes an exposure assessment which means that the type of manipulation carried out with the cell cultures is taken into account. the assessment of cell cultures harbouring pathogens follows the same principles as the assessment of the pathogens itself. first, the main organism characteristics (a comprehensive description of the pathogen) is considered by taking into account the following parameters (not by order of importance): (1) the pathogenicity and, when available, the infectious dose (2) the mode of transmission, (3) the host range, (4) the epidemiology (assignment of appropriate risk group may depend on the geographic localisation), possible reservoir and vector(s), and the ability to zoonosis (5) the stability and the persistence of the organism in the environment (i.e. survival outside the host). in addition, information related to the physicochemical properties of the pathogenic organism is considered such as: (1) susceptibility to disinfectants, (2) physical inactivation and (3) drug susceptibility (e.g. sensitivity and known resistance to antibiotics or antiviral compounds). finally, aspects related to the disease caused by the pathogen are also to be taken into consideration. this includes (1) the availability of an effective prophylaxis, (2) the availability of an efficient therapy and (3) any reported case of laboratory-acquired infection (s) (lais). although underestimated, many cases of lais related to the handling of cell cultures and/or containing virus suspension have been reported. among them are the reported laboratory worker's exposure to (recombinant) vaccinia viruses amplified in cell culture resulting into infections openshaw et al. 1991; mempel et al. 2003; moussatché et al. 2003; wlodaver et al. 2004; lewis et al. 2006 ; centers for disease control and prevention 2009b). recommendations to work safely with vaccinia virus have been reviewed recently together with an overview on the reported cases of lais involving this virus (isaacs 2012) . the risk assessment of cell cultures that are genetically modified basically follows a comparative approach: the characteristics of the gmo are compared to those of the non-modified (wild-type) organism from which it is derived under corresponding situations of use. the distinctive feature of the risk assessment of genetically modified cell cultures which consists of the evaluation of the recipient cell, the vector, the donor organisms and the inserted genetic material (insert) is developed in sect. 22.2.5. good knowledge and characterisation of the intrinsic properties of cells are key to successful and safe cell culturing. with respect to the biological risks and the risk assessment associated with the manipulation of animal cell cultures, three properties intrinsic to cell cultures should be considered : the species of origin, the cell type or type of tissue, organ from which the cell line is derived and the status of the culture ( fig. 22 .2). with respect to the species of origin and based on the fact that pathogens usually have specific species barriers, it is considered that the closer the genetic relationship of the cell culture is to humans, the higher the risk is to humans. the incidence to harbour organisms that could cause harm to human health is therefore considered higher in human or primate cells compared to cells of non-human origin (brown 1997) . accordingly, mammalian cells other than human or primate cells are considered to represent less risk, followed by avian and invertebrate cells. however, it should be kept in mind that some infectious agents are able to cross the species barrier and to persist in new host species, leading to zoonotic diseases. it is acknowledged since many years that more or less 70 % of the emerging infectious diseases are zoonotic (chomel et al. 2007) . well documented cases of viruses that have crossed the species barrier from animal reservoirs to humans include hantavirus (murine reservoir), haemorrhagic fever viruses (ebola, marburg) (peters et al. 1992 ), avian influenza virus (reperant et al. 2012) and severe acute respiratory syndrome (sars) associated coronavirus (ksiazek et al. 2003; herman et al. 2004) . these examples show that incidences of cross-species transfer can occur and that occupational risks related to exposure to infected animal tissues or cell cultures should not be underestimated (mahy and brown 2000; louz et al. 2005) . cells may dramatically differ in their in vivo half-life depending on the cell type or type of tissue from which these are derived. for example, intestinal and certain leukocytes have a half-life of a few days, human erythrocytes have approximately a 55-60-day half-life, healthy liver cells have a life span of several months, whereas, in adults, there is a slow loss of brain cells with little replacement. partly due to this fact, some cell lines can be more readily obtained than others. the establishment of cell lines is often obtained by a series of (generally uncontrolled) mutations that occur by culturing cells for a longer period. it is known that cells cultured for extensive periods of time display changing growth properties. a reduction of the doubling time, as a result of transformation, may give cells the ability to overgrow the rest of the population and to survive for a large (infinite) number of passages compared to primary cells with a finite life span. therefore, the establishment of cell cultures of a certain cell type upon extensive passage relies on the positive selection for cells that have a growth advantage. these transformed cells can have an increased tumorigenic potential and may present more risks of becoming/being fully neoplastic upon accidental (gugel and sanders 1986) or deliberate introduction into the human body. therefore, taking the tumorigenic potential into account, the following cell types may be ranked in increasing order of risk: epithelial and fibroblast cells, gut mucosa, endothelium, neural tissues, haematogenous (e.g. blood, lymphoid) cells and tissue. a third inherent property to consider is the status of cell culture. diagnostic and research activities involve the manipulation of primary cultures or cell lines as well as continuous cell lines derived from primary cultures. primary cell cultures and cell strains are produced directly from organs or tissues and are often the most accurate in vitro tool for reproducing typical cellular responses observed in vivo. however, as they are characterised by a finite life span, the time available for characterisation and detection of contaminating agents remains limited. also, because typical cell characteristics are often lost during the passage of cells, primary cell cultures are repeatedly obtained from fresh tissue, resulting in increasing risks for potential contaminating pathogens. a feature that distinguishes continuous cell lines from primary cell cultures is the ability to survive if not infinitely, at least for a great number of passages. these immortalised cells are obtained by isolating cells from tumours, by mutating primary cells with mutagens, by using viruses or recombinant dna to generate indefinitely growing cells or by cell fusioning of primary cells with a continuous cell line. due to their increased life span, the time left for thorough characterisation and detection of contaminating agents is considerably increased. within this respect, well-characterised cell lines present the lowest risks compared to primary cultures or less characterised cell lines as the origin, the source and suitability are well-known and well-defined. for cell lines obtained from external sources (e.g. different laboratory), crosscontamination of cell-lines and/or a lack of proof of identity is actually a widespread problem (buehring et al. 2004; capes-davis et al. 2010) . in order to have at least evidence of the species of origin of a cell line and to be able to conduct a thorough risk assessment, it may be necessary to fully characterise the used cell lines. for this purpose, a number of techniques are available such as cytogenetic analysis, dna fingerprinting, pcr, flow cytometry and isoenzyme analysis. (matsuo et al. 1999; cabrera et al. 2006 ). many micro-organisms benefit from a cell's machinery to complete their life cycles and to disseminate. hence the study of a pathogens' lifecycle or immunity escape mechanism requires the intentional in vitro infection of animal (or human) cells. the identification of potential hazards associated with infected cell cultures requires a consideration of the intrinsic cell properties and the inherent properties of the infecting pathogen. the latter implies an assessment of a number of pathogen specific criteria along with aspects such as the existence of effective treatment or prophylaxis. on the basis of these criteria the who defines a classification system that enables the categorisation of micro-organisms into four risk groups (world health organization 2004) . a fundamental rule is that the biological risk of infected cell cultures will depend on the infecting pathogen(s) class of risk. for example, cell cultures deliberately infected with hepatitis c virus (hcv) in order to produce virus particles are assigned to class of risk 3, as hcv is a class of risk 3 virus. human cells infected with an airborne pathogen like species of the mycobacterium tuberculosis complex are also assigned to class of risk 3 and are requiring the adoption of biosafety level 3 containment. however, as discussed below, the class of risk to which the infected cell cultures are assigned will not necessarily indicate the level of containment to be implemented as the latter will also be determined by the nature of the work carried out with these cells. an example is the infection of bovine leukocytes with theileria parva, a tick-transmitted, intracellular protozoan of veterinary importance and the causative agent of east coast fever among domestic livestock. it is an animal pathogen of risk group 3, which is not pathogenic to humans. the sporozoite form (infective form) invades bovine lymphocytes where it develops into a non-infective form (shizonts) and induces host cell transformation and clonal expansion of the cell. these infected bovine leucocytes may be categorised under class of risk 2 for animals, while the biosafety level (bsl1 or 2) appropriate for handling is determined by the presence or absence of the infectious form of the parasites. cell culture can also be coupled with electron microscopy to identify viral diseases of unknown cause as shown in a recent study published by the centers for disease control and prevention (goldsmith et al. 2013) . in case of outbreaks the harvested tissues from dead or living infected patients are inoculated to a permissive cell line (generally on vero e6 cells) and eventually subjected to electron microscopy for morphological analysis of the causal virus. although alternatives methods such as high throughput dna sequencing are available to identify a microorganism without a prior in vitro expansion, cell culture followed by electron microscopy remains the complementary approach of choice to molecular methods for the unbiased diagnosis of ill-defined infectious disease. some of the diagnostic activities presented by the authors required the adoption of bsl3 measures to handle the cell cultures. it illustrates how activities involving the in vitro amplification of unknown virus may represent a risk for the laboratory personnel and requires the adoption of an appropriate containment level and work practices. adventitious contamination of cell cultures is a major drawback for any activity that involves cell culturing (langdon 2004) . causative agents of cell contamination include bacteria, fungi, mycoplasms, parasites, viruses, prions and even other animal cells. beside the fact that contamination of cell cultures may place experimental results in question or may lead to the loss of cell cultures, one of the main biosafety concerns when manipulating animal cell cultures for research, diagnosis or production purposes is the fact that they may provide a support for contaminating agents that cause harm to human health. generally, bacterial or fungal contamination can be readily detected because of their capacity to overgrow cell cultures. typically, these organisms cause increased turbidity, ph shift of media (change in media colour), slower growth of the cells and cell destruction. antibiotics may be used to prevent cell bacterial contamination, however, continuous use of antibiotics in cultures may lead to development of resistant organisms with slow growing properties, which are much more difficult to detect by direct visual observation. compared to bacterial or fungal infections, mycoplasma contamination gives more problems in terms of incidence, detectability, prevention and eradication. mycoplasma, an intracellular bacterium, is one of the most common cell culture contaminants. it may go unnoticed for many passages and can change several cell properties such as growth, metabolism, morphology and genome structure (paddenberg et al. 1996; mcgarrity and kotani 1985) . it has also been reported to influence the yield of virus production in infected cells (hargreaves and leach 1970) . mycoplasmal contamination is also a biosafety concern, because some of the contaminating mycoplasma spp. belong to risk group 2. together with m. arginini, m. orale, m. pirum and m. fermentans, pathogenic organisms like m. gallisepticum (risk group 3 for animals), m. hyorhinis (risk group 2 for animals), m. pneumoniae and m. hominis (risk group 2 for humans) account for more than 96 % of mycoplasma contaminants in cell cultures. primary sources of contamination with m. orale, m. fermentans, and m. hominis in the laboratory are infected people who handle cell cultures and suspensions of viruses. sources of m. argini and m. hyorhinis are usually animal donors of tissues and biological constituents used for cell culture, e.g. calf serum and trypsin (razin and tully 1995; pinheiro de oliveira et al. 2013) . it was already reported that the contamination of cell cultures by mycoplasma occurs via aerosols (o'connell et al. 1964 ). viral contamination merits particular attention because infected cells may pose a serious harm to human health, especially when infected cells are able to release infectious particles. human cells may be infected by various viruses like hepatitis viruses, retroviruses, herpes viruses or papillomaviruses. although cell cultures from non-human origin may pose less risk, it should be emphasised that many viruses have a broad host range and can cross species barriers. since a number of non-human viruses are capable of infecting and/or replicating in human cells in vitro, their possibility to infect human cells in vivo if human exposure occurs should be carefully considered. well-known viral contaminants of primate tissues or cells from non-human origin that can cause human disease are listed in table 22 .1. while contamination with some viruses may be associated with changes in cell morphology or behaviour -such as the formation of syncytia (hiv, herpes viruses), swelling of cells (adenoviruses) or haemagglutination or haemadsorption -viral contamination may be harder to detect when cytopathic effects remain absent. viral contamination could also trigger adverse effects as a result of recombination events or phenotypic mixing between contaminating components and experimentally introduced agents, creating agents with new properties. for example, experimental results suggested that htlv-i or htlv-ii undergo phenotypic mixing with hiv-1 in htlv/hiv-1 co-infected cells, leading to an increase of the pathogenicity of hiv-1 by broadening the spectrum of its cellular tropism to cd4 negative cells (lusso et al. 1990 ). another example is the contamination of murine cell cultures by lymphocytic choriomeningitis virus (lcmv). lcmv is an arenavirus that establishes a silent, chronic infection in mice but causes aseptic meningitis, encephalitis or meningoencephalitis to humans. the significance of lcmv contamination has been reinforced by the description of cases of laboratory-acquired lcmv infections arising from contaminated murine tumour cell lines (mahy et al. 1991) . manipulation of lcmv infected material or material with an increased likelihood of lcmv contamination necessitates the whitley (2001) papovaviruses 2 butel ( adventitious contamination with parasites may be an issue when handling primary cell or organ cultures originating from a donor organism that is known or suspected to be infected with a specific parasite. as the life cycle of most parasites comprises distinct developmental stages, transmission and survival of the parasite will strongly depend on the ability of the invasive stage to recognize and invade specific host cells. but even with cells developing the non-infectious form of parasites, possible harmful effects remain to be considered since natural modes of transmission could be bypassed during the manipulation of infected cells. it is recognised that most of the parasitic laboratory acquired infections are caused by needle stick injuries (herwaldt 2001) . finally, the use of bovine-derived products as tissue culture supplements may also lead to the contamination with unconventional agents that cause transmissible spongiform encephalopathies (tse), the so-called prions (solassol et al. 2003; cronier et al. 2004; vorberg et al. 2004 ). contrary to the majority of the infectious agents, tse agents are resistant to most of the physical and chemical methods commonly used for decontamination of infectious agents. it has been shown that neuroblastoma cell lines, primary cultured neurons and astrocytes can serve as hosts (butler et al. 1988) . although many studies have suggested that the risk of propagation of tse agents in tissue culture cells cultivated in the presence of bovine serum potentially contaminated with tse was restricted to neurons or brain-derived cell cultures, it has been shown recently that non-neuronal cells can also support tse infection, suggesting that any cell line expressing normal host prion protein could have the potential to support propagation of tse agents (vilette et al. 2001; vorberg et al. 2004) . while the understanding of the transmission of prions is still in progress (natural transmission seems mainly to take place via oral route in human and animals), investigators using cell cultures need to take into account different routes by which these agents may be transmitted experimentally. mouse scrapie aerosol transmission has been successfully obtained in mice haybaeck et al. 2011) . in cervids, chronic wasting disease (cwd) was already proposed as a natural airborne pathogen (denkers et al. 2010 ). in the case of creutzfeldt jacob disease (cjd), there is to date no proof of release of prion into aerosols. animal cell cultures can also harbour unknown pathogens or whose tropism has not been defined yet. examples described in the literature include viruses such as hepatitis g (linnen et al. 1996) , hhv8 (moore et al. 1996) , tt virus (nishizawa et al. 1997) or human pneumovirus (van den hoogen et al. 2001) . cell cultures can be contaminated by different sources. infected organisms or infected animal cells or tissues from which a cell line has been established are the primary source of contamination. an accidental contamination can also occur through the material used for cell culturing including glassware, storage bottles and pipettes due to incorrect maintenance or sterilisation. before the use of disposable material the lip of the culture flask and the outside of the used pipette were important sources of contamination with mycoplasma (mcgarrity 1976). nowadays, the use of disposable and sterile pipettes has significantly decreased the likelihood of adventitious contamination. a third source of contamination resides in culture media and its components such as serum, basic culture media and salt solutions and enzymes (trypsin, pronase and collagenase). for example, media and additives derived from bovine sources are often contaminated with bovine viral diarrhoea virus (bvdv) (levings and wessman 1991) . as mentioned above the relative resistance of tse agents may also be an issue when using bovinederived products as tissue culture supplements. finally, non-filtered air supply, clothing, personnel and floor can be a source of airborne contamination (hay 1991) . genetically modified (gm) animal cell cultures are employed for a number of different activities. for example, the expression of transgenes and production of proteins of interest whose function depends on methylation, sulfation, phosphorylation, lipid addition, or glycosylation may necessitate the capacity of higher eukaryotic cells to perform post-translational modifications. gm animal cell cultures may also be chosen for the replication of defective recombinant or even wild type viruses. the risk assessment of gm cells should follow the five-step methodology as outlined in fig. 22 .1, which means that an evaluation of each individual aspect in the process of genetic modification should be performed. this includes an evaluation of the recipient cell, the vector, the donor organism properties and an assessment of the characteristics of the inserted genetic material. a comprehensive risk assessment of genetically modified cells expressing transgenes should also take into account the risk associated with the transgene products. a gene product may be intrinsically harmful (e.g. toxic properties) or could induce hazardous properties via its expression in gm cells, dependent upon the genome integration site, promoter activity and expression of regulatory sequences governing expression. the risk assessment for transgenes is not straightforward and demands appropriate consideration. comprehensive reviews have specifically addressed this topic (bergmans et al. 2008; van den akker et al. 2013 ). genetic modification may confer an expanded life-span, immortalisation or increased capacity for tumour induction. however, it is unlikely that recombinant properties obtained by genetic modification may have an adverse effect upon release of the recombinant animal or human cells into the environment. cells (genetically modified or not) have difficulties to survive in a hostile environment where control of temperature and osmolality is lacking or where cell-specific nutrients (e.g. glucose, vitamins, lipids) are not balanced or missing. hence, the survival of such primary cells or cell lines outside of proper conditions is unlikely to occur. apart from the fact that gm cell cultures may harbour pathogens and pose serious biological risks to human health (as discussed above), recombinant cells are more likely to cause harm when entering the body of animals or humans. however, the extent of the harmful effect remains hard to predict. it should be kept in mind that the lack of histocompatibility between recombinant cells and the host organism remains a major obstacle for these cells to survive and to multiply as the natural immune response of the healthy (immunocompetent) host will recognise foreign cells and eventually destroy them. this is also one of the main reasons why the culturing of cells originating from the laboratory worker is not allowed for research and diagnostic activities (risk associated with autologous cells). particular attention should be paid to the use of packaging cell lines. these are established cell lines that are deliberately and stably transfected with "helper constructs" to ensure the replication and packaging of replication deficient viral vectors. for example, in case of retroviral packaging cell lines, the expression of "helper genes" allows high-level constitutive production of viral proteins (e.g. gag, pol and env proteins), which are missing in the genome of the replication deficient viral vector but are crucial for viral replication. one of the main biosafety issues related to the use of packaging cell lines is the fact that replication-competent viruses may be generated as a result of (homologous) recombination between the replication deficient viral vector and viral sequences present in the packaging cell. these events could result in the formation of viruses with novel yet unwanted properties such as the generation of replication-competent viruses. one of the strategies to engineer safer generations of packaging cell lines consists in minimising the likelihood of generating replication-competent viruses by separating viral functional elements into different expression plasmids, thereby increasing the number of recombination events necessary to generate replication-competent viruses (dull et al. 1998) or by reducing or eliminating the sequence homology between the viral vector and the helper sequences. however, endogenous retrovirus genomes expressed in safer generations of retroviral packaging cell lines may still give rise to unwanted recombination events (chong et al. 1998) . this means that the possibility to generate replication-competent viruses cannot be ruled out. clearly, the risk group of the transfected packaging cell line will depend on the risk group of the viral vector itself. consequently, risk assessment of packaging cell lines should be based on the biosafety of the produced viral vectors, including an evaluation of their infectivity, spectrum of host range, capacity of integration (insertional mutagenesis), stability and physiological role of the transgene(s) if expressed (baldo et al. 2013 ). aside from the identification and characterisation of hazards intrinsic to the cell culture, a thorough risk assessment must also consider the exposure pathways through which cell cultures may present a risk to human health or the environment. this necessitates an evaluation of the type of manipulation, because processes, methods and/or equipment involved may increase or decrease the likelihood of exposure and hence the resulting potential risks. for instance, while established cell lines inherently present low risks, large scale operations involving the culturing of large volumes (from 10 to 1,000 l) are prone to contamination when inadequate containment measures are applied. this is exemplified by continuous processes such as cell cultivation in bioreactors where an appropriate design of seals, valves, pumps and transfer lines is required to guarantee long-term sterility of the operation to avoid inadvertent contamination. at the opposite, the handling of cell cultures belonging to risk group 2 may present less risk once they have been fixed by glutaraldehyde or formaldehyde/acetone for immunostaining and may therefore require less stringent containment measures manipulations that are common to research and diagnostic activities and warrant consideration with respect to the risk assessment of animal cell cultures are described hereunder: -procedures generating aerosols: pipetting, vortexing, centrifugation, opening of wet cups, etc.; -handling cells outside of a class ii bsc: flow cytometric analysis and cell sorting constitute a special case of cell manipulation in which cells are handled outside of a bsc. the use of a fixative is in many cases not appropriate (e.g. viable cell sorting for subsequent further cell culturing) and the risk of aerosol formation can be particularly high, especially during sorting experiments and upon instrument failure such as a clogged sort nozzle. all scientists in the field of flow cytometry must be aware of the potential hazards associated with their discipline and only experienced and well-trained operators should perform potentially biohazardous cell sorting. general recommendations approved by the international society of analytical cytology should help to set a basis for biosafety guidelines in flow cytometry laboratories (schmid 2012) . some standard operating procedures and methods have also been described for ensuring the cell sorting under optimal biosafety conditions even under bsl3 conditions (lennartz et al. 2005; perfetto et al. 2011 ). -altering culture conditions: changing the availability of cell-specific nutrients, growth factors, signal molecules or adopting co-culture techniques may have significant effects on animal cell cultures as it may result in altered neoplasia (stoker et al. 1990 ), altered expression of (proto)onco-genes or cell surface glycoproteins and release of endogenous viruses (cunningham et al. 2004) . as a consequence, changing culture conditions may lead to altered susceptibility of cultured cells to biologic agents such as viruses (anders et al. 2003; vincent et al. 2004 ). -manipulations involving use of needles or sharps: due to injuries cell material may be accidentally transferred directly to an operator's tissue and/or blood stream. -in vivo experiments involving animals: major risks are self-inoculation (needlestick injury) and exposure to aerosols. laboratory workers handling infected rodents or cell cultures originating from infected animals expose themselves at risk by directly exposing cuts, open wounds or mucus membranes with infected body fluids or by inhaling infectious aerosolized particles of rodent urine, faeces or saliva. the risk can be minimised by utilising animals or cell cultures from sources that are regularly tested for the virus. finally, the purpose of cell culturing should be taken into consideration as many clinical approaches such as stem cell therapy, gene therapy, xeno-or allotransplantation involve cell culturing ex vivo for therapeutic purposes. this latter clearly justifies more careful consideration regarding safety, ethical, social and regulatory issues, which will not be addressed in this chapter (food and drug administration; european medicines agency; ich 1997). the assessment of biological risks related to animal cell cultures and the type of manipulation allows the determination of an adequate containment level in order to optimally protect human health and the environment. the implementation of an appropriate containment level includes a list of general and more specific work practices and containment measures. table 22 .2 lists precautionary measures that should be applied whenever handling animal cell cultures. much of these measures focus on reducing the risk of contamination with adventitious agents. it should be emphasised that the drawn-up of an appropriate set of standard operating procedures and adequate training of the staff is of crucial importance. as a general rule, cell cultures known to harbour an infectious etiologic agent should be manipulated in compliance with containment measures recommended for the etiologic agent. when cell cultures are not known to harbour infectious agents, cells may be considered free of contaminating pathogens as long as a number of conditions are fulfilled. this implies the use of well-characterised cell lines or controlled cell sources for primary cells such as specified-pathogen-free (spf) animals. if no well-characterised cell lines or spf are available, tests for detection of likely contaminating agents should be negative. second, whenever cell cultures are manipulated, media sources should be pathogen free and appropriate containment measures should be adopted to reduce potential contaminations during sampling or subsequent manipulation of cells (re-feeding and washing steps). as the history of a cell culture may be poorly documented when a given cell culture is manipulated for the first time in the laboratory, it often remains unclear whether all appropriate measures have been implemented regardless of the fact that it may have been manipulated for years in another laboratory facility. in this case, cell cultures should be considered to be potentially infectious and should be manipulated in a class ii bsc. if the presence of adventitious agents of a higher risk group is considered likely, the cell line should be handled under the appropriate containment level until tests have proven the absence of such organisms. good documentation of the history of cell cultivation is mandatory. the extent to which cell cultures should be controlled on the likelihood of contaminants strongly depends on the nature of activity. for example, guidelines have been issued aiming at minimising any potential risk for transmission of infectious agents with respect the use of animal cell cultures for industrial production of biopharmaceuticals (european medicines agency; food and drug administration; ich 1997; world health organization 1998). hardly any guidance has been provided for the extent of detecting possible contaminants in case animal cell cultures are used for in vitro research or diagnostic activities, or for purposes other than therapeutics or production of biopharmaceuticals. the choice of the detection technique depends on the contaminating pathogen and often a combination of methods is recommended for important samples such as master cell banks. the implementation of bsl2 measures is adequate for most of the work carried out with cell cultures from human or primate origin. bsl1 measures may be considered provided that all manipulations occur in a class ii bsc and the cell culture is a well-characterised and certified cell line that presents no increased risk resulting from genetic modification or contaminating pathogen. the contained use to be in compliance with good cell culture practice (gccp), especially in industrial settings for vaccine production. to avoid opening of culture vessels or contact with culture fluid through a defective culture vessel, stopper or poor technique because of the ever present likelihood of contamination with airborne pathogens. to treat each new culture that is manipulated for the first time in the laboratory facility as potentially infectious. to clean up any culture fluid spills immediately with an appropriated and validated disinfection protocol. to work with one cell line at a time and disinfect the work surfaces between two operations involving cell lines. to aliquot growth medium and other substrates so that the same vessel is not used for more than one cell line. to mitigate cross-contamination by avoiding pouring actions. to proceed to the use of the biosafety cabinet (bsc) by adequately trained staff, t.i. turn on for a period before and after use, thoroughly disinfect bsc surfaces after each work session and do not clutter the bsc with unnecessary materials. to restrict the use of antibiotics in growth media. to quarantine new cell cultures to a dedicated bsc or separate laboratory until the culture has been shown negative in appropriate tests. to carry out a quality control of cells demonstrating the absence of likely contaminating pathogens on a regular basis or whenever necessary. to operate cell cultures from undefined sources as risk group/class of risk 2 organism. if the presence of adventitious agents of higher risk class is expected, the cell line should be handled under appropriate containment level until tests have proven safety. adapted from pauwels et al. (2007) in a bsl1 of viral infected cells could be envisaged if no viral particles are detectable in the supernatant of the infected cells. however, it should be emphasized that procedures for viral clearance are virus-host specific and that variables such as vector titre and the infection protocol can influence the degree and rate of clearance (bagutti et al. 2012) . since the implementation of good laboratory practices and the use of a bsc is usually the norm in most laboratories dealing with cell culturing, we think that bsl1 laboratories can relatively easily be upgraded to bsl2 facilities by implementing a restricted number of simple additional safety measures. it is important to notice that horizontal laminar air flows and clean benches minimise the risk of adventitious contamination of the cell cultures, however they offer no protection for the manipulator or the environment. bearing in mind that biosafety measures intend to provide a maximal protection of human health and the environment, it is important to note that the sole use of a horizontal laminar "clean bench" should be prohibited. based on, but not limited to, key features of risk assessment and the type of manipulation performed as discussed in former paragraphs, we developed a flow diagram providing the cell culture users a schematic guidance for the assignment of an appropriate containment level when manipulating human or primate cells in vitro (fig. 22.3) . this flowchart is indicative and should be applied and/or reconsidered according to case specific conditions and risk assessments proper to the activities performed. whenever possible approaches developed to ab initio reduce the risk associated with the handling of animal cell cultures should be favoured. such approaches involve the use of dedicated instruments or safer biological material. the examples hereunder illustrate how the choice to apply one or several of these approaches is determined on a case-by-case basis, depending on the intrinsic characteristics of the biological material and the intended use. during the last couple of years instruments enabling automated mechanical passaging and nutrient supply for in vitro cell expansion have been developed for primary cells, adherent and non-adherent mammalian cells (kato et al. 2010; thomas and ratcliffe 2012) . some of these developments also provide a safer approach with respect to biosafety considerations by including a biosafety module in the design of such automated platforms. for example a long-term cell culture device ensuring both the protection of the product and the operator has been designed for the culturing of embryonic stem cells in an antibiotic-free medium by means of an integrated automation platform using a class ii bsc confining the microwells (liquid handling robot contained in a bsc) (hussain et al. 2013) an automation system has also been deployed for the production (140-1,000 ml) of hiv-1 pseudovirus for hiv vaccine trials in compliance with gclp. this robust automated system for cultivation of 293 t/17 cells is contained in a class ii bsc that guarantees the protection of the workers, environment and the product. this system can be implemented to produce other biological reagents under standardised large-scale conditions (schultz et al. 2012) . lowering the hazards associated with the cell cultures handled is another approach that was applied in the characterisation of pandemic influenza viruses under emergency situations. while such activities typically require bsl3 conditions, inactivation protocols applied to influenza virus culture allows for performing the virological and immunological assays under bsl2 conditions (jonges et al. 2010) . another example where the assignment of a less stringent containment level was enabled relates to the use of insect cells and gm bacteriophage lambda capsids in cases where usually the maintenance of infectious stocks of highly pathogenic or emerging influenza viruses is involved (domm et al. 2014) . the bacteriophages are "decorated" by the viral glycoproteins of interest in an insect cell-derived system so as to use hemagglutinin displaying bacteriophages in hemagglutination-inhibition assay on pathogenic influenza viruses. the same approach was already applied for hiv-envelope protein (mattiacio et al. 2011) . with regards to hiv-1 in vitro testing, a non-infectious cell-based assay to assess the hiv-1 susceptibility to protease inhibitors was also developed recently (buzon et al. 2012) . here again, activities that normally require relatively high containment level can be performed in facilities with less expensive infrastructure. it also shows that careful consideration of the material handled can lead to costeffective choice while maintaining the same objectives. biosafety is an internationally recognized concept referring to the maximal protection of laboratory workers, public health and the environment from the possible adverse effects associated to the use of organisms and microorganisms (genetically modified or not). within this respect activities involving the use of animal cell cultures for fundamental research, r&d or in vitro diagnosis purposes pose biosafety considerations as well. before starting any of such activities biosafety considerations should be addressed by performing a biological risk assessment allowing the identification and characterisation of any potential adverse effect together with an evaluation of the likelihood and consequences should any effect happen. such an approach is made on a case-by-case basis, taking into account the type of manipulation and the type of cell culture handled. a risk assessment will result in biosafety recommendations in view of the implementation of an adequate containment level. considering the very limited persistence capacity of animal and human cells outside non-optimised culture conditions and the fact that many cell lines have a long history of safe use, it is generally considered unlikely that cell cultures may inherently cause harm to humans or the environment. the main hazard associated with the handling of animal cell cultures resides in the presence of adventitious pathogenic micro-organisms, which are often difficult to detect and hence less controllable. in contrast to their host cells, adventitious organisms can persist in more hostile conditions and may present risks for human health or the environment in case they are pathogenic (bean et al. 1982; walther and ewald 2004; kallio et al. 2006; kramer et al. 2006) . for this reason, a risk assessment of cell cultures will frequently lead to a risk assessment of the potential adventitious contaminants, the organisms used for cell's immortalisation (viruses, viral sequences, etc.) and/or the microorganisms intentionally used to experimentally infect them. though the assignment of biosafety containment level requirements cannot be generalised and should be performed on a case-by-case basis, it is recognised that most of the containment measures primarily aim at protecting cells from adventitious contamination in order to mitigate potential risks for the laboratory worker. except for authenticated cell lines proved to present no risk, the activities involving cell cultures from human or primate origin should generally be performed under containment level 2 involving the use of a class ii biosafety cabinet and good laboratory practice. whilst the occurrence of adverse effects related to the handling of cell cultures cannot be excluded, a thorough risk assessment and the implementation of the appropriate containment level offer an optimal protection for the laboratory worker and by extension, public health and the environment. continuous efforts have been made to mitigate the risk associated with the handling of cell culture in laboratory settings. these biorisk management (continued) measures (i.e. adoption of the appropriate containment level) can be coupled with the implementation of automation platforms allowing the reduction of cell culture cross-contamination and accidental contamination with infectious agents. it is anticipated that future efforts contributing to the improvement of the quality of the data necessary for the risk assessment, the containment measures and the increased awareness of biosafety considerations within the scientific community will also directly benefit the quality of research activities involving animal cell cultures. authentication is the process by which the true origin and identity of cell lines are determined and should form an essential part of any cell culture operation. biosafety in the context of this chapter, biosafety relates to the evaluation of the potential risks to human health and the environment associated with the use of genetically modified organisms (gmos) or pathogenic organisms. biosafety cabinet (class ii) safety cabinet with a front aperture through which the operator can carry out manipulations inside the cabinet and which is constructed so that the laboratory worker is protected, the product and cross contamination is low. the escape of airborne particulate contamination generated within the cabinet is controlled by means of an appropriate filtered internal airflow and filtration of the exhaust air (hepa filters). contained use any activity in which (micro)-organisms are genetically modified or in which such organism (pathogenic or not) are cultured, stored, transported, destroyed, disposed or used in any other way, and for which specific containment measures are used to limit their contact with the general population and the environment. culture type: primary cell cultures, diploid cell lines, continuous cell lines primary cell cultures are established directly from tissues of animals and are often the most appropriate in vitro tool for reproducing typical cellular responses observed in vivo. however, as typical cell characteristics are lost during passaging, these cultures must be obtained from fresh tissue that may contain or may become inadvertently contaminated with pathogens. consequently, primary cell cultures may potentially present increased risks compared to continuous, established cell lines. diploid cell lines are similar to primary cells, are considered non-tumourogenic and have a finite capacity for serial propagation. they are used for the preparation of viral vaccines and are from human or monkey origin. continuous cell lines are immortalized cells that may survive almost infinite serial passages. these cells are obtained by either isolating cells from tumours (neoplastic origin), primary cells treated with mutagens, oncogenic viruses or recombinant dna (oncogenes) or by cell fusioning of primary cells with a continuous cell line. as a consequence, the class of risk of these cell lines is often correlated to the class of risk of primary cells of whom they are derived. due to the "immortality" of the continuous cell lines, their ability to induce tumours has also to be considered. transfection gene transfer of dna in eukaryotic cells using non-viral delivery methods. transduction gene transfer of dna in eukaryotic cells using viral vectors. infection process occurring when a virus (wild type) that typically replicates and spreads into neighbouring cells mediates a gene transfer belonging to its own genome or extra genes it may carry. viral vector is a protein particle derived from a replicative virus that contains genetic information in the form of rna or dna. a viral envelope may be present as well. the approved list of biological agents, 3rd edn. health and safety executive disruption of 3d tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor washout kinetics of viral vectors from culture mammalian cells general considerations on the biosafety of virus-derived vectors used in gene therapy and vaccination survival of influenza viruses on environmental surfaces 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automated adherent human cell culture (mesenchymal stem cells) environmental risk assessment of replication competent viral vectors applied in clinical trials: potential effects of inserted sequences a newly discovered human pneumovirus isolated from young children with respiratory tract disease persistent infection of some standard cell lines by lymphocytic choriomeningitis virus: transmission of infection by an intracellular agent emergent human pathogen simian virus 40 and its role in cancer ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein cytokine-mediated downregulation of coxsackievirus-adenovirus receptor in endothelial cells susceptibility of common fibroblast cell lines to transmissible spongiform encephalopathy agents pathogen survival in the external environment and the evolution of virulence biology of b virus in macaque and human hosts, a review herpes simplex viruses laboratory-acquired vaccinia infection world health organization (1998) who requirements for the use of animal cells as in vitro substrates for the production of biologicals. who technical report series laboratory biosafety manual manuel of diagnostic tests and vaccines for terrestrial animals. chapter 1.1.2 biosafety and biosecurity in the veterinary microbiology laboratory and animal facilities acknowledgments the authors are grateful to their colleagues dr. didier breyer and dr. aline baldo (scientific institute of public health wiv-isp, brussels, belgium) for their useful review of this manuscript. key: cord-255249-jtx3ntil authors: gratz, kim l.; tull, matthew t.; richmond, julia r.; edmonds, keith a.; scamaldo, kayla m.; rose, jason p. title: thwarted belongingness and perceived burdensomeness explain the associations of covid‐19 social and economic consequences to suicide risk date: 2020-07-14 journal: suicide life threat behav doi: 10.1111/sltb.12654 sha: doc_id: 255249 cord_uid: jtx3ntil objective: the social and economic consequences of covid‐19 and related public health interventions aimed at slowing the spread of the virus have been proposed to increase suicide risk. however, no research has examined these relations. this study examined the relations of two covid‐19 consequences (i.e., stay‐at‐home orders and job loss) to suicide risk through thwarted belongingness, perceived burdensomeness, and loneliness. method: online data from a nationwide community sample of 500 adults (mean age = 40) from 45 states were collected between march 27 and april 5, 2020. participants completed measures assessing thwarted belongingness, perceived burdensomeness, loneliness, and suicide risk, as well as whether they (a) were currently under a stay‐at‐home order and (b) had experienced a recent job loss due to the pandemic. results: results revealed a significant indirect relation of stay‐at‐home order status to suicide risk through thwarted belongingness. further, whereas recent job loss was significantly correlated with suicide risk, neither the direct relation of job loss to suicide risk (when accounting for their shared relations to perceived burdensomeness) nor the indirect relation through perceived burdensomeness was significant. conclusions: results highlight the potential benefits of interventions targeting thwarted belongingness and perceived burdensomeness to offset suicide risk during this pandemic. , extraordinary social distancing interventions have been implemented in many states to slow the spread of the virus, including relatively restrictive shelter-in-place or stay-at-home orders issued in 42 states, the district of columbia, and puerto rico (mervosh, lu, & swales, 2020) . these orders, which have shuttered schools, universities, and nonessential businesses, urge individuals to stay at home unless it is absolutely necessary to leave, and promote strict physical distancing to slow the spread of the virus (cdc, 2020). from a public health perspective, the reasoning behind such interventions is clear: physically separating people is an effective strategy for preventing infectious diseases from spreading (ahmed, zviedrite, & uzicanin, 2018; jackson, mangtani, hawker, olowokure, & vynnycky, 2014; qualls et al., 2017) , including covid-19 (flaxman et al., 2020; thakkar, burstein, hu, selvajar, & klein, 2020 ). yet, despite the necessity of stay-at-home orders and other social distancing interventions from a disease prevention perspective, these measures are likely to have numerous unintended social and economic consequences that may adversely affect psychological outcomes during this time (galea, merchant, & lurie, 2020; reger, stanley, & joiner, 2020; thunström, newbold, finnoff, ashworth, & shogren, 2020) . indeed, pandemics of this nature have well-documented economic and social consequences (chen, huang, chuang, chiu, & kuo, 2011; reger et al., 2020; thunström et al., 2020) -some of which have been linked to psychological difficulties (montemurro, 2020; wang et al., 2020) , including suicide risk (see reger et al., 2020) . currently, in the united states, beyond the immediate physical health consequences of covid-19 (and related fear and distress associated with these consequences), two consequences of the covid-19 pandemic that stand out as particularly relevant to suicide risk are the social isolation related to stay-at-home orders and the widespread job loss related to the current economic crisis-both of which have been theoretically and/or empirically linked to suicide risk (e.g., classen & dunn, 2012; oyesanya, lopez-morinigo, & dutta, 2015; reger et al., 2020) . for example, with regard to the economic consequences of this pandemic, both theory and research support an association between involuntary job loss and suicide risk (classen & dunn, 2012; milner et al., 2014) , with recent job loss from mass-layoffs in particular (comparable to what is occurring currently in the united states) associated with increased suicide risk (classen & dunn, 2012) . likewise, the widespread social distancing interventions implemented to slow the spread of the virus (of which stay-at-home orders are the most restrictive) have been proposed to increase suicide risk by increasing social isolation and loneliness (reger et al., 2020) . specifically, although stay-at-home orders are designed to increase physical distancing in particular (and need not negatively impact social connections and connectedness through remote or virtual means), researchers have suggested that an unintended consequence of social distancing interventions may be an increase in social isolation and related feelings of loneliness (reger et al., 2020) . loneliness, in turn, is a well-documented suicide risk factor (e.g., calati et al., 2019; joiner, ribeiro, & silva, 2012; li, dorstyn, & jarmon, 2020 ) that evidences strong associations with suicidal ideation, suicide attempts, and suicide risk (e.g., calati et al., 2019; chang et al., 2017; li et al., 2020; stickley & koyanagi, 2016; stravynski & boyer, 2001) . beyond just examining the relations of pandemic-related stay-athome orders and job loss to suicide risk, research is needed to clarify the factors that may account for these relations. the interpersonal psychological theory of suicide (its; van orden et al., 2010) provides a particularly useful framework in this regard. according to this theory, the desire for suicide is driven by perceived burdensomeness (i.e., perceptions of being a burden to others) and thwarted belongingness (i.e., feeling disconnected from and lacking meaningful relationships with others). notably, although thwarted belongingness overlaps with loneliness, it is a broader construct that also captures the nature and extent of supportive and reciprocal interpersonal relationships. a recent meta-analysis provides empirical support for this theory and the proposed relations of perceived burdensomeness and thwarted belongingness to suicidal desire (chu et al., 2017) . with regard to the relevance of these factors to the relations of interest in this study, thwarted belongingness would be expected to play a particularly important role in the relation of stay-at-home orders to suicide risk, capturing the proposed unintended negative consequences of social distancing interventions on social connectedness (reger et al., 2020) . conversely, although a recent job loss could also contribute to thwarted belongingness (particularly if that job was a primary source of social connection), theory suggests the particular relevance of perceived burdensomeness to the relation between job loss and suicide risk. specifically, the inability to provide for loved ones or support oneself financially could increase the experience of being a burden on others, which, in turn, would increase the desire for suicide and suicide risk (cukrowicz, cheavens, van orden, ragain, & cook, 2011; van orden et al., 2010) . the present study examined the relations of covid-19-related stay-at-home orders and job loss to suicide risk, both directly and indirectly through thwarted belongingness and perceived burdensomeness. given that social distancing and related social isolation have been proposed to increase suicide risk through loneliness, we also examined the indirect relation of stay-at-home orders in particular to suicide risk through loneliness. we hypothesized that both recent job loss and stay-at-home order status would be associated with increased suicide risk. we also hypothesized the differential relevance of thwarted belongingness and perceived burdensomeness to the relations of stay-at-home order status and pandemic-related job loss, respectively, to suicide risk. specifically, we hypothesized that stay-at-home order status would be indirectly related to suicide risk through thwarted belongingness and loneliness, whereas recent job loss would be indirectly related to suicide risk through perceived burdensomeness. participants included a nationwide community sample of 500 adults from 45 states in the united states who completed online measures through an internet-based platform (amazon's mechanical turk; mturk) from march 27, 2020, through april 5, 2020. the study was posted to mturk via cloudresearch (cloudresearch.com), an online crowdsourcing platform linked to mturk that provides additional data collection features (e.g., creating selection criteria; chandler, rosenzweig, moss, robinson, & litman, 2019) . mturk is an online labor market that provides "workers" with the opportunity to complete different tasks in exchange for monetary compensation, such as completing questionnaires for research. data provided by mturkrecruited participants have been found to be as reliable as data collected through more traditional methods (buhrmester, kwang, & gosling, 2011) . likewise, mturk-recruited participants have been found to perform better on attention check items than college student samples (hauser & schwarz, 2016) and comparably to participants completing the same tasks in a laboratory setting (casler, bickel, & hackett, 2013) . studies also show that mturk samples have the advantage of being more diverse than other internet-recruited or college student samples (buhrmester et al., 2011; casler et al., 2013) . participants (47% women; 51.8% men; 0.2% transgender; 0.6% nonbinary; 0.4% other) ranged in age from 20 to 74 years (m age = 40.0 ± 11.6). all states in the united states were represented, with the exception of delaware, new hampshire, north dakota, vermont, and west virginia (see table 1 for the distribution of participants across states). most participants identified as white (85%), followed by black/african-american (8.4%), asian/asian-american (6.6%), latinx (1.9%), and native american (1.6%). regarding educational attainment, 11.8% had completed high school or received a ged, 35.6% had attended some college or technical school, 43% had graduated from college, and 9.6% had advanced graduate/professional degrees. most participants were employed full-time (69.2%), followed by employed part-time (16.2%) and unemployed (14.6%). annual household income varied, with 30.6% of participants reporting an income of <$35,000, 33.6% reporting an income of $35,000 to $64,999, and 35.8% reporting an income of ≥$65,000. with regard to participants' household composition, 58.6% reported living alone and the remaining 41.4% reported living with at least one other person (ranging from 2-8; mean = 3.2 ± 1.1). very few participants reported having sought out testing for covid-19 (1%) or having been infected with covid-19 (0.8%). all procedures received approval from the university's institutional review board. to ensure the study was not being completed by a bot (i.e., an automated computer program used to complete simple tasks), participants first responded to a completely automatic public turing test to tell computers and humans apart (captcha) prior to providing informed consent. on the consent form, participants were also informed that "…we have put in place a number of safeguards to ensure that participants provide valid and accurate data for this study. if we have strong reason to believe your data are invalid, your responses will not be approved or paid and your data will be discarded." data were collected in blocks of nine participants at a time, and all data, including attention check items and geolocations (i.e., geographical coordinates used to identify participants outside of the united states and/or in locations determined to be "bot farms" within the mturk community; see kennedy, clifford, burleigh, jewell, & waggoner, 2018) , were examined by researchers before compensation was provided. attention check items included three explicit requests embedded within the questionnaires (e.g., "if you are paying attention, choose '2' for this question"), two multiple-choice questions (e.g., "how many words are in this sentence?"), a math problem (e.g., "what is 4 plus 2"), and a free-response item (e.g., "please briefly describe in a few sentences what you did in this study"). participants who failed one or more attention check items were removed from the study (n = 53 of 553 completers). workers who completed the study and whose data were considered valid (based on attention check items and geolocations; n = 500) were compensated $3.00 for their participation. the ucla loneliness scale-version 3 (uls-3; russell, 1996; russell, peplau, & cutrona, 1980 ) is a 20-item self-report measure of perceptions of loneliness and social isolation. participants rate items (e.g., "no one really knows me well;" i lack companionship;" "there are people i feel close to [reverse scored]") based on how often they apply to themselves on a 4-point likert-type scale ranging from 1 (never) to 4 (often). higher scores are indicative of greater loneliness. the uls-3 has demonstrated adequate test-retest reliability and good construct validity (russell, 1996) . internal consistency in the present sample was acceptable (α = 0.94). the depression symptom index-suicide subscale (dsi-ss; metalsky & joiner, 1997) was used to measure current suicide risk. the dsi-ss is a 4-item screening measure that assesses the frequency and intensity of suicidal thoughts, plans, and impulses over the past 2 weeks. scores on this measure have been found to be positively associated with depression symptoms (cukrowicz et al., 2011; joiner, pfaff, & acres, 2002) and to be higher among individuals with (vs. without) a history of suicide attempts (capron et al., 2012) . for the present study, a continuous variable assessing the severity of current suicide risk was calculated by summing all four items (α = 0.94 in this sample). at the time of data collection, 82.4% (n = 412) of participants were under a stay-at-home order and 11% (n = 55) reported a recent job loss related to the pandemic. on the dsi-ss, 11.6% (n = 58) of participants were classified as having high suicide risk (operationalized as a score of ≥3 on this measure; joiner et al., 2002) . descriptive data for and correlations among the primary variables of interest are ta b l e 2 descriptive data for and correlations among the primary variables of interest (n = 500) presented in table 2 . results revealed significant positive zero-order associations between recent job loss (0 = no; 1 = yes) and both suicide risk and perceived burdensomeness. stay-at-home order status (0 = no; 1 = yes) was not significantly correlated with suicide risk; however, it was significantly positively correlated with thwarted belongingness and loneliness. the process (version 3.3) macro for spss (model 4; hayes, 2017) was used to examine the indirect relations of (a) recent job loss to suicide risk through perceived burdensomeness (thwarted belongingness and loneliness were not examined in this model due to their lack of significant associations with recent job loss); and (b) stay-athome order status to suicide risk through thwarted belongingness and loneliness (perceived burdensomeness was not examined in this model due to its lack of significant association with stay-at-home order status). in both models, age, sex, racial/ethnic background, income, and household composition (lives alone vs. lives with other people) were included as covariates, given their relevance to suicide risk and/or pandemic-related outcomes. all indirect relations were evaluated using bias-corrected 95% confidence intervals based on 10,000 bootstrap samples. with regard to the analysis examining the indirect relation of recent job loss to suicide risk through perceived burdensomeness, the overall model was significant, accounting for 29% of the variance in suicide risk, f (7, 492) = 28.62, p < .001. although the total relation of recent job loss to suicide risk (including both the direct relation and the indirect relation through perceived burdensomeness, represented in figure 1 as path c) was significant, the direct relation of recent job loss to suicide risk (i.e., the remainder of the relation not accounted for by the indirect relation through perceived burdensomeness, represented in figure 1 as c'; preacher & hayes, 2008) was not significant. further, although recent job loss was significantly associated with perceived burdensomeness and perceived burdensomeness was significantly associated with suicide risk in the model, the indirect relation of recent job loss to suicide risk through perceived burdensomeness was not significant (see figure 1 ). as for the analysis examining the indirect relation of stay-athome order status to suicide risk through thwarted belongingness and loneliness, the overall model was significant, accounting for 12% of the variance in suicide risk, f (8, 491) = 8.21, p < .001. of note, although stay-at-home order status was significantly uniquely associated with both thwarted belongingness and loneliness, only thwarted belongingness (and not loneliness) was significantly uniquely associated with suicide risk. in addition, results revealed a significant indirect relation of stay-at-home order status to suicide risk through thwarted belongingness, but not loneliness (see figure 2 ). the results of this study provide preliminary empirical support for the theorized relations of covid-19-related social and economic consequences to increased suicide risk (reger et al., 2020) . specifically, the results of this study highlight the differential relevance of thwarted belongingness and perceived burdensomeness to the relations of stay-at-home orders and pandemic-related job f i g u r e 1 indirect relation of recent job loss to suicide risk through perceived burdensomeness. loss, respectively, to suicide risk. providing partial support for study hypotheses, although the presence of a stay-at-home order was not significantly associated with greater suicide risk at a zero-order level, it was indirectly related to suicide risk through greater thwarted belongingness. these findings suggest that any association of stay-athome orders (at least in the short-term) to suicide risk is due to the association these orders have with increased social disconnection (reger et al., 2020) . interestingly, although the presence of a stay-athome order was significantly uniquely associated with both loneliness and thwarted belongingness, only thwarted belongingness was uniquely associated with suicide risk and explained the relation of stay-at-home order status to suicide risk in this sample. together, these results suggest that although stay-at-home orders may very well increase the potential for loneliness among adults in the united states, it is not loneliness specifically but a broader sense of disconnection and absence of meaningful relationships that accounts for the relation of stay-at-home orders to greater suicide risk. results of this study also provide partial support for study hypotheses pertaining to the relation of pandemic-related job loss to suicide risk. specifically, although recent job loss evidenced a significant zero-order correlation with suicide risk, it was not uniquely associated with suicide risk when perceived burdensomeness was included in the model. likewise, results provided no support for an indirect relation of job loss to suicide risk through perceived burdensomeness. these findings are most consistent with a proxy risk factor model (see kraemer, stice, kazdin, offord, & kupfer, 2001) , suggesting that the total relation of recent job loss to suicide risk is due to their shared association with perceived burdensomeness. although inconsistent with our hypotheses, these results are not without support in the literature, as there is some evidence to suggest that involuntary job loss in general is not associated with increased suicide risk in the short-term, outside of mass-layoff events (see classen & dunn, 2012) . instead, evidence suggests that the duration of time spent unemployed following a job loss may be more strongly associated with suicide risk (classen & dunn, 2012 several limitations warrant consideration. first, the use of cross-sectional data precludes any conclusions about the precise nature or direction of the associations examined here. in particular, although theory and research suggest that both job loss and social isolation may increase suicide risk (classen & dunn, 2012; oyesanya et al., 2015; reger et al., 2020) , our data cannot rule out the possibility that elevations in suicide risk reported in this study preceded or occurred concurrently with (but unrelated to) these factors. prospective, longitudinal studies are needed to clarify the extent to which the social and economic consequences of covid-19 and related stay-at-home orders increase suicide risk, as well as the mechanisms underlying these relations. another limitation is the exclusive reliance on self-report questionnaire data, which may be influenced by social desirability biases or recall difficulties. future research should incorporate structured clinical interviews and/or timeline follow-back procedures to assess suicide risk and its temporal relation to social distancing and economic difficulties. likewise, although the use of a diverse nationwide community sample is a strength of this study, the generalizability of our findings to particular at-risk groups (e.g., hospitalized patients, individuals with chronic medical conditions, health care workers) remains unclear. future research is needed to examine the relations of covid-19 and related social and economic consequences to suicide risk within these vulnerable groups in particular. finally, it is important to note that the results of this study speak to only the early associations of stay-at-home orders and covid-19related job loss to suicide risk among individuals in the united states. however, it is likely that the consequences and psychological impact of these factors may change over time. for example, and consistent with the proposed mechanisms through which stay-at-home orders and other social distancing interventions are thought to increase suicide risk (reger et al., 2020) , the psychological impact and negative consequences of these orders may intensify over time, with suicide risk increasing as the duration of these orders increases. likewise, research suggests that the duration of unemployment following an involuntary job loss is more strongly associated with suicide risk than the initial job loss (classen & dunn, 2012) ; thus, it is likely that the relation between pandemic-related job loss and suicide risk may increase over time, particularly in the context of the current economic crisis and ongoing stay-at-home and shelter in place orders (which decrease the likelihood of obtaining a new job in the near future). although research examining the early impact of this pandemic and associated factor on suicide risks is important, it is imperative that research continues to track these relations as the pandemic and related public health interventions persist over time. despite these limitations, the results of this study highlight the potential impact of covid-19 social and economic consequences on suicide risk among adults in the united states, as well as the relevance of thwarted belongingness and perceived burdensomeness to these associations. these results are consistent with theory and research highlighting the relevance of thwarted belongingness and perceived burdensomeness to suicide risk (e.g., chu et al., 2017; van orden et al., 2010) , and suggest that these may be important factors to target in the context of focused interventions aimed at decreasing suicide risk during this time. in the absence of effective covid-19 infection prevention efforts and/or pharmacological interventions (e.g., vaccines), large-scale public health interventions such as social distancing or stay-at-home orders are necessary to reduce the spread of the virus and infection-related mortality. however, in the context of these necessary public health interventions, our results speak to the need to also implement interventions aimed at mitigating the negative psychological consequences of both the social isolation and economic problems that can arise from or be exacerbated by stay-at-home orders. specifically, our results provide further support for recent suggestions to focus on increasing social connection and connectedness in the context of stay-at-home orders and other social distancing interventions, in an effort to offset the isolation, loneliness, and disconnection that may inadvertently accompany these orders (see reger et al., 2020) . likewise, among individuals who have experienced a job loss during this time, our findings suggest that interventions aimed at decreasing perceived burdensomeness and increasing individuals' awareness of and connection to their contributions to the lives of others may help to decrease suicide risk among this vulnerable population. finally, given both theoretical and emerging empirical literature suggesting increased suicide risk during this pandemic, it is important that crisis call centers continue to be funded and staffed to ensure that individuals who may have limited social contacts are able to seek help in emergency situations. likewise, it is imperative that evidence-based tele-mental health services are made available and accessible to vulnerable individuals throughout the duration of stay-at-home orders and other social distancing interventions (reger et al., 2020) . effectiveness of workplace social distancing measures in reducing influenza transmission: a systematic review amazon's mechanical turk: a new source of inexpensive, yet high-quality, data? suicidal thoughts and behaviors and social isolation: a narrative review of the literature role of anxiety sensitivity subfactors in suicidal ideation and suicide attempt history separate but equal? a comparison of participants and 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residents to stay at home. the new york times the hopelessness depression symptom questionnaire the effects of involuntary job loss on suicide and suicide attempts among young adults: evidence from a matched case-control study the emotional impact of covid-19: from medical staff to common people systematic review of suicide in economic recession asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models community mitigation guidelines to prevent pandemic influenza -united states suicide mortality and coronavirus disease 2019 -a perfect storm? jama psychiatry ucla loneliness scale (version 3): reliability, validity, and factor structure the revised ucla loneliness scale: concurrent and discriminant validity evidence covid-19 infection: origin, transmission, and characteristics of human coronaviruses estimating the burden of 2009 pandemic influenza a (h1n1) in the united states loneliness, common mental disorders and suicidal behavior: 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j. m. title: work, health, safety and well-being: current state of the art date: 2018-04-12 journal: managing health, safety and well-being doi: 10.1007/978-94-024-1261-1_1 sha: doc_id: 18125 cord_uid: khhzlt9y this introductory chapter will present a review of the current state of the art in relation to employee health, safety and well-being (hsw). the work environment and the nature of work itself are both important influences on hsw. a substantial part of the general morbidity of the population is related to work. it is estimated that workers suffer 270 million occupational accidents and 160 million occupational diseases each year. the chapter will first define hsw. it will then review the current state of the art by outlining key hsw issues in the contemporary world of work, identifying key needs. it will then discuss the evolution of key theoretical perspectives in this area by linking theory to practice and highlighting the need for aligning perspectives and integrating approaches to managing hsw in the workplace. this chapter focuses on the relationship between work, health, safety and wellbeing. the work environment and the nature of work itself are both important influences on health, safety and well-being (hsw). as a result, workplace health and safety or occupational health and safety have been key areas of concern for many years. traditionally, more focus has been placed on safety concerns in the workplace while health concerns became more prominent with the changing nature of work. well-being on the other hand, is increasingly being considered in relation to work and the workplace in recent years. a good starting point in understanding this evolution in focus and thinking is definitions. according to the oxford dictionary, safety is defined as the condition of being safe; freedom from danger, risk, or injury. safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. in terms of work, this mainly concerns physical aspects of the work environment. however, the changing nature of work was associated with the emergence of new types of risk relating to psychological and social aspects of the work environment. this brought about greater focus on health at work. a very influential definition that shaped thinking and action in subsequent years was the world health organization definition of health as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity (world health organization [who], 1948) . this definition promoted a more holistic view of health away from a mere focus on physical aspects towards considering social and mental health aspects. although the who definition already referred to a state of well-being, definitions of well-being include additional dimensions to health, such as social, economic, psychological, and spiritual. well-being refers to a good or satisfactory condition of existence; a state characterized by health, happiness, and prosperity. obviously achieving this state is not relevant to the workplace or work alone but rather an overall evaluation of one's life across many areas. as such, actions to improve hsw can be taken within the work context and outside of it. actions taken in the workplace represent workplace interventions that are implemented in the work setting and consider the characteristics of work environments and workers. on the other hand, actions taken outside the workplace represent public health interventions that are implemented in various settings (for example, in schools, communities or countries) and take into consideration the characteristics of particular populations. a key question in terms of hsw interventions when it comes to the workplace concerns responsibility. while every individual is responsible for their own actions in various contexts of life, in a specific setting like the work environment, additional responsibility lies with the employer since the work environment will expose workers to particular work characteristics that might in turn pose a certain level of risk to their hsw. while employer responsibility might be formalized under law, this is not the case across countries or in relation to all possible types of risks to workers' hsw, and in particular new and emerging risks, or risks that are either new or gain in prevalence with the changing nature of work. accordingly, it is important to consider not only legal duties that employers have towards their workforce but also ethical duties that will extend beyond legal compliance. in addition, while employers bear a legal responsibility towards their workforce, they also bear responsibility towards society. this has meant that enterprises have increasingly been held accountable towards society and that interventions in the workplace, whether legally required or not, are now being increasingly considered in terms of their impact beyond the workforce alone but rather society as a whole (see chapters 3, 4, and 5). this represents a blurring of boundaries between traditional occupational safety and health and public health initiatives that have also resulted in greater emphasis on the concept of well-being in addition to health and safety. at its first session in 1950, the joint international labour organization (ilo)/ world health organization (who) committee on occupational health defined the purpose of occupational health. it revised the definition at its 12th session in 1995 to read as follows: occupational safety and health should aim at: the promotion and maintenance of the highest degree of physical, mental and social well-being of workers in all occupations; the prevention amongst workers of departures from health caused by their working conditions; the protection of workers in their employment from risks resulting from factors adverse to health; the placing and maintenance of the worker in an occupational environment adapted to his physiological and psychological capabilities; and, to summarize, the adaptation of work to man and of each man to his job. almost 70 years later, the target set through this declaration seems ambitious in many parts of the world, both in developed and developing countries. to understand why, it is worth understanding the context underpinning developments in this area as well as current priorities and needs. in recent years, globalization of the world's economies and its repercussions have been perceived as the greatest force for change in the world of work, and consequently in the scope of occupational safety and health, in both positive and negative ways. liberalization of world trade, rapid technological progress, significant developments in transport and communication, shifting patterns of employment, changes in work organization practices, the different employment patterns of men and women, and the size, structure and life cycles of enterprises and of new technologies can all generate new types and patterns of hazards, exposures and risks. demographic changes and population movements, and the consequent pressures on the global environment, can also affect safety and health in the world of work. let us first consider key impacts on the changing nature of the work environment. different types of products and services, organizational structures and work processes, and tools and resources are used in the modern workplace. three main drivers have been proposed in relation to these changes. the first is globalization, a term which refers to the integration of national and regional economies, which became more prevalent since the nineteenth century. according to the organization for economic co-operation and development (oecd, 2008) , the rapid integration into world markets by six economies (brazil, russia, india, indonesia, china and south africa) was an important component of globalization during the past decades. globalization has led to increased competition across organizations, to a shift in the type of business operations in which companies are engaged, and to extensive outsourcing of activities, primarily to low-wage countries. flanagan (2006) examined the effects of globalization on working conditions (hours, remuneration and safety) and concluded that globalization has led to greater flexibility of the work process, with more part-time employment, temporary employment and independent contracting of staff (european agency for safety & health at work [eu-osha], 2007; kawachi, 2008) . houtman and van den bossche (2006) confirmed these conclusions on the basis of eurostat data, reporting that more employees in europe hold a temporary employment contract and yet more people will work 'on call'. oecd reports also confirm these trends. they also highlight that average wage growth has not been equivalent to growth in labour productivity, which is also an outcome of the erosions of the bargaining power of workers in the process of globalization (oecd, 2008). organizational restructuring which has been on the increase due to economic crises in different parts of the world may have been partly a cause of this. organizational restructuring is accompanied by job insecurity and can result in unemployment with subsequent negative impacts on hsw. however, restructuring should not only be considered a serious threat to individual hsw for those who lose their job (the 'direct victims') but also to their immediate environment (e.g. kieselbach et al., 2009 ). in addition, evidence during the past two decades showcases the impact of restructuring on the so-called 'survivors' as concerns health, well-being, productivity, and organizational commitment (kieselbach et al., 2009) . the second key development is the tertiarization of the labour market, manifested in increased demand for staff in the services sector and reduced employment opportunities in industry and agriculture. this became apparent in the early years of the twentieth century but in recent decades may have been reinforced by globalization, since the outsourcing of manual labour to low-wage countries left predominantly the service economy elsewhere (eu-osha, 2007; peña-casas & pochet, 2009) . the third key development relates to technological advancement and the emergence of the internet, which has led to many changes and innovations in work processes. many forms of manual work have become obsolete and staff must offer different skills and qualifications (joling & kraan, 2008) . moreover, 'new work', a term which amongst others refers to telework, i.e. working from home or a location other than the traditional office, is now more widespread. this can result in blurring the borders between working and private life. work can take place outside the traditional working hours as well as at home or when travelling. hence, it may impinge on the need for rest and recuperation, or interfere with personal commitments. also new forms of working methods such as lean production (a production practice according to which the expenditure of resources other than for the creation of value for the end customer is wasteful and should be eliminated, womack & jones, 2003) , and just-in-time production (a production strategy that strives to improve a business' return on investment by reducing in-process inventory and associated costs, womack & jones, 2003) have been introduced (euosha, 2007; kompier, 2006) . overall there has been concern of the effects new forms of work may have on the hsw of workers, organizations and communities (e.g. benach, amable, muntaner, & benavides, 2002; benavides, benach, diez-roux, & roman, 2000; quinlan, 2004; quinlan, mayhew, & bohle, 2001; sauter et al., 2002; virtanen et al., 2005) . it is also important to mention the prevalence of small and medium-sized enterprises (smes) that are believed to be responsible for over 50% of new jobs created globally. moreover, in most developing and emerging countries, they also employ more people than large enterprises do. however, occupational safety and health (osh) is often less well managed in smes, creating working conditions that are less safe and posing greater risks to the health of workers than larger enterprises (croucher, stumbitz, quinlan, & vickers, 2013) . in particular, smes have less time to devote to providing osh training and information due to economies of scale, and have less expertise in hsw. research also confirms a common lack of awareness of the cost implications of occupational accidents and diseases amongst sme owners and managers, as well as a tendency for smes to be reactive, rather than adopting proactive and preventive strategies towards osh (croucher et al., 2013) . however, there are also changes in the workforce that are associated with hsw in the workplace. the next section considers the most important of these. alongside the factors changing the nature of work itself, changes can also be seen in the working population, with noteworthy trends being: (a) the ageing workforce; (b) the feminization of the workforce; and (c) increased immigration (leka, cox, & zwetsloot, 2008) . let us now consider these issues in more detail. in industrialized countries, the share of people aged 60-plus has risen from 12% in 1950 to 22% and is expected to reach 32% (418 million) by 2050. in developing countries, the share of people aged 60-plus has risen from 6% in 1950 to 9% and is expected to reach 20% (1.6 billion) by 2050 (world economic forum [wef], 2012). the global population is projected to increase 3.7 times from 1950 to 2050, but the number of 60-plus will increase by nearly 10%, and the 80-plus by about 26%. women have a life expectancy of 4.5 years more than men and account for about 55% of the 60-plus group, rising to 64% of the 80-plus group, and 82% of the 100-plus group (wef, 2012) . in response to these global trends, four strategies have been proposed: raising the normal legal retirement age; using international migration to ameliorate the economic effects of population ageing; reforming health systems to have more emphasiz on disease prevention and health promotion; and rethinking business practices, encouraging businesses to employ more older workers, even on a part-time basis (wef, 2012) . according to the oecd (2013) most countries will have a retirement age for both men and women of at least 67 years by 2050, and this has already been implemented in many countries. this represents an increase from current levels of around 3.5 years on average for men and 4.5 years on average for women. the same report stresses that high levels of youth unemployment will lead to widespread poverty in old age as young people struggle to save for retirement. since population ageing in industrialized nations has been a prevalent trend in the past decades (ilmarinen, 2006) , lessons can be learned from it in relation to the workforce. most reviews and meta-analyses in the scientific literature make clear that there is no consistent effect of age on work performance (e.g., benjamin & wilson, 2005; griffiths, 1997; salthouse & maurer, 1996) . overall, older workers perform as well as younger workers. furthermore, there are many positive findings with regard to older workers. for example, older workers demonstrate less turnover and more positive work values than younger workers (warr, 1994) . they also exhibit more positive attitudes to safety and fewer occupational injuries (siu, phillips, & leung, 2003) although there is some evidence that it is tenure (time on the job) that should be examined rather than age per se (breslin & smith, 2006) . however, the evidence from epidemiological and laboratory-based studies paints a less favourable picture of older people's performance. such studies reveal age-related declines in cognitive abilities such as working memory capacity, attention capacity, novel problem-solving, and information processing speed. agerelated deterioration is also documented in motor-response generation, selecting target information from complex displays, visual and auditory abilities, balance, joint mobility, aerobic capacity and endurance (kowalski-trakofler, steiner, & schwerha, 2005) . as workers get older, they suffer from more musculoskeletal disorders (eurostat, 2010) , and they are more likely to report work-related stress (griffiths, 2007) . recent models of ageing and work propose that certain mediating factors underpin the relationship between chronological age, work performance and behaviour and might function at three levels: individual, organizational and societal. at the individual level, for example, experience, job knowledge, abilities, skills, disposition, and motivation may operate (kanfer & ackerman, 2004) . other mediating variables may reflect organizational policies and practices: for example, age awareness programmes, supervisor and peer attitudes, management style, the physical work environment and equipment, health promotion, workplace adjustments, and learning and development opportunities (griffiths, 1997) . however, policies and systems implemented so far have, in most countries, not been adequately successful in keeping people healthier and in employment for longer (oecd, 2013) . a further level of exploration for the relationship between age and work performance might be provided by examining global markets, the wider employment context and worker protection (johnstone, quinlan, & walters, 2005; quinlan, 2004) . as discussed, in developed countries there has been a decline in manufacturing and a recent export of some service sector work to developing countries. the way work is designed and organized has changed substantially with a growth in contingent or 'precarious' work and an increase in part-time work, home-based work, telework, multiple job-holding and unpaid overtime. these changes might make it increasingly difficult for older workers to gain or maintain employment, and such employment may entail inferior and unhealthy working conditions. these changes in work design and management have also been accompanied by changes in worker protection; for example, a decline in union density and collective bargaining, some erosion in workers' compensation and public health infrastructure and cutbacks in both disability and unemployment benefits -again contexts which are unlikely to favour vulnerable workers, such as older workers. as such older workers may be affected by increased exposure to certain occupational hazards; decreased opportunities to gain new knowledge and develop new skills; less support from supervisors, and discrimination in terms of selection, career development, learning opportunities and redundancy (chiu, chan, snape, & redman, 2001; maurer, 2001; molinie, 2003) . pronounced gender differences in employment patterns can be observed as a result of a highly segregated labour market based on gender (burchell, fagan, o'brien, & smith, 2007; fagan & burchell, 2002; vogel, 2003) . gender segregation refers to the pattern in which one gender is under-represented in some jobs and overrepresented in others, relative to their percentage share of total employment (fagan & burchell, 2002) . a growing body of evidence indicates that a high level of gender segregation is a persistent feature of the employment structure globally (e.g. anker, 1998; burchell et al., 2007; rubery, smith, & fagan, 1999) . some scholars have argued that estimates suggest that gender segregation in the labour market is so pervasive, that in order to rectify this imbalance approximately 75% of women would have to change jobs or professions (messing, 1998) . considering differences in employment patterns according to gender (and without taking into account sectors where both genders are represented, e.g. agriculture), women's jobs typically involve caring, nurturing and service activities for people, whilst men tend to be concentrated in managerial positions and in manual and technical jobs associated with machinery or physical products. since men and women are differently concentrated in certain occupations and sectors, with different aspects of job content and associated tasks, they are exposed to a different taxonomy of work-related risks (burchell et al., 2007; eu-osha, 2002) . for example, women are more frequently exposed to emotionally demanding work, and work in low-status occupations with often restricted autonomy, as compared to men. this differential exposure can result in differential impacts on occupational ill health for men and women (eu-osha, 2002; oecd, 2012) . furthermore, due to the gender division of labour, women and men play different roles in relation to children, families and communities with implications for their health (premji, 2011) . even though women are increasingly joining the paid workforce, in most societies they continue to be mainly responsible for domestic, unpaid work such as cooking, cleaning and caring for children, and so they carry a triple burden (e.g. loewenson, 1999) . women are also largely represented among unpaid contributing family workers, those who work in a business establishment for a relative who lives in the same household as they do (ilo, 2012) . balancing responsibilities for paid and unpaid work often leads to stress, depression and fatigue (duxbury & higgins, 2001; manuh, 1998) , and can be particularly problematic when income is low and social services and support are lacking. the lack of availability of child care may also mean that women must take their children to work where they may be exposed to hazardous environments. increased migration of workers from developing countries to developed countries or from poorer to more affluent developed countries is still the norm and increasing. migrant workers can be divided into highly-educated and skilled workers, both from developing and industrialized countries, and unskilled workers from developing countries (takala & hämäläinen, 2009) . they can also be classified as legal and illegal (or regular and irregular) migrant workers who have a different status and, therefore, varying levels of access to basic social services (who, 2007) . often lowskilled and seasonal workers are concentrated in sectors and occupations with a high level of occupational health and safety risks (who, 2007) . ethnic minority migrants have been found to have different conditions in comparison to other migrants, and to report lower levels of psychological well-being (shields & price, 2003) . women migrants represent nearly half of the total migrants in the world and their proportion is growing, especially in asia. they often work as domestic workers or caregivers while men often work as agricultural or construction workers (ilo, 2012) . in general, migrant workers tend to be employed in high risk sectors, receive little work-related training and information, face language and cultural barriers, lack protection under the destination country's labour laws and experience difficulties in adequately accessing and using health services. common stressors include being away from friends and family, rigid work demands, unpredictable work and having to put up with existing conditions (magana & hovey, 2003) . in addition, migrant workers' cultural background, anthropometrics and training may differ from those of nationals of host countries, which may have implications in relation to their understanding and use of equipment (kogi, 1997; o'neill, 2000) . as can be understood so far, both the nature of work and of workplaces as well as workforce characteristics depend on wider socioeconomic and political influences. a large body of literature has summarized and examined these influences under the area of the social determinants of health. the following section briefly considers these determinants. new forms of work organization and employment have to be considered within the wider picture of employment and working conditions across the world. labour markets and social policies determine employment conditions such as precarious or informal jobs, child labour or slavery, or problems such as having high insecurity, low paid jobs, or working in hazardous conditions, all of which heavily influence health inequalities. figure 1 .1 shows various interrelationships between employment, working conditions and health inequalities. let us consider unemployment and associated job insecurity as social determinants of health. in 2012 the ilo estimated that there were almost 26 million unemployed people in the eu, 18 million of whom were from eu-17 countries. overall, 197 million people were unemployed in 2012 with a quarter of the increase of four million in global unemployment being in the advanced economies, and three quarters being in other regions, with marked effects in east asia, south asia and sub-saharan africa (ilo, 2013a). the same report also highlighted that in those regions where unemployment did not increase further, job quality worsened as vulnerable employment and the number of workers living below or very near the poverty line increased. in the eu, the 2008 financial crisis resulted in unprecedented levels of youth unemployment, averaging 23% for the eu as a whole. the rates for young people (aged 15-24) not in employment, education or training are 22.4% in the south and peripheral eu countries, and 11.4% in the north and core of the eu (european commission [ec], 2013). in a pattern intensified by the 2008 financial crisis, structural unemployment has been growing and unemployment varies from 17.3% in the south of the eu and peripheries in 2012, to 7.1% in the north and central countries (ec, 2013) . a large proportion of jobs destroyed were in mid-paid manufacturing and construction occupations (european foundation for the improvement of living & working conditions [eurofound] , 2013). as a consequence of reduced employment opportunities, poverty has increased in the eu since 2007. household incomes are declining and 24.2% of the eu population is now at risk of poverty or exclusion. children are particularly affected as unemployment and jobless households have increased, together with in-work poverty (ec, 2013) . this has implications for quality of life and general population health beyond workplace health and safety due to the impact on personal finances. an ilo report summarized the potential impact of financial crises on organizations and health and safety as shown in table 1 .1. the surge of unemployment creates tension and negatively impacts public perceptions for social welfare, job security, and financial stability. increased job insecurity reflects the fear of job loss or the loss of the benefits associated with the job (e.g. health insurance benefits, salary reductions, not being promoted, changes in workload or work schedule). it is one of the major consequences of today's turbulent economies and is common across occupations, and both private and publicsector employees (ashford, lee, & bobko, 1989; ferrie et al., 2001; sverke, hellgren, & naswall, 2002) . several studies have shown that job insecurity has detrimental effects on the physical and mental health of employees, and on many organizational outcomes, including performance, job satisfaction, counterproductive behaviours, and commitment (e.g. ferrie et al., 2001; sverke et al., 2002) . increased unemployment has given rise to different forms of flexible and temporary employment, also through the introduction of relevant policies such as flexicurity. flexicurity is an integrated strategy for enhancing flexibility and security in the labour market. it attempts to reconcile employers' need for a flexible workforce with workers' need for security (ec, 2007) . however, several studies have warned of the possible negative outcomes of new types of work arrangements, highlighting that they could be as dangerous as unemployment for workers' health (benach & muntaner, 2007) . for example, workers on fixed-term contracts are commonly found to have inadequate working conditions by comparison with permanent employees. new forms of work organization and patterns of employment can be summarized in terms of flexible working practices including temporary and part-time employment, tele-working, precarious employment, and home working. although these new practices can result in positive outcomes such as more flexibility, a better worklife balance, and increased productivity, research has also identified several potential negative outcomes. for example, teleworkers may feel isolated, lacking support and career progression (e.g. ertel, pech, & ullsperger, 2001; schultz & edington, 2007) . in addition, temporary, part-time and precarious employment can result in higher job demands, job insecurity, lower control and an increased likelihood of labour force exit (benach et al., 2002; quinlan, 2004; quinlan et al., 2001) . workers engaged in insecure and flexible contracts with unpredictable hours and volumes of work are more likely to suffer occupational injuries (ilo, 2013a (ilo, , 2013b . although awareness and evidence in developing countries lags far behind those in the industrialized world, evidence has started to accumulate showing similar findings in developing countries (kortum, leka, & cox, 2011) . these various complex relationships between the wider socio-economic context, employment and working conditions have resulted in a more complex profile of risk factors that may affect hsw in the workplace. new forms of work organization and the move towards a service based economy have also resulted in new and emerging risks affecting the workforce, organizations and society. these will be considered next. an 'emerging osh risk' is often defined as any occupational risk that is both new and increasing (eu-osha, 2009). new means that the risk was previously unknown and is caused by new processes, new technologies, new types of workplaces, or social or organizational change; or, a long-standing issue is newly considered to be a risk due to changes in social or public perceptions; or, new scientific knowledge allows a long standing issue to be identified as a risk. a risk is increasing if the number of hazards leading to the risk is growing; or, the likelihood of exposure to the hazard leading to the risk is increasing (exposure level and/or the number of people exposed); or the effect of the hazard on workers' health is getting worse (seriousness of health effects and/or the number of people affected) (houtman, douwes, zondervan, & jongen, 2017 ). an article published on eu-osha's osh wiki on new and emerging risks summarizes them as follows (houtman et al., 2017) : • emerging physical risks: (1) physical inactivity and (2) the combined exposure to a mixture of environmental stressors that increase the risks of musculoskeletal disorders (msds), the leading cause of sickness absence and work disability. • emerging psychosocial risks: (1) job insecurity, (2) work intensification, high demands at work, and (3) emotional demands, including violence, harassment and bullying. • emerging dangerous substances due to technological innovation: (1) chemicals, with specific attention to nanomaterials, and (2) biological agents. the growing use of computers and automated systems, aimed at optimizing productivity, has caused an increase in sedentary work or prolonged standing at work, resulting in an increase in physical inactivity. work demands are also commonly cited as reasons for physical inactivity (e.g. trost, owen, bauman, sallis, & brown, 2002) as well as an increase in travelling time to work (houtman et al., 2017) . physical inactivity is associated with increased health risks such as coronary heart disease, type ii diabetes, and certain types of cancers and psychological disorders (depression and anxiety) (department of health, 2004; who, 2002; zhang, xie, lee, & binns, 2004) . another important result of inactivity is obesity which can lead to several adverse health effects, such as back pain, high blood pressure, cardiovascular disorders, and diabetes (houtman et al., 2017) . in addition, sedentary jobs are associated with an increased prevalence of musculoskeletal complaints or disorders, e.g. neck and shoulder disorders (e.g. korhonen et al., 2003) , and upper and lower back disorders (e.g. chen, mcdonald, & cherry, 2006) . such disorders may lead to sick leave and work disability (e.g. steensma, verbeek, heymans, & bongers, 2005) . the established health risks associated with sedentary work are premature death in general, type ii diabetes and obesity (van uffelen et al., 2010) . as concerns msds, there is a considerable body of research indicating that biomechanical or ergonomic risks in combination with psychosocial risks can generate work-related msds (e.g. bongers, ijmker, & van den heuvel, 2006; briggs, bragge, smith, govil, & straker, 2009; eu-osha, 2005) . psychosocial risk factors at work have a greater effect on the prevalence of musculoskeletal complaints when exposure to physical risk factors at work is high rather than when it is low. in addition, factors such as low job control, high job demands, poor management support or little support from colleagues, as well as restructuring, job redesign, outsourcing and downsizing have been shown to be causally related to increased risks in msds (houtman et al., 2017) . job insecurity has been discussed earlier and is an important stressor resulting in reduced well-being (psychological distress, anxiety, depression, and burnout), reduced job satisfaction (e.g. withdrawal from the job and the organization) and increased psychosomatic complaints as well as physical strains (e.g. wagenaar et al., 2011) . all these effects are negatively related to personal growth as well as to recognition and participation in social life (de cuyper et al., 2008) . additionally, decreased well-being and reduced job satisfaction of employees negatively affects the effectiveness of the organization (houtman et al., 2017) . there are several increasing demands workers are exposed to in the modern workplace including: quantitative (high speed, no time to finish work in regular working hours), qualitative (increased complexity), emotional (emotional load due to direct contact with customers i.e. service relationship situations), and often physical loads as well (houtman et al., 2017) . the widespread use of information and communication technology (ict) has led to work intensification. developments in technology use in terms of mechanization, automation, and computerization, has led to the substitution of human activities by machines. on the other hand, the use of computers and smart phones with internet access provides easy access to all kinds of information but may also lead to the expectation from colleagues, supervisors and clients that one is always available and can be contacted (e.g. by email). ict work may then lead to stress symptoms due to excessive working hours, workload and increasing complexity of tasks or isolation in home workers; information overload; pressure of having to constantly upgrade skills; human relationships replaced by virtual contacts; and physical impairments such as repetitive strain injuries and other msds due to using inadequate or ergonomically unadapted equipment (houtman et al., 2017) . psychosocial hazards such as high job demands and low control have been systematically found to be causally linked to cardiovascular heart disease (e.g. backé, seidler, latza, rossnagel, & schumann, 2012; eller et al., 2009) , msds (e.g. da costa & vieira, 2009) as well as mental health problems such as depression and anxiety (e.g. bonde, 2008; netterstrom et al., 2008) . in addition, long term absence and disability are causally related to these types of risks (e.g. duijts, kant, swaen, brandt, & van den zeegers, 2007) . furthermore, as the labour market shifts towards the service industry, emotional demands at work increase with harassment or bullying and violence contributing to this increase (houtman et al., 2017) . those affected by violence and harassment in the workplace tend to report higher levels of work-related ill health. the proportion of workers reporting symptoms such as sleeping problems, anxiety and irritability is nearly four times greater among those who have experienced violence, bullying and harassment than amongst those who have not (houtman et al., 2017) . nanotechnology has been defined as the design, characterization, production and application of structures, devices and systems by controlling shape and size at nanometre scale (eu-osha, 2013). due to their small size, engineered nanomaterials (enms) have unique properties that improve the performance of many products. nanomaterials have applications in many industrial sectors (currently the main areas are materials and manufacturing industry including automotive, construction and chemical industry, electronics and it, health and life sciences, and energy and environment). a key issue of enms is the unknown human risks of the applied nanomaterials during their life cycle, especially for workers exposed to enms at the workplace. workers in nanotechnology may be exposed to novel properties of materials and products causing health effects that have not yet been fully explored. the manufacture, use, maintenance and disposal of nanomaterials may have potential adverse effects on internal organs (eu-osha, 2013). although there is a considerable lack of knowledge, there are indications that because of their size, enms can enter the body via the digestive system, respiratory system or the skin. once in the body, enms can translocate to organs or tissue distant from the portal of entry. such translocation is facilitated by the propensity of the nanoparticles to enter cells, to cross membranes and to move along the nerves (iavicoli & boccuni, 2010) . the enms may accumulate in the body, particularly in the lungs, the brain and the liver. the basis for the toxicity appears to be primarily expressed through an ability to cause inflammation and to raise potential for autoimmune deficits, and may induce diseases such as cancer (houtman et al., 2017) . other dangerous substances concerns include diesel exposure and its link to lung cancer and non-cancer damage to the lung; and man-made mineral fiber exposure (classified as being siliceous or non-siliceous) and the link of their structure to inflammatory, cytotoxic and carcinogenic potential (houtman et al., 2017) . another three chemical risks have been identified as emerging with a view to allergies and sensitizing effects. they are epoxy resins, isocyanates and dermal exposure (eu-osha, 2009). epoxy resins have become one of the main causes of occupational allergic contact dermatitis. skin sensitization of the hands, arms, face, and throat as well as photosensitization have also been reported. isocyanates are powerful irritants to the mucous membranes of the eyes and of the gastrointestinal and respiratory tracts. direct skin contact can cause serious inflammation and dermatitis. isocyanates are also powerful asthmatic sensitizing agents (houtman et al., 2017) . finally, risks related to global epidemics are the most important biological risk issue. pathogens such as the severe acute respiratory syndrome (sars), ebola, and marburg viruses are new or newly recognized. in addition, new outbreaks of wellcharacterized outbreak-prone diseases such as cholera, dengue, measles, meningitis, and yellow fever still emerge (houtman et al., 2017) . it should be stressed that the profile of risks in the workplace constantly changes and there are additive effects that exacerbate negative impacts. the following section provides an overview of key challenges in relation to hsw in the modern workplace while also acknowledging the lack of research in relation to some of the new and emerging risks identified earlier. the ilo has published global estimates of fatal and non-fatal occupational (ilo, 2011) and fatal work-related diseases (ilo, 2013b). 2.3 million deaths occur annually across countries for reasons attributed to work. over 350,000 are caused by occupational accidents while the biggest mortality burden comes from work-related diseases, accounting for about 2 million deaths. globally, cardiovascular and circulatory diseases at 35% and cancers at 29% were the top illnesses responsible for 2/3 of deaths from work-related diseases, followed by occupational injuries at 15% and infectious diseases at 10%. as a result, approximately 6300 people die every day due to these causes: occupational accidents kill nearly 1000 people every day and work-related diseases provoke the death of approximately 5400 more individuals. there were also over 313 million non-fatal occupational accidents (requiring at least four days of absence from work) in 2010, meaning that occupational accidents provoke injury or ill health for approximately 860,000 people every day (ilo, 2013b). major industrial accidents are stark reminders of the unsafe conditions still faced by many. for example, the april 2013 collapse of the rana plaza building in bangladesh resulted in the death of 1129 individuals and injured 2500 more, mostly factory workers making garments for overseas retail chains. the international community has since expressed concerns about market pressures which strive to keep basic production costs low, the role of national authorities, and the responsibilities of multinational enterprises and other stakeholders in supply chains towards the health and safety of workers. hazardous sectors such as mining, construction, shipping, and in particular fishing continue to take a heavy toll on human lives and health. meanwhile, the nuclear industry continues to pose serious problems regarding the radiological protection of site workers and the environment. in particular, the protection of emergency workers at the fukushima daiichi power plant in japan has become a focus of international attention since the 2011 east japan earthquake. occupational health has recently become a much higher priority, in light of the growing evidence of the enormous loss and suffering caused by occupational diseases and ill health across many different employment sectors. even though it is estimated that fatal diseases account for about 85% of all work-related fatalities, more than half of all countries do not provide official statistics for occupational diseases (ilo, 2013b). these therefore remain largely invisible, compared to fatal accidents. moreover and as discussed previously, the nature of occupational diseases is changing rapidly, as new technologies and global social changes aggravate existing health risks and create new ones. for example, long-latency diseases include illnesses such as silicosis and other pneumoconioses, asbestos-related diseases and occupational cancers that may take decades to manifest. such diseases remain widespread, as they are often undiagnosed until they result in permanent disability or premature death. pneumoconioses account for a high percentage of all occupational diseases. for example, in latin america, there is a 37% prevalence rate of silicosis amongst miners, and this figure reaches 50% among miners over the age of 50. in vietnam, pneumoconioses account for 75.7% of all compensated occupational diseases (ilo, 2013b) . the use of asbestos has been banned in more than 50 counties, including all eu member states, but the number of deaths from asbestos-related diseases is increasing in many industrialized countries because of exposure that occurred during the 1960s and later. in germany and the uk, for example, the number of deaths from asbestos-induced mesothelioma has been increasing for some years and was expected to peak in 2015-16 (health & the number of cases of work-related stress, violence and psychosocial disorders has also been increasing. these have often been attributed at least in part to recession-driven enterprise restructuring and redundancies which can be very damaging psychologically. european studies have shown that a large and rapid rise in unemployment has been associated with a significant increase in suicide rates (e.g. lundin & hemmingsson, 2009 ). meanwhile, a review of mortality studies in 13 countries across the world has also shown an increase in cardiovascular mortality rates by an average of 6.4% in periods of crisis (falagas, vouloumanou, mavros, & karageorgopoulos, 2009) . the impact of the issues discussed in this section is presented in chapter 3. on the basis of the available evidence, it is now recognized that a new paradigm of prevention is required, one that focuses on work-related diseases and not only on occupational injuries. recognition, prevention and treatment of both occupational diseases and accidents, as well as the improvement of recording and notification systems are high priorities for improving the health of individuals and the societies they live in. several perspectives and associated approaches have been taken to promote hsw in the workplace over the years as priorities change and new issues and knowledge emerge. the following section will provide an overview of some key perspectives that have led to the development of modern holistic models to promote hsw in the workplace. the field of occupational health and safety has been defined as the science of the anticipation, recognition, evaluation and control of hazards arising in or from the workplace that could impair the hsw of workers, taking into account the possible impact on the surrounding communities and the general environment (alli, 2008) . given the broad scope of this definition, several disciplines are relevant to osh that relate to control of the multitude of hazards in the workplace. furthermore, since social, political, technological and economic changes are constantly impacting upon the workplace, the field of osh has been evolving to address new and emerging issues in line with different perspectives. some disciplines of relevance to osh include engineering, ergonomics, toxicology, hygiene, medicine, epidemiology, psychology, sociology, education, and policy. these disciplines often diverge in terms of theoretical foundation and as a result emphasize different aspects in terms of understanding and dealing with osh issues. however, in recent years there has been convergence in thinking about the work environment and a trend towards more holistic perspectives and approaches when considering hsw. indeed, while hsw issues were in the past approached from a mono-disciplinary perspective, multi-disciplinarity is now advocated as the necessary way forward. however, in practice osh professionals often still employ mono-disciplinary perspectives in dealing with accidents and diseases in the workplace, seeking to protect individual workers rather than preventing negative impacts of the work environment and promoting positive outcomes. solely focusing on ameliorating harm rather than promoting hsw has also been criticized in recent years by scholars emphasizing a salutogenic (health promoting) instead of a pathogenic (disease preventing) perspective. let us now consider some of these approaches further in relation to safety, health and well-being. it has been argued that occupational safety has developed and evolved through three ages: 1. a technical age, 2. a human factors age, and 3. a management and culture age (hale & hovden, 1998 ) (or as hudson, 2007 described them through a technical wave, a systems wave and a culture wave). several authors have since then suggested new ages in safety science. the first age of safety concerned itself with the technical measures to guard machinery, stop explosions and prevent structures collapsing. it lasted from the nineteenth century through until after the second world war and was interested in accidents having technical causes (hale & hovden, 1998) . the period between the world wars saw the development of research into personnel selection, training and motivation as prevention measures, often based on theories of accident proneness (see hale & glendon, 1987 for a review; burnham, 2009 for the accident-prone theory). this brought about the second age of safety, which developed separately to technical measures until the period of the 1960s and 1970s, when developments in probabilistic risk analysis and the rise and influence of ergonomics led to a merger of the two approaches in health and safety. there was a move away from an exclusive dominance of the technical view of safety in risk analysis and prevention, and the study of human error and human recovery or prevention came into its own (hale & hovden, 1998) . just as the second age of human factors was ushered in by increasing realizations that technical risk assessment and prevention measures could not solve all problems, so were the 1980s characterized by an increasing dissatisfaction with the idea that health and safety could be captured simply by matching the individual to technology. in the 1990s management and culture were the focus of development and research, based on many influential thinkers such as heinrich who published his ground-breaking safety management textbook in heinrich, 1931 , the sociotechnical management literature (e.g. elden, 1983; thorsrud, 1981; trist & bamforth, 1951) , the social organizational theory of lewin (1951) , the loss prevention approach (bird, 1974) , and the introduction of participative management in safety (e.g. simard & marchand, 1995) . however, reason (2000) contended that an over-reliance on osh management systems and insufficient understanding of, and insufficient emphasis on, workplace culture, can lead to failure because "it is the latter that ultimately determines the success or failure of such systems" (p.5). criticism of overreliance on systems was also influenced by the resilience engineering school that posited that instead of focusing on failures, error counting and decomposition, we should address the capabilities to cope with the unforeseen. the ambition is to 'engineer' tools or processes that help organizations to increase their ability to operate in a robust and flexible way. hopkins (2007) views safety culture as one aspect of organizational culture, or more particularly an organizational culture that is focused on safety. further, culture is viewed as a group, not an individual, phenomenon; efforts to change culture, should, in the first instance, focus on changing collective practices (the practices of both managers and workers) and the dominant source of culture is what leaders pay attention to. much of hopkins' work draws on reason's (1997) notion that a safe culture is an informed culture and sutcliffe's (2001, 2007) principles of collective mindfulness and high reliability organizations (i.e. organizations that are able to manage and sustain almost error-free performance despite operating in hazardous conditions where the consequences of errors could be catastrophic). collective mindfulness is based on the premise that variability in human performance enhances safety whilst unvarying performance can undermine safety, particularly in complex socio-technical systems. glendon, clarke, and mckenna (2006) argued that each of the first three periods of development build on one another and refer to this process of development as the fourth age of safety or the integration age where previous ways of thinking are not lost, but remain available to be reflected upon as multiple, more complex perspectives develop and evolve. however, as the limitations of osh management systems and safety rules that attempt to control behaviour have become evident, it has also been proposed that a fifth age of safety has emerged, the adaptive age; an age which transcends the other ages of safety. the adaptive age challenges the view of an organizational safety culture and instead recognizes the existence of socially constructed sub-cultures. the adaptive age embraces adaptive cultures and resilience engineering and requires a change in perspective from human variability as a liability and in need of control, to human variability as an asset and important for safety (borys, else, & leggett, 2009) . resilience engineering is similar to collective mindfulness since it also focuses on the importance of performance variability for safety. however, what sets resilience engineering apart from collective mindfulness is the focus on learning from successful performance (hollnagel, 2006) , i.e. why things go right as well as why things go wrong (also called the safety 2 approach (hollnagel, 2014) . one particular major development in the safety evolution was the move towards managing risks in the work environment. this implied that it is impossible to completely control all aspects of work to avoid negative outcomes, risks always remain. in an ever-changing work environment, a continuous assessment of risks is needed that will point to key risks that may pose a threat to workers' hsw. these then need to be managed following appropriate actions at various levels with the focus being on prevention. the risk management paradigm has been hugely influential not only in terms of managing safety but also managing health as will be discussed in the following sections. let us then consider it further next. in the wake of the chernobyl disaster in1986, sociologist ulrich beck published 'risikogesellschaft', later published in english as 'risk society: towards a new modernity' in 1992. beck argued that environmental risks had become the predominant product of industrial society. he defined a risk society as "a systematic way of dealing with hazards and insecurities induced and introduced by modernization itself" (beck, 1992, p.21) . while according to british sociologist anthony giddens (1990) , a risk society is a society that is increasingly preoccupied with the future (and also with safety), which generates the notion of risk. giddens (1999) defined two types of risks as external risks (for example natural disasters) and manufactured risks (for example, those derived from industrial processes. as manufactured risks are the product of human activity, authors like giddens and beck argue that it is possible for societies to assess the level of risk that is being produced, or that is about to be produced, in order to mitigate negative outcomes (i.e. responsibility with managing these risks lies with society and more precisely with experts able to do so). one such area is osh risk management. hazard, something that can cause harm if not controlled, is a key term in osh risk management. the outcome is the harm that results from an uncontrolled hazard. in the context of osh, harm describes the direct or indirect degradation, temporary or permanent, of the physical, mental, or social well-being of workers. a risk is a combination of the probability that a particular outcome will occur and the severity of the harm involved (nunes, 2016) . hazard identification or assessment is an important step in the overall risk assessment and risk management process. through this, hazards are identified, assessed and controlled/eliminated as close to source as reasonably as possible. as technology, resources, social expectations or regulatory requirements change, hazard analysis focuses control measures more closely towards the source of the hazard aiming at prevention. hazard-based programmes may not be able to eliminate all risks to hsw but they avoid implying that there are 'acceptable risks' in the workplace (nunes, 2016) . a risk assessment needs to be carried out prior to making an intervention. this assessment should identify hazards, identify all affected by the hazard and how, evaluate the risk, and identify and prioritize appropriate control measures. the calculation of risk is based on the likelihood or probability of the harm being realized and the severity of the consequences. the assessment should be recorded and reviewed periodically and whenever there is a significant change to work practices. the assessment should include practical recommendations to control the risk. once recommended controls are implemented, the risk should be re-calculated to determine if it has been lowered to an acceptable level (nunes, 2016) . risk assessment and calculation is usually easier as regards physical risks but more complex as regards biological, and even more so psychosocial, risks. despite this, the risk management paradigm has been applied to all these types of risks to hsw, and is used extensively both as concerns occupational injury and occupational health. it also represents the cornerstone of osh legislation across countries. osh management systems are based on this paradigm (see chapter 6 for more details). following the pdca (plan-do-check-act) cycle methodology (deming, 1986) , risk management is a systematic process that includes the examination of all characteristics of the work system where the worker operates, namely, the workplace, the equipment/machinery, materials, work methods/practices and work environment. the main goal of risk management is to eliminate or at least to reduce the risks that cannot be avoided or eliminated to an acceptable level. risk management measures should follow the hierarchy of control principles of prevention, protection and mitigation. worker participation is key in the process of risk management. the risk management process should be reviewed and updated regularly, for instance every year, to ensure that the measures implemented are adequate and effective. additional measures might be necessary if the improvements do not show the expected results (nunes, 2016) . periodic risk management is also important since workplaces are dynamic due to changes in equipment, substances or work procedures, and new hazards might emerge. another reason is that new knowledge regarding risks can become available, either leading to the need of an intervention or offering new ways of controlling the risk. the review of the risk management process should consider a variety of types of information and draw them from a number of relevant perspectives (e.g. staff, management, stakeholders). however, risk management has been criticized for focusing too heavily on avoiding (controlling) possible negative outcomes and not promoting positive and healthy work environments. this development in thinking has stemmed from a parallel move from pathogenic to salutogenic approaches in health and its management. this evolution in thinking about health and well-being will be considered next. approaches in occupational health and occupational hygiene have evolved in line with developments in several disciplines, including safety engineering, medicine and psychology. the risk management perspective is the cornerstone of occupational hygiene as is evident by its definition. the international occupational hygiene association (ioha, n.d.) refers to occupational hygiene as the discipline of anticipating, recognizing, evaluating and controlling health hazards in the working environment with the objective of protecting worker health and well-being and safeguarding the community at large. although occupational health definitions similarly place great focus on managing risk factors, they overall refer to the promotion and maintenance of health and well-being of employees. similarly to the evolution of perspectives in safety, these definitions have been influenced by the evolution of thinking on health and well-being over the years (schulte & vainio, 2010) . perspectives on health and illness started with a focus on pathogenesis, as pioneered and developed by williamson and pearse (1966) which is the study of disease origins and causes. pathogenesis starts by considering disease and infirmity and then works retrospectively to determine how individuals can avoid, manage, and/or eliminate that disease or infirmity. the dose-response relationship of the change in effect on an organizm caused by differing levels of exposure (or doses) to a stressor after a certain exposure time was influential in treating disease and illness (as was in chemical safety). this leads professionals using pathogenesis to be reactive because they respond to situations that are currently causing or threatening to cause disease or infirmity (becker, glascoff, & felts, 2010) . a major shift came in 1979 with antonovsky's concept of salutogenesis, the study of health origins and causes, which starts by considering health and looks prospectively at how to create, enhance, and improve physical, mental and social well-being (antonovsky, 1979) . the assumption of salutogenesis that action needs to occur to move the individual towards optimum health, prompts professionals to be proactive because their focus is on creating a new higher state of health than is currently being experienced (antonovsky, 1996) . the difference between the biomedical model (based on pathogenesis) and health promotion which is now the cornerstone of public health (based on salutogenesis) is a move away from risk and disease towards resources for health and life (eriksson & lindström, 2008) , initiating processes not only for health but wellbeing and quality of life. perceived good health is a determinant of quality of life. according to breslow (2006) , the first era of public health involved combating communicable diseases while the second dealt with chronic diseases. their focus was on developing and maintaining health since health provides a person the potential to have the opportunity and ability to move towards the life they want. to facilitate management of health in the first two eras, measurement of the signs, symptoms and associated risks of disease and infirmity were of paramount importance. in the third era of public health most people expect a state of health that enables them to do what they want in life. to facilitate management of an evolved health status, it is necessary to develop new health measures that must go beyond detecting pathogenesis and its precursors to measuring those qualities associated with better health (breslow, 2006) . however, salutogenesis also presumes that disease and infirmity are not only possible but likely because humans are flawed and subject to entropy (antonovsky, 1979) . according to a salutogenic perspective, each person should engage in health promoting actions to cause health while they secondarily benefit from the prevention of disease and infirmity. pathogenesis, on the other hand in a complementary fashion primarily focuses on prevention of disease and infirmity, with a secondary benefit of health promotion. both approaches are needed to facilitate the goal of better health and a safer and more health enhancing environment. pathogenesis improves health by decreasing disease and infirmity and salutogenesis enhances health by improving physical, mental, and social well-being. together, these strategies will work to create an environment that nurtures, supports, and facilitates optimal well-being (becker et al., 2010) . around the same time when salutogenesis was introduced, in a 1977 article in science, psychiatrist george l. engel introduced a new medical model, the biopsychosocial model. the biopsychosocial model is a broad view that attributes disease outcome to the intricate, variable interaction of biological factors (genetic, biochemical, etc.), psychological factors (mood, personality, behaviour, etc.), and social factors (cultural, familial, socioeconomic, medical, etc.) . it holds to the idea that biological, psychological, and social processes are integrally and interactively involved in physical health and illness. it was pioneering in advocating the premise that people's psychological experiences and social behaviours are reciprocally related to biological processes. as a result, interventions should address all these dimensions and not narrowly focus on limited perspectives (such as only the biological perspective for example). more focus was now placed on psychological and social factors in the understanding of health and illness. indeed, the traditional medical model of ill health was increasingly recognized as having achieved limited success in tackling occupational health conditions such as stress, anxiety, depression and msds (white, 2005) . these challenges which have been shown to now have an increasing prevalence in the workplace (as discussed earlier), do not have a clear underlying physical basis nor do they demonstrate a linear relationship between injury, pain and disability. instead, they appear to be strongly mediated by psychological and social factors. accordingly, waddell (2004) categorized such conditions as 'common health problems'. the challenges presented by common health problems contrasts with the past success of occupational medicine in dealing with conditions that have an identifiable cause and a clear relationship between dose and response (waddell & burton, 2006) . the psychological models that were developed within the fields of occupational, and occupational health psychology, mainly to make sense of the concept of stress, were similarly influenced by conceptualizations of health, illness and safety. early models viewed stress either as a noxious stimulus in the environment (engineering models, derived from engineering) or a response to exposure to aversive of noxious characteristics of the environment (physiological models, derived from medicine). contemporary models focus on the interaction between the environment and the individual and emphasize either explicitly or implicitly the role of psychological processes, such as perception, cognition, and emotion (psychological models). these appear to determine how the individual recognizes, experiences, and responds to stressful situations, how they attempt to cope with that experience and how it might affect their physical, psychological, and social health (cox & griffiths, 2010) . the risk management paradigm remains an influential perspective in dealing with new and emerging risks in the psychosocial work environment. however, while we are a long way from the challenge of work-related stress being tackled effectively, there has started to be a shift towards promoting well-being at work and not only preventing stress and its associated negative outcomes in terms of both health and safety. this shift has followed trends in public health (discussed earlier) and also psychology towards more positive concepts. the positive psychology movement, championed by seligman and csikszentmihalyi (2000) , is an attempt to shift the emphasis in psychology away from a preoccupation with the pathological, adverse and abnormal aspects of human behaviour and experience. the positive psychology literature offers a number of perspectives that help with understanding how well-being can arise in work situations (lunt et al., 2007) . for example, the concept of flow was introduced by csikszentmihalyi (1990) which can be defined as a subjective condition where an individual is fully absorbed in, and engaged with, the task he or she is carrying out, promoting an experience of competence and fulfillment. as is evident from our discussion on perspectives on hsw so far, several useful models have been proposed from various disciplines with parallel developments can be observed across these disciplines. however, it should also be noted that often scholars and practitioners operate in silos, ignoring the interplay among the various approaches, and lessons that can be learned from one another. the recent focus on well-being has brought about the question of whether approaches in the workplace should focus only on factors influencing the individual's experience in the work environment or wider influences, considering more the social determinants of health discussed at the beginning of this chapter. in line with this thinking, some holistic models have emerged that recognize the interplay between workplace and non-workplace factors in determining hsw that will be discussed next. the starting point in the development of holistic models of hsw is the recognition that safety and health are different to well-being. as discussed at the beginning of this chapter, well-being refers to a good or satisfactory condition of existence; a state characterized by health, happiness, and prosperity. in particular, three key concepts have been discussed as relevant to well-being: happiness, quality of life and resilience (lunt et al., 2007) . layard (2005) defined happiness as feeling good; its inverse is feeling bad and wishing for a different experience. factors that affect our levels of happiness include among others family relationships, our financial situation, work, community and friends, our health, personal freedom and personal values. quality of life overlaps with contemporary interpretations of happiness. quality of life is a subjective state that encompasses physical, psychological, and social functioning. a defining feature of quality of life is its basis on the perceived gap between actual and desired living standards. resilience of individuals has been described as partly a context dependent characteristic, in that what enables resilience in one environment may be less adaptive in another (lunt et al., 2007) . increasingly it is recognized that resilience is important at different organizational levels (teams, organizations) and that these different levels are to some degree interacting (e.g. schelvis, zwetsloot, bos, & wiezer, 2014) . it is also important to recognize that even though well-being at work may be primarily an employer's responsibility (as well as the worker's), well-being of the worker or workforce is also the responsibility of others in society (e.g. governments, insurance companies, unions, faith-based and non-profit organizations) or may be affected by non-work domains (schulte et al., 2015 -see also chapter 7). indeed, the well-being of the workforce extends beyond the workplace, and public policy should consider social, economic, and political contexts. schulte et al. (2015) also provide examples of holistic policy models aiming at the promotion of well-being in the workplace that include the who healthy workplace model and the niosh total worker health model (discussed in the next chapter). to promote hsw holistically, there needs to be synergy and integration among the various perspectives. to achieve this, these perspectives need to be aligned considering current knowledge and existing needs, developing capabilities, and mainstreaming a strategic approach in policy and practice. the following chapter considers key policy approaches to managing hsw at the macro level (international, regional, national), meso level (sectoral), and micro level (organizational). subsequent chapters further consider how alignment across perspectives can be achieved in policy and practice. this chapter has provided an overview of the current state of the art in relation to hsw in the workplace as regards key determinants, outcomes and perspectives. with the changing nature of work and new characteristics of the workforce, new challenges are emerging in the workplace. perspectives on how to address these challenges have changed in line with these developments as well as the evolution of knowledge and the impact of wider socio-economic and political factors. emerging issues such as psychosocial factors, the increasing prevalence of non-communicable diseases, and the shift towards well-being (and not merely safety and health) demand new ways of thinking in addressing hsw in the workplace. continuing to work in silos and adopting mono-disciplinary perspectives will not allow us to move forward in this complex landscape. a strategic alignment of perspectives and integrated approaches are needed. this book aims to promote a way forward by outlining and critically evaluating developments in hsw in the workplace, and providing a framework for action in policy and practice. fundamental principles of occupational health and safety gender and jobs: sex 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health organization, 2, 100. world health organization (who) raising awareness of stress at work in developing countries: a modern hazard in a traditional working environment: advice to employers and worker representatives world health organization (who) sedentary behaviours and epithelial ovarian cancer risk key: cord-282457-80htwxm0 authors: iserson, kenneth v. title: healthcare ethics during a pandemic date: 2020-04-13 journal: west j emerg med doi: 10.5811/westjem.2020.4.47549 sha: doc_id: 282457 cord_uid: 80htwxm0 as clinicians and support personnel struggle with their responsibilities to treat during the current covid-19 pandemic, several ethical issues have emerged. will healthcare workers and support staff fulfill their duty to treat in the face of high risks? will institutional and government leaders at all levels do the right things to help alleviate healthcare workers risks and fears? will physicians be willing to make hard, resource-allocation decisions if they cannot first husband or improvise alternatives? with our healthcare facilities and governments unprepared for this inevitable disaster, front-line doctors, advanced providers, nurses, ems, and support personnel struggle with acute shortages of equipment—both to treat patients and protect themselves. with their personal and possibly their family’s lives and health at risk, they must weigh the option of continuing to work or retreat to safety. this decision, made daily, is based on professional and personal values, how they perceive existing risks—including available protective measures, and their perception of the level and transparency of information they receive. often, while clinicians get this information, support personnel do not, leading to absenteeism and deteriorating healthcare services. leadership can use good risk communication (complete, widely transmitted, and transparent) to align healthcare workers’ risk perceptions with reality. they also can address the common problems healthcare workers must overcome to continue working (ie, risk mitigation techniques). physicians, if they cannot sufficiently husband or improvise lifesaving resources, will have to face difficult triage decisions. ideally, they will use a predetermined plan, probably based on the principles of utilitarianism (maximizing the greatest good) and derived from professional and community input. unfortunately, none of these plans is optimal. disasters recur on a regular basis. in any disaster, and especially in those caused by disease, the public expects healthcare professionals to be on the front lines. indeed, most healthcare professionals expect that of themselves and their colleagues. in most disasters, and certainly during the current covid-19 pandemic, frontline healthcare professionals face two key ethical issues: (1) whether to respond despite the risks involved; and (2) how to distribute scarce, lifesaving medical resources. in this paper, i discuss how healthcare healthcare ethics during a pandemic iserson existential threat of this new coronavirus early enough to fully prepare institutional, local, regional, national, and international mobilization and response. political expediency, hubris, scientifically ignorant leaders, and incomplete information led to this inadequate advance planning by minimizing the threat when it appeared, further delaying vital public health action. at this point, the most vital ethical decision in our war against an unseen enemy is the one over which each of us has direct control: will we stay to help in the fight? most disaster plans depend on physicians, nurses, support staff, and prehospital personnel to maintain healthcare's frontlines during crises. yet planners cannot automatically assume that all healthcare workers will respond. will our hospitals and clinics have enough physicians, advanced practitioners, nurses, technicians, maintenance, and administrative staff to keep the doors open, the computers running, the linens clean, the lights on, and the facilities safe? will our 9-1-1 systems still be able to dispatch medics, firefighters, and police? that depends on the iterative, possibly hourly or daily, decisions that each affected individual repeatedly makes. such decisions are not purely ethical, but rather are complex determinations based on religious and personal values, family and community responsibilities, health and financial stability, and risk assessment. in 2001, for example, the ama code of ethics was modified from "solemnly commit [ing] ourselves to apply our knowledge and skills when needed, though doing so may put us at risk" 1 to "physicians should balance immediate benefits to individual patients with ability to care for patients in the future." 2 the american college of emergency physicians, meanwhile, stated in its 2017 code of ethics for emergency physicians: ''courage is the ability to carry out one's obligations despite personal risk or danger. emergency physicians exhibit courage when they assume personal risk to provide steadfast care for all emergency patients, including those who are agitated, violent, infectious, and the like." 3 despite these professional ethical codes, nothingeither morally or legally-compels a response to risk-prone situations. other than military personnel, no one is required to respond to potentially life-threatening emergencies. professional oaths and codes may serve to guide practitioners, but they are not absolutes. the factors that guide people to respond are very personal; healthcare workers' individual behavior and that of our organizational, professional and political leadership can modify those factors to increase the number that are willing to respond. 4 the moral backbone of medical professionals-a duty to put the needs of patients first-may be tested as they determine whether to stay and carry out their professional roles or to step back and decrease their own personal risks. whether providers will stay depends on their own risk assessment and value system. the "duty to treat" when one's health, life, or personal well-being is threatened is not absolute. in a risk-prone situation, each of us will prioritize our personal and professional values, those traits in ourselves that we consider to be our fundamental driving forces. "most clinicians first assess the risks to our own and to our family's life, health, and safety. we may then factor in, to varying degrees, our religious beliefs and personal motivations, all colored by elements of our personality. next, we may consider professional factors, including the precepts in our healthcare profession's oaths and codes, as well as other ethical and religious dicta to which we subscribe. most clinicians will focus on their concrete professional responsibilities." 5 these professional factors include: • supporting/assuming the same risk as colleagues • collegial pressure/consequences of not helping • augmenting community welfare • fulfilling public expectation and trust • using societally underwritten special training and professional status • fulfilling implied consent to help those in need (social contract) emergency physicians may also feel that in these situations they are compelled to use their special knowledge about triage, allocation of scarce resources (eg, vaccines, prophylactic or treatment medications, or intensive care unit [icu] ventilators), public health mandates (eg, isolation or quarantine, or mandatory vaccination), and the use of altered standards of care. 4,6 when preparing for a disaster, planners should consider not how they expect people to respond, but rather why they are likely to respond. 7 the risks to physicians and other healthcare providers' will vary by the nature of the causative agent, the provider's activities and underlying health, and the protections offered and used. people decide which risks to accept or to avoid based on their own perceptions of the source and quality of the information they receive. 8, 9 quick, emotional impressions often precede and guide ''rational'' risk appraisals. 10 provider and population perception of their risk from covid-19 will probably not be congruent with reality. in part, this will be due to the discordant messages from many senior politicians and other officials, but also will be influenced by the realtime updates in scientific knowledge about the disease, its transmission, and possible protective measures. in crises, individuals must balance good information from valid media, government, and other sources to help identify the actual risks to themselves and their loved ones. providing the best current information about the risks as well as the opportunities to assist during a crisis will help healthcare professionals make defensible decisions in disaster settings. 5 transparent and consistent information generates the trust necessary for both caregivers and the population to develop a reasonable risk assessment during conditions of uncertainty. 11 issuing incomplete or conflicting information, as was done during the first months of the covid-19 outbreak, caused many providers to make decisions to respond based on heated emotions and inaccurate risk perceptions. people have been shown to naturally exaggerate the risk of phenomena that are unknown or "dreaded," such as those with delayed, irreversible or manmade effects; those that have new, unknown, or unobservable risks; those that are global; and those that are "hyped" by the media. 5 historical precedent and the nature of the medical profession demonstrate that we will have enough physicians and, probably, nurses to treat patients. other professional and non-professional staff needed to keep healthcare institutions operating may not be as willing to risk themselves. recent history suggests that we probably will not have enough support personnel because, although they may be at as much or more risk than healthcare professionals, their personal safety is often considered as an afterthought by administrators. "an important lesson from the sars outbreak is that, whereas most clinicians will ''stay and fight,'' vital support personnel, including those in materials and supply, logistics, cleaning, information technology communications, maintenance, and refuse removal, may feel no commitment to assist; moreover, they may feel undervalued, unprotected from risks, and ignored when they are omitted from vital communications." 12 if all the staff necessary to run medical facilities fail to receive timely, relevant and believable information, they may not respond, and the quality of available healthcare will deteriorate. widely distributing accurate risk assessments and descriptions of protective measures for staff will encourage the maximal number of clinicians and other necessary personnel to respond to the situation. therefore, disaster planners and managers should do everything possible to communicate the risks clearly to all members of the healthcare system and to provide them with as much support and security as possible. risk communication (figure 1 ) is "the exchange of real-time information, advice and opinions between experts and people facing threats to their health, economic or social well-being." 13 its purpose "is to enable people at risk to 14 in addition to providing information, research shows that to attain the maximal response during risk-prone and other disasters, planners must do everything practicable to mitigate perceived risks and to address other concerns that may prevent staff from being either able or willing to work in a disaster (table 1 ). to address one concern, on march 20, 2020, the american academy of emergency medicine issued a position statement saying, in part, that they believe "a physician, nurse, pa, first responder or other healthcare professional has the right to be removed from the schedule of work requiring direct contact with patients potentially infected with covid-19 for issues of personal health, such as being on immunosuppressive therapy or other similar concerns, without the risk of termination of employment." 15 rarely discussed, but a key part of maintaining our workforce, is to support the psychosocial needs of the healthcare team. according to medical anthropologist monica schoch-spana, "pandemics aren't just physical. they bring with them an almost shadow pandemic of psychological and societal injuries as well." 17 psychosocial support for healthcare workers in the current war against covid-19 will be akin to post-traumatic stress disorder treatment for soldiers manning the front lines for extended periods. people respond to the mitigating actions healthcare ethics during a pandemic risks differently, so experienced professionals will need to intervene before tragic, adverse events occur. in the current pandemic, some key resources are and will increasingly become scarce. physicians will need to consider how to distribute available resources and obtain or improvise others. the most ethical course of action is to do everything possible to delay having to ration. vital materials already in short supply include viral test kits and their associated equipment and reagents, personal protective equipment (ppe), ventilators, and hospital -especially icu -beds. while china rapidly erected new, prefabricated hospitals to treat patients and many countries around the world are establishing alternative care sites, the united states has been slow to act. often not considered, healthcare workers, especially those with expertise treating the critically ill, will inevitably become a scarce resource. however, as the situation changes, most healthcare workers will constantly reassess their decisions about responding. as increasing numbers of personnel get sidelined due to actual or suspected disease, exhaustion, or fear for themselves or their families. some active and retired personnel who initially stayed out of the fight or were sidelined due to illness or other circumstances may reassess their decision and join the battle. employing senior medical students and extending advance practitioners' scope of practice has been suggested as one way to ameliorate this problem. in england and wales, the national health service has asked about 65,000 retired doctors and nurses to return to work. in scotland, they are recalling those who retired within the past three years. if these clinicians have been away from practice for more than a short time, they will receive brief refresher training. 26 the institute of medicine, among others, have described how to best manage resource scarcity in a widespread disaster ( table 2 ). many of these strategies are discussed in more detail elsewhere. 27 during or after attempts at conservation, reutilization, adaption, and substitution are performed maximally, rationing will need to be implemented. 31 the ethical principle that guides rationing is distributive justice, which requires that scarce resources be distributed fairly, providing them to those most in need. specifically, it requires impartial and neutral decision makers to consistently apply rationing decisions across people and time (treating like cases alike). 32 this is based on utilitarian principles, including conservation of resources, fiduciary responsibility (stewardship), multiplier effect (does the person have a job that will save other lives?), immediate usefulness, medical success, and caretaker role. 33, 34 most ethicists agree, however, that such distribution should be equitable, although in some circumstances other distribution methods, such as first come, first served; equal distribution; and even, no distribution may be more rational. even with agreement about equitable distribution, scarcity often requires clinicians to prioritize which patients receive the resources. 33, 34 as the covid-19 pandemic extends its devastation, physicians around the world are already facing the daunting task of rationing lifesaving resources. this is upending their traditional method of treating the sickest first in emergency departments or "first come first served" in the icus. 31 in italy, physicians have reported limiting ventilators to those less than 60 years old, and china and spain have implemented medical resource rationing. the us government and many states that have developed rationing plans have yet to explicitly implement them. 35 many of these plans may be outdated, and none have been tested to determine whether they will save lives. in fact, a canadian study of h1n1 patients found that 70% of patients that a rationing plan would have removed from ventilators survived with continued ventilation. 36 dr. laura evans, an intensivist at the university of washington, is working with her state to devise a triage plan that would be doing "the most good for the most people and be fair and equitable and transparent in the process." yet the washington state health department recently issued a statement that "triage teams under crisis conditions should consider transferring patients out of the hospital or to palliative care if the patient's baseline functioning was marked by 'loss of reserves in energy, physical ability, cognition and general health.'" 36 rationing plans must conform to general ethical principles and to existing community moral standards. community input into these plans is vital for maintaining the public's trust in • prepare-e.g., anticipate challenges, develop plans, stockpile materials. identify leaders who can source or develop alternative supplies and equipment. identify and train risk communicators. plan to mitigate personnel difficulties in responding. • conserve-implement conservation strategies for supplies in shortage or anticipated shortage to ensure the minimum impact/compromise possible (e.g., determining "at-risk" groups with priority for therapies in shortage and overall strategies to conserve use of oxygen delivery devices [i.e., ventilators] or ppe. • substitute-provide an equivalent or near-equivalent medication or delivery device. • adapt-use of equipment for alternative purposes (e.g., anesthesia machine as ventilator) • re-use-plan to re-use a wide variety of materials after appropriate disinfection or sterilization (e.g., may include oxygen delivery devices). • re-allocate-if no alternatives exist, remove a resource from one area/patient and allocate to another who has a higher likelihood of benefit (i.e., greater chance of surviving or more post-disease years to live). healthcare ethics during a pandemic iserson clinicians, the institutions, and the organizations involved in disaster relief and resource allocation. a major ethical dilemma is that current rationing criteria may skew away from normally disadvantaged populations. in the past, allocation plans were developed by the healthcare community. in the current crisis, some planning groups have tried to address this by asking disparate communities throughout their region to offer input into the plans. 36 in all circumstances, rationing scarce medical resources is difficult and stressful. such distribution, rather than being based on politics, money or power, must be based on an equitable (fair), openly available, pre-existing plan. it may be beneficial to have emergency physicians and intensivists take the lead (under set protocols) in making these decisions, since they have had more experience than others in doing this on a regular basis. ideally, they will have support from their institutions' bioethics consultants, social workers, and chaplains. rationing will not end when medications to treat covid-19 are eventually identified or vaccines are produced for prevention. in the first weeks or months there will be limited amounts available, with massive public anguish over how they are being distributed. those involved in developing and implementing healthcare resource distribution will need to think ahead and include this eventuality in their plans. lastly, resource allocation is not the only option. disasters are the exact situations where clinicians and administrators need to "think outside the box" by expanding clinical roles and responsibilities, relaxing restrictive regulations, improvising medical equipment, and devising other solutions to scarcity. 27 until the pandemic ends, we will need to encourage our healthcare workforce to stay at their posts and to use their fortitude and intellect as they face the multiple challenges involved with their jobs. • physicians and other healthcare providers' individual risks will vary by the nature of the causative agent, the provider's activities and underlying health, and the protections offered and used. • provider and population perception of risk will probably not be congruent with reality. • history and the nature of the healthcare professions demonstrate that we will have enough professional personnel to treat patients. • history suggests that we will not have the necessary support personnel-unless we respect their jobs and their risks and communicate with them in an open and honest manner. • the distribution of scarce, lifesaving resources will first require searching for alternatives and then making triage decisions based on careful planning with, if possible, widespread input. declaration of professional responsibility ama code of medical ethics' opinion on physician duty to treat. opinion 9.067 -physician obligation in disaster preparedness and response available at: www.acep.org/ globalassets/new-pdfs/policy-statements/code-of-ethics-for-emergencyphysicians must i respond if my health is at risk? fight or flight: the ethics of emergency physician disaster response willingness of the local health department workforce to respond to infectious disease events: empirical, ethical, and legal considerations factors associated with the ability and willingness of essential workers to report to duty during a pandemic the social amplification of risk-assessing 15 years of research and theory the social amplification of risk: a conceptual framework feeling and thinking: preferences need no inferences iserson healthcare ethics during a pandemic heading into the unknown: everyday strategies for managing risk and uncertainty professional experiences-personal dangers. lecture given at the departments of emergency medicine and critical care michael's hospital world health organization. general information on risk communication available at: https:// www.youtube.com/watch?v=ramrf1huxyw aaem position statement on protections for emergency medicine physicians during covid-19. available at: www.aaem.org/resources/statements/position/ protections-for-eps-during-covid-19 centers for disease control and prevention. cerc in an infectious disease outbreak available at coronavirus will radically alter the u.s. the washington post. available at: www factors associated with the ability and willingness of essential workers to report to duty during a pandemic mitigating absenteeism in hospital workers during a pandemic factors associated with the willingness of healthcare personnel to work during an influenza public health emergency: an integrative review the role of risk perception in willingness to respond to the 2014-2016 west african ebola outbreak: a qualitative study of international healthcare workers will the nhs continue to function in an influenza pandemic? a survey of healthcare workers in the west midlands understanding the willingness of australian emergency nurses to respond to a healthcare disaster emergency medical services workers' willingness to work during pandemic influenza office of personnel management. pandemic information coronavirus: tens of thousands of retired medics asked to return to nhs. available at: www.bbc.com/news/uk-51969104 improvised medicine: providing care in extreme environments refining surge capacity: conventional, contingency, and crisis capacity crisis standards of care: a systems framework for catastrophic disaster response: volume 1: introduction and csc framework duty to plan: health care, crisis standards of care, and novel coronavirus sars-cov-2. national academy of medicine perspectives ethical considerations for decision making regarding allocation of mechanical ventilators during a severe influenza pandemic or other public health emergency ethical guidelines in pandemic influenza triage in medicine-part i: concept, history, and types triage in medicine-part ii: underlying values and principles coronavirus briefing: what happened today the hardest questions doctors may face: who will be saved? who won't? key: cord-275979-cx2h5bsw authors: scutelnic, adrian; heldner, mirjam r. title: vascular events, vascular disease and vascular risk factors—strongly intertwined with covid-19 date: 2020-10-08 journal: curr treat options neurol doi: 10.1007/s11940-020-00648-y sha: doc_id: 275979 cord_uid: cx2h5bsw purpose of review: to elucidate the intertwining of vascular events, vascular disease and vascular risk factors and covid-19. recent findings: strokes are a leading cause of disability and death worldwide. vascular risk factors are important drivers of strokes. there are unmodifiable vascular risk factors such as age and ethnicity and modifiable vascular risk factors. according to the interstroke study, the 10 most frequent modifiable vascular risk factors are arterial hypertension, physical inactivity, overweight, dyslipidaemia, smoking, unhealthy diet, cardiac pathologies, diabetes mellitus, stress/depression and overconsumption of alcohol. also, infection and inflammation have been shown to increase the risk of stroke. there is high-quality evidence for the clinical benefits of optimal primary and secondary stroke prevention. the covid-19 pandemic brought a new perspective to this field. vascular events, vascular disease and vascular risk factors—and covid-19—are strongly intertwined. an increased risk of vascular events—by multifactorial mechanisms—has been observed in covid-19 patients. also, a higher rate of infection with covid-19, severe covid-19 and bad outcome has been demonstrated in patients with pre-existing vascular disease and vascular risk factors. summary: at present, we suggest that regular interactions between healthcare professionals and patients should include education on covid-19 and on primary and secondary vascular prevention in order to reduce the burden of disease in our ageing populations. the infection, caused by a novel coronavirus, the socalled severe acute respiratory syndrome (sars)-coronavirus (cov)-2, has been named covid-19 (coronavirus disease 2019) by the who (https://www.who.int/). the clinical presentation of covid-19 varies. most people experience an asymptomatic infection or mild symptoms with no or mild pneumonia. in some people, severe symptoms are observed, and in few people, critical symptoms occur, with respiratory failure, septic shock and/or multiorgan dysfunction or failure, potentially leading to death. the fatality rate has been shown to vary widely depending on, e.g., age, sex, comorbidities, vascular disease and vascular risk factors [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] . without any interventions such as social distancing and hygiene measures, a person infected with sars-cov-2 is likely to transmit covid-19 to at least two persons [1] . the causality between vascular events, vascular disease and vascular risk factors-and covid-19-seems to be interconnected and multidirectional [12] . we carried out a literature search on pubmed, who's homepage, scopus, europepmc and cochrane central database with the following search terms (1) "covid-19" or "sars-cov-2" and "characteristics," (2) "covid-19" or "sars-cov-2" and "cerebrovascular," (3) "covid-19" or "sars-cov-2" and "cardiovascular," (4) "covid-19" or "sars-cov-2" and "stroke," (5)"covid-19" or "sars-cov-2" and "myocardial infarction," (6)"covid-19" or "sars-cov-2" and "co-morbidities" and (7) "covid-19" or "sars-cov-2" and all risk factors according to the interstroke study. the authors independently performed a search and screening for relevant articles through title and abstract. the literature search was finalized on july 18, 2020. in middle-east respiratory syndrome (mers) and sars local occlusion of small-and mid-sized vessels have been described, having caused venous thrombosis, embolism and ischaemic as well as haemorrhagic stroke [13] . vascular events also have been identified in patients infected by covid-19 [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] . here, we focus on vascular events in covid-19 patients affecting the arteries or the brain-supplying vessels only. in patients with pre-existing vascular disease and vascular risk factors, covid-19 likely advances the foreseeable vascular event to an earlier time point, but also previously healthy individuals with covid-19 can be affected by vascular events [17] . a retrospective cohort study showed higher rates of tia, ischaemic and haemorrhagic stroke at admission in patients with vs. without covid-19 (n = 173) (76.8% vs. 58.1%; p = 0.018) [16] . in an observational study (n = 388 covid-19 patients, 16% admitted to icu), ischaemic strokes were diagnosed in 2.5% of all patients within a median duration of hospitalization of 10 (7-15) days. two-thirds of those events were the reason for admission. acute coronary syndrome/myocardial infarction was diagnosed in 1.1% of all patients; in 75%, it was the reason for admission [22] . in a retrospective observational case series (n = 214, 41.1% with severe covid-19), a proportion of around 5% of hospitalized covid-19 patients also had a stroke. higher rates of stroke were seen in patients with severe vs. non-severe covid-19 (5.7% vs. 0.8%; p = 0.03). the same group later published another report (n = 221), in which they identified 85% of strokes as ischaemic, one intracranial haemorrhage and one cerebral venous thrombosis. thirty-eight percent of these stroke patients died. furthermore, the authors showed that besides those patients with severe covid-19, older patients and those with higher vascular risk profile or c-reactive protein or d-dimer levels were at significantly higher risk of stroke [15, 23] . a retrospective cohort study (n = 3556 covid-19 patients) identified 32 patients (0.9%) with radiologically proven ischaemic stroke, 75% of which had severe disease or died. stroke was the reason for admission in 43.8% of patients, and 15.6% had no covid-19 symptoms prior to ischaemic stroke [18] . this study showed cryptogenic vs. other stroke aetiology to be more frequent in covid-19 patients if compared with contemporary controls (65.6% vs. 30.4%; p = 0.003) and with controls from an earlier time period (65.6% vs. 25%; p g 0.001) [18] . in a case series, acute ischaemic stroke because of large vessel occlusion ( fig. 1 ) was reported as the presenting feature of covid-19 in five patients younger than 50 years old without otherwise severe covid-19. one patient had a history of mild stroke and diabetes mellitus, one an undiagnosed diabetes mellitus, one dyslipidaemia and arterial hypertension and two patients no vascular risk factors [24•] . a meta-analysis estimated the prevalence of ischaemic stroke in covid-19 patients to be 1.6% (95% ci 0.8-2.5%), although there was a substantial heterogeneity between studies (i 2 = 47%) [25] . the mechanisms increasing the risk of vascular events in covid-19 patients are multifactorial [12, 15, 22, 26] . studies have found pathological laboratory test results in covid-19 patients, especially in those with severe covid-19, such as elevated leukocyte counts, reduced lymphocyte counts and elevated levels of c-reactive protein, ddimer levels, ferritin and lactate dehydrogenase, indicating hypercoagulability patient with ischaemic stroke because of large vessel occlusion. an 86-year-old female patient was brought by ambulance to our emergency department because of left-sided hemiparesis, forced eye deviation towards the right and confusion. she had a history of atrial fibrillation, coronary heart disease and diabetes mellitus type 2. the initial evaluation revealed an nihss score of 17. because her levels of anti-xa were elevated due to recent intake of rivaroxaban, an endovascular therapy with thrombectomy (successful reperfusion: tici 2b) without intravenous thrombolysis was performed. one day after intervention, the clinical assessment showed a residual nihss score of 8 because of moderate left-sided hemiparesis, left-sided facial droop and dysarthria. that could potentially provoke vessel occlusion and embolism [15, 26] . pro-inflammatory cytokines are known to trigger hypercoagulability. however, in a retrospective cohort study, elevated levels of the cytokine interleukin-6 were discrepant with elevated d-dimer levels in non-survivors. interleukin-6 levels appeared to increase at 2 weeks after covid-19 onset, whereas d-dimer levels were already 10-fold increased by that time. this observation suggests that very high d-dimer levels observed in some covid-19 patients are not only secondary to systemic inflammation, but likely reflect true thrombotic disease, possibly induced by cellular activation triggered by sars-cov-2 [14] . antiphospholipid antibodies can be a cause of hypercoagulability with subsequent vessel occlusions. elevated titres of antiphospholipid antibodies have been detected in some patients with covid-19 and ischaemic stroke or acute limb ischaemia. however, causality remains uncertain [26] . sars-cov-2 may increase the risk of stroke by infection of the vascular endothelial cells causing endotheliitis. the resulting damage of the vasculature may lead to vascular events, including venous thrombosis, embolism and ischaemic or haemorrhagic stroke [27••] . moreover, an acute covid-19 cardiovascular syndrome (acovcs) has been described [12] . this may be caused by viral myocarditis, systemic inflammation, stress-related cardiomyopathy, or microvascular thrombosis. myocardial injury, heart failure and/or cardiac arrhythmia may occur leading to macrovascular thrombus formation and potentially to embolism or less frequently to hypoperfusion-the latter in patients with pre-existing high-grade vessel stenoses or occlusions of the brain-supplying arteries. also, venous thrombi might be dislodged and cause paradoxical embolism to the brain. to conclude, vascular events can occur in covid-19 patients by several mechanisms. these events may be clinically silent, occur as the presenting symptom, or during the disease course and potentially lead to disability and death. while vascular events in covid-19 patients have been detected in healthy persons, the risk is higher with severe covid-19, and also in patients with pre-existing vascular disease and vascular risk factors. a higher rate of infection with covid-19, severe covid-19, and worse outcome has been demonstrated in patients with pre-existing vascular disease and risk factors, compared with young and healthy persons [1, 6, 8-11, 28, 29] . in a meta-analysis (n = 1576, 280 with severe covid-19), the most prevalent co-morbidities in covid-19 patients turned out to be arterial hypertension (21.1%, 95% ci = 13.0-27.2%), diabetes mellitus (9.7%, 95% ci = 7.2-12.2%), cardiovascular disease (8.4%, 95% ci = 3.8-13.8%) and respiratory disease (1.5%, 95% ci = 0.9-2.1%) [28] . other studies showed similar results [1, [5] [6] [7] [8] [9] [10] [11] . a systematic review, meta-analysis/meta-regression (16 studies, n = 4448 covid-19 patients, 19.8% died, 56.7% with severe covid-19) revealed that besides pre-existing cardiovascular disease, cerebrovascular disease was also associated with poor outcome (rr 2.04, 95% ci = 1.43-2.91; p g 0.001), mortality (rr 2.38, 95% ci = 1.92-2.96; p g 0.001) and severe covid-19 (rr 1.88, 95% ci = 1.0-3.51; p = 0.05). the association was not influenced by gender, age, arterial hypertension, diabetes mellitus and respiratory comorbidities [29•] . a single-centre retrospective cohort study (n = 1875 covid-19 patients, 50 with previous stroke of which 90% were ischaemic) showed that previous vs. no previous stroke was more likely associated with acute respiratory distress syndrome (ards) (32% vs. 18.9%; p = 0.028), with non-invasive mechanical ventilation (30% vs. 17.5%; p = 0.037) and with death (14.0% vs. 8.3%; p = 0.019) [30] . in a descriptive study (n = 1591 icu-treated covid-19 patients), preexisting vascular disease was associated with severe covid-19 and in 21% of patients it was the second most frequent co-morbidity after arterial hypertension (49%) [11] . in another descriptive study of the clinical characteristics of 138 covid-19 patients, icu-treated patients (n = 36, 26.1%) were more likely to suffer from co-morbidities such as high blood pressure (58.3% vs. 21.6% in the non-icu group; p g 0.001), diabetes mellitus (22.2% vs. 5.9%; p = 0.009) and vascular disease (25% vs. 10.8%; p = 0.04). also, the icu group was significantly older (median age 66 vs. 51 years; p g 0.001) [1] . the elderly are more likely to suffer from co-morbidities and from additional vascular risk factors besides age [1] . furthermore, the immune system declines with age. in the elderly, there is lymphopenia, decreased regulatory t cell function and clearance of apoptotic cells by macrophages as well as elevated levels of pro-inflammatory cytokines interleukin-1beta, interleukin-6, interleukin-18 and tnf-alfa [31] . this may contribute to the burden of covid-19 in the elderly. in addition, lockdown, social distancing and economic downturn are potentially changing lifestyles, dietary and smoking habits, reducing physical activity and increasing obesity and mental health problems. these changes impact the vascular risk profile in some people [32, 33] . to conclude, optimal primary and secondary vascular prevention might reduce the burden of covid-19. below, we review specific and potentially modifiable vascular risk factors with respect to covid-19 and stroke. in a meta-analysis (n = 1576, 280 with severe covid-19), arterial hypertension was the most prevalent vascular risk factor in covid-19 patients (21.1%, 95% ci = 13.0-27.2%) [28] . also, outcome of covid-19 has been shown to be worse in patients with arterial hypertension [34] . while confounding factors such as age and co-morbidities may explain these findings, a role has been postulated for angiotensin-converting enzyme 2 (ace2) which is the binding site and entry receptor of sars-cov-2 [35••] . in patients with arterial hypertension, ace2 levels are increased in the blood, and this results in enhanced angiotensin ii effects. sars-cov-2 leads to a partial decrease in ace2 function, which also leads to enhanced angiotensin ii effects [36••] . angiotensin ii triggers inflammation, cell proliferation, hypertrophy, fibrosis and tissue remodeling curr treat options neurol (2020) 22:40 through angiotensin 1 (at1) receptor (so-called ace/angiotensin ii/at1 receptor axis) [37] . angiotensin-converting enzyme inhibitors (aceis) and angiotensin receptor blockers (arbs), which are frequently prescribed as antihypertensive drugs, increase the expression of ace2 in tissue. they have been discussed to have a potentially adverse, protective and/or biphasic effect on covid-19 [36••] . increased expression of ace2 in tissue may antagonize some detrimental effects of sars-cov-2. in contrast, aceis/arbs might negatively impact infection risk and outcome by increasing binding sites. a biphasic effect might be explained by the different phases of acute infection, which have been shown in covid-19 [36••] . some studies found a better covid-19 outcome associated with aceis/ arbs [38] [39] [40] [41] , while others did not [42] [43] [44] . one retrospective descriptive study (n = 113 covid-19 patients, 74 on aceis/arbs) found increased mortality in patients on aceis/arbs (or 3.66, 95% ci 1.11-18.18, p = 0.032) [45] . patients on aceis/arbs were older and more likely to have coronary artery disease. also, only patients with moderate or severe covid-19 were included. the authors acknowledged the possibility of unrecognized confounders and the low number of patients as study limitations. at present, current guidelines do not recommend to prophylactically prescribe aceis/arbs to decrease covid-19 infection risk and to improve outcome of covid-19, and they do not recommend to switch an established treatment for these antihypertensive drugs in covid-19 patients [38] . sudden cessation of antihypertensive drugs increases the risk of vascular events, and newly initiated antihypertensive drugs may be less effective and/or tolerated. physical activity has a positive impact on weight, blood pressure and glucose, dyslipidaemia, cigarette craving, anxiety/depression and systemic inflammation, which all increase vascular risk [46] . physical activity also improves immune response to vaccines and decreases duration and severity of viral illness mainly through increased levels of antiinflammatory cytokines (e.g., interleukin-10, interleukin-1 receptor antagonist) and through downregulation of expression/activation of toll-like receptors (tlrs) [47] . social distancing might facilitate personal instead of public transportation and thus increase physical activity. a cross-sectional analysis in one study found a doubling of the average daily use of a public bicycle sharing system in 2020 compared with the same period in 2019 [48] . however, social distancing and lockdown policies, economic downturn and fear of contracting covid-19 have also been found to negatively impact physical activity [49] . a descriptive study (n = 455,404, 187 countries) using data from a smartphone step-counting app found a 5.5% decrease of steps within 10 days and a 27.3% decrease within 30 days after declaration of the covid-19 pandemic [50] . an electronic survey (n = 2524) found significantly decreased levels of physical activity during covid-19 lockdown compared with before lockdown in all age groups (mean 2429 vs. 1577 metabolic equivalent task min/week; p g 0.0001) [51] . a study including 109 children with congenital heart disease showed a decrease of steps by 21-24% around march 11, when the who declared the covid-19 outbreak to be a pandemic [52] . one survey (n = 9456) showed that a decrease of physical activity during lockdown was associated with obesity (or 1.21, 95% ci = 1.02-1. 41 [33] . a prospective cohort study (n = 387,109 of whom 760 had covid-19 between march/april 2020) found physical inactivity (quantified using the international physical activity questionnaire) to be a risk factor for covid-19 (or 1.32, 95% ci 1.10-1.58) [53•] . physical activity might help to prevent infection and severity of covid-19, severity by attenuating the cytokine storm syndrome that occurs in some patients [47] . there are options for at-home physical activity that should be encouraged to avoid the negative consequences of an increased sedentary lifestyle [54] . overweight/obesity is associated with arterial hypertension, diabetes mellitus, dyslipidaemia, inflammation, endothelial dysfunction, hypercoagulability and cardiac arrhythmia, which all increase vascular risk. furthermore, overweight and obesity can restrict ventilation, diminish diaphragm excursion, forced respiratory volume and forced vital capacity and impair immune response to viral infections [3] . the covid-19 pandemic increases risk of overweight/obesity, by social distancing, lockdown policies, economic downturn, decreased physical activity and modifications of lifestyle [32, 33] . a cohort study (n = 100 individuals) found an increased weight after 49 days of lockdown in 40% of individuals [55] . a case-control study (n = 32,583, 12,304 patients with newly diagnosed covid-19) identified obesity to be a major risk factor for covid-19 (adjusted or 6.92, 95% ci 5.54-8.65; p g 0.0001) [56] . there is evidence that obesity/overweight increases the risk of severe covid-19. a descriptive multicentre study (n = 1687) found that patients who were overweight (bmi 25-29.9 kg/m 2 , or 1.32, 95% ci 1.03-1.69; p = 0.05), or had mild-to-moderate obesity (bmi = 30-39.9 kg/m 2 , or 1.8, 95% ci 1.39-2.35; p = 0.05), or had morbid obesity (bmi 9 40 kg/m 2 , or 1.74, 95% ci 1.08-2.8; p = 0.05) were likelier to have severe covid-19 vs. patients with normal weight [57] . other studies found similar results [2, 58, 59] . also, obesity has been shown to shift severe covid-19 to younger ages. a review of a dataset of 265 hospitalized covid-19 patients found a significant negative association between bmi and age (p = 0.0002). the median bmi was 29.3 kg/m 2 . twenty-five percent of individuals had a bmi g 26 kg/m 2 and 25% a bmi 9 34.7 kg/m 2 [4] . potential explanations for these results might be the findings mentioned earlier in this review linked to obesity and overweight, such as mechanical restriction of ventilation and impaired immune response but also the higher curr treat options neurol (2020) 22:40 expression of ace2 in adipose tissue [60] . overall, obese/overweight people are a special risk group of patients in light of covid-19 and are at risk of having more severe covid-19 [2] . a retrospective study (n = 597, of whom 171 had severe and 32 critical covid-19) observed a drop in high-(hdl-c) and low-density-lipoprotein cholesterol (ldl-c) during the covid-19 course [61] . the latter finding was associated with worse outcome. possible explanations for the drop in cholesterol include impaired lipid biogenesis because of liver injury, inflammatory-mediated modulation of lipid metabolism facilitating cholesterol clearance and increased vascular permeability due to infection and leakage of cholesterol molecules into the tissue [61] . in addition to lifestyle modifications, drugs are recommended to lower serum-cholesterol levels (https://www.who.int/). statins are widely used in patients with vascular disease on the basis of their lipid-lowering activity but also for their pleiotropic effects. they have an antiinflammatory effect, which is mainly mediated through pathways that lead to inhibition of nuclear factor kappa (nf-kb) [62] . like aceis/arbs, statins upregulate tissue ace2 [63] . the coronado study did not find a protective role of statins on the primary endpoint of endotracheal intubation or death in covid-19 patients with diabetes mellitus [58•] . moreover, statins have been shown to increase interleukin-18, which may facilitate severe covid-19 [63] . however, in a retrospective study (n = 13,981 covid-19 patients, 1219 received statins), compared with individuals without pre-existing statin intake, individuals with in-hospital statin intake had a lower crude 28-day mortality (rr 0.78, 95% ci 0.61-0.996; p = 0.046) [64• ]. also, statins were shown to have a protective effect against sars-cov2 in silico [65] . smoking probably has increased during the covid-19 pandemic due to stress/ depression, anxiety and fewer possibilities of outdoor physical and other activities. also, face-to-face interventions aimed at supporting those who quit smoking have been made difficult [66] . however, a single-centre descriptive study (n = 357) found a higher rate of smoking cessation during the covid-19 pandemic compared with 2019 (31.1% vs. 23.7%) [67] . interestingly, upregulation of tissue ace2 in smokers has been demonstrated [68] . a prospective cohort study (n = 387,109, 760 with covid-19) found smoking to be a risk factor for covid-19 (or 1.42, 95% ci 1.12-1.79) [53•] . smoking has been shown to impact outcome in covid-19. a meta-analysis including a large number of covid-19 patients (15 studies, n = 2473, 221 current and ex-smokers) showed that current smokers were more likely to have severe covid-19 compared with former and never smokers (rr 1.45, 95% ci = 1.03-2.04) [69] . one study (n = 78 covid-19 patients) identified smoking to be a strong risk factor for covid-19 disease progression (or 8.772, 95% ci = 1.942-40.000; p = 0.016). disease progression was defined as change from mild/moderate to severe or critical disease or mortality and as severe to critical disease or mortality [8] . a meta-analysis (n = 6515) found current vs. non-current smoking to be a risk factor for adverse outcome (or 1.53, 95% ci 1.06-2.2; p = 0.022) among hospitalized covid-19 patients [70] . contradicting the above results, a meta-analysis (n = 5960) showed a lower pooled prevalence of current smoking in hospitalized covid-19 patients (6.5%, 95% ci 4.9-8.2%) compared with the prevalence of smoking in the general population [71] . in conclusion, cessation of smoking reduces the risk of stroke and according to most data-at least indirectly-also the burden of covid-19. dietary habits have changed during the covid-19 pandemic. social distancing, lockdown and economic downturn have impacted grocery shopping. people started favouring long-lasting and less healthy foods. as some people started experiencing more mental health problems than normally, it is likely that some increased their intake of alcohol [71] . one analysis showed a growth of alcohol online sales of 50-500% compared with the same period in 2019 [72] . however, other people have decreased their alcohol consumption, since there suddenly were less social events and restricted access to alcohol [73] . an electronic survey (n = 1047) showed alcohol binge drinking having decreased significantly during lockdown. authors also reported that meal patterns during lockdown (type of food, eating out of control, intake of snacks between meals, number of main meals) were unhealthier [55] . however, a survey study from italy (n = 3533) found an increased adherence to mediterranean diet in the group aged 18-30 years during lockdown, compared with the younger and older populations (p g 0.001; p g 0.001, respectively) [74] . ethanol suppresses the function of the immune system [75] . a meta-analysis (n = 1998) did not find an association between alcohol consumption and severity of covid-19 (rr 1.09, 95% ci = 0.79-1.49; p = 0.6). however, the study did not consider the amount and duration of drinking [76] . as mentioned earlier in this review, acute covid-19 cardiovascular syndrome (acovcs) has been described, potentially increasing the risk of stroke [12] . as the interstroke study has shown for stroke, the interheart study has shown for cardiovascular events that with best management of the most frequent modifiable vascular risk factors, the vast majority of cardiovascular events could be prevented [77] . lockdown has been shown to increase the risk of diabetes mellitus [55, 78] . a cohort study (n = 100 non-diabetic individuals, follow-up 49 days) identified an increased risk of new diabetes mellitus of 7% [55] . a prospective cohort study (n = 387,109 individuals, 760 with covid-19) found more hospitalized covid-19 patients to have diabetes mellitus than not (9.5% vs. 4.8%) [53•] . a meta-analysis (n = 78,874) showed that diabetes mellitus was associated with severe covid-19 (or 2.10, 95% ci = 1.71-2.56; p g 0.001) and mortality (or 2.78, 95% ci = 2.09-3.44) [6] . also, in another meta-analysis (n = 1576, 280 with severe covid-19), diabetes mellitus was the most frequent vascular risk factor (9.7%, 95% ci = 7.2-12.2%), after arterial hypertension [28] . furthermore, a retrospective multicentre study (n = 7337 patients with covid-19, 952 with pre-existing diabetes mellitus) found that in-hospital well-controlled blood glucose (glycaemic variability 3.9-10 mmol/l) was associated with significantly lower mortality compared with patients with poor glycaemic control (or 0.13, 95% ci 0.04-0.44; p g 0.001) [79••] . several potential mechanisms increasing this risk of covid-19 in patients with diabetes mellitus have been proposed: (1) higher affinity of cellular binding of sars-cov-2 and higher levels of circulating furin facilitating virus entry, (2) increased ace2 expression in the lungs, (3) decreased viral clearance, (4) diminished t cell function, (5) increased susceptibility to inflammation and cytokine storm syndrome and (6) co-existence of vascular disease and risk factors [5] . of note, the coronado study, a multicentre observational study in hospitalized covid-19 patients with diabetes mellitus (n = 1,317,410 admitted to icu), did not find an association in univariate analysis between the primary endpoint (tracheal intubation and/or death within 7 days of admission) and age, type of diabetes mellitus, hba1c levels, diabetic complications, or antidiabetic therapy [58•] . noteworthy, in this study, the glycaemic control was not measured by serum glucose, potentially helping to explain the findings contradicting other studies. in conclusion, diabetes mellitus not only increases the risk of stroke but also increased the burden of covid-19 in most studies. antidiabetic drugs such as glucagon-like peptide-1 agonists, inhibitors of sodium-glucose transporter 2 and thiazolidinediones are known to increase the expression of ace2 [80] . a retrospective study (n = 403 patients with covid-19, 85 of whom with type 2 diabetes) found no significant effect of intake of dipeptidyl peptidase-4 on outcome [81] . another retrospective analysis (n = 283 patients with covid-19 and diabetes type 2) identified lower mortality rates in patients with vs. without metformin intake (p = 0.01) [82] . further high-quality data regarding outcome of covid-19 in patients with intake of antidiabetic drugs are yet lacking [83] . lockdown, social distancing, economic downturn, rapid transmission of infection, high number of deaths and lack of effective treatment strategies and vaccines may facilitate mental health problems not only in patients with preexisting mental disease but also in healthy persons, causing fear, anxiety, depression, stress reactions, posttraumatic stress disorder and sleep problems [32, 84] . an online survey (n = 1210) analysed mental health impact of the covid-19 outbreak. responders (53.8%, significantly more female) reported moderate to severe avoidance, intrusion and/or hyperarousal, 16 .5% (significantly more male) moderate to severe depressive symptoms and 28.8% (significantly more male) moderate to severe/extremely severe anxiety [32] . being a student or reporting poor/very poor self-rated health status was significantly associated with higher mental health impact compared with not being a student or compared with those with good/very good self-rated health status. uneducated status was significantly associated with depressive symptoms [32] . an internet-based, cross-sectional survey (n = 1160) showed higher rates of depression (assessed using epidemiological studies depression scale) and anxiety in quarantined vs. non-quarantined responders (36.05% vs. 16.12%) [85] . however, another survey study (n = 1443 participants in quarantine, 836 without quarantine) did not find an impact of quarantine status on depression likelihood (using patient health questionnaire-9) [86] . a cross-sectional study (n = 932) found female sex, young age, low annual income, current smoking and physical multimorbidity to be associated with mental health issues during the covid-19 pandemic [84] . mental disease has been identified to be a risk factor for infection with covid-19. possible explanations are cognitive impairment, little awareness of risk and diminished efforts regarding personal protection as well as confined conditions in psychiatric wards, which make social distancing and compliance with hygiene measures more difficult. also, access to timely health care may be difficult for patients with mental disease due to the stigma [87] . a cross-sectional study (n = 3947) found a higher likelihood of depression (assessed using patient health questionnaire-9) in people with suspected covid-19 symptoms (or = 2.88, 95% ci 2.18-3.8; p g 0.001). an online survey study (n = 770 covid-19 patients) found a prevalence of depression (using phq-9) of 43.1% in clinically stable patients [88] . one prospective cross-sectional study (n = 114 covid-19 patients) found a significant association of loss of smell and depression and anxiety (assessed using phq-2 and generalized anxiety disorder-2) [89] . to reduce the psychological impact of the covid-19 pandemic, the who published simple recommendations: getting up and going to bed at similar times every day, keeping up with personal hygiene, eating healthy meals at regular times, exercising regularly, allocating time for working and time for resting, making time for enjoyable things, minimizing newsfeeds, limiting the amounts of alcohol and drug consumption and limiting screen time (https:// www.who.int/). strategies to reduce the burden of mental disease related to covid-19 have been proposed such as development of teams of specialists qualified to address emotional distress, training of community health personnel in basic aspects of mental health care, use of online surveys to assess the scope of mental health problems, development of online materials for mental health education, provision of online counselling and self-help services, use of structured letters as a form of asynchronous telepsychiatry consultation and development of synchronous telemedicine services for diagnostic purposes as well as counselling. also, there is a need to make online mental health services accessible to individuals from lower socioeconomic background [89] . the relationship between vascular events, vascular disease and vascular risk factors-and covid-19-is strongly intertwined. there is a synergism between what is healthy and what makes us less vulnerable to contract covid19 and to what increases the risk of having severe covid-19 and bad outcome. not only optimal secondary but also primary vascular prevention might reduce the burden of covid-19 in our ageing populations. adrian scutelnic: acquisition and extraction of data, interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. mirjam r. heldner: supervision, acquisition and extraction of data, interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. open access funding provided by university of bern. data sharing is not applicable to this article as no new data were created or analysed in this review. conflict of interest adrian scutelnic has nothing to disclose. mirjam r heldner has served on the advisory board of amgen in 2019 and in 2020, outside the submitted work. this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation obesity a risk factor for severe covid-19 infection: multiple potential mechanisms obesity could shift severe covid-19 disease to younger ages covid-19 pandemic, coronaviruses, and diabetes mellitus diabetes as a 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serious health issues or self-perception of high risk during the uk covid-19 lockdown covid-19 patients with hypertension have more severe disease: a multicenter retrospective observational study the pathogenicity of sars-cov-2 in hace2 transgenic mice online ahead of print an experimental work with mice showing that sars-cov2 uses hace2 as entry receptor the science underlying covid-19: implications for the cardiovascular system a very interesting comprehensive analysis of the pathomechanisms of covid-19, also discussing its clinical implication what's new in the renin-angiotensin system? angiotensinconverting enzyme-2: a molecular and cellular perspective association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid-19 effects of angiotensin ii receptor blockers and ace (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with covid-19 and hypertension: a singlecenter retrospective study acei/arb use and risk of infection or severity or mortality of covid-19: a systematic review and meta-analysis the use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (covid-19): a systematic review and meta-analysis renin-angiotensin-aldosterone system inhibitors and risk of covid-19 impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on covid-19 in a western population. cardiovid registry association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with covid-19 diagnosis and mortality is the use of ace inb/ arbs associated with higher in-hospital mortality in covid-19 pneumonia patients? the role of physical activity in primary stroke prevention does high cardiorespiratory fitness confer some protection against pro-inflammatory responses after infection by sars-cov-2? social distancing and outdoor physical activity during the covid-19 outbreak in south korea: implications for physical distancing strategies jul 15;1010539520940929. online ahead of print impact of home quarantine on physical activity among older adults living at home during the covid-19 pandemic: qualitative interview study worldwide effect of covid-19 on physical activity: a descriptive study online ahead of print the impact of physical activity on psychological health during covid-19 pandemic in italy reduced physical activity during covid-19 pandemic in children with congenital heart disease lifestyle risk factors for cardiovascular disease in relation to covid-19 hospitalization: a community-based cohort study of 387,109 adults in uk an interesting study analyzing the association between vascular risk factors and risk of covid-19 coronavirus disease (covid-19): the need to maintain regular physical activity while taking precautions increase in the risk of type 2 diabetes during lockdown for the covid19 pandemic in india: a cohort analysis obesity is the comorbidity more strongly associated for covid-19 in mexico. a case-control study obesity and covid-19 in new york city: a retrospective cohort study phenotypic characteristics and prognosis of inpatients with covid-19 and diabetes: the coronado study a thorough description of the clinical characteristics and their impact on outcome of patients with diabetes mellitus and covid-19 obesity aggravates covid-19: a systematic review and meta-analysis two things about covid-19 might need attention tissue specific up regulation of ace2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications endothelial cell dysfunction and the pathobiology of atherosclerosis are certain drugs associated with enhanced mortality in covid-19? in-hospital use of statins is associated with a reduced risk of mortality among individuals with covid-19 statins and the covid-19 main protease: in silico evidence on direct interaction covid-19: risk of increase in smoking rates among england's 6 million smokers and relapse among england's 11 million ex-smokers the effect of the covid-19 pandemic on smoking cessation success tobacco smoking increases the lung gene expression of ace2, the receptor of sars-cov-2 prevalence, severity and mortality associated with copd and smoking in patients with covid-19: a rapid systematic review and meta-analysis current smoking, former smoking, and adverse outcome among hospitalized covid-19 patients: a systematic review and meta-analysis global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (interstroke): a case-control study covid-19 and alcohol in australia: industry changes and public health impacts alcohol use in times of the covid 19: implications for monitoring and policy eating habits and lifestyle changes during covid-19 lockdown: an italian survey opposing effects of alcohol on the immune system drinking no-links to the severity of covid-19: a systematic review and meta-analysis effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): case-control study newly diagnosed diabetes and diabetic ketoacidosis precipitated by covid-19 infection association of blood glucose control and outcomes in patients with covid-19 and pre-existing type 2 diabetes a very important study showing that in patients with diabetes mellitus glycemic control significantly improves outcome in patients with covid-19 activation of the glp-1 receptor by liraglutide increases ace2 expression, reversing right ventricle hypertrophy, and improving the production of sp-a and sp-b in the lungs of type 1 diabetes rats exposure to dpp-4 inhibitors and covid-19 among people with type 2 diabetes. a case-control study metformin treatment was associated with decreased mortality in covid-19 patients with diabetes in a retrospective analysis sglt-2 inhibitors for covid-19-a miracle waiting to happen or just another beat around the bush? primary care diabetes correlates of symptoms of anxiety and depression and mental wellbeing associated with covid-19: a crosssectional study of uk-based respondents. psychiatry res covid-19 related depression and anxiety among quarantined respondents. psychol health the immediate mental health impacts of the covid-19 pandemic among people with or without quarantine managements patients with mental health disorders in the covid-19 epidemic prevalence of depression and its association with quality of life in clinically stable patients with covid-19 covid-19 and mental health: a review of the existing literature publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations papers of particular interest, published recently, have been highlighted as:of major importance key: cord-272296-1gn1zhvt authors: huybrechts, krista f.; bateman, brian t.; zhu, yanmin; straub, loreen; mogun, helen; kim, seoyoung c.; desai, rishi j.; hernandez-diaz, sonia title: hydroxychloroquine early in pregnancy and risk of birth defects date: 2020-09-19 journal: am j obstet gynecol doi: 10.1016/j.ajog.2020.09.007 sha: doc_id: 272296 cord_uid: 1gn1zhvt background hydroxychloroquine (hcq) is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. quantifying the risk of congenital malformations associated with early pregnancy exposure to hcq is important both in the context of its ongoing use for rheumatological disorders as well as its potential future use for covid-19 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for covid-19 treatment having been negative. objective the study objective was to evaluate the risk of major congenital malformations associated with exposure to hcq during the first trimester, the period of organogenesis. study design we performed a population-based cohort study nested in the medicaid analytic extract (max, 2000-2014) and ibm marketscan research database (marketscan, 2003-2015). the source cohort included 2,045 hcq exposed and 3,198,589 unexposed pregnancies continuously enrolled in their respective insurance program from 3 months before the last menstrual period through at least one month after delivery; infants were enrolled for at least 3 months after birth. we compared the risk of congenital malformations in women with hcq use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (n= 1,867 hcq exposed; 19,080 unexposed pregnancies). the outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery, and specific malformation types for which there were at least 5 exposed events: oral clefts, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects. results overall, 54.8 per 1,000 infants exposed to hcq were born with a major congenital malformation versus 35.3 per 1,000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% ci, 1.27–1.81). patient characteristics were balanced in the restricted, propensity score matched cohort. the adjusted relative risk was 1.26 (1.04–1.54); it was 1.33 (1.08-1.65) for a daily dose ≥400mg and 0.95 (0.60-1.50) for <400mg. among the different malformation groups considered, more substantial increases in the risk for oral clefts, respiratory anomalies and urinary defects were observed, although estimates were imprecise. no pattern of malformations was identified. conclusions our findings suggest a small increase in the risk of malformations associated with first trimester hcq use. for most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. if hcq were shown to be effective for covid-19 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits. hydroxychloroquine (hcq) is an antimalarial drug widely used in the treatment of systemic 116 lupus erythematosus (sle) and other rheumatic disorders. it is generally considered to be safe 117 for treatment of autoimmune rheumatic conditions during pregnancy and continuation of hcq 118 during pregnancy is commonly recommended to improve disease management and pregnancy 119 outcomes. 1-3 studies have been too small, however, to evaluate teratogenicity. over the last 120 several months, there has been heightened interest in hcq due to it being a candidate drug for 121 the treatment and/or prophylaxis of coronavirus disease 2019 . health organization has discontinued the hcq arm of the solidarity trial evaluating its efficacy 128 for the treatment of hospitalized patients, 7 numerous randomized controlled studies are still 129 ongoing in particular to evaluate its effects for pre-exposure prophylaxis 8 and including a trial in 130 pregnant women. 9 131 most studies regarding the safety of hcq when used for malaria and for rheumatic disorders 132 like sle suggest no increase in the risk of common adverse obstetrical outcomes such as 133 spontaneous abortion, prematurity, and intrauterine growth restriction. [10] [11] [12] [13] however, data 134 regarding the risk of major congenital malformations associated with early pregnancy exposure 135 is very limited, with the largest published cohort study including fewer than 200 exposed 136 pregnancies (supplementary table 1 ). 13 quantification of the risk of congenital malformations 137 associated with early pregnancy exposure to hcq is therefore important both in the context of 138 its ongoing use for rheumatological disorders as well as its potential future use for 139 j o u r n a l p r e -p r o o f although based on the results of initial trials, its usefulness in this clinical context remains highly 140 uncertain. given the limited data currently available, we evaluated the risk for major congenital 141 malformations associated with hcq using two large healthcare utilization databases. include demographic and insurance enrollment information, medical visits and hospitalizations, 149 diagnoses and procedures received as an in-or outpatient, and prescriptions filled on an 150 outpatient basis. the development of the linked mother-infant pregnancy cohorts has been 151 described previously. 14,15 briefly, we identified all completed pregnancies in women 12 to 55 152 years of age and linked these pregnancies to liveborn infants by state, family identification 153 number and delivery/birth dates. using a validated algorithm, 16 we estimated the date of the last 154 menstrual period on the basis of the delivery date and diagnostic codes indicative of preterm 155 delivery. mothers were required to be continuously insured from 3 months before the start of 156 pregnancy until 1 month after delivery. infants were required to be insured from birth until 3 157 months thereafter, unless they died sooner. these restrictions did not affect the age or race 158 distribution in max, but resulted in a decrease in the proportion of who become medicaid 159 eligible due to the occurrence of pregnancy and a corresponding increase in the proportion who 160 become eligible based on other criteria. 17 pregnancies with exposure to a known teratogenic 161 medication (i.e., warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) 162 during the first trimester and pregnancies with a chromosomal abnormality were excluded. 163 j o u r n a l p r e -p r o o f exposure. women were considered exposed if they filled a prescription for hcq during the first 164 trimester of pregnancy (defined as date of the last menstrual period through day 90 of 165 pregnancy), the etiologically relevant exposure window for congenital malformations. the 166 reference group consisted of women without a prescription for hcq from 3 months before the 167 start of pregnancy through the end of the first trimester given hcq's long half-life and to reduce 168 the probability of exposure during early pregnancy from use of hcq dispensed at an earlier time 169 point. 170 outcomes. the outcome of interest was major congenital malformations overall. in secondary 171 analyses we also evaluated specific malformation types for which we observed at least 5 172 exposed events across the two cohorts: oral clefts, cardiac, respiratory, gastrointestinal, genital, 173 urinary, musculoskeletal, and limb defects. the presence of malformations was defined using 174 validated algorithms based on inpatient or outpatient diagnoses and procedures, which have 175 been shown to identify the outcomes with high specificity (i.e., more than one date with the 176 respective diagnostic codes recorded, or one diagnostic code and a code for a 177 procedure/surgery or infant death). 18 isolated congenital heart block was not included in the 178 definition for cardiac malformations because its risk is increased in babies born to women with 179 sle. 19 (supplementary table 2 covariates. potential confounders and proxies for confounders considered included 181 sociodemographic information (e.g., state of residence, age, race/ethnicity (max only)), 182 autoimmune rheumatic disorders (e.g., rheumatoid arthritis, sle, ankylosing spondylitis, 183 psoriatic arthritis), other maternal conditions (e.g., diabetes, hypertension, psychiatric 184 conditions, renal disease, neurological conditions, chronic respiratory conditions, anemia, 185 infections), concomitant medication use (e.g., systemic steroids, non-biologic and biologic 186 disease modifying antirheumatic drugs (dmards), psychiatric medications, nsaids, suspected 187 teratogens), and general markers of the burden of illness (e.g., maternal comorbidity index, 188 healthcare utilization measures) (table 1, supplementary table 3 and 4) . 189 analyses. baseline characteristics were compared between women exposed to hcq and the 190 reference group of unexposed women. relative risks (rr) with their 95% confidence intervals 191 (ci) were estimated using generalized linear models. as a first level of adjustment, the 192 reference group was restricted to women with a recorded diagnosis of autoimmune rheumatic 193 disorders commonly treated with hcq ('restricted cohort'). in fully adjusted analyses, exposed 194 and unexposed women in the restricted cohort were matched on their propensity score (ps), 195 using a 1:200 variable ratio matching and a 0.01 caliper ('restricted matched cohort'). the ps, 196 which reflects the probability of being treated with hcq, was estimated using a logistic 197 regression model including all (>80) pre-specified covariates. when evaluating the balance in 198 baseline characteristics in the restricted matched cohort, the counts for the unexposed group 199 were weighted to account for the variable ratio matching. we conducted analyses stratified by 200 dose, using the highest daily dose dispensed during the first trimester (< 400mg and ≥ 400mg 201 daily) as well as duration of exposure (≤60 days and >60 days). in a sensitivity analysis, both 202 the exposed and the reference group were restricted to women with a recorded diagnosis of 203 autoimmune rheumatic disorders. estimates from both cohorts were combined using a meta-204 analytic approach with random effects. 205 for all analyses presented, results were described as similar or different from the reference 206 group based on the magnitude of the point estimates, taking into account the precision of each 207 estimate as reflected in the width of its 95% ci. we focused on estimating magnitude of effects 208 in preference to dichotomizing the results as statistically significant or not. 20 the research was 209 approved by the institutional review board of brigham and women's hospital, which waived the 210 need for informed consent. the combined cohort included 2,045 pregnancies exposed to hcq during the first trimester 214 (686 in max and 1,359 in ms), and 3,198,589 unexposed pregnancies (1,881,069 in max and 215 1,317,520 in ms). the mean daily dose of hcq was 371mg (standard deviation, 379mg) and 216 61% of women used a daily dose of 400mg. among exposed women, 25.9% were exposed for 217 ≤30 days, 33.6% for 31 to 60 days, and 40.5% for >60 days during the first trimester. 218 women exposed to hcq tended to be older, had more comorbid conditions, took more 219 concomitant medications (especially pain medications, steroids, nsaids, and dmards) and 220 had greater health care utilization. after cohort restriction and adjustment through ps matching, 221 all covariates -including treatment indications -were well balanced ( table 3 the pooled risk of any congenital malformation was 54.8 per 1,000 hcq exposed infants 224 (n=112 events) and 35.3 per 1,000 unexposed infants in the general population (n=112,908 225 events), corresponding to a pooled unadjusted rr of 1.51 (95% ci, 1.27 -1.81). restricting the 226 reference group to women with rheumatic disorders resulted in an absolute risk of 44.1 per 227 1,000 unexposed infants (n=506 events out of 11,468) and a rr of 1.26 (95% ci, 1.04-1.53). 228 adjusting for all potential cofounding variables through ps matching did not result in further 229 attenuation of the association (rr=1.26; 95% ci, 1.04-1.54). estimates were consistent 230 between the two cohorts. the risk of malformations among the hcq exposed was the same 231 regardless of whether women had concomitant exposure to steroids. the adjusted rr was 1.33 232 (95% ci, 1.08-1.65) for a daily dose of ≥ 400mg and 0.95 (95% ci, 0.60-1.50) for <400mg. the 233 risk was not affected by the duration of exposure (figure 1) , and results were similar when 234 restricting both the exposed and the reference group to women with a recorded diagnosis of 235 autoimmune rheumatic disorders (supplementary table 5) . 236 j o u r n a l p r e -p r o o f in the context of few events, risk estimates for the specific malformation types considered were 237 relatively imprecise ( figure 2 ). the point estimates indicated an approximately 2 to 4-fold 238 increase in the risks for oral clefts (rr=3.70; 95% ci, 1.55-8.82), respiratory defects (rr=1.85; 239 95% ci, 0.94-3.64), and urinary defects (rr=2.21; 95% ci, 1.26-3.86), which were consistent 240 between the two cohorts. none of the hcq exposed cases of oral clefts had concomitant 241 exposure to steroids. the upper limit of the 95% ci for the pooled estimates suggested no more 242 than a 2-fold increase in risk for other specific malformation types with the exception of genital 243 defects (upper limit 95% ci=4.76). among the 112 exposed infants with malformations, 12 244 utilizing data from health plans that provide coverage for large populations of both commercially 250 and publicly insured individuals in the us, we identified a cohort of pregnant women with 251 chronic autoimmune rheumatic diseases and assessed the relative prevalence of major 252 congenital malformations in their newborns following exposure to hcq during early pregnancy. 253 women who filled prescriptions for hcq during the first trimester had a higher risk of 254 malformations in their newborn than the general population. upon restriction to women with the 255 indication (mainly sle and rheumatoid arthritis), the relative risk attenuated but was still 256 elevated. in utero exposed newborns had an adjusted risk of major congenital malformations 257 26% higher than unexposed overall, and 33% higher for daily doses of 400mg or greater (while 258 no increased risk was observed for lower doses based on the point estimate, reflecting the 259 estimate most consistent with the data). a more substantial increase in the risk for oral clefts, 260 respiratory anomalies and urinary defects was observed, although confidence intervals for 261 specific malformations were wide. no pattern of malformations was identified. 262 prior studies evaluating the safety of hcq in pregnancy included between 36 and 194 women 264 and overall suggested no increased risk of pregnancy losses, prematurity, intrauterine growth 265 retardation, pre-eclampsia, fetal distress or induction of delivery compared to reference 266 groups. 10, 12, [21] [22] [23] [24] since flares are associated with these and other complications and hcq is 267 effective at controlling them, drug use in pregnancy may improve pregnancy outcomes for 268 women with rheumatic disorders, 23 as well as reduce the risk for congenital heart block in the 269 neonate. 25 moreover, hcq use reduces the dose of prednisone needed during pregnancy. 12 270 however, most of these studies were too small to assess the risk of major malformations, and 271 many based their conclusion on the statistical significance of underpowered comparisons. 26 272 given that hcq crosses the placenta 21 and inhibits cell division and dna synthesis, 27 and that 273 initial reports suggested an increased risk of chromosomal damage attributable to chloroquine, 28 274 concerns regarding effects on the rapidly dividing embryonic cells remain. specific 275 malformations reported among exposed newborns included cleft lip and palate (1 out of 79) 12 276 and pulmonary hypoplasia in a preterm infant (1 out of 133). 21 moreover, two of the largest 277 studies found a meaningful, though not statistically significant, increased risk of malformations 278 overall. in one study, malformations were more common in the 194 hcq exposed (6.7%) than 279 in the reference (2.3%) group (adjusted rr 3.11; 95% ci, 0.99-9.77), with no clear pattern. 13 in 280 another study, the 114 hcq exposed had a prevalence of malformations of 7.2% (7/97) and the 281 reference group of 3.4% (15/440) with a p-value of 0.094, 22 again with no clear pattern. 282 for pregnant women with malaria or rheumatic disorders the benefits of hcq may still outweigh 284 the potential risk, 2 especially given that discontinuation of hcq after conception would not 285 necessarily prevent birth defects because the half-life is more than a month, and would increase 286 the risk for flares and their complications. therefore, our findings of a potential small increase in 287 the risk of malformations -while important for prescribers to be aware of -should not 288 necessarily alter the treatment recommendation for a given woman with malaria or rheumatic 289 disorders. for covid-19, it will depend on whether the currently ongoing clinical trials 290 demonstrate meaningful benefits of hcq in reducing covid-19 infection or its severity. while 291 initial trials using hcq to treat covid-19 have failed to demonstrate efficacy, trials regarding its 292 use for preexposure prophylaxis have not yet been reported. 293 in addition to several strengths (including a large and nationally representative population, as 295 well as robust control for confounding through restriction and matching), our study is also 296 subject to certain limitations, most of which would bias the results towards the null. first, we 297 included only women with a live-born delivery because abortions and stillbirths are incompletely 298 recorded in healthcare utilization data. this approach may have resulted in the exclusion of 299 pregnancies with the outcome, as fetuses with malformations are more likely to experience fetal 300 death or termination. therefore, the incidence of major malformations reported in this study 301 could underestimate the risk in pregnant women. if a higher proportion of women on hcq had 302 lethal malformations, more prenatal screening or a higher propensity to terminate an affected 303 pregnancy, this study would also underestimate the relative risk. however, differential 304 terminations have been shown to be an unlikely source of selection bias. 29 second, 305 identification of major congenital malformations was based on diagnosis and/or procedure 306 codes recorded in claims. misclassification would tend to bias relative risks towards the null 307 unless a higher proportion of malformation diagnoses were identified in women exposed to 308 hcq. while others and we have shown a high positive predictive value for malformations 13,18,30 , 309 the potential for some misclassification remains. third, information on hcq exposure is 310 obtained from claims of filled prescriptions. since some women may fill prescriptions for 311 medications but not use them, our study may misclassify unexposed pregnancies into the hcq 312 group, thus underestimating any potential effect; however, a large fraction of our cohort filled 313 prescriptions for hcq throughout the first trimester. fourth, it is possible that some women in 314 the reference group were taking immunomodulatory agents in lieu of hcq. if these agents were 315 teratogenic, we would be underestimating the effect of hcq. however, their use is negligible 316 during pregnancy and upon restriction and propensity score matching our exposed and 317 reference groups were balanced in the use of these medications. fifth, disease flares in women 318 with rheumatic disorders such as sle have been associated with poor pregnancy outcomes 319 and hcq use during pregnancy improves disease activity and reduces the antiphospholipid 320 syndrome. 12, 23 therefore, the reference group of women with the disease and without hcq 321 could have a higher risk, thus potentially underestimating the relative risk for flare-related 322 adverse pregnancy outcomes including fetal loss, fetal growth retardation and prematurity. 323 alternatively, it is possible that there is misclassification of the unexposed with respect to the 324 presence of underlying rheumatic disease or that women being treated with hcq have more 325 severe underlying disease than women without hcq. although neither rheumatic disorders nor 326 flares have been associated with congenital malformations, it is conceivable that women with 327 more severe disease receive higher doses of steroids and this may not be fully captured in our 328 data. however, recent studies 31,32 have refuted initial reports of strong associations between 329 steroids and oral clefts. 33 more directly, in the current study, the absolute risk of malformations 330 was the same among hcq exposed pregnancies with and without concomitant exposure to 331 systemic steroids, and none of the cases of oral clefts in the hcq exposed were exposed to 332 steroids. together, this suggests that steroid exposure is not a major threat to the validity of our 333 analyses. sixth, the max cohort included data through 2014 -the most recent data available at 334 the time of study conduct -and marketscan included data through 2015, to avoid the use of 335 icd-10 based algorithms for cohort creation and outcome identification that have not yet been 336 validated. however, the biological association between hcq exposure and malformations 337 should not change over time. finally, despite being the largest exposed cohort to date, the 338 numbers were small for specific malformation groups and confidence intervals were wide; 339 specific individual defects could not be examined. however, there is enough information to 340 suggest that the magnitude of a potential risk of malformations would not be on the order of that 341 associated with major teratogens. 342 in this study, there was no evidence of a large increase in prevalence of major congenital 344 malformations in the newborn from first-trimester maternal exposure to hcq. however, it is the 345 third study to suggest a moderate increased risk. for most patients with autoimmune rheumatic 346 disorders, the benefits of treatment during pregnancy will likely outweigh this risk. if proven 347 effective for covid-19 prophylaxis in ongoing randomized trials, the benefits of hcq would 348 need to be weighed against the potential risk in pregnancy. rheumatic disorders, the number of outcome events and the total number of deliveries in both 457 the hydroxychloroquine exposed and the unexposed group are not meaningful for absolute risk 458 estimation; therefore, counts after restriction to deliveries with rheumatic disorders but before 459 the propensity score matching are reported in figure 2 . table 1 selected patient characteristics for hydroxychloroquine exposed and unexposed pregnancies miscarriage risk was 13% in exposed and 4% in unexposed; and stillbirth 8% and 6%, respectively. among the 47 liveborn exposed, 1 had cleft lip and palate. in the 145 unexposed 3 fetuses had fatal congenital anomalies and 1 had an abdominal hernia. limited sample to estimate the relative risk of malformations. controlled study. in-and outpatient claims in the infant record between date of birth (dob) and dob+90 days and/or in the maternal record between delivery and delivery+30 days are considered. • ≥ 2 dates with a code for a malformation within the group o exception: codes 747.3x, 746.02, 745.5x, 747.0x require ≥ 2 dates with a code for a malformation of which at least one code is documented at ≥ 6 weeks after dob • ≥ 1 date with a code for a malformation within the subgroup and cardiac procedure o exception: code 746.02 • ≥ 1 date with a code for a malformation within the subgroup and infant died • if codes identified in the maternal record between lmp and lmp+105 days and there are no codes in the infant record between dob and dob+90 days (i.e., only maternal codes between delivery and delivery+30), the defect is considered a pre-existing maternal defect. • any of the subgroups of cardiovascular anomalies is present • ≥ 2 dates with a code for any of the cardiac malformations (regardless of the subgroup [1]) • ≥ 1 date with a code for any of the cardiac malformations [1] and cardiac procedure • ≥ 1 date with a code for any of the cardiac malformations [1] and infant died • if codes identified in the maternal record between lmp and lmp+105 days and there are no codes in the infant record between dob and dob+90 days (i.e., only maternal codes between delivery and delivery+30), the defect is considered a pre-existing maternal defect. • ≥ 2 dates with a code for the malformation group/subgroup o exception: for gastroschisis: if code 756.79 was used (before 10/2009), require ≥ 1 date with a code and icd-9 procedure 54.71 • ≥ 1 date with a code for the malformation group/subgroup and malformation-specific procedure • ≥ 1 date with a code for the malformation group/subgroup and infant died • if codes identified in the maternal record between lmp and lmp+105 days and there are no codes in the infant record between dob and dob+90 days (i.e., only maternal codes between delivery and delivery+30), the defect is considered a pre-existing maternal defect. • any of the malformation groups/subgroups mentioned above is present. [ (1) given the variable ratio matching, the counts for the unexposed group are weighted counts to demonstrate the balance in baseline covariates. (2) autoimmune rheumatic disorders were measured from 3 months before the start through the end of pregnancy (3) maternal conditions and concomitant medication use were measured from 3 months before the start of pregnancy through the end of the first trimester (4) women exposed to known teratogens have been excluded (i.e., warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide). suspected teratogens considered include danazol, methimazole, propylthiouracil, aminoglycosides, trimethoprim, triamterene, sulfasalazine, spasmophen, cholestyramine, potassium iodide, tetracycline, fluconazole (5) general markers of the burden of illness were measured during the 3 months before but not during pregnancy, as these measures may be affected by early detection of pregnancy complications cell size <11 for max cohort are suppressed in accord with the cms cell size suppression policy. abbreviations: hcq, hydroxychloroquine; n, number; nsaids, nonsteroidal anti-inflammatory drugs; dmards, disease modifying antirheumatic drugs; sd, standard deviation; stand diff, standardized difference american college of 352 rheumatology guideline for the management of reproductive health in rheumatic and 353 musculoskeletal diseases bsr and bhpr guideline on prescribing drugs in 355 pregnancy and breastfeeding-part i: standard and biologic disease modifying anti-356 rheumatic drugs and corticosteroids trends in use of hydroxychloroquine during 358 pregnancy in systemic lupus erythematosus patients from observational study of hydroxychloroquine in 361 hospitalized patients with covid-19 association of treatment with 364 hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid-365 19 in new york state a randomized trial of 367 hydroxychloroquine as postexposure prophylaxis for covid-19 drug evaluation during the covid-19 pandemic. the new england 373 journal of medicine 2020 hydroxychloroquine efficacy and safety in preventing sars-cov-2 infection and 375 covid-19 disease severity during pregnancy (covid-preg). nct04410562 available 376 at clinicaltrials.gov safety of hydroxychloroquine in 381 pregnant patients with connective tissue diseases: a study of one hundred thirty-three 382 cases compared with a control group brief report: risk of adverse fetal outcomes 386 associated with immunosuppressive medications for chronic immune-mediated diseases 387 in pregnancy harnessing the medicaid analytic extract 389 (max) to evaluate medications in pregnancy: design considerations identifying pregnancies in insurance claims data: methods and application to retinoid 393 teratogenic surveillance algorithms to estimate the beginning of pregnancy in administrative databases pregnancy outcome following first trimester exposure to chloroquine hydroxychloroquine and lupus pregnancy: review of a series of 36 cases hydroxychloroquine in pregnant patients with systemic lupus erythematosus hydroxychloroquine (hcq) in lupus pregnancy: double-blind and placebo-controlled study safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation hydroxychloroquine in lupus pregnancy outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers pregnancy outcome following in utero exposure to hydroxychloroquine: a prospective comparative observational study brief report: risk of adverse fetal outcomes associated with immunosuppressive medications for chronic immune-mediated diseases in pregnancy longterm outcomes of children born to mothers with sle exposed to hydroxychloroquine in pregnancy hydroxychloroquine and pregnancy on lupus flares in korean patients with systemic lupus erythematosus key: cord-048467-1dus0u4m authors: civaner, murat; arda, berna title: can "presumed consent" justify the duty to treat infectious diseases? an analysis date: 2008-03-06 journal: bmc infect dis doi: 10.1186/1471-2334-8-29 sha: doc_id: 48467 cord_uid: 1dus0u4m background: aids, sars, and the recent epidemics of the avian-flu have all served to remind us the debate over the limits of the moral duty to care. it is important to first consider the question of whether or not the "duty to treat" might be subject to contextual constraints. the purpose of this study was to investigate the opinions and beliefs held by both physicians and dentists regarding the occupational risks of infectious diseases, and to analyze the argument that the notion of "presumed consent" on the part of professionals may be grounds for supporting the duty to treat. methods: for this cross-sectional survey, the study population was selected from among physicians and dentists in ankara. all of the 373 participants were given a self-administered questionnaire. results: in total, 79.6% of the participants said that they either had some degree of knowledge about the risks when they chose their profession or that they learned of the risks later during their education and training. of the participants, 5.2% said that they would not have chosen this profession if they had been informed of the risks. it was found that 57% of the participants believed that there is a standard level of risk, and 52% of the participants stated that certain diseases would exceed the level of acceptable risk unless specific protective measures were implemented. conclusion: if we use the presumed consent argument to establish the duty of the hcw to provide care, we are confronted with problems ranging over the difficulty of choosing a profession autonomously, the constant level of uncertainty present in the medical profession, the near-impossibility of being able to evaluate retrospectively whether every individual was informed, and the seemingly inescapable problem that this practice would legitimize, and perhaps even foster, discrimination against patients with certain diseases. our findings suggest that another problem can be added to the list: one-fifth of the participants in this study either lacked adequate knowledge of the occupational risks when they chose the medical profession or were not sufficiently informed of these risks during their faculty education and training. furthermore, in terms of the moral duty to provide care, it seems that most hcws are more concerned about the availability of protective measures than about whether they had been informed of a particular risk beforehand. for all these reasons, the presumed consent argument is not persuasive enough, and cannot be used to justify the duty to provide care. it is therefore more useful to emphasize justifications other than presumed consent when defining the duty of hcws to provide care, such as the social contract between society and the medical profession and the fact that hcws have a greater ability to provide medical aid. in the course of providing health care service, health care workers (hcws) are continually exposed to many workrelated health risks. one of these risks is the exposure to infectious diseases. these diseases can include the flu, aids, tuberculosis, and hepatitis, and can be transmitted through physical contact, exposure to contaminated blood, or via the respiratory system. and, needless to say, such risks do indeed at times prove fatal. the consequences of occupational exposure to pathogens are not limited solely to bodily infections. each year, thousands of hcws are adversely affected by psychological trauma stemming from months of anxiously awaiting the results of serological tests, tests made necessary due to potential infection incidents. the anxiety experienced by hcws is related to the perception of risk from the incident and the resulting infection that may occur, and by the worry of what the reactions of others might be, such as colleagues, family, and friends, all who have to be informed. during this uncertain waiting period hcws will frequently experience intrusive thoughts, problems concentrating, difficulty sleeping, frequent loss of temper, and a decrease in sexual desire, which can act as a catalyst to exacerbate any pre-existing and unresolved emotional issues [1] . and if it turns out that the health care worker has indeed been infected by one of these contagions, the serious personal consequences to that health care worker can include the postponement of childbearing, damaged personal relationships, having to alter sexual practices, experiencing the side effects of prophylactic drugs, chronic disabilities, loss of employment, denial of worker compensation claims, possible need for a liver transplant, and premature death [2] . aids, sars, and the recent epidemics of the avian-flu have all served to remind us of the occupational risks faced everyday by hcws; the result being that the recent appearance of these diseases has forced this issue onto the common agenda and helped to spark renewed interest in the debate over the limits of the moral duty to treat. in seeking an answer to this question it is useful to have an understanding of the occupational risks faced by hcws as well as an understanding of the attitudes of hcws to these risks. for example, studies conducted in various countries have shown that, especially when there was a risk of being infected with aids, hcws may refuse to treat a patient on the grounds that there is a risk of being infected by this patient [3] [4] [5] [6] [7] [8] [9] [10] [11] . and despite the fact that the hepatitis viruses are transmitted more easily than hiv, it is the fear of being infected with hiv that causes many hcws to experience the greatest amount of stress and anxiety [12] . in a study which compared the relative risks of transmission of both hbv and hiv, the reasons for physicians' underlying fears of particular contagions were also inves-tigated and described. [13] . according to the study, people initially percieve the risk to be greater when there is a high likelihood of death involved with infection (as with hiv) even though there may be less risk of infection, as opposed to when there is a higher risk of infection but a lower risk of death involved with that infection (as with hbv). additionally, since the likelihood of sexually transmitting hbv between heterosexual partners is less than that of transmitting hiv, the consequences of hbv infection are again percieved to be less severe than the consequences of hiv infection. in this way, the hazards posed by hbv infection conflict less with the obligation to protect family members from harm. it was also found to be important that there is less of a stigma attached to having hbv than there is to having hiv. and, finally, the fact that there is a vaccine for hbv infection, which is more than 90 percent effective (for vaccinated hcws the risk of death from infection is reduced by a factor of nearly twenty), also was found to greatly influence the perceptions of the physicians. additionally, factors other than a fear of the contagion can contribute to the reluctance to treat a particular patient. some physicians and dentists express concern that if it is discovered that they treat patients with aids, then those patients who don't have hiv may shun their practice. still, other physicians insist they do not know enough about hiv infection and are too busy to learn [14] . another reason for which a physician may refuse to treat hiv-positive patients is that the physician feels they have a duty to protect their other patients, basing their reasoning on the principle of "first do not harm". by treating hiv-positive patients they claim that they may potentially be putting their other patients at risk for infection [15] . furthermore, as has been reported, there is always the possibility that when a hcw is able to reject the patient based on a more benign excuse, for example if the patient does not have enough money, it is even easier, and all the more likely, for treatment to be refused, even though this refusal was done in the interest of protecting the physical health of the individual health care provider [14] . in the literature, most studies have concentrated primarily on the attitudes and rationale behind the refusal to treat. before one can set out to effectively explore the attitudes of hcws however, it is important to first consider the question of whether or not the "duty to treat" might be subject to contextual constraints, such as providing health care to a patient suffering from an infectious disease which may be particularly contagious or for which adequate treatment measures may not yet be available. clark, in his article about physicians' duty to treat, claimed that there are three reasons in which such a duty is grounded [16] : "... since the ability to render aid is greater, the obligation to assist is (...) elevated. second, by consideration of daniels' argument that by freely joining a profession designed to combat disease, one consents to some standard of risk, and third, by realizing that the profession has flourished due to socially negotiated promises to be available in such times of duress." in his article "duty to treat or right to refuse", daniels argues that when a person chooses a career in a particular profession, it must be understood by all parties that this individual has both accepted and is willing to take the risks that are inherent to that profession [14] : "consent is crucial where obligations to take risks exist in various occupations or professions. for example, we assume that in choosing their careers, undergoing the training involved, and agreeing to follow the codes and practices regulating their work, firefighters and police have given consent to facing the significant risks they are obliged to take. there are strong parallels to medicine. people who enter medical fields clearly had alternatives. there is a general understanding that physicians face an increased risk of contagion from disease, an understanding refined during schooling and training." daniels proposes, however, that some situations can exceed the standard level of risk (slr) [14] : "for example, it is common to screen new house staff and nurses in medical centers to determine whether any individuals face special risks of contagion, such as immunosuppression or pregnancy. those at high risk may then be asked to avoid certain treatment situations, materials, or hospital areas.(...) protecting immunosuppressed providers is reasonable "risk management", a measure taken to reduce bad outcomes. but such special protection supports the claim that only standard risks are included in the duty to treat.(...) some nosocomial risks clearly take us beyond what duty requires." it is perhaps more illustrative if this argument (from this point on, this statement will simply be referred to as the "presumed consent") is written in classic form: health care services should be provided to patients who have a contagious disease. contracting an infectious disease while providing health care services to a patient with a contagious disease is an occupational risk. it is generally assumed that by joining the health care profession physicians have given their consent to be exposed to an increased risk of disease contagion. this assumption is based on the following facts: a. there is a general understanding that physicians face an increased risk of contagion from disease, an understanding refined during schooling and training. b. people who enter medical fields clearly had alternatives. some nosocomial risks clearly take us beyond what duty requires. there is a moral duty to treat patients who have a contagious disease so long as the risk to the hcw is below the slr. if we are to accept this argument, then the pressing question becomes how to determine and define the risks which are deemed to be standard and acceptable versus those which are believed to exceed and, indeed, outweigh the duty of the health care provider to treat. in order to begin to answer this question, it will be useful to investigate the nature of the choice (and all that goes along with making it) that an individual makes when they decide to enter a particular profession. for instance, how wise is it to assume that at the time of choosing their future profession the hcw was fully aware of the risks involved with such work? perhaps they were not made aware of the risks until their education and training. furthermore, if they were aware of, and fully appreciated, the risks prior to deciding on a particular profession, would they have even chosen that profession in the first place? and, finally, how is the slr to be determined, and which of the infectious diseases would then exceed this slr? in order to effectively analyze the presumed consent argument it is necessary to have an awareness of the diverse opinions and beliefs of hcws and, also, to understand their different motives and backgrounds. additionally, knowledge of what hcws feel about the risk concept and of how they feel about their duty to treat patients with contagious diseases can also be of great value to educators as they plan their curricula and it can be used by the authorities in charge of health care systems in order to better organize their services. the purpose of this study was to analyze whether or not the third premise grounds the duty to treat, namely, "it is generally assumed that by joining the health care profession physicians have given their consent to be exposed to an increased risk of disease contagion". in order to carry out this analysis, the opinions and beliefs of physicians and dentists regarding the occupational risks of infectious diseases were investigated; and, by extension, the argument that the notion of "presumed consent" may be grounds for supporting the hcws' duty to treat was also analyzed. for this cross-sectional survey, the study population was selected from among physicians and dentists in ankara, the capital of turkey. a self-administered questionnaire designed to assess the beliefs and opinions of the participants regarding the occupational risks of infectious diseases was used. this questionnaire was also used to obtain the socio-demographic information of the participants. the 17 items on the questionnaire were developed by reviewing previous studies in the literature [1, [3] [4] [5] [6] [7] [8] [9] [10] . a draft of the questionnaire was distributed to experienced health care professionals and later revised based on their criticism and suggestions. in both of the universities in which this study was conducted there are ethics committees which had been established for the purpose of determining the ethical appropriateness of pharmaceutical trials using humans; since our study involved only the use of a questionnaire and not an experimental drug, we did not apply for approval from either of these ethics committees. instead, written permission to carry out the study was granted by the dean of the faculty of medicine and by the chief manager of university hospitals. in addition, all of the potential participants were fully informed about the aim and structure of the study. furthermore, potential volunteers were all made aware that participation was strictly voluntary and that all of the answers they provide would be done so anonymously. the questionnaire was administered to a total of 373 health care workers: all of the 236 physicians who work in surgical specialties at the ankara university ibn-i sina hospital and to all of the 137 dentists in the gazi university faculty of dentistry. dentists were included in this study because, aside from being hcws themselves, there are a number of studies in the literature which show that dentists, citing various reasons, may also refuse to treat patients with contagious diseases. and, in order to better assess the fact on which the third premise of presumed consent is based, we decided to include only professional health care workers, instead of students and others who might still be in the process of deciding whether or not to currently enter the field. in total there were 230 participants, 101 physicians and 129 dentists, who completed the questionnaire, for an overall response rate of 61.7%. the questionnaire was later sent back to the non-respondents one month after the first survey, and 28 of these were completed and returned to us. the mean age of the participants was 33.8 â± 9.6 years, while 56.5% were male and 43.5% were female. additionally, the average amount of time that they had been working in the medical profession was found to be 8.5 years (min. 0, max. 40). all of the data was collected anonymously. the difference between the two groups, physicians and dentists, was compared using the chi-square test, with a p-value of <0.05 accepted as statistically significant. all analyses were carried out using spss 11.5. of the hcws surveyed in this study, roughly half stated that they understood that by choosing their profession they would be exposing themselves to an increased risk of contracting contagious disease (55.2%). and at the time of entering the faculty, 24.4% of the participants expressed that they were unaware of any increased risks; however, they later learned of these risks during their education and training. in other words, 79.6% of the participants stated that they had known about the risks either at the time they chose their profession or that they had later learned of the risks during their training and education. additionally, 6.5% of the participants answered that they had only come to realize the kinds of risks they would face after starting to work. the percentage of participants who claimed that if they had been aware of the risks earlier they would not have chosen to enter or continue in the medical profession was 5.2%. table 1 are statements which physicians and dentists chose as best reflecting their personal opinions regarding the occupational risks of infectious disease. in general, the physicians, prior to their education and training, were significantly more aware of the potential risks associated with their profession than were the dentists (p < 0.05). a significantly higher percentage of the dentists however, stated that they only learned of the occupational risks of dentistry during their education and training (p < 0.05). there was no statistically significant difference between the two groups in terms of the other opinions questioned. the participants were also asked whether or not they agree with the argument "when people choose, and continue to practice, the medical or dentistry profession, they are then required to accept all of the occupational risks resulting from the infectious diseases they might confront". the aim of this question was to determine whether or not the hcws each have their own individual working-definition for the slr. of the participants, 57.4% believed that there is such a level. 52.2% felt that certain diseases would exceed the level of acceptable risk unless specific protective measures were implemented, and 5.2% said that some diseases were always beyond the slr, no matter what precautions might be taken. no statistically significant difference was found between the physicians and the dentists. listed in table 2 are the diseases which, under certain circumstances, were cited as potentially exceeding the slr. among the participants who stated that there would be a slr for providing health care to the patients of specific diseases unless protective measures were implemented, aids and hepatitis c and b were the most frequently cited of these diseases (71.7%, 64.2%, and 56.7%, respectively). the participants who felt that some diseases would always exceed a slr expressed, that hepatitis b, tuberculosis, and bacterial meningitis always would go beyond the slr (41.7%, same for all). according to these participants, the occupational risk of potentially being infected with hiv is paramount to all other risks. percentage-wise, aids was the most frequently mentioned disease that would exceed the slr, more so than sars. all of the participants who answered that some diseases would be beyond the slr were then asked what criteria they used to make their determination. the most com-monly expressed criteria, in order, regarding the diseases, were the likelihood of transmission, whether or not protective measures are available, and whether or not immunization is possible (66.7%, 65.2%, and 58.3%, respectively). the distribution of these criteria among the physicians and dentists can be seen in table 3 . physicians expressed significantly more often than dentists that if there was no immunization or treatment available for a particular disease, then that disease would exceed the slr (p < 0.01). in terms of other criteria, there were no significant differences observed between the two groups. the primary aim of this paper is to evaluate the claim that presumed consent may constitute grounds for the moral duty to treat. the presumed consent argument is valid, because its conclusion should logically be accepted if its premises are taken into account. to analyze the soundness of the argument we carried out a survey investigating the opinions of hcws about the occupational risks of infectious diseases. in total, 79.6% of the participants said that they either had some degree of knowledge about the risks when they chose their profession or that they learned of the risks later during their education and training. in other words, one fifth of the participants either lacked adequate knowledge about the occupational risks when they chose their profession or were not sufficiently informed of these risks during their faculty education and training. this means that the assumption stated in premise 3 may be wrong for an important proportion of health care workers. it seems reasonable to suggest that the words "there is a general understanding" would be misleading if used to characterize a social concept of which the applicability and, indeed, the very existence, are yet to be established by sociological studies. it is also useful to discuss the other problems associated with presumed consent; in particular, the difficulty of choosing a profession autonomously, the constant level of uncertainty present in the medical profession, the nearimpossibility of being able to evaluate, in retrospect, whether or not every individual was informed, and the seemingly inescapable problem that this practice would legitimize, and perhaps even foster, discrimination against patients with certain diseases. if we are to use the presumed consent argument, then the findings of this study indicate that when a new epidemic of a contagious disease occurs, or when the medical profession is confronted with a disease for which no immunization or treatment options are available, some hcws are not bound by the duty to treat according to the presumed consent argument. this seems potentially problematic and demands serious consideration. how appropriate is it to describe the healthcare provider's responsibility and duty as stemming from their 'consent'? to address this question, it is helpful to reflect on the conditions required for an individual to be able to give consent that is well-informed. for an hcw's consent to be informed, the following should first be explained to them: (a) the risk posed by each of the contagious diseases known at that given time, (b) commonly agreed criteria and definitions of situations that would surpass the slr, and (c) the fact that there will always be a degree of uncertainty involved with working in the medical profession, as new risks may emerge at any point during one's professional life. if not necessarily when they choose their profession, then at least after being given the relevant knowledge during education and training, the person's choice should be regarded as informed. it should therefore be ensured that hcws are acquainted with each new and emerging risk, and with any methods of prevention developed during or after their education and training. if a person's choice is to be confidently regarded as informed, it is imperative that these conditions be met. of course, the question now becomes: how possible is it to satisfy all these conditions? it is quite easy to imagine more than one answer to this question, but one thing is for sure: any thoughtful answer would acknowledge that choice is determined both by factors that are under the control of the individual and by factors that are not. personal factors such as educational status, perception of the world and ambitions all influence an individual's choice of profession strongly. nevertheless, factors outside the individual's control also play a large role in determining that choice. the environment in which the person grew up -their family life, the jobs of their parents, their community, social class and cultureall contribute to forming that individual's background, which (needless to say) has a very large influence on the opportunities and choices available to them. even though a person may not have been sufficiently informed when they chose their profession, it can be argued that during their education and training they will learn all relevant knowledge about the occupational risks associated with working in the medical profession. if so, it is fair to assume that when this individual begins to work after graduation they will be willing to confront any of those risks. in theory at least, it can be presumed that every student who passes their exams and goes on to graduate from the faculty is informed of the risks; so it can be argued that all hcws who are currently active in their profession have consented to accept the risks posed by all the contagious diseases known at the time of their graduation. of course, the diverse factors that determine the quality of education, such as the particular educational methods used, the course content, the abilities and knowledge of the instructors, role-models, and the personal features and motivations of students, are all potential sources of variation. but for the sake of argument, let us assume that a standardized education program is implemented throughout all medical schools. if that were the situation, then the argument that the individual has been made aware of the occupational risks during education would be true to the extent that the education program addressed those risks sufficiently. nevertheless, it would be hard to claim that presumed consent is valid for every individual. for many people, a degree in medicine is very costly, both financially and in terms of time and energy. under such circumstances, it is difficult for a person to quit their schooling despite the awareness they gain of the occupational risks involved. individuals might feel pressured and confused by the two options confronting them: on the one hand, dropping out of medicine and forfeiting all the time, effort and money spent on schooling towards that aim; and on the other, reluctantly accepting the occupational risks, which may look frightening to the individual at that moment. of course, it is important to remember that the person chose the medical profession in the first place, and numerous positive and beneficial elements are associated with working within it, which may ultimately serve to temper and override the individual's fear of the risks. an additional source of pressure may be that, for whatever reasons, switching educational tracks is too difficult; it may appear too daunting or be financially untenable. it seems likely that in the end the individual will choose to continue with their education and embark on a career in medicine, despite hesitation and fear of the risks. it is difficult to describe a decision made under conditions of such uncertainty and stress as 'informed'. as can be seen, we do not choose our profession from among a wide array of possibilities spread out in front of us by thoroughly researching each one so that we are fully informed of its nature; everybody's options are different and it is a large and difficult task to make oneself sufficiently informed of them. moreover, as described above, the decision to quit medical school can be quite difficult: on one side of the dilemma there are occupational risks that must be accepted regardless of misgivings on the part of the individual; on the other side, very influential factors pressure the individual to continue their medical education. thus, the claim that "people who enter medical fields clearly had alternatives" is debatable and sometimes even doubtful. in theory it sounds right; nobody has to be a physician. but in practice, having alternatives does not mean that all our decisions are made freely or autonomously. theoretically, the fundamental problem with the presumed consent argument is that it cannot explain why there is always some degree of uncertainty about the occupational risks of working in the medical profession, particularly stemming from new and emerging diseases. quite simply, if there was little or no knowledge of a risk at the time the individual became informed and gave their (tacit) consent, then this individual never accepted the risk, implicitly or otherwise, because it was unknown at the time the individual was informed. from a historical perspective, it is possible to see that while the medical profession was once concerned only with treating diseases, its vocational responsibility came in time to include preventative, promotive and rehabilitative healthcare services. as the notions of human rights and patient rights have developed and become widespread, perceptions about the health profession have changed at the community level. diseases that once killed millions of people can now be treated with a simple medicament, but today we are faced with new and challenging diseases unheard of in the past. as a result, the continuous cycle of changespurred on by greater knowledge and technological advances and confrontations with new and untreatable diseases -serves to alter the identity and nature of the medical profession, and out of all this arises a constant degree of uncertainty. this characteristic uncertainty is present both when the individual chooses the profession and throughout their education and training periodand, indeed, for the entirety of their professional career. it is therefore not possible for someone to be fully informed when they choose their profession, nor is it possible for them to become fully informed during their education and training; nevertheless, the person should be informed about the uncertainty involved with working in the medical profession. in the light of this uncertainty, answers such as "if i had known i would not have chosen it" are not very meaningful, because there is no way to anticipate all the potential risks one might encounter in the course of a professional life. the only sure thing amid the uncertainty is that diseases such as sars and avian 'flu will always continue to emerge. so far in the discussion, the difficulties of satisfying the conditions needed to validate the presumed consent argument have been described. it seems virtually impossible to fulfill all these conditions satisfactorily. at this point it is important to discuss two particular problems regarding the argument itself. first, it seems nearly impossible to evaluate individually whether the choice made by every hcw to enter the medical profession was informed. the only way to do that would be laboriously to ask each hcw whether they were informed when they decided on the health care profession. even then, irrespective of whether the person's answer to this question reflects the truth, the only thing that could be learned from such a broad and extensive interrogation would be the individual's perception, not their actual knowledge. by extension, we could not question the participants' level of knowledge in this study, but rather how they perceive their level of knowledge. because it is futile to seek objectivity in people's perceptions, it would not be sound to use those perceptions to determine whether the hcw's choice was informed, and thus whether they have taken on the duty to treat. and if these perceptions are regarded as subjective, as they should be, then it would be very difficult to develop a set of standard criteria that could be used to establish whether a hcw has been informed. this would also complicate efforts to reach a consensus on forming criteria by which various levels of risk could be defined universally. unfortunately, such difficulties can only hamper efforts to protect the right of every patient to receive the best treatment available. the second problem is that there is very likely to be more discrimination against patients with certain diseases, as hcws use this argument to justify their refusal to treat those diseases. the world medical association's declaration of geneva, which states the basic moral values of the medical profession, specifies that there should be no discrimination, regardless of the circumstances: "i will not permit considerations of age, disease or disability, creed, ethnic origin, gender, nationality, political affiliation, race, sexual orientation, or social standing to intervene between my duty and my patient" [17] . however, the physicians' right to choose their patients is described by the same organization in another policy called "twelve principles of provision of health care in any national health care system" [18] : "any health care system should allow the patient to consult the physician of his choice, and the physician to treat only patients of his choice, without the rights of either being affected in any way." for regulations at the national level, it is generally held that if there is an urgent need for medical care [19, 20] , or if no other physician is available to whom the patient can apply [21, 22] , this right would be negated and the available physician must treat the patient. if we look at these obligations in reverse, we can see that the physician might refuse to provide health services to the patient if there is no urgent need for medical care and/or if another physician is around to whom the patient can be referred. besides, the physician might also refuse the patient on the grounds that their prejudices may adversely affect the advice or treatment that they provide [20] . in actuality, this flexibility was written into the regulations in order to ensure that the patient receives the highest quality care possible; but as can be seen, it could also be abused. and if the presence or absence of consent is used as a criterion to define the duty to treat, in addition the existing flexibilities, then a mechanism would be created by which hcws may freely, and perhaps excessively, discriminate among patients. to summarize, considering all the points discussed above, the soundness of the presumed consent argument can be doubted. therefore, it should not be claimed that there is a duty to treat on the basis of the presumed consent argument, as the argument itself is not persuasive. it is also important to note that 5.2% of our participants said that they would not have chosen this profession if they had been informed of the risks. in other words, most of those hcws who claimed that they were uninformed of the occupational risks when they entered the faculty, or were not fully informed of them during their education period, stated that they still would have chosen the medical profession even if they had been more aware of the risks. this finding tells us that, generally speaking, hcws place relatively little importance on being informed beforehand. further support for these findings comes from the answers given by the participants to the other questions. nearly half said that there is no slr, and the other half felt that the diseases they evaluate would not surpass slr if the appropriate protective measures are available. also, table 2 indicates that at least 28.3% of the participants thought that none of the diseases listed in that table would exceed the slr regardless of circumstances. it can therefore be concluded that a large majority of the hcws place more emphasis on their working conditions than on being informed beforehand. in addition, the criteria most commonly stated by the participants for determining the slr were the likelihood of transmission of a disease, whether protective measures are available and whether immunization is possible. each of these criteria is related to protecting the hcw from infection, not to the treatment or the effects of a particular disease. this means that as long as protective measures are available, the hcws would regard a given disease as below the slr, so it has nothing to do with being informed beforehand. besides, the only disease used as an example in this study that could be claimed to exceed the slr was sars; aids, hepatitis c, hepatitis b, tuberculosis and bacterial meningitis all fell below the slr according to these criteria. nevertheless, only 30.9% of the participants suggested that sars would surpass the slr. to put this into perspective, sars was not even observed until 2003, and the research in the present study was conducted in 2004 and 2005. therefore, most participants in this study were not aware of sars when they chose the medical profession, nor were they ever informed of it during education or training. they nonetheless felt that the duty to treat pertained even to patients with sars. all of this suggests that factors more useful and relevant than presumed consent influence the decision of hcws to choose and continue in the medical profession; these factors may include the social contract between society and the medical profession, and the greater ability of hcws to provide medical care [16] . it is these factors that should be investigated and emphasized when defining a moral duty to treat. this study could be limited by several factors. the first limitation could be due to a socially desirable response bias; some participants might have given what they perceived as the 'right' answers to the questions rather than the answers that reflect their opinion or belief. in order to address this concern, future studies could benefit by using qualitative methods, which provide more reliable results about the motives and opinions of participants. also, this study was not prospective, so recall bias might have affected the responses of the participants. furthermore, the extent to which the results of this study are applicable to hcws such as nurses or physicians who work in internal specialties is uncertain. future studies that include other hcws as participants may broaden our understanding of the beliefs and opinions of hcws, thereby allowing us to state our claims and shape our arguments more precisely. finally, it should be mentioned that the response rate for this study (61.7%) was slightly lower than is generally expected for a survey. nevertheless, despite all these methodological limitations, we believe that our findings support our conclusion about the persuasiveness of the presumed consent argument. if we use the presumed consent argument to establish the duty of the hcw to provide care, we are confronted with problems ranging over the difficulty of choosing a profession autonomously, the constant level of uncertainty present in the medical profession, the near-impossibility of being able to evaluate retrospectively whether every individual was informed, and the seemingly inescapable problem that this practice would legitimize, and perhaps even foster, discrimination against patients with certain diseases. our findings suggest that another problem can be added to the list: one-fifth of the participants in this study either lacked adequate knowledge of the occupational risks when they chose the medical profession or were not sufficiently informed of these risks during their faculty education and training. as we stated above, in order for a candidate hcw to be informed literally, three items should be explained to them: (a) the risk posed by each of the contagious diseases known at that given time, (b) commonly agreed criteria and definitions of situations that would surpass the slr, and (c) the fact that there will always be a degree of uncertainty involved with working in the medical profession, as new risks may emerge at any point during one's professional life. in this study it has been shown that at least some hcws may not be informed of (a). also, it is not currently possible to inform hcws of (b) since there are no widely-agreed criteria and definitions to allow for a universally accepted slr; and there is currently no standard education for all hcws to ensure that (c) is satisfied. considering this in addition to the problems mentioned above, the third premise of the presumed consent argument appears implausible and, consequently, the duty to treat cannot be grounded persuasively on the consent assumption. it is therefore more useful to emphasize justifications other than presumed consent when defining the duty of hcws to provide care, such as the social contract between society and the medical profession and the fact that hcws have a greater ability to provide medical aid. furthermore, in terms of the moral duty to provide care, it seems that most hcws are more concerned about the availability of protective measures than about whether they had been informed of a particular risk beforehand. it seems important that further research be carried out to improve understanding of the opinions and perceptions of hcws and the basis of their definitions, as this information could prove very helpful in defining a duty to treat that can be effectively put into practice. it is also important that a well-organized ongoing educational program that is needs-based and easily accessible be provided to hcws at both the graduate and postgraduate levels. in particular, this program must be continuously updated regarding aids and other diseases that may cause the hcws to behave discriminatively towards patients, even though these diseases are below the slr. such continuing medical education is the best answer to the justification "when i chose the profession/when i graduated, this disease did not exist!" for refusing treatment. emphasizing the social role of hcws, and educating them about the professional obligations derived from the social contract betweeen the profession and the wider social order, would further reduce that kind of reasoning. in addition, stricter standards for the duty to provide care should established by determining the criteria for a slr and identifying the situations and conditions that would exceed this slr. each of these measures could serve to remind hcws that they have a moral responsibility, as individual hcws, to be aware of professional obligations and to act as responsible members of the profession. moreover, the working environment of hcws should be provided with preventative measures that can be applied both generally and specifically and should emphasize their use. for a circumstance in which a preventative measure has been developed for a disease but is not available for treating a particular case, it would not be easy to justify the claim that there is an undeniable duty to provide care at that moment. international health care worker safety center: annual number of occupational percutaneous injuries and mucocutaneous exposures to blood or potentially infective biological substance knowledge, practices and attitudes towards hiv positive and aids patients among dental auxiliaries. east african medical journal do p: knowledge, attitudes, and practices among physicians on hiv/aids in quang ninh, vietnam. aids patient care and stds knowledge, attitudes, and practices regarding sexually transmitted infections among general practitioners and medical specialists in karachi survey of hiv/aids knowledge and attitudes of kuwaiti family physicians. family practice an investigation of dentists knowledge, attitudes and practices towards hiv+ and patients with other bloodborne viruses in south cheshire knowledge and attitudes of japanese dental health care workers towards hivrelated disease a knowledge, attitudes, beliefs and practices (kabp) survey on hiv infection and aids among doctors and dental surgeons in singapore oral care of hiv infected patients: the knowledge and attitudes of irish dentists discriminatory attitudes and practices by health workers toward patients with hiv/aids in nigeria the role of psychosocial assessment and support in occupational exposure management guidelines for prevention of transmission of human immunodeficiency virus and hepatitis b virus to health-care and public-safety workers duty to treat or right to refuse? hastings cent rep semmelweis revisited: the ethics of infection prevention among health care workers in harm's way: ama physicians and the duty to treat the world medical association: declaration of geneva the world medical association: twelve principles of provision of health care in any national health care system general medical council: good medical practice college of physicians and surgeons of alberta: physician/patient relationships -cpsa guideline turkish medical association: turkish medical association professional code of ethics right to refuse work becomes another sars issue we would like to thank to prof. huma ã�mã¼rlã¼, vice dean, for her helps to the survey's administration in gazi university faculty of dentistry, assoc. prof. alp ergã¶r for his comments on the first draft of the field study, and mr. anthony clark for his kind effort to polish the language of the text. as dr. singer says: "there is a threshold beyond which health care workers aren't obliged to take personal risks. we don't expect firefighters to jump into a burning pit, or police officers to throw themselves in front of a bullet. how health care workers define this threshold is an intensely personal decision. ... but obviously, it has serious implications for our collective response to a problem like sars." [23] . it is clear that to rely upon the presumed consent argument to define the duty to treat will not make our collective response to potential epidemics such as sars or avian 'flu any more effective or robust. hcws: health care workers; slr: standard level of risk the author(s) declare that they have no competing interests. mc and ba have contributed equally to the conception, design and writing of the manuscript. all authors read and approved the final manuscript. the questions referred to:â�¢ whether the participant knew when they chose their profession that they would have an increased risk of being infected by a contagious disease?â�¢ if the participant did not know of this occupational risk, whether or not they later learned of it during their training?â�¢ if they still have not been formally made aware of the risks, do they think that they have enough knowledge about the current risks that they face?â�¢ if they had known about the risks earlier, would they still have chosen this particular profession?â�¢ when somebody chooses to be a physician or a dentist, are they obligated to accept all of the occupational risks regarding infectious diseases?â�¢ if not, what criteria must we use to determine that a particular disease is below the slr?â�¢ which diseases are below the slr?publish with bio med central and every scientist can read your work free of charge the pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/8/29/prepub key: cord-275786-etli5c3a authors: magee, laura a.; khalil, asma; kametas, nikos; von dadelszen, peter title: towards personalized management of chronic hypertension in pregnancy date: 2020-07-18 journal: am j obstet gynecol doi: 10.1016/j.ajog.2020.07.026 sha: doc_id: 275786 cord_uid: etli5c3a abstract objectives chronic hypertension complicates 1-2% of pregnancies and it is increasingly common. women with chronic hypertension are easily-recognized and in touch with a wide variety of healthcare providers before, during, and after pregnancy, mandating that chronic hypertension in pregnancy be within the scope of many practitioners. we reviewed recent data on management to inform current care and future research. study design narrative review of published literature. results compared with normotensive women, women with chronic hypertension are at increased risk of maternal and perinatal complications. women wish to be involved in their care and are capable of measuring blood pressure (bp) at home. accurate devices for home bp monitoring are now available. the diagnostic criteria for superimposed preeclampsia remain problematic, as most guidelines continue to include deteriorating bp control in the definition. it has not been established how angiogenic markers may aid in confirmation of the diagnosis of superimposed preeclampsia when suspected, over and above information provided by routinely-available clinical data and laboratory results. while chronic hypertension is a strong risk factor for preeclampsia and aspirin decreases preeclampsia risk, the effectiveness specifically among women with chronic hypertension has been questioned. it is unclear whether calcium has an independent effect in preeclampsia prevention in such women. treating hypertension with antihypertensive therapy halves the risk of progression to severe hypertension, thrombocytopenia, and elevated liver enzymes, but a reduction in preeclampsia or serious maternal complications has not been demonstrated; however, the latter lack of evidence is possibly due to few events. also, treating chronic hypertension neither reduces nor increases fetal/newborn death or morbidity, regardless of the gestational age at which the antihypertensive treatment is started. antihypertensive agents are not teratogenic, but there may be an increase in malformations associated with chronic hypertension itself. at present, bp treatment targets used in clinic are the same as those used at home; although bp values tend to be inconsistently lower at home among hypertensive women. while starting all women on the same antihypertensive medication is usually effective in reducing bp, it remains unclear whether there is an optimal agent for such an approach, or how best to use combinations of antihypertensive medications. an alternative approach is to individualize care, using maternal characteristics and bp features beyond bp level (e.g., variability) that are of prognostic value. outcomes may be improved by timed birth between 38+0-39+6 weeks based on observational literature; confirmatory trial evidence is pending. postnatal care is facilitated by the acceptability of most antihypertensives (included angiotensin converting enzymes inhibitors) for use in breastfeeding. conclusions the evidence base to guide the care of pregnant women with chronic hypertension is growing and aligning international guidance. addressing outstanding research questions would inform personalized care of chronic hypertension in pregnancy. personal characteristics, symptoms, bp features beyond the bp level, and other physiological 26 characteristics are associated with adverse outcomes and offer opportunities to personalize care. 27 shortened title: personalized care of chronic hypertension 28 29 has been questioned. it is unclear whether calcium has an independent effect in preeclampsia 48 prevention in such women. treating hypertension with antihypertensive therapy halves the risk of 49 progression to severe hypertension, thrombocytopenia, and elevated liver enzymes, but a reduction 50 in preeclampsia or serious maternal complications has not been demonstrated; however, the latter 51 lack of evidence is possibly due to few events. also, treating chronic hypertension neither reduces 52 nor increases fetal/newborn death or morbidity, regardless of the gestational age at which the 53 antihypertensive treatment is started. antihypertensive agents are not teratogenic, but there may 54 be an increase in malformations associated with chronic hypertension itself. at present, bp 55 treatment targets used in clinic are the same as those used at home; although bp values tend to be 56 inconsistently lower at home among hypertensive women. while starting all women on the same 57 antihypertensive medication is usually effective in reducing bp, it remains unclear whether there is 58 an optimal agent for such an approach, or how best to use combinations of antihypertensive 59 medications. an alternative approach is to individualize care, using maternal characteristics and bp 60 features beyond bp level (e.g., variability) that are of prognostic value. outcomes may be improved 61 by timed birth between 38 +0 -39 +6 hypertension complicates up to 10% of pregnancies, and potentially twice that when considered per 79 woman (1). chronic hypertension complicates 1-2% of pregnancies, and rates are rising (2). while 80 this has been attributed to secular trends in age and body mass index (1), a relationship with black 81 race and rising maternal age, but not obesity or smoking, could be demonstrated in a population-82 based cross-sectional study of more than 150 million hospital deliveries in the united states (2). this 83 is a global phenomenon, with rates at least as high in resource-limited settings (3). 84 definition 85 clinical practice guidelines define chronic hypertension as a blood pressure (bp) ≥140/90mmhg 86 preconception or before 20 weeks' gestation (4). while this is consistent with how hypertension is 87 generally defined outside pregnancy, the american college of cardiology/american heart 88 association (acc/aha) have lowered their threshold for diagnosis to 130/80mmhg, with 130-89 139/80-89mmhg designated as stage 1 hypertension and ≥140/90mmhg as stage 2 (5). if 130/80 90 mmhg were the threshold for diagnosing chronic hypertension in pregnancy, more women would be 91 identified who have a heightened risk of preeclampsia (with risk being intermediate between those 92 with bp <130/80 mmhg [defined as normal if <120/80 mmhg and 'elevated' if systolic is 120-129] 93 and stage 2 chronic hypertension), preterm birth, and gestational diabetes (6). furthermore, women 94 with stage 1 hypertension would benefit from low-dose aspirin, based on a secondary analysis of a 95 larger trial (7). 96 women with chronic hypertension experience increased maternal and perinatal complications. by 98 systematic review (55 studies, 795,221 pregnancies), women with chronic hypertension have high 99 rates of superimposed preeclampsia (26%), cesarean delivery (41%), preterm delivery (28%), low 100 birthweight (17%), perinatal death (4%), and neonatal unit (nicu) admission (21%) (8). stillbirths 101 occur earlier, at a median of 28 vs. 35 weeks, with an absolute risk at 36 weeks (1/1000 births) that 102 equates to that among low-risk nulliparae at 41 weeks (9, 10). chronic hypertension is a singular 103 clinical risk factor for preeclampsia (11), that itself accentuates risk for adverse pregnancy outcomes 104 (12-15); however, development of preeclampsia, defined traditionally by new proteinuria, 105 inadequately accounts for the excess of complications. for example, preeclampsia accounts for 106 <50% of chronic hypertension-associated prematurity, small-for-gestational age (sga) infants and 107 nicu care (16-20). 108 early pregnancy evaluation 111 over 90% of pregnant women with chronic hypertension have underlying primary (formerly called 112 'essential') hypertension, related to genetics or lifestyle factors (21), and most will have been 113 identified preconception. extensive genetics studies have revealed two types of abnormalities: (i) 114 <20 rare mutations that are primarily genes regulating mineralocorticoid or renal pathways, 115 associated with substantial hypertension, and useful in a small number of families; and (ii) hundreds 116 of genetic variants associated with a very small increase in bp (i.e., ≈1 mmhg) that contribute to our 117 understanding of the pathogenesis of hypertension but not to the care of individuals (22). excessive 118 intake of sodium (i.e., >3g/d of sodium chloride) or alcohol, or a sedentary lifestyle are all 119 modifiable, lifestyle risk factors for hypertension outside pregnancy; while little is known about 120 altering salt intake in women with chronic hypertension in pregnancy and pregnant women are 121 advised not to drink alcohol, encouraging physical activity is emerging as an important intervention 122 in pregnancy to prevent pre-eclampsia (23). while less likely to be an issue in pregnancy, it is 123 noteworthy that many medications can increase bp; oral contraceptives and non-steroid anti-124 inflammatory drugs [nsaids] will have been stopped in pregnancy, but women may take over-the-125 counter decongestants, prescription drugs for medical indications (such as immunosuppressants or 126 antidepressants), or consume illicit drugs like cocaine. 127 an underlying, 'secondary', cause of hypertension may be related to problems in renal (e.g., chronic 128 kidney disease or renal artery stenosis), vascular (e.g., coarctation of the aorta), endocrine causes 129 (e.g., primary aldosteronism, pheochromocytoma, cushing syndrome, hypothyroidism or 130 thyrotoxicosis), or respiratory (e.g., obstructive sleep apnea) systems. while collectively, they are 131 thought to account for less than 10% of cases of hypertension, primary aldosteronism may be 132 underrecognized. with systematic screening, including aldosterone to renin ratios, 133 hyperaldosteronism is prevalent among individuals within stage 1 (16%) or stage 2 (22%) 134 hypertension, compared with normotensive individuals (11%) (24). 135 it is not cost-effective to perform a work-up for secondary causes of hypertension in all pregnant 136 women or all adults outside pregnancy. however, it is considered prudent to perform a basic work-137 up in early pregnancy if not performed before pregnancy. the objective is to rule-out obvious 138 secondary causes of hypertension and evaluate baseline cardiovascular risk, although most tests for 139 the latter are not recommended in pregnancy given differences in normal ranges and/or no 140 resultant change in management in pregnancy (table 1) . additional baseline tests may be useful for 141 later comparison when superimposed preeclampsia may be suspected (table 1) . of note, this 142 screening does not include hyperaldosteronism as associated hypertension usually improves in 143 pregnancy and the most commonly-used mineralocorticoid receptor antagonist (spironolactone) is 144 not recommended for use in pregnancy because of potential anti-androgen effects on male fetuses. 145 hypertension secondary to renal, vascular, or endocrine causes are suggested by age of onset <30 146 years, uncontrolled blood pressure with three antihypertensives, or condition-specific symptoms; 147 however many symptoms are associated with normal pregnancy (e.g., dizziness 148 the baseline risk of fetal malformations should be clarified numerically, as many women may not 152 appreciate that 1-5% of all pregnancies are complicated by major birth defects. additionally, 8 untreated chronic hypertension may further increase that risk, particularly for cardiovascular 154 defects, cleft lip or palate, and hypospadias (26-28). while the mechanism is not understood, 155 antihypertensive agents do not appear to be responsible (as discussed below), nor do they appear to 156 alter miscarriage risk (≈20%) (29, 30), although information is limited. 157 as approximately half of pregnancies are unplanned, women with chronic hypertension who are of 158 reproductive age would ideally be treated with antihypertensives that are safe in pregnancy. while 159 no antihypertensive medication is a proven human teratogen, initial associations between 160 angiotensin converting enzyme inhibitors (aceis) and birth defects may have suffered from residual 161 confounding from the underlying hypertension, as discussed above (31). subsequent work has not 162 been consistently reassuring. in a prospective cohort (n=138 women), aceis and angiotensin 163 receptor blockers (arbs) were associated with miscarriage (but not malformations), compared with 164 both hypertensive and normotensive controls; most women (79.8%) were exposed to aceis (32). 165 however, aceis, arbs, and other antihypertensive agents have been associated with teratogenicity 166 in a meta-analysis of five controlled cohort studies (786 infants exposed to aceis or arbs, 1723 to 167 other antihypertensives, and 1,091,472 unexposed) (33). the uk clinical practice guideline suggests 168 that thiazides are teratogenic (34), but this statement is not supported by animal or limited human 169 studies (35). given the inconsistent literature, it is acceptable to continue antihypertensive agents, 170 including aceis and arbs, until conception; this practice may be particularly important for women 171 taking aceis for renoprotection in chronic kidney disease (ckd). conception may normally take up to 172 12 months, and women over 30 years of age suffer more subfertility, so replacing medication 173 prepregnancy can mean that such women's medication is suboptimal for 1-2 years. 174 the safety of antihypertensive agents beyond early pregnancy is further discussed below, under 175 'antihypertensive therapy'. 176 177 home blood pressure monitoring (hbpm) 178 hbpm is recommended by most guidelines for care of hypertension outside pregnancy, based on 179 improved links between diagnoses and adverse outcomes, convenience, antihypertensive 180 compliance, and bp control (36). therefore, women with chronic hypertension may have used hbpm 181 preconceptionally; the covid-19 pandemic has broadened pregnancy hbpm implementation (37). 182 in pregnancy, women using hbpm report greater awareness of risks and empowerment (38, 39). currently, similar bp targets should be used for hbpm and office bp to inform care pathways. while 205 systematic review (7 studies, up to 140 women in late pregnancy) found that home bp is widely 206 variable and probably lower than in clinic for hypertensive women (48). importantly, subgroup 207 analyses before 20 weeks involved fewer than 100 women, and differences were seen primarily in 208 systolic bp (up to 16mmhg vs 7mmhg for diastolic bp [dbp]). second, when multivariable screening identified women at high risk of preeclampsia, and they were 237 administered 150mg/evening of aspirin, the risk of preterm preeclampsia was substantially reduced 238 (76), but women with chronic hypertension were the only subgroup not to benefit (76). this 239 observation is consistent with subgroup analyses in the relevant individual participant data meta-240 analysis (77) and two randomised trials, although aspirin was used in low dose (78, 79) and/or often 241 started after 20 weeks (78); a trial is planned (nct04356326). no practice guideline currently 242 recommends against administering aspirin to these women (4). these issues are discussed in detail 243 elsewhere(80). 244 calcium 245 increasing calcium intake to ≥1 g/day reduces the likelihood of preeclampsia in women with 246 low intake(81-83); most women in more-developed countries have adequate intake (84) 'tight' bp control in chips was achieved by a simple algorithm of antihypertensive up-or down-285 titration (figure 1) , using single or multiple medications. importantly, antihypertensive therapy was 286 decreased if dbp fell to 80mmhg or below, as frequently encountered in mid-pregnancy, and 287 therapy increased if systolic bp were ≥160mmhg, regardless of dbp, for safety. the mean bp 288 achieved in the 'tight' control group, 133/85mmhg (92), was in the lower half of the acc/aha 'stage 289 1 hypertension' range (5), and increasing antihypertensive medication when bp is 'high normal' 290 concurs with guidance from the royal college of obstetricians and gynaecologists (99). also of note 291 is that the bp achieved in 'less tight' control was not particularly high, at 139/90mmhg; the dbp goal 292 of 100mmhg was designed to minimize use of antihypertensives which were nevertheless required 293 by 73% of women post-randomization. while adherence to these algorithms was similar in 'less 294 tight' (74%) and 'tight' control (73%), adherence based on adjusting according to a range of ±5mmhg 295 around the target dbp was lower in 'less tight' (77%) than 'tight' control (82%, p=0.04), as clinicians 296 tended to leave current dosing of medication in 'tight' control when dbp was 86-89mmhg and 297 tended to increase medication in 'less tight' control when dbp was 96-99mmhg (92). it seems 298 unlikely that clinicians would be comfortable keeping bp below 130/80mmhg if acc/aha thresholds 299 were adopted. 300 four national/international practice guidelines (canada, uk, poland, isshp) now endorse 'tight' bp 301 control for all forms of pregnancy hypertension, based on the results of the chips trial (4). other 302 14 (smfm) considers as acceptable both 'tight' and 'less tight' control, by giving advice to maintain bp 304 at 120-159/80-104 mmhg in women with low-risk chronic hypertension. the american college of 305 obstetricians and gynaecologists recommends treating bp emergently when it reaches severe levels 306 (i.e., ≥160/110mmhg), but not at all before then unless there are comorbidities pending the results 307 of the chap trial (control of hypertension and pregnancy, nct02299414), as below (25). 308 there are two ongoing trials of an oral antihypertensive vs. another for non-severe pregnancy 309 hypertension. one is studying nifedipine vs. labetalol initiation to achieve 'tight' bp approach in each 310 group (giant panda, nihr128721), with randomization minimized by race. there is one ongoing 311 trial of antihypertensive therapy vs. 'treatment only when bp is severe' (chap) for women with 312 chronic hypertension randomized to treatment approaches similar to chips, with a primary 313 composite maternal and perinatal outcome and a co-primary of birthweight <10 th centile (100). 314 smfm is looking to chap to address two concerns. first, the average gestational age at recruitment 315 to chips was >20 weeks (i.e., 24 weeks); while this was related in part to 25% of women recruited 316 having gestational hypertension, the adverse effects of 'less tight' control were seen in particular 317 before 24 weeks (101). second, most women in 'less tight' control (77%) received an 318 antihypertensive before birth; this should be anticipated in chap as the interventions are similar. 319 reporting in 2023, chap will be powered to address whether 'tight' control benefits the mother (i.e., 320 fewer serious maternal complications) and baby (i.e., fewer preterm births), or causes more 321 newborn side effects (i.e., more sga infants). 322 initial antihypertensive therapy should be monotherapy from accepted first-line drugs; ≥60% of 324 women take only one agent prenatally (92). the most commonly-used and recommended 325 antihypertensive medications come from different drug classes. all cross the placenta. 326 labetalol is a combined alpha-and (nonselective) beta-blocker, used in oral and parenteral forms; 327 beta-blockade predominates, particularly when labetalol is administered parenterally. the overall 328 effect is vasodilatation without reflex tachycardia or a reduction in cardiac output. labetalol should 329 be used with caution in women with mild-moderate asthma (or another contraindication to 330 nonselective beta-blockade) and not at all in women with severe or decompensated asthma. (including placebo/no therapy) (106), many agents decreased the incidence of severe hypertension 364 compared with placebo/no therapy: nifedipine, methyldopa, pindolol, and ketanserin; nifedipine 365 decreased severe hypertension compared with furosemide, as did pindolol compared with 366 furosemide or amlodipine. both nifedipine and methyldopa decreased the incidence of placental 367 abruption compared with placebo/no therapy. atenolol increased the incidence of sga infants 368 compared with placebo/no therapy and other antihypertensives (labetalol, nifedipine, methyldopa, 369 and ketanserin). no differences were seen in preeclampsia, cesarean, preterm birth, or perinatal 370 death. the 95% cis around estimates of effect were often very wide, and one trial was counted twice 371 (107, 108). however, the results suggest that nifedipine and methyldopa are most beneficial. 372 vitamin d may enhance the effectiveness of nifedipine (109). 373 these data concur with the broader systematic review of antihypertensive vs. placebo/no therapy in 374 pregnancy (31 trials, 3485 women) and head-to-head comparisons of different antihypertensives (29 375 trials, 2774 women); generally the type of hypertensive disorder was unspecified (90). multiple 376 agents reduce the incidence of severe hypertension compared with no antihypertensive. however, 377 neither nifedipine nor methyldopa had previously been recognized to reduce abruption. while 378 comparison with methyldopa as the gold standard, has been reported to show that beta-blockers 379 (any, including labetalol) and calcium channel blockers taken together may reduce the risk of severe 380 hypertension, results were more different than could be expected by chance alone. also, beta-381 blockers, but not calcium channel blockers, may decrease the risk of preeclampsia compared with 382 placebo/no therapy, but when beta-blockers and calcium channel blockers were compared directly, 383 beta-blockers did not decrease preeclampsia as anticipated. of note, in the chips trial, women 384 treated with methyldopa (vs. labetalol) may have had better maternal and perinatal outcomes, 385 although there may have been residual confounding (110). 386 other relevant short-and long-term outcomes have been understudied. an example is an 387 unsubstantiated belief that both oral labetalol and methyldopa may alter fetal heart rate ( although more efficiently with nifedipine than iv hydralazine (103). using a minimally important 415 relative risk reduction of 10% between groups, an associated trial sequential analysis concluded that 416 there was no difference in effectiveness between iv labetalol and oral nifedipine or iv hydralazine, 417 but more data were needed to compare nifedipine and hydralazine. a second network meta-analysis 418 of first-line agents (17 trials, 1591 women) found that nifedipine more successfully treated severe 419 hypertension than iv hydralazine (116). 420 oral labetalol and oral methyldopa compared favorably to oral nifedipine in a recent indian trial for 421 severe pregnancy hypertension (115); an in-target bp (i.e., 120-150/70-100mmhg) was achieved 422 without fetal compromise at 6 hours in ≥75% of women in each group, similarly in the nifedipine 423 (84%) and labetalol (84%) groups, but slightly more often in the nifedipine vs. methyldopa 424 comparison (76%, absolute difference 7·1%, 95% ci 0·8, 13·5). however, more nifedipine group 425 babies received nicu care (for low birthweight) (18%) than labetalol (10%) or methyldopa (10%). 426 table 3 presents a dose-escalation protocol consistent with recommendations by the society of 427 obstetricians and gynaecologists of canada and acog, and incorporating oral treatment (25, 115, 428 117). the protocol is more conservative in places with regards to dosing (at the lower limit of 429 published ranges) and/or time for repeat dosing (at or beyond the upper limit of recommendations) 430 to harmonize between medications for ease of implementation in urgent care and to minimize the 431 risk of maternal hypotension. of note, a third dose of oral nifedipine capsules is given at 90min 432 because a dose of 20mg is not used, and when another agent is needed, one should choose from a 433 different drug class, and not hydralazine if nifedipine failed (or vice versa). successful treatment is 434 resolution of severe hypertension. consistent with acog guidance, routine antihypertensive therapy 435 should be instituted to avoid further episodes of severe hypertension(25). 436 no antihypertensive medication is a proven human teratogen. however, some agents may be best 438 avoided in pregnancy, given possible or proven concerns about fetotoxicity and the availability of 439 alternative agents. 440 atenolol, a cardioselective beta-blocker, may reduce fetal growth velocity (56, 106, 118-121) . 441 many practitioners are uncomfortable using thiazides and thiazide-like diuretics due to theoretical 442 concerns about reducing gestational plasma volume expansion (104); however, diuretics were not 443 associated with adverse outcomes when used throughout pregnancy for preeclampsia prevention. 444 their use is probably best limited to specific circumstances (e.g., medullary sponge kidney). 445 aceis and arbs should not be used in women once pregnant (grades c and d, respectively) (94); 446 while they do not appear to be teratogenic (33, 122, 123) , there may be an excess of miscarriage, 447 fgr, and neonatal morbidity following use in early pregnancy, even when the medication is stopped 448 in early pregnancy (124). however, such associations have been based on low-quality data (e.g., case 449 reports and series), inconsistently observed, and may relate to underlying hypertension (27, 125, 450 individualized antihypertensive therapy 452 outside pregnancy, age and race reflect different hemodynamic profiles in hypertension and 453 response to antihypertensive therapy (127, 128); high renin hypertension is associated with young 454 age and higher hr, or volume expansion, and low renin hypertension is associated with black race 455 (127). antihypertensive therapy guided by these phenotypes halves poor bp control, by giving aceis 456 or arbs to young and white patients, and calcium channel blockers to black patients (129), and is 457 recommended outside pregnancy for adult hypertension (130). 458 in observational work, demographic and hemodynamic parameters identify individual pregnant 459 women less likely to achieve bp control with oral labetalol (131). these women were more often 460 black, with lower hr and cardiac stroke volume (sv) ('vasoconstricted' or 'high resistance' 461 phenotype associated with more severe hypertension and fgr) and more likely to respond to a 462 vasodilator. in contrast, women with non-black race and higher hr and sv ('hyperdynamic' 463 phenotype) were more successfully treated with oral labetalol. importantly, maternal race alone was 464 a poor predictor of bp response to labetalol (area-under-the-receiver-operator curve only 0.65). in a 465 subsequent observational study of 84 hypertensive pregnancies, initiation and titration of 466 antihypertensive therapy (for bp ≥140/90mmhg) guided by this model resulted in a change in care 467 for 51% of women taking oral labetalol; 30% initially given labetalol required additional nifedipine, 468 and 20% initially given nifedipine required additional labetalol. severe hypertension requiring 469 admission to a high dependency unit was reduced by 60%, without fgr (132). 470 personalized hemodynamic assessment holds promise to deliver 'tight' bp control while optimizing 471 fetal growth and highlighting potential perinatal benefits. neither of two ongoing trials of 472 were associated with a greater likelihood of preeclampsia (defined by new proteinuria), 500 preeclampsia that was more severe, early delivery, and adverse maternal and perinatal outcomes 501 (144-146); one study confirmed the observations in a cohort of 123 women with chronic 502 hypertension and ckd (145). as angiogenic imbalance is associated with risks for both placental fgr 503 and stillbirth, it is possible that defining preeclampsia broadly would improve the diagnostic test 504 performance of angiogenic markers (147-151) . 505 detecting progression to preeclampsia when it occurs is why many professional organizations 507 emphasize evaluating maternal symptoms (113). in a systematic review of maternal risk stratification 508 in pregnancy hypertension (32 studies), minipiers (preeclampsia integrated estimate of risk score) 509 was the only model for all pregnancy hypertension types, has been externally validated (152), and 510 quantifies the risk of adverse maternal outcome by bp, symptoms, urinalysis (if performed), 511 gestational age and parity (of particular importance for nulliparous women). 'high-risk' women have 512 a predicted risk ≥25%, as a 'rule-in' test for adverse maternal outcome within 48hr (likelihood ratio 513 of 5.1) and correct classification (86%). an online calculator is available (153). 514 if preeclampsia develops, the adverse maternal outcomes can be predicted by the fullpiers model, 515 incorporating: gestational age, chest pain/dyspnea, pulse oximetry, platelet count, serum creatinine, 516 and ast/sgot or alt/sgpt) (154). using ≥10% to define high risk, fullpiers can be used as a 'rule-in' 517 test for adverse maternal outcome within 48hr, based on a good lr (9.2). an online calculator is 518 available (155). determining the added value of angiogenic markers is warranted (156, 157). 519 520 practise related to the timing of birth for women with chronic hypertension varies widely. in a 522 previously unpublished site survey of chips trial investigators, 70 respondents highlighted variable 523 practice, with delivery currently offered at 37 (16%), 38 (33%), 39 (20%), 40 (20%), and 41 (12%) 524 weeks gestation. observational data suggest that delivery between 38 +0 -39 +6 weeks may optimize 525 perinatal outcomes, by balancing stillbirth and neonatal morbidity risks (9, 158). these observational 526 data are complemented by limited trial data related to 50 egyptian women with chronic 527 hypertension (159), that suggest that earlier term delivery may benefit women without increasing 528 perinatal risks or cesarean deliveries. however, there are insufficient data available to assess the 529 impact of planned delivery at term (i.e., between 37 +0 to 41 +6 weeks) on maternal morbidity or 530 cesarean delivery (160). 531 the will trial (when to induce labour to limit risk in pregnancy hypertension; isrctn 77258279) is 532 randomizing both chronically-and gestationally-hypertensive women to either a policy of delivery at 533 38 0-3 weeks or expectant care until ≥40 +0 weeks (or as clinical need dictates). the co-primary 534 outcomes are maternal death or serious morbidity (fullpiers outcome(154); superiority) and nicu 535 admission for ≥ 4 hours (non-inferiority); cesarean delivery rate is the core secondary outcome. 536 as most trials have evaluated antepartum, rather than postpartum, antihypertensive therapy, 539 evidence is insufficient to guide clinical practice; however, it is reasonable to continue 'tight' bp 540 control postpartum. bp is likely to rise after a woman leaves hospital (peaking on days three to six 541 postpartum), postnatal stroke is increasing in incidence, and most antihypertensives are acceptable 542 for use in breastfeeding (searchable information in lactmed (161) women with chronic hypertension are at high-risk of pregnancy complications, but an easily-556 recognized group in touch with a wide variety of healthcare providers before, during, and after 557 pregnancy. we know that these women are at increased risk of maternal and perinatal 558 complications, that they are capable of measuring their bp values at home with accurate devices, 559 that treating their hypertension with antihypertensive therapy halves the risk of progression to 560 severe hypertension, and that they wish to be involved in their care. priorities for future research 561 include whether or not: additional characteristics of bp and other physiological variables can be used 562 to predict preeclampsia; low-dose aspirin reduces their risk of preeclampsia specifically and/or 563 calcium has an independent preventative effect; use of angiogenic markers with clinical factors and 564 routine laboratory testing improves care; hemodynamically-guided care improves outcomes in 565 comparison with antihypertensive therapy titrated to bp level and, if the latter, with which 566 antihypertensive agent is best to initiate treatment from among labetalol, nifedipine, and 567 methyldopa; and optimal timing of birth. all of this will bring us closer to offering women more 568 personalized care of their chronic hypertension in pregnancy. 569 570 medications or illicit substances that can increase bp (e.g., decongestants, nsaids, immunosuppressants, antidepressants, cocaine) * not performed in pregnancy as the normal range is higher and management would not be changed. † not routinely performed in pregnancy, but may be useful as part of haemodynamically-guided antihypertensive therapy. ‡ even if done previously to rule out secondary causes of hypertension. incidence and long-term outcomes of hypertensive disorders of pregnancy changes in the prevalence 575 of chronic hypertension in pregnancy, united states the incidence of 578 pregnancy hypertension in india, pakistan, mozambique, and nigeria: a prospective population-level 579 analysis guidelines -similarities/dissimilarities. 581 a systematic review of international clinical practice guidelines for pregnancy hypertension management of high blood pressure in adults: a report of the american 586 college of cardiology/american heart 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hypertensive pregnant population: cost-minimization study telemonitoring and 682 self-management in the control of hypertension (tasminh2): a randomised controlled trial effect of self-685 monitoring and medication self-titration on systolic blood pressure in hypertensive patients at high 686 risk of cardiovascular disease: the tasmin-sr randomized clinical trial self-management of 688 postnatal hypertension: the snap-ht trial the natural history of white coat hypertension 690 during pregnancy diagnosis of white coat hypertension and 692 pregnancy outcomes maternal and perinatal of white coat 694 hypertension during pregnancy: a systematic review and meta-analysis how do home 697 and clinic blood pressure readings compare in pregnancy? hypertension is home blood-pressure monitoring in 699 hypertensive disorders of pregnancy consistent with clinic recordings? reliability of home blood pressure monitoring devices in 702 pregnancy ahsn. my story: enabling home monitoring of hypertension in pregnancy london: nhs 708 innovation accelerator mobile phone apps for clinical decision support in 711 pregnancy: a scoping review are blood pressure level 713 and variability related to pregnancy outcome? analysis of control of hypertension in pregnancy 714 study data prevention of preeclampsia: a 716 randomized trial of atenolol in hyperdynamic patients before onset of hypertension methods and 719 considerations concerning cardiac output measurement in pregnant women: recommendations of 720 the international working group on maternal hemodynamics genetic and non-genetic risk factors for pre-723 eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies prediction of pre-726 eclampsia: review of reviews multicenter 728 screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: 729 comparison with nice guidelines and acog recommendations comparison of diagnostic 732 accuracy of early screening for pre-eclampsia by nice guidelines and a method combining maternal 733 factors and biomarkers: results of spree can adverse maternal and 735 perinatal outcomes be predicted when blood pressure becomes elevated? secondary analyses from 736 the chips (control of hypertension in pregnancy study) randomized controlled trial the performance of risk prediction 739 models for pre-eclampsia using routinely collected maternal characteristics and comparison with 740 models that include specialised tests and with clinical guideline decision rules: a systematic review prospective 743 evaluation of screening performance of first-trimester prediction models for preterm preeclampsia 744 in an asian population first-trimester 746 combined multimarker prospective study for the detection of pregnancies at a high risk of 747 developing preeclampsia using the fetal medicine foundation-algorithm first trimester combined 750 screening for preeclampsia and small for gestational age -a single centre experience and validation 751 of 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hypotensive treatment. i. perinatal factors and neonatal morbidity vitamin d enhances efficacy of oral nifedipine in 865 treating preeclampsia with severe features: a double blinded, placebo-controlled and randomized 866 clinical trial do labetalol and 868 methyldopa have different effects on pregnancy outcome? analysis of data from the control do commonly used oral 871 antihypertensives alter fetal or neonatal heart rate characteristics? a systematic review in-utero exposure to 874 antihypertensive medication and neonatal and child health outcomes: a systematic review diagnosis and 877 management of hypertension in pregnancy: summary of updated nice guidance the hypertensive 880 disorders of pregnancy: the 2020 isshp classification, diagnosis & management recommendations 881 for international practice oral antihypertensive 883 regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in 884 pregnancy: an open-label, randomised controlled trial 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sflt-1/plgf ratio, delfia xpress plgf 1-2-3 test, and brahms sflt-1 kryptor/brahms 957 plgf plus kryptor pe ratio) [dg23]. london: national institute of health and care excellence predictive value of 959 the sflt-1:plgf ratio in women with suspected preeclampsia soluble fms-like 961 tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4 weeks and 962 value of retesting angiogenic factors 964 in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during 965 pregnancy diagnostic and 967 predictive biomarkers for pre-eclampsia in patients with established hypertension and chronic 968 kidney disease angiogenic factor 970 abnormalities and risk of peripartum complications and prematurity among urban predominantly 971 obese parturients with chronic hypertension can placental growth factor in 973 maternal circulation identify fetuses with placental intrauterine growth restriction? placental 976 growth factor as a marker of fetal growth restriction caused by placental dysfunction diagnostic accuracy of 979 placental growth factor and ultrasound parameters to predict the small-for-gestational-age infant in 980 women presenting with reduced symphysis-fundus height diagnostic 983 performance of placental growth factor in women with suspected preeclampsia attending antenatal 984 facilities in maputo early 986 diagnosis of preeclampsia using placental growth factor: an operational pilot study in maputo a risk prediction 989 model for the assessment and triage of women with hypertensive disorders of pregnancy in low-990 resourced settings: the minipiers (pre-eclampsia integrated estimate of risk) multi-country 991 prospective cohort study partnerships and treatment prediction 996 of adverse maternal outcomes in pre-eclampsia: development and validation of the fullpiers model evidence: fullpiers (fullpiers calculator) vancouver: pregnancy evidence partnerships and treatment angiogenic factors in diagnosis, management, and 1002 research in preeclampsia angiogenic marker prognostic 1004 models in pregnant women with hypertension timing of delivery 1006 in women with chronic hypertension pregnancy 1008 outcomes of expectant management of stable mild to moderate chronic hypertension as compared 1009 with planned delivery planned early delivery versus expectant 1011 management for hypertensive disorders from 34 weeks gestation to term. cochrane database syst 1012 rev drugs and lactation database (lactmed) bethesda: national library of medicine (us) furosemide in postpartum management of severe 1016 preeclampsia: a randomized controlled trial key: cord-254647-axyx03eg authors: brocal, francisco; sebastián, miguel a.; gonzález, cristina title: advanced manufacturing processes and technologies date: 2018-11-16 journal: management of emerging public health issues and risks doi: 10.1016/b978-0-12-813290-6.00002-0 sha: doc_id: 254647 cord_uid: axyx03eg a general framework of the emerging risks linked with advanced manufacturing processes and technologies is showed. for this, the systemic and occupational nature of said risks is considered. to achieve this general objective, the chapter is organized in two parts. in the first part, a theoretical basis is developed. this theoretical basis is configured by an explanation of the emerging risk concept, as well as by the development of an overview of advanced manufacturing processes and technologies. in the second part, contents and tools of practical application are exposed. to do this, the main emerging risks are shown first. among the fields of application of these risks, some of the most important cross-cutting manufacturing technologies have been selected. one of the main risk governance frameworks is shown. subsequently, this framework is deployed with two of its main applications on emerging risks: the management and characterization of the risk. the first three industrial revolutions came about as a result of mechanization, electricity, and information technology (it). germany has proposed the concept of smart manufacturing to realize the fourth industrial revolution, that is, industry 4.0 (qian et al., 2017) . industry 4.0 is a "strategic pcast (2011) focuses in its report on advanced manufacturing, a family of activities that (1) depend on the use and coordination of information, automation, computation, software, sensing, and networking, and/or (2) make use of cutting-edge materials and emerging capabilities enabled by the physical and biological sciences, for example, nanotechnology, chemistry, and biology. according to that report, this involves new ways to manufacture existing products, and especially the manufacture of new products emerging from new advanced technologies technological change can reduce some risks while aggravating others or even creating new ones (oecd, 2003) . ilo (2010) indicates that in the occupational safety health (osh) field, recent decades have seen significant technological advances in the workplace, which, together with rapid globalization, have transformed work for many throughout the world. the effects of such changes on osh have also been significant, so that in some cases, more traditional hazards and risks have been reduced or eliminated, for example, through plant automation, but new technologies have also created new risks (ilo, 2010) . advanced manufacturing processes are characterized by innovative variables of a technological and organizational nature that tend to change with workplaces, processes and conventional work practices, and can generate, as well as traditional occupational risks, other so-called new and emerging risks (ners) (brocal and sebastián, 2015a) . this raises new challenges for workers and companies and, in turn, creates political demands, administrative and technical approaches that ensure high levels of safety and health at work (adapted from eu-osha, 2013). the general objective of this chapter is to show a general framework of the emerging risks 1 linked with advanced manufacturing processes and technologies. for this, the systemic and occupational nature of said risks is considered. to achieve this general objective, the chapter is organized in two parts. in the first part, a theoretical basis is developed. this theoretical basis is configured by an explanation of the emerging risk concept, as well as by the development of an overview of advanced manufacturing processes and technologies. among these manufacturing technologies, three of the most important have been selected in order to provide a broader overview. these three manufacturing technologies are: intelligent manufacturing, iot-enabled manufacturing, and cloud manufacturing. in the second part, contents and tools of practical application are exposed. to do this, the main emerging risks are shown first. among the fields of application of these risks, some of the most important cross-cutting manufacturing technologies have been selected in order to develop them in greater detail. these manufacturing technologies are: automation; human machine interfaces (hmis), and information and communication technologies (icts) . second, one of the main risk governance frameworks is shown. subsequently, this framework is deployed with two of its main applications on emerging risks: the management and characterization of the risk. finally, a brief summary of the chapter is presented, accompanied by the main conclusions. risk is defined in many ways (aven, 2010) , and many perspectives on risk are developed and used for specific disciplines and areas (aven, 2012) . however, considering the most common definitions of risk found in scientific standards and literature, aven (2010) states that the common feature of all these definitions is that the concept of risk comprises events (initiating events, scenarios), consequences (outcomes), and probabilities. as aven (2012) believes, though it is impossible to present and discuss all definitions of the risk concept suggested and used in scientific risk fields, the author proposes the categories of definitions/ perspectives on risk as used in professional/scientific contexts (table 2 .1). the iso 31000:2009 standard (iso, 2009a defines risk as the effect of uncertainty on objectives. likewise (continuing with the definitions of this standard), objectives can have different aspects (such as financial, health and safety, and environmental goals) and can apply at different levels (such as strategic, organization-wide, project, product and process). risk is often expressed in terms of a combination of the consequences of an event (including changes in circumstances) and the associated likelihood of occurrence (iso, 2009a) . in the specific field of occupational risk, ohsas 18001 standard defines risk as the combination of the likelihood of an occurrence of a hazardous event or the exposure and the severity of injury or ill health that can be caused by the event or exposure (aenor, 2007) . and the iso 45001 standard (the current version is the iso/dis 45001.2: 2017) defines an occupational health and safety risk as the combination of the likelihood of an occurrence of a work-related hazardous event or exposure, and the severity of injury or ill health that can be caused by the event or exposure (iso, 2017a) . the standard is currently being developed by a committee of occupational health and safety experts, and will follow other generic management system approaches such as iso 14001 (iso, 2015a) and iso 9001 (iso, 2015b) . it will take into account other international standards in this area such as ohsas 18001, the international labor organization's ilo-osh guidelines, various national standards, and the ilo's international labor standards and conventions (iso, 2017b) . the revision of this new standard, iso 45001, is in its final stage (aenor, 2017) . the final publication of the standards is expected in march 2018 (iso, 2017b). risk ¼ probability of an (undesirable) event (r ¼ p) 3 risk¼objective risk ¼ probability and scenarios/consequences/ severity of consequences (r ¼ p&c) 7 risk ¼ event or consequence (r ¼ c) 8 risk risk is the effect of uncertainty on objectives (r ¼ iso) irgc (2010a) considers that there are emerging risks of a systemic nature, which typically span more than one country, more than one economic sector, and may have effects across natural, technological, and social systems. these risks may be relatively low in frequency, but they have broad ramifications of human health, safety and security, the environment, economic well-being, and fabric of societies. irgc (2010b) aims to shed light on emerging risks with a perspective that has three elements: sources of risk, drivers of risk, and governance issues. irgc (2010a) defines as emerging a risk that is new, or a familiar risk that becomes apparent in new or unfamiliar conditions. the concept of familiarity assumes the existence of recognizable patterns and management regimes that are relatively stable and have proven to be effective if implemented according to certain rules. by contrast, emerging risks are characterized mainly by uncertainty regarding their potential consequences and/or probabilities of occurrence (irgc, 2015a) . irgc (2011) eu-osha defines ner through the reports cited as listed following by ner definition. in this definition, unlike the original sources cited (flaspöler et al., 2005; brun et al., 2007a brun et al., , 2007b brun et al., , 2009 , it is the codification (ci), which in this chapter is called "conditions," that defines an ner (brocal et al., 2017) . ner definition: any occupational risk that is both new and increasing: • by "new," we mean that: c1. the risk did not previously exist and is caused by new processes, new technologies, new types of workplace, or social, or organizational change; or, c2. a long-standing issue is considered as a new risk due to a change in social or public perceptions; or, c3. new scientific knowledge allows a long-standing issue to be identified as a risk. • the risk is "increasing" if the: c4. number of hazards leading to the risk is growing; or c5. the exposure to the hazard leading to the risk is increasing (exposure level and/or the number of people exposed); or c6. the effect of the hazard on workers' health is getting worse (seriousness of health effects and/or the number of people affected). the ner definition adopted by the eu-osha has been integrated into cwa 16649: 2013 (cen, 2013). however, as brocal et al. (2017) consider, such integration implies two modifications, a terminological modification and another of interpretation. so, instead of using the term "new and emerging risk," the term "emerging risk" is employed, which has been defined as "any risk that is both new and/or increasing." in this regard, one can deduce that the term "new and emerging risk" has been simplified from "emerging risk" (brocal et al., 2017) . such simplification can be seen, for example, in the work developed by . similarly, houtman et al. (2016) state that an "emerging osh risk" is often defined as "any occupational risk that is both new and increasing." in any case, as brocal (2016) indicates, these quotes reveal a clear problem with consensus about terminology and interpretation of the ner concept. similarly, flage and aven (2015) feel that the term "emerging risk" has an intuitive appeal and meaning, although a consistent and consensual definition is lacking. in addition, the ner definition has been developed without following any risk model reference, thus hindering its use in the ner identification and analysis (brocal and sebastián, 2015a,b) . to solve this problem, brocal and sebastián (2015a) have developed a new risk model whose objective is to characterize the ner. nevertheless, this model has two limitations (brocal et al., 2017) . first, the model does not contemplate the possibility of considering independently the new risks (nr) and increasing risks (ir). second, this model does not allow monitoring the evolution of ner over time, therefore it is not currently possible to determine, in general, the temporary validity of such risks. in order to solve these problems, brocal et al. (2017) have developed a theoretical framework for the modeling of the ner that allows its monitoring through the technology lifecycle (tlc), especially in industrial processes. zhu et al. (2013) considered two major classifications of manufacturing processes: the first by swift and booker (2013) classifies processes into casting, cutting, forming, and fabrication. the second by kalpakjian and schmid (2010) is more comprehensive; they classify processes into casting, machining and finishing, joining, sheet metal, polymer processing, and bulk deformation processes. as the traditional classifications have some difficulties in the identification of newly developed manufacturing technologies (zhu et al., 2013) , nassehi et al. (2011) proposed a technology-based classification method consisting of five categories, namely joining, dividing, subtractive, transformative, and additive technologies. zhu et al. (2013) , briefly describe these five categories: • joining technology: consists of processes by which two or more workpieces are joined to form a new workpiece; • dividing technology: dividing processes are the opposite of joining processes; • subtractive technology: subtractive/negative operations are material removal processes, by which material is removed from a single workpiece, resulting in a new workpiece; • transformative technology: a single workpiece is used to create another workpiece and the mass does not change; • additive technology: material is added to an existing workpiece to build a new workpiece, where the mass of the finished workpiece is greater than before. advanced manufacturing relies on new technologies that enable flexibility, agility, and the ability to reconfigure, as for example the following applicable areas: biomanufacturing, semiconductors, advanced materials, additive manufacturing, and nanomanufacturing (esmaeilian et al., 2016) . emerging technologies can have game-changing impacts on manufacturing models, approaches, concepts, and even businesses (zhong et al., 2017a) . as an and ahn (2016) indicate, several organizations have forecasted emerging technologies and reported on their forecasts, so that some well-known forecasts are "disruptive technologies" (mckinsey global institute), "10 breakthrough technologies" (mit), "next 5 in 5" (ibm), and "top 10 strategic technologies" (gartner group). the main results of these forecasts are discussed next. as mckinsey global institute indicates, economically disruptive technologies transform the way we live and work, enable new business models, and provide an opening for new players to upset the established order (manyika et al., 2013) . mckinsey global institute considers that the 12 potentially economically disruptive technologies are: mobile internet; automation of knowledge work; iot; cloud technology; advanced robotics; autonomous and near-autonomous vehicles; next-generation genomics; energy storage; 3d printing; advanced materials; advanced oil and gas exploration and recovery; and renewable energy (manyika et al., 2013) . every year mit technology review publishes a list containing 10 breakthrough technologies. the list for the year 2017 is as follows (mit, 2017): reversing paralysis; self-driving trucks; paying with your face; practical quantum computers; the 360-degree selfie; hot solar cells; gene therapy 2.0; the cell atlas; botnets of things; and reinforcement learning. ibm (2017) considers five innovations that will change our lives in the next 5 years: with artificial intelligence (ai), our words will be a window into our mental health; hyperimaging and ai will give us superhero vision; macroscopes will help us understand earth's complexity in infinite detail; medical labs "on a chip" will serve as health detectives for tracing disease at the nanoscale; and smart sensors will detect environmental pollution at the speed of light. every year gartner publishes a list containing the top 10 strategic technology trends. the list for the year 2017 is as follows(gartner group, 2017) : ai and advanced machine learning; intelligent apps; intelligent things; virtual and augmented reality; digital twin; blockchain and distributed ledgers; conversational system; mesh app and service architecture; digital technology platforms; and adaptive security architecture. the evolution of integrated and intelligent manufacturing (i2m) technology is driven not only by the market demand but also by technological advances. there are 10 major technologies ( fig. 2. 2) that can be identified as the key elements of the new manufacturing paradigm (chen, 2017) . zhong et al. (2017a) consider that the three major advanced manufacturing technologies are the following: intelligent manufacturing, iot-enabled manufacturing, and cloud manufacturing. these manufacturing technologies are briefly described in the following sections. intelligent manufacturing systems represent one of the latest developments in both manufacturing technologies and organization (dumitrache and caramihai, 2010) . the basic idea involves flexibility in systems, monitoring, and adaptation to changing needs (kumar, 2017) . the targeted objective is to gain the most benefit for product quality, cost reduction, and increase of efficiency in general (zillner et al., 2016) . qian et al. (2017) consider four objectives in relation to the layer of engineering technology: digitization, intellectualization, cyberization (to develop cyber-physical systems), and automation. at the same time, these authors consider four objectives in relation to enterprise production and operation: agility, high efficiency, environmental sustainability, and safety. intelligent manufacturing makes use of advanced computational technologies and the advancements in digital systems and machine learning processes to support decision-making, run selften major technologies for i2m (chen, 2017). sufficiently via networks of distributed control, and to self-adjust and self-correct should problems arise (oliff and liu, 2017) . systems' theory, communications, and nanotechnologies, all characterized by solid formal supports, have contributed decisively to a transition from the c2 paradigm (computer-control) to the c4 paradigm (computer, communication, cognition for control) (dumitrache, 2008) . intelligent manufacturing systems represent a reality in the framework of c4 paradigm and should be analyzed and designed as cyber-physical systems (cpss) (dumitrache and caramihai, 2010) . currently, there is an ongoing transformation of classical products and machinery toward cpss (becker and stern, 2016) . cpss link the physical world seamlessly with the virtual world of information technology and software (sztipanovits and ying, 2013) . main features of these systems are the real-time data exchange between various technical and computational elements enabled by communication technologies and data processing ability provided by embedded systems (becker and stern, 2016) . the introduction of both cps and the iot, where things are supposed to initiate both a process of preparation, design, planning, optimization, tasks for tools, and humans if necessary, is leading in a fourth industrial revolution referring to the future (mrugalska and wyrwicka, 2017) . this idea is represented schematically through table 2 .3. qian et al. (2017) consider that the intrinsic safety of the manufacturing process as well as enterprise information security must be ensured, and to realize the safe running of manufacturing processes by means of fault diagnoses and self-healing control techniques. for example, with advancements in networking and internet technologies, cyberattacks on physical systems are becoming a growing phenomenon (desmit et al., 2017). tarkoma and ailisto (2013) indicate that recent advances in radio, network, mobile, and cloud technologies have supported the development of the first-generation iot services and products. these authors consider that iot as a concept is not new as it was proposed over 10 years ago in the mit auto-id center, so that the concept has since gained momentum and importance, and now it is considered in europe, the united states, and asia, not only on the implementation and deployment level but also on the societal level. early iot applications are based on radio frequency identification (rfid) and wireless sensor network (wsn) technologies, and deliver tangible benefits in several areas, including manufacturing, logistics, trade, retail, and green/sustainable applications, as well as in other sectors (kefalakis et al., 2016) . the adoption of iot in manufacturing enables the transition of traditional manufacturing virtualization and integration systems into modern digitalized ones, generating significant economic opportunities through industries' reshaping (mourtzis et al., 2016) . for example, iot technologies such as rfid and wireless communications are used for capturing real-time machine status (zhong et al., 2017b) . industrial iot devices for manufacturing include sensors/actuators, computers with wireless networks, etc., which have contributed significantly to different aspects of manufacturing such as automation and tracking (he et al., 2017) . trappey el al. (2017) divides the iot architecture into four layers, as briefly described in table 2 .4. iot-enabled manufacturing is an advanced principle where typical production resources are converted into smart objects that are able to sense, interconnect, and interact with each other to automatically carry out the manufacturing activities (zhong, 2017) . considering the work developed by tao et al. (2014) , it can achieve the complete connection between terminal devices and the enterprise information management system for the automatic control of the iot-enabled manufacturing execution in workshops. therefore, three functions should be addressed: the access, identification, and control of the physical manufacturing execution process from materials and semifinished products to the final products (tao et al., 2014) . computers play an essential role in increasing efficiency, capability, and adaptability of manufacturing systems, as for example: computer integrated manufacturing, distributed manufacturing, agile manufacturing, cps, and cloud manufacturing (yu et al., 2015) . cloud computing is emerging as one of the major enablers for the manufacturing industry; it can transform the traditional manufacturing business model, help it to align product innovation with business strategy, and create intelligent factory networks that encourage effective collaboration (xu, 2012) . in general, cloud-related manufacturing research can be categorized into two types: cloud computing in manufacturing industry, and cloud manufacturing systems . perception deals with the types of sensors (e.g., sensors are used to detect temperature, weight, motion, vibration, etc.) and actuators that help the physical object to perceive. perception is used in upper layers to achieve the final goal of micro intelligence at the application layer. transmission transmission is the second layer in the iot ecosystem. the next step after perception (collection of sensor information) is to transmit the information to the upper layers. computation the computation layer describes means of receiving data, processing data, making decisions, and delivering the decisions to the application layer. the computation layer consists of hardware, software, algorithms, cloud computing, big data analysis, and security. application the application layer provides tactical understanding by using information collected and transmitted from lower layers. in 2010, bohu et al. (2010) put forward the concept of cloud manufacturing (xin-yu and wei-jia, 2011). cloud manufacturing is a new, networked, and intelligent manufacturing model that is service oriented, knowledge based, high performance, and energy efficient. in this model, state-of-the-art technologies such as informatized manufacturing, cloud computing, iot, semantic web, and highperformance computing are integrated in order to provide secure, reliable, and high-quality ondemand services at low prices for those involved in the whole manufacturing lifecycle (bohu et al., 2010) . ooi et al. (2018) note that cloud technology enables on-demand service and resource access, which revolutionized the computing service market. these authors consider that the flexibility and borderless resources provided by cloud technology motivated manufacturers to take advantage of the cloud application service in an effort to improve and innovate their manufacturing process. the cloud application service provided manufacturers with cloud-based software application, web-based management dashboard, and cloud-based collaboration, which bring the manufacturing process, management, and monitoring to the cloud, hence the birth of cloud manufacturing (ooi et al., 2018) . compared with cloud computing systems, one of the biggest challenges cloud manufacturing faces involves numerous types of physical resources, e.g., machine tools and robots . according to yu et al. (2015) , cloud manufacturing may either apply or not apply the cps 0 s cyber architecture. in other words, cyber systems in cloud manufacturing may choose to be networked or not, and more significantly, cloud manufacturing tries to imitate the paradigm of cloud computing in which design, manufacturing, and other resources are encapsulated as services (yu et al., 2015) . mobile cps has emerged with advances in cloud computing and wireless sensing technologies (chen, 2017) . liu et al. (2017) consider that a cps for manufacturing is not a manufacturing cloud if it does not use virtualization technique in cloud computing and service-oriented architecture in service computing. on the other hand, these authors note that a manufacturing cloud is not a cps if it does not have components for direct interactions with machine tools and other physical devices. liu et al. (2017) point out that it is necessary to integrate cloud manufacturing and cps for providing manufacturing services, which can directly operate and monitor machine tools in a manufacturing cloud. as a result, said authors indicate that a new paradigm of a cyber physical manufacturing cloud (cpmc) is created, so that a cpmc is a type of manufacturing cloud where machining tools can be directly monitored and operated over the internet from clouds . this section discusses the main emerging risks linked with advanced manufacturing processes and technologies. first, a general framework on emerging systemic risks related to new technologies is shown. next, this framework is expanded specifically to the osh field. third, some of the most important cross-cutting manufacturing technologies have been selected in order to develop them in greater detail. these manufacturing technologies are: automation, hmis, and icts. these manufacturing technologies are related to both occupational accidents and major accidents. therefore, the related emerging risks have a broad nature. in the report on emerging systemic risks developed by the oecd (2003), five categories of such risks are addressed: natural disasters, industrial accidents, infectious diseases, terrorism, and food safety. according to this report, three aspects of emerging technologies will influence risk: connectedness, the speed and pervasiveness of technological change, and the fundamental changes in the landscape they might induce. the analysis and main conclusions from oecd (2003) eu-osha took the first steps in the field of ners with the publication of four specific reports on emerging physical risks (flaspöler et al., 2005) , emerging biological risks (brun et al., 2007a) , emerging psychosocial risks (brun et al., 2007b) , and emerging chemical risks (brun et al., 2009 ). the methodology used in these reports to identify ners was based on the delphi method, using the likert 5-point scale to classify such risks. for each risk identified, the mean values (mvs) and the standard deviations were calculated. in this way, each risk was classified as "risk strongly agreed as emerging," "risk agreed as emerging," "undecided," "there is agreement that the risk is not emerging," or "there is strong agreement that the risk is not emerging." the top 10 ners of each of these reports are shown in tables 2.6e2.9. for this, the mvs have been taken into account. these ners are classified as "risks strongly agreed as emerging" and "risks agreed as emerging." brocal and sebastián (2015b) analyzed the ners included in the four specific reports on emerging physical risks (flaspöler et al., 2005) , emerging biological risks (brun et al., 2007a) , emerging psychosocial risks (brun et al., 2007b) , and emerging chemical risks (brun et al., 2009) . these authors considered only the ners classified as "risk strongly agreed as emerging" and "risk agreed as emerging." each risk classified as "undecided," "there is agreement that the risk is not emerging," and "there is strong agreement that the risk is not emerging," cannot be considered as ner. among the results obtained, brocal and sebastián (2015b) identified a set of technological aspects (table 2 .10) and organizational aspects (table 2 .11) linked to advanced manufacturing processes. in the prospective study on ner associated with new technologies in 2020 (ellwood et al., 2014) , the key technologies that may be introduced in green jobs by 2020, which may lead to ners in the workplace, are the following: wind energy (industrial scale); green construction technologies (buildings); bioenergy and the energy applications of biotechnology; waste processing; green transport; green manufacturing technologies and processes, including robotics and automation; electricity transmission, distribution, and storage, and domestic and small-scale renewable energy; and nanotechnologies and nanomaterials. it is expected that by 2020 approximately 20% of all goods manufactured around the world will be based to some extent on the use of nanotechnology (ilo, 2010). remote operation in environmentally sensitive areas. emerging risks related to interaction between natural hazards and technologies at the community level. adapted from cwa 16649:2013. poor awareness of thermal risks among low-status worker groups exposed to unfavorable thermal conditions (e.g., migrant workers in agriculture and construction areas working overtime in hot/cold areas such as greenhouses/cold stores). · high density of animals in confined spaces in contact with humans leading to increasing zoonosis cases (diseases jumping the species barrier from animals to humans). · high population density and increase in business trips, tourism, and immigration helping zoonoses and other infectious diseases to spread quickly worldwide. groups particularly at risk of contamination: staff involved in producing, processing and transporting livestock; airport staff and air crews; staff involved in border controls and policing; staff in health care sector; public transport; and staff in public services. the risk is often underestimated, which leads to a lack of preventive measures. 2 poor or difficult assessment of biological risks. 4.06 3 general increased use of antibiotics for human health care and for animal breeding in the food industry leading to the appearance of drug-resistant pathogens (e.g., methicillin-resistant staphylococcus aureus (mrsa), tubercule bacillius). health effects observed: increase in staff infected with mrsa in western hospitals; increasing antibiotic resistance of livestock farmers and in the population in general. 4 lack of information on biological risks in different workplaces (e.g., office workplaces, agriculture). poor maintenance of air-conditioning (whose use is increasing) and water systems (e.g., legionella, aspergillosis in hospitals). new knowledge about the presence of legionella will help the correct diagnosis of symptoms so far wrongly attributed to other diseases like flu. 3.92 6 inadequate training, poor knowledge of osh, or even poor basic awareness of risks of local authorities' staff (e.g., sewage, excavations, waste collection, etc.). 7 biohazards in waste treatment plants (e.g., selective sorting, manufacture of compost) leading to allergies, infectious diseases (bacteria, viruses), toxinic diseases (endotoxins, mycotoxins), and cancers (oncogenes). especially in composting facilities where there is a wide variety of microorganisms present at the different stages of the composting process, the risks are not completely identified yet. 8 bioaerosols and chemicals, the combined effects of which have been very little studied but lead to allergies. more knowledge will help identify the real multifactorial causes of symptoms for which monocausal explanations have been given so far. in the manufacturing sector, the following osh issues in particular need to be considered (this list is not comprehensive) (ellwood et al., 2014) : • new processes and materials leading to potential exposure to new (green) substances, including nanomaterials, or substances used or emitted (including dust) from new (green) manufacturing processes; • the extent of chemical use and the potential for exposure as manufacturing is distributed to smaller units as a result of rapid manufacturing techniques (3d printing); • the difficulty in monitoring osh in distributed manufacturing taking place in smaller businesses; • the increasing use of lasers in techniques such as rapid manufacturing; the potential physical risks from human-robot interaction as robots gain increasing autonomy and become freeroaming; • potential psychosocial risks: (a) the high cognitive load of the hmi, "lean" production and justin-time principles all have the potential to contribute to job intensity and pressure and to result in psychosocial problems; (b) the potential effect of renewable energy, with its intermittent nature currently, on shift work in those companies that take interruptible supplies, resulting in more unpredictable working hours; • workers possibly resorting to human performance-enhancing technologies as they feel the need to keep up with coworkers, and maybe even with robots (this could also be a feature of other sectors); and • a focus on safety as opposed to health in competitive scenarios owing to the greater impact of accidents on productivity (this could also be a feature of other sectors). cross-cutting issues are inevitably more general than those concerning specific technologies, but they are important, often more so. in the field of manufacturing processes, the following cross-cutting technologies can be specially considered (based on the study by ellwood et al., (2014) ): • rapid innovation: it may lead to a variety of osh risks, with new materials and new processes, and little time to learn how to use them safely; endotoxins: high concentrations in various industrial settings (e.g., in workplaces exposed to organic materials (straw, wood, cotton dust), waste treatment, poultry houses, swine confinement buildings) leading to asthma, loss of lung function, etc. 3.81 10 molds in indoor workplaces due to new construction methods and materials, due to the aim of saving energy and due to the lack of maintenance: exposure to fungal spores for office workers and especially workers involved in building restoration, leading to sensitization and allergies. 3.78 • new materials: they have the potential for major unexpected impacts on health and environment: nanomaterials, new insulating materials, new composites, smart materials, new organisms, biofuels, and by-products; • automation: it is most likely to be very positive for safety in the long term, but absolute reliability is essential; • human-machine and human-ict interfaces: they can give rise to complex risks (e.g., ergonomics and high cognitive load) and overreliance on ict. isocyanates leading to allergic reactions: exposure occurs not only at the production stage but also during further processing (e.g., thermal or chemical degradation of polyurethane, grinding and welding of products containing polyurethane, for example, in car repair shops). man-made mineral fibers (e.g., refractory ceramic fibers, carbon/graphite fibers, or composites): lack of knowledge on health effects of (new) fiber substitutes for asbestos, the use of which is increasing and for which exposure levels seem high enough for concern in certain areas. potential health effects: respiratory diseases, cancer. 10 construction industry (civil and industrial sector, including demolition, rebuilding, and renovation activities): exposure to dangerous substances (crystalline silica dust, asbestos, wood dust, diesel engine exhaust, welding fumes) leading to occupational cancers. the automation of manufacturing processes can produce emerging risks, linked both to the process and a whole (system), and to specific components, such as robots, hmis, and icts (brocal et al., 2018) . in this way, among the different manufacturing technologies that have been studied throughout this chapter, automation, hmis, and icts can be selected in order to expand them as possible sources of emerging risks. ellwood et al., (2014) indicate that in the field of manufacturing processes, such technologies can be considered as cross-cutting technologies. therefore, studying them can expand the overview of emerging risks. automation is the growing phenomenon of human labor being replaced by machinery and robotics (euromonitor international, 2013) . industrial automation is a vast and diverse discipline that encompasses processes, machinery, electronics, software, and information systems working together toward a common set of goals: increased production, improved quality, lower costs, and maximum flexibility (mehta and jaganmohan, 2014) . the reasons to automate manufacturing processes include increased quality and efficiency demands, as well as the presence of hazardous working conditions and the high cost of specialized manual laborers (botti et al., 2017) . granell et al. (2006) conducted a survey with the aim of discovering the perception of production managers and manufacturing engineers working in industry about concepts such as levels of automation and automation strategy, and to determine the current status of manufacturing and automation issues. the sample was derived from the association of swedish engineering industries. the factors and results when making decisions about automation are shown in table 2 .12. in the expert forecast on emerging physical risks related to osh published by eu-osha (flaspöler et al., 2005) , these emerging risks related to automation were identified: "automation leading to an increase in occupational accidents in maintenance and production tasks" and "automation leading to poor job content (repetitive and monotonous work) and consequently to musculoskeletal disorders (msds) and stress." thus, the two ners above can be classified into two groups, in light of their consequences (brocal et al., 2018) : a. accident risks: flaspöler et al. (2010) state that increased automation involves an increased risk of accidents from human errors, and they usually affect users, butdespecially in the case of high-risk industriesdhave the potential for serious consequences beyond the operator to include fellow workers, the community at large, and the environment. with this increased automation, operator tasks have been reduced from directly controlling the process to monitoring the control systems and controlling them (chidambaram, 2016) . this drop in hands-on knowledge and responsibility can lead to a lack of sufficient understanding of the underlying process, which can in turn lead to an accident due to someone doing something inappropriate or not knowing what to do when something goes wrong (stacey et al., 2017) . new technologies, when introduced poorly, entail the risk of increasing operators' mental workload and also of reducing their degree of control over the task, so that if the measures taken are not appropriate increases the risk of negative health effects such as stress and is likely to result in overreliance on automated safety systems (flaspöler et al., 2010) . b. psychosocial and musculoskeletal risks: these risks are intimately related, and can be studied together or independently, depending on prevention targets. from the joint perspective on new and emerging risks, flaspöler et al. (2010) states that in automated processes, psychosocial and musculoskeletal problems are caused by reduced physical activity, more static postures, and higher mental workload (e.g., when monitoring and controlling); less privacy at work (as technology allows closer and more intrusive supervision); and more decision-making problems. from the latest eu-osha european survey of enterprises on new and emerging risks (esener 2) 2 conducted in 2014 (eu-osha, 2014), and from the analysis of the survey performed by irastorza et al. (2016) , one can see that the risk of accidents with machines or hand tools is the most frequently reported risk factor in mining and quarrying (86% of establishments in the sector in the eu-28); water supply, sewerage, waste management and remediation activities (83%); construction (82%); electricity, gas, steam, and air conditioning supply (81%); agriculture, forestry and fishing (78%); and manufacturing (77%). in the esener 2 analysis conducted by irastorza et al. (2016) , the measures to prevent psychosocial risks are generally less likely to be implemented in construction and manufacturing, as well as in agriculture, forestry, and fishing. the two most frequently reported psychosocial risk factors across all sectors are: "having to deal with difficult customers, patients, pupils, etc." and "time pressure." regarding musculoskeletal problems, irastorza et al. (2016) synthesize that in the manufacturing sector, after risk of "accidents with machines or hand tools 77%," the most frequent risk factor was "repetitive hand or arm movements (58%)." stacey et al. (2017) indicate that use of computers and automated systems at work leads to immobile body postures and physical inactivity at work. physical inactivity is associated with increased health risks such as coronary heart disease, being overweight and obesity, certain types of cancers, and psychological disorders such as depression and anxiety (stacey et al., 2017) . the basic requirements for system control, including networks and hmis, are introduced together with basic principles of safety and guarding for automation systems (wilson, 2015) . the hmi governs the flow of information from the machine to the user (in terms of displays, warning sounds, etc.) and from the user to the machine (in terms of input or control devices such as keyboards, switches, levers, etc.) (flaspöler et al., 2010) . the use of ict is radically changing the collective experience of work, from a group of people who interact physically to a dispersed community of contacts, whose interaction may be more ad hoc (eurofound, 2016) . as messenger and lutz (2015) note, forms of ict, like smartphones and tablets, promise historic changes in the way we work, as they provide new possibilities for working anytime and anywhere. this new spatial independence changes the role of technology in the work environment, bringing both new opportunities and new challenges (messenger and lutz, 2015) . increasing complexity and increasing use of icts in automated manufacturing has led to hmi issues (ellwood et al., 2014) . ict, including ict-enabled technologies (ict-ets) such as robotics and ai, are likely to have major impacts on the nature and location of work over the next 10 years (stacey et al., 2017) . how humans will react to the continuous high cognitive load of increasingly complex hmis is still unknown (ellwood et al., 2014) . workers are more likely to make mistakes due to a poorly designed hmi (stacey et al., 2017) . there is also evidence that over the next decade there are likely to be significant and accelerating changes in relation to ict-ets, which will considerably change the nature of work across europe and affect most people in some way (stacey et al., 2017) . the expert forecast on emerging physical risks related to osh published by the eu-osha (flaspöler et al., 2005) states that a poor design of the interface may result in increased mental and emotional demands on the operator. hence a potential increase in the incidence of stress, human errors, and accidents. flaspöler et al. (2010) published a report that aimed to follow up the results obtained in this expert forecast. this report further researched hmi as an emerging risk, exploring whether complexity of hmis leads to safety and health risks such as increased mental and emotional strain for users. thus, the conclusions drawn in the report that merit mention include: • the design of hmi has important consequences for health and safety at work because of the growing potential for accidents and ill poor health for machine operators; • deficiencies in the hmi present two different risks: (a) psychosocial risk (stress can result from cognitive overload or underload); and (b) accident risk (occupational accidents and major accidents can result from operating errors); • the majority of machine users work in smes, mostly in manufacturing. according to koshti and joshi (2007) , many will recognize the most typical hmi "issues," as shown in table 2 .13. irgc (2005) puts forward an integrated analytic framework for risk governance that provides guidance for the development of comprehensive assessment and management strategies to cope with risks, in particular at the global level. the council of the society for risk analysis (sra) has developed a glossary about key generic concepts within the field of risk analysis (sra, 2015) . the glossary terms are divided into three categories: (1) terminology on basic concepts; (2) terminology on related concepts, methods, procedures; and (3) terminology on risk management actions. the definition of risk governance is one of these key terms. its definition is the following: risk governance as the application of governance principles to the identification, assessment, management, and communication of risk. governance refers to the actions, processes, traditions, and institutions by which authority is exercised and decisions are taken and implemented. risk governance includes the totality of actors, rules, conventions, processes, and mechanisms concerned with how relevant risk information is collected, analyzed, and communicated and management decisions are taken. irgc risk governance framework (irgc, 2005) is illustrated in fig. 2 .4. this framework is divided into three main phases: preevaluation, appraisal, and management. a fourth phase that includes the characterization and evaluation of risk is added. irgc (2005) places this phase between the appraisal and management phases and, depending on whether those charged with the assessment or those responsible for management are better equipped to perform the associated tasks, it can be assigned to either of themdthus concluding the appraisal phase or marking the start of the management phase. the risk process has communication as a companion to all phases of addressing and handling risk and is itself of a cyclical nature (irgc, 2005) . the user must constantly switch between screens to perform the steps required by a single procedure. display confusion this is the reverse problem, when too much information is presented on the same screen, with no obvious purpose or structure. inconsistent controls similar controllable objects that react differently depending on which display they are located, or conversely, many dissimilar controls all related to the same task. additional procedural steps unrelated to the equipment being controlled, but required by internal functions of the control system. this happens frequently when users are forced through several levels of submenus in order to reach the desired action. although computer performance keeps improving, software complexity increases at the same rate. the problem of slow response to user actions will usually be inferior during a plant upset, precisely when fast response is the most important. this happens when operators are deluged with system messages and alarms. the determination of the cause of equipment "trip" becomes a painstaking investigation through interminable alarm logs. this is perhaps the area where recent systems have improved the most. however, application programmers still require significant time investment to modify or expand existing systems. the risk science and safety literature and leaders in the study of human behavior agree that in many organizations, there is not enough effective communication (irgc, 2011) . however, the clear sequence of phases and steps offered by this process is primarily a logical and functional one and will not always correspond to reality (irgc, 2005) . irgc risk governance framework (irgc, 2005) is a worthwhile basis for diagnosing governance deficits, and is broad and flexible enough to be adapted to diverse governance issues and contexts. thereby, various organizations use this framework to structure their thinking and inspire guidelines, roadmaps, or models, for example (irgc, 2017) since the publication of the irgc framework, other guidance documents or frameworks have been published, such as iso 31000:2009, risk management e principles and guidelines (irgc, 2017) . iso 31000:2009 standard provides principles and generic guidelines on risk management, and it can be used by any public, private, or community enterprise, association, group, or individual. therefore, iso 31000:2009 is not specific to any industry or sector. it can be applied throughout the life of an organization, and to a wide range of activities, including strategies and decisions, operations, processes, functions, projects, products, services, and assets. likewise, iso 31000:2009 can be applied to any type of risk, whatever its nature, whether having positive or negative consequences (iso, 2009a) . iso 31000:2009 standard defines risk management as coordinated activities to direct and control an organization with regard to risk. this process includes the activities shown in fig. 2 .5. sra (2015) defines risk management as those activities to handle risk such as prevention, mitigation, adaptation, or sharing. it often includes trade-offs between costs and benefits of risk reduction and choice of a level of tolerable risk. among these activities ( fig. 2 .5), the risk assessment process can be considered key to successful risk management. iso 31000:2009 standard defines risk assessment as the overall process of risk identification, risk analysis, and risk evaluation. sra (2015) defines risk assessment as systematic process to comprehend the nature of risk, express and evaluate risk, with the available knowledge. the perspectives of the glossaries included in iso 31000: 2009 and sra (2015) should be considered different. in this regard, sra (2015) indicates that its glossary is unique in its approach compared to existing risk analysiserelated glossaries (including the iso 31000 on risk management terminology), with its incorporation of different perspectives and its between overall qualitative concepts and their measurements. in the case of emerging risks, irgc (2011) focuses on these risks in technology and industry. such focus is on how to overcome the major obstacles that commonly prevent organizations from improving their emerging risk management. for this, irgc (2011) presents 11 themes for the three categories of risk a, b, and c described in table 2 .2. each theme derives from one obstacle and is described in such a way as to provide clarity and operational significance for managers who have the task of identifying, assessing, evaluating, prioritizing, and managing the early phases of development of an emerging issue. these 11 themes interact considerably, but for conceptual clarity, irgc (2011) has grouped them according to the relevant dimensions of risk governance within which they fit best. these four dimensions of risk governance (from the broad, foundational level to the more specific) and the 11 themes are shown in fig. 2 .6 and are summarized in table 2 .14. the irgc guidelines for emerging risk governance (irgc, 2015a) describe key steps and associated methodologies for early identification and management of emerging risks. the process is described schematically in fig. 2 .7, and covers an overarching, flexible, and adaptable set of guidelines designed to deal with complex, evolving, and uncertain environments (irgc, 2015b). irgc (2015b) reviews other existing emerging risk governance frameworks. these emerging risk governance frameworks are the following: european union agency for network and information security, the european food safety authority, the swiss reinsurance company (sonar system), the cwa 16649:2013, and the dutch framework for identifying and managing emerging risks involved in the use of chemicals. the cwa 16649:2013 is one of the main results of integ-risk. this project has summarized its results in a set of major deliverables, labeled, at the end of the project by the developers, as the "big 7" of integ-risk. they are (jovanovi c and balo s, 2013): (1) integ-risk catalogue of emerging risks e riskears system; (2) integ-risk framework for emerging risk management; (3) the library of cwa 16649:2013 gives guidance on steps for applying/implementing the proposed ermf in industrial organizations. this ermf is heavily influenced by the irgc (2005) risk governance framework and the iso 31000:2009 risk management process. the main difference is that some issues that are included in other steps in irgc (2005) and/or iso 31000:2009 have been explicitly addressed as a separate step in the ermf, and a particular focus on capturing the earliest signs of an emerging risk (cwa 16649:2013) . the 10 steps of the ermf are illustrated in fig. 2 .8. risk characterization allows decision makers to distinguish scientific facts from policy orientations when analyzing risk assessment results (cwa 16649:2013) . the most controversial phase of handling risk, risk characterization and evaluation, aims at judging a risk's acceptability and/or tolerability (irgc, 2005) . in the report on emerging systemic risks developed by the irgc (2010b), it is indicated that some emerging risks do not prove to be as significant as originally feared, but others may prove to be worse than expected, with a high potential for major losses. in this report it is added that typically, the future consequences of emerging risks cannot be defined in monetary terms, at least not to any satisfactory degree of precision, so the conventional approaches to projecting loss size, relative frequencies, or probability distributions over time or severity of consequences are ineffective. indeed, it is often difficult to establish causality between the source of the emerging risk and its consequences using conventional technical or scientific data (irgc, 2010b). brocal and sebastián (2015a) have developed a new risk model whose objective is to characterize the ner. this characterization is based on the so-called risk model. this model describes a risk as a structure consisting of five components, being: the source of risk, causes, events, consequences, and the likelihood. this risk model is compatible with the risk characterization defined by sra (2005) . this definition is the following: risk characterization as a qualitative and/or quantitative picture of the risk; i.e., a structured statement of risk usually containing the elements: risk sources, causes, events, consequences, uncertainty representations/measurements (for example, probability distributions for different categories of consequencesdcasualties, environmental damage, economic loss, etc.) and the knowledge that the judgments are based on. irgc (2011) concludes that managers need to be open to the possibility of adverse future events and to plan for them, using the best information they can obtain. investments in increased vigilance, and the skills needed to identify and characterize emerging risks, could be highly beneficial in avoiding disasters (irgc, 2011) . from the work done by brocal and sebastián (2015a) , brocal et al. (2017) have developed a theoretical framework for the modeling of the ner that allows its monitoring through the tlc, especially in industrial processes. this new framework allows characterizing and differentiating the new qualities from the increasing qualities associated to risk. with this theoretical framework, brocal et al. (2018) have designed a technique that is compatible with standards iso 31000:2009 31000: (iso, 2009a and iso/iec 31010:2009 (iso, 2009b and permits the ners generated by a system and its components to be identified and characterized. this technique is called the technique to identify and characterize ners (tichner) and is one of the main results of the spanish research project a2nersys ("analysis and assessment of technological requirements for the design of a new and emerging risks standardized management system"). tichner can be applied at any stage of the lifecycle of a manufacturing process and it may also be used in combination with other risk identification techniques (brocal et al., 2018) . as scientific understanding of emerging risks may be changingdsometimes quite rapidlydthe challenge for risk managers in government and industry can be serious, and it is easy to criticize managers after a risk has emerged, regardless of how competent their ex ante decisions may have been, given the information available (irgc, 2010b). with this chapter, a general framework of the emerging risks linked with advanced manufacturing processes and technologies has been shown. these processes and technologies are part of the fourth industrial revolution, called industry 4.0, whose scientific interest is clearly increasing during the last years. the main aspects of this general framework are summarized herein along with their most relevant conclusions. from a global perspective, several organizations have forecasted emerging technologies and reported on their forecasts, such as "disruptive technologies" (mckinsey global institute), "10 breakthrough technologies" (mit), "next 5 in 5" (ibm), and "top 10 strategic technologies" (gartner group) . from a specific perspective, the advanced manufacturing processes can be classified into five categories, namely (nassehi et al., 2011) : joining, dividing, subtractive, transformative, and additive technologies. zhong et al. (2017a) consider that the three major advanced manufacturing technologies are the following: intelligent manufacturing, iot-enabled manufacturing, and cloud manufacturing. the general framework of the emerging risks linked with advanced manufacturing processes and technologies has been shown using the cwa 16649:2013 as main reference. next, this framework is expanded specifically to occupational field. in this field, the main results of reports by eu-osha have been shown. among these results, three emerging manufacturing technologies linked to emerging risks have been developed: automation, hmis, and icts. irgc (2005) puts forward an integrated analytic framework for risk governance, in particular at the global level. complementarily, the irgc (2011) focuses on these risks in technology and industry. since the publication of the irgc framework, other guidance documents or frameworks have been published, such as iso 31000:2009 standard. this standard provides principles and generic guidelines on risk management. cwa 16649:2013 gives guidance on steps for applying/implementing the proposed emerging risk management framework (ermf) in industrial organizations. this ermf is heavily influenced by the irgc (2005) and iso 31000:2009 frameworks. the irgc framework is divided into four main phases: preevaluation, appraisal, management and characterization, and evaluation of risk. risk characterization allows decision makers to distinguish scientific facts from policy orientations when analyzing risk assessment results (cwa 16649:2013) . from the work done by brocal and sebastián (2015a) , brocal et al. (2017) have developed a theoretical framework that allows characterizing and differentiating the new qualities from the increasing qualities associated to risk. with this theoretical framework, brocal et al. (2018) have designed a technique called tichner that permits the ners generated by a manufacturing process to be identified and characterized. the study of the emerging risks linked with advanced manufacturing processes and technologies requires risk governance approaches that consider the systemic and occupational nature of the risk. in this regard, the relationship between the prevention of the occupational accident and the major accident is especially important. for this, these approaches need to continue the path of improvement and development considering the scientific and technological aspects of the emerging risk. sistemas de gestión de la seguridad y salud en el trabajo (management systems the safety and health at work). ohsas 18001 nueva norma iso 45001 emerging technologiesdbeyond the chasm: assessing technological forecasting and its implication for innovation management in korea on how to define, understand and describe risk the risk conceptdhistorical and recent development trends. reliability engineering and system safety 99 future trends in human work area design for cyber-physical production systems introduction to cloud manufacturing integrating ergonomics and lean manufacturing principles in a hybrid assembly line incertidumbres y retos ante los riesgos laborales nuevos y emergentes [uncertainties and challenges when facing new and emerging occupational risks analysis and modeling of new and emerging occupational risks in the context of advanced manufacturing processes identification and analysis of advanced manufacturing processes susceptible of generating new and emerging occupational risks theoretical framework for the new and emerging occupational risk modeling and its monitoring through technology lifecycle of industrial processes technique to identify and characterize new and emerging risks: a new tool for application in manufacturing processes expert forecast on emerging biological risks related to occupational safety and health expert forecast on emerging psychosocial risks related to occupational safety and health expert forecast on emerging chemical risks related to occupational safety and health. euosha (european agency for safety and health at work) integrated and intelligent manufacturing: perspectives and enablers perspectives on human factors in a shifting operational environment an approach to cyber-physical vulnerability assessment for intelligent manufacturing systems deutsches institut für normung (din), 2015. industry 4.0: new iso strategic advisory group from model-based strategies to intelligent control systems intelligent manufacturing: a new paradigm green jobs and occupational safety and health: foresight on new and emerging risks associated with new technologies by 2020. eu-osha (european agency for safety and health at work) the evolution and future of manufacturing: a review european survey of enterprises on new and emerging risks (esener) [interactive survey european risk observatory a review on the future of work: robotics. discussion paper. eu-osha. bilbao: eu-osha (european agency for safety and health at work) second european survey of enterprises on new and emerging risks (esener) [interactive survey sixth european working conditions survey (ewcs) e overview report. publications office of the european union euromonitor international, 2013. the impact of automation and robotics on the global labour market industrial revolution brings industry back to europe. press release, brussels managing emerging technology-related risks emerging risk e conceptual definition and a relation to black swan type of events. reliability engineering and system safety 144 expert forecast on emerging physical risks related to occupational safety and health. eu-osha (european agency for safety and health at work) the human machine interface as an emerging risk gartner identifies the top 10 strategic technology trends for controlling levels of automation e a model for identifying manufacturing parameters smart manufacturing for the future statistical process monitoring for iot-enabled cybermanufacturing: opportunities and challenges monitoring new and emerging risks. osh. wiki. eu-osha (european agency for safety and health at work) risk management d risk assessment techniques. iso/iec 31010:2009, geneva. international labour organization (ilo), 2010. emerging risks and new patterns of prevention in a changing world of work white paper on risk governance. towards an integrative approach. irgc, geneva. available at: www.irgc.org. international risk governance council (irgc), 2010a. the emergence of risks. contributing factors. irgc, geneva. available at: www.irgc.org. international risk governance council (irgc), 2010b. emerging risks sources, drivers and governance issues. irgc, geneva. available at: www.irgc.org. international risk governance council (irgc), 2011. improving the management of emerging risks. irgc, geneva. available at: www.irgc.org. international risk governance council (irgc), 2015a. guidelines for emerging risk governance. international risk governance council (irgc), lausanne. available at: www.irgc.org. international risk governance council (irgc), 2015b. guidelines for emerging risk governance. appendix. international risk governance council (irgc) european agency for safety and health at work (eu-osha) esener-2) overview report: managing safety and health at work. european agency for safety and health at work integ-risk project: concept and first results recommendations for implementing the strategic iniciative industrie 4.0. acatech e national academy of science and engineering manufacturing engineering and technology chapter 2-open source semantic web infrastructure for managing iot resources in the cloud design of human machine interface for plc based automation system methods and materials for smart manufacturing: additive manufacturing, internet of things, flexible sensors and soft robotics. manufacturing letters. available online cyber-physical manufacturing cloud: architecture, virtualization, communication, and testbed mckinsey global institute chapter 1: industrial automation. industrial process automation systems three generations of telework industrial big data as a result of iot adoption in manufacturing towards lean production in industry 4.0. procedia engineering 182, 466e473 using formal methods to model hybrid manufacturing processes towards industry 4.0 utilizing data-mining techniques: a case study on quality improvement. procedia cirp 63, 167e172 cloud computing in manufacturing: the next industrial revolution in malaysia? expert systems with applications 93 oecd reviews of risk management policies report to the president on ensuring american leadership in advanced manufacturing fundamental theories and key technologies for smart and optimal manufacturing in the process industry. engineering 3, 154e160 society for risk analysis (sra), 2015. sra glossary. sra key trends and drivers of change in information and communication technologies and work location. foresight on new and emerging risks in osh. working report. european agency for safety and health at work (eu-osha) manufacturing process selection handbook: from design to manufacture strategic r&d opportunities for 21st century, cyber-physical systems, connecting computer and information systems with the physical world cciot-cmfg: cloud computing and internet of thingsbased cloud manufacturing service system the internet of things program: the finnish perspective a review of essential standards and patent landscapes for the internet of things: a key enabler for industry 4.0. advanced engineering informatics 33 ubiquitous manufacturing system based on cloud: a robotics application. robotics and computer-integrated manufacturing 45, 116e125 chapter 3-automation system components research and application of the management and control platform oriented the cloud manufacturing services from cloud computing to cloud manufacturing computer-integrated manufacturing, cyber-physical systems and cloud manufacturing e concepts and relationships. manufacturing letters 6, 5e9 internet of things (iot) enabled smart manufacturing for smes an iot-enabled real-time machine status monitoring approach for cloud manufacturing a review of hybrid manufacturing processes e state of the art and future perspectives towards intelligent manufacturing, semantic modelling for the steel industry. ifac-papers online 49 (20), 220e225 key: cord-284424-6gljl7n5 authors: brown, eric e.; kumar, sanjeev; rajji, tarek k.; pollock, bruce g.; mulsant, benoit h. title: anticipating and mitigating the impact of covid-19 pandemic on alzheimer's disease and related dementias date: 2020-04-18 journal: am j geriatr psychiatry doi: 10.1016/j.jagp.2020.04.010 sha: doc_id: 284424 cord_uid: 6gljl7n5 the covid-19 pandemic is causing global morbidity and mortality, straining health systems, and disrupting society, putting individuals with alzheimer's disease and related dementias (adrd) at risk of significant harm. in this special article, we examine the current and expected impact of the pandemic on individuals with adrd. we discuss and propose mitigation strategies for: the risk of covid-19 infection and its associated morbidity and mortality for individuals with adrd; the impact of covid-19 on the diagnosis and clinical management of adrd; consequences of societal responses to covid-19 in different adrd care settings; the effect of covid-19 on caregivers and physicians of individuals with adrd; mental hygiene, trauma, and stigma in the time of covid-19; and the potential impact of covid-19 on adrd research. amid considerable uncertainty, we may be able to prevent or reduce the harm of the covid-19 pandemic and its consequences for individuals with adrd and their caregivers. a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was detected in late 2019. it has been identified as the cause of covid-19, a respiratory illness of varying severity. on , with covid-19 affecting 113 countries or territories, the world health organization (who) declared covid-19 to be a pandemic of -alarming levels of spread and severity‖. 1 while the situation is rapidly evolving, this pandemic has already disrupted the world in three major ways due its direct health impact, its impact on the health care system, and the social and economic consequences of the response to the pandemic. during normal times, individuals with alzheimer's disease and related dementias (adrd) are among the most vulnerable persons in society, depending on family or professional caregivers for their day to day survival. this pandemic exacerbates further their vulnerability, due to both the morbidity and mortality from covid-19 and the indirect effects of the pandemic on the social supports and the health care system on which they depend. an understanding and appreciation of the current and potential impact of the pandemic on individuals with adrd can help in their care. these considerations can also influence the decisions of caregivers, health professionals, institutions, and policymakers. thus, in the context of a rapidly evolving situation, this special article discusses and proposes mitigation strategies for six major issues: (1) why individuals with adrd are at high risk for covid-19 and its associated morbidity and mortality; (2) how covid-19 will impact the diagnosis and clinical several features of adrd may increase the risk of contracting covid-19. some individuals with adrd may be unable to follow the recommendations from public health authorities to reduce the transmission of covid-19: hand hygiene; covering one's mouth and nose when coughing; monitoring for and reporting symptoms of covid-19; maintaining physical distance from others; and self-isolating by remaining alone at home. 2 some with mci or milder dementias may be unwilling or unable to comply due to apathy or depression. those with more severe dementias will not be able to understand, appreciate, or remember most of these recommendations due to the severity of their short-term memory loss and overall cognitive impairment. finally, behavioural and psychological symptoms of dementia (bpsd), such as motor agitation, intrusiveness, or wandering, may undermine efforts to maintain isolation. despite considerable uncertainty and variability in estimates of covid-19 outcomes, age and comorbid medical conditions have consistently been the most significant factors associated with a poor prognosis including hospitalization and death. [2] [3] [4] age is the best established risk factor both for adrd and for symptomatic and severe illness and mortality from this is illustrated by the situation in italy where over a third of confirmed cases and approximately 9 of 10 deaths are occurring in individuals 70 years and older. 3 precise estimates of outcomes will only be known in time, but they seem to depend on local circumstances such as demographics and resources, in particular the ability of the health care system to cope. beyond age, increased morbidity and mortality is expected in patients with adrd due to the association of adrd with physical comorbidities and other features of adrd. individuals with dementia are more likely to have cardiovascular disease, diabetes and pneumonia compared to individuals of the same age without dementia. 5 these conditions have been associated with poorer outcomes including death, in individuals with covid-19. 6 among 1099 cases of laboratory-confirmed covid-19 in china, pneumonia occurred in over 90% of cases. 7 absent the pandemic, mortality from pneumonia has been reported to be twice higher in individuals with dementia compared to those without dementia. 8 a rapid increase in the number of covid-19 cases is adversely affecting health systems and is causing a shortage of hospital beds and a strain on health care providers. 9 increased demand on health systems may also result in the diversion of resources away from patients with chronic diseases, including those with adrd. the suspension of elective and non-urgent care is occurring in many affected areas. the availability of urgent and intensive care resources becomes compromised when the prevalence of severe cases of covid-19 exceeds local resources. 10 individual with adrd may suffer disproportionally from constraints in resources due to the chronic nature of their illness and their specific care needs. the workup and diagnosis of adrd is vulnerable to disruption in several ways. as primary care providers and specialists are being redeployed to address medical emergencies, these physicians are not available to work up neurocognitive disorders. attending a clinic for one or more appointments and visits for blood work and neuroimaging expose frail individuals to risks that may exceed the benefits of timely evaluation and regular monitoring. in many jurisdictions, outpatient physicians have transitioned to providing virtual care, completing assessments and follow-ups by telephone or videoconferencing. these modalities may not be adequate to perform the physical and neurological examinations or some of the cognitive tests required when diagnosing mci or dementia or monitoring their progression. in some cases, it may be possible to provide an initial visit in person and follow-ups remotely. otherwise, diagnosis and care may have to be deferred or limited. the use of anticholinesterase inhibitors and memantine is common in patients with adrd. medications frequently used for the treatment of bpsd include antipsychotic, antidepressant, antiepileptic and other psychotropic medications. 11 patients who are stable on medications may be impacted if the supply of their medication is disrupted due to missed visits, disruption of pharmacy pickup or delivery, or supply chain problems. initiating a new medication during the pandemic may be associated with higher risk, particularly if components of routine screening are disrupted such as in-person clinical assessments, blood work, or electrocardiogram, or the ability to follow up on adverse events in a timely manner. rare but serious adverse events associated with mediations used in the treatment of adrd and bpsd-e.g., bradycardia, gastrointestinal symptoms, falls, fractures, cardiovascular events, or strokes-carry higher morbidity and mortality if access to urgent care is impeded. in the context of social isolation, individuals with adrd who rely on family or health professionals for reminders or assistance with taking their medications are at risk for sudden discontinuation of medications. the risk-benefit ratio of some medications in dementia may shift towards harm if adequate prescribing and monitoring is not possible. common non-pharmacologic interventions for adrd in general, and bpsd in particular, involve social and physical contact such as social groups, exercise groups, and pet therapy. a limitation on resources and a need for physical distancing will not merely suspend these interventions, it will also result in increased isolation, a lack of physical exercise, decreased social engagement, and a suspension of purposeful activity. while confined at home, many people are now using technology to socialize and even exercise in group; individuals with adrd may not be able to use electronic tools and software (see below). resolution of the pandemic may be associated with an increased demand for care that was deferred. individuals with adrd and their family may also need assistance to resume care and address complications that arose from the lack of follow-up and monitoring or from the disruption in health-promoting interventions. the societal response to the pandemic includes travel restrictions and home confinement (-lockdowns‖). people are encouraged or required to isolate socially and not to leave their home. non-essential businesses are shut down. the extent and duration of these social distancing measures is uncertain, but it may be significant and prolonged in some jurisdictions. in this context, many resources upon which patients with adrd depend may become unavailable. depending on the severity of their illness, individuals with adrd live in various settings and rely on the availability and accessibility of various resources. in the context of the covid-19 pandemic, these settings may influence both the risk and impact of societal consequences of covid-19. most individuals with milder adrd have minimal care needs and live in the community where they may have established robust supports. however, their ability to live in the community may be threatened if it depends on services that are disrupted by the pandemic. delivery services such as meals on wheels may be delayed or disrupted due to increased demand, closures, or supply chain failures. family or professional caregivers (e.g., home health care workers) providing in-home support for activities of daily living can also become unavailable due to increased demand, workers' illness, or required isolation due to exposure; some workers may also be prevented by their employer from working in multiple settings. individuals with adrd living in the community may be particularly vulnerable if they are unable to seek help should they fall ill. covid-19 can be associated with a sudden deterioration of respiratory status and cardiac complications. 12 thus, symptomatic patients require frequent check-ins, while maintaining physical distance. many individuals with adrd who rely on personal savings and investments are also at risk of financial adversity due to the economic consequences of the pandemic. as younger people, they may need to access government programs for financial support. also, they are less likely to drive a personal vehicle, 13 instead relying on mass transit or transportation services that increase their exposure and risk of infection. they may benefit from assistance in identifying safe means of transportation, and in reducing their need to leave home by facilitating deliveries and deferring non-essential travel. those living alone in the community may also suffer from loneliness due to increased isolation and disruption of group activities. creative ideas to incorporate alternative social physical activities safely within the home are needed. whereas people are turning to technology to stay socially connected and access services including health care, some individuals with adrd may have trouble using technology due to cognitive impairment. they need instruction and support to use of these tools. as with any disaster, individuals with adrd and their family need to make contingency plans for the provision of essential services. families' and caregivers' awareness of the potential risks and disruptions described above for patients with adrd living in the community may help mitigate their impact. potential mitigation strategies include increased support in the form of more frequent contact by telephone or video chat, problem solving to maintain delivery and caregivers' services, planning for potential disruption, or temporarily moving to a location where the required supports can be provided. paradoxically, some families may be able to temporarily provide support at home because they are unable to work due to lockdowns or other restrictions. many of the issues faced by individuals with adrd in the community also apply to those living in group and assisted living environments. in some cases, the increased risk of infection associated with large groups may shift the risk-benefit ratio towards returning to one's home, if it is an option. however, many individuals with adrd require a supportive living environment because of a decreased level of functioning. in these settings, physical touching and toileting, crowding and shared rooms, and staff working in multiple settings may further increase the risk of covid-19 transmission. as discussed above, features of moderate to severe dementia such as severe memory impairment, and bpsd such as wandering, and agitation may thwart attempts to promote the actions recommended to reduce risk of transmission. in the other direction, imposition of increased hand hygiene, isolation, or restriction of visitors and activities may worsen cognitive symptoms or bpsd, increasing further care needs and risks. individuals with adrd living in long term care (ltc) (-nursing homes‖) face all the challenges of those in supportive living environments, and additional risks. their higher dependence on caregivers and health care providers eliminates the possibility of physical distancing. in these settings, personal protective equipment (ppe) may be rationed for confirmed or suspected cases or even become unavailable. 9 when covid-19 affects ltc homes, it can have a high attack rate and case fatality rate-for example, a case fatality rate of 33.7%-34 fatalities among 101 affected residents-has been reported in a washington state ltc. 14 this home also experienced a significant disruption to staffing, with 50 health care workers reported to be infected. 14 many staff of ltc work at multiple facilities or in private homes increasing the risk of transmission and disruption of care beyond an impacted facility. patients with adrd are hospitalized due to bpsd, comorbid illness, or inability to care for themselves and lack of access to supportive services or ltc. 15 hospitals present the same risks as ltc, with additional risks. hospital staff and physicians are highly vulnerable to contracting covid-19: of the first 48,548 confirmed cases in china (as of february 14, 2020), 1,716 (3.7%) were health care workers and professionals, 2 as were 2,026 (9.0%) of the first 22,512 confirmed cases in italy (as of march 15, 2020) . 3 the risk of covid-19 nosocomial infection is high due to high staff ratios and turnover, high patient volumes, crowded rooms, rapid inflow of detected and undetected cases of covid-19, and constrained supply of ppe. for reasons discussed above (age, comorbidities, behavioral and cognitive problems), individuals with adrd are among those at highest risk of nosocomial infection. in many communities affected by covid-19, hospitals get strained or overwhelmed. 9 hospitalized individuals with adrd may be particularly affected because they are less able to monitor their care or advocate for themselves. decreased nursing time has been shown to be associated with increased medical errors and adverse events in dementia. 16 the need for hospitalization implies a more severe illness. patients with severe bpsd may be at even higher risk for the behaviours discussed above that elevate transmission of infection. on a south korean psychiatric ward, 101 of 103 inpatients were infected and 7 died during a covid19 outbreak. 17 upon admission, hospitals need to evaluate the risk to individuals with adrd and the risk to others, in the context of potential, suspected, or confirmed cases of covid-19. planning for these situations is needed to clarify the ethical issues, local legal framework, and institutional policies that impact a decision with respect to the need for and use of locked seclusion, chemical and physical restraints, and end of life or palliative care in high risk situations. 18 regardless of choices made by patients with adrd or their family members, health care interventions taken for granted may have to be rationed in some jurisdictions affected by the pandemic (see below). in addition to the usual settings in which patients with adrd receive care, the pandemic will force some patients into unexpected and suboptimal environments with their own challenges. hospitals dealing with or preparing for a surge in covid-19 patients are discharging or diverting some patients with milder cases to hotels, convention centres, tents, and shipping containers. 19 while the physical needs of some medically stable patients with adrd may be met in these alternative settings, their cognitive and behavioral needs may not. during the pandemic, the perennial lack of availability of safe and adequate housing options for individuals with adrd, combined with an unprecedented strain on medical and social resources, could create its own crisis, leading to unprecedented levels of morbidity and mortality in this frail population. as most patients with adrd depend on caregivers, the impact of the pandemic on formal and informal caregivers need to be considered. in the best of time, the physical and mental health of some caregivers is precarious. 20 during this pandemic, some caregivers may become ill, they may need to isolate and be unavailable, or they may develop anxiety and other mental health issues. as discussed above, due to the sudden unavailability of established services, family members may have to become caregivers for a relative with adrd. grief and its consequences are likely in family caregivers who have lost a loved one 21 and in professional caregivers who have lost a patient. 22 all of the above will lead to exhaustion and burnout. as discussed above, specific aspects of caring for individuals with adrd are incompatible with physical distancing. inadequate or unavailable ppe or training related to its use sets the stage for viral transmission. responding to agitation and threats of violence typically requires urgent interventions that impede proper ppe use and increase further the risk of viral exposure. 23 many patients with adrd have -do not resuscitate‖ status, including advanced directives not to transfer them to an acute medical floor. as a result, in some settings, if these patients develop covid-19, neurologists, geriatricians, geriatric psychiatrists, or primary care providers will have to practice out of their scope and care, managing the symptoms and distress associated with pneumonia. however, this issue goes beyond covid-19 and pneumonia. as discussed above, during this pandemic, many patients with adrd who want to receive the full spectrum of care, including intensive care and intubation, may not be able to access optimal acute care for any medical issue, not just covid-19. all physicians may have to treat a variety of medical issues that would have otherwise been treated by specialists. preparatory discussions with patients and family members are needed to clarify the goals of care should these dire circumstances arise; they are particularly crucial if advance discussion of code status have not yet occurred or are not clearly documented. health care workers involved in adrd care are already exposed to suffering and deaths. 14 their stress and anxiety may be further increased by the current risk to their own safety. the number of cases, deaths and societal impact of covid-19 has already exceeded those observed during the 2003 epidemic of severe acute respiratory syndrome (sars). as following sars, we need to be prepared to address the serious and long-term mental effects of covid-19 on health care workers, including post-traumatic stress disorder and depression. 24 the covid-19 pandemic threatens to disrupt not the active care of individuals of adrd, but also the basic routines that promote their mental health. the pandemic and its social consequences may cause fear, anxiety, and anger. they will disrupt all forms of social interaction, possibly for a prolonged period of time. a lack of physical closeness may lead to increased loneliness and sadness. exercise is recommended generally and specifically for individuals with adrd, and confinement reduces access to exercise. sleep disturbances is common in adrd and sleep may be further disrupted due to anxiety and loss of social rhythms (-zeitgeists‖). 25 in turn, lack of activities and sleep loss and stimulation may cause delirium in individuals with adrd, contributing further to morbidity and mortality. 26 like health care workers, individuals with adrd may experience the loss of friends and family due to covid-19. these losses may lead to grief, bereavement, or frank depression, a common feature of adrd. 27 the pandemic and its consequences may also be experienced as a trauma, followed by post-traumatic stress disorder. in turn, stress and trauma can accelerate cognitive decline. 28 age, illness, depression, trauma, and dementia are all risk factors for suicide. 29 during the pandemic, individuals with adrd may be doubly stigmatized. stigma is already a pervasive issue in adrd. 30 individuals with, or at risk of exposure to, covid-19 have been stigmatized. 31 risks of stigma include ostracization and denial of health and social services, 31 which comes at time of potential scarcity of resources to be allocated. 32 rationing raises triage issues beyond some of the logistical issues discussed above. will older individuals with mild adrd be able to access intensive care beds? if they are already on a ventilator, will they be taken off to reallocate these scarce resources to younger patients? how will these decisions be made ethically? what will be the psychological impact of triage on health professionals? a response to these complex questions is beyond the scope of this paper. however, some ethicists have proposed a framework to address these issues in the unprecedented context of the covid-19 pandemic. 32 the discussion above has focused exclusively on the immediate risks and impact of the as per the declaration of helsinki, -concern for the interests of the subject must always prevail over the interest of science and society.‖ 36 therefore, all research activities such as observational studies in which participants are exposed a potentially lethal infection (e.g., through face-to-face contact with research staff) without the possibility of any direct benefit should be suspended unless they can be continued entirely remotely. 33 when participation in a study entails provision of essential medical care (e.g., an intervention that is only available through a research trial), continuation of the study should be considered with the maximum possible mitigation of the risk of infection. 34 the us food and drug administration (fda) has issued some guidance regarding continuation of research participation for intervention studies and how to mitigate the risks to participants and to the integrity of the research studies during the pandemic. 37 adapting and protecting the integrity of research activities during a pandemic research activities have been and remain critical in advancing medical knowledge and alleviating the suffering for millions of future patients, 34 particularly in the field of adrd, for which no new medication has been approved since 2003. clinical investigators can explore creative ways to continue their studies while mitigating the risk of covid-19 infection both for research participants and staff. this may require modification of study protocols to collect safety and endpoint assessments remotely. some assessments (e.g., follow-up neuroimaging for a secondary outcome) may need to be deferred or missed. challenges in terms of selective retention, measurement errors, data missing not at random, and other confounds will need to be addressed in the analyses and reporting of the results. when a study cannot be done entirely remotely because it requires in-person visits (e.g., a trial requiring regular monitoring of safety lab tests), the increased risk of participation associated with in-person visits needs to be discussed explicitly with participants-or, in the cases of most studies involving participants with moderate to severe adrd, their substitute decision maker (sdm). the established relationship between participants (or their sdms) and the research staff will facilitate these discussions. institutional review boards (irbs) and data and safety management boards (dsmbs) would also need to be involved in reassessing the risk/benefit ratio of continuing participation in these studies. a few clinical trials may consider not just to continue following and monitoring current participants, but also to recruit new participants. except for some rare trials of purely psychosocial interventions, baseline assessments and safety lab tests would require in-person visits. again, this would require the involvement of the irb and dsmb and careful discussion with possible participants or their sdm and documentation of this consent process. as with any major crisis, the covid-19 pandemic will have a lasting impact on the way all clinical research, including adrd research, is carried out. the current challenging situation is forcing researchers to think how they could conduct most research procedures remotely. it will accelerate the adoption of technologies and tools that permit remote assessments. [38] [39] [40] in the field of adrd research, we believe it will impact most the traditional neuropsychological and functional assessments on which most primary outcomes for adrd interventions trials are based. 41 in the long term, adrd research will also benefit from these technological innovations because they should allow the recruitment and follow-up of much larger samples at reduced costs. finally, the covid-19 crisis may expedite the development of non-pharmacological interventions that can be delivered the home of participant, e.g., homebased cognitive training or physical exercise, or that use small portable devices that can be easily used in private homes, e.g., transcranial direct current stimulation and similar devices. 40 the covid-19 pandemic is disrupting the world and its health care systems in unprecedented ways. this pandemic also threatens the integrity and viability of current and future adrd research. local impact will vary and evolve depending on specific factors, including the incidence of covid-19, the associated death rates, the availability of resources, and the societal changes implemented to control the pandemic. these local variations combined with the heterogeneity of adrd make simple generic recommendations ineffectual. however, awareness of this possible impact and mitigation strategies adapted to individual and local circumstances may prevent or reduce the harm of this pandemic and its consequences for persons with adrd and their caregivers. eric brown: substantial contributions to the conception or design of the work and the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. sanjeev kumar: substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; and final approval of the version to be published bruce g. pollock: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and final approval of the version to be published. tark k. rajji: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and final approval of the version to be published. benoit h. mulsant: substantial contributions to the conception or design of the work and the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. coronavirus disease 2019 (covid-19) situation report -51 world health organization: coronavirus disease coronavirus disease 2019 (covid-19) in italy jama estimating clinical severity of covid-19 from the transmission dynamics in wuhan a claims data-based comparison of comorbidity in individuals with and without dementia clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of coronavirus disease 2019 in china n engl j med a systematic review and meta-analysis examining pneumonia-associated mortality in critical supply shortages -the need for ventilators and personal protective equipment during the covid-19 pandemic critical care utilization for the covid-19 outbreak in lombardy, italy: early experience and forecast during an emergency response jama 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future br fda guidance on conduct of clinical trials of medical products during covid-19 pandemic. u.s. food and drug administration digital biomarkers for alzheimer's disease: the mobile/wearable devices opportunity sensing technology to monitor behavioral and psychological symptoms and to assess treatment response in people with dementia feasibility of remotely supervised transcranial direct current stimulation and cognitive remediation: a systematic review telephone-based screening tools for mild cognitive impairment and dementia in aging studies: a review of validated instruments front key: cord-288494-6qybdxc4 authors: liao, qiaohong; ip, dennis k m; tsang, tim k; cao, bin; jiang, hui; liu, fengfeng; zheng, jiandong; peng, zhibin; wu, peng; huai, yang; lau, eric h y; feng, luzhao; leung, gabriel m; yu, hongjie; cowling, benjamin j title: a clinical prediction rule for diagnosing human infections with avian influenza a(h7n9) in a hospital emergency department setting date: 2014-08-05 journal: bmc med doi: 10.1186/s12916-014-0127-0 sha: doc_id: 288494 cord_uid: 6qybdxc4 background: human infections with avian influenza a(h7n9) virus are associated with severe illness and high mortality. to better inform triage decisions of hospitalization and management, we developed a clinical prediction rule for diagnosing patients with a(h7n9) and determined its predictive performance. methods: clinical details on presentation of adult patients hospitalized with either a(h7n9)(n = 121) in china from march to may 2013 or other causes of acute respiratory infections (n = 2,603) in jingzhou city, china from january 2010 through september 2012 were analyzed. a clinical prediction rule was developed using a two-step coefficient-based multivariable logistic regression scoring method and evaluated with internal validation by bootstrapping. results: in step 1, predictors for a(h7n9) included male sex, poultry exposure history, and fever, haemoptysis, or shortness of breath on history and physical examination. in step 2, haziness or pneumonic consolidation on chest radiographs and leukopenia were also associated with a higher probability of a(h7n9). the observed risk of a(h7n9) was 0.3% for those assigned to the low-risk group and 2.5%, 4.3%, and 44.0% for tertiles 1 through 3, respectively, in the high-risk group. this prediction rule achieved good model performance, with an optimism-corrected sensitivity of 0.93, a specificity of 0.80, and an area under the receiver-operating characteristic curve of 0.96. conclusions: a simple decision rule based on data readily obtainable in the setting of patients’ first clinical presentations from the first wave of the a/h7n9 epidemic in china has been developed. this prediction rule has achieved good model performance in predicting their risk of a(h7n9) infection and should be useful in guiding important clinical and public health decisions in a timely and objective manner. data to be gathered with its use in the current evolving second wave of the a/h7n9 epidemic in china will help to inform its performance in the field and contribute to its further refinement. electronic supplementary material: the online version of this article (doi:10.1186/s12916-014-0127-0) contains supplementary material, which is available to authorized users. human infections with novel avian-origin influenza a (h7n9) virus were first identified in march 2013, [1, 2] mainly in the eastern provinces of china [3] . a total of 131 human infections, dominated by severe illness and mortality, were confirmed in the spring wave in mainland china from march through may 2013 [4, 5] . with the adoption of suitable public health measures including closure of live poultry markets, few cases were identified over the summer months [6] . however, h7n9 has resurged in this winter, 2013-2014 [7] . in the context of preparing and responding to further waves of this evolving epidemic, the importance of early detection, diagnosis, isolation and reporting of a(h7n9) infections has been repeatedly emphasized [8] . accurate and objective risk prediction can help physicians to guide clinical management and inform triage decisions * correspondence: yuhj@chinacdc.cn † equal contributors 1 for optimizing the utilization of valuable clinical and public health resources that may easily be overwhelmed during an epidemic. however, no simple and reliable decision tool has yet been available for predicting the risk of a (h7n9) influenza in an objective and timely manner. our objective in this study was to develop a clinical prediction rule that would accurately identify patients with a(h7n9) influenza on their first presentation to a hospital emergency setting and to evaluate the predictive performance of this rule. we analyzed two databases that contained clinical and basic laboratory data from two groups of patients presenting similarly with acute respiratory infections to hospitals in china, including 121 laboratory-confirmed a(h7n9) cases and 2,603 patients who suffered from acute respiratory infections other than a(h7n9) influenza. outpatient clinics or emergency departments in hospitals represent a typical first step for patients with acute respiratory infections in china to present to the healthcare system, owing to the coverage of national health insurance programs and the lack of standalone primary healthcare clinics in either the public or private sector as an alternative [9] . the a(h7n9) database consisted of patients who presented clinically with symptoms of acute respiratory infection to hospitals in different provinces of china and were subsequently confirmed to have a(h7n9) virus infection between march and may 2013. in china, all laboratory-confirmed infections with a(h7n9) viruses are reported to the chinese center for disease control and prevention (china cdc, beijing, china) through a national surveillance system [10] . diagnostic confirmation of a(h7n9)virus infection was done either by the isolation of a(h7n9) virus or a positive real-time reversetranscription polymerase chain reaction (rt-pcr) assay for a(h7n9) in a respiratory specimen [10] . case definitions, surveillance for identification of influenza a(h7n9) cases, and laboratory test assays are described in previous reports [10] . the second database consisted of patients who presented similarly with acute respiratory infections to hospitals in jingzhou city, hubei province of china from 4 january 2010 through 30 september 2012. their clinical details were captured by a surveillance program for severe acute respiratory infection (sari) conducted by china cdc in four surveillance hospitals in jingzhou during that period [11] . all patients admitted to these four surveillance hospitals were screened by either a nurse or physician. a patient was defined as having sari if they had on their clinical presentation an elevated temperature (rectal or axillary temperature ≥37.3°c) and at least one sign or symptom of acute respiratory illness, including cough, sore throat, tachypnea, difficulty breathing, abnormal breath sounds on auscultation, sputum production, hemoptysis, chest pain or chest radiograph consistent with pneumonia. nasopharyngeal swabs were collected from these patients and tested for seasonal influenza and avian influenza h5n1 viruses by rt-pcr. as these samples were all collected before the first h7n9 human case was identified, they were not tested for a(h7n9) virus. for patients included in either of these databases, clinical information on the medical history and physical examination findings on their initial clinical presentation was abstracted retrospectively from their original medical records using a standard data abstraction sheet by trained nursing and medical officers at each hospital. patients younger than 14 years of age from both databases were not included in this study, as there are few patients <14 years of age with confirmed a(h7n9) virus infection, and their presenting symptoms, the approach of symptom ascertainment, overall clinical course and disease severity, disease epidemiology, and even health care seeking pattern and pathway were generally very different from that in adults and elderly persons [3] [4] [5] . additional information collected included age, sex, history of any poultry exposure, including exposure to live poultry markets within two weeks of symptom onset, influenza vaccination history, smoking history, pregnancy, history of underlying medical conditions, height (m), weight (kg) and clinical symptoms. the results of investigations performed on presentation included chest radiography (signs of consolidation and pneumonia), simple hematologic blood analysis including hemoglobin level (hgb) and leukocyte count (wbc), and c-reactive protein (crp). because we did not have sufficiently complete data (>60%) on some laboratory determinations for the entire sample (including platelet count, other serum biochemistry tests and clotting profile), we excluded these determinations from the analysis for all patients. the collection of data from confirmed a(h7n9) cases was determined by the chinese national health and family planning commission as part of public health investigations of emerging influenza outbreaks and was exempted from institutional review board assessment. collection of data of sari cases was approved by the ethical review committee of the china cdc. therefore, informed consents from the cases were not required. a two-step regression model was used to develop the prediction rule, so as to simulate the decision making process in the setting of a clinic or hospital emergency room where a patient first presents [12, 13] . in step 1, basic variables obtainable from the medical history and physical examination were employed to identify a subgroup of patients who were more likely to have a(h7n9) and, therefore, needed additional investigation and workup. variables used in this stage included age group (<60 years, ≥60 years), sex, poultry exposure history, influenza vaccination history, smoking history, and history of underlying chronic diseases, pregnancy, major presenting symptoms and physical findings. in step 2, simple radiologic and laboratory variables were added to significant predictors from step 1 (those having a p-value less than 0.05) to further refine the identification of subgroups having higher risk for a(h7n9). we used a univariate logistic regression model to identify significant (p ≤ 0.05) predictors of a final diagnosis of a(h7n9) and then entered them into a multivariable logistic regression model with backward selection. we removed variables that had a p-value greater than 0.05. interaction terms were tested as candidate variables, but none of these terms entered the final models. we derived each prediction rule using all available information on patients. we used multiple imputations [14, 15] (20 imputations) in the derivation process to make the most of all available non-missing data while preserving the uncertainty from the missing data in the results [16, 17] [see additional file 1: appendix]. a score-based prediction rule for a final diagnosis of a (h7n9) was then developed for each step from the final logistic regression equations using a regression coefficientbased scoring method [13] . a simple integer-based point score was assigned for each predictor variable, which was calculated by dividing the corresponding β-coefficients by the absolute value of the smallest coefficient in the final model and rounding up to the nearest integer. the overall risk score for each patient was calculated by adding the scores for each component together [18] . aiming to be used as a screening tool to capture as many of the a/h7n9 cases as possible, a cutoff was specified with a priori sensitivity of 0.99 in step 1 and 0.95 for the overall model (steps 1 and 2). total risk scores above the cutoff threshold were then categorized in tertiles as a risk prediction rule for ease of clinical implementation. performance of the risk prediction rule in predicting a(h7n9) infection was examined by sensitivity, specificity, likelihood ratios for both positive and negative test results, and area under the receiveroperating characteristic (roc) curve [19] . calibration was evaluated by using the hosmer-lemeshow chi-square statistic (p > 0.05 for all models) [20] . regression models were tested for possible overfitting by using linear shrinkage estimators [13, 21] . the prediction rule was internally validated with samples of the same size resampled with replacement from the original derivation data set using the bootstrap method [22] . the model was refitted as the original model derivation process on these bootstrap samples for 1,000 iterations [13, 21] to determine the degree of performance deterioration to be expected when applied on an independent sample of patients [21] . we also estimated the optimism-corrected estimates to correct for the absolute magnitude of bias for each performance index [23] . we performed all analyses with r software, version 3.0.1. as of the end of may 2013, 131 confirmed a(h7n9) cases were officially reported in mainland china. among these patients, 121 patients of 14 years of age or older presenting with acute respiratory infection to an emergency department and requiring hospitalization for medical reasons were included in this study [5] . two cases younger than 14 and eight cases having mild disease and confirmed by routine testing through sentinel influenzalike illness surveillance were excluded from the present study [9] . during the surveillance period from 4 january 2010 through 30 september 2012, 90,890 patients had been hospitalized in the four surveillance hospitals in jingzhou city. among these, 25,406 (28%) patients met the sari case definition within 24 hours of hospital admission. ninety percent (22, 777) were <14 years of age and excluded from the present study. among the 2,603 included patients, 2,310 (89%) had a nasopharyngeal swab specimen collected, and 430 (19%) tested positive for influenza viruses by rrt-pcr, including 258 (60%) with influenza a(h3n2), 36 (8%) with a(h1n1) pdm09 and 136 (32%) with influenza b. table 1 shows the demographic and clinical characteristics of these two groups of patients on presentation to the emergency hospital. on univariate analysis, factors that were associated with an increased risk of a(h7n9) infection included older age (≥60 years), male sex, history of poultry exposure, smoking history, history of underlying medical conditions, fever, cough, haemoptysis, shortness of breath and diarrhea (table 1 ). in step 1 of the clinical prediction rule, male sex and history of poultry exposure were independently associated with a final diagnosis of a(h7n9) on multivariable analysis. the presence of three respiratory symptoms, namely fever, haemoptysis and shortness of breath, were also independently associated with a final diagnosis of a(h7n9) ( table 2 ). other factors became insignificant (age group, underlying medical illnesses, cough and diarrhea) and were not retained. fifty-eight percent of the cohort with a total score less than the threshold of 43 was assigned to the low-risk group and did not proceed to step 2 [see additional file 2: figure s1 ]. in step 2, two additional laboratory findings including pneumonia/consolidation on chest radiograph and leukopenia (wbc <4,000/μl) were each independently associated with an increased risk of a(h7n9). on the other hand, finding of leukocytosis (wbc >11,000/μl), or an abnormally low (hgb < 12 g/dl) or high hemoglobin level (hgb ≥16 g/dl) were each independently associated with a decreased risk of a(h7n9). all of the previous five factors entered in step 1 had remained statistically significant after adding these two factors. no statistical evidence of overfitting, as demonstrated by linear shrinkage estimation (shrinkage factor, 0.981 (95% confidence interval (ci), 0.976 to 0.984) for step 1 and 0.967 (95% ci, 0.960 to 0.972) for step 2), was seen in either multivariable regression model. for the ease of use in a setting of a clinical consultation, the magnitude of association of each of these factors with a(h7n9)virus infection was quantified by a point scoring system as shown in table 3 . a total score of 68 or greater would indicate the presence of a high risk for a(h7n9) infection, with a prespecified sensitivity of 95% overall. forty-five percent of patients considered in step 2 were further assigned to the low-risk category [see additional file 2: figure s1 ]. the magnitude of the scores had good diagnostic utility. when stratified by tertiles with the two cut-points of 70 and 90, a gradation with increasing level of risk for a (h7n9) infection was demonstrated. the corresponding risk of a(h7n9) infection was 0.3% (95% ci, 0.0% to 0.6%) for those assigned to the low-risk group (in steps 1 or 2), 2.5% (95% ci, 0.5% to 4.5%) for tertile 1 (risk score, 68 to 70), 4.3% (95% ci, 2.2% to 6.4%) for tertile 2 (risk score, 71 to 90) and 44.0% (95% ci, 37.4% to 50.8%) for tertile 3 (risk score >90) in the high-risk group. a similar gradation of risk was also observed in the validation analysis ( figure 1 ). this clinical prediction rule achieved good discriminative ability. it gave a sensitivity of 0.93 and a specificity of 0.80 (optimism-corrected estimates) in the derivation process, which were broadly maintained, respectively, at 0.96 and 0.75 in the bootstrap internal validation process (table 4 ). on the other hand, the optimism-corrected area under the roc curve was 0.96 from both the derivation and the internal validation processes (figure 2 ). likelihood ratios for a positive result with an assignment to the highrisk group after step 2 were moderately strong at 4.62 and 3.85 for the derivation and internal validation processes, respectively. likelihood ratios for a negative result with assignment to the low-risk group after step 1 or step 2 were 0.090 and 0.056 for the derivation and internal validation processes, respectively. our study presents a decision rule for objectively predicting a(h7n9) infection in adult patients presenting with severe respiratory illness. factors of particular importance in the prediction rule, including poultry exposure history, fever, shortness of breath and leukopenia, agreed generally with findings reported from previous epidemiological and clinical studies [4] . we had chosen the model with the best performance in terms of both the high sensitivity and area under the roc curve, which were also maintained in the validation samples, to identify patients having a high risk for the infection at their initial clinical presentation so as to optimize resources during an epidemic. as generally recognized by previous reports, most laboratory-confirmed cases of a(h7n9) have had a high risk of disease progression and fatality [3, 5] . early initiation of antiviral treatment and provision of a suitable level of intensive care have been identified as important factors in determining the final outcome of patients hospitalized with a(h7n9) virus infection [24] . our decision tool allows an initial risk assessment to be performed by frontline physicians in a setting where simple laboratory and radiographic examination may not be readily available, based only on simple information obtainable from the history and physical examination. in a setting with greater resources, the risk estimation of those deemed to have a non-trivial risk at step 1 could be further refined by the availability of simple radiographic and laboratory testing results. the scoring system also helps to categorize those being predicted as high-risk into different risk strata to facilitate further clinical decision-making (including the need for further work up, admission decision and ward allocation, initial treatment regimen, level of care and monitoring, and so on) before a definitive diagnosis based on rt-pcr can be available, often at a much later time. despite the current belief that a(h7n9) virus may not be readily transmitted from person to person, [3, 10] the existence of limited person-to-person transmission in a close contact setting [25] also carries an implication for this risk stratification tool to better inform isolation decision and practice. depending on resource availability and surge capacity, patients assigned to different risk groups may need to be handled differently. generally, however, patients assigned to the low-risk group in either steps 1 or 2 should have little risk implication to justify their admission at that particular juncture either for monitoring or hospitalized care unless having other indications for admission. this strategy can help to reduce the demands on inpatient beds and testing capacity. on the other hand, persons having a total risk score exceeding the threshold (≥68) in step 2 should be considered for admission for further assessment and possible initiation of treatment. the provision of different levels of monitoring and treatment to such patients could be guided by the magnitude of the total risk score, which is predictive of the eventual risk of confirmed a(h7n9) infection. allocation of isolation facilities including individual negative-pressure isolation rooms may also be informed by the individual risk score in case there is any enhancement in human-to-human transmissibility. our study included all cases of clinically confirmed a (h7n9) infection that presented with a picture of acute respiratory infection in a hospital setting in the first epidemic in china from march through may. our control consisted of a suitable sample of patients who clinically presented in a comparable setting within the same geographical area and were captured by a large-scale surveillance network, in a period immediately prior to the a (h7n9) epidemic. although controls had not been directly tested for a(h7n9) virus, their recruitment in a period during which human a(h7n9) infection was absent or at least very unlikely [26] should have helped to avoid their potential contamination by unascertained a(h7n9) cases. however, our study does suffer from a number of potential limitations. first, as the h7n9 positive cases and the control patients were not gathered from exactly the same setting, subtle biases may still be introduced by potential variability in the degree of exposure ascertainment or data documentation in the two different settings. although this problem should have been partly addressed by excluding any variables that were not measured or were generally missing from either group, some measured variables may have been more thoroughly ascertained for a(h7n9) cases, especially in an epidemic setting. second, a small proportion of all confirmed a(h7n9) cases were either asymptomatic or only mildly symptomatic and had not been hospitalized [9] . because of the very different clinical picture, our prediction rule may not be applicable for assessing the risk of a(h7n9) infection in this group of patients. third, as our study had already included almost all confirmed cases of a(h7n9) reported during the initial epidemic in china, the decision rule could only be internally validated by bootstrapping but lacked a suitable sample for external validation. as a result, the actual performance and utility of this prediction rule in future epidemics remains to be determined. ideally, our rule can be further validated in the current evolving second obtained from internal validation by using a bootstrap analysis in which the cohort was resampled 1,000 times with replacement.likelihood ratio for a positive test result refers to the likelihood of assignment to the high-risk group after step 2. likelihood ratio for a negative test result refers to the likelihood of assignment to the low-risk group after steps 1 or 2. ci, confidence interval; roc, receiver-operating characteristic. wave of epidemic in chinawithin a setting where all cases presenting with acute respiratory infection (ari) can be captured and ascertained with a definitive testing for a/h7n9 irrespective of their initial risk stratification status. this can inform the assessment of its performance in the field and contribute to its further refinement. finally, as the prediction rule was derived mainly based on data of the a/h7n9 virus with little or no humanto-human transmission potential, its performance may become very different should the virus acquire the ability to do so. other factors that may affect performance of the model in future waves of the evolving epidemic may include variation in disease severity, changing risk perception and health care seeking behavior. while the prediction of absolute risk for having a(h7n9) infection could be affected by variation in local factors, robustness of the model for separating higher from lower risk should probably be preserved. when being applied in the field, frontline physicians should remain alert concerning the potential limitations associated with practice guidelines and our decision rule should only supplement, but never supersede, the physician's judgment in equivocal or borderline cases. human infection with a novel avian-origin influenza a (h7n9) virus compiling of comprehensive data of human infections with novel influenza a (h7n9) virus comparative epidemiology of human infections with avian influenza a h7n9 and h5n1 viruses in china: a population-based study of laboratory-confirmed cases clinical findings in 111 cases of influenza a (h7n9) virus infection human infection with avian influenza a h7n9 virus: an assessment of clinical severity effect of closure of live poultry markets on poultry-to-person transmission of avian influenza a h7n9 virus: an ecological study human infection with avian influenza a(h7n9) virus re-emerges in china in winter 2013 novel h7n9 influenza virus shows low infectious dose, high growth and efficient contact transmission in the guinea pig model detection of mild to moderate influenza a/h7n9 infection by china's national sentinel surveillance system for influenza-like illness: case series preliminary report: epidemiology of the avian influenza a (h7n9) outbreak in china the substantial hospitalization burden of influenza in central china: surveillance for severe, acute respiratory infection, and influenza viruses a prediction rule to identify low-risk patients with community-acquired pneumonia hospital authority sars collaborative group: a clinical prediction rule for diagnosing severe acute respiratory syndrome in the emergency department multiple imputation: a primer regression modeling strategies: with applications to linear models, logistic regression, and survival analysis statistical analysis with missing data multiple imputation after 18+ years presentation of multivariate data for clinical use: the framingham study risk score functions the meaning and use of the area under a receiver operating characteristic (roc) curve applied logistic regression predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model an introduction to the bootstrap. chapman & hall/crc pr multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors clinical, virological, and histopathological manifestations of fatal human infections by avian influenza a(h7n9) virus probable person to person transmission of novel avian influenza a (h7n9) virus in eastern china, 2013: epidemiological investigation serologic study for influenza a (h7n9) among high-risk groups in china submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we thank staff members of the bureau of disease control and prevention and health emergency response office of the national health and family planning commission and provincial and local departments of health for providing assistance with administration and data collection; staff members at county-, prefecture-, and provincial-level cdcs in the provinces where human a(h7n9) cases occurred for providing assistance with field investigation, administration and data collection. the views expressed are those of the authors and do not necessarily represent the policy of the china cdc. our prediction rule currently represents an important evidence-based decision tool for the triage of suspected cases of a(h7n9) infection when they first present clinically in an emergency department or primary care settings. this decision tool will be most useful in an evolving epidemic when the health system's surge capacity could be overwhelmed by the number of patients seeking care. with the current re-emergence of the a(h7n9) epidemic as the second wave in china, it would be a very timely and practical tool for helping both physicians working on the frontline to make important clinical decisions and public health professionals and health administrators to optimize the proper allocation of limited resources. additional file 1: appendix. details on the multiple imputation and validation processes involved in building the risk prediction model [14] [15] [16] [17] 23] .additional file 2: figure s1 . flowchart of influenza a(h7n9) infection stratified by risk categories. china cdc: chinese center for disease control and prevention; ci: confidence interval; crp: c-reactive protein; hgb: hemoglobin; roc: receiver-operating characteristic; rt-pcr: real-time reverse-transcription polymerase chain reaction; sari: severe acute respiratory infection; wbc: leukocyte count.competing interests dkmi reports receipt of research funding form hoffmann-la roche inc. bjc reports receipt of research funding from medimmune inc. and sanofi pasteur, and consults for crucell nv. gml has received speaker honoraria from hsbc and clsa. the authors report no other competing interests.authors' contributions hy and dkmi designed and supervised the study. ql, hj, fl, jz, zp, yh, lf, bc, zg and hy collected the data. ql, dkmi, tkt, hy, bjc, pw, ehyl and gml analyzed and interpreted the data. dkmi drafted the manuscript. all authors critically revised and approved the final manuscript. key: cord-034834-zap82dta authors: bai, xiao; sun, huaping; lu, shibao; taghizadeh-hesary, farhad title: a review of micro-based systemic risk research from multiple perspectives date: 2020-06-27 journal: entropy (basel) doi: 10.3390/e22070711 sha: doc_id: 34834 cord_uid: zap82dta the covid-19 pandemic has brought about a heavy impact on the world economy, which arouses growing concerns about potential systemic risk, taking place in countries and regions. at this critical moment, it makes sense to interpret the systemic risk from the perspective of the financial crisis framework. by combing the latest research on systemic risks, we may arrive at some precautions relating to the current events. this literature review verifies the origin of systemic risk research. by comparing the retrieved and screened systemic literature with the relevant research on the financial crisis, more focus on the micro-foundations of systemic risk has been discovered. besides, the measurement methods of systemic risks and the introduction of interdisciplinary methods have made the research in this field particularly active. this paper synthesizes the previous research conclusions to find the appropriate definition of systemic risk and combs the research literature of systemic risk from two lines: firstly, conducting the division according to the sub-branch fields within the financial discipline and the relevant interdisciplinary research methods, which is helpful for scholars within and outside the discipline to have a more systematic understanding of the research in this field. secondly predicting the research direction that can be expanded in this field. the study of systemic risk suddenly increased after the subprime crisis. compared with the previous financial crisis, although there is an overlap between the two, systemic risk includes not only the information asymmetry, liquidity, and crisis transmission pathways involved in the financial crisis, but also the research on the stability problems caused by the structure of the system itself, the quantification of systemic risks, and early warning issues. as a result, further research on the market microstructure and agent heterogeneity has also been triggered. meanwhile, cross-disciplinary research methods from other disciplines have been introduced, such as the introduction of complex network models when studying the structural stability of the system, linking the contagious effects of financial systemic risks to the transmission pathways of infectious diseases or bio-food chains [1] [2] [3] [4] [5] [6] , establishing new measures to measure systemic risk [7] [8] [9] [10] . different measurement methods in the financial sub-branch field are also applied to empirically verify and predict the tail loss of systemic risks [8, 11, 12] . what does systemic risk research study? what methods are used to study systemic risks? these are the questions that this review will always revolve around. the former one refers to a framework the scope of systemic risk and systematic risk is not the same. the latter refers to the risk factors shared by the entire economy, the non-distributable risk, also known as the market risk; it is opposite to non-systematic risk. systemic risk refers to the risk of an overall collapse of the entire system due to the impact of individual member units, and systemic collapse is reflected in the impact of most or all individual members [13] . according to the econlit economic literature database search results, the term "systemic risk" can be traced back to the speech of andrew f. brimmer, a fed official in 1988, at a joint annual meeting of aea (american economic association) and the society of government economists in new york (this speech was published in the journal of economic perspective the following year. see: [14] ), there are different views on the clear definition of systemic risk in academia. [14] first proposed the systemic risk and defined it as the occurrence and spread of a dilemma that is likely to seriously affect a country's financial order. the dilemma itself may be derived from micro factors or macro factors. the bis describes systemic risk as to the possibility that a party to a contract cannot perform an agreement and causes other contractors to default, and thus the chain reaction leads to a wider range of financial difficulties. this definition focuses on the overall risk of the system caused by the breach from microbodies. besides, darryl hendricks [15] defines it from the perspective of equilibrium theory: systemic risk refers to the risk of moving the system from one equilibrium to another worse equilibrium, and this risk is difficult to reverse due to the catalysis of many self-reinforcing mechanisms. following the systemic elaboration of systemic risks in 2003, [16] summarized the definitions of systemic risks and classified them into three categories: (1) the huge negative impact that the entire financial system faces at the same time, that is, systemic risks have the characteristics of simultaneity [17] ; (2) all or a part of the financial institutions face the same risk exposure, which means systemic risks have the same cause [18] ; (3) the impact can trigger a chain reaction. in other words, systemic risk is contagious [19] . [20] believe that these definitions have the following points in common: (1) systemic risk concerns are for all financial institutions; (2) systemic risk focuses on tail loss characteristics; (3) all need to consider the relevance and cross-cutting of the various institutions within the financial system. besides, there are differences and linkages between the concepts of systemic risk and financial crisis. [16] believes that systematicity is the most noteworthy cause of crisis formation and crisis development. the former is the reason and the characterization of the latter, that is, the financial crisis necessarily presents systemic risks, but systemic risks do not necessarily lead to financial crises. moreover, current systemic risk research is mainly limited to financial systemic risk issues within an economy. the financial crisis has a wider scope and more diversified forms of expression. for example, depending on the scope of the spread, a financial crisis can be divided into bank crisis (the bank run), currency crisis, bubble crisis of capital market speculation, sovereign debt crisis, etc., and may trigger a comprehensive economic crisis. on the other hand, systemic risk is similar to financial risk in that it is contagious, and most or all financial institutions in the system will face the same impact at the same time. however, systemic risk emphasizes the impact of financial institutions on the overall risk of the system, that is, the endogenous nature of systemic risks, while the financial crisis may origin from endogenous or exogenous causes, for instance, for iceland in the recent financial crisis, the us-centric financial crisis was transmitted to iceland's entire banking system, which led to the overall collapse of the country's economy [21] . besides, although systemic risks are not all triggered by the leverage (for example, on october 19, 1987 , due to the stock market crash, the us stock index futures prices plummeted, causing the margin account to not add in time, leading to the collapse of the broker), the impact on the system after it occurs must be amplified with leverage. therefore, the study of systemic risks is essentially related to the credit creation process and the degree of leverage. according to the different sectors created by credit, it can be divided into systemic risks of the banking system and the shadow banking system; according to the classification of financial markets and instruments that occur, it can be divided into systemic risks in the real estate market, banking system, bill market, securities market, bond market and derivatives market; according to the different debt departments, it can be divided into systemic risks of public debt (including systemic risks of sovereign debt), systemic risks of corporate debt, and systemic personal risks of households. on the other hand, because the financial crisis is highly correlated with the concept of systemic risk, the scope of the financial crisis and systemic risk research also has great overlap. by entering the keywords "financial crisis" and "risk", a total of 7375 ssci core documents and working papers published since 1992 were searched through web of science. by entering the keyword "systemic risk", a total of 1913 core documents and working papers of the same period were searched. through screening the titles and abstracts of all these papers by adding "financial markets", 1025 papers are selected out. with the help of the software citespace, further bibliometric analysis reveals that financial risk and systemic risk research have more crossovers, and the research concentrated areas are almost overlapping ( figure 1 ). the sub-branches of financial crisis research are numbered according to the timeline of theory development. it demonstrates that early crisis research mainly focused on macroeconomic issues [22] [23] [24] as time went by, there was a detailed exploration into specific financial markets and product markets [25, 26] . from another perspective, financial intermediaries and investor behaviors were discussed in terms of pricing credit risks [27, 28] . as financial intermediaries have similar research methods with corporate finance, more later attention was drawn to bank governance [29] . as the subprime crisis erupted, more studies were oriented to the stability of the financial system, which overlaps with the systemic risk research [7, 10, [30] [31] [32] . a new branch, the extreme value approach, is also adopted in systemic research. systemic risk research is not distinct from crisis research, as the former one also refers to such bank behaviors and liquidity problems. among the 10 subdivisions, more co-citation clusters are formed in regional contagion, monetary policy, credit risk pricing and systemic risk. within the systemic risk field, the co-citation cluster of multidisciplinary research is the largest one, also with most focus on the financial network. thus, by combing the literature on financial crisis theory and systemic risk research, it can be found that the research on systemic risk is closer to the micro-level than the original financial crisis research, although systemic risk management involves macro-level management and supervision. there are more studies on the micro-market structure and participant behavior, and more emphasis on systemic risk transmission and contagious research, as well as the endogenous mechanism research that pays more attention to the occurrence of risks; it can be said that systemic risk research is the further deepening and refinement of the theoretical research on the financial crisis. therefore, although the academic community still has differences in the definition of systemic risks, by comparing the concepts of systemic risk and financial crisis, and summarizing the definition of systemic risk in the academic world, the concept of systemic risk can be defined from an economic perspective: triggered by macro or micro-events, the institutions in the system are subjected to the sub-branches of financial crisis research are numbered according to the timeline of theory development. it demonstrates that early crisis research mainly focused on macroeconomic issues [22] [23] [24] as time went by, there was a detailed exploration into specific financial markets and product markets [25, 26] . from another perspective, financial intermediaries and investor behaviors were discussed in terms of pricing credit risks [27, 28] . as financial intermediaries have similar research methods with corporate finance, more later attention was drawn to bank governance [29] . as the subprime crisis erupted, more studies were oriented to the stability of the financial system, which overlaps with the systemic risk research [7, 10, [30] [31] [32] . a new branch, the extreme value approach, is also adopted in systemic research. systemic risk research is not distinct from crisis research, as the former one also refers to such bank behaviors and liquidity problems. among the 10 subdivisions, more co-citation clusters are formed in regional contagion, monetary policy, credit risk pricing and systemic risk. within the systemic risk field, the co-citation cluster of multidisciplinary research is the largest one, also with most focus on the financial network. thus, by combing the literature on financial crisis theory and systemic risk research, it can be found that the research on systemic risk is closer to the micro-level than the original financial crisis research, although systemic risk management involves macro-level management and supervision. there are more studies on the micro-market structure and participant behavior, and more emphasis on systemic risk transmission and contagious research, as well as the endogenous mechanism research that pays more attention to the occurrence of risks; it can be said that systemic risk research is the further deepening and refinement of the theoretical research on the financial crisis. therefore, although the academic community still has differences in the definition of systemic risks, by comparing the concepts of systemic risk and financial crisis, and summarizing the definition of systemic risk in the academic world, the concept of systemic risk can be defined from an economic perspective: triggered by macro or micro-events, the institutions in the system are subjected to negative impacts, and more organizations are involved in risk diffusion and the existence of internal correlations strengthens the feedback mechanism, causing the system as a whole to face the risk of collapse. the definition here emphasizes (1) events triggering harms to institutions and systems; (2) systemic risks that spillover and are contagious; (3) due to the psychological and behavioral characteristics of the micro-subjects, a self-reinforcing feedback mechanism is formed; (4) the potentially serious consequence of systemic risk is the overall collapse. we found that in web of science, from the journal of economics, finance, accounting, behavioral psychology, and management, from 1992 to march 2020, all the articles on systemic risk published in the ssci core journals totaled 1913 articles. from figure 2a , we can tell the research on systemic risk has ups and downs from year to year, echoing with worldwide risk events. besides, the search for working papers on systemic risk research on the nber website has exceeded 200 publications in the past 10 years. furthermore, the number of work papers published in this field newly released in 2020 is still considerable (figure 2b) . especially, under current circumstances, systemic risk research deserves further exploring, as the covid-19 pandemic struck the real economy by threatening human life first, then financial systems are impacted in terms of both assets and liabilities, which may further hurt real economies through systemic risk chains. another peak in this area can henceforth be expected. negative impacts, and more organizations are involved in risk diffusion and the existence of internal correlations strengthens the feedback mechanism, causing the system as a whole to face the risk of collapse. the definition here emphasizes (1) events triggering harms to institutions and systems; (2) systemic risks that spillover and are contagious; (3) due to the psychological and behavioral characteristics of the micro-subjects, a self-reinforcing feedback mechanism is formed; (4) the potentially serious consequence of systemic risk is the overall collapse. we found that in web of science, from the journal of economics, finance, accounting, behavioral psychology, and management, from 1992 to march 2020, all the articles on systemic risk published in the ssci core journals totaled 1913 articles. from figure 2a , we can tell the research on systemic risk has ups and downs from year to year, echoing with worldwide risk events. besides, the search for working papers on systemic risk research on the nber website has exceeded 200 publications in the past 10 years. furthermore, the number of work papers published in this field newly released in 2020 is still considerable (figure 2b) . especially, under current circumstances, systemic risk research deserves further exploring, as the covid-19 pandemic struck the real economy by threatening human life first, then financial systems are impacted in terms of both assets and liabilities, which may further hurt real economies through systemic risk chains. another peak in this area can henceforth be expected. the research literature on systemic risk is sometimes the overlap of the fine branches of the section 2.2 above. for example, the study of tail risk identification and quantification will involve specific empirical methods and recommendations including risk management. therefore, the literature review in this chapter is mainly summarized and reviewed from the following four aspects: the concept of systemic risk appears late, so systemic research on it is still being explored. however, according to the previous literature comparison, it has many similarities with the research theme of the financial crisis. the study of systemic risk formation mechanisms also draws on the research results of the formation mechanism of the financial crisis. therefore, in the study of the formation mechanism of systemic risk, the research context of the formation mechanism of the financial crisis is first outlined. the study on the formation mechanism of the financial crisis is mainly divided into two categories, namely, caused by emergencies or related to the economic cycle [34] . in the [35] and [36] , bank runs come from depositors' expected self-realization, which can explain some of the bank runs the research literature on systemic risk is sometimes the overlap of the fine branches of the section 2.2 above. for example, the study of tail risk identification and quantification will involve specific empirical methods and recommendations including risk management. therefore, the literature review in this chapter is mainly summarized and reviewed from the following four aspects: the concept of systemic risk appears late, so systemic research on it is still being explored. however, according to the previous literature comparison, it has many similarities with the research theme of the financial crisis. the study of systemic risk formation mechanisms also draws on the research results of the formation mechanism of the financial crisis. therefore, in the study of the formation mechanism of systemic risk, the research context of the formation mechanism of the financial crisis is first outlined. the study on the formation mechanism of the financial crisis is mainly divided into two categories, namely, caused by emergencies or related to the economic cycle [34] . in the [35, 36] , bank runs come from depositors' expected self-realization, which can explain some of the bank runs and the currency crisis, but it is difficult to use the model to make a prediction. [37] proposed that there is information asymmetry between banks and depositors. by establishing a global game model, the bank-runs problem is well explained, and the theoretical boundary value of bank runs is put forward. [38] extended this model to the mutual fund market and proposed an empirical approach to the global game model. the research of this branch is mainly related to the micro-market structure from the perspective of the micro-level and individual agent. another focus of research on the causes of the financial crisis is its procyclical nature. [39] pointed out that when the economy goes down, it is difficult for banks to realize the possibility of redemption. if depositors anticipate the impact of the economic downturn on the banking industry, they will withdraw funds from their banks, which may cause a run on the banks. [40] examined the economic volatility indicators of the united states from the end of the 19th century to the beginning of the 20th century and found that the leading indicators of the scale of debts of closed enterprises can accurately predict the occurrence of the banking crisis. [41] , however, systematically studied the us comprehensive monetary policy from 1867 to 1960, and found that the four financial crises that occurred during this period were all caused by panic, but not related to the real economy. this led to a series of subsequent empirical tests on the causes of the financial crisis [42, 43] , which conducted a more detailed investigation of the four financial crises and collected more extensive data. it has been empirically found that the first three financial crises were triggered by the impact of the real economy, while the fourth financial crisis broke out due to panic. the research on the systemic risk formation mechanism is carried out in the context of the establishment of the credible monetary system, and the degree of regulation of financial markets and the links between financial institutions and product innovations that have surpassed the previous era. therefore, against this backdrop, the occurrence of systemic risk not only means that the liquidity of the bank or the banking industry itself causes a banking crisis but also means that the liquidity of the inter-bank market or the lending market in which it is involved in financing is exhausted. furthermore, the resulting chain reaction, and even spread to other financial segment markets, eventually led to the collapse of the entire system. therefore, the research on the formation mechanism of systemic risk is divided into two directions. the first one is the research on the formation mechanism of the financial crisis, which focuses on the micro-level; dynamic analysis is used to explore the effects of interactions within the system between individual behaviors, organizations, and financial markets. the other one is to focus on the institutional roots of systemic risk from the perspective of normative economics, or law and sociology. [44] found that the frequency of financial crises in the world, such as the great depression, was, in recent decades, twice the sum of the number of financial crises in the bretton woods period and the gold standard period (1880-1893). this cannot but make people wonder whether the shortcomings of the credit monetary system itself lead to the risk of a financial crisis, because the marginal cost of credit currency issuance is almost zero compared to its face value. therefore, the central bank is more inclined to issue more than a limited amount of money to obtain money as a gain from credit capital investment or to achieve other policy objectives, especially when the central bank has a monopoly position and no other financial institution issues currency to compete with it. moreover, the central bank is not bound by a bankruptcy (the self-owned capital ratio can be extremely low), so this tendency is more obvious. besides, according to the guidelines proposed by the central bank theory founder walter bagehot that the central bank should follow (the loans provided by the central bank should set higher interest rates to prevent those who should not get loans, and the central bank should accept good bank collateral in the financial crisis to distinguish borrowers who are not solvent), this type of criterion, which can only rely on the central bank's self-discipline, can easily be broken before or even during the financial crisis, as the fed did in the 2007 subprime crisis. therefore, [45] believe that the financial crisis is essentially a lack of restraint of central bank behavior, resulting in excessive credit funds, which is caused by an excess supply of high-quality assets. this view is consistent with the findings of [30, [46] [47] [48] [49] [50] [51] , which showed that credit booms and asset price bubbles prevailed before the systemic banking crisis. [52] found that the financial crisis in many countries stemmed from the puncture of asset bubbles in the real estate market. as the financial crisis broke out, asset prices fell sharply and continued to have a major impact on real economic output and employment. further exploration of the deeper reasons, the premise of financial systemic risk accumulation as excessive debt, the root cause of excessive debt and what is the "degree" of liability, becomes an important part of the discussion of the formation mechanism of systemic risk. the discussion of this issue has even surpassed the scope of mainstream western economic theory, so it is difficult to see the whole picture in the previous classic systemic risk research literature. george bragues linked the act of capital interest-taking with the liberal democratic trend of thought, arguing that a large amount of lent funds had no tangible foundation beyond the credit creation ability of the banking system, and the fact that people exchange real goods and labor for this kind of currency without receiving any substantial return is unfair. it is the exploitation of the borrower by the lenders of the greeks proposed by philosopher aquinas. however, the idea of the rise of the liberal democratic notion that "everyone should be free to enter into a loan contract at an interest rate that is considered appropriate" justifies loan profitability. the function of credit creation in the banking system and the nature of profit-pursuing operation of capital will naturally lead to excessive debt of the overall economy, because "the main activity of finance is to create a huge debt chain and obtain more profits from it". that is, due to the existence of compound interest, even if there is no new debt, the scale itself will have endless compound growth. the growth rate of the real economy is relatively limited, and the duration of high-speed growth is short-lived [53] , which will inevitably lead to a continuous increase in leverage. therefore, when debts accumulate to a certain scale, credit funds will inevitably spread more than high-quality assets, and due to the decentralized nature of globalization (financial centers and distribution centers in the west, product centers in the east, savings in the east, debt accumulation in the west, [54] ), will become more dangerous, systemic risks and even the outbreak of financial crisis is inevitable. therefore, the free development of economy and capital may lead to disastrous consequences, requiring external supervision and constraints to restrict, and regulatory forbearance and legal loopholes are also important aspects of the study of systemic risk formation mechanisms. [55] believe that the outbreak of the subprime mortgage crisis stemmed from the sec's policy of exempting investment banks from restricting the regulation of the balance sheet liabilities in 2004, which was converted into an institutional voluntary supervision model, and the leverage ratio of investment banks generally rose sharply. the commodity futures modernization act, introduced in 2000, prevented state governments from using their laws to prevent wall street from using derivative financial instruments. [56] pointed out that relying on technocrats or over-reliance on technology to manage financial systemic risks will easily create an over-confidence illusion for regulators. as greenspan admitted at the october 2008 congressional hearing, he relied too much upon and believed in the "self-correction of the free market." jonathan c. lipson, a professor of law at temple university, believes that the design and trading of financial derivatives cds are divorced from the nature of their guarantees. unregulated over-the-counter trading has made this market far larger than the actual guarantee, which has created hidden dangers for the outbreak of the subprime mortgage crisis. compared with the research on the formation mechanism of the financial crisis, the research on systemic risk formation mechanisms is not entangled in whether it is related to the real economy, but whether it is at the macro level or the micro level, whether it is institutional research or event research. on the other hand, research is more dispersed, and the formation mechanism of systemic risk spans the research scope of financial disciplines, which deserves more in-depth and detailed discussion. [49] [50] [51] studied several financial crisis events from high-income and low-income countries, and found that the crisis would cause the average price of real estate to fall by 35% in the next six years; in the next three and a half years, asset prices fell by an average of 55%. in two years, real output fell by an average of 9%. in four years, the unemployment rate rose by 7%, while the government deficit averaged 86% higher than the pre-crisis level. once the systemic risk evolves into a financial crisis, the impact on the real economy is obvious. as [57] put it, this is because external factors that are not related to the fundamentals of the company will lead to market participation shocks caused by changes in capital participation. this will affect the price of securities in the capital market, and thus change the investment behavior of micro-enterprises. the investment of enterprises has externalities and ultimately affects the operation of the real economy. he believes that different financing models have different impacts on the real economy. the equity financing market is suitable for investment projects that use equity financing methods (such as high-tech enterprises). such enterprises have positive externalities to the real economy. therefore, although the bursting of the technology bubble hit the securities market in the early 21st century, investment in high-tech industries has accelerated technological progress and is conducive to the development of the real economy. the bond financing market is suitable for investment projects that use debt financing (such as fixed assets investment such as real estate). such investments are generally highly leveraged and have negative externalities to the real economy, so once the bubble bursts, the damage to the real economy is significant. the theoretical study of the impact of systemic risk on the real economy has been dissociated from the mainstream of macroeconomic research for a long time after keynes, because whether it considers from the real economic cycle model [58] [59] [60] or the keynesian is-lm model, the market is a complete market due to the alienation of individual heterogeneity or information asymmetry. therefore, the financing method of enterprises does not affect the value of enterprises (mm theorem), so similar financial friction and systemic risk issues are difficult to match with the traditional theoretical framework, which makes the research on such problems lack micro-foundations. until the new dynamic keynesian theoretical framework (dnk) based on the dsge method was put forward ((cee) [61] , (acel) [62] ), it was compatible with the assumption of price stickiness, and incorporated the investment and financing behaviors and leverage changes under the information asymmetry into the model. the financial accelerator theory proposed by bernanke et al., the bgg model [63] , has become a pioneer in this field. due to the limitation of the model's solution, dsge's utility function and production function setting are both in the form of linear functions or quasi-linear functions. however, linear functions cannot explain the nonlinear changes brought about by economic shocks, and leverage has a nonlinear relationship with the economic cycle. the former has the most direct connection with systemic risk occurrence [64] . to explain the nonlinear relationship between leverage and economic cycles, bernanke proposed a nonlinear investment and financing decision model linked to corporate net assets. in addition, because information asymmetry includes the cost of external investigations (costly state verification, csv), there exists a risk premium between corporate internal financing and external financing (external financial premium). the existence of the premium will make the financing situation of the enterprise worsen when the economic shock occurs, which will accelerate the decrease in investment and bring about the "financial accelerator effect". to simplify the research, bernanke expressed the functional forms of other economic sectors as linear relationships, focusing only on the internal and external financing differences of enterprises and the resulting crisis transmission mechanism. subsequent economists further extended financial frictions to the household sector, the banking system, and the government sector, and further explained the real estate market [65] , the monetary policy transmission mechanism of government departments [66] , and the risk transmission mechanism of the banking system [67, 68] through the dnk theoretical framework. the transmission path that affects the real economy through leverage is not limited to the ways depicted in figure 4 . the empirical study of the impact of systemic risk on the real economy is relatively infrequently referred only two of the top 100 works of literature in the annual average are related to this field. even empirical studies of the impact of the financial crisis on the real economy are few and far between, which may stem from the following reasons: 1. the number of observable systemic risk events is limited, and fewer samples are analyzed using time series or panel analysis; 2. in the quantification of systemic risks due to the existence of many differences, the results of using quantitative indicators to assess the impact of systemic risks on the real economy may vary. 3. because of the different ways of quantification, there will be large differences in the prediction of real economic fluctuations. if the results are not significant, the value of the research will be affected. [69] collected all systemic risk event samples after world war ii in the united states and europe to circumvent or mitigate the effects of the above problems, using 19 different methods to quantify and assess systemic risk. the quantile regression method was used to test the predictive power of systemic risk indicators on the deterioration of the real economy. it was found that only a small number of quantitative indicators can capture the risks of the macroeconomic downturn, and they can only be roughly predicted. another reason for the lack of theoretical research on the impact of systemic risk on the real economy is that traditional macroeconomic theory itself has a weak microfoundation, however, the systemic risk is mainly reflected in the systemic problems caused by the interaction of individual heterogeneous behaviours at the micro-level. by using traditional macroeconomic models, it is assumed that individual identity or limited heterogeneity has greater limitations. therefore, [3] believe that the agent model (agent model) should be introduced from other disciplines to better simulate the micro-individual behaviour, and to obtain a more realistic macroeconomic model. the empirical study of the impact of systemic risk on the real economy is relatively infrequently referred only two of the top 100 works of literature in the annual average are related to this field. even empirical studies of the impact of the financial crisis on the real economy are few and far between, which may stem from the following reasons: 1. the number of observable systemic risk events is limited, and fewer samples are analyzed using time series or panel analysis; 2. in the quantification of systemic risks due to the existence of many differences, the results of using quantitative indicators to assess the impact of systemic risks on the real economy may vary. 3. because of the different ways of quantification, there will be large differences in the prediction of real economic fluctuations. if the results are not significant, the value of the research will be affected. [69] collected all systemic risk event samples after world war ii in the united states and europe to circumvent or mitigate the effects of the above problems, using 19 different methods to quantify and assess systemic risk. the quantile regression method was used to test the predictive power of systemic risk indicators on the deterioration of the real economy. it was found that only a small number of quantitative indicators can capture the risks of the macroeconomic downturn, and they can only be roughly predicted. another reason for the lack of theoretical research on the impact of systemic risk on the real economy is that traditional macroeconomic theory itself has a weak micro-foundation, however, the systemic risk is mainly reflected in the systemic problems caused by the interaction of individual heterogeneous behaviours at the micro-level. by using traditional macroeconomic models, it is assumed that individual identity or limited heterogeneity has greater limitations. therefore, [3] believe that the agent model (agent model) should be introduced from other disciplines to better simulate the micro-individual behaviour, and to obtain a more realistic macroeconomic model. besides, the dnk model focuses more on the interpretation of risk-transfer pathways, and the endogenous interpretation of systemic risks is difficult. it is generally assumed that shocks are external, so it is difficult to predict the occurrence of crises. as to the endogenesis, based on the general theory, [70] proposed that capitalist economies had not shown to follow the neo-classical theory or in the "dis-equilibrium state" as keynesian economics stated, because of the functioning of sophisticated financial institutions. two sets of prices, for current outputs and capital assets, aligned within a capitalist economy are determined by different proximate variables, as well as consumption demand and investment demand having different horizons, the former upon shorter run expectations and the later on longer ones. both form the aggregate (effective) demand. consumption demand is a function of current factors, while investment demand is a function of the price of capital assets, supply price of investment goods, expected profits and external financing conditions. different from the micro-based general equilibrium methodology, minsky initiated his theory from a macroeconomic perspective, based on kalecki profit function, which always stands in a close or an open economy. by decomposition of the profit function, variables including monetary issues are demonstrated as follows: where ï� is the current profit of the whole economy, i is the current investment of the private department, df is the government deficit, sw is the savings of the private department, and c is the current consumption. thus, profits are not only determined by current productive factors, government activities, savings and consumption, but also by asset prices, which connect closely with financial markets. furthermore, profits, identified as cash flows, are the essential signals for investments, critically linking different payment commitments in the past, present and future. according to different cash flow commitments being availably financed, the financial system and debt structure are composed of a mixture of three types of financial postures (hedge finance, speculative finance and ponzi finance). as the natural growth of the economy, profits, in the form of cash flows, fluctuate due to the endogenous discrepancy in expectation horizons, which causes the ratios of the speculative finance and ponzi finance to increase in prosperous times, leaving the financial system to gradually become more sensitive to interest variations. when the current cash flows cannot sustain the current payment commitments, it initiates a deflationary break, and a financial crisis takes place. the implementation of mitigation policies can only alleviate the destruction yet not solve it, making the whole financial system more fragile to economic fluctuations. (financial instability hypothesis). since the complication of interactions between key factors, as well as variant vast, complicates markets in capitalist economies, minsky mainly demonstrated his theory in a narrative approach. thus, even though minsky's theory became the kernel of post-keynesian economics, it is difficult to further develop a comprehensive mathematical model ( [71] once put minsky's fih hypothesis into the framework of is-lm model to explain and get the equilibrium result, but the conditional formula that equates the price of investment goods and the price of assets implies the assumption that the capital market and the commodity market will automatically maintain the equilibrium. even though there are endogenous factors that cause deviation from the equilibrium of financial markets and commodity markets, the economy will return to equilibrium because of the implicitly assumed equality condition. besides, the decision of asset price depends solely on investment demand, which is also contrary to minsky's view, who emphasizes that the determination of asset price depends on various factors.). it was also confronted with various criticism. [72] proposed that, as in the upwards phases of an economy, investment increases cause a higher level of aggregate profits so that the leverage ratio does not necessarily increase. while, in the downside phases, investment decreases negatively affect the aggregate profits more than expected, which will increase the leverage ratio. the paradox of debt goes against minsky's theory. this contradiction should be directed to the preconditions of fih, which assume an extent of monopoly in commodity markets, so that producer can earn excess profits from market power. as the aggregate profits increase in the upward phases while the profit rates decrease, the over-increased investment would bring up leverage ratios, which could imperil future payment commitments. as in the downside phases, shrunk investments decrease aggregate profits while profit rates recover, which is good for bringing down leverage ratio. thus, in the framework of minsky' theory, the paradox of debt is explainable on the presumption of monopoly markets. further discussion can be referred to [73] . some studies try to expand the kaleckian model [74] [75] [76] by bringing a normal degree of capacity utilization into endogenous investment function. [77] utilize the profit share instead of the profit rate, [78] introduced external competition into an imperfect commodity market. all the adjustments provide a supplementary explanation of the demand regime. furthermore, monetary and financial variables are incorporated into the profit function [79, 80] . the late research intends to contain fih and the paradox of debt through a neo-kaleckian model [81] . moreover, by following a centre-periphery structure, the model explains how financial movements in the periphery associate with international financial markets' movements and external vulnerability. recent research in this field mainly focused on empirical research to support and verify fih in different economies [82] [83] [84] . minsky's achievements are more than fih. instead, he focused on the whole system, aiming at constructing a general theory to explain the whole operational law of capitalist economies, including the upward and the downward phases of the economic cycle. the discrepancy in horizons and the amplification mechanism, which is realized through the interaction between profits and investment activities, as well as the positive (negative) feedbacks between asset prices and liabilities, not only explains the endogenesis of financial crises but also demonstrates his economic vision in a dialectical way, so whether the economy attains an equilibrium gives way to the depiction of economic operation processes, as the former is only a temporary stability status compared with the whole process. with regard to the difference in expectations on consumption demand and investment demand, it should not be criticized as a lack of rationality; it should be interpreted as generalized rationality, as in the "wall street view", which is intended to be rationally applied to the real economy and sophisticated financial systems. early research on the formation of the financial crisis from the perspective of micro-market structure mainly began from the following two aspects: 1. information asymmetry; 2. liquidity. besides, there are studies on the impact of the financial crisis from the perspective of currency and interest rates and expectations. compared with the study on the financial crisis in the field of market microstructure, the study on the micro-market structure of systemic risk has increased the study of the complexity of the overall system, and it will be reviewed from the following three aspects: before the outbreak of the subprime mortgage crisis in 2007, the conclusions of the close relationship between institutions and the complex financial network's overall risk resilience were generally positive [22, 85, 86] , and it was considered that sufficiently decentralized inter-bank liabilities could produce a more stable financial system. nevertheless, some scholars then began to link the increase in systemic risk to the complexity of financial networks. for instance, [87] believes that as banks' counterparties increase, the probability of a systemic crash increase. [88, 89] demonstrated that the financial system itself has an amplification effect on the increase in systemic risk by modelling the inter-bank infection behavior. the research idea of this kind of amplification draws on the research methods of the previous network infection model [20, 90] , and the amplified transmission pathways are various. from assets and liabilities, studies by [91] showed that financially interrelated companies were more prone to systemic risk in the face of market shocks due to cross-shareholdings. similarly, [92] argued that the similarity of assets held between banks determines the extent to which relevant information was disseminated and the likelihood of a systemic crisis. by studying bank exposures in the us and europe, [93] argued that systemic risk was affected by common risk factors, and the interdependence of financial institutions was mainly due to systemic factors. [94, 95] used asset securitization as an example to explain the transmission path of a financial network to amplify systemic risk from the perspective of debt. it is believed that through the interconnected balance sheet network, asset securitization essentially magnifies the financial leverage of the entire financial system, thereby increasing the vulnerability of the system. [96] showed that the higher the degree of financial integration, the more stable the interbank interest rate under normal conditions, and the higher the interest rate soars during the crisis. combining the positive and negative views, [97] demonstrated through modelling that a closely linked financial system provides sufficient stability in the face of smaller market shocks. however, when the impact scale exceeds a certain threshold, the tightly connected financial network will amplify the risk and make the financial system more vulnerable, and the structure of the financial network has an important impact on the stability of the financial system. the research of complex financial networks draws on the game model and the research results of the previous network theory. the network theory originated from the seven bridges problem and then developed into the random graph theory, and then evolved into complex network theory. network theory and topological methods provided the basis for theoretical modelling of the structure of the research network itself [98] and also provided empirical methods [99] . because how individuals interacting with each other in the network and their importance can significantly affect the results of network structure and impact transmission, the current research in this field is still very popular. [100] pioneered the use of an interbank debt matrix to describe the network structure of the banking system. this idea was followed by scholars who later studied systemic risk [97, 101] . however, early network models used to be a non-direct model, which assumed that the connections between the participants are reciprocal and have the same interaction, even the same importance, such as if the inter-bank liability matrix is assumed to be positive, bank a's claims against bank b are the same as bank b's claims against bank a. this is because the inter-bank liability data is not available (therefore, in the empirical case, the inter-bank liability behavior will be further assumed, and the banking system liability matrix will be determined through technical processing such as the information entropy method). on the other hand, for the sake of simplifying model simulation, as [97] described, the simplified model and the same subject are to study the relationship between the structure of the financial network itself and financial stability. the results of many empirical tests are contrary to the assumptions of the theoretical model. [102] studied the italian interbank market structure from 1999 to 2010 and found that they are in line with the core-peripheral network structure, that is, a few banks continue to play a central role, maintaining lending with peripheral banks and providing liquidity to the market. while capital lending activities between core banks and non-core banks are rare, market liquidity at the time of the financial crisis is often caused by the reduction in borrowing by core banks, which means that the network distribution is not symmetrical. the core-peripheral network structure was first proposed by [103] , other related works are contributed by [104] , and [105, 106] covered the most core-periphery network structures and a further supplementary version [107] was published in 2017. a series of empirical studies showed that in other financial markets, such as india, mexico, the netherlands and the uk, the banking system network also presented the characteristics of the core-peripheral structure [108] [109] [110] . thus, more complicated networks with directional connections are introduced, which is more common in the financial contagion subdivision within the same e-n framework [111, 112] . moreover, since there are various types of connections between financial institutions, the financial network should have multi-layers, including credit, insurance, derivatives, collateral obligations cross-holding assets. the research on financial multi-layer networks is surging. [113] study the interaction of short-and long-term bilateral secured and unsecured lending. [114] study the mexican banking system on all market layers and find that market-based systemic risk indicators systematically underestimate expected systemic losses. the research on the relationship between financial market participants' behavior and systemic risk is more dispersed. the division of financial research segments can be mainly classified into behavioral finance research, corporate finance research, and micro-market structure research. participants vary in different financial markets, the relationships between their behavior and systemic risk, and the transmission pathway, are also various. according to the type of participant, the most studied is the bank. despite the trend of bank disintermediation, in the financial crisis, the irreplaceable role of the banking system and its impact on the financial system determined that it is still at the core of the financial system. the idea that competition promotes the efficiency of financial allocation has promoted the wave of financial liberalization in developed countries in europe and america since the 1970s (the second banking directive issued by the european union in 1989 allowed banks to engage in banking, insurance and other financial operations; in 1999 the us gramm-leach-bliley act also eased similar restrictions.). financial innovation products and means are constantly emerging, and competition among banks is becoming increasingly fierce, which brings about financial deepening [115] and improved resource allocation efficiency [116] , but it may also lead to instability in the banking system [117] . the relationship between interbank competition and the stability of the banking system has always been controversial. on the one hand, competition is conducive to reducing the cost of capital, thereby increasing the return on investment of enterprises, and increasing profitability, which maintains the controllable credit risk of banks and increases the stability of the system [118] . on the other hand, it will lead to bank rent-seeking behavior, especially the bank deposit insurance system will make banks tend to take more radical measures to pursue profits in a fiercely competitive environment [119] . on this basis, without deliberately screening customers, the systemic risk will be increased [22, 26, 120] . this is because it is difficult for perfect competition to exist in the competition between banks. the different scales and core-peripheral banking system structure will inevitably have a monopolistic effect on this market [121] , and there are moral hazards and adverse selection due to information asymmetry [122] . an extended study on the [118] models modifies the absolute inverse relationship between the two proposed [123, 124] , and presents that it should be u-shaped, that is, increased competition can improve the stability of the system and also make the banking system more vulnerable. the intensity of competition and other factors are the decisive factors that determine the negative or positive relationship between the two. [117] considered the role of policy incentives and constraints in the interaction between the two, and empirically tested and compared the relationship between the fierce competition in the banking industry and the stability of the banking system under different policy environments in different countries. it was found that the more standardized the regulation, the more developed the securities market, the more perfect the bank insurance system and the more efficient the credit information sharing, and that increased competition will increase the vulnerability of the system. the method of balance sheet effect is not only adopted to analyze banking defaults, but also applied to study other market participants' behavior. the fire sale and funding correspond to the activities of the bank's assets and liabilities, respectively. when there is a run (trader's run, deposit run or collateral run), the bank has to hedge the risk by recovering the loan in advance or raising the collateral mortgage rate, but there may be a risk of payment due to coordination failure. [34] believe that when the market lacks liquidity, banks have fewer opportunities to hedge their overall risk or deal with liquidity shocks. this will push banks to begin fire sales in response to future liquidity demands, which in turn will lead to excessive fluctuations in market capital prices. moreover, when monopolistic behavior exists in the interbank market, it will further reduce the effective supply of funds in the market [125] , and even market freeze appears. [30] classify liquidity risk into liquidity risk in the market and liquidity risk in trader financing. traders provide liquidity to the market through financing, but the trader's financing capabilities (such as equity and margin financing) rely on the liquidity of the asset market. however, market liquidity will suddenly dry up under certain circumstances and will affect many securities, resulting in large market fluctuations. it also leads to difficulties in the financing of traders and the realization of assets. the interaction between financing liquidity and market liquidity forms a liquidity spiral and triggers systemic risks. the liquidity spiral has a variety of transmission pathways, such as the loss spiral of erosion capital, and the guarantees spiral, which all lead to a fire sale. there are many different interpretations of the reasons for the formation of market liquidity shocks: (1) information asymmetry some of the research on financial crises caused by the lack of market liquidity is associated with information asymmetry, which is often one of the causes of liquidity exhaustion [122] . the financial crisis caused by information asymmetry is more typical in bank run events. the global game model proposed by [126] is also based on the assumption of information asymmetry, that is, participants can only obtain noisy observations, and the lack of common knowledge leads participants to choose risk-dominant equilibrium as the only equilibrium. this global game model is extended to the currency crisis model [127] and the bank crisis model [37] . when information asymmetry exists in the interbank market, it will exacerbate the liquidity of the market due to counterparty default risk, leading to system collapse [128] . moreover, the information asymmetry between the supervisory authority and the regulated institution will cause the central bank to misjudge. since regulators do not have a complete understanding of the asset quality of the entire banking system, therefore, even if a central bank participates in the interbank market to prevent the inefficient allocation of market resources due to adverse selection, moral hazard and monopolistic behaviour, the result of such hedging is difficult to be optimal [122] . (2) liquidity mismatch [129] believe that the common feature of financial markets in the recent financial crisis is that financial institutions generally have more serious mismatches in liquidity. for example, the terms of interest rate fluctuations in the subprime borrower's loan contract will affect their ability to repay and refinance. commercial banks are burdened with over-proportionate contingent liabilities relative to capital under unregulated off-balance sheet business. the rise in the proportion of investment banks that rely mainly on repurchasing commercial paper financing means that the proportion of the entire financial system that relies on market financing is rising, so the excessive leverage ratio is the risk of mismatch in liquidity. in the event of a liquidity shock, market liquidity is rapidly depleted by the balance sheet effect, resulting in the interaction of collateral run, bank run, and counterparty run. the central bank has to ease the crisis by releasing a large amount of liquidity, but this has further increased the moral hazard of financial institutions to increase leverage, which has further worsened the problem of liquidity mismatch. (3) actual demand shock [130] argued that the demand for liquidity stems from the mismatch between the supply and demand of goods by consumers in different spaces. once they needed to spend at different times in different locations, they constituted cross-regional liquidity needs, and banks needed to provide liquidity through the crediting behavior of the payment system or the interbank market. [22] agreed that random demand of consumers for liquidity will become a liquidity shock for a depository institution due to incomplete interbank market transmission. [86] suggested that systemic risk is mainly transmitted through the payment system, the interbank market and the derivatives market and that the random withdrawal demand of consumers at different times and in different places will have a liquidity impact on the payment system and the interbank market. the existence of the interbank market reduced the incentives for banks to hold non-profit cash; banks had solvency under certain conditions, while the market was caught in coordination failures. the financial accelerator model proposed by [63] explained the external financing premium problem faced by enterprises from the perspective of the incomplete credit market. the incentive mechanism of the company has prompted the agent to favour debt financing. when the negative impact causes the net value of the enterprise to decrease, the solvency declines, which in turn has an impact on the asset side of the loan bank. when the assets of the loan bank are impaired due to corporate default and further affect the scale of the risk reserves, the bank faces a liquidity shock, and the impact has a nonlinear amplification effect through the interbank market. other factors affecting market liquidity risk were institutional and systemic risk management systems, financial system structures, and the institution's own reputation risk [64] . moreover, the phenomena associated with liquidity shocks include market freeze, asset sales, contagion effects, and institutional bankruptcy, which also possibly appear when systemic risks occur. financial contagion occurs as the distress of one or a small group of banks risks the stability of other financial institutions, even ultimately spreading to the real economy. the financial contagion can occur due to both local contractual obligation connections, and global market connections, e.g., through the prices of assets due to mark-to-market valuation [131] . [100] established a framework for contagion analysis, which studies the spread of obligation default within the financial system due to unpaid liabilities. since there are various types of connections between financial firms, the shocks can transmit in the network via different channels, and the channels also interact with each other in some historic events. according to [132] taxonomy, there are mainly four types of channels: asset correlated contagion, default contagion, liquidity contagion, market illiquidity and asset fire sales. except for the default contagion, for the rest of the channels, the observed domino or spillover effects are demonstrated through the slump in mark-to-market prices. thus, contagion research can be classified into two main branches: default contagion and price-mediated contagion. (1) default contagion [133] explored how the probability and potential impact of contagion is influenced by aggregate and idiosyncratic shocks. they found that the robust-yet-fragile financial system has a low probability of such contagion. [134] extend the basic default contagion model by introducing default costs into the system. [135] assume minimal information about network structure, and through such key node-level quantities as asset size, leverage and the fraction of a financial institution's liabilities held by other financial firms, they derive explicit bounds on the potential magnitude of network effects on contagion and loss amplification. other models with extension in default costs include [90, 136, 137] . (2) price-mediated contagion these contagion models consider the mark-to-market asset price slumps due to the extreme tension in market liquidity and individual liquidity, as demonstrated in fire sales [138] [139] [140] [141] [142] [143] cross-holdings have also been studied [91, 136] . [144, 145] provide a framework for modelling asset prices during a fire sale. [131] generalizes the model of [142] by allowing for differing liquidation strategies. [146] study the three extensions that are bankruptcy costs, multiple assets and fire sales within a single model. the survey of empirical work on contagion can refer to [147] . empirical studies are revealing that financial contagion can not be well explained by the base model of obligation default [101, 135, 145, 148] . system stress tests are usually adopted to study the exposure of the whole system towards indirect contagion [138, 149] . in general, the network-based models are mainly rooted in the general equilibrium approach, which brings sufficient economic connotation to these models. it also means that systemic shocks are usually assumed from outside instead of endogeneity. thus, through limited amplification, contagions can suspend automatically and the whole system returns to a new equilibrium. even referring to the multiple assets models, the shock on the prices of assets and consequent price variations distribute independently with the network contagion, otherwise, the mathematical model shall be too complicated to be solved. however, the financial contagion research does offer great achievements in: (1) explaining the contagion path via networks of all types; (2) empirically revealing the impact of contagion on the whole financial system; (3) providing supportive evidence for capital requirements, mark-to-market accounting and limitation of the scale of interbank business. systemic risk identification and measurement are one of the most important aspects of systemic risk research. in recent years, the literature in this field has also increased. the indicators of systemic risk are ses [7] , mes [8] , klr [24] , covar [9] and capital shortfall [10] . some scholars have reversed the financial systemic risk through the market prices of derivatives (credit default swaps, cdss) issued by financial institutions [150, 151] . a survey of measurements on systemic risk can be referred to [152] , and they also offered codes for 31 such measures. besides, [5] adopted the herfindahl index to measure the concentration of credit portfolios of the emergency loans programs provided by the fed in the 2008-2010 crisis. they found that 22 strongly connected institutions received the most of the funds, while small dispersed shocks could have triggered the systemic default event, which indicates that the critical banks are "too-central-to-fail". i [153] constructed an insurance pricing model based on the put option framework of the merton model, including asset relevance, banking systemic risk and joint default rate, suggesting that systemic risk leads to low insurance pricing, which leads to insufficient liquidity in the event of a crisis. [154] used a multivariate extremum theory to model the tail dependence between multiple assets and adopted a non-parametric estimation to estimate and then to measure systemic risk. [155] studied the monthly yield data of hedge funds, banks, securities, insurance and other financial institutions based on principal component analysis combined with granger causality, and concluded that the internal correlation of these four types of finance has increased the systemic risk. [156] viewed the banking system as a credit portfolio, analyzing the value of the portfolio and the unanticipated losses to calculate systemic risk. [157] considered financial departments as a time-varying systemic risk of overall measurements, and defined systemic risk as to the conditional default probability, and analyzed the default probability through credit repayment. when the systemic risk is defined as a series of debt contract defaults, systemic risk is linked to credit risk. the biggest characteristic of credit risk is its tail effect. therefore, many researchers have introduced the copula model to simulate the tail dependence of financial institutions' extreme losses under systemic risk [11, 12] . [158] proposed a new systemic risk analysis framework, which incorporated marginal default probability, credit risk structure, consistent information multivariate density optimization (cimdo), generalized dynamic factor model and t-copula model into the framework. [149] propose the endogenous risk index (eri) to measure the spillovers across portfolios, as well as the indirect contagion index (ici) to capture the importance of a bank via measuring the loss it inflicts on other financial firms. the two indicators provide a complementary measure of interconnectedness. [159, 160] provide reviews on more recent measurement studies. therefore, it can be seen that, due to the tail characteristics and nonlinear characteristics of systemic risks, there are many methods for the quantitative assessment of systemic risks. all approaches and definitions should serve their purposes. due to the fast development of systemic risk research, this paper may not cover all the latest methods, while it can provide a series of frameworks for reference. according to the survey work, the approaches are classified into five categories: theoretical foundation, mathematical models, econometric methods, simulation and agent-based models. as to the simulation methods, more can be referred to [148] , which will not be discussed in this section. systemic risk research rests its theoretic root in equilibrium approaches, which follow a micro-based research paradigm. to achieve the equilibrium, the route of deduction shall be clarified, and the micro-based equilibrium or activities need to be coordinated with the purpose of general equilibrium by a series of preset hypotheses. to explain the frictions on financial markets, the preset conditions are adjusted accordingly, based on more convincing and practical micro-foundations. there are at least three types of endogenous inconsistencies: inconsistency in preference or expectation [22, 161] , heterogeneity [22, 26, 86] , information asymmetry [67, 86] , and bgg model [63] . besides, through obligation contracts [22, 26] or institutions' capitals [86] or other generalized agreements [162, 163] , connections are established within the financial system, which establishes the network analysis of contagions, domino effects and spillovers. as mentioned above, the study of the generation and transmission mechanism of systemic risk is in virtue of the dnk model framework. linking the activity entities and market structure at the micro-level with macroeconomic growth and volatility makes the performance of macroeconomic fluctuation of systemic risk possess a certain micro foundation. because systemic risk is accompanied by rising leverage, financial friction, large fluctuations before and after liquidity, and other derivative phenomena, it is closely related to individual heterogeneity and the characteristics of the market structure itself. to explain the impact of individual heterogeneity or heterogeneous expectations on financial market asset prices and the real economy, calvo and rotemberg's sticky-price model is used for reference. what's similar is the application of the two-sector model in the utility sector or the constraint function in the family sector, for example, [65] distinguish the buyers from the superior and sub-optimal levels and separate their constraint functions, explaining the intrinsic relationship between the rapid rise of mortgage loans and the rapid rise in housing prices before the subprime mortgage crisis. the game model is also a more common method for explaining financial friction and systemic risk. [36] proposed an analytical approach to coordinated games. by dividing the depositor's investment behaviour into two categories, patient and impatient, in the case of incomplete information, the investor will choose whether to withdraw the deposit to the bank in advance according to the expectation and then the bank run may occur due to the individual's rational behaviour. this model successfully explains the reasons for the bank's asset-liability maturity mismatch, and also explains the transmission mechanism that triggered the banking crisis. however, the deficiency is that there are multiple equilibriums in this model, and it is impossible to predict the occurrence of the bank run behaviour. the coordinated game model is then further optimized and expanded [37] . [126] proposed a method to ease public information hypotheses, allowing participants' post hoc observations to satisfy certain random distribution characteristics. the game based on this hypothesis is named as a global game. compared to the coordination model, the global game model eases the assumption of public knowledge and reduces the quantity of equilibrium. [127] introduced the global game method into the study of financial crisis theory and studied the mechanism of currency attack activities; the sequential global game method is also widely used in the fields of macroeconomics and financial crises. chinese scholars also used this model to explain the liquidity crisis of banks and the government's rescue policy [164] , and infectious mechanisms for the liquidity of informal financial institutions to formal financial institutions [165] . as for the modelling of contagion and spillover risks among financial intermediaries, the covariance of assets [7] or liabilities [7, 86, 90] was introduced based on micro-level maximization, in which the agent is either risk-neutral or risk-averse. asymmetric information assumption is also brought in. thus, the general equilibrium approach and its loose conditions can explain these endogenous questions: how participants react to an unexpected shock; what expectation they would form and action they would take thereafter; how the systemic risk is transmitted or spillovers occur within the system. however, although frictions are invited into the equilibrium models, they have to always assume the exogeneity of the shocks. another series of theoretical approaches are based on an analysis of evolutionary history and institutions, like marxism and minsky's theory. the latter inherited the former's essence in explanation of profits in that they both agree that profits go down as investment increases in the phases of economic expansion, and a crisis takes place when profits cannot cover the current payable obligations. while minsky further developed his theory by establishing a profit function on an identical equation, it follows a macro-micro-macro non-equilibrium paradigm, which unravels the necessity of present assumptions. through decomposition, the profit function can embrace various endogenous factors from different departments of an economy, including technical improvements, public policies and the financial institutions, etc., while marxism mainly attributes the profits to the surplus-labour and capital structure. minsky's methodology can also be applied to analyze the household and government behaviours and its subsequent effects on the financial system. this methodology solves the problem of exogeneity, as the financial crisis phases are integrated into a whole theory to explain the operation of capitalist economies. to avoid mathematical formalism, he insisted on delivering his theory via a narrative approach, which leaves more space for his successors to explore [82] [83] [84] , etc. network and contagion models are mainly established in the general equilibrium approach [166] . after [22] , the baseline of the network model is proposed by [100] , which is expanded from explaining default contagions to price-mediated contagions. based on that, [133] offered a model involving hard defaults, in which interbank debts of defaulted banks recover zero value. there are also other models with extensions on bankruptcy costs, multi assets and fire sales. [142] provides a framework to prove the existence of clearing asset prices and liability payments for equilibrium in a network contagion. [143] expand it to a dual-risky-asset equilibrium. no matter the eisenberg-noe model, or the gai-kapadia model or the amini framework, they all belong to static cascade models, which assume the structure and scale of the network itself be static. while networks can evolve due to the interactions of participants' inter-connections of assets and shocks from the outside, so random graph models are brought in [6, 132, 140, 142, [167] [168] [169] . moreover, to capture the stochastic and dynamic structure of the network with a vast volume of nodes, the mean-field models are borrowed from the discipline of physics, which can be applied to explain the herding effect and endogenous contagion [170, 171] . these models focus on quite simple interbank interactions that neglect defaults and contagion [137, 170, 172] . the latest models involve credit risk to explain default contagion [157, 173, 174] . since, in most economies, the interaction data of financial institutions in the system is difficult to derive, it is also impossible to acquire the specific counterparty-trading information from a bank's balance sheets. thus, alternatives are adopted to settle this problem, one of which is the maximum entropy approach. the debtrank approach is another measure to estimate the distress contagion without observing failing institutions [5] . the main methods used are the copula model to simulate the joint distribution of risk factors, and the introduction of option pricing models and multivariate extreme value theory, or principal factor analysis to extract key factors using the dcc-garch model to model the correlation between multiple assets [8] , and to establish multivariate quantitative indicators. furthermore, to verify the economic structure variation as systemic risk takes place, var is usually adopted [82] [83] [84] tc. [175] proposed the introduction of an agent-based model (abm) to solve individual heterogeneity problems, and monte carlo simulation can be used to predict the impact of micro-subject heterogeneity on macroeconomic variables. compared with the game model, abm is more compatible with more differences and can link the internal economic evolution logic with external data consistency. the key contributions by [176, 177] are to incorporate the leverage accelerator into agent-based simulated network models. the limitation of such models is that it is difficult to calibrate and test their results. in addition to financial heterogeneity issues, systemic risk draws more attention to the stability of the system itself, and complex network models are borrowed to solve such problems. because of its similar structure to infectious diseases and bio-food chains, the financial system network links various financial institutions through financial flows, and triggers a domino effect due to risk events in individual institutions [22, 97, 178] . however, the financial network system is more complicated than the natural food web or infectious disease transmission. this is because the activities of participating individuals are interactive, the interactions are not always symmetrical, the behavioral choices of the entity change with expectations or event shocks, and the results of behaviors are also characterized by uncertainty. this makes the financial system's structural stability research more complicated and has to restrict the behavioral characteristics of the system to individuals through many strict preconditions [3] . the methods for identifying and quantifying systemic risks have been discussed previously. therefore, in general, the system of research methods for systemic risk is as in figure 5 . in addition to financial heterogeneity issues, systemic risk draws more attention to the stability of the system itself, and complex network models are borrowed to solve such problems. because of its similar structure to infectious diseases and bio-food chains, the financial system network links various financial institutions through financial flows, and triggers a domino effect due to risk events in individual institutions [22, 97, 178] . however, the financial network system is more complicated than the natural food web or infectious disease transmission. this is because the activities of participating individuals are interactive, the interactions are not always symmetrical, the behavioral choices of the entity change with expectations or event shocks, and the results of behaviors are also characterized by uncertainty. this makes the financial system's structural stability research more complicated and has to restrict the behavioral characteristics of the system to individuals through many strict preconditions [3] . the methods for identifying and quantifying systemic risks have been discussed previously. therefore, in general, the system of research methods for systemic risk is as in figure 5 . systemic risk is understood from the perspective of classical economics as the transformation between multiple economic equilibriums. from the perspective of risk management, it is tail risk management. from the perspective of behavioral finance, it is because the micro-subjects' psychological and behavioral characteristics form a self-reinforcing feedback mechanism, which belongs to the systemic overall collapse risk from the perspective of complex network theory. from systemic risk is understood from the perspective of classical economics as the transformation between multiple economic equilibriums. from the perspective of risk management, it is tail risk management. from the perspective of behavioral finance, it is because the micro-subjects' psychological and behavioral characteristics form a self-reinforcing feedback mechanism, which belongs to the systemic overall collapse risk from the perspective of complex network theory. from a broader perspective, it also covers the fields of sociology, psychology, and political science. there are a thousand hamlets in the eyes of a thousand people. different starting points focus on different problems, and the methods used are different. it is also the complexity and change of systemic risk that attracts researchers to constantly try to innovate. the systemic risk research branch is extensively involved, both in connection with traditional financial crisis research and expanding research on system structure and risk warning. financial systemic risk research can be said to be the most intersecting field between finance and even economics and other disciplines. the main research methods used are both tools of traditional economic theory, as well as social network models and natural science experimental simulations. for the generation of systemic risks, the endogenous problems of shocks are difficult to solve using traditional economic models. therefore, dnk's dsge model often assumes that shocks are exogenous; to predict systemic risks, it is urgent to introduce interdisciplinary approaches to innovate research on endogenous factors. on the other hand, the adoption of complex network models often requires many rigorous assumptions that are outside of reality, and these assumptions may exclude the potential risk factors of reality. after all, the financial system itself is much more complicated than the food chain, while other new interdisciplinary research methods also have insufficient internal economic explanatory power. it is, therefore, necessary to use appropriate analytical tools based on specific issues of the specific financial sector. to better sort out the hotspots, the latest 5 years' (2015-2020) systemic risk research was analyzed and was connected with the development of crisis research, 733 articles in total. it turns out that two divisions are mainly focused on ( figure 6 ). intersecting field between finance and even economics and other disciplines. the main research methods used are both tools of traditional economic theory, as well as social network models and natural science experimental simulations. for the generation of systemic risks, the endogenous problems of shocks are difficult to solve using traditional economic models. therefore, dnk's dsge model often assumes that shocks are exogenous; to predict systemic risks, it is urgent to introduce interdisciplinary approaches to innovate research on endogenous factors. on the other hand, the adoption of complex network models often requires many rigorous assumptions that are outside of reality, and these assumptions may exclude the potential risk factors of reality. after all, the financial system itself is much more complicated than the food chain, while other new interdisciplinary research methods also have insufficient internal economic explanatory power. it is, therefore, necessary to use appropriate analytical tools based on specific issues of the specific financial sector. to better sort out the hotspots, the latest 5 years' (2015-2020) systemic risk research was analyzed and was connected with the development of crisis research, 733 articles in total. it turns out that two divisions are mainly focused on ( figure 6 ). a total of 733 articles are screened and analyzed according to their titles, keywords, abstracts and references. among the 10 subdivisions, more co-citation clusters are formed in systemic risk measurement, financial market structure, and financial stability. this map reveals that more recent studies focus on network stabilization and systemic risk measurements. although the extreme value approach was brought into this area, it caught only a small amount of attention. furthermore, the high concentration on risk measurement may imply that the measuring methods gradually mature, which leaves limited room for subsequent researchers. considering the ongoing worldwide recession, the research directions that may be further expanded in the future are as follows: a total of 733 articles are screened and analyzed according to their titles, keywords, abstracts and references. among the 10 subdivisions, more co-citation clusters are formed in systemic risk measurement, financial market structure, and financial stability. this map reveals that more recent studies focus on network stabilization and systemic risk measurements. although the extreme value approach was brought into this area, it caught only a small amount of attention. furthermore, the high concentration on risk measurement may imply that the measuring methods gradually mature, which leaves limited room for subsequent researchers. considering the ongoing worldwide recession, the research directions that may be further expanded in the future are as follows: (1) more work on models with multiple shocks and spillover effects be done. no matter endogenous or exogenous shocks, the contagion rotation shall not be limited to a specific market or intermediaries. more than one spillover risk is discussed within a model. moreover, at present, there are many types of research on systemic risks in the banking system, the real estate market and the foreign exchange market. there are few studies on the systemic risks of the shadow banking [179, 180] and internet financial markets, which may be related to the lack of available data and difficulties in providing supporting empirical studies. (2) dynamic multi-layer networks expect further exploration, especially when the prices of assets have a connection with the financial contagions. (3) more empirical studies of the impact of systemic risk on the real economy are necessary. it is expected that recent advances in large-scale data and computing tools benefit systemic risk studies, acquiring more real-world and large-scale data for empirical analysis [181] . 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macroeconomics systemic risk on different interbank network topologies bankruptcy cascades in interbank markets risk-sharing and contagion in networks shadow credit in the middle market: the decade after the financial collapse shadow banking shadowed in banks' balance sheets: evidence from china's commercial banks key: cord-278870-pct184oa authors: finell, eerika; vainio, annukka title: the combined effect of perceived covid-19 infection risk at work and identification with work community on psychosocial wellbeing among finnish social sector and health care workers date: 2020-10-19 journal: int j environ res public health doi: 10.3390/ijerph17207623 sha: doc_id: 278870 cord_uid: pct184oa it has been well documented that both risk perception and group identification are related to psychosocial well-being. however, their combined effect has rarely been analyzed. we examined the combined effect of perceived risk associated with covid-19 infection at work and work community identification on psychosocial well-being (i.e., frequency of stress symptoms) among health care and social sector workers in finland (n = 1279). data were collected via an online questionnaire in june 2020 and analyses of covariance were conducted. perceived covid-19 infection risk at work was classified into high, medium and low risk. in total, 41% of participants reported a high risk. after all background variables were included, participants who reported high perceived infection risk and low work community identification reported stress symptoms more often than those who reported high perceived risk and high identification (p = 0.010). similarly, the former differed significantly from all other comparison groups (medium and low risk, p < 0.001), being the most stressed. we found that perceived infection risk and work community identification were not related to each other. our conclusion is that high work community identification can buffer employee stress when faced with a high perceived health risk. in the context of the covid-19 pandemic, work organizations with a high infection risk should advance the possibility of employees’ identification with their work community. a new coronavirus disease, caused by the sars-cov-2 virus and identified as covid-19, was first acknowledged in china in 2019 and rapidly became a global threat to the health of many employees working in the social and health care sectors. there is evidence that covid-19 has a disproportional impact on health care workers both physically and psychologically, causing a high incidence of disease, death, and a number of psychological problems, including stress, depression and anxiety [1] [2] [3] [4] . although psychological symptoms have been found to be particularly high among those working on the frontline during the pandemic [5] [6] [7] [8] , non-frontline heath care workers have also reported such symptoms [9] . moreover, these symptoms have been more severe among females and younger workers [4, 10, 11] , as well as for those with prior mental health problems [12, 13] . in addition to these cases, social sector workers, who have seldom been acknowledged in the recent covid-19 literature, have also faced risk of infection in their work [14] . for example, in england and wales, social care workers had a significantly raised rate of death between march and may 2020 [2] . it is clear that covid-19 is causing psychological stress to social sector and health care workers due to the increased risk of personnel infection, fear of spreading the disease, concern for one's own family if one becomes sick [3] , lack of knowledge on the disease as well as deaths among other professionals [15] . on the one hand, perceived health risk is important in order to motivate individuals to engage in health-protective behaviors [16] . on the other hand, the perceived risk is associated with increased stress symptoms, in particular when the management of the risk is at least partly beyond one's own behavioral control [17, 18] . among health care and social sector workers, the perceived infection risk is dependent on the protective measures taken by organizational infrastructures and governments. accordingly, confidence in protective measures has been found to be associated with reduced psychological symptoms [13, 19, 20] . various protective strategies against covid-19-related occupational stress and its negative effects have been considered, ranging from resilience enhancement to providing adequate organizational support systems [12] [13] [14] . curiously, in the context of social sector and health care workers, the role of organizational group processes has rarely been discussed. according to the "social cure" perspective to social identity, group membership has a positive impact on well-being and health [21] -an association shown to be prevalent among medical service workers [22] . groups can provide powerful psychological resources to their members, such as social support, which can reduce stress symptoms [23] [24] [25] . for example, people who identify with a group perceive other group members' social support more positively than people who do not. in addition, those reporting high levels of work community identification are more confident of receiving support from other group members when needed than those less inclined to identify [23, 25] . thus, when occupational organizations consider protective strategies against stress that is related to covid-19 infection risk at work among social sector and health care workers, promoting identification with their work community might be one key protective factor that can buffer this stress. this article analyses the combined effect of the perceived risk associated with covid-19 infection at work with work community identification on psychosocial well-being (i.e., frequency of stress symptoms) among health care and social sector workers in finland. we analyze both groups because in finland, social sector and health care workers often work in the same organizations and institutions as part of multi-professional teams. to our knowledge, the buffering effect of group identification on the relationship between perceived health risk and stress symptoms has yet to be empirically tested. drawing on the "social cure" perspective [25] , we test our main hypothesis that those social sector and health care workers who report both a high perceived covid-19 infection risk at work and low work community identification suffer significantly more often from stress symptoms than those who report high perceived covid-19 infection risk and high work community identification. the data were collected through the union of health and social care professionals in finland, which distributed the invitation and the link to an online questionnaire to its members. in total, 1555 members filled in and submitted the online questionnaire, with a response rate of 5%. in the first page, participants were informed about the aim of the research and had the opportunity to scroll through the form before answering questions; participants were not obliged to respond to any of the items, ensuring full voluntarism could be guaranteed, and informed consent was positively required. only participants who provided informed consent, were in paid or salaried employment, and were 18-64 years old were included. the final sample included 1279 participants. the data were collected between 28 may and 16 june 2020 using the limesurvey program. the ethics committee of the tampere region approved this study (41/2020). the outcome measure was self-reported stress symptoms (i.e., stress symptoms) measured by four items: "during last two months, how frequently you have suffered from": (a) fatigue, apathy or lack of energy; (b) difficulties in falling asleep or recurrent awakenings at night; (c) tenseness, nervousness or irritability; (d) feeling that it is "all just too much"? these items were drawn from the finnish quality of work life survey [26] and have often been used as indicators of stress and mental exhaustion [27, 28] . in these analyses, the items were measured on a five-point scale, with the number selected corresponding to the frequency of symptoms experienced: 0 = never, 1 = less often, 2 = once or twice a month, 3 = a few times a week, and 4 = almost daily. the items were summed and then divided by the total number of items the participants responded to. the rate was calculated if at least two items were answered. the reliability was good (cronbach's alpha = 0.84). the perceived risk associated with covid-19 at work (i.e., perceived risk at work) was measured by one item: how likely do you consider the following things will happen in relation to your work in six months: i will have covid-19 infection in my workplace. a similar item has been used elsewhere [29] . see also [30] . the response scale varied from "very likely" (1) to "very unlikely" (5) . responses reporting that the risk had already materialized (n = 6), as well as those who reported that the question did not apply to them (n = 82), were coded as missing values. the item was recategorized with 0 corresponding to the risk is unlikely (values 4 and 5 in the original scale), 1 corresponding to the risk is intermediate (value 3 in the original scale) and 2 corresponding to the risk is likely (values 1 and 2 in the original scale). the work community identification was measured by two items adapted by doosje et al. ("i feel strong ties with other members of my work community", "my work community is an important part of me") [31, 32] . the five response options varied between 'totally disagree' (1) and 'totally agree' (7) . the items were summed and divided by the number of items (mean = 5.11, standard deviation (sd) = 1.43). the rate was calculated if at least one item was answered. responses reporting that the question did not apply to them (n = 18) were coded as missing values. the reliability was good (cronbach alpha = 0.88). then, the summed variable was recategorized into two categories, using the mean as a cut-off value (0 = low identification; 1 = high identification). finally, we formed one new combined variable. we combined perceived risk at work and work community identification as follows: 1 = low risk and high identification, 2 = low risk and low identification, 3 = medium risk and high identification, 4 = medium risk and low identification, 5 = high risk and high identification, and 6 = high risk and low identification. the background variables were gender, age, number of people living in the household, highest level of education, occupational group, working time pattern (e.g., two-shift work, three-shift work) and whether the participant belonged to a covid-19 infection risk group. the working time pattern was controlled because shift work is associated with insomnia [33] . the occupational group was determined through the following response options: 0 = social sector work and 1 = health care work. if requested, participants had the possibility to report another occupational group. in total, 11 participants reported that they worked both in social sector and health care work. due to the small frequency of this latter category, it was not included in the analysis and was coded as a missing value [34] . a further 9 participants reported that they worked in the education sector. these participants were categorized alongside those who worked in the social sector (0 = social sector work, 1 = health care work). in addition, we controlled the perceived risk associated with covid-19 in one's spare time (i.e., perceived risk in spare time): how likely do you consider the following thing will happen in your spare time in next six months: i will have covid-19 infection in my spare time. the response scale varied from very likely (1) to very unlikely (5) . the item was recategorized as the perceived risk at work, as explained above. responses reporting that the risk had already materialized (n = 6) were coded as missing values. finally, we assessed trust in the finnish authorities by a single item: i trust the finnish authorities in their treatment of the coronavirus pandemic. the response scale varied from totally agree (1) to totally disagree (5). the effects of all the variables on perceived risk at work and work community identification were examined using cross-tabulations and analyses of variance. the effects of all the variables on stress symptoms were examined using analyses of variance and pearson correlation coefficients. the main and combined effects of perceived risk at work and work community identification on stress symptoms were subjected to an analysis of covariance (ancova). this analysis was carried out using ibm spss statistics for windows, version 25.0. (ibm corp., armonk, ny, usa) the missing data were handled by using listwise deletion. the percentage of missing data varied from 0% (age) to 10% (perceived risk in spare time). the mean of the missing values was 2% per variable. the majority of the participants were women, aged between 35 and 44 years, and had tertiary education. table 1 presents the frequencies and means of all the variables, as well as their associations with the predictors and the outcome variable. in total, 41% of participants reported a high risk of covid-19 infection at work. perceived risk at work was significantly associated with all background variables with the exception of gender, highest education, occupational group, and belonging to a covid-19 risk group (see table 1 ). the risk perception decreased with age, so that whilst 67% of the youngest age group reported a high risk, only 32% of those in the age group 55-64 reported the same. those who reported medium risk lived in significantly bigger households (mean = 3.20, sd = 1.36) than those who reported low (mean = 2.92, sd = 1.30) or high risk (mean = 3.01, sd = 1.36). a higher percentage of those who had two-shift work (48%), three-shift work (46%) or who worked atypical hours (49%) reported a higher covid-19 infection at work than those who had regular day (36%) or evening/night work (23%). in addition, 18% of participants who reported high perceived risk at work also reported high perceived risk in their spare time, whereas the percentage among medium-and low-risk groups was 8% and 7%, respectively. finally, those who reported high risk had significantly less trust in the finnish authorities to effectively manage the coronavirus pandemic (mean = 2.44, sd = 1.05) than those who reported low (mean = 2.18, sd = 1.07) or medium risk (mean = 2.28, sd = 0.90). there was no significant association found between perceived risk and work identification. from the background variables, the work community identification was only significantly associated with working time patterns and having trust in the finnish authorities (see table 1 ). those who had three-shift work, or worked atypical hours, reported higher work identification (56% and 68%, respectively) than those in two-shift work (50%), regular day work (48%), or regular evening or night work (21%). finally, those with low work identification had less trust in the finnish authorities to manage the pandemic (mean = 2.45, sd = 1.04) than those with high identification (mean = 2.22, sd = 0.96). stress symptoms were significantly associated with all the background variables except the number of people living in the household, occupational group, working time pattern and perceived risk in spare time (see table 1 ). women reported stress symptoms (mean = 2.29, sd = 0.93) more often than men (mean = 2.01, sd = 0.96), participants from the age group 25-34 reported symptoms the most often (mean = 2.52, sd = 0.87) and their stress level differed significantly from all the others except those in the 18-24 age group. similarly, those who had secondary education reported these symptoms more often (mean = 2.42, sd = 0.93) than those with tertiary education (mean = 2.24, sd = 0.94). in addition, participants who belonged to a covid-19 risk group reported stress symptoms more often (mean = 2.42, sd = 0.97) than those who did not (mean = 2.22, sd = 0.93). finally, the lower the level of trust participants reported in the finnish authorities to manage the coronavirus pandemic, the greater the propensity to report stress symptoms. both predictors were significantly associated with stress symptoms (see table 1 ). participants who perceived a high risk of covid-19 infection in their workplace reported stress symptoms more often than those who perceived only a medium or low risk. this association was still significant after all the background variables were included in the model (f(2, 1001) = 30.84, p < 0.001, ηp 2 = 0.06). estimated marginal means and standard errors of unadjusted and adjusted models are reported in table 2 below. similarly, participants with low work identification reported stress symptoms more often than those with high work identification. once again, this association was still significant after all the background variables were included in the model (f(1, 1018) = 13.87, p < 0.001, ηp 2 = 0.01). estimated marginal means and standard errors of unadjusted and adjusted models are reported in table 3 . in light of these results, we examined the combined effect of perceived risk at work and work community identification on stress symptoms. the estimated marginal means, standard errors and pairwise comparisons of unadjusted and adjusted models are reported in table 4 . in the unadjusted model, the combined effect was significantly associated with stress symptoms (f(5, 1178) = 22.01, p < 0.001, ηp 2 = 0.09). participants who reported high perceived risk and low work identification reported stress symptoms with significantly greater frequency than those who reported high perceived risk and high identification. all the mean differences between this category and other combined categories were significant. after inserting all the background variables into the model, the combined effect was still significantly associated with stress symptoms (f(5, 997) = 15.25, p < 0.001, ηp 2 = 0.07). similarly, the means of participants who reported both high risk and low work identification still differed significantly from all the other categories. there were no statistically significant interactions between perceived risk and work identification in the unadjusted (f(2, 1178) = 0.43, p = 0.650) or fully adjusted models (f(2, 986) = 0.49, p = 0.611). 1.75 0.07 1 < 2 ** ,a , 1 < 3 ***, 1 < 4 ***, 1 < 5 ***, 1 < 6 *** 2. low risk + low identification 121 2.07 0.08 2 > 1 ** ,a , 2 < 4 * ,b , 2 < 5 ***, 2 < 6 *** 3. medium risk + high identification 206 2.13 0.06 3 > 1 ***, 3 < 4 * ,c , 3 < 5 ***, 3 < 6 *** 4. medium risk + low identification 211 2.33 0.06 4 > 1 ***, 4 > 2 * ,b , 4 > 3 * ,c , 4 < 6 *** 5. high risk + high identification 249 2.43 0.06 5 > 1 ***, 5 > 2 ***, 5 > 3 ***, 5 < 6 * ,d 6. high risk + low identification 241 2.63 0.06 6 > 1 ***, 6 > 2 ***, 6 > 3 ***, 6 < 4 ***, 6 < 5 * ,d 1. low risk + high identification 150 1.80 0.07 1 < 2 ** ,e , 1 < 3 ***, 1 < 4 ***, 1 < 5 ***, 1 < 6 *** 2. low risk + low identification 117 2.08 0.08 2 > 1 ** ,e , 2 < 4 * ,f , 2 < 5 ** ,g , 2 < 6 *** 3. medium risk + high identification 199 2.14 0.06 3 > 1 ***, 3 < 4 * ,h , 3 < 5 ** ,i , 3 < 6 *** 4. medium risk + low identification 204 2.32 0.06 4 > 1 ***, 4 > 2 * ,f , 4 > 3 * ,h , 4 < 6 ** ,g 5. high risk + high identification 236 2.41 0.06 5 > 1 ***, 5 > 2 ** ,g , 5 > 3 ** ,i , 5 < 6 * ,j 6. high risk + low identification 235 2.62 0.06 6 > 1 ***, 6 > 2 ***, 6 > 3 ***, 6 < 4 ** ,g , 6 < 5 * ,j 1. low risk + high identification 148 1.79 0.09 1 < 2 ** ,k , 1 < 3 ***, 1 < 4 ***, 1 < 5 ***, 1 < 6 *** 2. low risk + low identification 116 2.09 0.10 2 > 1 ** ,k , 2 < 4 * ,l , 2 < 5 ** ,g , 2 < 6 *** 3. medium risk + high identification 198 2.15 0.08 3 > 1 ***, 3 < 5 ** ,i , 3 < 6 *** 4. medium risk + low identification 199 2.32 0.08 4 > 1 ***, 4 > 2 * ,l , 4 < 6 *** 5. high risk + high identification 236 2.41 0.08 5 > 1 ***, 5 > 2 ** ,g , 5 > 3 ** ,i , 5 < 6 * ,b 6. high risk + low identification 230 2.63 0.08 6 > 1 ***, 6 > 2 ***, 6 > 3 ***, 6 < 4 ***, 6 < 5 * ,b 1. low risk + high identification 133 1.82 0.10 1 < 2 * ,m , 1 < 3 ** ,i , 1 < 4 ***, 1 < 5 ***, 1 < 6 *** 2. low risk + low identification 106 2.09 0.11 2 > 1 * ,m , 2 < 5 ** ,n , 2 < 6 *** 3. medium risk + high identification 172 2.14 0.09 3 > 1 ** ,i , 3 < 5 ** ,a , 3 < 6 *** 4. medium risk + low identification 178 2.27 0.09 4 > 1 ***, 4 < 6 *** 5. high risk + high identification 219 2.40 0.09 5 > 1 ***, 5 > 2 ** ,n , 5 > 3 ** a , 5 < 6 * ,b 6. high risk + low identification 207 2.63 0.09 6 > 1 ***, 6 > 2 ***, 6 > 3 ***, 6 < 4 ***, 6 < 5 * our results support the hypothesis that those with low work community identification and high perceived covid-19 infection risk at work show greater frequencies of stress symptoms than those with high identification and high perceived infection risk. the former group differed significantly from all other comparison groups in reporting the most stress symptoms. in addition, participants who reported high work community identification and low perceived covid-19 infection risk at work reported significantly fewer stress symptoms than any other group. finally, participants who reported a medium infection risk and low identification only showed significant differences from those who reported either high risk and low identification or no stressors at all (e.g., no risk and high identification). these findings show that higher levels of work community identification may act as a buffer against stress factors in the field of social sector and health care work, especially when employees perceive a high health risk in their workplace. as the social cure model argues, group identification is an important source of security, support and belonging and its effect on well-being has been demonstrated in many studies [25] . to our knowledge, however, this is the first study which has demonstrated this relationship in the context of the covid-19 pandemic and risk perception. our results contribute to the extant literature in a number of other ways. first, the findings lend support to previous analyses reporting a link between risk perceptions and stress [17, 18] by showing a strong relationship between higher perceptions of covid-19 infection risk in the workplace and the increased frequency of stress symptoms. secondly, work community identification and stress symptoms were also related. participants reporting low levels of work community identification also reported stress symptoms more often than those reporting high levels of work community identification. this also supports findings that have been found before, albeit in a different context [35] . in contrast, work community identification and covid-19 infection risk at work were not significantly associated with each other. this contradicts previous research suggesting that the greater the identification with a group, the lower the perceived risk is likely to be [36, 37] . this claim was predicated on the basis that group identification increases trust. although it is likely that this occurs in particular contexts (e.g., family celebrations) [38] , this is unlikely to be the case in all circumstances. one important factor that might explain this inconsistency is the degree to which people are able to control their risk. in our cases, social sector and health care workers rarely have sufficient control over the risk factors, or necessary resources, that are able to make meaningful reductions to their perceived risk (e.g., proximity to infection; having enough personal protective equipment). thus, people can report high levels of work community identification, and exhibit high levels of trust, but if the loci of risk controls are out of reach of the community, then group identification is unlikely to relate positively to perceptions of risk. this opens an important avenue for future research, namely, to explore in greater detail, and in more diverse contexts, how levels of control over risk-management resources affect the relationships between group identification and risk perception. finally, empirical research that has analyzed the well-being of social sector workers during covid-19 pandemic is rare [14] . our social sector and health care workers did not significantly differ in risk perception, work community identification or frequencies of stress symptoms. these occupational groups often work in the same organizations and institutions as part of multi-professional teams and thus share the same covid-19 risk. more research analyzing the well-being of social sector workers is needed in the context of covid-19. our results have strong practical implications. the findings can make a valuable contribution to the development of strategies for social sector and health care professionals to maintain their well-being under stressful working conditions during the covid-19 pandemic. given that risk perception and stress are mutually related [17, 18] , their interplay may produce a vicious circle which can end up in exhaustion and burn out. the social cure approach suggests that developing greater group identity is a powerful psychological resource in a such context [25] . our results highlight the role of work community identification in contributing to social sector and health care workers' ability to cope with stressors that cannot be avoided at work. for example, employers can strengthen the sense of community in their organizations by providing opportunities to share experiences within the group in a safe way and develop mutual trust as well as by recognizing and acknowledging the powerful role of collective strategies that the work community has successfully used in the past and adapting them to current environment [22] . naturally, our findings have their limitations. the data are cross-sectional; thus, our reasoning is strongly based on previous research and theories. in addition, although our sample was representative of members of the union of health and social care professionals in finland, the response rate was lower than we would have preferred, and it is possible that those with higher levels of concern about their work condition had a greater motivation to answer than those who perceived that their work conditions were risk free or of low risk. these factors limit the generalizability of the results. in addition, the effect size was quite small. although work community identification may act as a buffer, practical factors such as having enough personal protective equipment are of course essential for controlling the stress caused by covid-19 infection risk. cross-cultural, longitudinal and experimental data are needed to confirm the findings. our findings have shown that participants who report low work community identification and high perceived covid-19 infection risk at work were significantly more stressed than other participants. this finding indicates that the combined effect of work community identification and risk perception needs to be considered in efforts to reduce the psychological stress social sector and health care workers face during the covid-19 pandemic. our findings provide further support to the notion that group processes are essential to people's psychosocial well-being and that this is especially salient in times of health crises. covid-19 and mental health: a review of the existing literature office for national statistics. coronavirus (covid-19) related deaths by occupation, england and wales: deaths registered between 9 the covid-19 pandemic and the health care providers; what does it 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outbreaks on healthcare workers: rapid review of the evidence they are essential workers now, and should continue to be: social workers and home health care workers during covid-19 and beyond les professionnels de santé face à la pandémie de la maladie à coronavirus (covid-19 the precautionary principle and risk perception: experimental studies in the emf area the negative effects of workplace injury and illness on workplace safety climate perceptions and health care worker outcomes perception is reality: how patients contribute to poor workplace safety perceptions psychological effects of the sars outbreak in hong kong on high-risk health care workers long-term psychological and occupational effects of providing hospital healthcare during sars outbreak advancing the social identity approach to health and well-being: progressing the social cure research agenda: applying the social cure group identification and self-efficacy associated with quality of life in emergency medical services volunteers: a cross-sectional investigation taking the strain: social identity, social support, and the experience of stress the effects of social support on sleep quality of medical staff treating patients with coronavirus disease 2019 (covid-19) in january and february 2020 in china the new psychology of health: unlocking the social cure three decades of working conditions. findings of finnish quality of work life surveys psychiatric illness in general practice: a detailed study using a new method of case identification validity of a single-item measure of stress symptoms covid-19: risk perception and coping strategies risk perceptions of covid-19 around the world perceived intragroup variability as a function of group status and identification guilty by association: when one's group has a negative history individual vulnerability to insomnia, excessive sleepiness and shift work disorder amongst healthcare shift workers. a systematic review the chi-square test of independence analytic review of social identification and health in organizational contexts when trust goes wrong: a social identity model of risk taking the psychology of health and well-being in mass gatherings: a review and a research agenda a social identity perspective on covid-19: health risk is affected by shared group membership we want to thank the union of health and social care professionals for the data collection. the authors declare no conflict of interest. key: cord-291679-jfxqipt8 authors: yang, seongwoo; cho, sung-il title: middle east respiratory syndrome risk perception among students at a university in south korea, 2015 date: 2017-06-01 journal: am j infect control doi: 10.1016/j.ajic.2017.02.013 sha: doc_id: 291679 cord_uid: jfxqipt8 background: the 2015 middle east respiratory syndrome (mers) outbreak in south korea was a serious threat to public health, and was exacerbated by the inappropriate responses of major institutions and the public. this study examined the sources of confusion during the mers outbreak and identified the factors that can affect people's behavior. methods: an online survey of the risk perception of university students in south korea was performed after the epidemic had peaked. the questionnaire addressed the major social determinants in south korea during the mers epidemic. the analysis included data from 1,470 subjects who provided complete answers. results: the students had 53.5% of the essential knowledge about mers. women showed higher risk perception than men, and trust in the media was positively associated with risk perception (p < .001). additionally, risk perception was positively associated with overreaction by the public (odds ratio, 2.80; 95% confidence interval, 2.17-3.60; p < .001). these findings suggest that media content affected the public's perception of mers risk and that perception of a high level of risk led to overreaction. conclusions: risk perception was associated with most of the social factors examined and overreaction by the public. therefore, providing accurate information and data to the public, establishing trust, and facilitating the development of an attitude will all be important in future crises. the first middle east respiratory syndrome (mers) case was confirmed in south korea on may 20, 2015. the last case was diagnosed on july 4 and summed up to a total of 186 confirmed cases, almost half of which were in seoul. after that, south korea officially declared the end of the mers epidemic on december 23, 2015. during the mers outbreak, 38 died and 16,752 had been quarantined (fig 1) . 1 the case fatality rate of mers in south korea was approximately 20.4%, lower than that on the arabian peninsula (approximately 45%). 2 public apprehension was exacerbated because the government did not disclose timely information about the status of the epidemic or hospitals' names and procedures related to mers infection. therefore, the public were unaware of the appropriate actions to take, but were provided with relevant information by the media. indeed, several citizens created web sites that listed confirmed and suspected mers patients. 3 however, the public also received inaccurate information from the internet and social media; this increased the level of concern over mers and resulted in rumors. the government of south korea stated that any person who disseminated an untrue rumor would be prosecuted, but this failed to reduce the level of panic. although this action was supposed to prevent secondary damage, it was similar to the censorship of the media in china, where the propaganda departments of the chinese communist party directly supervised the media flow when the severe acute respiratory syndrome (sars) outbreak occurred in 2003. 4 the chinese government attempted to maintain political, social, and economic stability by minimizing the sars crisis through the withholding of information; however, a reverse effect occurred. nevertheless, the chinese government assigned responsibility for censorship of the media, including the internet, to local agencies. 5 in the new media age, in which social media (including the internet, short message services, and mobile applications) are centralized, the government restricts freedom of expression in the same way as it has restricted such freedom among traditional media sources, such as newspapers, radio, and television. 6 the control of the acquisition of information is more difficult in this new age because social media are tools not only for the dissemination, sharing, and seeking of health information but also for the expression of feelings and the sharing of personal experiences and opinions. 7, 8 therefore, organizations need to build effective communication tools to respond to emerging infectious disease (eid) outbreaks because the public may express scientific skepticism about scientific topics and participation in decision-making. 9 during epidemics, people usually require guidance on how to behave from a trusted source. the government and public institutions are the ideal sources because people tend to rely on the national administration. for this reason, trust in these institutions plays a main role in the public's acceptance of policies and actions. 10 the world health organization suggested that outbreak communication should incorporate the following 5 key factors: (1) building, maintaining, or restoring trust; (2) announcing early; (3) maintaining transparency; (4) understanding the public; and (5) planning of all aspects of the response to an outbreak. 11 therefore, risk communication enhances the decision-making ability of laypeople, and can be examined by assessing risk perception. 12 trust in not only the government and public agencies but also in the media and other institutions may be associated with risk perception. therefore, the instigation of fear among the public by the media may contribute to social panic, particularly in emergency situations. the term risk perception usually refers to individuals' judgments about and evaluations of hazards to which they might be exposed. 13 therefore, risk perception might be among the social phenomena related to exposure to the risk of disease. in addition, perceived risk influences health behavior both positively and negatively. 14 during the mers outbreak in south korea, negative behaviors were observed, such as oversensitive or inappropriate reactions. some children of health care workers at hospitals treating mers patients were prevented from attending school. meanwhile, self-quarantined subjects occasionally escaped out of their homes until the level of infection subsided. these reactions of citizens reflect distrust in the government and accelerated noncompliance with the directions provided by the korea centers for disease control and prevention. this finding is important because overreaction is an indicator of the level of trust in the government among the public and may provoke another social problem related to moral panic. 15 fear causing the behaviors described previously mentioned is likely related to risk perception and a low level of trust in the government and society. however, because risk perception may be related to a number of unknown determinants, it is important to identify factors that may affect risk perception. sjöberg examined risk perception using several approaches, 16 and reported that 30%-40% of risk perception could be explained by risk sensitivity, attitude, and a specific fear model. in other models, <20% of risk perception was explained. there were also some studies regarding risk perception. previous studies of risk perception related to nuclear explosions and infectious diseases addressed the relationship between perceived risk and various social predictors, such as knowledge, social trust, and attitude. 17, 18 however, previous literature on the determinants of risk perception has been limited. the aim of this study was to determine whether risk perception was associated with personal and social variables, including trust in the media, the health care field, and government. additionally, we sought to identify the associations of risk perception and social variables with compliance with self-quarantine guidelines and overreaction during the mers epidemic. in this study, knowledge, trust, personal characteristics, and other social determinants were considered the main factors affecting risk perception and overreaction. we developed a questionnaire based on previous studies of perception of the risk of sars and ebola conducted outside of south korea. [19] [20] [21] the questionnaire comprised the following 5 components: knowledge of mers (9 items), risk perceptions about mers (7 items), trust in society and governmental health policy (5 items), preventive behavior (11 items), and particular situations relating to mers (7 items). sociodemographic information was also obtained. korean-and english-language versions of the questionnaire were developed to enable inclusion of foreign students in the survey (supplementary appendix s1). the english-language version of the questionnaire was backtranslated into korean for quality control purposes. questions regarding knowledge of mers were used to estimate the level of accuracy of the following information: the selfrecognized level of knowledge, the concept of mers, route of transmission, the concept of close contact, symptoms, the concept of the incubation period, characteristics of mers, self-quarantine, and treatment of mers. evidence for these questions was from the mers response guidelines of the korea centers for disease control and prevention. 22 the cumulative knowledge score of the participants was calculated (range, 0-8; 1 point for each correct response [ie, in agreement with the evidence]). because all questions referred to information provided in governmental guidelines, the survey was regarded as providing an estimate of respondents' essential knowledge. risk perceptions were assessed using revised versions of the ebola risk perception surveys conducted in germany 20 and israel. 21 risk perception was assessed using levels of agreement with the following statements: "i think that i will contract mers if i come into contact with a mers patient (risk perception 1)," "i think that i might contract mers even if i do not come into contact with a mers patient (risk perception 2)," "my health will be severely damaged if i contract mers (risk perception 3)," "i think mers is more severe than other respiratory diseases (risk perception 4)," "even if i fall ill with another disease, i will not go to hospital because of mers (risk perception 5)," "mers will inflict serious damage on my community (risk perception 6)," and "mers may spread in korea again someday (risk perception 7)." the questions were responded to on a 5-point likert scale. in addition, because risk perception is a continuous variable, it was classified into 4 groups according to quantile (very high, high, low, and very low). a revised questionnaire regarding trust in society, media, and health policy was developed from the korean general social survey (kgss). the kgss has been validated in south korea and is conducted periodically nationwide. several questions in the kgss estimate the levels of trust among respondents in society, the media, central and local government, the national assembly, the medical profession, and nongovernmental organizations (ngos). such trust was expected to be associated with trust in health policy because governmental actions tend to reflect governmental policies. finally, questions regarding particular situations related to mers were classified into the following 2 categories: overreaction and compliance with self-quarantine. a large proportion of the population of south korea was unaware of the appropriate actions during the mers epidemic. these categories measure the characteristics of individuals not inclined to abide by the self-quarantine guidelines. therefore, this section assessed the following personal characteristics: degree of optimism about the health policies of south korea, willingness to sacrifice for society, responsiveness to an emergency situation, and attitude toward self-quarantine and overreaction. attitude toward self-quarantine was measured with a question asking whether respondents were willing to prioritize quarantine adherence above all personal needs (responses were categorized as yes and no). the overreaction section comprised the following 2 questions: (1) how would you react if you realized your children were in the same class as those of someone suspected (or confirmed) to have mers (including school and extracurricular activities)?; and (2) how would you react if you realized your children were in the same class as those of medical workers at hospitals with mers patients (including school and extracurricular activities)? the responses to the formerly involved overreactions, for example, "(do not) allow my relatives or children of my family to attend school," and those to the latter were the opposite, such as "i think children of medical workers at hospitals with mers patients should (not) be allowed to attend school." each question was assumed to indicate overreaction to the behavior of oneself and others. a presurvey including 152 participants was performed to assess the reliability and validity of the questionnaire and the direction of the responses. the presurvey was conducted both in the field using a tablet personal computer or laptop and online using an online survey application (surveymonkey, san mateo, ca). data for the main survey were collected by e-mailing students at seoul national university. the cronbach α values for the 2 new measures developed for this study, trust and risk perception, were 0.8307 and 0.6755, respectively, in the main survey. students at seoul national university were selected for the study. we considered this population appropriate for several reasons. first, they are not likely to include people associated with hospitals. second, younger individuals tend to have access to up-to-date information through smartphones or the internet. third, the subjects had similar levels of academic attainment and demographic characteristics. finally, because of the need for a timely investigation, this setting assured the benefit of accessibility and cost-efficiency. for the main survey, e-mails containing the link connected to the online survey setting were sent to all of the 30,727 students at seoul national university, including undergraduates, postgraduates, and foreign students. survey e-mails were sent on 3 occasions at weekly intervals from october 6-23, 2015. of the 30,727 students, 1,487 (4.8%) provided a complete response. after exclusion of those with missing responses, a total of 1,470 subjects were included in the study. this survey and research were approved by the institutional review board of seoul national university (no. 1508/002-003). relationships between levels of risk perception and demographic factors were evaluated by the χ 2 test, and the mean and se values were estimated. to evaluate correlations among independent variables, spearman correlation coefficients were calculated. correlation coefficients among explanatory variables were all <0.5, which was regarded as not having multicollinearity. 23 variables were selected for inclusion by stepwise calculation of the akaike information criterion. moreover, to prevent multicollinearity, a test of variation inflation factors was performed for each analysis. to assess the associations of demographic factors, knowledge, trust in social organizations, intention to sacrifice, and responsiveness to emergency situations with risk perception, multiple linear regression analyses were used. each question regarding risk perception was aggregated to produce a cumulative score indicative of the overall effect of risk perception. prior to analysis, the variables were tested using a q-q plot to verify the normality of their distribution andwith the exception of knowledge-were confirmed to be continuous because the ordinal values differed only slightly from a normal distribution. 24 risk perception was estimated on a scale of 1-7, and its relationship with predictors was assessed. in addition, to identify the association of risk perception with overreaction to the epidemic and compliance with self-quarantine, multiple logistic regression analyses were performed. odds ratios (ors) were calculated for self-quarantine and overreaction. analyses were conducted using sas version 9.4 (sas institute, cary, nc). sociodemographic variables and levels of risk perception are shown in table 1 . more than half of the participants were men (57.01%), 24-26 years of age (30.54%), citizens of south korea (95.51%), and postgraduate students (52.04%). a high frequency of risk perception was detected in women (n = 152; 52.6%), those 24-26 years of age (n = 97; 33.56%), students from south korea (n = 281; 97.23%), and postgraduate students (n = 166; 57.44%). the mean knowledge score was 5.35 ± 1.41 out of 10. therefore, respondents had approximately 53.5% of the essential knowledge about mers. the mean score for trust in the medical profession was higher than those for other social components (3.63 ± 0.95); the mean score for trust in the central government was lowest (2.37 ± 1.03) ( table 2 ). in terms of the media section, the item regarding trust in newspapers was excluded from the analysis because of its lack of validity according to the variable selection process. women had a higher risk perception score than men, not only overall (by 0.17/5 points; β = 0.17; p < .001), but also in all other risk perceptions from 1-7 (table 3) . older age was negatively associated with risk perception 2 (concern over contracting mers through indirect contact) (β = −0.07; p = .004) and positively associated with risk perceptions 4 (considering mers to be more severe than other respiratory diseases) (β = 0.09; p < .001), 6 (concern over damage to the community because of mers) (β = 0.05; p = .026), and 7 (future reemergence of mers) (β = 0.06; p < .001). in addition, only risk perception 6 (damage to the community) was significantly positively associated with korean ethnicity (β = 0.44; p < .001). knowledge influenced only risk perceptions 1 and 7. that is, knowledge was related to concern over contracting mers through direct contact (β = 0.04; p = .015) and reemergence of mers (β = 0.05; p = .004). knowledge was associated with risk perception, which does not support the hypothesis of this work. trust in the media (broadcasting) was positively associated with cumulative risk perception (β = 0.06; p < .001) and risk perceptions 1 (concern over contracting mers through direct contact), 3 (severity of mers), 4 (considering mers to be more severe than other respiratory diseases), and 6 (concern over damage to the community because of mers). however, trust in the medical profession (β = −0.04; p = .027) and the central government of south korea (β = −0.05; p = .014) was negatively associated with overall risk perception. risk perceptions 2 and 4 (relevant to disease traits) were related to trust in the medical profession. in addition, risk perceptions 5, 6, and 7 (relevant to community traits) were related to trust in the central government. in contrast, trust in local government (β = 0.04; p = .046) and ngos (β = 0.06; p < .001) was positively associated with risk perception. trust in local government and ngos was associated with risk perceptions 5 and 6 and risk perceptions 1, 3, 4, and 6, respectively. compared with the results for trust in the central government, those for trust in local government seemed to have similar effect sizes, but with a different direction of estimates. however, trust in ngos was associated with the perception of the risk of transmission and that to personal health. this suggests that ngos are believed to contribute to communities in various ways, including by providing medical services. trust in society was not associated with the overall risk perception but was negatively associated with concern over damage to the community (β = −0.11; p = .002). finally, trust in health policy was negatively associated with risk perception (β = −0.05; p = .014). risk perceptions 2 and 7 were related to trust in the health policy of the government of south korea. optimism about future health policy (β = −0.04; p = .024), willingness to sacrifice (β = −0.06; p = .004), and active responsiveness to an emergency (β = 0.18; p < .001) were associated with risk perception. only risk perception 3 was associated with optimism regarding health policy (β = −0.09; p = .009). willingness to sacrifice was negatively associated with risk perceptions 1, 3, and 5. in addition, responsiveness to an emergency was positively associated with risk perceptions 1, 2, 3, 4, 6, and 7. therefore, respondents who were pessimistic about health policy and unlikely to sacrifice themselves in specific situations and respond actively to an emergency exhibited a higher perception of risk. ors were calculated to estimate the associations among risk perception, knowledge, personal characteristics, and compliance with self-quarantine ( table 4 ). the proportions of men and women who indicated they would comply with the self-quarantine guideline were 82.7% and 87.2%, respectively. women were more likely to comply with self-quarantine (or, 1.50; 95% confidence interval [ci], 1.10-2.06; p = .010), as were older subjects (or, 1.22; 95% ci, 1.01-1.46; p = .037) and those with a greater level of knowledge (or, 1.22; 95% ci, 1.10-1.35; p < .001). additionally, subjects with more trust in the medical profession (or, 1.35; 95% ci, 1.14-1.60; p = .001) and those who were willing to sacrifice (or, 1.50; 95% ci, 1.20-1.88; p < .001) and actively respond to emergencies (or, 1.31; 95% ci, 1.03-1.67; p = .028) were also more likely to comply with a self-quarantine order. the proportions of positive responses to items about overreactions in one's own behavior (self-behavior) and overreactions in response to the behavior of others were 79.9% and 42.9%, respectively. knowledge (or, 0.90; 95% ci, 0.82-0.99; p = .037) and trust in society (or, 0.81; 95% ci, 0.66-0.98; p = .029) were negatively associated with overreaction in self-behavior (table 5 ). however, responsiveness to an emergency (or, 1.32; 95% ci, 1.05-1.66; p = .016) and risk perception (or, 2.80; 95% ci, 2.17-3.60, p < .001) were positively associated with overreaction in self-behavior. in terms of overreaction to the behavior of others (table 6) , korean respondents (or, 0.486; 95% ci, 0.28-0.84; p = .010), those with a greater level of knowledge (or, 0.79; 95% ci, 0.73-0.86, p < .001), and those with a higher level of trust in the medical profession (or, 0.70; 95% ci, 0.61-0.80, p < .001) were unlikely to overreact to the behavior of others. however, respondents with a higher level of trust in local government (or, 1.19; 95% ci, 1.02-1.38; p = .024) and higher risk perception (or, 1.86; 95% ci, 1.52-2.28, p < .001) were more likely to overreact to the behavior of others. therefore, risk perception was associated with a change in behavior during an epidemic. the findings of this study indicate that risk perception is associated with various social factors. risk perception was correlated with sex and the level of trust in social organizations. these findings indicate that risk perception interacts with demographic and personal attitudinal factors at a collective level, as previously suggested. 25 women had a higher risk perception than men. trust in the media (television), local government, and ngos exhibited positive associations with risk perception, whereas trust in central government, the medical profession, and health policy exhibited negative ones. these results suggest that people are aware of the different roles of central and local government. additionally, these results identify the types of determinant that affect whether people overreact when an infectious outbreak occurs. women and those with low levels of trust in central government, the medical field, and health policy were more likely to overreact. on the other hand, people with high levels of trust in the media, local government, and ngos may be hypersensitive when an eid outbreak occurs. furthermore, the higher risk perception was associated with only overreaction, not compliance to self-quarantine. hypersensitivity that leads to overreaction can be explained by perceived media dependency 26 ; however, this may have been related only to television in this research. moreover, differences in the effects of trust in central and local governments on risk perception may be explained by south koreans' perceptions of the roles of these government bodies. central and local governments do not always appear to smoothly coordinate the emergency response, and this may be related to ongoing challenges about decentralization from the central governmental system. 27 another important finding is related to the role of the media during a crisis. in this study, trust in the media positively affected risk perception and overreaction, supporting that the mass media influence perceptions of disasters and risks; however, they cannot change an epidemic event itself. 4 restrictions on the availability of information by the government can exacerbate the impact of a disaster, especially in the new media age, in which person-centered media is emphasized; this was the case in the 2003 sars outbreak in china and the 2015 mers outbreak in south korea. regardless of the political system (ie, even in democratic states), the absence of risk communication may yield unexpected results. therefore, the world health organization outbreak guidelines 11 regarding building public trust and establishing a transparent flow of information need to be followed. respondents in this study were moderately knowledgeable about mers, possessing 53.5% of the essential knowledge. this finding may reflect a higher mean level of education of the respondents compared with the general population, but indicates that the public is not ignorant about environmental and health-related matters. 28 from another point of view, this finding can be said to contradict the deficit model, which holds that the public lacks knowledge. 29 on the emergence of a novel infectious disease, people tend to be receptive to health-related information conveyed by new media, including the internet and mobile phones. for these reasons, the role of the mass media is particularly important because they usually provide widespread coverage of eids and convey information to the public. 30 furthermore, the level of knowledge about mers was not associated with risk perception. this is not in agreement with a previous report of a correlation between knowledge and perception of the risk of nuclear explosions. 31 notwithstanding these considerations, knowledge of mers was directly associated with overreaction and compliance with self-quarantine. this suggests that greater knowledge of unfamiliar diseases reduces the likelihood of undesirable behavior, which can lead to social problems. personal characteristics, including willingness to sacrifice and responsiveness to an emergency, were negatively and positively, respectively, associated with risk perception. in addition, while responsiveness to an emergency was associated directly with overreaction and compliance with self-quarantine, willingness to sacrifice was associated only with compliance with self-quarantine. personal characteristics were associated with responsive behaviors; however, the reasons for these associations could not be determined. one possibility is nationalism. individuals who regard nations as abstract communities with shared emotional bonds governed by rules and/or norms tend to be altruistic. 32 therefore, people in table 5 associations of risk perception, knowledge, and personal characteristics with overreaction in one's own behavior societies governed by established, systematic rules are less likely to exhibit unusual behaviors that may lead to social panic. moreover, inaccurate information is disseminated through social media platforms, such as twitter, facebook, and google. the enormous influence of social media during the 2014-2015 ebola outbreak in west africa has led to exaggerated concerns even among the population in the united states with negligible risks. 33 indeed, the mass media can also incite panic, which is related to fear and antisocial behavior 34 ; however, when they do their job properly, they can inform the public accurately about current conditions. two studies in which a mobile health communication tool was used demonstrated the effectiveness of a social media-based approach in terms of changing vaccination behavior. 35, 36 furthermore, the provision of appropriate and timely public health information by social media and the mobile health tool could accelerate the detection of disease outbreaks and enhance the public's response, 37 thereby minimizing adverse health and economic effects. 38 the findings of our study are depicted in schematic form in figure 2 . in this model, risk perception was related to various factors such as sex, trust, and other personal characteristics. there was a notable aspect of risk perception: it was directly associated with overreaction, but not with compliance to self-quarantine. this suggests that risk perception motivates self-protective behavior, possibly resulting in overreaction. however, it does not automatically result in compliance to quarantine, which is generally perceived as protecting others, rather than oneself. in this sense, risk perception is a double-edged sword: at an optimal level, it helps the public protect themselves from infection and thereby deter the spread of epidemic; however, when excessive and characterized by fear, it can lead to other social problems, such as overreaction and discrimination. sandman reported that risk perception is comprised of hazard and outrage. 39 the mers outbreak caused fear and anxiety among the population, which might have resulted in an overreaction to both the response of the government and the behaviors of themselves and others. 40 our model also points to the importance of trust in medical experts and proper knowledge. these 2 factors demonstrate the potential to maximize the benefit by promoting compliance and reducing overreaction. therefore, risk communication should not just scare people, but should create a context in which there is trust and a flow of knowledge and clear information between the authorities and the public. these conditions should prevent adverse effects, particularly in democratic states. the existing literature emphasizes these essential components of risk management and risk communication. 41, 42 to date, there are a limited number of studies on risk perception of infectious diseases (including mers); therefore, this work makes an important contribution to the field. several factors affecting perceived risk were evaluated (eg, trust in the media or health policy, personal characteristics), which were not assessed in previous studies. although knowledge and trust have been previously reported to be associated with perceived risk, 17, 18 this study further explored possible effects of risk perception and their implications in responding to an epidemic. eids are unfamiliar to the general public and are likely to be overestimated in the risk, 31 possibly leading to social panic. to prevent this, it is important to boost the risk communication with fostering trust and relevant knowledge, which requires transparency. this study had limitations. first, the survey involved students at a university; therefore, the participants might have different levels of concern about the epidemic compared with the general public. however, the participants represented the younger population with a homogeneous educational level with fewer confounding factors. therefore, the findings were still likely meaningful for understanding the characteristics of risk perception in the essence. second, the response rate was rather low (4.8%). most online surveys have much lower response rates than person-to-person interviews. 43 the students who had a greater perception of the risk might have been better motivated to participate in the study. even if the associations found in this study may be weaker in a larger population, it is informative to identify the direction and structure of the interrelationships among the factors. future studies should investigate whether the findings from this study are applicable in more diverse populations. furthermore, developing and testing more specific approaches to building trust and sharing knowledge during an epidemic would be needed. in responding to the public health emergency, collaboration is important among various social institutions, such as central and local governments, media, and medical community. more research is needed to explore the roles and relationships of these agents for effective risk communication. in conclusion, risk perception was found to be associated with social trust and personal attitudes toward emergency situations in this study. risk perception was associated with overreaction, possibly by fear-induced changes in behavior. however, knowledge about the nature of disease mitigated this possibility and enhanced compliance to quarantine guidelines. understanding the determinants of risk perception contributes to effective communication. building trust and sharing knowledge are important to ensure a rapid response to disease outbreaks, and to prevent unnecessary behaviors among members of the public. taking stock of the first 133 mers coronavirus cases globally-is the epidemic changing? middle east respiratory syndrome in the republic of korea: transparency and communication are key media, crisis, and sars: an introduction how censorship in china allows government criticism but silences collective expression convergence, content industries and media governance public anxiety and information seeking following the h1n1 outbreak: blogs, newspaper articles, and wikipedia visits pandemics in the age of twitter: content analysis of tweets during the 2009 h1n1 outbreak risk communication and infectious diseases in an age of digital media trust and social representations of the management of threatened and endangered species outbreak communication: best practices for communicating with the public during an outbreak risk perception and communication cross-cultural risk perception: a survey of empirical studies risk perception and self-protective behavior moral panic and social theory beyond the heuristic factors in risk perception risk perception of aids and reported sexual behaviour among students in secondary schools and colleges in tanzania epidemics and fear ebola risk perception in germany what does the public know about ebola? perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey an introduction to data analysis & presentation when can categorical variables be treated as continuous? a comparison of robust continuous and categorical sem estimation methods under suboptimal conditions society and health: sociology for health professionals no alternatives? the relationship between perceived media dependency, use of alternative information sources, and general trust in mass media public trust in government in japan and south korea: does the rise of critical citizensmatter? citizen science: a study of people, expertise and sustainable development the case for a 'deficit model' of science communication sars wars: an examination of the quantity and construction of health information in the news media knowledge and risk perception among nuclearpower-plant employees why do people sacrifice for their nations? ebola and the social media moral panic: from sociological concept to public discourse assessing vaccination sentiments with online social media: implications for infectious disease dynamics and control stage-based mhealth communication interventions for hpv education social media in public health responding to global infectious disease outbreaks: lessons from sars on the role of risk perception, communication and management hazard versus outrage in the public perception of risk. effective risk communication mers-cov outbreak in south korea-public policy trumped by fear and politics social trust and the management of risk risk management in post-trust societies the adequacy of response rates to online and paper surveys: what can be done? we thank all members, hye-rin park, jee-eun yi, kang-jin kim, nam-kyu cho, nara lee, and yunisa astiarani who participated in conducting the survey together in community health field training, one of the programs of a master's course at the graduate school of public health. we also thank the supporting from bk21 plus. supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ajic.2017.02.013. key: cord-278759-pykihnup authors: koh, yiwen; hegney, desley; drury, vicki title: nurses' perceptions of risk from emerging respiratory infectious diseases: a singapore study date: 2012-03-21 journal: int j nurs pract doi: 10.1111/j.1440-172x.2012.02018.x sha: doc_id: 278759 cord_uid: pykihnup koh y, hegney d, drury v. international journal of nursing practice 2012; 18: 195–204 nurses' perceptions of risk from emerging respiratory infectious diseases: a singapore study the recent emergence of virulent respiratory infectious diseases such as severe acute respiratory syndrome (sars) and influenza a/h1n1 viruses predisposes nurses to occupational risks. this qualitative study investigated how chinese singaporean nurses perceived the risks of exposure to these infectious diseases and the factors that influenced this risk perception. data were collected through face‐to‐face interviews and were analyzed using braun and clarke's process of thematic analysis. three themes emerged: living with risk; the experience of sars; and acceptance of risk. the nature of nursing work was perceived to place participants at risk of infection. another significant finding of this study is that the government's, organizations' and nurses' perceptions of new emerging respiratory infectious diseases were influenced by their previous experience with sars. similar to previous studies, nurses working at the ‘front line’ believed that infection from these diseases was an unavoidable occupational hazard. emerging infectious diseases, defined as diseases that have 'newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range', 1 are the second leading cause of death worldwide. 2, 3 significant acute respiratory tract infections which have emerged in the 21st century include severe acute respiratory syndrome (sars) in 2003, the avian influenza a/h5n1 virus in 2004 and the influenza a/h1n1 virus in 2009. these viruses have the same mode of transmission via respiratory droplets and person-to-person contact. 4 they have high attack rates, are highly contagious and can spread rapidly within global populations, leading to a global pandemic. these features pose a problem for health authorities and healthcare professionals. 5 a key review conducted by leppin and aro, which examined empirical studies focusing on individuals' risk perceptions towards emerging acute respiratory infectious diseases, found that few studies had explicitly defined the meaning of 'risk perception'. the authors identified key constructs of health-care workers' (hcws) risk perceptions within the organization. these were: personal health risks; health risk to others; social isolation; and acceptance of risks. 6 these constructs will now be discussed and where applicable, any data provided specifically on the perceptions of nurses will be highlighted. hcws are exposed to emerging acute respiratory infectious diseases as a result of their close contact with infected patients. 7 the majority of literature has focused on the risks from sars-infected patients. [8] [9] [10] in particular, many studies report that hcws perceived a high level of infection transmission and consequent adverse outcomes such as sars infection and/or death. [11] [12] [13] in contrast, however, grace et al. found that hcws perceived a low likelihood of being infected with sars. 14 in many studies there were personal and organizational characteristics that were more likely to increase the hcw's perceived personal health risk. personal factors included: being younger; 15 being female; 16 working as a nurse (in comparison with a physician); 15, 16 perceiving that the virus was lethal; 15 daily exposure to sars patients; 17 perceiving little personal control over their exposure to the virus; 8 and having a high impact of event scale score, indicating emotional distress. 10 organizational factors found by some authors to increase hcw's perceived risks included: a perception of the insufficiency and ineffectiveness of the health-care organization's infection control measures; 12, 15 inability of the health-care organization to provide timely updates and information; 11 and their inability to fulfil additional work responsibilities required of them during an outbreak. 11 however, grace et al. found that hcws in their study did not perceive the effectiveness of the hospital infection control measures and the hospital's ability to provide education and updates to influence their risk perceptions. 14 due to the nature by which emerging acute respiratory infectious diseases are transmitted (through social contact among populations), an individual's risk perception would inherently contain a social dimension. 6 in some studies it has been reported that hospitals implemented socialization restrictions, such as discouraging face-to-face interactions within the hospital and eating out, in order to reduce disease transmission between staff. 18, 19 the use of personal protective equipment (ppe) was seen to act as a communication and interaction barrier. 20 although one study reported that being deployed to work in other work units with new colleagues as being a factor that would increase the perception of risk, 20 other studies indicated that there was a greater sense of collegiality and togetherness with other hcws during the sars outbreak. 15, 21 a hcw is as much a family member and a friend as he or she is a hcw. in several studies hcws expressed fear of inadvertent transmission of the disease to family and friends during the sars outbreak. 8, 10, 15 hcws were particularly worried about more vulnerable family members such as children and the elderly. 15, 22 these findings, however, were not supported in maunder et al.'s study where the majority of hcws believed their loved ones were not at risk during the sars outbreak. 23 in spite of these perceived risks, the majority of hcws expressed acceptance and believed that these risks were an occupational necessity. 13, 24 however, not all hcws were willing to accept this risk. 8 acceptance of risk has been found to be higher in physicians, male hcws and older hcws in contrast to nurses, females and younger hcws, respectively. 10, 16 hcws' acceptance of risk was also found to be correlated with their perceived availability of institutional measures for risk management. 16 it can be seen from this discussion that there is a substantial amount of research examining how hcws perceive the risks of emerging acute respiratory infectious diseases such as h1n1 and sars; 17, 25 however, few studies have focused specifically on nurses. thus this study aimed to provide some data on this gap in the literature. additionally, there have been no published studies, to date, that explore nurse's perceptions of risk from different types of respiratory infectious diseases (e.g. between sars and type a influenza-h1n1). as such, this study also aimed to fill this gap in knowledge. the study explored the perceptions of 10 singaporean nurses of chinese cultural background. singapore was chosen because the first author was a four year baccalaureate nursing student, was a chinese singaporean and was attached to the major infectious diseases hospital in singapore. to contextualize the study, we now provide a brief explanation of the sars and h1n1 outbreaks in singapore. the sars outbreak in singapore saw a total of 238 probable cases and 33 deaths during the infection period in 2003, with hcws constituting 41% of the total infected cases. 26, 27 during the sars outbreak, many containment measures were implemented in order to control the rising rates of infection in health-care facilities. these measures were seen to lower the sars transmission rate and singapore was removed from the who's list of areas with local sars transmission on 31 may 2003. 27 following the sars experience, policies and preparation were further carried out to prepare singapore for future pandemics, specifically, against a possible influenza a/h5n1 pandemic which had re-emerged in early 2004. 4 all of these measures were subsequently employed during the h1n1 pandemic outbreak in april 2009 but were gradually reduced in intensity as the h1n1 pandemic outbreak was found to be far less severe in contrast to sars. the aim of the study was to investigate how singaporean chinese nurses practicing in hospital and community settings perceived the risks of exposure to both h1n1 and sars and the strategies that influenced this risk perception. this study employed a qualitative approach to data collection and analysis. this approach was driven by the theoretical paradigm of interpretivism, which posits that humans are constantly trying to make sense of the world and their lived experience. 28 this paradigm was chosen to enable the researchers to explore and understand how nurses experienced and perceived the phenomenon of being exposed to emerging acute respiratory infectious diseases in their workplaces and how this life world and their consequent behaviour was affected by factors such as the cultural and societal context they are within. 29 purposive sampling was used to recruit participants. purposive sampling is a strategy in which researchers deliberately select information sources that will yield the most productive amount of information with regard to the aims of the research study. 28, 30 as such, nurses who were in constant close contact with patients who were infected with emerging acute respiratory infectious diseases and who had worked through both the sars and the h1n1 outbreak were chosen as they were information-rich and able to offer insights into the phenomenon of being exposed to such diseases. following contact with one hospital and one primary care provider (polyclinic), 10 chinese singaporean registered nurses (five from each workplace) participated in taperecorded face-to-face, semi-structured interviews at a place of their choosing. the inclusion criteria were: having previously nursed both patients with sars and h1n1; and of chinese ethnic background. nurses of other races were excluded from the study, as they may have different perceptions from chinese registered nurses, and this study did not seek to ascertain if there were cultural differences between the nursing care provided by the four main ethic groups (chinese, malay, indian and eurasian) in singapore. additionally, nurses employed in other health facilities in singapore were also excluded from the study. the final recruited sample included senior staff nurses, nurse clinicians and nurse managers and their years of experience ranged from 7 to 43 years. a total of 10 participants were chosen as it was postulated that this number would provide sufficient numbers to achieve data saturation and this was the case in this study. 31 participants from both hospital and community settings were interviewed in order to ascertain if there were any similarities or differences in the perceptions of nurses from these different contexts. 32 the study was approved by the directors of nursing at the hospital and polyclinic. a flyer outlining the study was circulated to the nurses, and nurses who wished to participate contacted the primary author of this paper. if they met the inclusion criteria, an interview was arranged at a convenient place for them. a face-to-face semi-structured interview as chosen to allow exploration, in depth, of the phenomena of interest. 33 the questions asked were: 'can you tell me what you know about emerging infectious respiratory diseases?'; 'in singapore, we have been exposed to sars and h1n1. i'd like you to think back to when you first heard of them and tell me about your initial thoughts'; 'tell me about your role in the recent h1n1 pandemic'; 'tell me what you think the role of the government is towards healthcare professionals during a pandemic such as h1n1 and sars'; 'has the latest pandemic affected your work practices and scope of practice'; 'did the h1n1 pandemic affect your ability to care? if so, please can you describe how and why and what you did to try to overcome this. what about during the sars epidemic? was there a difference between the h1n1 and sars? if so, can you tell me about it'; 'tell me about any effects that working in healthcare with a pandemic had on your social and family life'. interviews ranged from 30 to 90 minutes. all interviews were conducted in english and did not require translation. following completion of the interview, the tapes were transcribed verbatim. the data collected were analyzed using braun and clarke's six phase process of thematic analysis to generate categories and themes from the data. 34 data analysis focused specifically on how the participants perceived their experiences of being exposed to h1n1 within their workplaces in the context of a previous sars experience. forty initial codes, which may be defined as the most fundamental element of the raw data which is meaningful to the phenomenon being explored, 34 were generated. these formed the basis of themes across the data sets and relevant data extracts were collated and placed under each code. the underlying meaning of the codes were then analyzed and organized into potential major themes through the use of thematic maps. this culminated in three themes. prior to this analysis, to confirm concepts emerging from the data, the qualitative data analysis program leximancer 35 was used. several measures, based on lincoln and guba's four criteria: credibility, dependability, confirmability and transferability as cited in polit and beck, 30 were used to enhance the trustworthiness of this study. credibility of research findings was enhanced by the use of investigator triangulation 36, 37 and the use of a personal/reflexive journal. 38 to enhance dependability and confirmability of the study, all documentation, such as the researcher's reflex-ive journal, communication with research participants, decisions made together by the research team, as well as all procedures and data relevant to the study, were kept as part of an audit trail. 39 to facilitate transferability, thick descriptions explicating the context and settings in which the study was undertaken and other research steps were included. 40 purposive sampling was also employed to enhance transferability of the findings. 38 three major themes were identified: living with risk; the experience of sars; and the acceptance of risks. these themes were generated by several sub-themes within the data which will now be discussed. the nature of their work, which involved interaction with patients, colleagues and members of the public who were possibly infected with h1n1, was perceived by the participants to place them at several risks: infection by patients; infection from sources other than patients; and health risk to others. this was especially so for front line nurses in both the hospital and polyclinic settings as they had greater exposure to infected patients. for example, a hospital-based participant who screened members of the public for h1n1 expressed her concern about being more exposed to risk and thus being infected unknowingly: similarly, a nurse working in a polyclinic also noted that as front line workers, they were also at increased risk. interestingly, this nurse believes that because of the primary care setting, these nurses are at an increased risk to nurses compared with nurses employed in a hospital: ipeople apart from their patients, participants also deemed themselves to be at risk of infection from their colleagues: in the tea room we all, you know, sometimes sharing food . . . [so] we feel that . . . h1n1 will spread among the nurses, you know, very fast (b3 hospital nurse). additionally, some participants also perceived that they were at risk from the visitors and members of the public who visited the health care organization. this was especially the case if members of the public were seen to be noncompliant with infection control procedures of the organization: some participants were not concerned about themselves, rather they were concerned that they would, because of their exposure to infected patients, colleagues or visitors to the organization, inadvertently infect their family: this fear was heightened for those who lived with elderly parents who were seen as being at higher risk of being infected with h1n1: some participants were also concerned about infecting their colleagues: importantly, the participants' risk perceptions towards the h1n1 outbreak were found to be situated within the context of their previous sars experience. specifically, the experience affected how they perceived the lethality of the h1n1 virus and their level of pandemic preparedness. however, based on their past experience with sars, the participants were initially worried during the early stages of the h1n1 outbreak as they did not know whether the h1n1 virus would be as lethal: with the progression of the disease outbreak and scientific findings demonstrating that the h1n1 virus was milder and treatable with an antiviral drug, oseltamivir phosphate (tamiflu), participants' risk perceptions gradually lessened: more importantly, participants had low risk perceptions during the h1n1 outbreak because they perceived themselves and the organization to be sufficiently prepared for a pandemic outbreak as a result of their experience with sars. specifically, participants noted that many riskmitigating organizational strategies were already in place within the organization as a result of the sars experience: additionally, participants recognized that more organizational strategies had been instituted in the hospital and the polyclinics after the sars outbreak to specifically prepare for future pandemics. one of which was pandemic exercises to prepare the polyclinics for the surge in patient load during a possible influenza outbreak: pre-pandemic and pandemic influenza vaccinations and adequate ppe were also prepared in order to protect the participants against the outbreak. this preparation also allayed the fears of participants: previously during sars period there's been a shortage of n95 mask, but i, this time round i think we should be more prepared already so not so [i was] worried also. (b4 hospital nurse) apart from organizational preparedness, participants also perceived themselves to be personally prepared as a result of their sars experience and knew what riskmitigating strategies to carry out when exposed to h1n1: because i have experienced sars before . . . so i'm more prepared of what i need to do when i nurse this kind of patients (b5 hospital nurse). one such risk-mitigating strategy was their use of ppe when exposed to infected patients: actually every patient . . . should be a suspect . . . . so everybody that come in, with a cough and cold, we assume they are h1n1 especially with high fever. so we don't take risk you see. wear mask (a5 polyclinic nurse). another risk-mitigating strategy employed was hand washing when appropriate: all the participants believed that nursing people with an infectious disease and being subsequently exposed to that disease was an unavoidable occupational hazard: when we're in nursing we're actually facing risk, deadly disease . . . h1n1, airborne diseases . . . [but] i don't resign because of airborne disease or deadly disease. that should not be an excuse for me to step down . . . . but i guess it's . . . our job. and somehow or rather after taking it as a job, it becomes our responsibility . . . . i think nurses are willing to go an extra mile for the public (a3 polyclinic nurse). as such, they continued to interact with and care for their patients as they did before the h1n1 outbreak: i really just, you know, just contact with the patient . . . . when i take care of the patient, i don't feel that "oh i better don't go near to the patient or whatever" (b3 hospital nurse). nurses are often exposed to a variety of occupational hazards within their workplaces, in particular, infectious diseases, some of which may cause death. 41, 42 with the resurgence of emerging acute respiratory infectious diseases such as sars and pandemic influenza in the 21st century, research investigating nurses' risk perceptions towards their exposure is more than ever pertinent. the data show that the nurses in this study have similar concerns to previous research on hcw's perceptions of risk from sars and other emerging acute respiratory infectious diseases in that these nurses were concerned about risks to their personal health (from patients, from colleagues and visitors to the organization). 6, 10 they were also concerned about the health risks that their employment as a nurse might cause to others, 6, 19 in particular those more vulnerable such as the elderly. finally, the study findings clearly indicate that although participants perceived themselves to be at risk of infection, all of them were accepting of these risks as they saw it to be part of their professional obligation. hcws surveyed in studies about their risk perceptions during sars and possible pandemic influenza pandemics likewise expressed the same perceptions and willingness to serve in such pandemics. 8, 10, 43, 44 in addition to the similarities of previous research, particularly into perceptions of risk and sars, this study adds to the existing knowledge in several ways. first, it was apparent that the nurses were fearful of being infected by others-patients, colleagues, visitors to the organization. this fear was heightened by patients or visitors or colleagues who did not comply with the infectious disease precautions, in particular the use of ppe. second, it appears that previous experience of one pandemic prepared these nurses for subsequent epidemics. third, it is apparent that personal, organizational and government strategies, also based on previous experience, increased the confidence of the nurses in this study. in addition to infected patients, the participants believed that colleagues and members of the public visiting the hospital were a source of infection. no studies were found that explored similar perceptions of hcws towards their colleagues or the members of the public. however, studies examining the public's practice of social distancing within the community during the sars outbreak in order to help contain the spread of the sars virus, may lend relevance to the topic at hand. given the asymptomatic yet transmissible characteristics of early stage sars infection, 45 social distancing was encouraged by the government as one way to contain the spread of the disease. 6, 46 hence, it is possible that the participants' perceptions were rooted in the same principles that governed the measure of social distancing, suggesting that participants recognized that anyone, and not just their patients, could possibly be infected. this study also clearly illustrates the impact the sars outbreak had on the participants. it was evident that their risk perceptions towards the h1n1 outbreak were situated within the context of their previous sars experience. in contrast to their perception of sars, participants' risk perceptions were low during the h1n1 outbreak once they perceived the h1n1 virus to be mild and treatable. the influence of the perceived lethality of the virus on risk perceptions has been examined in several studies, which found that hcws who perceived higher risks of death from sars virus had higher overall risk perceptions. 10, 15 in addition, participants' appraisal of the severity of the virus and their aforementioned perceived vulnerability to it appear to be constructs of the protection motivation theory, which represents a form of cognitive judgment in determining risks to oneself. 6 as such, participants who perceived that they were healthy, and the h1n1 to be less severe, were less likely to perceive themselves at risk of being affected. the use of the polyclinics as 'flu clinics' was part of the government's strategy to shift the clinical burden from the tertiary to the primary care setting. 4 this was particularly important during the h1n1 outbreak where approximately 25% of the population was estimated to seek care for influenza symptoms. 47 participants' risk perceptions were also found to be low during the h1n1 outbreak because of their perceived organizational and personal pandemic preparedness as a result of their experience with sars. their past experience during sars had equipped them with the knowledge of personal risk-mitigating strategies, several of which had already become habits for some of the participants. furthermore, these strategies-having had successfully mitigated the risk of exposure to participants during sars-were perceived as being effective, hence lowering their risk perceptions from the outset and throughout the h1n1 outbreak. these findings are similar to brewer et al. who postulated that individuals may have already factored in the effects of their risk-mitigating behaviour when determining their levels of personal risk. 48 to date, no studies pertaining to emerging acute respiratory infectious diseases have been found to examine this unique relationship, that is, the distinction between behaviour-conditioned and behaviour-unconditioned risk perceptions. 6 there are several limitations to this study. first, the findings of this study are not meant to be generalized to the whole population of nurses due to the nature of qualitative research. 49 there is, however, an element of transferability of the study findings especially in view of the similarity of some of the findings to previous studies, especially those about sars. this interpretative qualitative study examined the perceptions of risk of exposure to emerging acute respiratory infectious diseases, specifically sars and influenza a/h1n1. there were three major themes which emerged from the data. these were: living with risk, the experience of sars and acceptance of risk. for the nurses in this study, the nature of their work was perceived to place them at higher risk than other health-care professionals due to the frontline nature of nursing work. this perception was accepted as an occupational hazard and did not affect their willingness to care for patients with sars or other acute respiratory infectious diseases. in this study, the participants were more concerned about how their work would cause harm to others in the community, particularly their family with whom they were in close contact. the fear of becoming infected was heightened by their exposure not only to other health professionals who could potentially be infected but also patients and visitors to the health facility. this was heightened when others did not adhere to infectious disease protection protocols such as the washing of hands and/or the wearing of ppe. a significant finding of the study is that nurses, government and organizations' perceptions of new emerging respiratory infectious disease (and their response to it) is influenced by their previous experience-particularly with sars. however, the data suggest that although the initial response to the influenza a/h1n1 was severe containment-especially in singapore, once the virulence of influenza a/h1n1 was found to be less severe, the participants perceived there was less risk to themselves and their family. thus the participants' appraisal of the severity of the virus and their perceived vulnerability to it appear to be constructs of the protection motivation theory, which represents a form of cognitive judgement in determining risk to oneself. the challenge of emerging and re-emerging infectious diseases infectious diseases: considerations for the 21st century global trends in emerging infectious diseases preparing for an influenza pandemic in singapore the public's response to severe acute respiratory syndrome in toronto and the united states risk perceptions related to sars and avian influenza: theoretical foundations of current empirical research duty of care or medical heroism psychological impact of severe acute respiratory syndrome on health workers in a tertiary hospital perception in relation to a potential influenza pandemic among healthcare workers in japan: 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research: received and interpretivist views of science essentials of nursing research: methods, appraisal and utilization, 6th edn qualitative research in health: an introduction. sydney: allen & unwin factors in risk perception qualitative methods for assessing health care. quality and safety in health care using thematic analysis in psychology from words to meaning to insight understanding reliability and validity in qualitative research quality in qualitative research contributions of qualitative research to the validity of intervention research critiquing research for use in practice qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? communicable respiratory threats in the ed: tuberculosis, influenza, sars, and other aerosolized infections nurses' ability and willingness to work during pandemic flu healthcare workers' perceptions of the duty to work during an influenza pandemic preventing local transmission of sars: lessons from singapore nonpharmaceutical public health interventions for pandemic influenza: an evaluation of the evidence base sars: prudence, not panic risk perceptions and their relation to risk behavior qualitative research and the generalizability question: standing firm with proteus key: cord-199156-7yxzj7tw authors: chan, ho fai; skali, ahmed; savage, david; stadelmann, david; torgler, benno title: risk attitudes and human mobility during the covid-19 pandemic date: 2020-06-10 journal: nan doi: nan sha: doc_id: 199156 cord_uid: 7yxzj7tw behavioral responses to pandemics are less shaped by actual mortality or hospitalization risks than they are by risk attitudes. we explore human mobility patterns as a measure of behavioral responses during the covid-19 pandemic. our results indicate that risk-taking attitude is a critical factor in predicting reduction in human mobility and increase social confinement around the globe. we find that the sharp decline in movement after the who (world health organization) declared covid-19 to be a pandemic can be attributed to risk attitudes. our results suggest that regions with risk-averse attitudes are more likely to adjust their behavioral activity in response to the declaration of a pandemic even before most official government lockdowns. further understanding of the basis of responses to epidemics, e.g., precautionary behavior, will help improve the containment of the spread of the virus. guarantee our survival. it is no coincidence that we are all well aware of the proverb "better safe than sorry". risk entails a complete probabilistic knowledge of something occurring, which allows a decision regarding what action to take. however, not only are we boundedly rational human beings (22) subject to emotions (23) such as fear, but the complexity of the environment and situation, the limited available information on contextual factors of other humans, or dynamic changes may not allow us to have a clear idea about the actual probability we face 3 . in addition, calculating the probability of risk is not the same as actually perceiving it, and humans use less accurate heuristics to make judgments that also include perception of risk. our biases often disrupt our risk assessments in both positive and negative ways by limiting access to information (searches), limited cognitive understanding (noise), and through our own personal experiences. thus, subjective perceptions or emotional responses may be triggered by human traits or other factors. for example, we adjudge risk differently based on the physical distance between ourselves and the danger, i.e., we feel safer if the danger is further away, and we are less likely to continuously monitor it over an extended duration (24) . this may work relatively well for traditional dangers like fires or floods, but the spread of a pandemic is invisible, and only media reports of those in hospital give any rough clue to its presence. as such, it is likely that we fail to correctly use local transmission (infection) rates as a guide of its proximity or distance to us and the level of threat it poses. risk as a feeling is less driven by actual probabilities and more by our instinctive and intuitive reaction to danger (20, p. 70 ). risk-taking has often been classified as a stable personality trait (25) , although situational or contextual factors can also matter (see, e.g., [26] [27] [28] . an individual's risk type and their perception of risk are highly correlated, such that they interact to exacerbate the underlying risk type. that is: risk seekers are likely to have a worse perception of risk and not only are they willing to accept more gambles, but their estimations of the gambles are underweighted, leading to greater adoption of risk than the individual intended (29) . in addition, we humans are also subject to framing biases, reacting differently depending on the way in which information is presented (e.g., positively or negatively, see 30) 4 . this framing can increase or decrease our willingness to take or avoid risk, especially where losses are concernedthe loss of life from contracting the virus is the ultimate loss. thus, preferences are not set in stone and are open to change, especially after we experience losses; i.e., an individual may be more risk-seeking following losses and risk-averse following gains (10, (31) (32) (33) . feelings elicited during a pandemic have an impact on everyday activities (34) and individuals are required to make trade-offs that are affected by their risk behavior. is it safe to go out shopping, to the park, to use public transportation etc.? what are the chances of getting infected? how do we need to respond? risk attitudes matter as individuals are aware that going into public places increases the possibility of being infected; if there was to be an infection, this would be subsequently regretted. risk-averse individuals may respond more to unfamiliar risks that are perceived as uncontrollable (35) . during pandemics, states also may become more controllinghistorically, social mobility restrictions or regulations are common in pandemics. for example, anti-plague regulations banned funerals, processions, sale of clothing, and gatherings in public assemblies, all of which reduced opportunities for trade, and imposed severe penalties when those rules were not followed. community bonds might be destroyed if people lose the opportunity to, for example, grieve, pay final respects, or assemble (1) . the level of social mobility in our current situation is interesting, as during this phase there is no real treatment or vaccination, which means that citizens need to rely on precautionary behavior. as the reality of the covid-19 outbreak emerged, we saw that states started to introduce social distancing and isolation measures to deal with the pandemic and the lack of a vaccine. in this article, we take a look at key social or human mobility factors related to retail and recreation, grocery stores and pharmacies, parks, transit stations, workplaces, and private residences. to measure risk-taking attitude, we use the global preference survey (36, 37) , which analyzed risk at the country level by combining experimental lottery choice sequences using a staircase method (choice between a fixed lottery in which individual could win x or zero and varying sure payments) and self-assessment based on the willingness to take risks (see method section for more details). we then extended this data to obtain regional level information. exploring how risk attitude affects social mobility at the regional level is interesting as risk behavior can be seen as the product of an interplay between individuals, actions of others, and the community or social environment (4) . risk is therefore deeply embedded in specific sociocultural backgrounds (38) , with country and geographical differences in risk-taking reported by scholars such as (36) (e.g., higher risk-taking values in africa and the middle east while western european countries are relatively risk-averse). in the context of a pandemic where a population is attempting social isolation or are in lockdown, we see that shopping behaviors change (drop) and large swathes of the workforce have lost their jobs, which means that the entire population has been directly affected by the pandemic if not the virus. it is therefore interesting to explore how citizens' responses to an epidemic are driven by risk attitudes or preferences at the community or regional level. in particular, we are interested in how individual behavior responses to global announcementssuch as the covid-19 outbreak classification as a pandemic 5 by the who can be shaped by risk attitudes. we suggest that people in risk-taking environments may be less likely to respond and engage in behavioral change which reduces risk. we are also interested in comparing situations with higher or lower opportunity costs in human mobility. the opportunity costs of staying home are defined as the cost incurred by not enjoying the benefit of going out (benefits associated with the best alternative choice). for this, we explore differences between weekdays and the weekend. as many individuals are still working during the week, even while being at home, there is more psychological pressure to be active during the weekend, which increases the opportunity costs of staying at home. not going out requires more psychological costs to fight against previously formed habits, as it is difficult to abandon the way in which we are accustomed to act. we therefore hypothesize that regions with higher risk attitudes are less likely to follow precautionary strategies when opportunity costs are higher and are therefore are less likely to deviate from their outside activities during the weekend relative to the baseline. lastly, we also examine whether people adjust their behavior when living in a population with a larger proportion of older people at greater risk of more serious illness from contacting the virus. we expect that regions with a higher share of over 65 individuals would show a greater reduction in mobility. in particular, risk-averse regions may display stronger mobility deviations from their original baseline (stronger reduction). we examined the relationship between the changes in human mobility during the outbreak of coronavirus disease and the average risk preferences of individuals in 58 countries (with 776 regions from 33 countries with subnational regions data) 6 . our main goal is to see if individuals in areas with higher (lower) levels of willingness to take risks are less (more) likely to reduce their exposure to social interactions by going to public places between 15 feb 2020 and 09 may 2020. the outcome variables measure the daily changes (in percentage) in location visits compared to the median value of the same day of the week in the 5-week baseline period, during 3 january and 6 february 2020. to see whether mobility changes are related to risk tolerance, we first regressed the each of the six mobility measures on risk-taking preference, namely, retail & recreation, grocery & pharmacy, parks, transit stations, workplaces, and residential. in each regression, we controlled for whether the day is a weekend, an indicator distinguishing our sample time period by the day when the world health organization (who) declared the covid-19 outbreak a pandemic (11 march 2020) , the total number of confirmed cases per 1,000 people, number of days since the first confirmed coronavirus related death in the country 7 , percentage of population over 65, population density (per squared km of land area), percentage of urban population, average household size, unemployment rate, per capita income (in logs), daily average temperature, and a set of indicators on government responses that covers recommending and requesting closure of school, workplace, public transport, stay at home, cancellation of public events, and restriction on gatherings and internal movement (39) . consequently, our results regarding risk attitudes can be interpreted as independent of government lockdown measures. to this end, we employed a random-effects linear model to estimate the linear effect of risk-preference on mobility and linear interaction effects of risk and other covariates, namely, pandemic declaration, weekend, and the share of population over 65. as expected, we see an overall reduction in visits to all localities for almost all regions other than residential places, particularly in the earlier weeks in the sample period (see fig. 1 ). interestingly, a large proportion of observations showed an increase in visits to parks, even in the earlier phase. examining the general relationship between risk attitude and the change in mobility in the entire sample period, we find some evident relationship to two most control variables report the expected effect on change in human mobility. specifically, there is a reduction in outings and an increase in staying home as severity increases, such as after the who declared coronavirus outbreak a global pandemic, increase in the number of case per population (except for parks and residential, in which the relationship is positive and significant at 10% level and not significant, respectively), and most lockdown measures 8 (see supplementary table s1 ). we also find that, on average, there is a greater reduction in visits to retail and recreational places (β=4 (table s1 ). markers represent the daily change in visits to the six locations for each region during the entire sample period 9 , with different colors showing observations over time (from most blue (first week of the sample period) to yellow (middle of the sample period) to most red (last week of the sample period)). does the pandemic declaration increase the effect of risk-attitude? we examine the interaction between willingness to take risks and pandemic declaration to assess if the effect of risk-taking on mobility is evident. we find evidence suggesting the declaration is a strong 9 for visualization purpose, we excluded the jammu and kashmir (india) region. moderator of the risk-mobility effect. it is relevant to note that the declaration of the pandemic precedes lockdown measures of most governments. we see that the reduction in outdoor activities (or increase in staying home) can be observed before covid-19 was declared a pandemic by the who, especially for visits to places classified as retail and recreation, transit stations, and workplaces (see fig. 2 10 . we find that, with respect to risk preferences, the changes to visitation patterns (compared to their respective baseline) are relatively greater for areas with lower average willingness to take risk, following the pandemic declaration. specifically, we find the reduction in visits to grocery and pharmacy, transit stations, and workplaces prior to declaration is negatively correlated with willingness to take risk. however, interrogating the interaction terms between risk-taking and pandemic declaration revealed a more interesting 10 nonetheless, the findings in our robustness checks (table s8) suggest that visits to grocery and pharmacy also decreased significantly after the pandemic declaration, which is also in line with the estimate obtained from table s1. behavioral pattern; that is, the additional reduction in out-of-home activities after the declaration is much more dramatic for areas with more less risk-tolerating individuals. we found a statistically significant interaction effect on each of the outcome variables except for residential places (retail and recreation: β=6. 715 fig. 2 ). it is also important to note that the pre-and post-declaration change in visitation pattern differences are smaller for higher risk-tolerance areas and vice versa, indicating that areas with higher average risk-taking are less likely to respond to the negative change in environmental status. the six panels show the predicted percentage change in visit to locations classified as retail and recreation, grocery and pharmacy, parks, transit stations, workplaces, and residential, compared to the respective baseline values, before and after who declared covid-19 as a pandemic on 11 march 2020, over average individual risk preference. estimates are obtained from table s2 , for illustration, predicted changes are calculated over five points of the risk-taking variable (at the 1 st , 25 th , 50 th , 75 th , and 99 th percentiles of the distribution), which we categorized into five levels of willingness to take risk: very low, low, neutral, high, and very high, respectively. mobility patterns weekdays vs. weekends. next, we examine whether the tendency to change the frequency of visits to different localities during weekdays and weekends is mediated by risk attitude. as fig. 3 table s9 in si appendix). moreover, we find that the mediation effect is more apparent after the declaration of pandemic, suggesting the effect manifests alongside severity. specifically, we reran the analysis including the interaction between the risk preference-weekend mediation effect and pandemic declaration dummy (triple interaction term). we visualized the results in fig. 4, showing the difference in average marginal effects of weekends (in contrast to weekdays) before and after the pandemic announcement, over levels of risk-taking (pre-and post-declaration average marginal effects of weekends is shown in fig. s1 and predicted change in mobility in fig. s2 ). we find that the tendency to reduce going out during the weekends compared to weekdays increases significantly with the levels of risk-tolerance for all nonresidential and work locations, particularly in the post-declaration period (retail recreation: these results are highly robust to our checks (see fig. s3 and table s10 in si appendix). the six panels show the difference in average marginal effects of weekends on visits to locations classified as retail and recreation, grocery and pharmacy, parks, transit stations, workplaces, and residential pre-and post-pandemic declaration periods, over risk-tolerance levels. estimates are obtained from table s4 ; for illustration, predicted changes are calculated over five points of the risk-taking variable (at the 1 st , 25 th , 50 th , 75 th , and 99 th percentiles of the distribution), which we categorized into five levels of willingness to take risks: very low, low, neutral, high, and very high, respectively. actual risk. next, we examine the relationship between mobility changes, risk attitude, and proportion of elderly in the population to test if the relationship between mobility and risk is moderated by the share of population at higher risk of dying from covid-19. we thus regressed change in mobility on willingness to take risk and share of population over 65 and the interaction between the two (see fig. 5 ). we found that areas with a larger population at table s11 ). moreover, we found a significant interaction effects on mobility of retail and the six panels show the predicted change in visits to locations classified as retail and recreation, grocery and pharmacy, parks, transit stations, workplaces, and residential, over risk-tolerance levels and the proportion of over 65s in the population. estimates are obtained from table s5 . as with plato's cave, there are stark differences between how we perceive risk and the reality or the calculated level of risk, which can result in totally different behavioral outcomes. risk attitudes clearly shape behavioral responses to pandemics. the actual health risks of the covid-19 pandemic are (most likely) low for most groups apart from the elderly (40, 41) . in terms of mortality, the overall health consequences of covid-19 could be similar to a pandemic influenza 13 (42) . nevertheless, risk attituderather than actual riskinfluence real behavioral activity. our results demonstrate the sharp shifts in the relation between behavioral activity and risk attitudes before and after declaration of covid-19 as a pandemic, as well as shifts before and after the first related death was recorded. the first thing that becomes apparent is that behavior and our willingness to take on risks have both shifted dramatically since the baseline period in mid-february. at this stage, only three deaths were recorded outside mainland china 14 (one in hong kong, japan, and the philippines) and life was proceeding as normal. there was no imminent perception of a threat of the worldwide pandemic to come, reflected in the baseline reporting of behavior and the willingness to take risks. however, when we compare this to the first and second sample period, we observe mostly negative shifts in behavior (excluding residential) but a mixed set of reactions to risk. several categories saw a substantial negative shift in visits, including retail & recreation, transit stations, and workplaces; compared to the baseline, visiting behaviors had already started to drop off before the pandemic announcement but dropped off again afterward. during this first period, we can see that social distancing and work from home was starting to make an impact, as people stopped travelling to and from work (especially through crowded transit stations) and also stopped engaging in non-essential retail shopping (therapy). after the pandemic was officially announced, we see a second wave of behavioral shifts as more people reduce their travel, shopping and more either lose their jobs or are in shutdown mode. however, we do observe an interesting shift in risk attitudes across these three categories as they all exhibit a slightly positive trend in the period before the announcement, but they all shift to a much stronger negative risk trend after the announcement. given that 'flattening the curve' was the strategic focus for most governments, the social distancing message appears to have been received even prior to most lockdown measures. conversely, grocery & pharmacy, parks, and residential had much smaller shifts both before and after the announcements when compared to the baseline. however, the shifts in grocery & pharmacy and parkswhile much smaller than the other categoriesappear to undergo a large risk preference-mobility shift; that is, the first set of behavioral changes results in a positive sloping risk function that flipped into a negative sloped function after the pandemic announcement. while seemingly at odds with expectations, one may want to consider what the announcement of the pandemic would have meant to most individuals. with a looming threat of lockdown and isolation, at this point individuals would have ramped up shopping to stock up for likely upcoming government lockdown. in addition, those with an affinity for the outdoors may have wanted to enjoy their parks and outdoor lifestyle as much as possible before it was banned. this is in line with the reported shifts in the number of visits, which while still negative overall, indicate that the change to number of visits is less negative than prior to the announcement. the odd one out is the residential visits category; while small, we can still observe double increases in visitation numbers both pre and post the official pandemic announcement, and there is no change in the function representing the willingness to take risks. when interpreting these statistics, we need to bear in mind the 'normal' weekly habits of people; that is, work during the week and undertake other activities/pastimes on the weekends. in order to ensure we capture the shift in behavior, we compare the weekday behaviors and risk attitudes to that of the weekends. our result demonstrates that there are a few differences between weekdays and weekends, as one would expect that on weekends there are slightly more activities taking place other than work. furthermore, we see little variance in the slopes of weekdays and weekends risk attitudes. the large negative shifts across all categories except workplaces after the official declaration, but much smaller variations between weekdays and weekends before the declaration, further supports the discussion above: that the behavior had already started to change well before the declaration of a pandemic, with many individuals starting to increase their weekend activities. however, after the pandemic was announced, a raft of measures that tried to limit the spread of the virus resulted in a very large change in most economies due to closure of businesses and job losses. this fundamental change in economic activities and loss of work left very little to differentiate weekends from weekdays for a large number of people, which is reflected in the large negative changes in the comparisons. prior to the announcement, we see that the function on willingness to take risk is fairly flat or slightly downward sloping, but risk perceptions change significantly for all categories after the announcement. the most interesting changes are in workplace and residential, exhibiting a relatively large increase in the willingness to take high risks: this could be explained through people wanting to visit family and friends or the increased willingness to work despite the risk of infection. in general, throughout our analysis we observe that less risk-tolerating regions more actively adjust their behavioral patterns in response to the pandemic. risk seeking regions are less responsive to protective measures. thus, the tendency towards being more careless or more cautious carries substantial behavioral implications that is also affected by different levels of opportunity costs, as evidenced by the weekend effect. regional differences seem to matter, offering support for a "regional personality factor" in risk taking. as with individuals who allocate themselves to more risky professions there are regions that are likely more likely acting as "stunt persons", "fire-fighter", or "race-car driver regions". risk takers therefore seem to demonstrate a lower preference for their own and communal safety, as demonstrated that risk averse regions with higher percentages of 65+ people are more actively to increase social isolation by staying at home. such behavioral differences due to risk preferences may indicate different levels of homeostatic responses. risk aversion seems to promote a stronger fluctuation around a target level. for example, if you are driving on a motorway and it starts to rain or snow, what do you do? our result would imply that risk averse individuals may be more likely to slow down to reduce the likelihood of having an accident. risk averse individuals have a higher need for risk compensation. thus, the level of risk at which a person feels best is maintained homeostatically in relation to factors such as emotional or physiological experiences (19) . overall, the lack of adjustment among risk taking regions is interesting, as many settings that explore risk taking behavior are connected to the possibility of attracting social fame and praise, financial gains, or other potential positive outcomes. in our setting, the risks are strongly attached to the loss of their own and other's health or life without achieving major gains, although positive utility gains also arise from not restricting one's usual activities. it seems like the risk takers are more "pathologically" stable during such environmentally challenging circumstances. it is almost as if risk taking regions are more determined to maintain settings as activity-oriented, while risk averse regions are more goaloriented in achieving social distancing. the current analysis is interesting, as a large number of studies exploring the implications of risk are based on cross-sectional samples or between-subject designs in laboratory settings. in this case, the danger is more prolonged, lasting over several weeks or months, compared with other risk situations such as driving a car. automatic or response "scripts" become less relevant as individuals have the chance to think about their actions and adjust their behavior accordingly. strategic, tactical, or operational factors become more dominant while perceptual, emotional, and motivational factors remain active. in addition, individuals do not face a single "either-or" decision but are required to constantly evaluate their choices to go out or stay at home. thus, cognitive reevaluation is a core feature in our setting, and is based on dynamic feedback loops. risk loving regions are also less likely to adjust their behavior based on external stimulus such as the who announcement of classifying covid-19 as a pandemic. a core limitation is that we are only able to explore human behavior at the regional and not individual level. studies that use individual data could focus in more detail on individual differences such as age or gender or differences in affective reactions or perceived locus of control and could try to disentangle perceptions (risk preferences) partly from actual risk as statistics provide detailed information on the actual age risk profile. such a study would provide a better understanding of habit changes, as well as potentially reveal motivational reasons for behavioral changes or behavioral stickiness. to reduce levels of uncertainty or ambiguity, individuals will try to gain control over a situation or they will change their preferences to better the fit the situation, and thus try to gain control in a secondary way (19) . other psychological factors such as overconfidence may also matter. in addition, we do not have information about the actual level of social mobility in the baseline time period. if that information were available, one could argue that those who had the highest levels of mobility prior to the lockdown have had the largest relative loss; we should therefore observe this group exhibiting the most risk seeking behavior and breaking the lockdown rules. on the other hand, those who previously had the least amount of social mobility have in relative terms only suffered a small lossand should be much less likely to break the lockdown rules. however, this may adjust over time, as individuals habituate to the changes and reset their reference points. this fits nicely into the suggestion that "a person who has not made peace with his losses is likely to accept gambles that would be unacceptable to him otherwise" (29, p. 287), which is consistent with risk preference changes in a disaster situation (10). risk is a fascinating topic as we have two forces in place. based on evolutionary theory, people are risk-inclined but also control-inclined. risk taking is necessary to cope with environmental changes and the constant level of uncertainty and danger. on other hand, control of the environment is required to reduce risks that go beyond the desired levels or that may pose danger to one's survival (19) . the pandemic declaration caused a fundamental shift in behavior, independently of government lockdown measures. future studies could explore in more detail how information dissemination and media reporting are connected to behavioral responses and the level of risk taking within regions. removal of the lockdown policies is likely to be undertaken cautiously and slowly rather than via one large change. it is unclear at this stage how changesparticularly among the risk averse regionshave already led to new habit formation that will not readjust to previously normal settings. future studies will provide more insights into such a question. mobility. we obtained the mobility measures on country and regional level from the covid-19 community mobility reports (43) table s7 to s11 in si appendix). we obtain the measure of risk preference from the globally representative global preferences survey collected in 2012 using the gallup world poll (36, 37) , which is aggregated into the country (n=76) and regional (n=1,126) level. risk preferences of the respondents were elicited through a qualitative question (self-rated perceived risk preference on a 11-point scale) and a set of quantitative questions using the staircase method, where respondents were asked to choose between varying sure payments and a fixed lottery, in which the individual could win x with some probability p or zero. the responses from the two questions were combined (with roughly equal weights) to produce the overall individual risk preference measure (37) . for subnational regions where both mobility measures and risk preference measures are available at the region levels, we employed the regional aggregated combining datasets. to join datasets together for our analysis, we use regions defined in the google mobility dataset as our point of reference. in general, for regions with mobility measures but not from another dataset (i.e., risk attitude or average daily temperature is unavailable for that region), we employ its country values. the resulting number of countries in our final sample is 58, after merging all variables used in this study, with a total of 776 subnational regions from 33 countries (see table s6 in si appendix). the total number of region-day observations ranges from 58,284 to 67,073, depending on the availability of mobility measures. to examine the main question of how mobility patterns during the covid-19 outbreak change according to risk attitude, we analyzed the data using random-effects linear model. standard errors are clustered on the smallest geographic unit in each regression. data and codes used in this study can be found on open science framework (https://osf.io/7bxqp/). this section presents the checks for robustness of our results, which are shown in table s7 to s11 for the six sets of regressions conducted in the main text, respectively. the first two checks concern including regions with censored mobility value in the sample of the analysis. for the overall risk-mobility relationship (comparing estimates from table s7 to . this suggests that the tendency to further reduce mobility on the weekends than during the week for low risk-tolerance regions (as compared to high risk-tolerance regions) is evident before pandemic declaration. moreover, we see that the results with triple interactions between risk preference, weekend, and pandemic declaration resembles to that in the main text, albeit for regions with very high risk preference, the preand post-declaration difference in the weekend reduction in mobility is less precisely estimated in the second sample restriction, in particular for retail and recreation, grocery and pharmacy, and parks. lastly, we found some of the estimates of the risk preference-risk pool interaction terms is similar to that in the main analysis. for retail & recreation, the first exclusion rule figure 1 in the main text. random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. reference categories are: before who declares covid-19 as pandemic, weekdays and no measures taken for all government response indicators. figure 2 in the main text. random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. reference categories are: before who declares covid-19 as pandemic, weekdays and no measures taken for all government response indicators. figure 3 in the main text. random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. reference categories are: before who declares covid-19 as pandemic, weekdays and no measures taken for all government response indicators. figure 4 in the main text and supplementary figures s1 and s2 . random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. reference categories are: before who declares covid-19 as pandemic, weekdays and no measures taken for all government response indicators. figure 5 in the main text. random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. reference categories are: before who declares covid-19 as pandemic, weekdays and no measures taken for all government response indicators. with at least one censored values on the outcome mobility measures excluded. robust 2 = regions with at least one censored values on any mobility measures excluded. robust 3 = government response indicators recoded as no measures taken if policy is not applied countrywide. random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. we controlled for the day since first confirmed death, share of population over 65, number of confirmed cases (in logs), population density, and the set of government response indicators in each regression. reference categories are: before who declares covid-19 as pandemic, weekdays and no measures taken. 768 notes: robust 1 = regions with at least one censored values on the outcome mobility measures excluded. robust 2 = regions with at least one censored values on any mobility measures excluded. robust 3 = government response indicators recoded as no measures taken if policy is not applied countrywide. random-effects gls regression estimates. standard errors (clustered at regional level) in parentheses. † p < .10; * p < .05; ** p < .01; *** p < .001. we controlled for weekend dummy, pandemic declaration dummy, days since first confirmed death, number of confirmed cases (in logs), population density, and the set of government response indicators in each 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for united nations, department of economic and social affairs, population division. database on household size and composition the free encyclopedia. workweek and weekend global historical climatology network -daily (ghcn-daily), version 3. noaa national climatic data center an overview of the global historical climatology network-daily database we received no specific funding for this work. we thank d. johnston for helpful feedback. the authors declare no competing interests. key: cord-217984-ry0z7orj authors: krabichler, thomas; teichmann, josef title: deep replication of a runoff portfolio date: 2020-09-10 journal: nan doi: nan sha: doc_id: 217984 cord_uid: ry0z7orj to the best of our knowledge, the application of deep learning in the field of quantitative risk management is still a relatively recent phenomenon. this article presents the key notions of deep asset liability management (deep~alm) for a technological transformation in the management of assets and liabilities along a whole term structure. the approach has a profound impact on a wide range of applications such as optimal decision making for treasurers, optimal procurement of commodities or the optimisation of hydroelectric power plants. as a by-product, intriguing aspects of goal-based investing or asset liability management (alm) in abstract terms concerning urgent challenges of our society are expected alongside. we illustrate the potential of the approach in a stylised case. mismatches between opposing fixed and floating prices along a whole term structure are omnipresent in various business fields and raise substantial business risks. already humble approaches lead to analytically intractable mathematical models entailing high-dimensional allocation problems with constraints in the presence of frictions. this impediment often leads to over-simplified modelling (which still needs sophisticated technology), uncovered risks or overseen opportunities. spectacular successes of deep learning techniques in language processing, image recognition, learning games from tabula rasa, or risk management, just to name a few, are stimulating our imagination that asset-liability-management (alm) might enter a new era. this novel approach, briefly denoted «deep alm», raises a huge field of mathematical research questions such as feasibility, robustness, inherent model risk and inclusions of all economic aspects. if we answer these questions, this could possibly change the alm practice entirely. alm is a research topic that may be traced back to the seventies of the previous century when martin l. leibowitz and others developed cash-flow matching schemes in the context of the so-called dedicated portfolio theory; see [15] . in the eighties and nineties, alm was an intensively studied research topic in the mathematical community. this unanimously important branch of quantitative risk management has been dominated by techniques from stochastic control theory; e.g., see [8] by giorgio consigli and michael a. h. dempster or [16] by karl frauendorfer and michael schürle for articles utilising dynamic programming. further aspects of the historical evolution are treated in [29] by ronald j. ryan. however, already over-simplified modelling involves a high complexity both from the analytical and the technological viewpoint. a cornerstone in this regard is [23] by martin i. kusy and william t. ziemba. they consider a rather advanced and flexible alm model by specifying an economic objective (e.g., the maximisation of the present value of future profits), a series of constraints (e.g., regulatory requirements and liquidity assurance) and penalty costs for constraint violations. prevalent approaches applied in the industry such as solely immunising oneself against parallel shifts of the yield curve have remained suboptimal until this day; e.g., see [32] by martin spillmann, karsten döhnert and roger rissi for a recent exposition. particularly, the empirical approach with static replicating portfolios described in the section 4.2 of [32] is often applied in mid-sized retail banks. although the impact of stress scenarios is investigated in the light of regulatory requirements, the holistic investment and risk management process of many treasury departments remains insufficient. more sophisticated approaches, such as for instance optionadjusted spread models (e.g., see [2] by martin m. bardenhewer) , have not become established in the financial industry. therefore, despite many achievements, it is fair to say that alm has not entirely fulfilled its high expectations. the fresh approach on deep hedging by hans bühler, lukas gonon, josef teichmann and ben wood (see [7] ) might pave a way for a new era in quantitative risk management. it is clear that classical yet analytically intractable problems from alm can be tackled with techniques inspired from deep reinforcement learning in case of an underlying markovian structure; see [17] by ian goodfellow, yoshua bengio and aaron courville for a comprehensive overview of deep learning and [33] by richard s. sutton and andrew g. barto for an introduction to reinforcement learning in particular. reinforcement learning has found many applications in games (e.g., see [31] by a research team of google's deepmind), robotics (e.g., see [22] by jens kober, j. andrew bagnell and jan peters) and autonomous vehicles (e.g., see [21] by a joint publication of valeo and academic partners). recent monographs on machine learning for financial applications are [25] by marcos lópez de prado and [12] by matthew f. dixon, igor halperin and paul bilokon. regarding applications of neural networks for hedging and pricing purposes, some 200 research articles have accumulated over the last 30 years; [28] by johannes ruf and weiguan wang provides a comprehensive literature review. only a handful of these articles exploit the reinforcement learning paradigm. in contrast to this obvious applications of deep reinforcement learning to alm, deep hedging approaches to alm are simpler but still providing the solution relevant for business decisions. notice, however, that neither markovian assumptions are needed, nor value functions or dynamic programming principles: deep alm will simply provide an artificial asset liability manager who precisely solves the business problem (and not more) in a convincing way, i.e. provides alm strategies along pre-defined future scenarios and stress scenarios. the fundamental ideas will be further elaborated on in the sections below. to the best of our knowledge, we are the first to tackle alm systematically by deep hedging approaches. there are many fundamental problems arising in mathematical finance that cannot be treated analytically. exemplarily, explicit pricing formulae for american options in continuous time are yet unknown even in the simplest settings such as the black-scholes-framework. this is incredible in that most exchange traded options are of american style. optimal stopping problems in genuine stochastic models involve so-called parabolic integro-differential inequalities, which can be numerically approximated by classical methods up to three dimensions; e.g., see the section 10.7 in [20] . the curse of dimension impedes the feasibility of classical finite element methods for applications involving more than three risk drivers. with today's computational power of a multi-core laptop, the runtime in six dimensions would last many centuries. a popular circumvention is the regression based least squares monte-carlo method proposed by francis a. longstaff and eduardo s. schwartz; see [24] . some statisticians perceive machine learning as a generalisation of the regression technique. in this sense, a spectacular success was achieved by sebastian becker, patrick cheridito and arnulf jentzen when they utilised deep neural networks to price american options in as much as 500 dimensions below 10 minutes; see [4] for further details. one is forced to abandon the fundamental desire of directly solving a very complex mathematical equation and must approve of the paradigm shift to the deep learning principle: «what would a clever and non-forgetful artificial financial agent with a lot of experience and a decent risk appetite do?». this change of mindset opens the room for many possibilities not only in quantitative finance. computationally very intensive techniques such as nested monte-carlo become obsolete. we aim at utilising these advances to tackle problems that were formulated back in the eighties, e.g., by martin i. kusy and william t. ziemba (see [23] ), and have remained unsolved for the desired degree of complexity ever since. thus, the technological impact of deep alm for the financial industry might be considerable. the markov assumption, roughly speaking that future states only depend on the current state and not the past, usually leads to comparatively tractable financial models. real world financial time series often feature a leverage effect (i.e., a relationship between the spot and the volatility) and a clustering effect (i.e., a persistence of low and high volatility regimes). unless volatility becomes a directly traded product itself (which generally is not the case) and is perceived as an integrable part of the state, an effective hedging strategy can hardly be found analytically. this leads to the concept of platonic financial markets that was introduced in [9] by christa cuchiero, irene klein and josef teichmann. generally observable events and decision processes are adapted to a strict subfiltration of its counterpart that is generated by the obscure market dynamics. this concept goes in a similar direction as hidden markov models; e.g., see the textbook [14] by robert j. elliott, lakhdar aggoun and john b. moore for a reference. regarding deep alm, this inherent intractability of platonic financial markets is not an impediment at all. certainly, the replication portfolios along a trained deep neural network only depend on generally observable states. however, the financial market dynamics do not have to satisfy any markovianity restrictions with respect to the observable states and/or traded products. the deep neural network jointly learns the pricing and the adaptation of hedging strategies in the presence of market incompleteness and model uncertainty; e.g. see [13] by nicole el karoui and marie-claire quenez and [1] by marco avellaneda, arnon levy and antonio parás for further details. hence, deep alm unifies key elements of mathematical finance in a fundamental use case. an essential prerequisite for the viability of deep alm in a treasury department is to come up with a sufficiently rich idea of the macro-economic environment and bank-specific quantities such as market risk factors, future deposit evolutions, credit rate evolutions and migrations, stress scenarios and all the parameterisations thereof. in the end, the current state of a bank must be observable. in contrast to dynamic programming, machine learning solutions are straightforward to implement directly on a cash-flow basis without any simplifications (e.g., a divisibility into simpler subproblems becomes redundant), and their quality can be assessed instantaneously along an arbitrarily large set of validation scenarios. moreover, the paradigm of letting a smart artificial financial agent (similar to an artificial chess player) with a lot of experience choose the best option allows to tame the curse of dimension, which is the pivotal bottleneck of classical methods. further aspects such as intricate price dynamics, illiquidity, price impacts, storage cost, transaction cost and uncertainty can easily be incorporated without further ado; all these aspects are hardly treated in existing frameworks. despite the higher degree of reality, deep alm is computationally less intensive than traditional methods. risk aversion or risk appetite respectively can be controlled directly by choosing an appropriate objective associated with positive as well as negative rewards in the learning algorithm. regulatory constraints can be enforced through adequately chosen penalties. hence, deep alm offers a powerful and high-dimensional framework that supports well-balanced risk-taking and unprecedented risk-adjusted pricing. it surpasses prevalent replication strategies by far. moreover, it allows to make the whole financial system more resilient through effective regulatory measures. the article is structured as follows. in the section 2, we describe a prevalent replication methodology for retail banks. furthermore, we specify similar use cases from other industries. subsequently, we explain the key notion of deep alm in the section 3. a hint about the tremendous potential of deep alm is provided in the section 4 in the context of a prototype. while accounting for the regulatory liquidity constraints, a deep neural network adapts a non-trivial dynamic replication strategy for a runoff portfolio that outperforms static benchmark strategies conclusively. the last section elaborates on implications of deep alm and future research. common misunderstandings from the computational and regulatory viewpoint are going to be clarified. 2.1. the treasury case of a retail bank. the business model of a retail bank relies on making profits from maturity transformations. to this end, a substantial part of their uncertain liability term structure is re-invested. the liability side mainly consists of term and non-maturing deposits. major positions on the asset side are corporate credits and mortgages. residual components serve as liquidity buffers, fluctuation reserves and general risk-bearing capital. the inherent optimisation problem within this simplified business situation is already involved. whereas most cash-flows originating from the liability side are stochastic, the bank is obliged to ensure a well-balanced liquidity management. regarding short-and long-term liquidity, regulations require them to hold a liquidity coverage ratio (lcr) and a net stable funding ratio (nsfr) beyond 100%. in contrast, market pressure forces them to tighten the liquidity buffers in order to reach a decent return-on-equity. asset-liability-committees (alco) steer the balance sheet management through risk-adjusted pricing and hedging instruments. due to the high complexity, many banks predominantly define and monitor static replication schemes. it is worth noticing that alcos nowadays often meet only once a month and supervise simplistic measures such as the modified duration and aspects of hedge accounting on loosely time-bucketed liabilities. many opportunities are overseen, and many risks remain unhedged; e.g., see the introductory chapter of [32] . crucial business decisions are inconsistent over time and rather reactionary than pro-active. table 1 illustrates the replication scheme of a generic retail bank. it is inspired from section 4.2 in [32] . the notional allocated to fixed income currently amounts to eur 100m, which are rolled-over monthly subject to some static weights. the first line corresponds to a liquidity buffer that is held in non-interest bearing legal tender. exemplarily, 15% or eur 15m of the currently allocated capital are invested in fixed income instruments with a maturity of 1y. this portion is again split into equal portions, such that roughly the same volume matures each month. in order to end up with a closed cycle, this refers to as maintaining 12 tranches with a volume of eur 1.25m (= 1/12 × 15m). this redemption amount is re-invested again over a horizon of 1y at the latest market rates. the same roll-over procedure is conducted for all other maturities. this leaves us with 202 rolling tranches in total. under the current premises, 6 tranches with a total volume of eur 24.125m mature each month and are re-invested consistently. the portfolio weights are only revised from time to time. they are typically the result of empirical and historical considerations. on the one hand, it is lucrative to increase the portion in longer terms as long-term yields are often but not always higher than short-term yields. on the other hand, if only a small portion is released each month, this leaves the bank with a significant interest and liquidity risk. this static scheme is typically accompanied with selected hedging instruments such that the sensitivities with respect to parallel shifts of the yield curve or the so-called modified durations for the asset and liability side roughly coincide. certainly, dynamic strategies (including a restructuring of all tranches) are superior to their static counterparts regarding profit potential and resilience of the enterprise. however, dealing directly with 202 tranches is often not feasible computationally. if we only add a simple dynamic feature and allow for arbitrary weights in the monthly re-investment process, this already introduces a considerable additional complexity from the analytical viewpoint. even if one reduces the dimensionality of the yield curve dynamics, one faces an intricate nested optimisation exercise over all re-investment instances. utilising traditional methods such as dynamic programming and accounting for a reasonable set of constraints is far from being trivial. moreover, due to the necessary model simplifications, it is uncertain whether this additional complexity really pays off. it is therefore not surprising that many retail banks have been implementing a rather static replication scheme as described above. in the near future, this is likely to change once the novel and computationally much less intensive deep alm with a huge potential will be deployed. 2.2. similar use cases. the notion of replication schemes may be applied analogously to other use cases. in the following, we describe three of them. 2.2.1. actuarial perspective. the situation described above can be transferred oneto-one to the situation of insurance companies. the aspects that change are completely different regulatory circumstances, the asset illiquidity of hedging instruments (the retrocession) and the stochastic cash-flow generation as well as separate extreme risks on the liability side. life insurance companies and pension funds must account for the exact product terms and the mortality characteristics of their policyholders. this includes, for instance, longevity and pandemic risks. non-life insurance companies model the annual loss distribution and its unwinding over consecutive years. procurement. the producing industry is faced with a long and complex process chain. several raw commodities need to be bought, delivered, stored, processed and designed into a consumer product. in order to control the inherent business risks and ensure profitability, a maturity transformation in the procurement process becomes inevitable. even though the exact amount of the required materials is yet unknown, the company's exposure towards adverse price movements needs to be hedged accordingly. despite the seemingly large daily trading volumes, any order comes with a price impact. controlling the inventory is also worthwhile due to funding and storage cost. therefore, slightly more involved than the treasury case described above, we have an alm optimisation in the presence of illiquidity, storage cost, transaction cost and uncertainty. the technological advances regarding renewable energy and the deregulation are having a huge impact on electricity markets. wind and solar energy make the electricity prices weather-dependent and more volatile. still, some segments of future markets have remained comparatively illiquid. a peculiarity of the electricity market are its intricate price dynamics (including negative prices) and a wide range of more or less liquidly traded future contracts over varying delivery periods (e.g., intraday, day ahead, weekend, week, months, quarters, years). this makes the estimate of hourly price forward curves (hpfc) that account for seasonality patterns (intraday, weekday, months), trends, holiday calendars and aggregated price information inferred from various future contracts (base, peak and off-peak) a very challenging exercise. electricity producers may incur significant losses due to adverse contracts with locked-in tariffs and mis-timed hydropower production in reservoirs. this environment forces the suppliers to conduct a rigorous alm, which comprises, for instance, a competitive pricing of fixed-forfloating contracts and daily optimised power production plans. the situation of delivering competitive yet still profitable margins in the presence of uncertainty is a situation banks have been accustomed to for decades (with a different commodity and different rate dynamics). deep alm can be tailored to this very situation and provides exactly the technological solution to this delicate business problem. all one needs to establish is an appropriate scenario generator for the future markets and the hpfc. many business-specific peculiarities can hardly be reflected by traditional optimisation techniques. as an illustration, a turbine cannot be turned on and off on an hourly basis. this simple-looking constraint renders the dynamic programming principle impossible. however, this constraint can be accounted for in deep alm without further ado by incorporating suitable penalties. beyond professional judgment, practical problems arising in alm are often tackled either by linear programming or dynamic programming. the latter requires that the problem is divisible into simpler subproblems. for non-linear and highdimensional cases, one typically exploits monte-carlo techniques in order to derive or validate strategies empirically along a handful of criteria. as a matter of fact, the level of sophistication for replicating strategies remains fairly limited due to the high intricacy and the lack of an adequate constructional approach. deep alm makes all these impediments obsolete. one directly implements the arbitrarily complex rule book of the use case and lets a very smart and non-forgetful artificial financial agent gain the experience of many thousand years in a couple of hours. by incentivising the desired behaviour and stimulating a swift learning process, one reaches superhuman level in due course. we consider a balance sheet evolution of a retail bank over some time grid {0, 1, 2, . . . , n } in hours, days, weeks or months. the roll-forward is an alternating process between interventions and stochastic updates over time; see figure 1 . at each time instance t, an artificial asset-liability-manager, subsequently denoted the «artificial financial agent» (afa), assesses the re-investment of matured products as well as the restructuring of the current investment portfolio. this involves various asset classes, not just fixed income instruments. correspondingly, the afa is active in both the primary market of newly issued instruments and the secondary market of previously issued and circulating instruments. there may be further eligible transformations of this initial state with transaction cost, e.g., granting further credits or building additional liquidity buffers. the balance sheet components a t (assets), l t (liabilities) and e t (equity) come with the superscripts «pre» and «post», which refer to as before and after the balance sheet restructuring respectively. preceding interventions, an auxiliary step for the calculation of taxes may be necessary. subsequently, the economic scenario generator performs a stochastic roll-forward of the balance sheet. all accounts are updated to the latest circumstances and macro-economic factors, e.g., certain products pay off cash amounts such as coupons or dividends, certain products need to be written off due to the bankruptcy of the referenced entity, clients withdraw certain portions of their deposits, etc. it needs to be noted that the described situation is kept simplistic for illustrative purposes. it is the main target of future research work to reach an acceptable level of sophistication in order to make the technology eligible for real world alm. the superiority of the dynamic replication scheme requires that the trained afa can perfectly trade-off benefits from a restructured portfolio and the incurred transaction cost of the restructuring. furthermore, the trained afa must impeccably weigh up different objectives such as complying with regulatory constraints, earning a risk-adjusted spread, maintaining an adequate level of liquidity, keeping sufficient figure 2 . figure 2 . deep neural network architecture margins for adverse scenarios, etc. the fundamental idea is to parameterise the decision process at each time instance t through a deep neural network (dnn) and to incrementally improve its performance through techniques inspired from machine learning. by concatenating these deep neural networks along the time axis, one ends up at a holistic dynamic replication strategy that easily deals with non-stationary environments. the learning process incentivises the maximisation of an adequately chosen reward function by incrementally updating the weights of the feedforward networks through backpropagation; see figure 2 . this idea allows to tame the curse of dimension. these new possibilities of deep alm allow for a more frequent supervision while accounting for arbitrarily many side constraints and complicated market frictions such as illiquidity and offsetting effects of transaction cost in hedges. thus, the full power of dynamic strategies can be deployed. traditional numerical schemes describe an algorithm either in order to solve an equation or in order to optimise a certain functional. typically, algorithms are only accepted by the mathematical community if they come with two supplements, namely a proof that the recipe terminates with a certain accuracy at the desired level, on the one hand, and a statement about the rate-of-convergence, on the other hand. in the context of deep alm, we coin the notion of convincing strategies because we are likely not able to prove that the randomly initialised deep neural network will end up at some optimal replication strategy. in fact, we intend to derive non-trivial but still realistic dynamic replication strategies within a reasonable time that significantly outperform those strategies currently used in the financial industry. from the mathematical viewpoint, deep alm entails a delicate paradigm shift. the results will be derived empirically based on scenarios representing the experience of many thousand years. by repeating the learning process a few times, we will corroborate the robustness of the approach. furthermore, we will validate and challenge the performance of the deep neural network on unseen testing data. if the gradient descent algorithm can only further reduce the training loss with some overfitting strategy at the cost of the validation loss, we have ended up at a local optimiser. even though we will not be able to prove global optimality, the strategy might still reach superhuman level and, thus, be more than convincing. we aim at optimising the replication strategy when unwinding a runoff portfolio over ten years in the context of an equity index and a large fixed income universe. at every time instance, roughly 200 bonds are active. this prototype demonstrates the feasibility of deep alm in a stylised case. in the end, every balance sheet roll-forward is a superposition of runoff portfolios. furthermore, we give an indication about the potential of dynamic replication strategies. the liabilities are backed by a static legacy investment portfolio. roughly two thirds of the assets are invested in the fixed income market and 10% are invested in equities. the remainder is held in cash. every month, six new bonds are issued in the primary market with the face amount of 100 monetary units and the maturities 1m, 3m, 6m, 1y, 5y and 10y. the first three series only pay a coupon at the final redemption date, the other three pay semi-annual coupons. at issuance, all bonds trade at par. the legacy investment portfolio has attributed equal portions to all of the six bond series and has conducted an equally distributed roll-over strategy based on historical data from the european central bank (ecb). future yield curve scenarios are simulated consistent with a principal component analysis. for simplicity, we assume that there is no secondary market. hence, bonds cannot be sold on in the market and must be held to maturity. furthermore, we preclude credit defaults. regarding equities, we generated scenarios based on a discretised geometric brownian motion. changing the position in equities involves proportional transaction cost. due to legal requirements, at least 10% of the asset portfolio must be held in cash; this is just an arbitrary choice in order to incorporate a regulatory constraint. any discrepancy is penalised monthly with a high interest rate. the initial balance hosts assets worth 100 monetary units. the term structure of liabilities with the same face amount is spread across the time grid according to some beta distribution. a well-established approach to tackle quantitative finance problems with deep reinforcement learning is to follow the standard routine inspired from games. a game is a stochastic environment in which a player can act according to a set of rules and can influence the course of events from start to finish to a certain degree. the game terminates after a prespecified number of rounds. a rule book includes the model drivers and their interdependence, the constraints and the penalties for constraint violations, the control variables and the objective function. notably, we actually do not solve the game for all initial states nor do we assume any markovian structure. we implemented the 'game' according to the rule book specified below in a jupyter notebook such that the random outcome of any strategy could be simulated arbitrarily often. to this end, we defined an economic scenario generator that hosted the yield curve dynamics and spot prices for equities. having this environment in place, one can test the performance of any naïve or traditionally derived replication portfolio. the step of translating the rule book into model dynamics is crucial for understanding the game, for ensuring a well-posed optimisation problem and for streamlining the logic of the subsequent tensorisation. the evolution of r n -valued quantities can be inferred from historical time series with a principal component analysis as proposed by andres hernandez in [19] . subsequently, the game is embedded in a deep neural network graph architecture using tensorflow such that an afa can run many games in parallel and adaptively improve its performance. the graph constitutes of many placeholders and formalises the logic of the game. the first decision process of the afa is managed through the randomly initialised weights of a neural network with a handful of hidden layers. its input layer is a parameterisation of the initial state, concerning both the balance sheet structure and the market quotes, and the output layer characterises the eligible balance sheet transformation. the balance sheet roll-forward is accomplished by connecting the output of the neural network with a whole bunch of efficient tensor operations reflecting the balance sheet restructuring, new inputs for the non-anticipative scenario updates and the input layer of the next decision process. iterating this process yields the desired deep neural network. we are given a discrete time grid t 0 = {0, 1, 2, . . . , n } in months, where n = 120 refers to as a planning horizon of ten years. the initial term structure of liabilities with the face amount of 100 monetary units is spread across the time grid according to a beta distribution with the parameters a = 1.5 und b = 2.5, i.e., if f a,b denotes the corresponding cumulative distribution function, then the cash-flow . therefore, it holds and all other components are zero. when going from one time instance to the next, b (1) is paid off and one simply applies to the scheme b the linear update operator a k-fold application of the update operator is denoted by u k . we utilise data from the european central bank (ecb) in order to model the historical and future yield curves. ecb publishes for each working day the svensson parameters β 0 , β 1 , β 2 , β 3 , τ 1 and τ 2 of its yield curve. the corresponding yield curve is the vector we fix some historical time series in r n and conduct a principal component analysis. to this end, we assume stationary daily yield curve increments ∆x with expected value e[∆x] ≡ µ ∈ r n and covariance matrix cov(∆x) ≡ q ∈ r n ×n . we spectrally decompose q = λlλ into the normalised eigenvectors λ ∈ r n ×n and the ordered eigenvalues l = diag{λ (1) , λ (2) , . . . , λ (n ) } with λ (1) ≥ λ (2) ≥ . . . ≥ λ (n ) . the last historical yield curve is the day when we acquire the runoff portfolio. the stochastic yield curve increments from one month to the next are consistently sampled according to where we choose n = 3 and z k ∼ n 0, σ k 2 for σ k = √ 22 · λ (k) . the factor 22 accounts for the number of trading days per month. if i denotes the maturity in number of months, the legacy bond portfolio has been investing each month a face amount of 15/i monetary units in that particular bond series for i ∈ i := {1, 3, 6, 12, 60, 120}. this is consistent with the replication scheme from table 1. 4.4. the equity market. we assume that the stochastic process s = (s t ) t∈t0 follows a discretised geometric brownian motion, i.e., it holds for all t ∈ t with initial level s 0 = 100, drift m = 5% and volatility s = 18%. changing the position in equities involves proportional transaction cost κ = 0.50%. the balance sheet. we proceed iteratively. let y t ∈ r n denote the current yield curve for t ∈ t 0 \{n } and d t consistent discount factors. before restructuring, the left hand side of the balance sheet with a total present value of a pre t consists of three additive components: the held cash c pre t , the legacy bond portfolio with the value v pre and the relu activation function φ(x) = max{x, 0}. the input layer consists of the leverage ratio e pre for i ∈ i of the latest bond series. the output layer reveals the outcome of the restructuring at the time instance t. the first six components represent the holdings h 4.8. the roll-forward. let b post t ∈ r n denote the aggregated future cash-flows of the whole fixed income portfolio after restructuring at time t. furthermore, let π (1) : r n −→ r denote the projection onto the first component. if one does not adhere to the regulatory constraint of holding at least 10% of the assets in cash, one is penalised with liquidity cost of p = 24% per annum on the discrepancy. once the yield curve has been updated stochastically to the state y t+1 with consistent discount factors d t+1 and the equity index has been updated stochastically to the state s t+1 , this leaves us with the roll-forward objective. for different maturities t ∈ t, a common approach in mathematical finance is to maximise e u e post denotes the iso-elastic utility function with constant relative risk aversion γ ≥ 0. this is not directly applicable in our case since we cannot prevent e post t from becoming negative. instead, we aim at maximising provided that the final equity distribution is positive, the case γ = 1 corresponds to the quest for the growth optimal portfolio that maximises the expected log-return; see [27] . an intriguing alternative is quadratic hedging, where one aims at minimising for some annualised target return-on-equity r > 0. either case leads to convincing strategies. results. the optimisation is only non-trivial for non-negative yield curves. if the mid-term yields are consistently negative (as they have been in the eur area for quite some years), holding cash is superior to the considered fixed income investments (within the simplified premises specified above). as starting point, we choose the ecb yield curve as per december 31, 2007. in that case, the initial value of the liabilities amount to l pre 0 = 86.0 monetary units. as outlined above, the exercise of optimising the equity distribution after the settlement of all liabilities is extremely challenging with conventional methods. the investment universe consists at each time instance of 204 active assets, namely the fixed income universe, an equity index and legal tender. we propose a simple benchmark strategy that allocates the available cash beyond 10% of a pre t to bonds with a maturity of 1m, provided that the coupons are positive. equities are divested linearly over time. moreover, we train an afa on 10 000 unwinding scenarios following the ideas of deep alm. an until only recently inaccessible dynamic strategy outperforms the benchmark strategy conclusively after a short learning process of roughly 10 minutes. using another 10 000 previously unseen validation scenarios, the following chart illustrates the final equity distributions after ten years for a classical static strategy in blue and for the dynamic strategy in orange. the dynamic strategy does not involve extreme risk taking. it simply unveils hidden opportunities. the systematic excess return-on-equity with respect to the benchmark is beyond 2% per annum; see the real potential can hardly be foreseen. one achievement will lead to another and trigger further accomplishments. despite the optimism, the technique is not mature enough and requires an adequate level of research. market participants across all use cases, who we spoke with, like the intriguing idea of deep alm. however, only a few dare being the first movers in this precompetitive phase. alm is at the heart of risk management for any enterprise in the financial industry. in the light of the new opportunities, it is not acceptable how simplistic and ineffective prevalent replication schemes are to this day. all of us are directly affected by unhedged risks of bank deposits, insurance policies and pension funds. this can be illustrated exemplarily with finland whose banking sector caused a devastating financial crisis in the early 1990s. in the aftermath, official unemployment rates escalated to roughly 18%. deep alm offers a powerful framework that supports well-balanced risk-taking and unprecedented risk-adjusted pricing. thus, its rigorous application may prevent a financial crisis sooner or later. likewise, we are all exposed to the climate change. hence, it is becoming increasingly important to spend resources wisely. deep alm promotes this attitude with significant efficiency gains in the procurement of commodities and the hydropower production. these are promising prospects for deep alm indeed. necessity of further research. some people argue that machine learning will facilitate the enterprise risk management, make it more effective and make some of the current tasks even redundant. we agree that the new opportunities will allow for more consistent and sound risk taking. however, we are convinced that legitimate applications of deep alm will entail a lot of additional work since the previously inaccessible analyses do not come for free. moreover, they will raise a huge portion of new economic challenges and obligations. thus, it is essential that the research community prepares a solid ground for this technological transformation. feasibility. optimising a whole term structure of assets and liabilities by utilising techniques inspired from deep reinforcement learning is a novel approach and its feasibility needs to be demonstrated. in the light of recent advances, we are optimistic that this goal can be achieved in due course. nonetheless, this challenge opens a great field of research questions from the mathematical, computational and economic viewpoints. regarding feasibility, it is an important concern that we do not just want to feed an utterly complex mathematical system into a powerful supercomputer and see whether we get something out. in contrast, we aim at formulating and optimising dynamic replication schemes that meet the requirement of industrial applicability, on the one hand, and operability on a moderately enhanced computer, on the other hand. particularly, this involves an assessment whether the behaviour of the trained afa is interpretable, whether it follows sound economic reasoning and whether the non-anticipative dynamic replication strategies fulfil the basic requirement of practical viability. solving a high-dimensional utility maximisation problem that entails unrealistic leverage or arbitrary rebalancing frequencies is futile for real world applications. for this purpose, deep alm must trade off many objectives such as cost and benefit of liquidity, drawdown constraints, moderate leverage ratios, profit expectation, regulatory interventions, risk appetite, short sale restrictions, transaction cost, etc. most aspects can be accounted for in the model by means of penalties that incentivise the afa's behaviour accordingly. others such as drawdown constraints and profit expectation typically enter the target function of the optimisation. finding the right balance between all the different goals without adversely affecting the robustness of the learning process entails some engineering work. however, once a convincing and stable economic model choice has been established, this has a tremendous impact on the economic research field. previously inaccessible price tags to crucial economic notions such as, for instance, cost of liquidity for a retail bank can be evaluated quantitatively. all one needs to do is to line up performance measures of trained afas when short sale restrictions of the cash position are enforced and dropped respectively. goal-based investing. a closely related subject to deep alm is goal-based investing; e.g., see [6] by sid browne for a neat mathematical treatment. one aims at maximising the probability to reach a certain investment goal at a fixed maturity. from the theoretical viewpoint with continuous rebalancing, this is equivalent to replicating a volume-adjusted set of digital options (unless the target return is smaller or equal than the risk-free rate). despite being very intuitive, this result is only of limited use for practical applications. discrete rebalancing and the payoffdiscontinuity at the strike lead, as one gets closer and closer to maturity, to an inherent shortfall risk way beyond the invested capital. it needs to be investigated whether browne's setting can be modified accordingly for real world applications. this involves more realistic dynamics of the economic scenario generator, exogenous income (as inspired by section 7 of [6] ), maximal drawdown constraints and a backtesting with historical time series. 5.5. generalisation. if we take one step further and look at alm as an abstract framework, deep alm may contribute crucially to urgent challenges of our society such as combating the climate change or dealing with pandemics. it trains a player to reach a certain goal while minimising the involved cost. regarding the climate change, there is a complex trade-off in implementing protection measures, incentivising behavioural changes, transforming the energy mix, etc. regarding covid-19, rigorous emergency policies were enforced throughout the world in order to protect individual and public health. these measures involved extreme cost such as temporary collapses of certain industries, closed schools, restricted mobility, etc. these are again high-dimensional problems, which cannot be tackled with classical methods. deep alm is a first step towards these more difficult challenges. 5.6. impediments. a challenge will be to overcome the common misunderstanding that deep learning requires a lot of historical data (that banks or commodity companies usually do not have), that deep learning is an incomprehensible black box, and that regulators will never approve of deep alm. firstly, the above approach does not require any historical data. all one needs are model dynamics of ordinary scenarios and stress scenarios. the training data can be fully built on these premises synthetically. secondly, the performance of deep neural networks can be validated without further ado along an arbitrarily large set of scenarios. to our mind, this is one of the most striking features of deep alm (which is not satisfied by traditional alm models). traditional hybrid pricing and risk management models entailed an intensive validation process. this intensive work becomes obsolete and can be invested into stronger risk management platforms instead. thirdly and lastly, as long as one provides the regulators with convincing arguments regarding the accuracy and resilience of the approach (e.g., in terms of a strong validation and model risk management framework), they will never object to use deep learning. 5.7. regulatory perspective. the complex regulatory system in place is supposed to make the financial system less fragile. however, designing and implementing effective policies for the financial industry, which do no promote wrong incentives and which are not (too) detrimental to economic growth, is very demanding. this is highlighted exemplarily in the imf working paper [30] . an illustration that certain measures do not necessarily encourage the desired behaviour can be found in [18] by martin grossmann, markus lang and helmut dietl. initially triggered by the bankruptcy of herstatt bank (1974), the basel committee on banking supervision has established a framework that specifies capital requirements for banks. it was revised heavily twice since its publication in 1988. the current framework, also known as «basel iii» (see [3] ), was devised in the aftermath of the 2007/2008 credit crunch. amongst others, it proposed requirements for the lcr and the nsfr. the impact of these liquidity rules was empirically assessed in [10] by andreas dietrich, kurt hess and gabrielle wanzenried. due to limited historical data and the intricate complexity between the plethora of influencing factors, the true impact of the new regime can hardly be isolated. deep alm opens an extremely appealing new way of appraising the effectiveness of regulatory measures. to this end, one investigates how a very smart and experienced afa changes her behaviour when certain regulatory measures are enabled or disabled respectively. this approach allows to truly identify the impact of supervisory interventions and the compatibility amongst each other. these quantitative studies will be a promising supplement of deep alm. 5.8. model risk management. the supervisory letter sr 11-7 of the u.s. federal reserve system («fed») has become a standard for considerations of model risk management; see [5] . controlling the inherent model risk and limitations will be a key challenge before deep alm may be exploited productively. while the performance of proposed strategies can be checked instantaneously for thousands of scenarios within the model, an assessment of the discrepancy between the deep alm model and the real world is a crucial research topic. once a robust deep alm learning environment has been established, these aspects can be explored by means of various experiments. for instance, one can analyse the sensitivities of the acquired replication strategies with respect to the model assumptions or the performance of those in the presence of parameter uncertainties. these uncertainties may concern both the assumed states (e.g., the term structure of deposit outflows) and the concealed scenario generation for both the training and the validation (e.g., the drift assumptions of equities). 5.9. risk policy perspective. another intriguing question is the quest for locally stable strategic asset allocations. typically, the trained neural network will reshuffle the balance sheet structure right from the beginning. characterising noaction regions corresponds to locally optimal initial states. concerning the model risk management, revealing the link between different model assumptions and the internal risk policies, on the one hand, and the no-action regions, on the other hand, will be powerful tool for risk committees. pricing and hedging derivative securities in markets with uncertain volatilities modeling non-maturing products. liquidity risk measurement and management by basel iii: a global regulatory framework for more resilient banks and banking systems (revised version deep optimal stopping board of governors of the federal reserve system reaching goals by a deadline: digital options and continuous-time active portfolio management deep hedging dynamic stochastic programming for asset-liability management a fundamental theorem of asset pricing for continuous time large financial markets in a two filtration setting the good and bad news about the new liquidity rules of basel iii in western european countries the impact of the liquidity coverage ratio on swiss retail banks machine learning in finance dynamic programming and pricing of contingent claims in an incomplete market hidden markov models investing: the collected works of martin l. leibowitz management of non-maturing deposits by multistage stochastic programming deep learning why taxing executives' bonuses can foster risk-taking behavior model calibration with neural networks computational methods for quantitative finance deep reinforcement learning for autonomous driving: a survey reinforcement learning in robotics: a survey a bank asset and liability management model valuing american options by simulation: a simple least-squares approach advances in financial machine learning on the pricing of corporate debt: the risk structure of interest rates a benchmark approach to quantitative finance neural networks for option pricing and hedging: a literature review the evolution of asset/liability management emerging issues in banking regulation. imf working papers a general reinforcement learning algorithm that masters chess, shogi, and go through self-play asset liability management (alm) in banken e-mail address: thomas.krabichler@ost.ch e-mail address: josef key: cord-273789-sbppgkza authors: donohoe, holly; pennington-gray, lori; omodior, oghenekaro title: lyme disease: current issues, implications, and recommendations for tourism management date: 2014-08-20 journal: tour manag doi: 10.1016/j.tourman.2014.07.006 sha: doc_id: 273789 cord_uid: sbppgkza lyme disease is a bacterial infection spread through the bite of an infected tick. in the last few decades, the number and spatial reach of new cases has increased globally and in the united states, lyme disease is now the most commonly reported vector-borne disease. despite this evolving public health crisis, there has been little-to-no discussion of the implications for tourism supply and demand. this paper reviews the scientific literature to identify lyme disease risk factors and the implications for tourism management are discussed. the major contribution of this paper is a set of recommendations for tourism managers who may be tasked with mitigating the risks for visitors and employees as well as the potential impacts of lyme disease on destination sustainability. lyme disease is the world's fastest growing vector-borne zoonotic disease with cases reported in over 60 countries and endemic foci in north america, europe, and asia (who, 2013) . the world health organization (who, 2013) reports that the risk is generally low except for those travelling to rural areas, particularly campers, hikers, and workers in countries or areas at risk. however, this assessment may give a false sense of security for people working or travelling in areas where the risk of lyme disease is uncertain and it may breed complacency amongst those responsible for occupational, travel, or public health. the northeastern united states is traditionally defined as the endemic global center for lyme disease and the public health risk is highest in this area. in 1982, systematic surveillance for lyme disease was initiated by the u.s. centers for disease control and prevention (cdc, 2013a), with 11 states reporting 491 cases. in 1990 a standardized case definition was approved and by 2012, the number of cases reported had increased over 200 percent (cdc, 2013b; ciesielski et al., 1989) . the cdc (2013a) states that only 10 percent of lyme disease cases are being recorded which translates into approximately 300,000 estimated cases in the united states each year (fig. 1) . a majority (95 percent) have been concentrated in the northeast, yet cases have been reported in every state and in many countries around the world and their geospatial analysis reveals that lyme disease has extended well beyond traditionally defined endemic areas (cdc, 2013b; diuk-wasser et al., 2012) . lyme disease case rates have been increasing exponentially at the global scale while in the united states it has become the number one and most medically significant vector-borne infectious disease (abbott, 2006; piesman & eisen, 2008) . while it is possible to surmise that better diagnostics and increased reporting are responsible for case rate trends in the united states and other parts of the world, case rates vary because of social, environmental, and economic variables such as climate and ecological change, tick and host species range expansion, human demographics and behaviour, land use patterns, clinical practice, disease reporting standards, surveillance technologies, and true incidence (daniels, falco, schwartz, varde, & robbins, 1997; grenfell & harwood, 1997; horowitz et al., 2013) . lyme disease is caused by borrelia burgdoferi e a bacterial pathogen transmitted to humans through the bite of an infected tick. the pathogen is sylvatic; meaning that it cycles between wild animal hosts and vectors. humans are not the primary host and as such are usually incidental or dead-end hosts. although the symptoms have been observed since the 19th century, it has only been 30 or so years since the etiological agent and the primary vector(s) for lyme disease were recognized and their medical significance reported. the infection is characterized by a distinctive bull's eye rash that occurs in 60e80 percent of patients (cdc, 2011) . from the early symptoms of fever, headache, muscle and joint pain to the more serious symptoms such as cognitive impairment, cardiac abnormalities, arthritis, and paralysis, the impacts on individual health are noteworthy (who, 2012) . diagnosis is completed through a clinical examination and confirmed through serological tests and treatment consists of oral or intravenous antibiotics. currently, there is no vaccine available for human use but several are available for veterinary use (willadsen, 2006) . although the medical and scientific communities have been pursuing the problem for years, tourism has been slow to recognize that lyme disease can affect both tourism supply and demand. in the supply context, outdoor workers in endemic areas are at increased risk because of their frequent exposure to ticks and tick habitat (piacentino & schwartz, 2002) . antecedent studies have established that outdoor workers are up to 10 times more likely to be infected than the general population (bowen, schulze, hayne, & parkin, 1984; smith et al., 1988) . given that a proportion of individuals employed in the tourism, parks, and outdoor recreation sectors are required to spend some to all of their time working outdoors, the potential threat to individual and industry health is cause for concern. for those infected, days to weeks of sick time may be required to complete treatment and the medical costs can be significant. in addition to the social costs, the u.s. department of labor reports that workplace illnesses have a major impact on an employer's economic sustainability and profit margin. the annual number of nonfatal illnesses has been estimated at 430,000 with direct cost of $12 billion and indirect costs of approximately $100 billion (leigh, 2011) . direct costs include workers' compensation payments, and it is estimated that employers pay $1 billion per week for direct workers' compensation costs (u.s. department of labor, 2014) . workers' compensation covers less than 25 percent of these costs, so all members of society share the economic burden. indirect costs include but are not limited to training replacement employees, implementation of corrective measures, lost productivity, and costs associated with lower employee morale and absenteeism. the direct medical costs associated with lyme disease in the united states are estimated at 2.5 billion dollars annually but the true cost of lyme disease is the profound impacts on personal health and well-being (maes, lecomte, & ray, 1999; magnarelli, 2009; zhang et al., 2006) . from a demand perspective, the who reports that the risk to those travelling to endemic areas of the world is generally low but nonetheless, they warn travellers to avoid tick-infested areas and tick exposure on their dedicated lyme disease webpage for international travellers (http://www.who.int/ith/diseases/lyme/en). when outdoor activities are planned during a trip to an endemic area for tick-borne disease, a tourist is at risk and the who's assessment can be misleading (falco & fish, 1989; hayes, 2010; raoult et al., 2001; smith et al., 1988) . their risk can be magnified because tourists may not have all of the necessary information or access to resources that would enable them to make informed decisions regarding lyme disease prevention before and during travel (jonas, mansfeld, paz, & potasman, 2011; kelly-hope, purdie, & kay, 2002) . for tourists who are aware of health risks before choosing a destination, s€ onmez and graefe (1998) and kozak, crotts, and law (2007) report that perceived risk can be a strong predictor for avoiding certain regions or changing travel plans. dixon et al. (2010) report that the macroeconomic consequences of a health threat or crisis are highly sensitive to demand-side effects such as the reductions in international tourism and leisure activities that result from elevated risk perceptions. for example, during the severe acute respiratory syndrome (sars) pandemic, traveller's health risk perceptions had a significant effect on international tourism demand. over 8000 cases and 774 deaths in 26 countries were reported in 2003 with a majority of cases occurring in asia (who, 2004) . the initial spread of sars was exponential with predictive models showing that if uncontrolled, a majority of people would become infected wherever it was introduced (dye, 2003) . air travel to areas affected by the advisories decreased dramatically during the epidemic (kuo, chen, tseng, ju, & huang, 2008; zeng, carter, & de lacy, 2005) . in east asia, tourist arrivals dropped by 41 percent during the month of april compared to the same period in 2002, with china, hong kong, singapore, and vietnam reporting the greatest losses (pine & mckercher, 2004; wilder-smith, 2006) . growth of the broader travel and tourism economy, which measures visitor spending and capital investment around the world, slowed to 2.9 percent down from 5 percent in previous years and international arrivals fells 1.2 percent (world travel and tourism council, 2003) . while lyme disease is certainly not a pandemic and it cannot be spread person to person, like sars and other infectious disease risks, it can prompt fear and anxiety that most certainly can affect a traveller's perceptions and by extension; it can affect their travel choices and behaviours (birnbrauer, pennington-gray, & donohoe, 2013 ). herrington's (2004) national survey of american risk perceptions regarding ticks and lyme disease found perceived risk to be a predictor of behavioural change. those who had seen ticks, had heard about lyme disease, were concerned about being bitten, or knew someone who had lyme disease were more likely to engage in tick-bite prevention such as avoiding tick habitat and wearing insect repellent. brewer et al.'s (2004) research confirms that higher risk judgements encourage people to engage in protective behaviour, indicating a causal relationship between perceived risk and behaviour modification. although empirical research has yet to confirm as much, lyme disease beliefs and attitudes have likely been having an impact on the decision-making processes and behaviours of outdoor workers, recreationists and travellers (hanson & edelman, 2003) . knowing that lyme disease poses a real and growing threat to the tourism industry, the purpose of this paper is to first, review the scientific literature to identify lyme disease risk factors and second, to critically assess the implications for tourism management. a search for scholarly journal articles about lyme disease was performed using pubmed, proquest global, and google scholar on july 6, 2013. the search parameters were narrowed to identify articles where "lyme disease" occurred in the title then additional words were added to winnow down the results to relevant articles: "travel", "tourism", "recreation(al)", "park(s)", "occupation(al)", "risk", and "prevention" (table 1) . no temporal restrictions were used. after removing duplicates, 132 unique scholarly articles were identified and reviewed. the search for articles with "lyme disease" and "travel" or "tourism" resulted in 0 articles in all three search engines. the fact that lyme disease has not been examined in the context of tourism and travel is no surprise because the tourism domain has not traditionally focused the research lens on health risks. there is a research and knowledge gap regarding health risk generally and lyme disease specifically, as well as their potential and real impacts on the tourism industry. it should be noted that a similar pubmed search using "tick-borne disease" and "tourism" yielded 15 papers dealing with other tick-borne diseases that occur independent of or in conjunction with lyme disease. anaplasma, babesia, bartonella, ehrlichia, and rickettsia for example, may be just as significant as lyme disease in some parts of the world yet they are equally underappreciated in the travel and tourism context. these papers were consulted in the preparation of this paper and they are also included in the analysis that follows. when "recreation/al" and "parks" was added to the search, 7 articles were identified, 5 of which were case or exploratory studies of ixodes scapularis tick populations and their hosts in select recreational parks in canada (morshed, scott, fernando, mann, & durden, 2003; scott et al., 2008) , italy (curioni et al., 2004) , and the united states (daniels et al., 1997; falco & fish, 1989; lane et al., 2006) . two articles surveyed parks visitors (hallman, weinstein, kadakia, & chess, 1995) and recreational destination workers (rees & axford, 1994) about their lyme disease knowledge, tickexposure, tick-bite prevention behaviours and/or clinical history with the disease. of the 13 articles where "occupation(al)" or "work(er)" appeared, the majority were seroprevalence studies of individuals working in the forestry, parks, land management, and agricultural sectors in various locations around the world (e.g. cisak, w ojcik-fatla, zają c, sroka, & dutkiewicz, 2012; goldstein et al., 1990; guy, bateman, martyn, heckels, & lawton, 1989; nakama, muramatsu, uchikawa, & yamagishi, 1994; smith et al., 1988; stanchi & balague, 1993) . one study from the united states reported the results of a survey of workers regarding their knowledge of lyme disease and their behaviour regarding tick-bite prevention and one article provided a comprehensive review of the occupational risks (piacentino & schwartz, 2002) . over 60 articles were found that contained "lyme disease" and "risk" in the title. a majority of these articles assumed a natural science perspective (i.e. epidemiology, medicine, microbiology, and zoology) and reported on the spatial and temporal factors affecting ticks, the causative agent e the borrelia pathogen(s), host species, environment, and human exposure (e.g. allan, keesing, & ostfield, 2003; glass et al., 1995; guerra et al., 2002; maher, nicholson, donnelly, & matyas, 1996; ogden et al., 2008) . a minority of the papers focused on behavioural risks and a review of these papers revealed a consensus that human exposure to ticks is the central risk factor for infection (e.g. diuk-wasser et al., 2012; fish, 1995) while knowledge and prevention act as risk mediators (e.g. mckenna, faustini, nowakowski, & wormser, 2004; smith, wileyto, hopkins, cherry, & maher, 2001) . articles that contained the key word "prevention" did so primarily as a recommendation for public agencies responsible for reducing the burden of infection. piesman and eisen (2008) and poland (2001) provide a review of lyme and tick-borne disease prevention strategies and mowbray, amlôt, and &rubin (2012) provide a review of education and communication interventions to prevent tick-borne disease. a critical synthesis of this body of research was completed to identify lyme disease risk factors as they have potential implications for tourism management. it is the aforementioned factors e exposure, knowledge, and personal protection behaviour -that comprise the discussion in the sections that follow. 3.1. tick exposure i. scapularis or the blacklegged tick is the primary vector for lyme disease in the united states. in the united states and other areas of the world, dozens of tick species have been implicated in the spread of lyme and lyme-like borrelia pathogens to humans and animals (e.g. barbour, maupin, teltow, carter, & piesman, 1996; burgdorfer, 1984; clark, 2004; clark, leydet, & hartman, 2013; harrison et al., 2010; mather & mather, 1990; nakao, miyamoto, & fukunaga, 1994; piesman & sinsky, 1988; piesman, clark, dolan, happ, & burkot, 1999) . epidemiological studies have explored the relationship between ticks, climate, seasonality, host species, and disease risk in a variety of local or regional contexts (e.g. estrada-peña, 2003; sumilo et al., 2008; wielinga et al., 2006) . predictive models have been developed using remote sensing, satellite imagery, geographical information systems, and advanced statistical analysis (e.g. daniels et al., 1997; diuk-wasser et al., 2012; werden et al., 2014) . the research indicates that vegetation and climate are the two central predictors of suitable/unsuitable habitats for tick species and it is therefore possible to identify high-risk areas and potential emergent areas for lyme disease. the areas with the highest risk for human exposure are those that contain suitable tick habitat, ticks capable of transmitting the lyme disease pathogen, and have high host activity (gray et al., 1998; schulze, jordan, & hung, 1995) . empirical approaches have laid the groundwork for a better understanding of the relationship between environmental factors and tick distribution. however, they fail to account for the vital role that human behaviour plays in the disease transmission process. the global increase in interaction between humans and wildlife through population growth, economic development, and an increasingly mobile society that brings people into endemic areas for work and leisure is amplifying personal risk (kollaritsch et al., 2011; quine et al., 2011; rizzolli, hauffe, vourc'h, neteler, & rosa, 2011) . the rapid expansion of the tourism industry and air travel is of concern as the importation of pathogens and vectors by travellers (purposefully or not) and specifically ticks and tick-borne disease pathogens is a real threat to human and ecological health (e.g. daugschies, 2001; hall, 2006; holzer, 2005; schuster et al., 2008) . european case reports demonstrate statistical relationships between outdoor recreation in tick-infested forests and tick-borne disease infection (e.g. daniel, danielov a, k rí z, jirsa, & no zi cka, 2003; kahl & radda, 1988; sumilo et al., 2008) . early case studies in the united states failed to show a significant increase in risk associated with outdoor recreation (e.g. bowen et al., 1984; ciesielski et al., 1989; falco & fish, 1989) but smith et al.'s (1988) research found that persons who had spent more than 30 h per week in outdoor activities in endemic areas were 2.5 times more likely to test positive for lyme disease. since the 1980s, a small body of literature has evaluated the occupational risk for lyme disease. in new york, schwartz and goldstein et al. (1990) confirmed that lyme disease is a hazard of outdoor work and a study in new jersey found that outdoor workers were nearly five times more likely to have contracted lyme disease than indoor workers (bowen et al., 1984) . in the broader international and tickborne disease contexts, the research shows similar relationships between tick exposure and infection. in lithuania, motiejunas, bunikis, barbour, & sadziene (1994) report that those at highest risk for a tick-borne disease (established through seropositivity testing) are outdoor workers (32 percent tested positive/n ¼ 6187). recent case studies in europe (e.g. bartosik, sitarz, szyma nska, & buczek, 2011; bochnickova & szilagyiova, 2011; franke, hildebrandt, meier, straube, & dorn, 2011; jameson & medlock, 2011) confirm that ticks, lyme and other tick-borne disease pathogens are common across europe and they pose a significant occupational risk to outdoor workers. two studies in poland involving serological testing of both ticks and humans confirmed that those who perform work in forest environments are regularly exposed to tick-borne disease pathogens and as such, are at a higher risk of infection. two dutch studies of lyme disease seroprevalence in outdoor workers showed a statistically significant risk (or, 3.7; 95 percent ci, 1.5e9.7 and or, 15.0; 95 percent ci, 5.5e42.0) relative to the control group (kuiper et al., 1991; van charante, groen, mulder, rijpkema, & osterhaus, 1998) . in 2002, piacentino and schwartz published a meta-analysis of articles on the occupational risk of lyme disease and report that the scientific evidence demonstrates that those who work outdoors in endemic areas are at an increased risk for contracting lyme disease because of their exposure to ticks. it is evident in this body of literature that exposure to ticks is the single most significant human risk factor and the first line of defence against tick bites should be avoidance of these areas completely or seasonally (during periods of high tick activity), or where appropriate, control of the tick population. given the geospatial expansion of tick species, increasing human mobility and encroachment into tick habitat, and the attendant expectation that future interactions between humans and ticks are likely to increase, vigilance and on-going monitoring is required as new and extant tick-borne pathogens pose potential threats to public health. lyme disease risk is magnified when individuals are not aware of the risks, do not mitigate risks, are not familiar with infection signs and symptoms, and do not know where to seek information or support . it is widely accepted that knowledge plays an important role in mediating lyme disease risk as it is a pivotal precursor to preventative behaviour (piacentino & schwartz, 2002; poland, 2001 ). herrington's (2004) national survey found that a majority of americans know about ticks and the risks they present to human health. in the tourism and recreation context, hallman et al. (1995) found that over 80 percent of people surveyed at three state parks in new jersey reported knowing about lyme disease and could name at least one bite prevention strategy (table 2 ). in recreational and agricultural settings in poland, bartosik et al. (2011) found that workers do not know about the health risks associated with ticks and they are not protecting themselves against tick bites while at work. in the forestry sector, cisak et al. (2012) found that workers possess only basic tick-borne disease knowledge. in france, a study of nearly 3000 outdoor workers revealed that a majority would like to have access to educational materials so that they can make informed decisions about tick-bite prevention (thorin et al., 2008) . it is difficult to draw conclusions on the basis of the limited study of lyme and associated tick-borne disease knowledge, but the literature suggests that knowledge varies geographically and although it has not yet been correlated, it may be that knowledge is higher in areas where lyme and/or other tick-borne diseases are endemic and therefore the risk is higher and investments in educational interventions may be greater. in the latter case, the science appears more developed and it suggests that educational interventions do influence an individual's lyme disease knowledge. for example, gould et al. (2008) evaluated resident behaviours following an intensive community-wide education program and found that 99 percent were aware of the risks and were taking steps to prevent tick exposure. gray et al. (1998) assessed knowledge of lyme disease among a sample of students before and after an educational intervention and found that general knowledge of ticks and lyme disease improved. jenks and trapasso (2005) found that knowledge of tick removal and the signs and symptoms of infection improved following a one-on-one educational intervention by a physician. maher et al. (2004) measured the impact of a lyme disease education program for children in the united states and found that participants had more knowledge of ticks and more confidence in their ability to do a tick check. fox (2009) reports that individuals were more knowledgeable about wearing protective clothing following an educational intervention while knowledge of other personal protection measures was not significantly changed. this body of work provides empirical evidence that the communication of objective and clear messages about tick-borne disease and tick exposure can be effective for increasing public knowledge as well as an individual's ability to make informed decisions about personal protection. concomitantly, prevention investments specifically targeted at increasing public knowledge are an important risk mediator because knowledge can empower the individual to choose to engage in personal protection behaviours. not knowing about lyme disease is most certainly a risk factor for those living or visiting endemic areas for work or leisure. it is widely accepted in the health risk literature that behaviour plays an important role in minimizing disease risk . behavioural modification related to lifestyle, hygiene, and personal protection is the primary method for the prevention of infectious diseases where prophylactics are unavailable. for example, noroviruses are the most common cause of epidemic gastroenteritis on cruise ships and they are responsible for at least 50 percent of all gastroenteritis outbreaks worldwide (goodgame, 2006; hall et al., 2011) . hand hygiene (washing with soap and water) is the single most important method for preventing infection and controlling transmission (hall et al., 2011) . to prevent mosquito-borne infectious diseases such as dengue fever and west nile virus, personal protection through the use of insect repellents and the avoidance of outdoor activity during peak mosquito feeding times is recommended in conjunction with communitybased chemical and biological control investments (renganathan et al., 2003) . in the case of malaria, the use of insecticide-treated bed nets has been shown to minimize human-vector contact and the incidence of infection by up to 50 percent (choi et al., 1995) . in the absence of a lyme disease vaccine for human use, the u.s. centers for disease control (2013a) recommends personal protection measures for avoiding tick bites and infection: (1) avoid tick areas; (2) avoid direct contact with ticks; and (3) remove ticks from your body (table 2 ). if tick habitats cannot be avoided, there are simple things that individuals can do to minimize the risk for tick bites and pathogen exposure (see table 2 ). wearing protective clothing mechanically decreases direct skin exposure and wearing light-coloured clothing makes it more likely that the tick will be detected and removed before it finds a feeding site (garcia-alvarez, palomar, & oteo, 2013) . repellents containing deet (n, n-diethylmeta-toluamide) applied to skin and permethrin-based insecticides applied to clothing have been shown to effectively decrease the risk of tick bites and they are reasonably safe to use (patey, 2007; piesman & eisen, 2008) . recently, vaughn et al. (2014) evaluated the protective effectiveness of factory-based and longlasting permethrin (insecticide) treated uniforms among a cohort of outdoor workers in north carolina. the incidence of workrelated tick bites reported by the treatment group was significantly lower than the control group and the treated uniform prevented 95% of tick bites. the results indicate that long-lasting permethrin impregnated uniforms can be highly effective for deterring tick bites for up to one year. if a tick bite should occur, the tick should be removed using the proper technique of grabbing the tick close to the skin and pulling gently upward with tweezers (tick removal guide: http://www.cdc. gov/ticks/removing_a_tick.html). the tick should be saved in a sealed container and provided to a physician for testing when the victim seeks medical attention (due, fox, medlock, pietzsch, & logan, 2013; garcia-alvarez et al., 2013) . in this regard, knowing the early signs and symptoms of infection are important for early diagnosis and treatment (symptom guide: http://www.cdc.gov/ ticks/symptoms.html). it is important to note that not all bites will result in infection because not all lyme disease transmissioncapable ticks carry the pathogen. and, the public health risk for lyme disease is affected by spatiotemporal patterns of the tick vector, its life stage, preferred host species (i.e. mice, deer), as well as seasonality, climate, and a range of other environmental factors (adelson et al., 2004; diuk-wasser et al., 2006; ostfeld et al., 2001; qui, dykhuizen, acosta, & luft, 2002; schulze, jordan, schulze, mixson, & papero, 2005) . it is equally important to note that while numerous personal protection strategies have been recommended by public health authorities (table 2) , they vary in cost, acceptability, and effectiveness, and their uptake has been universally poor (corapi et al., 2007) . research in areas where lyme disease is endemic has demonstrated that despite adequate knowledge about its symptoms and transmission, individuals are not taking action to protect themselves from the risk of infection. in the tourism and recreation context for example, hallman et al. (1995) reported that over 80 percent of visitors surveyed in new jersey state parks could name at least one tick bite prevention measure but a majority (60 percent) took no precautions. shadick, daltroy, phillips, liang, & liang (1997) study of residents and visitors to martha's vineyard in massachusetts found that knowledge about lyme disease alone was not a predictor for protective behaviours and visitors were less likely to protect themselves than residents. a similar study conducted ten years later found that visitors to nantucket (located next to martha's vineyard) were significantly more likely to take precautions when visiting if they had been exposed to a lyme disease education program while on the ferry to this island destination . in the united kingdom, a study of early lyme disease patients found that participants were more likely to perform tick checks, monitor for symptoms, and seek medical attention after a countryside visit (i.e.) rather than take precautions before and during the potential exposure (marcu, barnett, uzzell, vasileiou, & susan, 2013) . those who regularly frequented the countryside were the least likely to perform during-visit precautions (marcu et al., 2013 ). herrington's (2004) national survey of americans found that despite knowing about lyme disease risk, a majority (60 percent) of those surveyed were not taking action to prevent tick bites. conversely, gould et al.'s (2008) study of knowledge, attitudes, and behaviours of connecticut residents e a highly endemic area of the united states, found that 84 percent knew some to a lot about lyme disease, 56 percent felt they were very or somewhat likely to get lyme disease in the coming year, 99 percent used personal protective behaviours to prevent lyme disease, and 65 percent reported using environmental tick controls (e.g. pesticide application on personal property). in the occupational context, "adherence to national institute for occupational safety and health-recommended tick bite prevention methods is poor" in the united states and the same is suggested in the literature for other parts of the world (vaughn et al., 2014: 473) . in poland for example, cisak et al. (2012) found less than 30 percent of the forestry workers they surveyed were practising tick-bite prevention. bartosik et al. (2011) found that high-risk workers do not possess knowledge of the potential consequences of a tick bite, are unlikely to take protective measures beyond insect repellent application, and those from urban areas were less likely to protect themselves. the mixed results from the study of residents, visitors, and outdoor workers suggest that a variety of factors are influencing the adoption of personal protection and that more research is needed to better understand how they vary spatially, temporally, socioeconomically, or otherwise (bayles, evans, & allan, 2013) . a limited number of controlled trials have attempted to empirically measure the relationship between knowledge, tick-bite prevention, and seropositivity (laboratory confirmed measure of infection). daltroy et al. (2007) conducted a randomized trial of a lyme disease educational program whereby approximately 30,000 visitors to nantucket -a high-risk area in massachusetts, were provided with educational materials before arriving. after their visit, study participants reported their tick-bite prevention while in nantucket and provided a blood sample for serological screening. the study found that visitors who were knowledgeable about lyme disease were significantly more likely to practice tick-bite prevention during their visit and were also significantly less likely to be infected with lyme disease during their stay. at 2 months post visit, 144 participants self-reported that they had been infected with lyme disease and 43 of these were confirmed by physicians. the analysis showed lower rates of self-reported illness among those who received educational materials and long-term visitors (>2 weeks) were more likely to have lower relative risk than short-term visitors. similarly, malouin et al. (2003) assessed the impact of a lyme disease educational campaign in maryland and found a significant difference between the intervention and non-intervention control group in terms of knowledge and the self-reported use of prevention methods but no significant serological difference between groups was observed. in their study of outdoor workers in new york state, schwartz and goldstein (1990) found that when workers were knowledgeable and they practised personal protection, the occupational risk for lyme disease infection was significantly diminished (as measured by tick exposure odds ratios). a recent study looked at a variety of environmental and behavioural/ personal risk factors for seropositivity and found that exposure and age were associated with positive lyme serology and wearing protective clothing was significantly associated with negative serology (finch et al., 2014) . this lean body of literature suggests that taking action to prevent tick bites before, during, and after visiting a natural and/or known tick area (see table 2 ) can be effective for preventing lyme disease and that knowledge is a precursor to the adoption of personal protection behaviours (beaujean, bults, van steenbergen, & voeten, 2013) . this finding is congruent with theoretical explanations found in the health education literature. the health belief model was one of the first theories of health behaviour and it remains one of the most widely recognized and applied in the field. the model suggests that an individual's readiness to take action, is influenced by their beliefs about their susceptibility to a health threat, perceptions of the benefits of taking action to prevent it versus the perceived barriers to taking action, and confidence in their ability to take action (self-efficacy) (rosenstock, 1974) . this model has been used to better understand an individual's decisionmaking and behaviours related to infectious disease risk (e.g. glanz, rimer, & viswanath, 2008; harrison, mullen, & green, 1992; janz & becker, 1984) and recently it has been shown to be useful for understanding the grey area between tick-borne disease knowledge and personal protection behaviour (e.g. bayles et al., 2013; beaujean, et al., 2013) . in the same vein, the theory of planned behaviour posits that behaviour can be deliberative and planned and that an individual's attitude toward a behaviour, the perceived control they have over a behaviour, as well as normative beliefs and subjective norms act to shape an individual's behaviours (ajzen, 1991 (ajzen, , 2002 . theory of reasoned action suggests that a person's behaviour is determined by his/her intention to perform the behaviour and that this intention is, in turn, a function of his/her attitude toward the behaviour and his/her subjective norm (fishbein & ajzen, 1975) . the difference between these two theories being that the former suggests that attitude and control are predictors of behavioural intention and action while the later suggests behavioural intention is the most important determinant of behaviour (madden, ellen, & ajzen, 1992) . while knowledge about a health threat is a precursor to an individual's transition from knowledge to action, there are numerous theories and models that posit a variety of factors to explain the adoption [or not] of health risk prevention behaviours. concomitantly, it must be acknowledged that theories such as these do not capture or model the complexity of behavioural change in the context of health and wellbeing. if it were a simple equation (e.g. increased knowledge of health risk ¼ behavioural change), then nearly everyone would lead healthy lifestyles, they would protect themselves against health risks, and many illnesses would be non-existent. however, it is not as simple as a linear or causal relationship and there are many factors that affect health behaviour. for example, marcu et al. (2013) and beaujean et al. (2013) report that individuals don't comply with tick bite prevention recommendations because they interfere with their enjoyment of the outdoors (e.g., they refuse to wear long clothes on a hot day), they believe the risk of tick bites is low (perceived susceptibility), they do not believe that the recommendations are effective (e.g., insect repellent does not always prevent bites), and they are not confident in their ability to identify a tick or a tick bite. in this case, an improved understanding of the individuals and segments at risk for lyme and other tick-borne diseases as well as the factors that do or do not influence their behaviours is needed to inform the development of targeted and tailored public health interventions (bayles et al., 2013; beaujean et al., 2013; mowbray et al., 2012) . the epidemiological evidence is strongly indicative of a causeeffect relationship between tick exposure and lyme disease infection. although the science is embryonic when it comes to the relationship between knowledge, personal protection behaviour, and lyme disease risk, it certainly suggests that these factors can act as risk moderators and mediators. short of major changes in tick ecology, vaccine availability, tick control, and human behaviour, predictive models suggest that lyme disease will continue to be a public health threat in an increasing number of areas around the world. when we examine this issue through a tourism lens, it is clear that lyme disease is posing a real and growing threat to both supply and demand in endemic and emergent areas of the world. decisions regarding the primary prevention of vector-borne diseases such as lyme disease are as a matter of course, made at the national, state, or regional level and do not involve tourism industry stakeholders but should. in the past, a plethora of methods for large-scale lyme disease prevention including vaccines, biological and chemical tick control methods have been adopted by government agencies at a variety of scales (garcia-alvarez et al., 2013) . in 1998, the united states federal drug administration (fda) approved the lymerix™ vaccine and the cdc advisory committee on immunization practices (acip) recommended vaccination for those living in high risk areas (nigrovic & thompson, 2007) . although it was shown to reduce new infections in vaccinated adults by 76 percent, the manufacturer voluntarily withdrew the product from the market in 2002 amidst reports of side-effects, a government investigation, a class-action lawsuit, negative media coverage, and declining sales (nigrovic & thompson, 2007) . in the absence of a human vaccine, a variety of chemicals have been used to reduce the overall tick population but the effect has proven short-lived, their use impractical on a largescale basis, and chemical resistance has been observed in tick species (george, 2006) . wildlife management has been explored as a less-toxic alternative but attempts to limit the primary host population through hunting, landscape modifications, and movement restrictions (e.g. fencing) have produced mixed results and they too are impractical on a large-scale basis (heymann, 2008; piesman & eisen, 2008) . while these interventions may have blunted the tick population and pathogen lifecycle, "they have clearly not been sufficient to lower the number of [lyme] cases, and the epidemic continues to gain momentum" (hayes & piesman, 2003 : 2424 . given that these efforts have not yet achieved the desired end, willadsen (2006: 161) argues that "the achievement of the full potential of vaccination, the application of biocontrol agents and the coordinated management of the existing technologies all pose challenging research problems." with an eye to the future, scholars are expressing hope that the development and application of new scientific tools and technologies (i.e. molecular techniques) will have the capacity to revolutionize tick control methods and policies into the future or better yet, they will manifest an effective human vaccine (garcia-alvarez et al., 2013; sonenshine, kocan, & de la fuente, 2006; willadsen, 2006) . in the absence of such a vaccine or other suitable prophylactic and effective tick control methods, piesman and eisen (2008: 336) argue that lyme disease education is the single most important area in which public health agencies, employers, and other stakeholders can invest to reduce the burden of infection. they argue that the next logical step in prevention is to "ensure ready access to objective information empowering the individuals de facto responsible for control of ticks and tick-borne diseases to make rational and informed decisions regarding their personal risk of exposure to tick-borne pathogens and to take appropriate actions to mitigate risk of tick bites and pathogen exposure." in the united states for example, the cdc has an active tick-borne disease prevention program with a dedicated focus on lyme disease and many state health agencies have developed similar public health education programs. however, they fail to account for the unique characteristics of tourists who may not be familiar with the local area and health risks, and they are unlikely to know where to seek local health risk information. the implications are such that the tourism industry and the tourists upon which it depends are left vulnerable to the real and perceived risk of lyme disease. perhaps it is best that disease prevention be left in the hands of public health experts, but this does not negate the role that tourism bodies can play, in partnership with public health and other organizations, to address the growing lyme disease problem in many parts of the world. it is recommended that tourism industry associations, destination management organizations (dmo), and convention and visitors bureaus (cvb) for example, represent the industry's unique interests, characteristics, needs, and concerns in the public health decision-making forum at national, state, and regional levels (e.g. form a task group). and it is important that these same industry stakeholders assume a leadership role in the dissemination and operationalization of any public health interventions that affect those providing travel and tourism services and those consuming them. when considering the day-to-day management of tourism in high-risk destinations and emergent areas for lyme disease, parsons (1996) and pennington-gray et al. (2009) recommend that managers take a proactive rather than reactive management approach to potential health threats so that they can mitigate the risks and deal with the threat more effectively. ritchie (2004) and pennington-gray, thapa, kyriaki, cahyanto, and mclaughlin (2011) recommend the development of a multi-phase management plan to help destinations and/or attractions, accommodations, and other servicing businesses avoid or limit the severity of the threat's impact on supply and demand. the plan should address: (1) how to prevent the threat, (2) what to do in the event of, and (3) how to recover. in the later cases, generalizable tourism crisis management guidance is available in the literature (e.g. faulkner, 2001; ritchie, 2004; young & montgomery, 1997) . in the specific lyme disease context, it is strongly recommended that tourism managers become informed and take action to protect visitors and employees from the risk of acquiring lyme and other tick-borne diseases. public health authorities should be consulted about the risks for tick-borne disease in the area and any potential "hotspots" for high tick activity and disease risk should be identified and marked. for example, brochures could be provided to visitors upon entry into state or national parks and warning signs could be posted at trail heads, picnic areas, or other high human activity areas where the risk for a tick encounter exists. similarly, park managers could provide brochures and workshops to employees so that they can be made aware of the risks and the ways to protect themselves and park visitors. in endemic areas, travellers arriving by air or ferry or other could be provided with an informative pamphlet in arrival, departure, or visitors centres. public health authorities and local pest management experts should be consulted when making tick control decisions at tourism attractions so as to avoid costly, illegal, or harmful mistakes. where it is feasible or appropriate, tourism managers should seek out a biological tick control expert to recommend strategies for tick and/or wildlife control (e.g. deer fencing). for example, removing leaf litter and cutting back tall grass and brush in high human activity areas is a simple and low cost way to reduce ticks and tick encounters in tourism destinations. it is also recommended that tourism management stakeholders seek out educational materials from public health authorities and make them available to employees and visitors. in the united states, the cdc has a free toolkit that includes downloadable fact sheets in english, spanish, and portuguese and pamphlets and trail signs can be ordered free of charge (http://www.cdc.gov/lyme/toolkit/index. html). in michigan, the public health authority has made available a downloadable fact sheet entitled "preventing lyme disease in recreational camp settings" that provides recommendations for staff and visitor protection (http://www.michigan.gov/documents/ emergingdiseases/camp_guidelines_321958_7.pdf). the california department of public health has developed an interactive website to provide information about infected ticks as part of its statewide vector-borne disease surveillance program. the data on the map represents ticks collected and tested by the california department of public health as well as vector control and public health agencies in the state (http://cdphgis.maps.arcgis.com/apps/socialmedia/ index.html?appid¼8d99fb1135d1424f9d8a8711acb7d459). this website is a useful model for developing publicly available risk maps for tick-borne diseases in other areas of the world. tourism managers can provide invaluable information to surveillance programs such as the one in california by reporting tick encounters and providing ticks collected in and around tourism attractions to the local authorities for testing. this information is valuable because it can inform public health authorities about emerging outbreaks and it is a pragmatic way in which the tourism industry can take an active role in the monitoring of tick-borne diseases on a local-to-global scale. the world health organization (2012) published the international travel and health book and it contains authoritative information about the geographical distribution, risk for travellers, and recommended precautions for lyme disease and a myriad of other health risks (http://www.who.int/ith/en/). on a biannual basis, the cdc (cdc & brunette, 2013) publishes health information for international travel or the "yellow book" as it is commonly known (http://www.cdc.gov/features/yellowbook). while it is written primarily for health practitioners, international corporations, volunteer organizations, travel industry professionals, and travellers often refer to this book for recommendations for addressing health risks and international travel. making the aforementioned resources available to employees and visitors by providing copies onsite or sharing the web links to these multimedia resources would enable access to authoritative information before, during, and after travel. tourism managers can use existent resources such as the ones mentioned and/or they can invest in the development of their own communication plan and tools so as to account for the unique risks, visitor or employee demographics, or other conditions specific to their site. for example, rocky mountain national park developed a downloadable brochure that details the health risks and unique ecology associated with ticks in the park (http://www. nps.gov/romo/planyourvisit/upload/ticks_2008.pdf). it is also recommended that an occupational risk workshop or training module be offered so as to improve employee knowledge of the risks and the action they can take to prevent the disease and educate visitors. it must be stressed that regardless of the intervention, whether it be tick control or educational programs, tourism management stakeholders should consult and collaborate with travel health experts and public health authorities if we are to make any gains in tackling this health and safety issue. there is a role for tourism and it is recommended that tourism stakeholders partner with appropriate agencies and organizations, become active in local surveillance efforts, and co-develop educational or other interventions. this breadth of expertise and perspective is required for addressing and yielding positive results with respect to the complexity that is lyme and tick-borne disease control. this paper has critically reviewed and synthesized the literature concerned with lyme disease and three human risk factors have been identified. exposure was confirmed to be the only prognostic factor for infection while knowledge and personal protection behaviour were identified as mediating risk factors. the review noted that the research concerned with these risk factors is lean albeit evolving and there is much to be learned from all relevant scientific domains from anthropology, to entomology, to pathology, to zoology. by extension, there is a lot of work required to translate science into real-world solutions. piesman and eisen (2008: 336) state this future research need succinctly: "academic research on tick-borne diseases must be brought into the real world and effective methods for the prevention of tick-borne disease must be made cheap, easy, and safe." research funding is best spent developing a vaccine but until such a vaccine is deemed safe for widespread use or an effective tick control method is developed, research concerned with the aforementioned risk factors is needed to better inform public health interventions targeting the minutiae of human behaviour. in the tourism context, we must first expand beyond our geographical understanding so that we can better understand the spatial reach of lyme disease and destinations at-risk. risk maps are commonly used as a decision support tool by public health agencies, the medical community, and those who are tasked with protecting individual or community health. while the cdc (2010) makes an updated national risk map (based on surveillance data) available every few years, there is much for the tourism industry to learn from the fine-scale surveillance and mapping of disease epidemiology, tick populations, human behaviour, and the environment. as previously stated, tourism managers can play an active role in disease surveillance by monitoring and reporting what is happening on the ground at tourism attractions and destinations. in the global context, understanding has been constrained by research primarily focused on north america and europe. future research should focus on other endemic and emergent areas of the world. specific attention should be paid to destinations where nature-based activities are the primary touristic attraction as the potential impact of lyme and other tick-borne diseases could be significant for destination sustainability. research is also needed to better document and predict the scale and scope of the lyme disease risk associated with human activities and behaviours. in completing this review, it is apparent that behavioural research is an important but inadequately studied aspect of lyme disease prevention. activity-based risk research has focused on outdoor activities generally and outdoor work and outdoor recreation specifically. future research should focus on identifying differences, if at all, between different kinds of outdoor work and/or outdoor recreation activities. insight into these differences would certainly help tourism managers categorize the risks and plan accordingly. decisions concerning personal protection against lyme disease are made at the individual level yet little is known about perceptions of risk and other potential catalysts for protective behaviour. future research should focus on identifying unknown factors and better understanding known factors as well as their influence on an individual's choice to engage in protective behaviour. in the tourism context, the catalyst(s) may be different between the general population, tourists, and outdoor workers and this certainly requires research investments if the industry is to plan a response. future research should also be concerned with improving our very limited understanding of the impacts that lyme disease is having on the tourism industry. based on this review, we can surmise that it is having an impact on employee health, travel choices, and the economic sustainability of tourism in endemic areas but empirical research is needed to identify the scale and scope of past, present, and future impacts. theoretically driven research is needed to improve our knowledge of the relationships between public health, tourism, and the natural environment so that tourism management stakeholders can be empowered to be active agents in evolving and transdisciplinary efforts to prevent, manage, and recover from lyme disease outbreaks. holly donohoe, ph.d. is an assistant professor in the department of tourism, recreation and sport management at the university of florida. central to her research are critical examinations of tourism planning, management and marketing while evaluation science and its use of select methods and techniques for risk, impact, and policy analysis are considered her realm of expertise. current research includes projects related to vector-borne diseases and their impact on the tourism industry. studies range from baseline studies of public awareness, the analysis of public health and tourism crisis management policy frameworks, to the assessment of occupational risk for tourism a nd re creation prof essionals in at-risk environments. dr. lori pennington-gray is the director of the tourism crisis management institute at the university of florida. she received her ph.d from michigan state university (1999), her ms from the pennsylvania state university (1994) and her bs from waterloo university in canada (1993) . she has expertise in tourism marketing, planning and development, policy and crisis management. she has been involved with a number of tourism studies globally and has worked with a number of countries on tourism policy initiatives. dr. pennington-gray has published more than 40 refereed articles, has brought in more than $2m in external research dollars and made over 100 presentations. dr. pennington-gray teaches both undergraduate and graduate students the concepts of tourism policy, planning, marketing and crisis management. oghenekaro omodior, is a doctoral student in the department of tourism, recreation and sports management at the university of florida. he received his undergraduate training in medical laboratory sciences and a master of science degree in clinical biochemistry from olabisi onabanjo university in nigeria and masters of public health from the university of south carolina. karo's research is concerned with spatial patterns and public 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infectious diseases, division of vector-borne diseases the business case for safety and health long-lasting permethrin impregnated uniforms: a randomizedcontrolled trial for tick bite prevention tick control: thoughts on a research agenda geography, deer, and host biodiversity shape the pattern of lyme disease emergence in the thousand islands archipelago of ontario longitudinal analysis of tick densities and borrelia, anaplasma, and ehrlichia infections of ixodes ricinus ticks in different habitat areas in the netherlands international travel and health international travel and health: lyme borreliosis (lyme disease crisis management and its impact on destination marketing: a guide for convention and visitors bureaus short-term perturbations and tourism effects: the case of sars in china economic impacts of lyme disease key: cord-281390-rk7ijexa authors: zhou, li; turvey, calum g.; hu, wuyang; ying, ruiyao title: fear and trust: how risk perceptions of avian influenza affect chinese consumers’ demand for chicken date: 2016-09-30 journal: china economic review doi: 10.1016/j.chieco.2016.06.003 sha: doc_id: 281390 cord_uid: rk7ijexa abstract this article quantifies the impact of h7n9 bird flu on chicken demand and consumer willingness to pay (wtp) in china. we measure risk perception, fear and trust against actual reduction in consumption and stated change in wtp for safe chicken between 2012 and 2013. through a survey conducted in each year on the same chinese urban consumers, we found that the consumption of chicken never increased after the emergence of h7n9 in 2013, and wtp for safe chicken did not necessarily increase relative to generic risks associated with consuming chicken in 2012. factors such as the fear of h7n9's spreading, the impact of distrust (especially the distrust in government) enhanced the deviation of consumption and wtp; and the sheer mentioning of h7n9 is more important and negative than whether it was associated with a risk-perception reducing or risk-perception elevating message given to consumers. on feb. 19, 2013 a new type of avian influenza (ai), h7n9, was reported in shanghai, and once again chinese consumers were faced with a food scare. unlike the sars (severe acute respiratory syndrome) epidemic a decade ago, h7n9 virus showed no signs of human-to-human transmission, and the source of human infections was unclear with a lot of the patients having no obvious contact with poultry. to date no vaccine has been launched, and many chinese consumers are fearful of this unknown risk. it is difficult to assess the potential economic impact of ai because the h7n9 virus itself is not sufficiently understood and people's response to an outbreak is uncertain. in this paper, we have at our disposal changes in chicken consumption and changes in wtp for safe chicken, and our interest is in understanding why and when consumption of chicken decreases under a health scare (h7n9 avian influenza), and whether the willingness-to-pay (wtp) for safe chicken increases, decreases or remains the same. we developed questions related to the consumption of chicken before and during the h7n9 epidemic in 2013. in 2012 we surveyed 860 consumers in seven chinese cities to gain a general understanding of safe chicken consumption by the revealed preference method, and determined their wtp for safe chicken in a generic sense. with the onset of the epidemic in 2013 we contacted the same consumers, recording again their chicken consumption, but queried their wtp with specific wording related to h7n9. through this two-round survey of chinese consumers, we are able to measure with specificity the incremental impact of h7n9 on actual quantities of chicken consumed, and changes to their wtp for safe chicken. however, since none of our respondents actually contracted h7n9, and the risk of contraction was very small, the utility of health adjustment can only be attributed to cognitive elements and risk perception. the main objective of this article is to explore the impact of risk perceptions such as fear and trust on food consumption. this has been a topic of considerable interest to economists (e.g. hayes, shogren, shin, & kliebenstein, 1995; brown, longworth, & waldron, 2002; wang, mao, & gale, 2008; turvey, onyango, cuite, & hallman, 2010; ortega, wang, olynk, wu, & bai, 2012; lim, hu, maynard, & goddard, 2014) . in many cases, how consumers respond to a food risk is a matter of judgment and affect with an effective response determined by how one perceives the goodness or badness about an event or stimulus (finucane, alhakami, slovic, & johnson, 2000; slovic, finucane, peters, & macgregor, 2004) , the images that they form of the disease (jackson, 2006) or the availability of risk (tversky & kahneman, 1973) . with a credence component, individuals need more than personal experience to judge the safety of a food item, and often rely on third-party information (e.g. the supplier or government) to regain trust and reduce uncertainty (bocker & hanf, 2000; lang & hallman, 2005) . with the 2013 survey we included a number of questions to measure risk perceptions (affect) along the lines of kraus and slovic (1988) . the objective of this paper is to quantify the effect of consumer risk perceptions induced by h7n9 on their demand. it sheds light on these issues with several important contributions. first, we measure the actual reduction in consumption and stated change in wtp due to an observed contemporaneous ai shock. by exploiting the 2013 outbreak of h7n9 and replicating the 2012 survey with the same respondents, we provide a rare glimpse into consumer behavior that can't easily be replicated in a laboratory setting. second, we take advantage of the change in measured wtp between 2012 and 2013 to identify relative welfare shifts amongst consumers. in our context wtp represents the amount of income that the consumer is willing to give up to consume a given quantity of safe chicken equivalent to what is normally purchased or consumed under normal conditions. because the wtp captures the compensating variation required to return the consumer to a steady-state chicken consumption level, the wtp measure reflects the relative change in utility between the 2012 and 2013 states of nature. it therefore captures an indirect and relative measure of welfare loss. the third contribution, and perhaps most important, is the econometric investigation of the effects of risk perceptions and trust on changes in chicken consumption and changes in wtp. we find that with the introduction of h7n9, the correspondence between chicken demands (actual consumption) and safe chicken demands (wtp) is not conforming for some individuals, and that changes in consumption and changes in wtp can be linked directly to perceptions of risk. these results suggest that food safety cannot be remedied by market forces alone, and to consider problems of food safety in the absence of psychological considerations may prove fruitless. the fourth contribution is a finding that consumers' heterogeneous responses to food safety risks in different cities appear to support psychological models of risk attenuation and amplification. at the consumer level, fear, risk and vulnerability are important economic determinants of response to food safety. feeling good or bad about a particular risk is referred to by slovic et al. (2004) as "affect". if fear is defined at the level of cognition, then affect represents an impact that can exacerbate or countenance the more logical reasoning of cognition. the effect is measured by its degree of amplification which may or may not be attenuated or rational (pidgeon, kasperson, & slovic, 2003) and may linger far longer than the life of the stimuli. in other words, the economic implication of a food safety incident is dynamic (liu, huang, & brown, 1998; caswell & mojduszka, 1996) and may display properties of hysteresis (turvey et al., 2010) . while not often used to investigate risk perceptions related to food quality or food scares, hallman, hebden, aquino, cuite, and lang (2003) have used similar queries to understand consumer attitudes towards genetically modified food, turvey, onyango, schilling, and hallman (2009) to investigate consumer response to mad cow disease, lim et al. (2014) to examine the interaction between consumer risk perceptions and their preference for beef from different countries, and turvey et al. (2010) to investigate risk perceptions on hypothetical incidents of agro-terrorism and bird flu. animal disease epidemics and consumer food safety concerns can negatively influence meat markets. much research has been conducted on this topic, including, for example, burton and young (1997) on bovine spongiform encephalopathy (bse) in the beef market in great britain, lim, hu, maynard, and goddard (2013) on a similar issue in canada, and the ai in the u.s. by turvey et al. (2009) . some studies showed that the marginal impact of risk on meat demand was small, with short-lived lagged effects on demand (smith, van ravenswaay, & thompson, 1988; dahlgran & fairchild, 1987; robenstein & thurman, 1996; lusk & schroeder, 2004; piggott & marsh, 2004) . dahlgran and fairchild (1987) tested the marginal effect of negative information about salmonella contamination on chicken demand, and found the effects were b 1%, with rapid recovery of consumer's demands. in the united states, the recent cases of mad cow revealed lower fear or higher trust amongst consumers and very little affect as markets rapidly returned to the initial equilibrium states (turvey et al., 2010) . however, the limited effect may have been due to the low risk level. for example, setbon, raude, fischler, and flahault (2005) found a strong correlation between the perceived risk associated with consuming beef during the bse crisis in france and the perceived risk reduced beef consumption. recent studies have integrated risk perceptions such as trust and fear into economic models (e.g. meijboom, visak, & brom, 2006; hassouneh, radwan, serra, & gil, 2012) . heterogeneous consumer risk perceptions have been suggested and tested in the existing literature. one study carried by yang and goddard (2011) found that consumer groups in canada responded differently to a perceived bse food safety issue. the aggregate beef consumption of bse impacts in canada was different than those in the united kingdom, germany, and japan (burton & young, 1996; verbeke & ward, 2001; mazzocchi, lobb, traill, & cavicchi, 2008; lim et al., 2013) . furthermore, food safety risk perceptions are not only related to socioeconomic characteristics, experiences and culture, but also to trust in various information sources including product labels, government, academic researchers, dieticians and physicians (dosman, adamowicz, & hrudey, 2001; lobb, mazzocchi, & traill, 2007; mazzocchi et al., 2008; tonsor, schroeder, & penning, 2009; lang & hallman, 2005) . as noted by kornelis, jonge, frewer, and dagevos (2007) , the availability of multiple sources of information does not imply that every consumer equally weights or even uses the same sources. consumers' risk behavior is influenced by the information providers (slovic, 1993 (slovic, , 1999 . some studies investigating food safety use a single food safety index (e.g. burton & young, 1996) . in contrast, we measure consumer risk perceptions of food safety resulting from different types of fear and different sources of trust which may differ amongst individuals and markets. in our empirical investigation to follow we have two critical measures for 2012 and 2013; the first is the actual consumption of chicken as revealed by respondents, and the second is wtp for safe chicken. the measured chicken consumption captures the marshallian demand for chicken under market conditions including a quality differential which may be endogenous to price. the change in consumption when due to price effects, holding quality constant, captures movements along a single demand curve. but if prices are relatively constant, and the change is in quality, then demand will shift from one demand curve to another in price-quantity space. the second measure is the change in wtp between 2012 and 2013 which captures changes in expenditure holding utility constant. it may be convenient to think of this utility function capturing the substitution between the reference good (chicken) and other goods. the characteristic demand theory presented by lancaster (1971) assumes that products are consumed because of the utility derived from their characteristics. food safety is an attribute valued by consumers (antle, 1996; wang et al., 2008) . consumers' actual consumption and stated wtp for each attribute (e.g. safety) can therefore be isolated. at first we used a simple linear model to analyze the impact of fear and trust on actual consumption. cons 2013 is the consumption for chicken in 2013. fear and trust are vectors of observable characteristics of individual risk perceptions respectively. z is the vector of control variables such as: (1) knowledge about ai; (2) new information about ai; (3) city dummies for controlling the ai incidence and price differences; (4) other basic characteristics including gender, age, family size, the proportion of children and/or elderly in a household, education and income; and (5) lagged consumption and wtp to identify the initial demand. μ is a random variable accounting for unobservable characteristics. the model can be written as: second, we calculated the stated wtp and also used a linear model to analyze the effect of fear and trust. wtp 2013 is the wtp for safe chicken in 2013. the independent variables in equation (2) are the same as in last equation. secondly, we analyzed the dynamics considering both of the consumption and wtp. there could be nine situations for the change of consumption and wtp: the three cases associated with δcons n 0 did not exist in our data. some of the remaining cases are straightforward, but some need attention (for example, when δwtp = 0). to better understand the relationship between consumption and wtp, as well as the shock elasticity (eq. (3)), we parse the different possible combinations in δwtp and δcons into the 6 possibilities observed in our data. we present a multinomial model relative to the δwtp = 0 and δcons = 0 group. at last, we combine these various concepts to provide a measure of the percentage change in the marshallian demand given a percentage change in wtp. this 'shock' elasticity measure is given by with boundaries η ∈ (−∞, ∞), the 'shock' elasticity provides a measure of relative (in comparison to absolute) welfare loss from an unforeseen food risk. in general we expect that this ratio would be negative; that is, a measureable increase in wtp would correspond with a measurable decrease in quantity consumed due to health concerns. however, the wtp is actually comprised of an additional demand component, health. thus the expenditures do not only represent a demand for a return to consumption of chicken, but also include, endogenously, a demand for safe chicken and healthy food. while chicken has close substitutes priced in the market, health itself is a non-tradeable, non-marketable good for which a near-linear indifference curve cannot be expected. substitutability for health can only be expressed through consumption changes in chicken, but the intensity of fear about poor health will be captured in the wtp. the denominator of elasticity measures the relative change in incremental expenditures consumers are willing to make in order to reduce risk to the initial welfare measure (in 2012). thus the elasticity measure captures the relative change in observed marshallian demand to wtp. if η = 0, demand response to the new h7n9 information is marshallian neutral, and if δwtp= 0, the elasticity is undefined. we do find amongst our respondents situations in which δwtp ≤0 is a curious outcome, especially since we find no consumer willing to increase consumption in the presence of h7n9. if this holds with a strict equality, then consumers are not differentiating the risk from h7n9 from other generic food safety risks, and the elasticity measure is undefined because of wtp indifference. but if wtp decreases, this could signify that consumers do not perceive h7n9 as being more risky than generic food safety risks. this would be indicated by a non-negative elasticity measure for δcons≤0. if η =0 then δcons= 0, which indicates that consumers have not reduced consumption or changed marshallian demand, even though there is a change in wtp. when η = − 1 the percentage change in wtp exactly offsets the change in marshallian demand. however, because of the integrability condition, this should not be interpreted as 1:1 tradeoff between wtp and marshallian demand, but rather as demand falls consumers would be willing to pay an equivalent amount to restore consumption to initial levels. for −1 b η b 0 the change in marshallian demand is less than the change in wtp, indicating that for consumers in this situation the utility loss from quality exceeds the utility loss from consumption. they are less likely to consume chicken. in contrast if η b −1, the change in consumption exceeds the change in wtp for safety. to varying degrees these consumers will have a guttural response to food safety and their own personal health well in excess of their wtp for reduced risk. in the survey of 2013, we added questions about fear and trust for h7n9 (see table 1 ). in accordance with kraus and slovic (1988) , we designed seven questions with answers from 1 to 5 (strongly agree = 5, agree = 4, neutral = 3, disagree = 2, strongly disagree = 1) to reflect the characteristics of fear: (1) i would not eat any other new food; (2) consuming ai infected chicken would kill me immediately; (3) ai risk cannot easily be reduced or controlled; (4) ai risk is increasing; (5) ai can kill many people; (6) ai is contagious among humans; and (7) i am personally at risk for ai. to determine how specific information sources may influence consumer behavior, consumer trust (strongly trust = 5, trust = 4, neutral = 3, mistrust = 2, strongly mistrust = 1) on nine information sources were surveyed, they were (1) ministry of agriculture, (2) ministry of health, (3) research institutes, (4) local government, (5) tv news, (6) network news, (7) scholars, (8) friends/family/relatives, and (9) chicken sales staff. we also investigated consumer knowledge in 2013 by asking five knowledge questions about n7h9. that is, where does h7n9 virus come from? how long is the dormant period of h7n9? what are the common symptoms of human h7n9 infection? do you know the antigenic variation of h7n9? what are the transmission routes of h7n9? generally each respondent answered more than two questions correctly. each time consumers answered a question correctly, a counter variable takes one. furthermore, a subset of participants was randomly subjected to one of three information treatments. the first provided no additional information on h7n9. the two other treatments were designed to communicate positive and negative images of h7n9 which could either decrease or increase risk perceptions. for the risk-perception reducing information respondents were told that experts pointed out that, in general, "the ai virus is not strong enough to resist the external environment, high temperature, uv light, various disinfectants, and is easy to be killed. the virus can be eliminated in one minute at 100°c. the chicken can be safe to eat after being cooked thoroughly". risk-perception elevating information included the statement "the incubation period of the h7n9 virus is generally b7 days. the disease can progress rapidly, although transmission of h7n9 virus between human beings has not been reported yet, there is a risk that mutations in the virus could ease the spread". as a hypothesis, risk reducing information was to build trust while risk-perception elevating information was generally associated with fear. the risk-perception reducing and riskperception elevating treatments were each assigned to 20% of the samples, while the remaining 60% were not provided with any new information about h7n9. the main purpose of this research is to investigate the impact of china's bird flu (h7n9) on consumer demand for chilled chicken (rather than live chicken) in 2013. our approach was to take advantage of the emergence of the h7n9 in 2013 and compare consumers' behavior "without ai" in 2012 to "with ai" in 2013. the survey was fielded in seven chinese cities including: nanjing, changzhou, zhenjiang, lianyungang, linyi, zaozhuang, and chengdu. according to outbreaks of h7n9 in 2013, we divided the seven cities (which were surveyed in both years) into three types: cities in the "high incidence" province (nanjing, changzhou, zhenjiang, and lianyungang in jiangsu province), cities in the "low incidence" province (linyi and zaozhuang in shandong province) and cities in the "zero incidence" province (chengdu in sichuan province). nanjing, chengdu and linyi were selected to represent larger cities, changzhou and lianyungang represented medium-sized cities, and zhenjiang and zaozhuang for smaller cities. 2 the surveys were administered to the same group of respondents in april 2012 and 2013. in 2012 we asked generic questions regarding food safety in chilled chicken without any mentioning of h7n9 and in 2013 in the midst of the outbreak we resurveyed the group again. since these respondents were surveyed both times (before and after the h7n9 outbreak), the data formed a "natural experiment". the survey in 2012 was a food safety survey which contained questions regarding the wtp for a safe chicken, actual consumption of chicken per week, 3 education, income and other demographic information (e.g. gender, age). the survey in 2013 was in april which was within 60 days of the 2013 bird flu outbreak. in addition to the wtp for a safe chicken and actual consumption of chilled chicken per week, the questionnaire in 2013 also contained the question about the information, knowledge, fear and trust regarding h7n9. in order to calculate the wtp, we assumed that there were two types of chilled chicken on the market. one was ordinary chicken, which had an average chance of being contaminated. the other was safe chicken which was treated by ozone disinfectant, a substance mainly used to control bird flu. both surveys began with moderators providing each subject with a neutral description of the food irradiation process. we labeled the ordinary chilled chicken at 30 rmb per chicken (1.5 kg). this represented the average chilled chicken price in the supermarkets of the seven cities. then we asked the wtp for safe chicken. respondents were asked to choose a premium payment card with values of 0, 10, 20, and 30. if the respondent selected a premium higher than 30 rmb, then he/she was asked to write down the specific amount (e.g. 35 rmb) above the ordinary chilled chicken price. 4 in the wtp card question, if the individual chose a card value c i as the highest acceptable price, the true wtp would lie somewhere between card value c i and the next card value c i + 1 (c i + 1 n c i ). thus the chosen wtp card reflects the lower bound of wtp (cameron, 1987) . for example, if a respondent indicated that he/she is willing to pay 30 rmb for a safe chicken, then the true wtp must be between 30 and 40 rmb, with 30 rmb being the lower bound. an alternative approach is to model wtp through a random utility framework (see example of hu, woods, bastin, cox, & you, 2011) . in this paper, we do not apply the method hu et al. (2011) approach so our measure of wtp will understate (by an amount b10 rmb) the true wtp. thus our estimate is conservative. the study was conducted during the very first large scale outbreaks of bird flu in recent years in china. most consumers did not have a good knowledge about bird flu and how to protect themselves from it. as a result, consumers' perceptions on the issue and actions to avoid bird flu can be expectedly overheated during this period. to generate results that are more in line with what the market may be during a less intensified time, we would like to be conservative in both wtp estimates and factors affecting wtp. econometrically, cameron (1987) showed that the ols/gls type of regression generates less efficient parameter estimates. nevertheless, the less efficient ols/gls approach is consistent with our goal of offering a more conservative measure since it will make it less likely to reject the null hypothesis that a coefficient is zero. this enables us not to exaggerate factors that may have an impact on wtp. in the 2013 survey, the same respondents (contacted by telephone) were asked whether they were willing to pay for an increased price of safe chicken. in the face of the ai outbreak, the respondents were presented the same wtp questions as were in 2012. respondents were also allowed to enter an amount they would be willing to pay. in the original 2012 survey, surveyors interviewed respondents at random in front of major supermarkets during both weekends and week days. the sampling strategy for conducting interviews in the downtown area of the seven cities does not allow the sample results to be generalized to the chinese population as a whole; however, such a sample may be appropriate for studying h7n9. 5 surveyors (students from local colleges) were trained to collect data at supermarkets in april 2012. in april 2013, the surveyors carried out a 15~30 min follow-up telephone interview with the consumers who were intercepted in 2012 and whose contact information was kept. repeated calls were placed until respondents agreed to participate again in 2013. a total of 860 people were surveyed in 2012, and 94% of them also replied to a follow up survey in 2013. in total, we use a final sample size of n = 802 participants. there were 129, 110, 99, 109, 129, 100, and 126 observations in nanjing, changzhou, zhenjiang, lianyungang, linyi, zaozhuang, and chengdu respectively. all individuals in the sample indicated that they ate chilled chicken before the outbreak of h7n9. in return for participating, each subject was offered a payment of 50 yuan in both 2012 and 2013. in our survey (see table 1 ), over 40% of respondents were main shoppers in their households. about half were female and the average age was 38.73. 29% of the respondents had high school education, 47% had undergraduate education, and 6% had postgraduate education. the average monthly pre-tax income per adult in 2013 was 4579 rmb ($u.s. 727). the average family size was about 4 persons. in table 1 , most of respondents thought it would be fatal if they ate infected chicken (mean of question "consuming ai infected chicken would kill me immediately" is 4.04), but personally believe they are not at risk (mean of question "i am personally at ai risk" is 2.56). we found that research institutes and ministry of health were relatively trusted by consumers and chicken sales staffs were always distrusted. the mean and standard deviation of the counter variable (knowledge) are 2.39 and 1.27 respectively. in this section we provide an overview of results related to changes in chicken consumption and wtp between 2012 and 2013. with the exception of h7n9 in 2013, the economic and food safety conditions were unremarkably similar, so that as an 'event' the emergence of avian influenza can be viewed as a systemic treatment effect. this treatment effect is later modified in the econometric analyses to capture local effects at cities in which ai was endemic and those where no bird flu was recorded. table 2 crosstabulates the actual change in chilled chicken consumption per week (one chicken is 1.5 kg). the first observation is that no individual surveyed increased chicken consumption over the period. only 18.2% (n = 146) remained at the same consumption level. overall, the effects of h7n9 caused approximately 82% of the consumers decreasing chicken consumption, with 56% (n = 449) halting consumption entirely. 6 table 3 compares wtp for the two years. since the price of regular chicken was 30 rmb, an indication of 30 rmb implies a 0 wtp for safe chicken. in the upper off-diagonal and in the last column it is shown that 47% (n = 377) of respondents increased 4 in 2012, respondents were indeed allowed to give a wtp higher than 60 rmb per chicken (premium higher than 30 rmb per chicken). it was a self-writing option. but nobody actually revealed a wtp higher than 60 rmb per chicken in 2012. it may reflect that the respondents were not so worried about the food safety of chicken in 2012; but their food safety concerns were raised significantly with h7n9 in 2013. 5 up to may 1st, a total of 128 cases of h7n9 human infection had been confirmed in mainland china. to be specific, there are 46 cases in zhejiang, 33 cases in shanghai, 27 cases in jiangsu, 5 cases in jiangxi, 4 cases in fujian, 4 cases in henan, 4 cases in anhui, 2 cases in shandong, 2 cases in hunan, and 1 case in beijing. shanghai, nanjing, and some other cities suspended live poultry transactions and prohibited the entry of exotic live poultry. so sampling in jiangsu, shandong and sichuan province could be appropriate to represent the "high incidence" province, "low incidence" province and "zero incidence" province separately. 6 the reduced consumption is unlikely to be a result of increasing price because the market price of chilled chicken has actually decreased from 16. table 4 combines the relationships in tables 2 and 3 by matching chicken consumption in 2012 with wtp in 2013. virtually all categories indicated decreased consumption between 2012 and 2013 with the only exception of the 30 rmb (zero premium) for the 0.25 chicken category. this is because of a reduction in other categories, e.g. from 1 chicken to 0.25 chicken. the critical observation, however, is in the 0-chicken column which shows that 449 consumers would not choose to consume chicken, even though they had a positive wtp for safe chicken. of these, 55.7% (n = 250 or 31.2% of all consumers) would be willing to pay n60 rmb, a premium of n30 rmb above market prices for safe chicken. we estimated the models using fgls (feasible generalized least squares) and found that the results did not change according to ols estimation technique. table 5 we would generally expect a variable to have opposite signs in consumption and wtp, and this is what we find for the most part. three risk perception variables were significant: "eating ai infected chicken will immediately kill me" is a measure of dread. the more consumers believed in this statement, the lower consumption (β = −0.045) and the higher wtp (β = 2.718) was. respondents who perceived the incident to be on the rise would decrease consumption and increase wtp (β = −0.018, β = 3.913). a rising incidence of ai might signify loss of control by the government. duration and intensity might also be captured by "ai is contagious among humans" which led to a decrease in consumption, but had no effect on wtp. variables "ai can kill many people" and "i am personally at risk for ai" were not significant in either equation, suggesting that consumers might find it difficult to internalize risk, or even death, from ai. this is quite different from the significant variable "eating ai infected chicken will immediately kill me" which was conditioned on actually eating infected chicken. in other words, while consumers might believe that eating an infected chicken would lead to death, this might not be the same perception as the more ubiquitous risk of harm without the knowledge of consumption. the extent by which consumers trusted information and information sources could also be important determinants of consumption and wtp. however, our results did not reveal this relationship. consumers who generally trusted the research 5 chicken 155 21 26 0 0 0 202 1 chicken 78 108 30 26 0 0 242 2 chickens 35 0 41 3 18 0 97 3 chickens 1 0 0 2 2 6 11 total 449 199 97 31 20 6 802 note: the table cross-tabulates the actual change in chilled chicken consumption per week (one chicken is 1.5 kg). for example, "0.25 chicken" means someone consumes one chilled chicken within a 4 week period. the table reports the number of observations in each category. institutes, friends and relatives would consume less. this might signify a loss in confidence in these sources. likewise, significant reductions in wtp, not actual consumption, were related only to trust in local government. what appeared to be the most significant effect was the amplification of risks associated with specific cities. in the high incidence cities of nanjing, changzhou, zhengjiang and lianyungang, consumption was negatively affected by being in these cities compared to being in the zero-incidence city chengdu (the omitted category in the regression). in zhengjiang the amplification of risk actually led to an increase in wtp (β = 19.345) compared to those in chengdu. the impact on wtp was not significant for nanjing and changzhou, but negative for lianyungang (β = −11.300). for low incidence cities linyi, there was no significant impact on consumption compared to chengdu, but there was significant reductions in wtp (β = −30.220). although somewhat mixed, relative to expectations, the results are generally supportive of an amplification response to consumption and wtp due to the different levels of exposure to ai in the cities studied. relative to no additional statement at all, providing either risk-perception reducing information or risk-perception elevating information, had negative impact on consumption (β = −0.049 and −0.033 respectively). it appeared that providing any details about h7n9, whether positively or negatively led to heightened perception of risk thus lower consumption. it may reflect that the consumers may not trust in the additional information. they have built up risk-perception about h7n9 by themselves which is not susceptible to the interference of external information provided by investigators. so no matter whether the additional information is positive or negative, once the h7n9 is mentioned, the consumers will show high levels of fear and low levels of trust (in the additional information) and will reduce their consumption. the group seeing additional information did not change their wtp. knowledge about h7n9 appeared to have no effect on consumption or wtp. in table 5 , we find that lagged consumption had a significant positive effect on cons 2013 , while lagged wtp did not impact wtp 2013. in addition, we investigated restricted variable models. (1) firstly, we restricted the risk perception variables to be zero. in all cases the wald statistic indicated the collective significance of these variables but the adjusted r 2 statistic dropped in all equations compared to those in table 5 . an important observation in models with risk perceptions unrestricted and with trust, cities, and stimulus variables restricted, the signs and significance of the risk perception variables remained the same. thus, we conclude that the risk perception variables were robust to model specification. (2) secondly, we restricted the trust variables, and again in all models the wald statistic indicates that, collectively, trust contributes to the explanatory power of the regressions, although we note that the drop in adjusted r-square from the baseline regression in table 5 is significantly smaller. indeed, as with the baseline results in table 5 , where different variable groupings were excluded, the trust variables did not materially improve the explanation of consumption and wtp. this confirms our previous conclusion that trust may not be as powerful an influence on food consumption and wtp as the risk perception variables. (3) thirdly, the city incidence variables are also important. collectively restricting the city dummy variables to zero affects the explanatory power of the base regression (wald statistics are significant). the respective adjusted r-square for base model and restricted regression across models are (0.624, 0.496), (0.240, 0.100), (0.513, 0.151), and (0.231, 0.049) respectively. these results show the robustness of our main results. in combination with the risk perception variables, the evidence is clear and robust to model specification that when it comes to food consumption and wtp risk perceptions, and the social amplification of risk as measured by the endemic nature of h7n9 dominate choices. (4) at last, we removed the risk perception reducing and elevating variables, to find little effect on model fit. in table 6 , we present a multinomial model relative to the δwtp = 0 and δcons = 0 group. the results were very much consistent with those in table 5 for δcons b 0. however, for δcons = 0 we found very little significance of the risk perception with "ai risk cannot be easily controlled" and "ai is contagious among humans" being the exceptions. we did find that in terms of 0 23 42 29 29 16 54 3 29 5 1 1 50 rmb 0 36 61 28 58 15 64 7 30 3 0 0 40 rmb 0 35 77 50 67 24 65 9 22 6 5 2 30 rmb 0 105 70 92 48 42 59 12 16 6 5 3 total 0 449 250 199 202 97 242 31 97 20 11 6 note: the table cross-tabulates the actual change in chilled chicken wtp and consumption (one chicken is 1.5 kg). the table reports he number of observations in each category. 7 to investigate the potential correlation in the errors between the wtp and consumption equations we also estimated the equations using 3sls with cons 2013 and wtp 2013 as endogenous variables. the 3sls model showed that cons 2013 and wtp 2013 did not impact each other simultaneously, and the hausman test failed to indicate an endogenous relationship between wtp and consumption. furthermore, the 3sls model did not materially or qualitatively change the main results in table 5 . note: asterisk (*), double asterisk (**) and triple asterisk (***) denote variables significant at the 10%, 5% and 1% significance levels respectively. multinomial logistic regression (base case: δwtp = 0 & δcons = 0). note: asterisk (*), double asterisk (**) and triple asterisk (***) denote variables significant at the 10%, 5% and 1% significance levels respectively. trust, if they trusted the ministry of agriculture, consumers were more likely to change their consumption or wtp. the coefficient of "i trust the ministry of agriculture" is significant and positive in 4 out of 5 equations, which indicates the effect of trust in the ministry of agriculture should be heterogeneous. the reason may lie in that the ministry of agriculture is the major official news source with much of the good or bad news regarding h7n9 reported by it. 8 it is possible that upon hearing or reading h7n9 news from the ministry of agriculture, respondents may react differently because their understanding of h7n9 is ambiguous. the city incidence variables also provided some interesting results, the most striking being that none of the incidence variables were significant for consumers who increased wtp but did not change consumption. for those individuals whose wtp in 2012 was lower, their wtp in 2013 increased. yet, there was an increased likelihood that consumers with a decrease in wtp and no change in consumption came from high incidence cities. similar levels of significance applied to the other logit groupings (other situations). likewise, risk-perception reducing or elevating information had virtually no influence on membership of the two δcons = 0 groups while having much stronger influence on the likelihood of being in the δcons b 0 groups. knowledge of h7n9 did not appear to have a strong or consistent influence on group membership. habit formation also had an influence on group membership. the higher the wtp observed for safe food in 2012 the less likely that membership would belong to δwtp n 0, and would be more likely to be in the δwtp b 0 group. this suggested that with the revelation of h7n9, consumers actually would reassess their wtp. in other words, if wtp in 2012 was high, the change in wtp would be smaller, probably because "food safety" in 2012 already took ai into overall considerations of food-related risks. similarly, the more chicken consumed in 2012 the more likely the consumers would be in the δcons b 0 groups. finally, we calculated the relative (shock) elasticity and provide results in table 7 . the purpose of doing this is to measure differences in actual chicken consumption against the desire for safe chicken to the risk perception (and others factors). here we take the absolute value of the elasticity so that an increase in the regression coefficient would indicate increases in elasticity. an expected elasticity is one in which an increase in wtp for safe chicken coincided with a decrease in chicken consumption. there were 419 samples with an expected elasticity (denominator ≠ 0 & η ≤ 0) which came from the groups of δcons b 0 & δwtp n 0; δcons = 0 & δwtp b 0; and δcons = 0 & δwtp n 0. we found that trust seemed not to be important for the shock elasticity, but fear 2 (eating ai infected chicken will immediately kill me) significantly enhanced the shock elasticity. there were 191 samples with an unexpected elasticity (denominator ≠ 0 & η n 0) which came from the group of δcons b 0 & δwtp b 0. we found that trust in network news would cause the unexpected elasticity to increase while fear 2 (eating ai infected chicken will immediately kill me) had an opposite effect. although we believe that the problem of multicollinearity is moderate and the results of independent fear and trust questions are more easily understood, we further investigated the robustness of our assumption by extracting fear and trust factors using 8 for example, there can be both negative and positive information in one news story; the headline "gov't pumps more funds into h7n9-hit poultry sector" reported that "the latest figures from the china animal agriculture association show that the industry has recorded n40 billion yuan in losses since the h7n9 outbreak in march" and "to prevent the spread of the h7n9 virus, the government has ordered poultry to be culled in some areas since march. it also closed live poultry markets to reduce human contact with birds". http://english.agri.gov.cn/hottopics/ah/201308/t20130819_20124. note: asterisk (*), double asterisk (**) and triple asterisk (***) denote variables significant at 10%, 5% and 1% respectively. principal component analysis (pca). the estimated results show that our estimations are robust. we report the model with pca as follows; first, we calculated the z-value for each fear and trust variables. two "fear" factors were extracted. the kmo value was 0.706, and the chi-square for bartlett's test was 889.336. the eigenvalues of the first two components were n 1. these two factors explained 50.725% of the total variance. we defined the first factor of fear as micro-fear (or fear related to getting sick) which was composed of fear 6 (score = 0.719), fear 7 (score = 0.608), fear 1 (score = 0.593) and fear 5 (score = 0.511), and we defined the second factor of fear as macro-fear which was composed of fear 4 (score = 0.716), fear 3 (score = 0.705) and fear 2 (score = 0.676). we extracted three trust factors; the kmo value was 0.818, and the chi-square for bartlett's test was 2608.522. the eigenvalues of the first three components were n1. these three factors explained 67.321% of the total variance. we defined the first factor of trust as "official-trust" which was composed of trust 1 (score = 0.832), trust 2 (score = 0.823), trust 4 (score = 0.764), trust 3 (score = 0.750) and trust 7 (score = 0.647); the second factor of trust was defined as "private-trust" which was composed of trust 8 (score = 0.775), trust 6 (score = 0.746) and trust 5 (score = 0.547); and the third factor of trust was "supplier-trust" which was composed of trust 9 (score = 0.932). table 8 in the multinomial logistic regression, we found that no matter how wtp responded, fear in general would reduce chinese consumers' actual chicken consumption. at the same time, the reactions in their wtp were heterogeneous. this suggests that the greater the perceived risk, the more complex consumers may behave; that is, some would keep their wtp unchanged, some would be willing to pay higher premium to buy safe chicken, and some would decrease their wtp because of the mistrust in food safety. for the last case, the possible reason is that somebody may treat the so called safe chicken as a "giffen good" or inferior good because they did not believe it could be as safe as it was claimed. these individuals would decrease their consumption and wtp simultaneously. for shock elasticities, while trust may have only minimal effect, fear factors on the other hand had significant effect moving consumers to different shock elasticity groups. in this article we examined the psycho-economic impact of h7n9 avian influenza on chinese consumer demand and wtp for safe chicken. our sample of 802 consumers were first surveyed in 2012 before the emergence of h7n9 in 2013, and then resurveyed after the h7n9 discovery. two key pieces of information gathered were actual chicken consumption and wtp for safe chicken. in addition, the 2013 survey queried consumers on various aspects of knowledge, risk perceptions, and trust. the cities where respondents were located were identified, allowing for an assessment related to the intensity of infection. the most interesting observation from an economic point of view is that while consumption never increased for consumers between 2012 and 2013, the emergence of h7n9 did not necessarily lead to an increase in wtp relative to generic foodrelated risks in 2012. we found from these natural conditions that the wtp for safe chicken did not necessarily increase with reductions in chicken consumption. chicken, has many close meat substitutes including beef and lamb (wong, selvanathan, & selvanathan, 2015; säll & gren, 2015) , 9 suggesting that the iso-utility indifference curve would be linear and that δcons δwtp b0. but this is not found generally, suggesting that wtp does not always follow the marshallian demand when it comes to food quality and safety. instead, we show that psychological factors related to risk perception can affect the relationship between δcons and δwtp in many different ways, positive or negative, shifting demand up or down. on this point our analysis is in agreement with hanemann (1991) and shogren, shin, hayes, and kliebenstein (1994) that when health is considered as a credence attribute of food, the non-substitutability of health in private or public markets adds varying degrees of curvature to the indifference curves leading to δcons δwtp relationships that are not linear in scale. note: asterisk (*), double asterisk (**) and triple asterisk (***) denote variables significant at the 10%, 5% and 1% significance levels respectively. 9 wong et al. (2015) model the demand for the various types of meat in australia using data from 1962 to 2011 and find that the cross-price elasticities of chickenpork and chicken-mutton are negative, indicating that are pairwise complements; and cross-price elasticities of chicken-beef and chicken-lamb are positive indicating that are pairwise substitutes. säll and gren (2015) also find a similar result, that is chicken-pork are pairwise complements and chicken-beef are pairwise substitutes. from the behavioral point of view, our results can be explained by behavioral factors rooted in social psychology. these hold across various robustness checks. the perception of risk generally led to decrease in demand and increased wtp, but the risks perceived were not necessarily the same for either. trust in different institutions and information sources did not appear to be a strong determinant of consumer response in consumption or wtp, perhaps because the information provided by those sources are mixed and at times ambiguous; but risk amplification did. consumers in cities in which h7n9 was endemic were far more responsive than those in cities that had low or no incidence. our results are similar to some previous studies. for example, haab, whitehead, parsons, and price (2010) stated that consumers, in order to protect their health from the risk of seafood, would decrease their consumption of seafood. yang and goddard (2011), and lim et al. (2013) found that consumers were willing to pay more for safe beef to avoid the risk associated with bse in canada. thus fear is found to be the impetus for consumers to eat less and pay a higher premium for safe chicken. we also believe that trust (in different institutions and information sources) and fear may work simultaneously but with opposite roles, (bocker & hanf, 2000; meijboom et al., 2006) but we find no meaningful relationship to support this. perhaps this is because our survey timeframe was within 60 days of the start of the h7n9 epidemic which was the peak period of this round, and so consumer ambiguity and uncertainty may dominate any messages from trusted sources (e.g. the ministry of agriculture). this has also important policy implications for information from private sources but more specifically public sources such as the government and scholars. the findings from ortega, wang, wu, and olynk (2011) indicates that while the trust in the government may seem to be eroding in the face of recent food safety scandals in china, consumers were less confident on non-government food safety controls than government-led control measures, and this seems to be consistent with our findings. it may take a long time to regain consumers' confidence and demand when consumers are already confused and oversaturated by the media (hassouneh et al., 2012) . our results differ from previous studies in other ways. for example, wessells, kline, and anderson (1996) and parsons, morgan, whitehead, and haab (2006) found that seafood consumption decreased with negative information and increased with some types of positive information. smith et al. (1988) ; hu, adamowicz, and veeman (2009); haab et al. (2010) found that negative food safety information tends to decrease consumption, while positive information does not necessarily have the opposite effect. we find that reinforcing any information about h7n9, positive or negative, reinforced negative consumption and perceptions. perhaps this is because trust in positive information is still not high in china (sirieix, kledal, & sulitang, 2011; chen, 2013) . for example, wu, wang, zhu, hu, and wang (2015) found that the wtp for certified traceable food in china was very "limited". this therefore suggests that government and private entities involved in food safety labeling, information and consumer education have a substantial amount of work to do to gain the trust of the chinese consumers. finally, with the evidence at hand, we recommend that further research explore changes in consumption and wtp from a psychological point of view. it seems on the surface that the change in consumption might well be an emotional response to risk, while the changes to wtp a rational response to risk. recent models in psychology based on this dual process in a utility framework (kahneman, 2011; schulze & wansink, 2012; loewenstein & o'donoghue, 2004; mukherjee, 2010) could possibly add clarity to the complex interactions of food safety, and risk perceptions. schulze and wansink (2012) , for example, show consumers' responses to perceived risk as a mix of proportional and dichotomous (safe/unsafe, good/bad) responses that are relatively more continuous in situations where deliberation is possible, and more dichotomous in emotional or stressful circumstances. their dualprocess model seems to reconcile what is observed in our data. for example our findings that different aspects of risk perceptions affect consumption, while other affect wtp suggest that a more complex model may be at play. efficient food safety regulation in the food manufacturing sector confidence lost and partially regained: consumer response to food scares food safety and development of the beef industry in china the impact of bse on the demand for beef and other meats in great britain measuring meat consumers' response to the perceived risks of bse in great britain the impact of grouping coarseness in alternative grouped-data regression models using information labeling to influence the market for quality in food products the effects of different types of trust on consumer perceptions of food safety: an empirical study of consumers in beijing municipality the demand impacts of chicken contamination publicity-a case study socioeconomic determinants of health and food safety-related risk perceptions the affect heuristic in judgments of risks and benefits effects of information about invasive species on risk perception and seafood demand by gender and race public perceptions of genetically modified foods: a national study of american knowledge and opinion. 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meat: evidence from futures markets effects of an environmental tax on meat and dairy consumption in sweden toxics, toyotas, and terrorism: the behavioral economics of fear and stigma risk perception of the "mad cow disease" in france: determinants and consequences resolving differences in willingness to pay and willingness to accept organic food consumers' trade-offs between local or imported, conventional or organic products: a qualitative study in shanghai perceived risk, trust and democracy trust, emotion, sex, politics, and science: surveying the risk-assessment battlefield risk as analysis and risk as feelings: some thoughts about affect, reason, risk, and rationality sales loss determination in food contamination incidents: an application to milk bans in hawaii factors impacting food safety risk perceptions risk, fear, bird flu and terrorists: a study of risk perceptions and economics risk perceptions, consumer response and the first u.s. mad cow case availability: a heuristic for judging frequency and probability a fresh meat almost ideal demand system incorporating negative tv press and advertising impact chinese consumer demand for food safety attributes in milk products seafood safety perceptions on anticipated consumption under varying information treatments modelling the meat consumption patterns in australia chinese consumers' preferences and willingness to pay for traceable food quality and safety attributes canadian consumer responses to bse with heterogeneous risk perceptions and risk attitudes this research uses data from the china health and nutrition survey (chns). the work was supported by the "national natural sciences foundation (71573130)", "national natural sciences foundation (71203094)", "qing lan project", "a project funded by the priority academic program development of jiangsu higher education institutions (papd)", "china center for food security studies, nanjing agricultural university" in china, as well as the w.i. meyers endowment funds at cornell university. we thank prof. zhigang xu and doctoral student michael richaille for beneficial comments. key: cord-290901-bfho5w04 authors: figuié, muriel title: global health risks and cosmopolitisation: from emergence to interference date: 2013-03-20 journal: sociol health illn doi: 10.1111/j.1467-9566.2012.01539.x sha: doc_id: 290901 cord_uid: bfho5w04 according to beck’s ‘world at risk’ theory, global risks push nations towards a cosmopolitisation of their health policy and open opportunities for a democratic turn. this article provides an empirical analysis of beck’s theory, based on the experience of vietnamese authorities from 2003 to 2007 in managing the emerging avian flu virus. it shows how vietnam’s framing of avian flu has shifted, under the pressure from international organisations and the us administration, from an epizootic and zoonotic risk (or a classic risk) to a pandemic threat (or a late modern risk). vietnam’s response was part of its overall strategy to join the world trade organization and it was limited by vietnam’s defence of its sovereignty. this strategy has been successful for vietnam but has limited the possibility of cosmopolitan and democratic transformations. the case study highlights the constructed dimension of risks of late modernity and their possible instrumentalisation: it minimises the role of a community of fear relative to a community of trade. international health organisations and western nations are exerting growing pressure on other countries to cooperate in managing health risks such as emerging diseases, as demonstrated during the recent episodes of severe acute respiratory syndrome (sars) and avian flu (scoones 2010). this pressure is being exerted on countries with different perceptions of risks and with different agendas (renn 2008, taylor-gooby and zinn 2006) . in this article i examine how risks defined as 'global' by stakeholders in the international community push nations toward a cosmopolitisation of their risk management policies, together with the mechanisms used and the intended and unintended outcomes. i use beck's world at risk theory (beck 2009 ) to study one empirical case: vietnam's management of a recent emerging disease, the highly pathogenic avian influenza (hpai), which is associated with the avian flu virus (h5n1), and popularly known as avian flu, avian influenza or bird flu. this study covers the period from 2003 to 2007, a period of intense international activity in avian flu management. i will discuss the link between global risks and cosmopolitisation, as identified by beck. the following sections show how avian flu has been framed by international organisations and how vietnam has complied with this definition, under pressure from the us administration and international organisations such as the world health organization (who), the world organization for animal health (oie) and the food and agriculture organization (fao) . i analyse the mechanisms of this convergence and its consequences for vietnam. finally, the discussion addresses the role of country reputation, national sovereignty, community of interests, community of fear and values as driving forces for a cosmopolitisation of health policy. i conducted a comprehensive review of all the grey literature documents on avian flu issued by the vietnamese ministries of health, and agriculture and rural development, of official documents on vietnam's strategy for avian flu (known as the 'red book' and the 'green book') and regulations adopted by the vietnamese government, as well as expert reports from international and foreign organisations (fao, who, agrifood consulting international and agence franc¸aise de de´veloppement). in-depth interviews were conducted in 2007 and 2008 with key informants involved directly in vietnamese avian flu management. in total, 20 people were interviewed, half of whom were working in public or private vietnamese organisations (and representing the ministry of agriculture and rural development [mard] , the ministry of health [moh] and the veterinary services of two provinces, as well as representatives of the private sector). the other half were stakeholders from the international community (members of the fao avian influenza team; experts in infectious diseases working for the who, members of the partnership for avian and human influenza (pahi) , representatives of foreign non-governmental organisations (ngos) active on the topic and one member of the leadership of an international hospital). interviewees were asked to relate the role of the different stakeholders in the avian flu management over time and the major points of debates and controversies. most interviews were conducted in english, with a few in vietnamese through a translator. interviewees were guaranteed anonymity. some people have been interviewed twice or even three times. the interviews were recorded wherever possible and transcribed for further in-depth analysis. additional information was collected from the websites of the fao, oie and who on avian flu and sars, on the 'one world one health' strategic framework adopted by these organisations, on the international health regulation of the who, and on the terrestrial animal health code of oie. the theory of risk society (beck 1992) describes the transition of societies from first modernity (or industrial societies) to second modernity (or late modernity). second modernity is characterised by global risks or, more exactly, global anticipated uncertainties. for beck (2009) global risks (or late modern risks) are both real and constructed. on the realist side, global risks are manmade, produced by industrial modernisation and linked to globalisation. they are incalculable, since their destructive potential to health and the environment may have long-term and large-scale effects. on the constructivist side, global risks are produced by the ambition of late modern societies to anticipate and control potential catastrophes. as anticipated catastrophes, global risks take the form of contested knowledge: 'their reality can be dramatised or minimised, transformed or simply denied according to the norms which decide what is known and what is not' (beck 2009: 30) . consequently, late modern societies are confronted with a diversity of viewpoints and values from which risks can be evaluated. this situation creates the potential for new forms of risk governance involving a wide network of stakeholders and creating opportunities for an 'involuntary democratization' (beck 2009: 60) . beck's theory has been widely criticised for its eurocentrism, even by beck himself ( beck and grande 2010 , dingwall 1999 , mythen 2007 . in response, beck and his associates have developed the world at risk theory (beck 2009, beck and grande 2010) . they have introduced the concept of cosmopolitan modernities in order to take into account the varieties of modernity according to specific national cultures and histories and their global interdependencies. one of the main issues addressed by the world at risk theory is: how do countries on different paths towards modernity, and with different risk perceptions, cooperate or not, in order to confront shared global risks? this question emphasises the realist dimension of global risk, since it opposes the diversities in risk perceptions to the nature of late modern risks. beck has been criticised for the ambiguous status of risk in his theory. according to burgess (2006) , in many works inspired by this theory, risks remain given, objectified and decontextualised, despite a proclaimed constructionist approach: their scientific and politically manufactured dimensions are often neglected. for mythen (2007: 800, quoting lash: 51) , 'so far as perceptions of risk are concerned beck leans heavily towards the realist position'. this article attempts to show that the framing of a risk as a global risk (that is, according to beck's definition, as a potential threat) varies according to stakeholders and over time. it will contextualise and exemplify beck's assertion that: global risks provide a basis of legitimation for political institutions and social movements that press for more humane forms of globalisation, which does not preclude, of course, that this cosmopolitan moment can be instrumentalised for ideological purposes. (beck 2009: 20-1) avian flu: a classic and a modern risk h5n1, the virus responsible for avian flu (more exactly, responsible for a hpai) may be framed either as a classic risk or as a risk of second modernity. experts of international organisations consider avian flu and emerging diseases in general as products of a globalised environment requiring global answers (fao et al. 2008 , oie 2009 , who 2007b . the virus first appeared in hong kong in 1997 and then re-emerged in vietnam and china in 2003 before spreading to more than 62 other countries over the last nine years: today more than ever the international spread of diseases or other risks threatens health, economies, and security. no country can 'go it alone' in protecting its citizens from the threats. (who 2007b: 2) and the director of the oie, dr b. vallat (2007: 1) declared: 'indeed, a single country failing to control animal disease outbreaks could put the entire world at risk'. is this characteristic enough to define avian influenza as a risk of second or late modernity? different authors (burgess 2006 , boudia and jas 2007 , dingwall 1999 , me´ric et al. 2009 ) have criticised beck's claim about the newness of risks of global scale and his lack of a historical perspective. but risks of second modernity are not just global risks -they are an anticipation of threat. avian flu poses a three-dimensional risk. firstly, it is an epizootic disease, that is, a disease causing high mortality in an animal population; in this case poultry raised by farmers and wild birds. secondly, it is also a zoonotic disease: it can be transmitted from poultry to humans but its impact has been limited compared to other infectious diseases (352 fatalities worldwide since 2003). but thirdly, experts fear that the virus might mutate into a form that is transmissible from human to human, which could provoke a human influenza pandemic with high mortality. this mutation could be just a question of time: as dr nabarro, the un coordinator for avian flu declared in answering the question 'what is the probability of a pandemic?' to a journalist from the poultry diseases network, 2007): [w]e cannot say with any certainty at all when it would happen, where it would start, how severe it would be. so the only certainty we can share with each other is that it would happen one day. in a joint press release on 27 january fao et al. (2004) describe avian flu as a serious threat to humanity. different stakeholders (such as farmers, consumers and policymakers), living on different paths of modernity with different risk cultures may focus on one dimension or another of avian flu: epizootic, zoonotic or pandemic. as an epizootic or zoonotic disease, h5n1 is a classic risk. as a pandemic threat, avian flu is a risk of second modernity, according to beck's definition. and that is the way international organisations have framed it. avian flu (h5n1) marks a new stage in the internationalisation and globalisation of action to control health. first, the management of this risk by international health organisations indicates 'a colonisation of the future', in the words of beck (2003: 29) . it marks the unprecedented ambition of the institutions in charge of managing human and animal health risks to prepare the world for a virus that still does not exist but which could emerge from a mutation of h5n1. secondly, the discourses produced by international organisations mark the end of a discourse that everything is under control. in a who handbook on avian flu published for journalists (who 2005b) one can read: 'the great unknown: why there are no certain answers for the big questions' (p. 4) as well as, throughout the text: 'we don't know' (p. 5), 'unpredictable' (p. 10), 'uncertain' (p. 10). thirdly, h5n1 and sars have opened the way for global health governance with an extended scope of intervention for international organisations and greater interference (see calain 2007 for the who strategy). new who and oie regulations encourage nations to go beyond routine measures on borders and to adopt preventive measures at the source of contamination, that is, within affected countries. member states' obligations have been extended to the declaration of any 'extraordinary public health event which constitutes a public health risk to other states through the international spread of disease, and may require a coordinated international response' (who 2005c: 1). lastly, the who and oie are now authorised to take note of any information source on disease outbreaks in addition to official notifications from national administrations. dr chan, director-general of who (2007a: xv), noted: 'this reflects a new reality in a world of instant communications: the concealment of disease outbreaks is no longer a viable option for governments'. the framing of avian flu by international organisations (who, oie, fao) illustrates a high porosity between the spaces of international stakeholders involved in health issues and academic researchers on risk society. the new paradigm 'one world one health' elaborated by international organisations (fao et al. 2008 ) calls countries and actors (private, public; administration and civil society; experts of animal, human and environment health) to transcend boundaries, to progressively construct shared perceptions of health risks and to build coordinated responses to global health issues. this paradigm reflects what beck calls a community of fate and a community of responsibility. but the current results are far from 'cosmopolitan moment' (beck 2009: 47) in which nations see themselves as parts of a community of threat and fate and voluntarily contribute to global cooperation. according to beck (2009: 57) global risks could open up 'a moral and political space that can give rise to a culture of responsibility that transcends borders and conflicts' but this opportunity has not been seized in the case of avian flu. conversely, scoones (2010) has shown that the new global health governance is dominated by a northern perspective that ignores the structural inequalities of access to resources and exposure to risk. moreover it forces poor countries to focus on a potential catastrophe when they already lack the resources to address classic infectious diseases like meningitis or malaria (calain 2007) . global risks push for a globalisation of health governance. but global risks also presuppose the existence of international organisations that manufacture uncertainties through a performative discourse justifying an extended scope of intervention for themselves. did the perception and framing of avian flu by international health organisations converge in vietnam or did it reveal a clash in risk cultures? global risks being in beck's theory, a product, as well as a driving force of late modernisation, vietnam's experience of modernisation needs to be described before answering this question. studies have been conducted to provide beck's risk theory with an empirical basis and to confront it with the contexts of non-western countries, including asian countries (see calhoun 2010 and the articles in the british journal of sociology 2010). these studies have underlined specific characteristics associated with modernisation in emerging asiatic countries. firstly, the rapidity of processes such as industrialisation, urbanisation and economic liberalisation, lead to the almost simultaneous development of first modernity and the transition to a second one, resulting in a compressed modernity ( beck and grande 2010 , chang 2010 , kyung-sup 2010 . secondly, 'global risks as a driving force of second modernity are more relevant in east asia as a result of the side effects of the rush to development' (han and shim 2010: 465) . thirdly, the economic and political transition has meant 'the protracted coexistence of socialist, capitalist or even (neo) traditionalist components of the political economy, thereby imposing an ultra-complex (compressed) modernity' as shown by kyung-sup (2010: 457) in analysing china. these works focus on global risks as a structural, objective factor and do little to document their local framing and local perception. the recent history of the socialist republic of vietnam illustrates this rush to development and the transition towards an ultra-complex modernity. in the 1980s vietnam was considered one of the world's poorest countries (vietnam development report 2004) and was economically and politically isolated. the country is now classified as a middle income country by the international monetary fund and is a member of numerous international organisations and forums. following the establishment of the communist government in 1955, the victory over american armed forces in 1974 and the invasion of cambodia in 1978, vietnam suffered a us trade embargo and an international boycott. vietnam also lost considerable support following the collapse of the soviet union. in the 1980s the domestic economic situation was a disaster, resulting in famines. in reaction, vietnam implemented from 1986 important economic and political reforms (known as doi moi). at the international level vietnam's objective was to become integrated in the international community. but according to do hien (2004: 171, my translation) , at that time, 'winning back the confidence of the international community was an almost impossible challenge'. nevertheless, vietnam succeeded within a relatively short time. the country started by restoring its relationship with china following the end of the conflict in cambodia (1989) and then by amplifying its relations with neighbouring south-east asian countries. vietnam made an important gesture when it agreed to cooperate with the usa over the 'missing in action ' affair (1986) . this led to the lifting of the trade embargo (1994), after which vietnam regained access to international credit (from the asian development bank and the international monetary fund) and was integrated into the coalition of south-east asian countries in 1995 (do hien 2004) . when avian flu emerged in vietnam these successes were considered by vietnamese authorities as steps towards a longer term objective: vietnam's integration into the world trade organization. at the national level, the liberalisation of the former planned economy has provoked unprecedented economic growth with positive outcomes such as poverty alleviation, the reduction of malnutrition and increased wealth (vietnam development report 2004) . the political consequences are more complex. bao an and de tre´glode´(2004) have shown how, through these reforms and in a very pragmatic way, vietnamese authorities combine contradictory forces: economic and social dynamics with ideological and political continuity, a project of modernisation with patriotic, historic and cultural references. according to these authors, the role of the state and the communist party has not been weakened by this modernisation process. the process is kept within the ruling system of a bureaucratic-authoritarian state with a single party. the state has retained its monopoly in decision-making and the party is responsible for guaranteeing the continuity of moral values throughout the economic development process. nevertheless, the growing gap between rules and practices opens space for initiatives but without allowing the emergence of a real opposition (bao an and de tre´glode´2004). these characteristics of vietnam's modernisation have affected vietnam's cooperation with the international community to deal with avian flu. the first human casualties caused by the re-emergence of the h5n1 were officially recorded in vietnam and china in 2003 . this put vietnam, according to international organisations such as the who, oie and fao, in the sars virus is transmissible from human to human, but the mode of transmission of h5n1 to humans was then unclear. the vietnamese authorities and the who had been criticised for their slow response to sars. in the case of avian flu, vietnamese authorities were supported by the international organisations (who, oie and fao) for a prompt answer. they took unprecedented measures: a massive culling operation of 17 per cent of all poultry in less than three months (agrifood consulting international [aci] 2007), as well as the restriction of all transport of poultry across provincial and national borders: if there had been only avian flu, people would have thought the who was going mad, overreacting. but before, when we had the sars, the who were criticised for not acting quickly enough. (doctor, international medical cooperation, interview, 2 may 2008) the vietnamese communist party published decrees and actively intervened in the preventative culling operation, mobilising the army as well as the party-affiliated associations of the patriotic front ( gue´nel and klingberg 2010, tuong 2010) . the network of actors mobilised closely resembles that which is normally seen in this country in the event of floods, typhoons or even past armed conflicts: the rapidity of vietnam's response can be explained by its history. this country has had to mobilise the population on numerous occasions throughout the past. i was born in peacetime, but i am imbued with this vietnamese culture of collective struggle. (representative from the ministry of agriculture, interview, 23 may 2008) as one expert in an international organisation noted: vietnamese people are accustomed and prepared to face situations of emergency. they do not have to worry about media, public opinion, or sectoral interests … and they have no complexes. moreover the chain of command, the communist party and the army, is very efficient. (international expert, interview, 10 december 2007) in contrast with this initial mobilisation, avian flu lost its place on the political and media agenda a few months later. regular outbreaks were recorded among poultry but human mortality remained low compared with the past sars outbreak and other infectious diseases already present in vietnam. the population's anxiety receded: consumers resumed poultry consumption after a dramatic drop (figuie´and fournier 2008) and poultry farmers finally perceived avian flu as just another epizootic disease ( desvaux and figuie´2011) . the problem was reduced to a veterinary problem to be managed by the ministry of agriculture. at the same time, developed countries were adopting national protective strategies such as the production and stockpiling of vaccines and masks (gilbert 2007) . phase 2: avian flu, a modern risk in the last three months of 2005 the international community gave a new impetus and new orientation to the treatment of avian flu in vietnam. in 2005 the number of countries notifying h5n1 to the oie increased dramatically and the virus reached europe (with the first human cases in europe occurring in turkey in january 2006), increasing the pandemic threat for western countries. the same year the us congress commissioned an assessment of the actions undertaken by the international community and by the main countries affected by the virus, including vietnam. the report underlined numerous inadequacies in the surveillance and control of the virus. in line with the lessons learned from terrorist attacks, the us government was now convinced that it should not rely for homeland security solely on the surveillance and the protection of its own territory but that it had to increase its involvement at the international level to manage the sources of threat (congressional research service [crs] 2006) . in september 2005 us president george w. bush, addressing the united nations world summit, announced his country's decision to invest in and coordinate the formation of a new international partnership aimed at preventing an influenza pandemic. the president required all countries to be transparent on their epidemiological status (bush 2005) . in addition, the appointment of a senior united nations system coordinator for avian and human influenza, dr nabarro, marked the globalisation of avian flu management. the who had already reinforced its presence in vietnam at the time of sars and it was now the turn of the fao to widen the scope of its local activity. bilateral cooperation developed primarily with the usa, as well as with japan and new zealand. ngos also increased their presence in vietnam (academy for educational development, association ve´te´rinaires sans frontie`res and care). the un agencies in vietnam supervised the coordination of the donors and demanded in the middle of 2005 a greater involvement from the vietnamese authorities: in particular, they asked for a direct and permanent line of communication with the vietnamese prime minister (interview). vietnam came under increased pressure to attend to the pandemic threat. un agencies asked for greater involvement from the ministry of health and the vietnamese government was pressed to formulate a plan for human pandemic influenza preparedness and responses (the red book). this was the condition for obtaining a portion of the funds that the international community had committed to this cause (interview). the us government succeeded in imposing the presence, at the who office in hanoi, of one of their military experts (from the center for disease control and prevention, atlanta) against the will of the vietnamese authorities (interview). vietnamese official government declarations became more frequent and the number of articles addressing the problem of avian flu in the press reached a new peak. the prime minister responded to un pressure by addressing the nation for the first time since the beginning of the epizootic disease through an official telegram (telegram no. 1686 ⁄ ttg-nn), in which he announced reinforced measures to prevent and fight against avian flu. new laws were produced with the assistance of the fao and oie (mard and moh 2010) . the participation of the private sector became more widely solicited. through new regulations, new hygiene standards, a credit policy and even local tax policies, the government consistently promoted the development of a modern industrial poultry farming sector to the detriment of small-scale farming (aci 2007). the state even passed the role of public health protection, traditionally its own responsibility (in particular in communist countries) onto the private sector, by a health ministry radio announcement in which people were told, 'if you don't want to catch the virus, buy your poultry at the supermarket'. why did vietnam, a country with a reputation of strong adherence to national sovereignty, adopt the international framing of avian flu as a pandemic threat? and what was the extent of their compliance as a result of this adoption? policy transfer studies (delpeuch 2009 ) have shown that policy transfer is not a purely rational process oriented towards problem-solving. many factors come into play when selecting and reframing imported policies, such as path dependency and cognitive and cultural factors. for the vietnamese government, there were two political issues associated with avian flu management. as noted by a european expert: europe came here to analyse the problem in a scientific manner and to define a strategy based on science. but the objective of the government is completely different! it aims at keeping stability in the country and to protect its reputation. (interview, 27 april 2008) the first phase of avian flu management proved to be beneficial for political stability, the centralisation of power and the promotion of a nationalist project. following the deregulatory market reforms of 1986, provincial authorities gained new economic power and autonomy from the central government. tuong (2010) has shown that the management of avian flu became an opportunity for the central government to affirm its authority, regardless of the local reality (as with the authoritarian imposition of massive culling measures). central authorities used avian flu to blame local authorities for all mismanagement, pointing to their incompetence and corruption. the media presented the victory over the virus as a question of national honour and as popular mobilisation behind the party against a new common enemy (gue´nel and klingberg 2010, tuong 2010) . in contrast, during the second phase, the virus became an opportunity for vietnam to consolidate a 20-year period of reintegration into the international diplomatic community. when h5n1 emerged, the usa, vietnam's former enemy, was the last obstacle to its entry to the world trade organisation (wto). vietnam had yet to complete bilateral negotiations with the usa in order to obtain the status of a permanent normal trade relations (pntr) nation from the us congress (for more details see the us association of southeast asian nations business council 2006). these negotiations were part of a vietnam-usa normalisation process depending on a number of key issues such as human rights, religious freedom, intellectual property rights and bird flu, as quoted by a us congress report (crs 2005 this is a question which concerns not only this country, but all the world's countries. we must share this responsibility. of course, the culling of chickens is a significant economic loss for the population, especially the poor, rural farmers … but the government is determined, and is also responsible to the rest of the world. (ministry of health representative, interview, 17 december 2007) . for one of the international experts involved since the beginning, the first phase in vietnam's risk management was just a mistake: for a long period, vietnam has been seen as an enemy for the rest of the world. but during the last 15 years, the government's objective has been to integrate the international community. when vietnamese authorities understood the global dimension of the risk [hpai], they reacted very quickly. sure, they made some mistakes in 2004, but this did not last. (interview, 24 april 2008) vietnam has been considered as being at the top of the class for complying with the requirements of the us administration and un agencies, as confirmed by many of interviewees. but what were the real consequences of such compliance? is it transformative cooperation or just lip-service? vietnam's compliance with international requirements brought risks to national sovereignty. the authorities adopted the framing of avian flu as a pandemic threat (that is as a risk of second modernity) and cooperated with the international community to manage a global manufactured uncertainty. they delivered transparent information on the outbreaks (according to our interviewees) and implemented a vaccination programme. nevertheless, changes in vietnamese policies have remained limited. firstly, in the field many regulations adopted by the authorities were not applied or were applied for a short period only. for example, a ban on duck breeding has never been applied and live poultry markets, however much they were prohibited, have quickly resumed. according to mard (2007) , the implementation of one major decision (decision 394 on biosecurity measures in the avian chain) has been limited. this discrepancy between norms and practices is a common feature of vietnamese policy, according to bao an and de tre´glode´(2004) : it is a way for vietnamese authorities to manage the contradictions of the country's development process: in this case, contradictions between the objective of international integration and the defence of national sovereignty. secondly, the authorities have recognised in their national strategy for avian flu (the red book) the need to rely on a wide web of stakeholders in order to manage the virus (international organisations, ngos and the private sector). however, these stakeholders have been kept away from the decision-making process: they do not take part in the national steering committee (nsc) for avian influenza disease control and prevention (established by decision no. 13 ⁄ 2004 ⁄ qd-ttg, dated 28 january 2004) . this committee brings together representatives of ministries (including agriculture, health, trade, finance, transport and the environment) but does not include any representatives of civil society and its discussions are confidential. international and foreign organisations were also excluded from this committee. debates with these organisations, and the coordination of their numerous activities, have been the role of the partnership for avian and human influenza (pahi), created in 2005. according to one member of this partnership, this structure (the nsc and pahi) clearly indicates the strategy of the vietnamese authorities vis-a´-vis cooperation and protection of national sovereignty: the functioning of the nsc demonstrates the sovereignty of vietnam … the vietnamese government affirms that it is completely open [and] ready to furnish any information, but that does not mean that international organisations can intervene in the nsc. the information is divulged via the pahi to the international organisations. (expert from pahi, interview, 24 april 2008) the democratic turn that, according to beck, could be produced by global risks did not occur in vietnam. and the capacity of transformations potentially induced by new global risks is shown to be limited compared to path dependency effects linked to vietnam political characteristics. as mentioned by one of our interviewees, a member of the pahi: vietnam plays the game because there is benefit to it. that is true that there are conditionalities linked to foreign aid. but donors are sometimes so naive. (interview, 24 april 2008) there were dual benefits for vietnam at national and international levels. modern risks are characterised by their potential for political destabilisation because they question the capacity of states to protect their citizens. but being global, they also question states' sovereignty as well as their reputation in the eyes of the other countries over their contribution to global goods. however, in a very clever way, vietnam exploited a number of opportunities associated with avian flu, both keeping the international community at a safe distance while adeptly navigating the unfamiliar path of global governance, changing its image in the world from that of a carrier of a global health risk to one of a good global citizen and finally consolidating the communist heritage at a local level while advocating greater public health control via the market. this demonstrates the varieties of modernity. the vietnamese representatives interviewed during this research were proud to underline that, in managing avian flu, vietnam was not like china (because vietnam remained accountable) nor was it like laos (because vietnam did not relinquish its sovereignty when the avian flu broke out), and that it was not like indonesia (because vietnam had always shown cooperation). but vietnam's major success in avian flu management should be assessed from its primary result: vietnam became the wto's 150th member on 11 january 2007. this vietnamese case has been studied using the analytical framework offered by beck's world at risk theory. i have paid attention particularly to the constructed dimension of global risks, to the relations of definition as relations of domination and to the possibilities of instrumentalisation. this focus downplays global risks as structural factors that drive cosmopolitisation and democratisation. it also shows the community of fear to be a less powerful driver of cosmopolitisation than the community of trade. agrifood consulting international (aci) (2007) the economic impact of highly pathogenic avian influenza doi moi et mutations du politique risk society: towards a new modernity la socie´te´du risque globalise´revue sous l'angle de la menace terroriste, cahiers internationaux de sociologie varieties of second modernity: the cosmopolitan turn in social and political theory and research risk and 'risk society' in historical perspective the making of the risk-centred society and the limits of social risk research president of the united states of america exploring the international arena of global public health surveillance, health, policy and planning beck, asia and second modernity the second modern condition? compressed modernity as internalized reflexive cosmopolitization international responses to global spread of avian flu comprendre la circulation internationale des solutions d'actions publiques: panorama des policy transfer studies formal and informal surveillance systems risk society': the cult of theory and the millenium? les relations internationales du vieˆt nam depuis 1991 avian influenza in vietnam: chicken-hearted consumers? risk analysis world organization for animal health (oie), world health organization (who) (2004) unprecedented spread of avian influenza requires broad collaboration. fao ⁄ oie ⁄ who call for international assistance. press release. who media center available at ftp: ⁄ ⁄ ftp.fao.org ⁄ docrep ⁄ fao ⁄ 011 ⁄ aj137e ⁄ aj137e00 les crises sanitaires de grande ampleur: un nouveau de´fi? paris: institut national des hautes etudes de se´curite´(inhes) press coverage of bird flu epidemic in vietnam redefining second modernity for east asia: a critical assessment the second modern condition? compressed modernity as internalized reflexive cosmopolitization provincial summary reports on implementing prime minister decision 394 ⁄ qd-ttg. hanoi: ministry of agriculture and rural development avian and pandemic influenza. vietnam's experience. hanoi: ministry of agriculture and rural development and ministry of health la 'socie´te´du risque'. analyse et critique david nabarro warns of an inevitable influenza pandemic power, politics and accountability: vietnam's response to avian influenza available at http: ⁄ ⁄ www.usvtc.org ⁄ trade ⁄ wto ⁄ pntr memo available at http: ⁄ ⁄ www.oie.int ⁄ for-the-media ⁄ editorials ⁄ detail ⁄ article ⁄ protecting-the-world-from-emerging-diseases-linked-to-globalisation ⁄ vietnam consultative group world health organization (who) (2005a) introduction to the ihr 2005, world health organization, ihr brief, 1. available at http: ⁄ ⁄ www.who.int ⁄ ihr ⁄ ihrbrief1en.pdf outbreak communication. world health organization handbook for journalists: influenza pandemic international health regulations. notification and other reporting requirements under the ihr a safer future: global public health security in the 21st century available at http: ⁄ ⁄ www.who. int ⁄ whr ⁄ 2007 ⁄ media_centre ⁄ slides_en influenza: cumulative number of confirmed human cases of avian influenza a(h5n1) reported to who one world, one health. oie bulletins online, 2 ⁄ world organization for animal health (oie) (2012) wahid interface. country information this research was conducted with the support of the gripavi and ardigrip projects, funded by the french ministry of foreign and european affairs and the french ministry of research. key: cord-293316-kip8mrjo authors: de sa, j.; mounier-jack, s.; coker, r. title: risk communication and management in public health crises date: 2009-09-10 journal: public health doi: 10.1016/j.puhe.2009.07.017 sha: doc_id: 293316 cord_uid: kip8mrjo nan as the world faces its first influenza pandemic in 40 years, it has been argued that we have never been better prepared. concern about emerging infectious diseases has fuelled significant public health and political developments, such as the coming into force of the international health regulations (ihr). since the turn of the century, the world health organization (who) has documented a historically unprecedented number of emerging infectious disease outbreaks, and lessons drawn from their management have confirmed the critical importance of effective communications, specifically through formal channels such as who and in the public domain. in concert with novel emerging infectious diseases, the communication landscape itself has also changed radically. we now live in an era of real-time electronic communications; consequently, approaches to surveillance are being transformed. data sources, information messengers, mechanisms of data and information transfer and audiences are all changing. instant and global transmission of information has become a powerful ally, along with peer pressure, for who in ensuring that member states comply with new obligations to swiftly declare outbreaks considered to be of public health importance. there is now significant global attention and accompanying investment which should, the authors suggest, be used as an opportunity to improve strategic and operational communication capacity to respond not only to pandemic influenza but also to other public health threats. there are many concepts of communication in relation to risk associated with outbreaks. as these are relatively new concepts, this article will consider approaches relating to highlighting public health threats and supporting operational management, addressing these as the communication of risk and subsequent risk management. strategic considerations are critical to both, although information, messengers, communication tools and audiences may differ. the communication of risk refers to the process by which information regarding outbreaks is identified and shared with the purpose of increasing awareness amongst key stakeholders of the threat. key stakeholders for public health threats include who, national governments and the public. risk management, by contrast, refers to the management processes associated with response to the outbreak, for which communication is crucial at each stage. three examples are used to explore the challenges and demands of communicating effectively and coherently given this changing landscape. this brief paper will attempt to show the progress made, draw lessons to be learned and outline the ways forward. the outbreak of severe acute respiratory syndrome (sars) in 2002-2003 was an unprecedented public health emergency played out on the international stage. the disease, caused by a novel coronavirus, resulted from spread of the virus from civet cats to humans in the food markets of southern china; once individuals were hospitalized, the virus spread nosocomially to infect other patients and staff. the first reports of this novel disease outbreak came from the local media, and were later substantiated by e-mail messages. these caused international concern, in part because it was feared that a new influenza pandemic was emerging, and heightened as formal confirmation from chinese authorities was not forthcoming. 1 whilst the international community remained largely powerless, there being no legal mandate to ensure that china clarified what was occurring, cases appeared in other countries, further raising the stakes. thus, the sars story highlighted a number of challenges to the communication of risk. first, with the advent of, and wide access to, the internet and e-mail, information through informal and largely unverifiable sources can be transmitted to worldwide audiences within the public domain ahead of information sharing through formal channels. second, because of the speed of movement of people, diseases can emerge in countries far from their source before outbreaks or the pathogens that cause them have been confirmed or identified. sars galvanized the international community to finally conclude drafting of the revised ihr. the ihr bind who member countries to not only notify all events that may constitute a public health emergency, but also to respond to requests for verification of information. who has also produced outbreak communication guidelines to aid in the dissemination of information to the public, recognizing that 'expertise [in communications] has become as essential to outbreak control as epidemiological training and laboratory analysis'. 2 the boundaries between risk communication and management are not, however, sharply delineated, as illustrated by the controversy surrounding h5n1 influenza virus sharing. indonesia is one of the countries hardest hit by outbreaks of h5n1. virus sharing with the international community is the mechanism by which, first, viruses developing pandemic potential can be tracked (risk communication), and second, vaccines can be developed to meet global need (risk management). indonesia refused to virus share, not because it was opposed to the sharing of technical information to better understand the threat posed by h5n1 avian influenza, but because it felt excluded from equitable access to the resulting vaccine, meaning that its management of a subsequent pandemic would be constrained. 3 it could be argued that indonesian authorities currently view virus sharing as an important element in risk management and thus a sovereign issue, although the international community, by contrast, views virus sharing as a critical element of risk communication and, by extension, a global risk management issue. differing interpretations of international treaties are possible and resolution is proving challenging. 4 ultimately, the debate is centred on the boundary between the governance of risk communication and risk management, the former now being mandated through international laws, with the latter remaining, to a large degree, a national sovereignty responsibility. implicit to better risk communication is a belief that better risk management will automatically follow. surveillance is, after all, 'information for action'. communication, co-operation and coordination are necessary at an international level. however, they are also, as the illustration below highlights, necessary at national and subnational levels. in august 2005, hurricane katrina made landfall on the gulf coast of the usa. the worst consequences were felt in new orleans, louisiana, where the levee system was breached and billions of dollars of damage occurred. the storm also caused significant loss of life and many people were displaced from their homes. the magnitude of the hurricane was anticipated, the risk having been communicated at both local and national level. however, this risk warning was not heeded appropriately. for example, although mandatory evacuation was eventually ordered, there was little provision for the large numbers involved or for those citizens who could not evacuate themselves. the aftermath of the storm, with many people left living in squalid conditions, also revealed a risk management process that left much to be desired. 5 one notable example was in the coordination of a bi-partisan emergency federal health policy response, attempts at which were blocked by the white house, citing multiple concerns including relevance and cost. the subsequent delay resulted in profound health, economic and political consequences. 6 several lessons may be drawn for the risk management of disease outbreaks. firstly, although risk communication may occur, it does not automatically result in a co-ordinated risk management response. second, this occurred in the usa, a country which clearly has the public health and disaster management resources to deal with such a problem. however, these resources were not mobilized effectively, efficiently or in a timely manner. at the heart of many of the problems were fractured communication systems. among operational problems, there were failures in communication technologies subsequent to the weather conditions and, whilst some decisions required extensive information, others were made on the basis of unverified rumours reported by the media, leading to incoherent responses. 5 communication failures occurred between the local, state and federal agencies, and there was a lack of clear roles and responsibilities. although new orleans had experienced previous hurricanes and had a disaster management plan, the plan was clearly operationally fragile. it is important to ensure that national strategic plans are operational. recent reviews have reported that this does not yet seem to be the case. [7] [8] [9] the confusion and lack of clarity in the response to hurricane katrina show that traditional ways of working and their dependency on traditional communication systems may falter in the heat of a crisis. new ways of communicating allied to clearly defined roles and responsibilities may be needed. in the changing landscape outlined, there are clearly many challenges for effective risk communication and risk management. in terms of the communication of risk, this article has focused on progress on the international stage. it is recognized that challenges still remain at national level, but the diversity of these is beyond the scope of this brief paper. as illustrated by the examples above, tensions exist at national level between international commitments to communicate risk and risk management responses. however, because of the speed of movement of people and goods, global risk management is now as fragile as the weakest link in the community of nations. the challenge is, as with risk communication, to develop an operational framework that acknowledges national sovereignty but is also cognisant of national and individual interdependencies and connectedness. the global response is building effectively upon the 'dry-run' of sars, and lessons can be drawn from other public health crises such as hurricane katrina. the current global influenza pandemic and the attendant international attention offer an opportunity that should not be squandered. the almost unprecedented energy, political commitment and resources committed to this need to be built upon and harnessed, integrated and extended to support effective responses to public health threats. as the current h1n1 pandemic unfolds, it will be interesting to see how well lessons drawn from earlier public health emergencies have been learned. 10 ethical approval none sought. none declared. sars and emerging infectious diseases: a challenge to place global solidarity above national sovereignty world health organization. who outbreak communication guidelines. geneva: who jakarta: sulaksana watinsa indonesia influenza virus samples, international law, and global health diplomacy communicating throughout katrina: competing and complementary conceptual lenses on crisis communication federal health policy response to hurricane katrina: what it was and what it could have been pandemic influenza preparedness in the asia-pacific region pandemic influenza preparedness in africa is a profound challenge for an already distressed region: analysis of national preparedness plans pandemic influenza preparedness in latin america: analysis of national strategic plans influenza a (h1n1) and pandemic preparedness under the rule of international law none declared. key: cord-285628-36gyix12 authors: stull, jason w.; weese, j. scott title: hospital-associated infections in small animal practice date: 2015-03-31 journal: veterinary clinics of north america: small animal practice doi: 10.1016/j.cvsm.2014.11.009 sha: doc_id: 285628 cord_uid: 36gyix12 hospital-associated infections (hais) occur in veterinary hospitals of all types and sizes, and their frequency is likely to increase. urinary tract infections, pneumonia, bloodstream infections, surgical site infections, and infectious diarrhea are the hais most frequently identified in veterinary medicine. a hospital infection control program, consisting of an infectious disease control officer, written protocols, and staff training, is critical to reducing hais and promoting patient, staff, and client health. infection control protocols (plans) should include discussion of hand hygiene and use of personal protective equipment, cleaning and disinfection, patient management, with-in hospital surveillance, and antimicrobial stewardship. compared with people. however, this may be countered with greater patient hygiene challenges, greater difficulty with patient compliance (eg, licking wounds), and a lesser "culture" of infection control. although current data are limited for the veterinary field, similar (or even higher) hai rates have been reported compared with human studies, such as hais in 16% of intensive care unit patients in one study. 3 during a 5-year period, 82% of veterinary teaching hospitals in north america and europe reported at least one hai outbreak and 45% reported multiple outbreaks. many of these outbreaks required restricted patient admissions (58%) or closure of the hospital or section (32%). 4 therefore, although hais are poorly quantified in veterinary medicine, they are undeniably a concern. there are many potential adverse events from hais in veterinary patients. animals suffering from hais may have an increased hospital stay (with accompanying increased cost to the client or clinic). these patients may also suffer permanent health consequences, or hais may result in death of the pet. multidrug-resistant organisms (mdros) are often involved in hais, complicating treatment and resulting in poor patient outcomes and extensive outbreaks. furthermore, some veterinary hospital-associated (ha) pathogens (eg, methicillin-resistant staphylococcus aureus [mrsa] , salmonella) can be transmitted to staff or pet owners, resulting in human illness. additionally, as veterinary medicine advances, there may be parallel increases in hai risk through the use of more invasive procedures, more use of invasive devices (eg, urinary catheters, intravenous catheters), more immunosuppressant therapies, and a greater intensity of critical care management. patients that might not have survived their underlying disease in the past may now be alive, but highly susceptible to infection. perhaps most important to this topic is the assumption in human medicine that 10% to 70% of all hais are preventable through the use of practical infection-control measures. 5 large economic benefits are estimated to occur with the implementation of infection-control interventions ($6-$32 billion cost savings in the united states alone). 2 the proportion of hais that are preventable in veterinary medicine is unknown, but is likely to be similar, and even a 10% reduction in infections could constitute a major impact on patient health, owner cost, and owner and clinician satisfaction. the routine use of simple infection prevention practices can likely dramatically reduce hais. infection control is the term best suited to the goal in small animal veterinary medicine of preventing (or, more practically speaking, limiting) the introduction and/or spread of pathogens with a group of patients and caregivers. central to this goal is the establishment and refinement of an infection-control program at each animal hospital. every hospital's infection-control program will be different, reflecting the unique pathogen risks, facility and personnel characteristics, animal populations served, and level of risk tolerance of the practice. however, at a minimum, each practice's program should include the following: an infectious disease control officer (otherwise known as an infection-control practitioner); a written infection-control protocol (plan); regular training of staff about hospital infection-control protocols (and documentation of this training and assessment of comprehension); monitoring of both disease rates and infection-control protocol compliance. together, the components of the program should address the hai risks for patients and staff and recommended or required protocols to reduce these risks. the end stull & weese result will be a safer working environment for staff, optimal care for all patients, and protection of public health. although good infection-control practices are not the only feature defining excellence in patient care, it is impossible to achieve excellent patient care without them. the standard of what is "acceptable" from an infectioncontrol standpoint is changing in veterinary medicine, and it is clear that the "bar" is being raised in terms of the expected standard of care. in human medicine, urinary tract infections (utis), pneumonia, surgical site infections (ssis), and bloodstream infections (bsis) account for approximately 80% of all hais. 6 in veterinary medicine, these sites along with gastrointestinal disease (infectious diarrhea) are likely to be the most common hais, although other conditions, such as upper respiratory tract infection, dermatophyte infection, iatrogenic blood-borne pathogen infection, and infections of a wide range of invasive devices can also occur. each of these main areas is discussed later, highlighting (where available) incidence, risk factors for disease, and commonly identified pathogens. because ssis are being exclusively covered in a separate article in this issue, they are not discussed here. catheter-associated utis are one of the more common hais in small animal veterinary medicine, although veterinary data are often limited by the failure to differentiate bacteriuria (a potentially benign condition) from uti (disease). studies have reported catheter-associated bacteriuria occurring in 10% to 32% of hospitalized dogs, with a subset of these exhibiting clinical signs or other evidence of infection. [7] [8] [9] [10] the interference of normal defense mechanisms by urinary catheters, such as mucosalsecreted adhesion inhibitors, along with patient comorbid factors and some catheter handling factors, facilitate bacterial colonization of the catheter and ascension of the organism or organisms into the bladder. these pathogens may be endogenous to the patient, arising from the rectum or perineum, or directly from the hospital environment or people through contamination of the drainage system or bag. if the collection system has been contaminated, bacteria can ascend into the bladder through the catheter if there is retrograde flow of urine. retrograde urine flow can occur if the collection system is elevated above the level of the patient; if collection lines are flushed, or if there is obstruction to flow in the collection system. in addition, biofilms (a complex structure of microorganisms and extracellular matrix) can be produced by bacteria on surfaces of urinary catheters. biofilm formation can be associated with poor antimicrobial penetration, antimicrobial resistance, and treatment failure. 11 in human medicine, several factors, such as recumbent position, mechanical ventilation, and use of endotracheal or nasogastric tubes, are likely to increase the risk for ha pneumonia. 12, 13 this topic has been minimally investigated in the veterinary field, in large part because of the limited use of mechanical ventilation. in one study, escherichia coli and acinetobacter spp were commonly identified in feline ha ventilatorassociated pneumonia cases. 14 although not included in the human surveillance definition, aspiration pneumonia is not uncommon in small animal medicine and can occur in patients hospitalized for a wide range of disorders as well as otherwise healthy patients undergoing sedation or anesthesia. in addition to those factors listed for human ha pneumonia, factors that increase aspiration pneumonia, such as hospital-associated infections laryngeal or esophageal disorders and decreased mentation or recumbency, likely increase hai risk. [15] [16] [17] if these patients have been hospitalized for multiple days before aspiration, it is more likely that the oropharynx is colonized with organisms from the hospital environment or hands of staff, and the pneumonia may be more likely to involve mdros, particularly if patients have been treated with antimicrobials. in the human literature, most ha bsis are associated with intravascular devices. duration of catheterization has been recognized as the most important risk factor for the development of catheter-related (cr) bsis (most developing 4-5 days after placement). 18 despite this increased risk, studies have not documented a benefit with prophylactic catheter changes (eg, every 3 days). in human medicine, the current recommendation is for catheters to be removed as soon as medically indicated, but for routine changes to be avoided. a similar approach is appropriate in veterinary medicine. veterinary studies have revealed that jugular and intravenous catheters are frequently contaminated with enteric or environmental pathogens. 9, 19 several factors have been positively associated with intravenous catheter contamination/colonization in dogs and cats, including receipt of dextrose infusion, longer duration of catheter placement, and patient immunosuppression (presence of immunosuppressive diseases or receipt of immunosuppressive drugs). 20 commonly isolated organisms include staphylococci, e coli, enterobacter spp, proteus spp, and klebsiella spp. [19] [20] [21] contamination may occur from the hands of people placing or handling the catheter, the patient's own flora, or the hospital environment. however, there is little evidence indicating that contaminated but not infected catheters (ie, catheters from which bacteria can be isolated but where the catheter insertion site and vein are clinically normal) pose a risk for subsequent bsi. as a result, routine culture of catheters at time of removal or culture of catheter insertion sites is not recommended because skin bacteria are expected to be present. veterinary outbreaks involving cr bsis have been associated with inadequate skin preparation or contaminated materials used in skin preparation, 21, 22 something that is of most concern when antiseptic solutions or wipes are prepared by refilling bottles or containers, which can become contaminated with biocide-resistant bacteria over time. ha gastrointestinal infections are usually recognized when there is a noted increase (outbreak) of infectious diarrhea in hospital patients. although identification of diarrhea is simple, determination of the cause is often difficult, even for known pathogens. in small animal veterinary facilities, salmonellosis is the most frequently reported gastrointestinal hai 4,23 ; however, it is unclear whether that is because it poses the greatest risk or (more likely) it is more readily identified and reported compared with other potential causes. in nonhospitalized small animal populations, several risk factors for salmonella colonization or infection have been identified, including animal species (eg, reptiles, amphibians, young poultry, exotics), consuming a raw animal-based diet or treats (eg, raw meat/eggs, rawhides), exposure to livestock, and recently receiving a probiotic. 24, 25 these factors may substantially increase the risk of shedding salmonella, 14% to 69% shedding in dogs with one or more of these risk factors as compared with less than 5% typically noted in dogs without these risk factors. 25, 26 however, the true scope of this issue is unclear because most outbreaks go unnoticed or testing is not performed, but, conversely, clusters of diarrhea seem to be uncommon in most facilities. pathogens involved in small animal hais often have one or more of the following characteristics: opportunistic pathogen in companion animals and/or humans, environmentally stable, or multidrug-resistant. many pathogens involved in hais are opportunistic pathogens that can be found in healthy animals, highlighting the inability to prevent entrance of all potential pathogens into a veterinary facility. the frequency of each pathogen varies for each veterinary practice (in part influenced by antimicrobial use/pressure, geography, animal species, vaccine coverage of animals in "catchment" area, level of care provided). in addition, environmentally stable pathogens (eg, parvovirus, clostridial spores, dermatophytes) have a demonstrated clear "advantage," increasing the chance of transmission. given the close interaction between veterinary staff and patients as well as the often poor hand hygiene practices documented in veterinary practices, human commensals with zoonotic potential are represented by hais in veterinary medicine. finally, increased resistance to antimicrobials is a common feature of most nosocomial bacteria. several pathogens are a concern from a small animal infection-control standpoint (box 1). although a wide range of pathogens may be involved in hais, currently there is a strong focus on the emerging epidemic of multidrug-resistant bacteria because of dramatic increases in infections, limited antimicrobial options, and potential public health consequences. these mdros are not inherently more virulent than antimicrobial susceptible organisms, but treatment options are limited, something that ultimately can worsen the prognosis. the us centers for disease control and prevention has recently assessed domestic antibiotic resistance threats for people based on box 1 pathogens of concern in a small animal clinic hospital-associated infections clinical and economic impact, incidence, transmissibility, availability of effective antimicrobials, and barriers to prevention. several pathogens of importance relative to veterinary hais were included as "serious antibiotic resistance threats," namely, acinetobacter spp, extended spectrum b-lactamase-producing enterobacteriaceae (esbls), pseudomonas aeruginosa, salmonella spp, and mrsa. 27 as animals and people may share common infection sources or transmit these pathogens to each other, this concern is equally important in the veterinary field, and all of the abovenamed pathogens can be found in veterinary patients. given these relatively novel threats and the often limited knowledge by veterinary personnel on this group of pathogens, the attention here is focused on mdros as hais. in human medicine, hais are often captured through voluntary or mandatory hospital reporting. as such, the occurrence (and trends) of hais are fairly well-established. in the united states, recent data indicate bacteria are responsible for 90% of hais, with commonly identified groups including staphylococcus aureus, enterococcus spp, e coli, coagulase-negative staphylococci (cons), klebsiella spp, p aeruginosa, enterobacter spp, and acinetobacter baumannii. 28 despite the importance of this field, current knowledge of many aspects of the epidemiology of important mdros and pathogens responsible for hais in veterinary medicine is unclear (eg, prevalence, risk factors, and transmission dynamics). unfortunately, companion animal veterinary medicine has been slow to implement surveillance systems; however, this is changing. currently, most data come from limited retrospective studies of clinical isolates, likely resulting in geographic and culturebased bias, potentially misrepresenting the frequency of these pathogens and potentially overestimating the prevalence of antimicrobial resistance if culture submissions are biased toward infections that failed to respond to empirical therapy. regardless, based on the reported veterinary ha outbreaks or supposition from the human literature, several important mdros responsible for hais are identifiable: s aureus, staphylococcus pseudintermedius, enterococci, salmonella spp, acinetobacter spp, e coli, and other enterobacteriaceae, and pseudomonas spp. the specific resistance profiles and treatment options for common multidrug-resistant (mdr) pathogens have recently been summarized. 29 the reader is directed to the article elsewhere in this issue of veterinary clinics of north america: small animal practice by guardabassi and prescott entitled, "antimicrobial stewardship in small animal veterinary practice: from theory to practice," which expands on the topic of mdros in hais and antimicrobial stewardship. staphylococcus s pseudintermedius and to a lesser extent s aureus are common causes of veterinary hais. 30 both are frequently carried on the skin and mucosal surfaces of dogs and people (respectively), creating the potential for both endogenous infection (infection caused by bacteria the animal was harboring at the time of hospital admission) and acquisition of the pathogen during hospitalization directly or indirectly from other patients, the environment, or human caregivers. the emergence of methicillin resistance in these species (methicillin-resistant s pseudintermedius [mrsp] and mrsa) has had important implications for hai prevention and control. methicillin resistance is mediated by the meca gene, which results in resistance to b-lactam antimicrobials (penicillins, cephalosporins, and carbapenems). in addition, resistance to other classes of antimicrobials is frequently observed: lincosamides (clindamycin), fluoroquinolones, macrolides (erythromycin), tetracyclines, trimethoprim-sulfonamides. 29, 31, 32 mrsa is an important pathogen in human hais, being a common cause of ssis and various other types of infections. 33 to a lesser extent, mrsa has also been noted in veterinary hais. 34 risk factors for veterinary mrsa hais have not been well studied, but prior antimicrobial use, prior hospitalization, ownership by veterinary or human health care workers/students, and longer hospitalization (>3 days) have been associated with mrsa colonization or infection in dogs. [35] [36] [37] [38] furthermore, the use of fluoroquinolones and cephalosporins has been linked to the emergence of mrsa in people and may play a role in veterinary species. 39 it is important to note that an abnormally high proportion of veterinarians are colonized with mrsa as compared with the general public. 40 as such, they may serve as a source for hais in their patients if infection-control practices (notably hand hygiene) are substandard. this also likely indicates deficiencies in standard infection control and hygiene practices that allow for transmission of mrsa between veterinary personnel and animals. mrsp has rapidly spread in canine populations, often with high levels of antimicrobial resistance, 41 something that is of tremendous concern because s pseudintermedius is the leading opportunistic pathogen in dogs (and, to a lesser degree, cats). it is the most common cause of ssis in some regions, 42 and treatment may be complicated because of the high level of resistance. in one study, more than 90% of mrsp isolates were also resistant to 4 additional antimicrobial classes. 43 recent prior hospitalization and b-lactam antimicrobial administration have been associated with mrsp infections, 44 suggesting hospital-associated transmission may be a factor in mrsp disease. the topic of cons deserves mention. veterinary diagnostic laboratories often consider these species as a group and speciation is rarely performed. cons are frequently identified as commensals in small animal species, with high methicillin resistance in healthy animals. with the exception of highlycompromised individuals, it has been generally assumed that cons, even those that are multidrug resistant, are of limited clinical concern. that assumption has been challenged to some degree and some cons species may be more clinically relevant than others; however, this group remains a less common cause for concern compared with s pseudintermedius and s aureus. however, their commonness as skin or mucous membrane commensals can complicate interpretation of culture results because differentiating infection from contamination may be challenging. e coli is a frequent component of the commensal gastrointestinal microbiota and is an important pathogen, particularly in utis. mdre coli is frequently shed in the feces of both community and hospitalized small animals. [45] [46] [47] multiple factors have been associated with dogs shedding or acquiring mdr e coli during hospitalization, including duration of hospitalization (>3 days) and treatment with antimicrobials shortly before or while hospitalized (cephalosporins, metronidazole). 38, 48 antimicrobial resistance is an important problem with e coli and other enterobacteriaceae (eg, enterobacter). although b-lactamase-producing isolates have been common for some time, there has been a recent emergence of esbls producers, which provide resistance to a broad range of b-lactam antimicrobials, including thirdgeneration cephalosporins. in addition, esbls are conferred resistance to other antimicrobial classes through genetic linkage with resistance mechanisms. 49 extended spectrum b-lactamase-producing e coli has been identified as the source of veterinary hais, occurring as ssis and catheter-associated utis, with observed hospital contamination. 50, 51 other genera in the enterobacteriaceae family (ie, klebsiella, enterobacter) are considered to be important in human hais; however, less is known of their involvement in veterinary infections. one of the most important drug classes for treatment of esbl-producing bacteria is carbapenems (eg, meropenem). unfortunately, carbapenemase-producing enterobacteriaceae (or carbapenem-resistant enterobacteriaceae; cre) (including e coli) have emerged as a significant problem in human health care. additional resistance mechanisms are often present, rendering isolates virtually pan-resistant, and ability for cres to spread rapidly in health care settings with extension into the community. 52 high mortality (>40%) has been documented for invasive human cre infections. 53 carbapenemase-producing e coli have recently been identified in small animals, with suggested nosocomial transmission. 54 nosocomial transmission currently seems to be a rare, albeit concerning, occurrence, and one that is likely to increase as cres increase in prevalence in the human population, with subsequent exposure of pets. enterococci are often found in the gastrointestinal tract of animals and humans. two species, enterococcus faecium and enterococcus faecalis, are most often involved in disease, including hais, although enterococci tend to be of limited virulence and typically cause infections in compromised hosts. enterococci are inherently resistant to several antimicrobial classes, including cephalosporins, some penicillins, fluoroquinolones, clindamycin, and trimethoprim. 55 they may also acquire resistance to various other antimicrobial classes and, although they are typically of limited virulence, they may be difficult to eliminate in cases when disease develops. vancomycin-resistant enterococci (vre) are an increasing concern in human medicine, with vancomycin resistance noted in up to 83% of e faecium involved in hais. 28 to date, vre appears to be rare in companion animals. 56 however, other mdr enterococci are regularly recognized in small animals and have been identified in hais. 30, 57, 58 enterococci are often identified as utis (including catheter-associated); however, infections at other anatomic sites occur (eg, ssis, bsis, pneumonia). the high degree of antimicrobial resistance, ability to propagate for extended periods in small animal hosts as a commensal, and environmental persistence make enterococci particularly challenging when involved in hais. it is important to note that isolation of enterococcus species (regardless of antimicrobial resistance) does not always indicate treatment is indicated. without clinical signs in an otherwise immune-competent animal, it may be warranted to withhold treatment and monitor the patient. when isolated in a patient with clinical signs (notably infections of the urinary tract, wound, or body cavity), treatment should often be directed at the organism or organisms also isolated that are thought to be primarily responsible for clinical disease. 29 often, that involves ignoring the enterococcus and targeting therapy toward another, more convincing, pathogen, such as e coli. salmonella is most frequently a concern in equine facilities, but has been identified as a source of sporadic illness and hospital-associated outbreaks in small animal hospitals. 23, 59 an important concern with salmonella hais is the occurrence of zoonotic transmission with accompanying human infections. 23, 59 because most infections in dogs and cats are subclinical, there is a high risk for inadvertent hospital-wide environmental contamination and nosocomial transmission. reported factors leading to an increased risk of salmonella shedding in small animals include consumption of raw meat diets, exposure to livestock, and receiving a probiotic in the previous 30 days. 25, 60 as with e coli, esbl-producing strains are a concern for antimicrobial resistance and have been identified in small animals. 61 given its environmental stability, potential shedding by healthy animals, and significant zoonotic health hazard to clinic staff and clients, salmonella needs to be considered an important companion animal nosocomial pathogen. acinetobacter is well-recognized as an important ha pathogen in human medicine, in part because of recently recognized high levels of antimicrobial resistance in a baumannii. more than 60% of a baumannii human isolates involved in hais were mdr in one study. 28 given its role as an opportunistic pathogen in small animals, ability to persist in the environment for extended periods, and documented outbreaks in veterinary facilities, it is also a concern for veterinary medicine. 30, 62, 63 documented hais involving a baumannii include intravenous and urinary catheters, surgical drain infections, ssis, pneumonia, and bsis. 62 multidrug resistance is frequently encountered with pseudomonas spp. this along with their noted persistence in the hospital environment makes pseudomonas spp a concern for hais. in humans, most infections are ha and occur in immunocompromised hosts. 64 in companion animal species, pseudomonas spp infections often involve the skin, urinary system, and ears, 65-67 along with ssis and invasive device infections. 68, 69 biofilm formation by pseudomonas spp can further complicate treatment. identification of within hospital clusters of pseudomonas infections should prompt investigation of potentially contaminated environmental, equipment (eg, endoscope), or consumable (eg, catheter preparation supplies) sources. the admission of sick animals occurs daily in most if not all small animal veterinary facilities. furthermore, every animal admitted to the veterinary clinic, healthy or not, can reasonably be assumed to be shedding multiple microorganisms that could cause infection in humans or animals, given the opportunity. as such, there is always a risk for the introduction and spread of hais and for exposure to zoonotic pathogens. the level of risk will be determined, in part, by the population of animals served (eg, young, elderly, immunocompromised), pathogens circulating in the community animals, proportion of patients for which protective or increased-risk practices are taken by their owners (eg, vaccination, husbandry practices to reduce pathogen acquisition), intensity of care typically provided for patients, and clinic infection-control practices and adherence to these practices by staff and clients. veterinary clinic staff will not be able to alter many of these risks; however, infection-control practices is an area that with some planning and dedicated time, can be relatively easy to address. although complete prevention of hais is the goal, given the nature of patient care, bacterial adaptation, and complexity of many pathogens (subclinical shedding, insensitive diagnostic tests), it is inevitable they will continue to occur. methods to reduce the risk of hais are paramount. in general, methods to reduce hais can be divided into the following main categories: hand hygiene and use of personal protective equipment (ppe; ie, clothing and/or gloves to reduce contamination of staff, patients, and the environment); cleaning and disinfection (environmental surfaces and patient equipment); patient management (eg, cohorting patients based on risk, isolating high-risk patients, discontinuing the use of higher risk devices when indicated); surveillance (identification of infected or colonized patients, hais, and source/ risk factors); antimicrobial stewardship (prudent antimicrobial use); education and training (clients, staff). these methods will not only reduce overt problems such as hospital-associated outbreaks but also reduce the likelihood of patient colonization with a ha pathogen, which can become part of the patient's resident microbiota, potentially increasing disease risk at a later date and posing a risk to other animals and humans. each of these areas should be addressed in a hospital's infection-control manual. several "model" plans are widely available to use as a starting point for developing an individualized hospital plan; infection-control officers are encouraged to review these resources. 70, 71 individual articles in this issue of veterinary clinics of north america: small animal practice are devoted to each of these areas, so they are only briefly discussed here. unfortunately, studies on the area indicate only a minority of small animal veterinary hospitals have written infection-control plans (0%-31%). 72, 73 given the relative ease of putting together an infection-control plan and potential health, legal, and financial benefits of doing so, every clinic should invest the time and effort to make this a priority. hand hygiene (washing hands with soap and water or using an alcohol-based hand rub) and use of ppe, such as nonsterile gloves and gowns, are simple techniques that can reduce the risk of hais. effective use of hand hygiene and appropriate ppe use reduces the risk of contamination of personal clothing, reduces exposure of skin and mucous membranes of veterinary staff to pathogens, and reduces transmission of pathogens between patients by veterinary personnel. unfortunately, several studies indicate that veterinarians and staff do a poor job at performing hand hygiene between patients (w20%) or using ppe when indicated (6%-37% depending on the situation). 72, 74 cleaning and disinfection recent evidence suggests environmental contamination in human hospitals increases the risk for hais, 75 whereas interventions that reduce environmental contamination have assisted with cessation of ha outbreaks or reduction of hais. 76, 77 the same connection is assumed to occur in veterinary medicine. effective cleaning and disinfection of hospital equipment and environmental surfaces play an important role in reducing hais. in order for a disinfectant to work properly, the surface or item must first be clean (free of visible organic material) and the product must be applied at the manufacturer's suggested dilution and contact time (amount of time the disinfectant is in contact with the item before being removed). disinfectants should be selected based on several criteria, including the product's spectrum of activity, susceptibility to inactivation by organic matter, and potential pathogens in the environment. given the close contact between veterinary patients and their hospital housing, environmental contamination is inevitable. furthermore, staff caring for these patients is at increased risk for spreading the pathogen through contact with the patient or its stull & weese environment. to protect other patients and clinic staff, special attention to patient housing is important in managing infectious patients. isolation procedures, use of dedicated medical equipment, and patient cohorting are important stopgaps in the transmission of hais for animals suspected to be infectious. in addition, specific patient care procedures may be helpful in reducing hais associated with catheters, aspiration pneumonia, bsis, infectious diarrhea, and ssis. resident small animals are sometimes kept at veterinary facilities as blood donors, companionship for staff, or other reasons. because these animals may harbor mdr pathogens and be sources or propagation of hospital contamination or outbreaks, special attention should be devoted to hospital policies for these animals regarding staff-animal contact and restricted movement (not permitting direct contact with patients or patient areas, including areas for exercise and elimination). 78, 79 surveillance the early identification of hais is critical for effective infection control. identification of "abnormal" (increases in disease incidence or patterns) depends on a reasonable understanding of "normal." understanding of endemic rates can be useful to allow for comparison with other facilities, to establish benchmarks for ongoing surveillance, to serve as a baseline for interventions, to allow for more accurate counseling of clients about risks (eg, ssi rates), and to provide a greater overall awareness of the importance of hais and corresponding control measures. it is not unusual for hai outbreaks to "smolder" below the radar of veterinary staff for extended periods because of the lack of centralized data reporting or communication, resulting in substantial environmental contamination, patient morbidity (and potentially mortality), and even increased zoonotic disease risk for staff and clients. key elements of early hai identification include (1) a surveillance program tailored to the risks and needs of the veterinary practice and (2) routine use of diagnostic culture and susceptibility data to establish practice-specific baseline levels of pathogen prevalence and antimicrobial resistance and detect changes from this baseline. careful selection and appropriate use of antimicrobials are important steps in combating patient mdro development and subsequent contamination and transmission in the hospital environment. antimicrobials should be avoided when a bacterial infection has not been confirmed. antimicrobials used in the initial treatment of an infection should be selected based on the effectiveness against the most likely organisms causing the infection (something that can be facilitated by having good passive surveillance data) as well as patient (eg, renal function, comorbidities) or drug (eg, penetration, route of administration, frequency of administration) factors. whenever possible, a culture should be submitted to determine the true susceptibility pattern of the bacteria involved. local therapy can be an important option that is often overlooked. during their careers, approximately two-thirds of veterinarians report a major animalrelated injury resulting in lost work or hospitalization. 71, 80 animal bite injuries and infections are a large contributor to this hazard, but zoonotic infections (eg, mrsa, dermatophytosis [ringworm], salmonellosis) are also frequently reported. 23, 81 educating staff and clients on zoonotic disease risks and enforcing in-hospital infection-control protocols to reduce these risks will be beneficial to the health of people and patients. all veterinary personnel and visitors should be familiar with the hospital's infectioncontrol plan and policies. the infection-control officer is integral to the successful development, maintenance, and enforcement of an infection-control plan. in the human health care field, infection-control practitioners are formally trained and certified, with the infectioncontrol program typically overseen by a physician with specialized training in infectious diseases, infection control, and/or microbiology. in veterinary medicine, this type of approach is only practiced in large facilities (mainly teaching hospitals), yet the basic concepts remain the same for veterinary facilities of any type and size. a functional infection-control program can be directed by a single infectioncontrol practitioner in a veterinary hospital, with minimal time requirements. this individual can be a technician or veterinarian who has an interest in infection control. the skills required (eg, general understanding of infection-control concepts) can be obtained on the job and need not be a prerequisite for the position, and the limited time requirement under normal circumstances means that a new position does not need to be added. rather, direction of the infection control can usually be undertaken by an existing staff member. of greatest importance for the individual filling this position is an interest in the topic, motivation to make improvements in the clinic's infection-control policies, and the support of clinic leaders (eg, practice owners, veterinarians). without full support by clinic leaders (eg, time to perform the required duties, financial investments, serving as a role model by following clinic infection-control policies), the infection-control officer, and resulting program, is unlikely to be successful. hais have been reported in veterinary medicine and their frequency is likely to increase with the increase in intensive care practices in many veterinary hospitals. prolonged hospitalization and the use of invasive devices and procedures increase the risk of hais. all staff members should be educated on the risks and signs associated with hais so that cases can be detected early and managed appropriately. ultimately, a multifaceted approach is necessary to address hais in small animal veterinary medicine, including prudent antimicrobial use, strengthening surveillance of hais in companion animals, improving infection-control practices (eg, hand hygiene, ppe, cleaning and disinfection, patient management), instilling an infection-control culture among veterinary staff, and improving health care and public education of antimicrobials. a hospital infection-control program, consisting of an infectious disease control officer, a written protocol, and staff training, is a key component to unifying these elements and successful reduction of hais in small animal veterinary practice. estimating health care-associated infections and deaths in u.s. hospitals the direct medical costs of healthcare-associated infections in u.s. hospitals and the benefits of prevention using syndromic surveillance to estimate baseline rates for healthcare-associated infections in critical care units of small animal referral hospitals van metre dc. characteristics of biosecurity and infection control programs at veterinary teaching hospitals the preventable proportion of nosocomial infections: an overview of published reports cdc/nhsn surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting evaluation of catheter-associated urinary tract infections and multi-drug-resistant escherichia coli isolates from the urine of dogs with indwelling urinary catheters incidence of catheter-associated urinary tract infection among dogs in a small animal intensive care unit nosocomial infection surveillance in a small animal intensive care unit urinary tract infection resulting from catheterization in healthy adult dogs biofilms and catheter-associated urinary tract infections circulating immune parameters predicting the progression from hospital-acquired pneumonia to septic shock in surgical patients supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial indications for and outcome of positivepressure ventilation in cats: 53 cases outcome of and postoperative complications in dogs undergoing surgical treatment of laryngeal paralysis: 140 cases postoperative pulmonary complications in dogs undergoing laparotomy: anesthetic and perioperative factors incidence of and risk factors for postoperative pneumonia in dogs anesthetized for diagnosis or treatment of intervertebral disk disease risk of local and systemic infection with polyethylene intravenous catheters. a prospective study of 213 catheterizations surveillance of infections associated with intravenous catheters in dogs and cats in an intensive care unit bacterial and fungal colonisation of peripheral intravenous catheters in dogs and cats inadequate skin preparation as a cause of intravenous catheterrelated infection in the dog a prospective study of intravenous catheter contamination salmonella typhimurium outbreak associated with veterinary clinic evaluation of pet-related management factors and the risk of salmonella spp. carriage in pet dogs from volunteer households in ontario perceptions, practices, and consequences associated with foodborne pathogens and the feeding of raw meat to dogs salmonella shedding in racing sled dogs antibiotic resistance threats in the united states antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention antibiotic treatment of resistant infections in small animals transmission of opportunistic pathogens in a veterinary teaching hospital inducible clindamycin-resistance in methicillin-resistant staphylococcus aureus and methicillin-resistant staphylococcus pseudintermedius isolates from dogs and cats methicillin-resistant staphylococcus pseudintermedius in a veterinary teaching hospital severe surgical site infection in community hospitals: epidemiology, key procedures, and the changing prevalence of methicillin-resistant staphylococcus aureus suspected transmission of methicillinresistant staphylococcus aureus between domestic pets and humans in veterinary clinics and in the household epidemiological profiling of methicillin-resistant staphylococcus aureus-positive dogs arriving at a veterinary teaching hospital methicillin-resistant and -susceptible staphylococcus aureus infections in dogs risk factors for methicillinresistant staphylococcus aureus (mrsa) infection in dogs and cats: a casecontrol study acquisition and persistence of antimicrobial-resistant bacteria isolated from dogs and cats admitted to a veterinary teaching hospital the effect of antibiotics on methicillin-resistant staphylococcus aureus methicillin-resistant staphylococcus aureus colonization in veterinary personnel clonal spread of methicillin-resistant staphylococcus pseudintermedius in europe and north america: an international multicentre study economic impact of tibial plateau leveling osteotomy surgical site infection in dogs evaluation of susceptibility test breakpoints used to predict meca-mediated resistance in staphylococcus pseudintermedius isolated from dogs factors associated with methicillin-resistant versus methicillin-susceptible staphylococcus pseudintermedius infection in dogs prevalence of antimicrobial-resistant escherichia coli in dogs in a cross-sectional, community-based study occurrence of antimicrobial resistant bacteria in healthy dogs and cats presented to private veterinary hospitals in southern ontario: a preliminary study risk factors for multidrug-resistant escherichia coli rectal colonization of dogs on admission to a veterinary hospital risk factors for dogs becoming rectal carriers of multidrug-resistant escherichia coli during hospitalization infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices characterization of multidrug-resistant escherichia coli isolates associated with nosocomial infections in dogs emergence and spread of two distinct clonal groups of multidrug-resistant escherichia coli in a veterinary teaching hospital in australia vital signs: carbapenemresistant enterobacteriaceae outcomes of carbapenem-resistant klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies emergence of oxa-48 carbapenemase-producing escherichia coli and klebsiella pneumoniae in dogs vancomycin-resistant enterococci: consequences for therapy and infection control monitoring of antimicrobial resistance in healthy dogs: first report of canine ampicillin-resistant enterococcus faecium clonal complex 17 susceptibility to vancomycin and other antibiotics of 165 enterococcus strains isolated from dogs in italy dogs leaving the icu carry a very large multi-drug resistant enterococcal population with capacity for biofilm formation and horizontal gene transfer multidrug-resistant salmonella typhimurium in four animal facilities comparison of antimicrobial resistance patterns of salmonella spp. and escherichia coli recovered from pet dogs from volunteer households in ontario (2005-06) prevalence, distribution and characterisation of ceftiofur resistance in salmonella enterica isolated from animals in the usa from 1999 to the role of acinetobacter baumannii as a nosocomial pathogen for dogs and cats in an intensive care unit multidrug-resistant acinetobacter baumannii in veterinary clinics pseudomonas aeruginosa carriage, colonization, and infection in icu patients characterization of antimicrobial resistance of pseudomonas aeruginosa isolated from canine infections evidence-based veterinary dermatology: a systematic review of interventions for treatment of pseudomonas otitis in dogs comparison of three techniques for the diagnosis of urinary tract infections in dogs with urolithiasis cardiovascular device infections in dogs: report of 8 cases and review of the literature an infected hip prosthesis in a dog diagnosed with a 99mtc-ciprofloxacin (infecton) scan infection prevention and control best practices for small animal veterinary clinics compendium of veterinary standard precautions for zoonotic disease prevention in veterinary personnel: national association of state public health veterinarians veterinary infection control committee infection control practices and zoonotic disease risks among veterinarians in the united states evaluation of specific infection control practices used by companion animal veterinarians in community veterinary practices in southern ontario evaluation of an educational campaign to increase hand hygiene at a small animal veterinary teaching hospital does improving surface cleaning and disinfection reduce health care-associated infections? a targeted strategy to wipe out clostridium difficile role of environmental cleaning in controlling an outbreak of acinetobacter baumannii on a neurosurgical intensive care unit outbreak of clostridium difficile-associated disease in a small animal veterinary teaching hospital resident cats in small animal veterinary hospitals carry multi-drug resistant enterococci and are likely involved in crosscontamination of the hospital environment a review of published reports regarding zoonotic pathogen infection in veterinarians a survey of veterinarian involvement in zoonotic disease prevention practices key: cord-289008-c4cu3vrp authors: wallis, christopher j.d.; novara, giacomo; marandino, laura; bex, axel; kamat, ashish m.; karnes, r. jeffrey; morgan, todd m.; mottet, nicolas; gillessen, silke; bossi, alberto; roupret, morgan; powles, thomas; necchi, andrea; catto, james w.f.; klaassen, zachary title: risks from deferring treatment for genitourinary cancers: a collaborative review to aid triage and management during the covid-19 pandemic date: 2020-05-03 journal: eur urol doi: 10.1016/j.eururo.2020.04.063 sha: doc_id: 289008 cord_uid: c4cu3vrp context: the coronavirus disease 2019 (covid-19) pandemic is leading to delays in the treatment of many urologic cancers. objective: to provide a contemporary picture of the risks from delayed treatment for urologic cancers to assist with triage. evidence acquisition: a collaborative review using literature published as of april 2, 2020. evidence synthesis: patients with low-grade non–muscle-invasive bladder cancer are unlikely to suffer from a 3–6-month delay. patients with muscle-invasive bladder cancer are at risk of disease progression, with radical cystectomy delays beyond 12 wk from diagnosis or completion of neoadjuvant chemotherapy. prioritization of these patients for surgery or management with radiochemotherapy is encouraged. active surveillance should be used for low-risk prostate cancer (pca). treatment of most patients with intermediateand high-risk pca can be deferred 3–6 mo without change in outcomes. the same may be true for cancers with the highest risk of progression. with radiotherapy, neoadjuvant androgen deprivation therapy (adt) is the standard of care. for surgery, although the added value of neoadjuvant adt is questionable, it may be considered if a patient is interested in such an approach. intervention may be safely deferred for t1/t2 renal masses, while locally advanced renal tumors (≥t3) should be treated expeditiously. patients with metastatic renal cancer may consider vascular endothelial growth factor targeted therapy over immunotherapy. risks for delay in the treatment of upper tract urothelial cancer depend on grade and stage. for patients with high-grade disease, delays of 12 wk in nephroureterectomy are not associated with adverse survival outcomes. expert guidance recommends expedient local treatment of testis cancer. in penile cancer, adverse outcomes have been observed with delays of ≥3 mo before inguinal lymphadenectomy. limitations include a paucity of data and methodologic variations for many cancers. conclusions: patients and clinicians should consider the oncologic risk of delayed cancer intervention versus the risks of covid-19 to the patient, treating health care professionals, and the health care system. patient summary: the coronavirus disease 2019 pandemic has led to delays in the treatment of patients with urologic malignancies. based on a review of the literature, patients with high-grade urothelial carcinoma, advanced kidney cancer, testicular cancer, and penile cancer should be prioritized for treatment during these challenging times. the rapid spread of coronavirus disease 2019 , caused by the a novel betacoronavirus known as severe acute respiratory syndrome coronavirus-2 (sars-cov-2), throughout the world has had dramatic effects on individuals and health care systems far beyond those infected with sars-cov-2 [1] . the heavy demand for resources, exacerbated by limited excess health system capacity, means that health care systems have become quickly overwhelmed and hospitals have become sources for virus transmission. in response, professional bodies have recommended reprioritizing surgical cases [2] depending on the risks of covid-19 to individual patients and health care workers caring for patients potentially infected with sars-cov-2, and the need to conserve health care resources along with the risk from delaying cancer care. a severe sars-cov-2 phenotype is seen more commonly in men and older, more comorbid patients [3] . these characteristics are common in many patients with urologic malignancies. baseline characteristics among 1591 patients admitted to the intensive care unit j o u r n a l p r e -p r o o f (icu) in the lombardy region, italy, showed that the median age was 63 yr (interquartile range [iqr] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] , 82% were male, 68% had more than one comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing icu-level care at the time of data cut-off [4] . work from china further demonstrated that patients with cancer had a higher incidence of covid-19 than expected in the general population and had more severe manifestation of the disease, with a significantly higher proportion requiring invasive ventilation in the icu or dying [5] . recent data suggest that approximately 20% of asymptomatic covid-19-positive patients may die after an elective operation [6] . to better inform decision making regarding deferring treatment of urologic cancers at this time, we undertook a collaborative review of the available data on the association between treatment delays and important oncologic outcomes including survival in patients with urologic cancers. to rapidly provide information, a formal systematic review was not undertaken. instead, a scoping narrative review was performed. following agreement on manuscript structure, a literature review was performed by teams based on clinical specialty (urologic oncology, radiation oncology, and medical oncology). to this end, pubmed was searched from inception until april 2, 2020 to identify studies examining the association between delays in treatment and clinical outcomes, including upstaging, recurrence, and mortality for patients with bladder cancer (bc; both muscle-invasive and non-muscle-invasive disease), prostate cancer (pca), kidney cancer, upper tract urothelial cancer, germ cell tumors, and penile cancer. where available, we relied on previously published systematic reviews and metaanalyses, supplemented by a narrative review of key studies and those published since the systematic review. the available data were qualitatively synthesized and presented, stratified by tumor site and urologic versus medical oncology intervention. in the absence of high-quality literature evidence, an expert opinion was given by the authors for this review. following agreement on manuscript structure, the authors drafted relevant sections of this narrative review according to their expertise. the resulting manuscript was critically revised by all authors. the final manuscript represents the consensus of the authors. according to estimates, there were 549 000 new cases of bc and 199 000 deaths worldwide in 2018 [7] . among these cases, about 47% are estimated to be ta/tis at initial presentation, 21% stage i, 11% stage ii, 4% stage iii, and 6% stage iv disease in the usa [8] . most cases are in men, and the average age of onset is over 70 yr. with regard to mortality risk from covid-19, 63% of patients with bc have one comorbidity (such as hypertension, cardiovascular, or pulmonary), 32% have two or more comorbidities, and the risks of dying from bc or from a competing diseases are similar at 5 yr after diagnosis [9, 10] . low-grade non-muscle-invasive bladder cancer (nmibc) is relatively an indolent disease. long-term bc-specific mortality rates are around 1-2% [11] , and active surveillance j o u r n a l p r e -p r o o f (as) for recurrent low-and intermediate-risk nmibcs is an important management option [12] . guidelines suggest discharge after 12 or 60 mo if the patient is recurrence free [13, 14] symptoms, such as the onset of visible hematuria, should be re-evaluated (eg, with cytology and either radiologic imaging or clinic cystoscopy) to assess their disease status. for high-grade nmibc, progression to muscle invasion/metastases occurs in 15-40% and 10-20% of patients may die from bc [15, 16] . primary treatments include bacillus calmette-guérin (bcg) immunotherapy and radical cystectomy (rc) [17] . early re-resection reveals muscle invasion in up to 8% of initial pta and 32% of pt1 tumors [18] . the risks of progression in patients whose re-resection contains no tumor are lower (at around 10% every 5 yr [19, 20] ). given limited surgical capacity during the covid-19 pandemic and a lack of prospective data showing superiority of either approach, in our view, bcg is the preferred choice for most patients who have had their tumors visually resected. the use of re-resection should be individualized according to covid-19 risk (local incidence and patient risk factors), bc risk, and initial turbt features (eg, can be omitted if there are pta and muscle in the first specimen). there are suggestions that bcg may enhance antibody response to sars-cov-2 j o u r n a l p r e -p r o o f [21, 22] . rc should be considered in patients at low risk of covid-19 mortality and with highrisk disease features, for example, presence of high-grade pt1 plus tis, or tumors with lympho(vascular) invasion, variant histology (eg, micropapillary disease), residual grade 3/highgrade urothelial carcinoma on re-resection, or pt1 stage [23] [24] [25] . with respect to bcg therapy, while maintenance full-dose bcg is superior to alternatives, most benefit appears to come from the induction and first maintenance doses (so-called 6 + 3) [26] . as such, it appears reasonable in times of high sars-cov-2 prevalence to discontinue subsequent maintenance bcg instillations in persons at risk of covid-19, who have responded to induction (6) and first maintenance (+3) bcg. if the covid-19 pandemic subsides, we recommend continuation of to 12 mo of maintenance therapy. with regard to starting bcg, progression rate and re-resection data suggest that if bcg is deferred for 3-6 mo, restarting with a cystoscopy  re-resection may be most suitable. in patients who undergo rc for bcg-unresponsive nmibc, with or without further intravesical therapy, the delay caused by an additional (unsuccessful) course of intravesical therapy did not result in differences in 5-yr overall survival (os) or cancer-specific survival (css) despite a median delay of 1.7 yr [27] . finally, due to covid-19 pandemic, especially in geographic areas where the infection is causing a health care emergency, physicians should be aware of the potential risk of stage migration due to simplification of diagnostic procedures such as turbt. it is possible that urologists may opt for simpler minimally invasive procedures such as cystoscopy and biopsy, or even noninvasive procedures such as radiologic imaging prior to defining the therapeutic workup. we urge caution and highlight the importance of the turbt specifically in these highrisk patients [28] . in patients with high-grade nmibc, induction bcg and one course of maintenance therapy (6 + 3) should be offered as first-line therapy. re-resection may be deferred in lower-risk cases (eg, pta), but should not be abandoned in higher-stage (pt1) or higher-risk disease, especially if no muscle was present in the initial resection. the decision to start bcg immediately or defer it (following a repeat resection) depends on the risk of infection with sars-cov-2 and an unfavorable course of covid-19, bladder tumor risk, and health care capacity. rc should be offered for higher-risk tumors, if hospital capacity allows and if patient comorbidities do not put them at a higher postoperative risk. maintenance bcg after the first 3-mo booster series may be omitted until risks of covid-19 become lower. the effect of delays in surgical intervention has been explored thoroughly in muscleinvasive bladder cancer (mibc). a recent systematic review (19 studies) and a meta-analysis (10 studies) provide a contemporary picture of these data [29] . there was considerable variation in the nature of the delay investigated: from the diagnosis to rc (10 studies), from turbt to rc (seven studies), from first clinic visit to rc (or radiotherapy; one study), from referral to first treatment (one study), and from neoadjuvant chemotherapy (nac) to rc (four studies). assessing the delay between bc diagnosis and survival, four of nine studies assessing the question found a significant association between delay from diagnosis to rc and survival. russell and colleagues [29] meta-analyzed the available studies assessing this question. in three studies with data that could be pooled, the authors found an increased risk of death for patients operationalizing delay as the interval between turbt and rc, four of six studies assessing this question found an association with survival. utilizing a cubic spline to model the nonlinear relationship, kulkarni and colleagues [30] found that the risk of death began to rise, beginning at 40 d between turbt and rc. in this case, russell et al [29] meta-analyzed five studies and found a nonsignificant pooled effect estimate of 1.18 (95% ci 0.99-1.41) for os, with significant between-study heterogeneity (i 2 = 73%). finally, five studies assessed the question of whether the time duration between completion of nac and rc was associated with survival outcomes. two studies demonstrated that prolonged time between nac and rc was associated with adverse survival outcomes, and an additional study demonstrated that delays were associated with upstaging. boeri et al [31] found that patients who had >10 wk between the last cycle of nac and rc had significantly worse cancer-specific mortality (3 yr free rate: 70.3% at 10 wk vs 44.3% at >10 wk) and overall mortality (3 yr free rate: 63.5% at 10 wk vs 42.1% at >10 wk). chu et al [32] found similar results, while three other analyses failed to support these results. specifically, if we look at the data relevant to the context of the current covid-19 pandemic, audenet and colleagues [33] found that delays of >8 wk in nac were associated with an increased risk of upstaging, but no harm in delays up to 6 mo from diagnosis to rc, assuming that nac was administered in the meantime. in this case, a meta-analysis of three studies with data suitable for pooling failed to demonstrate a significant association between delays from the termination of nac to rc with survival (hr 1.04, 95% ci 0.93-1.16; i 2 = 82%) [29] . lin-brande et al [34] examined outcomes for patients with variant histology undergoing rc. the authors dichotomized surgical delays using thresholds of 4, 8, and 12 wk. on multivariable analysis, for patients with variant histology, no significant difference in os was apparent when "early" versus "late" surgery was dichotomized at 4 wk (hr 0.92, 95% ci 0.32-2.59) or 8 wk (hr 1.50, 95% ci 0.68-3.29), but significant differences were apparent when delayed surgery was defined as surgery beyond 12 wk following diagnosis (hr 3.45, 95% ci 1.51-7.86). taken together, these data suggest that prolonged delays (exceeding 90 d) between diagnosis/turbt and rc are associated with worse survival, with the caveat that the data are mixed and pooled results demonstrate considerable heterogeneity. the european association of urology (eau) guidelines advise to maintain the delay below the 12 wk threshold [35] . further, when nac is employed, impact of delays in rc no longer appear to be significant. an analysis of funnel plots indicates that there is a publication bias toward studies that demonstrate worse survival associated with delays, suggesting that this finding may be exaggerated in the literature [29] . previous studies also reported shorter survival in patients who experienced a delay in definitive surgery, while they received nac [32] . this potential risk for patients receiving preoperative chemotherapy may be exacerbated during the covid-19 pandemic due to the predicted higher frequency of treatment-related side effects in patients developing an infection during treatment, as anticipated by chinese authors [5, 36] . there are no positive adjuvant studies for os. this therapy should be avoided during the pandemic as the risks of chemotherapy increase the risk-benefit ratio further [37] . additionally, radiotherapy (trimodal therapy with radiosensitizing chemotherapy) could be considered an alternative based on individual hospital and patient factors [38] . adjuvant therapy has no role. the use and choice of systemic therapies in patients with new bc metastases should be individualized according to symptoms, risk of infection with sars-cov-2, and unfavorable course of covid-19, and likely prognosis. cytotoxic chemotherapy remains the treatment of choice for the majority of patients with advanced or metastatic bc. a regime comprising cisplatin and gemcitabine with granulocyte colony-stimulating factor, rather than methotrexate, vinblastine, doxorubicin/adriamycin, and cisplatin (mvac), should be considered, given the higher likelihood of neutropenia in patients receiving mvac [39] , which may be dangerous during the covid-19 pandemic. in patients with previously untreated programmed death ligand-1 (pd-l1)-positive locally advanced and metastatic urothelial carcinoma, immune-checkpoint inhibitors may be more attractive than cytotoxic chemotherapy due to a reduced likelihood of immunosuppression [40] . however, immune-checkpoint blockade is associated with potentially serious side effects, including those requiring icu-level resources and need for high-dose glucocorticoids [41] , which may be in short supply in the current environment. anecdotally, we have noted that both patients and health care professionals seem nervous about starting or pursuing immune therapy due to the belief that serious pulmonary complications from covid-19 may be due to excessive inflammatory response caused by checkpoint inhibition. there are few data to support this view, and so an individualized approach is recommended. our consensus is that first-line treatment should be commenced when possible for metastatic urothelial carcinoma and should not be stopped without justification (table 1 ) [42] . immunotherapy rather than chemotherapy may be given preferentially to patients with pd-l1positive tumors. during the covid-19 pandemic, risks and benefits of systemic therapy should be considered on an individual level, taking into account disease characteristics (ie, pd-l1 positivity), tumor load and dynamics, patient performance status, geographical covid-19 burden, and hospital resources. palliative chemotherapy should be deferred at this time. pca is the commonest noncutaneous male malignancy in the western world [43] . according to estimates, there were 1 276 000 new cases of pca and 359 000 deaths worldwide in 2018 [7] . at diagnosis, 78% of the patients are estimated to present localized disease, 12% regional disease, and 5% metastatic disease in the usa [44] . with regard to the current pandemic, pca is more common in men at risk of adverse outcomes from covid-19. for example, the incidence of pca increases with age and in black men [43] , and >50% of affected men have one or more comorbidities [45] . for the vast majority of men, it will be more prudent j o u r n a l p r e -p r o o f to perform pca investigations, including imaging or biopsy, when the risks from covid-19 are lower. urologists have recognized for many years that definitive intervention (radical prostatectomy [rp] or radiotherapy) may be delayed for long durations (years and potentially indefinitely) for patients with low-risk pca, as as is very rarely associated with adverse clinical outcomes in this population [46] [47] [48] . however, metastasis-free survival (mfs) and pca-specific survival are significantly worse for patients with gleason 3 + 4 disease undergoing as compared with those with gleason 3 + 3 disease [49] . thus, it appears that for men with intermediate-risk disease (and presumably also for those with high-risk disease), there is risk to a surveillance strategy. in our literature review, two relevant review articles were identified: one was a narrative review [50] and the other a systematic review [51] . the narrative review of bourgade and colleagues [50] concluded that the heterogeneous nature of pca meant that generalizable conclusions could not be drawn, in routine care, on the basis of three cited studies. van den bergh and colleagues [51] provided a more comprehensive systematic review including 17 studies, of which 13 assessed patients treated with rp, three studies assessed patients treated with radiotherapy, and one study assessed patients treated with either modality. as should be the preferred management strategy for patients with low-risk pca. patients considering focal therapy may safely defer treatment until the pandemic is over. while van den bergh and colleagues [51] [52] found no significant differences in pathologic findings (positive surgical margins, extraprostatic extension, seminal vesicle invasion, or lymph node involvement) or use of adjuvant therapy between patients who received surgery within 3 mo and those who received surgery 3-6 mo following diagnosis, when stratified by biopsy gleason grade group (ggg). similarly, there were no differences in 2-or 5-yr biochemical recurrence-free survival (rfs) or j o u r n a l p r e -p r o o f 2-, 5-, or 10-yr mfs between patients receiving earlier surgery and those who had delayed treatment, when stratified by biopsy ggg. delays up to 6 mo from diagnosis were not associated with adverse pathologic findings (gleason upgrading, extraprostatic extension, seminal vesicle invasion, positive surgical margins, or lymph node involvement) [53, 54] or pca-specific mortality [54] , across risk strata and including patients with intermediate-risk localized disease, high-risk localized disease, and high-risk locally advanced disease [54] . fossati and colleagues [55] examined even longer durations of delay between diagnosis and surgery. among 2653 patients treated with rp at san raffaele hospital in milan, the authors used nonparametric curve fitting models to assess the relationship between the time from diagnosis to surgery and oncologic outcomes, including biochemical recurrence and clinical recurrence. the median time from diagnosis to surgery was 2.8 mo. among all patients, the authors identified a significant association between the time to surgery and risk of biochemical recurrence (hr 1.02, p = 0.0005) and clinical recurrence (hr 1.03, p = 0.0002), although this relationship was nonlinear. utilizing nonparametric curve fitting, the authors identified that the risk of biochemical recurrence increased significantly with delays of >18 mo. in sensitivity analyses, this effect was seen only in patients with high-risk disease. among patients with highrisk disease, an increased risk of biochemical recurrence was seen with presurgical delays exceeding 12 mo. however, others have found that safe delays may be considerably shorter. berg et al [56] found that among their cohort (which was much less contemporary), the risk of adverse pathologic findings increased beyond 60 d for patients with intermediate-risk disease and 30 d for patients with high-risk disease. meunier and colleagues [57] found that there was an j o u r n a l p r e -p r o o f increased risk with delays of >90 and 60 d for patients with gleason 3 + 4 disease and gleason 8 disease, respectively. while zanaty et al [58] found no significant association between the time to surgery and pathologic outcomes, regardless of preoperative risk stratification, they found a significant increase in the risk of biochemical recurrence for patients with high-risk disease who waited longer than 90 d. finally, a recent analysis from the mayo clinic suggested that patients with high-risk disease who waited for >6 mo without neoadjuvant androgen deprivation therapy (adt) had an increased risk of biochemical recurrence, although they did not assess shorter time intervals [59] . the analyses presented thus far have examined patients who received no therapy during the delay to definitive local treatment. however, neoadjuvant adt may offer an option to temporize patients at particularly high risk of progression during forecasted delays. in a cochrane systematic review and meta-analysis of randomized or quasirandomized clinical trials, kumar and colleagues [60] found that, while there was a marginal benefit in terms of disease recurrence (or 0.74, 95% ci 0.55-1.00), there was no benefit or harm to neoadjuvant adt compared with immediate rp in terms of pca-specific survival (or 0.99, 95% ci 0.75-1.32) or os (or 1.11, 95% ci 0.67-1.85) for patients with localized and locally advanced pca. while neoadjuvant adt has not been adopted routinely on the basis of a failure to improve survival outcomes compared with early definitive treatment, in the current environment, these data may be viewed in another manner: namely, that neoadjuvant adt may offer the ability to defer definitive intervention safely without compromising long-term outcomes. in the post-rp setting, based on recently presented, but unpublished, evidence from raves [61] and radicals [62] trials, early salvage is a preferable option as compared with immediate, adjuvant irradiation when needed. for patients with intermediate-and high-risk disease, delays of 3-6 mo appear not to be associated with adverse pathologic outcomes, biochemical recurrence, or survival outcomes. some data suggest that these intervals may be longer (up to 12 mo in patients with high-risk disease [55] ). neoadjuvant adt prior to radiotherapy is the standard of care usually for 2-3 mo. it might be prolonged much longer for those at particularly high risk of progression or recurrence if radiotherapy has to be delayed until after peak health care resource utilization associated with covid-19. for surgery, although added value of neoadjuvant adt is questionable, it might also be considered if a patient is interested in such an approach. while the majority of the literature assessing delays in the treatment of pca has assessed patients undergoing rp, van den bergh et al [51] identified four studies assessing patients treated with radiotherapy. notably, none of these included patients receiving brachytherapy. while three of these studies reported no significant difference in biochemical rfs, mfs, css, or os, nguyen et al [63] found that treatment delays, particularly those exceeding 2.5 mo, were associated with worse biochemical control in patients with high-risk disease. there is no biologic rationale to suggest that treatment delays should differentially affect patients opting for radiotherapy, rather than rp, in the treatment of localized pca. thus, it is likely safe to delay treatment for 3-6 mo for these patients. in circumstances where treatment is offered, covid-19-related risks differ somewhat for patients receiving surgery and radiotherapy. whereas surgery entails short hospitalization j o u r n a l p r e -p r o o f with the use of operating room resources, radiotherapy requires multiple outpatient visits. it is unclear which will contribute a greater patient-and system-level covid-19-related risk. where radiotherapy is planned to be administered, a recent cochrane database systematic review and meta-analysis of 10 studies including 8278 patients demonstrated that for those with intermediate-and high-risk pca, hypofractionation is associated with equivalent oncologic outcomes (mfs, disease-specific survival, and os), as well as functional outcomes [64] . use of an ultrahypofractionated schedule (five to seven fractions) is both in line with clinical guidelines [65] and a way to reduce resource utilization and individual patient exposure [66] . utilization of a longer period of neoadjuvant adt may allow for resolution of the current limitations in health care resources before the planned initiation of radiotherapy. a recent paper by zaorsky et al [66] introduced the concept of a remote visits, avoidance, deferment, and shortening of radiotherapy (rads) framework to determine the appropriate management for patients with pca in the covid-19 pandemic. men starting radiotherapy can safely defer treatment for 3-6 mo. hypofractionation (either moderate, 19-20 fractions over 3.8-4 wk [69] , or extreme, five to seven fractions-an stereotactic body radiotherapy approach) may decrease health care burden and patient sars-cov-2 exposure. neoadjuvant adt allows safe deferral of radiotherapy until resolution of the current covid-19-related health care resource pressures. the treatment of both metastatic hormone-sensitive pca (mhspc) and castrationresistant pca (mcrpc) over the past decade has evolved to provide several treatment options for these patients. debate continues as to the proper sequencing of these agents, specifically regarding chemotherapy and androgen-receptor (ar) targeted therapies. in the current landscape of the covid-19 pandemic, there is a paucity of data with regard to treatment delays in the metastatic setting; thus, the following recommendations are based on expert opinion. first, frontline treatment should be commenced where possible and oral ar targeted therapies should be prioritized over chemotherapy (table 1 ) [42] . although there is a proven survival benefit for docetaxel in the mhspc [70] [71] [72] and mcrpc [73] setting, the associated side effects (ie, neutropenia) that may require hospitalization should be avoided at this time. second, in patients requiring second-and third-line therapy, ar targeted therapies that have not been used previously should be prioritized. third, for patients currently on chemotherapy, it may be prudent to minimize the number of chemotherapy cycles and/or prolonging the cycle length. patients with metastatic pca should commence treatment, prioritizing ar targeted therapies over chemotherapy. glucocorticoid use should be minimized and patients should be considered for longer-duration adt injections. on a global scale, renal cell carcinoma (rcc) represents the sixth and 10th most diagnosed cancer in men and women, and accounts for 5% and 3% of all cancers in males and females, respectively. for both sexes, incidence rates increased in the uk by 1.8-2.2% annually, while they decreased or stabilized in other northern european countries [74] . at presentation, 65% of patients are estimated to have localized disease, 16% regional disease, and 16% metastatic disease in the usa [44] . although declining, primary metastatic rcc still represents a significant fraction of the cases at the time of diagnosis and mortality rates remain stable despite the introduction of new systemic therapies [43] . patients at an increased risk of covid-19 are comparable with the kidney cancer population, more likely males, hypertensive patients, and patients with more than one comorbidity [4] . we identified a single narrative review [50] but no systematic reviews assessing delays in treatment of kidney cancer. the following is a narrative summation of the primary literature identified. as with low-risk pca, numerous studies have demonstrated that small renal masses (srms) may be observed safely on an as protocol [75, 76] . among 457 patients treated at fox chase cancer center, mcintosh et al [75] found a median initial linear growth rate of 1.9 mm/yr (iqr 0-7), which was not associated with os. the cumulative incidence of delayed intervention was 9% at 1 yr, 22% at 2 yr, 29% at 3 yr, 35% at 4 yr, and 42% at 5 yr. importantly, delayed intervention was also not associated with os (hr 1. authors from the university of michigan have also assessed the effect of delayed resection (at least 6 mo from presentation) after initial as for srms [77] . in this study, 401 patients underwent early resection and 94 (19%) underwent delayed resection. the median time to resection was 84 d (iqr 59-121) in the early intervention group and 386 d (iqr 272-702) in the delayed intervention group. importantly, there was no difference in adverse final pathology (grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage pt3) comparing those who underwent early versus late intervention. taken together, there are robust data supporting as for masses <4 cm, even up to 5 yr after initial diagnosis, without age restriction [76, 78] . while biopsy is often useful in the management suggesting that delays of months to years are unlikely to affect the resectability of these tumors. unfortunately, the small number of patients with ct2 disease precludes meaningful conclusions regarding these patients. in a retrospective review of 722 patients undergoing partial or radical nephrectomy for relatively large kidney tumors (mean tumor size of 6.4  4.4cm; 64.7% pt1b and 49.0% pt2), stec et al [81] found that the mean time from initial visit to surgery was 1. disease, delays of 3-6 mo do not appear to affect outcomes adversely. we were unable to identify any study assessing the impact of delayed surgical intervention among patients with locally advanced kidney cancer; thus, the impact of delayed intervention is essentially unknown. however, several large institutional studies have described timing of preoperative imaging for assessing renal vein/inferior vena cava (ivc) thrombus, which may guide urgency of surgical timing. while woodruff et al [82] recommended the longest interval between imaging (computed tomography [ct]/magnetic resonance imaging) and surgery being no longer than 30 d, studies from the mayo clinic and berlin, germany, report a median interval from imaging to resection of 4 and 16 d, respectively [83, 84] . the data are scant regarding the safety of delaying surgery in patients with ct3 renal masses, in particular those with renal vein or ivc tumor thrombus involvement. these patients should be prioritized for surgical intervention, given the locally advanced nature of their disease, unknown j o u r n a l p r e -p r o o f risk of delayed resection, and potential for significant symptomatic complications including bleeding and ivc occlusion. the immediate surgery or surgery after sunitinib malate in treating patients with metastatic kidney cancer (surtime [nct01099423]) trial randomized 99 patients to immediate cytoreductive nephrectomy (cn) followed by sunitinib or sunitinib followed by cn followed by two courses of adjuvant sunitinib. while significantly underpowered due to poor accrual, the trial reported a 28-wk progression-free rate of 42% in the immediate cn arm and 43% in the deferred cn arm (p = 0.6) [85] . intention-to-treat analysis of the secondary outcome of os demonstrated significantly longer survival among patients in the delayed cn arm (median 32.4 mo) than in the immediate cn arm (median 15.1 mo; hr 0.57, 95% ci 0.34-0.95). further, the carmena trial, which enrolled mostly poor-risk patients, was a noninferiority trial and used sunitinib, demonstrated no survival benefit from the addition of cn to systemic therapy in 450 asymptomatic patients with metastatic kidney cancer [86] . thus, cn should be avoided during the pandemic with delayed surgery, in keeping with the surtime approach, considered as an alternative to immediate nephrectomy in those who need surgery. in the current landscape, upfront systemic therapy should be prioritized over cn in asymptomatic patients with metastatic kidney cancer. nephrectomy should be reserved for symptomatic patients. j o u r n a l p r e -p r o o f in patients with locally advanced or metastatic rcc, the decision to start systemic therapy and the selection of agents depend on symptoms, patient comorbidities, and tumor risk stratification. apart from imperative indications due to the covid-19 pandemic, the notion of deliberate treatment delays in selected patients with metastatic rcc, particularly those with international metastatic rcc database consortium (imdc) good-risk disease, has previously been assessed in a number of studies, including two narrative reviews [87, 88] , two prospective studies [89, 90] , six retrospective studies [91] [92] [93] [94] [95] [96] , and a further three abstracts of retrospective studies. in each, the majority of patients initiated treatment at disease progression. in the largest prospective study of this approach to date, rini et al [90] [96] found that a delay of >6 wk in the initiation of systemic therapy did not significantly affect the cancer-specific outcomes. finally, the survival implications of delayed initiation of targeted therapy have also been investigated at the population level using the national cancer database (ncdb) data [95] . time to initiation of targeted therapy was defined as "early" (within 2 mo), "moderately delayed" (2-4 mo), "delayed" (4-6 mo), and "late" (>6 mo). on multivariable logistic regression analyses, delayed treatment initiation was not independently associated with worse os. there is no consensus as to the optimal therapeutic agent(s) to use during the covid-19 pandemic; thus, it is advisable to follow the eau guidelines, which provide first-, second-, and third-line options based on imdc favorable-versus intermediate/poor-risk disease [97] . depending on the outcome prioritized (pfs, os, or toxicity), different agents may appear preferable [98, 99] . while checkpoint inhibitor-based regimes have demonstrated os advantages compared with sunitinib, in the context of the current pandemic, it is worth considering that these came at the cost of more severe treatment-related adverse events (traes) [100] , including those that may require hospitalization. among the 436 n + i patients in checkmate 214 who had immune-mediated traes, 35% received high-dose glucocorticoids [100] . thus, although vascular endothelial growth factor (vegf) targeted therapy is associated with inferior os compared with immunotherapy, in the context of the covid-19 pandemic, these agents may be considered given their decreased risk of severe toxicity. patients with treatment-naïve favorable-and intermediate-risk disease who are asymptomatic or minimally symptomatic with limited disease burden may be considered for as until disease progression during the covid-19 pandemic. for poor-risk patients and those requiring treatment, there is no consensus regarding the optimal first-line therapy; however, vegf targeted therapy is less likely to require toxicity-related hospitalization and/or glucocorticoids than immunotherapy regimens. as with kidney cancer, we identified only a single narrative review [50] and thus based our conclusions on the available primary literature. the management of upper tract urothelial carcinoma (utuc) is typically directed by a combination of disease grade (low vs high) and patient comorbidity. numerous studies have demonstrated that a period of endoscopic management of low-grade utuc is safe [101] . the impact of delayed radical nephroureterectomy (rnu) for those requiring a more aggressive intervention is less clear. four studies were identified that assessed the impact of delaying rnu for diagnostic ureteroscopy  biopsy. in patients eventually undergoing rnu, single-center studies have shown that delays in surgery due to ureteroscopy beforehand did not affect survival in cohorts of patients with predominately low-grade disease (high grade comprising approximately one-third of cohort) or mixed disease characteristics (high grade comprising approximately 50% of cohort), although undergoing two ureteroscopic treatments prior to rnu was associated with an increased risk of intravesical recurrence in patients with predominately high-grade disease (high grade comprising approximately 70% of cohort) [102] . subsequently, a study from the french collaborative national database on upper urinary tract urothelial carcinoma evaluated the j o u r n a l p r e -p r o o f influence of ureteroscopy prior to rnu on css, rfs, and mfs [103] . as expected, time from diagnosis to rnu was longer among patients undergoing ureteroscopy (79.5 vs 44.5 d, p = 0.04). however, there were no differences in 5-yr css, rfs, or mfs, even in a subset of patients with confirmed muscle-invasive disease. not specifically assessing delays due to ureteroscopy, two institutional studies have assessed the impact of delayed rnu on pathologic and survival outcomes, both using a 3-mo first, where utuc exists in a solitary renal unit, intervention should be considered j o u r n a l p r e -p r o o f expeditiously, even in the case of low-grade disease, to protect long-term renal function. second, accurate grading and staging are much more difficult in utuc than in urothelial carcinoma of the bladder [106, 107] . patients with suspected utuc may be initially investigated with urine cytology and ct urogram, forgoing diagnostic ureteroscopy unless there is considerable diagnostic uncertainty. patients with low-grade utuc are often managed with nephron-sparing approaches and thus are likely to have minimal to no risk with a surgical delay. in patients with high-grade disease, delays of up to 12 wk may not be associated with changes in survival, despite worse pathologic outcomes. according to estimates, there were 71 100 new cases of testicular cancer and 9500 deaths worldwide in 2018 [7] . among those cases, 63% are estimated to have localized disease, 12% regional disease, and 12% metastatic disease in the usa [8] . limited data, and no systematic reviews, were identified with respect to delays in treatment, including both orchiectomy and retroperitoneal lymph node dissection (rplnd), for testis cancer. urologic oncology dogma has been that testis masses should be treated with radical orchiectomy as soon as possible. in the ncdb, macleod et al [108] found that most patients underwent orchiectomy within several days of diagnosis, with the highest quartile of delay corresponding to a 2-d delay. thus, they defined a delayed orchiectomy as the 90th percentile j o u r n a l p r e -p r o o f (11 d from presentation) . however, the authors did not assess whether delays in orchiectomy were associated with pathologic or survival outcomes. in patients with clinical stage i germ cell tumors (gcts), as, rather than adjuvant therapy, is a standard of care [109] [110] [111] . although there are no randomized trials comparing these approaches, the available data suggest no difference in survival [112] . we were unable to identify any studies that assessed the effect of delayed rplnd for metastatic gcts. surgery is rarely indicated for patients with metastatic seminoma, and in the current environment, only imperative indications should be considered. for patients with nonseminomatous germ cell tumors (nsgcts), chemotherapy is typically the preferred initial approach. historically, nsgct patients with postchemotherapy masses <1 cm are observed; however, the impact of delaying postchemotherapy rplnd for masses larger than 1 cm is unknown. for patients with advanced gcts, data are limited. however, the association between timely delivery of standard chemotherapy and the probability of cure is well recognized [113] . according to estimates, there were 35 000 new cases of penile cancer and 15 100 deaths worldwide in 2018 [7] . no systematic or narrative reviews, and little primary literature, assessing the effect of delays in management of penile cancer were identified, likely due to its rarity. no studies assessing delays between initial presentation/diagnosis and primary penectomy (partial, total, or radical) were identified. however, delays between initial appearance of a penile lesion and first medical consultation are common due, in part, to social stigma. de rose et al [114] found that this interval averaged 53 d among 113 patients with penile cancer. the eau guidelines recommend modified inguinal lymphadenectomy or dynamic sentinel-node biopsy for all patients with intermediate-or high-risk tumors and nonpalpable nodes [115] , given the risk for micrometastatic disease [116] . among 23 patients, those who received early inguinal lymphadenectomy (median time to surgery 1.7 mo, range 0-6 mo) had significantly lower 5-yr cancer-specific mortality than those who underwent delayed intervention (median time to surgery 14 mo, range 7-24 mo; 5-ysr css 91% vs 13%; p = 0.007) [117] . in the largest study to date, the group at the moffitt cancer center assessed the impact of early (<3 mo, n = 51) and delayed (3 mo, n = 33) lymphadenectomy on regional recurrence and disease-free survival (dfs) [118] . over a median follow-up of 21 mo, early lymphadenectomy resulted in improved 5-yr rfs (77.0% vs 37.8%; hr 0.48, 95% ci 0.21-0.98) and 5-yr dfs (64.1% vs 39.5%), compared with those in men undergoing delayed lymphadenectomy. for these reasons, and considering the ineffectiveness of chemotherapy in this tumor type, the use of perioperative systemic therapy in lymphadenectomy candidates should be carefully considered case by case after multidisciplinary discussion. we were unable to identify studies assessing the risk of delayed intervention of the primary penile carcinoma; however, given the rarity of this malignancy, symptomatology, and high risk for metastatic progression, it seems reasonable to avoid delays in primary surgical treatment. additionally, inguinal lymphadenectomy for men with clinicopathologic indications should occur within 3 mo of treating the primary lesion. clinical trials represent a key platform of comprehensive cancer centers and may provide unique therapeutic options in patients with aggressive malignancies with limited standard therapies. these opportunities may still be provided to patients during the covid-19 outbreak, but likely require thorough evaluation on a case-by-case basis [119] . considerations should be made as to whether clinical investigators and supporting staff are able to comply safely with the trial requirements and guarantee patients' compliance. j o u r n a l p r e -p r o o f furthermore, a patient's ability and risk to travel for therapy during a time of rigorous social distancing and household quarantine must be considered. in an attempt to offer optimal therapeutic options with inclusion in clinical trials, investigators should carefully evaluate the risks of adding extra delays in treatment initiation due to administrative issues or bureaucratic constraint related to covid-19 pandemic and extra visits requiring travel associated with a higher risk of infection in this mostly vulnerable population. early evidence from china has suggested that investigators who continue to enroll to clinical trials during the covid-19 pandemic should expect frequent protocol violations, with an average deviation of 27  13 d [120] . while acknowledging the significant psychologic burden associated with a cancer diagnosis, likely magnified by delays in treatment, physicians who treat cancer patients must be good stewards of limited health care resources, particularly in the time of a pandemic. as a result, it is important to prioritize the timely care of patients for whom delays are most likely to result in adverse outcomes, also taking into account the patient's age, comorbidities, symptoms, and life expectancy. this review aims to assist with case triage and patient counseling by summarizing the available data on outcomes of delays in treatment for patients with urologic cancers. author contributions: zachary klaassen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. clinical characteristics of coronavirus disease 2019 in china considerations in the triage of urologic surgeries during the covid-19 pandemic severe outcomes among patients with coronavirus disease 2019 (covid-19)-united states baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region cancer patients in sars-cov-2 infection: a nationwide analysis in china clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of covid-19 infection epidemiology of bladder cancer: a systematic review and contemporary update of risk factors cancer treatment and survivorship statistics effects of age and comorbidity on treatment and survival of patients with muscle-invasive bladder cancer competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients non-invasive urothelial neoplasms: according to the most recent who classification expectant management of small, recurrent, noninvasive papillary bladder tumors bladder cancer: diagnosis and management of bladder cancer risk-adapted management of low-grade bladder tumours: recommendations from the international bladder cancer group (ibcg) treatment strategy for newly diagnosed t1 high-grade bladder urothelial carcinoma: new insights and updated recommendations comparative outcomes of primary, recurrent, and progressive high-risk non-muscle-invasive bladder cancer european association of urology guidelines on nonmuscle-invasive bladder cancer (tat1 and carcinoma in situ)-2019 update repeat transurethral resection in non-muscleinvasive bladder cancer: a systematic review long-term outcomes from re-resection for high-risk non-muscle-invasive bladder cancer: a potential to rationalize use recurrence, progression and cancer-specific mortality according to stage at re-tur in t1g3 bladder cancer patients treated with bcg: not as bad as previously thought covid-19 and bacillus calmette-guérin (bcg): what is the link? bcg vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials prognostic factors and risk groups in t1g3 non-muscleinvasive bladder cancer patients initially treated with bacillus calmette-guerin: results of a retrospective multicenter study of 2451 patients what is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? a european association of urology muscle invasive and metastatic bladder cancer guidelines panel systematic review society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of bladder carcinoma the timing of radical cystectomy for bacillus calmette-guerin failure: comparison of outcomes and risk factors for prognosis transurethral resection of bladder tumour: the neglected procedure in the technology race in bladder cancer a systematic review and meta-analysis of delay in radical cystectomy and the effect on survival in bladder cancer patients longer wait times increase overall mortality in patients with bladder cancer delaying radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer is associated with adverse survival outcomes delays in radical cystectomy for muscle-invasive bladder cancer a delay 8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging assessing the impact of time to cystectomy for variant histology of urothelial bladder cancer updated 2016 eau guidelines on muscle-invasive and metastatic bladder cancer clinical characteristics of covid-19-infected cancer patients: a retrospective case study in three hospitals within wuhan, china effectiveness of adjuvant chemotherapy for locally advanced bladder cancer radiotherapy with or without chemotherapy in muscleinvasive bladder cancer efficacy and safety of dose-dense chemotherapy in urothelial carcinoma clinical outcome after progressing to frontline and second-line anti-pd-1/pd-l1 in advanced urothelial cancer adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials advice regarding systemic therapy in patients with urological cancers during the covid-19 pandemic cancer statistics cancer statistics, 2020 co-morbidities in a retrospective cohort of prostate cancer patients feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer ten-year mortality, disease progression, and treatmentrelated side effects in men with localised prostate cancer from the protect randomised controlled trial according to treatment received active surveillance for intermediate risk prostate cancer: survival outcomes in the sunnybrook experience impact of the length of time between diagnosis and surgical removal of urologic neoplasms on survival timing of curative treatment for prostate cancer: a systematic review evaluating the impact of length of time from diagnosis to surgery in patients with unfavourable intermediate-risk to very-high-risk clinically localised prostate cancer the effect of time from biopsy to radical prostatectomy on adverse pathologic outcomes is time from diagnosis to radical prostatectomy associated with oncological outcomes? evaluating the effect of time from prostate cancer diagnosis to radical prostatectomy on cancer control: can surgery be postponed safely? delay from biopsy to radical prostatectomy influences the rate of adverse pathologic outcomes does the delay from prostate biopsy to radical prostatectomy influence the risk of biochemical recurrence? does surgical delay for radical prostatectomy affect biochemical recurrence? a retrospective analysis from a canadian cohort impact of time from biopsy to surgery on complications, functional and oncologic outcomes following radical prostatectomy neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer a phase iii multi-centre randomised trial comparing adjuvant versus early salvage radiotherapy following radical prostatectomy: results of the trog 08.03 and anzup "raves" trial timing of radiotherapy (rt) after radical prostatectomy (rp): first results from the radicals rt randomised controlled trial (rct) the impact of a delay in initiating radiation therapy on prostate-specific antigen outcome for patients with clinically localized prostate carcinoma hypofractionation for clinically localized prostate cancer hypofractionated radiation therapy for localized prostate cancer: an astro, asco, and aua evidence-based guideline prostate cancer radiotherapy recommendations in response to covid-19 duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trial 9910 short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the trog 96.01 randomised trial conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, noninferiority, phase 3 chhip trial chemohormonal therapy in metastatic hormonesensitive prostate cancer addition of docetaxel, zoledronic acid, or both to firstline long-term hormone therapy in prostate cancer (stampede): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial comparison of abiraterone acetate and docetaxel with androgen deprivation therapy in high-risk and metastatic hormone-naive prostate cancer: a systematic review and network meta-analysis docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer incidence and mortality of kidney cancer: temporal patterns and global trends in 39 countries active surveillance for localized renal masses: tumor growth, delayed 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oncologic impact of a delay between diagnosis and radical nephroureterectomy due to diagnostic ureteroscopy in upper urinary tract urothelial carcinomas: results from a large collaborative database a delay in radical nephroureterectomy can lead to upstaging upper tract urothelial carcinoma: impact of time to surgery utility and diagnostic accuracy of ureteroscopic biopsy in upper tract urothelial carcinoma clinical staging of upper urinary tract urothelial carcinoma for t staging: review and pictorial essay disparities in access and regionalization of care in testicular cancer optimal management of high-risk stage i nonseminomatous germ cell tumor: surveillance is the preferred option conditional risk of relapse in surveillance for clinical stage i testicular cancer non-risk-adapted surveillance for stage i testicular cancer: critical review and summary contemporary assessment of long-term survival rates in patients with stage i nonseminoma germ-cell tumor of the testis: populationbased comparison between surveillance and active treatment after initial orchiectomy dose-response and dose-survival advantage for high versus low-dose cisplatin combined with vinblastine and bleomycin in disseminated testicular cancer. a southwest oncology group study risk factors for the delay in the diagnosis of penile lesions: results from a single center in italy eau guidelines on penile cancer: 2014 update dynamic sentinel node biopsy in penile cancer: initial experiences at a swedish referral centre impact of delay in inguinal lymph node dissection in patients with carcinoma of penis delay to inguinal lymph node dissection greater than 3 months predicts poorer recurrence-free survival for patients with penile cancer the shifting landscape of genitourinary oncology at the time of covid-19 pandemic: how italian oncologists react. results from a national survey the surgical volume, safety, drug administration and clinical trials during covid-19: single center j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f f palliative ctx was tested with a specific number of cycles. the risk associated with stopping before this has not been assessed, nor the principles of delaying chemotherapy. there are subgroups of prostate and urothelial cancer patients for whom continuing ctx to the full number of cycles may be associated with more risk than benefit. patients will need to participate in this discussion.g assuming similar efficacy between the regimens.j o u r n a l p r e -p r o o f key: cord-258498-0mvxwo3w authors: shah, saleha title: covid-19 and paediatric dentistrytraversing the challenges. a narrative review date: 2020-08-21 journal: ann med surg (lond) doi: 10.1016/j.amsu.2020.08.007 sha: doc_id: 258498 cord_uid: 0mvxwo3w the coronavirus disease (covid-19) pandemic has become a major global public health emergency with a focus on preventing the spread of this virus for controlling this crisis. a dental setting is at a high risk of cross infection amid patients and dental practitioner's owing to the spread of infection via droplets suspended in the air by infected symptomatic or asymptomatic subjects. this review article informs about measures which reduce facility risk, manage symptomatic patients and protect personal health care and management with reference to paediatric dentistry. the routine aerosol generating procedures are not designed to offer protection against transmission of pathogens and the standard protective measures do not offer adequate effectiveness against patients generating aerosol in the incubation period, are unaware of the infection or conceal information regarding their infection. 5, 6 dental healthcare personnel (dhcp) are all paid and unpaid persons serving in dental healthcare settings with a potential for direct or indirect exposure to patients or infectious materials (body substance, contaminated medical supplies, devices, equipment, environmental surfaces, air). a dhcp is placed in the very high exposure risk category by osha via high potential for exposure to known or suspected viral sources for covid-19 during specific dental procedures. 5, 6, 7 the risk of sars-cov-2 transmission via aerosols generated during dental procedures cannot be eliminated when practicing in the absence of airborne precautions (airborne infection isolation rooms or single-patient rooms, respiratory protection program, n95 respirators). it is vital to reduce the risk of infections in a dental setting by infection control measures since unrecognized asymptomatic and presymptomatic infections have a likelihood of transmission in healthcare settings. sars-cov2 is sensitive to heat and ultra-violet rays. it is inactivated at 56°c for 30 minutes and by lipid solvents ethanol, 75% ether, disinfectants containing peracetic acid, chloroform and chlorine but not by chlorhexidine 7, 8 this is essential in the reliable and effective protection of dhcp from exposure to pathogens. it includes engineering controls, administrative controls and personal protective equipment (ppe). the optimal way to prevent airborne transmission is via a combination of interventions from the hierarchy of controls including elimination (physical removal of hazard), substitution (replacing hazard), engineering controls, administrative controls and ppe (least effective control owing to a high level of worker involvement and dependence on proper fit and correct use). source control entails coverage of the mouth and nose by a cloth face or a facemask to aid the reduction of risk of transmission of sars cov-2 from both symptomatic and asymptomatic people via respiratory secretions. 7,8, paediatric dental practice aims to maintain the well-being and safety of children during this pandemic by redesigning, reconsidering and reflecting on the dental care practices and staying up to date with the current evidence based guidance and recommendations for child oral health care. hence a risk assessment of the practice should be carried out to identify the measures required to minimize the risk of covid-19 transmission. administrative controls and work practices: these work practices and policies reduce or prevent hazardous exposures. the practice should be cleaned thoroughly and clutter removed to facilitate frequent cleaning and disinfection. toys, magazines and other frequently touched objects in the waiting area which cannot be cleaned or disinfected regularly are removed from the waiting area. devise a protocol for receiving mails and deliveries. the number of dental setting/hospital/outpatient patients is limited and screened for respiratory illness prior to healthcare. triage by telemedicine (telephones, video-call applications on cell phones, video monitoring or tablets) and manages patients suspected of covid-19 without a face to face visit. if the signs and symptoms are present then the appointment is rescheduled. clinical care is limited to one patient at a time. the essential personnel should only be allowed to enter a patient care area. limit dhcp during a procedure to those essential for procedure support and patient care. this avoids multiple room entry and bundling. entry of known or suspected covid-19 should be restricted by the dhcp or allowed to enter with ppe. dhcp at higher risk for severe illness from covid-19 (old age, chronic medical conditions, pregnant) should be excluded from caring for confirmed or suspected covid-19. dhcp recovered from covid-19 (protective immunity) care for covid-19 patient. 9, 10, 11, 12, 13, 14, 15, 30, 31, 32, 33, 34 dhcp should be monitored and managed with application of flexible sick leaves. hcp should monitor themselves regularly for fever and covid-19 symptoms. they should stay at home if they feel unwell and cover their faces or leave the workplace if they start feeling unwell at work. every hcp should be screened for fever and symptoms consistent with covid-19 (fever >100.0of, cough, shortness of breath, and sore throat) when their shift commences. testing should also be done if temperature is <100.0 o f or with other symptoms consistent with covid-19. if covid-19 is ruled out based on time and test and the dhcp has an alternate diagnosis (tested positive for influenza); the criteria for return to work should be based on that diagnosis. they should continue wearing a mask subsequent to returning to work, self-monitor for symptoms and reevaluate with a medical facility. 24, 27, 28, 29 a dhcp should be trained on the use of n95 respirators (putting on, removal, limitations, maintenance, check seal, repair, replace) when caring for patients in aerosol generating procedures. they should undergo medical clearance and fit testing. a qualitative fit test is a pass/fail test relying on individual sensory detection whereas a quantitative fit test is a numerical measure of the effectiveness. cohorting confirmed patients of covid-19 in one area to confine their care prevents patient contact and minimizes the use of respirators. just-in-time fit testing is the ability of a healthcare facility for larger scale evaluation, training and fit testing of hcp prior to receiving patients during a pandemic. an annual fit may be temporarily suspended during expected shortages. 9, 10, 11, 12, 13, 14, 15, 30, 31, 32, 33, 34 the set up should include clean or sterile accessible supplies and instruments for specific dental procedure only. instruments should be stored in covered storage (drawers and cabinets) to maintain decontamination. they should be supplied when needed and disposed when the dental procedure concludes. safety and quality assurance checks on radiographic equipment should be performed. aed should be tested as well. all the emergency drug kits should be checked for expiry. ensure that the rechargeable items are fully charged and operational. check the drinking water dispenser for staff use and recommission by manufacturer's instructions. the computer updates should be checked and installed. minimally invasive/atraumatic restorative techniques (hand instruments) should be prioritized, aerosol-generating procedures via dental handpiece and air/water syringe should be avoided and ultrasonic scalers discontinued. when aerosol-generating procedures are necessary use four-handed dentistry to droplet spatter and aerosols may be minimized via a high evacuation suction and dental dam. preprocedural mouth rinses (pmrs) with an antibacterial product (chlorhexidine gluconate, essential oils, povidone-iodine or cetylpyridinium chloride) may reduce the level of oral microorganisms in aerosols and spatter generated during dental procedures however (ppmr) do not have evidence regarding their clinical effectiveness to reduce sars-cov-2 viral loads or to prevent transmission. 9, 10, 11, 12, 13, 14, 15, 30, 31, 32, 33, 34 engineering controls: barriers (glass/plastic windows/curtains) in reception areas where patients report on arrival (intake desk, triage station, information booth, pharmacy and drop-off/pick-up windows are placed to reduce the risk of exposure between the potentially infectious patients and dhcp. aerosol-generating procedures for patients confirmed or suspected of covid-19 should take place in an airborne infection isolation room (aiir). air should be exhausted directly outside or filtered directly via a high-efficiency particulate air (hepa) filter before recirculating. the expedient patient isolation room method involves high-ventilation-rate, negative pressure, inner isolation zone within a "clean" larger ventilated zone by a portable fan device with high-efficiency particulate air (hepa) filtration. it increases effective air changes per hour of clean air to the room thereby reducing the risk to persons entering without respiratory protection. twelve air changes per hour are recommended for a renovation or new construction. the ventilated headboard is a special inlet system to provide an improved air intake for a corresponding high-efficiency particulate air (hepa) fan/filter unit ventilation system with proper engineering controls (filtration, exchange rate) should be installed and maintained to provide movement of airflow in a direction from a clean (dhcp workstation or area) to a contaminated area (sick patient/clinical patient) (appropriate filtration, exchange rate) should be installed and maintained. air supply in the receptionist area with return air louvers positioned in the waiting area achieves this effect. a heating, ventilation and air conditioning (hvac) professional can increase the filtration efficiency to the highest level without deviation from designed airflow as well as increase the percentage of outdoor air supply. demand controlled ventilation (temperature setpoint and/or occupancy controls) should be limited during occupied hours and up to 2 hours post occupancy to ensure that ventilation remains unchanged. bathroom exhaust fans should run continuously during work hours. a portable hepa air filtration unit may be considered during and following an aerosol procedure. these units reduce particle count (droplets) and turn over time in the room rather than just relying on the building hvac system capacity. a hepa unit should be placed within the vicinity (chair) of a patient but not behind dhcp and the dhcp should not be positioned between the unit and the patient's mouth. the position of a unit ensures that the air is not pulled into or past the breathing zone of the dhcp. an upper-room ultraviolet germicidal irradiation (uvgi) is used as an adjunct to higher ventilation and air cleaning rates. follow environmental cleaning and disinfection procedure with hospital-grade disinfectant 9, 10, 11, 12, 13, 31, 32, 33, 34, 35, 36 patient placement dental treatment should ideally be provided in an individual patient room when possible. in open floor plan dental facilities with open floor plans the spread of pathogens man be prevented by a distance of at least 6 feet between patient chair, easy-to-clean floor-to-ceiling barriers to enhance the effectiveness of a portable hepa air filtration systems without interfering with the fire sprinkler systems and physical barriers between chairs for patients. the dental operatory should be parallel to the direction of airflow where feasible. in vestibule-type office layouts consider patient orientation by placing the head near the return air vents, away from pedestrian corridors, and towards the rear wall. the maximum number of patients who can receive care at the same time in the dental facility safely is determined by the layout of the facility, number of rooms and the time needed to clean and disinfect the operatories. it is advised that dhcp should wait at least 15 minutes after the conclusion of dental treatment and exit of the patient to commence the room cleaning and disinfection process. this allows droplets to sufficiently fall from the air after a dental procedure. 3, 24 personal protective equipment: respiratory protection (ppe) standard precautions assume that each person is potentially infected or colonized with pathogens which may be transmitted in a healthcare setting. standard precautions entail a n95 (standard and surgical medical respirators) or facemask, eye protection (goggles, protective eye wear with solid waste shields, or a full face shield), and a gown or protective clothing during procedures which produce splash, spatter of blood or body fluid and known/suspected covid-19 patients. a respirator is a ppe device worn on the face, covering least the nose and mouth to reduce the risk of inhaling hazardous airborne particles (dust and infectious agents), gases, or vapors. respirators are certified by cdc/national institute for occupational safety and health (niosh). surgical respirators are indicated for respiratory protection in airborne pathogens (tuberculosis, measles, varicella) and fluid hazard (high-velocity splashes, sprays, splatters of blood or body fluid) hence preferred over a facemask. an effective face seal of a respirator requires qualitative or quantitative measurement. the highest level of surgical mask should be used. a faceshieid is worn over a standard n95 when a surgical n95 is unavailable. n95 masks need to be conserved during the crisis period. conventional capacity provides patient care sans any alteration in existing daily practices. contingency capacity practices may be used provisionally during expected periods of n95 respirator shortages without significant impact on patient care. 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23 alternatives to n95 masks include filtering facepiece respirators n99, n100, p95, p99, p100, r95, r99, and r100, elastomeric half-mask (replace filter cartridges) and full facepiece air purifying respirators, powered air purifying respirators (loose fitting hoods or helmets) reusable (paprs). all of these provide equivalent or higher protection than n95 respirators when worn properly. filtering facepieces with an exhalation valve are not used in a sterile surgical setting since the unfiltered exhaled air compromises a sterile field. n95 may be retained, reserved and used beyond the shelf life during shortage in the pandemic. they may be re-used by one hcp for multiple encounters with different patients but removed (doffing) after each encounter. the time in between re-use should not exceed the 72 hours expected survival time for sars-cov2. n95 contaminated with gross blood, respiratory or nasal secretions and/or other bodily fluids should be discarded. contamination may be reduced/ prevented by wearing a facemask over it. 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23 a facemask block respiratory secretions produced by the dhcp from contaminating other persons and surfaces (source control) when worn with instructions in symptomatic patients suspected of covid-19 or other respiratory infection (fever, cough) but not n95. dhcp should wear a facemask at all times while they are in the dental setting as a part of universal source control. they should be instructed to not touch or adjust their mask or cloth face cover and perform hand hygiene immediately before and after. cloth face covering should not substitute a respirator or facemask. dhcp whose job does not require ppe (clerical) may wear cloth face covering. dhcp (dentists, hygienists, assistants) may wear cloth face covering when not engaged in direct patient care and switch to a respirator or a surgical mask when ppe is required. dhcp when leaving the facility at the end of their shift should remove their respirator or surgical mask and wear cloth face covering. self-contamination is prevented by changing or laundering a cloth face covering saturated with respiratory secretions, soiled, dampened or posing difficulty for breathing. hand hygiene must be performed before and after touch/adjustment of face cloth or face mask.n95 and face mask should be used according to the type of activity. a dhcp at a distance greater than 6 feet from a symptomatic patient does not need a face mask or n95. facemask may be used in a dhcp within 6 feet of an asymptomatic patient for provision of direct patient care. in other countries respirators for occupational use are approved according to country-specific standards. manufacturers sans niosh approval should only include products approved by and received from china. if the remaining supply of n95 is absent consider hepa with facemasks. extended use of facemasks and respirators should is undertaken only when the facility is at contingency or crisis capacity and has implemented all likely applicable engineering and administrative controls. 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 37, 38 hand hygiene: hand hygiene is indicated after all patient contact, contact with infectious material and prior to wearing and removing ppe (gloves) to remove any possible pathogen transfer to bare hands. abhr with 60-95% alcohol or washing hands with soap and water for at least 20 seconds is advisable. for visibly soiled hands use soap and water before abhr. hand hygiene supplies should be available for the dhcp in every care location. 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23 use eye protection (goggles, disposable face shield) and remove them prior to leaving the operatory. reusable eye protection (goggles) must be cleaned and disinfected according to manufacturer's instructions. the disposable eye protection should be discarded after use. personal eyeglasses and contact lenses are inadequate. 24, 25, 26, 27 gloves: clean and non-sterile gloves should be worn upon entering the patient care area. they should be removed and discarded followed by immediate hand hygiene. if they are torn or heavily contaminated they should be changed. they should be educated about the signs and symptoms and diagnoses of skin reactions associated with glove use 24, 25, 26, 27 gown: a clean isolation gown is worn upon entry; changed if soiled and removed to be discarded in a waste or linen container before leaving. cloth gowns are laundered post use. gown shortage should be prioritized for aerosol generating procedures, splashes and sprays where high-contact patient care activities favor transfer of pathogens to the hands and clothing of dhcp. 24, 25, 26, 27 sequences recommended for donning and doffing ppe: j o u r n a l p r e -p r o o f before entering a patient care area perform hand hygiene and don a clean protective clothing or gown that covers skin and personal clothing likely to be soiled by potentially infectious material like blood, saliva, or other materials. if a gown and protective clothing become soiled they should be changed. a surgical mask or respirator is worn and the mask ties are secured on the crown of the head (top tie) and base of the neck (bottom tie). if loops are present hook the mask around ears. respirator straps should be placed on the crown of the head and base of the neck and checked for a user seal check each time. eye protection should not include personal eyeglasses and contact lenses. hand hygiene is followed by putting on clean non-sterile gloves. they should be changed when torn or heavily contaminated prior to entering the room. 24 after completion of dental care gloves are removed and the gown or protective clothes are discarded in a dedicated container for waste or linen. disposable gowns are discarded after each use and protective clothes are laundered after each use. exit the patient care area and perform hand hygiene, remove eye protection carefully by grabbing the strap and pulling upwards and away from head without touching the front of the eye protection. clean and disinfect reusable eye protection prior to reuse by the manufacturer's reprocessing instructions but discard disposable eye protection after use. remove and discard surgical mask or respirator without touching the front. for a surgical mask untie (or unhook from the ears) and pull it away from the face carefully without touching the front. for a respirator remove the bottom strap by touching the strap only and bring it over the head carefully. for the top strap; grasp it and bring it over the head to pull the respirator away from the face without touching the front. finally perform hand hygiene to follow standard precautions. 24 before arrival: appoint each group of patients one personnel from the dental clinic who can be reachable 24/7 in case of an emergency in order to asses and determine the need to be seen. when scheduling appointments (elective) provide instructions to the patient to call ahead of the visit and discuss the need to defer/reschedule their appointment if they experience fever or symptoms of covid-19 on the day of their appointment/visit. impart advice about their own cloth face covering, irrespective of their symptoms before entering the dental facility. schedule an appointment for possible covid-19 patients by triage to determine the need for appointment versus management at home. if the patient has to attend an appointment they must call beforehand to inform triage personnel about their symptoms of covid-19 as well as follow appropriate preventive actions throughout the visit to contain the respiratory secretions. if a face cloth is difficult to tolerate hold a tissue instead). if a patient is arriving via transport by emergency medical services (ems) allow the healthcare facility to prepare for receiving the patient. 24 upon arrival and during the visit: monitor and limit the points of entry to the dental facility as well as post visual alert posters, signs in appropriate language for instructions on respiratory hygiene, hand hygiene, cough etiquette, facemask or face cover. provide 60-95% alcohol-based hand rub, tissues and no-touch receptacles for disposal at the entrances, waiting rooms, check-in, elevators and cafeterias. minimize overlap in dental appointments and ask the patients and attending visitors to wear a face covering or mask prior to entry irrespective of symptoms of fever and covid-19. set up physical barriers (plastic or glass windows) to limit close contact between triage dhcp and potentially infectious patients. establish an outdoor triage station to screen individuals prior to entering the facility. the triage dhcp must wear a respirator/mask, eye protection and gloves for taking vitals and assessing patients for care until covid-19 is considered unlikely. 24 prioritize triage of suspected symptomatic covid-19 patients. dhcp should inquire about the presence of fever, symptoms of covid-19, or contact with patients with possible covid-19 from every patient at the time of patient check-in. covid-19 symptomatic patient should be isolated in an examination room with door closed and waiting space separated by 6 feet or more with easy access to respiratory hygiene supplies. they should not be allowed to wait among other patients. if they opt to wait in a personal vehicle or outside the facility they may be contacted by mobile phone when their turn arrives. in an afebrile patient (temperature < 100.4˚f) and otherwise without symptoms consistent with covid-19 may be provided dental care using appropriate engineering and administrative controls, work practices, and infection control considerations. the patient should be asked to wear a face cover at the completion of dental care prior to leaving the treatment area. all new fevers and symptoms consistent with covid-19 should be monitored. inadvertent treatment of a patient confirmed to have covid-19 later may occur even when dhcp screen patients for respiratory infections. the patient should be therefore be requested to inform the dental clinic if they become symptomatic or are diagnosed with covid-19 within 14 days following the dental appointment. in a patient with fever strongly associated with a dental diagnosis (pulpal and periapical dental pain and intraoral swelling) but no other symptoms consistent with covid-19; care can be provided with appropriate protocols. 24 additional strategies to minimize chances for exposure: this depends on factors like level of sars-cov-2 community transmission, number of covid-19 being cared for at a facility, healthcare-associated transmission and anticipated ppe or staffing shortages. the potential for patient harm if care is deferred needs to be determined. it is better to modify or cancel inperson group healthcare activities and implement virtual methods or schedule smaller in-person group sessions with a face cover and a distance of 6 feet apart. postpone all the dental elective procedures, surgeries and non-urgent outpatients. if a patient with a dental emergency is highly likely to cause harm by deferring treatment it is advisable to provide care without delay in facilities less heavily affected by covid-19; provide care without delay in your facility as opposed to transferring them or provide care without delay while resuming regular care practices. 24, 25, 26 facility considerations: dental equipment considerations: the manufacturer's instructions should be reviewed for instructions for use (ifu) on dental equipment for office closure, period of non-use and reopening for all equipment and devices. it may require maintenance and/or repair after a non-use period. test the quality of water for duwl prior to dental care to ensure that the standards for safe drinking water are met (< 500 cfu/ml). assess the need to shock duwl of any devices and products that deliver water used for dental procedures. the standard maintenance and monitoring of duwl should be continued according to the ifus of the dental operatory unit and the duwl treatment products. in the presence of dampness or mold (musky smell), determine the source of water entry, clean it up and remediate. indoor temperature and humidity must be maintained within recommended ranges. 30, 31, 32, 33 the autoclaves and instrument cleaning equipment should be cleaned routinely and maintained in accordance with the manufacturer's schedule. sterilizers should be checked with a biological indicator and matching control after a period of non-use prior to reopening. maintenance air compressor, vacuum and suction lines, radiography equipment, high-tech equipment, amalgam separators and other dental equipment according to manufacturer's instructions. 30, 31, 32, 33, 34 semicritical items in contact with mucous membranes or non-intact skin have a lower risk of transmission. they are heat-tolerant hence sterilized by using heat. a semicritical heat-sensitive item is processed with high-level disinfection. noncritical care items have the least risk of transmission via intact skin hence cleaned only but if an article is visibly soiled it is cleaned following disinfection with an epa-registered hospital disinfectant. in case of visible contaminated with blood or opim use epa-registered tubercocidal hospital disinfectant. blood spill can be managed by an epa-registered hospital disinfectant effective against hbv and hiv, epa-registered hospital disinfectant with a tuberculocidal claim (intermediate-level disinfectant) or an epa-registered sodium hypochlorite product. the central processing area should be divided into sections for receiving, cleaning, and decontamination; preparation and packaging; sterilization and storage. 34 the handpeice should be run to run to discharge water, air, or a combination for a minimum of 20-30 seconds after each patient to physically flush out material that may enter the turbine and air and waterlines heat methods can sterilize dental hand pieces and other intraoral devices attached to air or waterlines. manufacturer instructions should be followed for cleaning, lubrication, and sterilization should be followed to ensure their effectiveness and longevity of hand pieces. handles or dental unit attachments of saliva ejectors, high-speed air evacuators, and air/water syringes should be covered with impervious barriers which are refreshed after each use. visible contamination requires cleaning with an intermediate disinfectant prior to replacing the barriers. 30, 31, 32, 33, 34 radiograph cross-contaminate equipment and environmental surfaces with blood or saliva hence use an aseptic technique, wear gloves when taking radiographs and handling contaminated film packets, wear additional ppe (mask, eyewear, gown) for blood or other body fluid spatter. heat-tolerant intraoral radiograph accessories may be heat sterilized for semicritical items like film-holding and positioning devices before patient use digital radiography sensors and other high-technology instruments (intraoral camera, electronic periodontal probe, occlusal analyzers, lasers) are semicritical devices which may be cleaned, heat-sterilized or high level disinfected. 30, 31, 32, 33, 34 reprocess heat-sensitive critical and semi-critical instruments by using sterilant/high-level disinfectants or low temperature sterilization method (ethylene oxide). single-use devices are usually heat-intolerant cannot be reliably cleaned. syringe needles, prophylaxis cups and brushes, and plastic orthodontic brackets, prophylaxis angles, saliva ejectors, high-volume evacuator tips and air/water syringe tips, cotton rolls, gauze, irrigating syringes should be disposed after each use. endodontic burs, files, broaches, diamond and carbide burs should be considered single use. laboratory items (burs, polishing points, rag wheels, laboratory knives) should be heat-sterilized, disinfected or discarded. heat-tolerant items used in the mouth (metal impression tray, face bow fork) should be heat-sterilized. articulators, case pans and lathe should be cleaned and disinfected. semicritical instruments needed for immediate use or use within a short time may be sterilized unwrapped on a tray or a container system. critical instruments for immediate reuse can be sterilized unwrapped if the instruments are transported in a sterile covered container during removal from the sterilizer and transport to the point of use however critical items should not be stored unwrapped. 30, 31, 32, 33, 34 personnel subject to occupational exposure should receive training for infection-control in combination with standard precautions, engineering, work practice, and administrative controls to reduce occupational exposures to blood to prevent transmission of hbv, hcv, and hiv. dhcp are at a significant risk for acquiring or transmitting hepatitis b, influenza, measles, mumps, rubella and varicella which are vaccine-preventable. they should be vaccinated for hepatitis b vaccine however routine immunization for tb is not recommended. the vaccine for hepatitis c vaccine is still unavailable and the risk of hiv transmission in dental settings is extremely low. hbsag-positive persons should be counseled about hbv transmission prevention and for medical evaluation. 39 environmental infection control: environmental cleaning and disinfection procedures should be followed correctly and consistently. water should be run through pipes and taps in surgeries, kitchen, bathrooms and showers. a liquid chemical sterilant/high-level disinfectant should not be used as a holding solution or an environmental surface disinfectant. after working on a patient without suspected or confirmed covid-19; wait 15 minutes after completion of clinical care and exit of each patient to begin to clean and disinfect room surfaces of the dental operatory. this allows droplets to fall from the air after a dental procedure to perform sufficient disinfection. entrance in the operatory is delayed until time elapsed allows air changes to remove potentially infectious particles. cleaning and disinfection procedures include cleaning of frequently touched surfaces or objects and aerosol generating areas with cleaners and water followed by application of environmental protection agency-registered, hospital-grade disinfectant based on contact times shown on the product's label. alternative methods for disinfection which can be instituted include ultrasonic waves, high intensity uv radiation, and led blue light however their efficacy against covid-19 virus is unknown. sanitizing tunnels are not recommended for use by cdc. 39, 40, 41, 42, 43 the purpose of laundry is to protect the worker from exposure to potentially infectious materials throughout the stages of collecting, management and arranging of contaminated materials via ppe, work practice, containing, labels, ergonomics and hazard communication. hot water washing is recommended at 160°f (71°c) at least for a minimum of 25 minutes. chlorine residual of 50-150 ppm is attained during the bleach cycle and chlorine bleach is activated at 135°f-145°f (57.2°c-62.7°c) water temperature. rinse cycles add a mild acid (sour) to neutralize the alkalinity in water soap, or detergent. dry cleaning is an alternative cleaning process utilizing organic solvents (perchloroethylene) for removal of soil from fabrics that may have been damaged in conventional laundering. waste should be handled with ppe and wastewater treatment facilities include oxidation with hypochlorite (chlorine bleach) and peracetic acid and inactivation via uv irradiation. puncture-and chemical-resistant/heavy duty utility gloves should be worn for instrument cleaning and decontamination procedures. ppe should be worn during cleaning when splashing or spraying is anticipated. food service utensils should be managed in accordance with the infection control policy. 39, 40, 41, 42, 43 extracted teeth are potentially infectious hence disposed in medical waste bins. extracted teeth sent to a dental laboratory for shade or size comparisons should be cleaned, surface-disinfected with an eparegistered hospital disinfectant with intermediate-level activity (tuberculocidal). extracted teeth containing dental amalgam should not be placed in a medical waste container that uses incineration for final disposal since they may be given to recycling company. they may be returned to the patient on request hence standard maintenance does not apply. dental prostheses, appliances, and items used in fabrication (impressions, occlusal rims, bite registrations) must be managed by optimum communication and coordination between the laboratory and dental practice with appropriate cleaning and disinfection with an epa-registered hospital tuberculocidal disinfectant. parenteral medication should be administered with an aseptic technique. a single syringe should not be used for multiple patients even if the needle has been changed perform surgical hand antisepsis by an antimicrobial soap and water, or soap and water followed by alcohol-based hand scrub prior to wearing sterile surgeon's gloves. 39, 40, 41, 42, 43 risk assessment and work restrictions for dhcp with potential exposure to covid-19: the close contact with vulnerable individuals in dental settings requires a conservative approach to monitoring and applying work restrictions to prevent transmission from potentially contagious dhcp to patients, other hcp/dhcp and visitors. the contact tracing of exposed dhcp and application of work restrictions depends upon the degree of sars-cov-2 community transmission (minimal-no, moderate) and their resources. high-risk exposures involve exposure of dhcp eyes, nose, or mouth to material potentially containing sars-cov-2 particularly from aerosol-generating procedure (prolonged exposure for 15 minutes or more). exposure not included as higher risk include body contact with the patient without ppe and hand hygiene and touching the eye, nose, or mouth with the same hands. exposures can occur from a suspected case of covid-19 or from a person under investigation (pui). a record should be maintained for a dhcp exposed to puis. if the test results are delayed over 72 hours or the patient is covid-19 positive then the work restrictions apply. a dhcp with prolonged close contact with a patient, visitor, or dhcp with confirmed covid-19 should be excluded from work for 14 days after last exposure, self-monitored for fever or symptoms consistent with covid-19 and contact their medical evaluation and testing facility if fever or symptoms consistent with covid-19 develop. 44 dhcp with risk exposures other than high exposure risk do not require work restrictions. they should follow infection prevention and control practices by wearing a facemask at work, self-monitoring for fever or symptoms consistent with covid-19, not reporting to work when ill and undergoing screening for fever or symptoms consistent with covid-196 when their shift commences. a dhcp who develops fever or symptoms consistent with covid-196 should immediately self-isolate and contact a medical evaluation and testing facility. dhcp with travel or community exposures should inform their health facility for guidance on need for work restrictions. for covid-19 confirmed symptomatic individuals consider the exposure window to be 2 days before symptom onset through the time period. for covid-19 confirmed asymptomatic individuals determining the infectious period can be challenging. they must be considered potentially infectious commencing 2 days post exposure until they fulfill the criteria for discontinuation of transmission-based precautions. if the date of exposure is undetermined, use a starting point of 2 days prior to the positive test through the time period when the individual fulfills the criteria for discontinuation of transmission-based precautions. when reopening a practice post covid-19 shutdown follow the dental practice reopening guidelines. 44 dental caries risk assessment: it is based on patient specific risk indicators including prior caries experience and longitudinal evaluation of caries progression. longitudinal evaluation at each visit considers cavitation of white spot lesion and increased dimension. progression in the existing white spot lesion is considered an increased risk status. other caries risk factors include a high frequency of fermentable carbohydrate, maternal caries and socioeconomic status of the family. surgical management of the enamel carious lesions is based on visual detection, shadowing under the enamel and radiographic enlargement of lesion. active surveillance of caries monitors initial carious lesion progression instead of definitive treatment. active surveillance strategies include preventive therapy with compliance and recall. 45 children are considered at a low caries risk if they have no caries, no new lesion in 1 year, no white spot lesions and belong to a high socioeconomic status. they receive a clinical examination at twelve months and a diagnostic radiograph at twenty four months. preventive therapy includes tooth brushing twice a day with a fluoride toothpaste twice a day and fissure sealants. restorative therapy is not indicated. 45 children considered at a medium risk of caries have or have had one or more lesions per year and belong to a middle socioeconomic status. they require a diagnostic examination at twelve months and a radiographic assessment between twelve to fourteen months. preventive regimen includes tooth brushing with fluoride toothpaste, a six monthly application of topical fluoride and provision of fissure sealants. restorative therapy entails active surveillance of carious white spot lesions and proximal enamel lesions. progressive and cavitated carious lesions maybe managed by restorative therapy or by an aerosol free topical application of silver diamine fluoride. 45 children are considered to be at a high risk if they have or have had one or more proximal lesion, have more than two lesions per year, have white spot lesions or enamel defects, active caries in a mother or caregiver, wear appliances, have a high sugar consumption and belong to low socioecenonmic status. they require a clinical examination at an interval of three months, a radiograph at an interval of six months and dietary analysis. preventive care includes tooth brushing with a fluoride toothpaste twice a day, systemic fluoride supplements, professional topical fluoride application every 3 months, fissure sealants and brushing with a high potency fluoride gel in a child over 6 years of age. restorative care includes surveillance of white spot lesions, restoration of proximal caries and restoration of progressing and cavitated lesions or treatment with topical application of silver diamine fluoride. 45 early childhood caries (ecc): early childhood caries (ecc) is defined as one or more decayed (non-cavitated or cavitated lesions), missing (due to caries) or filled tooth surfaces in any primary tooth in a child under 6years. severe early childhood caries (secc) is defined as any sign of smooth-surface caries in a child < 3 years of age, and from ages 3 through 5, one or more cavitated, missing (due to caries), or filled smooth surfaces in primary maxillary anterior teeth or a decayed, missing, or filled score of greater than or equal to four (age 3), < than or = to five (age 4), or < than or = to six (age 5). 46 caries disease process initiates as early as the first year in the life of a child. this highly prevalent global chronic disease is cost intensive and impacts the quality of life of a child and their parents. cries management is child specific management of caries process via primary, secondary and tertiary prevention. ecc reduction approaches focus on inter-professional care to ensure access to oral health for infants/toddlers and raise awareness regarding the adverse sugar consumption effects. 47 primary prevention encompasses prenatal health care, avoidance of night time bottle feed with sugary drinks or milk, restricting sugar intake and frequency for children younger than 24 months, avoiding frequent/nocturnal breast or bottle feeding after 1 year, exposure to dietary fluoridate (water, milk, salt), use of an age appropriate amount of fluoride toothpaste containing at least 1000ppm fluoride for brushing at least twice a day, dental visit in the first year of life and regular applications of 5% fluoride. secondary prevention comprises of more frequent fluoride application with fissure sealing for arresting caries progression prior to cavity formation. tertiary prevention combines non-invasive and invasive management for cavitated lesions. topical application of silver diamine fluoride arrest and prevent noncavitated and progressive cavitated dentinal lesions in an aerosol free environment. 47 fluoride: fluoride is the cornerstone of caries prevention. it functions by arresting or inactivating carious lesions as a therapeutic agent in nrct (non-restorative caries treatment). addition of optimum fluoride level to community water supply (0.5 to 1.1 mg/l) helps reduce the caries prevalence safely and effectively. hence this stable public health practice benefits all the residents irrespective of their level of education, oral hygiene practices, socioeconomic background, employment status or access to oral health care. 48 brushing the teeth twice a day with a fluoridated toothpaste containing 1000ppm f at least and with an age appropriate amount on a tooth brush reduces caries effectively. the recommended use of fluoride toothpaste in a child upto first two years is 1000ppm f, twice a day with a grain sized amount of 0.125g. for a child between two to six years of age the recommended use of fluoride toothpaste is 1000ppm f, twice a day with a pea sized amount of 0.25g. in a child over six years of age the recommended use of fluoride toothpaste is 1450 ppmf, upto full length of brush amount of 0.5-1.0g. hence this is a convenient, widespread, inexpensive and culturally approved approach to caries prevention in a safe and effective manner. the amount of toothpaste used is important since children tend to swallow the toothpaste which poses a risk for fluorosis. the recommended use of fluoride toothpaste based on standard prevention in children less than 3 years is 1000 -1500ppm f. enhanced prevention for children over 3years includes 1350-1500 ppm f and for children over ten years includes 2800ppm f. 48 professional topical fluoride varnish application containing 5% f (22,600ppmf) or gel containing 1.23% f (12,300ppmf) may reduce caries in children. in a child over 6 years of age and at a high risk of caries 0.5% fluoride gels and pastes are recommended. fluoride supplements consisting of tablets/lozenges and drops may be considered in fluoridated water deficient area. their intake should not exceed 0.07mg/kg body weight daily and should be used with care to prevent oral topical effects. non-cavitated and cavitated dentinal lesions can be arrested or prevented successfully by the use of aerosol free sdf 38% silver diamine fluoride containing 5% fluoride (44,800ppmf). 48 minimally invasive dentistry: the current paradigm shift focuses on minimally invasive management strategies which arrest caries by assessing the caries risk, early detection of caries, implementing prevention measures, promoting enamel and dentine remineralization, instituting minimally invasive surgical interventions and repairing restorations conservatively as opposed to replacement. these techniques work well in conjunction with fluoride exposure and good oral hygiene for both non-cavitated and cavitated lesions. they allow the reversal of demineralized lesions (non cavitated) thereby arresting naturally. proximal non-cavitated lesions may be managed by a micro invasive infiltration method. cavitated lesions can be arrested by topical application of aerosol free 38% sdf (silver diamine fluoride). surgical intervention advocates a minimal cavity design, conservative caries removal from deep lesion and adhesive restorative material. 49 erosion: it is an irreversible tooth structure loss arising by chemical dissolution via intrinsic sources (gastric acid) or extrinsic sources (diet) but not bacterial acid. the thin and less mineralized enamel of primary dentition renders it more susceptible to erosion. bulimia erodes the lingual surface of upper incisors whereas gastrooesophageal reflux erodes the molars. dietary acid can erode any surface but it is avoidable by cutting down acidic food and beverage exposure. diagnosis necessitates the need for discerning the etiology if the diagnosis is by location and level of erosion. management includes regular monitoring and the use of a fluoride containing toothpaste or mouthwash containing stannous fluoride, addressing the etiology addressed and delaying the restorative intervention for monitoring. minimally invasive techniques may be applied for restoration of teeth which hurt. a medical referral is indicated for patients with dental erosion due to gerd and bulimia. 50 periodontal disease: periodontal assessment for primary teeth includes clinical and radiographic evaluation of the gingiva, periodontium, alveolar bone levels and tooth mobility. permanent dentition should be assessed subsequent to complete eruption. triaging helps evaluate conditions which may have four combinations. they may have healthy gingiva with healthy bone, healthy gingiva with diseased bone (eg hypophosphatasia), diseased gingiva with healthy bone (eg herpetic gingivostomatitis) and diseased gingiva with diseases bone (neutrophil defects). 51 generalized gingivitis continuing over 2 weeks is viral in origin due to an underlying systematic cause. they require periodontal culturing to rule out anaerobic bacteria triggering an aggressive immune j o u r n a l p r e -p r o o f response (papillon-lefevre syndrome or neutorpenias). a medical referral with regular follow up assists in ruling out chronic idiopathic neutropenia, cyclical neutropenia and leukemia. hypophosphatasia may be considered in a non-traumatic premature primary incisor loss before 4 years of age with a concomitant diagnosis of cementum pathology. langerhan's cell histiocytosis may be deliberated in premature eruption of primary molars in the neonatal period. diagnosis is confirmed upon presence of birbeck granule in specimen for gingival biopsy from the molar region. 51 effectiveness and compliance of medication for enhancing immune response in patients with systemic disease (gcf in cyclical neutropenia or insulin treatment in insulin-dependent diabetes) is ascertained by regular monitoring of gingival and periodontal health. stem cell transplant may be carried out to improve immunity for improved periodontal health in children in chronic granulomatous disease and leukocuyte adhesion deficiency disorder however it is very rare. 51 mih is a qualitative, enamel developmental defect which involves one or more posterior teeth with or without permanent anterior. they present as a demarcation, creamy/white to yellow to brown patches with or without post eruptive breakdown and sensitivity. it may range from mild to severe and impair tooth brushing. primary molars with hypomineralization predispose the permanent dentition to a higher risk of mih. early diagnosis concomitant with prevention and restorative care prevents subsequent progressive breakdown, hypersensitivity and pulpal inflammation. 51 the adhesive restorations should include sound enamel since bonding for sealants and composites is compromised. atypical amalgam restorations needing more retentive features may aggravate the tooth defect and result in a high failure. gic temporization despite a high failure rate can be utilized. aesthetics in mild incisors may be conservatively managed by combining etching, bleaching and sealing. severe cases may be managed by microabrasion or composite veneers and a full coronal coverage for the molars. restorations have a poor long term outcome in this dental anomaly. if one or more teeth are affected with severe mih and pain consider extracting the first permanent molars prior to the eruption of second permanent molars (8-9 y). the occlusion will determine the need for an orthodontic alignment. recall will prevent failure of restorations, recurrent caries and post eruptive breakdown. sensitivity may be managed by topical fluoride varnish application and arginine desensitization paste however hypersensitivity may require local anaesthesia for restorative management. 52 developing dentition: malocclusion in the developing dentition needs recognition, risk factor identification (environmental, etiologic, premature primary tooth loss), diagnosis and optimum treatment. this contributes to a stable, functional and aesthetic occlusion in the permanent dentition. the developing dentition is evaluated clinically (palpation), by radiographs and functional analysis for habits, airway, tooth size and shape, anomalies, anterior and posterior crossbite, skeletal discrepancy, periodontal health for achieving a diagnosis. breast feeding reduces non-nutritive habits which may otherwise require management appropriate for the child's development, comprehension, malocclusion and the ability to cope with treatment. space maintainers prevent space loss due to premature primary tooth loss. minor interceptive orthodontics can manage aesthetics in an increased overjet which predisposes the incisors to an increased risk of trauma. 53 special care dentistry: in special care dentistry basic advice and dental intervention have a high impact on pain management and clinical outcomes. during the pandemic triaging, ranking, conceding and making challenging choices have become a daily actuality. telecommunication can enhance communication and provide psychological counseling and advice for special needs patients however phobia, learning disabilities and attention deficit hyperactivity disorder (adhd) do not tolerate any form of local anaesthesia require sedation and general anaesthesia which is currently suspended. they can benefit from alternative techniques (gradual exposure, behavioral management, hypnotherapy, professional cognitive behavioral therapy (cbt), desensitization methods, virtual goggles for distraction) in a more adjustable dental service. there is a need to balance and weight the clinical decisions and review service capacity and patient's safety regularly. 54 dental emergency treatment: commonly presenting acute oral conditions/problems need a modified and consistent management approach. management of dental emergencies focuses on triage, relief from pain (analgesia) or infection (antimicrobial) and provision of care via remote consultation (videocall or telephone). referral is indicated in unmanageable severe or uncontrolled symptoms with adequate documentation. 55, 56 dental triage of usually presenting dental conditions categorizes patients into three types. the first type requires advice and self-help. they have mild -moderate symptoms which can be managed remotely by analgesics and antimicrobials. the second type requires urgent care. they have severe or uncontrolled symptoms which are unmanageable by a patient and require the patient to see a dentist in a designated urgent dental care center. the third type is emergency care for emergency conditions which require immediate attention. 55 acute apical abscess includes pain (localized to a single tooth); swelling of the gingiva, face or neck; fever, listlessness, lethargy and loss of appetite in children under 16 years of age. management by selfhelp includes analgesics and antibiotics (swelling/systemic infection) with a recall after 48-72 hours. urgent care by extraction or drainage is needed for spreading infection without airway compromise or continuing or recurrent symptoms. emergency care is indicated for spreading infection with an airway compromise or trismus. 55 acute periodontal abscess/perio-endo lesions include pain and tenderness of gingival tissue, increased tooth mobility, fever and swollen/enlarged regional lymph nodes, presence of swelling on gingiva and gingival suppuration. management by self-help includes analgesics and antibiotics (swelling/systemic infection) with a recall after 48-72 hours. urgent care is for spreading infection without airway compromise or continuing or recurrent symptoms. emergency care is indicated for spreading infection with an airway compromise or trismus. 55 acute pericoronitis includes pain around a partially erupted tooth, swelling of gingiva around the erupting tooth, discomfort on swallowing, limited mouth opening, halitosis (unpleasant mouth odour), fever, nausea and fatigue. advice and self help include analgesia, chlorhexidine mouthwash/gel or warm salt water mouthwash, gentle toothbrushing of the affected area with a small head toothbrush in combination with benzdyamine mouthwash, antibiotics (swelling/systemic infection) and recall after 48-72 hours. urgent care by extraction is for spreading infection without airway compromise or continuing or recurrent symptoms. emergency care is indicated for spreading infection with an airway compromise and/or severe trismus. 55 necrotizing ulcerative gingivitis/periodontitis include pain (localized/generalized), swelling, gingival bleeding, halitosis, gingival ulceration, fever and malaise. advice and self help include optimal analgesia, chlorhexidine or hydrogen peroxide mouthwash/gel, gentle toothbrushing of the affected area with a small head toothbrush in combination with benzdyamine mouthwash or spray and metronidazole as the antibiotic drug of choice. 55 reversible pulpitis includes intermittent or stimuli associated toothache with tenderness to percussion. advice and self help care recommend analgesia, repair of a missing filling with an emergency temporary repair kit from a pharmacy or online, avoidance of hot or cold food and to call back if the sypmtoms worsen. 55 irreversible pulpitis includes sharp and spontaneous pain which lasts for several hours and keeps the patient awake and pain which is difficult to localize to a single tooth, it may be dull or throbbing and worsened by heat and alleviated by cold. advice and self help recommend analgesia, cold water rinses and to call back if symptoms worsen. urgent care is needed when the severe and uncomfortable pain prevents sleeping or eating. management includes extraction at an urgent dental care centre. 55 dentine hypersensitivity includes sharp, sudden or short duration pain and exposed root surface secondary to gingival recession. advice and self help recommend application of desensitizing toothpaste to the affected area and avoidance of stimulus which include cold or acidic food and drinks. 55 dry socket includes pain which arises 24-48 hours after extraction in the vicinity of site of extraction. the socket is tender with an unpleasant taste or odour and occasional swelling. advice and self help include analgesis, warm salt water mouthwash and antibiotics in infection (spreading or systemic) or a patient who is immunocompromised. urgent care is required for dressing if the pain is severe, uncontrollable and prevents sleeping or eating. 55 post extraction haemorrhage entails bleeding which may be immediate, within a few hours secondary to inadequate initial hemostasis or within a few weeks due to possible infection. advice and self help include no spitting or rinsing, gentle rinses with warm but not hot salt water mouthwash to remove the excess blood, placing a rolled up piece of cotton or gauze moistened with saline or water on the socket and firmly biting on it to maintain a solid and continuous pressure for 20 minutrs prior to checking for bleeding. the patient is advised to avoid smoking, exercising, drinking alcohol or disturbing the clot after the bleeding has stopped. urgent care is required when the bleeding stops but is not brisk and persistent. emergency care is recommended when the bleeding fails to stop, is brisk and persistent. the patient should be asked about anticoagulant medication (warfarin, clopidogrel, aspirin). 55 oral ulceration include pain (lip and/or oral cavity), ulceration, inflammation, abnormal appearance and dehydration or listlessness or agitation if severe. advice and self help for ulcers less than three weeks include chlorhexidine mouthwash under 7y, analgesia or topical benzdyamine oromucosal spray, soft diet, keeping the dentures clean or use a repair kit for trauma from an adjacent tooth. if the ulcers are due to primary herpetic gingivostomatitis, herpes zoster infection or in an immunocompromised patient consider antiviral agents (acyclovir or penciclovir) in the early stages. urgent care is advised for ulcers persisting over three weeks. if the ulcers are due to an underlying medical condition then a medical practitioner should be consulted. emergency care is for oral ulceration with severe dehydration. 55 cracked, fractured, loose or displaced tooth fragments lead to pain (generalized or localized), tenderness to bite, sensitivity to hot cold and sweet food, open cavity, missing section of a tooth or filling, sharp edge on the tooth, mobile tooth or fragment, mobility or loss of restoration, soft tissue trauma (tongue, lip, cheek ), gingival inflammation or recurrent caries. emergency care is indicated for inhalation of a piece of tooth, filling or restoration. advice and self help for broken or fractured teeth and filling includes emergency temporart repair kit for sensitive teeth, analgesia and call back if pain persists. prosthesis (crown, bridge or veneer) may be repaired by an emergency repair kit with analgesics for pain relief. 55 ill fitting or loose dentures result in pain (general, localized), difficulty in speech and mastication. advice and self help include analgesia, removal of denture and routine dental care when the services have resumed. 55 trauma from a fractured or displaced orthodontic appliance causes pain and soft tissue injury. emergency care is required if the airway is compromised or the patient inhales or ingests pieces of a fractured appliance such as brackets. however brackets pass the bowel without incident. for advice and help the patient maybe referred to the orthodontic guidelines (british orthodontic society). 55 avulsed, displaced or fractured teeth encompass a fracture of tooth or loss of structure, increased tooth mobility or several teeth mobile as a unit, displacement or elongation or an empty socket. urgent care if a permanent tooth has been avulsed (knocked out) includes handling the tooth with care by the crown (white part) and avoid touching the root, washing the tooth briefly for ten seconds under cold running water if dirty, re-implant it in the socket and bite on it with a handkerchief gently to hold it in position. if it is not possible to re-implant the tooth, it may be transported in milk (not water) or in the mouth between molars and inside of the cheek. a permanent tooth which has moved out of its usual position to affect the bite should be referred to an urgent care center. a permanent tooth fracture involving pulp should also be referred to an urgent dental care center. a permanent tooth fracture of the enamel and dentine requires advice and self help for applying a desensitizing toothpaste, analgesia and soft diet. a primary tooth which has moved out of its position and interferes with the bite requires urgent care. if a primary tooth has displaced without affecting the bite advice and self help should include information about soft diet and analgesia. a primary tooth which has been avulsed (knocked out) requires advice and self help for analgesia and soft diet however it should not be re-implanted. 55 dento-alveolar injuries include pain, bleeding, swelling, teeth/dentures which do not meet together, mobility, praesthesia, other problems related specifically to bone fractures (nose bleed, diplopia, visual loss). emergency management is necessitated for severe bleeding which does not stop within 15-30 minutes, significant facial trauma, head injury or loss of consciousness and inhalation of a tooth or a tooth fragment. advice and self help for cases which do not have an emergency includes cleaning the affected area by gentle rinsing with a mild antiseptic, removing foreign objects from the mouth, applying ice pack to the soft tissue injury and swelling, applying pressure with a finger to stop bleeding and analgesia. antibiotics are not indicated for non-emergency situations. 55 hence successful outcomes depend on an optimum advice and timely emergency dental care. moderate dental pain can be managed in adults by paracetamol, 2 x 500mg tablets upto four times daily (4-6 hourly for 5 days or with ibuprofen, 2 x 200mg tablets upto four times a day (4-6 hourly) first after food. severe dental pain can be managed by increasing the dose of ibuprofen to 3 x 200mg tablets upto four times a day right after food or combining ibuprofen with paracetamol after food without exceeding the daily dose/frequency or by diclofenac, 1 x 50mg tablet upto three times a day in combination with paracetamol. maximum dose of drug in twenty four hours is 4 g paracetamol, 2.4 g ibuprofen and 150 mg diclofenac. contraindications for diclofenac and a high dose of ibuprofen (more than 1.6 g daily) include moderate or severe asthma, renal impairment or hypersensitivity to aspirin. the regimen for adult patient requiring a proton pump inhibitor include iansoprazole, 1 x 15 mg capsule daily for 5 days or omerprazole, 1 x 20mg capsule daily for 5 days. 56 analgesic doses for children: dental pain is managed in children by paracetamol suspension (120 mg/5 ml or 250 mg/5 ml) or tablet (500 mg). the age dependent dose can be given upto four times a day. the dose recommended for 6-12 month old is 120mg, 2-3 years is 180mg, 4-5 years is 240 mg, 6-7 years is 240-250 mg, 8-9 years is 360-375 mg, 10 -11 years is 480-500 mg, 12-15 years in 480 -750 mg and 16-17 years is 500mg -1g. the alternative drug is ibuprofen sugar free suspension (100 mg/5 ml) or tablet (200 mg). this age dependent drug is given upto three times a day. the recommended dose for 1-3 years is 100 mg, 4-6 years is 150 mg, 7-9 years is 200 mg and 10 -11 years is 300 mg. the doses for 6-11 months is 50 mg and x 400 mg tablet, three times a day. the dose of amoxicillin or phenoxymethylpenicillin may be doubled in severe infections (extra oral swelling, eye closing or trismus). 56 antimicrobials for children: dental infections in children can be managed by amoxicillin, phenoxymethylpenicillin or metronidazole. amoxicillin is administered as a sugar free oral suspension (125 mg/5 ml or 250 mg/5 ml) or capsule (250 mg). the age dependent dose can be given three times a day. the dose for 6-11 months is 125 mg, 1-4 years is 250 mg, 5-11 years is 500 mg and 12-17 years is 500 mg. the dose of amoxicillin for severe dental infections in children from 6 months to 11 years the may be increased upto 30 mg/kg (max 1g) for 3 times a day. for severe infection in children between 12-17 years the dose of amoxicillin maybe doubled. phenoxymethylpenicillin is available as a sugar free oral solution (125 mg/5 ml or 250mg/5 ml) or tablets (250 mg). the age dependent dose can be given upto 4 times a day. the dose for 6-11 months is 62.5 mg, 1-5 years is 125 mg, 6 -11 years is 250mg and 12 -17 years is 500 mg. for severe infections in children upto 11 years the dose of phenoxymethylpenicillin can be increased upto 12.5 gm/kg for four times a day. for severe infections in children aged 12-17 years the dose maybe increased upto 1g for four times a day. metronidazole is available as an oral suspension (200 mg/5 ml) or a tablet (200 mg). the dose dependent medicine can be administered upto three times a day unless indicated otherwise. the dose for 1-2 years is 50 mg, 7-9 years is 100mg and 10-17 years is 200 mg. the dose for 3-6 years is 100mg given twice a day as opposed to thrice a day. 56 first line of antimicrobials for dental infections: acute apical abscess, acute periodontal abscess/perioendo lesions are managed by a 5 day course of amoxicillin, phenoxymethyl penicillin or metronidazole whereas acute pericoronitis, necrotizing ulcerative gingivitis/ periodontitis can be managed by a 3 day course of metronidazole or amoxicillin. 56 it is necessary to check the patient's current use of analgesics before advising or prescribing analgesics. paracetamol in many over the counter preparations should be identified in all medications which have been ingested. an overdose is dangerous because it may cause fatal hepatic damage that is sometimes not apparent for 4-6 days. refer a patient for an emergency assessment if they ingest a therapeutic excess of more than the recommended daily dose [8 x 500 mg tablets for adults] and more than or equal to 75 mg/kg in any 24-hour period. paracetamol is the analgesic of choice for women who are breastfeeding. for a pre-term, or low birthweight infant seek advice from a gp. absorption, distribution, metabolism, or excretion of paracetamol may be affected by an underlying medical condition. paracetamol is a suitable analgesic option in most people with liver disease but dose reduction might be required for some patients with moderate or severe acute hepatitis. for people taking anticoagulants paracetamol is considered safer than aspirin or nsaids because it does not affect platelets or cause gastric bleeding. patients should have their usual inr check planned and inform their clinician if they have been using paracetamol regularly. use paracetamol and ibuprofen with caution in children (asthma). a gp should be contacted when uncertain about a patient's medical condition, current medication or suitable analgesia. 56 use nsaids with caution and if absolutely necessary use the lowest effective dose for the shortest time possible. patients already taking an nsaid (prescribed or not) regularly for a non-dental condition should not take an additional nsaid to control dental pain. ibuprofen should be prescribed with caution for patients taking low dose aspirin since the administration of additional nsaid may reduce the cardioprotective benefit of low dose aspirin and increases the risk of gi bleeds. in patients taking low dose aspirin, if an nsaid is necessary to control the pain, consider ibuprofen up to 1200 mg maximum daily with a ppi or contact the gmp for advice. elderly patients at increased risk of cardiovascular, renal, and serious adverse effects including gi bleeding and perforation, which may be fatal should be prescribed ibuprofen with caution not exceeding 1200 mg ibuprofen per day with a ppi. diclofenac is contraindicated. monitoring blood pressure, renal function, and features of heart failure may be required 1-2 weeks after starting or increasing the dose of an nsaid. avoid nsaid's in people with dehydration, due to risk of acute kidney injury. chronic alcoholism and alcohol dependence increases the gi risk is increased with nsaids hence avoid nsaids if possible or prescribe with a ppi. prescribe ibuprofen with caution to people with cerebrovascular disease, ischaemic heart disease, peripheral arterial disease, or risk factors for cardiovascular events like hypertension, hyperlipidaemia, diabetes mellitus and smoking. prescribe it with caution in cardiac impairment or mild to moderate heart failure (nsaids may impair renal function) but not in severe heart failure. prescribe up to 1200 mg per day as a first-line option (lower dose than the 4 x 400 mg per day regimen recommended in the bnf for dental pain). for higher doses liaise with the patient's gmp. monitor blood pressure, renal function, and features of heart failure may be required 1-2 weeks after starting or increasing the dose of an nsaid. liaise with the patient's gmp to discuss. if in doubt about the severity of the patient's heart failure or appropriate analgesics, consult with their gmp. prescribe nsaids with caution to people with inflammatory bowel disease (nsaids may increase the risk of developing or cause exacerbations of ulcerative colitis or crohn's disease). prescribe nsaids with caution to people with mild to moderate hepatic impairment (do not prescribe in severe hepatic impairment). dose reductions and monitoring of liver function may be necessary. prescribe nsaids with caution to people with severe renal impairment and avoid if possible since sodium and water retention may occur leading to deterioration in renal function and, possibly renal failure. if the patient cannot avoid using an nsaid and has impaired renal function, monitor renal function 1-2 weeks after starting or increasing the dose of an nsaid. avoid concomitant use of nsaids with anticoagulants (e.g. warfarin, dabigatran) if possible. all nsaids can cause gi irritation and reduce platelet aggregation, which can worsen any bleeding event. if concurrent use is necessary be aware of the potential risks of bleeding. consider giving gastroprotection. liaise with the patient's gmp if a ppi is required but is not currently prescribed. prescribe nsaids with caution for patients with bleeding disorders (e.g. haemophilia, von willebrand disease and clotting factor deficiencies). consult with the patient's gmp or haematologist. 56 discussion: the role of dental professionals in preventing the transmission of covid-19 is critically important since it has the most risk of spreading the virus than any profession in relation to covid-19. dentistry follows the principle of universal precautions for cross-infection control to safe guard the dental health care professionals and the patients. hence the strict cross infection control measures and the awareness of j o u r n a l p r e -p r o o f infectious diseases transmission are leading to a better level of infection prevention control and better personal protective measures in a dental setting. acute/chronic oral medicine issues are managed over the phone and medication regimens are continued as previously prescribed to avoid detrimental effects of sudden change in pharmacotherapy. organized urgent dental care delivered by dhcp in appropriate ppe (gowns, gloves, ffp3 masks and eye protection) with high-volume aspiration and other measures to reduce/avoid the production of droplets, splatter and aerosols by dental drills and saliva. the profound impact of the sars-cov2 pandemic on dentistry necessitates that a paediatric dentist stays up to date with the current resources and evidence based guidance on dental care for children. the revised consensus guidelines highlight revised infection control protocols, management of suspected and possible cases of covid-19 virus and risk based management of pediatric dental emergencies with medication or intervention. patients treated for covid-19 in icu will require care since they are at a high risk of deterioration of oral health. 57, 58 conclusion: covid-19 viral transmission concern necessitates the implementation of specific protocols to reduce the risk and spread of infection from patient to another person or medical tools and equipment. this narrative review article discusses and suggests the modification of patient management, clinical practice, introduction of devices and organizational practices during the covid-19 and the way forward with reference to paediatric dentistry. paracetamol is considered safer than aspirin or nsaids because it does not affect platelets or cause gastric bleeding. patients should have their usual inr check planned and inform their clinician if they have been using paracetamol regularly. use paracetamol and ibuprofen with caution in children (asthma). a gp should be contacted when uncertain about a patient's medical condition, current medication or suitable analgesia. 56 use nsaids with caution and if absolutely necessary use the lowest effective dose for the shortest time possible. patients already taking an nsaid (prescribed or not) regularly for a non-dental condition should not take an additional nsaid to control dental pain. ibuprofen should be prescribed with caution for patients taking low dose aspirin since the administration of additional nsaid may reduce the cardioprotective benefit of low dose aspirin and increases the risk of gi bleeds. in patients taking low dose aspirin, if an nsaid is necessary to control the pain, consider ibuprofen up to 1200 mg maximum daily with a ppi or contact the gmp for advice. elderly patients at increased risk of cardiovascular, renal, and serious adverse effects including gi bleeding and perforation, which may be fatal should be prescribed ibuprofen with caution not exceeding 1200 mg ibuprofen per day with a ppi. diclofenac is contraindicated. monitoring blood pressure, renal function, and features of heart failure may be required 1-2 weeks after starting or increasing the dose of an nsaid. avoid nsaid's in people with dehydration, due to risk of acute kidney injury. chronic alcoholism and alcohol dependence increases the gi risk is increased with nsaids hence avoid nsaids if possible or prescribe with a ppi. prescribe ibuprofen with caution to people with cerebrovascular disease, ischaemic heart disease, peripheral arterial disease, or risk factors for cardiovascular events like hypertension, hyperlipidaemia, diabetes mellitus and smoking. prescribe it with caution in cardiac impairment or mild to moderate heart failure (nsaids may impair renal function) but not in severe heart failure. prescribe up to 1200 mg per day as a first-line option (lower dose than the 4 x 400 mg per day regimen recommended in the bnf for dental pain). for higher doses liaise with the patient's gmp. monitor blood pressure, renal function, and features of heart failure may be required 1-2 weeks after starting or increasing the dose of an nsaid. liaise with the patient's gmp to discuss. if in doubt about the severity of the patient's heart failure or appropriate analgesics, consult with their gmp. prescribe nsaids with caution to people with inflammatory bowel disease (nsaids may increase the risk of developing or cause exacerbations of ulcerative colitis or crohn's disease). prescribe nsaids with caution to people with mild to moderate hepatic impairment (do not prescribe in severe hepatic impairment). dose reductions and monitoring of liver function may be necessary. prescribe nsaids with caution to people with severe renal impairment and avoid if possible since sodium and water retention may occur leading to deterioration in renal function and, possibly renal failure. if the patient cannot avoid using an nsaid and has impaired renal function, monitor renal function 1-2 weeks after starting or increasing the dose of an nsaid. avoid concomitant use of nsaids with anticoagulants (e.g. warfarin, dabigatran) if possible. all nsaids can cause gi irritation and reduce platelet aggregation, which can worsen any bleeding event. if concurrent use is necessary be aware of the potential risks of bleeding. consider giving gastroprotection. liaise with the patient's gmp if a ppi is required but is not currently prescribed. prescribe nsaids with caution for patients with bleeding disorders (e.g. haemophilia, von willebrand disease and clotting factor deficiencies). consult with the patient's gmp or haematologist. 56 transmission of covid-19 to health care personnel during exposures to a hospitalized patient covid-19 in a long-term care facility -king county presentation published at cdc/niosh topic page: aerosols, national institute for occupational safety and health cdc guidance for dental settings: interim infection prevention and control guidance for dental settings during the covid-19 response novel coronavirus-important information for clinicians guidelines for infection control in dental health-care settings-2003 who.int. 2020. coronavirus situation report-83 suggestions on the prevention of covid-19 for health care workers in department of otorhinolaryngology head and neck surgery refining surge capacity: conventional, contingency, and crisis capacity impact of multiple consecutive donnings on filtering facepiece respirator fit aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 simple respiratory mask simple respiratory protection-evaluation of the filtration performance of cloth masks and common fabric materials against 20-1000 nm size particles guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings. last update filtering out confusion: frequently asked questions about respiratory protection, fit testing osha's respiratory protection standard niosh-approved n95 particulate filtering facepiece respirators updated air purifying respirators for use in health care settings during response to the covid-19 public health emergency approved respirator emergency use authorization (eua)external icon recommended guidance for extended use and limited reuse of n95 filtering facepiece respirators in healthcare settings considerations for recommending extended use and limited reuse of filtering facepiece respirators in healthcare settings engineering controls to reduce airborne, droplet and contact exposures during epidemic/pandemic response in-depth report: expedient methods for surge airborne isolation within healthcare settings during response to a natural or manmade epidemic. cincinnati, oh: u.s. department of health and human services framework for healthcare systems providing non-covid-19 clinical care during the covid-19 pandemic the impact of the covid-19 epidemic on the utilization of emergency dental services discontinuation of transmission-based precautions and disposition of patients with covid-19 in healthcare settings criteria for return to work for healthcare personnel with suspected or confirmed covid-19 disinfectants for use against sars-cov guidance for reopening buildings after prolonged shutdown or reduced operation niosh testing and remediation of dampness and mold contamination guidance for reopening buildings after prolonged shutdown or reduced operation environmental control for tuberculosis: basic upper-room ultraviolet germicidal irradiation guidelines for healthcare settings tlvs and beis: based on the documentation of the threshold limit values for chemical substances and physical agents & biological exposure indices guidelines for infection control in dental health-care settings-2003pdf icon epa list n: disinfectants for use against sars-cov-2 (covid-19 laundry and bedding: guidelines for environmental infection control in health-care facilities clinical questions about covid-19: questions and answers interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (covid-19) in healthcare settings guidance for risk assessment and work restrictions for healthcare personnel with potential exposure to covid-19 iapd foundational articles and consensus recommendations: caries risk assessment and care pathways american academy of paediatric dentistry. caries risk assessment and management for infants, children and adolescents. reference manual iapd foundational articles and consensus recommendations: management of early childhood caries iapd foundational articles and consensus recommendations: use of fluoride for caries prevention iapd foundational articles and consensus recommendations: minimal invasive dentistry iapd foundational articles and consensus recommendations: management of dental erosion iapd foundational articles and consensus recommendations: paediatric periodontal disease iapd foundational articles and consensus recommendations: management of molar incisor hypomineralization iapd foundational articles and consensus recommendations: management of the developing dentition dentistry and coronavirus (covid-19)-moral decision-making drugs for the management of dental problems during covid-19 pandemic the workers who face the greatest coronavirus risk. the new york times evaluating the protection afforded by surgical masks against influenza bioaerosols: gross protection of surgical masks compared to filtering facepiece respirators appoint each group of patients one personnel from the dental clinic who can be reachable 24/7 in case of an emergency in order to asses and determine the need to be seen water should be run through pipes and taps in surgeries, kitchen, bathrooms and showers when reopening a practice post covid-19 shutdown follow the dental practice reopening guidelines paracetamol in many over the counter preparations should be identified in all medications which have been ingested. an overdose is dangerous because it may cause fatal hepatic damage that is sometimes not apparent for 4-6 days. refer a patient for an emergency assessment if they ingest a therapeutic excess of more than the recommended daily dose [8 x 500 mg tablets for adults] and more than or equal to 75 mg/kg in any 24-hour period. paracetamol is the analgesic of choice for women who are breastfeeding. for a pre-term, or low birthweight infant seek advice from a gp. absorption, distribution, metabolism, or excretion of paracetamol may be affected by an underlying medical condition. paracetamol is a suitable analgesic option in most people with liver disease but dose reduction j o u r n a l p r e -p r o o f the following information is required for submission. please note that failure to respond to these questions/statements will mean your submission will be returned. if you have nothing to declare in any of these categories then this should be stated. all authors must disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. i do not have any financial or personal relationships with the other people or organizations which could 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study concept or design, data collection, data analysis or interpretation, writing the paper, others, who have contributed in other ways should be listed as contributors.saleha shah-sole author j o u r n a l p r e -p r o o f in accordance with the declaration of helsinki 2013, all research involving human participants has to be registered in a publicly accessible database. please enter the name of the registry and the unique identifying number (uin) of your study.you can register any type of research at http://www.researchregistry.com to obtain your uin if you have not already registered. this is mandatory for human studies only. trials and certain observational research can also be registered elsewhere such as: clinicaltrials.gov or isrctn or numerous other registries. name of the registry: unique identifying number or registration id: hyperlink to your specific registration (must be publicly accessible and will be checked): the guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish hence a risk assessment of the practice should be carried out to identify the measures required to minimize the risk of covid-19 transmission.added to refine the manuscript:the practice should be cleaned thoroughly and clutter removed to facilitate frequent cleaning and disinfection.devise a protocol for receiving mails and deliveries.dhcp recovered from covid-19 (protective immunity) care for covid-19 patient. 9, 10, 11, 12, 13, 14, 15, 30, 31, 32, 33, 34 safety and quality assurance checks on radiographic equipment should be performed. aed should be tested as well. all the emergency drug kits should be checked for expiry. ensure that the rechargeable items are fully charged and operational. check the drinking water dispenser for staff use and recommission by manufacturer's instructions. the computer updates should be checked and installed. key: cord-279935-asg71qtr authors: beasley, lana o.; ciciolla, lucia; jespersen, jens e.; chiaf, ashleigh l.; schmidt, mallory; shreffler, karina m.; breslin, florence j.; bakhireva, ludmila n.; sanjuan, pilar m.; stephen, julia m.; coles, claire d.; chambers, christina d.; kable, julie a.; leeman, lawrence; singer, lynn t.; zellner, jennifer; morris, amanda s.; croff, julie m. title: best practices for engaging pregnant and postpartum women at risk of substance use in longitudinal research studies: a qualitative examination of participant preferences date: 2020-10-28 journal: advers resil sci doi: 10.1007/s42844-020-00019-1 sha: doc_id: 279935 cord_uid: asg71qtr there are significant barriers in engaging pregnant and postpartum women that are considered high-risk (e.g., those experiencing substance use and/or substance use disorders (sud)) into longitudinal research studies. to improve recruitment and retention of this population in studies spanning from the prenatal period to middle childhood, it is imperative to determine ways to improve key research engagement factors. the current manuscript uses a qualitative approach to determine important factors related to recruiting, enrolling, and retaining high-risk pregnant and postpartum women. the current sample included 41 high-risk women who participated in focus groups or individual interviews. all interviews were analyzed to identify broad themes related to engaging high-risk pregnant and parenting women in a 10-year longitudinal research project. themes were organized into key engagement factors related to the following: (1) recruitment strategies, (2) enrollment, and (3) retention of high-risk pregnant and parenting women in longitudinal research studies. results indicated recruitment strategies related to ideal recruitment locations, material, and who should share research study information with high-risk participants. related to enrollment, key areas disclosed focused on enrollment decision-making, factors that create interest in joining a research project, and barriers to joining a longitudinal research study. with regard to retention, themes focused on supports needed to stay in research, barriers to staying in research, and best ways to stay in contact with high-risk participants. overall, the current qualitative data provide preliminary data that enhance the understanding of a continuum of factors that impact engagement of high-risk pregnant and postpartum women in longitudinal research with current results indicating the need to prioritize recruitment, enrollment, and retention strategies in order to effectively engage vulnerable populations in research. there are significant barriers to recruiting and retaining individuals with overlapping vulnerabilities (i.e., substance use disorders (sud)) in the pregnancy or postpartum period (davis, yao, & bierer, 2019; mchugh votaw, sugarman, & greenfield (2018) wetherington & roman, 1998) . this may result in challenges for generalizability and therein create a relatively sparse knowledge base about the long-term outcomes for these women and their children including the environmental, mental health, physiological, and neurological factors. filling these knowledge deficits and gaps requires ongoing assessment because research tools including those for recruitment and retention change; in addition, substance exposures in pregnancy change (e.g., prescription opioid exposure, cannabis use), thereby shifting methods to reach target populations of interest and methods to measure outcomes of interest. it is imperative for the field to identify and address engagement in research, to ensure representation of pregnant and postpartum women that use substances. engagement in longitudinal studies will allow a more complete understanding of maternal and child health outcomes as a result of new and emerging trends in prenatal substance exposure. enhanced understanding of participants' perspectives on engagement and study participation will allow researchers to more fully address this pressing research and public health need. prenatal exposure studies began in earnest in the 1970s, after the identification and diagnosis of fetal alcohol syndrome (jones & smith, 1973) . careful participant selection and comparison selection were and are necessary to classify effects of prenatal exposures. protectionist and paternalistic regulations (e.g., the national research act of 1974, and federal regulations designating pregnant women as a vulnerable population) excluded women from health research and limited the field's understanding about how sex and gender shape substance use and sud (davis, et al. 2019; wetherington & roman, 1998; institute of medicine, 1994; institute of medicine, 1999a) . research studies on substance exposures during pregnancy expanded rapidly in the past 30 years, in recognition of the cocaine epidemics of the 90s, and the current increases in prenatal opioid and methamphetamine exposures (gabrhelík, et al. 2020) . indeed, research that focused specifically on prenatal exposures and other women's health issues has been encouraged by journal editors, policymakers, and funding agencies including the nih helping end addiction longterm (heal) initiative. despite bioethical, legal, and social concerns regarding the risks and benefits of research participation for pregnant and postpartum women who use alcohol and drugs (davis, et al. 2019) , the inclusion of vulnerable populations who are marginalized or stigmatized in research on sensitive topics has not demonstrated undue harm or exposure to unacceptable risk, and in fact, has been associated with potential benefits, such as altruism, catharsis, and gained knowledge (alexander, pillay, & smith, 2018) . of course, it is important for researchers to adopt careful experimental design and safeguards that will uphold the principal of non-maleficence and protect vulnerable participants from harm (alexander et al., 2018; sikeweyiya & jewkes, 2013) . exclusion of substance using populations may violate important bioethical principles of human subjects research, particularly the principles of autonomy, beneficence, and justice (alexander et al., 2018) . exclusion from research not only strips individuals from making decisions about their own autonomy and denies them potential benefits of participating, but also exposes them to greater societal marginalization and may ultimately place them at increased risk of harm due to deficits in critical health knowledge and exposure to inappropriate or ineffective treatments (alexander et al., 2018; johnson et al., 2014; institute of medicine, 1999b) . unfortunately, prenatal exposures to alcohol, tobacco, and other drugs are rising (substance abuse and mental health services administration, 2018), with 1 in 4 pregnancies exposed to tobacco (18.9%), alcohol consumption (10.0%), or illicit drug use (4.7%) (ebrahim & gfroerer, 2003; havens, simmons, shannon, & hansen, 2009 ). specifically, opioid exposed pregnancies have increased from 1.5 to 6.5 per 1000 pregnancies (haight, ko, tong, bohm, & callaghan, 2018 ). yet, cannabis exposures are the most prevalent drug exposure, with nearly 7-8% reported exposure in the first trimester (alshaarawy & anthony, 2019) . rising rates of substance exposure correspond to increasing health risks and adverse outcomes at great societal cost and burden to systems of health care and social services, as well as criminal justice. notably, researchers involved in the nida-funded perinatal-20 treatment research demonstration program that focused on sud treatment for pregnant and postpartum women identified seven clinical factors that contributed to significant difficulty and complexity in the recruitment and retention of women in substance use treatment research, including as follows: (1) severity of sud, (2) legal system involvement, (3) housing instability, (4) interpersonal relationship challenges, (5) parenting responsibilities, (6) employment challenges, and (7) need for more intensive services. these difficulties with recruitment and retention contribute to additional complications for research, including biased samples of convenience recruited through referrals from social and health agencies, limited sample diversity, deviations from the research design, and ethical issues associated with risk and benefits of participation and involvement with the criminal justice or child welfare system. in particular, when research designs do not involve the possibility of direct benefit due to participation (i.e., observational versus intervention studies), it is important to understand the unique reasons and motivations that drive decision-making about research participation (hallowell et al., 2010) . due to all of the aforementioned factors that potentially inhibit the inclusion and engagement of high-risk participants (i.e., participants previously or currently using substances), it is imperative to understand the motivations for engagement in research among high-risk participants, focusing specifically on understanding motivation for research participation, factors that influence decision-making about participation, and barriers to participation. the current study reports results from a qualitative research study conducted as part of an 18-month, multi-site pilot study aimed to develop and demonstrate feasibility of an experimental design for a 10-year, prospective, longitudinal investigation of normative childhood brain development, beginning in pregnancy. a major aim of the 10-year study will be to determine factors that alter brain development including prenatal exposure to opioids and other psychoactive substances, as well as other prenatal and childhood environmental exposures. this goal necessitates recruiting pregnant women previously or currently using substances, as well as a large group of pregnant women who are at low risk of prenatal substance use. two of the primary aims of the pilot are (1) developing and testing recruitment and retention strategies and (2) addressing ethical and legal challenges of conducting research with a stigmatized and vulnerable population. the current qualitative study is one arm of the 5-site consortium to improve understanding, from a qualitative perspective, the continuum of engagement of low-and highrisk participants in research. this manuscript focuses on the results of the distinct needs and responses of high-risk participants. specifically, the objectives in this analysis were to address important factors that impact best practices in (1) promoting longitudinal research to high-risk participants, (2) enrolling high-risk participants in research, and (3) retaining high-risk participants in research studies. individual interviews and one focus group were conducted with a total of 41 women (five participated in a focus group). women were at high-risk of prenatal or postnatal substance use and were identified through medical clinics, other research study involvement, or sud treatment programs. recruitment took place across five sites in the usa located in california, georgia, new mexico, ohio, and oklahoma (see table 1 for demographic information). high-risk pregnant and postpartum women were defined in the current study as a parenting or pregnant woman who had used alcohol and tobacco and/or had a current or past history of sud. some participants were currently receiving sud treatment. contact was made through trained research personnel located at each specific site with 41 total participants taking part in the current study (california, n = 3; georgia, n = 4; new mexico, n = 9, ohio, n = 8; oklahoma, n = 17). only one focus group that included five women was combined with the individual interviews. the one focus group was conducted in new mexico prior to group restrictions imposed due to covid-19. qualitative methods for the research team, study design, and analysis followed the guidelines recommended by tong, sainsbury, and craig (2007) . qualitative study recruitment began with sites contacting participants in person or by phone and describing the current study and qualitative interview process. all women who expressed interest in participating were scheduled for either a focus group or individual interview depending on whether the interview took place prior to or following covid-19 restrictions regarding in-person gatherings. interviews conducted during the covid-19 restrictions were conducted individually by phone. all participants gave oral informed consent. during the consent process, a brief overview of the qualitative study and all safety measures taken to ensure confidentiality were discussed. trained qualitative research assistants collected all qualitative data from march 2020 through june 2020. before engaging in focus groups/individual phone interviews, all participants completed an in-person or online survey that included a demographic questionnaire and watched a short video describing the protocols planned for the larger, longitudinal study including neuroimaging (e.g., mri), neurodevelopmental, and biospecimen collection. for the focus group, snacks were provided. participants received a $50-75 incentive for their participation, and this varied based on site. all focus groups and individual interviews were audio-recorded and lasted approximately 45-60 min. transcription work was conducted by qualitative team members or a transcription company, with team members crosschecking all transcripts to verify accuracy. during the transcription process, all identifying information was removed to ensure privacy. all procedures were approved by the sirb for the 5-site consortium. focus group and individual interview guides for the current project were developed by the first author, in conjunction with the evaluation team and other sites within the research consortium reviewing and revising the guide as needed. focus group and individual interviews were coded individually and combined for data analysis. all coding and data analysis was conducted at one site. recordings were transferred securely according to irb-approved methods. it is important to note that focus group and individual data themes were examined a priori and themes were congruent and therefore data were merged. qualitative data was analyzed using the nvivo © 11 software. five qualitative researchers worked together to develop a codebook focused on broad themes influenced by the semistructured interview guide. thematic analysis was used to define specific themes within the broader categories (braun & clarke, 2014) . the codebook was developed using an agreed upon coding scheme with themes not being predetermined but rather emerging from the data. upon completion of the codebook, two teams consisting of two qualitative researchers coded all transcriptions using developed coding templates. cleaning of data took place as needed (broader codes enveloping smaller codes). once coded, inter-coder reliability was established using simple percent agreement, which is a commonly used method for assessing reliability in qualitative studies (lombard, snyder-duch, and bracken, 2006; stemler, 2004) . average inter-coder reliability was over 85%. in the "results" section, themes are described in more detail. the validity of the current research findings are enhanced by several design factors such as the calculation of salient factors using percentage of comments and the team-based approach used for coding. specifically, calculating the percentage of comments from participants related to specific themes allowed the research team to ensure that themes discussed in the current paper were saturated or were discussed frequently in focus group/individual interviews. therefore, relying on percent of comments strengthens demonstration of saturation in the current study. further, the majority of qualitative data were collected from individual interviews (n = 36) rather than a focus group (n = 5), which allows for a more in-depth conversation. specifically, during individual interviews, comments were able to be probed deeply with rich content emerging throughout the qualitative data, rather than simple agreement or disagreement that often emerges from focus group data collection. additionally, the fact that both primary researchers as well as consortium partners were involved in developing the focus group/individual interview guide is a strength, increasing the likelihood that the items on the interview guide validly and comprehensively captured the intent of the research aims. qualitative results for the current study focused on a continuum of engagement of high-risk participants in a multi-year prospective longitudinal, cohort design research study. specifically, themes were organized into key engagement factors related to the following: (1) promoting research to high-risk participants, (2) enrollment of high-risk participants in research, and (3) retention of high-risk participants in a multi-year prospective longitudinal, cohort design research study. key socioeconomic and demographic variables for the study participants are presented in table 1 . the current sample was more racially/ethnically diverse than the general us population, with most participants identifying as white (56%), followed by hispanic/latino (15%), black/african american (10%), multi-racial (10%), american indian (7%), and asian (2%). many participants reported they had never married (51%) with other participants reporting they were currently married (27%), living with a significant other (8%), or divorced (10%). many participants reported completing high school (22%) with an additional 27% reporting obtaining a ged. the average monthly income was $1470.73 per month (sd = $1978.95) and most participants reported receiving some form of government assistance (90%). best ways to promote research studies to high-risk participants participants were asked about the best ways to promote a longitudinal research study to recruit participants and their children into studies with participants explaining the best recruitment locations, ideal individuals to share research study information, and the best type of recruitment material. participants reported that social media is an ideal platform to reach participants (31% of comments). specific social media locations include facebook, instagram, and online mother groups. one participant explained, "a lot of people use social media. so, if it got posted to somebody's account, then you could share it with all of your friends. so, i think that would be great." participants also reported that medical offices (15% of comments) and community/state agencies (10% of comments) were good locations to share information about research studies. an example quote includes: and maybe … when i go to (local agency) for counseling and you know, my mental health needs for me and my kids, therapy anything like that. they always have all kinds of [information] … are you struggling with this, are you interested in this, here's a study to help you earn extra money, are you a single mom, do you have this or that, well then you may qualify for this study that we're doing. other suggested locations included bus stops (8% of comments), billboards (7% of comments), and grocery/ convenience stores (7% of comments). participants also reported that child-friendly locations (i.e., library, parks; 6% of comments) and educational settings (4% of comments) were good locations to share study information. one participant explained, "maybe flyers at childcare centers and stuff like that, where they have the younger school-aged kids from infant to whatever. i know a lot of moms frequent those places." when participants were asked about locations they would trust the most to receive information, it was disclosed that medical offices such as doctor offices/clinics, state agencies (e.g., women and children food programs, other human services), and educational settings were considered most trustworthy. participants also discussed the type of material they would recommend using to promote research studies with participants explaining they would use commercials (28% of comments), brochures (23% of comments), and radio (15% of comments) to share information about research studies. it was also reported that using news/newspapers (6% of comments), online marketing strategies (6% of comments), and sharing information through word of mouth (4% of comments) would be most effective. in terms of the individuals that would be best to share research study information, participants stated that study information would best come from medical personnel (42% of comments), friends (15% of comments), family members (13% of comments), other participants (9% of comments), and professionals (9% of comments). professionals included counselors/therapists, daycare personnel, clergy, and staff at resources centers. participants were also asked who they would find the most trustworthy in sharing information with them and disclosed doctors (57% of comments), family/other mothers (14% of comments), and friends (12% of comments) would be most trusted. an example quote regarding who participants would trust the most was: …when you think of doctors you think you can trust them more, because they're there to help you take care of your kids or take care of yourself … the doctor isn't going to try to scam you out of something so when you get information from them about a study … you tend to want to read about what they are giving you. research enrollment decision-making participants were asked if any information could be provided during recruitment to help them make the decision of whether or not to enroll in a 10-year research project that includes data collection from them and their children. the most frequent request for more information involved study procedures (45% of comments). specifically, participants wanted to know more information about data collection, including procedures related to neuroimaging such as magnetic resonance imaging (mris), biosampling, and frequency of procedures. an example quote of wanting more information on study procedures was: …looking at everything that might be required of participants, it seems kind of … a bit invasive and like kind of a large commitment in regards to [sic] coming for mris and sending blood work, the diapers, giving hair, things like that. participants also explained that they wanted to know additional information about the purpose of the study (22% of comments) with participants explaining that they wanted an explanation of the research study in its entirety and how it related to child development. another area that participants explained they needed more information about was study logistics (17% of comments) with participants explaining they would like to know the location of the study and commitment involved with being in the study. in terms of research commitment, one participant shared needing to know "… times and dates to make sure everything is scheduled right … trying to get a couple of days in at the job and … just timing stuff." participants were also asked if there was anyone they would need to speak with to make a decision about enrolling in research involving themselves and their child(ren). participants indicated they would speak to a variety of key individuals, including their significant other or the biological father of the child (52% of comments), family members (23% of comments), and medical personnel (16% of comments). participants reported that several things would make them interested in joining a research study with the most frequent being understanding the research benefits (48% of comments) to others (66% of comments) and themselves (34% of comments). an example quote regarding research benefits to others was: i think if participating contributes to information that can help other moms in the future, if there's more information that can be gained or developed out of this study that can be provided to other moms, before they get pregnant, as they're pregnant, to help in their baby's development. i feel like that's, in some part a small contribution i can make. participants also reported that for research studies that involved their children, there was a strong interest in being provided study results about their children (28% of comments). this included information on brain development and overall child development. one participant explained, "it seemed like something that would be really interesting is to find out more information about your own child …not? just brain development. that's really something that interests me." participants also reported that compensation would impact their interest in joining a research study (10% of comments) with several participants indicating that a potential increase in compensation over time would be attractive. specifically, one participant explained, "i would say maybe increase the compensation as the years go on because … it's hard to stick with a program." barriers to joining a research study participants also discussed barriers to joining a research study. participants reported that a busy schedule (35% of comments) could make it difficult to join a research study. this includes challenges regarding the time commitment for the study and also balancing their work schedule around research study demands. other barriers included transportation difficulties (32% of comments), travel time and location of the study (11% of comments), and having childcare while participating in research activities (11% of comments). many comments from participants regarding barriers were concerns about taking part in a research study. primary concerns included potential risks to the fetus/child (31% of comments) both during pregnancy and after the child is born. one participant explained, "just making sure no harm to the baby … i mean i understand the blood samples but just making sure it's 100% safe." other concerns included ensuring that participant personal and research information was kept confidential (31% of comments) as well as understanding the invasiveness of biospecimen collection (20% of comments). in terms of confidentiality, an example quote from a participant was: …a reassurance that the information would stay private and … the only thing that made me a little uncomfortable was when you were like "we will have to take your identifying information but then it will be destroyed." i feel like there might be something to substantiate that it's going to be destroyed, and not just a word of mouth thing. supports needed to stay in a research study additional advice was collected from participants regarding what would help them stay in a research study after enrollment. participants reported a variety of research supports that would be helpful to stay in a research project (31% of comments). specific research supports included providing childcare during data collection, compensation for time spent in research, and provision of transportation as needed for families. related to this theme, one participant explained that "… childcare on site is probably a huge one" and another participant reported that "transportation would be very helpful." it was also explained that specific research study logistics are important to consider in supporting participants to stay in a research study (21% of comments). these included receiving regular research updates including the benefits of the study, having well-trained research staff, research staff engaging in regular contact with participants, families being close to the research/data collection site, and families being provided advanced notice of data collection. with regard to receiving research updates, a participant explained: …getting kind of feedback about … here's what you contributed and here's what … we're gonna use … information on what we found, about your baby's development ... for me that would be important. flexibility was another key area of importance for participants (16% of comments). specifically, it was reported that flexibility of the participant schedule, when research appointments are scheduled, and who brings the child to research appointments are important to support ongoing research engagement. an example quote regarding flexibility was: so, i don't know how long an appointment would take. but if appointments could be, quick, able to work around my schedule, flexible, and maybe offer something like what we're doing now (phone interview). if we're not able to meet, like some kind of tele-health option. that would make it so much easier. participants also reported that home visits could potentially increase their ability to stay in a research study (18% of comments) as it would make visits more convenient. it is important to note that some families reported concerns with home visits indicating that not all families feel comfortable with research personnel coming into their home. another theme that emerged included the importance of becoming familiar with research staff (8% of comments) as it creates comfort in staff working with children involved in the research study. participants explained barriers to staying in a research study after enrollment with the most frequent barrier being family-related barriers (61% of comments) including work schedule, family moves, generally busy schedule, lack of childcare, and child(ren) not being interested in the study (when older). with regard to family moves, a participant shared "… it would depend on where i moved and if you guys had the same research study where i moved to." specific research study logistics (30% of comments) were also reported as a potential barrier to staying in a research project with participants explaining barriers related to transportation, time commitment, and frequency of data collection. specific to time commitment/frequency of data collection, one participant explained wanting more information on "how often do you want me to come in? how long are we gonna be there?" best ways to stay in contact with high-risk participants participants were also asked about the best way to stay in contact with participants during a longitudinal research study with participants reporting that collecting contact information from family members is recommended (26% of comments). specific to information important to collect from participants, personal information such as phone number (23% of comments), email (19% of comments), social media information (11% of comments), and home address (11% of comments) were reported as ideal. the current qualitative data describes a continuum of factors that impact engagement of high-risk participants (i.e., those currently or in the past using substances) in a 10-year complex longitudinal research study. this continuum included factors that impact research promotion strategies, enrollment, and retention of high-risk participants in research studies (see fig. 1 ). recruiting a representative sample of pregnant high-risk participants for a longitudinal study is challenging. however, considering promotion strategies, it is evident that there are a number of avenues whereby researchers may have success both finding and creating contact points with high-risk participants. our findings illustrate how the construct of research promotion is multifaceted. responses from interviews included three major factors: (1) the location where research material is shared, (2) the type of material used, and (3) the person sharing the research material all potentially impact marketing success. considering recruitment locations, participants frequently recommended social media, followed by medical offices, and community/state agencies. in regard to social media, studies have increasingly indicated social media as a key location to gain access to individuals who may be harder to reach, including high-risk individuals (betsch, 2014; frandsen, walters, & ferguson, 2014) . additionally, marketing through social media can contribute to reduced recruiting costs, shorter recruiting periods, and better population representation (maloni, przeworski, & damato, 2013; whitaker, stevelink, & fear, 2017) . social media has become increasingly common as a major component of research recruitment strategies in recent years (fusar-poli et al., 2016; whitaker, et al. 2017) . television commercials, brochures, and radio ads were the three most often recommended mediums. these more traditional marketing methods have been used in research for decades; however, barriers in the use of television and radio advertisements have become more relevant in recent years. for example, many of those who watch television have begun resorting to streaming services. these streaming services often allow users to skip ads, or even remove ads all together. additionally, online radio services with ad-free options have become increasingly common (wlömert & papies, 2016) . however, although these trends are occurring in the general population, less is known regarding how changes in television and music consumption have changed specifically for pregnant and parenting women with sud. medical personnel, family members, and friends comprised the limited sources for trusted information on research studies for participants. this suggests close interpersonal relationships are important to consider during recruitment. moreover, doctors and nurses may be successfully engaged in the recruitment process where feasible. this is consistent with research newington and metcalfe (2014) showing that forming collaborations with trusted medical professionals aided in both identifying and gaining access to eligible, hard-to-reach participants. adding to support this, when asked who they would trust the most to receive research recruitment information materials from, the most common answer among participants was doctors. the decision to enroll in a long-term research study with few or no direct benefits for participants is complex and multifaceted (hallowell et al., 2010) . for pregnant and parenting women who use drugs and/or alcohol, the decision can be further complicated by concerns about privacy and safety, logistics related to participation, and details about study procedures and how they relate to child development. the interview and focus group responses from our participants indicated that comprehensive information about specific study procedures and the purpose of the study was most important for informing research participation, with particular interest in understanding the commitment and burden (i.e., time, effort) associated with participation. additionally, almost a third of participants reported concerns about safety and invasiveness of study procedures, particularly the risks to their child, as well as concerns about confidentiality and maintaining the privacy of their personal information. in addition to the concerns about privacy, participants expressed a desire for reassurance that they could trust the research team, and to that end, it was fig. 1 recruitment, enrollment and retention strategies of high-risk participants in research important that study procedures were clearly explained so that they could weigh the risks of participating with potential benefits. this speaks to the importance of autonomy in decisionmaking and informed consent practices, whereby participants' ability to weigh the costs and (potential) benefits of participation and to make the decision for themselves should be valued and respected (alexander et al., 2018) . interestingly, when participants were asked about factors that would influence motivation to participate in nontherapeutic research, a number of participants spoke about understanding the perceived benefits for others as well as for themselves. consistent with previous research showing that altruism was a key motivator for research participation (alexander et al., 2018; hallowell et al., 2010) , current participants indicated that "helping other moms in the future" was an important factor in driving motivation. specifically, participants explained that related to others, they wanted to know more about how research knowledge could support other participants and children as well as how physicians could support young children and families. although altruism has been associated with positive health benefits (post, 2005) , the indirect benefits of charitable helping, such as positive mood and enhanced meaning, can be difficult to articulate and capture, especially when the help provided does not have a clearly defined beneficiary or observable impact (i.e., helping an unknown other, sikeweyiya & jewkes, 2013) . notably, altruistic motivation was more likely to occur among participants who were better informed about research generally and what might be gained through research participation at the level of the community or society more broadly (sikeweyiya & jewkes, 2013) . these findings suggest that altruism is a motivating factor that could be more directly addressed in marketing and informed consent processes, with additional information provided to potential participants about the value of research participation more generally, as well as how participants' specific data will help others, as much as it can be known or anticipated. direct compensation for participating was also identified as an important factor in deciding whether to participate in research. the decision to participate in research is shaped by personal situations and life factors, in particular, money and time. even among participants who reported altruism as a motivating factor, many expected a mutually beneficial interaction that both contributed to the betterment of society and compensated them directly (owen-smith et al., 2016; sikeweyiya & jewkes, 2013) . previous research has shown that participants who are older or have financial hardship were more likely to expect a direct material compensation for participation (sikeweyiya & jewkes, 2013) . if the real costs of study participation are not covered, then study participation can add to an already financially burdened household. in attempting to recruit high-risk or vulnerable populations into research, it is important to consider material compensation as both a motivating factor and a factor that reduces barriers to participation in the context of socioeconomic hardship without introducing undue coercion. a number of participants spoke of concerns about balancing research participation around their work schedules, as well as the costs associated with participation in terms of time, transportation, and childcare. thus, consistent with previous research with vulnerable populations (owen-smith et al., 2016) , compensation that adequately compensates time (especially if any work needs to be missed or childcare must be obtained), effort, and inconvenience is an important factor for motivating enrollment, with special attention given to unique participant needs and preferences regarding type of incentive (george, duran, & norris, 2014; owen-smith et al., 2016) . transportation has also been identified as a barrier in multiple studies involving high-risk families (e.g., mendez, 2010) , and providing transportation is necessary to ensure a diverse sample. one of the most common threats to internal validity to any longitudinal research is attrition and loss to follow-up bias. therefore, the thoughtful implementation of retention strategies can prove critical for conducting research among highrisk populations (dumka, garza, roosa, & stoerzinger, 1997) . in regard to such strategies, three major themes emerged when considering how to enhance study retention: (1) specific supports that can help participants remain in the research study, (2) barriers to be aware of that can potentially make it difficult to continue study participation, and (3) the best channels for staying in contact with participants over the course of the study. participants most often reported needs of support in areas of childcare, transportation, and being compensated for their time. these findings align well with previous research, as childcare and transportation needs tend to be more common among vulnerable populations (dilworth-anderson, 2011; haley et al., 2014a, b) . as such, offering support in terms of transportation assistance and compensation could prove beneficial in terms of retention. additionally, many participants recommended home visits by research staff as a potential solution to transportation and childcare barriers. however, it should be noted that while home visits may aid in reducing potential barriers, a number of participants in the current study voiced that they would not feel comfortable with individuals coming in their home. therefore, prior to the use of home visits, researchers must ensure that families feel comfortable with visits taking place within the home or consider giving participants an option of laboratory-only visits. these options support participant decision-making, a recurring theme among participants. logistical factors mentioned to increase retention included providing participants with regular research updates, advanced notice for study appointments, and a sense of familiarity with research staff. in line with these recommendations, studies that consistently engage with participants via appointment reminders and research updates can foster a sense of anticipation and progress in participants (kim, hickman, gali, orozco, & prochaska, 2014) . moreover, a number of researcher characteristics can contribute to participant engagement and retention including being well experienced with the services provided/research protocols, flexibility, being nonjudgmental, and being culturally competent (beasley et al., 2018; o'brien et al., 2012) . high-risk participants often face a disproportionate number of barriers to remaining engaged in research studies (kim et al., 2014) . indeed, it has been documented that retention rates for vulnerable families are often mitigated by higher instances of unpredictable negative life events (e.g., car problems, unreliable phone access, eviction) while possessing fewer resources to compensate for them (heinrichs, bertram, kuschel, & hahlweg, 2005; nicholson et al., 2011) . additionally, it has been found that low-income, high-risk families tend to move more often than those in elevated ses categories, while also being at a higher risk for experiencing evictions and homelessness (phinney, 2013) . participants in the current study mentioned barriers related to work schedules, inconsistent daily routines, a lack of childcare, and the potential lack of child interest when children are older. despite these barriers, a number of studies have made attempts to work around some of these issues. for example, studies have been successful in addressing schedule barriers by allowing participants to designate appointment times that would be most convenient for their family (dumka et al., 1997) , by meeting participants in-person at a hospital or clinic appointment (kim et al., 2014) or by offering services within the home to reduce transportation and child care needs (fifolt, lanzi, johns, strichik, & preskitt, 2017) . moreover, it has been found in vulnerable populations that providing childcare and an environment that is child-friendly can ease parents' burden as well and boost young children's motivation and interest in participating (chaffin et al., 2009; dumka et al., 1997) . the most common methods for maintaining contact with participants throughout the 10-year study period that were recommended by participants were personal phone number, email, social media, and home address, in that order. while personal phone numbers can provide the most immediate access to an individual, mobile phone numbers have been found to change more often than other modes of contact, such as email or even social media accounts (haley et al., 2014a, b) . therefore, gathering as many contact modalities as possible, as well as contact information from two close friends or family members, can contribute to better participant tracing and retention rates (haley et al., 2014a, b; nicholson et al., 2011) . this study may be limited in generalizability by sample demographics. caution should be used in applying the findings of these high-risk participants to all women at-risk of substance use in pregnancy. this study was also limited because the research method changed during the course of the study due to covid restrictions, resulting in the combination of a focus group with individual interviews. in addition, almost half of the women interviewed were from the oklahoma site. findings should be interpreted in light of these limitations. overall, the current study adds vital information to understanding the complexities of marketing, enrollment, and retention strategies when conducting research with participants that are at high risk for substance exposed pregnancies. several key factors proved to be important across a variety of areas related to enrollment and retention. specifically, transportation was found to influence enrollment decision-making, as a barrier to joining a research project and as a support that was needed to stay in a research project. childcare is another area that was reported to impact enrollment and retention. these results indicate the importance of understanding transportation and childcare availability during data collection and to consider ways to support participants in accessing the study location with child supports in place. other key areas that were discussed within enrollment and retention were benefits of the study and compensation. specifically, participants reported that understanding the benefits to self and others was important. these findings indicate the importance of reporting potential benefits and compensation not only when recruiting participants to enroll in a research project, but also to continue this conversation to retain research participants. lastly, across enrollment and retention, busy schedule of participants is an important consideration. leaning on another theme within the retention strategies, it is important to remain flexible with scheduling data collections so that participants are able to work appointments around a potentially chaotic schedule. a potential research barrier in the current study is the possibility that participants might have difficulties in conceptualizing the continuum of engagement in a longitudinal research study without actually being enrolled and experiencing the study. to mediate this barrier, many of the participants in the current study had been involved in other research in an effort to include participants that had some research experience. additionally, answers to qualitative questions were varied and robust which indicates that participants had a wealth of ideas regarding engagement in research. another potential limitation of the current study was that all participants were considered "high-risk." to remediate this limitation, researchers from the current study are currently analyzing qualitative data to determine potential key differences in engaging low-risk versus high-risk participants in longitudinal research. it is important to note that although it was not specifically examined in this study, it is crucial for researchers and staff to be trained in, and understand, culturally competent methods for recruitment, data collection, and retention. this is particularly the case for building trust among researchers and participants from different cultural and high-risk backgrounds. for example, bicultural research staff and bilingual team members are needed, as well as specific training regarding cultural norms and sensitivity (see mendez, 2010; beasley et al., 2020) . overall, researchers need to be aware of barriers to enrollment and study engagement strategies for recruiting and retaining high-risk participants in research. future research should focus on understanding further behaviors and techniques in supporting high-risk participants, as engaging this population is essential for understanding developmental trajectories of risk and resilience among children starting already at risk for mental and physical health difficulties. funding this work was supported by the national institute on drug abuse (nida) research grant numbers r34da050343 (lob, jmc, and asm) and r34 da050237 (lnb, js, and ll). conflict of interest the authors declare that they have no conflict of interest. disclaimer the views and opinions expressed in this manuscript are those of the authors only and do not necessarily represent the views, official policy, or position of the u.s. department of health and human services or any of its affiliated 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occupational safety and health and environmental risks date: 2008 journal: risks in modern society doi: 10.1007/978-1-4020-8289-4_4 sha: doc_id: 24088 cord_uid: 020rgz5t occupational safety and health (osh) activities were started in the industrialized countries already 150 years ago. separated and specific actions were directed at accident prevention, and the diagnosis, treatment and prevention of occupational diseases. as industrialization has advanced, the complexity of safety and health problems and challenges has substantially grown, calling for more comprehensive approaches. such development has expanded the scope, as well as blurred the borders between specific activities. in the modern world of work, occupational safety and health are part of a complex system that involves innumerable interdependencies and interactions. these are, for instance, safety, health, well-being, aspects of the occupational and general environment, corporate policies and social responsibility, community policies and services, community social environment, workers’ families, their civil life, lifestyles and social networks, cultural and religious environments, and political and media environments. a well-functioning and economically stable company generates resources to the workers and to the community, which consequently is able to maintain a positive cycle in development. a high standard of safety and health brings benefits for everyone: the company, the workers and the whole community. these few above-mentioned interactions elucidate the need for an integrated approach, and the modelling of the complex entity. if we picture osh as a house, this integrated approach could be the roof, but in order to build a stable house, it is also necessary to construct a solid basement as a foundation to the house. these basement "stones" are connected to each other, and are described in more detail in sections 4.1-4.3. section 4.1 focuses on the existing hazards, while section 4.2 mainly considers the exposure of workers to health hazards. health, due to its complexity, however, is not only influenced and impaired by work-related hazards, but also by hazards arising from the environment. these two sub-chapters are thus linked to section 4.3. in addition, the safety levels of companies may affect the environment. the strategies and measures needed for effective risk management, as described in section 4.1, therefore also contribute to reducing the risks to the environment. in the case of work that is done outdoors, the hazards arising from the environment understandably have to be given special attention. here, the methods applied to tackle the usual hazards at workplaces are less effective. it is necessary to develop protective measures to avoid or minimize hazards present in the environment. namely, agriculture, forestry and construction involve these types of hazards, and affect high numbers of workers on a global scale. finally, hazards in the environment or in leisure-time activities can lead to strain and injuries which -combined with hazards at work -may result in more severe health consequences. as an example one can mention the hazardous substances in the air causing allergies or other illnesses. another example is the strain on the musculoskeletal system from sports and leisuretime activities causing low back pain and other musculoskeletal disorders. depending on the type of hazard, the three topics, namely, safety, health and the environment, may share the common trait that the proper handling of risks, i.e., how to reduce probabilities and/or consequences of unwanted events is not always possible within a risk management system. this is true when one moves into the realm of uncertainty, i.e., when there is uncertain, insufficient or no knowledge of the consequences and/or probabilities (see chapter 5). 1. integrated multi-sectorial bodies for policy design and planning (national safety and health committee). 2. comprehensive approach in osh activities. 3. multi-disciplinary expert resources in inspection and services. 4. multi-professional participation of employers' and workers' representatives. 5. joint training in integrated activities. 6. information support facilitating multi-professional collaboration. international labour office (ilo) (2003) international labour conference, 91st session, report vi, ilo standards-related activities in the area of occupational safety and health: an in-depth study for discussion with a view to the elaboration of a plan of action for such activities. sixth item on the agenda. international labour office, geneva. what are the main challenges arising from the major societal changes for business/companies and workers/employees? how can these challenges be met in order to succeed in the growing international competition? what is the role of occupational safety and health (osh) in this context? the above-mentioned changes create new possibilities, new tasks and new risks to businesses in particular, and to the workers as well. in order to optimize the relation between the possibilities and the risks (maximize possibilities -minimize risks) there is a growing need for risk management. risk management includes all measures required for the target-oriented structuring of the risk situation and safety situation of a company. it is the systematic application of management strategies for the detection, assessment, evaluation, mastering and monitoring of risks. risk management was first considered exclusively from the point of view of providing insurance coverage for entrepreneurial risks. gradually the demands of jurisdiction grew, and the expectations of users and consumers increased with regard to the quality and safety of products. furthermore, the ever more complex problems of modern technology and ultimately the socioeconomic conditions have led to the development of risk management into an independent interdisciplinary field of work. risks can be regarded as potential failures, which may decrease trust in realizing a company's goals. the aim of risk management is to identify these potential failures qualitatively and quantitatively, and to reduce them to the level of a non-hazardous and acceptable residual risk potential. the development and formulation of a company's risk policy is regarded as the basis of effective risk management. this includes, first and foremost, the management's target concept with respect to the organization of work, distribution of labour, and competence of the departments and persons in charge of risk management. risk issues are important as far as acceptance of technology is concerned. it is not enough to reduce the problem to the question of which risks are tolerable or acceptable. it appears more and more that, although the risks themselves are not accepted, the measures or technologies causing them are. value aspects have an important role in this consideration. a positive or negative view of measures and technologies is thus influenced strongly by value expectations that are new, contradictory and even disputed. comparing risks and benefits has become a current topic of discussion. the relation between risks and benefits remains an unanswered question. the general public has a far broader understanding of the risks and benefits of a given technology than the normal understanding professed by engineering sciences which is limited to probability x harm. the damage or catastrophe potential, qualitative attributes such as voluntary nature and controllability also play an important role in the risk assessment of a technology. a normative setting for a certain, universally accepted risk definition according to engineering science is therefore hardly capable of consensus at the moment. the balanced management of risks and possibilities (benefits) is capable of increasing the value of a company. it may by far surpass the extent of legal obligations: for example, in germany, there is a law on the control and transparency for companies (kontrag) . the respective parameters may be defined accurately as follows: • strategic decisions aim to offer opportunities for acquiring benefit, taking into consideration risks. • risks that can have negative consequences to the technological capacities, the profitability potential, the asset values and the reputation of a company, as well as the confidence of shareholders are identified and measured. • the management focuses on important possibilities and risks, and addresses them adequately or reduces them to a tolerable level. the aim is not to avoid risks altogether, but to create opportunities for promoting proactive treatment of all important risks. the traditional occupational health hazards, such as physical, chemical and biological risks, as well as accidents, will not totally disappear as a consequence of change, nor will heavy physical work. about 30-50% of workers are still exposed to such hazards. there is thus need to still develop risk assessment, prevention and control methods and programmes for these often well-known hazards. in many industrialized countries, prevention and control programmes have had a positive impact by reducing the trends of occupational diseases and accidents, particularly in big industries. some developing countries, however, show an increase in traditional hazards. international comparisons, however, are difficult to make because of poor coverage, underreporting, and poor harmonization of concepts, definitions and registration criteria. statistics on occupational accidents are difficult to compare, and therefore data on their total numbers in europe should be viewed with caution. the majority of countries, however, have shown declining trends in accident rates irrespective of the absolute numbers of accidents. some exceptions to this general trend have nevertheless been seen. the accident risk also seems to shift somewhat as regards location, so that instead of risks related to machines and tools, particularly the risks in internal transportation and traffic within the workplace grow in relative importance. this trend may increase in future, particularly as the work place, as well as the speed and volume of material flows are increasing. a threat is caused by lengthened working hours, which tend to affect the vigilance of workers and increase the risk of errors. small-scale enterprises and micro-enterprises are known to have a lower capacity for occupational health and safety than larger ones. in fact, a higher accident risk has been noted in medium-sized companies, and a lower risk in very small and very large enterprises. we can conclude that this is due to the higher mechanization level and energy use in small and medium-sized enterprises (sme) compared with micro-enterprises, which usually produce services. on the other hand, the better capacity of very large enterprises in safety management is demonstrated by their low accident rates. the production of chemicals in the world is growing steadily. the average growth has been between 2-5% a year during the past 2-3 decades. the total value of european chemical production in 1998 was about usd 500 billion, i.e. 32% of the world's total chemical production, and it has increased 35% in the 10-year period of 1985-1995. the european union (eu) is the largest chemical producer in the world, the usa the second, and japan the third. there are some 100,000 different chemical entities in industrial use, but only about 2,500 are so-called high-production volume (hpv) chemicals produced (and consumed) in amounts exceeding 1,000 tons a year. the number of chemicals produced in amounts of 10-1,000 tons a year is about 25,000. but volume is not necessarily the most important aspect in chemical safety at work. reactivity, toxicological properties, and how the chemicals are used, are more important. the european chemical companies number some 39,000, and in addition there are 36,000 plants producing plastics and rubber. surprisingly, as many as 96% of these are smes employing fewer than 50 workers, and 70% are micro-enterprises employing fewer than 10 workers. thus, the common belief that the chemical industry constitutes only large firms is not true. small enterprises and self-employed people have much less competence to deal with chemical risk assessment and management than the large companies. guidance and support in chemical safety is therefore crucial for them. the number of workers dealing with chemicals in the european work life is difficult to estimate. the chemical industry alone employs some 1.7 million workers in europe, i.e. about 7% of the workforce of manufacturing industries. about 30%, i.e. over 500,000 work in chemical smes. but a much higher number of workers are exposed in other sectors of the economy. there is a distinct trend showing that the use of chemicals is spreading to all sectors, and thus exposures are found in all types of activities: agriculture, forestry, manufacturing, services and even in high-tech production. the national and european surveys on chemical exposures in the work environment give very similar results. while about 25% of the eu work-ers were exposed to hazardous chemicals, the corresponding figure in central and eastern european countries may be much higher. the workers are exposed simultaneously to traditional industrial chemicals, such as heavy metals, solvents and pyrolytic products, and to "new exposures", such as plastics monomers and oligomers, highly reactive additives, cross-linkers and hardeners, as well as to, for example, fungal spores or volatile compounds in contaminated buildings. this implies that some 40 million people in the eu15 are exposed at work, and usually the level of exposure is one to three orders of magnitude higher than in any other environment. about the same proportion (25% of the workforce, i.e. 500,000) of the finnish workers in the national survey reported exposure. the chemicals to which the largest numbers of workers are exposed occur typically in smes; they are e.g. detergents and other cleaning chemicals, carbon monoxide, solvents, environmental tobacco smoke, and vegetable dusts. european directives on occupational health and safety require a high level of protection in terms of chemical safety in all workplaces and for all workers. risk assessment and risk management are key elements in achieving these requirements. the risk assessment of chemicals takes place at two levels: a) systems-level risk assessment, providing a dose-response relationship for a particular chemical, and serving as a basis for standard setting. risk assessment at the systems level is carried out in the pre-marketing stage through testing. this consequently leads to actions stipulated in the regulations concerning standards and exposure limits, labelling and marking of hazardous chemicals, limitations in marketing, trade and use. in this respect, the level of safety aimed at remains to be decided. is it the reasonably achievable level or, for example, the level achieved by the best available technology? the impact is expected to be system-wide, covering all enterprises and all workers in the country. this type of risk assessment is an interactive practice between the scientific community and the politically controlled decision making. a high level of competence in toxicology, occupational hygiene and epidemiology is needed in the scientific community. and the decision makers must have the ability to put the risk in concern into perspective. in most countries the social partners also take part in the political decision making regarding occupational risks. b) workplace risk assessment directed at identifying the hazards at an individual workplace and utilizing standards as a guide for making decisions on risk management. risk assessment at workplace level leads to practical actions in the company and usually ensures compliance with regulations and standards. risk assessment is done by looking at the local exposure levels and comparing these with standards produced in the type a) risk assessment. risk management is done through preventive and control actions by selecting the safest chemicals, by controlling emissions at their source, by general and local ventilation, and by introducing safe working practices. if none of the above is effective, personal protective devices must be taken into use. noise is a nearly universal problem. the products of technology, which have freed us from the day-to-day survival struggle, have been accompanied by noise as the price of progress. however, noise can no longer be regarded as an inevitable by-product of today's society. not only is noise an undesirable contaminant of our living environment, but high levels of noise are frequently present in a variety of work situations. many problems arise from noise: annoyance, interference with conversation, leisure or sleep, effects on work efficiency, and potentially harmful effects, particularly on hearing. in short, noise may affect health, productivity, and well-being. the selection of appropriate noise criteria for the industry depends on knowledge of the effects of noise on people, as well as on the activities in which they are engaged. many of the effects are dependent on the level, and the magnitude of the effects varies with this level. hearing damage is not the only criterion for assessing excessive noise. it is also important to consider the ability and ease of people to communicate with each other. criteria have therefore been developed to relate the existing noise environment to the ability of the typical individual to communicate in areas that are likely to be noisy. the effects of noise on job performance are difficult to evaluate. in general, one can say that sudden, intermittent, high-intensity noise impedes efficient work more than low-intensity and steady-state noise. the complexity of the task with which noise interferes plays a major role in determining how much noise actually degrades performance. two common ways in which noise can interfere with sleep are: delaying the onset of sleep, and shifting sleep stages. one effect of noise that does not seem to depend strongly on its level is annoyance. under some circumstances, a dripping water faucet can be as annoying as a jackhammer. there are no generally accepted criteria for noise levels associated with annoyance. if the noise consists of pure tones, or if it is impulsive in nature, serious complaints may arise. new information and communication technologies (ict) are being rapidly implemented in modern work life. about 65% of workers have computers at work, and about 35% are e-mail and internet users. there are three main problem areas in the use of new ict at work. these are: 1) the visual sensory system, 2) the cognitive processes, and 3) the psychomotoric responses needed for employing hand-arm systems. all three have been found to present special occupational health and even safety problems, which are not yet fully solved. the design of new more user-friendly technology is highly desirable, and the criteria for such technology need to be generated by experts in neurophysiology, cognitive psychology and ergonomics. it is important to note that the productivity and quality of information-intensive work requiring the use of ict depends crucially on the user-friendliness of the new technology interface, both the hardware and software. communication and information technologies will change job contents, organization of work, working methods and competence demands substantially in all sectors of the economy in all countries. a number of new occupational health and safety hazards have already arisen or are foreseen, including problems with the ergonomics of video display units, and musculoskeletal disorders in shoulder-neck and arm-hand systems, information overload, psychological stress, and pressure to learn new skills. the challenge to occupational health and safety people is to provide health-based criteria for new technologies and new types of work organization. it is also important to contribute to the establishment of healthy and safe work environments for people. in the approved and draft standards of the international standardization organization, iso, there are altogether about 50 different targets dealing with the standardization of eyesight-related aspects. vision is the most important channel of information in information-intensive work. from the point of view of seeing and eye fatigue, the commonly used visual display units (vdu) are not the most optimal solutions. stability of the image, poor lighting conditions, reflections and glare, as well as invisible flicker, are frequent problems affecting vision. the displays have, however, developed enormously in the 1990s, and there is evidence that the so-called flat displays have gradually gained ground. information-intensive work may increasingly load the vision and sense of hearing, particularly of older workers. even relatively minor limitations in vision or hearing associated with ageing have a negative effect on receiving and comprehending messages. this affects the working capacity in information-intensive work. the growing haste in information-intensive work causes concern among workers and occupational health professionals. particularly older workers experience stress, learning difficulties and threat of exclusion. corrective measures are needed to adjust the technology to the worker. the most important extension of the man-technology interface has taken place in the interaction of two information-processing elements: the central nervous system and the microprocessor. the contact is transmitted visually and by the hands, but also by the software which has been developed during the 1990s even more than the technology itself. many problems are still associated with the immaturity of the software, even though its user-friendliness has recently greatly improved. the logic and structure of the software and the user systems, visual ergonomics, information ergonomics, the speed needed, and the forgiving characteristics of programs, as well as the possibility to correct the commands at any stage of processing are the most important features of such improvements. also the user's skills and knowledge of information technology and the software have a direct effect on how the work is managed and how it causes workload. the user-friendliness and ergonomics of the technology, the disturbing factors in the environment, haste and time pressure, the work climate, and the age and professional skills of the individual user, even his or her physical fitness, all have an impact on the cognitive capacity of a person. this capacity can to a certain extent be improved by training, exercise and regulating the working conditions, as well as with expert support provided for the users when difficulties do occur. the use of new technologies has been found to be associated with high information overload and psychological stress. the problem is not only typical for older workers or those with less training, but also for the super-experts in ict who have shown an elevated risk of psychological exhaustion. there are four main types of ergonomic work loads: heavy dynamic work that may overload both the musculoskeletal and cardiovascular system; re-petitive tasks which may cause strain injuries; static work that may result in muscular pain; and lifting and moving heavy loads, which may result in overexertion, low back injury, or accidental injuries. visual ergonomics is gaining in importance in modern work life. the overload of the visual sensory system and unsatisfactory working conditions may strain the eye musculature, but can also cause muscle tension in the upper part of the body. this effect is aggravated if the worker is subjected to psychological stress or time pressure. in addition to being a biological threat, the risk of infections causes psychological stress to workers. the improved communication between health services and international organizations provides help in the early detection and control of previously unknown hazards. nevertheless, for example, the danger related to drug abusers continues to grow and present a serious risk to workers in, for example, health services and the police force. some new viral or re-emerging bacterial infections also affect health care staff in their work. the increase in the cases of drug-resistant tuberculosis is an example of such a hazard. the goal of preventive approaches is to exert control on the cause of unwelcome events, the course of such negative events or their outcome. in this context, one has to decide whether the harmful process is acute (an accident) or dependent on impact duration and stimulus (short-, medium-, and long-term). naturally, the prevention approaches depend on the phases of the harmful process, i.e. whether the harm is reversible, or whether it is possible only to maintain its status, or to slow down the process. it is assumed here that a stressful factor generates an inter-individual or intra-individual strain. thus the effects and consequences of stress are dependent on the situation, individual characteristics, capabilities, skills and the regulation of actions, and other factors. the overall consideration is related to work systems characterized by work contents, working conditions, activities, and actions. system performance is expected of this work system, and this system performance is characterized by a performance structure and its conditions and requirements (figure 4 .2). the performance of the biopsychosocial unit, i.e. the human being, plays an important role within the human performance structure (see figures 4.2 and 4.3). the human being is characterized by external and internal features, which are closely related to stress compatibility, and thus to strain. in this respect, preventive measures serve to optimize and ensure performance, on the one hand, and to control stress and strain, on the other. preventive measures aim to prevent bionegative effects and to facilitate and promote biopositive responses. • the internal factors affecting performance are described by performance capacity and performance readiness. • performance capacity is determined by the individual's physiological and psychological capacity. • performance readiness is characterized by physiological fitness and psychological willingness. • the external factors affecting performance are described by organizational preconditions/requirements and technical preconditions/requirements. • regarding the organizational requirements, the organizational structure and organizational dynamics are of significance. • in the case of technical requirements, the difficulties of the task, characterized by machines, the entire plant and its constructions, task content, task design, technical and situation-related factors, such as work layout, anthropometrics, and quality of the environment, are decisive (table 4 .1). mental stress plays an increasing role in the routine activities of enterprises. through interactive models of mental stress and strain, it is possible to represent the development of mental strain and its impairing effects (e.g. tension, fatigue, monotony, lack of mental satisfaction). it is important to distinguish the above-mentioned impairing effects from each other, since they can arise from different origins and can be prevented or eliminated by different means. activities that strain optimally enhance health and promote safe execution of work tasks. stress essentially results from the design parameters of the work system or workplace. these design parameters are characterized by, e.g.: • technology, such as work processes, work equipment, work materials, work objects; • anthropometric design; • work techniques, working hours, sharing of work, cycle dependence, job rotation; • physiological design that causes strain, fatigue; • psychological design that either motivates or frustrates; • information technology, e.g. information processing, cognitive ergonomic design; • sociological conditions; and • environmental conditions, e.g. noise, dust, heat, cold. the stress structure is very complex, and we therefore need to look at the individual parameters carefully, taking into account the interactions and links between the parameters at the conceptual level. the design parameters impact people as stress factors. as a result, they also turn into conditions affecting performance. such conditions can basically be classified into two types: a person's internal conditions, characterized in particular by predisposition and personality traits, and a person's external conditions, determined mainly by the design parameters. when we look at performance as resulting from regulated or reactive action, we find three essential approaches for prevention: • the first approach identifies strain. it is related to anatomical, biochemical, histological, physiological characteristic values, typical curves of organ systems, the degree of utilization of skills through stress, and thus the degree of utilization of the dynamics of physiological variables in the course of stress. • the second approach is related to the control of strain. the aim is to identify performance limits, the limits of training and practice, and to put them into positive use. adaptation and fatigue are the central elements here. • the third approach for prevention is related to reducing strain. the aim is to avoid harm, using known limits as guidelines (e.g. maximum workplace concentration limit values for harmful substances, maximum organspecific concentration values, biological tolerance values for substances, limit values for noise and physical loads). however, the use of guideline values can only be an auxiliary approach, because the stress-strain concept is characterized by highly complex connections between the exogenous stress and the resulting strain. an objectively identical stress will not always cause the same level of strain in an individual. due to action regulation and individual characteristic values and curves of the organ systems (properties and capabilities), differences in strain may occur. seemingly identical stress can cause differing strain due to the superposition of partial stress. combinations of partial stress can lead to compensatory differences (e.g. physiological stress can compensate for psychological stress) or accumulation effects. partial stress is determined by the intensity and duration of the stress, and can therefore appear in differing dimensions and have varying effects. in assessing overall stress, the composition of the partial stress according to type, intensity, course and time is decisive. partial stress can occur simultaneously and successively. in our considerations, the principle of homeostasis plays an important role. however, optimizing performance is only a means to an end in a prevention programme. the actual purpose is to avoid harm, and thus to control strain. harm is a bionegative effect of stress. the causative stress is part of complex conditions in a causal connection. causal relationships can act as dose-effect relationships or without any relation to the dose. in this respect, the causative stress condition can form a chain with a fixed or variable sequence; it can add up, multiply, intensify or have an effect in only specific combinations, and generate different effects (e.g. diseases). we are thus dealing with a multicausal model or a multi-factor genesis. low back pain is an example of a complex phenomenon. the incidence of musculoskeletal disorders, especially low back pain, is rapidly increasing. several occupational factors have been found to increase the risk for low back pain. some studies indicate that psychosocial and work-related conditions are far more accurate in the prognosis of disability than are physical conditions. chronic low back pain is perceived as a phenomenon which encompasses biological, social and psychological variables. according to the model of adaptation, the goal of reducing risks is to increase a person's physical abilities (i.e. flexibility, strength, endurance), the use of body mechanics, techniques to protect the back (following the rules of biomechanics), to improve positive coping skills and emotional control. the following unfavourable factors leading to back pain have been identified at workplaces: • the lifting of too heavy loads. • working in a twisted or bent-down position. • work causing whole-body vibration. • working predominantly in a sitting position. • carrying heavy loads on the shoulders. the prevention of acute back pain and the prevention of work disability must entail several features. one important element is work safety, which can be maximized by screening a worker's physical and intellectual capacities, by ensuring ergonomic performance of the work procedures, and by increasing awareness of proper working techniques that do not strain the back. the use of adaptation programmes makes it possible to attain a higher performance level and to be able to withstand more strain (figure 4.4) . research-based methods of training optimize and improve performance. they are a means for controlling stress and strain with the aim of preventing bionegative effects and facilitating and promoting biopositive responses. the stress (load) and strain model and human performance can be described as follows: • causative stress generates an inter-individual or intra-individual strain. • the effects and consequences depend on a person's properties, capabilities, skills and the regulation of actions, individual characteristics of the organ systems, and similar factors. • within the performance structure, the performance of the biopsychosocial unit, i.e. the human being, plays an important role. the human being is characterized by external and internal factors, which in turn are closely related to stress compatibility and thus to strain. the connection between stress and harm plays a significant role in the research on occupational health hazards. how should this connection be explored? different hypotheses exist in replying to this question, but none of them have been definitively proven. the three most common hypotheses today are: stress occurring in connection with a person's life events. the number and extent of such events is decisive. problem-coping behaviour and/or social conditions are variables explaining the connection between stress and harm. 3. the additive stress hypothesis. the ability to cope with problems and the social conditions has an effect on harm which is independent of the stress resulting from life events. when we refer to the complexity of risks in this context of occupational safety our focus shall be on the enterprise. there are different kinds of risks to be found in enterprises. many of them are of general importance, i.e. they are in principle rather independent of an enterprise's size or its type of activity. how to deal with such risks shall be outlined to some extent here. in order to treat those risks at work successfully resources are needed whose availability often depends on the enterprise's situation. the situation in enterprises usually is a determining indicator for available resources to control and develop safety and health and thus performance of the enterprise and its workers and employees through appropriate preventive measures. this situation has been described to some extent in chapter 2. big companies usually have well-developed safety and health resources, and they often transfer appropriate policies and practices to the less developed areas where they operate. even in big enterprises, however, there is fragmentation of local workplaces into ever smaller units. many of the formerly in-built activities of enterprises are outsourced. new types of work organizations are introduced, such as flat and lean organizations, increase of telework and call centres, many kinds of mobile jobs and network organizations. former in-company occupational health services are frequently transferred to service providers. this leads to the establishment of high numbers of micro-enterprises, small scale enterprises (sses), small and medium-sized enterprises (smes) and self-employed people. sses and smes are thus becoming the most important employers in the future. from a number of studies there is evidence that at least among a part of sses and smes awareness of osh risks is low. both managers and workers often do not see the need to improve occupational safety and health or ergonomic issues and their possibilities and benefits by reducing or eliminating risks at work. as these types of enterprises, even more the self-employed, do not have sufficient resources or expertise for implementing preventive measures, the need for external advisory support, services and incentives is evident and growing. interpersonal relations in sses and smes being generally very good provides a strong chance for effectively supporting them. other special features in the structure of small and medium-sized enterprises to be considered are: • direct participation of the management in the daily activities; • the management structure is designed to meet the requirements of the manager; • less formal and standardized work processes, organizational structures and decision processes; • no clear-cut division of work: -wide range of tasks; and -less specialization of the employees; • unsystematic ways of obtaining and processing information; • great importance of direct personal communication; • less interest in external cooperation and advice; • small range of internal, especially long-term and strategic planning; and • stronger inclination of individual staff members to represent their own interests. the role of occupational health services (ohs) in smes is an interdisciplinary task, consisting of: • risk assessment: -investigation of occupational health problems according to type of technology, organization, work environment, working conditions, social relationships. • surveillance of employees' health: -medical examinations to assess employees' state of health; and -offering advice, information, training. • advice, information, training: -measures to optimize safety and health protection; and -safe behaviour, safe working procedures, first aid preparedness. different kinds of risks are found in enterprises (see table 4 .2). these different types of risks need to be handled by an interlinked system to control the risks and to find compromises between the solutions. figure 4 .7 illustrates these linkages. the promotion of safety and health is linked to several areas and activities. all of these areas influence the risk management process. the results of risk treatment not only solve occupational health and safety problems, but they also give added value to the linked fields. specific risk management methods are needed to reach the set goal. one needs to know what a risk is. the definition of risk is essential: a risk is a combination of a probability -not frequency -of occurrence, and the associated unwelcome outcome or impact of a risk element (consequence). risk management is recognized as an integral part of good management practice. it is a recurring process consisting of steps which, when carried out in a sequence, allow decision making to be improved continuously. risk management is a logical and systematic method of identifying, analyzing, evaluating, treating, monitoring and communicating risks arising during any activity, function, or process in a manner enabling the organization to minimize losses and maximize productive opportunities. different methods are available for analyzing problems. each method is especially suited to respond to certain questions and less suited for others. a complex "thinking scheme" is necessary for arranging the different analyses correctly within the system review. such a scheme includes the following steps: 1. defining the unit under review: the actual tasks and boundaries of the system (a fictitious or a real system) must be specified: time, space and state. 2. problem analysis: all problems existing in the defined system, including problems which do not originate from the system itself, are detected and described. 3. causes of problems: all possible or probable causes of the problems are identified and listed. 4. identifying interaction: the dependencies of the effect mechanisms are described, and the links between the causes are determined. 5. establishing priorities and formulating targets: to carry out this step, it is necessary to evaluate the effects of the causes. 6. solutions to the problems: all measures needed for solving the individual problems are listed. the known lists usually include technical as well as non-technical measures. since several measures are often appropriate for solving one problem, a pre-selection of measures has to be done already at this stage. however, this can only be an approach to the solution; the actual selection of measures has to be completed in steps 7 and 8. 7. clarifying inconsistencies and setting priorities: as the measures required for solving individual problems may be inconsistent in part, or may even have to be excluded as a whole, any inconsist-encies need to be clarified. a decision should then be made in favour or against a measure, or a compromise may be sought. 8. determining measures for the unit under review: the measures applicable to the defined overall system are now selected from the measures for the individual problems. 9. list of questions regarding solutions selected for the overall system: checking whether the selected measures are implementable and applicable for solving the problems of the overall system. 10. controlling for possible new problems: this step consists of checking whether new problems are created by the selected solution. the close link between cause and effect demands that the processes and sub-processes must be evaluated uniformly, and risks must be dealt with according to a coordinated procedure. the analysis is started by orientation to the problem. this is done in the following steps: 1. recognizing and analyzing the problem according to its causes and extent, by means of a diagnosis and prediction, and comparison with the goals aimed at. 2. description and division of the overall problem into individual problem areas, and specifying their dependencies. 3. defining the problem and structuring it according to the objectives, time relation, degree of difficulty, and relevance to the goal. 4. detailed analysis of the causes, and classification in accordance to the possible solution. the analysis of the problem should be integrated into the overall analytical process in accordance with the thinking schemes described earlier. the relevance and priorities related to the process determine the starting point for the remaining steps of the analysis. analyses are divided into quantitative and qualitative ones. quantitative analyses include risk analyses, that is, theoretical safety-related analysis methods and safety analyses, e.g. classical accident analyses. qualitative analyses include failure mode and effect analyses, hazard analyses, failure hazard analyses, operating hazard analyses, human error code and effect analyses, information error and effect analyses. the theoretical safety-related analysis methods include inductive and deductive analyses based on boolean models. inductive analyses are, e.g. fault process analyses. deductive analyses are fault tree analyses, analytical processes and simulation methods. theoretical safety-related analysis methods which are not based on boolean models are stochastic processes, such as markow's model, risk analyses and accident analyses which, as a rule, are statistical or probability-related analyses. a possible scheme to begin with is shown in figure 4 .9. since absolute safety, entailing freedom from all risks, does not exist in any sphere of life, the task of those dealing with safety issues is to avert hazards and to achieve a sustainable reduction of the residual risk, so that it does not exceed a tolerable limit. the extent of this rationally acceptable risk is also influenced by the level of risk which society intuitively considers as being acceptable. those who propose definitions of safety are neither authorized nor capable of evaluating the general benefit of technical products, processes and services. risk assessment is therefore focused at the potential harm caused by the use or non-use of the technology. the guidelines given in "a new approach to technical harmonization and standards" by the council resolution of 7 may 1985 are valid in the european union. the legal system of a state describes the protective goals, such as protection of life, health, etc., in its constitution, as well as in individual laws and regulations. as a rule, these do not provide an exact limit as to what is still a tolerable risk. this limit can only be established indirectly and unclearly on the basis of the goals and conceptions set down by the authorities and laws of a state. in the european union, the limits are expressed primarily in the "basic safety and health requirements". these requirements are then put into more concrete terms in the safety-related definitions issued by the bodies responsible for preparing industrial standards. compliance with the standards is voluntary, but it is presumed that the basic requirements of the directives are met. the term which is opposite to "safety" is "hazard". both safe and hazardous situations are founded on the intended use of the technical products, processes and services. unintended use is taken into account only to the extent that it can be reasonably foreseen. the risks present in certain events are, in a more narrow sense, unwelcome and unwanted outcomes with negative effects (which exceed the range of acceptance). unwelcome events are • source conditions of processes and states; • processes and states themselves; and • effects of processes and states which can result in harm to persons or property. an unwelcome event can be defined as a single event or an event within a sequence of events. possible unwelcome events are identified for a unit under review. the causes may be inherent in the unit itself, or outside of it. in order to determine the risks involved in unwelcome events, it is necessary to identify probabilities and consequences. the question arises: are the extent and probability of the risk known? information is needed to answer this question. defining risk requires information concerning the probability of occurrence and the extent of the harm of the consequences. uncertainty is given if the effects are known but the probability is unknown. ignorance is given if both the effects and the probability are unknown. figure 4 .10 shows the risk analysis procedure according to the type of information available. since risk analyses are not possible without practical, usable information, it is necessary to consider the nature of the information. the information is characterized by its content, truth and objectivity, degree of confirmation, the possibility of being tested, and the age of the information. the factors determining the content of the information are generality, precision and conditionality. the higher the conditionality, the smaller is the generality, and thus the smaller the information content of the statement. truth is understood as conformity of the statement with the real state of affairs. the closer that the information is to reality, the higher is its information content, and the smaller its logical margin. the degree of controllability is directly dependent on the information content: the bigger the logical margin, the smaller the information content, and thus the higher the probability that the information content will prove its worth. in this respect, probability plays a role in the information content: the greatest significance is attributed to the logical hypothetical probability and statistical probability of an event. objectivity and age are additional criteria for any information. the age and time relation of information play a particularly important role, because consideration of the time period is an important feature of analysis. as a rule, information and thus the data input in the risk analysis consist of figures and facts based on experience, materials, technical design, the organization and the environment. in this regard, most figures are based on statistics on incidents and their occurrences. factual information reveals something about the actual state of affairs. it consists of statements related to past conditions, incidents, etc. forecast-type predictions are related to real future conditions, foretelling that certain events will occur in the future. explanatory information replies to questions about the causes of phenomena, and provides explanations and reasons. it establishes links between different states based on presumed cause-effect relationships. subjunctive information expresses possibilities, implying that certain situations might occur at present or in the future, thus giving information about conceivable conditions, events and relationships. normative information expresses goals, standards, evaluations and similar matters; it formulates what is desirable or necessary. the main problem with risk analyses is incomplete information, in particular regarding the area of "uncertainty". in the eu commission's view, recourse to the so-called precautionary principle presupposes that potentially dangerous effects deriving from a phenomenon, product or process have been identified via objective scientific evaluation, and that scientific evaluation does not allow the risk to be determined with sufficient certainty. recourse to the precautionary principle thus takes place in the framework of general risk management that is concretely connected to the decision-making process. if application of the precautionary principle results in the decision that action is the appropriate response to a risk, and that further scientific information is not needed, it is still necessary to decide how to proceed. apart from adopting legal provisions which are subject to judicial control, a whole range of actions is available to the decision-makers (e.g. funding research, or deciding to inform the public about the possible adverse effects of a product or procedure). however, the measures may not be selected arbitrarily. in conclusion, the assessment of various risks and risk types which may be related to different types of hazards requires a variety of specific risk assessment methods. if one has dependable information about the probability and consequences of a serious risk or risky event, one should use the risk assessment procedure shown in figure 4 .11. • major industrial accidents; • damage caused by dangerous substances; • nuclear accidents; • major accidents at sea; • disasters due to forces of nature; and • acts of terrorism. • dangerous substances discharged (fire, explosion); • injury to people and damage to property; • immediate damage to the environment; • permanent or long-term damage to terrestrial habitats, to fresh water, to marine habitats, to aquifers or underground water supplies; and • cross-border damage. • technical failure: devices, mountings, containers, flanges, mechanical damage, corrosion of pipes, etc.; • human failure: operating error, organizational failure, during repair work; • chemical reaction; • physical reaction; and • environmental cause. system analysis is the basis of all hazard analyses, and thus needs to be done with special care. system analysis includes the examination of the system functions, particularly the performance goals and admissible deviations in the ambient conditions not influenced by the system, the auxiliary sources of the system (e.g. energy supply), the components of the system, and the organization and behaviour of the system. geographical arrangements, block diagrams, material flow charts, information flow charts, energy flow charts, etc. are used to depict technical systems. the objective is to ensure the safe behaviour of the technical systems by design methods, at least during the required service life and during intended use. qualitative analyses are particularly important in practice. as a rule, they are form sheet analyses and include failure mode and effect analyses, which examine and determine failure modes and their effects on systems. the preliminary hazard analysis looks for the hazard potentials of a system. the failure hazard analysis examines the causes of failures and their effects. the operating hazard analysis determines the hazards which may occur during operation, maintenance, repair, etc. the human error mode and effect analysis examines error modes and their effects which occur because of wrong behaviour of humans. the information error mode and effect analysis examines operating, maintenance and repair errors, fault elimination errors and the effects caused by errors in instructions and faulty information. theoretical analysis methods include the fault tree analysis, which is a deductive analysis. an unwelcome incident is provided to the system under review. then all logical links and/or failure combinations of components or partial system failures which might lead to this unwelcome incident are assembled, forming the fault tree. the fault tree analysis is suited for simple as well as for complex systems. the objective is to identify failures which might lead to an unwelcome incident. the prerequisite is exact knowledge about the functioning of the system under review. the process, the functioning of the components and partial systems therefore need to be present. it is possible to focus on the flow of force, of energy, of materials and of signals. the fault process analysis has a structure similar to that of the fault tree analysis. in this case, however, we are looking for all unwelcome incidents as well as their combinations which have the same fault trigger. analysis of the functioning of the system under review is also necessary for this. analyses can also be used to identify possible, probable and actual risk components. the phases of the analysis are the phases of design, including the preparation of a concept, project and construction, and the phases of use which are production, operation and maintenance. in order to identify the fault potential as completely as possible, different types of analyses are usually combined. documentation of the sufficient safety of a system can be achieved at a reasonable cost only for a small system. in the case of complex systems, it is therefore recommended to document individual unwelcome incidents. if solutions are sought and found for individual unwelcome incidents, care should be taken to ensure that no target conflicts arise with regard to other detail solutions. with the help of the fault tree, it is possible to analyse the causes of an unwelcome incident and the probability of its occurrence. decisions on whether and which redundancies are necessary can in most cases be reached by simple estimates. four results can be expected by using a fault tree: 1. the failure combination of inputs leading to the unwelcome event; 2. the probability of their occurrence; 3. the probability of occurrence of the unwelcome event; and 4. the critical path that this incident took from the failure combination through the fault tree. a systematic evaluation of the fault tree model can be done by an analytical evaluation (calculation) or by simulation of the model (monte-carlo method). a graphic analysis of the failure process is especially suited to prove the safety risk of previously defined failure combinations in the system. the failure mode and effect analysis and the preliminary hazard analysis as mentioned previously, no method can disclose all potential faults in a system with any degree of certainty. however, if one starts with the preliminary hazard analysis, then at least the essential components with hazard potential will be defined. the essential components are always similar, namely, kinetic energy, potential energy, source of thermal energy, radioactive material, biological material, chemically reactive substance. with the fault tree method, any possible failure combinations (causes), leading to an unwelcome outcome, can then be identified additionally. re-160 are especially suited for identifying failures in a system which pose a risk. liability parameters can be determined in the process, e.g. the frequency of occurrence of failure combinations, the frequency of occurrence of unwelcome events, non-availability of the system upon requests, etc. the failure effect analysis is a supplementary method. it is able to depict the effects of mistakes made by the operating personnel, e.g. when a task is not performed, or is performed according to inappropriate instructions, or performed too early, too late, unintentionally or with errors. it can pinpoint also effects resulting from operating conditions and errors in the functional process or its elements. an important aspect of all hazard analyses is that they are only valid for the respective case under review. every change in a parameter basically requires new analyses. this applies to changes in the personnel structure and the qualification of persons, as well as to technical specifications. for this reason, it is necessary to document the parameters on which each analysis is based. the results of the hazard analyses form the basis for the selection of protective measures and measures to combat the hazards. if the system is modified, the hazards inherent in the system may change, and the measures to combat the hazards may have to be changed as well. this may also mean that the protective measures or equipment which existed at time x for the system or partial system in certain operating conditions (e.g. normal operation, set-up operation, and maintenance phase) may no longer be compatible. different protective measures, equipment or strategies may then be needed. however, hazard analyses do not merely serve to detect and solve potential failures. they form the basis for the selection of protective measures and protective equipment, and they can also test the success of the safety strategies specified. a selection of methods used for hazard analysis is given in annex 2 to section 4.1. risk assessment is a series of logical steps enabling the systematic examination of the hazards associated with machinery. risk assessment is followed, whenever necessary, by actions to reduce the existing risks and by implementing safety measures. when this process is repeated, it eliminates hazards as far as possible. risk assessment includes: • risk analysis: -determining the limits of machinery; -identifying hazards; and -estimating risks. • risk evaluation. risk analysis provides the information required for evaluating risks, and this in turn allows judgements to be made on the safety of e.g. the machinery or plant under review. risk assessment relies on decisions based on judgement. these decisions are to be supported by qualitative methods, complemented, as far as possible, by quantitative methods. quantitative methods are particularly appropriate when the foreseeable harm is very severe or extensive. quantitative methods are useful for assessing alternative safety measures and for determining which measure gives best protection. the application of quantitative methods is restricted to the amount of useful data which is available, and in many cases only qualitative risk assessment will be possible. risk assessment should be conducted so that it is possible to document the used procedure and the results that have been achieved. risk assessment shall take into account: • the life cycle of machinery or the life span of the plant. • the limitations of the machinery or plant, including the intended use (correct use and operation of the machinery or plant, as well as the consequences of reasonably foreseeable misuse or malfunction). • the full range of foreseeable uses of the machinery (e.g. industrial, nonindustrial and domestic) by persons identified by sex, age, dominant hand usage, or limiting physical abilities (e.g. visual or hearing impairment, stature, strength). • the anticipated level of training, experience or ability of the anticipated users, such as: -operators including maintenance personnel or technicians; -trainees and juniors; and -general public. • exposure of other persons to the machine hazards, whenever they can be reasonably foreseen. having identified the various hazards that can originate from the machine (permanent hazards and ones that can appear unexpectedly), the machine designer shall estimate the risk for each hazard, as far as possible, on the basis of quantifiable factors. he must finally decide, based on the risk evaluation, whether risk reduction is required. for this purpose, the designer has to take into account the different operating modes and intervention procedures, as well as human interaction during the entire life cycle of the machine. the following aspects in particular must be considered: • construction; transport; • assembly, installation, commissioning; • adjusting settings, programming or process changeover; • instructions for users; • operating, cleaning, maintenance, servicing; and • checking for faults, de-commissioning, dismantling and safe disposal. malfunctioning of the machine due to, e.g. • variation in a characteristic or dimension of the processed material or workpiece; • failure of a part or function; • external disturbance (e.g. shock, vibration, electromagnetic interference); • design error or deficiency (e.g. software errors); • disturbance in power supply; and • flaw in surrounding conditions (e.g. damaged floor surface). unintentional behaviour of the operator or foreseeable misuse of the machine, e.g.: • loss of control of the machine by the operator (especially in the case of hand-held devices or moving parts); • automatic (reflexive) behaviour of a person in case of a machine malfunction or failure during operation; • the operator's carelessness or lack of concentration; • the operator taking the "line of least resistance" in carrying out a task; • behaviour resulting from pressure to keep the machine running in all circumstances; and • unexpected behaviour of certain persons (e.g. children, disabled persons). when carrying out a risk assessment, the risk of the most severe harm that is likely to occur from each identified hazard must be considered, but the greatest foreseeable severity must also be taken into account, even if the probability of such an occurrence is not high. this objective may be met by eliminating the hazards, or by reducing, separately or simultaneously, each of the two elements which determine the risk, i.e. the severity of the harm from the hazard in question, and the probability of occurrence of that harm. all protective measures intended to reach this goal shall be applied according to the following steps: this stage is the only one at which hazards can be eliminated, thus avoiding the need for additional protective measures, such as safeguarding machines or implementing complementary protective measures. 3. information about the residual risk. information for use on the residual risk is not to be a substitute for inherently safe design, or for safeguarding or complementary protective measures. risk estimation and evaluation must be carried out after each of the above three steps of risk reduction. adequate protective measures associated with each of the operating modes and intervention procedures prevent operators from being prone to use hazardous intervention techniques in case of technical difficulties. the aim is to achieve the lowest possible level of risk. the design process is an iterative cycle, and several successive applications may be necessary to reduce the risk, making the best use of available technology. four aspects should be considered, preferably in the following order: 1. the safety of the machine during all the phases of its life cycle; 2. the ability of the machine to perform its function; 3. the usability of the machine; and 4. the costs of manufacturing, operating and dismantling the machine. the following principles apply to technical design: service life, safe machine life, fail-safe and tamper-proof design. a design which ensures the safety of service life has to be chosen when neither the technical system nor any of its safety-relevant partial functions can be allowed to fail during the service life envisaged. this means that the components of the partial functions need to be exchanged at previously defined time intervals (preventive maintenance). in the case of a fail-safe design, the technical system or its partial functions allow for faults, but none of these faults, alone or in combination, may lead to a hazardous state. it is necessary to specify just which faults in one or several partial systems can be allowed to occur simultaneously without the overall system being transferred into a hazardous state (maximum admissible number of simultaneous faults). a failure or a reduction in the performance of the technical system is accepted in this case. tamper-proof means that it is impossible to intentionally induce a hazardous state of the system. this is often required of technical systems with a high hazard potential. strategies involving secrecy play a special role in this regard. in the safety principles described here, redundant design should also be mentioned. the probability of occurrence and the consequences of damage are reduced by multiple arrangements, allowing both for subsystems or elements to be arranged in a row or in parallel. it is possible to reduce the fault potential of a technical system by the diversification of principles: several different principles are used in redundant arrangements. the spatial distribution of the function carriers allows the possibilities to influence faults to be reduced to one function. in the redundant arrangements, important functions, e.g. information transmission, are therefore designed in a redundant manner at different locations. the measures to eliminate or avoid hazards have to meet the following basic requirements: their effect must be reliable and compulsory, and they cannot be circumvented. reliable effect means that the effect principle and construction design of the planned measure guarantee an unambiguous effect, that the components have been designed according to regulations, that production and assembly are performed in a controlled manner, and that the measure has been tested. compulsory effect includes the demand for a protective effect which is active at the start of a hazardous state and during it, and which is deactivated only when the hazardous state is no longer present, or stops when the protective effect is not active. technical systems are planned as determined systems. only predictable and intended system behaviour is taken into account when the system is designed. experience has shown, however, that technical systems also display stochastic behaviour. that is, external influences and/or internal modifications not taken into consideration in the design result in unintended changes in the system's behaviour and properties. the period of time until the unintended changes in behaviour and/or in properties occur, cannot be accurately determined; it is a random variable. we have to presume that there will be a fault in every technical system. we simply do not know in advance when it will take place. the same is true for repairs. we know that it is generally possible in systems requiring re-pair to complete a repair operation successfully, but we cannot determine the exact time in advance. using statistical evaluations, we can establish a timedependent probability at which a "fault event" or "completion of a repair operation" occurs. the frequency of these events determines the availability of the system requiring repair. technical systems are intended to perform numerous functions and, at the same time, to be safe. the influence of human action on safety has to be taken into account in safety considerations as well (i.e. human factor). a system is safe when there are no functions or action sequences resulting in hazardous effects for people and/or property. risks of unwelcome events (in the following called "risk of an event") are determined on the basis of the experience (e.g. catalogue of measures) with technical systems. in addition to this, safety analyses are used (e.g. failure mode and effect analysis, hazard analysis, failure hazard analysis, operating hazard analysis, information error analysis), as well as mathematical models (e.g. worst-case analysis, monte-carlo procedure, markow's models). unwelcome events are examined for their effects. this is followed by considerations about which design modifications or additional protective measures might provide sufficient safety against these unwelcome events. the explanations below present the basic procedure for developing safety-relevant arrangements and solutions, i.e. the thinking and decision-making processes, as well as selecting criteria that are significant for the identification of unwelcome events, the risk of an event, the acceptance limits and the adoption of measures. before preparing the final documentation, it is essential to verify that the limit risk has not been exceeded, and that no new unwelcome events have occurred. the sequence scheme describes the procedure for developing safety arrangements and for finding solutions aiming to avoid the occurrence of unwelcome events which exceed the acceptance limits, by selecting suitable measures. in this context, it is assumed that: • an unwelcome event is initially identified as a single event within a comprehensive event sequence (e.g. start-up of a plant), and the risk of an event and limit risk are determined. • the selection of technical and/or non-technical measures is subject to a review of the content and the system, and the decision regarding a solution is then made. • the number of applicable measures is limited, and therefore it may not be possible to immediately find a measure with an acceptable risk for a preliminary determination of the unwelcome event. • implementation of the selected solution can result in the occurrence of a new unwelcome event. • in the above cases, a more concrete, new determination of the unwelcome event and/or the unit under review, or the state of the unit under review, and another attempt at deciding upon measures may lead to the desired result, although this may have to be repeated several times before it is successful. in the case of complex event sequences, several unwelcome events may become apparent which have to be tackled by the respective set of measures. in accordance with the sequence scheme, the unit under review and its state have to be determined first. this determination includes information on, e.g., • product type, dimension, product parts/elements distinguished according to functional or construction aspects, if applicable; • intended use; • work system or field of application; • target group; • supply energy, transformed in the product, transmitted, distributed, output; • other parameters essential to safety assessment according to type and size of the product; • known or assumed effects on the product or its parts (e.g. due to transport, assembly, conditions at the assembly site, operation, maintenance); • weight, centre of gravity; • materials, consumables; • operating states (e.g. start-up, standstill, test run, normal operation); • condition (new, condition after a period in storage/shutdown, after repair, in case of modified operating conditions and/or other significant changes); and • known or suspected effects on humans. the next step is the identification of unwelcome events. they are source conditions of processes and states, or processes and states themselves. they can be the effects of processes and states which can cause harm to people or property. an unwelcome event can be a single event or part of a sequence of events. one should look for unwelcome events in sequences of processes and functions, in work activities and organizational procedures, or in the work environment. care has to be taken that the respective interfaces are included in the considerations. deviations and time-dependent changes in regard to the planned sequences and conditions have to be taken into account as well. the risk of an unwanted event results from the probability statement which takes into account both • the expected frequency of occurrence of the event; and • the anticipated extent of harm of the event. the expected frequency of occurrence of an event leading to harm is determined by, e.g., • the probability of the occurrence itself; • the duration and frequency of exposure of people (or of objects) in the danger zone, e.g. -extremely seldom (e.g. during repair), -seldom (e.g. during installation, maintenance and inspection), -frequently, and -very frequently (e.g. constant intervention during every work cycle); • the influence of users or third parties on the risk of an event. the extent of harm is determined by, e.g., • the type of harm (harm to people and/or property); • the severity of the harm (slight/severe/fatal injury of persons, or corresponding damage to property); and • number of people or objects affected. in principle, the safety requirements depend on the ratio of the risk of an event to the limit risk. criteria for determining the limit risk are, e.g., • personal and social acceptance of hazards; • people possibly affected (e.g. layman, trained person, specialized worker); • participation of those affected in the process; and • possibilities of averting hazards. the safety of various technical equipment with comparable risk can, for instance, be achieved • primarily by technical measures, in some cases; and • mainly by non-technical measures, in other cases. this means that several acceptable solutions with varying proportions of technical and non-technical measures may be found for a specific risk. in this context, the responsibility of those involved should be taken into consideration. technical measures are developed on the basis of e.g. the following principles: • avoiding hazardous interfaces (e.g. risk of crushing, shearing); hazard sources (e.g. radiation sources, flying parts, hazardous states and actions as well as inappropriate processes); • limiting hazardous energy (e.g. by rupture disks, temperature controllers, safety valves, rated break points); • using suitable construction and other materials (e.g. solid, sufficiently resistant against corrosion and ageing, glare-free, break-proof, non-toxic, non-inflammable, non-combustible, non-sliding); • designing equipment in accordance with its function, material, load, and ergonomics principles; • using fail-safe control devices employing technical means; • employing technical means of informing (e.g. danger signal); • protective equipment for separating, attaching, rejecting, catching, etc.; • suction equipment, exhaust hoods, when needed; • protection and emergency rooms; and • couplings or locks. technical measures refer to, e.g., • physical, chemical or biological processes; • energy, material and information flow in connection with the applied processes; • properties of materials and changes in the properties; and • function and design of technical products, parts and connections. the iterative (repeated) risk reduction process can be concluded after achieving adequate risk reduction and, if applicable, a favourable outcome of risk comparison. adequate risk reduction can be considered to have been achieved when one is able to answer each of the following questions positively: • have all operating conditions and all intervention procedures been taken into account? • have hazards been eliminated or their risks been reduced to the lowest practicable level? • is it certain that the measures undertaken do not generate new hazards? • are the users sufficiently informed and warned about the residual risks? • is it certain that the operator's working conditions are not jeopardized by the protective measures taken? • are the protective measures compatible with each other? • has sufficient consideration been given to the consequences that can arise from the use of a machine designed for professional/industrial use when it is used in a non-professional/non-industrial context? • is it certain that the measures undertaken do not excessively reduce the ability of the machine to perform its intended function? there are still many potential risks connected with hazardous substances about which more information is needed. because the knowledge about the relation between their dose and mode of action is not sufficient for controlling such risks, more research is needed. the following list highlights the themes of the numerous questions related to such risks: • potentially harmful organisms; • toxicants, carcinogens; • pesticides, pollutants, poisonous substances; • genetically engineered substances; • relation between chemical and structural properties and toxicity; • chemical structure and chemical properties and the relation to reactivity and reaction possibilities of organic compounds to metabolic reaction and living systems; • modes of action, genotoxicity, carcinogenicity, effects on humans/animals; • potentially harmful organisms in feedstuffs and animal faeces; • viruses and pathogens; • bacteria in feedstuffs and faeces; • parasites in feedstuffs and animal faeces; • pests in stored feedstuffs; • probiotics as feed additives; and • preservatives in feedstuffs. violent actions damaging society, property or people have increased, and they seem to spread both internationally as well as within countries. these new risks are difficult to predict and manage, as the very strategy of the actors is to create unexpected chaotic events. certain possibilities to predict the potential types of hazards do exist, and comprehensive predictive analyses have been done (meyerson, reaser 2002) . new methodologies are needed to predict the risk of terrorist actions, and also the strategies for risk management need to be developed. due to the numerous background factors, the preparedness of societies against these risks needs to be strengthened. table 4 .3 lists important societal systems which are vulnerable to acts of terrorism. the situation in the developing countries needs to be tackled with specific methods. one has to answer the following questions: • what specific examples of prevention instruments can be offered? • what are the prerequisites for success? • how can industrialized countries assist the developing countries in carrying out preventive actions? • how should priorities be set according to the available resources? one possibility is to start a first-step programme, the goal of which is higher productivity and better workplaces. it can be carried out by improving • storage and handling of materials: -provide storage racks for tools, materials, etc.; -put stores, racks etc. on wheels, whenever possible; -use carts, conveyers or other aids when moving heavy loads; -use jigs, clamps or other fixtures to hold items in place. • work sites: -keep the working area clear of everything that is not in frequent use. • machine safety: -install proper guards to dangerous tools/machines; -use safety devices; -maintain machines properly. • control of hazardous substances: -substitute hazardous chemicals with less hazardous substances; -make sure that all organic solvents, paints, glues, etc., are kept in covered containers; -install or improve local exhaust ventilation; -provide adequate protective goggles, face shields, earplugs, safety footwear, gloves, etc.; -instruct and train workers; -make sure that workers wash their hands before eating and drinking, and change their clothes before going home. • lighting: -make sure that lighting is adequate. • social and sanitary facilities: -provide a supply of cool, safe drinking water; -have the sanitary facilities cleaned regularly; -provide a hygienic place for meals; -provide storage for clothing or other belongings; -provide first aid equipment and train a qualified first-aider. • premises: -increase natural ventilation by having more roof and wall openings, windows or open doorways; -move sources of heat, noise, fumes, arc welding, etc., out of the workshop, or install exhaust ventilation, noise barriers, or other solutions; -provide fire extinguishers and train the workers to use them; -clear passageways, provide signs and markings. • work organization: -keep the workers alert and reduce fatigue through frequent changes in tasks, opportunities to change work postures, short breaks, etc.; -have buffer stocks of materials to keep work flow constant; -use quality circles to improve productivity and quality. risk combination of the probability of an event and its consequences. the term "risk" is generally used only when there is at least a possibility of negative consequences. in some situation, risk arises from the possibility of deviation from the expected outcome or event. outcome of an event or a situation, expressed in quality and in quantity. it may result in a loss or in an injury or may be linked to it. the result can be a disadvantage or a gain. in this case the event or the situation is the source. in connection with every analysis it has to be checked whether the cause is given empirically, or follows a set pattern, and whether there is scientific agreement regarding these circumstances. note 1 there can be more than one consequence from one event. note 2 consequences can range from positive to negative. the consequences are always negative from the viewpoint of safety. extent to which an event is likely to occur. note 1 iso 3534-1:1993 gives the mathematical definition of probability as "a real number in the interval 0 to 1 attached to a random event. it can be related to a long-run relative frequency of occurrence or to a degree of belief that an event will occur. for a high degree of belief the probability is near 1". note 2 frequency rather than probability may be used in describing risk. degrees of belief about probability can be chosen as classes or ranks such as: rare/unlikely/moderate/likely/almost certain, or incredible/improbable/ remote/occasional/probable/frequent. remark: informal language often confuses frequency and probability. this can lead to wrong conclusions in safety technology. probability is the degree of coincidence of the time frequency of coincidental realization of a fact from a certain possibility. coincidence is an event which basically can happen, may be cause-related, but does not occur necessarily or following a set pattern. it may also not occur (yes-or-no-alternative). data for probability of occurring with specific kinds of occurrence and weight of consequences can be: in a statistical sense: empirical, retrospective, real in a prognostic sense: speculative, prospective, probabilistic occurrence of a particular set of circumstances regarding place and time. an event can be the source of certain consequences (empirically to be expected with certain regularity). the event can be certain or uncertain. the event can be a single occurrence or a series of occurrences. the probability associated with the event can be estimated for a given period of time. task range by which the significance of risk is assessed. note 1 risk criteria can include associated costs and benefits, legal and statutory requirements, socio-economic and environmental aspects, the concerns of stakeholders, priorities and other inputs to the assessment. the way in which a stakeholder views a risk based on a set of values or concerns. note 1 risk perception depends on the stakeholder's needs, issues and knowledge. note 2 risk perception can differ from objective data. exchange or sharing of information about risk between the decision-makers and other stakeholders. overall process of risk analysis and risk evaluation. systematic use of information to identify sources and to estimate the risk. note 1 risk analysis provides a basis for risk evaluation, risk treatment, and risk acceptance. note 2 information can include historical data, theoretical analyses, informal opinions, and the concerns of stakeholders. process used to assign figures, values to the probability and consequences of a risk. note 1 risk estimation can consider cost, benefits, the concerns of stakeholders, and other variables, as appropriate for risk evaluation. process of comparing the estimated risk against given risk criteria to determine the significance of a risk. process of selection and implementation of measures to modify risk. note 1 risk treatment measures can include avoiding, optimizing, transferring or retaining risk. actions implementing risk management decisions. note 1 risk control may involve monitoring, re-evaluation, and compliance with decisions. process, related to a risk, to minimize the negative and to maximize the positive consequences (and their respective probabilities). actions taken to lessen the probability, negative consequences or both, associated with a risk. limitation of any negative consequences of a particular event. decision not to become involved in, or action to withdraw from, a risk situation. sharing with another party the burden of loss or benefit of gain, for a risk. note 1 legal or statutory requirements can limit, prohibit or mandate the transfer of a certain risk. note 2 risk transfer can be carried out through insurance or other agreements. note 3 risk transfer can create new risks or modify existing ones. note 4 relocation of the source is not risk transfer. acceptance of the burden of loss, or benefit of gain, from a particular risk. note 1 risk retention includes the acceptance of risks that have not been identified. note 2 risk retention does not include means involving insurance, or transfer in other ways. this includes risk assessment, risk treatment, risk acceptance and risk communication. risk assessment is risk analysis, with identification of sources and risk estimation, and risk evaluation. risk treatment includes avoiding, optimizing, transferring and retaining risk. → risk acceptance → risk communication harm physical injury or damage to the health of people or damage to property or the environment [iso/iec guide 51]. note 1 harm includes any disadvantage which is causally related to the infringement of the object of legal protection brought about by the harmful event. note 2 in the individual safety-relevant definitions, harm to people, property and the environment may be included separately, in combination, or it may be excluded. this has to be stated in the respective scope. potential source of harm [iso/iec guide 51]. the term "hazard" can be supplemented to define its origin or the nature of the possible harm, e.g., hazard of electric shock, crushing, cutting, dangerous substances, fire, drowning. in every-day informal language, there is insufficient differentiation between source of harm, hazardous situation, hazardous event and risk. circumstance in which people, property or the environment are exposed to one or more hazards [iso/iec guide 51]. note 1 circumstance can last for a shorter or longer period of time. event that can cause harm [din en 1050] . 1 the hazardous event can be preceded by a latent hazardous situation or by a critical event. combination of the probability of occurrence of harm and the severity of that harm [iso/iec guide 51]. note 1 in many cases, only a uniform extent of harm (e.g. leading to death) is taken into account, or the occurrence of harm may be independent of the extent of harm, as in a lottery game. in these cases, it is easier to make a probability statement; risk assessment by risk comparison [din en 1050] thus becomes much simpler. note 2 risks can be grouped in relation to different variables, e.g. to all people or only those affected by the incident, to different periods of time, or to performance. the probabilistic expectation value of the extent of harm is suitable for combining the two probability variables. note 4 risks which arise as a consequence of continuous emission, e.g. noise, vibration, pollutants, are affected by the duration and level of exposure of those affected. risk which is accepted in a given context based on the current values of society [iso/iec guide 51]. the acceptable risk has to be taken into account in this context, too. note 2 safety-relevant definitions are oriented to the maximum tolerable risk. this is also referred to as limit risk. note 3 tolerability is also based on the assumption that the intended use in addition to a reasonably predictable misuse of the products, processes and services, is complied with. freedom from unacceptable risk [iso/iec guide 51]. note 1 safety is indivisible. it cannot be split into classes or levels. note 2 safety is achieved by risk reduction, so that the residual risk in no case exceeds the maximum tolerable risk. existence of an unacceptable risk. note 1 safety and danger exclude one another -a technical product, process or service cannot be safe and dangerous at the same time. means used to reduce risk [iso/iec guide 51]. note 1 protective measures at the product level have priority over protective measures at the workplace level. preventive measure means assumed, but not proven, to reduce risk. risk remaining after safety measures have been taken [din en 1050] . note 1 residual risk may be related to the use of technical products, processes and services. systematic use of available information to identify hazards and to estimate their risks [iso/iec guide 51]. determination of connected risk elements of all hazards as a basis for risk assessment. decision based on the analysis of whether the tolerable risk has been exceeded [iso/iec guide 51]. overall process of risk analysis and risk evaluation [iso/iec guide 51]. use of a product, process or service in accordance with information provided by the supplier [iso/iec guide 51]. note 1 information provided by the supplier also includes descriptions issued for advertising purposes. use of a product, process or service in a way not intended by the supplier, but which may result from readily predictable human behaviour [iso/iec guide 51]. safety-related formulation of contents of a normative document in the form of a declaration, instructions, recommendations or requirements [compare en 45020, safety related]. the information set down in technical rules is normally restricted to certain technical relations and situations; in this context, it is presumed that the general safety-relevant principles are followed. a procedure with the aim to reduce risk of a (technical) product, process or service according to the following steps serves to reach the safety goals in the design stage: • safety-related layout; • protective measures; • safety-related information for users. function inevitable to maintain safety. a function which, in case of failure, allows the tolerable risk to be immediately exceeded. depending on the situation, it is possible to use one method or a combination of several methods. intuitive hazard detection spontaneous, uncritical listing of possible hazards as a result of brainstorming by experts. group work which is as creative as possible. writing ideas down (on a flip chart) first, then evaluating them. technical documentation (instructions, requirements) is available for many industrial plant and work processes, describing the hazards and safety measures. this documentation has to be obtained before continuing with the risk analysis. the deviations between the set point and the actual situation of individual components are examined. information on the probability of failure of these elements may be found in technical literature. examining the safety aspects in unusual situations (emergency, repair, starting and stopping) when plans are made to modify the plant or processes. a systematic check of the processes and plant parts for effects in normal operation and in case of set point deviations, using selected question words (and -or -not -too much -too little?). this is used in particular for measurement, control units, programming of computer controls, robots. all possible causes and combinations of causes are identified for an unwanted operating state or an event, and represented in the graphic format of a tree. the probability of occurrence of an event can be estimated from the context. the fault tree analysis can also be used retrospectively to clarify the causes of events. additional methods may be: human reliability analysis a frequency analysis technique which deals with the behaviour of human beings affecting the performance of the system, and estimates the influence of human error on reliability. a hazard identification and frequency analysis technique which can be used at an early stage in the design phase to identify and critically evaluate hazards. operating safety block program a frequency analysis technique which utilizes a model of the system and its redundancies to evaluate the operating safety of the entire system. classifying risks into categories, to establish the main risk groups. all typical hazardous substances and/or possible accident sources which have to be taken into account are listed. the checklist may be used to evaluate the conformity with codes and standards. this method is used to estimate whether coincidental failures of an entire series of different parts or modules within a system are possible and what the probable effects would be. estimate the influence of an event on humans, property or the environment. simplified analytical approaches, as well as complex computer models can be used. a large circle of experts is questioned in several steps; the result of the previous step together with additional information is communicated to all participants. during the third or fourth step the anonymous questioning concentrates on aspects on which no agreement is reached so far. basically this technique is used for making predictions, but is also used for the development of new ideas. this method is particularly efficient due to its limitation to experts. a hazard identification and evaluation technique used to establish a ranking of the different system options and to identify the less hazardous options. a frequency analysis technique in which a model of the system is used to evaluate variations of the input conditions and assumptions. a means to estimate and list risk groups; reviews risk pairs and evaluates only one risk pair at a time. overview of data from the past a technique used to identify possible problem areas; can also be used for frequency analysis, based on accident and operation safety data, etc. a method to identify latent risks which can cause unforeseeable incidents. cssr differs from the other methods in that it is not conducted by a team, and can be conducted by a single person. the overview points out essential safety and health requirements related to a machine and simultaneously to all relevant (national, european, international) standards. this information ensures that the design of the machine complies with the issued "state of the art" for that particular type of machine. the "what-if" method is an inductive procedure. the design and operation of the machine in question are examined for fairly simple applications. at every step "what-if" questions are asked and answered to evaluate the effect of a failure of the machine elements or of process faults in view of the hazards caused by the machine. for more complex applications, the "what-if" method is most useful with the aid of a "checklist" and the corresponding work division to allocate specific features of the process to persons who have the greatest experience and practice in evaluating the respective feature. the operator's behaviour and professional knowledge are assessed. the suitability of the equipment and design of the machine, its control unit and protective devices are evaluated. the influence of the materials processed is examined, and the operating and maintenance records are checked. the checklist evaluation of the machine generally precedes the more detailed methods described below. fmea is an inductive method for evaluating the frequency and consequences of component failure. when operating procedures or operator errors are investigated, then other methods may be more suitable. fmea can be more time-consuming than the fault tree analysis, because every mode of failure is considered for every component. some failures have a very low probability of occurrence. if these failures are not analyzed in depth this decision should be recorded in the documentation. the method is specified in iec 812 "analysis techniques for system reliability -procedure for failure mode and effects analysis (fmea)". in this inductive method, the test procedures are based on two criteria: technology and complexity of the control system. mainly, the following methods are applicable: • practical tests of the actual circuit and fault simulation on certain components, particularly in suspected areas of performance identified during the theoretical check and analysis. • simulation of control behaviour (e.g. by means of hardware and/or software models). whenever complex safety-related parts of control systems are tested, it may be necessary to divide the system into several functional sub-systems, and to exclusively submit the interface to fault simulation tests. this technique can also be applied to other parts of machinery. mosar is a complete approach in 10 steps. the system to be analyzed (machinery, process, installation, etc.) is examined as a number of sub-systems which interact. a table is used to identify hazards and hazardous situations and events. the adequacy of the safety measures is studied with a second table, and a third table is used to look at their interdependency. a study, using known tools (e.g. fmea) underlines the possible dangerous failures. this leads to the elaboration of accident scenarios. by consensus, the scenarios are sorted in a severity table. a further table, again by consensus, links the severity with the targets of the safety measures, and specifies the performance levels of the technical and organizational measures. the safety measures are then incorporated into the logic trees and the residual risks are analyzed via an acceptability table defined by consensus. ilo (1987) 1994, 1995, 1996, 1997, 1998, 1999 the risks to health at work are numerous and originate from several sources. their origins vary greatly and they cause vast numbers of diseases, injuries and other adverse conditions, such as symptoms of overexertion or overload. traditional occupational health risk factors and their approximate numbers are given in table 4 .4. the exposure of workers to hazards or other adverse conditions of work may lead to health problems, manifested in the workers' physical health, psysical workload, psychological disturbances or social aspects of life. workers may be exposed to various factors alone or in different types of combinations, which may or may not show interaction. the assessment of interacting risk factors is complex and may lead to substantial differences in the final risk estimates when compared with estimates of solitary factors. examples of interaction between different risk factors in the work environment are given in table 4 .5. the who estimate of the total number of occupational diseases among the 3 billion workers of the world is 160 million a year. this is likely to be an under-estimate due to the lack of diagnostic services, limited legislative coverage of both workers and diseases, and variation in diagnostic criteria between different parts of the world. the mortality from occupational diseases is substantial, comparable with other major diseases of the world population such as malaria or tuberculosis. the recent ilo estimate discloses 2.4 million deaths a year from work-related causes in the world including deaths from accidents, dangerous substances, and occupational diseases. eightyfive percent (85%) of these deaths take place in developing countries, where the diagnostic services, social security to families and compensation to workers are less developed. although the risk is decreasing in the industrialized world, the trend is increasing in the rapidly industrializing and transitory countries. a single hazard alone, such as asbestos exposure, is calculated to cause 100,000 cancers a year with a fatal outcome in less than two years after diagnosis (takala 2005). the incidence rates of occupational diseases in well registered industrialized countries are at the level of 3-5 cases/10,000 active employees/year, i.e., the incidence levels are comparable with major public health problems, such as cardiovascular diseases, respiratory disorders, etc. in the industrialized countries, the rate of morbidity from traditional occupational diseases, such as chemical poisonings, is declining, while musculoskeletal and allergic diseases are on the increase. about 200 biological factors that are hazardous to workers' health have been identified in various work environments. some of the new diseases recognized are blood-borne infections, such as hepatitis c and hiv, and exotic bacterial or viral infections transmitted by increasing mobility, international travelling and migration of working people. also some hospital infections and, e.g., drug-resistant tuberculosis, are being contracted increasingly by health care personnel. in the developing countries the morbidity picture of occupational diseases is much less clear for several reasons: low recognition rates, rotation and turnover of workers, shorter life expectancy which hides morbidity with a long latency period, and the work-relatedness of several common epidemic diseases, such as malaria and hiv/aids (rantanen 2003). the estimation of so-called work-related diseases is even more difficult than that of occupational diseases. they may be about 10-fold more prevalent than the definite occupational diseases. several studies suggest that siegfried radandt, jorma rantanen and ortwin renn work-related allergies, musculoskeletal disorders and stress disorders are showing a growing trend at the moment. the prevention of work-related diseases is important in view of maintaining work ability and reducing economic loss from absenteeism and premature retirement. the proportion of work-relatedness out of the total morbidity figures has been estimated and found surprisingly high (nurminen and karjalainen 2001 , who 2002 ) (see table 4 .6). the public health impact of work-related diseases is great, due to their high prevalence in the population. musculoskeletal disorders are among the three most common chronic diseases in every country, which implies that the attribution of work is very high. similarly, cardiovascular diseases in most industrialized countries contribute to 50% of the total mortality. even a small attributable fraction of work-relatedness implies high rates of morbidity and mortality related to work. the concept of disease is in general not a simple one. when discussing morbidity one has to recognize three different concepts: 1. illness = an individual's perception of a health problem resulting from either external or internal causes. 2. disease = an adverse health condition diagnosed by a doctor or other health professional. 3. sickness = a socially recognized disease which is related to, for example, social security actions or prescription of sick leave, etc. when dealing with occupational and work-related morbidity, one may need to consider any of the above three aspects of morbidity. a recognized occupational disease, however, belongs to group 3, i.e. it is a sickness defined by legal criteria. medical evidence is required to show that the condition meets the criteria of an occupational disease before recognition can be made. there are dozens of definitions for occupational disease. the content of the concept varies, depending on the context: a) the medical concept of occupational disease is based on a biomedical or other health-related etiological relationship between work and health, and is used in occupational health practice and clinical occupational medicine. b) the legal concept of occupational disease defines the disease or conditions which are legally recognized as conditions caused by work, and which lead to liabilities for recognition, compensation and often also prevention. the legal concept of occupational disease has a different background in different countries, often declared in the form of an official list of occupational diseases. there is universal discrepancy between the legal and medical concept, so that in nearly all countries the official list of recognized occupational diseases is shorter than the medically established list. this automatically implies that a substantial proportion of medically established occupational diseases remain unrecognized, unregistered, and consequently also uncompensated. the definition of occupational disease, as used in this chapter, summarizes various statements generated during the history of occupational medicine: an occupational disease is any disease contracted as a result of exposures at work or other conditions of work. the general criteria for the diagnosis and recognition of an occupational disease are derived from the core statements of various definitions: 1. evidence on exposure(s) or condition(s) in work or the work environment, which on the basis of scientific knowledge is (are) able to generate disease or some other adverse health condition. 2. evidence of symptoms and clinical findings which on the basis of scientific knowledge can be associated with the exposure(s) or condition(s) in concern. 3. exclusion of non-occupational factors or conditions as a main cause of the disease or adverse health condition. point 3 often creates problems, as several occupationally generated clinical conditions can be caused also by non-occupational factors. on the other hand, several factors from different sources and environments are involved in virtually every disease. therefore the wordings "main cause" or "principal cause" are used. the practical solution in many countries is that the attribution of work needs to be more than 50%. usually the necessary generalizeable scientific evidence is obtained from epidemiological studies, but also other types of evidence, e.g. well documented clinical experience combined with information on working conditions may be acceptable. in some countries, like finland, any disease of the worker which meets the above criteria can be recognized as an occupational disease. in most other countries, however, there are official lists of occupational diseases which determine the conditions and criteria on which the disease is considered to be of occupational origin. in 1985 who launched a new concept: work-related disease (who 1985) . the concept is wider than that of an occupational disease. it includes: a) diseases in which the work or working conditions constitute the principal causal factor. b) diseases for which the occupational factor may be one of several causal agents, or the occupational factor may trigger, aggravate or worsen the disease. c) diseases for which the risk may be increased by work or work-determined lifestyles. the diseases in category (a) are typically recognized as legally determined occupational diseases. categories (b) and (c) are important regarding the morbidity of working populations, and they are often considered as important targets for prevention. in general, categories (b) and (c) cover greater numbers of people, as the diseases in question are often common noncommunicable diseases of the population, such as cardiovascular diseases, musculoskeletal disorders, and allergies and, to a growing extent, stressrelated disorders (see table 4 .6). the concept of work-related disease is very important from the viewpoint of occupational health risk assessment and the use of its results for preventive purposes and for promoting health and safety at work. this is because preventive actions in occupational health practice cannot be limited only to legally recognized morbidity. the lists of occupational diseases contain great numbers of agents that show evidence on occupational morbidity. according to the ilo recommendation r194 (2002): list of occupational diseases, the occupational diseases are divided into four main categories: 1. diseases resulting from single causes following the categories listed in table 4 .4. the most common categories are physical factors, chemical agents, biological factors and physical work, including repetitive tasks, poor ergonomic conditions, and static and dynamic work. 2. diseases of the various organs: respiratory system, nervous system, sensory organs, internal organs, particularly liver and kidneys, musculoskeletal system, and the skin. 3. occupational cancers. 4. diseases caused by other conditions of work. research on risk perception shows differences in how different types of risks are viewed. instant, visible, dramatic risk events, particularly ones that cause numerous fatalities or severe visible injuries in a single event generally arouse much attention, and are given high priority. on the other hand, even great numbers of smaller events, such as fatal accidents of single workers, arouse less attention in both the media and among regulators, even though the total number of single fatal accidents in a year may exceed the number of fatalities in major events by several orders of magnitude. occupational diseases, with the exception of a few acute cases, are silent, develop slowly, and concern only one or a few individuals at a time. furthermore, the diseases take months or years to develop, in extreme cases even decades, after the exposure or as a consequence of accumulation of exposure during several years. as occupational health problems are difficult to detect and seriously under-diagnosed and under-reported, they tend to be given less priority than accidents. the perception of occupational disease risk remains low in spite of their severity and relatively high incidence. particularly in industrialized countries, the extent of occupational health problems is substantially greater than that of occupational accidents. on a global scale, the estimated number of fatalities due to occupational accidents is 375,000 and the respective estimate for fatalities due to work-related diseases is 1.8 million a year, giving a fatal accident/fatal disease ratio of 1 to 5. the corresponding ratio in the eu-15 is 1 to 20 (takala 2005). the risk distribution of ods is principally determined by the nature of the work in question and the characteristics of the work environment. there is great variation in the risk of ods between the lowest and highest risk occupations. in the finnish workforce, the risk between the highest risk and the lowest risk occupations varies by a factor of 30. the highest risk occupations carry a risk which is 4-10 times higher than the average for all occupations. the risk of an occupational disease can be estimated on the basis of epidemiological studies, if they do exist in the case of the condition in question. on the other hand, various types of economic activity, work and occupations carry different types of risks, and each activity may have its own risk profile. by examining the available epidemiological evidence, we can recognize high-risk occupations and characterize the typical risks connected with them ( figure 4 .12, table 4.7). as an example, the risk of occupational asthma, dermatosis or musculoskeletal disorders is common in several occupations, but not in all. there may be huge differences in risks between different occupations. the 10 occupations carrying the highest risk for occupational asthma, occupational skin diseases and work-related tenosynovitis, in 1986-1991, are shown in table 4 .8. assessment of the risk of occupational diseases has an impact on research priorities. table 4 .9 shows the priorities for research in four countries. the similarity of the priorities is striking, revealing that the problems related to the risks of occupational diseases are universal. the diagnosis of occupational diseases is important for the treatment of the disease, and for prevention, registration and compensation. the diagnosis is based on information obtained from: a) data on the work and the work environment usually provided by the employer, occupational health services, occupational safety committee, or expert bodies carrying out hygienic and other services for the workplace. b) information on the health examination of individual workers. the authorities in many countries have stipulated legal obligations for high-risk sectors to follow up the workers' health and promote early detection of changes in their health. occupational health services keep records on examinations. c) workers with special symptoms (for example, asthmatic reactions) are taken into the diagnostic process as early as possible. epidemiological evidence is a critical prerequisite for recognizing causal relationship between work and disease. epidemiology is dependent on three basic sources of information on work and the work environment: (a) exposure assessment that helps to define the "dose" of risk factor at work, (b) the outcome assumed to occur as a biological (or psychological) response to the exposures involved, and (c) time, which has a complex role in various aspects of epidemiology. all these sources are affected by the current dynamics of work life which has major impact on epidemiological research and its results. exposure assessment is the critical initial step in risk assessment. as discussed in this chapter, accurate exposure assessment will become more difficult and cumbersome than before in spite of remarkable achievements in measurement, analysis and monitoring methods in occupational hygiene, toxicology and ergonomics. great variations in working hours and individu-alization of exposures, growing fragmentation and mobility increase the uncertainties, which are multiplied. structural uncertainty, measurement uncertainty, modelling uncertainty, input data uncertainty and natural uncertainty amplify each other. as a rule, variation in any direction in exposure assessment tends to lead to underestimation of risk, and this has severe consequences to health. personal monitoring of exposures, considering variations in individual doses, and monitoring internal doses using biological monitoring methods help in the control of such variation. a monofactorial exposure situation in the past was ideal in the assessment because of its manageability. it also occurs usually as a constant determinant for long periods of time and can be regularly and continuously measured and monitored. this is very seldom the case today, and exposure assessment in modern work life is affected by discontinuities of the enterprise, of technologies and production methods, and turnover of the workforce, as well as the growing mobility and internationalization of both work and workers. company files that were earlier an important source of exposure and health data no longer necessarily fulfil that function. in addition, the standard 8-h time-weighted average for exposure assessment can no longer be taken as a standard, as working hours are becoming extremely heterogeneous. assessment of accurate exposure is thus more and more complex and cumbersome, and new strategies and methods for the quantification of exposure are needed. three challenges in particular can be recognized: a) the challenge arising from numerous discontinuities, fragmentation and changes in the company, employment and technology. although in the past company data were collected from all sources that were available, collective workroom measurements were the most valuable source of data. due to the high mobility of workers and variation in the work tasks, personal exposure monitoring is needed that follows the worker wherever he or she works. special smart cards for recording all personal exposures over years have been proposed, but so far no system-wide action has been possible. in radiation protection, however, such a personal monitoring system has long been a routine procedure. b) the complex nature of exposures where dozens of different factors may be involved (such as those in indoor air problems) and acting in combinations. table 4 .4 gives a list of exposing factors in modern work life, many of which are difficult to monitor. c) new, rapidly spreading and often unexpected exposures that are not well characterized. often their mechanisms of action are not known, or the fast spread of problems calls for urgent action, as in the case of bovine spongiform encephalopathy (bse) in the 1990s, sars outbreak in 2003, and in the new epidemics of psychological stress or musculoskeletal disorders in modern manufacturing. the causes of occupational diseases are grouped into several categories by the type of factor (see table 4 .4). a typical grouping is the one used in ilo recommendation no. 194 . the lists of occupational diseases contain diseases caused by one single factor only, but also diseases which may have been caused by multifactorial exposures. exposure assessment is a crucial step in the overall risk assessment. the growing complexity of exposure situations has led to the development of new methods for assessing such complex exposure situations. these methods are based on construction of model matrices for jobs which have been studied thoroughly for their typical exposures. the exposure profiles are illustrated in job exposure matrices (jem) which are available for dozens of occupations (heikkilä et al. 2005 , guo 2005 . several factors can cause occupational diseases. the jem is a tool used to convert information on job titles into information on occupational risk factors. jem-based analysis is economical, systematic, and often the only reasonable choice in large retrospective studies in which exposure assessment at the individual level is not feasible. but the matrices can also be used in the practical work for getting information on typical exposure profiles of various jobs. the finnish national job-exposure matrix (finjem) is the first and so far the only general jem that is able to give a quantitative estimation of cumulative exposure. for example, finjem estimates were used for exposure profiling on 43 chemical exposures and several other cancer-risk factors for 393 occupational categories. the jem analysis has been further developed into task specific exposure matrices charting the exposure panorama of various tasks (benke et al. 2000 (benke et al. , 2001 . as the previous mono-causal, mono-mechanism, mono-outcome setting has shifted in the direction of multicausality, multiple mechanisms and multioutcomes, the assessment of risks has become more complex. some outcomes, as mentioned above, are difficult to define and measure with objective methods and some of them may be difficult to recognize by exposed groups themselves, or even by experts and researchers. for example, the objective measurement of stress reactions is still imprecise in spite of improvements in the analysis of some indicator hormones, such as adrenalin, noradrenalin, cortisol, prolactin, or in physical measurements, such as galvanic skin resistance and heart rate variability. questionnaires monitoring perceived stress symptoms are still the most common method for measuring stress outcomes. thanks to well organized registries, particularly in germany and the nordic countries, data on many of the relevant outcomes of exposure, such as cancer, pneumoconiosis, reproductive health disturbances and cardiovascular diseases can be accumulated, and long-term follow-up of outcomes at the group level is therefore possible. on the other hand, several common diseases, such as cardiovascular diseases, may have a work-related aetiology, but it may be difficult to show at individual level. the long-term data show that due to changes in the structure of economies, types of employment, occupational structures and conditions of work, many of the traditional occupational diseases, such as pneumoconiosis and acute intoxications have almost disappeared. several new outcomes have appeared, however, such as symptoms of physical or psychological overload, psychological stress, problems of adapting to a high pace of work, and uncertainty related to rapid organizational changes and risk of unemployment. in addition, age-related and work-related diseases among the ageing workforce are on the increase (kivimäki et al. 2006 , ilmarinen 2006 . these new outcomes may have a somatic, psychosomatic or psychosocial phenotype, and they often appear in the form of symptoms or groups of symptoms instead of well-defined diagnoses. practising physicians or clinics are not able to set an icd (international statistical classification of diseases and health-related conditions)-coded diagnosis for them. in spite of their diffuse nature, they are still problems for both the worker and the enterprise, and their consequences may be seen as sickness absenteeism, premature retirement, loss of job satisfaction, or lowered productivity. thus, they may have even a greater impact on the quality of work life and the economy than on clinical health. many such outcomes have been investigated by using questionnaire surveys among either representative samples of the whole workforce or by focusing the survey on a specific sector or occupational group. the combination of data from the surveys of "exposing factors", such as organizational changes, with questionnaire surveys of "outcomes", such as sickness absenteeism, provides epidemiological information on the association between the new exposures and the new outcomes. there are, however, major problems in both the accurate measurement of the exposures and outcomes, and also, the information available on the mechanisms of action is very scarce. epidemiology has expanded the focus of our observations from crosssectional descriptions to longitudinal perspectives, by focussing attention on the occurrence of diseases and finding associations between exposure and morbidity. such an extension of vision is both horizontal and vertical, looking at the causes of diseases. time is not only a temporal parameter in epidemiology, but has also been used for the quantification of exposure, measurement of latencies, and the detection of acceleration or slowing of the course of biological processes. as the time dimension in epidemiology is very important, the changes in temporal parameters of the new work life also affect the methods of epidemiological research. the time dimension is affected in several ways. first, the fragmentation and discontinuities of employment contracts, as described above, break the accumulation of exposure time into smaller fragments, and continuities are thus difficult to maintain. collecting data on cumulative exposures over time becomes more difficult. the time needed for exposure factors to cause an effect becomes more complex, as the discontinuities typical to modern work life allow time for biological repair and elimination processes, thus diluting the risk which would get manifested from continuous exposure. the dosage patterns become more pulse-type, rather than being continuous, stable level exposures. this may affect the multi-staged mechanisms of action in several biological processes. the breaking up of time also increases the likelihood of memory bias of respondents in questionnaire studies among exposed workers, and thus affects the estimation of total exposures. probably the most intensive effect, however, will be seen as a consequence of the variation in working hours. for example, instead of regular work of 8 hours per day, 40 hours per week and 11 months per year, new time schedules and total time budgets are introduced for the majority of workers in the industrial society. the present distribution of weekly working hours in finland is less than 30 hours per week for one third of workers, regular 35-40 hours per week for one third, and 45-80 hours per week for the remaining third. thus the real exposure times may vary substantially even among workers in the same jobs and same occupations, depending on the working hours and the employment contract (temporary, seasonal, part-time, full-time) (härmä 2000 , piirainen et al. 2003 . such variation in time distribution in "new work life" has numerous consequences for epidemiological studies, which in the past "industrial society" effectively utilized the constant time patterns at work for the assessment of exposures and outcomes and their interdependencies. the time dimension also has new structural aspects. as biological processes are highly deterministic in terms of time, the rapid changes in work life cannot wait for the maturation of results in longitudinal follow-up studies. the data are needed rapidly in order to be useful in the management of working conditions. this calls for the development of rapid epidemiological methods which enable rapid collection of the data and the making of analyses in a very short time, in order to provide information on the effects of potential causal factors before the emergence of a new change. often these methods imply the compromising of accuracy and reliability for the benefit of timeliness and actuality. as occupational epidemiology is not only interested in acute and short-term events, but looks at the health of workers over a 30-40-year perspective, the introduction of such new quick methods should not jeopardize the interest and efforts to carry out long-term studies. epidemiology has traditionally been a key tool in making a reliable risk assessment of the likelihood of the adverse outcomes from certain levels of exposure. the new developments in work life bring numerous new challenges to risk assessment. as discussed above, the new developments in work life have eliminated a number of possibilities for risk assessment which prevailed in the stable industrial society. on the other hand, several new methods and new information technologies provide new opportunities for collection and analysis of data. traditionally, the relationship between exposure and outcome has been judged on the basis of the classical criteria set by hill (1965) . höfler (2005) crystallizes the criteria with their explanations as the following: 1. strength of association: a strong association is more likely to have a causal component than is a modest association. 2. consistency: a relationship is observed repeatedly. 3. specificity: a factor influences specifically a particular outcome or population. 4. temporality: the factor must precede the outcome it is assumed to affect. ing dose of exposure or according to a function predicted by a substantive theory. 6. plausibility: the observed association can be plausibly explained by substantive matter (e.g. biological) explanations. 7. coherence: a causal conclusion should not fundamentally contradict present substantive knowledge. 8. experiment: causation is more likely if evidence is based on randomized experiments. 9. analogy: for analogous exposures and outcomes an effect has already been shown. the hill criteria have been subjected to scrutiny, and sven hernberg has analyzed them in detail from the viewpoint of occupational health epidemiology. virtually all the hill criteria are affected by the changes in the new work life, and therefore methodological development is now needed. a few comments on causal inference are made here in view of the critiques by rothman (1988), hernberg (1992) and höfler (2005) : the strength of association will be more difficult to demonstrate due to the growing fragmentation that tends to diminish the sample sizes. the structural change that removes workers from high-level exposures to lower and shorterterm exposures may dilute the strength of effect, which may still prevail, but at a lower level. consistency of evidence may also be affected by the higher variation in conditions of work, study groups, multicultural and multiethnic composition of the workforce, etc. similarly, in the multifactorial, multi-mechanism, multi-outcome setting, the specificity criterion is not always relevant. the temporal dimension has already been discussed. in rapidly changing work life the follow-up times before the next change and before turnover in the workforce may be too short. the outcomes may also be defined by the exposures that have taken place long ago but have not been considered in the study design because historical data are not available. the biological gradient may be possible to demonstrate in a relatively simple exposure-outcome relationship. however, the more complex and multifactorial the setting becomes, the more difficult it may be to show the doseresponse relationship. the dose-response relationship may also be difficult to demonstrate in the cases of relatively ill-defined outcomes which are difficult to measure, but which can be detected as qualitative changes. biological plausibility is an important criterion which in a multimechanism setting may at least in part be difficult to demonstrate. on the other hand, the mechanisms of numerous psychological and psychosocial outcomes lack explanations, even though they undoubtedly are work-related. the missing knowledge of the mechanism of action did not prevent the establishment of causality between asbestos and cancer in a pleural sack or a lung. as many of the new outcomes may be context-dependent, the coherence criterion may be irrelevant. similarly, many of the psychosocial outcomes are difficult to put into an experimental setting, and it can be difficult to make inferences based on analogy. all of the foregoing implies that the new dynamic trends in work life challenge epidemiology in a new way, particularly in the establishment of causality. knowledge of causality is required for the prevention and management of problems. the hill criteria nevertheless need to be supplemented with new ones to meet the conditions of the new work life. similarly, more definitive and specific criteria and indicators need to be developed for the new exposures and outcomes. many of the challenges faced in the struggle to improve health and safety in modern work life can only be solved with the help of research. research on occupational health in the rapidly changing work life is needed more than ever. epidemiology is, and will remain, a key producer of information needed for prevention policies and for ensuring healthy and safe working conditions. the role of epidemiology is, however, expanding from the analysis of the occurrence of well-defined clinical diseases to studies on the occurrence of several other types of exposure and outcome, and their increasingly complex associations. as the baseline in modern work life is shifting in a more dynamic direction, and many parameters in work and the workers' situation are becoming more fragmented, incontinuous and complex, new approaches are needed to tackle the uncertainties in exposure assessment. the rapid pace of change in work life calls for the development of assessment methods to provide up-todate data quickly, so that they can be used to manage these changes and their consequences. many new outcomes which are not possible to register as clinical icd diagnoses constitute problems for today's work life. this is particularly true in the case of psychological, psychosocial and many musculoskeletal outcomes which need to be managed by occupational health physicians. methods for the identification and measurement of such outcomes need to be improved. the traditional hill criteria for causal inference are not always met even in cases where true association does exist. new criteria suitable for a new situation should be established without jeopardizing the original objective of ascertaining the true association. developing the bayesian inference further through utilization of a priori knowledge and a holistic approach may provide responses to new challenges. new neural network softwares may help in the management of the growing complexity. the glory of science does not lie in the perfection of a scientific method but rather in the recognition of its limitations. we must keep in mind the old saying: "absence of evidence is not evidence of absence". instead, it is merely a consequence of our ignorance that should be reduced through further efforts in systematic research, and particularly through epidemiology. and secondly, the ultimate value of occupational health research will be determined on the basis of its impact on practice in the improvement of the working conditions, safety and health of working people. changing conditions of work, new technologies, new substances, new work organizations and working practices are associated with new morbidity patterns and even with new occupational and work-related diseases. the new risk factors, such as rapidly transforming microbials and certain social and behavioural "exposures" may follow totally new dynamics when compared with the traditional industrial exposures (self-replicating nature of microbials and spreading of certain behaviours, such as terrorism) (smolinski et al. 2003 , loza 2007 . several social conditions, such as massive rural-urban migration, increased international mobility of working people, new work organizations and mobile work may cause totally new types of morbidity. examples of such development are, among others, the following: • mobile transboundary transportation work leading to the spread of hiv/aids. • increased risk of metabolic syndrome, diabetes and cardiovascular diseases aggravated by unconventional working hours. • increased risk of psychological burnout in jobs with a high level of longterm stress. • virtually a global epidemic of musculoskeletal disorders among vdu workers with high work load, psychological stress and poor ergonomics. the incidences of occupational diseases may not decline in the future, but the type of morbidity may change. the direction of trend in industrialized countries is the prominence of work-related morbidity and new diseases, while the traditional occupational diseases such as noise injury, pneumoconiosis, repetitive strain and chemical intoxications may continue to be prevalent in developing countries for long periods in the future. the new ergonomics problems are related to light physical work with a considerable proportion of static and repetitive workload. recent research points to an interesting interaction between unergonomic working conditions and psychological stress, leading to a combined risk of musculoskeletal disorders of the neck, shoulders and upper arms, including carpal tunnel syndrome in the wrist. the muscle tension in static work is amplified by the uncontrolled muscular tension caused by psychological stress. furthermore, there seems to be wide inter-individual variation in the tendency to respond with spasm, particularly in the trapezius muscle of neck, under psychological stress. about 40% of the health complaints of working-aged people are related to musculoskeletal disorders, of which a substantial part is work-related. the epidemics have been resistant against preventive measures. new regulatory and management strategies may be needed for effective prevention and control measures (westgaard et al. 2006, paoli and merllié 2001) . the 21st century will be the era of the brain at work and consequently of psychological stress. between 35% and 50% of eu workers in certain occupations report psychological stress due to high time pressure at work (parent-thirion et al. 2007 ). the occurrence of work-related stress is most prevalent in occupations with tight deadlines, pressure from clients, or the high level of responsibility for productivity and quality given to the workers. undoubtedly, the threat of unemployment increases the perception of stress as well. as a consequence, for example, in finland some 40% of workers report symptoms of psychological overload and about 7% show clinical signs of burn out. these are not the problems of low-paid manual workers only, but also, for example, highly educated and well-paid computer super-experts have an elevated risk of burnout as a consequence of often self-committed workload (kalimo and toppinen 1997) . unconventional and ever longer working hours are causing similar problems. for example, one third of finns work over 45 hours a week, and of these 25% work over 50 hours, and 8% often work 65-80 hours per week. it is important to have flexibility in the work time schedules, but it is counterproductive if the biologically determined physiological time rhythms of the worker are seriously offended. over 40% have a sleep deficit of at least one hour each day, and 22% are tired and somnolent at work (härmä et al. 2000) . the toughening global competition, growing productivity demands and continuous changes of work, together with job insecurity, are associated with increased stress. up to 30-50% of workers in different countries and different sectors of the economy report high time pressure and tight deadlines. this prevents them from doing their job as well as they would like to, and causes psychological stress. psychological stress is particularly likely to occur if the high demands are associated with a low degree of self-regulation by the workers (houtman 2005) . stress, if continuous, has been found to be detrimental to physical health (cardiovascular diseases), mental health (psychological burnout), safety (accident risks), and musculoskeletal disorders (particularly hand-arm and shoulder-neck disorders). it also has a negative impact on productivity, sickness absenteeism, and the quality of products and services. the resulting economic losses due to sickness absenteeism, work disability and lower quality of products and services are substantial. the prevention of stress consists not only of actions targeted at the individual worker. there is also a need for measures directed at the work organization, moderation of the total workload, competence building and collaboration within the workplace (theorell 1997). the support from foremen and supervisors is of crucial importance in stress management programmes. another type of psychological burden is the stress arising from the threat of physical violence or aggressive behaviour from the part of clients. in finland some 4% of workers have been subjected to insults or the threat of physical violence, 13% have experienced sexual harassment, and 10% mental violence or bullying at work. the risk is substantially higher for female workers than for men. stress has been found to be associated with somatic health, cardiovascular diseases, mental disorders and depression. one of the new and partly re-emerging challenges of occupational health services is associated with the new trends in microbial hazards. there are several reasons for these developments, for instance, the generation of new microbial strains, structural changes in human habitations with high population densities, growing international travel, and changes possibly in our microbiological environment as a consequence of global warming. of the 10 to 100 million species in the world, about 3 million are microbes. the vast majority of them are not pathogenic to man, and we live in harmony and symbiosis with many of them. we also use bacteria in numerous ways to produce food, medicines, proteins, etc. the pathogenic bacteria have been well controlled in the 20th century; this control had an enormous positive impact on human health, including occupational health. but now the microbial world is challenging us in many ways. new or re-emerging biological hazards are possible due to the transformation of viruses, the increased resistance of some microbial strains (e.g. tuberculosis and some other bacterial agents) and the rapid spread of contaminants through extensive overseas travelling (smolinski et al. 2003) . the scenarios of health hazards from the use of genetically manipulated organisms have not been realized, but biotechnological products have brought along new risks of allergies. a major indoor air problem is caused by fungi, moulds and chemical emissions from contaminated construction materials. new allergies are encountered as a consequence of the increasingly allergic constitution of the population and of the introduction of new allergens into the work environment. health care personnel are increasingly exposed to new microbial hazards due to the growing mobility of people. evidence of high rates of hepatitis b antigen positivity has been shown among health care workers who are in contact with migrants from endemic areas. along with the growing international interactions and mobility, a number of viral and re-emerging bacterial infections also affect the health of people engaged in health care and the care of the elderly, as well as personnel in migrant and refugee services, in social services and other public services. this section applies the general framework for risk governance (chapter 3) to the area of environmental risks. why should we include this topic in a book that is dominantly dealing with occupational health risks and safety issues? there are two major reasons for this decision: 1. most risks that impact health and safety of human beings are also affecting the natural environment. it is therefore necessary for risk managers to reflect the consequences of risk-taking activities with respect to workers, the public and the environment. these risk consequences are all interconnected. our approach to foster an integral approach to risk and risk management requires the integration of all risk consequences. 2. environmental risks are characterized by many features and properties that highlight exemplary issues for many generic risk assessment and management questions and challenges. for example, the question of how to balance benefits and risks becomes more accentuated, if not human life, but damage to environmental quality is at stake. while most people agree that saving human lives takes priority over economic benefits, it remains an open question of how much environmental change and potential damage one is willing to trade off against certain economic benefits. this section is divided into two major parts. part 1 will introduce the essentials of environmental ethics and the application of ethical principles to judging the acceptability of human interventions into the environment. part 2 addresses the procedures for an analytic-deliberative process of decision making when using the risk governance framework developed in chapter 3. it should be noted that this section draws from material that the author has compiled for the german scientific council for global environmental change and that has been partially published in german in a special report of the council (wbgu 1999). the last section on decision making has borrowed material from an unpublished background document on decision making and risk management that dr. warner north and the author had prepared for the us national academy of sciences. should people be allowed to do everything that they are capable of doing? this question is posed in connection with new technologies, such as nanotubes, or with human interventions in nature, such as the clearance of primaeval forests so that the land can be used for agriculture. intuitively everyone answers this question with a definitive "no": no way should people be allowed to everything that they are capable of doing. this also applies to everyday actions. many options in daily life, from lying to minor deception, from breaking a promise up to going behind a friend's back, are obviously actions that are seen by all well-intentioned observers as unacceptable. however, it is much more difficult to assess those actions where the valuation is not so obvious. is it justified to break a promise when keeping the promise could harm many other people? actions where there are conflicts between positive and negative consequences or where a judgement could be made one way or the other with equally good justification are especially common in risk management. there is hardly anyone who wilfully and without reason pollutes the environment, releases toxic pollutants or damages the health of individuals. people who pursue their own selfish goals on the cost and risk of others are obviously acting wrongly and every legislator will sanction this behaviour with the threat of punishment or a penalty. but there is a need for clarification where people bring about a benefit to society with the best intentions and for plausible reasons and, in the process, risk negative impacts on others. in ethics we talk about "conflicting values" here. most decisions involving risks to oneself or others are made for some reason: the actors who make such interventions want to secure goods or services to consumers, for example, to ensure long-term jobs and adequate incomes, to use natural resources for products and services or to use nature for recycling waste materials from production and consumption that are no longer needed. none of this is done for reasons of brotherly love, but to maintain social interests. even improving one's own financial resource is not immoral mere for this reason. the list of human activities that pose risks onto others perpetrated for existential or economic reasons could be carried on into infinity. human existence is bound to taking opportunities and risks. here are just a few figures: around 12,000 years ago about 5 million people lived on the earth. under the production conditions those days (hunter-gatherer culture) this population level was the limit for the human species within the framework of an economic form that only interfered slightly with man's natural environment. the neolithic revolution brought a dramatic change: the carrying capacity of the world for human beings increased by a factor of 10 and more. this agrarian pre-industrial cultural form was characterized by tightly limited carrying capacity, in around 1750 the earth was capable of feeding approx. 750 million people. today the world supports 6 billion people -and this figure is rising. the carrying capacity in comparison to the neolithic age has thus increased thousand-fold and continues to grow in parallel to new changes in production conditions (fritsch 1993; kesselring 1994; mohr 1995) . the five "promethean innovations" are behind this tremendous achievement of human culture: mastering fire, using the natural environment for agriculture, transforming fossil fuels into thermal and mechanical energy, industrial production and substituting material with information (renn 1996) . with today's settlement densities and the predominantly industrial way of life, the human race is therefore dependent on the technical remodelling of nature. without doubt, it needs this for survival, especially for the well-being of the innumerable people, goods and services that reduce the stock of natural resources. with regard to the question of the responsibility of human interventions in nature, the question cannot be about "whether" but -even better -about "how much", because it is an anthropological necessity to adapt and shape existing nature to human needs. for example, the philosopher klaus michael meyer-abich sees the situation as follows: ". . . we humans are not there to leave the world as though we had never been there. as with all other life forms, it is also part of our nature and our lives to bring about changes in the world. of course, this does not legitimise the destructive ways of life that we have fallen into. but only when we basically approve of the changes in the world can we turn to the decisive question of which changes are appropriate for human existence and which are not" (meyer-abich 1997). therefore, to be able to make a sensible judgement of the balance between necessary interventions into the environment and the risks posed by these interventions to human health and environmental quality, the range of products and services created by the consumption of nature has to be considered in relation to the losses that are inflicted on the environment and nature. with this comparison, it can be seen that even serious interventions in nature and the environment did not occur without reflection, but to provide the growing number of people with goods and services; these people need them to survive or as a prerequisite for a "good" life. however, at the same time it must be kept in mind that these interventions often inflict irreversible damage on the environment and destroy possible future usage potentials for future generations. above and beyond this, for the human race, nature is a cradle of social, cultural, aesthetic and religious values, the infringement of which, in turn, has a major influence on people's well-being. on both sides of the equation, there are therefore important goods that have to be appreciated when interventions in nature occur. but what form should such an appreciation take? if the pros and cons of the intervention in nature have to be weighed against each other, criteria are needed that can be used as yardsticks. who can and may draw up such criteria, according to which standards should the interventions be assessed and how can the various evaluative options for action be compared with each other for each criterion? taking risks always involves two major components: an assessment of what we can expect from an intervention into the environment (be it the use of resources or the use of environments as a sink for our waste). this is the risk and benefit assessment side of the risk analysis. secondly, we need to decide whether the assessed consequences are desirable. whereas the estimate of consequences broadly falls in the domain of scientific research and expertise, with uncertainties and ambiguities in particular having to be taken into account (irgc 2005, klinke and renn 2002) , the question about the foundations for evaluating various options for action and about drawing up standards guiding action is a central function of ethics (taylor 1986) . ethics can provide an answer to the question posed in the beginning ("should people be allowed to do everything that they are capable of doing?") in a consistent and transparent manner. in section 4.3.2, environmental ethics will be briefly introduced. this review is inspired by the need for a pragmatic and policy-oriented approach. it is not a replacement for a comprehensive and theoretically driven compendium of environmental ethics. environmental ethics will then be applied to evaluate environmental assets. in this process, a simple distinction is made between categorical principles -that must under no circumstances be exceeded or violated -and compensatory principles, where compensation with other competing principles is allowed. this distinction consequently leads to a classification of environmental values, which, in turn, can be broken down into criteria to appreciate options for designing environmental policies. in section 4.3.3, these ideas of valuation will be taken up and used to translate the value categories into risk handling guidelines. at the heart of the considerations here is the issue of how the aims of ethically founded considerations can be used to support and implement risk-based balancing of costs and benefits. for this purpose, we will develop an integrative risk governance framework. the concept of risk governance comprises a broad picture of risk: not only does it include what has been termed "risk management" or "risk analysis", it also looks at how risk-related decision making unfolds when a range of actors is involved, requiring co-ordination and possibly reconciliation between a profusion of roles, perspectives, goals and activities. indeed, the problem-solving capacities of individual actors, be they government, the scientific community, business players, ngos or civil society as a whole, are limited and often unequal to the major challenges facing society today. then the ideas of the operational implementation of normative and factual valuations are continued and a procedure is described that is capable of integrating ethical, risk-based and work-related criteria into a proposed procedural orientation. this procedure is heavily inspired by decision analysis. answering the question about the right action is the field of practical philosophy, ethics. following the usual view in philosophy, ethics describes the theory of the justification of normative statements, i.e. those that guide action (gethmann 1991 , mittelstraß 1992 , nida-rümelin 1996a , revermann 1998 . a system of normative statements is called "morals". ethical judgements therefore refer to the justifiability of moral instructions for action that may vary from individual to individual and from culture to culture (ott 1999) . basically, humans are purpose-oriented and self-determined beings who act not only instinctively, but also with foresight, and are subject to the moral standards to carry out only those actions that they can classify as good and justifiable (honnefelder 1993) . obviously, not all people act according to the standards that they themselves see as necessary, but they are capable of doing so. in this context, it is possible for people to act morally because, on the one hand, they are capable of distinguishing between moral and immoral action and, on the other, are largely free to choose between different options for action. whether pursuing a particular instruction for action should be considered as moral or immoral is based on whether the action concerned can be felt and justified to be "reasonable" in a particular situation. standards that cross over situations and that demand universal applicability are referred to as principles here. conflicts may arise between competing standards (in a specific situation), as well as between competing principles, the solution of which, in turn, needs justification (szejnwald-brown et al. 1993) . providing yardsticks for such justification or examining moral systems with respect to their justifiability is one of the key tasks of practical ethics (gethmann 1998) . in ethics a distinction is made between descriptive (experienced morality) and prescriptive approaches, i.e. justifiable principles of individual and collective behaviour (frankena 1963 , hansen 1995 . all descriptive approaches are, generally speaking, a "stock-taking" of actually experienced standards. initially, it is irrelevant whether these standards are justified or not. they gain their normative force solely from the fact that they exist and instigate human action (normative force of actual action). most ethicists agree that no conclusions about general validity can be drawn from the actual existence of standards. this would be a naturalistic fallacy (akademie der wissenschaften 1992, ott 1999) . nevertheless, experienced morality can be an important indicator of different, equally justifiable moral systems, especially where guidance for cross-cultural behaviour is concerned. this means that the actual behaviour of many people with regard to their natural environment reveals which elements of this environment they value in particular and which they do not. however, in this case, too, the validity of the standards is not derived from their factuality, but merely used as a heurism in order to find an adequate (possibly culture-immanent) justification. but given the variety of cultures and beliefs, how can standards be justified inter-subjectively, i.e. in a way that is equally valid to all? is it not the case that science can only prove or disprove factual statements (and this only to a certain extent), but not normative statements? a brief discourse on the various approaches in ethics is needed to answer this question. first of all, ethics is concerned with two different target aspects: on the one hand, it is concerned with the question of the "success" of one's own "good life", i.e. with the standards and principles that enable a person to have a happy and fulfilled life. this is called eudemonistic ethics. on the other hand, it is concerned with the standards and principles of living together, i.e. with binding regulations that create the conditions for a happy life: the common good. this is called normative ethics (galert 1998 , ott 1999 . within normative ethics a distinction is made between deontological and teleological approaches when justifying normative statements (höffe 1987) . deontological approaches are principles and standards of behaviour that apply to the behaviour itself on the basis of an external valuation criterion. it is not the consequences of an action that are the yardstick of the valuation; rather, it is adhering to inherent yardsticks that can be used against the action itself. such external yardsticks of valuation are derived from religion, nature, intuition or common sense, depending on the basic philosophical direction. thus, protection of the biosphere can be seen as a divine order to protect creation (rock 1980 , schmitz 1985 , as an innate tendency for the emotional attachment of people to an environment with biodiversity (wilson 1984) , as a directly understandable source of inspiration and joy (ehrenfeld 1993) or as an educational means of practising responsibility and maintaining social stability (gowdy 1997) . by contrast, teleological approaches refer to the consequences of action. here, too, external standards of valuation are needed since the ethical quality of the consequences of action also have to be evaluated against a yardstick of some kind. with the most utilitarian approaches (a subset of the teleological approaches) this yardstick is defined as an increase in individual or social benefit. in other schools of ethics, intuition (can the consequence still be desirable?) or the aspect of reciprocity (the so-called "golden rule": "do as you would be done by") play a key role. in the approaches based on logical reasoning (especially in kant), the yardstick is derived from the logic of the ability to generalize or universalize. kant himself is in the tradition of deontological approaches ("good will is not good as a result of what it does or achieves, but just as a result of the intention"). according to kant, every principle that, if followed generally, makes it impossible for a happy life to be conducted is ethically impermissible. in this connection, it is not the desirability of the consequences that captures kant's mind, but the logical inconsistency that results from the fact that the conditions of the actions of individuals would be undermined if everyone were to act according to the same maxims (höffe 1992) . a number of contemporary ethicists have taken up kant's generalization formula, but do not judge the maxims according to their internal contradictions; rather, they judge them according to the desirability of the consequences to be feared from the generalization (jonas 1979 or zimmerli 1993 should be mentioned here). these approaches can be defined as a middle course between deontological and teleological forms of justification. in addition to deontological and teleological approaches, there is also the simple solution of consensual ethics, which, however, comprises more than just actually experienced morality. consensual ethics presupposes the explicit agreement of the people involved in an action. everything is allowed provided that all affected (for whatever reason) voluntarily agree. in sexual ethics at the moment a change from deontological ethics to a consensual moral code can be seen. the three forms of normative ethics are shown in figure 4 .13. the comparison of the basic justification paths for normative moral systems already clearly shows that professional ethicists cannot create any standards or designate any as clearly right, even if they play a role in people's actual lives. much rather it is the prime task of ethics to ensure on the basis of generally recognized principles (for example, human rights) that all associated standards and behaviour regulations do not contradict each other or a higher order principle. above and beyond this, ethics can identify possible solutions that may occur with a conflict between standards and principles of equal standing. ethics may also reveal interconnections of justification that have proved themselves as examination criteria for moral action in the course of their disciplinary history. finally, many ethicists see their task as providing methods and procedures primarily of an intellectual nature by means of which the compatibility or incompatibility of standards within the framework of one or more moral systems can be completed. unlike the law, the wealth of standards of ethics is not bound to codified rules that can be used as a basis for such compatibility examinations. every normative discussion therefore starts with the general issues that are needed in order to allow individuals a "good life" and, at the same time, to give validity to the principles required to regulate the community life built on common good. but how can generally binding and inter-subjectively valid criteria be made for the valuation of "the common good"? in modern pluralistic societies, it is increasingly difficult for individuals and groups of society to draw up or recognize collectively binding principles that are perceived by all equally as justifiable and as self-obliging (hartwich and wewer 1991, zilleßen 1993) . the variety of lifestyle options and subjectiernization. with increasing technical and organizational means of shaping the future, the range of behaviour options available to people also expands. with the increasing plurality of lifestyles, group-specific rationalities emerge that create their own worldviews and moral standards, which demand a binding nature and validity only within a social group or subculture. the fewer cross-society guiding principles or behaviour orientations are available, the more difficult is the process of agreement on collectively binding orientations for action. however, these are vital for the maintenance of economic cooperation, for the protection of the natural foundations of life and for the maintenance of cohesion in a society. no society can exist without the binding specification of minimum canons of principles and standards. but how can agreement be reached on such collectively binding principles and standards? what criteria can be used to judge standards? the answers to this question depend on whether the primary principles, in other words, the starting point of all moral systems, or secondary principles or standards, i.e. follow-on standards that can be derived from the primary principles, are subjected to an ethical examination. primary principles can be categorical or compensatory (capable of being compensated). categorical principles are those that must not be infringed under any circumstances, even if other prin-219 fication of meaning (individualization) are accompanying features of mod-ciples would be infringed as a result. the human right to the integrity of life could be named here as an example. compensatory principles are those where temporary or partial infringement is acceptable, provided that as a result the infringement of a principle of equal or higher ranking is avoided or can be avoided. in this way certain freedom rights can be restricted in times of emergency. in the literature on ethical rules, one can find more complex and sophisticated classifications of normative rules. for our purpose to provide a simple and pragmatic framework, the distinction in four categories (principles and standards; categorical and compensatory) may suffice. this distinction has been developed from a decision-analytical perspective. but how can primary principles be justified as equally valid for all people? although many philosophers have made proposals here, there is a broad consensus today that neither philosophy nor any other human facility is capable of stating binding metacriteria without any doubt and for all people, according to which such primary principles should be derived or examined (mittelstraß 1984) . a final justification of normative judgements cannot be achieved by logical means either, since all attempts of this kind automatically end either in a logical circle, in an unending regression (vicious cycle) or in a termination of the procedure and none of these alternatives is a satisfactory solution for final justification (albert 1991). the problem of not being able to derive finally valid principles definitively, however, seems to be less serious than would appear at first glance. because, regardless of whether the basic axioms of moral rules are taken from intuition, observations of nature, religion, tradition reasoning or common sense, they have broadly similar contents. thus, there is broad consensus that each human individual has a right to life, that human freedom is a high-value good and that social justice should be aimed at. but there are obviously many different opinions about what these principles mean in detail and how they should be implemented. in spite of this plurality, however, discerning and well-intentioned observers can usually quickly agree, whether one of the basic principles has clearly been infringed. it is more difficult to decide whether they have clearly been fulfilled or whether the behaviour to be judged should clearly be assigned to one or several principles. since there is no finally binding body in a secular society that can specify primary principles or standards ex cathedra, in this case consensus among equally defendable standards or principles can be used (or pragmatically under certain conditions also majority decisions). ethical considerations are still useful in this case as they allow the test of generalization and the enhancement of awareness raising capabilities. in particular, they help to reveal the implications of such primary principles and standards. provided that primary principles are not concerned (such as human rights), the ethical discussion largely consists of examining the compatibility of each of the available standards and options for action with the primary principles. in this connection, the main concerns are a lack of contradictions (consistency), logical consistency (deductive validity), coherence (agreement with other principles that have been recognized as correct) and other, broadly logical criteria (gethmann 1998) . as the result of such an examination it is entirely possible to reach completely different conclusions that all correspond to the laws of logic and thus justify new plurality. in order to reach binding statements or valuations here the evaluator can either conduct a discussion in his "mind" and let the arguments for various standards compete with each other (rather like a platonic dialogue) or conduct a real discussion with the people affected by the action. in both cases the main concern is to use the consensually agreed primary principles to derive secondary principles of general action and standards of specific action that should be preferred over alternatives that can be equally justified. a plurality of solutions should be expected especially because most of the concrete options for action comprise only a gradual fulfilment and infringement of primary principles and therefore also include conflicting values. for value conflicts at the same level of abstraction there are, by definition, no clear rules for solution. there are therefore frequently conflicts between conserving life through economic development and destroying life through environmental damage. since the principle of conserving life can be used for both options a conflict is unavoidable in this case. to solve the conflicts, ethical considerations, such as the avoidance of extremes, staggering priorities over time or the search for third solutions can help without, however, being able to convincingly solve this conflict in principle to the same degree for all (szejnwald-brown et al. 1993) . these considerations lead to some important conclusions for the matter of the application of ethical principles to the issue of human action with regard to the natural environment. first of all, it contradicts the way ethics sees itself to develop ethics of its own for different action contexts. just as there can be no different rules for the logic of deduction and induction in nomological science, depending on which object is concerned, it does not make any sense to postulate an independent set of ethics for the environment (galert 1998) . justifications for principles and moral systems have to satisfy universal validity (nida-rümelin 1996b). furthermore, it is not very helpful to call for a special moral system for the environment since this -like every other moral system -has to be traceable to primary principles. instead, it makes sense to specify the generally valid principles that are also relevant with regard to the issue of how to deal with the natural environment. at the same time standards should be specified that are appropriate to environmental goods and that reflect those principles that are valid beyond their application to the environment. as implied above, it does not make much sense to talk about an independent set of environmental ethics. much rather, general ethics should be transferred to issues relating to the use of the environment (hargrove 1989) . three areas are usually dealt with within the context of environmental ethics (galert 1998 ): • environmental protection, i.e. the avoidance or alleviation of direct or indirect, current or future damage and pollution resulting from anthropogenic emissions, waste or changes to the landscape, including land use, as well as the long-term securing of the natural foundations of life for people and other living creatures (birnbacher 1991a ). • animal protection, i.e. the search for reasonable and enforceable standards to avoid or reduce pain and suffering in sentient beings (krebs 1997 , vischer 1999 ). • nature conservation, i.e. the protection of nature against the transforming intervention of human use, especially all measures to conserve, care for, promote and recreate components of nature deemed to be valuable, including species of flora and fauna, biotic communities, landscapes and the foundations of life required there (birnbacher 1991a) . regardless which of these three areas are addressed we need to explore which primary principles be applied to them. when dealing with the environment, the traditional basic and human rights, as well as the civil rights that have been derived from them, should be just as much a foundation of the consideration as other areas of application in ethics. however, with regard to the primary principles there is a special transfer problem when addressing human interventions into nature and the environment: does the basic postulate of conservation of life apply only to human beings, to all other creatures or to all elements of nature, too? this question does not lead to a new primary principle, as one may suspect at first glance. much rather, it is concerned with the delineation of the universally recognized principle of the conservation of life that has already been specified in the basic rights canon. are only people included in this principle (this is the codified version valid in most legal constitutions today) or other living creatures, too? and if yes, which ones? should non-living elements be included as well? when answering this question, two at first sight contradictory positions can be derived: anthropocentrism and physiocentrism (taylor 1986 , ott 1993 , galert 1998 . the anthropocentric view places humans and their needs at the fore. nature's own original demands are alien to this view. interventions in nature are allowed if they are useful to human society. a duty to make provisions for the future and to conserve nature exists in the anthropocentric world only to the extent that natural systems are classed as valuable to people today and subsequent generations and that nature can be classed as a means and guarantor of human life and survival (norton 1987 , birnbacher 1991b . in the physiocentric concept, which forms an opposite pole to the anthropocentric view, the needs of human beings are not placed above those of nature. here, every living creature, whether humans, animals or plants, have intrinsic rights with regard to the chance to develop their own lives within the framework of a natural order. merit for protection is justified in the physiocentric view by an inner value that is unique to each living creature or the environment in general. nature has a value of its own that does not depend on the functions that it fulfils today or may fulfil later from a human society's point of view (devall and sessions 1984 , callicott 1989 , rolston 1994 , meyer-abich 1996 . each of these prevailing understandings of the human-nature relationship has implications that are decisive for the form and extent of nature use by humans (elliot 1995 , krebs 1997 . strictly speaking, it could be concluded from the physiocentric idea that all human interventions in nature have to be stopped so that the rights of other creatures are not endangered. yet, not even extreme representatives of a physiocentric view would go so far as to reject all human interventions in nature because animals, too, change the environment by their ways of life (e.g. the elephant prevents the greening of the savannah). the central postulate of a physiocentric view is the gradual minimization of the depth of interventions in human use of nature. the only interventions that are permitted are those that contribute to directly securing human existence and do not change the fundamental composition of the surrounding natural environment. if these two criteria were taken to the extreme, neither population development beyond the boundaries of biological carrying capacity nor a transformation of natural land into pure agricultural land would be allowed. such a strict interpretation of physiocentrism would lead to a radical reversal of human history so far and is not compatible with the values and expectations of most people. the same is true for the unlimited transfer of anthropocentrism to dealings with nature. in this view, the use of natural services is subjected solely to the individual cost-benefit calculation. this can lead to unscrupulous exploitation of nature by humans with the aim of expanding human civilization. both extremes quickly lead to counter-intuitive implications. when the issue of environmental design and policy is concerned, anthropocentric and physiocentric approaches in their pure form are found only rarely, much rather they occur in different mixtures and slants. the transitions between the concepts are fluid. moderate approaches certainly take on elements from the opposite position. it can thus be in line with a fundamentally physiocentric perspective if the priority of human interests is not questioned in the use of natural resources. it is also true that the conclusions of a moderate form of anthropocentrism can approach the implications of the physiocentric view. table 4 .10 provides an overview of various types of anthropocentric and physiocentric perspectives. if we look at the behaviour patterns of people in different cultures, physiocentric or anthropocentric basic positions are rarely maintained consistently (bargatzky and kuschel 1994 ; on the convergence theory: birnbacher 1996) . in the strongly anthropocentric countries in the west, people spend more money on the welfare and health of their own pets than on saving human lives in other countries. in the countries of the far east that are characterized by physiocentrism, nature is frequently exploited even more radically than in the industrialized countries of the west. this inconsistent action is not a justification for one view or the other, it is just a warning for caution when laying down further rules for use so that no extreme -and thus untenable -demands be made. also from an ethical point of view, radical anthropocentrism should be rejected just as much as radical physiocentrism. if, to take up just one argument, the right to human integrity is largely justified by the fact that causing pain by others should be seen as something to avoid, this consideration without a doubt has to be applied to other creatures that are also capable of feeling pain (referred to as: pathocentrism). here, therefore, pure anthropocentrism cannot convince. in turn, with a purely physiocentric approach the primary principles of freedom, equality and human dignity could not be maintained at all if every part of living nature were equally entitled to use the natural environment. under these circumstances people would have to do without agriculture, the conversion of natural land into agricultural land and breeding farm animals and pets in line with human needs. as soon table 4 .10 different perspectives on nature. adapted from renn and goble (1996: 4). as physiocentrism is related to species and not to individuals as is done in some biocentric perspectives human priority is automatically implied; because where human beings are concerned, nearly all schools of ethics share the fundamental moral principle of an individual right to life from birth. if this right is not granted to individual animals or plants, a superiority of the human race is implicitly assumed. moderate versions of physiocentrism acknowledge a gradual de-escalation with respect to the claim of individual table 4 .10 different perspectives on nature (continued). adapted from renn and goble (1996: 4). life protection. the extreme forms of both physiocentrism and anthropocentrism are therefore not very convincing and are hardly capable of achieving a global consensus. this means that only moderate anthropocentrism or moderate biocentrism should be considered. the image of nature that is used as a basis for the considerations in this section emphasizes the uniqueness of human beings vis-à-vis physiocentric views, but does not imply carte blanche for wasteful and careless dealings with nature. this moderate concept derives society's duty to conserve nature -also for future generations -from the life-preserving and life-enhancing meaning of nature for society. this is not just concerned with the instrumental value of nature as a "store of resources", it is also a matter of the function of nature as a provider of inspiration, spiritual experience, beauty and peace (birnbacher and schicha 1996) . in this context it is important that human beings -as the addressees of the moral standard -do not regard nature merely as material and as a way towards their own self-realization, but can also assume responsibility for conservation of their cultural and so-cial function, as well as their existential value above and beyond the objective and technically available benefits (honnefelder 1993) . one of the first people to express this responsibility of human stewardship of nature in an almost poetic way was the american ecologist aldo leopold, who pointed out people's special responsibility for the existence of nature and land as early as the 1930s with the essay "the conservation ethics". his most well-known work "a sand county almanac" is sustained by the attempt to observe and assess human activities from the viewpoint of the land (a mountain or an animal). this perspective was clearly physiocentric and revealed fundamental insights about the relationship between humans and nature on the basis of empathy and shifting perspectives. his point of view had a strong influence on american environmental ethics and the stance of conservationists. although this physiocentric perspective raises many concerns, the idea of stewardship has been one of the guiding ideas for the arguments used in this section (pickett et al. 1997) . we are morally required to exercise a sort of stewardship over living nature, because nature cannot claim any rights for itself, but nevertheless has exceptional value that is important to man above and beyond its economic utility value (hösle 1991) . since contemporary society and the generations to come certainly use, or will use, more natural resources than would be compatible with a lifestyle in harmony with the given natural conditions, the conversion of natural land into anthropogenically determined agricultural land cannot be avoided (mohr 1995) . many people criticized human interventions into natural cycles as infringements of the applicable moral standards of nature conservation (for example, fastened onto the postulate of sustainability). but we should avoid premature conclusions here, as can be seen with the example of species protection. for example, where natural objects or phenomena are concerned that turn out to be a risk to human or non-human living creatures, the general call for nature conservation is already thrown into doubt (gale and cordray 1994) . not many people would call the eradication of cholera bacteria, hiv viruses and other pathogens morally bad (mittelstraß 1995) if remaining samples were kept under lock and key in laboratories. also, combating highly evolved creatures, such as cockroaches or rats meets with broad support if we ignore the call for the complete eradication of these species for the time being. an environmental initiative to save cockroaches would not be likely to gain supporters. if we look at the situation carefully, the valuation of human behaviour in these examples results from a conflict. because the conservation of the species competes with the objective of maintaining human health or the objective of a hygienic place to live, two principles, possibly of equal ranking, come face to face. in this case the options for action, which may all involve a gradual infringement of one or more principles, would have to be weighed up against each other. a general ban on eradicating a species can thus not be justified ethically, in the sense of a categorical principle, unless the maintenance of human health were to be given lower priority than the conservation of a species. with regard to the issue of species conservation, therefore, different goods have to be weighed up against each other. nature itself cannot show society what it is essential to conserve and how much nature can be traded for valuable commodities. humans alone are responsible for a decision and the resulting conflicts between competing objectives. appreciation and negotiation processes are therefore the core of the considerations about the ethical justification of rules for interventions. but this does not mean that there is no room for categorical judgements along the lines of "this or that absolutely must be prohibited" in the matter of human interventions into the natural environment. it follows on from the basic principle of conserving human life that all human interventions that threaten the ability of the human race as a whole, or a significant number of individuals alive today or in the future, to exist should be categorically prohibited. this refers to intervention threats to the systemic functions of the biosphere. such threats are one of the guiding principles that must not be exceeded under any circumstances, even if this excess were to be associated with high benefits. in the language of ethics this is a categorical principle, in the language of economics a good that is not capable of being traded. the "club" of categorical prohibitions should, however, be used very sparingly because plausible trade-offs can be thought up for most principles, the partial exceeding of which appears intuitively. in the case of threats to existence, however, the categorical rejection of the behaviour that leads to this is obvious. but what does the adoption of categorical principles specifically mean for the political moulding of environmental protection? in the past, a number of authors have tried to specify the minimum requirements for an ethically responsible moral system with respect to biosphere use. these so-called "safe minimum standards" specify thresholds for the open-ended measurement scale of the consequences of human interventions that may not be ex-ceeded even if there is a prospect of great benefits (randall 1988, randall and farmer 1995) . in order to be able to specify these thresholds in more detail the breakdown into three levels proposed by the german scientific council for global environmental change is helpful (wbgu 2000) . these levels are: • the global bio-geochemical cycles in which the biosphere is involved as one of the causes, modulator or "beneficiary"; • the diversity of ecosystems and landscapes that have key functions as bearers of diversity in the biosphere; and • the genetic diversity and the species diversity that are both "the modelling clay of evolution" and basic elements of ecosystem functions and dynamics. where the first level is concerned, in which the functioning of the global ecosystem is at stake, categorical principles are obviously necessary and sensible, provided that no one wants to shake the primary principle of the permanent preservation of the human race. accordingly, all interventions in which important substance or energy cycles are significantly influenced at a global level and where globally effective negative impacts are to be expected are categorically prohibited. usually no stringently causal evidence of the harmful nature of globally relevant information is needed; justified suspicion of such harmfulness should suffice. later in this chapter we will make a proposal for risk valuation and management how the problem of uncertainty in the event of possible catastrophic damage potential should be dealt with (risk type cassandra). on the second level, the protection of ecosystems and landscapes, it is much more difficult to draw up categorical rules. initially, it is obvious that all interventions in landscapes in which the global functions mentioned on the first level are endangered must be avoided. above and beyond this, it is wise from a precautionary point of view to maintain as much ecosystem diversity as possible in order to keep the degree of vulnerability to the unforeseen or even unforeseeable consequences of anthropogenic and nonanthropogenic interventions as low as possible. even though it is difficult to derive findings for human behaviour from observations of evolution, the empirically proven statement "he who places everything on one card, always loses in the long run" seems to demonstrate a universally valid insight into the functioning of systemically organized interactions. for this reason, the conservation of the natural diversity of ecosystems and landscape forms is a categorical principle, whereas the depth of intervention allowed should be specified on the basis of principles and standards capable of compensation. the same can be said for the third level, genetic and species protection. here too, initially the causal chain should be laid down: species conservation, landscape conservation, maintaining global functions. wherever this chain is unbroken, a categorical order of conservation should apply. these species could be termed primary key species. this includes such species that are not only essential for the specific landscape type in which they occur, but also for the global cycles above and beyond this specific landscape type thanks to their special position in the ecosystem. probably, it will not be possible to organize all species under this functional contribution to the surrounding ecosystem, but we could also think of groups of species, for example, humus-forming bacteria. in second place there are the species that characterize certain ecosystems or landscapes. here they are referred to as secondary key species. they, too, are under special protection that is not necessarily under categorical reservations. their function value, however, is worthy of special attention. below these two types of species there are the remaining species that perform ecosystem functions to a greater or lesser extent. what this means for the worthiness for protection of these species and the point at which the precise limit for permitted intervention should be drawn, is a question that can no longer be solved with categorical principles and standards, but with the help of compensatory principles and standards. generally, here, too, as with the issue of ecosystem and landscape protection, the conservation of diversity as a strategy of "reinsurance" against ignorance, global risks and unforeseeable surprises is recommended. it remains to be said that from a systemic point of view, a categorical ban has to apply to all human interventions where global closed loops are demonstrably at risk. above and beyond this, it makes sense to recognize the conservation of landscape variety (also of ecosystem diversity within landscapes) and of genetic variety and species diversity as basic principles, without being able to make categorical judgements about individual landscape or species types as a result. in order to evaluate partial infringements of compensatory principles or standards, which are referred to in the issue of environmental protection, we need rules for decision making that facilitate the balancing process necessary to resolve compensatory conflicts. in the current debate about rules for using the environment and nature, it is mainly teleological valuation methods that are proposed (hubig 1993 , ott 1993 . these methods are aimed at: • estimating the possible consequences of various options for action at all dimensions relevant to potentially affected people; • recording the infringements or fulfilments of these expected consequences in the light of the guiding standards and principles; and • then weighing them according to an internal key so that they can be weighed up in a balanced way. on the positive side of the equation, there are the economic benefits of an intervention and the cultural values created by use, for example, in the form of income, subsistence (self-sufficiency) or an aesthetically attractive landscape (parks, ornamental gardens, etc.); on the negative side, there are the destruction of current or future usage potentials, the loss of unknown natural resources that may be needed in the future and the violation of aesthetic, cultural or religious attributes associated with the environment and nature. there are therefore related categories on both sides of the equation: current uses vs. possible uses in the future, development potentials of current uses vs. option values for future use, shaping the environment by use vs. impairments to the environment as a result of alternative use, etc. with the same or similar categories on the credit and debit side of the balance sheet the decision is easy when there is one option that performs better or worse than all the other options for all categories. although such a dominant (the best for all categories) or sub-dominant option (the worst for all categories) is rare in reality, there are examples of dominant or sub-dominant solutions. thus, for example, the overfelling of the forests of kalimantan on the island of borneo in indonesia can be classed as a sub-dominant option since the short-term benefit, even with extremely high discount rates, is in no proportion to the long-term losses of benefits associated with a barren area covered in imperata grass. the recultivation of a barren area of this kind requires sums many times the income from the sale of the wood, including interest. apparently there are no cultural, aesthetic or religious reasons for conversion of primary or secondary woodland into grassland. this means that the option of deforestation should be classed as of less value than alternative options for all criteria, including economic and social criteria. at best, we can talk about a habit of leaving rainforests, as a "biotope not worthy of conservation", to short-term use. but habit is not a sound reason for the choice of any sub-optimum option. as mentioned at the start of this chapter, habit as experienced morality, does not have any normative force, especially when this is based on the illusion of the marginality of one's own behaviour or ignorance about sustainable usage forms. but if we disregard the dominant or sub-dominant solutions, an appreciation between options that violate or fulfil compensatory standards and principles depends on two preconditions: best possible knowledge of the consequences (what happens if i choose option a instead of option b?) and a transparent, consistent rationale for weighing up these consequences as part of a legitimate political decision process (are the foreseeable consequences of option a more desirable or bearable than the consequences of option b?) (akademie der wissenschaften 1992). adequate knowledge of the consequences is needed in order to reveal the systemic connections between resource use, ecosystem reactions to human interventions and socio-cultural condition factors (wolters 1995) . this requires interdisciplinary research and cooperation. the task of applied ecological research, for example, is to show the consequences of human intervention in the natural environment and how ecosystems are burdened by different interventions and practices. the economic approach provides a benefit-oriented valuation of natural and artificial resources within the context of production and consumption, as well as a valuation of transformation processes according to the criterion of efficiency. cultural and social sciences examine the feedback effects between use, social development and cultural self-perception. they illustrate the dynamic interactions between usage forms, socio-cultural lifestyles and control forms. interdisciplinary, problem-oriented and system-related research contribute to forming a basic stock of findings and insights about functional links in the relationship between human interventions and the environment and also in developing constructive proposals as to how the basic question of an ethically justified use of the natural environment can be answered in agreement with the actors concerned (wbgu 2000) . accordingly, in order to ensure sufficient environmental protection, scientific research, but especially transdisciplinary system research at the interface between natural sciences and social sciences is essential. bringing together the results of interdisciplinary research, the policy-relevant choice of knowledge banks and balanced interpretation in an environment of uncertainty and ambivalence are difficult tasks that primarily have to be performed by the science system itself. how this can happen in a way that is methodslogically sound, receptive to all reasonable aspects of interpretation and yet subjectively valid will be the subject of section 4.3.3. but knowledge alone does not suffice. in order to be able to act effectively and efficiently while observing ethical principles, it is necessary to shape the appreciation process between the various options for action according to rational criteria (gethmann 1998) . to do this it is, first of all, necessary to identify the dimensions that should be used for a valuation. the discussion about the value dimensions to be used as a basis for valuation is one of the most popular subjects within environmental ethics. to apply these criteria in risk evaluation and to combine the knowledge aspects about expected consequences of different behavioural options with the ethical principles is the task of what we have called risk governance. what contribution do ethics make towards clarifying the prospects and limits of human interventions into the natural environment? the use of environmental resources is an anthropological necessity. human consciousness works reflexively and humans have developed a causal recognition capacity that enables them to record cause and effect anticipatively and to productively incorporate assessed consequences in their own action. this knowledge is the motivating force behind the cultural evolution and the development of technologies, agriculture and urbanization. with power over an ever-increasing potential of design and intervention in nature and social affairs over the course of human history, the potential for abuse and exploitation has also grown. whereas this potential was reflected in philosophical considerations and legal standards at a very early stage with regard to moral standards between people, the issue of human responsibility towards nature and the environment has only become the subject of intensive considerations in recent times. ethical considerations are paramount in this respect. on the one hand, they offer concrete standards for human conduct on the bases of criteria that can be generalized, and, on the other hand, they provide procedural advice about a rational and decision-and policy-making process. a simple breakdown into categorical rules and prohibitions that are capable of being compensated can assist decision makers for the justification of principles and standards on environmental protection. as soon as human activities exceed the guidelines of the categorical principles, there is an urgent need for action. how can we detect whether such an excess has happened and how it can be prevented from the very outset that these inviolable standards and principles be exceeded? here are three strategies of environmental protection to be helpful for the implementation of categor-ical guidelines. the first strategy is that of complete protection with severe restrictions of all use by humans (protection priority). the second strategy provides for a balanced relationship between protection and use, where extensive resource use should go hand in hand with the conservation of the ecosystems concerned (equal weight). the third strategy is based on optimum use involving assurance of continuous reproduction. the guiding principle here would be an intensive and, at the same time, sustainable, i.e. with a view to the long term, use of natural resources (use priority). the following section will present a framework for applying these principles into environmental decision making under risk. the main line of argument is that risk management requires an analytic-deliberative approach for dealing effectively and prudently with environmental risks. assessing potential consequences of human interventions and evaluating their desirability on the basis of subsequent knowledge and transparent valuation criteria are two of the central tasks of a risk governance process. however, the plural values of a heterogeneous public and people's preferences have to be incorporated in this process. but how can this be done given the wealth of competing values and preferences? should we simply accept the results of opinion polls as the basis for making political decisions? can we rely on risk perception results to judge the seriousness of pending risks? or should we place all our faith in professional risk management? if we turn to professional help to deal with plural value input, economic theory might provide us an answer to this problem. if environmental goods are made individual and suitable for the market by means of property rights, the price that forms on the market ensures an appropriate valuation of the environmental good. every user of this good can then weigh up whether he is willing to pay the price or would rather not use the good. with many environmental goods, however, this valuation has to be made by collective action, because the environmental good concerned is a collective or open access good. in this case a process is needed that safeguards the valuation and justifies it to the collective. however, this valuation cannot be determined with the help of survey results. although surveys are needed to be able to estimate 234 the breadth of preferences and people's willingness to pay, they are insufficient for a derivation of concrete decision-making criteria and yardsticks for evaluating the tolerability of risks to human health and the environment. • firstly, the individual values are so widely scattered that there is little sense in finding an average value here. • secondly, the preferences expressed in surveys change much within a short time, whereas ethical valuations have to be valid for a long time. • thirdly, as outlined in the subsection on risk perception, preferences are frequently based on flawed knowledge or ad hoc assumptions both of which should not be decisive according to rational considerations. what is needed, therefore, is a gradual process of assigning trade-offs in which existing empirical values are put into a coherent and logically consistent form. in political science and sociological literature reference is mostly made to three strategies of incorporating social values and preferences in rational decision-making processes (renn 1997) . firstly, a reference to social preferences is viewed solely as a question of legitimate procedure (luhmann 1983 , vollmer 1996 . the decision is made on the basis of formal decision-making process (such as majority voting). if all the rules have been kept, a decision is binding, regardless of whether the subject matter of the decision can be justified or whether the people affected by the decision can understand the justification. in this version, social consensus has to be found only about the structure of the procedures; the only people who are then involved in the decisions are those who are explicitly legitimated to do so within the framework of the procedure decided upon. the second strategy is to rely on the minimum consensuses that have developed in the political opinion-forming process (muddling through) (lindbloom 1959 (lindbloom , 1965 . in this process, only those decisions that cause the least resistance in society are considered to be legitimate. in this version of social pluralism groups in society have an influence on the process of the formation of will and decision making to the extent that they provide proposals capable of being absorbed, i.e. adapted to the processing style of the political system, and that they mobilize public pressure. the proposal that then establishes itself in politics is the one that stands up best in the competition of proposals, i.e. the one that entails the fewest losses of support for political decision makers by interest groups. the third strategy is based on the discussion between the groups involved (habermas 1971 , renn 2004 ). in the communicative exchange among the people involved in the discussion a form of communicative rationality that everyone can understand evolves that can serve as a justification for collectively binding decisions. at the same time, discursive methods claim to more appropriately reflect the holistic nature of human beings and also to provide fair access to designing and selecting solutions to problems. in principle, the justification of standards relevant to decisions is linked to two conditions: the agreement of all involved and substantial justification of the statements made in the discussion (habermas 1981) . all three strategies of political control are represented in modern societies to a different extent. legitimation conflicts mostly arise when the three versions are realized in their pure form. merely formally adhering to decisionmaking procedures without a justification of content encounters a lack of understanding and rejection among the groups affected especially when they have to endure negative side effects or risks. then acceptance is refused. if, however, we pursue the opposite path of least resistance and base ourselves on the route of muddling through we may be certain of the support of the influential groups, but, as in the first case, the disadvantaged groups will gradually withdraw their acceptance because of insufficient justification of the decision. at the same time, antipathy to politics without a line or guidance is growing, even the affected population. the consequence is political apathy. the third strategy of discursive control faces problems, too. although in an ideal situation it is suitable for providing transparent justifications for the decision-making methods and the decision itself, in real cases the conditions of ideal discourse can rarely be adhered to (wellmer 1992) . frequently, discussions among strategically operating players lead to a paralysis of practical politics by forcing endless marathon meetings with vast quantities of points of order and peripheral contributions to the discussion. the "dictatorship of patience" (weinrich 1972) ultimately determines which justifications are accepted by the participants. the public becomes uncertain and disappointed by such discussions that begin with major claims and end with trivial findings. in brief: none of the three ways out of the control dilemma can convince on its own; as so often in politics, everything depends on the right mixture. what should a mixture of the three elements (due process, pluralistic muddling through and discourse) look like so that a maximum degree of rationality can come about on the basis of social value priorities? a report by the american academy of sciences on the subject of "understanding environmental risks" (national research council 1996) comes to the conclusion that scientifically valid and ethically justified procedure for the collective valuation of options for risk handling can only be realized within the context of -what the authors coin -an analytic-deliberative process. analytic means that the best scientific findings about the possible consequences and conditions of collective action are incorporated in the negotiations; deliberative means that rationally and ethically transparent criteria for making trade-offs are used and documented externally. moreover, the authors consider that fair participation by all groups concerned is necessary to ensure that the different moral systems that can legitimately exist alongside each other should also be incorporated in the process. to illustrate the concept of analytic-deliberative decision making consider a set of alternative options or choices, from which follow consequences (see basic overview in dodgson et al. 2000) . the relationship between the choice made, and the consequences that follow from this choice, may be straightforward or complex. the science supporting environmental policy is often complicated, across many disciplines of science and engineering, and also involving human institutions and economic interactions. because of limitations in scientific understanding and predictive capabilities, the consequences following a choice are normally uncertain. finally, different individuals and groups within society may not agree on how to evaluate the consequences -which may involve a detailed characterization of what happens in ecological, economic, and human health terms. we shall describe consequences as ambiguous when there is this difficulty in getting agreement on how to interpret and evaluate them. this distinction has been further explained in chapter 3 (see also klinke and renn 2002) . environmental assessment and environmental decision making inherently involve these difficulties of complexity, uncertainty, and ambiguity (klinke and renn 2002) . in some situations where there is lots of experience, these difficulties may be minimal. but in other situations these difficulties may constitute major impediments to the decision-making process. to understand how analysis and deliberation interact in an iterative process following the national research council (nrc) 1996 report, one must consider how these three areas of potential difficulty can be addressed. it is useful to separate questions of evidence with respect to the likelihood, magnitude of consequences and related characteristics (which can involve complexity and uncertainty) from valuation of the consequences (i.e. ambiguity). for each of the three areas there are analytical tools that can be helpful in identifying, characterizing and quantifying cause-effect relationships. some of these tools have been described in chapter 3. the integration of these tools of risk governance into a consistent procedure will be discussed in the next subsections. the possibility to reach closure on evaluating risks to human health or the environment rests on two conditions: first, all participants need to achieve closure on the underlying goal (often legally prescribed, such as prevention of health detriments or guarantee of an undisturbed environmental quality, for example, purity laws for drinking water); secondly, they need to agree with the implications derived from the present state of knowledge (whether and to what degree the identified hazard impacts the desired goal). dissent can result from conflicting values as well as conflicting evidence. it is crucial in environmental risk management to investigate both sides of the coin: the values that govern the selection of the goal and the evidence that governs the selection of cause-effect claims. strong differences in both areas can be expected in most environmental decision-making contexts but also in occupational health and safety and public health risks. so for all risk areas it is necessary to explore why people disagree about what to do -that is, which decision alternative should be selected. as pointed out before, differences of opinion may be focused on the evidence of what is at stake or which option has what kind of consequences. for example: what is the evidence that an environmental management initiative will lead to an improvement, such as reducing losses of agricultural crops to insect pests -and what is the evidence that the management initiative could lead to ecological damage -loss of insects we value, such as bees or butterflies, damage to birds and other predators that feed on insects -and health impacts from the level of pesticides and important nutrients in the food crops we eat? other differences of opinion may be about values -value of food crops that contain less pesticide residue compared to those that contain more, value of having more bees or butterflies, value of maintaining indigenous species of bees or butterflies compared to other varieties not native to the local ecosystem, value ascribed to good health and nutrition, and maybe, value ascribed to having food in what is perceived to be a "natural" state as opposed to containing manufactured chemical pesticides or altered genetic material. separating the science issues of what will happen from the value issues of how to make appropriate trade-offs between ecological, economic, and human health goals can become very difficult. the separation of facts and values in decision making is difficult to accomplish in practical decision situations, since what is regarded as facts includes a preference dependent process of cognitive framing (tversky and kahneman 1981) and what is regarded as value includes a prior knowledge about the factual implica-tions of different value preferences (fischhoff 1975) . furthermore, there are serious objections against a clear-cut division from a sociological view on science and knowledge generation (jasanoff 1996) . particularly when calculating risk estimates, value-based conventions may enter the assessment process. for example, conservative assumptions may be built into the assessment process, so that some adverse effects (such as human cancer from pesticide exposure) are much less likely to be underestimated than overestimated (national research council 1983) . at the same time, ignoring major sources of uncertainty can evoke a sense of security and overconfidence that is not justified from the quality or extent of the data base (einhorn and hogarth 1978) . perceptions and world views may be very important, and difficult to sort out from matters of science, especially with large uncertainties about the causes of environmental damage. a combination of analytic and deliberative processes can help explore these differences of opinions relating to complexity, uncertainty, and ambiguity in order to examine the appropriate basis for a decision before the decision is made. most environmental agencies go through an environmental assessment process and provide opportunities for public review and comment. many controversial environmental decisions become the focus of large analytical efforts, in which mathematical models are used to predict the environmental, economic, and health consequences of environmental management alternatives. analysis should be seen as an indispensable complement to deliberative processes, regardless whether this analysis is sophisticated or not. even simple questions need analytic input for making prudent decisions, especially in situations where there is controversy arising from complexity, uncertainty, and ambiguity. in many policy arenas in which problems of structuring human decisions are relevant, the tools of normative decision analysis (da) have been applied. especially in economics, sociology, philosophical ethics, and also many branches of engineering and science, these methods have been extended and refined during the past several decades. (edwards 1954 , howard 1966 , north 1968 , howard et al. 1972 , north and merkhofer 1976 , behn and vaupel 1982 , pinkau and renn 1998 , van asselt 2000 , jaeger et al. 2001 . da is a process for decomposing a decision problem into pieces, starting with the simple structure of alternatives, information, and prefer-ences. it provides a formal framework for quantitative evaluation of alternative choices in terms of what is known about the consequences and how the consequences are valued (hammond et al. 1999 , skinner 1999 . the procedures and analytical tools of da provide a number of possibilities to improve the precision and transparency of the decision procedure. however, they are subject to a number of limitations. the opportunities refer to: • different action alternatives can be quantitatively evaluated to allow selection of a best choice. such evaluation relies both on a description of uncertain consequences for each action alternative, with uncertainty in the consequences described using probabilities, and a description of the values and preferences assigned to consequences. (explicit characterization of uncertainty and values of consequences) • the opportunity to assure transparency, in that (1) models and data summarizing complexity (e.g., applicable and available scientific evidence) (2) probabilities characterizing judgement about uncertainty, and (3) values (utilities) on the consequences are made explicit and available. so the evaluation of risk handling alternatives can be viewed and checked for accuracy by outside observers. (outside audit enabled of basis for decision) • a complex decision situation can be decomposed into smaller pieces in a formal analytical framework. the level of such composition can range from a decision tree of action alternatives and ensuing consequences that fits on a single piece of paper, to extremely large and complex computerimplemented models used in calculating environmental consequences and ascribing probabilities and values of the consequences. a more complex analysis is more expensive and is less transparent to observers. in principle, with sufficient effort any formal analytical framework can be checked to assure that calculations are made in the way that is intended. (decomposition possible to include extensive detail) on the other hand, there are important limitations: • placing value judgements (utilities) on consequences may be difficult, especially in a political context where loss of life, impairment of health, ecological damage, or similar social consequences are involved. utility theory is essentially an extension of cost-benefit methods from economics to include attitude toward risk. the basic trade-off judgements needed for cost-benefit analysis remain difficult and controversial, and often, inherently subjective. (difficulties in valuing consequences) • assessing uncertainty in the form of a numerical probability also poses difficulties, especially in situations when there is not a statistical data base on an agreed-on model as the basis for the assessment. (difficulty in quantifying uncertainty, assigning probabilities) • the analytical framework may not be complete. holistic or overarching considerations or important details may have been omitted. (analytical framework incomplete) • da is built upon an axiomatic structure, both for dealing with uncertainty (i.e., the axiomatic foundation of probability theory), and for valuing consequences (i.e., the axiomatic basis for von neumann-morgenstern utility theory). especially when the decision is to be made by a group rather than an individual decision maker, rational preferences for the group consistent with the axioms may not exist (the "impossibility" theorem of arrow, 1951) . so in cases of strong disagreements on objectives or unwillingness to use a rational process, decision analysis methods may not be helpful. decision analytical methods should not be regarded as inherently "mechanical" or "algorithmic", in which analysts obtain a set of "inputs" about uncertainty and valuing consequences, then feed these into a mathematical procedure (possibly implemented in a computer) that produces an "output" of the "best" decision. da can only offer coherent conclusions from the information which the decision maker provides by his/her preferences among consequences and his/her state of information on the occurrence of these consequences. where there is disagreement about the preferences or about the information, da may be used to implore the implications of such disagreement. so in application, there is often a great deal of iteration (sensitivity analysis) to explore how differences in judgement should affect the selection of the best action alternative. da thus merely offers a formal framework that can be effective in helping participants in a decision process to better understand the implications of differing information and judgement about complex and uncertain consequences from the choice among the available action alternatives. insight about which factors are most important in selecting among the alternatives is often the most important output of the process, and it is obtained through extensive and iterative exchange between analysts and the decision makers and stakeholders. the main advantage of the framework is that it is based on logic that is both explicit and checkable -usually facilitated by the use of mathematical models and probability calculations. research on human judgement supports the superiority of such procedures for decomposing complex decision problems and using logic to integrate the pieces, rather than relying on holistic judgement on which of the alternatives is best (this is not only true for individual decisions, see heap et al. 1992 : 36ff., jungermann 1986 ; but also for collective decisions, see heap et al. 1992 : 197ff., pettit 1991 . one should keep in mind, however, that "superior" is measured in accordance with indicator of instrumental rationality, i.e. measuring means-ends effectiveness. if this rationality is appropriate, the sequence suggested by da is intrinsically plausible and obvious. even at the level of qualitative discussion and debate, groups often explore the rationale for different action alternatives. decision analysis simply uses formal quantitative methods for this traditional and common-sense process of exploring the rationale -using models to describe complexity, probability to describe uncertainty, and to deal with ambiguity, explicit valuation of consequences via utility theory and other balancing procedures, such as cost-benefit or cost-effectiveness analyses. by decomposing the problem in logical steps, the analysis permits better understanding of differences in the participants' perspective on evidence and values. da offers methods to overcome these differences, such as resolving questions about underlying science through data collection and research, and encouraging tradeoffs, compromise, and rethinking of values. based on this review of opportunities and shortcomings we conclude that decision analysis provides a suitable structure for guiding discussion and problem formulation, and offers a set of quantitative analytical tools that can be useful for environmental decisions, especially in conjunction with deliberative processes. da can assist decision makers and others involved in, and potentially affected by, the decision (i.e., participants, stakeholders) to deal with complexity and many components of uncertainty, and to address issues of remaining uncertainties and ambiguities. using these methods promises consistency from one decision situation to another, assurance of an appropriate use of evidence from scientific studies related to the environment, and explicit accountability and transparency with respect to those institutionally responsible for the value judgements that drive the evaluation of the alternative choices. collectively the analytical tools provide a framework for a systematic process of exploring and evaluating the decision alternatives -assembling and validating the applicable scientific evidence relevant to what will happen as the result of each possible choice, and valuing how bad or how good these consequences are based on an agreement of common objectives. yet, it does not replace the need for additional methods and processes for including other objectives, such as finding common goals, defining preferences, revisiting assumptions, sharing visions and exploring common grounds for values and normative positions. the value judgements motivating decisions are made explicit and can then be criticized by those who were not involved in the process. to the extent that uncertainty becomes important, it will be helpful to deal with uncertainty in an orderly and consistent way (morgan and henrion 1990). those aspects of uncertainty that can be modelled by using probability theory (inter-target variation, systematic and random errors in applying inferential statistics, model and data uncertainties) will be spelled out and those that remain in forms of indeterminacies, system boundaries or plain ignorance will become visible and can then be fed into the deliberation process (van asselt 2000, klinke and renn 2002) . the term deliberation refers to the style and procedure of decision making without specifying which participants are invited to deliberate (national research council (nrc) 1996, rossi 1997) . for a discussion to be called deliberative it is essential that it relies on mutual exchange of arguments and reflections rather than decision making based on the status of the participants, sublime strategies of persuasion, or social-political pressure. deliberative processes should include a debate about the relative weight of each argument and a transparent procedure for balancing pros and cons (tuler and webler 1999) . in addition, deliberative processes should be governed by the established rules of a rational discourse. in the theory of communicative action developed by the german philosopher jürgen habermas, the term discourse denotes a special form of a dialogue, in which all affected parties have equal rights and duties to present claims and test their validity in a context free of social or political domination (habermas 1970 (habermas , 1987b . a discourse is called rational if it meets the following specific requirements (see mccarthy 1975 , habermas 1987a , kemp 1985 , webler 1995 . all participants are obliged: • to seek a consensus on the procedure that they want to employ in order to derive the final decision or compromise, such as voting, sorting of positions, consensual decision making or the involvement of a mediator or arbitrator; • to articulate and criticize factual claims on the basis of the "state of the art" of scientific knowledge and other forms of problem-adequate knowledge; (in the case of dissent all relevant camps have the right to be represented); • to interpret factual evidence in accordance with the laws of formal logic and analytical reasoning; • to disclose their relevant values and preferences, thus avoiding hidden agendas and strategic game playing; and • to process data, arguments and evaluations in a structured format (for example a decision-analytic procedure) so that norms of procedural rationality are met and transparency can be created. the rules of deliberation do not necessarily include the demand for stakeholder or public involvement. deliberation can be organized in closed circles (such as conferences of catholic bishops, where the term has indeed been used since the council of nicosia), as well as in public forums. it may be wise to use the term "deliberative democracy" when one refers to the combination of deliberation and public or stakeholder involvement (see also cohen 1997 , rossi 1997 . what needs to be deliberated? firstly, deliberative processes are needed to define the role and relevance of systematic and anecdotal knowledge for making far-reaching choices. secondly, deliberation is needed to find the most appropriate way to deal with uncertainty in environmental decision making and to set efficient and fair trade-offs between potential over-and under-protection. thirdly, deliberation needs to address the wider concerns of the affected groups and the public at large. why can one expect that deliberative processes are better suited to deal with environmental challenges than using expert judgement, political majority votes or relying on public survey data? • deliberation can produce common understanding of the issues or the problems based on the joint learning experience of the participants with respect to systematic and anecdotal knowledge (webler and renn 1995 , pidgeon 1997 ). • deliberation can produce a common understanding of each party's position and argumentation and thus assist in a mental reconstruction of each actor's argumentation (warren 1993 , tuler 1996 . the main driver for gaining mutual understanding is empathy. the theory of communicative action provides further insights in how to mobilize empathy and how to use the mechanisms of empathy and normative reasoning to explore and generate common moral grounds (webler 1995). • deliberation can produce new options and novel solutions to a problem. this creative process can either be mobilized by finding win-win solutions or by discovering identical moral grounds on which new options can grow (renn 1999) . • deliberation has the potential to show and document the full scope of ambiguity associated with environmental problems. deliberation helps to make a society aware of the options, interpretations, and potential actions that are connected with the issue under investigation (wynne 1992, de marchi and ravetz 1999) . each position within a deliberative discourse can only survive the crossfire of arguments and counter-arguments if it demonstrates internal consistency, compatibility with the legitimate range of knowledge claims and correspondence with the widely accepted norms and values of society. deliberation clarifies the problem, makes people aware of framing effects, and determines the limits of what could be called reasonable within the plurality of interpretations (skillington 1997) . • deliberations can also produce agreements. the minimal agreement may be a consensus about dissent (raiffa 1994) . if all arguments are exchanged, participants know why they disagree. they may not be convinced that the arguments of the other side are true or morally strong enough to change their own position; but they understand the reasons why the opponents came to their conclusion. in the end, the deliberative process produces several consistent and -in their own domain -optimized positions that can be offered as package options to legal decision makers or the public. once these options have been subjected to public discourse and debate, political bodies, such as agencies or parliaments can make the final selection in accordance with the legitimate rules and institutional arrangements such as majority vote or executive order. final selections could also be performed by popular vote or referendum. • deliberation may result in consensus. often deliberative processes are used synonymously with consensus-seeking activities (coglianese 1997 ). this is a major misunderstanding. consensus is a possible outcome of deliberation, but not a mandatory requirement. if all participants find a new option that they all value more than the one option that they preferred when entering the deliberation, a "true" consensus is reached (renn 1999) . it is clear that finding such a consensus is the exception rather than the rule. consensus is either based on a win-win solution or a solution that serves the "common good" and each participant's interests and values better than any other solution. less stringent is the requirement of a tolerated consensus. such a consensus rests on the recognition that the selected decision option might serve the "common good" best, but on the expense of some interest violations or additional costs. in a tolerated consensus some participants voluntarily accept personal or group-specific losses in exchange for providing benefits to all of society. case studies have provided sufficient evidence that deliberation has produced a tolerated consensus solution, particularly in siting conflicts (one example in schneider et al. 1998) . consensus and tolerated consensus should be distinguished from compromise. a compromise is a product of bargaining where each side gradually reduces its claim to the opposing party until they reach an agreement (raiffa 1994) . all parties involved would rather choose the option that they preferred before starting deliberations, but since they cannot find a win-win situation or a morally superior alternative they look for a solution that they can "live with" knowing that it is the second or third best solution for them. compromising on an issue relies on full representation of all vested interests. in summary, many desirable products and accomplishments are associated with deliberation (chess et al. 1998) . depending on the structure of the discourse and the underlying rationale deliberative processes can: • enhance understanding; • generate new options; • decrease hostility and aggressive attitudes among the participants; • explore new problem framing; • enlighten legal policy-makers; • produce competent, fair and optimized solution packages; and • facilitate consensus, tolerated consensus and compromise. in a deliberative setting, participants exchange arguments, provide evidence for their claims and develop common criteria for balancing pros and cons. this task can be facilitated and often guided by using decision analytic tools (overview in merkhofer 1984) . decision theory provides a logical framework distinguishing action alternatives or options, consequences, likelihood of consequences, and value of consequences, where the valuation can be over multiple attributes that are weighted based on tradeoffs in multi-attribute utility analysis (edwards 1977) . a sequence of decisions and consequences may be considered, and use of mathematical models for predicting the environmental consequences of options may or may not be part of the process (humphreys 1977 , bardach 1996 , arvai et al. 2001 ): a) the structuring potential of decision analysis has been used in many participatory processes. it helps the facilitator of such processes to focus on one element during the deliberation, to sort out the central from the peripheral elements, provide a consistent reference structure for ordering arguments and observations and to synthesize multiple impressions, observations and arguments into a coherent framework. the structuring power of decision analysis has often been used without expanding the analysis into quantitative modelling. b) the second potential, agenda setting and sequencing, is also frequently applied in participatory settings. it often makes sense to start with problem definition, then develop the criteria for evaluation, generate options, assess consequences of options, and so on. c) the third potential, quantifying consequences, probabilities and relative weights and calculating expected utilities, is more controversial than the other two. whether the deliberative process should include a numerical analysis of utilities or engage the participants in a quantitative elicitation process is contested among participation practitioners . one side claims that quantifying helps participants to be more precise about their judgements and to be aware of the often painful trade-offs they are forced to make. in addition, quantification can make judgements more transparent to outside observers. the other side claims that quantification restricts the participants to the logic of numbers and reduces the complexity of argumentation into a mere trade-off game. many philosophers argue that quantification supports the illusion that all values can be traded off against other values and that complex problems can be reduced to simple linear combinations of utilities. one possible compromise between the two camps may be to have participants go through the quantification exercise as a means to help them clarify their thoughts and preferences, but make the final decisions on the basis of holistic judgements (renn 1986) . in this application of decision analytic procedures, the numerical results (i.e. for each option the sum over the utilities of each dimension multiplied by the weight of each dimension) of the decision process are not used as expression of the final judgement of the participant, but as a structuring aid to improve the participant's holistic, intuitive judgement. by pointing out potential discrepancies between the numerical model and the holistic judgements, the participants are forced to reflect upon their opinions and search for potential hidden motives or values that might explain the discrepancy. in a situation of major value conflicts, the deliberation process may involve soliciting a diverse set of viewpoints, and judgements need to be made on what sources of information are viewed as responsible and reliable. publication in scientific journals and peer review from scientists outside the government agency are the two most popular methods by which managers or organizers of deliberative processes try to limit what will be considered as acceptable evidence. other methods are to reach a consensus among the participants up front which expertise should be included in the deliberation or to appoint representatives of opposing science camps to explain their differences in public. in many cases, participants have strong reasons for questioning scientific orthodoxy and would like to have different science camps represented. many stakeholders in environmental decisions have access to expert scientists, and often such scientists will take leading roles in criticizing agency science. such discussions need to be managed so that disagreements among the scientific experts can be evaluated in terms of the validity of the evidence presented and the importance to the decision. it is essential in these situations to have a process in place that distinguishes between those evidence claims that all parties agree on, those where the factual base is shared but not its meaning for some quality criterion (such as "healthy" environment), and those where even the factual base is contested (foster 2002) . in the course of practical risk management different conflicts arise in deliberative settings that have to be dealt with in different ways. the main conflicts occur at the process level (how should the negotiations be conducted?), on the cognitive level (what is factually correct?), the interest level (what benefits me?), the value level (what is needed for a "good" life?) and the normative level (what can i expect of all involved?). these different conflict levels are addressed in this subsection. first of all, negotiations begin by specifying the method that structures the dialogue and the rights and duties of all participants. it is the task of the chairman or organizer to present and justify the implicit rules of the talks and negotiations. above and beyond this, the participants have to specify joint rules for decisions, the agenda, the role of the chairman, the order of hearings, etc. this should always be done according to the consensus principle. all partners in the negotiations have to be able to agree to the method. if no agreement is reached here the negotiations have to be interrupted or reorganized. once the negotiation method has been determined and, in a first stage, the values, standards and objectives needed for judgement have been agreed jointly, then follows the exchange of arguments and counter arguments. in accordance with decision theory, four stages of validation occur: • in a first stage, the values and standards accepted by the participants are translated into criteria and then into indicators (measurement instructions). this translation needs the consensual agreement of all participants. experts are asked to assess the available options with regard to each indicator according to the best of their knowledge (factual correctness). in this context it makes more sense to specify a joint methodological procedure or a consensus about the experts to be questioned than to give each group the freedom to have the indicators answered by their own experts. often many potential consequences remain disputed as a result of this process, especially if they are uncertain. however, the bandwidth of possible opinions is more or less restricted depending on the level of certainty and clarity associated with the issue in question. consensus on dissent is also of help here in separating contentious factual claims from undisputed ones and thus promotes further discussion. • in a second stage, all participating parties are required to interpret bandwidths of impacts to be expected for each criterion. interpretation means linking factual statements with values and interests to form a balanced overall judgement (conflicts of interests and values). this judgement can and should be made separately for each indicator. in this way, each of the chains of causes for judgements can be understood better and criticized in the course of the negotiations. for example, the question of trustworthiness of the respective risk management agencies may play an important role in the interpretation of an expected risk value. then it is the duty of the participating parties to scrutinize the previous performance of the authority concerned and propose institutional changes where appropriate. • third stage: even if there were a joint assessment and interpretation for every indicator, this would by no means signify that agreement is at hand. much rather, the participants' different judgements about decisionmaking options may be a result of different value weightings for the indicators that are used as a basis for the values and standards. for example, a committed environmentalist may give much more weight to the indicator for conservation than to the indicator of efficiency. in the literature on game theory, this conflict is considered to be insoluble unless one of the participants can persuade the other to change his preference by means of compensation payments (for example, in the form of special benefits), transfer services (for example, in the form of a special service) or swap transactions (do, ut des). in reality, however, it can be seen that participants in negotiations are definitely open to the arguments of the other participants (i.e. they may renounce their first preference) if the loss of benefit is still tolerable for them and, at the same time, the proposed solution is considered to be "conducive to the common good", i.e. is seen as socially desirable in public perception. if no consensus is reached, a compromise solution can and should be reached, in which a 'fair' distribution of burdens and profits is accomplished. • fourth stage: when weighing up options for action formal methods of balancing assessment can be used. of these methods, the cost-benefit analysis and the multi-attribute or multi-criteria decision have proved their worth. the first method is largely based on the approach of revealed "preferences", i.e. on people's preferences shown in the past expressed in relative prices, the second on the approach of "expressed preferences", i.e. the explicit indication of relative weightings between the various cost and benefit dimensions (fischhoff et al. 1982) . but both methods are only aids in weighing up and cannot replace an ethical reflection of the advantages and disadvantages. normative conflicts pose special problems because different evaluative criteria can always be classified as equally justifiable or unjustifiable as explained earlier. for this reason, most ethicists assume that different types and schools of ethical justification can claim parallel validity, it therefore remains up to the groups involved to choose the type of ethically legitimate justification that they want to use (ropohl 1991 , renn 1997 . nevertheless, the limits of particular justifications are trespassed wherever primary principles accepted by all are infringed (such as human rights). otherwise, standards should be classed as legitimate if they can be defended within the framework of ethical reasoning and if they do not contradict universal standards that are seen as binding for all. in this process conflicts can and will arise, e.g. that legitimate derivations of standards from the perspective of group a contradict the equally legitimate derivations of group b (shrader-frechette 1988). in order to reach a jointly supported selection of standards, either a portfolio of standards that can claim parallel validity should be drawn up or compensation solutions will have to be created in which one party compensates the other for giving up its legitimate options for action in favour of a common option. when choosing possible options for action or standards, options that infringe categorical principles, for example, to endangering the systematic ability of the natural environment to function for human use in the future and thus exceeding the limits of tolerability are not tolerable even if they imply major benefits to society. at the same time, all sub-dominant options have to be excluded. frequently sub-dominant solutions, i.e. those that perform worse than all other options with regard to all criteria at least in the long term, are so attractive because they promise benefits in the short term although they entail losses in the long term, even if high interest rates are assumed. often people or groups have no choice other than to choose the sub-dominant solution because all other options are closed to them due to a lack of resources. if large numbers of groups or many individuals act in this way, global risks become unmanageable (beck 1996) . to avoid these risks intermediate financing or compensation by third parties should be considered. the objective of this last section of chapter 4 was to address and discuss the use of decision analytic tools and structuring aids for participatory processes in environmental management. organizing and structuring discourses goes beyond the good intention to have all relevant stakeholders involved in decision making. the mere desire to initiate a two-way communication process and the willingness to listen to stakeholder concerns are not sufficient. discursive processes need a structure that assures the integration of technical expertise, regulatory requirements, and public values. these different inputs should be combined in such a fashion that they contribute to the deliberation process the type of expertise and knowledge that can claim legitimacy within a rational decision-making procedure (von schomberg 1995). it does not make sense to replace technical expertise with vague public perceptions, nor is it justified to have the experts insert their own value judgements into what ought to be a democratic process. decision analytic tools can be of great value for structuring participatory processes. they can provide assistance in problem structuring, in dealing with complex scientific issues and uncertainty, and in helping a diverse group to understand disagreements and ambiguity with respect to values and preferences. decision analysis tools should be used with care. they do not provide an algorithm to reach an answer as to what is the best decision. rather, decision analysis is a formal framework that can be used for environmental assessment and risk handling to explore difficult issues, to focus debate and further analysis on the factors most important to the decision, and to provide for increased transparency and more effective exchange of information and opinions among the process participants. the basic concepts are relatively simple and can be implemented with a minimum of mathematics (hammond et al. 1999) . many participation organizers have restricted the use of decision analytic tools to assist participants in structuring problems and ordering concerns and evaluations, and have refrained from going further into quantitative trade-off analysis. others have advocated quantitative modelling as a clarification tool for making value conflicts more transparent to the participants. the full power of decision analysis for complex environmental problem may require mathematical models and probability assessment. experienced analysts may be needed to guide the implementation of these analytical tools for aiding decisions. skilled communicators and facilitators may be needed to achieve effective interaction between analysts and participants in the deliberative process whose exposure to advanced analytical decision aids is much less, so that understanding of both process and substance, and therefore transparency and trust, can be achieved. many risk management agencies are already making use of decision analysis tools. we urge them 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the craft and theory of public participation: a dialectical process a brief primer on participation: philosophy and practice system, diskurs, didaktik und die diktatur des sitzfleisches konsens als telos der sprachlichen kommunikation? in: giegel biophilia: the human bond with other species rio" oder die moralische verpflichtung zum erhalt der natürlichen vielfalt risk and social learning: reification to engagement die modernisierung der demokratie im zeichen der umweltproblematik wandelt sich die verantwortung mit technischem wandel? key: cord-283287-073r80s7 authors: farhoudian, ali; baldacchino, alexander; clark, nicolas; gerra, gilberto; ekhtiari, hamed; dom, geert; mokri, azarakhsh; sadeghi, mandana; nematollahi, pardis; demasi, maryanne; schütz, christian g.; hash-emian, seyed mohammadreza; tabarsi, payam; galea-singer, susanna; carrà, giuseppe; clausen, thomas; kouimtsidis, christos; tolomeo, serenella; radfar, seyed ramin; razaghi, emran mohammad title: covid-19 and substance use disorders: recommendations to a comprehensive healthcare response. an international society of addiction medicine practice and policy interest group position paper date: 2020-04-12 journal: basic clin neurosci doi: 10.32598/bcn.11.covid19.1 sha: doc_id: 283287 cord_uid: 073r80s7 coronavirus disease 2019 (covid-19) is escalating all over the world and has higher morbidities and mortalities in certain vulnerable populations. people who use drugs (pwud) are a marginalized and stigmatized group with weaker immunity responses, vulnerability to stress, poor health conditions, high-risk behaviors, and lower access to health care services. these conditions put them at a higher risk of covid-19 infection and its complications. in this paper, an international group of experts on addiction medicine, infectious diseases, and disaster psychiatry explore the possible raised concerns in this issue and provide recommendations to manage the comorbidity of covid-19 and substance use disorder (sud). oronavirus disease 2019 (covid-19) is a new member of the coronavirus family that infect humans . it first emerged in the wuhan region of china in november 2019 (lai shih, ko, tang, & hsueh, 2020) . by march 2020, the world health organization (who) assessed the global situation of covid-19 as a pandemic. patients with cardiovascular diseases, chronic respiratory diseases, people aged 60 or older, and males have a higher risk of mortality than the rest of the population huang et al., 2020; wang et al., 2020) . frequently reported clinical symptoms at the onset of the disease include pyrexia (83%-98%), cough (46%-82%), myalgia or fatigue (11%-44%), and shortness of breath (31%) huang et al., 2020; wang et al., 2020) . sore throat and, less commonly, sputum production, headache, hemoptysis, and diarrhea have also been reported (chan et al., 2020) . in more severe cases, covid-19 can cause pneumonia, severe and acute respiratory syndrome, and sometimes (1%-3% of all infected cases) death (world health organization, 2020b) . currently, the medications used for severe cases of covid-19 include chloroquine phosphate (gao, tian, & yang, 2020) , hydroxychloroquine sulfate (javadi et al., 2006) , lopinavir/ritonavir (li & de clercq, 2020; lim et al., 2020) , oseltamivir (li & de clercq, 2020; vetter, eckerle, & kaiser, 2020) , and ribavirin (li & de clercq, 2020) . but none have been approved by regulatory authorities for use against covid-19. the most common strategies, as advised by who, include preventative measures such as quarantine and limitations of movement in infected areas (hellewell et al., 2020; wu, leung, & leung, 2020) , interruption of human-to-human transmission, early identification and isolation, providing appropriate care for patients, identifying and reducing transmission from the animal source, and minimizing the social and economic impact through the new coronavirus created a complex situation for all sections of the communities around the world. health care providers are in the frontline of intervening to stop the spread of covid-19. meantime people who use drugs (pwud) are at increased risk during this pandemic since they are a stigmatized and marginalized populations. health service providers who are providing different needs for pwud in treatment and/or harm reduction settings should always keep themselves safe with using standard ppe based on the who recommendations. additionally pwuds live in crowded locations and so screening and early identification of covid-19 patients are important to break the cycle of transmission. it is recommended that protocols for opioid substitution therapy modify with complete adherence to patients' safety regarding both opioid drug risks and covid-19 infections. it is important to have in mind that different stages of ost needs different approaches. pwuds are more vulnerable to stress and other mental health problems. this makes psychological interventions such as cognitive-behavioral therapy and other modalities very important to have for pwuds during these difficult and challenging times to assist and sustain treatment. medical conditions such as respiratory illness, renal insufficiency, chronic pain and cardiovascular disorders are also important medical conditions that should be addressed appropriately among pwuds with covid-19. health service providers in both fields of addiction treatment and covid-19 treatment and prevention systems should be aware regarding special situations arising in the overlap of drug use and covid-19 illness. march, april 2020, vol 11, num 2 [covid-19] farhoudian, a., et al. (2020) . covid-19 and substance use disorders. bcn, 11 (2), 133-150. multispectral partnerships (world health organization, 2020a). bai and colleagues mentioned some covid-19 transmission from asymptomatic patients as a challenge for preventive activities (bai et al., 2020) . in most countries, people who use drugs (pwud) are stigmatized and marginalized population with lower access to healthcare. they suffer from poorer health, weaker immune function, chronic infections, various issues with respiratory, cardiovascular, and metabolic systems, as well as a range of psychiatric comorbidities (ahern, stuber, & galea, 2007; stuber, galea, ahern, blaney, & fuller, 2003) . pwud are a marginalized group who experience high rates of morbidities, three to five times higher compared to the general population (o'connell, 2004) . cheung et al. estimated that the risk of death among young pwud homeless women in toronto is 5 to 30 times higher than their housed counterparts (bohnert & ilgen, 2019; fernandez-quintana et al., 2019) . substance use imposes different health problems, which may complicate superimposed infection with co-vid-19. for instance, chronic high alcohol consumption significantly increases the risk of acute respiratory distress syndrome (mccarthy et al., 2020) . during the 2009 h1n1 epidemic, a history of opium inhalation had been identified as a risk factor for admission to an intensive care unit (icu) with confirmed h1n1 (tabarsi et al., 2011) . additionally, it is essential to understand how pwud differently perceive danger and risk-taking behaviors during an epidemic, making them more risk averse (manfredi & d'onofrio, 2013; rhodes, 1997) . pwud have a higher rate of smoking and different studies estimated the current smoking rate of more than 70% among them (duan et al., 2017; sutherland et al., 2016; weinberger, gbedemah, & goodwin, 2017) . several studies found smoking a significant risk factor for middle east respiratory syndrome (mers) transdmission (alraddadi et al., 2016; nam, park, ki, yeon, kim, & kim, 2017; sherbini iskandrani, kharaba, khalid, abduljawad, & hamdan, 2017) . a literature review did not reveal even one article focusing on substance use disorder (sud) and covid-19. therefore, a group of international experts on addiction medicine, infectious diseases, and disaster management teamed up to explore the comorbidity of covid-19 infection with substance use disorder and identify the necessary recommendations for health service providers and policymakers in this situation. although the majority of covid-19 infections are mild, the number of severe cases in a pandemic has the potential to overwhelm any healthcare system. consequently, health authorities may be required to repurpose health services and facilities away from pwud. when such an incident occurs, a business continuity protocol will cover several contingency measures so that organizations supporting pwud will continue to provide their essential services. a response to both covid-19 and drug use involves government, different sectors of the community and health authorities (who director-general's opening remarks at the media briefing on covid-19 on march 5, 2020) to implement evidence-based prevention programs as well as engaging different stakeholders for policy coordination (volkow, poznyak, saxena, gerra, & unodc-who informal international scientific network, 2017) . generally, drug use prohibition and criminalization approaches result in higher stigmatization and discrimination against pwud (boyd & macpherson, vancouver area network of drug users, 2018; santos da silveira, andrade de tostes, wan, ronzani, & corrigan, 2018) . this approach puts pwud at a higher risk of viral transmission. governments, health authorities, and other relevant stakeholders should identify the provision of services for pwud as essential services to support a comprehensive and proactive response to the challenges that covid19 places on this population, especially when they are under treatment (ekhtiari et al., 2019). pwud have poor access to health services due to stigma and discrimination (ahern, stuber, & galea, 2007; salamat, hegarty, & patton, 2019) . they are among the pervasive hard-to-reach populations. for example, studies show that drug use is one of the significant barriers to taking the influenza vaccine (bryant et al., 2006; kong, chu, & giles, 2020) . many homeless pwud communities live in crowded groups in shelters and or shooting galleries with no or minimal air conditioning facilities. additionally, poor hygiene, risky behaviors such as sharing drug-using paraphernalia and intoxication put pwud at higher risk of covid-19 infection. one of the other risk factors for pwud and people who inject drugs (pwid) is their weaker immune system due to a range of factors. these factors include long-term/high-dose administration of opioid drugs (liang, liu, chen, ji, & li, 2016; sacerdote, franchi, gerra, leccese, panerai, & somaini, 2008) , malnutrition (haber, demirkol, lange, & murnion, 2009; vila et al., 2019) , homelessness (haber et al., 2009) , and longterm alcohol and methamphetamine use (nelson, zhang, bagby, happel, & raasch, 2008; roy et al., 2011) . despite lacking evidence for introducing hiv as a risk factor for covid-19 (british hiv association, 2020), there are some concerns regarding the access to treatment services for people living with hiv/aids (plwha) and their adherence to antiretroviral therapy (dadkha, mohammadi, & mozafari, 2008) . this situation could finally increase the rate of mortality among plwha. on the other hand, respiratory infections among pwud are common and, in many cases, do not present with recognized symptoms of these diseases (dimassi & rushton, 2009; bradley drummond et al., 2011; gordon & lowy, 2005) . tuberculosis is another respiratory infection that is more common among pwud (perlman, salomon, perkins, yancovitz, paone, & jarlais, 1995) even in high-income countries heuvelings et al., 2017) . care providers are at the front line of any outbreak response. they are not only at the risk of infection but are also prone to burnout and psychological distress. in a study conducted on frontline staff involved in the severe acute respiratory syndrome (sars) epidemic, it was found that they had high levels of burnout, psychological distress, and posttraumatic stress (maunder et al., 2006) . this situation is compounded with evidence that counselors and therapists for pwud are well-known as having a higher rate of burnout (vilardaga et al., 2011) during usual practice. staff working in harm reduction settings, where most of the health service providers are peer groups, should be adequately supported. this support should prevent cross-viral exposure, psychological distress (hashemian et al., 2015; lancee, maunder, & goldbloom, 2008) , psychiatric disorders (tang, pan, yuan, & zha, 2017; , discrimination (gilchrist et al., 2011) , and physical and psychological violence (world health organization, 2020b). concerns regarding infection and the above mentioned stressful events may affect their effectiveness in an outbreak (abolfotouh, alqarni, al-ghamdi, salam, al-assiri, & balkh, 2017) . all staff should have access to personal protection equipment (ppe). they should perform hand hygiene frequently, use alcohol-based hand rub/gels if their hands are not visibly soiled or with soap and water when they are visibly soiled. they must keep at least one meter distance from affected individuals, wear a medical mask when in the same room with an affected individual, and dispose of the material immediately after use. they should clean their hands immediately after contact with respiratory secretions, cover the nose and mouth with a flexed elbow or disposable tissue when coughing and sneezing, and refrain from touching eyes, nose, or mouth with potentially contaminated hands (world health organization, 2020b). also, they must avoid close contact with anyone that has fever or cough (world health organization, 2020b) and finally improve airflow in living space by opening windows as much as possible (world health organization, 2020b). self-isolation of individual staff is paramount if there are signs of an infection (heymann & shindo, 2020; world health organization, 2020a) . pwud staff still need to retain their crucial role at a distance either through digital technology or phone and continue their pwud management and treatment plan, such as the provision of daily ost medication (tschakovsky, 2009 ). there is no convincing evidence that the paraphernalia and devices for drug use are the primary sources of virus transmissions in the latest epidemics of coronaviruses (alagaili, briese, amor, mohammed, & lipkin, 2019) . however, as the main source of viral transmission has been defined to occur through the droplets, it makes sense to advise pwud populations to avoid sharing cigarettes, pipes , water pipes and hookahs, and so on (knishkowy & amitai, 2005; munckhof, konstantinos, wamsley, mortlock, & gilpi, 2003) . one should continue providing clean needle and syringes and 'take-home' naloxone (thn) when appropriate. infected patients are most virulent during the prodromal period. in the case of being mobile and carrying on usual activities, they play an essential part in spreading the infection to the other parts of the community (heymann & shindo, 2020). in such conditions, it is imperative to have an effective mechanism for the active and rapid detection of signs and symptoms and patient's isolation (hellewell et al., 2020; shamaei et al., 2009) . during the h1n1 pandemic in 2009, one of the risk factors for death or admission at intensive care units was a delay in diagnosis (tabarsi et al., 2011) . early detection in pwud can be difficult as covid-19 symptoms could be confused with a withdrawal syndrome (dimassi & rushton, 2009; bradley drummond et al., 2011; gordon & lowy, 2005) . it is highly recommended that a mechanism be implemented for the frequent screen-ing of covid-19 in pwud within harm reduction and treatment settings (salamat, hegarty, & patton, 2019; van olphen, eliason, freudenberg, & barnes, 2009 ). any pandemic affects illicit drug distribution networks (rahimi movaghar, farhoudian, rad goodarzi, sharifi, yunesian, & mohammadi, 2006) . sometimes this situation persuades pwud to seek treatment services for help, but usually, they switch to a more hazardous consumption. the iranian covid pandemic generated the highest incidence of mortality secondary to methanol toxicity (at least 44 dead from drinking toxic alcohol in iran after coronavirus cure rumor, 2020; tainted alcohol claims more lives than coronavirus in khuzestan province, iran, 2020). however, opioid substitution therapy (ost) provision of controlled medication has become the main focus of the continuity plans around pwud to make sure that such provision is not interrupted during the covid-19 lockdown strategies (being imposed by several governments). any close personal contact may be harmful and risky for covid-19 transmission. methadone syrup and buprenorphine tablets or film are often provided to pwud after bringing out their blister packs. despite no evidence, this action might increase the chance of viral transmission by exposing both staff and pwud. it is recommended that dispensing clinics be trained to handle the process of tablet delivery with minimum hand contact. take-home doses of medications can be provided for more extended periods in situations of quarantine, selfisolation, or lockdown and health service disruptions. the maximum time for take-home doses of drugs is recommended when the dose and social situation are stable. treatment seeking individuals should be adequately informed about the changes in the practice, and they should receive appropriate support in case of uncertainty and concerns. however, decisions should be taken on a case by case basis. in summary, individuals under buprenorphine maintenance treatment (bmt) can receive accelerated take-home doses after two weeks of initiation. in particular, the people can receive this protocol who are at least on 60 mg methadone or 8 mg daily buprenorphine and have no signs of withdrawal symptoms, do not experience craving (mokri, ekhtiari, edalati, & ganjgahi, 2008) , are abstinent based on self-reporting, and provide negative toxicological tests. this condition should be reviewed every 14 days if the individuals provided with take-home doses are not showing the stability mentioned above. buprenorphine take-home doses are probably safer than methadone take-home doses. if the person is in isolation and unable to pick up their medication personally, it can be delivered to their homes, or they can authorize someone else to collect the medication. opioid substitution therapy (ost) is among a category of treatment modalities that is normally considered to need regular and frequent supervision of patients, especially early in treatment. it is recommended that a more flexible ost program needs to be taken into account during the covid pandemic . given the safety profile of buprenorphine, it would seem to be the preferred substitution treatment for individuals who want to initiate treatments. it is faster and safer (maremmani & gerra, 2010) to reach an effective maintenance dose of buprenorphine compared to methadone, in fact it can be done on the first day of treatment. some of the medications under consideration for the treatment of covid-19 can significantly inhibit and/or stimulate methadone metabolism, puting patients at the risk of withdrawal or toxicity (lüthi, huttner, speck, & muelle, 2007; winton & twilla, 2013) . methadone specifically in high doses may prolong qt interval and cause fatal arrhythmias (krantz, lewkowiez, hays, woodroffe, robertson, & mehle, 2002) . possible cardiomyopathy in infected patients may increase the chance of torsade's de pointes arrhythmia (lüthi et al., 2007) and, particularly if combined with chloroquine which also prolongs the qt interval. withdrawal symptoms from buprenorphine are milder than that of methadone in case of interruption to the supply of medication, at least in the short term. where available, the long acting (monthly) subcutaneous injections are an alternative to providing take home doses. even transdermal buprenorphine should be considered where no other alternatives exist. multiple patches can be given simultaneously if necessary to achieve a therapeutic dose for opioid dependence treatment. additionally, benzodiazepine prescription for myalgia or stressful circumstances due to covid-19 may also increase the risk of toxicity during methadone mainte-nance treatment (mmt). during the pandemic period, it is more likely that individuals with drug use disorders or those who are in treatment seek out benzodiazepines or other tranquillizers (dorn, yzermans, & van der zee, 2007; fassaert et al., 2007) . benzodiazepines misuse may mask signs and symptoms of covid-19 infection and could escalate respiratory distress. patients are at a higher risk of methadone overdose in the initial stabilization period of methadone prescription (cornish, macleod, strang, vickerman, & hickman, 2010; degenhardt, randall, hall, law, butler, & burns, 2009) . for mmt patients, the authors do not recommend relaxing the methadone dose protocol at this phase of treatment however they do suggest avoiding unnecessary visits and rigor, on a case by case basis. if accelerated induction is necessary, an additional dose of 30-40 mg can be followed by a further dose if someone has been observed 2 hours after their initial methadone dose. if they are still experiencing withdrawal at this time, they can safely be given a further dose. for buprenorphine, individuals can be rapidly inducted to optimal maintenance doses (16-24 mg daily). clinicians should consider increasing the dose if the individuals are still experiencing daily cravings, ongoing opioid use, or opioid withdrawal. however, clinicians should be sensitized in the differentiation between withdrawal syndromes, including myalgia, insomnia, sweating, fatigue, and nausea with signs and symptoms of viral covid-19 infection. pupil size is the best guide to distinguish opioid withdrawal from the symptoms of covid-19 as this infection does not affect pupil size. it should be possible to see pupil size even with video consultations. although the prescription period of anti-viral treatment is usually less than two weeks and the induction of hepatic metabolic enzymes takes more than the regular time for antiretroviral therapy (art) prescription, the clinicians should be careful about the changes of methadone level in these patients during and more specifically after termination or discharge of the treatment for co-vid-19. change from split doses to multiple daily doses is a strategy in patients who receive antiviral therapy. as a result of the induction of methadone metabolism, some patients may need a mild increase in their previous methadone dosage after a few days of initiating antiviral treatment. for buprenorphine, double doses can be given every other day for people who are not considered safe to receive take-home doses. in exceptional situations, some patients on mmt or bmt fulfill the criteria for completion of their ost. termination is a stressful process (berger & smith, 1978) and needs close supervision and constant consultation. besides, the emotional distress associated with opioid withdrawal may increase the risk of suicidal ideation. termination of mmt and bmt increases the stress, so more attendance at treatment centers are needed, and it is not recommended during the covid-19 epidemic. some people who use opioids may wish to cease their opioid use during the outbreak, either due to reduced availability of opioids or the difficulty accessing treatment services. the most straightforward approach to detoxification, if available, would be single high dose buprenorphine. doses ranging from 32 to 96 mg have been used for this purpose (ahmadi, jahromi, ghahremani, & london, 2018) . alternative approaches include clonidine or a combination of symptomatic medications (world health organization, 2009). individuals with moderate to severe signs of cov-id-19 infection need medications consisting of a cocktail of art, antimicrobials, and analgesics. these medications may interfere with urine or saliva test results. for instance, quinolones (e.g. moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, ciprofloxacin), rifampin, tolmetin (a non-steroidal anti-inflammatory drug) may yield a false-positive result in opiates urine drug screening (reisfield, goldberger, & bertholf, 2009 ). chloroquine demic, the clinicians should assess the benefits of the urinary or saliva testing at this critical circumstance, especially as this will potentially increase unnecessary risks due to close contacts. in this pandemic, it seems that information is spreading more extensively and rapidly in comparison to the sars outbreak in 2003. however, this condition may result in a worsening of public fear, panic, and distress. social isolation may also make individuals susceptible to more psychological distress. consequent economic depression after a pandemic also causes uncertainty and threats to future welfare (strong, 1990) . the unpredictable future is exacerbated by myths and misinformation that are often driven by fake news and public misunderstanding (bao, sun, meng, shi, & lu, 2020) . some patients will experience grief over the loss of loved ones. the relationship between adverse life events and brain stress systems have a prominent role in addiction disease (koob, 2008 (koob, , 2009 (koob, , 2013 . pwud are much more vulnerable to stress and crisis followed by lapse and relapse to ex-drug users (goeders, 2003; koob et al., 2014; milidvojevic & sinha, 2018; somaini et al., 2012) . as a result of stressful events and disasters, mental health problems emerge or exacerbate (farhoudian, hajebi, bahramnejad, & katz, 2013; farhoudian, rahimi movaghar, rad goodarzi, younesian, & mohammad, 2006) . in such circumstances, healthy individuals may start drug use (farhoudian et al., 2006; somaini et al., 2012) , and several patients may relapse into their previous drug use and start their high-risk behaviors (brandon, vidrine, & litvin, 2007; farhoudian et al., 2006; rahimi movaghar, et al., 2006) . anxiety, worry, depression, irritability, and anger in pwud should be considered as a prodromal sign of lapse or relapse into a new episode of drug use. psychosocial interventions are a vital element in the treatment of pwud, especially in people using stimulants and having mental problems (de crescenzo et al., 2018) . in this period, internet-based psychotherapy is highly recommended as a replacement. internet consultation, including phone calls, video chat, and short messages, have great potential to make psychological assessment and treatment more cost-effective. computer-assisted therapy appears to be as effective as a face-toface treatment for treating anxiety disorders and depression (taylor & luce, 2003) . although it requires some equipment and knowledge, it offers a good alternative for more isolated locations, which is relevant in this pandemic. negative emotional states, including fear, anxiety, and boredom, as well as social withdrawal and or isolation, are the main emotions that patients will experience during the covid-19 pandemic. cbt has been recognized as one of the most beneficial interventions for pwud (lee & rawson, 2008) . stress reduction as a technique of cbt, either alone or in combination with pharmacotherapies, may prove beneficial in increasing quality of life and reducing cravings and promoting abstinence in clients seeking treatment for sud (goeders, 2003) . clinicians should help their patients to identify, manage, and reduce their negative emotional states associated with relapse and apply techniques of behavioral activation compatible with specific circumstances of each patient. coping skills training and crisis intervention are the most common types of cbt interventions to be recommended. matrix model is a multi-element package of therapeutic strategies to produce an integrated outpatient treatment experience (rawson & mccann, 2005; rawson et al., 1995) . treatment is delivered in an intensive outpatient program primarily in structured group sessions targeting the necessary skills. it is recommended that the meetings could be held individually instead of group format, hoping to lessen the risk of covid-19 infection. the recommended parts based on the manual (services among iranian people living with hiv and aids: a qualitative study, 2019) for the period of covid19 pandemic include: 1. rp17: taking care of yourself; 2. rp18: emotional triggers; 3. rp20: recognizing stress; 4. rp22: reducing stress; 5. rp24: acceptance; 6. rp29: coping with feelings and depression; 7. rp elective c: recreational activities. incentive-based treatment approaches (i.e. contingency management [cm] ) are effective interventions in reducing addictive behaviors in pwud (ainscough, mcneill, strang, calder, & brose, 2017; benishek et al., 2014; lee & rawson, 2008; messina, farabee, & rawson, 2003; rawson et al., 2006) . evidence also supports the cm beneficial effect on the treatment of these individuals targeting infectious disease control (herrmann , matusiewicz, stitzer, higgins, sigmon, & heil, 2017) . to take advantage of cm in the prevention of cov-id-19, the desired behaviors (e.g. washing hands every hour, cleaning hands, etc.) and their scores or prizes (e.g. take-home doses) should be clearly defined and inserted into the list, just like other desired behaviors (e.g. negative urine test). perceived social support from relatives and friends is a major predictor for retention in treatment for pwud shirinbayan, rafiey, vejdani roshan, narenjiha, & farhoudian, 2010) and the main factor of psychological resilience to disaster (radfar, nematollahi, & arasteh, 2016; rodriguez-llanes, vos, & guha-sapir, 2013) . considering the importance of family support, clinicians are advised to engage family and care providers more than ever during the pandemic. attracting other sources of social support such as guaranteed wages and an increase in social security payments will help the individual to pass this period with a better outcome. opioids such as methadone are respiratory depressants, and tolerance develops very slowly and incompletely. when patients under mmt acquire covid-19, they should be more closely monitored for both worsening respiratory functions and methadone toxicity. abrupt cessation of methadone must be avoided because anxiety and agitation due to withdrawal syndrome may induce or worsen cardiorespiratory complications (friedman, kamel, perez, & hamada, 2003; kienbaum, thurauf, michel, scherbaum, gastpar, & peters,, 1998) . the prevalence of kidney impairment in hospitalized covid-19 patients is high, and renal insufficiency increases the risk for in-hospital deaths (cheng et al., 2020) . studies indicate that heroin users, especially pwid, suffer from nephropathy (cunningham, brentjens, zielezny, andres, & venuto, 1980; do sameiro faria, sampaio, faria, & carvalho, 2003; may, helderman, eigenbrodt, & silva, 1986) . other studies confirm that individuals using amphetamine (ginsberg, ertzman, & schmidt-nowara, 1970; rifkin, 1977) , cocaine (merigian & roberts, 1987; norris et al., 2001; sharff, 1984) , alcohol (de marchi, cecchin, basile, bertotti, nardini, & bartoli, 1993; perneger, whelton, puddey, & klag, 1999) , and potent cannabis (abodunde, nakda, nweke, & veera, 2012; gudsoorkar & perez jr, 2015) are more likely to suffer from renal failure. it might be logically concluded that people with a history of drug consumption are more prone to contract renal insufficiency when they are infected to covid-19; however, there is not any revealing evidence so far. evidence suggests that renal insufficiency does not affect the metabolism of methadone in mmt patients (murtagh, chai, donohoe, edmonds, & higginson, 2007) . despite this issue, patients in acute renal failure due to covid-19 should be monitored for signs of methadone toxicity because of other reasons for renal insufficiency. heart diseases increase the risk factors of death due to covid-19 to 6% in affected individuals with hypertension, 7.3% in diabetics, and 10.5% in patients with other cardiovascular diseases (murtagh et al., 2007) . individuals with a history of alcohol or drug use are more likely to have cardiac pathology. excessive alcohol consumption (fabrizio & regan, 1994; mirijello et al., 2017) , amphetamine (giv, 2017; o'neill et al., 2004) , heroin (routsi et al., 2007) , and cocaine (barton duell, 1987) are all associated with the increased risk of cardiac pathology. contracting covid-19 sometimes can result in moderate to severe pain including myalgia, sore throat, and headache that requires pain management. it is recommended that acute pain in pwid with covid-19 is managed in consultation with pain or addiction specialists. people who use opioids regularly will require additional opioids for the management of pain (athanasos, smith, white, somogyi, bochner, & ling, 2006; doverty et al., 2001) . buprenorphine as a high-affinity partial agonist of mu-receptors has an analgesic effect in divided doses, but stops effecting other opioid analgesics and hinders acute pain management in case of necessity (harrington & zaydfudim, 2010) . in this case, buprenorphine can be ceased and opioid analgesics used or buprenorphine can be continued and non-opioid medications such as clonidine, pregabalin/gabapentin and ketamine can be used (goel et al., 2019) . health services will need to rapidly adapt to the cov-id-19 situation. they will need to establish a mechanism of making decisions quickly and under stress, to identifying the essential services to be continued, to develop new mechanisms of patient flow (including screening, batching and referral), to redistribute staff from non-essential roles, and maintaining the continuity of essential supplies (communications, 2020) . to reduce the risk of transmission, it is generally recommended that nonessential services close, or make their services available by telephone or on-line. when face-to-face services are required, some modifications may need to be made to the service system, for the identification of cases, the protection of staff, the reduction of transmission, and to ensure the continuity of essential services (interim guidline for healthcare facilities, 2020). when health services remain open in a pandemic, they should first invite all visitors to wash their hands before they touch anything. then they should screen all new visitors with whatever sars-cov-2 screening mechanism is appropriate for the local conditions. this may include a combination of temperature (where possible measured with a non-touch thermometer), clinical symptoms (cough, shortness of breath, sore throat), and epidemiological criteria (recent travel, contact with cases, health care worker). where, possible, patients meeting the testing criteria should be tested on-site and then directed to isolate themselves awaiting the results. for testing and any subsequent clinical interaction, staff should wear personal protective equipment (ppe) to protect themselves from transmission. if the client is coughing, it is preferable they should also wear a surgical mask (world health organization, 2020c). transmission is through to be mostly via droplet spread when people who are infected sneeze, cough or talk. staff and patients should wash their hands frequently and be careful what they touch. surfaces should be cleaned after they have potentially contaminated. depending on the availability of ppe and the risk in the local community, it may be appropriate for staff to wear masks and gloves, or even gowns and eye protection. patients with symptoms should wear a mask to prevent transmission through cough and sneezing. patients can be divided into three risk groups, those with confirmed sars-cov-2 virus, patients who meet criteria for testing awaiting test results, and other patients with differing levels of ppe depending on the availability of ppe. preferably, patients with different risk levels should be treated in different parts of the health service. staff and patients should keep a distance from each other (world health organization, 2020c). in addition to providing ost, services should take the opportunity to encourage cessation of smoking by prescription of nrt, and by the distribution of naloxone and overdose resuscitation. in preparation of staff members being sick or isolated awaiting test results, each staff member involved in ost treatment should have at least one other staff member who can continue their role if they are sick. where possible, staff may separate into different teams who have even less contact, so that if one person is sick then the risk of all needing to isolate themselves is reduced (guide on business continuity planning for covid-19, 7 february, 2020). pwud are a marginalized hard-to-reach population living in crowded groups with lower access to healthcare. they usually suffer from poorer health, weaker immune function, chronic infections, as well as various issues with physical and psychiatric comorbidities. consequently, they have a higher risk of contracting co-vid-19 and its transmission and casualties. we believe that substance use and covid-19 have a complicated relationship with each other. in summary, we suggest the following items: health authorities should develop and apply specific strategies for pwud for early covid-19 identification and patient isolation, interrupting transmission, providing appropriate care, attending medical issues, and minimizing negative social impact. health authorities are responsible for providing adequate healthcare for pwuds. they may be required to repurpose and reorient health services through a business continuity team. this team implements evidence-based programs and makes decisions on how the organizations will continue to provide their services. also, they make sure that all ost patients have adequate access to their opioid drugs. treatment sectors should provide essential requirements, as well as software and programs tailored to their own clients' needs. staff may also teach the patients the hygiene rules, self-monitoring for signs of illness, and rapid reporting of the disease in case of occurrence. a mechanism for frequently screening for signs and symptoms of infection should be established. internet and mobile-based social media communications should be considered as the first-line approaches for education and appropriate interventions. opioid users face increased challenges; some concerns are about their take-home doses and repetitive visits that make it impossible for them to stay at home. this pandemic could be considered as an extraordinary circumstance; the clinicians should facilitate ost protocol for clinically stable patients and cancel all group-based interventions or therapies. healthcare workers in substance use treatment facilities are also facing a higher risk of infection, burnout, distress, psychiatric disorders, discrimination, and violence. the essential right for each service provider, no matter a peer group or professional service provider, is to be safe and secure, in both physical and mental health aspects. misinformation, social isolation, ensuing economic depression, and possible grief reactions may result in exacerbation of public fear, panic, and distress that can be followed by lapse and relapse in ex-drug users. stress reduction, crisis interventions, coping skills training, motivational interviewing, and tailored and modified relapse prevention interventions, modification in contingency-based management for rewarding virus transmission preventive behaviours, attracting family support, managing patients' vocational problems are the main helpful psychosocial interventions. in this period, internet-based psychotherapy and phone counseling are highly recommended. there are many medical considerations regarding pwud that other physicians in charge of the management of co-vid-19 treatment should keep in their minds. clinicians should be careful in the differentiation between withdrawal signs and symptoms and those of covid-19 infection. pwud may have different clinical manifestations due to various etiologies. healthcare providers should consider different possible manifestations and, more importantly, avoid any type of medical stigma or discrimination against pwud. pwud regularly self-medicate their physical and mental problems with drugs, which may mask critical covid-19 symptoms. a number of drug-drug interactions between substance of use, addiction treatment medications, and covid-19 medications must be considered in terms of toxicity, withdrawal, and exacerbation of fatal side effects. there is also a possible overlap of pathological laboratory results of the cbc and liver enzymes in pwud and people with covid-19 infection. histories of renal failure, cardiovascular and metabolic diseases are more likely to emerge in pwud that put them at higher risk of morbidity and mortality after contracting covid-19 pain management in pwud, specifically opioid users and patients under ost, has some complexity, which calls for the involvement of joint expertise. the study has been conducted with no funds from external sources. original idea, wrote initial topics and headlines, and the first draft: ali farhoudian and seyed ramin radfar; participated in the literature review, writing, editing, and revision of the report and reached consensus on the conclusion: all authors. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. we are immensely grateful to dr. richard rawson, professor at integrated substance abuse programs, university of california, los angeles, and dr. richard schottenfeld, senior research scientist at yale school of medicine, for their comments during the process of writing the manuscript. the views expressed are those of the author (s) and not necessarily dr. richard rawson and or dr. richard schottenfeld. authors also respectfully dedicate the article to the souls of all healthcare providers who lost their precious lives in the fight against covid-19. cannabinoid hyperemesis syndrome presenting with recurrent acute renal failure an assessment of the level of concern among hospital-based health-care workers regarding mers outbreaks in saudi arabia stigma, discrimination and the health of illicit drug users. drug and 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of 72314 cases from the chinese center for disease control and prevention pathological findings of covid-19 associated with acute respiratory distress syndrome. the lancet respiratory medicine cocaine use disorder is associated with changes in th1/th2/th17 cytokines and lymphocytes subsets a novel coronavirus from patients with pneumonia in china covid-19 in wuhan: immediate psychological impact on 5062 health workers. medrxiv coronavirus disease 2019 (covid-19): a perspective from china key: cord-283917-jumgb0hs authors: li, hang long; cheung, bernard m. y. title: the proportion of adult americans at risk of severe covid-19 illness date: 2020-10-26 journal: j gen intern med doi: 10.1007/s11606-020-06325-9 sha: doc_id: 283917 cord_uid: jumgb0hs nan the covid-19 pandemic has affected more than 23 million people worldwide, including 5.6 million americans. because of these numbers, identifying the population(s) at risk is important. the us centers for disease control and prevention (cdc) announced on july 17, 2020, that conditions including obesity, diabetes mellitus (dm), chronic kidney disease (ckd), heart disease, and chronic obstructive pulmonary disease (copd) are well-established risk factors predisposing individuals to severe illness from covid-19. 1 other probable risk factors with less robust evidence include asthma and hypertension. we aimed to estimate the proportion of adult americans at risk from severe covid-19 illness. in this analysis, participants in the united states national health and nutrition examination survey (nhanes) 2011-2016 2 aged ≥ 20 years were included. pregnant participants and those with missing relevant laboratory/examination/selfreported data were excluded. the prevalence and 95% confidence intervals (95% ci) of established risk factors (obesity, dm, ckd, heart disease, and copd), probable risk factors (asthma, stroke, hypertension, taking immunosuppressive agents, and liver disease), and any risk factors (established or probable risk factors) were calculated. subgroups according to age (< 50 and ≥ 50 years), sex, ethnicity, education, and income level were compared. data analysis was performed using the r statistical package "survey" (version 3.6.3). altogether, 7744 nhanes participants with a mean age of 49.5 years were included (table 1) . overall, the prevalence of having ≥ 1 established, probable, or any risk factor were 58.9% (95% ci 56.7-61.0), 55.5% (95% ci 53.2-58.0), and 73.7% (95% ci 71.6-76.0), respectively (table 2) . obesity was the most common established risk factor (41.0%), followed by dm (24.0%) and ckd (18.4%). hypertension was the most common probable risk factor (50.1%), followed by asthma (8.9%) and stroke (3.6%). obesity and hypertension were consistently the leading risk factors in both age groups: the prevalence of obesity and hypertension in the younger age group were 38.9% and 31.1%, respectively, whereas in the older age group, 43.0% and 68.4% had obesity and hypertension, respectively. older participants were more likely to have ≥ 1 any risk factor; 86.2% of people aged ≥ 50 years had ≥ 1 any risk factor, compared to 60.9% in people aged < 50 years (p < 0.001). whereas obesity was almost equally common in the young and the old, dm, ckd, heart disease, copd, stroke, and hypertension were all much more common in people aged 50 years or older. there were minor differences in the percentage of people with ≥ 1 established and ≥ 1 any risk factor according to sex, ethnicity, education, and income level, but the percentages remained around 60% and 75%, respectively. non-hispanic asian appeared to have a lower risk. this is the first study to estimate the proportion of the americans in the general population at risk from severe covid-19 illness using data from a nationally representative survey. alarmingly, three-quarters of adult americans are at risk. covid-19 is a threat to people across all age groups, sexes, ethnicities, education, and income levels. consequently, the three-quarters of adult americans at risk should stay at home as much as possible during a pandemic. they should observe strict social distancing and personal hygiene measures, such as face covering and hand disinfection. 3 they should have priority access to masks, viral tests, treatment facilities, drugs, and vaccines. 4 our study shows that obesity and hypertension are the leading risk factors for severe covid-19 illness, especially in those aged < 50 years. those at risk should seriously consider lifestyle modifications, including weight control, healthy diet, alcohol moderation, smoking cessation, and regular physical activity. these can also alleviate other risk factors including dm, ckd, and asthma, and help reduce the adverse psychological consequences of social distancing. 5 a limitation of nhanes is the reliance on self-reported medical history that might cause underestimation of risk factors. moreover, we have not included cancer as it is highly heterogeneous, or less common conditions such as sickle cell anemia and post-transplant immunodeficiency. in conclusion, an alarming three-quarters of americans are at increased risk of severe covid-19 illness. obesity and hypertension are the leading risk factors. individuals with increased risk should strictly follow social distancing and personal hygiene measures and adopt lifestyle modifications. data are presented as weighted mean ± standard error, or weighted percentage (95% confidence interval) dm, diabetes mellitus; ckd, chronic kidney disease; copd, chronic obstructive pulmonary disease p values for age group comparison were obtained by multivariate logistic regression, adjusted for sex and ethnicity, where appropriate, or by chisquare test, where appropriate obesity was defined as body mass index (bmi) ≥ 30 kg/m 2 dm was defined as (1) answered "yes" to "(other than during pregnancy), have you ever been told by a doctor or other health professional that you have diabetes or sugar diabetes?" or (2) glycosylated hemoglobin ≥ 6.5%, or (3) fasting glucose ≥ 126 mg/dl heart disease was defined as answering "yes" to any of the questions below: (1) "has a doctor or other health professional ever told you that you had congestive heart failure?" or (2) "has a doctor or other health professional ever told you that you had coronary heart disease?" or (3) "has a doctor or other health professional ever told you that you had a heart attack (also called myocardial infarction)?" ckd was defined as (1) answering "yes" to "have you ever been told by a doctor or other health professional that you had weak or failing kidney?" or (2) estimated glomerular filtration rate (egfr) < 60 ml/min/1.73 m 2 using the chronic kidney disease epidemiology collaboration (ckd -epi) equation, or (3) urine albumincreatinine ratio ≥ 30 mg/g copd was defined as answering "yes" to either of the questions below: (1) "has a doctor or other health professional ever told you that you had emphysema?" or (2) "has a doctor or other health professional ever told you that you had chronic bronchitis?" asthma was defined as answering "yes" to both of the questions below: (1) "has a doctor or other health professional ever told you that you have asthma?" and (2) "do you still have asthma?" stroke was defined as answering "yes" to the question "has a doctor or other health professional ever told you that you have asthma?" liver disease was defined as answering "yes" to both of the questions below: (1) "has a doctor or other health professional ever told you that you had any kind of liver condition?" and (2) "do you still have a liver condition?" hypertension was defined as (1) having at least three of the blood pressure measurements on the day of examination as ≥ 130 mmhg for systolic measurement or ≥ 80 mmhg for diastolic measurement, or (2) answering "yes" to "have you ever been told by a doctor or other health professional that you had hypertension, also called high blood pressure?" publisher's note: springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. covid-19) people who need to take extra precautions physical distancing, face masks, and eye protection to prevent person-to-person transmission of sars-cov-2 and covid-19: a systematic review and meta-analysis ethics and covid-19: resource allocation and priority-setting the mental health consequences of covid-19 and physical distancing: the need for prevention and early intervention conflict of interest: the authors declare that they do not have a conflict of interest. key: cord-294184-jte9xx5e authors: macleod, jack; mezher, sermed; hasan, ragheb title: surgery during covid-19 crisis conditions: can we protect our ethical integrity against the odds? date: 2020-06-12 journal: j med ethics doi: 10.1136/medethics-2020-106446 sha: doc_id: 294184 cord_uid: jte9xx5e covid-19 is reducing the ability to perform surgical procedures worldwide, giving rise to a multitude of ethical, practical and medical dilemmas. adapting to crisis conditions requires a rethink of traditional best practices in surgical management, delving into an area of unknown risk profiles. key challenging areas include cancelling elective operations, modifying procedures to adapt local services and updating the consenting process. we aim to provide an ethical rationale to support change in practice and guide future decision-making. using the four principles approach as a structure, medline was searched for existing ethical frameworks aimed at resolving conflicting moral duties. where insufficient data were available, best guidance was sought from educational institutions: national health service england and the royal college of surgeons. multiple papers presenting high-quality, reasoned, ethical theory and practice guidance were collected. using this as a basis to assess current practice, multiple requirements were generated to ensure preservation of ethical integrity when making management decisions. careful consideration of ethical principles must guide production of local guidance ensuring consistent patient selection thus preserving equality as well as quality of clinical services. a critical issue is balancing the benefit of surgery against the unknown risk of developing covid-19 and its associated complications. as such, the need for surgery must be sufficiently pressing to proceed with conventional or non-conventional operative management; otherwise, delaying intervention is justified. for delayed operations, it is our duty to quantify the long-term impact on patients’ outcome within the constraints of pandemic management and its long-term outlook. as a surgical department operating under covid-19 (severe acute respiratory syndrome coronavirus 2) crisis conditions, a multitude of ethical, practical and medical dilemmas are encountered. instruction to halt all elective surgical work has received high uptake across centres nationwide; however, urgent surgical cases are ongoing. conventional thinking of gold standard management must be updated to consider possible consequences of operating in this high-risk environment. this directly impacts what procedure is performed, when and where it is carried out. each change presents ethical dilemmas that requires careful considerations. working in cardiac surgery within an active tertiary care centre, the impact of covid-19 on our working pattern has been significant. the caseload has now reduced from an average of 15 cases/week to 3-5 cases/week after 30 march 2020. although this is primarily due to the aforementioned cancellation of elective work, procurement of theatres as intensive treatment unit (itu) bed spaces and modification of the required interventions have also reduced caseload. with the resultant limitation to operative facilities, careful case selection is imperative to minimise harm: only the most urgent patients with no feasible alternatives can be listed. the royal college of surgeons published guidelines on good practice for surgical teams during covid-19 on 31 march. 1 the recommended changes are in keeping with those outlined above; however, advice on operation selection when more than one procedure is available is lacking. national health service (nhs) england also published specific guidelines for cardiothoracic surgery which does not address these issues clearly. 2 emergency patients with multivessel coronary disease are receiving percutaneous coronary intervention (pci) rather than the gold standard coronary artery bypass grafting (cabg). the short-term benefits are clear: with reduced recovery time and systemic insult, the risks of covid-19 exposure and associated complications will be significantly reduced. one must also ask; how does this affect long-term outcomes? does the short-term benefit outweigh the long-term risk? extrapolating the situation of pci versus cabg in multivessel coronary disease, the 5-year mortality has been shown to be 14.6% versus 9.2%, respectively; equating to a 58.7% increased risk of death at 5 years with pci. 3 although there is some conflicting evidence, it is undoubtable that, for some patients, cabg provides better long-term outcomes. 4 similar situations exist across other surgical specialities. 5 with consideration of the above, is delivering the gold standard surgery safely possible through alternative pathways? other opportunities to deliver the gold standard surgery safely are changing the location or time of procedures. having a 'clean' hospital that performs operations would provide a safe space, theoretically eliminating covid-19 risk. to implement this, both private hospitals and designated surgical units have been suggested. given the persistent viral spread despite nationwide lockdown, and widespread personal protective equipment shortages, keeping any hospital clean for an extended period of time would be very demanding, if not impossible. to stratify patients who can be delayed until infective risk declines, scoring tools such as the heart 6 and euroscore 2 (the european system for cardiac operative risk evaluation 2) tools 7 can be used, but clinical judgement plays an essential role under such unprecedented times. indeed, in a high-risk population, triaging and potential delay of patients' management adds to the unpredictably of the long-term consequences of such decisions. coupling the unclear risk profile of covid-19 with a lack of alternatives to provide the gold standard surgery, what is the ethical justification for performing a substitute procedure on this cohort of patients? how can we ethically provide the traditional gold standard, or alternative, operation to patients during the covid-19 crisis? in times of dissonance with moral norms, it is essential to use an ethical framework to guide decision-making. this allows a structured method of resolving conflicting moral duties. one such framework has formed the basis of healthcare ethics: initially proposed by beauchamp and childress in 1979, the four principles of patient care are beneficence, non-maleficence, respect for autonomy and justice. 8 beneficence and non-maleficence wd ross established the concept of prima facie duties, acts that are morally obligatory unless overridden by another. 9 beneficence is one such duty defined as an act done to benefit. 8 it is often paired with non-maleficence a principal engrained within medicine as primum non nocere-physician do no harm, a phrase with unclear origins. 10 as all interventions confer risk, it is important to distinguish the difference between the weighed risks of positive intervention within beneficence and physically causing harm. the theory of utilitarianism holds that whatever maximises population benefit is the most ethical decision. 11 it is a form of consequentialism; in principle, one can perform a minor harmful process in order to create a major beneficial process. this raises questions in regards to how we determine 'an optimal outcome' as discussed in the justice section. gold standard operations are those with the best evidencebased outcomes and lowest risk profiles. 12 historic research does not reflect covid-19-related mortality or the current limitations within the nhs, as such operative risk will be considerably higher than previous. less invasive procedures, such as pci, have smaller evidence bases than surgery 3 ; hence, they have not been first-line treatment options historically. their inferiority to the gold standard should be weighed up against the possible protection from covid-19-associated risk. does the current climate mean we can change the gold standard regardless of the challenge around quantifying risk? 13 although the gold standard will remain unknown we can, at the very least, meet the obligations of beneficence and non-maleficence, without clear covid-19 data, through only performing lifesaving operations. multiple operations across the uk are being delayed to open space in hospitals for possible patients with covid-19. this governmental decision has determined that the viral risk to the population is greater than the risk of cancelling all routine procedures. as described above, a maleficent act can be accepted if a largely beneficent act is the result; thus, the prima facie duty can be overruled. the net morbidity and mortality from delaying all nhs procedures are uncalculatable, resultantly a utilitarian argument becomes impossible. locally, it is necessary to make projected mortality-based decisions in relation to the safest way to delay procedures. kantian ethics traditionally described respecting autonomy through individual importance: each person is an end, not a means, in themselves, holding their own categorical imperative and should be treated accordingly. 14 beauchamp and childress expanded on this by presenting two prerequisites for autonomy: (1) liberty (freedom from influencing factors) and (2) agency (capacity for intentional action). 8 these influential pieces have shaped our modern view of respecting autonomy, whereby an individual is deemed to have capacity unless proven otherwise. the mental capacity act 2019 enforces this principle and describes the ability to understand, weigh up, retain and communicate information as the fundamental requirements for decision-making. 15 to ensure compliance with set legal standards when making a decision regarding surgery, written consent is obtained. the validity of this consent relies on the accuracy of information provided to the patient. operating in current crisis conditions, previously modelled mortality rates are not accurate as they do not account for the increased risk from contracting covid-19. update to quoted mortality statistics must be increased in line with local experience to the best of provider ability, to ensure informed consent. with regards to the gold standard procedure, one could argue that in the midst of unclear risk profiles patient choice should take precedence. taking this 'fully autonomous' approach as opposed to a more guided approach to management decisions yields some negative consequences. patients lacking confidence, who will be significant in number during crisis conditions, feel abandoned when presented with management options without clinician recommendation. 16 in addition, davies and elwyn 16 showed that these patients suffer lasting feelings of guilt should negative consequences arise as a result. as such, it should be remembered that patient choice is a right and not a mandatory requirement. another issue with patient autonomy arises when exploring patient perceptions. take the example of the man who refuses to undergo urgent surgery due to the fear of contracting covid-19. there is no organic reason for him to lack capacity and his decision could be respected. it is for this reason that walker argued in 2008 that current frameworks do not sufficiently account for internal control factors. 17 in following, surgeons must explore patient perceptions regarding covid-19 to facilitate a fully informed decision in the current era. the alignment of institutional policy with principles of justice is of fundamental importance to maintain citizen, employee and governmental trust. 18 these requirements at least persist, if not amplify, through crisis conditions with scarce resources. indeed, no situation exists where all alternative choices are equally unjust. 19 it follows that when the question 'who should we operate on during this crisis when capacity has been significantly reduced?' is asked, an optimal answer may be derived. three principles are primarily used to resolve microallocation problems such as this; these are needs, maximising and egalitarian principles. 20 according to needs principles, patients who are most acutely unwell should be operated on regardless of potential for current controversy recovery. maximising principles aim to increase population health by intervening on those who can benefit the most. egalitarian principles advise that all people should be given an equal opportunity to a long life of health, favouring younger patients. although clinicians are generally stated to favour a needs principle for patient selection, 20 surgeons ensure sufficient benefit from operating to justify the incurred risk. this demonstrates a combination of needs and maximising principles. the current practice of delaying elective surgery and operating on emergency cases is in keeping with this rationing principle. despite covid-19's primary tendency to envelop itu and ward areas, acute surgical cases may still overload departmental capacity necessitating complex decision-making. clinicians in these situations undoubtedly judge each case individually, however, must carefully act with a consistent balance of needs, maximising and egalitarian principles. a simple testing method is presented for this below. the standard, proposed by beauchamp and childress, to judge systemic alignment with just principles is whether two cases of similar presentation are treated differently. 8 achieving this in a realm of guideline-deficient practice requires active planning: a lack of evidence to guide decisions exacerbates the existing natural variation in management 21 between clinicians. indeed, local protocols must be devised early to reduce these otherwise inevitable management discrepancies, maintaining essential equality of opportunity for patients. it is only through such grounded actions that we may act justly and therefore withstand any possible future scrutiny. the current covid-19 crisis has placed a new type of demand on the healthcare system in the uk. the pandemic results in unknown variables being pushed to the forefront of clinical decision-making, raising a plethora of ethical issues. as such, to continue providing the gold standard surgical procedures ethically, certain conditions must be met. first, we can continue operating as long as there is clear net benefit to the patients, that is, emergency cases. for those patients requiring acute treatment, an alternative to the conventional gold standard can be performed if its known inferiority is outweighed by the reduced risk of covid-19-related complications. given these options structured local protocols must be devised to reduce variability and therefore preserve patient equality of opportunity. the decision to operate must involve the patient; capacity and perceptions around covid-19 need to be explored. in addition, for valid consent to be obtained, operative risk discussion must include covid-19-related mortality. if withholding the decision to operate, we should consider the harm caused: detailed effects of this harm need to be quantified to guide future disaster management. altogether, whether the conscientious clinician opts for conventional, non-conventional or non-operative management during this crisis, retaining the patient's best interest at the heart of our practice will preserve our professional integrity. contributors jm and sm contributed equally to this paper. rh provided a supervisory role in editing and finalising the manuscript. they have extensive expertise in arranging cardiac surgery, specifically with patient interaction forming a crucial portion of daily workload. it was initially drafted after covid-19 drastically cut down our departments operating capacity raising a variety of ethical issues to be addressed. the lack of clear guidance lead to discussion in regards to how we treat urgent cardiac surgery patients to the best of our department's ability. jm and sm wrote, edited and reviewed the manuscript and approved the final draft. sources were found via analysing key ethical texts, found via medline. jm is the guarantor of the article. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. covid-19: good practice for surgeons and surgical teams -royal college of surgeons clinical guide for the management of cardiothoracic surgery patients during the coronavirus pandemic coronary artery bypass grafting vs. percutaneous coronary intervention for patients with three-vessel disease: final fiveyear follow-up of the syntax trial clinical outcomes with percutaneous coronary revascularization vs coronary artery bypass grafting surgery in patients with unprotected left main coronary artery disease: a meta-analysis of 6 randomized trials and 4,686 patients endovascular versus open repair of abdominal aortic aneurysm in 15-years' follow-up of the uk endovascular aneurysm repair trial 1 (evar trial 1): a randomised controlled trial the heart score for the assessment of patients with chest pain in the emergency department: a multinational validation study principles of biomedical ethics the right and the good origin and uses of primum non nocere--above all, do no harm! the history of utilitarianism evaluation of diagnostic tests when there is no gold standard. a review of methods medical ethics: four principles plus attention to scope groundwork for the metaphysics of morals 1785 mental capacity (amendment) act advocating mandatory patient 'autonomy' in healthcare: adverse reactions and side effects medical ethics needs a new view of autonomy a theory of justice. original tragic choices tragic choices . guido calabresi, philip bobbitt principles of justice in health care rationing non-clinical influences on clinical decision-making: a major challenge to evidence-based practice competing interests none declared. patient consent for publication not required.provenance and peer review not commissioned; internally peer reviewed. data availability statement there are no data in this work.this article is made freely available for use in accordance with bmj's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by bmj. you may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. key: cord-290820-28ggcjx0 authors: lim, michael anthonius; pranata, raymond title: sports activities during any pandemic lockdown date: 2020-07-04 journal: ir j med sci doi: 10.1007/s11845-020-02300-9 sha: doc_id: 290820 cord_uid: 28ggcjx0 nan the coronavirus disease 2019 (covid-19) pandemic forced the world's population to alter daily routines, including exercise habits. this unusual situation has physical, psychological, and behavioral consequences to all individuals, including elite and recreational athletes. life in lockdown has been difficult because everyone has to stay safe and healthy, while at the same time abiding by new norms. currently, mitigation strategies have been widely implemented to contain the spread of covid-19. these measures include lockdown, social distancing, personal protective measures, and environmental and surface cleaning [1] . furthermore, the practice of physically active lifestyles is recommended to counteract health and mental consequences of the covid-19 pandemic [2] . while sedentary behavior certainly has no effect on the immunity, exercising in moderation is associated with improved immune competency and a reduced risk of illness. overtraining and high-intensity exercise induce transient immune dysfunction and are associated with a greater risk of illness, including upper respiratory tract infections, but this may not apply to elite sportsmen [3, 4] . post-exercise immune depression, especially after a strenuous training, may be explained by an impaired cell-mediated immunity [5] . various modalities, such as soccer, football, and triathlons, are considered high-intensity sports. consequently, these activities lead to an open window of susceptibility to infection [6] . the introduction of the new routines in the context of covid-19 will allow certain outdoor exercises, which facilitate sars-cov-2 (severe acute respiratory syndrome coronavirus 2) transmission due to increased ventilation rates during exercise and possible mass gathering at sporting venues, stadiums, jogging tracks, parks, or any recreational areas. currently, there are no solid guidelines regarding the use of face masks for outdoor exercises during the covid-19 pandemic. we advise people to wear face masks during low to moderate-intensity exercises outside such as brisk walking and jogging, while maintaining a safe physical distance (2 m away) and personal hygiene in public. however, the use of face masks may compromise breathing and oxygen uptake in high-intensity, which are not recommended during these times. with the resumption of normal life during covid-19 taking effect immediately, guidelines for outdoor exercise, recreational activities, and returning to competitive sports must be enacted with caution. to help delay and mitigate covid-19 spread, staying at home is still encouraged and the centers for disease control and prevention (cdc) recommends daily physical activity for both children (60 min/day) and adults (30 min/day). each sport and activity is categorized by risk, but the general classification is (1) low risk: exercise at home, alone or with shared household members, with owned and sanitized equipment; (2) medium risk: exercise at public, alone or with shared household members no more than 5 people, with own and sanitized equipment; and (3) group exercise with non-household members in private or public, not physically distant, with shared equipment [7] . the risk of opportunistic infection is more likely to be influenced by the pre-exercise physical, nutritional, and psychological well-being. it is known that regular and frequent exercise enhances rather than suppresses the immune response in individuals of all ages, and thus protects them from infections [8] . in addition to exercise, appropriate immunenutritional support as well as proper management of psychological stress and sleep hygiene can reduce infection risk [5, 9] . adoption of a proper diet and physical activity will event u a l l y b o o s t i m m u n i t y ( i m m u n e a c t i v a t i o n , immunosenescence, and vaccination efficacy) and metabolic systems (obesity, diabetes, and metabolic syndrome) [10] . during the self-isolation period, the majority of people grew accustomed to a sedentary lifestyle with less physical activity, fewer daily step counts, and rarely exercise, while athletes and certain people train individually to keep themselves fit and healthy [11] . returning to normal exercise and sports activities is set to be a fascinating yet challenging time. in fact, many formerly fit individuals struggle to achieve their previous physical performance when stepping out to exercise in the age of covid-19. detraining or a prolonged break from training leads to the deconditioning of physiological systems (e.g., musculoskeletal, neuromuscular, respiratory, and cardiovascular systems) as well as physical capabilities (e.g., power, strength, flexibility, speed, and endurance) [12] . a randomized clinical trial by kramer et al. [13] found that healthy adults with no physical activity have significantly lower aerobic capacity and lean mass compared with their counterparts who performed three minutes of hopping exercise, six days per week, for 60 days. in addition, the bone mineral density, knee extension strength, knee flexion strength, and peak power output of the bed-rest group are significantly reduced, while the jumping group preserved these parameters. covid-19 caused the suspension of sporting events, closure of gyms and fitness centers, and restrictions on outdoor activities. these factors led athletes to modify their exercise programs and train at home, most of which are not supervised by medical staff or coaches. several athletes have a mini gym and/or fitness equipment at home to train individually. during this period, their aim should be to maintain or at least not lose their current fitness level [14] . the use of telehealth or other audiovisual-guided sessions for expert opinions is also useful during this difficult time. cooperation with a multidisciplinary team involving medical staff, nutritionists, coaches, trainers, and psychologists can help athletes manage all the factors that influence performance, including physical conditioning, nutrition, hydration, sleep quality, and mindset. assuming a reduction in strength, flexibility, endurance, proprioceptive, and neuromuscular control, there is a greater risk of injury faced by athletes when transitioning from an unprecedented lockdown to high-level sports-specific practice. learning from the national football league (nfl) lockout in 2011 [15] , following the premature transition from the end of lockout to the beginning of competitive fixtures, there was an unprecedented number of achilles tendon ruptures during the training camp and preseason. two-thirds of the players who ruptured their achilles tendon returned to play in the nfl after achilles tendon repair and around 11 months of rehabilitation, while the rest never went back to competition. these injuries likely represent career-changing and frequently career-ending moments for professional athletes. despite maximum efforts from the club medical staff, there was a higher relative risk of reinjury during resumption of a full-contact training, pointing to lingering neuromuscular deficits in the athletes (table 1) . covid-19 lockdown can have similar impacts on other team-sports competitions. for example, soccer-specific training necessitates acceleration and deceleration, changes in direction, and chasing the ball at full speed. to date, blisters and minor injuries have been reported by a number of players following the return-to-pitch training, and we may see an increase in loadrelated problems (e.g., hamstrings, adductors, achilles tendons, and patella tendons) and more serious injuries (e.g., ligaments and meniscuses) in the future. zone7, an artificial intelligence platform specialized in predicting injury risk, conducted research in the english premier league, which suggested an increase in injury incidence by 25% due to a congested schedule (eight matches plus training in 30 days) [16] . therefore, the return to training and competitive action must be gradual, accompanied by regular risk assessment, and preceded by sports-specific medical assessment. four phases have been suggested, beginning with small group training, then entire team training, followed by national league competition, and finally international competitions. each player must be tested negative in two successive rt-pcr (reverse transcription polymerase chain reaction) sars-cov-2 pharyngeal swabs over a five-day interval, followed by continuous tests and monitoring [17] [18] [19] . functional movement, maximal oxygen consumption (vo 2 max), and lactic threshold heart rate (lthr) should be evaluated to help stratify the risk of injury and fatigue and indicate the level of current performance based on biomechanical, aerobic, and anaerobic capacity [20] [21] [22] . for healthy individuals, prolonged sitting during work or stay at home should be avoided while incorporating a healthy diet and physically active lifestyle into their daily routines is encouraged [23] . sedentarism negatively impacts neuromuscular system (rapid muscle wasting, nerve fibers degeneration, and neuromuscular junction damage), muscle protein metabolism (suppression of muscle protein synthesis and upregulation of protein breakdown), impaired glucose homeostasis (reduced insulin sensitivity), cardiorespiratory system (reduced aerobic capacity), and energy balance (excessive fat deposition, systemic inflammation, and antioxidant activation) [24] . besides maintaining productivity, their goal should be to avoid unnecessary weight gain and adopt a healthier and more sustainable lifestyle as a habit. at present, virtual gym classes and personal coaching are widely available online, while appointments for medical consultation are within the fingertips of the general population. with a more flexible schedule, healthy individuals can adjust their exercise modality, frequency, volume, and intensity with home-based exercises [2] . they must know their limits and abstain from any forms of exhaustive, strenuous, or high-intensity training, which can compromise the immune system. meanwhile, moderateintensity endurance training and resistance training are recommended to boost immunity and maintain fitness and health. with all these options, the covid-19 pandemic and related restrictions should no longer be an excuse for not maintaining a physically active lifestyle. older individuals and those with underlying comorbidities, such as hypertension, diabetes, cardiovascular and cerebrovascular diseases, coagulopathy, kidney and liver problems, and chronic lung disease, are categorized as high-risk groups for contracting severe covid-19 [25] [26] [27] [28] [29] [30] [31] [32] . under such a pandemic, they are forced into social isolation and quarantine at home, and most of these individuals are being physically inactive and mentally stressed (e.g., depression and anxiety) [33] . this may eventually increase the risk of mortality and morbidity in this group. these high-risk individuals should adls, activities of daily living aim to preserve their performance of activities of daily living (adls), such as eating, dressing, showering, toileting, and stair climbing. home-exercise using various safe, simple, and easily applicable training methods is well suited to maintain fitness levels while and avoiding airborne covid-19 [34] . a multicomponent exercise program that includes strength, aerobic, balance, and coordination training is considered the best fit for elderly [2] . the addition of social elements to improve compliance and reduce the risk of mental problems is feasible with the support by internet, media, and audiovisual technology. considering the availability of telehealth in many medical specialties, people with advanced age and chronic diseases can consistently access this internet-based service. telerehabilitation will undoubtedly help most chronically disabled individuals to exercise at home in an effective yet sustainable way [35] . conflict of interest the authors declare that they have no conflict of interest. coronavirus disease-2019: a tocsin to our aging, unfit, corpulent, and immunodeficient society physical exercise as therapy to fight against the mental and physical consequences of covid-19 quarantine: special focus in older people how much is too much? 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costa, andré santana; vidal, diogo guedes; dinis, maria alzira pimenta title: workers’ healthcare assistance model (wham): development, validation, and assessment of sustainable return on investment (s-roi) date: 2020-04-30 journal: int j environ res public health doi: 10.3390/ijerph17093143 sha: doc_id: 292409 cord_uid: hz5qj1fw the present study aimed to present and validate the worker´s healthcare assistance model (wham), which includes an interdisciplinary approach to health risk management in search of integral and integrated health, considering economic sustainability. through the integration of distinct methodological strategies, wham was developed in the period from 2011 to 2018, in a workers’ occupational health centre in the oil industry in bahia, brazil. the study included a sample of 965 workers, 91.7% of which were men, with a mean age of 44.9 years (age ranged from 23 to 73 years). the kendall rank correlation coefficient and hierarchical multiple regression analysis were used for the validation of wham. the assessment of sustainable return on investment (s-roi) was made using the wellcast roi™ decision support tool, covering workers with heart disease and diabetes. wham can be considered an innovative healthcare model, as there is no available comparative model. wham is considered robust, with 86% health risk explanatory capacity and with an 85.5% s-roi. it can be concluded that wham is a model capable of enhancing the level of workers’ health in companies, reducing costs for employers and improving the quality of life within the organization. more than ever, life, as we know, will never be the same. the world is currently experiencing the coronavirus pandemic (covid-19) [1] , an unforeseeable health development that is affecting the entire global population, and consequently healthcare assistance models across the globe. there is now an urgent need to look at human health through the "one health" lens [2] , to design and implement programs, policies, legislation, and research in a cooperative manner among all sectors of society to achieve better public health outcomes. in addition to the recognition of the success of the current healthcare models in the relief of pain and the treatment of multiple pathologies, several criticisms are gaining support, pointing out the limitations relating to the attention to patient health. these issues include approaches that take an undifferentiated view of the individual, which is focused exclusively on the part of the body that is sick; the focus on the curative actions of diseases, injuries, and damages; the advancement of medicalization; and the generalization of hospital care using technology. in the past, if a medical doctor was seen as a figure possessing the knowledge necessary to cure the patient, nowadays that figure is seen as one part of a team, with the patient being the final decision-maker in their health outcomes. the world health organization has chosen to strengthen people-centred care and integrated health services as priority strategies to transform health services to meet the health challenges of the 21st century [3] . this favours the emergence of integrated care models, which are seen as possible solutions to the growing demand for improvement in the patient experience, especially in patients with chronic conditions. considering economic sustainability in the search for integral and integrated health, this study aims to present and validate a model of workers' healthcare, the workers´healthcare assistance model (wham), which embraces an interdisciplinary approach towards health risk management. in light of the literature review, the following three research hypotheses were formulated: hypotheses (h1). wham promotes integral and integrated care; hypotheses (h2). wham is robust and has greater explanatory capacity for workers' health risks; hypotheses (h3). wham is economically sustainable and provides a significant return on investment. a review of the literature in the field of occupational health highlights discussions relating to "assistance models", a term that varies based on the conceptualization, which can include "assistance modalities or technological models" [4, 5] ; "ways to promote health" [6] ; "assistance models" [4, 6, 7] ; "technical, techno-assistance, and technical assistance models" [4, 8] ; "modes of intervention" [7] ; "attention models" [9] [10] [11] ; and "care models". the result of this diversity of terms is the already identified difficulty in conceptualizing assistance models. healthcare assistance models are understood as technological combinations with different purposes, which are used to solve problems and meet needs within a given context and population and in a given territory (individuals, groups, or communities), to organize health services or to intervene in situations, depending on the epidemiological profile and investigation of health problems and risks [12] . these logical systems organize the functioning of care networks, articulating the relationships between network components and health interventions. in turn, these are defined according to the prevailing view of health, demographic and epidemiological situations, and social determinants of health at a given time and in a given society and place [13] . according to campos [5, 6] , the conceptualization of an assistance model, technological model, or assistance modality must go beyond mere organizational and technical design, showing a new way of producing assistance actions anchored in the organization of the state. according to silva [14] , biomedicine has become the hegemonic model in the provision of health services in brazil and other countries around the world, influenced by accumulated knowledge and the paradigm of science. in this process, the daily requirements in the health sector stand out, such as the relationships between people; the involvement and co-responsibility of managers, health professionals, and patients in healthcare; as well as the bond, reception, and humanization of healthcare assistance practices [15] . from a technological point of view, there is a predominance of the use of the so-called "hard technologies" (equipment), to the detriment of light technologies (professional-patient relationships) [8, 16] . thus, diagnostic tests are a priority, but patients are not necessarily considered in terms of their suffering. this approach has been the target of criticism at the international level, starting from the 1970s and gaining greater importance in the second half of the 1980s [11, 17] . in terms of the biomedical model, there is a certain neglect of the importance of the determinants of the health-disease process; that is, the focus on the disease and not on the elements that contribute to health promotion, underestimating that cultural, ethical, and social aspects condition lifestyles and that these are also determinants in the same process [13, 14, 18] . merhy [8] contributes to the debate about the need to change the hegemonic assistance model, arguing that it is necessary to impact the core of care. in this sense, it is necessary to invest in relational-type light technologies, focusing on the needs of users and reversing the investment in hard or light-hard technologies, which can be translated into standards, equipment, and materials. thus, light technologies are used and combined with people and resources to achieve certain objectives, which are gathered in an organized manner and consolidated as essential elements of health services [19] . regardless of the scope, health services are always complex. the processes are standardized by regulatory bodies, service providers, and class representatives, among others. they have highly specialized and qualified workers who, belonging to different class councils, have interests that do not always converge [20] . team composition characteristics in health services must be highlighted, recognizing these team members as the main actors responsible for the implementation of technologies aligned to a healthcare assistance model. faria [21] draws attention to the fact that actions performed in a given place to deal with a certain problem may not apply to other situations, considering the historical-political context that influences a situation. therefore, the use of healthcare assistance models invariably requires the selection of certain constructs that support them. thus, they can be used in an alternative or adapted way, as long as they enable the achievement of similar results. to incorporate new health needs, healthcare assistance models can be considered to have influenced the organization of care models, being more focused on specific populations, such as the chronically ill. a comprehensive care model defines how health services are offered, providing the best care and service practices for a person or population group as they evolve through a condition, injury, or event, aiming for people to receive the right care, at the right time, by the right team, and in the right place [22] . the field of occupational health is a fertile environment for the development of interdisciplinary practices [23] [24] [25] [26] , as it encompasses knowledge from different disciplines, requiring constant and complex interactions between professionals in the fields of epidemiology, the environment, engineering, and healthcare, among others. the framing of occupational health in a biomedical healthcare assistance model favours the development of disjointed and ineffective interventions regarding the needs presented by workers, while the biopsychosocial model is often used in their work environments. according to annadale [27] , the biomedical healthcare assistance model only focuses on the physical processes, i.e., the pathology, biochemistry, and physiology of a disease, neglecting the roles of social factors or individual subjectivity. in this context, it is necessary to discuss a model of assistance in occupational health that is capable of reviewing the central characteristics of the biomedical healthcare assistance model, including: (i) organization of practices focused on the identification of signs and symptoms and the treatment of diseases, with health promotion not being a priority; (ii) assistance is organized based on individual spontaneous demand, with an emphasis on specialization and the use of hard technologies; (iii) the work is developed in a fragmented, hierarchical manner and with inequality across different professional categories; (iv) difficulty in implementing the integrated care due to the lack of understanding of the individual as a multidimensional human being, as well as the lack of communication and integration between the services involved; (v) health planning is seldom used as a management tool; (vi) the training of health professionals is specialized, based on the hegemony of scientific knowledge; and (vii) themes such as interdisciplinary, people-centered care, attachment, and welcoming are not prioritized. another aspect of great relevance in the current global context of scarcity of resources, particularly in the current context of covid-19, is the prioritization of investments ineffective, integral, and integrated interventions, which can be achieved through a model that contemplates the management of occupational health risks, considering the social health determinants [28, 29] , global disease burden [30] , environmental aspects [31, 32] , sustainable development goals [33, 34] and in particular, working conditions that affect an individual's health [35] . in the current context, the effectiveness of a healthcare assistance model must include economic sustainability in addition to health gains, to know how much the company has earned due to investments made in a certain area, with the sustainable return on investment (s-roi) being a very important metric for this assessment. measuring the s-roi [36] [37] [38] of preventive programs is not an easy task, due to the large number of variables that influence this calculation. the main variable is patient health, which can improve or worsen unpredictably. analyzing the s-roi in preventive programs identifies the financial impact a program generates concerning the amount invested, which must be considered in the long term. disease prevention actions bring future returns, mainly to the reduction of healthcare assistance costs. if the individual participates in preventive programs, the probability of developing diseases or discovering them in advanced stages decreases. over the past 20 years, several studies [39] [40] [41] [42] [43] [44] [45] [46] [47] have addressed this issue and there is growing evidence that workplace programs can generate acceptable financial returns for employers investing in them. a study of johnson and johnson employees [39] showed a difference in the increase in the average annual costs of internment between workers involved and not involved in lifestyle improvement programs and changes in the workplace, representing $43 and $76, respectively, thus representing a considerable increase in percentage terms. the study by munir et al. [45] aimed to conduct a cost-benefit analysis of the stand more at work (smart) workplace intervention, designed to reduce sitting time. a net saving of $2.18813 (95% ci; $−4.3804; $4.8143) per employee was found as a result of productivity increase. peik and others [46] applied the research and development (rand) europe model, a program designed to expand access to up to 40 evidence-based clinical preventive services for all employees and eligible family members, as part of a unique global health initiative at the country level to estimate the return on investment over a five-year timeframe. the study concluded that this program generates a global return of $4.28-$11.88 (after investment cost). gao and co-workers [47] assessed the economic performance of a workplace-delivered intervention to reduce sitting time among desk-based workers. the incremental cost-efficacy ratios ranged from $6.28/minute reduction in workplace sitting time to $8.45/minute reduction in overall sitting time. the intervention was cost-effective over the lifetime of the cohort when scaled up to the national workforce, and provides important evidence for policy-makers and workplaces regarding the allocation of resources to reduce workplace sitting. the present study was carried out from 2011 to 2018, in a workers' occupational healthcare centre in the oil industry in bahia, brazil. it involved the integration of distinct methodological strategies for the development of wham, such as the development of a conceptual model, action research, statistical validation, and s-roi analysis. the study involved two experts who had been working in the field of occupational health for fifteen years, with an emphasis on ergonomics and health management, an interdisciplinary approach, and a database composed of a population group and sample of workers, numbering 1275 and 965 individuals, respectively (table 1) . data analyses were carried out using spss version 25 for windows (ibm corporation, new york, ny, usa). diagnostics and intervention prevalence were presented as absolute and relative frequencies. correlations among modifiable health risk factors and health outcomes were performed through the kendall rank correlation coefficient. correlations among health indicators and the interdisciplinary risk coefficients were also performed using the kendall rank correlation coefficient. hierarchical multiple regression analysis was used to calculate the independent contributions of occupational medicine interdisciplinary, dentistry interdisciplinary, physical education interdisciplinary, nursing interdisciplinary, and nutrition interdisciplinary risk coefficients, to provide an estimate of incremental variance accounting for the workers' health risk index (whri) [48] . this index had already been published, resulting from the classification of workers into three risk ranges-"low", "moderate", and "high". the durbin-watson test was applied to detect the presence of autocorrelation at lag 1 in the residuals (prediction errors), through which the hierarchical multiple regression analysis multicollinearity was verified. to lead the application of the wham, the "guidelines for implementing the workers' healthcare assistance model (wham)" were developed, which are presented in the supplementary materials (word s1). the "workers' healthcare assistance model" is understood as the organization of the conditions necessary to carry out a person-centred care process, about the method, staff, and instruments. the term "process" used in the context of healthcare makes it possible to identify, understand, describe, explain, and predict the needs of a person, family, or community at a given moment in the health and disease process, demanding professional care by health specialists. therefore, wham presupposes a set of actions, through certain means of action, regulated by a course of thinking; that is, through a conception of workers' health, wham's origin and its potential to transform itself or to be transformed. to compose the wham, the interdisciplinary workers' health approach instrument (iwhai) [49] , a tool that had already been published, was used as a data collection instrument, aiming to collect data from 43 health indicators. to map the diagnoses, the health taxonomies were used, while the whri [48] was used to prioritize the health risks of the workers. figure 1 shows the main stages of integrating the wham. int. j. environ. res. public health 2019, 16, x 5of18 through the kendall rank correlation coefficient. correlations among health indicators and the interdisciplinary risk coefficients were also performed using the kendall rank correlation coefficient. hierarchical multiple regression analysis was used to calculate the independent contributions of occupational medicine interdisciplinary, dentistry interdisciplinary, physical education interdisciplinary, nursing interdisciplinary, and nutrition interdisciplinary risk coefficients, to provide an estimate of incremental variance accounting for the workers' health risk index (whri) [48] . this index had already been published, resulting from the classification of workers into three risk ranges-"low", "moderate", and "high". the durbin-watson test was applied to detect the presence of autocorrelation at lag 1 in the residuals (prediction errors), through which the hierarchical multiple regression analysis multicollinearity was verified. to lead the application of the wham, the "guidelines for implementing the workers' healthcare assistance model (wham)" were developed, which are presented in the supplementary materials (word s1). the "workers' healthcare assistance model" is understood as the organization of the conditions necessary to carry out a person-centred care process, about the method, staff, and instruments. the term "process" used in the context of healthcare makes it possible to identify, understand, describe, explain, and predict the needs of a person, family, or community at a given moment in the health and disease process, demanding professional care by health specialists. therefore, wham presupposes a set of actions, through certain means of action, regulated by a course of thinking; that is, through a conception of workers' health, wham's origin and its potential to transform itself or to be transformed. to compose the wham, the interdisciplinary workers' health approach instrument (iwhai) [49] , a tool that had already been published, was used as a data collection instrument, aiming to collect data from 43 health indicators. to map the diagnoses, the health taxonomies were used, while the whri [48] was used to prioritize the health risks of the workers. figure 1 shows the main stages of integrating the wham. the data collection stage aimed to identify health problems, as well as the efficient and targeted recording of the workers' needs in its broadest sense. for this, the iwhai [49] was chosen. it allows structured data collection, covering the disciplines of medicine, dentistry, nursing, nutrition, and physical education, as well as environmental, occupational, behavioural, personal, and metabolic the data collection stage aimed to identify health problems, as well as the efficient and targeted recording of the workers' needs in its broadest sense. for this, the iwhai [49] was chosen. it allows structured data collection, covering the disciplines of medicine, dentistry, nursing, nutrition, and physical education, as well as environmental, occupational, behavioural, personal, and metabolic factors. it is composed of in 5 dimensions with 43 indicators, totalling 215 sub-indexes with closed response coding, where zero represents non-existent or inadequate control of risk and four represents optimal control of risk, arranged in the following scale: 0 = non-existent or inadequate; 1 = tolerable; 2 = reasonable; 3 = good; 4 = excellent. for the diagnostics mapping stage, it was necessary to define taxonomies that encompass the complexity of the workers' health field, especially those related to the health, environment, and work triad. the following codes were used for medical, dental, nursing, nutritional, and physical education factors: (i) international classification of diseases (icd 11) [50] ; international classification of nursing practice (cipe ® ) [51, 52] ; international dietetics and nutritional terminology (idnt) [53] ; and the international classification of functioning, disability, and health (icf) [54] . for the intervention design stage, it was necessary to define classifications that encompass proposals for interventions, which include ecological and occupational care. for each mapped diagnosis, an intervention must be associated. during the attendance of the worker, priority is given to diagnoses for health indicators that are classified as control or health conditions: 0 = non-existent or inadequate; 1 = poor; 2 = reasonable. this consists of a discussion amongst the interdisciplinary health team to validate the perceptions [55] raised by professionals in each area during the attendance of workers, sharing the diagnoses and interventions proposed by each discipline. the iwhai [49] was used as a guiding instrument for data collection. for support of the team decisions regarding the hierarchy of priority interventions, the whri [48] was used, allowing multidisciplinary (by dimension) and interdisciplinary (association of all dimensions) risk classifications. the classifications comprise three ranges: "low", "moderate", and "high". since 64% of the sample age is above 40 years and the gender proportion of male to female is very high, the effects of these factors were controlled in this step by the whri [48] assessment. as the workers' ages increase, the risk indicator also increases; the same happens for male and female workers for some sex-related diseases, such as the higher susceptibility by men to develop cardiovascular diseases and alcohol abuse. for this reason, when whri [48] is applied, each worker will have two risk indicators influencing the indicators of health behaviours and outcomes: a risk indicator related to the workers' age, whereby the older the worker, the higher their risk indicator; and another risk related to their sex, whereby female or male gender will have different impacts on health behaviours and outcomes. the final whri [48] score is mediated by the workers' age and sex. the whri [48] dimension that has the greatest weight in the interdisciplinary context is designated as the worker case manager (wcm) and will assume technical responsibility concerning care management. the care plan (cp) is an interdisciplinary document, composed of relevant iwhai indicators with their respective diagnoses and associated interventions, in addition to the definitions of the implementation and deadline. for the implementation of the cp, the wcm must bring together the interdisciplinary intervention team (iit), ratify the cp, and proceed with the treatment of the proposed actions through interdisciplinary assistance, group work, and collective and environmental interventions. after validation of the cp by the iit, the workers are involved in discussing the cp and implementing it at the individual level. the assessment stage deals with the follow-up and monitoring of the workers to the effectiveness of the implemented health interventions. for this, it is necessary to systematically reassess the whri [48] . the attendance took place in a single period (shift) by each member of the interdisciplinary team, with an average time of 40 min for each consultation and a total time of 3.5 h for each worker in the health service. to validate the wham, the data collected in 2018 were used in a representative sample of the population of 965 workers, where attendance by the interdisciplinary team occurred at the same time. through statistical tests, the intention was to identify the prevalent diagnoses and interventions, how the modifiable factors are related to health outcomes in this sample, and the impact each dimension has on the whri [48] , i.e., if the joint use of these dimensions contributes to greater robustness and explanatory capacity of the wham. to assess the cost-benefit (cb) relationship of implementing wham, interventions directed at workers with coronary heart disease (chd) and diabetes in the period ranging from 2011 to 2018 were analyzed. the effectiveness of the intervention was based on the results of epidemiological studies over this period. brazilian national data were used to estimate the average annual benefits of preventing direct medical costs for diseases. the analytical tool wellcast roi™ [56] , developed to justify the approval of disease prevention and management programs, was used to calculate the s-roi. for this, the following steps were taken: (i) determine the incidence of the pre-program disease; (ii) determine all costs associated with the disease, either medical costs (for chd patients, the framingham model [57] was used to calculate incidence pre and post-program for a period of 10 years, assuming changes in low-density lipoprotein (ldl) cholesterol, and systolic and diastolic pressure risk factors; for patients with diabetes mellitus, the reduction in the progression of diabetes comorbidities over 10 years was calculated, based on the reduction of glycemia, considering the retinopathy, kidney disease, neuropathy, and microangiopathy comorbidities) or economic costs (monthly salary data, loss of daily productivity, medical inflation rate, among other rates estimated by wellcast roi™); (iii) define the program and its cost; (iv) determine the effectiveness of the program in reducing costs; (v) subtract post-program costs from pre-program costs to determine reductions; and (vi) apply the concepts of net present value (npv), internal rate of return (irr), and cb to determine the s-roi. in all stages of the study, the recommendations and guidelines of resolution 466/2012 [58] of the brazilian ministry of health on ethical aspects regulating research with human beings, approved by the research ethics committee of the bahia school of medicine and public health and certificate of presentation for ethical consideration (caae) 84318218.2.0000.5544, were followed. all subjects gave their informed consent for inclusion before participating in the study. the prevalent diagnoses and their respective interventions by dimension are presented in detail in table 2 . in the physical education dimension, the most prevalent diagnosis is "regular aerobic capacity" (76.3 %), with the most prevalent intervention being "encourage thinking about starting a physical activity program, warning about the harm of physical inactivity" (84.8 %). in the field of nursing, the "impaired ability to perform leisure activities" (100.0 %) stands out as the most prevalent diagnosis, followed by the need to "promote ergonomic comfort" (99.0 %) as the most necessary intervention. in the field of medicine, "primary essential hypertension" emerges as the diagnosis with the highest prevalence among workers (87.2 %), preceded by "encourage health-seeking behaviour" (95.5 %) as the intervention with the greatest application within this sample. at the nutritional level, "excessive alcohol intake" is the most prevalent (99.0 %), with the intervention with the greatest application focusing on the need for "adequate macronutrients" (87.6 %). finally, in the field of dentistry, the most prevalent diagnosis is identified as "other somatoform disorders related to stressful events-bruxism" (97.1 %), with the predominant intervention being "guide to restorative treatment with external dentist" (72.9 %). table 3 shows the statistically significant correlations between modifiable health behaviours and health outcomes. moderate correlations in table 3 (τb ≥ 0.30) are identified as follows: between diabetes mellitus and altered blood glucose (τb = 0.65), energy balance intake (τb = 0.48), and the level of food knowledge (τb = 0.46); between arterial hypertension and the contemplation stage for physical activity (τb = 0.31); between the musculoskeletal pathology and the feeling of pain (τb = 0.40); between psychiatric pathology and energy balance intake (τb = 0.36); between triglycerides and energy balance intake (τb = 0.32); between caries and oral hygiene quality (τb = 0.30); between periodontal disease and periodontal condition (τb = 0.76), oral hygiene quality (τb = 0.58), level of food knowledge (τb = 0.31), altered blood glucose (τb = 0.45), energy balance intake (τb = 0.44), and simple carbohydrate intake (τb = 0.33). the results are shown in table 4 show which indicators are most correlated with each coefficient of each dimension of interdisciplinary risk. the values presented in table 4 make it clear which indicators are most correlated with multidisciplinary risk; the worse an indicator is, the more the risk increases. thus, in the field of physical education, it appears that the indicator of the contemplation stage for physical activity is the one that is most strongly correlated (τb = 0.59). in nursing, the physical aspects of ergonomic risks have the most significant correlation (τb = 0.44). in the field of medicine, diabetes mellitus is the most disturbing indicator (τb = 0.60). in nutrition, alcohol consumption presents the strongest correlation (τb = 0.45). finally, the highest correlation of all is for oral lesion on soft or hard tissue, which is the most significant indicator in the field of dentistry (τb = 0.82). hierarchical regression analysis was applied to understand whether the variables or dimensions under analysis explain a statistically significant amount of the variance of the dependent variable to be tested-in this case, the whri [48] ( table 5) . a comparison of stages is made by gradually adding each independent variable in each stage, to understand if the combination of the dimensions explains more than considering them separately. table 5 . hierarchical multiple regression analysis scheme. step 1 step 2 step 3 step 4 step 5 after analyzing the robustness of wham, its economic sustainability was assessed using the wellcast roi™ tool. for the analyzed time period and based on the npv of usd 23,363.29/per worker, the irr of 85.5%, and the cb of 1.85:1, the s-roi was determined, suggesting that wham is economically sustainable. given its complexity, the field of healthcare requires the mobilization of specialists from different areas, with the aim of promoting comprehensive and integrated care for workers. based on an approach aimed at changing behaviors and adopting healthier lifestyles, going beyond the mere medicalization or treatment of diseases, the interdisciplinary care on which the wham model is based resulted in the data presented in table 2 . in view of the most prevalent diagnoses identified for each of the integrated dimensions, an intervention was generated that promotes worker autonomy and the maintenance of healthy lifestyles and behaviors, such as physical activity, healthy eating, non-consumption of alcohol and tobacco, good oral hygiene, balanced social and environmental relations, and decent work habits [55] . at this level, hypertension or diabetes mellitus diagnosis is highlighted, suggesting healthy behaviors or healthier eating habits interventions. as eng and collaborators [59] state, the workplace is a key space for guidance around healthy behaviors and the reduction of non-communicable diseases (ncds), such as diabetes mellitus and arterial hypertension. viterbo and co-authors [23] report that long-term interdisciplinary practice has had very positive and significant effects on reducing ncds. hochart and lang [60] also mention in their study that the implementation of a comprehensive care program in the workplace with the aim of modifying health risk behaviors resulted in a decrease in workers in the high and medium risk ranges and in the maintenance of health for those that were in the low risk range. the same is true for the issue of oral health, a problem that is related to other serious diseases [61, 62] , and which is solved through the implementation of regular programs for the adoption of oral hygiene behavior among workers, as reported by viterbo and collaborators [63] . supporting these results, and in order to reinforce the importance of an integral look at workers' health, table 3 presents the results between the behaviors (modifiable factors) and the results for workers' health. an overview of these results makes the connections between behaviors and health outcomes even more evident, as well as between the results themselves. in this case, an individual look at a worker would not allow one to understand them as a whole, contributing to fragmentation. certain associations exemplify this idea, namely between the level of food knowledge and the type of food, identified by the energy balance intake, altered blood glucose, and diabetes mellitus. a similar relationship was identified in a review by sami and co-authors [64] , in which guidance towards healthier eating practices reduced the level of diabetes and prevented associated complications. the study by holynska and colleagues [65] showed that the level of food knowledge is effectively related to nutrient intake, as this study also demonstrated. in line with this, breen et al. [66] argued that the level of food knowledge enhances the choice of food, thus optimizing the quality of life of people with diabetes. table 4 shows the results of the indicators that are most correlated with the risk of each analyzed dimension, making it possible to identify those that contribute most to the increased risk in that dimension. the strongest correlation belongs to the field of dentistry, more specifically for oral lesions increasing the health risk of these workers. according to warnakulasuriya et al. [67] , conducting screening programs using valid visual inspection method to detect potentially malignant oral disorders within a workplace is not only feasible, but also effective. in terms of physical activity, the indicator that has the strongest correlation is that of the contemplation stage for physical activity; that is, the predisposition to start a physical activity. in the review by jirathananuwat and pongpirul [68] , the 48 studies analyzed demonstrated that the workplace can play an important role in promoting regular physical activity among workers. ergonomic risks in the workplace are, in this context, assumed to be the most correlated with risk in the field of nursing. this has been documented in several studies, namely by skovlund et al. [69] and welch et al. [70] . since workers spend long hours of their day at the workplace, an additional concern regarding workplace ergonomics must be considered, as correct adaptation will result not only in promoting the well-being of workers, but also in reducing medical costs for employers, as reported by munir et al. [45] , gao et al. [47] , and welch et al. [70] . in terms of pathologies, diabetes mellitus is the indicator that most contributes to risk in the dimension of medicine. in the reviews by hafez [71] and gan [72] , the workplace is an important space for effective reduction of diabetes mellitus. some of the results in this study will have a direct implication in the workplace context, thus a more detailed specific analysis is necessary. the results regarding the wham robustness (table 5 ) make it clear that the combination of technical and scientific knowledge in the work context results in a better understanding of the workers' global health. this result makes it possible to effectively verify that the interdisciplinary approach translates into gains in health, and that it must be adopted as a matrix in all work contexts, particularly those referring to a higher exposure risk and greater number of employees, as already identified in the studies by viterbo et al. [23] , clark et al. [73] , and costa et al. [74] . considering that health promotion and prevention actions can influence the health habits and behaviors of workers, they can also reduce health costs. the literature review [38, [75] [76] [77] suggests that programs based on behavior change theory and using personalized communication and individualized counselling for high-risk individuals are likely to produce a positive return on the amount invested in these programs. the assessment of s-roi in the specific model under investigation (wham) corroborates other studies carried out in the workplace [41, 44, 45, 47] , showing positive financial results and reinforcing the advantages of applying wham, which in addition to directing investment in health strategies that are proven to be a priority, enables the optimization of financial resources, resulting in an s-roi of 85.5% for interdisciplinary, integral, and integrated interventions for the community of workers with a high risk level. the search for a healthcare model for workers that is oriented towards integrated care, expanded health needs, economic sustainability, and which overcomes the problems arising from the hegemony of the biomedicine paradigm, such as the excessive use of technologies and focus on curative actions of diseases, is one of the great challenges of the brazilian health system today. this scenario is strongly present in brazilian scientific production and is reflected in national and international policies through legislation and public initiative. the results obtained with the practical application of wham in the oil industry in bahia, brazil, demonstrated the potential of the model, where the articulated and hierarchical management of the various indicators of workers' health makes it possible to direct practices aimed at the cause and not at the effect or symptom. at the individual level, the model presented an interdisciplinary diagnosis of the health conditions of each worker, correlating the modifiable health factors and their respective impacts. the presentation of information to individuals promoted autonomy and empowered workers to change behaviors that negatively interfere with health conditions. at the collective level, the application of the model demonstrated the correlation between health indicators and interdisciplinary risk in the studied context, encouraging the creation of strategies aimed at the most critical conditions, as well as the design of preventive interventions. the robustness of the model highlights this same potential, in addition to the related optimization of financial resources of 85.5% for interdisciplinary interventions. the absence of a similar model in occupational health is a limitation of this study since comparative analyses in the context of this work are not possible. the application of wham in different healthcare contexts is suggested in future studies, as well as carrying out analyses of the model's effectiveness by comparing the population's epidemiological results and studying the s-roi. the different theoretical contributions to the theme of this study, as well as the results found, lead to the understanding that wham can be considered as a model capable of encompassing the complexity of the field of occupational health, considering the interdisciplinary approach, risk management, and comprehensive and integrated care, in addition to accounting for economic sustainability for companies investing in healthcare. the proximal origin of sars-cov-2 the one health concept-the health of humans is intimately linked with the health of animals and a sustainable environmen health services delivery programme division of health systems and public health duas faces da mesma moeda: microrregulação e modelos assistenciais na saúde suplementar. in [national agency for supplementary health. two faces of the same coin: microregulation and care models in supplementary health modelos assistenciais e unidades básicas de saúde: elementos para debate [care models and basic health units: elements for debate modelos de atenção e vigilância da saúde [health care and surveillance models cartografia do trabalho vivo modelos de atenção e a saúde da família [models of care and family health programa saúde da família: a construção de um novo modelo de assistência [family health program: the construction of a new care model modelos de atenção à saúde no brasil [health care models in brazil in políticas e sistema de saúde no brasil communication on health and safety risk control in contemporary society: an interdisciplinary approach. ciência saúde coletiva saúde coletiva cuidado das condições crônicas na atenção primária à saúde: o imperativo da consolidação da estratégia da saúde da família [the care of chronic conditions in primary health care: the imperative of consolidating the modelos assistenciais em saúde: desafios e perspectivas [health care models: challenges and perspectives the health care model: concepts and challenges for primary health care in brazil technology of relations as device of humanized attendance in basic attention to health in the perspective of access, sheltering and attachment modelos tecnoassistenciais em saúde: o debate do campo da saúde coletiva [techno-health care models: the debate in the field of public use of light technologies as a strategy for changing the health profile of workers with chronic conditions in the oil industry administração em saúde: autogestão de consultórios e clínicas dos modelo assistencial e atenção básica à saúde [care model and primary health care understanding the process to develop a model of care: an. aci framework; agency for clinical innovation implementation of an interdisciplinary approach to promote workers global health status in the oil industry, brazil (2006-2015) interdisciplinarity: an articulating movement in the field of worker's health significados e limites das estratégias de integração disciplinar: uma reflexão sobre as contribuições da saúde do trabalhador resgatando conhecimentos e práticas sobre as relações trabalho-saúde [the field of occupational health: rescuing knowledge and practices about work-health relations the sociology of health and medicine: a critical introduction the social determinants of health: developing an evidence base for political action final report to world health organization commission on the social determinants of health; national institute for health and clinical excellence social determinants and lifestyles: integrating environmental and public health perspectives fatores de risco relacionados à carga global de doença do brasil e unidades federadas [risk factors related to the global burden of disease in brazil and federated units environment and human health health monitoring and intervention plan on oil industry workers: results from a case-study. in occupational and environmental safety and health ii sustainable development goals indicators: a methodological proposal for a multidimensional fuzzy index in the mediterranean area desenvolvimento sustentável e saúde do trabalhador nos estudos de impacto ambiental de refinarias no brasil impact of working environment on job satisfaction a cost-benefit analysis of three older adult fall prevention interventions a review and analysis of the health and cost-effective outcome studies of comprehensive health promotion and disease prevention programs the health and cost benefits of work site health-promotion programs impact of worksite health promotion on health care costs and utilization. evaluation of johnson & johnson's live for life program worksite health promotion: its evolution and the johnson & johnson experience a return on investment evaluation of the citibank, n.a., health management program building program participation: strategies for recruitment and retention in worksite health promotion programs health spending projections through 2016: modest changes obscure part d's impact. health aff. (millwood) impacts of workplace health promotion and wellness programs on health care utilization and costs: results from an academic workplace a cost and cost-benefit analysis of the stand more at work (smart work) intervention projected return on investment of a corporate global health programme economic evaluation of a randomized controlled trial of an intervention to reduce office workers' sitting time: the "stand up victoria health risk assessment in oil industry in bahia, brazil: the worker's health risk index (whri) development and validation of an interdisciplinary worker's health approach instrument (iwhai) world health organization icd-11-international classification of diseases 11th revision. the global standard for diagnostic health information sistematização da assistência de enfermagem em unidade de terapia intensiva classificação internacional para a prática de enfermagem: instrumental tecnológico para a prática profissional [international classification for nursing practice: technological instrument for professional practice academy of nutrition and dietetics. international dietetics and nutritional terminology (idnt) reference manual: standard language for the nutrition care process world health organization. international classification of functioning, disability and health; world health organization health behaviors as a mediator of the association between interpersonal relationships and physical health in a workplace context the framingham heart study and the epidemiology of cardiovascular disease: a historical perspective approves regulatory norms of research involving human beings; national health council resolution no 466 of december 12 impact of a workplace health promotion program on employees' blood pressure in a public university impact of a comprehensive worksite wellness program on health risk, utilization, and health care costs periodontitis and diabetes: a two-way relationship the association between oral hygiene and periodontitis: a systematic review and meta-analysis. int effectiveness of an oral health program among brazilian oil workers. in occupational and environmental safety and health ii effect of diet counseling on type 2 diabetes mellitus the level of nutrition knowledge versus dietary habits of diabetes patients treated with insulin diabetes-related nutrition knowledge and dietary intake among adults with type 2 diabetes is workplace screening for potentially malignant oral disorders feasible in india? promoting physical activity in the workplace: a systematic meta-review association between physical work demands and work ability in workers with musculoskeletal pain: cross-sectional study process evaluation of a workplace-based health promotion and exercise cluster-randomised trial to increase productivity and reduce neck pain in office workers: a re-aim approach workplace interventions to prevent type 2 diabetes mellitus: a narrative review shift work and diabetes mellitus: a meta-analysis of observational studies developing and evaluating an interdisciplinary clinical team training program: lessons taught and lessons learned communication of environmental risks to potentially exposed workers: an experience in the oil industry, bahia, brazil. in occupational and environmental safety and health ii financial impact of health promotion programs: a comprehensive review of the literature meta-evaluation of worksite health promotion economic return studies: 2005 update a review and analysis of the clinical and cost-effectiveness studies of comprehensive health promotion and disease management programs at the worksite: update vi 2000-2004 key: cord-310195-am3u7z76 authors: waller, j.; rubin, g. j.; potts, h. w. w.; mottershaw, a.; marteau, t. m. title: immunity passports for sars-cov-2: an online experimental study of the impact of antibody test terminology on perceived risk and behaviour date: 2020-05-10 journal: nan doi: 10.1101/2020.05.06.20093401 sha: doc_id: 310195 cord_uid: am3u7z76 objective: to assess the impact of describing an antibody-positive test result using the terms immunity and passport or certificate, alone or in combination, on perceived risk of becoming infected with sars-cov-2 and intention to continue protective behaviours. design: 2 by 3 experimental design. setting: online with data collected between 28th april and 1st may 2020. participants: 1,204 adults registered with a uk research panel. intervention: participants were randomised to receive one of six descriptions of an antibody test and results showing sars-cov-2 antibodies, differing in the terms used to describe the type of test (immunity vs antibody) and the test result (passport vs certificate vs test). main outcome measures: the primary outcome was the proportion of participants perceiving no risk of becoming infected with sars-cov-2 given an antibody positive test result. other outcomes include intended changes to frequency of hand washing and physical distancing. results: when using the term immunity (vs antibody), 19.1% of participants [95% ci: 16.1 to 22.5] (vs 9.8% [95% ci: 7.5 to 12.4]) perceived no risk of catching coronavirus at some point in the future given an antibody-positive test result (aor: 2.91 [95% ci: 1.52 to 5.55]). using the terms passport or certificate, as opposed to test, had no significant effect (aor: 1.24 [95% ci: 0.62 to 2.48] and aor: 0.96 [95% ci: 0.47 to 1.99] respectively). there was no significant interaction between the effects of the test and result terminology. across groups, perceiving no risk of infection was associated with an intention to wash hands less frequently (aor: 2.32 [95% ci: 1.25 to 4.28]) but there was no significant association with intended avoidance of physical contact with others outside of the home (aor: 1.37 [95% ci: 0.93 to 2.03]). conclusions: using the term immunity (vs antibody) to describe antibody tests for sars-cov-2 increases the proportion of people believing that an antibody-positive result means they have no risk of catching coronavirus in the future, a perception that may be associated with less frequent hand washing. the way antibody testing is described may have implications for the likely impact of testing on transmission rates. at the height of the first wave of the covid-19 pandemic, about a third of the world's population is estimated to have been in lockdown, with all but essential workers largely confined to home (1) . without an effective treatment or vaccine, testing for infection combined with contact tracing and isolation will be central to effective strategies to ease populations out of lockdown while keeping the basic reproduction number (r0) below one (2) . testing for antibodies to sars-cov-2 is a possible complement to testing for active infection to identify those who have developed antibodies to the virus and so may be able to return to work and other activities without significantly increasing transmission rates (3) . these tests have been variously described in the media as immunity passports (4, 5) , immunity certificates (6,7) immunity cards (8) and release certificates (9) . unfortunately, the use of these terms implies a certainty unmatched by current evidence about antibody tests (10) . uncertainties inherent in tests for antibodies to sars-cov-2 include the extent and duration of immunity conferred (11) . they also include the uncertainties inherent in any test regarding the proportion of those who would be correctly identified. this depends upon the test performance -its sensitivity and specificity -as well as the population prevalence of the tested condition (12) . given these uncertainties, those who receive a test result indicating the presence of antibodies will have a residual risk of becoming infected by sars-cov-2 in the future. understanding that there is this residual risk -albeit one that is difficult to quantify at present -will be important to minimise transmission that could arise from those receiving "antibody positive" test results. if people testing positive perceive that they have no risk of becoming infected by the virus, they may ignore any future symptoms of infection and facilitate transmission if they fail to self-isolate appropriately. such a perception may also overgeneralise to a belief that they are unable to transmit infection through contact with contaminated surfaces. regardless of antibody status, all individuals can indirectly transmit the virus between surfaces by touch. hand washing or sanitising therefore need to remain frequent. evidence from other testing programmes suggests that interpreting a low risk result to mean no risk can be reduced by verbal and numerical expressions of residual risk when presenting test results (13, 14) . but even before testing programmes are in place, the terms commonly used to describe these tests -immunity passport or certificates -may inadvertently be fuelling a misplaced sense of certainty about their results. it is unknown whether describing these tests as being for immunity -as opposed to antibodies -or their results as passports or certificates increases misunderstanding of the residual risk inherent in an antibody-positive . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 10, 2020. . https://doi.org/10.1101/2020.05.06.20093401 doi: medrxiv preprint test result and thereby reducing adherence to protective behaviours and increasing risk of transmission (15) . this study was designed to test two hypotheses: describing a test indicating the presence of antibodies using the term immunity (vs antibody), and describing test results as passports or certificates (vs test), increases the likelihood that those with this test result erroneously perceive they have no risk of becoming infected in the future with coronavirus. ethical approval for this study was granted by the king's college london research ethics committee (reference: mra-19/20-18685). the protocol was preregistered on the open science framework https://osf.io/tjwz8/ study 2 the statistical analysis plan was pre-specified and uploaded to the open science framework prior to receipt of the data https://osf.io/tjwz8/ study 2 an initial study with similar methods was conducted https://osf.io/tjwz8/ study 1 but, due to an error, the intervention was not correctly programmed. this study is therefore not reported. the study was an online experiment using a 2 × 3 factorial design, with participants randomised, with an equal allocation ratio, to one of six groups varying in the description of an antibody test and a result showing the presence of antibodies. these descriptions differed only in the term used for what was being tested (immunity vs antibody) and the term used for the test result (passport vs certificate vs test). a quota sample of 1,204 adults was recruited via predictiv, the behavioural insights team's online experimentation platform (https://www.bi.team/bi-ventures/predictiv/) comprising 500,000 adults in the uk. quotas were based on age, gender and uk region to achieve a sample broadly representative of the uk population. 1373 clicked on the link to enter the study of whom 1214 subsequently completed the study. ten were excluded for failing to meet quality checks. participants were reimbursed in points (equivalent to £1) which could be redeemed in cash, gift vouchers or charitable donations. participants did not know the topic of the study prior to participation. due to the rapid nature of this research, the public was not involved in the development of the study. the sample size was chosen pragmatically without reference to a specific power calculation. we are fitting a full model with an interaction. conservatively, we then had an 80% chance of detecting, at a 5% significance level, an increase in the primary outcome measure from 50% in a baseline group to 64% in another group. participants were randomised to groups by random number generation. a random number between 1 and 6 was generated for every participant upon entry to the study to determine which description they saw, with each of the six numbers corresponding to one of the six description. as this is based on true randomness, the number of participants within each group can vary due to chance. the intervention comprised a description of antibody testing and test results indicating the presence of antibodies [see box 1 for one example and s1 for wording of all six descriptions]. these differed across six groups in test name of results indicating the presence of antibodies. all descriptions included the information that the result would mean a lower risk of future infection and transmission, and that people with this result could return to work earlier. wording of the items used for each measure is shown in supplementary materials (s2). scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future, and therefore also • lower risk of passing it on to others those who test 'positive' would get an immunity passport. they could return to work early. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 10, 2020. . https://doi.org/10.1101/2020.05.06.20093401 doi: medrxiv preprint primary outcome proportion of participants perceiving an antibody-positive test result to mean no risk of catching coronavirus in the future, assessed in response to a question with four response options. perceived likelihood of catching coronavirus in the future, assessed on a visual analogue scale from 0% to 100%. intention to engage in handwashing less or more frequently than now, given an antibodypositive test result: assessed in response to a question with five response options. intention to avoid physical contact with others outside the home more or less frequently than now, given an antibody-positive test result: assessed in response to a question with five response options. interest in undergoing the test if offered today: assessed in response to a question with four response options. demographic characteristics: age, gender, level of education and geographical region of residence. employment status, planned to be included, was omitted due to a technical error. a detailed statistical analysis plan is available on the open science framework, specified prior to receipt of the data https://osf.io/tjwz8/ study 2. binary logistic regression was used to assess the impact of test type (immunity/antibody) and result type (passport/certificate/test) on the odds of believing the antibody test result means there is no risk of future infection. an interaction term was included in the model (16) . the analysis was repeated adjusting for age (including a quadratic function to model a non-linear relationship), gender, education and region based on prior results showing these are predictors of risk beliefs. binary logistic regressions were run (as above) for the secondary outcomes: intention to wash hands less, intention to engage less in social distancing and intention to undergo the test. unadjusted and adjusted odds ratios and 95% confidence intervals are reported. logistic regression was run to assess the extent to which intentions to engage in less frequent handwashing or social distancing measures is predicted by perceiving the test result to mean no risk of being infected in the future by coronavirus. as only a very small proportion of participants gave a 'zero' response on the sliding scale of future risk, we used a linear regression model to examine this outcome, rather than a binary (zero vs. other) logistic regression as pre-specified in the analysis plan. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. . https://doi.org/10.1101/2020.05.06.20093401 doi: medrxiv preprint data were collected using an online survey platform, predictiv. upon entry to the study, participants were informed that they were to be asked some questions about coronavirus and that it would take about five minutes to complete. participants were then shown one of six brief descriptions of an antibody test for coronavirus (see s1 for full text for each of the six descriptions). they were then asked five questions, assessing the primary and secondary outcomes. participants' demographic characteristics were accessed from the survey platform. the sample comprised 606 women and 598 men with a median age of 36 years. around a quarter had some graduate-level education (24.2%) and there was good representation of all uk regions (see table 1 ). distribution of sample characteristics by exposure group is shown in table 1 . responses to the five outcome questions for the whole sample and by experimental group are shown in table 2 perceived level of future risk (on a scale of 0 to 100%) showed a complex, trimodal distribution. the median was 35% with an interquartile range from 18% to 51%. only 5% of respondents put their risk at 0%. overall, 63% put their risk below 50%. 10% put their risk at 50%, which was the modal response. 24% put their risk at greater than 50%, but below 100%. 3% of respondents put their risk at 100%: that is, they said they were certain to contract the virus. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. proportion answering 'no risk' in each sub-group % (95% ci) (n=1204) odds ratio (95% confidence interval) mutually adjusted (n=1204) figure 1 ]. there was no significant effect of result type and no significant interaction. we analysed the continuous measures of future perceived risk of infection using a linear model (anova) with two levels for test type, three levels for result type, and an interaction term. overall, there was no significant effect: f5,1198 = 1.46, p = 0.20, adjusted r2 < 1%. we repeated the analysis adjusting for demographic factors as covariates. overall, there was a significant effect: f13,1165 = 1.88, p = 0.03, adjusted r2 = 1%. this was because of a significant effect of age: as age increased, perceived risk decreased. there remained no significant effect of the experimental variables. logistic regression analyses examining the impact of test type, result type and their interaction on intentions to wash hands and avoid physical contact less frequently and on willingness to have the test are shown in supplementary tables 1 and 2. neither test type, result type nor their interaction were significantly associated with these behavioural outcomes. logistic regression analyses were used to examine belief that the result meant 'no risk' as a predictor of intention to wash hands and avoid physical contact less frequently, given a positive result (see figure 2 and supplementary . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. using the term immunity -as opposed to antibody -to describe antibody tests for sars-cov-2 doubled the proportion who erroneously perceived they would have no risk of becoming infected with the virus in the future if they were given an antibody-positive test result, from 9.8% for antibody to 19 these was no significant association with intended frequency of avoiding physical contact with others outside of the home. interest in undergoing the test was high -with 85.2% saying they would probably or definitely have it if offered -and was unaffected by the terms used to describe the tests. this study was designed to test two hypotheses, providing strong support for the first, that describing a test indicating the presence of antibodies using the term immunity (vs antibody) increases the likelihood that those with this test result erroneously perceive they have no risk of becoming infected in the future with coronavirus. this likely reflects a certainty about risk of future infection implicit in lay understandings of the term immunity that is not implied by the term antibody (17) . qualitative studies could explore this and other potential mechanisms for the effect observed. the results of this study did not support the second hypothesis that describing test results as passports or certificates increases the likelihood that those with this test result erroneously perceive they have no risk of becoming infected in the future with coronavirus. this does not mean that these terms are unproblematic however, only that they did not influence the specific perceptions that we explored. qualitative studies are warranted to understand the broader meanings these terms have in the context of testing for antibodies for sars-cov-2 and other contexts. responses on the sliding scale of future risk showed a high variability and were largely unexplained by the experimental intervention or other variables measured. this may point to considerable uncertainty in the public as to how to interpret test results. it also likely reflects the well-described tendency of people to use a 50% response to indicate uncertainty rather than a true judgement of probability (18) . we also saw that about a quarter of respondents on the first question stated their risk was "average" or "higher". this may point to considerable uncertainty in the public as to how to interpret test results use of the top end of the scale is hard to interpret but may either reflect a failure to read the information carefully and . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. . https://doi.org/10.1101/2020.05.06.20093401 doi: medrxiv preprint therefore a misunderstanding of the meaning of the result, or participants' using information beyond the experiment to assess their risk and not adequately considering the hypothetical test result when making their response. while we found no evidence for a direct effect on protective behaviours of the terms used to describe antibody tests results, there was indirect evidence that perceiving no risk of future infection might reduce frequency of handwashing. this finding is tentative, given it is based on behavioural intentions in response to a hypothetical antibody-positive result. nonetheless the potential for antibody testing to increase viral transmission must be considered alongside the potential benefits the tests might have in allowing the easing of lockdown restrictions. clear communication about the ongoing need for handwashing, in particular, will be essential and raising public awareness of the main mechanisms through which sars-cov-2 is transmittedthrough air and surfacesmight help improve adherence. this, in addition to acknowledgment of the imperfect nature of the tests, will give the public a more accurate representation of the meaning and implications of an antibody test result and a better understanding of how to reduce the risk of transmission. such communications need to emphasise that transmission can occur through contact regardless of antibody status. such communications also need to be rigorously evaluated to ensure their effectiveness at communicating these points both to those undergoing antibody tests as well as to general populations that are now having to learn to live with sars-cov-2. this study provides the first experimental evidence for the potentially adverse impact on risk perceptions and protective behaviours of commonly used terms to describe sars-cov-2 antibody tests and their results. as such, it provides timely evidence to inform policy and research to mitigate these effects to realise the potential benefits of such tests. the study has several limitations. first, participants were responding to a hypothetical test and asked to imagine that they had received a test result that had detected antibodies. findings from such studies can generalise to clinical settings (19, 20) but some caution is warranted. second, the protective behaviours of handwashing and physical distancing were measured using single items assessing behavioural intentions following a hypothetical test result. third, the sample size was insufficient to detect effect sizes that could be important at a population level. it is possible, for example, that the use of the terms certificate or passport might impact on risk perception, but the current study lacked the power to detect this. fourth, while quotas were used to achieve a sample broadly representative of the uk population, research panels are not representative of the general population (21, 22) . we found no evidence that the impact of the interventions in this study was modified by demographic characteristics of the participants, providing some reassurance about the generalisability of results across age groups, gender, educational level and geographical region of the uk. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. the results of this study have several implications for research and policy. the effectiveness of antibody tests for sars-cov-2 will depend not only on the extent and duration of any immunity conferred and the performance of a test, but also upon a good understanding of the meaning of tests results among those offered them. first, the use of the term immunity should be avoided in phrases to describe antibody tests, whether described as passports, certificates or tests. second, research is needed to evaluate different ways of informing those offered tests and receiving tests results to minimise the proportion erroneously perceiving an antibody-positive test result to mean no risk of becoming infected with the virus. it should also focus on maximising understanding that -regardless of antibody-status -anyone can indirectly transmit the virus by touching a contaminated surface and infecting the next surface they touch. hand washing or sanitising therefore need to remain frequent. research is also needed with those undergoing actual tests, powered to detect effects judged meaningful in the context of a population-based testing programme and involving measures of actual behaviour. interest in sars-cov-2 antibody testing is high -across many countries, employers and populations. while such testing could contribute to wider strategies to ease lock-down restrictions, their use may have an adverse impact on transmission-related behaviour. this appears to vary with the way the tests are described. using the term immunity (vs antibody) to describe antibody tests increases the proportion of people believing that an antibodypositive result means they have no future risk of coronavirus, a perception that may be associated with less frequent handwashing and hence increased risk of transmission. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 10, 2020. scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future -and therefore also • lower risk of passing it on to others those who test 'positive' would get an immunity passport. they could return to work early. scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future -and therefore also • lower risk of passing it on to others those who test 'positive' would get an immunity certificate. they could return to work early. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 10, 2020. scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future -and therefore also • lower risk of passing it on to others those who test 'positive' would get a result showing immunity. they could return to work early. scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future -and therefore also • lower risk of passing it on to others those who test 'positive' would get an antibody passport. they could return to work early. scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future -and therefore also • lower risk of passing it on to others those who test 'positive' would get an antibody certificate. they could return to work early. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 10, 2020. scientists are developing tests to see who has already had coronavirus. no test is 100% effective. this means that those who test 'positive' would have: • lower risk of catching coronavirus in the future -and therefore also • lower risk of passing it on to others those who test 'positive' would get a result showing antibodies. they could return to work early. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 10, 2020. oxford covid-19 government response tracker, blavatnik school of government world health organization. critical preparedness, readiness and response actions for covid-19. world health organization disease control, civil liberties, and mass testing -calibrating restrictions during the covid-19 pandemic immunity passports' could speed up return to work after covid-19. the guardian delta's ceo said he would support an 'immunity passport' program or other steps to jumpstart travel as the airline reports its first quarterly loss in more than 5 years. business insider people could be given coronavirus 'immunity certificates' to leave lockdown early. the independent mass coronavirus antibody tests have serious limits. bloomberg.com [internet coronavirus immunity cards for americans are 'being discussed'. politico chile to push ahead with coronavirus 'release certificates' despite who warning. reuters evaluation of antibody testing for sars-cov-2 using elisa and lateral flow immunoassays. medrxiv prepr what policy makers need to know about covid-19 protective immunity. the lancet understanding sensitivity and specificity with the right side of the brain numbers or words? a randomized controlled trial of presenting screen negative results to pregnant women women's understanding of a "normal smear test result": experimental questionnaire based study immunity passports' in the context of covid-19 factorial versus multi-arm multi-stage designs for clinical trials with multiple treatments fuzzy' virus: indeterminate influenza biology, diagnosis and surveillance in the risk ontologies of the general public in time of pandemics verbal and numerical expressions of probability: 'it's a fifty-fifty chance'. organ behav hum decis process the impact of genetic testing for crohn's disease, risk magnitude and graphical format on motivation to stop smoking: an experimental analogue study effect of communicating dna based risk assessments for crohn's disease on smoking cessation: randomised controlled trial office for national statistics we thank steve reicher for comments on an earlier draft of the study protocol . cc-by-nc-nd 4.0 international license it is made available under a all authors have completed the unified competing interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; and no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. hwwp declares consultancy fees from babylon health; all authors declare no other relationships or activities that could appear to have influenced the submitted work. the authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned have been explained. anonymised data will be made available upon reasonable request. the study was conceptualised by tmm, jw & gjr. am completed data collection. jw & hp analysed the data. all authors contributed to, and approved, the final manuscript. key: cord-302336-zj3oixvk authors: clift, ash k; coupland, carol a c; keogh, ruth h; diaz-ordaz, karla; williamson, elizabeth; harrison, ewen m; hayward, andrew; hemingway, harry; horby, peter; mehta, nisha; benger, jonathan; khunti, kamlesh; spiegelhalter, david; sheikh, aziz; valabhji, jonathan; lyons, ronan a; robson, john; semple, malcolm g; kee, frank; johnson, peter; jebb, susan; williams, tony; hippisley-cox, julia title: living risk prediction algorithm (qcovid) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study date: 2020-10-21 journal: bmj doi: 10.1136/bmj.m3731 sha: doc_id: 302336 cord_uid: zj3oixvk objective: to derive and validate a risk prediction algorithm to estimate hospital admission and mortality outcomes from coronavirus disease 2019 (covid-19) in adults. design: population based cohort study. setting and participants: qresearch database, comprising 1205 general practices in england with linkage to covid-19 test results, hospital episode statistics, and death registry data. 6.08 million adults aged 19-100 years were included in the derivation dataset and 2.17 million in the validation dataset. the derivation and first validation cohort period was 24 january 2020 to 30 april 2020. the second temporal validation cohort covered the period 1 may 2020 to 30 june 2020. main outcome measures: the primary outcome was time to death from covid-19, defined as death due to confirmed or suspected covid-19 as per the death certification or death occurring in a person with confirmed severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in the period 24 january to 30 april 2020. the secondary outcome was time to hospital admission with confirmed sars-cov-2 infection. models were fitted in the derivation cohort to derive risk equations using a range of predictor variables. performance, including measures of discrimination and calibration, was evaluated in each validation time period. results: 4384 deaths from covid-19 occurred in the derivation cohort during follow-up and 1722 in the first validation cohort period and 621 in the second validation cohort period. the final risk algorithms included age, ethnicity, deprivation, body mass index, and a range of comorbidities. the algorithm had good calibration in the first validation cohort. for deaths from covid-19 in men, it explained 73.1% (95% confidence interval 71.9% to 74.3%) of the variation in time to death (r(2)); the d statistic was 3.37 (95% confidence interval 3.27 to 3.47), and harrell’s c was 0.928 (0.919 to 0.938). similar results were obtained for women, for both outcomes, and in both time periods. in the top 5% of patients with the highest predicted risks of death, the sensitivity for identifying deaths within 97 days was 75.7%. people in the top 20% of predicted risk of death accounted for 94% of all deaths from covid-19. conclusion: the qcovid population based risk algorithm performed well, showing very high levels of discrimination for deaths and hospital admissions due to covid-19. the absolute risks presented, however, will change over time in line with the prevailing sars-c0v-2 infection rate and the extent of social distancing measures in place, so they should be interpreted with caution. the model can be recalibrated for different time periods, however, and has the potential to be dynamically updated as the pandemic evolves. objective to derive and validate a risk prediction algorithm to estimate hospital admission and mortality outcomes from coronavirus disease 2019 (covid-19) in adults. population based cohort study. setting and participants qresearch database, comprising 1205 general practices in england with linkage to covid-19 test results, hospital episode statistics, and death registry data. 6 .08 million adults aged 19-100 years were included in the derivation dataset and 2.17 million in the validation dataset. the derivation and first validation cohort period was 24 january 2020 to 30 april 2020. the second temporal validation cohort covered the period 1 may 2020 to 30 june 2020. the primary outcome was time to death from covid-19, defined as death due to confirmed or suspected covid-19 as per the death certification or death occurring in a person with confirmed severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in the period 24 january to 30 april 2020. the secondary outcome was time to hospital admission with confirmed sars-cov-2 infection. models were fitted in the derivation cohort to derive risk equations using a range of predictor variables. performance, including measures of discrimination and calibration, was evaluated in each validation time period. results 4384 deaths from covid-19 occurred in the derivation cohort during follow-up and 1722 in the first validation cohort period and 621 in the second validation cohort period. the final risk algorithms included age, ethnicity, deprivation, body mass index, and a range of comorbidities. the algorithm had good calibration in the first validation cohort. for deaths from covid-19 in men, it explained 73.1% (95% confidence interval 71.9% to 74.3%) of the variation in time to death (r 2 ); the d statistic was 3.37 (95% confidence interval 3.27 to 3.47), and harrell's c was 0.928 (0.919 to 0.938). similar results were obtained for women, for both outcomes, and in both time periods. in the top 5% of patients with the highest predicted risks of death, the sensitivity for identifying deaths within 97 days was 75.7%. people in the top 20% of predicted risk of death accounted for 94% of all deaths from covid-19. the first cases of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection were reported in the uk on 24 january 2020, with the first death from coronavirus disease 2019 (covid-19) on 28 february 2020. as of 18 august 2020, more than 41 000 deaths from covid-19 had occurred in the uk and more than 773 000 deaths globally. 1 in the initial absence of any vaccination or prophylactic or curative treatments, the uk government implemented social distancing and shielding measures to suppress the rate of infection and protect vulnerable people, thereby trying to minimise the risk of serious adverse outcomes. 2 3 emerging evidence throughout the course of the pandemic, initially from case series and then from cohorts of patients with confirmed sars-cov-2 doi: 10.1136/bmj.m3731 | bmj 2020;371:m3731 | the bmj infection, has shown associations of age, sex, certain comorbidities, ethnicity, and obesity with adverse covid-19 outcomes such as hospital admission or death. [4] [5] [6] [7] [8] [9] [10] [11] the knowledge base regarding risk factors for severe covid-19 is growing. as many countries are cautiously attempting to ease "lockdown" measures or reintroduce measures if rates are rising, an opportunity exists to develop more nuanced guidance based on predictive algorithms to inform risk management decisions. 12 better knowledge of individuals' risks could also help to guide decisions on mitigating occupational exposure and in targeting of vaccines to those most at risk. although some prediction models have been developed, a recent systematic review found that they all have a high risk of bias and that their reported performance is optimistic. 13 the use of primary care datasets with linkage to registries such as death records, hospital admissions data, and covid-19 testing results represents a novel approach to clinical risk prediction modelling for covid-19. it provides accurately coded, individual level data for very large numbers of people representative of the national population. this approach draws on the rich phenotyping of individuals with demographic, medical, and pharmacological predictors to allow robust statistical modelling and evaluation. such linked datasets have an established track record for the development and evaluation of established clinical risk models, including those for cardiovascular disease, diabetes, and mortality. [14] [15] [16] we aimed to develop and validate population based prediction models to estimate the risks of becoming infected with and subsequently dying from covid-19 and of becoming infected and subsequently admitted to hospital with covid-19. the model we have developed is designed to be applied across the adult population so that it can be used to enable risk stratification for public health purposes in the event of a "second wave" of the pandemic, to support shared management of risk and occupational exposure, and in early targeting of vaccines to people most at risk. an ongoing companion study will externally validate the models, using datasets across all four nations of the uk, and will be reported separately. this study was commissioned by the chief medical officer for england on behalf of the uk government, who asked the new and emerging respiratory virus threats advisory group (nervtag) to establish whether a clinical risk prediction model for covid-19 could be developed in line with the emerging evidence. the protocol has been published. 17 the study was conducted in adherence with tripod 18 and record 19 guidelines and with input from our patient advisory group. study design and data sources we did a cohort study of primary care patients using the qresearch database (version 44). qresearch was established in 2002 and has been extensively used for the development of risk prediction algorithms across the national health service (nhs) and for epidemiological research. by april 2020, 1205 practices in england were contributing to qresearch, covering a population of 10.5 million patients. the database is linked at individual patient level, using a project specific pseudonymised nhs number, to hospital admissions data (including intensive care unit data), positive results from covid-19 real time reverse transcriptase polymerase chain reaction tests held by public health england, cancer registrations (including detailed radiotherapy and systemic chemotherapy records), the national covid-19 shielded patient list in england, and mortality records held by nhs digital. we identified a cohort of people aged 19-100 years registered with participating general practices in england on 24 january 2020. we excluded patients (approximately 0.1%) who did not have a valid nhs number. patients entered the cohort on 24 january 2020 (date of first confirmed case of covid-19 in the uk) and were followed up until they had the outcome of interest or the end of the first study period (30 april 2020), which was the date up to which linked data were available at the time of the derivation of the model, or the second time period (1 may 2020 until 30 june 2020) for the temporal cohort validation. the primary outcome was time to death from covid-19 (either in hospital or outside hospital), defined as confirmed or suspected death from covid-19 as per the death certification or death occurring in an individual with confirmed sars-cov-2 infection at any time in the period 24 january to 30 april 2020. the secondary outcome was time to hospital admission with covid-19, defined as an icd-10 (international classification of diseases, 10th revision) code for either confirmed or suspected covid-19 or new hospital admission associated with a confirmed sars-cov-2 infection in the study period. we selected candidate predictor variables on the basis of the presence of existing clinical vulnerability group criteria (table 1) , associations with outcomes in other respiratory diseases, or hypothesised to be linked to adverse outcomes on clinical/biological plausibility and likely to be available for implementation. they are summarised in box 1 and supplementary box a. we defined variables according to information recorded using read codes in general practices' electronic health records at the start of the study period. the exception to this was information on chemotherapy, radiotherapy, and transplants, which was based on linked hospital records. we randomly allocated 75% of practices to the derivation dataset, which we used to develop the models. we evaluated the models' performance in the remaining 25% of practices (the validation set). all models were fitted separately in men and women. the outcomes of interest are subject to competing risks. for the primary outcome of death from covid-19, the competing risk is death due to other causes. for the secondary outcome of hospital admission, the competing risk is death from any cause before admission. we fitted a sub-distribution hazard (fine and gray 21 ) model for each outcome to account for competing risks. individuals who did not have the outcome of interest were censored at the study end date, including those who had a competing event. for all predictor variables, we used the most recently available value at the entry date (24 january 2020). we used second degree fractional polynomials to model non-linear relations for continuous variables (age, body mass index, and townsend material deprivation score, an area level score based on postcode 20 ). initially, we fitted a complete case analysis by using a model within the derivation data to derive the fractional polynomial terms. for indicators of comorbidities and medication use, we assumed the absence of recorded information to mean absence of the factor in question. data were missing in four variables: ethnicity, townsend score, body mass index, and smoking status. we used multiple imputation with chained equations under the missing at random assumption to replace missing values for these variables. for computational efficiency, we used a combined imputation model for both outcomes. the imputation model was fitted in the derivation data and included predictor variables, the nelson-aalen estimators of the baseline cumulative sub-distribution hazard, and the outcome indicators (death from covid-19 and hospital admission with covid-19). we carried out five imputations. each analysis model was fitted in each of the five imputed datasets. we used rubin's rules to combine the model parameter estimates and the baseline cumulative incidence estimates across the imputed datasets. we initially sought to fit models using all predictor variables. owing to sparse cells, some conditions were combined if clinically similar in nature (such as rare neurological disorders). we examined interactions between body mass index and ethnicity and interactions between predictor variables and age, focusing on predictor variables that apply across the age range (asthma, epilepsy, diabetes, severe mental illness). we explored the use of penalised models (lasso) to screen variables for inclusion, but this retained all the predictor variables and most interaction terms. 17 in line with the protocol, we subsequently removed a small number of variables with low numbers of events and adjusted (sub-distribution) hazard ratios close to 1 (as these will have minimal effect on predicted risks) or with uncertain clinical credibility, defined as counterintuitive results in light of the emerging literature. lastly, we combined regression coefficients from the final models with estimates of the baseline cumulative incidence function evaluated at 97 days to derive risk equations for each outcome. we used all the available data in the database. we did all model evaluation using the validation data with two separate periods of follow-up. the first validation study period was the same as for the derivation cohort: 24 january to 30 april 2020. the second temporal validation covered the subsequent period of 1 may 2020 to 30 june 2020. this was carried out with the same validation cohort except for exclusion of patients who died during 24 january to 30 april 2020. in the validation cohort, we fitted an imputation model to replace missing values for ethnicity, body mass index, townsend score, and smoking status. this excluded the outcome indicators and nelson-aalen terms, as the aim was to use covariate data to obtain a prediction as if the outcome had not been observed to reflect intended use. we applied the final risk equations developed from the derivation dataset to men and women in the validation dataset and evaluated r 2 values, brier scores, and measures of discrimination and calibration for the two time periods. 22 where lower values indicate better accuracy. 25 d statistics (a discrimination measure that quantifies the separation in survival between patients with different levels of predicted risks) and harrell's c statistics (a discrimination metric that quantifies the extent to which people with higher risk scores have earlier events) were evaluated at 97 days (the maximum followup period available at the time of the derivation of the model) and 60 days for the second temporal validation, with corresponding 95% confidence intervals. 26 we assessed model calibration by comparing mean predicted risks with observed risks by twentieths of predicted risk for each of the validation cohorts. observed risks were derived in each of the 20 groups by using non-parametric estimates of the cumulative incidences. additionally, we did a recalibration for the mortality outcome, using the method proposed by booth et al by updating the baseline survivor function based on the temporal validation cohort with the prognostic index as an offset term. 27 we also applied the algorithms to the validation cohort for the first time period to define the centile thresholds based on absolute risk. we also defined centiles of relative risk (defined as the ratio of the individual's predicted absolute risk to the predicted absolute risk for a person of the same age and sex with a white ethnicity, body mass index of 25, and mean deprivation score with no other risk factors). we calculated the performance metrics in the whole validation cohort and in the following pre-specified 17 we evaluated performance by calculating harrell's c statistics in individual general practices and combining the results using a random effects meta-analysis. 28 patient and public involvement patients were involved in setting the research question and in developing plans for design and implementation of the study. patients were asked to aid in interpreting and disseminating the results. overall study population overall, 1205 practices in england met our inclusion criteria. of these, 910 practices were randomly assigned to the derivation dataset and 295 to the validation cohort. the practices had 8 256 158 registered patients aged 19-100 years on 24 january 2020. we included 6 083 102 of these in the derivation cohort, and the validation dataset comprised 2 173 056 people. table 2 shows the baseline characteristics of patients in the derivation cohort. of these patients, 3 035 409 (49.9%) were men and 990 799 (16.3%) were of black, asian, or other minority ethnic (bame) background. in the derivation cohort, 10 776 (0.18%) patients had a covid-19 related hospital admission and 4384 (0.07%) had a covid-19 related death during the 97 days' follow-up, of which 4265 (97.3%) were recorded on the death certificate and 119 (2.71%) were based only on a positive test (and of these <15 were based on a test more than 28 days before death). admissions and deaths due to covid-19 occurred across all regions, with the greatest numbers in london, which accounted for 3799 (35.3%) of admissions and 1287 (29.4%) of deaths. of those who died, 2517 (57.4%) were male, 732 (16.7%) were bame, 3616 (82.5%) were aged 70 and over, 1417 (32.3%) had type 2 diabetes, 1311 (29.9%) had dementia, and 1033 (23.6%) were identified as living in a care home. the characteristics of the validation cohort were similar to those of the derivation cohort, as shown in supplementary tables a and b. in the first validation period (24 january to 30 april 2020), 1722 deaths and 3703 hospital admissions due to covid-19 occurred. in the second validation period (1 may to 30 june 2020), 621 deaths and 1002 admissions due to covid-19 occurred. the variables included in the final models were fractional polynomial terms for age and body mass index, townsend score (linear), ethnic group, domicile (residential care, homeless, neither), and a range of conditions and treatments as shown in figure 1, figure 2, figure 3 , and figure 4. these conditions and treatments were cardiovascular conditions (atrial fibrillation, heart failure, stroke, peripheral vascular disease, coronary heart disease, congenital heart disease), diabetes (type 1 and type 2 and interaction terms for type 2 diabetes with age), respiratory conditions (asthma, rare respiratory conditions (cystic fibrosis, bronchiectasis, or alveolitis), chronic obstructive pulmonary disease, pulmonary hypertension or pulmonary fibrosis), cancer (blood cancer, chemotherapy, lung or oral cancer, marrow transplant, radiotherapy), neurological conditions (cerebral palsy, parkinson's disease, rare neurological conditions (motor neurone disease, multiple sclerosis, myasthenia, huntington's chorea), epilepsy, dementia, learning disability, severe mental illness), other conditions (liver cirrhosis, osteoporotic fracture, rheumatoid arthritis or systemic lupus erythematosus, sickle cell disease, venous thromboembolism, solid organ transplant, renal failure (ckd3, ckd4, ckd5, with or without dialysis or transplant)), and medications (≥4 prescriptions from general practitioner in previous six months for oral steroids, long acting β agonists or leukotrienes, immunosuppressants). figure 1 and figure 2 show the adjusted hazard ratios in the final models for covid-19 related death in the derivation cohort in women and men. figure 3 and figure 4 show the adjusted hazard ratios for the final models for covid-19 related hospital admission in the derivation cohort. supplementary figures a and b show graphs of the adjusted hazard ratios for body mass index, age, and the interaction between age and type 2 diabetes for deaths and hospital admissions due to covid-19 (which showed higher risks associated with younger ages). supplementary figures c and d show fully adjusted hazard ratios for variables for the full model, including variables that were not retained in the final model (for example, adjusted hazard ratios close to one or those which lacked clinical credibility). other variables with too few events for inclusion were hiv, sphingolipidoises, short bowel syndrome, polymyositis, dermatomyositis, ehlers-danlos syndrome, biliary cirrhosis, hepatitis b and c, haemochromatosis, non-alcoholic fatty liver disease, chronic pancreatitis, drug misuse, asplenia, cholangitis, scleroderma, sjogren's syndrome, and pregnancy. supplementary figures e and f show fully adjusted hazard ratios for a combined outcome of either covid-19 related death or hospital admission. this gave very similar absolute risks to the hospital admission outcome. table 3 shows the performance of the risk equations in the validation cohort for women and men over 97 days for the main study period and for the temporal validation cohort evaluated from 1 may 2020 to 30 june 2020. overall, the values for the r 2 , d, and c statistics were similar in women and men. values for the mortality outcome tended to be higher than those for the hospital admission outcome. for example, in the first validation period, the equation explained 74% of the variation in time to death from covid-19 in women; the d statistic was 3.46, and harrell's c statistic was 0.933. the corresponding values in men were 73.1%, 3.37, and 0.928. the results for the second validation period were similar except for covid-19 related admissions in women, for which the explained variation and discrimination were lower than for the first period (explained variation 45.4%, d statistic 1.87, and harrell's c statistic 0.776). supplementary tables c-f show the corresponding results by region, age band, and fifth of deprivation and within each ethnic group in men and women in both validation periods. performance was generally similar to the overall results except for age, for which the values were lower within individual age bands. figure 5 shows funnel plots of harrell's c statistic for each general practice in the validation cohort versus the number of deaths in each practice in men and women in the first validation period. the summary (average) c statistic for women was 0.916 (95% confidence interval 0.908 to 0.924) from a random effects meta-analysis. the corresponding summary c statistic for men was 0.919 (0.912 to 0.926). we have developed and evaluated a novel clinical risk prediction model (qcovid) to estimate risks of hospital admission and mortality due to covid-19. we have used national linked datasets from general practice and national sars-cov-2 testing, death registry, and hospital episode data for a sample of more than 8 million adults representative of the population of england. the risk models have excellent discrimination (harrell's c statistics >0.9 for the primary outcome). although the calibration for the hospital admission outcome was good in both time periods, some under-prediction existed for the mortality outcome in the second validation cohort, which improved after recalibration. the recalibration method could be used to transport the risk models to other settings or time periods with different absolute risks of covid-19. qcovid represents a new approach for risk stratification in the population. it could also be deployed in several health and care applications, either during the current phase of the pandemic or in subsequent "waves" of infection (with recalibration as needed). these could include supporting targeted recruitment for clinical trials, prioritisation for vaccination, and discussions between patients and clinicians on workplace or health risk mitigation-for example, through weight reduction as obesity may be an important modifiable risk factor for serious complications of covid-19 if a causal association is established. 10 although qcovid has been specifically designed to inform uk health policy and interventions to manage covid-19 related risks, it also has international potential, subject to local validation. one of the variables in our model (the townsend measure of deprivation) may need to be replaced with locally available equivalent measures, or some recalibration may be needed. previous risk prediction models based doi: 10 29 30 comparison with other studies although similarities exist between our study and the recently reported analysis of risk factors from another english general practice database using a different clinical computer system, our project had a different aim-namely, to develop and evaluate a risk prediction model. we used a more comprehensive outcome (including deaths in patients with positive tests for sars-cov-2), a much wider range of predictors, and a more granular assessment of ethnicity and body mass index. our c statistic for mortality (>0.92) is substantially higher than the previous study's reported value of 0.77. 31 other prediction models have been reported, although these focus on other outcomes of covid-19, including risk of admission to intensive care or death following a positive test, or clinical decision tools that integrate biochemical and imaging parameters to aid diagnostis. 13 however, most such studies are at high risk of bias, as they have been developed in highly selected cohorts, have limited transparency, are likely to have optimistic reported performance, or did not use covid-19 specific data. 13 this study represents a substantial improvement on previously developed risk algorithms in terms of the size and representativeness of the study population, the richness of data linkages enabling accurate ascertainment of cases (including both in-hospital and out of hospital deaths) across the health network, and the breadth of candidate predictor variables considered. importantly, it analyses risks at the population level, rather than risks in people with confirmed or suspected infection, and may have relevance for shielding or other policies that seek to mitigate risk of viral exposure. complexities of modelling several complexities of modelling adverse risks from covid-19 in the general population warrant discussion. we used a general population approach which, although not able to incorporate all determinants of being infected, offers an overall estimate of risk of adverse outcomes from covid-19 that could be used in discussions between clinicians and patients about adjustment of lifestyle or occupational and behavioural factors that could limit viral exposure. our model predicts risks of "catching covid-19 and then having a severe outcome," on the basis of data collected during the first peak of the pandemic. the endpoint in this study examines a risk trajectory that comprises two elements: becoming infected, which is predominantly a function of behavioural/environmental factors including occupation, local infection rate, and numbers of social interactions; and risk of hospital admission and death due to the infection, which is arguably primarily driven by "vulnerability" (that is, biological/ physiological factors including age, sex, body mass index, comorbidities, and medications). although producing a prediction model for risk of "death if infected" is feasible in principle, this approach is not yet possible owing to the approach to testing in the uk and the context of an as yet incompletely quantified degree of asymptomatic background transmission. limited covid-19 testing data are available, but the difficulty is that no systematic community testing was done in the uk during the study period, so only patients unwell enough to attend hospital were tested. this means that a risk score developed in those who tested positive would overestimate risks of severe outcomes. as more widespread testing is done and those data become available, we will be able to update the model to take background infection rates into account and also model regional differences. although the absolute risk levels will of course change over time, depending on the incidence of the disease, our analysis over two validation time periods indicates that the relative risk measures and discrimination are likely to remain stable. secondly, the model estimates the absolute risk for a non-infected individual in the general population of becoming infected and then dying (or needing to be admitted to hospital) from the virus over a 97 day period. although many more than 40 000 people have died from covid-19 in the uk to date, when the denominator is a population of multi-millions, the absolute risk for most people may be low. therefore, when conveying this type of risk score to an individual, due emphasis is needed on the different meanings of absolute and relative risk. thirdly, the absolute risk of catching covid-19 depends not only on the incidence of the infection but also on the number of people one gets close to. for this reason, non-pharmacological interventions such as social distancing and shielding were introduced in the uk during the study period. we have included some measures of multi-occupancy, as we have factored care homes into the analysis. the data generated during the study period will therefore be affected by the uptake of harrell's c statistic 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 twentieth of predicted risk at 97 days 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twentieth of predicted risk at 97 days interventions such as social distancing and shielding, intended to mitigate the risks of sars-cov-2 infection. this could result in underestimation of some model coefficients and hence underestimation of absolute risk in people who were shielded. also, as this is a prediction model derived from an observational study, the associations estimated for individual predictor variables should not be interpreted as causal effects. however, ethical questions must be considered regarding how the tools may be used. we have presented two ways of stratifying risk based on either absolute or relative risk measures with associated centile values, but the choice of whether to have a threshold (given that risk is a continuous measure), and if so what threshold, will depend on the purpose for which the risk assessment tool is to be used, the available resources, and the ethical framework for decision making. we have analysed this within the "four ethical principles" framework that is widely used in medical decision making. the four principles are autonomy, beneficence, justice, and non-maleficence. 32 the new risk equations, when implemented in clinical software, are designed to provide more accurate information for patients and clinicians on which to base decisions, thereby promoting shared decision making and patient autonomy. they are intended to result in clinical benefit by identifying where changes in management are likely to benefit patients, thereby promoting the principle of beneficence. justice can be achieved by ensuring that the use of the risk equations results in fair and equitable access to health services that is commensurate with patients' level of risk. lastly, the risk assessment must not be used in a way that causes harm either to the individual patient or to others (for example, by introducing or withdrawing treatments where this is not in the patient's best interest), thereby supporting the non-maleficence principle. how this applies in clinical practice will naturally depend on many factors, especially the patient's wishes, the evidence base for any interventions, the clinician's experience, national priorities, and the available resources. the risk assessment equations therefore supplement clinical decision making and do not replace it. with these caveats, the predicted risk estimates can be used to identify people at higher risk, to inform shared decision making between healthcare professionals and service users, or for population level stratification. strengths and limitations of study our study has some major strengths, but some important limitations, which include the specific factors related to covid-19 along with others that are similar to those for a range of other widely used clinical risk prediction algorithms developed using the qresearch database. [14] [15] [16] key strengths include the use of a very large validated data source that has been used to develop other risk prediction tools; the wealth of candidate risk predictors; the prospective recording of outcomes and their ascertainment using multiple national level database linkage; lack of selection, recall and respondent biases; and robust statistical analysis. we have used non-linear terms for body mass index and age. we examined interaction terms, which show increased risks at younger ages for adults with type 2 diabetes. we also established a new linkage to the systemic anti-cancer therapy (sact) database for chemotherapy prescribed and administered in secondary care (which may not be recorded well in general practice software) to circumvent possible missing data for this important variable. specific limitations include the occurrence of shielding during the study period and that the study was conducted during the first phase of the uk epidemic. we have accounted for many risk factors for covid-19 mortality, but risks may be conferred by some rare medical conditions or other factors such as occupation that have not yet been observed or are poorly recorded in general practice or hospital data. in particular, the model does not include two important predictorsnamely, prevailing infection rate and personal social distancing measures. a lack of comprehensive testing has led to some missing data on covid-19 admissions and/or deaths, which means that development of a valid model for predicting death in people infected with sars-cov-2 is not yet possible. we acknowledge that absolute risks are changing during the course of the pandemic, so these should be interpreted with caution. however, we would expect predictors of risk, relative risk measures, and discrimination to be more stable over time, which is consistent with the results from our temporal validation. although this tool was modelled on the best available data from the first wave of the pandemic, it will be updated as further testing and outcome data accrue, immunity levels change, and (potentially) a vaccine becomes available. nevertheless, having a risk score available at this stage of the pandemic may be useful to identify people at high risk before a vaccine or treatment is available. we have reported a validation in each of two time periods using practices from qresearch, but these practices were completely separate from those used to develop the model. we have used this approach previously to develop and validate other widely used prediction models. when these have been further externally validated on completely different clinical databases, by ourselves and others, the results have been very similar. [33] [34] [35] work is already under way to evaluate the models in external datasets across all four nations of the uk and to integrate the algorithms within nhs clinical software systems. this study presents robust risk prediction models that could be used to stratify risk in populations for public health purposes in the event of a "second wave" of the pandemic and support shared management of risk. we anticipate that the algorithms will be updated regularly as understanding of covid-19 increases, as more data become available, as behaviour in the population changes, or in response to new policy interventions. it is important for patients/carers and clinicians that a common, appropriately developed, evidence based model exists that is consistently implemented and is supported by the academic, clinical, and patient communities. this will then help to ensure consistent policy and clear national communication between policy makers, professionals, employers, and the public. impact assessment of nonpharmaceutical interventions against coronavirus disease 2019 and influenza in hong kong: an observational study effects of non-pharmaceutical interventions on covid-19 cases, deaths, and demand for hospital services in the uk: a modelling study clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study covid-19 and african americans clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study clinical course and mortality risk of severe covid-19 no commercial reuse: see rights and reprints variation in covid-19 hospitalizations and deaths across new york city boroughs writing group form obesity uk, obesity empowerment network, uk association for the study of obesity. obesity and covid-19: a call for action from people living with obesity obesity is a risk factor for severe covid-19 infection: multiple potential mechanisms prevalence of co-morbidities and their association with mortality in patients with covid-19: a systematic review and meta-analysis shielding from covid-19 should be stratified by risk prediction models for diagnosis and prognosis of covid-19 infection: systematic review and critical appraisal development and validation of qrisk3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study development and validation of qdiabetes-2018 risk prediction algorithm to estimate future risk of type 2 diabetes: cohort study development and validation of qmortality risk prediction algorithm to estimate short term risk of death and assess frailty: cohort study protocol for the development and evaluation of a tool for predicting risk of short-term adverse outcomes due to covid-19 in the general uk population transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (tripod): the tripod statement record working committee. the reporting of studies conducted using observational routinely-collected health data (record) statement the black report. penguin a proportional hazards model for the subdistribution of a competing risk explained variation for survival models a new measure of prognostic separation in survival data multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors assessing the performance of prediction models: a framework for traditional and novel measures comparing the predictive powers of survival models using harrell's c or somers' d temporal recalibration for improving prognostic model development and risk predictions in settings where survival is improving over time external validation of clinical prediction models using big datasets from e-health records or ipd meta-analysis: opportunities and challenges improvement in cardiovascular risk prediction with electronic health records non-invasive risk scores for prediction of type 2 diabetes (epic-interact): a validation of existing models factors associated with covid-19-related death using opensafely medical ethics: four principles plus attention to scope an independent external validation and evaluation of qrisk cardiovascular risk prediction: a prospective open cohort study an independent and external validation of qrisk2 cardiovascular disease risk score: a prospective open cohort study predicting the 10 year risk of cardiovascular disease in the united kingdom: independent and external validation of an updated version of qrisk2 web appendix: supplementary materials imperial college london, london, uk we acknowledge the contribution of emis practices who contribute to qresearch and emis health and the universities of nottingham and oxford for expertise in establishing, developing, or supporting the qresearch database. this project involves data derived from patient level information collected by the nhs, as part of the care and support of cancer patients. the data are collated, maintained, and quality assured by the national cancer registration and analysis service, which is part of public health england (phe). access to the data was facilitated by the phe office for data release. the hospital episode statistics data used in this analysis are reused by permission from nhs digital, which retains the copyright in that data. we thank the office for national statistics (ons) for providing the mortality data. nhs digital, phe, and the ons bear no responsibility for the analysis or interpretation of the data. we express our gratitude to anne rigg, nisha shaunak, tom charlton, ana montes, claire harrison, susan robinson, david wrench, matthew streetly, omer bengal, doraid alrifai, and rajjinder nijjar for aiding the authors (notably pj and jhc) with the classification of agents on the sact dataset linkage used in this study and to david coggon for general comments on the study protocol and interpretation.contributors: jhc, cc, akc, rk, kdo, ph, and nm led study conceptualisation. all authors contributed to the development of the research question and study design, with development of advanced statistical aspects led by jhc, cc, rk, kdo, and akc. jhc, akc, cc, jb, and pj were involved in data specification, curation, and collection. jhc and akc developed, checked, or updated clinical code groups. jhc did the statistical analyses, which were checked by cc. jhc developed the software for the web calculator. all authors contributed to the interpretation of the results. akc and jhc wrote the first draft of the paper. all authors contributed to the critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. the corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. jhc is the guarantor. funding: this study is funded by a grant from the national institute for health research (nihr) following a commission by the chief medical officer for england, whose office contributed to the development of the study question, facilitated access to relevant national datasets, and contributed to interpretation of data and drafting of the report. produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems; cc reports receiving personal fees from clinrisk, outside this work; ah is a member of the new and emerging respiratory virus threats advisory group; pj was employed by nhs england during the conduct of the study and has received grants from epizyme and janssen and personal fees from takeda, bristol-myers-squibb, novartis, celgene, boehringer ingelheim, kite therapeutics, genmab, and incyte, all outside the submitted work; akc has previously received personal fees from huma therapeutics, outside of the scope of the submitted work; rl has received grants from health data research uk outside the submitted work; as has received grants from the medical research council (mrc) and health data research uk during the conduct of the study; cs has received grants from the dhsc national institute of health research uk, mrc uk, and the health protection unit in emerging and zoonotic infections (university of liverpool) during the conduct of the study and is a minority owner in integrum scientific llc (greensboro, nc, usa) outside of the submitted work; kk has received grants from nihr, is the national lead for ethnicity and diversity for the national institute for health applied research collaborations, is director of the university of leicester centre for black minority ethnic health, was a steering group member of the risk reduction framework for nhs staff (chair) and for adult care staff, is a member of independent sage, and is supported by the nihr applied research collaboration east midlands (arc em) and the nihr leicester biomedical research centre (brc); rhk was supported by a ukri future leaders fellowship (mr/s017968/1); kdo was supported by a grant from the alan turing institute health programme (ep/t001569/1); no other relationships or activities that could appear to have influenced the submitted work. the views expressed are those of the author(s) and not necessarily those of the nihr, the nhs, or the department of health and social care. data sharing: to guarantee the confidentiality of personal and health information, only the authors have had access to the data during the study in accordance with the relevant licence agreements. access to the qresearch data is according to the information on the qresearch website (www.qresearch.org).the lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.dissemination to participants and related patient and public communities: patient representatives from the qresearch advisory board have advised on dissemination of studies using qresearch data, including the use of lay summaries describing the research and its findings.provenance and peer review: not commissioned; externally peer reviewed. this is an open access article distributed in accordance with the terms of the creative commons attribution (cc by 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. see: http://creativecommons.org/licenses/by/4.0/. key: cord-009694-e59kuwf1 authors: nan title: opinion of the scientific panel on animal health and welfare (ahaw) on a request from the commission related with the risks of poor welfare in intensive calf farming systems date: 2006-06-06 journal: efsa j doi: 10.2903/j.efsa.2006.366 sha: doc_id: 9694 cord_uid: e59kuwf1 nan summary efsa has been requested by the european commission to issue a scientific opinion on animal health and welfare aspects of intensive calf farming systems and their ability to comply with the requirements of the well-being of calves from the pathological, zootechnical, physiological and behavioural points of view. in particular the commission asked efsa to update the findings of the scientific veterinary committee (animal welfare section) report, on the welfare of calves of 9 november 1995, in the light of more recent data on this issue. where relevant the possible food safety implications of different farming systems should also be considered. in this report a risk assessment was made and the relevant conclusions and recommendations are forming the scientific opinion by the ahaw panel. the svc (1995) report contains information on measurements of welfare, needs of calves, descriptions of current housing systems, chapters on types of feed and feeding systems, weaning of calves, housing and pen design, climate, mananimal relationships, dehorning and castration. further chapters covered economical considerations of systems and for improving welfare. in the report conclusions were made on general management, housing, food and water and economics. the present report "the risks of poor welfare in intensive calf farming systems" is an update o the previous svc report with the exception of economical aspects which are outside of the mandate for this report. the various factors potentially affecting calves' health and welfare, already extensively listed in the 1995 report of the scientific veterinary committee animal welfare section (svc, 1995) , are updated and subsequently systematically determined whether they constitute a potential hazard or risk. to the latter end their severity and likelihood of occurrence in animal (sub) populations were evaluated and associated risks to calf welfare estimated, hence providing the basis for risk managers to decide which measures could be contemplated to reduce or eliminate such risks. in line with the terms of reference the working group restricted itself to (in essence a qualitative) risk assessment although it is agreed that welfare and health of calves can be substantially affected in the course of and as a result of transport and slaughter, this report does not consider animal health and welfare aspects of calves during transport and slaughter but such information can be found in a recently issued comprehensive report of the scientific committee on animal health and animal welfare (scahaw), on "the welfare of animals during transport (details for horses, pigs, sheep and cattle)" which was adopted on 11 march 2002 (dg sanco, 2002) and in the efsa report "welfare aspects of animal stunning and killing methods" (ahaw 04/027). in relation with the food safety aspects, main foodborne hazards associated with calf farming are salmonella spp., human pathogenic-verotoxigenic escherichia coli (hp-vtec), thermophilic campylobacter spp., mycobacterium bovis, taenia saginata cysticercus and cryptosporidium parvum/giardia duodenalis. present knowledge and published data are insufficient to produce a universal risk assessment enabling quantitative food safety categorization/ranking of different types of calf farming systems. nevertheless, the main risk factors contributing to increased prevalence/levels of the above foodborne pathogens, as well as generic principles for the risk reductions are known. the latter are based on the implementation of effective farm management (e.g. qa, husbandry, herd health plans, biosecurity) and hygiene measures (e.g. gfp-ghp). in general, the conclusions made in the previous svc report remain. however, recent research has provided for some additional conclusions. the risk analysis is presented in the tables of annex 1. the graphics in this table are not intented to represent numerical relationships but rather qualitative relations. in some instances the exposure could not be estimated due to lack of data, in which cases the risks where labelled "exposure data not available". the following major and minor risks for poor animal health and welfare have been identified for one or several of the various husbandry systems considered: the hazards of iron deficiency and insufficient floor space are considered to be very serious, the hazard of inadequate health monitoring is considered to be serious and the hazards of exposure to inadequate hemoglobin monitoring, allergenic proteins and too rich diet are considered to be moderately serious. for these hazards, there is no consensus on the exposure of calves mainly due to lack of data and that is why it is recommended that further studies should be made to provide evidence for an exposure assessment. regarding castration and dehorning (and disbudding) without anaesthetic drugs, there is a variation in relation to national legislation why the risk of poor welfare in relation to castration and dehorning has a wide range between countries. council directive 91/629/eec 1 laying down minimum standards for the protection of calves as amended by council directive 97/2/ec 2 requires the commission to submit to the council a report, based on a scientific opinion, on intensive calf farming systems which comply with the requirements of the wellbeing of calves from the pathological, zootechnical, physiological and behavioural points of view. the commission's report will be drawn up also taking into account socio-economic implications of different calf farming systems. it should be noted that the scientific veterinary committee (animal welfare section) adopted a report on the welfare of calves 3 on 9 november 1995 which should serve as background to the commission's request and preparation of the new efsa scientific opinion. in particular the commission requires efsa to consider the need to update the findings of the scientific veterinary committee's opinion in light of the availability of more recent data on this issue. where relevant the possible food safety implications of different farming systems should also be considered. efsa has been requested by the european commission to issue a scientific opinion on animal health and welfare aspects of intensive calf farming systems and their ability to comply with the requirements of the well-being of calves from the pathological, zootechnical, physiological and behavioural points of view. in particular the commission requires efsa to update the findings of the scientific veterinary committee (animal welfare section) report on the welfare of calves of 9 november 1995 in light of more recent data on this issue. where relevant the possible food safety implications of different farming systems should also be considered. the mandate outlined above was accepted by the panel on animal health and welfare (ahaw) at the plenary meeting, on 14/15 march 2005. it was decided to establish a working group of ahaw experts (wg) chaired by one panel member. therefore the plenary entrusted a scientific report and risk assessment to a working group under the chairmanship of prof. bo algers. the members of the working group are listed at the end of this report. the scientific report is considered for the discussion to establish a risk assessment and the relevant conclusions and recommendations forming the scientific opinion by the ahaw panel. according to the mandate of efsa, ethical, socio-economic, cultural and religious aspects are outside the scope of this scientific opinion. 3.1. the working group set out to produce a document in which the various factors potentially affecting calves' health and welfare [already extensively listed in the 1995 report of the scientific veterinary committee animal welfare section (svc, 1995) , are updated and subsequently to systematically determine whether these factors constitute a potential hazard or risk. to the latter end their severity and likelihood of occurrence in animal (sub) populations were evaluated and associated risks to calf welfare estimated, hence providing the basis for risk managers to decide which measures could be contemplated to reduce or eliminate such risks. it should be noted, however, that this does not imply that a hazard that has a serious effect on just a few animals should not be dealt with by managers on farm level as the suffering imposed on some animals constitute a major welfare problem for those individuals. in line with the terms of reference the working group restricted itself to (in essence qualitative) risk assessment, i.e. only one of three elements essential to risk analysis a risk assessment approach was followed, similar to the one generally adopted when assessing microbiological risks, i.e. along the lines suggested at the 22nd session of the codex alimentarius commission (cac, 2002) . incidentally, these guidelines have been characterized by the cac as 'interim' because they are subject to modifications in the light of developments in the science of risk analysis and as a result of efforts to harmonize definitions across various disciplines. cac's guidelines are in essence exclusively formulated for the purpose of assessing risks related to microbiological, chemical or physical agents of serious concern to public health. consequently -considering their disciplinary focus -the working group had to adapt the cac definitions to serve their purpose. these adapted definitions, have, in alphabethical order, been included in chapter 2 (see risk analysis terminology) the objectives of this report are to review and report recent scientific literature on the welfare including the health of intensively reared calves, to report on recent findings as an update to the scientific veterinary committee's previous report, to make a qualitative risk assessment concerning the welfare of intensively kept calves. where relevant, food safety implications of different farming systems are also considered. the report is structured in five major parts. the first three follow the scientific veterinary committee's previous report "on the welfare of calves" with introductory chapters 4-7 on background, measurements and needs in relation to calf welfare, chapter 8 describing housing, diet and management and chapter 9 describing comparison of systems and factors. in chapter 10 common disease and use of antibiotics is described. the other two parts involve aspects of meat quality and food safety (chapter 11) and the risk assessment (chapters 12). conclusions and recommendations from the previous svc document together with updated conclusions derived from recent research findings are presented in chapter 13. effect of transport and slaughter on calves' health and welfare although it is agreed that welfare and health of calves can be substantially affected in the course of and as a result of transport, this report does not consider animal health and welfare aspects of calves during transport because there is already a comprehensive recent report of the scientific committee on animal health and animal welfare (scahaw), on "the welfare of animals during transport (details for horses, pigs, sheep and cattle)" which was adopted on 11 march 2002 (dg sanco, 2002 . the report takes into account all aspects related with transport that could affect the health and welfare of cattle and calves, including the direct effects of transport on the animals and the effects of transport on disease transmission. the loading methods and handling facilities for cattle, the floor space allowance, the relationships of stocking and the density requirements, the vehicle design, space requirements and ventilation for cattle transporters (see also the ahaw scientific opinion related to standards for the microclimate inside animal road transport vehicles, efsa-q-2003-085), the behaviour of cattle during road transport, the road conditions, long distance transport and the travel times are also reviewed. recommendations for all these aspects are also given in that report. feeding and housing systems, weaning strategies and quality of solid and liquid feed 4.1.1. feeding systems and weaning strategies recommendations without a fully functional rumen, calves will be unable to utilise nutrients provided in the post-weaning dry feed diet. attention must paid to type of forage and consistent of particle size of starter grain in order to achieve a proper rumen development. calf weaning should be based on the amount of dry feed calves ingest per day, not on their age or weight, and calf starter should be made available five to 10 days after birth. a calf consuming 0.7 kg of dry feed or more on three consecutive days is ready for weaning. when calves are fed low levels of milk to encourage early consumption of dry food, weaning can be done abruptly. in contrast, if milk is given in large amounts, weaning may require two to three weeks of slow transition to avoid a setback in growth. the provision of solid feeds with adequate content and balance to veal calves is a prerequisite for the development of a healthy and functional rumen, the prevention of abnormal oral behaviours, and the stimulation of normal rumination activity. although some solid feeds may exacerbate problems with abomasal ulcers in milk-fed veal calves, properly balanced rations seem to moderate this effect. nutritional factors are clearly involved in the etiology of abomasal ulcers in veal calves. important elements include the consumption of large quantities of milk replacer and the interaction between a milk replacer diet and the provision of roughage. if vegetable proteins are not properly treated, milk replacers may cause hypersensitivity reactions in the gut, which may compromise calf welfare. it is recommended that solid feeds provided to veal calves, in addition to milk replacer, are adequately balanced in terms of the amount of fibrous material, which will promote rumination, and other components such as proteins and carbohydrates, which stimulate rumen development and support a healthy function of the digestive system. since milk replacer formulations are frequently changing, it is recommended to carefully and consistently examine allergenic properties and other possibly detrimental effects of all milk replacers before they are used on a large scale. if the concentration of haemoglobin in the blood of calves drops below 4.5 mmol l -1 , the ability of the calf to be normally active as well as lymphocyte count and immune system function are substantially impaired, and there is reduced growth rate. below 5.0 mmol l -1 , veal calves exhibit a number of adaptations to iron deficiency, including elevated heart rate, elevated urinary noradrenaline and alterered reactivity of the hpa axis. there is a lack of data on the variability in groups of calves. hence, when haemoblogin levels are found to be below 6.0 mmol l -1 in groups of young veal calves, it is field practice to give supplementary iron. for older calves, including those in the last four weeks before slaughter, efficient production is possible in individual calves whose haemoglobin concentration is above 4.5 mmol l -1 . if the concentration of haemoglobin in blood is not checked at all, there is a high risk of anaemia that is associated with poor welfare, for all calves fed a diet with a very low iron content. anaemia can be identified and quantified adequately if checks are carried out on veal production calves of 2-4 weeks, for example, when the calves are brought into a unit, between 12-14 weeks of fattening, and during the last four weeks before slaughter. if the concentration of haemoglobin in the blood of a group of calves during the last four weeks before slaughter is a mean of 4.5 mmol l -1 , some calves may have a concentration substantially lower than the group-mean, and hence their welfare may be poor. in order to avoid anaemia levels that are associated with poor welfare because normal activity is difficult or not possible and other functions are impaired, it is advisable that diets should be provided that result in blood haemoglobin concentrations of at least 6.0 mmol l -1 throughout the life of the calf. in order to avoid serious impairment of immune system function and hence poor welfare, no individual calf should have a blood haemoglobin concentration lower than 4.5 mmol l -1 . in most cases this is achieved by adjusting the concentration of iron in the diet and having an adequate checking system so that the above condition is avoided. other treatment may be needed for calves with clinical conditions which cause anaemia but which are not related to diet. since the lowest haemoglobin concentrations in the blood of veal calves are usually reached during the last four weeks before slaughter, these blood concentrations should be checked at this time. such controls would help to see if measures are necessary to be taken or not. a checking system using a mean level, but whose aim is to avoid the risk of a low haemoglobin concentration in any individual lower than 4.5 mmol l -1 would have to use a mean substantially higher than 4,5 mmol l -1 , probably 6 mmol l -1 , and an appropriate sample size. in order to avoid poor welfare associated with anaemia, as explained in the conclusions (above), measurements of average blood haemoglobin concentration are not a satisfactory means of avoiding poor welfare but the use of a minimum level of 4.5 mmol l -1 for individual calves would achieve this. there is a lack of data on the haemoglobin levels and variation in groups in slaughtering calves. to gain more information as a basis for further actions and recommendations, it is advisable to perform sampling of calves at slaughter, by checking the haemoglobin level on a random basis in groups of calves. space and pen design recommendations space should be enough to allow animals to fulfill their needs for social behaviour, lying and grooming. as the pen shape affects the use of space by animals, pens should be rectangular rather than square and pen space should be divided into different usable areas. as the floor type affects the resting and lying postures of calves it should be comfortable. wet floors should be avoided due to thermal and resting problems. degree of social contact conclusions group housing can help calves to acquire social skills. some experience of mixing is important as calves that have been reared for a while in groups dominate calves that have always been in individual crates. when calves are mixed together in the first few days of life, and then kept for some weeks in a social group, there may be poor welfare because of the following risks: 1. especially when individuals are provided with inadequate access to teats and roughage in the diet, cross-sucking and other abnormal sucking behaviour may occur. 2. some individuals may be unaccustomed to the food access method, for example they may have only received food via a teat, and may find it difficult to drink from a bucket. 3. calves coming from different buildings, perhaps from different farms, may carry different pathogens and hence there is a risk of disease spread in all the calves that are put in the same airspace or are otherwise exposed to the pathogens. since calves are social animals, they should be kept in social groups wherever possible. these groups should be stable with no mixing or not more than one mixing. it is advisable for calves in the first two weeks of life not to be mixed with other animals. if calves from different buildings, perhaps different farms, are to be mixed in a pen or are to be put in different pens in the same airspace, quarantining animals for 3-4 weeks can reduce disease in the calves and hence prevent poor welfare. although cross-sucking can sometimes be minimised by provision of teats, water and roughage, if this is not possible, mixing into groups could be delayed for three to four weeks. calves fed by various means may require careful supervision after being put into groups in order that they learn how to feed effectively. temperature, ventilation and air hygiene calf rearing causes significant emissions of substances such as nitrate, phosphate, heavy metals and possibly antibiotics in manure and liquid effluents. in addition, there are odours, gases, dusts, micro-organisms and endotoxins in the exhaust air from animal houses. also in the handling of manure in storage and during application of manure and during grazing. these effluents can have distinct impacts on air, water, soil, biodiversity in plants, forest decay and also on animals and including humans. calf houses possess a high potential for emissions of ammonia and other gases. dust, endotoxins and micro-organisms are emitted in lower amounts than from pig or poultry production. odour, bioaerosols, ammonia, nitrogen, phosphorous and heavy metals may either have a local or a regional impact. gases such as methane and nitrous oxide contribute to global warming. respiratory disorders are the second largest reason for morbility and mortality in calf rearing. the most important causes are environmental conditions such as hygiene, management and the physical, chemical and biological factors in the environment. ventilation plays a decisive role in reducing the incidence of respiratory disease. temperatures below 5 âºc can compromise lung function. ammonia concentrations of more than 6 ppm seem to increase respiratory infections. relative humidity of more than 80 % bear the risk of increased heat dissipation and can help bacteria to survive in airborne state. air velocities close to the animals of more than 0.5 m/s can significantly increase respiratory sounds in calves. sufficient air space in confined buildings can help to reduce the concentration of airborne bacteria. calf houses contain relatively high amounts of endotoxins (640 eu) (eu: endotoxin unit, see scientific report, www.efsa.eu.int) there is concern that antibiotic residues may contribute to the development of bacterial resistance. local and regional environmental problems are enhanced by high animal densities and insufficient distances between farms and residential areas. the exact quantitative contribution of calf rearing to environmental pollution and its impact on water, air, soil vegetation and nearby residents is not yet well understood. when housing systems are compared, although dust emission levels will seldom pose problems for the health of calves, ammonia emission levels may be high enough to exacerbate calf disease, especially when calves are kept in slatted floor units. the development of low emission production systems should be encouraged including mitigation techniques, e.g. biofilters, bioscrubbers, covered manure pits and shallow manure application. in particular there is need to reduce ammonia emissions from slatted floor units or to reduce the usage of such systems. adequate and efficient feeding regimes are required with minimal wastage of nitrogen and phosphorous and limited use of growth promoters and drugs. there is an urgent need for cooperative research to design appropriate ventilation systems to improve health and welfare of calves kept in confined rearing conditions. temperatures for young calves should range between 5 and 26 âºc. ammonia concentrations should be kept as low as possible preferably not more than 6 ppm. housing and management should aim a reducing dust, bacteria and endotoxin concentrations in the animal house air. minimum ventilation rates of 10 m 3 per 100 kg live weight should be applied. human-animal relationships recommendation stockpersons should be appropriately trained so that they have sufficient skills in rearing calves. they should have a positive attitude towards animals and work with them in order to minimise stress and to maintain a high quality of health control. rough contact (e.g. use of painful device such as an electric prod, loud noises) should be avoided and gentle contacts (e.g. talking softly, stroking, offering food) should be encouraged. this sort of contact is of particular importance for calves in groups or with their dam that tend not to approach humans readily. dehorning and castration if cattle are to be dehorned, it is recommend to disbud young cattle rather than to dehorn older ones. disbudding by cautery is recommended over other methods. local anaesthesia (e.g. 5-6 ml lidocaã¯ne or lignocaã¯ne 2% around the corneal nerve) and analgesia with an nsaid (e.g. 5 ml flunixin meglumine or 3 -3.75 mg ketoprofen 10% / kg body weight) should be given 15-20 min before disbudding. if cattle are to be castrated, it is recommended to castrate calves as early as possible (no later than 1.5 mo and preferably at 1 wk of age), to use the burdizzo method, and to provide appropriate anaesthesia and analgesia (e.g. 3 ml lignocaine 2% in each testicle through the distal pole and 3 mg ketoprofen 10% / kg body weight injected intravenously both 20 min before castration). prevention of typical calf diseases in the first 6 months of life such as diarrhoea and enzootic bronchopneumonia requires a systematic approach by improving management and housing conditions, specifically the preparation of the cow, hygiene of the calving environment, including dry clean bedding and high air quality, immediate supply with maternal antibodies, no mixing with older animals and careful attention and a rapid response to any sign indicating disease. main foodborne hazards associated with calf farming are salmonella spp., human pathogenic-verotoxigenic escherichia coli (hp-vtec), thermophilic campylobacter spp., mycobacterium bovis, taenia saginata cysticercus and cryptosporidium parvum/giardia duodenalis. the prevalence-level of infection and/or contamination of calves with, and further spread of, foodborne pathogens on farms depend on the status and the inter-relationship of different contributing factors that are inherently highly variable. present knowledge and published data are insufficient to produce a universal risk assessment enabling quantitative food safety categorization/ranking of different types of calf farming systems. nevertheless, generic principles for risk reductions for the main foodborne pathogens at calf farm level are known and are based on the implementation of effective farm management (e.g. qa, husbandry, herd health plans, biosecurity) and hygiene measures based on gfp-ghp. for quantitative food safety risk categorization of farming systems individually, and/or their related ranking, further scientific information is needed. accordingly, related research should be encouraged. the conclusions of the scientific veterinary committee report on the welfare of calves are presented in table 1 below together with additions relevant in the light of this update of the svc report. the best conditions for young rearing calves involve leaving the calf with the mother in a circumstance where the calf can suckle and can subsequently graze and interact with other calves.c agreed 5 where the calf will be separated from its mother at an early age, evidence suggests that it is normally beneficial for the calf if the mother is allowed to lick the calf thoroughly for a few hours after birth.c agreed r whenever possible, cows should be given the opportunity to lick the calf during at least three hours after parturition. 6 it is important that the calf should receive sufficient colostrum within the first six hours of life and as soon as possible after birth, in conditions which facilitate antibody absorption, preferably by suckling from the mother, so as to ensure adequate immunoglobulin levels in the blood. r where necessary, suckling assistance or additional colostrum should be provided for calves left to suckle from the dam.r agreed agreed 7 calves need resources and stimuli which are normally provided by their mothers. all calves should be given adequate food and water, appropriate conditions of temperature and humidity, adequate opportunities to exercise, good lying conditions, appropriate stimuli for sucking during the first few weeks of life and social contacts with other calves from one week of age onwards. specific aspects of housing and management which fulfill these conditions are detailed. agreed 8 young calves reared without their mothers should receive considerate human contact, preferably from the same stockperson throughout the growing period.r agreed stockpersons should be appropriately trained so that they have sufficient skill in the rearing of calves. they should have positive attitudes towards animals and to working with them in order to handle them while minimising stress and to maintain a high quality of health control. rough contacts (e.g. use of a painful device such as an electric prod, or loud noises) should be avoided and gentle contacts (e.g. talking softly, petting, offering food) should be encouraged. these contacts are of particular importance for calves in groups or with their dam that may tend not to approach humans easily. where calves cannot be kept with their mother, the system where welfare is best is in groups with a bedded area and an adequate space allowance available to them.c agreed. r see 13 below. the welfare of calves is very poor when they are kept in small individual pens with insufficient room for comfortable lying, no direct social contact and no bedding or other material to manipulate. c agreed r as the floor affects the resting and lying posture of calves they should be useful to have a comfortable floor. wet floors should be avoided due to thermal and resting problems. 11 tethering always causes problems for calves. calves housed in groups should not be tethered except for periods of not more than one hour at the time of the feeding of milk or milk substitute. individually housed calves should not be tethered. r calves are vulnerable to respiratory and gastro-intestinal disease and welfare is poor in diseased animals. better husbandry is needed to minimize disease in group housing conditions but results that are as good as those from individual housing can be obtained. c every calf should be able to groom itself properly, turn around, stand up and lie down normally and lie with its legs stretched out if it wishes to do so. r in order to provide an environment which is adequate for exercise ,exploration and free social interaction, calves should be kept in groups. calves should never be kept at too high stocking density. the following requirements are based on evidence of increasingly poor welfare as space allowance decreases. the space allowance should provide, especially for allowing resting postures, an area for each calf of at least (its height at the withers) x (its body length from the tip to its nose when standing normally to the caudal edge of the tuber ischii or pin bone x 1.1). the length measurements takes account of the forward and backward movements involved in standing up and lying down. this calculation takes account of differences in size amog breeds and with age. as a guideline, for holstein calves this area is 1.4 m 2 at 8 weeks, 1.8 m 2 at 16 weeks and 2.1 m2 at 22 weeks. r r since calves are social animals, they should be kept in social groups wherever possible. these groups should be stable with no mixing or not more than one mixing. it is advisable for calves in the first two weeks of life not to be mixed with other animals. c when calves are mixed together in the first few days of life, and then kept for some weeks in a social group, there may be poor welfare because of the following risks: -especially when individuals are provided with inadequate access to teats and roughage in the diet, cross-sucking and other abnormal sucking behaviour may occur. -some individuals may be unaccustomed to the food access method, for example they may have only received food via a teat, and may find it difficult to drink from a bucket. -calves coming from different buildings, perhaps from different farms, may carry different pathogens and hence there is a risk of disease spread in all the calves that are put in the same airspace or are otherwise exposed to the pathogens. r if calves from different buildings, perhaps different farms, are to be mixed in a pen or are to be put in different pens in the same airspace a quarantine situation should be used in order to reduce disease in the calves and hence prevent poor welfare. for a given space allowance per calf, increasing group size results in a larger total area and hence better possibilities for exercise, social interaction and improved environmental complexity. c larger groups are preferred because of the better possibilities for providing an adequate environment but there are limits to the numbers of animals which should be in one building section and risks associated with mixing of calves from different sources should be considered. r agreed r the space provided for calves should be enough to allow animals to fulfill their needs for social behaviour, lying and grooming. space allowance per animal should be greater for groups of 2 -5 animals and for feeding systems, and pen shapes or flooring materials that necessitate extra space availability. if the preferred system, group housing, is not possible then individual pens whose width is at least the height of the calf at the withers and whose length is at least the length of the calf from the tip of its nose when standing normally to the caudal edge of the tuber ischii or pin bone x 1.1 should be used. this space requirement is calculated on the basis of the space required for normal agreed r as the pen shape affects the use of space by animals, pens should maximize the perimeter and pen space should be divided into different usable areas. movements and evidence of increasingly poor welfare r 18 appropriate bedding for example straw is recommended. bedding must be changed at appropriate intervals and every calf should have access to a dry lying area. slatted floors must not be slippery and must not be a cause of tail tip necrosis. r agreed see 10 above 19 buildings should be adequately ventilated taking into account of the number of animals present and the external conditions. the air space in the building should be 6m 3 per calf up to 6 weeks of age and an amount of air space which increases with age is needed for older calves.r agreed c -calf rearing causes significant emissions such as nitrate, phosphate, heavy metals and possibly antibiotics in manure and liquid effluents as well as odour, gases, dusts, micro-organisms and endotoxins in the exhaust air from animal houses, from manure storage facilities, during application of manure and during grazing. -these effluents can have distinct impacts on air, water, soil, and thus also on animals. -calf houses possess a high potential for emissions of ammonia and other gases. dust, endotoxins and micro-organisms are emitted in lower amounts than from pig or poultry production. -respiratory disorders are the second largest reason for morbidity and mortality in calf rearing. the most important reason are environmental conditions such as hygiene, management and the physical, chemical and biological factors of the aerial environment. -ventilation plays a decicive role in reducing the incidence of respiratory diseases. temperatures below 5 c can compromise lung function. -ammonia concentrations of more than 6 ppm seem to increase respiratory affections. relative humidity of more than 80 % bear the risk of increased heat dissipation and can help bacteria to survive in airborne state. -air velocities close to the animals of more than 0.5 m/s can increase respiratory sounds in calves significantly. -sufficient air space in confined buildings can help to reduce the concentration of airborne bacteria. -calf houses contain relatively high amounts of endotoxins. -there is concern that antibiotic residues may contribute to the development of bacterial resistance. -environmental problems in calf houses are enhanced by high animal densities, insufficient distances between farms. -when housing systems are compared, although dust emission levels will seldom pose problems for the health of calves, ammonia emission levels may be higher enough to exacerbate calf disease, especially in slatted floor units. r -the development of low emission production systems should be encouraged including mitigation techniques, e.g. biofilters, bioscrubbers, covered manure pits and shallow manure application. in particular there is need to reduce ammonia emissions from slatted floor units or to reduce the usage of such systems. -adequate and efficient feeding regimes are required with minimal wastage of nitrogen and phosphorous and limited use of growth promoters and drugs. -there is an urgent need for cooperative research to design appropriate ventilation systems to improve health and welfare of calves kept in confind rearing conditions. -temperatures for young calves should range between 5 and 26 c. -ammonia concentrations should be kept as low as possible, preferably not more than 6 ppm. -housing design and management procedures should aim to reduce dust, bacteria and endotoxin concentrations in the animal house air. -minimum ventilation rates of 10 c 3 per 100 kg live weight should be applied. calves which lack specific nutrients, including iron, which are given poorly balanced diet, and which are not provided with adequate roughage in the diet after four weeks of age can have serious health problems, can show serious abnormalities of behaviour, and can have substantial abnormalities in gut development. c every calf should receive a properly balanced diet with adequate nutrients.r agreed r it is recommended that solids feeds provided to veal calves, in addition to milk replacer, are adequately balanced in terms of the amount of fibrous material, which will promote rumination, and other components such as proteins and carbohydrates, which stimulate rumen development and support a healthy function of the digestive system. c if the concentration of haemoglobin in the blood of calves drops below 4.5 mmol l -1 , the ability of the calf to be normally active as well as the lymphocyte count and immune system function are substantially impaired, and there is reduced growth rate. below 5.0 mmol l -1 , veal calves exhibit a number of adaptations to iron deficiency, including elevated heart rate, elevated urinary noradrenaline and alterered reactivity of the hpa axis. hence it is normal practice to identify young veal production calves with less than 6.0 mmol l -1 haemoglobin in plasma and to provide supplementary iron in addition to that normally included in the diet. for older calves, including those in the last four weeks before slaughter, efficient production is possible in individual calves whose haemoglobin concentration is above 4.5mmol l -1 . if the concentration of haemoglobin in blood is not checked at all, there is a high risk of anaemia that is associated with poor welfare, for all calves fed a diet with very low iron content. anaemia can be identified and quantified adequately if checks are carried out on veal production calves of 2-4 weeks, for example, when the calves are brought into a unit, between 12-14 weeks of fattening, and during the last four weeks before slaughter. if the concentration of haemoglobin in the blood of a group calves during the last four weeks before slaughter is a mean of 4.5 mmol l -1 , some calves may have a concentration substantially lower than the group-mean, and hence their welfare may be poor. r in order to avoid anaemia levels that are associated with poor welfare because normal activity is difficult or not possible and other functions are impaired, it is advisable that diets should be provided that result in blood haemoglobin concentrations of at least 6.0mmol l -1 throughout the life of the calf. in order to avoid serious impairment of immune system function and hence poor welfare, no individual calf should have a blood haemoglobin concentration lower than 4.5mmol l -1 . in most cases this is achieved by adjusting the concentration of iron in the diet and having an adequate checking system so that the above condition is avoided. other treatment may be needed for calves with clinical conditions which cause anaemia but which are not related to diet, r since the lowest haemoglobin concentrations in the blood of veal calves are usually reached during the last four weeks before slaughter, these blood concentrations should be checked at this time. such controls would help to see if measures are necessary to be taken or not. a checking system using a mean level, but whose aim is to avoid the risk of a low haemoglobin concentration in any individual lower than 4.5 mmol l-1, would have to use a mean substantially higher than 4,5 mmol l-1, probably 6 mmol l-1. in order to avoid poor welfare associated with anaemia, as explained in the conclusions (above), measurements of average blood haemoglobin concentration are not a satisfactory means of avoiding poor welfare but the use of a minimum level of 4.5 mmol l -1 for individual calves would achieve this. 21 some non-milk proteins are inappropriate for use in a milk substitute fed to calves because they produce allergenic reactions. some carbohydrates cannot be easily or properly digested by calves and they may cause digestive upset. no milk substitute should be fed to calves unless it can be easily digested and does not cause harmful reactions in the calves. r acidification of milk can reduce the incidence of diarrhoea, but any forms of acidified milk which are unpalatable to calves or which harm the calves should not be used. r every calf should be fed fermentable material, appropriate in quality and sufficient in quantity to maintain the microbial flora of the gut and sufficient fibre to stimulate the development of villi in the rumen. roughage, in which half of the fibre should be at least 10 mm in length, should be fed to calves. they should receive a minimum of 100 g of roughage per day from 2 to15 weeks of age, increasing to 250 g per day from 15 to 26 weeks of age but it would be better if these amounts would be doubled. the development of the rumen should be checked by investigating villi development in a proportion of calf guts after slaughter. r agreed r without a fully functional rumen, calves will be unable to utilise nutrients provided in the post-weaning dry feed diet. attention should paid to type of forage and consistent of particle size of starter grain in order to achieve a proper rumen development. calf weaning should be based on the amount of dry feed calves ingest per day, not on their age or weight, and calf starter should be made available five to 10 days after birth. a calf consuming 0.7 kg of dry feed or more on three consecutive days is ready for weaning. when calves are fed low levels of milk to encourage early consumption of dry food, weaning can be done abruptly. in contrast, if milk is given in large amounts, weaning may require two to three weeks of slow transition to avoid a setback in growth. there are clear signs of increased disease susceptibility and immunosuppression in calves up to 13 weeks of age, whose blood haemoglobin concentration is below 4.5 mmol/liter. however, in some studies the antibiotic treatment was not higher in calves whose haemoglobin was near to 4mmol/litre than in calves whose level was near to 5mmol/litreat 20 weeks of age. studies of exercise in anaemic calves show that there can be problems during exercise at a level of 5,5 mmol/litre. c all calves should be fed in such a agreed see 23 way that their haemoglobin level does not fall below a minimum of 4.5 mmol/litre. r 25 where calves are fed a diet which is lower in iron than 50mg/kg, an adequate sample of animals should be checked at 12 and 24 weeks of age in order to find out whether the blood haemoglobin concentration is too low. r agreed see 23 young calves have a very strong preference to suck a teat or teat-like object. it is preferable for calves to be fed milk or milk substitute from a teat during the first four weeks of life. calf welfare is improved if a non-nutritive teat is provided during the first four weeks of life especially if they are not fed from a teat. c when young group-housed calves are fed milk or milk substitute, the social facilitation effects of having a group of teats close together are beneficial. it is also advisable for several teats to be provided in groups of older calves. transponder controlled feeder systems have been found to work well. c the feeding to calves of large quantities of milk or milk substitute in a single daily meal can cause digestive problems. hence when calves are fed more than 10% of body weight in milk or milk substitute each day, this should be fed in at least two meals per day. r calves fed ad libitum, or close to this level should not be weaned off milk or milk replacer until they are consuming a minimum of 750 g of concentrates per head per day in the week prior to weaning. where calves are fed restricted quantities of milk or milk replacer before weaning they should not be weaned until they are consuming a minimum of 1000 g of concentrates per head per day in the week prior to weaning. r calves which are diseased and calves which are in hot conditions often need to drink water as well as milk or milk substitute and all calves drink water if it is available. the provision of milk or milk substitute is not an adequate alternative for provision of water. hence calves should be provided daily with water to drink. it is recommended that drinkers be provided in all pens. r agreed r prevention of typical calf diseases in the first 6 months of life such as diarrhoea and enzootic bronchopneumonia requires a systematic approach by improving management and housing conditions, specifically the preparation of 24 the cow, hygiene of the calving environment, including dry clean bedding and high air quality, immediate supply with maternal antibodies, no mixing with older animals and careful attention and early reaction of all signs of any beginning diseases. dehorning calves between 1 -3 weeks by cauterisation with adequate anaesthesia and analgesia (no precision given) castrate calves at 3 months with adequate anaesthesia and analgesia (no precision given) r dehorning: if cattle are to be dehorned, it is recommended to disbud young cattle rather than to dehorn older ones. disbudding by cauterisation is recommended over other methods. local anaesthesia (e.g. 5-6 ml lidocaã¯ne or lignocaã¯ne 2% around the corneal nerve) and analgesia with a non steroidal anti-inflammatory drug (5 ml flunixin meglumine or 3 -3.75 mg ketoprofen 10% / kg body weight) shall be performed 15-20 min before disbudding. r castration:if cattle are to be castrated, it is recommended to castrate calves as early as possible (no later than 1.5 mo and preferably at 1 wk of age), to use the burdizzo method, and to provide appropriate anaesthesia and analgesia (e.g. 3 ml lignocaine 2% in each testicle through the distal pole and 3 mg ketoprofen 10% / kg body weight injected intravenously both 20 min before castration). -main foodborne hazards associated with calf farming are salmonella spp., human pathogenic-verotoxigenic escherichia coli (hp-vtec), thermophilic campylobacter spp., mycobacterium bovis, taenia saginata cysticercus and cryptosporidium parvum/giardia duodenalis. -the prevalence-level of infection and/or contamination of calves with, and further spread of, foodborne pathogens on farms depend on the status and the inter-relationship of different contributing factors that are inherently highly variable. -present knowledge and published data are insufficient to produce a universal risk assessment enabling quantitative food safety categorization/ranking of different types of calf farming systems. -nevertheless, generic principles for risk reductions for the main foodborne pathogens at calf farm level are known and are based on the implementation of effective farm management (e.g. qa, husbandry, herd health plans, biosecurity) and hygiene measures based on gfp-ghp recommendations for future research . it is recommended that future research should be conducted within the following areas: -hemoglobin levels and iron deficiences of veal calves aged 12-24 weeks. -the monitoring of haemoglobin in groups of calves using representative samples -exposure to allergenic proteins -solid and liquid food balance. exposure to too rich diets and changes in feed composition. -space requirements -health monitoring systems and the effect of such on clinical health in calves -infection transmission (respiratory and digestive diseases) due to direct contact between calves in relation to social benefits of mixing -pain relief when disbudding, dehorning and castrating calves -design of appropriate ventilation systems for calves in confined rearing conditions -health and environmental effects of feeding minerals as antimicrobial agents -for quantitative food safety risk categorization of farming systems individually, and/or their related ranking, further scientific information is needed. accordingly, related research should be encouraged. references used in this scientific opinion are available and listed in the scientific report published at the efsa web (www.efsa.eu.int). the ahaw panel wishes to thank the members of the working group chaired by panel member summary efsa has been requested by the european commission to issue a scientific opinion on animal health and welfare aspects of intensive calf farming systems and their ability to comply with the requirements of the well-being of calves from the pathological, zootechnical, physiological and behavioural points of view. in particular the commission asked efsa to update the findings of the scientific veterinary committee (animal welfare section) report on the welfare of calves of 9 november 1995 in light of more recent data on this issue. where relevant the possible food safety implications of different farming systems should also be considered. in this report a risk assessment was made and the relevant conclusions and recommendations are forming the scientific opinion by the ahaw panel. the svc (1995) report contains information on measurements of welfare, needs of calves, descriptions of current housing systems, chapters on types of feed and feeding systems, weaning of calves, housing and pen design, climate, mananimal relationships, dehorning and castration. further chapters covered economical considerations of systems and for improving welfare. in the report conclusions were made on general management, housing, food and water and economics. the present report "the risks of poor welfare in intensive calf farming systems" is an update o the previous svc report with the exception of economical aspects which are outside of the mandate for this report. the various factors potentially affecting calves' health and welfare, already extensively listed in the 1995 report of the scientific veterinary committee animal welfare section (svc, 1995) , are updated and subsequently systematically determined whether they constitute a potential hazard or risk. to the latter end their severity and likelihood of occurrence in animal (sub) populations were evaluated and associated risks to calf welfare estimated, hence providing the basis for risk managers to decide which measures could be contemplated to reduce or eliminate such risks. in line with the terms of reference the working group restricted itself to (in essence a qualitative) risk assessment although it is agreed that welfare and health of calves can be substantially affected in the course of and as a result of transport and slaughter, this report does not consider animal health and welfare aspects of calves during transport and slaughter but such information can be found in a recently issued comprehensive report of the scientific committee on animal health and animal welfare (scahaw), on "the welfare of animals during transport (details for horses, pigs, sheep and cattle)" which was adopted on 11 march 2002 (dg sanco, 2002) and in the efsa report "welfare aspects of animal stunning and killing methods" (efsa, 2004b) . in relation with the food safety aspects, main foodborne hazards associated with calf farming are salmonella spp., human pathogenic-verotoxigenic escherichia coli (hp-vtec), thermophilic campylobacter spp., mycobacterium bovis, taenia saginata cysticercus and cryptosporidium parvum/giardia duodenalis. present knowledge and published data are insufficient to produce a universal risk assessment enabling quantitative food safety categorization/ranking of different types of calf farming systems. nevertheless, the main risk factors contributing to increased prevalence/levels of the above foodborne pathogens, as well as generic principles for the risk reductions are known. the latter are based on the implementation of effective farm management (e.g. qa, husbandry, herd health plans, biosecurity) and hygiene measures (e.g. gfp-ghp). in general, the conclusions made in the previous svc report remain. however, recent research has provided for some additional conclusions. the risk analysis is presented in the tables of annex 2. the graphics in this table are not intented to represent numerical relationships but rather qualitative relations. in some instances the exposure could not be estimated due to lack of data, in which cases the risks where labelled "exposure data not available". the following major and minor risks for poor animal health and welfare have been identified for one or several of the various husbandry systems considered: the hazards of iron deficiency and insufficient floor space are considered to be very serious, the hazard of inadequate health monitoring is considered to be serious and the hazards of exposure to inadequate hemoglobin monitoring, allergenic proteins and too rich diet are considered to be moderately serious. for these hazards, there is no consensus on the exposure of calves mainly due to lack of data and that is why it is recommended that further studies should be made to provide evidence for an exposure assessment. regarding castration and dehorning (and disbudding) without anaesthetic drugs, there is a variation in relation to national legislation why the risk of poor welfare in relation to castration and dehorning has a wide range between countries. tables which clarify the risk assessment have been included in annex 2. calf a calf is a young bovine which is significantly younger and smaller in size than an adult of the same species and breed and which is not reproductively active. there is a gradual transition from a newborn animal, dependent on milk, to an animal with many adult characteristics. few people would use the term calf for domestic cattle of 10 -12 months whilst most would call an animal of 5 months or somewhat older a calf. in this report, calf is used for animals of up to 8 months of age. however, in deciding on the end of the calf stage, any definition based on age or weight is arbitrary. the term calf is not normally restricted to animals that are unweaned or monogastric rather than having some degree of development of the rumen for its specialist function. the removal of the horn bud or the actual horn depending on the breed and the age of the animal. endotoxin unit (eu) endotoxin activity of 0.2 ng of reference endotoxin standard, ec-2 or 5 eu/ng (fda). to convert from eu's into ng, the conversion is 10 eu/ng. a process where water bodies receive excess nutrients that stimulate excessive plant growth (i.e. water pollution). intensively reared calf a calf which is not kept extensively at pasture. according to the council of europe european convention for the protection of animals kept for farming purposes, (chapter i, article 1), "modern intensive animal farming systems are systems in which mainly technical facilities are used that are primarily operated automatically and in which the animals depend on the care of and supply from the farmer". nsaid non-steroidal anti-inflammatory drug. the process by which a mother mammal allows a young animal to obtain milk from its teats. odds ratio (or) the odds ratio is a measure of effect size particularly important in bayesian statistics and logistic regression. infection of the navel. meat produced from animals slaughtered at 28-40 weeks of age and supplied with roughage from at least 2 months of age onwards. there is not any classification system for veal carcasses agreed across the eu. the only existing classification system would rather relate to a general beef carcass classification system, which comprises the following 5 categories: however, these categories are valid for cattle having a live weight of more than 300 kg. consequently, some member states have issued their own national schemes for veal carcass classification. in trade, there is agreement between importing and exporting countries that veal originates from calves which were fed predominantly milk replacers, and which displays a light colour. the age limit is around 8 months. some countries such as the netherlands market meat of animals of the age of 12 to 14 months, as pink veal. the eu subsidies scheme represents an important incentive for pink veal production. the determination of the relationship between the magnitude of exposure of calves to a certain hazards and the severity and frequency of associated adverse effects on calf welfare. the quantitative and qualitative evaluation of the likelihood of hazards to welfare occurring in a given calf population. any factor, occurring from birth to slaughter, with the potential to cause an adverse effect on calf welfare. the qualitative and quantitative evaluation of the nature of the adverse effects associated with the hazard. considering the scope of the exercise of the working group the concerns relate exclusively to calf welfare. the identification of any factor, from birth to slaughter, capable of causing adverse effects on calf welfare. a function of the probability of an adverse effect and the severity of that effect, consequent to a hazard for calf welfare. the process of determining the qualitative or quantitative estimation, including attendant uncertainties, of the probability of occurrence and severity of known or potential adverse effects on welfare in a given calf population based on hazard identification, hazard characterisation, and exposure assessment. unaltered remain the following cac (codex alimentarius commission) definitions (note: for completeness all definitions used by cac -while not necessarily used in this document -have been included): a risk assessment that provides numerical expressions of risk and an indication of the attendant uncertainties (stated in the 1995 expert consultation definition on risk analysis). a risk assessment based on data which, while forming an inadequate basis for numerical risk estimations, nevertheless, when conditioned by prior expert knowledge and identification of attendant uncertainties, permits risk ranking or separation into descriptive categories of risk. a process consisting of three components: risk assessment, risk management and risk communication. a scientifically based process consisting of the following steps: i) hazard identification, ii) hazard characterisation, iii) exposure assessment and iv) risk characterisation. the interactive exchange of information and opinions concerning the risk and risk management among risk assessors, risk managers, consumers and other interested parties. output of risk characterisation. the process of weighing policy alternatives in the light of the results of risk assessment and, if required, selecting and implementing appropriate control options (i.e. prevention, elimination, or reduction of hazards and /or minimization of risks) options, including regulatory measures. a method to examine the behaviour of a model by measuring the variation in its outputs resulting from changes to its inputs. characteristics of a process where the rationale, the logic of development, constraints, assumptions, value judgements, decisions, limitations and uncertainties of the expressed determination are fully and systematically stated, documented, and accessible for review. a method used to estimate the uncertainty associated with model inputs, assumptions and structure/form. the process by which a young mammal obtains milk from the teat of its mother or another lactating female by sucking. the term veal refers to the meat produced from calves, principally those of the species bos taurus and bos indicus. there are several meat products from calves. they are generally distinguished by their colour: "pale" or "white" veal is generally produced from an animal under 6 months of age and fed mostly milk or milk replacer; "pink" veal is generally produced from an animal of up to 8 months fed larger amounts of solid foods and possibly weaned. meat from calves of 8-12 months is called young beef. weaning, weaned in mammals, weaning is a gradual process during which the young animal receives less and less milk from its dam and consumes more and more solid food. it is accompanied by changes in the dam-offspring relation. in farming, calves are often separated from their dams soon after birth and receive milk (or milk replacer) from humans or a machine. although separated from the dam, calves are considered as un-weaned as long as they are fed milk. suckler calves are left with their dam for some months and are generally weaned some time before the next calving by separating them suddenly from the dam. calves normally commence eating solid food at 2-3 weeks, although some start earlier, and they eat enough solid food for development of a functional rumen to start by about 6 weeks of age. a weaned animal is one that no longer needs to suckle and so does not consume milk in any significant quantity indicating that the weaning process has finished. council directive 91/629/eec 1 laying down minimum standards for the protection of calves as amended by council directive 97/2/ec 2 requires the commission to submit to the council a report, based on a scientific opinion, on intensive calf farming systems which comply with the requirements of the wellbeing of calves from the pathological, zootechnical, physiological and behavioural points of view. the commission's report will be drawn up also taking into account socio-economic implications of different calf farming systems. it should be noted that the scientific veterinary committee (animal welfare section) adopted a report on the welfare of calves 3 on 9 november 1995 (svc, 1995) which should serve as background to the commission's request and preparation of the new efsa scientific opinion. in particular the commission requires efsa to consider the need to update the findings of the scientific veterinary committee's opinion in light of the availability of more recent data on this issue. where relevant the possible food safety implications of different farming systems should also be considered. efsa has been requested by the european commission to issue a scientific opinion on animal health and welfare aspects of intensive calf farming systems and their ability to comply with the requirements of the well-being of calves from the pathological, zootechnical, physiological and behavioural points of view. in particular the commission requires efsa to update the findings of the scientific veterinary committee (animal welfare section) report on the welfare of calves of 9 november 1995 in light of more recent data on this issue. where relevant the possible food safety implications of different farming systems should also be considered. the mandate outlined above was accepted by the panel on animal health and welfare (ahaw) at the plenary meeting, on 14/15 march 2005. it was decided to establish a working group of ahaw experts (wg) chaired by one panel member. therefore the plenary entrusted a scientific report and risk assessment to a working group under the chairmanship of prof. bo algers. the members of the working group are listed at the end of this report. this report is considered for the discussion to establish a risk assessment and the relevant conclusions and recommendations forming the scientific opinion by the ahaw panel. according to the mandate of efsa, ethical, socio-economic, cultural and religious aspects are outside the scope of this scientific opinion. in 1995, the scientific veterinary committee of the european commission published the report on the welfare of calves. the svc (1995) report contains information on measurements of welfare, needs of calves, descriptions of current housing systems, chapters on types of feed and feeding systems, weaning of calves, housing and pen design, climate, mananimal relationships, dehorning and castration. further chapters covered economic considerations of systems and for improving welfare. in the report conclusions were made on general management, housing, food and water and economics. the present report "the risks of poor welfare in intensive calf farming systems" is an update of the previous svc report with the exception of economic aspects which are out of the mandate for this report. this report represents an update of the previous svc report (1995) with a risk assessment perspective. factors which are important for calf welfare include housing (space and pen design, flooring and bedding material, temperature, ventilation and air hygiene), feeding (liquid feed, concentrates, roughage) and management (grouping, weaning, human-animal relations). the measures used to assess welfare include behavioural and physiological measures, patho-physiological measures and clinical signs as well as production measures. as explained in the glossary, in this report young bovines are called calves up to a maximum of eight months of age and veal is the meat of a calf. countries with substantial production of veal are france, italy, the netherlands, belgium, spain and germany. significant veal production exists also in portugal, austria and denmark, the production of white veal, from calves that have been fed predominantly milk replacer and which has a light colour, takes place largely in france, the netherlands, belgium and italy. the eu subsidies scheme represents an important incentive for pink veal production. most calves produced for further rearing are in france, germany, uk, ireland and italy. the ways of keeping calves vary considerably from country to country and between breeds. most dairy calves are separated from their dam at birth and artificially fed whereas calves from beef breeds generally suckle their dam. according to eu statistics, in 2004 in the eu (25) 4,499,381 calves were reared for slaughter (table 1) and 20,630,237 calves were reared for other reasons than slaughter (table 2 ). in total (table 3 ) 755,226 tonnes of calf meat were produced in eu (15) which probably implies that about 825,000 tonnes were produced in eu (25) during 2004. human consumption of meat from calves decreased slightly from 1995 to 2001 in eu (15) ( table 4 ). : item and element selected in the eurostat database to make the query and extract the data the working group set out to produce a document in which the various factors potentially affecting calves' health and welfare [already extensively listed in the 1995 report of the scientific veterinary committee animal welfare section (svc, 1995) , are updated and subsequently to systematically determine whether these factors constitute a potential hazard or risk. to the latter end their severity and likelihood of occurrence in animal (sub) populations were evaluated and associated risks to calf welfare estimated, hence providing the basis for risk managers to decide which measures could be contemplated to reduce or eliminate such risks. it should be noted, however, that this does not imply that a hazard that has a serious effect on just a few animals should not be dealt with by managers on farm level as the suffering imposed on some animals constitute a major welfare problem for those individuals. in line with the terms of reference the working group restricted itself to (in essence qualitative) risk assessment, i.e. only one of three elements essential to risk analysis a risk assessment approach was followed, similar to the one generally adopted when assessing microbiological risks, i.e. along the lines suggested at the 22nd session of the codex alimentarius commission (cac, 2002) . incidentally, these guidelines have been characterized by the cac as 'interim' because they are subject to modifications in the light of developments in the science of risk analysis and as a result of efforts to harmonize definitions across various disciplines. cac's guidelines are in essence exclusively formulated for the purpose of assessing risks related to microbiological, chemical or physical agents of serious concern to public health. consequently -considering their disciplinary focus -the working group had to adapt the cac definitions to serve their purpose. these adapted definitions, have, in alphabethical order, been included in chapter 2 (see risk analysis terminology). the objectives of this report are to review and report recent scientific literature on the welfare including the health of intensively reared calves, to report on recent findings as an update to the scientific veterinary committee's previous report, to make a qualitative risk assessment concerning the welfare of intensively kept calves. where relevant, food safety implications of different farming systems are also considered. the report is structured in five major parts. the first three follow the scientific veterinary committee's previous report "on the welfare of calves" with introductory chapters 4-7 on background, measurements and needs in relation to calf welfare, chapter 8 describing housing, diet and management and chapter 9 describing comparison of systems and factors. in chapter 10 common disease and use of antibiotics is described. the other two parts involve aspects of meat quality and food safety (chapter 11) and the risk assessment (chapter 12). conclusions and recommendations from the previous svc document together with updated conclusions derived from recent research findings are presented in the scientific opinion (www.efsa.eu.int). effect of transport and slaughter on calves' health and welfare although it is agreed that welfare and health of calves can be substantially affected in the course of and as a result of transport, this report does not consider animal health and welfare aspects of calves during transport because there is already a comprehensive recent report of the scientific committee on animal health and animal welfare (scahaw), on "the welfare of animals during transport (details for horses, pigs, sheep and cattle)" which was adopted on 11 march 2002 (dg sanco, 2002 . the report takes into account all aspects related with transport that could affect the health and welfare of cattle and calves, including the direct effects of transport on the animals and the effects of transport on disease transmission. the loading methods and handling facilities for cattle, the floor space allowance, the relationships of stocking and the density requirements, the vehicle design, space requirements and ventilation for cattle transporters (see also the ahaw scientific opinion related to standards for the microclimate inside animal road transport vehicles; efsa, 2004), the behaviour of cattle during road transport, the road conditions, long distance transport and the travel times are also reviewed. recommendations for all these aspects are also given in that report. the following general requirements in relation to animal welfare were annexed as a protocol to the eu treaty of amsterdam in 1997: "in formulating and implementing the community's agriculture, fisheries, transport, and internal market policies, the community and the member states shall pay full regard to the welfare requirements of animals, while respecting the legislative provisions and customs of member states relating to religious rites, cultural traditions and regional heritage." in the introduction to the proposed eu constitution, the following extended wording is included: "in formulating and implementing the european union's agriculture, fisheries, transport, internal market, research and technological development and space policies, the union and the member states shall pay full regard to the welfare requirements of animals, as sentient beings, while respecting the legislative provisions and customs of member states relating to religious rites, cultural traditions and regional heritage." this wording reflects the ethical concerns of the public about the quality of life of the animals. it also takes into account customs and cultural traditions. farm animals are subject to human imposed constraints and for a very long time the choice of techniques has been based primarily on the efficiency of production systems for the provision of food. however it is an increasingly held public view that we should protect these animals against mistreatment and poor welfare. in order to promote good welfare and avoid suffering, a wide range of needs must be fulfilled. these needs may require the animal to obtain resources, receive stimuli or express particular behaviours (hughes and duncan, 1988; jensen and toates, 1993; vestergaard, 1996) . to be useful in a scientific context, the concept of welfare has to be defined in such a way that it can be scientifically assessed. this also facilitates its use in legislation and in discussions amongst farmers and consumers. welfare is clearly a characteristic of an individual animal and is concerned with the effects of all aspects of its genotype and environment on the individual (duncan, 1981) . broom (1986) defines it as follows: the welfare of an animal is its state as regards its attempts to cope with its environment. welfare therefore includes the extent of failure to cope, which may lead to disease and injury, but also ease of coping or difficulty in coping. furthermore, welfare includes pleasurable mental states and unpleasant states such as pain, fear and frustration (duncan, 1996; fraser and duncan, 1998) . feelings are a part of many mechanisms for attempting to cope with good and bad aspects of life and most feelings must have evolved because of their beneficial effects (broom, 1998) . although feelings cannot be measured directly, their existence may be deduced from measures of physiology, behaviour, pathological conditions, etc. feelings cannot be directly measured and therefore care is necessary to avoid uncritical anthropomorphic interpretations (morton et al., 1990) . good welfare can occur provided the individual is able to adapt to or cope with the constraints to which it is exposed. hence, welfare varies from very poor to very good and can be scientifically assessed. measures which are relevant to animal welfare during housing, i.e. largely longterm problems, are described by broom and johnson (1993) and by broom (1996 broom ( , 2004a . production criteria have a place in welfare assessment. however, although failure to grow, reproduce etc. often indicates poor welfare, high levels of production do not necessarily indicate good welfare. physiological measurements can be useful indicators of poor welfare. for instance, increased heart-rate, adrenal activity, or adrenal activity following acth challenge, or reduced heart-rate variability, or immunological response following a challenge, can all indicate that welfare is poorer than in individuals which do not show such changes. the impaired immune system function and some of the physiological changes can indicate the pre-pathological state (moberg, 1985) . in interpreting physiological measurements such as heart rate and adrenal activity it is important to take account of the environmental and metabolic context, including activity level. behavioural measures are also of particular value in welfare assessment (wiepkema, 1983) . the fact that an animal avoids an object or event, strongly gives information about its feelings and hence about its welfare (rushen, 1986) . the stronger the avoidance the worse the welfare whilst the object is present or the event is occurring. an individual, whom is completely unable to adopt a preferred lying posture despite repeated attempts will be assessed as having poorer welfare than one which can adopt the preferred posture. other abnormal behaviour which includes excessively aggressive behaviour and stereotypes, such as tongue-rolling in calves, indicates that the perpetrator's welfare is poor. very often abnormal activities derive from activities that cannot be expressed but for which the animal is motivated. for example, calves deprived of solid foods and hence lacking the possibility of nutritive biting, develop non-nutritive biting. whether physiological or behavioural measures indicate that coping is difficult or that the individual is not coping, the measure indicates poor welfare. studies of the brain inform us about the cognitive ability of animals and they can also tell us how an individual is likely to be perceiving, attending to, evaluating, coping with, enjoying, or disturbed by its environment so can give direct information about welfare (broom and zanella, 2004) . in studies of welfare, we are especially interested in how an individual feels. as this depends upon highlevel brain processing, we have to investigate brain function. abnormal behaviour and preferred social, sexual and parental situations may have brain correlates. brain measures can sometimes explain the nature and magnitude of effects on welfare. the word "health", like "welfare", can be qualified by "good" or "poor" and varies over a range. however, health refers to the state of body systems, including those in the brain, which combat pathogens, tissue damage or physiological disorder (broom and kirkden, 2004; broom, 2006) . welfare is a broader term than health, covering all aspects of coping with the environment and taking account of a wider range of feelings and other coping mechanisms than those associated with physical or mental disorders. disease, implying that there is some pathology, rather than just pathogen presence, always has some adverse effect on welfare (broom and corke, 2002 ). the pain system and responses to pain are part of the repertoire used by animals to help them to cope with adversity during life. pain is clearly an important part of poor welfare (broom, 2001b) . however, prey species such as young cattle and sheep may show no behavioural response to a significant degree of injury (broom and johnson, 1993) . in some situations responses to a wound may not occur because endogenous opioids which act as analgesics are released. however, there are many occasions in humans and other species when suppression of pain by endogenous opioids does not occur (melzack et al., 1982) . studies of the brain inform us about the cognitive ability of animals and they can also tell us how an individual is likely to be perceiving, attending to, evaluating, coping with, enjoying, or disturbed by its environment so can give direct information about welfare (broom and zanella, 2004) . in studies of welfare, we are especially interested in how an individual feels. as this depends upon high-level brain processing, we have to investigate brain function. abnormal behaviour and preferred social, sexual and parental situations may have brain correlates. brain measures can sometimes explain the nature and magnitude of effects on welfare. the majority of indicators of good welfare which we can use are obtained by studies demonstrating positive preferences by animals (dawkins, 1990) . methods of assessing the strengths of positive and negative preferences have become much more sophisticated in recent years. the price which an animal will pay for resources, or pay to avoid a situation, may be, for example, a weight lifted or the amount of energy required to press a plate on numerous occasions. the demand for the resource, i.e. the amount of an action which enables the resource to be obtained, at each of several prices can be measured experimentally. this is best done in studies where the income available, in the form of time or energy, is controlled in relation to the price paid for the resource. when demand is plotted against price, a demand curve is produced. in some studies, the slope of this demand curve has been measured to indicate price elasticity of demand but in recent studies (kirkden et al., 2003) it has become clear that the area under the demand curve up to a particular point, the consumer surplus, is the best measure of strength of preference. once we know what animals strongly prefer, or strongly avoid, we can use this information to identify situations which are unlikely to fulfil the needs of animals and to design better housing conditions and management methods (fraser and matthews, 1997) . however, as pointed out by duncan (1978 duncan ( , 1992 , all data from preference studies must be interpreted taking account of the possibilities that, firstly, an individual may show a positive preference for something in the shortterm which results in its poor welfare in the long-term, and secondly, that a preference in a simplified experimental environment needs to be related to the individual's priorities in the more complicated real world. each assessment of welfare will pertain to single individual and to a particular time range. in the overall assessment of the impact of a condition or treatment on an individual, a very brief period of a certain degree of good or poor welfare is not the same as a prolonged period. however, a simple multiplicative function of maximum degree and duration is often not sufficient. if there is a net effect of poor welfare and everything is plotted against time, the best overall assessment of welfare is the area under the curve thus produced (broom, 2001c) . 7 . the needs and functioning of calves 7.1. the concept of needs in assessing the needs and functioning of calves, many different approaches can be taken. one is to study, at a fundamental level, the physiology and behaviour of cattle and the ways in which they have evolved, in order to try to understand their causation and function. needs are in the brain but may be fulfilled by obtaining resources, physiological change, or carrying out a behaviour. in order to conclude that a need exists to show certain behaviour, it is necessary to demonstrate that the calves used in modern production systems are strongly motivated to show the behaviour and that, if the need is not provided for, there are signs of poor welfare such as abnormal behaviour or physiology or pathological effects (see chapter 6). where the housing design allows the animals to show the behaviour that they need to show, this will promote the avoidance of poor welfare. a need is a requirement, which is a consequence of the biology of the animal, to obtain a particular resource or respond to a particular environmental or bodily stimulus. an animal may have a need that results in the existence at all times of mechanisms within the brain and abilities to perceive stimuli and respond appropriately. however, this does not mean that every individual at all times needs to carry out the response. for example, a calf has a need to avoid attack by a predator but it does not need to carry out anti-predator behaviour if no individual perceived as a predator is present. there are some needs which require urgent fulfilment, otherwise the body functioning will be impaired and in the medium or long term, the animal may suffer. for example, an adequate amount of an essential nutrient or avoidance of exposure to a serious disease. there are other needs which, if not fulfilled lead to frustration and excessive activities in an attempt to fulfil the need. the resulting poor welfare may be extreme and prolonged. needs to avoid predation and other danger mean that animals have a negative experience in some situations. close human presence and handling of animals may elicit physiological and behavioural anti-predator responses. the avoidance of such situations can also be considered as a need. calves require space to perform activities such as resting, feeding, exploring, interacting and escaping from perceived danger. to assess what risks of poor welfare are involved when the housing circumstances do not allow certain activities, it can be helpful to consider why the calves are intrinsically motivated to perform the activities. the selection criteria applied to modern cattle genotypes have resulted in changes in morphological phenotype. although these have not altered the categories of needs of calves, they may have altered rates of growth and energy partitioning so that the timing of problems and the probability that they will arise may be changed. the overall need of calves is to maintain bodily integrity while growing and preparing for adult life. in order to do this, calves have a series of needs that are relevant to the housing and management conditions imposed upon them by humans. the needs of calves are described in detail by broom (1991 broom ( , 1996 . in listing needs and in later consideration of how to provide for them, it is assumed that extreme human actions, such deliberately creating a large wound or infecting an animal with a dangerous pathogen, will not occur. the list of needs is not in order of importance. some of the needs mentioned here are discussed at greater length in the previous report. 7.2.1. to breathe calves need air that has sufficient oxygen and a low level of noxious gases in it. calves may be adversely affected by some of the gaseous products of the breakdown of animal faeces and they show preferences that help them to avoid any harm that they may cause. calves need to rest and sleep in order to recuperate and avoid danger. they need to use several postures which include one in which they rest the head on the legs and another in which the legs are fully stretched out (de wilt, 1985; smits, 1989, 1991) . sleep disruption may occur if comfortable lying positions cannot be adopted or if there is disturbance to lying animals because they are trodden on or otherwise disturbed by other calves. exercise is needed for normal bone and muscle development. calves choose to walk at intervals if they can, show considerable activity when released from a small pen and have locomotor problems if confined in a small pen for a long period (warnick et al., 1977; dellmaier et al., 1985; trunkfield et al., 1991) . calves living in natural conditions would be very vulnerable to predation when young. as a consequence, the biological functioning of calves is strongly adapted to maximise the chance of recognition of danger and escape from it. calves respond to sudden events and approaches by humans or other animals perceived to be potentially dangerous with substantial sympathetic nervous system and hypothalamic-pituitary-adrenocortical (hpa) changes. these physiological changes are followed by rapid and often vigorous behavioural responses. fear is a major factor in the life of calves and has a great effect on their welfare. 7.2.5. to feed and drink 7.2.5.1. sucking the calf needs to attempt to obtain nutrients at a very early stage after birth and shows behavioural responses that maximise this chance. as a consequence, from an early age, calves have a very strong need to show sucking behaviour and if a calf is not obtaining milk from a real or artificial teat, it sucks other objects (broom, 1982 (broom, , 1991 metz, 1984; hammell et al., 1988; jung and lidfors, 2001) . the need of the calf is not just to have the colostrum or milk in the gut but also to carry out the sucking behaviour on a suitable object (jensen, 2003) . further, the sucking is of importance for the release of gastrointestinal hormones. it has been shown in calves that oxytocin is released during milk ingestion. the amount released, however, was less in calves drinking their milk from a bucket compared with calves suckling the dam (samuelsson, 1996) . peripheral oxytocin stimulates the release of glucagon from the pancreas whereas central oxytocin increases hunger and the release of gastrointestinal hormones promoting growth (stock et al., 1990; bjã¶rkstrand, 1995) . in the early days after birth, calves are motivated to suck and obtain milk. however, calves also have a need to obtain sufficient water and will drink water even when fed milk. if the temperature is high, calves will drink water if it is available and sick calves will also choose to drink water. if water is not available, over-heated calves and sick calves may become dehydrated. sick calves may become dehydrated even when water is offered. calves with acidosis with or without diarrhoea often lose their suckling reflex. this may also happen in calves with hypoglycaemia and septicaemia (berthold, pers. com). after the first few weeks of life, calves attempt to start ruminating. if they have received no solid material in their diet, calves still try to ruminate but cannot show the full rumination behaviour. in addition to the need to suck when young, calves need to manipulate material with their mouths. they try to do this whether or not they have access to solid material and they will seek out solid material that they subsequently manipulate. (van putten and elshof, 1978; webster, 1984; webster et al., 1985) . calves eat solid food better when water is offered simultaneously. certain rapidly digestible carbohydrates are necessary for the development of ruminal papillae with associated physiological development and fibrous roughage helps the anatomical development of the rumen. so it is clear that calves need appropriate solid food in their diet after the first few weeks of life; first, food that is digested rapidly and provide fatty acids; then fibrous foods. rumen development is enhanced when calves are fed with concentrates, water and roughage such as hay. 7.2.8. to explore exploration is important as a means of preparing for the avoidance of danger and is a behaviour shown by all calves (kiley worthington and de la plain, 1983; fraser and broom, 1990) . exploration is also valuable for establishing where food sources are located. calves need to explore and it may be that higher levels of stereotypes (dannemann et al., 1985) and fearfulness (webster and saville, 1981) in poorly lit buildings or otherwise inadequate conditions are a consequence of inability to explore. 7.2.9. to have social contact 7.2.9.1. maternal contact the needs of young calves are met most effectively by the presence and actions of their mothers. in the absence of their mothers, calves associate with other calves if possible and they show much social behaviour. the need to show full social interaction with other calves is evident from calf preferences and from the adverse effects on calves of social isolation (broom and leaver, 1978; dantzer et al., 1983; friend et al., 1985; lidfors, 1993) . to minimise disease during the first few hours of life, the vigorous attempts of the calf to find a teat and suckle should result in obtaining colostrum from the mother. this colostrum includes immunoglobulins that provide passive protection against infectious agents. hence the needs of the calf have an evident function that is not just nutritional. calves also show preferences to avoid grazing close to faeces. they also react to some insects of a type which may transmit disease. if infected with pathogens or parasites, calves will show sickness behaviour that tends to minimise the adverse effects of disease (broom and kirkden, 2004) . young calves, less than four weeks of age, are not well adapted to cope with stressful events such as handling and transport, often suffering very high rates of mortality and the younger the calves are, the higher their mortality (staples and haugse, 1974; mormã¨de et al., 1982 ) many succumbing to pneumonia or scouring, within four weeks of arrival at the rearing unit (staples and haugse, 1974 ). an inability to mount an effective glucocorticoid response, which is adaptive in the short term, may be a contributing factor to the high levels of morbidity and mortality which occur in young calves (knowles et al., 1997) as may neutrophilia (simensen et al., 1980; kegley et al., 1997) , lymphopaenia (murata et al., 1985) and suppression of the cell mediated immune response (kelley et al., 1981; mackenzie et al., 1997) . to groom grooming behaviour is important as a means of minimising disease and parasitism and calves make considerable efforts to groom themselves thoroughly (fraser and broom, 1990 ). calves need to be able to groom their whole bodies effectively. to thermoregulation calves need to maintain their body temperature within a tolerable range. they do this by means of a variety of behavioural and physiological mechanisms. 7.2.12.1. selection of location when calves are over-heated, or when they detect that they are likely to become over-heated, they move to locations that are cooler. if no such movement is possible, the calf may become disturbed, thus exacerbating the problem and other changes in behaviour and physiology will be employed. responses to a temperature that is too low will also involve location change if possible. 7.2.12.2. body position over-heated, or potentially over-heated, calves adopt positions that maximise the surface area from which heat can be lost. such positions often involve stretching out the legs laterally if lying and avoiding contact with other calves and with insulating materials. if too cold, calves fold the legs and lie in a posture that minimises surface area. 7.2.12.3. water drinking over-heated calves will attempt to drink in order to increase the efficiency of methods of cooling themselves. to avoid harmful chemical agents calves need to avoid ingesting toxic substances and to react appropriately if harmful chemical agents are detected within their bodies. 7.2.14. to avoid pain calves need to avoid any environmental impact or pathological condition that causes pain. the text in this section refers to current situation in eu countries. calf housing in other countries may be different. replacement dairy calves 8.1.1. diet brief description of the diet of replacement heifer calves. this has not really changed since the 1995 report. following birth, calves receive (or should receive) colostrum and are than reared with whole milk or milk replacer. calves are weaned; weaning ages and weaning strategies may differ according to region or country. briefly mention current weaning strategies. calves receive starter and, for example, hay and maize silage to promote rumen development. according to the latest eu regulation on the housing of calves (council directive eu 97/2/ec), group housing is compulsory for calves older than 8 weeks, unless there is any need for isolation certified by a veterinarian. individual housing of rearing calves younger than 8 weeks, is quite common in the european dairy industry. below, the most important housing systems for replacement heifer calves are briefly listed. 8.1.2.1. hutches: partially closed, outside area hutches are made of plywood, plastic or fibre glass. if hutches are made from a synthetic opaque material, this prevents the greenhouse effect inside the hutch and reduces heat stress. if reflective material is used (light coloured), the sun rays are reflected which reduces the risk for overheating. the size of hutches may vary from 1.2-1.5 m width and 2.0-2.4 m length. a layer of sand, e.g. 15 cm gravel or crushed stone can be placed under the calf hutch. litter may be provided preferably as straw, as it provides the warmest surface temperature (panivivat et al., 2004) , but also wood shavings, sawdust or newspapers are used and the layer should be thick enough to provide a comfortable and dry bed. calf hutches provide three different environments, as the inside is dry and protected from the weather and outside the calf is able to get limited exercise and sunlight. the calf can be also position itself half in and half out, getting sunlight and being protected from wind. hutches should be placed where they catch the most sunlight and avoiding hot, windy and wet locations. nevertheless, during hot summer conditions hutches should be placed in a shady area to avoid overheating. in the rear wall, a hole that can be closed provides better air ventilation within the hut in warm weather. in the hutches, the calf can be kept using wire panels in a building with an outdoor run, preferably of more than 2.0 m 2 , enabling some contact to other calves. calves can also be fed outside using a milk bucket support, a dry feed recipient support and a hay rack. other hutch types locate feed and water pails inside the hutch. individual pens are situated in a roofed building. the area should be wellventilated so that the air is dry and fresh, but draught has to be avoided. separation from adult cows is advantageous with respect to disease prevention. pens are either made from hard material with concrete walls or dismountable with three solid sides (i.e. plywood) and an open front (see figure 1 ). walls have to be perforated according to council directive eu 97/2/ec in holdings with more than five calves, which allow at least limited social contact with other calves, one of the key needs of calves. the open front gets fresh air to the calf and makes them easier to feed through a bucket support provided on the front. hardwood is normally used for the floor, which is covered with a litter that is thick enough, dry and clean. totally slatted floors are in use also, made of wood, plastic or metal, but require more care for air temperature. the 0.90 -1.00 m x 1.50 -1.60 m pen can be put 300 mm above the ground allowing for draining and the removal of urine. dismountable individual pens should be designed in such a way that they can be taken apart and stored when they are not needed, and also easily cleaned with a skid-steer loader or small bucket tractor. in case of cold weather, a plywood cover can be placed over the rear portion of the pen to preserve heat produced by the calf. in hot weather, a removable panel at the rear of the shelter can be opened to provide additional air exchange. collective hutches may house a group of between 2 and 6 calves. the hutches are made of synthetic materials or wood. the inside of the hutch is provided with litter and some hay may be put in a rack. roughage is distributed at a feeding barrier and anti-freeze drinking devices are needed if freezing temperatures may occur. with collective hutches fastened on concrete, a good outdoor run has a non-slippery surface. manure and bedding have to be removed manually or the collective hutch has to move over a few metres distance by means of a tractor and guide-blocks. as for the individual hutches, the location has to be chosen carefully to avoid overheating during summer and provide protection from wind and rain entering the hutch during cold seasons, but give as much sunlight as possible. when sufficient straw and proper ventilation is provided these are the most suitable facilities for young replacement heifer calves. if the calves stay there for several months it is necessary to provide a passage on slippery free concrete. if the floor of this passage is quite rough this will prevent slipping. the concrete floor may be replaced by a slatted floor provided that the spacing between slats agrees with the age of the animals. the lying area can be built in different ways and littered with different materials. in the deep litter system, the dung is removed at regular intervals from every few weeks to twice per year. 8.1.2.5. group pens inside another common system for group housing of replacement heifer calves is group housing inside, in straw littered pens usually with 4-6 calves per pen. calves may enter such group housing already after 2 weeks of individual housing. the regulatory change with regard to calf housing together with a general trend towards larger dairy farms has increased the interest in group housing systems for rearing calves during the milk feeding period (hepola, 2003; jensen, 2003) . in addition to systems with small groups of calves (4-6 animals per group) kept on straw and usually bucket-fed, calves are increasingly kept in larger groups (10 up to about 40 calves) with computer-controlled automatic milk feeders. an automatic milk feeder may contain two milking dispensers, and each milking dispenser can be used for about 30 calves. to prevent hierarchic and health problems within the group, calves are grouped with a limited age difference between the animals. calves receive milk replacer according to their needs or ad libitum. when calves are fed according to their needs, a radio-frequency electronic identifier can be used, with a transponder inserted in the collar, in an ear tag, injected under the skin or inside a ruminal bolus swallowed by the animal. the diet of the vast majority of veal calves in the european union is determined by the market demand for "white meat", i.e. meat with low myoglobin content. the production of white veal meat comes from a tradition of fattening calves thanks to a diet based on milk, which is naturally poor in iron, and slaughtering the animals when they are young. nowadays most veal calves are fed milk replacers that contains a variable proportion of milk powder and which iron content is maintained at a low level. this results in relatively low blood haemoglobin levels. an average blood haemoglobin level at slaughter between 4.5 and 5.0 mmol/l is compatible with an acceptable meat colour. as haemoglobin levels increase, the number of animals whose meat is darker in colour increases. in order to prevent calves from having haemoglobin levels that are too low, early in the production phase, the iron supply in the milk replacer fed during the first 7-8 weeks of the fattening period (starter) is usually about 50 ppm, whereas iron supply in the milk replacer fed during the remainder of the fattening period (fattener) is 10 ppm. moreover, blood haemoglobin levels are generally monitored, most intensively upon arrival at the fattening unit, and calves with levels below age-dependent thresholds are treated with iron, either individually or group-wise. thus, blood haemoglobin levels usually gradually decline across the fattening period, and the lowest average levels are supposed to be reached during the last four weeks prior to slaughter. some veal calves are still fed raw milk. in case of dairy breeds, the cows are generally milked and the milk is given to calves in buckets. in case of beef breeds, the calves are led twice a day for suckling their dam or another cow. according to the latest amendment to the annex of council directive 91/629/eec (commission decision 97/182/ec) calves should receive sufficient iron to ensure an average blood haemoglobin of at least 4.5 mmol/l, and calves over two weeks old should be provided daily with some fibrous feed which should increase from 50 to a minimum of 250 grams per day from the beginning to the end of the fattening period. the main types of solid feed given to veal calves differ somewhat between the veal producing countries in europe. in france and italy solid feeds for veal calves usually consist of chopped straw or pelleted dry feed consisting of both fibrous (e.g. straw) and concentrate-like (e.g. cereal) materials. in the netherlands, maize silage is a popular roughage source for white veal calves, provided that the iron content is not too high (an upper limit of 110-120 pp/kg dry matter is generally imposed). maize silage is usually fed in relatively high amounts, with maximum daily amounts of up to 1.5 kg (500 gr dry matter)/calf/day. other feeds used in the veal industry include chopped straw and rolled barley. white veal calves are fattened for approximately 26 weeks in italy and the netherlands, and for 20-22 weeks in france. besides the production of white veal meat, several systems exist across europe that lead to the production of so-called "pink veal meat". the main differences from the more conventional production of white veal are that the calves are reared for a longer period and they receive higher amounts of solid foods. as a consequence the muscles have a higher content of myoglobin, hence the darker colour of the meat. in france, the calves are most often from suckler beef breeds; they are reared with their dam and may be weaned before the end of rearing. in the netherlands, pink veal meat is generally produced from calves of dairy breeds. pink veal calves are weaned at 8-9 weeks of age. after weaning, they receive a diet of ad lib roughage (frequently maize silage) and by-products. pink veal calves are not restricted with regard to dietary iron supply and, consequently, develop normal haemoglobin levels and the associated "red" (pink) meat colour. the age at slaughter can vary from calves of 5-8 months to young bred animals of 8-11 months with the slaughter age of individuals depending on the production rate. these products are labelled to help consumers to distinguish them from white veal meat. in line with the latest eu regulation (council directive eu 97/2/ec), individual housing of veal calves has been officially abolished in the european union. already in the 1980s extensive studies were initiated with the aim to develop a practically feasible husbandry system for group housing of veal calves. at present the systems involve both large and smaller groups. housing of calves is in groups of 2-7 animals, with a slight trend towards larger group sizes (12-20 calves per group). the floor can be bedded with straw or wood shavings but is more commonly made of wooden slats. wooden slats require less labour and straw or woodshavings easily become dirty and wet. calves are kept in individual pens, sometimes called "baby-boxes" for a period of 6-8 weeks upon arrival at the fattening unit to prevent overt preputial sucking thereafter and to be able to monitor more closely the health of calves. baby boxes are usually made of galvanised or wooden partitions placed inside the group pen. in these boxes, calves are bucket-fed individually. after 6-8 weeks, these temporary partitions are removed and calves are free to move around in the pen. calves are fed milk replacer in a trough or in individual buckets. a crucial management procedure associated with trough feeding is the regular re-grouping of calves, to maintain homogeneous groups in terms of calf weight and particularly drinking speed throughout fattening. experimental work confirmed the feasibility of this procedure in that calves could be repeatedly regrouped without effects on their health, growth rate and a number of physiological measures of stress . in this latter study, aggression between calves was rare, and calves seemed to habituate to repeated mixing. individual calves not thriving on milk replacer because of drinking problems, are provided with floating teats or with a teat-bucket. veal calves are sometimes kept in pairs. this type of housing results in less availability of space for movement and social opportunities than in larger groups of calves but is reported to have no disadvantages in health, weight gain and the occurrence of cross-sucking (chua et al., 2002) . suckling veal calves are generally accomodated in small groups. as in the rearing of dairy calves, automatic feeding systems have been extended to veal production systems, particularly since increasingly sophisticated computer technology is becoming available for sensor-aided recognition of individual animals, and to control feeding times and intake. calves are usually housed in large groups (40-80 calves) and receive milk replacer via an automatic feeding machine. with such feeders, calves suck to obtain their milk. the floor generally consists of wooden slats, or concrete in combination with wooden slats. some veal calves are kept on straw bedded floors, or have access to rubber mats or concrete covered by rubber. calf rearing and animal environmental pollution 8.3.1. general introduction in the 1995 report there was a short chapter on calf production and environmental pollution referring to gases (ammonia, nitrous oxide, carbon dioxide). manure resulting from calf production was seen as a fertiliser only. this chapter briefly describes in a condensed way the impact of modern animal calf production affects the environment of the animals. modern animal production is a source of solid, liquid and gaseous emissions which i.a. can be harmful to the animals. solid and liquid manure and waste water contain nitrogen and phophorus which are the most important plant nutrients, but are harmful when applied to agricultural land in excess amounts thereby leading to pollution of ground water by nitrates, surface water with phosphorous causing eutrophication and soil with heavy metals such as zinc and copper which are used as growth promotors in the feed stuff, all of which can affect the animals if returned to them. a third group of potentially hazardous effluents are drug residues, such as antibiotics, which may be present in the excreta of farm animals after medical treatment and which are passed to the environment during grazing or spreading of animal manure where they may conceivably contribute to the formation of antibiotic resistance in certain strains of bacteria. the same risk arises when sludge and waste water from sewage plants containing residues of antibiotics and other drugs from human consumption are discharged as fertiliser in the soil and water body of agricultural land. the most important aerial pollutants from calf rearing systems are odours, some gases, dust, micro-organisms and endotoxins, together also addressed as bioaerosols (seedorf and hartung, 2002) , which are emitted by way of the exhaust air into the environment from buildings and during manure storage, handling and disposal. aerial pollutants can give cause for concern for several reasons. e.g. an animal's respiratory health may be compromised by these pollutants. in fattening units, up to 100 % of all calves may show signs of pneumonia, pleuritis or other respiratory disease within the first three weeks of housing when the calves come together from different herds (see chapter on temperature, ventilation and air hygiene). the travel distance of viable bacteria from animal houses via the air is presently estimated at 250 m (mã¼ller and wieser, 1987) downwind why there is a possible transmission between animal houses. very little is known about the distribution characteristics of dust particles, endotoxins, fungi and their spores, in the air surrounding animal houses. recent investigations showed dispersion of staphylococcae sp. (bioaerosols) up to 500 m (schulz et al., 2004 ) from a broiler barn. the contribution of calf production is presently unknown. it is estimated that calves produce about 5.3 kg fresh manure and 7.5 kg slurry per animal and day. this is a share of 4.6 % in the total amount of fresh manure produced in cattle farming (richter et al., 1992) . manure suspected to contain pathogens such as salmonella should be stored for at least 4 months without adding or removing material and subsequently applied to arable land where it is ploughed in, or it is disinfected before any further use. the second area of concern is the emission compounds such as gases, odours, dust, micro-organisms and other compounds like endotoxins which are regularly present in calf house air where they can cause or exacerbate respiratory disorders in animal and work force. the quantities emitted from calf houses are summarised in seedorf et al. (1998b) there are considerable emission amounts from calf husbandry. the emissions of micro-organisms are higher than from dairy or beef barns but distinctly lower than from pig or poultry production (seedorf et al., 1998a) . the same is true for endotoxins which are one log lower in cow barns but distinctly higher in pig and poultry houses. the dust emissions can be 10 times higher in piggeries and 100 times higher in broiler barns . the ammonia concentration is usually lower than in piggeries or laying hen houses. however this depends greatly on the housing and manure management system. in a us study johnson et al. (2001) reported that cow-calf, stocker and feedlot phases contribute considerable amounts of nitrous oxide and methane to the emissions from cattle production. 9. comparison of systems and factors 9.1. feeding and housing systems, weaning strategies and quality of solid and liquid feed 9.1.1. feeding systems the main potential problems associated with the housing of calves in large groups with automatic feeders include: cross sucking, i.e., non-nutritive sucking of parts of another calf's body (in particular the ears, mouth, navel, udder-base and, in case of bull calves, the scrotum and prepuce) (plath et al., 1998; bokkers and koene, 2001; jensen, 2003) , competition for access to the feeder (jensen, 2003; , and health problems, in particular a high incidence of respiratory disease (maatje et al., 1993; plath et al., 1998; svensson et al., 2000 svensson et al., , 2003 hepola, 2003; engelbrecht pedersen et al., 2005) . a number of factors have been identified that are likely associated with some of these problems, although conflicting results have been reported. cross-sucking is linked with the sucking motivation of calves and, hence, measures to reduce the motivation of calves for non-nutritive sucking may reduce the occurrence of cross-sucking (de passillã©, 2001 ). an increased milk allowance also reduced non-nutritive sucking on a teat as well as cross-sucking in group-housed calves in one experiment (jung and lidfors, 2001 ), but did not affect cross-sucking in another (jensen and holm, 2003) . reducing the milk flow rate decreased nonnutritive sucking on a teat in individually housed calves (haley et al., 1998) , but failed to influence cross-sucking in group-housed ones (jung and lidfors, 2001; jensen and holm, 2003) . alternatively, it has been suggested that hunger may also control the level of non-nutritive sucking and possibly cross-sucking (jensen, 2003) . this idea is consistent with the observations that the duration of unrewarded visits to an automatic feeding station increased during gradual weaning (jensen and holm, 2003) , and that under practical farm conditions the frequency of cross-sucking among dairy calves around weaning is increased with decreasing availability or energy density of solid feeds (keil et al., 2000; keil and langhans, 2001) . in contrast to other calves, white veal calves are not weaned, receive large amounts of milk replacer and usually obtain only restricted amounts of solid food. these additional factors may also affect and perhaps exacerbate crosssucking in systems with an automatic feeder (jensen, 2003) . results by veissier et al. (2002) showing that bucket-fed group-housed veal calves show less cross-sucking than those fed by an automatic feeder again seem to implicate factors other than sucking motivation per se in the development and expression of cross-sucking. on the other hand, rearing calves in large groups with an automatic feeder allows more interactions between calves and offers calves the possibility to suck milk. competition for access to an automatic milk feeder was increased in groups of 16 or 24 calves in comparison with groups of 8 or 12, respectively (herrmann and knierim, 1999; jensen, 2004) , and under dietary conditions of relatively low milk allowance and reduced milk flow rate (jensen and holm, 2003) . protecting calves from displacement at the feeder may also be accomplished by fitting a closed feeding stall to the station (weber and wechsler, 2001) . in comparison with the usual setup, this modification increased the duration of visits to the feeder as well as the duration of non-nutritive sucking on the teat after milk ingestion, and significantly reduced the frequency of cross-sucking within 15 minutes after milk ingestion. however, the incidence of cross-sucking performed without prior milk ingestion was not affected by the design of the feeder (weber and wechsler, 2001) . in a recent comprehensive review, jensen (2003) observes that there is a lack of knowledge on the effect of different weaning methods on cross-sucking. she also concludes that future research should focus on preventive measures to reduce cross-sucking and problems with aggression in automatically fed calves, including the establishment of appropriate numbers of calves per feeder. the apparent increase in health problems of calves kept in large groups with automatic feeders might be related to group size rather than to feeding system. a comparison of two different group sizes of calves fed by an automatic milk feeder showed that calves housed in groups of 12-18 had a higher incidence of respiratory illness and grew less than calves housed in groups of 6-9 (svensson and liberg, 2006) . similarly, placement of preweaning heifer calves in groups of 7 or more was associated with high calf mortality in a large scale epidemiological survey (losinger and heinrichs, 1997) . interestingly, in a study by kung et al. (1997) , group-housed calves fed by an automatic feeding system for milk supply had fewer days of medication than those kept individually in separate calf hutches. these authors also emphasize the importance of good management and frequent observations of calves as an integral part of a successful rearing program. likewise, howard (2003) specifically links good and correct management practices with the prevention of disease and successful group housing of dairy calves. natural weaning in cattle takes place when young animals are around 8-9 months of age. depending on productive system, weaning can usually occur between 1 and 10 months of age. dairy calves are usually reared away from their dams and they are given milk or milk replacer until weaning at 6 to 8 weeks of age. however holstein calves can be weaned at 3 to 5 weeks of age (early weaning). beef calves are usually weaned at 6 to 10 months of age depending on season of birth. early weaning of beef calves may be considered as a management practice in poor climate conditions and where forage quality is poor later in the grazing season. several studies have shown that it is possible to wean calves at very young ages based on concentrate intake (svc, 1995) . however, regardless of the productive system, weaning is effective and does not cause health and welfare problems to calves when it occurs as a smooth transition from an immature to mature ruminant with an adequate size and development of the reticulo-rumen for efficient utilisation of dry and forage based diets. at birth, the reticulum, rumen, and omasum of the calf are undeveloped, nonfunctional and small in size compared to the abomasum and rumen remains underdeveloped during the first 2-3 months of age. calves being ruminant animals require a physically and functionally developed rumen to consume forages and dry feeds. however, the rumen will remain undeveloped if diet requirements for rumen development are not provided. solid feed intake stimulates rumen microbial proliferation and production of microbial end products, volatile fatty acids, which initiate rumen epithelial development . solid feeds are preferentially directed to the reticulo-rumen for digestion, however they differ in efficacy to stimulate rumen development. recent studies have shown that addition of yeast culture (2%) increased calf grain intake, but did not affect rumen development in young calves ; while papillae length and rumen wall thickness were significantly greater in 4 week old calves fed calf starters containing steamflaked corn over those fed dry-rolled and whole corn when these corn supplements made up 33% of the calf starter showing that the type of grain processing can influence rumen development in young calves. forages seem to be the primary stimulators of rumen muscularization development and increased rumen volume (zitnan et al., 1998) . large particle size, high effective fibre content, and increased bulk of forages or high fibre sources physically increase rumen wall stimulation, subsequently increasing rumen motility, muscularization, and volume coverdale et al., 2004) . besides, solid feeds other than forages or bulky feedstuffs can be effective in influencing rumen capacity and muscularization. coarsely or moderately ground concentrate diets have been shown to increase rumen capacity and muscularization more than finely ground or pelleted concentrate diets, indicating that extent of processing and/or concentrate particle size affects the ability of concentrates to stimulate rumen capacity and muscularization (beharka et al., 1998; greenwood et al., 1997) . therefore, it seems that concentrate diets with increased particle size may be the most desirable feedstuff for overall rumen development, due to their ability to stimulate epithelial development, rumen capacity, and rumen muscularization . calf weaning should be based on the amount of dry feed calves ingest per day, not on their age or weight, and calf starter should be made available five to 10 days after birth. but, as pointed out from recent research attention must paid to type of forage and consistent of particle size of starter grain in order to achieve a proper rumen development. a calf consuming 0.7 kg of dry feed or more on three consecutive days is ready for weaning. when calves are fed low levels of milk to encourage early consumption of dry food, weaning can be done abruptly. in contrast, if milk is given in large amounts, weaning may require two to three weeks of slow transition to avoid a setback in growth. early weaning systems should not be used if the animals are in a negative energy balance. 9.1.3. quality of solid and liquid feed 9.1.3.1. solid feed: concentrates and roughage traditionally, veal calves were fattened on a diet consisting exclusively of milk replacer. calves fed in this manner show a number of welfare problems (reviewed in the previous report), including abnormal behaviours and disease associated with lack of rumen development. to better safeguard the welfare of calves, provision of (some) solid feed to veal calves has become compulsory according to the latest amendment to the annex of council directive 91/629/eec (commission decision 97/182/ec). however, provision of roughage to veal calves fed a regular milk replacer diet, has clearly been demonstrated to increase the incidence of abomasal ulcers, in particular in the pyloric part (which connects to the duodenum) (wensink et al., 1986; welchman and baust, 1987; breukink et al., 1991) . thus, recent studies have largely focussed concurrently on the effects of provision of roughage on calf behaviour, abomasal lesions and rumen development, in an attempt to identify feeds that may benefit veal calf welfare without compromising abomasal integrity. in a comprehensive eu-funded project, a range of different types of roughage/solid feeds (straw, maize silage, maize cob silage, rolled barley and beet pulp) in different amounts (250 versus 500 gr dry matter) and of different particle sizes and physical characteristics (i.e., chopped versus ground, dried versus fresh, un-pelleted versus pelleted) were given to veal calves in addition to milk replacer in large-scale multifactorial trials (chain management of veal calf welfare, 2000; cozzi et al., 2002; mattiello et al., 2002) . control treatments consisted of milk replacer only, and milk replacer with ad lib access to hay. another control group consisted of bull calves reared in a similar way to normal dairy calves, i.e. the animals received ad libitum hay and concentrates and were weaned at 7 weeks of age. in comparison with milk replacer only, those types of roughage that were richest in fibrous material, i.e. straw (regardless of amount and physical structure) and hay, significantly reduced the level of abnormal oral behaviours (composed of tongue rolling, tongue playing and compulsive biting/sucking of substrates), and concomitantly increased the level of rumination. weaned calves exhibited no abnormal oral behaviours. higher levels of rumination in veal calves as a function of the fibre content of the solid feed were also reported by morrisse et al. (1999 morrisse et al. ( , 2000 . in line with these findings, veissier et al. (1998) , observed reduced levels of biting at substrate and more chewing behaviour in veal calves provided with straw compared with un-supplemented controls. previously, it has been suggested that a sucking deficit causes abnormal oral behaviours in calves (sambraus, 1985) . more recent data, however, clearly identify the lack of appropriate roughage as a major determinant of abnormal oral behaviours in veal calves. correspondingly, bokkers and koene (2001) found no differences in abnormal oral behaviours between group-housed veal calves fed either by bucket or by an automatic feeder. results obtained in veal calves are also fully consistent with data in cows (redbo et al., 1996; redbo and nordblad, 1999) and other ruminants such as giraffes (baxter and plowman, 2001) , which all link increased levels of abnormal oral behaviours with feeds poor in fibre. in agreement with previous data, most roughages provided to milk-fed veal calves significantly increased the incidence of abomasal lesions, particularly ulcers in the pyloric region, in comparison with the feeding condition without additional roughage (chain management of veal calf welfare, 2000; . incidences of abomasal ulcers (expressed as the percentages of calves with one or more lesions) among weaned bull calves, calves fed milk only, and veal calves given supplemental roughages were 0, between 20-25, and between 50-80%, respectively. this suggests that the interaction between roughage and a milk replacer diet rather than roughage per se, is involved in the etiology of abomasal ulcers in veal calves. these findings support the hypothesis that pyloric ulcers in milk-fed veal calves may be caused by local ischaemia followed by focal necrosis as a consequence of strong contractions of the pyloric wall when large volumes of milk are consumed. provision of roughage, in turn, would then exacerbate an existing problem in that roughage particles exert a mechanically abrasive effect on a sensitive abomasal mucosa, and delay the healing of any lesions already present (unshelm et al., 1982; dã¤mmrich, 1983; krauser, 1987; welchman and baust, 1987; breukink et al., 1991) . this explanation may also fit the observations that veal calves fed either hay or a combination of concentrates and straw exhibited similar incidences of abomasal ulcers to those fed milk replacer only (chain management of veal calf welfare, 2000; veissier et al., 1998) . these roughages represent more balanced feeds, accompanied by better rumen fermentation. this may have improved ruminal digestion of fibres, thereby preventing sharp undigested particles entering the abomasum. other factors proposed or examined in relation to the pathogenesis of abomasal ulcers in calves include stress, infection with bacteria, trace mineral deficiencies, and prolonged periods of severe abomasal acidity (lourens et al., 1985; mills et al., 1990; jelinski et al., 1995; de groote et al., 1999; palmer et al., 2001; ahmed et al., 2001 ahmed et al., , 2002 ahmed et al., , 2005 . however, so far none of these factors have been convincingly related to abomasal ulcers in veal calves. calves fed milk only, showed a high incidence of ruminal hairballs. in different experiments between 70-80% of milk-fed veal calves had hairballs (chain management of veal calf welfare, 2000; cozzi et al., 2002) . feeding roughage gave a profound reduction of hairballs; depending on the type of roughage the incidence varied between 0-30 %. similarly, morisse et al. (1999) reported a marked reduction of ruminal hairballs in calves fed pelleted straw and cereals. this reduction was thought to result from a continuous elimination of ingested hair by improved ruminal motility. however, it may well be that abnormally high self-licking behaviour is reduced when roughage is provided. it is suggested that further optimising the composition of roughage in terms of adequate rumen development and rumen function, may eventually result in feeds that promote rumination and reduce abnormal oral behaviours without damaging the digestive apparatus (chain management of veal calf welfare, 2000; morisse, 2000; mattiello et al., 2002) for all newborn calves, receiving an adequate amount of high quality colostrum is essential for their health and survival. in comparison with mature milk, colostrum contains greater concentrations of total solids and of fat, protein, vitamins and minerals. most importantly, colostrum provides the calf with immunoglobulins (igg), which are vital for its early immune protection. in addition, colostrum contains a range of other non-nutrient and bioactive components including various types of cells, peptide hormones, hormone releasing factors, growth factors, cytokines and other bioactive peptides, oligosaccharides and steroid hormones. these factors modulate the microbial population in the gastrointestinal tract, have profound effects on the gastrointestinal tract itself (e.g. cell proliferation, migration, differentiation; protein synthesis and degredation; digestion, absorption, motility; immune system development and function), and in part exert systemic effects outside the gastrointestinal tract on metabolism and endocrine systems, vascular tone and hemostasis, activity and behaviour, and systemic growth (waterman, 1998; blum, 2006) . the highest quality colostrum, or true colostrum, is obtained from the very first milking after parturition. thus, provision of first colostrum to newborn calves is one critical factor for successful calf rearing. the timing of provision of colostrum is also crucial since the ability of the calf's small intestine to absorb large proteins such as igg decreases rapidly following birth. consumption of sufficient colostrum within the first 24 h of life is needed not only for an adequate immune status but also to produce the additional important and favourable effects on metabolic and endocrine traits, and on vitality. finally, colostrum should be regularly provided for a sufficient length of time, preferably for the first three days after birth (hadorn et al., 1997; waterman et al., 1998; rauprich et al, 2000) . although the importance of colostrum for calf health and survival is generally recognized, actual practices in calf rearing do not always favour adequate colostrum intake in newborn calves, and may therefore pose a risk for their welfare. after the period of colostrum feeding, calves can be switched to whole milk or a high quality milk replacer. in the case of rearing calves, both sources of liquid feed are used, although the majority of dairy calves are currently reared on a milk replacer diet. milk replacers are usually less costly than saleable whole milk, and the feeding of raw waste milk may pose several health and contamination risks, including the transfer of infectious diseases to the calf, and problems with antibiotic residues or overdoses (wray et al., 1990; selim and cullor, 1997; waltz et al., 1997) . at present, good quality milk replacers may provide comparable performance to whole milk. however, pasteurization of waste milk prior to feeding it to calves may also represent an effective and viable alternative for minimizing health risks (stabel et al., 2004) . results from a recent clinical survey by godden et al. (2005) even suggested that dairy calves fed pasteurized waste milk have a higher growth rate and lower morbidity and mortality rates than do calves fed conventional milk replacer. with the exception of production systems involving suckler cows, veal calves are generally fattened on milk replacer diets. over time, formulations of commercially available milk replacers for veal calves (as well as those for dairy calves) have become more and more sophisticated. at the same time, economic pressures continuously prompt the industry to reduce feeding costs and to consider alternative components and raw materials. originally, proteins in milk replacers were milk-based, and skim milk powder constituted the major protein source. subsequently, milk replacers based on whey powder became available. approximately during the last two decades, attempts have been made to replace animal-based proteins in milk replacers by vegetable proteins, mainly from soybean and wheat and, to a lesser extent, pea and potato. initially, some of these attempts met with little success because of health problems in the calves. for example, compared to calves fed diets based on skim milk powder, calves fed milk replacers containing heated soybean flour developed severe immunemediated gut hypersensitivity reactions characterized by partial atrophy of the small intestinal villi, malabsorption, diarrhoea, and large infiltrations of the small intestine by immune cells, accompanied by the presence of high antibody titres against soy antigens in plasma and intestinal mucous secretions (lalles et al., 1995a (lalles et al., , 1995b (lalles et al., , 1996 (lalles et al., , 1998 dreau et al., 1995; dreau and lalles, 1999) . however, the nutritional utilization of vegetable proteins can be improved by a variety of technological treatments including, for example, heating, protein hydrolysis, and ethanol extraction. such treatments reduce anti-nutritional factors and antigenic activity, and increase protein digestibility by denaturing three-dimensional structures (lalles et al., 1995c (lalles et al., , 1995d . at present a number of processed plant proteins are successfully applied in combination with milkbased protein sources in milk replacers for (veal) calves, including hydrolysed soy protein isolate and hydrolysed wheat gluten. recent research in the area of plant proteins in milk replacer formulas is focussed on understanding mechanisms underlying the flow of proteins in duodenal digesta, and the interaction of dietary peptides with the gut, in particular at the level of the mucus layer (montagne et al., 2001 (montagne et al., , 2003 (montagne et al., , 2004 . results of this type of work may further enhance the use of plant proteins in milk replacers for calves. in addition to an enhanced risk for gut problems, low quality milk replacers may also cause dysfunction of the oesophageal groove reflex, which may result in ruminal acidosis. in this respect, temperature is also an important quality feature; a too cold drinking temperature of the milk replacer attenuates the oesophageal groove reflex (gentile, 2004) . if vegetable proteins are not properly treated, milk replacers may cause hypersensitivity reactions in the gut, which may compromise calf welfare. low iron dietary supply is a prerequisite for the production of white veal. the blood haemoglobin level in veal calves towards the end of fattening (between 4.5 and 5.0 mmol/l), is generally considered a threshold below which iron deficiency anaemia occurs (bremner, 1976; sprietsma, 1979a, 1979b; postema, 1985; lindt and blum, 1994a) , although some authors have argued that this level is already below a critical value (welchman et al., 1988) . when calves were forced to walk on a treadmill, those with a mean haemoglobin level of 5.5 mmol/l consumed more oxygen and exhibited higher cortisol levels after walking than calves whose haemoglobin level was 6.6. or 6.9 mmol/l (piguet et al., 1993) . on the other hand, blood lactate after transport was not significantly different between groups of calves with average haemoglobin levels of 4.6 and 6.6. mmol/l, respectively (lindt and blum, 1994b) . there is a large body of evidence showing that iron deficiency anaemia may compromise immunocompetence, in particular cellular immune function, in a range of species including laboratory rodents and humans (dallman, 1987; dhur et al., 1989; galan et al., 1992; latunde-dada and young, 1992; ahluwalia et al., 2004) . in human children, iron-deficiency states have been epidemiologically associated with increased morbidity due to respiratory infection and diarrhoea (keusch, 1991; de silva et al., 2003; levy et al., 2005) . this justifies the question of whether dietary iron supply and associated haemoglobin levels are sufficient to guarantee adequate health in white veal calves. previous results concerning the relationship between clinical health and anaemia in veal calves are scarce, and were inconclusive. using very small numbers of calves, mã¶llerberg and moreno-lopez (1975) found no difference between iron anaemic and normal calves in the clinical response to infection with an attenuated parainfluenza-3 virus strain, whereas sã¡rkã¶zy et al. (1985) reported a depressed immune response as reflected in significantly lower antibody levels in anaemic calves compared with controls following inoculation with a live adenovirus. in a study by gygax et al. (1993) , cellular immune function was depressed, and disease incidence, especially of respiratory infections, was increased in calves fed low amounts of iron. however, in this particular study, haemoglobin levels dropped considerably below the value of 4.5 mmol/l. a more recent study (van reenen et al., 1999) , therefore, aimed to examine immunocompetence in a bovine herpes viral (bhv1) infection model in white veal calves with blood haemoglobin levels maintained at all times above or just at 4.5 mmol/l. calves daily supplemented with extra iron exhibited normal haemoglobin levels across the entire experiment (average approximately 7.5 mmol/l), whereas white veal calves had average haemoglobin levels at the time of bhv1 infection and at slaughter of approximately 5.3 and 4.9 mmol/l, respectively. dietary iron supply did not affect the reactions of calves to bhv1 infection (clinical signs, viral excretion in nasal fluid, antibody reponse), white blood cell and lymphocyte counts, and growth rate. by contrast, in comparison with calves with high haemoglobin levels, white veal calves exhibited a higher heart rate during milk intake, had consistently elevated levels of urinary noradrenaline, and showed enhanced plasma acth and reduced plasma cortisol responses in a number of hpa axis reactivity tests. these latter findings concur with increased heart rate and catecholamines in urine, and altered responsiveness of the hpa axis in iron-deficient or anaemic humans and laboratory rodents (voorhess et al., 1975; dillman et al., 1979; dallman et al., 1984; groeneveld et al., 1985; saad et al., 1991) . these physiological changes are part of an elaborate adaptive response to iron deficiency (beard, 1990; rosenzweig and volpe, 1999) , which also involves alterations in glucose metabolism (blum and hammon, 1999) . veal calves with blood haemoglobin levels clearly below 4.5 mmol/l demonstrated reduced growth rates as well as a large depression in white blood cell and lymphocyte counts (reece and hotchkiss, 1987; gygax et al., 1993) . thus, it is suggested that maintaining blood haemoglobin in individual veal calves over 4.5 mmol/l induces a number of physiological adaptations which seem universal for iron-deficient mammals in general, but do not harmfully compromise biological capacities in terms of growth and immunocompetence. in actual practice, however, the haemoglobin threshold of 4.5 mmol/l is currently considered at the group rather than at the individual level. for example, an average haemoglobin level of 4.5 mmol in a group of finished veal calves is assumed to be exactly at the lower threshold value. however, depending on the variation between individuals, if a group of calves has an average haemoglobin level of 4.5 mmol/l, then some individuals within that group may have levels well below this lower threshold value. in fact, based on an analysis of the variation between calves in blood haemoglobin levels, it has been argued that the haemoglobin threshold for anaemia of a group of veal calves should be higher than that of an individual calf, i.e. an average level of 6.25 rather than 5 mmol/l (van hellemond and sprietsma, 1979a) . in order to prevent anaemia during fattening, blood haemoglobin levels are monitored to some extent in white veal calves, and animals are treated with supplemental iron according to age-dependent haemoglobin thresholds. however, systematic monitoring generally occurs only on two occasions: within the first 2-3 weeks upon arrival at the fattening unit, in all animals, and between 12-14 weeks of fattening, in a sample of calves. outside these instants, individual calves may receive iron supplementation in the presence of clinical signs of iron deficiency. but once clinical signs are apparent, haemoglobin levels are usually well below 4.5 mmol l -1 (blaxter et al., 1957; bremner et al., 1976) . since blood haemoglobin levels are not routinely monitored in veal calves beyond the 14 th week of fattening, there is a likelihood of too low haemoglobin levels occurring in part of the animals, in particular towards the end of fattening, when low haemoglobin levels are most likely to occur. general housing calves kept indoors are housed in an environment where several important factors interact such as space, pen design, social contacts, flooring and bedding material as well as climate. in experimental studies, usually one or a few of these factors are varied and the others controlled for. however in larger epidemiological studies many of these factors vary and their interaction can be measured. in a study of 3081 heifer calves in 122 swedish dairy herds the effect of draught, cleanliness of the animals, hygiene level of the farm, placing of the calf pens, nature of the pen walls, air volume per animal, management factors such as status of the caretaker and feeding routines was evaluated by means of a two-level variance component logistic model. the placing of calf pens along an outer wall was significantly associated with the risk of diarrhoea (odds ratio (or): 1.92, p<0.01), the risk for respiratory disease was significantly associated with an ammonia concentration below 6 ppm (or: 0.42, p<0.05) while the or for moderately to severely increased respiratory sounds was significantly associated with draught (or: 3.7, p<0.02) (lundborg et al., 2005) . odds ratios for respiratory disease were increased in calves housed in large-group pens with an automatic milk-feeding system (or: 2,2) . the 1995 report highlights that the housing systems of calves and the available space affect the development and determine which behaviours the animals are able to perform. the 1995 report (svc, 1995) recommends the minimum space for both single crate and group pen and it points out how lack of space can affect health and welfare of reared calves (maatje and verhoeff, 1991; dantzer et al., 1983; friend et al., 1985) . the 1995 report also suggests that shape of the pen can be important to the animal. recent studies confirmed that the space available can affect both behavioural and physiological traits and productive performances of cattle. however, the majority of them compare behaviour, production or other indicators of calves reared in individual crates versus group pens (vessier et al., 1998; andrighetto et al., 1999; jensen, 1999; verga et al., 2000; cozzi et al., 2000; bokkers and koene, 2001) or tethered or single pen (terosky et al., 1997; wilson et al., 1999) which were already discussed in chapter 8. little research has been done to directly compare behavioural and physiological indicators of welfare in calves reared in pens of various space allowances. in dairy calves it has been shown that spatial environment stimulated play: calves in small group pens performed less locomotory play that the ones kept in larger pens (jensen et al., 1998; jensen and kyhn, 2000) . it has been reported in a preliminary study that dairy calves kept, from birth to 1 month of life in larger stalls (1.00 m x 1.50 m) showed a higher percentage of lying behaviour and grooming than calves kept in smaller stalls (0.73 m x 1.21 m); besides, lymphocyte proliferation was significantly higher in calves reared in large stalls (ferrante el al., 1998) . it is known that cattle prefer to use the perimeter of pens rather than the central area (stricklin et al., 1979; hinch et al., 1982; fraser and broom, 1997) . the ratio between the number of corners in the pen and number of animals seems to influence the individual space, the space that calves try to keep to other calves, as showed by simulation models (stricklin et al., 1995) . therefore pen shapes maximising the perimeter to area ratio might be preferable for cattle (jã³hannesson and sã¸rensen, 2000) . for this reason it has been pointed out that measurements such as pen perimeter, the number of corners and the diagonal distance of the pen could be important for dairy cattle (jã³hannesson and sã¸rensen, 2000) . however there is a lack of knowledge on this topic on calves. in a study on veal calves most of the animals lying next to the wall, the quieter and drier part of the pen, stood more on the side of the far pen and eliminated in the feeding area (stefanowska et al., 2002) . calves kept in a large group (26 animals) and fed using an automatic milk replacer showed an elevated use of the area around the partition of the pen and they spent little time in the centre of the area. (morita et al., 1999) , this use of the pen space could lead to a pen design functionally divided into a walking and feeding area and a lying area. the 1995 report concludes that slatted floors must not be slippery, it also recommends appropriate bedding, for example straw, and that every calf should have access to a dry lying area. the report highlights that housing and management conditions can affect the posture adopted when lying and resting in calves. 9.4.1. recent findings regarding importance of floor and bedding materials slatted floors have been used for many years as convenient for intensive housing for beef cattle but concerns have been expressed about their effects on animal welfare (scahaw, 2001) . the type of surface not only affects the movements of getting up and lying down, lying and resting behaviour of the fattening animals but also other behavioural traits and physiological indicators of stress (scahaw, 2001) . moreover when cattle can choose between different floor types they prefer deep litter to slatted floor especially for resting. many studies were conducted in order to analyse the floor comfort in the lying area in dairy and in beef cattle (for a list of references see tuyttens, 2005; scahaw, 2001) . the group pens for veal calves do not have separate lying areas and therefore the animals spend all their time on the same surface. if the floor is too hard for lying or too slippery, discomfort, distress and injury may result. a suitable floor is very important for calves as adequate rest is essential for the good welfare of young growing animals, moreover a positive correlation between the amount of rest and growth rates has been observed for growing cattle (mogensen et al., 1997; hanninen et al., 2005) . adequate resting is important both for sleep and temperature regulation. veal calves are often housed on slatted floors, commonly made of hardwood, a product that is controversial because it often comes from unsustainable forestry in tropical countries (stefanowska et al., 2002) , or on concrete floors due to the fact that bedding material is costly and requires more labour and can cause problems in manure handling systems. wooden slatted floors can absorb liquid from manure and a wet surface is not comfortable for moving and lying (verga et al., 1985) . even if straw bedding provides better floor comfort to animals than slatted or concrete floors, suitable alternatives to reduce or eliminate the use of straw bedding are available for cattle (tuyttens, 2005) . recent studies have investigated the effect of the texture (how soft) and the thermal properties of floor on lying postures and resting behaviour of calves. in cool or drafty floors calves spent less time resting on the side and rest curled up in order to conserve heat (hanninen et al., 2003) . in contrast with adult dairy cows which rested longer and lay down more frequently on softer floors, there was no effect of type of floor (concrete floor or rubber mats) on resting behaviour of dairy calves (hanninen et al., 2005) . in another experiment where veal calves could choose to use a hardwood slatted floor surface or a synthetic rubber coated floor surface the calves preferred the wooden floor for lying (stefanowska et al., 2002) . moreover the animals rested in the drier part of the pen (stefanowska et al., 2002) . from these studies it seems that the texture of the floor is not as important to calves as to older animals, whereas thermal comfort seems to affect lying and lying postures. panivivat et al. (2004) investigated growth performance and health of 60 dairy calves bedded with five different types of materials (granite fines, sand, rice hulls, long wheat straw, wood shavings) for 42 days during august to october from birth. overall average daily gain and dry matter intake of calves did not differ with bedding type, although during week 2, calves housed on rice hulls had the greatest dry matter intake and those housed on wood shavings had the lowest. during week 2, calves housed on granite fines and sand were treated more often for scours, and calves housed on long wheat straw received the fewest antibiotic treatments (week by bedding material interaction). granite fines formed a harder surface than other bedding, and calves housed on granite fines scored the dirtiest. long wheat straw had the warmest surface temperature, and rice hulls and wood shavings were warmer than granite fines and sand. serum cortisol, alpha (1)-acid glycoprotein, immunoglobulin g concentrations, and the neutrophil:lymphocyte ratio were not affected by bedding type. on day 0, coliform counts were greatest in rice hulls. after use, coliform counts were greatest in long wheat straw (week by bedding material interaction). growth rates of calves bedded for 42 d with 5 bedding types did not differ; however, the number of antibiotic treatments given for scours was greatest on granite fines and sand; coliform counts in the bedding were highest in rice hulls before use and in long wheat straw after 42 days of use. degree of social contact the 1995 report recommends that calves are cared for by their dam after birth so that they are licked and receive colostrum and that calves are not deprived of social contact, especially with other calves because 1) calves for social contacts; 2) calves isolated from other calves express more abnormal activities (e.g. excessive grooming, tongue rolling), are hyper-reactive to external stimuli and their subsequent social behaviour is impaired; and 3) in combination with restricted space or lack of straw, individual housing induces a chronic stress state as assessed through enhanced responses to an acth challenge. 9.5.1. recent findings regarding contacts with the dam the bond between dam and calf is likely to develop very soon after birth: calves separated from their dam at 24h can recognise the vocalizations of their own dam one day later (marchant-forde et al., 2002) in their review about early separation between dairy cows and calves, flower and weary (2003) conclude that, on the one hand, behavioural reactions of cows and calves to separation increase with increased contacts but, on the other hand, health and future productivity (weight gain for the calf, milk production for the cow) are improved when the two animals have spent more time together. calves reared by their dam do not develop cross-sucking while artificially reared calves do so (margerison et al., 2003) . the provision of milk through a teat, a long milk meal, and the possibility to suck a dry teat can decrease non-nutritive sucking in artificially reared calves but do not abolish it (review by jensen, 2003; lidfors and isberg, 2003; veissier et al., 2002) . the presence of adult cows other than the dam do not help calves to get accustomed to new rearing conditions, as observed by schwartkorf-genswein et al. (1997) for calves submitted to feedlot conditions. 9.5.2. recent findings regarding contacts with other calves recent studies confirmed that calves are motivated for social contact. such a motivation was shown using operant conditioning by holm et al. (2002) ; furthermore calves that are housed individually engage in more contacts with their neighbours than calves housed in pairs (raussi et al., 2003) . the presence of a companion can reduce emotional responses of calves. this, for instance, is the case when group housed calves are exposed to a novel situation like a novel object (boivin et al., 1999) , a novel arena (jensen et al., 1997) , a sudden event (veissier et al., 1997) , or a lorry (lensink et al., 2001) . humans are not a good substitute for social contacts. individually housed calves interact more with their neighbours compared with pair-housed calves, even when they receive additional contacts from the stockperson (e.g. stroking, letting suck fingers, speaking softly) (raussi et al., 2003) . (see section on humananimal relationships). 9.5.3. comparison between individual housing vs. group housing individual housing can be stressful to calves as measured by adrenal responses to acth (raussi et al., 2003) . group housed calves are generally more active than individually housed calves as far as gross activity is concerned (more time spent moving or eating, less time spent idling or lying) (babu et al., 2004; raussi et al., 2003) . group housing can benefit production: xiccato et al. (2002) found that calves housed in fours put on more weight than calves tethered in individual crates. however, this seems not to be the case when the calves are not tethered in individual crates (veissier et al., 1998) . group housed calves are less easy to handle. human contact is thus essential for them to become accustomed to humans and to react less to handling (lensink et al., 2001; mogensen et al., 1999) . group housing can help calves acquiring social skills (boe and faerevik, 2003) . some experience of mixing is of particular importance: calves that have been reared for a while in a group dominate calves that have always been in individual crates (veissier et al., 1994) . by contrast, it is not clear whether repeated mixing would be beneficial or harmful to calves veissier et al., 2001) . recent research (e.g. svenson et al., 2003 and svensson and liberg, 2006) suggests that transfer from individual pen to group-housing during the second week of life is disadvantageous for health reasons (see chapter 10) and, that a delay in mixing until the calf is 2 weeks old may be preferable. additional research seems necessary to establish what mixing age would be preferable from a health and welfare perspective. 9.6. temperature, ventilation and air hygiene the importance of the aerial environment inside a calf house for the health status of the animals was stressed in the 1995 report, and it still seems to be one of the major factors which cause morbidity and mortality (svensson et al., 2006) . bioaerosols (micro-organisms, dust), low air temperatures together with high air humidity, gases such as ammonia, draught, insufficient air space and poor ventilation form a complex environmental situation which can be detrimental particularly for the respiratory health of young calves (lundborg et al. 2005; svc, 1995) . 9.6.1. temperature and relative humidity a healthy calf consuming a sufficient amount of feed has a wide zone of thermal neutrality. there is no difference in the performance of healthy, normal eating calves at temperatures ranging between 0 âºc and 20 âºc provided it is dry and not exposed to draughts. above 25 âºc conditions in confined calf houses can start to become uncomfortable. moran (2002) suggests that the ideal temperature and relative humidity for calves are 17 âºc and 65 %, respectively. however, there is a large number of influencing factors to consider which can alter the situation for a calf substantially. lower critical temperatures for a calf in calm air and full feed are different whether it stands (-3 âºc) or is lying on dry concrete (-6 âºc) or on dry straw (-8 âºc) (thickett et al. 1990 ). the younger the animal the higher is its demand for the thermal environment. by 1 week of age, the lower critical temperature in still air is approximately 8 âºc (webster, 1984) . this temperature can be significantly changed by draught, wet coat and feeding level. young calves start to shiver at 8 âºc when they are exposed to draught even if their coat is dry and they are fed sufficient feed. when fed on maintenance only level shivering starts at 12 âºc. if their coat is wet and they are exposed to draught shivering starts at 13 âºc when on full feed and 19 âºc when fed on a low level (moran, 2002) . no signs of shivering are observed at 3 âºc when the coat is dry with no draught and feeding is at a normal level. cold stress in calves can be prevented by providing dry lying areas, appropriate feeding and draught free ventilation. dry bedding such as straw significantly improves thermal comfort for the lying calf. in summer situations reduced feeding (but with sufficient water supply!) or feeding calves in the cooler evening or at a reduced animal density per pen and increased ventilation rates can help to lower heat stress. heat stress can also be reduced through constructing sheds with insulated roofs and well ventilated walls. calf houses with a solid wall construction and a high capacity to store energy combined with an efficient ventilation system can also contribute to create comfortable environmental temperatures for young calves kept indoors all year (din 18910, 2004) . the preferred environmental temperature for calves is not fixed, it largely depends on management and other environmental factors such as wind speed and humidity of the air. the generally accepted range of relative humidity for calf barns is between 60 and 80 % with an optimum around 65 % which is not too humid to dissipate excess heat and not too dry to dry out the respiratory pathways predisposing the mucous membranes to infectious and noxious agents present in the inhaled air. air humidities of more than 80 % can lead to condensation on the walls and ceiling increasing the risk of wetting the animals by water dripping off these surfaces. high relative humidities can also impair the insulation properties of the walls increasing heat losses. cold and humid air at high velocities can considerably increase the heat loss of animals. lundborg et al. (2005) showed that draughts greater than 0.5 m/s measured close to the animal, significantly increased the odds ratio for moderate to severe respiratory sounds. the higher the humidity the higher the risk of wet skin and cooling and shivering. high air humidity increases the probability that bacteria survive in an airborne state and are transmitted between animals in the same pen and between animal pens (wathes, 1994) . there are existing numerous reports from 1960s onwards of the survival of bacteria and viruses employing simple regression models to describe the loss of viability of microbes over time. however, these models lack an insight into biophysical and biochemical mechanisms of cell and virus death. as long as we do not understand these mechanisms, the measures to reduce the air pollutants are limited to either increased ventilation or increased air space. the smaller the air space per animal the more sophisticated the ventilation system must be. the influence of air space was demonstrated by wathes (1994) showing that doubling of the air space in a calf barn from 6 to 12 mâ³ per calf had the same effect on the concentration of airborne bacteria as a six fold increase in ventilation rate (air exchange rate). an air space of 6 to 8 mâ³ per calf was recommended by hilliger (1990) from experience. 9.6.2. air quality aerial pollutants in confined animal houses are widely recognised as detrimental for respiratory health. primary and opportunistic microbial pathogens may cause directly infectious and allergic diseases in farm animals, and chronic exposure to some types of aerial pollutants may exacerbate multi-factorial environmental diseases, such as enzootic bronchopneumonia. the factors can be inadequate environmental conditions, e.g. too low temperatures, high ammonia concentrations and poor ventilation resulting in low air quality. poor air and surface hygiene in calf buildings are nearly always associated with intensive systems of husbandry, poor standards of management and high stocking densities (wathes 1994) . the most common aerial pollutants in calf housing are summarised in table 9 .1. gases such as ammonia (nh 3 ), hydrogen sulphide (h 2 s), carbon dioxide (co 2 ), and more than hundred trace gases form an airborne mixture of bioaerosols composed of about 90 % organic compounds and can also contain endotoxin, antibiotic residues and further trace components. significantly high amounts of endotoxins were found in calf house air while bacteria and dust are relatively low compared with pig and poultry houses and suggest that a high number of gram-negative bacteria are present in the air. the average concentration of 64 ng/mâ³ endotoxin given in table 9 .1 represents about 640 eu (endotoxin units) according to the new nomenclature. it seems rather high in comparison to a formerly proposed occupational threshold of 50 eu for humans at the work place (rylander and jacobs, 1997) . it can be assumed that high endotoxin concentrations in calf house air may substantially contribute together with the other bioaerosol compounds and the physical environment to the high level of respiratory disorders in young calves up to 105 days (assie et al., 2004) . in general, there is little detailed knowledge on the specific composition of bioaerosols in calf keeping systems and which factors cause respiratory diseases. assie et al. (2004) found e.g. a tendency to higher repiratory disorders in non-weaned calves reared in loose-housing yards compared with tied-cow stalls. the highest incidence rates of cases were observed between november and january, while daily meteorological conditions obviously did not influence incidence rates. one of the most detrimental gases in calf barns is ammonia which is formed by bacterial degradation of nitrogen containing compounds in urine and faeces. it is the most widespread naturally occurring alkaline gas in the atmosphere and a strong irritant in animals and humans. concentrations in the air of more than 20 ppm can impair the proper functioning of the mucous membranes of the respiratory tract and predispose to infection. in a recent study lundborg et al. (2005) found that the risk for respiratory disease was significantly associated with an ammonia concentration below 6 ppm (or: 0.42; p<0.05). high concentrations of hydrogen suphide can be released in high amounts from stored liquid calf manure when it is stirred up before removal from the slurry pit of the barn. concentrations of about 700 ppm are acute fatal. the composition of the inhalable and respirable particles in animal houses is associated with compounds such as dried dung and urine, skin dander and undigested feed. the majority of bacteria found in shed airspace have been identified as gram-positive organisms, with staphylococci spp. predominating (cargill et al., 1998) . a survey by heinrichs et al. (1994) showed the importance of good ventilation which removes dust and other respirable particles as well as noxious gases and is essential for calf health. adequate ventilation is seen as vital to help to reduce the incidence of respiratory disease. air inlets should be above calf height and the outlet at least 1.5 m above the inlet (howard, 2003) . however, heating and ventilation in combination with an air filtration system significantly improved the environment in a calf house but did not completely eliminate pneumonia (bantle et al., 1994) . this may have to do with other factors such as ambient temperature. in a recent study by reinhold and elmer (2002) some compromise in lung function (compared with controls) was seen in calves exposed to an ambient temperature of 5 âºc. 9.6.2.3. light in the past, veal calves were often kept in dark to reduce muscle activity but the requirements for light have increased over the last 20 years from 15 to 20 lux (bogner and grauvogel, 1984) , to over 20 lux (irps, 1985) to 80 lux for at least 10 h and according to daylight circadian rhythm. (tierschutz-nutztierhaltungsverordnung germany, 2001) . there is wide agreement that calves need light for orientation in their boxes or pens and for social contact. a precise threshold has not been determined. there is a need for air movement around calves to supply fresh air and to remove excessive heat, moisture and air pollutants (gases, dust, microorganisms). good ventilation systems provide this exchange. however, high air speeds close to the animals can lead to draughts and should be avoided. draughts happen when part of an animal is hit by an air stream with a higher velocity than the ambient air movement and which has a substantially lower temperature than the surrounding air, causing a feeling of cold and physiological reaction in that particular part of the body. draught can lead to poor welfare and disease when it continues and the animal cannot escape, e.g. when it is tethered. it is generally recommended that wind speeds around animals should be between 0.1 m/s in winter (least value) and about 0.6 m/s in summer. these values strongly depend on relative humidity and temperature of the air and whether the skin of the animals is dry or wet, full fleece or shorn. in confined buildings this complex relationship between the various factors is strongly influenced by the ventilation system and the ventilation rate which is necessary for the number of animals kept in the animal house. it seem useful to develop a more comprehensive model for the interaction of the different air quality compounds and the air exchange rate to improve our understanding of the welfare and health impacts arising from the air environment. 9.6.3. ventilation ventilation plays an essential role in improving air quality in calf barns. this applies to free ventilated and forced ventilated houses. calculations of ventilation rates are usually based on heat removal in summer and moisture removal in winter, and give some guideline temperatures and humidities of the air which should not be exceeded (e.g. cigr, 1994; din 18910, 2004) . ventilation rates in calf barns can only be calculated satisfactorily for confined buildings. minimum ventilation rates around 10 mâ³ per 100 kg live weight should be sufficient to keep the air quality within acceptable limits if the air distribution system ensures an even air exchange in all parts of the building. such guidelines (cigr) and norms (din 18910, 2004) cannot guarantee healthy calves but they can substantially help in designing confined calf houses. it seems useful to standardise the air quality and ventilation requirements for confined calf houses in europe in order to reduce respiratory disorders, suffering of the animals and economic losses. the 1995 report highlights two aspects of human-animal relationships: the skills and motivations of caretakers to raise healthy calves, which are of particular importance for indoor calves and in large groups and are linked to the health status of calves; the physical contacts between caretakers and calves to improve subsequent reactions of calves to humans. it recommends careful monitoring (by the same person throughout rearing) and careful handling to habituate calves to human contacts. recent studies confirmed that the stockpersons have a great impact on both the productivity (e.g. growth) and the welfare of farm animals (stress responses, fear reactions during handling) (boivin et al., 2003; reviewed by hemsworth and coleman, 1998) . the effect of stockmanship is two-fold: good stockmanship leads to healthy animals and less stressful human-animal interactions. stockman skills are associated with positive attitudes towards work and towards animals. in calf production, a better health status is observed on farms where the caretaker (also the owner) believes that calves are sensitive animals and he/she has a positive attitude towards farming tasks in calf production (lensink et al., 2001b) contacts given by stockpersons to animals depend also on human attitudes. stockmen that are positive towards gentle contacts with calves (e.g. stroking, talking) are more likely to provide calves with such contacts (lensink et al., 2000a) . it is not only the duration of contact but also its nature that plays a role. gentle contacts (e.g. stroking, talking, letting a calf suck fingers, offering food) lead to calves approaching humans as they have less fear of handling (boivin et al., 1998; jago et al., 1999; lensink et al., 2000b) . whereas rough contacts (e.g. hitting with a stick, use of nose tongs or an electric prod) lead to fear reactions in presence of humans (rushen et al., 1999) . the electric prod seems particularly stressful to calves (croney et al., 2000) and noises (metal clanging, shouts by humans) will also increase stress during handling (waynert et al., 1999) . during transport to slaughter, less fear responses to handling (e.g. due to regular previous experience of gentle contact) not only improves the welfare of calves but also improves meat quality (lower ph and lighter colour) (lensink et al., 2000c; lensink et al., 2001a) . cattle are able to distinguish between familiar and unfamiliar persons (rybarczyk et al., 2003; taylor and davis, 1998) . among familiar persons, they distinguish between those who have been rough with them and those who have been gentle (e.g. stroking, brushing, and offering food) (de passillã© et al., 1996) . compared with individually housed calves, calves housed in groups tend not to approach humans and are more difficult to handle (lensink et al., 2001b) . the presence of the dam can lower the effectiveness of gentle contacts with animals (boivin et al., 2002) . contact early after birth can be more effective that contact provided later; however, regular contact is necessary to maintain a lower level of fear responses to humans (boivin et al., 2003) . the 1995 report recommended: to dehorn calves between 1 -3 weeks by cauterisation with adequate anaesthesia and analgesia (no details given) to castrate calves at 3 months with adequate anaesthesia and analgesia (no details given) 9.8.1. dehorning dehorning means the removal of horns while disbudding (on young animals) corresponds to the removal of horn buds. disbudding can be performed by cautery, or by rubbing or covering the horn buds with a chemical (naoh, koh or colloidon), or by amputation with a specifically designed sharp tool, a scoop. recent publications confirmed that disbudding and dehorning are painful to cattle (stafford and mellor, 2005) . the existence of pain is deduced from observations of an increase in blood cortisol for several hours after dehorning and from specific pain related behaviour: head shaking, ear flicking (faulkner and weary, 2000) disbudding without anaesthesia or analgesia is painful to calves, even when young, and dehorning with a wire-saw is painful to cows even if anaesthesia is carried out (taschke and folsch, 1997) . disbudding by cautery (hot iron, electric tool) and chemical disbudding (naoh) are less painful than disbudding with a scoop (stilwell g. et al., 2004a; stilwell g. et al., 2004b; sylvester et al., 1998) . local anesthesia (5-6 ml lidocaine or lignocaine 2% around the corneal nerve 15-20 min before disbudding) can abolish the pain that immediately follows cautery and largely diminishes the pain caused by disbudding by other methods; the effects last for the few hours and when the nerve block has lost its effect, pain ensues stilwell et al., 2004b; sutherland et al., 2002b) . local anesthesia plus analgesia with a non-steroidal anti-inflammatory drug (nsaid)(e.g. 5 ml flumixin meglubine or 3 -3.75 mg/kg ketoprofen (10%) 15 min before disbudding) abolish pain caused by cautery but only reduces it in the case of disbudding with a scoop (unless it is followed by cautery) (sylvester et al., 1998; faulkner and weary, 2000; sutherland et al., 2002a; stilwell et al., 2004b) . in their review, stafford and mellor (2005) concluded that cautery is the less painful method for disbudding and that optimal pain relief is obtained with xylazine sedation, local anaesthesia and analgesia with a non-steroidal antiinflammatory drug. the 1995 report recommend that when cattle are to be castrated this should be done at around 3 months of age and under appropriate anaesthesia and analgesia. methods to castrate cattle are: clamping (generally with a burdizzo clamp), constriction of the blood supply with a rubber ring, and surgical removal (cutting of the scrotum then traction on the testes and spermatic cords or cutting across the spermatic cross). calves are castrated as early as 1 week up to over 6 months (see review of practices used in uk by kent et al., 1996) . castration is painful whatever the method used and whatever the age of the calf (molony et al., 1995; robertson et al., 1994) . acute pain is deduced from the observation of increases in blood cortisol and abnormal postures (immobility), and behaviours such as foot stamping and kicking. chronic pain is deduced from the observation of activities targeting at the site of castration (e.g. licking, head turning, alternate lifting of the hind legs, and slow movements of the tail) as well as abnormal standing. burdizzo clamping and surgery induce acute pain for at least 3 h (molony et al., 1995; obritzhauser et al., 1998; robertson et al., 1994) . burdizzo is less painful than surgery but may also cause pain for longer (at least 48 h) due to scrotal inflammation (stilwell, pers. comm.) . castration with a rubber ring causes both acute and chronic pain for at least 1.5 mo (molony et al., 1995) castration is less painful for 1 wk old calves than for 3-6 wk old calves (robertson et al., 1994) and it is less painful at 1.5 months than at older ages (ting et al., 2005) . local anesthesia (3 ml lignocaine 2% into each testicle through the distal pole) abolishes the acute pain associated with castration by a ring or a band (stafford k.j. et al., 2002) . it reduces but does not abolish acute pain associated with castration by surgery or clamping (fisher et al., 1996; stafford et al., 2002) . analgesia with a nsaid drug (e.g. ketoprofen 10% 3mg/kg body weight) reduces the pain associated with clamping (ting et al., 2003) . some analgesics (e.g. caprofen, 1,4 mg/kg body weight) are effective for longer than 24h and are thus more likely to provide more effective pain relief (stilwell, comm. pers.) . local anaesthesia plus analgesia appears to eliminate the acute pain due to castration by surgery or clamping . the most important diseases in young calves are diarrhoea and respiratory disease (olsson et al., 1993; sivula et al., 1996; virtala et al., 1996a , donovan et al., 1998 lundborg, 2004) . a prospective study was carried out on 94 randomly selected beef herds in the midi-pyrenees region in france (bendali et al., 1999) . the objective was to describe diarrhoea and mortality in beef calves from birth to 30 days of age. calves (3,080) were followed from december 1995 to april 1996, and a total of 700 visits allowed records of herd management practices, individual data and environmental conditions to be collected. the incidence rate for diarrhoea during the neonatal period was 14.6%, and varied markedly between herds. eighteen herds did not suffer from diarrhoea, while five herds had an incidence of more than 50%. results indicate that 52% of diarrhoea appears during the first week and only 15% after the second week of life. the greatest risk of diarrhoea for a calf was during the first and second weeks of life (7.9 and 6.5 times, respectively). the month of birth was also significantly associated with morbility, the highest incidence was observed in december and march (17.6% and 23.6%, respectively) . the global mortality rate was 3.6% and was two-times higher in december than in other months. forty per cent of herds did not exhibit mortality, and 10% had mortality rates greater than 10%. in a study of calf health in 100 cow-calf herds in switzerland, busato et al. (1997) found that of 1270 calves included in the study 22% of the calves had been treated by a veterinarian. of those, 36% of the treatments were given because of diarrhoea and 27% because of respiratory disease. another swiss study (frei et al., 1997) showed that in 113 swiss dairy herds, the incidence density (id) per 100 animal-years of diarrhoea, omphalitis (infection of the navel), respiratory diseases and other diseases were 35.0, 13.9, 13.5 and 7.2 respectively. in a study of nine herds and 892 calves with swedish red and whites, swedish holsteins and some crossbreeds the effect of group size on health was studied (svensson and liberg, 2006) . after transfer to group pens (at 21-53 days of age) 19.0% of the calves had diarrhoea, 9.8% had omphalophlebitis/umbilical abscess, 31.3% had a clinical respiratory-tract disease and 1.4% had weak calf syndrome. of all calves, in 7.3% there was associated general condition impairment. in 37.4% of the diarrhoea cases antibiotics were used as treatment and of the clinical respiratory-tract cases 54% were treated with antibiotics. several factors have been associated with an increased risk of infectious disease during the first 90 days of life, particularly factors affecting serum immunoglobulin concentration. in a study of 122 dairy herds in south-west sweden, svensson et al. (2003) clinically monitored the health of 3081 heifer calves from birth until 90 days of age. 23% of the calves developed one or more diseases during this period. most of the 317 diarrhoea cases were mild (68%) whereas of the 221 cases of respiratory disease 43% were severe. the total morbidity was 0.081 cases per calf-month at risk and the incidence rates of arthritis, diarrhoea, omphalophlebitis, respiratory disease and ringworm were 0.002, 0.035, 0.005, 0.025 and 0.009 cases per calf-month at risk respectively. odds ratios were calculated for severe diarrhoea in calves born in the summer (or: 1.7) and receiving colostrums through suckling instead of a bucket or nipple (or: 1.8). it has been shown that calves left with their mothers have a delayed/longer time to ingest colostrum and often fail to ingest adequate volumes (rajala and castrã©n, 1995) . svensson and liberg (2006) found that the health status of the mother cow 280-50 days before calving, length of dry period, retained placenta and somatic cell count were predisposing risk factors for respiratory disease in the calf. svensson et al. (2003) were also able to demonstrate that the odds ratios for respiratory disease and increased respiratory sounds were increased in calves housed in large group pens with an automatic milk-feeding system (or: 2.2 and 2.8). similar results have been reported by maatje et al. (1993) and plath (1999) . there was a decreased odds ratio for respiratory disease if calving was supervised (or: 0.7) . if birth was taking place in individual maternity pens or in tie stalls instead of in cubicle or group maternity pen, the odds ratio for increased respiratory sounds was 0.5 or 0.6 respectively. 30% of the diarrhoea cases were treated with antibiotics whereas 47% of the respiratory cases were treated using antibiotics. in another study of nine farms, svensson and liberg (2006) found that in pens for six to nine calves there was a significantly reduced risk of clinical respiratory tract disease (or: 0.69-0.72) compared with pens with 12-18 calves and there was also an association with the age at transfer to the group pen. the risk of diarrhoea was not affected by housing the calves in differently sized groups. however, calves housed in large sized groups grew significantly less quickly (approximately 40 g/day) than calves housed in groups of six to nine. serological responses to respiratory viruses (e.g. bovine respiratory syncytical virus, parainfluenza virus, corona virus and viral diarrhoea virus) showing that animals within a herd are usually either all seropositive or all seronegative, indicate that infections spread to all calves in the herd when introduced or activated (hã¤gglund et al., in press) and hence that aerosol is an important means for the spread of viruses. however, an infected animal is not equivalent to a diseased animal. it has been shown that calves housed in adjacent pens can maintain quite different levels of disease. svensson and liberg (2006) reported that calves in a group of 16 had a significantly higher incidence of clinical respiratory disease that calves in an adjacent pen kept in groups of 8. engelbrecht (2005) reported calves transferred to group pens in a batchwise manner had significantly higher prevalence of diarrhoea and respiratory disease than calves in adjacent pens that were transferred to and from the group pen continuously. in both studies calves had no direct contact with calves in adjacent pens. these results indicate an important role of direct contact for the transmission of respiratory disease and hence the importance in disease control of decreasing direct contact between calves within the same building by means of solid walls. svensson and liberg (2006) also reported that the age at transfer from single pens to group pens was associated with the risk of respiratory disease, indicating that delaying transfer to after two weeks of age might be preferable for health reasons. enteritis is the most common disease in calves less than a month old (virtala et al., 1996b; wells et al., 1996; radositis et al., 1999) . diarrhoea is caused by dietary factors or caused by infections due to viruses, bacteria or parasites. routines in distributing colostrum to the calf are crucial for transferring immunoglobins to the calf and to obtain a good health. (rajala and castrã©n, 1995; liberg and carlsson, 1998) . enteritis is clinically recognized by the observation of faeces with a looser consistency than normal. colour as well as smell of the faeces might be affected. diseased animals exhibit fever and may be inactive usually as a result of dehydration and possibly acidosis (radositis et al., 1999) . usually it is not possible to differentiate between different agents causing the diarrhoea by clinical findings. rotavirus is worldwide a major cause of diarrhoea and it is an often detected agent among young calves with enteritis (e.g. bjã¶rkman et al., 2003) . rotavirus affects calves usually between 1 and 8 weeks of age and the diarrhoea can vary from very mild to lethal (de leeuw et al., 1980) . the virus is excreted through faeces of infected animals and is very resistant for several months, that is why cleaning of pens is necessary to break the infectious path (saif and theil, 1990) . bovine coronavirus is most commonly seen in calves at about 1 week of age (fenner et al., 1987) . escherichia coli k99+ may cause diarrhoea in young calves although it is a part of the normal intestinal flora. poor routines for transferring colostrum to the calf, stress etc. might trigger a diarrhoea outbreak (wray and thomlinson, 1975) . severity of the disease may vary but with a high proportion of mortality (radositis et al., 1999) . only amoxicillin is recommended for the treatment of diarrhoea caused by e. coli bacteria associated by systemic illness. in calves with diarrhoea and no systemic illness (normal appetite for milk, no fever), the health of the calves should be monitored carefully and no antibiotics should be administered (constable, 2004) . bovine viral diarrhoea may occur at any age. the infection causes an immunosuppression in infected animals which may lead to infections with other intestinal or respiratory pathogens (elvander et al., 1998; de verdier klingenberg, 2000) and it may increase the mortality rate in the herd (ersbã¶ll et al., 2001) . salmonella spp, mainly s dublin and s typhimurium can affect calves usually between 2 and 6 weeks of age. the pathogen is introduced into the herd via infected feed, water, pastures, cattle or humans or via other animals entering the herd. calves are infected orally and clinical signs are fever and bloody diarrhoea (carter and chengappa, 1991) . clostridial infections in the gastrointestinal tract are sometimes a problem in calves. usually, the calf, less than 10 days of age, develops haemorrhagic, necrotic enteritis and enterotoxemia, often associated with clinical abdominal pain. affected calves exhibit tympany, hemorrhagic abomasitis and ulcerations in abomasum (songer and miskimins, 2005) . as yet, relatively little is known about the etiology aside of the participation of c. perfringens type a. overfeeding or feeding which decreases gut motility is suggested to contribute to the occurrence of the disease (songer and miskimins, 2005) eimeria spp. are frequently present in cattle in europe (bã¼rger, 1983) . predominantly e. ellipsoidalis was found in housed calves in east germany (hiepe et al., 1978) and the distribution may differ from country to country. svensson (1993) found a predominance of e. alabamensis in swedish dairy calves. clinically, signs are rarely seen but diarrhoea can occur usually as a result of exposure at the first grazing season in areas contaminated with oocysts (svensson, 1993) . there is evidence that infection rates have increased since the prohibition of tethering (berthold, pers. com.). emeria bovis and emeria zuernii are other intracellular protozoan parasites belonging to the same group and with a worldwide distribution (urquhart et al., 1991) . it is often seen in calves between 1-6 months of age (holliman, 2000) . the disease is triggered by stress such as very cold or hot climate (urquhart et al., 1991) . cryptosporidial infection in calves less than 30 days old is significantly associated with the risk of infection in the dairy herd. the risk increases when animals are grouped together and when hygiene and management practices are deficient (attwill et al., 1999; mohammed et al., 1999) . factors associated with a decreased risk of infection in preweaning calves were shown to be use of ventilation in calf rearing areas, daily addition of bedding, feeding of milk replacer, daily disposal and cleaning of bedding and use of antibiotics. in addition, postweaning moving of animals was also associated with a decreased risk of infection with c. parvum (mohammed et al., 1999) . perryman et al. (1999) showed that with appropriate supply of immune colostrum, diarrhoea can be prevented. two species are distinguished: c. parvum and c. andersoni, although only c. parvum has been shown to be associated with diarrhoea . cryptosporidia parvum is an intracellular protozoan parasite belonging to coccidiae. in the uk c. parvum has been considered to be one of the most common agents in neonatal diarrhoea in calves (reynolds et al., 1986) . in denmark it was found mixed with other enteropathogens in 45% of diseased calves (krogh and henriksen, 1985) . in two recent swedish studies it was found in 19% and 11% respectively of calves with diarrhoea (de verdier klingenberg and svensson, 1998; bjã¶rkman et al., 2003) . the most common form of respiratory disease affecting young calves is enzootic pneumonia (ames, 1997; radositis et al., 1999) . it is considered to be a multifactorial disease with causative agents, individuals and environmental factors as important components (ames, 1997) . enzootic pneumonia usually affects calves between 1 and 6 months of age (radositis et al., 1999) . the signs usually found are fever, nasal discharge, coughing and increased respiratory sounds when lung auscultation is performed. secondary bacterial infections may occur which might increase the fever. diagnosis of etiological factors may be achieved from serological examinations, viral examinations from nasal discharge or at autopsy. bovine respiratory syncytical virus (brsv) is a worldwide present agent with seasonal peaks during autumn and winter (baker and frey, 1985) . the virus is thought to be transmitted from infected animals, by transmission of humans or by airborne transmission (van der pohl et al., 1993; elvander, 1996) . morbidity can be high but mortality is usually low . another virus with a milder course of disease is para-influenza-3 virus but the virus can cause immunosuppression predisposing to secondary bacterial infections (adair et al., 1999) . the most common bacterial pathogens in calves with respiratory disease are pasteurella multocida and manheimia hemolytica (mosier, 1997; bengtsson and viring, 2000) . these agents are usually found in the bovine nasopharynx and may, as a result of viral disease proliferate and colonise the lungs of the calf (kiorpes et al., 1988) . haemophilus somnus was shown to be commonly present in danish calves (tegtmeier et al., 1996) where no such agents were found in swedish calves (bengtsson and viring, 2000) . arcanobacterium pyogenes and staphylococcus aureus (carter and chengappa, 1991) as well as mycoplasma spp. (ames, 1997) are other agents found in immune depressed calves with other infections. infections may occur in the umbilical cord (radositis et al., 1999) of newborn calves. various bacteria are found and through a bacteraemia infection may spread to to joints, meninges and internal organs (radositis et al., 1999) . omphalitis is painful in response to palpation of the umbilicus. arthritis is often secondary to an umbilical infection and usually affects the calf during its first month resulting in warm and swollen joints, fever and lameness (radositis et al., 1999) . the effect of environmental factors on the risk of diarrhoea and respiratory disease was studied by lundborg et al. (2005) in the same 122 farms and 3081 calves as previously reported by svensson et al. (2003) . they found that the placing of calf pens along an outer wall was associated with a significantly higher risk of diarrhoea (or: 1.92 ). an ammonia level below 6 ppm was significantly associated with the risk of respiratory disease (or: 0.42) but variations of ammonia levels were low, while the odds ratio for increased respiratory sounds was associated with a bvdv infection in the herd (or: 2.39) and draught (or: 3.7). absence of draught was associated with the risk for infectious diseases other than diarrhoea and respiratory disease (or: 0.42), a finding which could not be explained by the authors. an increased calf mortality rate in herds with a bvdv infection has also been reported by ersbã¶ll et al. (2001) and the eradication of bvdv infection in a dairy herd has been demonstrated to decrease the incidence of calf diarrhoea (de verdier klingenberg et al., 1999) . typically, clinical experience is that the incidence and prevalence of infectious respiratory disease is much higher in rearing systems where the calves have been bought and transported from several farms where they were born to a specific rearing farm than if they are reared on the farm they were born on. calves reared indoors commonly develop complex respiratory diseases. bergmann (1987) reported that 62% of calves of a large fattening unit with several thousand calves suffered from bronchopneumonia within the first six month of their life. similar figures were reported from herrmann (1987) with a prevalence of 50 to 61%, lã¤mke et al. (1989) 45% and busato et al. (1997) 52%. the disease seems to be continuously present and does not come or go in form of isolated outbreaks. therefore kielstein et al. (1975) called it enzootic pneumonia. it is a typical multifactorial disease caused by a variety of different types of micro-organisms which are always present but becoming a nuisance only when additional factors contribute (grunert, 1993) . the most prominent reasons for losses of calves in the first weeks of life are respiratory and digestive disorders (katikaridis 2000; girnus, 2004) . losses can reach 6 to 12 per cent in the first six months of rearing (berchtold et al. 1990 and others). estimations show that the financial losses are reaching 100 million â�¬/year in germany (biewer, 2001) . this sum does not cover the costs of veterinary treatment and reduced growth rates of the calves. there are several epidemiological studies on the different diseases in calves in the first couple of weeks of life (katikaridis, 2000; biewer, 2001; girnus 2004 , svenson et al., 2006 . heinrichs (1991) reported that 64% to 70% of 2,273 fallen calves coming for post-mortem dissection showed digestive disorders. calves 4 weeks of age died predominantly of respiratory diseases (40% to 70%). an investigation of 3,334 calves less than 4 months shows that enzootic bronchopneumonia can already start with the age of 2 weeks (buhr, 1996) . the calves were not older than 4 months. 49 % displayed abomasum enteritis. 32% of the animals suffered from pneumo-abomasal enteritis. only 4.5% of the fallen animals suffered from a distinct pneumonia. an epidemiological survey of calf losses in free range and suckling cow herds showed that the percentage of calf losses is increased with herd size. 97% of herds with less than 20 suckling cows had a calf mortality of less than 10%. in herds with more than 300 cows, these were 9% of all investigated farms, calf losses were higher than 10% (laiblin and metzner, 1996) . main disorders were again diseases of the digestive tract (50 %) and respiratory tract (38%). the authors calculated that the disease risk for calves born from cows that were housed during the calving season was 2.45 times higher compared with cows kept the whole year on free-range. the epidemiological data from the vast majority of investigations suggest considerable differences in morbidity and mortality of calves among different farms. this implies that the management and housing conditions greatly influence heath, welfare and survival of calves in the first 6 months of their life. the situation was not substantially improved by vaccination of cows against a cocktail of infectious agents causing diarrhoea. there are no experimental studies available to indicate whether or not there is any advantage to calf welfare of preventing individuals in separate pens from social contact as opposed to a disadvantage to calf welfare of greater spread of disease with housing where such social contact is possible. in general, disease spread occurs in buildings with continous air space and contact is not a clearly identified factor. however, recent results indicate an important role of direct contact for the transmission of respiratory disease and hence the importance in disease control of decreasing direct contact between calves within the same building by means of solid walls (see chapter 8/9/10). antibiotic resistance although the use of antibiotics as growth promoters is being progressively restricted through eu regulations, they are still used in large quantities in calf rearing for both prophylactic and therapeutic purposes. in those instances where calves are not reared on site but transported to other locations and mixed in groups, the incidence of clinical illness is high and the use of antibiotics is frequent. in a study of antibiotic resistance, berge et al. (2003) found high levels of multiple resistance in calf commensal faecal escherichia coli both on farms with calf production and on dairy farms. the investigators found that escherichia coli from calves on dedicated calf-rearing facilities was more likely to be multiple-resistant than e. coli from dairy-reared calves (or: 2.4) (berge et al., 2005a) . in her phd thesis, berge (2004) showed that both prophylactic use of antibiotics in milk replacer and individual antibiotic therapy increased the resistance of faecal e. coli in calves. e. coli isolates from calf ranches were the most resistant, with in order of decreasing levels, isolates from feedlots, dairies and beef cow-calf farms. on organic dairies fewer resistant e. coli isolates were found in comparison with conventional dairies. e. coli isolates from beef cow-calf farms were less resistant if the farms were on remote locations compared to those on locations close with dairy intense areas. the use of antibiotics to treat clinical illness will increase the welfare of the animal given that the drug has a beneficial clinical effect. however, the frequent use of antibiotics results in increasing resistance in bacteria such as e. coli and thus poses a threat to the welfare of calves in a longer perspective as well as to man (aarestrup and wegener, 1999) . in a clinical trial on a calf ranch in california, it was shown that the most important factor for decreasing morbidity and mortality was to ensure adequate passive transfer through colostrum (berge et al., 2005c) . thereafter, the ability to use antibiotics for clinical treatment of disease was important to decrease morbidity and mortality. the use of antibiotics in the milk replacer had a minor protective effect on calf health. the authors concluded that in order to minimize prophylactic use of antibiotics, adequate passive transfer of colostrum needs to be assured. furthermore measures need to be taken to optimize nutrition, decrease environmental stress and pathogen load on the farms. in the same study, the antibiotic resistance patterns of the commensal faecal e. coli of calves receiving antibiotics in the milk-replacer, antibiotics for clinical disease, and no antibiotic therapy were compared (berge et al., 2004) . the study showed the emergence of highly multiple resistant e. coli in the calves receiving antibiotics in the milk-replacer. the commensal faecal e. coli were predominantly resistant to at least 10 of 12 antibiotics tested. the resistance covered the antibiotics available for clinical therapy. antibiotic treatments for clinical disease resulted in a transitory shift to more resistant faecal e. coli, but the effect was not detectable approximately 7 days post-treatment. the effect of clinical therapy with antibiotics was similarly assessed in steers in south dakota. in a feedlot study a single dose injectable florfenicol to steers resulted in transitory shifts to increasing levels of multiple resistant e. coli in the faeces. the e. coli from the treated steers were not only more resistant to chloramphenicol (same antibiotic group as florfenicol), but were increasingly resistant to several other antibiotics in other antibiotic classes. (berge et al., 2005b) in dairy cattle it has been estimated (kelton et al., 1998 ) that between 2 and 55% of all lactations include a mastitis infection. most of these cases are treated with antibiotics. milk must be withheld from sale during the treatment and for the compulsory withdrawal period. such "waste milk" is often fed to calves as it is the most economical alternative from the farmer's perspective. earlier studies have previously given various results on how antibiotic resistance develops as a result of the use of this procedure. recently, a controlled, multiple-dose experiment by langford et al. (2003) found an increasing resistance of gut bacteria to antibiotics with increasing concentrations of penicillin in milk fed to dairy calves. in a multi-farm study in california (berge et al., 2006) including 26 dairies, no association was found between increasing levels of antibiotic resistance in calf faecal e. coli and the consumption of waste milk. it should, however, be noted that mastitis in these dairies are predominantly treated with intra-mammary antibiotics (cephalosporins) and injectable antibiotics are rarely used for mastitis treatments (berge, non-published data) . the use of rearing systems for calves that increase the incidence of disease and thus the use of antibiotics for either preventive or clinical purposes should be avoided. further, there is a risk that the use of "waste milk" for calves will increase antibiotic resistance in gut bacteria in calves. 11. food safety aspects of calf farming foodborne hazards that can be present on calf farms include biological and chemical hazards. biological hazards associated with calf farming include following main examples: a) bacterial foodborne pathogens salmonella spp., human pathogenic vtec (hp-vtec), thermophilic campylobacter spp., and mycobacterium bovis; and b) parasitic foodborne pathogens tania saginata cysticercus and cryptosporidium/giardia. on-farm control of chemical foodborne hazards is outside the scope of this chapter and will not be considered. faecal shedding of foodborne pathogens can occur in calves and adult bovines without symptoms of disease; but the shedding pattern may differ between the two age categories. in the conventionally reared animal the intestinal tract becomes colonised from birth by combinations of bacterial species until the characteristic and complex flora in the adult animal is achieved. in the early stages of the process infections with bacterial pathogens are common. once the indigenous flora is established it resists colonization by pathogens and other 'foreign' strains by competitive exclusion . the gut flora of the bovine species changes with ruminal development and the population of faecal coliforms of the adult differ markedly, both qualitatively and quantitatively, from that of the young; particularly that of veal calves fed milk replacer (smith, 1961 some early studies (gronstol et al., 1974a; gronstol et al., 1974b) , based on experimental salmonella infection of calves, described virulence, spread of infection and the effects of stress on the carrier status. hinton et al. (1983 hinton et al. ( , 1984a hinton et al. ( , 1984b determined the incidence of salmonella typhimurium (dt 193 and dt 204) excretion by veal calves fed milk replacer and report that, while initially low on in-take at around 6 days of age, its incidence rose to a peak by 14 days. the level of salmonella contamination of the environment also affects the incidence of infection in housed animals (hinton et al., 1985a (hinton et al., , 1985b . provided calves are reared in separate fattening units and slaughtered on separate slaughterlines the incidence of salmonellae in calves can be maintained at a very low level (guinã©e et al., 1964) . during meat inspection clinical salmonellosis is sometimes diagnosed in a herd of veal calves; however, the prevalences are usually of the order of magnitude of per thousand and the strains isolated are generally restricted to salmonella typhimurium (occasionally) and more commonly, salmonella dublin (up to 90%). although salmonellae may not be isolated from faeces, significant proportions of calves slaughtered commercially (4.3-14.3 %) have contamination involving hepatic lymph nodes, liver, mesenteric lymph nodes and, because of cross contamination, they may ultimately also be isolated from the carcass surface (nazer and osborne, 1976; wray and sojka, 1977) . studies conducted in the netherlands in the late 1970's indicate that microorganisms may be released from lymph nodes through transport stress and may appear in the faeces. this results in young veal calves being cross-infected in transit and at markets; however, in dutch studies faecal samples from no more than 3.5% of the animals were found to contain salmonellae on arrival at the fattening units (van klink and smulders, 1990) . moreover, within 3 weeks of arrival, faeces samples become negative again (van zijderveld et al., 1982) . subsequent studies by the same workers (van zijderveld et al., unpublished, cited by van klink and smulders, 1990) indicate that faecal samples from calves which had survived clinical salmonellosis also become culture-negative, albeit only after 6 weeks. these findings suggest that, provided stressful transport conditions are avoided and sufficient hygienic care is taken to avoid cross infection during transport to the abattoir, the extent of introduction of salmonellae to the veal slaughterline is indeed extremely low. this is substantiated by repeated failure to isolate salmonellae from carcass surfaces of veal calf populations, and from their livers and offal meats (van klink and smulders, 1990) . as with other bacterial foodborne pathogens, antimicrobial resistance in salmonella shed by calves represents an additional food safety risk. numerous studies have shown that use of antimicrobials in food producing animals selects for resistance in non-typhoid salmonella spp. and that such variants have been spread to humans (who, 2004; walker et al., 2000; fey et al., 2000) . in general, antimicrobial resistance in s. typhimurium isolates from bovines in the eu was widespread in 2004, with highest prevalence of resistance to ampicilin, sulfonamide, tetracycline and streptomycin (efsa zoonosis report, 2005b), but the data does not relate specifically to calves. vtec is a group of e. coli that produces one or more verocytotoxins (vt) also known as shiga toxins (stx), but not all members of this group cause foodborne disease in humans. in the opinion on verotoxigenic e. coli (vtec) in foodstuffs (scvph, 2003c) , vtec that have been associated with causing human disease were referred to as human pathogenic vtec (hp-vtec). foods of bovine origin (e.g. beef, milk) have been implicated in a number of foodborne outbreaks caused by hp-vtec (borczyck et al., 1987; chapman et al., 1993; martin et al., 1986; pennington, 1998; scvph, 2003a) ; these include several serotypes (e.g. o157, o26, o103, o111 and o145). when adult cattle were inoculated with vtec o157, they showed no outward signs of infection and the organism was cleared from the gastrointestinal tract within two weeks (wray et al., 2000) . the organism seems to be a constituent of their naturally-occurring microflora, and longitudinal studies show most cattle occasionally carry e. coli o157 in their faeces (hancock et al., 1997; lahti, 2003) . however, the prevalence of infection with hp-vtec of, and the shedding patterns in, cattle can vary due to variable factors including age, immunocompetence status, husbandry conditions, season and geographical areas. prevalence of vtec o157 is usually higher in younger animals (synge, 2000; cray and moon, 1995; hancock et al., 1997; mechie et al., 1997; van donkersgoed et al., 1999) . in calves, the prevalence of e. coli o157:h7 can range from zero to 20.0% prior to weaning, and often increases after weaning (bonardi et al., 1999; laegried et al., 1999) . calves normally show no, or little, sign of infection, perhaps only some excess faecal mucus (myers et al., 1984; synge and hopkins, 1992; brown et al., 1997; richards et al., 1998; wray et al., 2000) ; the shedding rate can fall rapidly in the first two weeks after inoculation and continue intermittently for several weeks. in the first three months of life on contaminated farms, faecal prevalence can increase from around 35% to 53%, possibly due to the decline in maternal immunity (busato et al., 1999) . fasting showed little effect on the carriage and excretion of e. coli o157 in calves (harmon et al., 1999) . less information is available on non-o157 hp-vtec in calves that have potential to cause enterohaemorrhagic disease in humans, so establishing indicators for virulence and clarifying the epidemiology of such serotypes is needed. thermophilic campylobacter spp. according to the biohazard scientific report on campylobacter in animals and foodstuffs (efsa, 2005a) , the most important species of campylobacter are the thermophilic species c. jejuni ssp. jejuni, c. coli and c. lari; other species which are known to cause human illness are c. upsaliensis, c. fetus ssp. fetus and c. jejuni ssp. doylii. the most common species recovered in human disease is c. jejuni. campylobacter spp. can be found throughout the intestine of cattle, but the level of the organism in the rumen is significantly lower than that found in the small intestine and in faeces (stanley et al., 1998) . the class of cattle also has an effect on the level of campylobacter spp. found in the faeces; faeces may contain around 10 4 cfu/g in calves, around 10 2 cfu/g in beef cattle and around 70 cfu/g in adult dairy cattle. campylobacter spp. are more often found in the faeces and intestine than in the rumen, while campylobacter jejuni prevalence is much less than that of campylobacter hyointestinalis (ataby and corry, 1998; grau, 1988) . campylobacter jejuni has been found in calves in 97% of beef farms, campylobacter coli in 19% and campylobacter hyointestinalis in 82% (busato et al., 1999) . within the herds, zero to over 50% of the calves may be excreting campylobacter spp.; 38% of the calves may be positive for campylobacter spp. in herds without evidence of diarrhoeal disease (myers et al., 1984) . in this study, 72% of the isolates were c. jejuni. in a study of veal calves at slaughter, c. jejuni was found in 74% of calf rumen samples (in low numbers; <100/g) and in 54% of calf faecal samples (grau, 1988) , whilst c. hyointestinalis was found in 83% of calf rumen samples (in numbers >10 5 /g) and in 71% of faecal samples. the coats of the calves were also contaminated, as 58% were positive for c. jejuni and 71% for c. hyointestinalis. as with other bacterial foodborne pathogens, antimicrobial resistance in thermophilic campylobacter spp. shed by calves represents an additional food safety risk. in 2004, although the total number of isolates was relatively small and the data are not related specifically to calves, some eu member states reported relatively high prevalence of resistance to quinolones, fluoroquinolones and tetracyclines in campylobacter spp. including c. jejuni from bovines (efsa zoonosis report, 2006) which can be an emerging public health concern. 11.5. mycobacterium bovis efsa 2004a, opinion on the risk assessment of a revised inspection of slaughter animals in areas with low prevalence of cysticercus); therefore, the parasite will not be further considered here. cryptosporidium parvum and giardia duodenalis are protozoan parasites that have caused disease in humans primarily via contaminated water or foods (e.g. salads), but also via chicken salad and milk drinks. high prevalences of cryptosporidium and giardia in veal calves (the age group 1-6 weeks) have been reported (van der giessen et al., 2003) . however, in this study, all isolates from the former group belonged to the pathogenic cryptosporidium parvum genotype 2, whilst only few isolates from the latter group showed similarities with giardia isolates from humans. other authors also reported presence of these protozoan parasites, cryptosporidium (de visser et al., 1987) and giardia (trullard 2002; mcdonough et al., 1994) in veal calves. risk evaluation and principles of food safety assurance at calf farm level the prevalence-level of infection and/or contamination of calves with, and further spread of, foodborne pathogens at calf farms depend on a large number of risk factors that are inherently variable even at single-farm level. the complexity of the problem is further exacerbated by the existence of a number of different farming systems for veal calves in the eu; and even within each of the main farming categories (e.g. intensive vs extensive) a large number of "epidemiological" subcategories exists that differ with respect to one or more risk factors. therefore, presently, both knowledge and published data are insufficient to produce a universal risk assessment enabling quantitative categorization of different types of calf farms and/or their quantitative comparison/ranking with respect to main foodborne pathogens. nevertheless, the role of some main factors contributing to an increase in prevalence and/or in levels of foodborne pathogens in food animals on farms (including calves) are reasonably well understood, as are the generic principles of their control. they are indicated in a condensed form in table 11 .1. it is logical that calves from farming systems in which fewer of the contributing factors exist and where the controls are more complete/efficient will represent lower foodborne pathogen-risk than calves from farming systems having opposite contributing factors-controls situation. therefore, future food safety risk categorization of individual farming system, or related between-systems comparisons, would be dependent upon obtaining and analysing quantitative information on: a) status/levels of contributing factors; b) status/levels of hazards of main concern; and c) existence and effectiveness of their controls. increased "importation" and spread of pathogens via animals "asymptomatic excretors" animal supply only from known, epidemiologically "equivalent" sources; "all in-all out" system presence of animal diseases spread of zoonotic agents in calves global disease control programmes; heard health plans *good farming practice-good hygiene practice 12. risk assessment 12.1. introduction to risk assessment approach when the ahaw panel of efsa was confronted with the tasks of updating the 1995 report (svc, 1995) , the working group members were asked to make it on the basis of a risk assessment , and particularly to consider the possible effects on the calf and, where relevant, on food safety. it appeared entirely feasible for the working group members to follow this part of a risk analysis approach where risks were defined as those concerning the welfare of calves. the risk of concern in this report is that the welfare of the calves will be poor. this may involve an increased risk of injury, of disease, of negative feelings or of failure to cope. the time span of such poor welfare might vary from short to long and severity can vary from low to high. a member experienced in risk assessment procedures was included in the working group from the start. initially, the procedure adopted for the risk assessment was identified and presented to the participants of the whole working group. when identifying the hazards, it has been assumed that the managers of the farm and animal keepers have a basic knowledge, that they have undergone training, that they are aware that the particular constraints on the farm do not hamper their work (e.g. lack of facilities on a farm). however, it is pointed out that under practical conditions hazards may interact, e.g. inadequate air flow may interact with poor air quality, inadequate clinical health monitoring may interact with inadequate haemoglobin monitoring, etc. the identification of hazards and consequential risks to welfare, as well as the risk assessment approach, were agreed by the working group. steps of the risk assessment a. multidisciplinary approach the expert working group it was selected on the basis of having expertise in animal science, ethology, veterinary medicine, risk assessment and food safety. b. listing of potential hazards, hazard characterization and exposure assessment the first step was to describe the needs of calves (see chapter 7 and listed below). then, 36 hazards that might compromise those needs were identified (table 12. 2) and related to each specific need (table 12. 3). the hazards were characterized in relation to the impact they have on the animal. the exposure to the hazard might vary between different rearing systems. for this purpose a set of different rearing categories was developed (table 12 .1) as well as scoring categories for the hazard characterisation, exposure assessment and risk evaluation (table 12 .4). b.a. small groups, bucket fed (not suckling) + solid foods, weaned at 2 -3 months b.b. groups with an automatic feeding system (not suckling) + solid foods, weaned at 2-3 months b.c. feed lots (high density groups within outside pens) b.d. hutches outside, bucket fed (not suckling) + solid foods, weaned at 2-3 months beef calves c.a. suckler calves in small groups kept inside, led twice a day to the dam for suckling up to 6-9 months the hazards were identified and characterized, as well as, an estimate of the probable exposure. however, to ensure that these estimates of exposure correspond with current practice in various european calf production systems, a group of veterinarians, experts in clinical practice in calf production, named the "consultation group", was identified. criteria for invitation were the following; predominantly engaged in clinical practice; extensive clinical experience in calf medicine; and covering various geographical areas where calf production is significant in the eu. another important criterion was that the consultant should not be affiliated with the calf production industry. in total 7 veterinarians accepted an invitation to assist in the exposure assessment. the experience of the individuals covered the various husbandry systems and important veal producing countries in europe. the consultation group prompted that for the exposure assessment, a quintile distribution (i.e. five classes of 20% increments) of exposure classes be adopted. in some instances the estimates of the wg and the consultation group on exposure did not agree in which case the opinion of the consultation group was interpreted to represent the factual situation. in other instances the exposure could not be estimated due to lack of data, in which cases the risks were labelled "uncertain". for hazards characterized as moderately to very serious, this uncertainty is highlighted. table 1 in annex 1 show the agreed scoring between the wg members and the "consultation group" for the hazard characterisation, exposure assessment and risk evaluation. inadequate colostrum intake -quantity 1b) inadequate colostrum intake -quality 1c) inadequate colostrum intake -duration 2) iron deficiency resulting in haemoglobin levels below 4.5 mmol/l 3) deficiency of other minerals (cu, se) 4) insufficient access to water (not milk) (especially during warm season) 5) allergenic proteins 6) insufficient appropriately balanced solid food 7) overfeeding (too rich diet) 8) underfeeding 9) too low temperature of milk or milk replacer 10) exposure to excessively contaminated feed that results in pathology 11) no access to natural teat or artificial teat housing 12) high humidity and too high or low a temperature 13) indoor draughts 14) inadequate ventilation, inappropriate airflow, and air distribution within the house, airspeed, temperature 15) poor air quality (ammonia, bio-aerosols and dust)) 16) poor air quality ( major risk 1 ; 0 is considered not applicable c. assessment of whether hazards pose risks (substantiation by scientific evidence) as a consequence of the hazard characterisation and exposure assessment, the risk for poor animal welfare and health was assessed by integrating the hazard character with exposure according to the table 12 .5 below. the risk was assessed as "major" if the hazard was judged to have a very serious effect and the exposure was frequent or very frequent or if the hazard was serious and exposure was very frequent. the risk was assessed to be "minor" if the hazard was very serious and exposure was rare, if hazard was moderately serious and exposure was moderately frequent or if hazard was adverse and exposure was very frequent. the hazards of iron deficiency and insufficient floor space is considered to be very serious, the hazard of inadequate health monitoring is considered to be serious and the hazards of exposure to inadequate hemoglobin monitoring, allergenic proteins and too rich diet is considered to be moderately serious. for these hazards, there is not enough information on the exposure of calves mainly due to lack of data why it is recommended that further studies should be made to provide evidence for an exposure assessment. regarding the hazard 35) castration and dehorning without anesthetic and analgesic drugs, there is a variation in relation to national legislation as to why the risk of poor welfare in relation to castration and dehorning is widely different between countries. further, there is a variation in the use of analgesia during the time after the surgery is carried out which also affects the welfare of the calf. the ahaw panel wishes to thank the members of the working group chaired by panel member the needs and functioning of calves the needs of calves hutches: partially closed, outside area individual pens: open front structure straw yard with bedded lying area 1.2.6. group pens with automatic milk feeder 3. calf rearing and animal environmental pollution 3.2. the quantitative share of calf production in the pollution problem 35 10. calf diseases and use of antibiotics human pathogenic-verotoxigenic escherichia coli (hp-vtec) on calf farms risk evaluation and principles of food safety assurance at calf farm level listing of potential hazards, hazard characterization and exposure assessment assessment of whether hazards pose risks (substantiation by scientific evidence) annex 1. hazard characterisation and exposure assessment the effects of antibiotic usage in food animals on the development of antimicrobial resistance of importance for humans in campylobacter and escherichia coli cytotoxic interactions between bovine parainfluenza type 3 virus and bovine alveolar macrophages immune function is impaired in iron-deficient, homebound, older women effect of orally administered cimetidine and ranitidine on abomasal luminal ph in clinically normal milk-fed calves effect of feeding frequency and route of administration on abomasal luminal ph in dairy calves fed milk replacer effect of orally administered omeprazole on abomasal luminal ph in dairy calves fed milk replacer dairy calf pneumonia. the disease and its impact effect of type of housing on veal calf growth performance, behavior and meat quality incidence of respiratory disorders during housing in non-weaned charolais calves in cow-calf farms of pays de la loire (western france) age, geographic, and temporal distribution of fecal shedding of cryptosporidium parvum oocysts in cow-calf herds effect of individual versus group rearing on ethological and physiological responses of crossbred calves bovine respiratory syncytical virus bovine respiratory syncytical virus ventilation system to reduce pneumonia in a warm calf house: a case study the effect of increasing dietary fibre on feeding, rumination and oral sterotypies in captive giraffes (giraffa camelopardalis) neuroendocrine alterations in iron deficiency effects of form of the diet on anatomical, microbial, and fermentative development of the rumen of neonatal calves pattern of diarrhoea in newborn beef calves in south-west france 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10.3389/fpsyg.2020.01806 sha: doc_id: 293041 cord_uid: 7ndp05ru response inhibition is an important component of executive function and plays an indispensable role in decision-making and other advanced cognitive processes. at the same time, we need an effective way to improve decision-making in the face of complex and limited information. this study mainly explored the influence of response inhibition training on college students’ risky decision-making. the recruited students were randomly divided into the training group (n = 28) and the control group (n = 28). the training group engaged in go/nogo and stop-signal tasks for 2 weeks, while the control group was given the task of reading and summarizing popular science articles related to self-control. the stroop task and balloon analog risk task were used to evaluate the pretest and posttest performance in inhibitory control and risky decision-making tasks, respectively, for all subjects. the results showed that response inhibition training can be effectively transferred to interference control task performance. the results showed that both the reward acquired and adjusted balloon analog risk task score (adj bart) significantly improved compared to the pretest in the training group, while the control group showed no significant differences in the reward acquired and the adj bart between the pretest and the posttest. although response inhibition training increased risky behaviors in the balloon analog risk task, it substantially reduced overly conservative behaviors and participants gained more money. there are all kinds of risky decisions that we make in life. from daily shopping to financial investments, people always need to make choices with limited time and information resources. many studies have shown that people's decision-making is influenced by gender, individual characteristics, emotional states, cognitive abilities, irrelevant information, and so on (sun et al., 2015; stanovich, 2018; talukdar et al., 2018; weller et al., 2018) . however, little is known about whether a simple and an operational training method can effectively affect decision-making. in the dual-process theories of decision-making, system 1 processes are often automatic, fast, and easily affected by emotion, while system 2 processes are relatively slow and rational process, in which the most important function of system 2 is the successful override of system 1 (stanovich and west, 2008; evans and stanovich, 2013; stanovich, 2018) . moreover, the selection of alternative responses in the decision-making process also depends frontiers in psychology | www.frontiersin.org on the continuous effectiveness of regulatory control processes (moeller et al., 2001) . that is, to achieve better decision-making, it is necessary to continuously control their own dominant responses and irrelevant interference information, which is undoubtedly closely related to the ability of inhibitory control. the purpose of this paper is to determine whether primary cognitive training can effectively change high-level decisionmaking behavior. if the method of improving risky decisionmaking ability through primary cognitive training (such as inhibitory control) is proven and widely accepted, it will greatly advance the research process in the field of decision-making and will certainly provide a direction for future development. inhibitory control, one of the important components of executive function, is the ability to suppress irrelevant, interfering, incorrect or inappropriate goal-directed dominant responses, impulses, behavioral choices, and automatic behavioral habits (barkley, 1997; miyake et al., 2000; munakata et al., 2011; enge et al., 2014) . inhibitory control can be roughly divided into reaction inhibition and interference control; the former mainly focuses on the suppression of the dominant response, while the latter focuses on the suppression of irrelevant information. many studies have shown that inhibitory control plays an important role in verbal communication (bishop and norbury, 2005) , reading comprehension (wang and gathercole, 2015; potocki et al., 2017) , memory retrieval (depue et al., 2010; penolazzi et al., 2014) , and mathematical ability (gilmore et al., 2013) and is involved in other higher cognitive processes, such as problem-solving and decision-making (sakagami et al., 2006; shenoy and yu, 2011) . in addition, inhibitory control training can affect working memory and fluid intelligence (liu et al., 2015) , and there have already been some practical applications in controlling addictive behavior, losing weight, reducing diet consumption, and improving mental illness (houben, 2011; bartholdy et al., 2016) . therefore, inhibitory control can be considered a basic ability that people must have. the traditional view is that inhibitory control is an internal top-down execution process (aron et al., 2004 ). an increasing amount of research results shows that top-down implementation of frontal regions is not always necessary to inhibit control behaviors and the participation of these inhibitory regions can be automatically driven by specific stimuli (lenartowicz et al., 2011) . manuel et al. compared event-related potentials (erps) before and after auditory go/nogo task training and found decreased activity in the left parietal cortex (manuel et al., 2010) , suggesting that the repeated and stable association between the stimulus and inhibition response in the go/nogo task resulted in the gradual separation of top-down connectivity in the frontal lobe, thus facilitating rapid automatic inhibition. this is also the purpose of inhibitory control training, that is, training the slow thought suppression process into an automated, faster process. there are many disputes about whether there is a close relationship between performance in the inhibitory control task and the risky decision-making task. kertzman et al. (2018) used the performance on the go/nogo task, the matching familiar figures test (mfft), and the stroop task as indicator of inhibition ability and used the iowa task performance as an indicator of risk and found no direct correlation between the two (kertzman et al., 2018) . they suggested that although there is some overlap between inhibitory control and the cognitive processing of risky decision-making, they may represent two relatively independent abilities. this may have something to do with the limitations of the iowa gambling task itself. previous studies have demonstrated that short-term stop-signal task (sst) training can reduce risk-taking behavior in gambling tasks (verbruggen et al., 2012; stevens et al., 2015) . they designed a special training study and systematically studied the generalization model of promoting automatic inhibition and developing a top-down control inhibition training program. simply training people to control their exercise behavior induced them to make cautious and risk-averse decisions for at least 2 h and the effect was comparable to that found in previous studies that used transcranial direct current stimulation (tdcs) to control risk (fecteau et al., 2007) . the previous studies examined only immediate changes after training and the decision task selection typically included a single task. on the basis of previous studies, we chose the balloon analog risk task that has strong operability with initial results that are relatively stable and we appropriately increased the time interval between cognitive training and posttest decision-making task assessment. after excluding the immediate effects of training, we wanted to demonstrate that classic response inhibition training can also effectively change performance in this task. it can make the response suppression training more stable, more generalizable, and more convincing for improvements in risky decision-making. this paper proposes a hypothesis: classic response inhibition training can reduce risk behavior in the balloon simulation risk task, thereby resulting in more rewards. a total of 56 university students were randomly divided into a training group (18 men and 10 women; mean age = 19.54 years, sd = 1.20) and a control group (18 men and 10 women; mean age = 19.46 years, sd = 1.55). there was no significant difference in age between the two groups [t (54) = 0.193, p = 0.848]. subjects were included based on the following inclusion criteria: they were 18-22 years old, physically and mentally healthy, right-handed, with normal vision or correctedto-normal vision, and had not participated in other relevant psychological experiments. the exclusion criteria were as follows: neurological disorders, alcohol or other substance abuse or overdependence, mental illness, and treatment with any psychotropic substance. the training process in our experiment is all person-by-person training. under the condition of limited manpower and financial resources, the workload of these subjects is close to the maximum. however, post hoc power calculation is calculated by gpower 3.1.9.2 with a sample size of 56 participants, a significance level of 5% and an effect size of 0.2. the calculated power value is 0.95, proving that the sample size is sufficient. this research was approved and strictly implemented the recommendations of the local ethics committee. all subjects were given detailed experimental instructions and agreed to participate in the experiment. then, they signed the informed consent in accordance with the declaration of helsinki and were entitled to a certain payment after the experiment was completed. the training group adopted the go/nogo task and sst as training tasks that were presented using e-prime 3.0. all experiment started with a short practice phase to make sure that the subjects understood the rules of the task completely. all training tasks were completed in the laboratory over a total of 4 weeks. the two groups were assessed with the stroop task and the balloon analog risk task to evaluate the pretest and posttest performance on inhibitory control and risky decision-making tasks at weeks 1 and 4. in the intervening 2 weeks in the training group, two classic paradigms were simultaneously used and cross trained. the whole training schedule consisted of 30-min sessions, three times per week. during each training session, the two tasks alternated twice. in this study, two kinds of response inhibition training tasks were adopted. on the one hand, to increase the generalization effect of training, the inhibitory control ability was improved by automatic inhibition and top-down control inhibition (spierer et al., 2013) . on the other hand, with this kind of pure training, the more obvious the training boost will be and the more likely that the change in gambling task performance was due to improved inhibitory control. the control group read popular science articles related to self-control and were required to complete a task of summarizing the articles. the time and frequency for this task were consistent with the cognitive training of the training group. there were double triangles ("go") and single triangles ("nogo") used as stimuli in the task. the participants had to make a button-press response to the double triangle and inhibit their response to the single triangle. go and nogo stimuli were randomly presented in a 3:2 ratio. all stimuli were presented for 100 ms in the center of the screen with a 1,200 ms interstimulus interval. the experimental phase consisted of go stimuli of 240 trials and nogo stimuli of 160 trials. there was a pause at the halfway point of this task and the participants could take a break or press any key to continue the experiment. the optimal performance of the task is to minimize the response time and the number of errors (the sum of the number of omission errors and commission errors). the task is the classic response inhibition task paradigm that has been widely used and is also recognized as a method that reflects inhibitory control abilities in a relatively simple and pure way (congdon et al., 2012; wostmann et al., 2013; enge et al., 2014) . the participants were required to press the "f " or "j" key when the "f " or "j" letter (go signal), respectively, appeared, and during a relatively low proportion of trials (30%) with obvious red dots (stop signal) appearing after the go signal, to immediately suppress the impulse to press the button. the task consisted of 200 trials, including 120 no-stop stimuli and 60 stop stimuli. the center of the screen shows a fixation point (+) of 250 ms before all the stimuli appear, and there is a 1,000 ms interval after the button response. in the no-stop stimulus, the most presentation time of the go signal was 1,250 ms. if the subject does not press the button in time, the screen will show "too slow". in the stop stimulus, the stop signal will appear later than the go signal and the stimulus presentation time is still 1,250 ms at most. if the subject does not immediately suppress the key, there will also be an interval of 1,000 ms. the difference between this task and the go/nogo task is that each stop signal is preceded by a reaction impulse and the clever experimental design allows a measure of behavioral inhibition time (verbruggen and logan, 2009; verbruggen et al., 2019; i.e., stop-signal reaction time, ssrt). the tracking method was used to automatically adjust the time when the stop signal appeared (i.e., stop-signal delay, ssd) and the initial value was set at 250 ms. when the inhibition was successful, the ssd increased by 50 ms, while the inhibition failed, and the ssd decreased by 50 ms to ensure that the successful inhibition rate of the subjects was approximately equal to 50%. then, the ssrt value can be calculated (ssrt was equal to the average go reaction time minus the average ssd). the stroop task, which is commonly used for inhibitory control and relatively complicated in processing, was used to evaluate the ability of stimulus interference to inhibit or selectively focus on target-related stimuli (turner et al., 2017) . the participants were asked to select the corresponding key according to the four colors of red, blue, green, and yellow fonts. all stimuli were presented for 100 ms followed by fixation point (+) for 250 ms and there was a 1,000 ms interval after the subject responded. the task consisted of 160 trials. four colors and four fonts were randomly matched and presented (every font was matched with four different colors, so that the ratio of consistent trials to inconsistent trials was 1:3) and consistent and inconsistent response times (rt) were recorded. the conflict effect (incongruent trials rt -congruent trials rt) and conflict score (conflict effect/congruent trials rt) were calculated to evaluate the two groups before and after the inhibitory control ability training (maraver et al., 2016) . the balloon analog risk task was used to evaluate risky behaviors and is a decision-making task that can effectively simulate realistic risky behaviors that are relatively stable under laboratory conditions (lejuez et al., 2002) . the experimental programming of this task was based on computer programming (c++) prepared and rendered on the computer screen. the participants can make money by inflating the balloon with a click of the mouse (earning 2 yuan per inflation, which was included in the temporary account), but if the balloon bursts, they lose the money they made during the round (the temporary account). at the same time, the participants can choose to stop the pump at any time and the temporary account is transferred into the permanent account. each balloon is blown between 1 and 32 times and there is a predetermined explosion point (randomly set by the computer). the participants were asked to conduct 30 balloon trials to make money and were given the sum from their permanent accounts for the 30 balloon trials. the only way to make money is to stop the balloon before it explodes. the subjects were also told that the goal was to inflate the balloon as large as possible without exploding to maximize the benefit. the final benefit of each subject was recorded and average adjusted pumps (i.e., adj bart; adj bart = total number of unexploded balloon pumps/number of unexploded balloons) was calculated to measure the performance and impulsivity in the task. first, a curve was drawn between the performance in the two tasks in the training group and the training time. then, two independent sample t-tests were conducted on the pretest values of the stroop task and balloon analog risk task for the two groups and no significant difference was found between the two groups at pretest. because the experiment adopted a mixed design with between-and within-subjects factors, mixed-model anovas of 2 (control group and training group) × 2 (pretest and posttest) factors were used to evaluate the transfer effect of response inhibition training to stroop performance and its impact on balloon analog risk task performance. finally, we further analyzed the correlation between the initial threshold and the change amount of the training group. since both tasks were completed twice in one training session, we took the average of the two as the performance for that training session. repeated-measures anovas were conducted to compare the performance in the first session with that of the sixth session. as shown in figure 1 , both go rt and ssrt were gradually reduced from the first to the last training session in their respective tasks and the differences reached statistical significance [go rt: f (1,27) = 34.987, p < 0.001, η 2 = 0.564; ssrt: f (1,27) = 38.416, p < 0.001, η 2 = 0.587]. in the two tasks, the error rate did not significantly change from the first to the sixth training session [go/nogo task: f (1,27) = 3.057, p = 0.092, η 2 = 0.102; sst: f (1,27) = 0.028, p = 0.869, η 2 = 0.001; figure 2 ]. however, there was a downward trend in the go/nogo task, especially across the first four training sessions. the pretest conflict effect [t (54) figure 3 , we also found a significant time × group interaction effect [conflict effect: f (1,54) = 6.821, p = 0.012, η 2 = 0.112; conflict score: f (1,54) = 5.664, p = 0.021, η 2 = 0.095]. through simple effect analysis, two groups of effects were obtained. the conflict effect and conflict score in the training group after training were significantly lower (p < 0.001), while no significant difference between pretest and posttest performance was found in the control group [conflict effect: f (1,27) = 1.025, p = 0.320, η 2 = 0.037; conflict score: f (1,27) = 0.697, p = 0.411, η 2 = 0.025; table 1 ]. the inhibitory control ability in the training group was improved compared with that of the control group because of the training. frontiers in psychology | www.frontiersin.org 5 july 2020 | volume 11 | article 1806 as shown in figure 4 , there was no significant difference between the two groups in the pretest adj bart [t (54) we further analyzed the correlation between the initial threshold and the change in the training group and found a significant negative correlation (reward: r = −0.734, p < 0.001; adj bart: r = −0.620, p < 0.001; figure 5 ). the results indicated that adj bart and reward acquired by the training group after training significantly increased compared with that before training. moreover, the subjects with lower pretest indexes had a greater range of changes through training. from the results of the whole experiment, we not only improved the performance of the training task through 2 weeks of response inhibition training (go/nogo and stop-signal tasks), but also more importantly, we found the migration effect of training in the untrained stroop task and balloon analog risk task. the fact that inhibition control plays an important role in people's complex decision-making process has been verified. there was a gradual improvement in the performance of the training group in two classic response inhibition tasks. the error rate in the go/nogo task (the ratio of the sum of omission errors and commission errors) showed a downward trend over the first four training sessions and increased in the later sessions. moreover, it can be seen from the results of the last two training sessions that the task response decreased while the error rate increased. this may have been because the participants were too reactive, which sometimes led to a rebound in error rates. in the later sessions, there was a gradual balance between the reaction time and the error number, and finally, it tended to be stable. therefore, although the error rate during the last four training sessions showed a slight upward trend, the overall response time showed a downward trend and an obvious training effect could still be seen. the error rate in the sst refers to the proportion of errors in the go response, not the proportion of suppression failures. the low error rate during the first exposure may have been due to the relatively small allocation of cognitive resources in the process of inhibition. with the increase in the allocation of cognitive resources in the inhibition process, the accuracy of keystrokes is ignored and the error rate changes little or slightly increases. however, we can still see the improvement in task performance from the trend in the ssrt scores. there was a significant difference in the effect of the two kinds of training, and it was also found that the pursuit of reaction speed might lead to a decrease in accuracy in the later periods of training, and eventually, the two tended to stabilize. in addition, enge et al. also found that in the latter stage of training in the sst, ssd and mean go reaction time were simultaneously reduced, which would eventually lead to the reverse increase in ssrt (enge et al., 2014) . in this experiment, this phenomenon occurred in some subjects, but the overall trend was not found. lower conflict scores in the stroop task in the training group after training suggested that response inhibition training could be transferred to interference control. this also showed that the two classic response inhibition task training methods are effective. friedman and miyake used latent variable analysis to demonstrate that almost all inhibition tasks have a common inhibitory control mechanism (friedman and miyake, 2004) . although brydges et al. (2012) later used erp technology to show that the two tasks engaged two different cognitive components (brydges et al., 2012) , they were still closely related, and performance could be transferred (maraver et al., 2016) . from the adj bart in the balloon analog risk task, it can be concluded that the training of response inhibition led to an increase in the subjects' risky behaviors, which seems to contradict our hypothesis. however, at the same time, the reward acquired in the task increased after the training. according to the value gained by pumping up the balloon and the probability of explosion, the value of the first 16 rounds of pumping is greater than the value of the nonpumping rounds. it is not until the seventeenth turn that pumping up the balloon becomes irrational (lejuez et al., 2002) . therefore, from the perspective of profits obtained, the subjects were too conservative to avoid balloon explosion, thereby losing the chance to win more money before training. this also explained our increased risk-taking behavior and benefits after training. we therefore suggest that the key decision for balloon analog risk task is not to inflate (this is a continuous process) but to decide when to stop inflating and put the contents of the temporary account into the permanent account. only by making a rational decision to stop inflating (properly suppressing decisions that are too early or too late) can the maximal amount of reward be obtained. each inflation is actually equivalent to a go reaction, and it is the ability of response inhibition that is needed as the basis for the critical and appropriate stopping of inflation. the results of increasing risk-taking behaviors in this paper were inconsistent with those of the previous study (verbruggen et al., 2012) . although many gambling tasks are task paradigms for evaluating risky decision-making, different tasks represent different risky decision-making processes (buelow and blaine, 2015) . the stopping of inflation in the balloon analog risk task may be more related to the ability to response inhibition, which may also have contributed to the inconsistent results across different tasks. we further analyzed the significant negative correlation between the initial threshold and the change amount in the training group and found that the lower the initial value was, the more significant the improvement. this suggested, to some extent, that people with lower initial values were more likely to improve (schmaal et al., 2013) . therefore, we should probably focus more on the lower level of the population, where the limited training intensity could achieve a higher training effect. there are many other factors that affect inhibitory control training. it is widely recognized that emotion and motivation affect cognitive inhibition processes, higher decision-making processes, and other neural or psychological functions (padmala and pessoa, 2011; turner et al., 2018) . in the traditional sense, it is considered that subcortical structures, such as the amygdala, ventral striatum, and hypothalamus, are mainly responsible for processing emotions and behaviors, while cortical structures, such as the dorsolateral prefrontal cortex and anterior cingulate cortex, are responsible for activating cognitive control and higher executive functions (pessoa, 2008) . therefore, appropriate incentives and positive feedback will effectively improve the training effect of the subjects. in addition, some studies failed to achieve transfer effects of training (enge et al., 2014; zhao et al., 2015; kable et al., 2017) , which may be because the differences were not significant due to the insufficient number of subjects or the training time and intensity did not reach the threshold needed to transfer tasks (kable et al., 2017) . as shown in figure 4 , there were also some subjects with opposite results, but this pattern of results were mainly concentrated in those with higher starting values. if the primary group chosen were primarily high-level people, then grouplevel indifference would be inevitable. therefore, the initial level of grouping will also affect the training effect. the basis for improving decision-making through training in response inhibition is brain plasticity (i.e., a change in behavior and its underlying brain anatomy based on experience; spierer et al., 2013) . these changes can facilitate the acquisition of new skills, the improvement of acquired abilities, and the recovery of defective or impaired functions (kelly and garavan, 2005) . changes in behavior and brain plasticity induced by training have been demonstrated at different levels of executive function. research has shown that people's inhibitory control ability is closely related to the inferior frontal gyrus and dorsolateral prefrontal cortex (aron et al., 2004) . at the same time, these brain regions also play an important role in risky decision-making tasks (chiu et al., 2012) . during the training of the inhibitory control tasks, the corresponding brain regions will be repeatedly activated and the connections between the corresponding brain regions will be increased, which will inevitably affect the neural connections in the decisionmaking process. although there is no neuroscientific evidence, it is likely that this is one of the important reasons that response inhibition training changes subsequent performance in decision-making tasks. the results of the control group also showed that reading about self-control skills alone was not enough to improve the participants' inhibitory control skills, which also reflected the need for cognitive training of response inhibition. first, the selection range of the subjects was relatively limited, leading to limited generalization. second, the training time was short, and there was no long-term tracking due to the effect of novel coronavirus, so the duration of the transfer effect cannot be determined at present. third, the degree of improvement in the balloon analog risk task performance in the training group was relatively limited, which may also be related to shorter training time and lower intensity. fourth, as the training group needs to spend a lot of time in the whole training process, our subjects may be potentially inadequate. the problem of subject size is also a shortcoming of most cognitive training studies. because of this, slight differences in some experimental conditions may lead to different migration outcomes or no migration effects between many similar training studies. in addition, for the measurement of inhibitory control and risky decision-making, a variety of evaluation indicators should be used, such as questionnaires, behavioral observation, and imaging techniques such as erps and magnetic resonance imaging (mri), rather than cognitive task paradigms on computers. a single score from the inhibition task or risky decision-making task cannot represent the complex control processes that may be correlated with each other, so it is necessary to use multiple tasks to evaluate the inhibitory control ability and risky decision-making (dougherty et al., 2005) . this study confirms that classic response inhibition training can increase risk-taking behavior in the balloon analog risk task, improve their overly conservative behaviors, properly inhibit them to obtain more benefits, and substantially increase economic rationality. during the whole experiment, various experimental conditions were strictly controlled and the training and transfer effects were statistically significant. it is particularly important that compared with inhibiting the near transfer between control tasks, the risky decision-making task can be considered a far transfer (crespi et al., 2018) and this experiment is a good attempt at selecting a cognitive training far transfer task. research on the transfer effect of inhibitory control training to higher cognitive function and the tracking of training will also become the focus of future research in this field. however, at the same time, we must also make it clear that these higher cognitive processes are not just inhibitory control processes, and whether there is a more general, fundamental process is debatable. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by air force medical university. the patients/ participants provided their written informed consent to participate in this study. px completed the experiment and wrote it. dw and yc assisted the experiment and analyzed the data. zw provided technical guidance and site support. wx grasped the idea and financial support. all authors contributed to the article and approved the submitted version. inhibition and the right inferior frontal cortex behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of adhd 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individual differences in decision-making competence: personality and gender differences reliability and plasticity of response inhibition and interference control wesley says": a children's response inhibition playground training game yields preliminary evidence of transfer effects key: cord-299343-gsrgf4dd authors: wilson, a. m.; aviles, n.; beamer, p. i.; szabo, z.; ernst, k. c.; masel, j. title: quantifying sars-cov-2 infection risk within the apple/google exposure notification framework to inform quarantine recommendations date: 2020-07-19 journal: nan doi: 10.1101/2020.07.17.20156539 sha: doc_id: 299343 cord_uid: gsrgf4dd background: bluetooth-based exposure notification apps can supplement manual contact tracing to reduce sars-cov-2 transmission. their speed, scalability, and privacy preservation are generally acknowledged, but less exploited are smartphones' accurate measurement of duration, and ability to automatically calculate risk from multiple inputs. methods: we model uncertainty in the shape of an exhaled virus-containing plume, inhalation parameters, and distance as a function of bluetooth attenuation. we assume relative rates of viral shedding depend on the timing of exposure relative to symptom onset. we calibrate an exponential dose-response curve on the basis of the infection probabilities of household contacts. the conditional probability of current or future infectiousness, conditioned on how long post-exposure an exposed individual has been free of symptoms, decreases during quarantine, with shape determined by the distribution of incubation periods, proportion of asymptomatic cases, and distribution of asymptomatic shedding durations. it can be adjusted for negative test results using bayes theorem. findings: as an example of our calculations, fifteen minutes of close contact with a high-shedding individual, given a 15% asymptomatic infection rate and no testing, would require 5and 14-day quarantine for their risk of current or future infectiousness to fall below 0.84% and 0.14% risk, respectively. interpretation: the covid-watch app is currently programmed either to use a threshold on initial infection risk to determine 14-day quarantine onset, or on the conditional probability of current and future infectiousness conditions to determine both quarantine and duration. either threshold can be set by public health authorities. assess risk quantitatively according to a formula that combines all available data on exposure(s). more precise measures of duration can be combined with the (considerable) uncertainties in bluetooth assessments of distance and in the modeled level of infectious shedding of the index case, to determine the probability of infection from that exposure. determining the threshold for entering quarantine based on probability of infection should yield better results than from combining three binary thresholds for duration, distance, and the infectious period of the index case. determining the threshold for exiting quarantine based on the conditional probability of current or future infectiousness can optimize the reduction in disease transmission per day of quarantine recommended. the aim of contact tracing and subsequent quarantine is to reduce transmission at an individual and population level. the effective reproductive number r(t) must fall below 1, which can occur through a combination of measures rather than contact tracing alone, before the number of cases will decline. however, decreasing r(t) still has many benefits even if not brought below one. it flattens the curve to spread out the burden on healthcare over time, it buys society more time to build healthcare capacity, and it improves the odds that herd immunity can be delayed until a vaccine becomes available. even if herd immunity is eventually reached, it reduces the degree to which herd immunity is overshot. 10 conservative criteria and durations for quarantine, to which all quarantined individuals adhere, provide the best chance for containment. who recommendations for quarantine were explicitly designed for containment 7 , and have since been made even more conservative in their cdc and european iterations. however, these conservative approaches assign equal risk and corresponding response to all contacts that meet their respective definitions, despite significant variation in the actual risk of infection. overly broad recommendations for quarantine could lead to low quarantine adherence 11 particularly in low-resource communities, defeating efforts to contain and slow disease spread. it may be more effective to estimate risk as accurately and consistently as possible in order to balance feasibility of adherence to the measures and risk of subsequent ongoing transmission from the exposure. to illustrate this problem, we note that the average number of close contacts per infected individual has been estimated to be 59, 12 with well-resourced manual contact tracing able to trace 27-31. 13,14 high community prevalence of infection, e.g. currently estimated as ~3.9% in arizona 15 at the time of writing (july 15) (including estimated undiagnosed infections, but also including individuals already isolated), combined with digital methods that are likely to pick up many contacts not meeting current public health definitions of a contact and high app uptake could result in as high a proportion of people recommended to be in quarantine as a general order to stay home regardless of exposure status. eu guidance suggests that during app rollout, quarantine could be recommended only to those at highest risk as a way to avoid quarantining large numbers of people unnecessarily, which may result in low acceptability and uptake of the app. 16 because of this, we advocate for exposure notification strategies that target quarantine recommendations to those who are most likely to be infected (and thus infectious). if an app were nearly universally adopted by all smartphone users (e.g., if google/apple pushed it via the operating system), and within a week it recommended that half the population enter quarantine, people may cease to pay attention to the notifications or adhere to the recommendations, negating any benefit potentially offered by the app. setting higher thresholds for quarantine could help avoid this scenario. public health authorities can also use quantitative risk assessments to prioritize limited resources such as testing, assistance with the delivery of food and other essentials, and quarantine facilities such as hotels, targeting them toward those most likely to be infected and hence infectious. here we lay out a framework for such quantitative risk assessment, based on the capabilities of bluetooth proximity sensing under the decentralized protocol of the google/apple exposure notification (gaen) api. the risk of infection depends on dose, 17 which in turn depends on the shedding rate of the infected individual (affecting the amount of the pathogen in the air), and on the duration and distance of the interaction. as days go by without onset of symptoms, the probability of future infectiousness decreases, because the probability is conditioned on lack of symptoms for an increasing stretch of time. to be consistent, quarantine would end when the risk of infection falls below the same risk threshold used to decide who should enter quarantine. this procedure would assign shorter quarantines following lower risk interactions, with the steepest slope around the median incubation period. note that this assumes that variation is in probability of infection, rather than in dose conditional on infection (given that higher dose is likely to lead to shorter incubation time) -we return to this point in the discussion. clear messaging is still possible, with the app either giving only the date on which quarantine ends, or summarizing quantitative information through a daily risk score that falls each day in the absence of symptoms or positive test results. the app can also recommend an optimal date for testing. when a user reports positive infection status, the gaen framework ( figure 1 ) allows apps to assign a "transmission risk level" to each day that they might have been shedding, and to communicate this level to the receiver's phone via a temporary exposure key (tek). these transmission risk levels can be assigned on the basis of date of symptom onset or test date. on the receiver's device, the gaen framework can record the bluetooth attenuation as a rough estimate of distance, and the duration of exposure. overview of risk assessment approach for a single exposure. we report on preliminary calibration to inform infection risk calculated on the receiver's phone. here we propose a risk scoring system for use in a gaen or similar framework. we parameterize it based on currently available data about covid-19 infection risk factors, while proposing a system flexible enough to be continually improved as more is learned about viral dynamics. we demonstrate how this risk scoring system could be applied either to an approach aimed at slowing transmission in a community outbreak far from containment, or with a more stringent threshold in a community where outbreaks have been contained within a country's borders but there is still need for active monitoring and surveillance because borders are not closed. our group plans to pilot and evaluate the covid-watch app using portions of this scheme on the campus of the university of arizona. our microbial exposure model estimates the airborne spread of viral particles from an emitter's mouth following a gaussian plume formation, and their subsequent inhalation by contacts. we use a monte carlo approach to average across a variety of sources of variability and uncertainty that affect the estimated inhaled dose. the gaen v1.1 framework records durations only up to 30 minutes, in order to protect anonymity of covid-positive patients by limiting the risk that users will be able guess the source of their exposure, while still meeting contact definitions that invoke minimum exposure duration of 15 minutes. we note that when a high risk threshold is chosen by a community attempting to limit the proportion of the population under quarantine, this 30-minute cap will prevent the app from achieving resolution among high risk exposures, and thus prevent it from targeting quarantine recommendations and material resources to those at highest risk of being infected and subsequently infecting others. the gaen allows for durations to be recorded separately within three bins of attenuation, thus allowing a total exposure duration of 90 minutes if the attenuation varies in the necessary manner over the exposure. we calculate a weighted sum of the three durations, using the weights to capture the differences in expected dose (number of inhaled particles over an exposure time). note that gaen v1. 5 (not yet released) will lift this cap, but will impose limits to our ability to differentiate among transmission risk levels (discussed below). we focus here on gaen v1.1, but our scheme can be adapted for later versions. to inform our choice of weights, we first sample distance as a function of which bin attenuation falls within, and then we capture uncertainty in angle relative to the plume through random sampling. the average interpersonal distance during close contact in a graduate student office in china was found to be 0.81 m, 18 making 1 m a good threshold for distances likely to reflect face to face interactions, where the plume is directed at the exposed individual. at greater distances, many individuals will not be directly facing one another but rather side-by-side or in another geometric formation regarding the emission plume and the inhalation zone of the one being exposed. we also sample from variance in inhalation and exhalation rates. we set the weights to represent relative mean doses as a function of attenuation. while it has been demonstrated that wind velocity and relative humidity are important factors for determining droplet and fine aerosol dispersion and deposition, 19, 20 as is mask usage, these are uncertain factors that are not recorded by the app, especially considering that interactions may occur indoors or outdoors. therefore, our approach to the risk per exposure focuses on the distance, duration of the interaction, infection status, and relative shedding rates of individuals in the interaction. by not accounting for deposition, and by assuming that masks are either not worn or not worn effectively, we will tend to overestimate dose at greater distances, and in the presence of masks. this will implicitly lower the app-imposed risk tolerance of individuals who comply with public health guidelines that recommend masks and physical distancing, and who might therefore also be more inclined to comply with quarantine recommendations. the 2-meter rule was based on the assumption that transmission is via large droplets for which deposition occurs over this distance -this no longer appears to be the case, 21, 22 supporting our assignment of some risk to greater distances. from this dose calculated as the weighted sum of exposure durations, we use an exponential dose-response curve to calculate the probability of infection. this curve has a single composite parameter representing the product of the conversion from arbitrary units to viral particles and the probability with which each viral particle might independently initiative infection. we calibrate the value of this composite parameter so that probabilities of infection given long exposures match those observed for household contacts. the overall approach is summarized in figure 1 , describing how each of the following modeling pieces are used to inform an infection risk. parameter values and their descriptions and sources can be seen in table 1 for calculations performed by the app and in table 2 for parameters we used during calibration. transmission risk level in the gaen api is a proxy for the magnitude of viral shedding and can be set by the app on the basis of a simple questionnaire administered to users reporting a positive diagnosis. we use this to inform expected shedding . the first question we ask to inform transmission risk levels is "what day did your symptoms start"? a curve fit to known transmission events suggests peak transmission the day before symptom onset, and essentially no transmission more than three days before symptom onset. 23 however, this might be confounded with behavioral changes with symptom onset, with ascertainment bias in terms of which transmission events are easiest to document, with possible errors in the direction of transmission given the variability of incubation periods, and with assumptions regarding the shape of the curve. worse, the analysis appears to have significant technical flaws. 24 a second source of information is quantitative pcr. however, this may reflect non-infectious viral remnants, especially late in the course of disease, where the proportion of culture-positive pcr results tends to decrease. 25, 26 however, this decline is also expected from a simple doseresponse curve, where the probability of culture-positivity decreases as the amount of shedding decreases late in infection, i.e. the decline in infectivity might be quantitative rather than qualitative. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . angle between the zaxis and the xy-plane used while informing weights. if ≤ 1m, φ= π/2,if > 1m,φ randomly sampled from triangular(min= π/4, mode= π/2, max= 3π/4) 1 m. cutoff for face-to-face interaction informed by 37 θ angle between x and y axes used while informing weights. if ≤ 1m, θ = 0,if > 1m, θ randomly sampled from uniform(0, 2π) 1 m. cutoff for face-to-face interaction informed by 37 while informed by the two sources of data above, we focus the most on data in which virus was successfully cultured from patient samples, as a clear indication of infectivity. arons et al. 26 took prospective samples throughout a nursing home, and were able to culture virus from six days before symptom onset until nine days after symptom onset, with little quantitative trend in shedding rate conditional on a positive test. in hospitalized patients, wölfel et al. 28 were unable to isolate live virus from cultures more than 8 days post symptom onset, despite pcr evidence of high shedding. in one case report, live virus has been isolated 18 days after symptom onset, but this seems to be an outlier. 38 bullard et al. 25 quantified both tcid50 and pcr for 7 days post symptom onset, and saw an approximately 10-fold decline in infectious dose. we note that culture methods may not be sensitive enough to capture low concentrations. 26 we nevertheless use this tcid50 data as motivation in assuming a 10-fold dynamic range in shedding rates as a function of day relative to symptom onset. more studies measuring infectivity in a quantitative manner are needed. encouragingly, agreement of culture data to epidemiological modeling improved after corrections to the latter were made. 24 a final source of information comes from detailed taiwanese contact tracing 14 , who found a 1.0% symptomatic attack rate (95% ci 0.6-1.6%) for those exposed within five days of symptom onset, and 0% (95% ci 0-0.4%) for those exposed after. risk from exclusively pre-symptomatic exposure was 0.7% (95% ci 0.2%-2.4%). we use 6 of the 8 transmission risk levels in the gaen api to capture this range, evenly spaced on a log scale between 10 and 100 in arbitrary units, reserving the use of levels 7 and 8 for individuals for testing purposes and any future functionality. these levels could also be . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . manipulated for testing purposes, e.g. to help learn, if individuals voluntarily enter exposure details into a manual contact tracing database, how transmission risk varies in the real world, rather than just in tcid50 studies, as a function of a symptomatic status and time. we note that transmission risk levels have been deprecated in the announced gaen v1.5, and replaced with only two possible levels of infectiousness. while the functionality of v1.1 should be preserved, we note that usage of transmission risk levels would need to be standardized across different apps in order to ensure interoperability. in the description below, we outline not just our use of v1.1, but also the use we would make of six levels of infectiousness if they were to again be made available in a future api version. the assignments we use in this framework can of course be improved as more data become available. our call for more than two levels of infectiousness comes from the fact that a systematic 10-fold difference in tcid50 has been observed, and that such a large difference seems to warrant more levels. based on a holistic reading of the four sources of evidence described above, we assign the maximum level of 6 from one day pre-symptom onset to two days post-symptom onset. five or six days before symptom onset we assign level 1, four days before we assign level 2, three days before level 3, and two days before level 5. three days after symptom onset we assign level 5, four days after level 4, five days after level 3, 6-7 days after level 2, and 8-11 days after level 1. for users who report a positive test but no symptoms, there is likely a reason they were tested, and so we ask for the most likely day of exposure, if known. if provided, we assume that shedding did not begin until two days after exposure, at the earliest. we also ask for the date of sampling for the positive test (which can be reported by the healthcare provider rather than the app user) and assume peak shedding at around this time. subject to the constraint from day of exposure, we assign transmission risk level 3 to dates within with one day of the test, and level 2 to dates between 2 and 4 days of the test, although as discussed below, one study reports substantially longer shedding than these 9 days. 33 there is some evidence that viral shedding is lower in asymptomatic vs. symptomatic cases, 30, 39 while another study indicates the shedding magnitudes may be similar. 40 note that we assume that those with no symptoms at the time they receive a positive test result are asymptomatic rather than pre-symptomatic -should test turnaround times be sufficiently fast, it would be useful for users to be able to report symptom onset after the fact and trigger a change to previously reported transmission risk levels, and we recommend that this functionality be added, together with restoring a greater number of transmission risk levels, in future versions of the gaen framework. we model a gaussian plume 41 originating from the emitter's face at (0,0,0). the x axis represents the direction that the transmitter is facing and breathing toward with breath velocity (m/s). diffusion causes spread away from y=0 or z=0. the viral concentration is then , , (1.1) . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. where is virus emitted per second and is equal to the product of shedding rate, , (in arbitrary units proportional to copies/m 3 ) and an exhalation rate, , (taken from measured inhalation rates in m 3 /s), yielding arbitrary units proportional to copies per second being generated (eq 1.1). we sample our exhalation rates from a normal distribution of inhalation rates where mean and standard deviation, 16.3 and 4.15 m 3 /day, respectively, were informed by the 16-21 year old range from table 6 -1 in the exposure factors handbook (2011). 34 to avoid negative exhalation rates, this distribution was left-truncated at zero. the velocity of breath (m/s) was determined by dividing the exhalation rate (m 3 /s) by the cross-sectional area of an open mouth (m 3 ), which is the area over which air is assumed to be exhaled at the plume source. the crosssectional area was informed by a uniform distribution with minimum and maximum crosssectional areas measured for an open mouth with a "large bite" configuration, ranging from 23 to 59 cm 2 . 35 to capture the shape of the plume, we use: assuming moderately stable conditions, and were randomly sampled from uniform distributions with minimums and maximums of 0.08-0.25 and 0.03-0.07, respectively. 36 we note that inhalation and exhalation rates are both likely important to risk. for example, one infected dance instructor spread covid-19 to 7/26 other instructors at a four hour workshop, 42 representing a similar risk as for household contacts, despite the presumption that most were at >2 m. distance for most of this time. limited air circulation or increased respiratory rates are important factors that cannot be captured in the gaen approach, but the four-hour duration of the workshop could be, combined with considerable uncertainty in the relationship between bluetooth attenuation and distance, in order to correctly capture the high risk of such a scenario. an inhaled dose of viral particles due to person-to-person interactions was estimated based on the duration of the interaction (minutes) ( ), the concentration of virus in the air at this x-y-z coordinate during the interaction (arbitrary units of viral particles/m 3 ) , , , and inhalation rates (m 3 /minute) ( ), inhalation rates were randomly sampled from the same distribution as exhalation rates but allowing for a different value per iteration. as with exhalation rates, we left-truncated the distribution to avoid negative inhalation rates and therefore negative doses. using the model described above, we sample a distance compatible with the attenuation bin in question, and then sample angle, inhalation and exhalation rate, and cross-section of an open . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . mouth to obtain a mean dose/time for that attenuation bin. our code holds shedding rate and exposure duration constant at 50 arbitrary units/m 3 and 30 minutes, in order to isolate the effect of distance on differences in dose between attenuation buckets. preliminary alpha testing data on gaen v.1.1 (unpublished dataset) provided us with a set of distances between phones, combined with measured attenuations, across a range of phone models, and possible interference from nearby objects. note that improvements made in the forthcoming gaen v1.5 are expected to improve our ability to estimate distance as a function of attenuation. while useful, we note that new experimental data would be required for recalibration. note that our method is not based on mapping thresholds in distance to thresholds in bluetooth attenuation, but instead on resampling from the probability distribution of distance as a function of attenuation. from this preliminary dataset, we sample the distance in meters from the emitter by sampling from the observed probability of distance given a certain bluetooth attenuation. for distances ≤ 1 meter, we assume face to face interactions, consistent with distances measured for "interpersonal" interactions 37 . therefore, for interactions in this close range (≤ 1m), we assumed two people interacting are directly in front of each other along the x-axis (φ = π /2, θ=0). for interactions beyond the close range (>1m), we sample θ from a uniform 360 degrees (min=0, max=2π), and the angle between the z axis and the xy-plane, φ, was randomly sampled from a triangular distribution (min=π/4, mode=π/2, max=3π/4). we then convert from spherical units to (x,y,z) to apply eq. 1. we assumed that scenarios where the person exposed was behind the emitter (x<0) resulted in a zero dose. to select the threshold values (a, b) demarcating 3 attenuation bins, we optimized the differences in mean dose between two randomly sampled attenuation measurements. specifically, we maximized the value of where , and are the average doses from eq. 4, averaged across monte carlo sampling described in the section above, corresponding to bins (0, a), (a, b), and (b, +), and , , and are the probabilities that an attenuation will fall within that bin. we used preliminary experimental data, for the distribution of pairs of distance and attenuation, we found an optimal partition pair of attenuation thresholds, with ~10-fold difference in weights. note that this is of the same order as the 10-fold difference in transmission risk values. variation in duration among real exposures is larger, and will be able to be recorded in gaen v1.5. this procedure for setting weights will need to be repeated as more data is collected and/or any changes are made in how the gaen api calculates bluetooth attenuation. future data could include both controlled settings to measure the distance-attenuation relationship and hence values of , , and , combined with more natural settings to inform the , , and values likely to be seen in real use. we use an exponential dose response curve, which is derived from the assumption that each host is susceptible and that each virus has an independent probability of survival and . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . subsequent initialization of infection, so that "organisms among replicated doses" follow a poisson distribution. 17 in our case, this probability , multiplied by a constant to convert from arbitrary units to number of viruses, sets the parameter in the equation where dose comes from a shedding rate multiplied by a weighted sum of time spent within 3 attenuation ranges. an exponential dose-response curve is superior to the approximate beta-poisson for some viruses, according to evaluations by the center for advancing microbial risk assessment (camra) through their qmra wiki: http://qmrawiki.org/content/recommendedbest-fit-parameters. these viruses include adenovirus, enterovirus, poliovirus, and sars-cov-1. our weighted sum of durations and our estimates are both in arbitrary units. we therefore fit to obtain infection probabilities that are compatible with household spread, where infection risk is relatively well documented, albeit still quite uncertain. asymptomatic infection and low test sensitivity can both deflate estimated infection risks, while indirect chains of infection via a third household member can inflate them. a meta-analysis by curmei et al. 29 attempted to correct for these complications, and estimated a secondary attack rate of household contacts of 30%. we assume exposure is equivalent to 8 hours with the maximum shedding rate in the lowest attenuation. we found that λ=3.78 x 10 -6 yields infection probability of 0.30 for this scenario. note that the best way to calibrate λ would be after the app is piloted or rolled out, with manual contact tracers compiling exposure characteristics and relating them to the rate of subsequent infection. our calibration is necessarily highly approximate but should not affect the rank order of risks. so far, we have estimated the probability of infection from an exposure. to calculate the probability of infection on a subsequent day, conditional on no symptoms until that day, we apply a discount factor based both on time elapsed without symptoms and also any negative test results. we multiply the probability of infection from an exposure with this discount factor to determine the remaining risk of infectiousness from a given exposure. traditional quarantine guidelines are binary (either 14 days from date of last exposure, or no quarantine required). however, the risk of onward transmission declines as a function of time elapsed since exposure, because the probability of infection is a conditional probability, and each day without symptoms provides more information to make current or future infectiousness less likely. a consistent approach to risk, combined with a desire to impose quarantine days in the most efficient manner possible to combat disease spread, suggests that individuals should quarantine for longer following a higher-risk exposure (figure 2a vs 2b) . . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . applying a consistent risk tolerance causes quarantine duration to be a function both of initial risk and of the tolerated degree of risk. initial risk in a) is from 15 minutes of close contact with an individual around the time of symptom onset, that in b) is with someone at the margins of the infectious period who is shedding at a 10-fold lower rate. the lowest risk threshold shown with grey shading is that implied by a 14 day quarantine duration. we assume 15% of infections are asymptomatic and that no testing is performed. day 0 is included in the total quarantine times, i.e. a 14 day quarantine means that the individual is released on day 14. to calculate residual risk of infection as a function of initial risk plus time since exposure, we use the probability distribution of incubation periods from lauer et al. 32 , available at https://iddynamics.jhsph.edu/apps/shiny/activemonitr/. note that it is possible that incubation periods are even more dispersed than reported here 43 ; this could be coded to lengthen quarantine recommendations. to calculate risk of current or future infectiousness, we assume a fraction of symptomatic vs. asymptomatic cases and take an average of the discount factors applying in each case. across a population, 15% of infections are estimated to be asymptomatic. 30, 31 younger users are more likely to be asymptomatic 44 , so the fraction of asymptomatic cases could be personalized on the basis of user age if that information is collected on a voluntary basis. for the symptomatic cases, we discount according to the probability of subsequently developing symptoms, given that symptoms have not appeared yet. for the asymptomatic cases, we combine the incubation periods from lauer et al. 32 with the distribution of shedding durations from long et al. 33 , including both symptomatic and asymptomatic cases in the latter. while long et al. report slightly longer durations for asymptomatic shedding, three other studies [45] [46] [47] , for which we were unable to obtain the data, report the opposite. we assume that shedding begins 3 days before what would have been the day of symptom onset if symptomatic, or else immediately upon infection, whichever occurs later. using this assumption, we calculate the probability distribution of the day that shedding ends, given both the distribution of incubation periods and the distribution of shedding durations. long shedding periods ensure less discounting for the asymptomatic fraction ( figure 3a ) that can be mitigated by testing ( figure 3b , described in section below). note that strictly speaking, our "quarantine" recommendations are, through their treatment of the possibility of undiagnosed asymptomatic infection, a combination of quarantine and isolation. figure 3 . the fraction of infected individuals who are asymptomatic and the availability of testing both strongly affect quarantine lengths. a.) quarantine following 15 minutes of close contact with an index case at time of peak shedding must be longer to mitigate the risk of asymptomatic infection in the exposed individual. b) a negative test result, shown here as taking place on day 4, can greatly shorten the long quarantine that would otherwise be required for a young individual for whom infection has a 50% chance of being asymptomatic. we apply bayes theorem with 70% sensitivity and 100% specificity. day 0 is included in the total quarantine times. we currently consider the harm from the release of any infectious individual to be equivalent to that from the release of any other. extensions of our approach could take into account greater harm from someone never quarantined and hence shedding for the full duration relative to someone released prematurely partway through asymptomatic or pre-symptomatic shedding, for whom a portion of the harm has already been mitigated. this would lead to steeper discounting. gaen v1.1 will not record either a single long exposure or multiple exposures from a single individual beyond the 30 minutes cap for each of three attenuation bins, although this will change in v1.5. however, it will record exposures happening on different days (considered to change at midnight utc) as independent exposures. to calculate total risk, we combine the probabilities of each exposure , each discounted as described in the section above, as 1 ∏ 1 . we communicate total risk, and determine the appropriateness of quarantine, based on this combined probability. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . for earlier release. from bayes theorem, and taking the false positive rate as negligible, a negative test result changes the probability of infection from to 1 1 ⁄ , where is the false negative rate. this could be taken as 0.3 48, 49 or made dependent on the timing of the test relative to exposure, 50 which would require distinct application between multiple exposures in its application. figures 2 and 3 illustrate scenarios of a single exposure. when there are multiple exposures, quarantine durations are determined with respect to total risk. the risk threshold for initiation and completion of quarantine are the same. in other words, risk is treated in an internally consistent fashion to achieve the maximum possible benefit from a given number of recommended quarantine days across a population. the degree to which a public health authority chooses to be conservative vs. to minimize quarantine can be set through the selection of the risk threshold, as illustrated in figure 2 . when the threshold is set well below the probability that a randomly chosen member of the population is currently infected, it should be recognized that individuals agreeing to download and comply with the recommendations of the app are implicitly agreeing to adhere to higher standards than those implied by the current absence of a general stay-at-home order. at the time of writing (july 15), this rate is ~3.9% in arizona. 15 such a high risk threshold is not currently practical in gaen v1.1 due to the restriction on recording long duration exposures, which prevents discrimination among high risks, but will become possible in v1.5. we note that our formula for calibrating absolute risk is imperfectly calibrated, but better calibration is not likely to change this fact. kucirka et al. 50 report a false negative rate as a function of the timing of a pcr test relative to symptom onset. they assume a fixed incubation period of 5 days, and use this both as a filter on their data, and to express their results in terms of time since exposure. we reran their code for different incubation periods, and calculated false negative rates in terms of time since exposure as a weighted average across different incubation periods as estimated by lauer et al. 32 and reported in table 1 . before use as in bayes theorem above, they should be adjusted in a form of survivorship analysis; if testing is conditional on no symptoms to date, then the ratio of pre-symptomatic : asymptomatic individuals in the reference group will depend on time since exposure. approximating all as asymptomatic, we can use these false negative rates to recommend an optimal day for testing. for example, we could choose the days on which the probability of obtaining positive test results is highest. we calculate this probability as the sensitivity on that day × the conditional probability of infection on that day given no symptoms to date. given exposures on multiple days, the sum of this product can be computed to choose a date for testing. alternative criteria for optimization could also be devised, e.g. explicitly prioritizing highly exposed individuals whose calculated quarantine in the absence of a test would exceed 14 days. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . to set the risk threshold used by our scheme to recommend quarantine, we consider the current advice for 14-day quarantine following 15 minutes of exposure in contact close enough to be logged as low attenuation. the risk of such an exposure depends on the degree of shedding, which is a function of the timing of exposure, e.g. relative to the onset of symptoms of the index case if symptomatic. an index case shedding at the peak rate has a 1.11% infection risk, which falls to a 0.14% probability of current or future infectiousness after 14 days of quarantine during which no symptoms appear. note that this initial infection risk is broadly compatible with the attack rate reported in taiwan (1.0%, 95% ci: 0.6-1.6%) for those interacting with index cases in the first 5 days of symptom onset, 14 which is similar to the 0.88% (51/5,785) attack rate reported in south korea. 51 based on this scenario, we use 0.14% as a benchmark threshold for the risk of current or future infectiousness, or as a default setting for public health authorities who seek to approximate the risk tolerance implied by current recommendations. note that current advice treats the larger risk of longer exposure the same, making a 0.14% threshold more conservative because it is calculated to generate a 14-day quarantine for a minimal duration of exposure. however, this is at least partly offset by our assuming maximal shedding in calculating this benchmark example. in other words, while this threshold approximates the risk tolerance of current advice, the details of who is recommended for quarantine and for how long will be different in our quantification of total risk than it would be if we were to combine independent binary thresholds for infectious period of index case, duration of exposure, and distance to produce a quarantine duration of uniform length. this leads to more consistent treatment of risk to yield the greatest benefit in terms of transmission prevented per day of quarantine recommended. another benefit to using the quantitative risk framework described here is that the threshold can easily be adjusted by public health authorities to respond to local conditions. this could mean raising the threshold to in order to prevent excessive quarantine recommendations that might discourage both app uptake and quarantine compliance, or it could mean lowering it in populations that have achieved local containment and wish to be highly conservative against the threat of reintroduction. a single exposure currently saturates at a maximum set by gaen v1.1 of 30 minutes in each of the three attenuation bins, likely representing a high-risk interaction of significantly longer than 90 minutes. the formulae described above assign an infection probability of 3.59% given maximum transmission risk level, results in an estimated 26-day quarantine/isolation in the absence of testing for the risk of current or future infectiousness to fall below 0.14%. a similarly maximal interaction, i.e. with 30 minutes in each attenuation bin, but with an index case at the minimum transmission risk level, corresponding to exposure timing that is not risk-free but falls just outside the window currently used by manual contact tracers, yields an infection probability of 0.36%, requiring 7 days of quarantine. variation in quarantine length is to be expected -if total risk is scored consistently, some quarantines will be longer and others shorter, in order for residual infection probability, conditional on time elapsed without symptoms, to fall below a threshold set by the public health authority as acceptable. the calculations above assume that 15% of infections are asymptomatic. if we assume that 50% infections are asymptomatic, e.g. in a young age group, even a 15-minute contact registered as low attenuation and with peak shedding in the index case would require a 26 day quarantine/isolation to meet a 0.14% threshold (figure 3) . note that the degree to which the risk of asymptomatic infection lengthens quarantine/isolation depends on our assumption about the distribution of shedding durations. we used those from long et al. 33 because it was the only paper for which the raw data was available. more data on this point is needed, including the need to make available data from studies that have already been done [45] [46] [47] . more data is also needed to confirm whether late shedding is of non-viable virus, or if late shedding is merely at low rates that fall below the sensitivity of cell culture assays to detect viable virus. we currently assume the latter. if exactly the same prolonged, high-risk interaction were all recorded in the low attenuation bin, only 30 minutes would be recorded. in this case the app would calculate infection risks of 2.21% and 0.22%, and quarantine durations of 21 days and 5 days for the maximum and minimum transmission risk levels, respectively. this illustrates how the 30-minute cap on exposure durations can lead to inconsistent quarantine recommendations by amplifying chance variation in how bluetooth attenuations are recorded. we acknowledge that extended durations are less privacy-preserving, because they increase the ability of exposed individuals to guess the source of their exposure. however, we feel that other solutions to this problem might exist, such as concealing all exposure details such as date and exposure duration within an app, and revealing only the total risk. at some point, the privacy considerations need to be weighed against the interests of better controlling disease spread with the most efficient requests for quarantine. note that the 15-minute close contact exposure with an index case at time of peak shedding, discussed above as our reference case, yields infection probabilities of 1.11% only if it is all successfully recorded in the low attenuation range. if the contact were logged in the medium attenuation bin instead, e.g. because the phone was in a bag, it would instead yield an infection probability of 0.61%, resulting in 9 days instead of 14 days quarantine to fall below a 0.14% risk threshold. for high attenuation, risk is 0.11%, resulting in no quarantine. these differences reflect the degree to which bluetooth can distinguish distance under the current gaen api. improvements to gaen and/or more data on the relationships between risk, distance, and attenuation might change our assessment of this degree. the default calibration with a 0.14% risk threshold sets the threshold for some amount of quarantine at around 15 minutes of contact, sometimes more and sometimes less depending on the assessed level of viral shedding and on stochastic variation in how bluetooth attenuation is recorded. the noisy relationship between attenuation and distance means that quarantine recommendations will include exposures at significantly greater than 2 m distance. however, these exposures are not risk-free either, in particular if taking place in an indoor environment, especially in cases with heavy breathing, such as exercise environments 42 or choir rehearsals, 52 where aerosols may mix throughout the room and also deposit on surfaces. when the risk threshold is set high, e.g. to modestly below the current prevalence of infection in arizona, it becomes difficult to get significant quarantine following single exposures, whose maximum risk is 3.59%. relaxing the 30-minute cap on durations is necessary in order to get resolution among higher risks. unless the cap on duration is removed, few single exposures will approach, let alone exceed, the overall probability of current infection in arizona. note that when the infection risk of the average person in the population is high, we believe that stay home orders or population-level shutdowns are essential to reduce transmission, meaning that individual quarantines from the app would be replaced by a blanket quarantine order for all but essential workers. under these circumstances, a gaen app might still have utility for . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . essential workers. however, a gaen app could be an inferior but still useful option should the political will for population-level shutdowns not exist. the need for consistent guidance to the public is an important consideration for implementing tailored risk scoring and modified quarantine recommendations. if for the sake of a consistency, a public health authority is not willing to authorize variable quarantine recommendations, as is currently the case in arizona, but only 0 or 14 day quarantines from time of the last individually significant exposure, then the threshold for going into quarantine at all would need to become more strict in order to maintain the same overall risk among the population under quarantine. in other words, retaining the same average probability of current or future infectiousness among the quarantined population would require some exposed individuals to no longer go into quarantine at all, in addition to others lengthening their quarantine out to 14 days. with a binary 0 or 14 day quarantine, the amount by which disease transmission is prevented per day of quarantine will be lower. to avoid mixed messaging regarding quarantine durations, one option is to suppress all details about individual exposures from the user's view, including their date. this has the additional advantage of decreasing the risk that users will be able to guess who exposed them, further preserving privacy. the app could then communicate only total risk, either as a binary recommendation for which days to quarantine, or also as a quantitative score in order to "gameify" the process of quarantine and give users positive feedback for each day they succeed in remaining at home until it falls to a lower level. further research is needed to assess the most effective messaging strategies. conflicting messages can still arise if manual contact tracers trace an individual who also received an exposure notification. in this case, it is likely that the two recommend different end dates for quarantine. this is to be expected from our procedure for recommending variable quarantine durations, but we note that even if the app were to issue 14 day quarantine recommendations only, it could still arise because the individual has been exposed more than once, on different days, and the manual contact tracer is following up an index case who may not have used the app. until there is reliable data on app performance, we recommend that the manual contact tracer's protocol should override whatever the app says. should the app turn out to perform well, an alternative procedure might eventually be to go with whichever protocol recommends the longer quarantine. an intermediate possibility is for the manual contact tracer to ask for exposure notification details, to determine whether it may be a different exposure to the one being manually traced. here we quantify relative risk using monte carlo simulations and roughly calibrate it to absolute risk based on limited information from the infection probability of household contacts. errors in calibration are likely but will generally not affect the rank order of risks. for example, adjusting the risk threshold of 0.14% for quarantine will have similar effects to adjusting the value of λ. knowledge of absolute vs. relative risk does have some effect once some saturation in risk begins to occur, little of which will occur unless much longer durations are recorded. the ability to adjust the risk threshold provides communities with flexibility in deciding how readily quarantine should be recommended and for how long. communities that have achieved containment might choose to set a stricter threshold, mitigating the harms of longer quarantine through testing individuals once or twice, lowering their risk following each negative test. communities with high prevalence might raise the threshold if it seems likely that the number of quarantine recommendations being issued by the app will cause it to fall out of use, reasoning that a harm reduction strategy for app use is better than using quarantine guidelines that the population is unwilling or unable to comply with. the covid-watch app is currently programmed either to use a threshold on infection risk to determine 14-day quarantine onset, or on risk of current and future infectiousness to determine both quarantine and duration. either threshold can be set by public health authorities flexibly in the light of external factors such as level of community transmission, jurisdictional comfort with uncertainty related to exposure notification applications, and current public health science and recommendations. overall, we capture a 10-fold difference in risk due to the dependence of shedding rates on the timing of exposure. variation in bluetooth attenuation also provides about a 10-fold ability to distinguish risk, based on our simulations and limited preliminary distance-attenuation data. apps can measure duration far more accurately than distance, but the gaen v1.1 duration cap of 30 minutes, combined with the use of 5 minute windows, mean that only ~6-fold differences in risk are captured in this way, or up to ~18-fold when longer exposures absorb the stochastic variation in attenuation, or much longer in gaen v1.5 where there is no cap on duration. with 15% cases being asymptomatic and no testing, the risk of current or future infectiousness falls ~9-fold over the first 14 days of quarantine. under gaen v1.5, risk will sometimes differ more between two individuals entering quarantine than when comparing the same individual before vs. after a 14-day quarantine. for this reason, our scheme could recommend quarantines significantly longer than 14 days. to avoid the hardship this would inflict, such individuals could be given priority access to testing, with negative test results acting to shorten (but not eliminate) their quarantine. public health authorities could also opt to truncate quarantine at the current 14 days, i.e. to set a risk threshold only with respect to initial infection risk, and not with respect to the conditional probability of current or future infectiousness. this is the approach currently scheduled for pilot in arizona. we caution that our derived relationship between bluetooth attenuation and infection risk is extremely approximate and model-dependent, as are our settings of transmission risk levels. both need to be calibrated with real world data on app users who report their app-recorded exposures to manual contact tracing efforts, who then track which users go on to test positive, and who are therefore able to mine the data to quantify the quantitative relationship between exposure details (duration, attenuation, transmission risk level) and probability of infection. transfer of this data to manual contact tracers' contact management databases is critical to improve the targeting of quarantine recommendations to those at highest risk of being infected, which will make most efficient use of each day of quarantine recommended in order to reduce transmission. short of this, more quantitative data on infectivity would be extremely valuable. our determination of shedding duration relies heavily on the prospective sampling of all individuals in a skilled nursing facility 26 , where many patients subsequently got sick. daily samples during similar outbreaks could be used to quantify how shedding varies both among individuals and as a function of time relative to symptom onset. tcid50 data would be ideal, but even ct values . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156539 doi: medrxiv preprint can be valuable for this purpose. however, the fact that the settings we originally chose based on infectivity data turned out to agree with the subsequently published correction to an influential epidemiological approach 24 is encouraging. the complete approach described here no longer recommends quarantine until the probability of current or future infectiousness falls a fixed amount relative to initial probability (estimated here as ~9-fold less than initial) and independently of what that initial probability is, but instead quarantine until the absolute probability falls below a threshold. a potential benefit of shorter quarantines is that they might significantly reduce the harms imposed by quarantine, 11 and increase compliance 53 (although see mcvernon et al 54 ). quarantining for 14 days post-exposure may be exceptionally challenging for essential workers, individuals without sick leave, or those who would endure significant financial hardship due to lost wages. however, in populations with low risk tolerance but without testing access, quarantines calculated by our scheme might be long, especially if age is taken into account, with younger individuals issued longer quarantine periods to account for their greater risk of asymptomatic infection. if using the discounting portion of our approach, risk values can be used to prioritize such individuals for testing to avoid quarantines of over 14 days.. as the conditional probability of current or future infectiousness (conditioned on the exposed individual being asymptomatic) fluctuates throughout their quarantine period, messaging can also change. e.g., during the initial high risk days, users might be offered concrete resources such as grocery delivery, or the option to quarantine in a specialized facility in order to protect other household members, before transitioning to self-quarantine once risks falls. even with self-quarantine, an app might distinguish between the days on which staying home is the highest priority vs. merely desirable. as programmed in covid-watch on the basis of the unpublished dataset mentioned above, each day without symptoms lowers the residual risk of current and future infectiousness. to communicate this to users, one option is for the app to display both current and projected risk of infectiousness on a simple scale of 1 to 10, so users can see how that risk will fall with each day of quarantine. this visualization might change perceptions. e.g., an individual who wants to comply with a 14 day quarantine, but does not feel able to, might rush out to get groceries before starting their quarantine in earnest, while shedding virus pre-symptomatically. visualizing projected risk into the future would then give the message that if the exposed individual can only make do for one more day before leaving the home for essentials, that will help, because if they do not develop symptoms, their risk will be lower even after a single day longer. risk communication in an app could focus on day to day coaxing of this form. note that with symptom onset sometimes as early as two days after exposure, and given the possibility of pre-symptomatic shedding, we currently ignore the possibility that shedding might not yet have begun. current testing turnaround times are mostly long, making this reasonable. however, if same-day tests become more widely available, our approach could be extended to directly communicate the risk of current infectiousness, rather than as is currently the case, the risk of current or future infectiousness. a significantly lower risk of infectiousness will be present on the day of exposure and perhaps also the day after. delays in going into public to prepare for a long quarantine could inadvertantly lead to pushing individuals past the latent period before . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156539 doi: medrxiv preprint they go into public; displaying a full projected timeline of the projected risk of infectiousness could avert this, at the risk of significantly more complex messaging than "stay home until friday". note that low dose exposures, e.g. to asymptomatic individuals, may result in longer incubation periods, 43 suggesting that low initial risk scores should have longer rather than shorter quarantines. we ignore this by assuming that risk scores primarily capture uncertainty in the likelihood of infection with a minimal dose, and not variation in the infecting dose once above the minimal. to see how this assumption arises from our model, note that the exponential doseresponse curve we use assumes that each virus has an independent probability of initiating infection. the number of viruses responsible for the initial infection follows a poisson distribution. when the absolute probability of infection per contact is low, as is the case for covid-19, most infections will be initiated by only a single virus. even for the 30% infection rate of household contacts, the probability under a poisson distribution that infection is initiated with two or more viruses is only 3.7%. without significant variation in the number of initiating viruses per infected patient, we no longer expect incubation time to depend on dose. however, our dose-response curve is calculated for the mean dose, rather than integrated across the probability distribution of possible doses. if real-world calibration data were collected, we would have a better basis to estimate, in natural settings, the variation in dose given similar assessed risk, e.g. due to high variance in shedding among transmitting individuals. if variance is high enough, then initiation with multiple viruses might be common enough to matter for high infection probabilities. our simplifying assumption might therefore require overly long quarantines following very high risk exposures, but unless the variance is extreme, it might not significantly distort estimated probabilities among the range of lower risk exposures. we also note that the long quarantines we recommend for high risk exposures are driven more by the right tail of the distribution of asymptomatic shedding durations than by the right tail of the distribution of incubation periods. this further reduces the scope for the incubation time effect to distort the quarantine recommendations. our framework can be used not only to guide recommendations for who should quarantine and for how long, but also to allocate associated resources including quarantine facilities, grocery delivery and other social support, and priority for access to scarce tests. both manual contact tracing and digital exposure notification require rapid testing to be effective. given limited tests, targeting those at highest risk of infection will do the most good in finding new positive cases who are early enough in the course of infection for these approaches to stem transmission the most. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. 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meta-analysis the role of asymptomatic sars-cov-2 infections: rapid living systematic review and meta-analysis. medrxiv the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application clinical and immunological assessment of asymptomatic sars-cov-2 infections exposure factors handbook quantifying children's microlevel activity data from existing videotapes human behavior during close contact in a graduate student office prolonged virus shedding even after seroconversion in a patient with covid-19 unpacking who's asymptomatic covid-19 transmission comments suppression of a sars-cov-2 outbreak in the italian municipality of vo'. nature theoretical and experimental study of gaussian plume model in small scale system cluster of coronavirus disease associated with fitness dance classes a systematic review and meta-analysis reveals long and dispersive incubation period of covid-19. medrxiv age-dependent effects in the transmission and control of covid-19 epidemics associations of clinical characteristics and antiviral drugs with viral rna clearance in patients with covid-19 in guangzhou the natural history and transmission potential of asymptomatic sars-cov-2 infection comparison of clinical characteristics of patients with asymptomatic vs symptomatic coronavirus disease evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-ncov infections correlation of chest ct and rt-pcr testing in coronavirus disease 2019 (covid-19) in china: a report of 1014 cases variation in false-negative rate of reverse transcriptase polymerase chain reaction-based sars-cov-2 tests by time since exposure high sars-cov-2 attack rate following exposure at a choir practice we thank marm kilpatrick for literature pointers, jacob steinhardt for comments on a draft manuscript, sameer halai for the schematic that inspired figure 2 , all of the covid-watch team for agreeing to include our risk scoring scheme into their app, and joyce schroeder for her skillful leadership of the covid-watch pilot at the university of arizona. funding was provided by the university of arizona. key: cord-269343-qwgmn06t authors: livingston, gill; huntley, jonathan; sommerlad, andrew; ames, david; ballard, clive; banerjee, sube; brayne, carol; burns, alistair; cohen-mansfield, jiska; cooper, claudia; costafreda, sergi g; dias, amit; fox, nick; gitlin, laura n; howard, robert; kales, helen c; kivimäki, mika; larson, eric b; ogunniyi, adesola; orgeta, vasiliki; ritchie, karen; rockwood, kenneth; sampson, elizabeth l; samus, quincy; schneider, lon s; selbæk, geir; teri, linda; mukadam, naaheed title: dementia prevention, intervention, and care: 2020 report of the lancet commission date: 2020-07-30 journal: lancet doi: 10.1016/s0140-6736(20)30367-6 sha: doc_id: 269343 cord_uid: qwgmn06t nan the number of older people, including those living with dementia, is rising, as younger age mortality declines. however, the age-specific incidence of dementia has fallen in many countries, probably because of improvements in education, nutrition, health care, and lifestyle changes. overall, a growing body of evidence supports the nine potentially modifiable risk factors for dementia modelled by the 2017 lancet commission on dementia prevention, intervention, and care: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and low social contact. we now add three more risk factors for dementia with newer, convincing evidence. these factors are excessive alcohol consumption, traumatic brain injury, and air pollution. we have completed new reviews and meta-analyses and incorporated these into an updated 12 risk factor life-course model of dementia prevention. together the 12 modifiable risk factors account for around 40% of worldwide dementias, which consequently could theo retically be prevented or delayed. the potential for prevention is high and might be higher in low-income and middle-income countries (lmic) where more dementias occur. our new life-course model and evidence synthesis has paramount worldwide policy implications. it is never too early and never too late in the life course for dementia prevention. early-life (younger than 45 years) risks, such as less education, affect cognitive reserve; midlife (45-65 years) , and later-life (older than 65 years) risk factors influence reserve and triggering of neuropathological developments. culture, poverty, and inequality are key drivers of the need for change. individuals who are most deprived need these changes the most and will derive the highest benefit. policy should prioritise childhood education for all. public health initiatives minimising head injury and decreasing harmful alcohol drinking could potentially reduce young-onset and later-life dementia. midlife systolic blood pressure control should aim for 130 mm hg or lower to delay or prevent dementia. stopping smoking, even in later life, ameliorates this risk. passive smoking is a less considered modifiable risk factor for dementia. many countries have restricted this exposure. policy makers should expedite improvements in air quality, particularly in areas with high air pollution. we recommend keeping cognitively, physically, and socially active in midlife and later life although little evidence exists for any single specific activity protecting against dementia. using hearing aids appears to reduce the excess risk from hearing loss. sustained exercise in midlife, and possibly later life, protects from dementia, perhaps through decreasing obesity, diabetes, and cardio vascular risk. depression might be a risk for dementia, but in later life dementia might cause depression. although behaviour change is difficult and some associations might not be purely causal, individuals have a huge potential to reduce their dementia risk. in lmic, not everyone has access to secondary education; high rates of hypertension, obesity, and hearing loss exist, and the prevalence of diabetes and smoking are growing, thus an even greater proportion of dementia is potentially preventable. amyloid-β and tau biomarkers indicate risk of progression to alzheimer's dementia but most people with normal cognition with only these biomarkers never develop the disease. although accurate diagnosis is important for patients who have impairments and functional concerns and their families, no evidence exists to support pre-symptomatic diagnosis in everyday practice. our understanding of dementia aetiology is shifting, with latest description of new pathological causes. in the oldest adults (older than 90 years), in particular, mixed dementia is more common. blood biomarkers might hold promise for future diagnostic approaches and are more scalable than csf and brain imaging markers. wellbeing is the goal of much of dementia care. people with dementia have complex problems and symptoms in many domains. interventions should be individualised and consider the person as a whole, as well as their family carers. evidence is accumulating for the effectiveness, at least in the short term, of psychosocial interventions tailored to the patient's needs, to manage neuropsychiatric symptoms. evidence-based interventions for carers can reduce depressive and anxiety symptoms over years and be cost-effective. keeping people with dementia physically healthy is important for their cognition. people with dementia have more physical health problems than others of the same age but often receive less community health care and find it particularly difficult to access and organise care. people with dementia have more hospital admissions than other older people, including for illnesses that are potentially manageable at home. they have died disproportionately in the covid-19 epidemic. hospitalisations are distressing and are associated with poor outcomes and high costs. health-care professionals worldwide around 50 million people live with dementia, and this number is projected to increase to 152 million by 2050, 1 rising particularly in low-income and middleincome countries (lmic) where around two-thirds of people with dementia live. 1 dementia affects individuals, their families, and the economy, with global costs estimated at about us$1 trillion annually. 1 we reconvened the 2017 lancet commission on dementia prevention, intervention, and care 2 to identify the evidence for advances likely to have the greatest impact since our 2017 paper and build on its work. our inter disciplinary, international group of experts presented, debated, and agreed on the best available evidence. we adopted a triangulation framework evaluating the consistency of evidence from different lines of research and used that as the basis to evaluate evidence. we have • three new modifiable risk factors for dementia • new evidence supports adding three modifiable risk factors-excessive alcohol consumption, head injury, and air pollution-to our 2017 lancet commission on dementia prevention, intervention, and care life-course model of nine factors (less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and infrequent social contact). • modifying 12 risk factors might prevent or delay up to 40% of dementias. • be ambitious about prevention • prevention is about policy and individuals. contributions to the risk and mitigation of dementia begin early and continue throughout life, so it is never too early or too late. these actions require both public health programmes and individually tailored interventions. in addition to population strategies, policy should address high-risk groups to increase social, cognitive, and physical activity; and vascular health. • specific actions for risk factors across the life course • aim to maintain systolic bp of 130 mm hg or less in midlife from around age 40 years (antihypertensive treatment for hypertension is the only known effective preventive medication for dementia). • encourage use of hearing aids for hearing loss and reduce hearing loss by protection of ears from excessive noise exposure. • reduce exposure to air pollution and second-hand tobacco smoke. • prevent head injury. • limit alcohol use, as alcohol misuse and drinking more than 21 units weekly increase the risk of dementia. • avoid smoking uptake and support smoking cessation to stop smoking, as this reduces the risk of dementia even in later life. • provide all children with primary and secondary education. • reduce obesity and the linked condition of diabetes. sustain midlife, and possibly later life physical activity. • addressing other putative risk factors for dementia, like sleep, through lifestyle interventions, will improve general health. • tackle inequality and protect people with dementia • many risk factors cluster around inequalities, which occur particularly in black, asian, and minority ethnic groups and in vulnerable populations. tackling these factors will involve not only health promotion but also societal action to improve the circumstances in which people live their lives. examples include creating environments that have physical activity as a norm, reducing the population profile of blood pressure rising with age through better patterns of nutrition, and reducing potential excessive noise exposure. • dementia is rising more in low-income and middleincome countries (lmic) than in high-income countries, because of population ageing and higher frequency of potentially modifiable risk factors. preventative interventions might yield the largest dementia reductions in lmic. summarised best evidence using, where possible, goodquality systematic reviews, meta-analyses, or individual studies, where these add important knowledge to the field. we performed systematic literature reviews and meta-analyses where needed to generate new evidence for our analysis of potentially modifiable risk factors for dementia. within this framework, we present a narrative synthesis of evidence including systematic reviews and meta-analyses and explain its balance, strengths, and limitations. we evaluated new evidence on dementia risk in lmic; risks and protective factors for dementia; detection of alzheimer's disease; multimorbidity in dementia; and interventions for people affected by dementia. nearly all the evidence is from studies in highincome countries (hic), so risks might differ in other countries and interventions might require modification for different cultures and environments. this notion also underpins the critical need to understand the dementias related to life-course disadvantage-whether in hics or lmics. our understanding of dementia aetiology is shifting. a consensus group, for example, has described hippocampal sclerosis associated with tdp-43 proteinopathy, as limbic-predominant age-related tdp-43 encephalopathy (late) dementia, usually found in people older than 80 years, progressing more slowly than alzheimer's disease, detectable at post-mortem, often mimicking or comorbid with alzheimer's disease. 3 this situation reflects increasing attention as to how clinical syndromes are and are not related to particular underlying pathologies and how this might change across age. more work is needed, however, before late can be used as a valid clinical diagnosis. the fastest growing demographic group in hic is the oldest adults, those aged over 90 years. thus a unique opportunity exists to focus on both human biology, in this previously rare population, as well as on meeting their needs and promoting their wellbeing. the number of people with dementia is rising. predictions about future trends in dementia prevalence vary depending on the underlying assumptions and geographical region, but generally suggest substantial increases in overall prevalence related to an ageing population. for example, according to the global burden of diseases, injuries, and risk factors study, the global age-standardised prevalence of dementia between 1990 and 2016 was relatively stable, but with an ageing and bigger population the number of people with dementia has more than doubled since 1990. 4 however, in many hic such as the usa, the uk, and france, age-specific incidence rates are lower in more recent cohorts compared with cohorts from previous decades collected using similar methods and target populations 5 (figure 1) and the age-specific incidence of dementia appears to decrease. 6 all-cause dementia incidence is lower in people born more recently, 7 proba bly due to educational, socio-economic, health care, and lifestyle changes. 2,5 however, in these countries increasing obesity and diabetes and declining physical activity might reverse this trajectory. 8, 9 in contrast, age-specific dementia prevalence in japan, south korea, hong kong, and taiwan looks as if it is increasing, as is alzheimer's in lmic, although whether diagnostic methods are always the same in comparison studies is unclear. [5] [6] [7] modelling of the uk change suggests a 57% increase in the number of people with dementia from 2016 to 2040, 70% of that expected if age-specific incidence rates remained steady, 10 such that by 2040 there will be 1·2 million uk people with dementia. models also suggest that there will be future increases both in the number of individuals who are independent and those with complex care needs. 6 figure 1 : incidence rate ratio comparing new cohorts to old cohorts from five studies of dementia incidence 5 iidp project in usa and nigeria, bordeaux study in france, and rotterdam study in the netherlands adjusted for age. framingham heart study, usa, adjusted for age and sex. cfas in the uk adjusted for age, sex, area, and deprivation. however, age-specific dementia prevalence is increasing in some other countries. iid=indianapolis-ibadan dementia. cfas=cognitive function and ageing study. adapted from wu et al, 5 by permission of springer nature. hazard ratio incidence ratio (95%ci) in our first report, the 2017 commission described a life-course model for potentially modifiable risks for dementia. 2 life course is important when considering risk, for example, obesity and hypertension in midlife predict future dementia, but both weight and blood pressure usually fall in later life in those with or developing dementia, 9 so lower weight and blood pressure in later life might signify illness, not an absence of risk. [11] [12] [13] [14] we consider evidence on other potential risk factors and incor porate those with good quality evidence in our model. figure 2 summarises possible mechanisms of protection from dementia, some of which involve increasing or maintaining cognitive reserve despite pathology and neuropathological damage. there are different terms describing the observed differential susceptibility to agerelated and disease-related changes and these are not used consistently. 15, 16 a consensus paper defines reserve as a concept accounting for the difference between an individual's clinical picture and their neuropathology. it, divides the concept further into neurobiological brain reserve (eg, numbers of neurones and synapses at a given timepoint), brain maintenance (as neurobiological capital at any timepoint, based on genetics or lifestyle reducing brain changes and pathology development over time) and cognitive reserve as adaptability enabling preser vation of cognition or everyday functioning in spite of brain pathology. 15 cognitive reserve is changeable and quantifying it uses proxy measures such as education, occupational complexity, leisure activity, residual approaches (the variance of cognition not explained by demographic variables and brain measures), or identification of functional networks that might underlie such reserve. [15] [16] [17] [18] [19] [20] early-life factors, such as less education, affect the resulting cognitive reserve. midlife and old-age risk factors influence age-related cognitive decline and triggering of neuropathological developments. consistent with the hypothesis of cognitive reserve is that older women are more likely to develop dementia than men of the same age, probably partly because on average older women have had less education than older men. cognitive reserve mechanisms might include preserved metabolism or increased connectivity in temporal and frontal brain areas. [17] [18] [19] [20] [21] people in otherwise good physical health can sustain a higher burden of neuropathology without cognitive impairment. 22 culture, poverty, and inequality are important obstacles to, and drivers of, the need for change to cognitive reserve. those who are most deprived need these changes the most and will derive the highest benefit from them. smoking increases air particulate matter, and has vascular and toxic effects. 23 similarly air pollution might act via vascular mechanisms. 24 exercise might reduce weight and diabetes risk, improve cardiovascular function, decrease glutamine, or enhance hippocampal neurogenesis. 25 higher hdl cholesterol might protect against vascular risk and inflammation accompanying amyloid-β (aβ) pathology in mild cognitive impairment. 26 numbers of people with dementia in lmic are rising faster than in hic because of increases in life expectancy and greater risk factor burden. we previously calculated that nine potentially modifiable risk factors together are associated with 35% of the population attributable fraction (pafs) of dementia worldwide: less education, high blood pressure, obesity, hearing loss, depression, diabetes, physical inactivity, smoking, and social isolation, assuming causation. 2 most research data for this calcu lation came from hic and there is a relative absence of specific evidence of the impact of risk factors on dementia risk in lmic, particularly from africa and latin america. 27 calculations considering country-specific prevalence of the nine potentially modifiable risk factors indicate paf of 40% in china, 41% in india and 56% in latin america with the potential for these numbers to be even higher depending on which estimates of risk factor frequency are used. 28, 29 therefore a higher potential for dementia prevention exists in these countries than in global estimates that use data predominantly from hic. if not currently in place, national policies addressing access to education, causes and management of high blood pressure, causes and treatment of hearing loss, socioeconomic and commercial drivers of obesity, could be implemented to reduce risk in many countries. the higher social contact observed in the three lmic regions provides potential insights for hic on how to influence this risk factor for dementia. 30 we could not consider other risk factors such as poor health in pregnancy of malnourished mothers, difficult births, early life malnutrition, survival with heavy infection burdens alongside malaria and hiv, all of which might add to the risks in lmic. diabetes is very common and cigarette smoking is rising in china while falling in most hic. 31 preventing dementia meta-analysis found variation of the rates of dementia within china, with a higher prevalence in the north and lower prevalence in central china, estimating 9·5 million people are living with dementia, whereas a slightly later synthesis estimated a higher prevalence of around 11 million. 30, 32 these data highlight the need for more focused work in lmic for more accurate estimates of risk and interventions tailored to each setting. risk factors in early life (education), midlife (hypertension, obesity, hearing loss, traumatic brain injury, and alcohol misuse) and later life (smoking, depression, physical inactivity, social isolation, diabetes, and air pollution) can contribute to increased dementia risk (table 1) . good evidence exists for all these risk factors although some late-life factors, such as depression, possibly have a bidirectional impact and are also part of the dementia prodrome. 33, 34 in the next section, we briefly describe relevant newly published and illustrative research studies that add to the 2017 commission's evidence base, including risks and, for some, mitigation. we have chosen studies that are large and representative of the populations, or smaller studies in areas where very little evidence exists. we discuss them in life-course order and within the life course in the order of magnitude of population attributable factor. higher childhood education levels and lifelong higher educational attainment reduce dementia risk. 2,35-37 new work suggests overall cognitive ability increases, with education, before reaching a plateau in late adolescence, when brain reaches greatest plasticity; with relatively few further gains with education after age 20 years. 38 this suggests cognitive stimulation is more important in early life; much of the apparent later effect might be due to people of higher cognitive function seeking out cognitively stimulating activities and education. 38 it is difficult to separate out the specific impact of education from the effect of overall cognitive ability, 38, 39 and the specific impact of later-life cognitive activity from lifelong cognitive function and activity. 39, 40 cognitive maintenance one large study in china tried to separate cognitive activity in adulthood from activities for those with more education, by considering activities judged to appeal to people of different levels of education. 40 it found people older than 65 years who read, played games, or bet more frequently had reduced risk of dementia (n=15 882, odds ratio [or]=0·7, 95% ci 0·6-0·8). the study excluded people developing dementia less than 3 years after baseline to reduce reverse causation. this finding is consistent with small studies of midlife activities which find them associated with better late-life cognition; so for example, in 205 people aged 30-64 years, followed up until 66-88 years, travel, social outings, playing music, art, physical activity, reading, and speaking a second language, were associated with maintaining cognition, independent of education, occupation, late-life activities, and current structural brain health. 41 similarly, engaging in intellectual activity as adults, particularly problem solving, for 498 people born in 1936, was associated with cognitive ability acquisition, although not the speed of decline. 42 the use it or lose it hypothesis suggests that mental activity, in general, might improve cognitive function. people in more cognitively demanding jobs tend to show less cognitive deterioration before, and sometimes after retirement than those in less demanding jobs. 43, 44 one systematic review of retirement and cognitive decline found conflicting evidence. 45 subsequently, a 12-year study of 1658 people found older retirement age but not number of years working, was associated with lower dementia risk. 46 those retiring because of ill health had lower verbal memory and fluency scores than those retiring for other reasons. 47 another study found a two-fold increase in episodic memory loss attributable to retirement (n=18 575, mean age 66 years), compared to non-retirees, adjusting for health, age, sex, and wealth. 48 similarly, in a cohort of 3433 people retiring at a mean age of 61 years, verbal memory declined 38% (95% ci 22-60) faster than before retirement. 44 a cognitive intervention or cognition-orientated treatment comprises strategies or skills to improve general or spe cific areas of cognition. 50 computerised cognitive training programmes have increasingly replaced tasks that were originally paper-and-pencil format with computerbased tasks for practice and training. 51 three systematic reviews in the general population found no evidence of generalised cognition improvement from specific cognitive interventions, including computerised cognitive training, although the domain trained might improve. [52] [53] [54] a meta-analysis of 17 controlled trials of at least 4 hours of computerised cognitive training, (n=351, control n=335) for mild cognitive impairment, found a moderate effect on general cognition post-training (hedges' g=0·4, 0·2-0·5); 55 however few high quality studies and no long-term high quality evidence about prevention of dementia currently exists. a meta-analysis of 30 trials of computerised, therapy-based and multimodal interventions for mild cognitive impairment found an effect on activities of daily living (d=0·23) and metacognitive outcomes (d=0·30) compared to control. 56 a third systematic review identified five high quality studies, four group-delivered and one by computer, and concluded the evidence for the effects of cognitive training in mild cognitive impairment was insufficient to draw conclusions. 53 a comprehensive, high quality, systematic overview of meta-analyses of cognitive training in healthy older people, those with mild cognitive impairment and those with dementia, found that most were of low standard, were positive and most reached statistical significance but it was unclear whether results were of clinical value because of the poor standard of the studies and heterogeneity of results (figure 3). 51 in the only randomised controlled trial (rct) of behavioural activation (221 people) for cognition in amnestic mild cognitive impairment, behavioural activation versus supportive therapy was associated with a decreased 2-year incidence of memory decline (relative risk [rr] 0·12, 0·02-0·74). 57 hearing loss had the highest paf for dementia in our first report, using a meta-analysis of studies of people with normal baseline cognition and hearing loss present at a threshold of 25 db, which is the who threshold for hearing loss. in the 2017 commission, we found an rr of 1·9 for dementia in populations followed up over 9-17 years, with the long follow-up times making reverse causation bias unlikely. 2 a subsequent meta-analysis using the same three prospective studies measuring hearing using audiometry at baseline, found an increased risk of dementia (or 1·3, 95% ci 1·0-1·6) per 10 db of worsening of hearing loss. 58 a cross-sectional study of 6451 individuals designed to be representative of the us population, with a mean age of 59·4 years, found a decrease in cognition with every 10 db reduction in hearing, which continued to below the clinical threshold so that subclinical levels of hearing impairment (below 25 db) were significantly related to lower cognition. 59 although the aetiology still needs further clarification, a small us prospective cohort study of 194 adults without baseline cognitive impairment, (baseline mean age 54·5 years), and at least two brain mris, with a mean of 19 years follow-up, found that midlife hearing impair ment measured by audiometry, is associated with steeper temporal lobe volume loss, including in the hippocampus and entorhinal cortex. 60 a 25-year prospective study of 3777 people aged 65 years or older found increased dementia incidence in those with self-reported hearing problems except in those using hearing aids. 61 similarly, a cross-sectional study found hearing loss was only associated with worse cognition in those not using hearing aids. 62 a us nationally representative survey of 2040 people older than 50 years, tested every two years for 18 years, found immediate and delayed recall deteriorated less after initiation of hearing aid use, adjusting for other risk factors. 63 hearing aid use was the largest factor protecting from decline (regression coefficient β for higher episodic memory 1·53; p<0·001) adjusting for protective and harmful factors. the long follow-up times in these prospective studies suggest hearing aid use is protec tive, rather than the possibility that those developing dementia are less likely to use hearing aids. hearing loss might result in cognitive decline through reduced cognitive stimulation. the international classification of disease (icd) defines mild tbi as concussion and severe tbi as skull fracture, oedema, brain injury or bleed. single, severe tbi is associated in humans, and mouse models, with widespread hyperphosphorylated tau pathology, and mice with apoe ε4 compared to apoe ε3 allele have more hippocampal hyper-phosphorylated tau after tbi. 64, 65 tbi is usually caused by car, motorcycle, and bicycle injuries; military exposures; boxing, horse riding, and other recreational sports; firearms; and falls. 66 a nationwide danish cohort study of nearly 3 million people aged 50 years or older, followed for a mean of 10 years, found an increased dementia (hr 1·2, 95% ci 1·2-1·3) and alzheimer's disease risk (1·2, 1·1-1·2). 67 dementia risk was highest in the 6 months after tbi (4·1, 3·8-4·3) and increased with number of injuries in people with tbi (one tbi 1·2, 1·2-1·3; ≥5 tbis 2·8, 2·1-3·8). risk was higher for tbi than fractures in other body areas (1·3, 1·3-1·3) and remained elevated after excluding cognitive training cognitive stimulation mixed cognition-oriented treatments favours control favours intervention those who developed dementia within 2 years after tbi, to reduce reverse causation bias. 67 similarly, a swedish cohort of over 3 million people aged 50 years or older, found tbi increased 1-year dementia risk (or 3·5, 95% ci 3·2-3·8); and risk remained elevated, albeit attenuated over 30 years (1·3, 1·1-1·4). 68 icd defined single mild tbi increased the risk of dementia less than severe tbi and multiple tbis increased the risk further (or 1·6, 95% ci 1·6-1·7 for single tbi; 2·1, 2·0-2·2 for more severe tbi; and 2·8, 2·5-3·2 for multiple tbi). a nested case control study of early onset clinically diagnosed alzheimer's disease within an established cohort also found tbi was a risk factor, increasing with number and severity. 69 a stronger risk of dementia was found nearer the time of the tbi, leading to some people with earlyonset alzheimer's disease. military veterans have a high risk of occupational tbi, and formal record keeping allows long-term follow-up. a study of 178 779 veterans with tbi with propensitymatched veterans without tbi found dementia risk was associated with tbi severity (hr 2·4, 95% ci 2·1-2·7 for mild tbi without loss of consciousness; 2·5, 2·3-2·8 for mild tbi with loss of consciousness; and 3·8, 3·6-3·9 for moderate to severe tbi). 70 similarly women veterans with tbi had increased risk of dementia compared to those without tbi (1·5, 1·0-2·2). 71 a cohort study of 28 815 older adults with concussion, found the risk of dementia doubled, with 1 in 6 developing dementia over a mean follow-up of 3·9 years, although those taking statins had a 13% reduced risk of dementia compared to those who were statin-free. they suggest future rcts as statins might mitigate injury-related brain oedema, oxidative stress, amyloid protein aggregation, and neuroinflammation. 72 the term chronic traumatic encephalopathy describes sports head injury, which is not yet fully characterised and covers a broad range of neuropathologies and outcomes, with current views largely conjecture. 73 the evidence has subsequently been strengthened by a study on scottish former soccer players reporting that they are more likely than controls to have alzheimer's disease specified on their death certificates (hr 5·1, 95% ci 2·9-8·8) and to have been prescribed any dementiarelated medications (or 4·9, 95% ci 3·8-6·3) but not on medical records. 74 the study controlled for socioeconomic class based on residential address, which in footballers might be less linked to level of education. persistent midlife hypertension is associated with increased risk of a late life dementia. in the framingham offspring cohort comprising 1440 people, elevated systolic blood pressure (≥140 mm hg in midlife; mean age 55 years) was associated with an increased risk of developing dementia (hr 1·6, 95% ci 1·1-2·4) over an 18 year follow-up period. 12 in this study risk increased further if hypertension persisted into later life (mean age 69 years; hr 2·0, 95% ci 1·3-3·1). in the same cohort, people in late midlife (mean age 62 years) with ideal cardiovascular parameters (current non-smoker, body mass index [bmi] 18·5-25 kg/m², regular physical activity, healthy diet, optimum blood pressure <120/<80 mm hg, cholesterol, and normal fasting blood glucose) were compared to people with at least one of these risks. 75 those with ideal cardiovascular parameters had a lower 10-year risk of all-cause dementia (hr 0·8, 95% ci 0·1-1·0), vascular dementia (0·5, 0·3-0·8) and clinically diagnosed alzheimer's disease (0·8, 0·6-1·0). in a uk cohort study of 8639 civil servants, a single measure of systolic blood pressure of 130 mm hg or higher at age 50 years but not at age 60 or 70 years was associated with increased risk of dementia (1·4, 1·1-1·7). 13 in those with persistent systolic blood pressure of 130 mm hg or higher, from mean age 45 to 61 years, dementia risk is increased even if free of cardiovascular disease relative to those without hypertension (1·3, 1·0-1·7). a further cohort study has provided potential insights into mechanisms, reporting that midlife hypertension, defined as from age 40 years, was associated with reduced brain volumes and increased white matter hyperintensity volume but not amyloid deposition. 76 of note, blood pressure declines in later life and this decline is associated with and, potentially caused by, dementia development (hr 2·4, 95% ci 1·4-4·2). 12, 13, 77 antihypertensive drugs, aspirin, and statins the us and puerto rico systolic blood pressure intervention trial (sprint) in 9361 hypertensive adults aged 50 years and older, was stopped early because of significantly fewer cardiovascular events and deaths occurring in the intensive treatment arm (aiming for systolic <120 mm hg, n=4678) in comparison with standard treatment (systolic <140 mm hg, n=4683). 78 cognitive assessment continued after stopping the trial intervention in sprint mind. 79 in the intensive compared with the standard treatment group, there were 7·2 dementia cases as opposed to 8·6 cases/1000 personyears (hr 0·8; 95% ci 0·7-1·0) within on average 2 years from the end of the intervention period and 5 years after baseline. pre-specified secondary outcomes were also reduced in the intensive arm for mild cog nitive impairment (14·6 vs 18·3 cases/1000 person-years; hr 0·8, 95% ci 0·7-1·0), combined mild cognitive impairment or dementia (20·2 vs 24·1 cases/1000 person-years; hr 0·9, 95% ci 0·7-1·0) 79 making this the first trial to suggest reduction of risk for mild cognitive impairment. those who were lost to follow-up were at greater risk of dementia than those who continued but follow-up rates did not differ according to intervention group. 80 four meta-analyses of blood pressure medications to lower high blood pressure with six studies overlap have provided combined estimates of effects. all metaanalyses suggest reduced dementia in those in the interventions arms for outcomes of any dementia as well as clinically diagnosed alzheimer's disease. the first included randomised controlled trials (rcts) of any drug to lower blood pressure and reported a reduction in risk of around 10% at marginal significance (rr 0·9, 95% ci 0·9-1·0). 81 meta-regression showed risk lowered more if the achieved systolic pressure differential was larger between the intervention and control group. the second included 15 trials and observational studies of diuretics involving 52 599 people (median age 76 years) with 6·1 years median follow-up (dementia hr 0·8, 95% ci 0·8-0·9 and alzheimer's disease 0·8, 0·7-0·9). 82 the third included used individual participant data from six observational studies; (dementia 0·9, 0·8-1·0 and alzheimer's disease 0·8, 0·7-1·0; figure 4). 83 the fourth focused on people prescribed calcium channel blocker only, included 10 rcts and observational studies comprising 75 239 hypertensive older adults (median age 72 years, median follow-up 8·2 years) found lowered dementia risk (rr 0·7, 95% ci 0·6-0·9). 84 a 2019 metaanalysis addressing which class of anti-hypertensive drug to use to lower risk of either incident dementia or cognitive decline, found over 50 000 participants in 27 studies and reported no consistent difference in effect according to which class of drug was used. 85 a cochrane review reported good evidence that statins given to older people at risk of vascular disease do not prevent cognitive decline or dementia. 86 one rct found 100 mg aspirin versus placebo in 19 114 healthy adults older than 65 years did not reduce dementia (hr 1·0, 95% ci 0·8-1·2), death, physical disability, or cardiovascular disease over a period of 4·7 years. 87 studies of physical activity are complex. patterns of physical activity change with age, generation, and morbidity and are different across sex, social class, and cultures. the studies suggest a complicated relationship with the potential for both risk reduction and reverse causation. meta-analyses of longitudinal observational studies of 1-21 years duration showed exercise to be associated with reduced risk of dementia. 2 a further overview of sys tematic reviews concluded that there is convincing decreased incident dementia evidence for physical activity protecting against clinically diagnosed alzheimer's disease. 88 since the 2017 commission, the hunt study of 28 916 participants aged 30-60 years has been published, reinforcing the previous literature in this area. at least weekly midlife moderate-to-vigorous physical activity (breaking into a sweat) was associated with reduced dementia risk over a 25-year period of follow-up (hr 0·8, 95% ci 0·6-1·1) but the confidence intervals were wide. 89 in contrast the whitehall study reporting on the 28-year follow-up of 10 308 people, found that more than 2·5 hours of self-reported moderate-to-vigorous physical activity per week, lowered dementia risk over 10, but not 28 years. 33 very long-term studies are unusual; however, one 44-year study recruited 191 women (mean age 50) purposively to be representative of the swedish population and reported that 32% of the participants with low baseline peak fitness, 25% with medium, and 5% with high fitness developed dementia (high vs medium hr 0·1, 95% ci 0·03-0·5, low vs medium 1·4, 0·7-2·8). 90 an individual-level meta-analysis of 19 observational studies of relatively younger adults included 404 840 participants' data (mean baseline age 45·5 years; mean follow-up duration 14·9 years), reporting an increased incidence of all-cause dementia (hr 1·4, 95% ci 1·2-1·7) and clinically diagnosed alzheimer's disease (1·4, 1·1-1·7) in those who were physically inactive in the 10-year period before diagnosis. 91 notably, however, no difference in dementia risk measured 10-15 years before time of dementia incidence was found except in those with comorbid cardio-metabolic disease (rr 1·3, 95% ci 0·8-2·1). people might stop exercising due to prodromal dementia so inactivity might be either a consequence or a cause or both in dementia and might be more of a risk in those with cardiovascular morbidity. as with other outcomes, exercise might be required to be sustained and continue nearer the time of risk. 92 since the 2017 commission several meta-analyses and systematic reviews have been published with three high quality meta-analyses which we include. the first included 39 rcts with an unclear total number of participants examining moderate or vigorous exercise of any frequency lasting 45-60 min per session in cognitively normal adults aged older than 50 years. this analysis reported global cognitive improvements (standard mean difference [smd]=0·3, 95% ci 0·2-0·4) for moderate or vigorous resistance (13 studies) or aerobic exercise (18 studies) lasting 45-60 min per session with no difference between them but no effect found for yoga. 93 a second meta-analysis of rcts in people with mild cognitive impairment found global cognition improved in the intervention group (0·3, 0·1-0·5) with aerobic exercise having a higher effect (0·6, 0·5-0·6). 94 this study did not have dementia as an outcome measure. a third meta-analysis of rcts of longer term exercise found five studies (four lasting 12 months and one 24 months) with 2878 participants with normal baseline cognition. 95 the incidence of dementia was 3·7% (n=949) for exercisers and 6·1% (n=1017) for controls (random effect rr 0·6, 95% ci 0·3-1·1; fixed effect as no evidence of heterogeneity 0·7, 0·4-1·0). the authors concluded that the study showed no significant effect of exercise for reducing dementia, mild cognitive impairment, or clini cally significant cognitive decline but was underpowered. who guidelines have been published since the 2017 commission, suggesting specific activity levels drawing on these, and one further systematic review which considered sex differences on the effect of exercise. 96, 97 it concluded the evidence points towards physical activity having a small, beneficial effect on normal cognition, with a possible effect in mild cognitive impairment, mostly due to aerobic exercise. 97 evidence about the effect of specific types of exercise, such as progressive muscle resistance training, on dementia risk is scarce. in the 2017 commission we reported on diabetes as a risk factor for dementia. distinguishing between treated and untreated diabetes as a risk factor for dementia is challenging in observational studies. in a pooled metaanalysis from over 2·3 million individuals with type 2 diabetes across 14 cohort studies, including 102 174 with dementia, diabetes was associated with an increased risk of any dementia (rr 1·6, 95% ci 1·5-1·8 for women and 1·6, 1·4-1·8 for men). 98 the risk of dementia increased with the duration and severity of diabetes. the effect of different diabetic medications on cognition or dementia outcomes remains unclear as few studies have investigated this area. 99 however, one meta-analysis of cohort studies of diabetes reported that, cross sectionally, people with diabetes taking metformin had lower prevalence of cognitive impairment (three studies or 0·6, 95% ci 0·4-0·8) and, longitudinally, reduced dementia incidence (six studies hr 0·8, 95% ci 0·4-0·9) compared with those taking other medications or no medication. 100 however another analysis did not find a protective effect of metformin for incident dementia (three studies, rr 1·1, 95% ci 0·5-2·4) with possible harm with insulin therapy (1·2, 1·1-1·4); but this did not account for severity of diabetes of those with type 2 diabetes on insulin. 99 a cochrane review reported intensive compared to standard diabetes control trials with 5 year follow up (n=11 140), showing no impact on cognitive decline (1·0, 95% ci 0·9-1·1) or dementia (1·3, 0·9-1·9). 101 overall type 2 diabetes is a clear risk factor for development of future dementia; however, whether any particular medication ameliorates this risk is unclear. intensive diabetic control does not decrease the risk of dementia. studies of individual cardiovascular risk factors usually control for other cardiovascular risks, which cluster in individual people. this does not take into account the combinations and contexts in which risk occurs. a uk study of 7899 people aged 50 years followed up for 25 years, calculated a cardiovascular health score based on four behaviour-related (smoking, diet, physical activity, bmi) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics each coded on a three-point scale (0, 1, 2). 100 a better score was associated with a lower risk of dementia (hr 0·9, 95% ci 0·9-1·0 per 1 point scale increment), for both behaviour-related (hr/1 point increment in subscales 0·9, 95% ci 0·8-0·9) and biological subscales (0·9, 0·8-1·0), main tained in people free of cardiovascular disease over the follow-up (0·9, 95% ci 0·8-1·0). these authors also reported an association of the score on the scale with hippocampal atrophy and total brain volume but not white matter hyperintensities. this finding underlines the importance of clustering of cardio vascular risk factors in midlife, as studies of individual risk factors in this sample had not shown a significant association, when controlling for other individual risks. 33 heavy drinking is associated with brain changes, cognitive impairment, and dementia, a risk known for centuries. 102 an increasing body of evidence is emerging on alcohol's complex relationship with cognition and dementia outcomes from a variety of sources including detailed cohorts and large-scale record based studies. alcohol is strongly associated with cultural patterns and other sociocultural and health-related factors, making it particularly challenging to understand the evidence base. a french 5-year longitudinal study of over 31 million people admitted to hospital, found alcohol use disorders (harmful use or dependence as defined in icd) were associated with increased dementia risk, calculated separately for men and women (women hr 3·3, 95% ci 3·3-3·4, men 3·4, 3·3-3·4). 103 the relationship of dementia with alcohol use disorders was particularly clear in the earlier onset dementias (age less than 65 years) in which 56·6% had an alcohol use disorder noted in their records (n=57 353; 5·2% all dementias). a systematic review incorporating 45 studies of light to moderate drinking using a variety of definitions reported a reduced risk of dementia compared with not drinking (rr 0·7; 95% ci 0·6-0·91). 104 risk was not reported separately for men and women. drinking less than 21 units of alcohol per week (1 unit of alcohol=10 ml or 8 g pure alcohol) might be associated with a lower risk of dementia. 105,106 a 5-year follow-up study of 13 342 men and women volunteers from uk biobank aged 40-73 years who drank, included few heavy drinkers and did not analyse abstainers. 106 the study reported that those who drank more than 12 units per week declined slightly more in reaction time in a perceptual matching task than those who drank less (β2=−0·07, 95% ci −0·09 to −0·04). 106 the uk whitehall study with 23 years follow-up, included 9087 participants aged 35-55 years at baseline. 107 drinking more than 21 units per week and long-term abstinence were both associated with a 17% (95% ci 4-32 and 13-23 respectively) increase in dementia compared to drinking less than 14 units. drinking more than 14 units was also associated with right sided hippocampal atrophy on mri. 108 overweight is an emerging concern, given the changing bmi across the world's ageing population. new evidence supports the relationship between increased bmi and dementia from a review of 19 longitudinal studies including 589 649 people aged 35 to 65 years, followed up for up to 42 years. it reported obesity (bmi ≥30; rr 1·3, 95% ci 1·1-1·6) but not being overweight (bmi 25-30; 1·1, 1·0-1·2) was associated with late-life dementia. 109 in a further meta-analysis of individual level data from 1·3 million adults (aged ≥18 years), which included two studies from the meta-analysis cited above, 109 higher body mass measured before probable preclinical and prodromal dementia was associated with increased dementia risk (rr 1·3, 1·1-1·7/5-unit increase in bmi). 11 a meta-analysis of seven rcts (468 participants) and 13 longitudinal studies (551 participants) of overweight and obese adults without dementia, mean age 50 years, found weight loss of 2 kg or more in people with bmi greater than 25 was associated with a significant improvement in attention and memory. all but one of the studies included participants aged younger than 65 years. the rcts reported memory improvement over 8-48 weeks (smd=0·4, 95% ci 0·2-0·6) and short-term longitudinal studies found improvement over a median of 24 weeks (smd=0·7, 95% ci 0·5-0·8); however, data about the long-term effects or the effect of weight loss in preventing dementia are absent. 110 smokers are at higher risk of dementia than nonsmokers, 2 and at a higher risk of premature death before the age at which they might have developed dementia, introducing some bias and uncertainty in the association between smoking and risk of dementia. 111, 112 stopping smoking, even when older, reduces this risk. among 50 000 men aged older than 60 years, stopping smoking for more than 4 years, compared to continuing, substantially reduced dementia risk over the subsequent 8 years (hr 0·9; 95% ci 0·7-1·0). 113 worldwide, 35% of nonsmoking adults and 40% of children are estimated to be exposed to second-hand smoke; 114 although literature on the impact of this exposure and dementia risk is scarce. one study indicated that in women aged 55-64 years, second-hand smoke exposure was associated with more memory deterioration and the risk increased with exposure duration even after controlling for other confounding factors. 115 depression is associated with dementia incidence, with a variety of possible psychological or physiological mechanisms. it is also part of the prodrome and early stages of dementia. reverse causation is possible whereby depressive symptoms result from dementia neuropathology that occurs years before clinical dementia onset. these explanations are not mutually exclusive. as in diabetes, few studies considering depression as a risk factor for dementia have distinguished between treated and untreated depression. in a meta-analysis of 32 studies, with 62 598 participants, with follow-up from 2 to 17 years, a depressive episode was a risk factor for dementia (pooled effect size 2·0, 95% ci 1·7-2·3). 116 meta-regression analysis revealed a non-significant trend for the association between depression and incident dementia to be weaker when the length of follow-up was longer. the norwegian hunt study, suggested that symptoms of psychological distress predicted dementia 25 years later however with wide bounds of uncertainty (hr 1·3, 95% ci 1·0-1·7). 89 two further studies differentiate between late-life and earlier life depressive symptoms. the uk whitehall study, in a follow-up of 10 189 people, reports that in late life these symptoms increase dementia risk but not at younger ages (follow-up 11 years hr 1·7; 95% ci 1·2-2·4; follow-up 22 years 1·0, 0·7-1·4). 34,117 a 14-year longitudinal study of 4922 initially cognitively healthy men, aged 71-89 years, found depression was associated with 1·5 (95% ci 1·2-2·0) times the incidence of dementia but this association was accounted for by people developing dementia within 5 years of depression. 118 the use of antidepressants did not decrease this risk. a study of 755 people with mild cognitive impairment and with a history of depression from the australian longitudinal alzheimer's disease neuroimaging initiative, considered the effect of selective serotonin-reuptake inhibitor (ssri) treatment, such as citalopram, known to reduce amyloid plaque generation and plaque formation in animal models. 119 the study found that more than 4 years of such treatment was associated with delayed progres sion to clinically diagnosed alzheimer's disease. people treated with antidepressants seem likely to differ from those who are not treated. thus, the question of whether antidepressant treatment mitigates dementia risk remains open. social contact, now an accepted protective factor, enhances cognitive reserve or encourages beneficial behaviours, although isolation might also occur as part of the dementia prodrome. several studies suggest that less social contact increases the risk of dementia. although most people in mid and later life are married, by the time they reach older age, disproportionate numbers of women are widowed as they outlive their husbands, thus reducing their social contact. in these generations, marital status is therefore an important contributor to social engagement. additionally, most marriages are in the relatively young, and married people usually have more interpersonal contact than do single people-this gives a long-term estimate of the effect of social contact. a systematic review and meta-analysis including 812 047 people worldwide found dementia risk to be elevated in lifelong single (rr 1·4, 95% ci 1·1-1·9) and widowed people (1·2, 1·0-1·4), compared with married people and the association was consistent in different sociocultural settings. 120 studies adjusted for sex and we do not know if a differential risk between men and women exists. differences persisted in studies that adjusted for education and physical health so might be attributable to married people having more social contact, rather than solely because they tend to have better physical health and more education, although residual confounding is possible. a systematic review and meta-analysis of 51 longitudinal cohort studies of social isolation and cognition included 102 035 participants aged 50 or more years at baseline, with follow-up of 2-21 years. 121 high social contact (measured through either or both of social activity and social network) was associated with better late-life cognitive function (r=0·05, 95% ci: 0·04-0·065) and no differences according to sex or length of time followed up. a new meta-analysis found that in long-term studies (≥10 years), good social engagement was modestly protective (n=8876, rr=0·9, 95% ci 0·8-1·0); but loneliness was not associated with dementia risk. 122 no long term (>10 years) studies of loneliness and dementia outcomes have been done. a uk 28-year follow-up study of 10 308 people found that more frequent social contact at age 60 years was associated with lower dementia risk over 15 years of follow-up (hr for one standard deviation social contact frequency 0·9, 95% ci 0·8-1·0). this finding suggests more frequent social contact during late middle age is associated with a modest reduction in dementia risk, independent of socio-economic and other life style factors. 123 a japanese longitudinal cohort study of 13 984 adults aged older than 65 years with a mean of 10 years follow-up calculated a five-point social contact scale based on: marital status; exchanging support with family members; having contact with friends; participating in community groups; and engaging in paid work. it found the score to be linearly associated with reduced dementia risk; those who scored highest on the five-point scale were 46% less likely to develop incident dementia compared with those in the lowest category. 124 despite clear cultural variation in the meaning and perception of social isolation, findings of protective effect of more social contact are largely consistent in different settings and for either sex across the studies and metaanalyses. 118, 120, 121 little evidence of the effects of social interventions on dementia exists but a systematic review of low quality rcts of 576 adults aged 60 or more years with normal cognition found facilitated meeting and discussion groups were associated with improved global cognition and increased brain volume at follow-up. 118 air pollution and particulate pollutants are associated with poor health outcomes, including those related to non-communicable diseases. attention has turned to their potential effect on the brain. animal models suggest airborne particulate pollutants accelerate neurodegenerative processes through cerebrovascular and cardiovascular disease, aβ deposition, and amyloid precursor protein processing. 125, 126 although the higher levels of dementia from air pollutants are still subject to the potential for residual confounding, the effects on animal models are evidence of physiological effects over and above those driven by life-course deprivation. high nitrogen dioxide (no 2 ) concentration (>41·5 µg/m³; adjusted hr 1·2, 95% ci 1·0-1·3), fine ambient particulate matter (pm) 2·5 from traffic exhaust (1·1, 1·0-1·2) [127] [128] [129] and pm 2·5 from residential wood burning (hr=1·6, 95% ci 1·0-2·4 for a 1 μg/m³ increase) are associated with increased dementia incidence. traffic often produces no 2 and pm 2·5 and it is hard to separate their effects, although evidence for additive effects of different pollutants exists. [127] [128] [129] a systematic review of studies until 2018 including 13 longitudinal studies with 1-15 years follow-up of air pollutants exposure and incident dementia, found exposure to pm 2·5, no 2, and carbon monoxide were all associated with increased dementia risk. 24 the attributable burden of dementia and excess death from pm 2·5 in one large 10-year us study was particularly high in black or african american individuals and socio-economically disadvan taged communities and related to particulate pm 2·5 concentrations above the us guidelines. 130 mechanisms by which sleep might affect dementia remain unclear, but sleep disturbance has been linked with β-amyloid (aβ) deposition, 131,132 reduced glymphatic clearance pathways activation, 133 low grade inflammation, increased tau, hypoxia 132,134 and cardiovascular disease. 135 sleep disturbance is hypothesised to increase inflammation which raises aβ burden, leading to alzheimer's disease and further sleep disturbance. 136 two meta-analyses showed similar findings. the first was a synthesis of longitudinal studies with an average of 9·5 years follow-up and the second reported crosssectional and prospective cohort studies of mixed quality with different methods of measuring sleep. sleep disturbances were defined broadly, often self-reported and including short and long sleep duration, poor sleep quality, circadian rhythm abnormality, insomnia, and obstructive sleep apnoea. all these disturbances were associated with a higher risk of all-cause dementia (rr 1·2; 95% ci 1·1-1·3) 137 and clinically diagnosed alzheimer's disease (1·6, 1·3-1·9) compared with no sleep disturbance, although not all cohort studies excluded those with cognitive impairment or dementia at baseline from their analyses. 138 a u-shaped association has been reported between sleep duration and risk of mild cognitive impairment or dementia with higher risks of dementia with less than 5 hours (hr=2·6; 95% ci 1·4-5·1) compared with more than 5 and less than 7 and more than 10 hours sleep (2·2, 1·4-3·5) and risks for allcause dementia and clinically diagnosed alzheimer's disease being similar. 135, [139] [140] [141] the postulated mechanisms of reduced sleep leading to accumulation of alzheimer's type pathology is inconsistent with the evidence that both more sleep and less sleep are associated with increased risk of dementia. new onset late-life sleep disturbance, a few years before clinical dementia, might be part of the natural history of the dementia syndrome, appearing to be a risk factor, or reflect other disorders, for example, mood disturbances or cardiovascular disease. 135, 142 hypnotic use might increase risks although this is unclear and a 2018 study 139 suggests that findings of a connection were related to reverse causality and confounders. 143 when benzodiazepine use was considered, in one study, sleep length was no longer significant 139 but not in all studies. 135 those taking hypnotics were at greater risk of dementia than those who did not regardless of sleep duration. 139 medication for sleep disturbance might be harmful and benzodiazepines are associated with falls, hospital admissions, and possibly dementia. 139, 144 diet nutrition and dietary components are challenging to research with controversies still raging around the role of many micronutrients and health outcomes in dementia. observational studies have focused on individual components ranging from folate and b vitamins, vitamin c, d, e, and selenium amongst others as potential protective factors. 88 there has been a move towards considering the evidence base for whole diets in the last 5 years, particularly high plant intake such as in the mediterranean diet (high intake of vegetables, legumes, fruits, nuts, cereals, and olive oil; low intake of saturated lipids and meat) or the similar nordic diet, rather than individual nutrients, which might reduce cognitive decline and dementia. 145 one example is a longitudinal cohort study of 960 partici pants, ages 58-99 years, in which those reporting the highest intake of green leafy vegetables, equivalent to 1·3 servings per day, had less cognitive decline over 4·7 years than those reporting the lowest intake (β=0·05 standardised units 95% ci 0·02-0·07). 146 the authors report this difference as being equivalent to being 11 years younger. a further prospective cohort study with three midlife dietary assessments in 8255 people, followed up for a mean of nearly 25 years, found neither healthy dietary pattern nor mediterranean diet protected from dementia, except in those with cardiovascular disease, suggesting that diet might influence dementia risk by protecting from the excess risk of cardiovascular risk factors. 147 as well as whole diets, there has been some interest in multi-nutrient interventions. a systematic review and a cochrane review including rcts of supplements (a, b, c, d, and e; calcium, zinc, copper, and multivitamins trials, n-3 fatty acids, antioxidant vitamins, and herbs) found a lack of evidence for supplement use to preserve cognitive function or prevent dementia in middleaged (45-64 years) or older people (aged 65 years and older). 148, 149 cochrane reviews found no evidence for beneficial effects on cognition of those with mild cognitive impairment of supplementation with b vitamins for 6 to 24 months 150 or with vitamin e in preventing progression from mild cognitive impairment to dementia. 151 a 24-month rct of 311 people of a multi-nutrient drink containing docosahexaenoic acid, vitamins b12, b6, folic acid, and other nutrients; found no significant effect on preventing cognitive deteriora tion in prodromal alzheimer's dis ease. 152 the authors comment that the control group's cognitive decline was much lower than expected, leading to an inadequately powered trial. meta-analysis of two rcts with 471 participants with normal cognition found the mediterranean diet improved global cognition compared to controls (smd 0·2, 95% ci 0·0-0·4). 153 a further meta-analysis identified five rcts (n=1888) with a weak effect on global cognition (smd 0·2, 95% cl 0·0-0·5) 154 but no benefit of mediterranean diet for incident cognitive impairment or dementia. the who guidelines recommend a mediterranean diet to reduce the risk of cognitive decline or dementia, as it might help and does not harm, but conclude vitamins b and e, polyunsaturated fatty acid, and multicomplex supplementation should not be recommended. 97 the finger rct was a 2-year multidomain intervention to prevent cognitive decline and dementia in 1260 people with cardiovascular risk factors aged 60-77 years, recruited from a finnish national survey. similar multidomain studies were discussed in the 2017 commission. 2 finger found a small group reduction in cognitive decline in the intervention group compared with control (comprehensive neuropsychological test battery z score 0·02, 95% cl 0·00-0·04) regardless of baseline sociodemographic, socio-economic, cognitive, or cardiovascular status. 155 however, in a subgroup analysis, greater beneficial effects were observed on processing speed in individuals with higher baseline cortical thickness in alzheimer's disease areas. 156 the healthy ageing through internet counselling in the elderly (hatice) study recruited 2724 older people (≥65 years) in the netherlands, finland, and france with two or more cardiovascular risk factors. 157, 158 it compared an interactive internet platform plus remote support by a coach, aiming to improve self-management of vascular risk factors, with a non-interactive control platform with basic health information. a small improvement in the cardiovascular risk composite primary outcome was observed in the intervention group compared with the control group at 18 months, mainly through weight loss, and the dementia risk score was slightly lower in those who received the intervention (mean difference −0·15, 95% ci −0·3 to −0·0). a larger effect was observed in the younger age group (65-70 years) and those with the lowest level of education, who had a higher baseline risk, suggesting that targeting high-risk popula tions might be more effective. several multi domain preventive trials are ongoing-for example, world wide fingers. we incorporated excessive alcohol consumption, tbi, and air pollution into our life-course model of dementia, as well as the original nine risk factors, because of the updated evidence. to calculate new rrs for excessive alcohol consumption, tbi and air pollution, we systematically reviewed the literature and did new metaanalyses for excessive alcohol consumption and tbi. for the other nine factors, we used values for rr and risk factors prevalence from our previous analysis and calculated communality using the same method as in the 2017 commission. 2 we used a representative sample of over 10 000 uk community-dwelling adults, to calculate communality (clustering of risk factors) of 11 risk factors for which data existed, 159 to allow calculation of each factor's unique risk. as we could find no datasets measuring tbi, with the other 11 risk factors of interest, we could not calculate its communality. we therefore used the mean of the other 11 communalities to calculate a weighted paf, so we could include tbi. we used cohabitation as a proxy measure for social contact, and urbanicity for air pollution exposure. our analysis found four principal components, explaining 55% of the total variance between the eleven risk factors, suggesting substantial overlap. the appendix (p 2) shows the paf formula and the steps in calculating communality and we detail our new meta-analyses we searched, from inception to oct 29, 2019, embase, allied, and complementary medicine, medline, and psycinfo terms "dementia" or "dement*" or "ad" or "vad", "alzheimer*" and "alcohol" or "ethanol" or "alcohol*" or "drink*" or "drunk*" to update an earlier review. 160 we used inclusion criteria: original populationbased cohort studies measuring drinking during midlife, as alcohol intake tends to fall with age; 161 alcohol consumption quantified at baseline by units or number of drinks (one drink, 1·5 units) per week; and all-cause dementia ascertained at follow-up using validated clinical measures. we contacted authors for additional data. 162 three studies met our inclusion criteria. 107, 162, 163 we converted hrs to rrs 164 and used raw data 162 to calculate rr, 165 for our random effects meta-analysis using generic inverse variance methods. the rr associated with drinking-more than 21 units (168 g) of alcohol weeklycompared with lighter drinking was 1·18 (95% cl 1·06-1·31; figure 5 ). we used health survey england figures for heavier drinking prevalence to calculate paf as we could not find a worldwide estimate. the weighted paf was 0·8. to estimate the rr of tbi of all severities for all cause dementia, we searched embase, medline, and psycinfo from jan 1, 2016, to oct 21, 2019, updating an earlier search, 166 using terms ("traumatic brain injury" or "head injury" or "brain injury" or tbi) and (neurodegeneration or "cognitive dysfunction" or dementia or "alzheimer's disease" or "parkinson's disease" or "frontotemporal dementia"). we converted hr figures to rr. 164, 167 we used inclusion criteria: original population-based cohort studies, baseline tbi of all severities reported, and allcause dementia ascertained at follow-up using validated clinical measures. we combined four new studies meeting inclusion criteria 67, 68, 71, 168 with the four studies meeting criteria from the original review in a random effects metaanalysis. 166 the pooled rr was 1·84 (95% ci 1·54-2·20) for all cause dementia from all severities of tbi (figure 6) although there was heterogeneity in study-specific estimates, possibly because of different popula tions. we used the tbi adult population prevalence of 12·1% from a metaanalysis to calculate paf. 173 the weighted paf was 3·4. 169 chu et al (2016) 168 fann et al (2018) 67 gardner et al (2014) 170 nordström et al (2014) 171 nordström et al (2018) 68 wang et al (2012) 173 total (95% ci) heterogeneity τ 2 =0·05, χ 2 =579·69, df=7 (p<0·00001); i 2 =99% test for overall effects: z=6·69 (p<0·00001) 0·2 0·5 1 2 5 a 2019 systematic review synthesised observational studies, finding consistently increased risk of dementia from air pollution, but heterogeneous comparator groups precluded meta-analysis. 24 we updated the search, using the same search terms and searching medline, embase, and psycinfo from sept 20, 2018, (the end date of the last search) to oct 22, 2019. we included longitudinal studies with assessment of all cause air pollution exposure; use of formal assessment of cognitive function at baseline; report of incident all-cause dementia, data from adults (age ≥18 years); and a minimum follow-up of 6 months. as meta-analysis was not possible, we used data from the only study of allcause air pollution with the outcome of all-cause dementia, with low-moderate risk of bias. this population-based, observational cohort was from canada, where pollutant concentrations are among the lowest in the world and examined 2 066 639 people, with a mean baseline age of 67 years. 174 we calculated the rr of dementia for those in the three highest quartiles compared to the lowest was 1·09 (1·07-1·11) . the attributable fraction for exposure to the highest three quartiles versus the lowest quartile of pm 2·5 and no 2 was 6·1% (4·8-7·5). the weighted paf was 2·3. table 1 displays the prevalence, commu nality, relative risk, unweighted and weighted pafs adjusted for communality. figure 7 shows the updated life-course model of potentially modifiable risk factors for dementia, including the three new risk factors. this commission is the most comprehensive ana lysis to date and updates the 2017 commission with emerging risk factor evidence convincing enough to calculate paf for potentially reversible risk factors. we reviewed the literature systematically for the chosen risk factors and provided illustrative new literature to update our synthesis and identify data to calculate communality. we find a hopeful picture with an estimate of around 40% of all cases of dementia being associated with 12 potentially modifiable risk factors. we have made assumptions to calculate this new model. we used global figures for dementia risk although we know the risk factors prevalence varies between countries and most global research is from hic, so lmic are under-represented because of lack of data. we have assumed a causal relationship between risk factors and dementia, although we have been cautious and not included risk factors with less good evidence. no single database exists with all 12 risk factors together, but we found 11 of the factors in a uk database and used the mean figure for communality calculations for tbi. we calculated communality for the other 11. we do not know how far findings of communality in other geographical populations might differ, or in those with a differing distribution of age groups or sex. we found that social isolation was not explicitly measured and had to use proxies, such as cohabitation when considering prevalence, which are approximate. specifically, evidence for the association of alcohol misuse with dementia comes from hic and future studies from lmic are needed to complete the picture. exposure to air pollution changes over a lifetime and is inextricably linked to poverty and deprivation. however, the effects on animal models suggests specific physiological effects over and above those driven by life-course deprivation. we also considered the overlap with education for this and other risk factors and the correction for education, strongly inversely linked to deprivation, will address at least some of the confounding. however, the results in one study which reported the effect of air pollution on incident dementia showed very little early life difference in estimates before and after adjustment for education and other risk factors, suggesting little residual confounding exists. 174 we were also unable to metaanalyse data on pollution and thus unlike the other relative risks, the figure comes from only one study, from an area of low pollution so is likely to be an underestimate. the longitudinal evidence linking potentially modifiable risk factors to dementia generally fulfils causality criteria in observational data (strength, consistency, biological plausibility, temporality, dose-response, coherence, and quasi-experimental studies, for example, more education or using hearing aids). when measuring a risk nearer to the age of dementia onset, then it is more likely that prodromal change affects, or even causes it. alternatively, a risk factor might act on preclinical pathology or even cause dementia near the time of exposure. thus, excessive alcohol, and tbi are particularly important in young-onset dementia, although many early onset dementias relate to genetic risks. risk factors might also matter more at a time of higher biological vulnerability, which the studies we have drawn on cannot establish. the length of exposure required for risk or protection effect, and their interrelationships as they change across life is unclear-it seems probable that longer or more intense exposure has stronger effects. additionally, as our communality figures show, risk factors overlap. we cannot establish from these data if having multiple risk factors has an additive or synergistic effect. association does not prove causation, however, as already noted, the reductions in prevalence and incidence in several hic suggests that at least some of the risk factors estimated here do have a causal relationship with the clinical expression of dementia. we judge that sufficient new evidence supports adding three additional modifiable risk factors for dementia to our 2017 commission model (excessive alcohol, traumatic brain injury, and air pollution). we have been able to add updated evidence on the nine risk factors implicated in the 2017 commission (education, hypertension, hearing impairment, smoking, obesity, depression, inactivity, diabetes, and social contact). reduction of these risk factors might be protective for people with or without a genetic risk, although study findings have not been entirely consistent. [175] [176] [177] [178] as we noted in the 2017 commission, others have previously calculated an estimate of the risk associated with apoε4 at 7% taking into account some other risk factors and this estimate highlights how relatively important potentially modifiable risk factors are in dementia. 2, 179 for some risk factors, the pattern of risk and the individual's other health, both physical and mental, might be especially important. currently, the evidence suggests a mediterranean or scandinavian diet might have value in preventing cognitive decline in people with intact cognition, particularly as one component of a healthy lifestyle, although how long the exposure has to be or during which ages is unclear. we do not recommend taking additional vitamins, oils, or mixed dietary supplements as a means of preventing dementia as extensive testing in trials has not led to signals of beneficial effects. data from rcts on interventions to prevent cognitive decline, all-cause dementia, or alzheimer's disease are few. for some key life influences, only observational data, particularly related to natural experiments such as changing the statutory education age, are possible. these influences should be investigated systematically wherever possible. others can theoretically be investigated but the long follow-up required for midlife risk and protective factors and non-random attrition in longer studies are challenging. using intermediate endpoints, such as cognition, and dementia onset in research remains uncertain because no intermediate markers with such a close relationship to dementia outcomes exist that it would be possible to predict with certainty for any given individual, age, and sex. overall, the evidence for treating hypertension is strongest and high blood pressure throughout midlife increases the risk of dementia even without stroke. although a need for more evidence is apparent, recommendations should not wait, as clear indications of ways to reduce the chances of developing dementia without causing harm will also lead to other health and wellbeing benefits. our recommended strategies for dementia risk reduction include both population-wide and targeted interventions (panel). it is important to remember that more socially disadvantaged groups, including black, asian, and minority ethnic groups, are particularly at risk. although we have more to learn about effectiveness, avoiding or delaying even a proportion of potentially modifiable dementias should be a national priority for all. not all dementia will be preventable and we present the latest evidence on intervention and care for dementia. to date the emphasis has been on specific subtypes of dementia, most notably on alzheimer's disease, which has been conceptualised over the years in a variety of changing diagnostic criteria-eg, dsm iv and dsm v. 180, 181 intense efforts have been put into biomarkers for early preclinical detection of the disease process before it becomes dementia. biomarkers need to show reliability and validity, and for dementias they also need to be very closely and clearly related to clinical syndrome outcomes in the way that, for example, human papillomavirus is for cervical cancer, and hypertension has been for stroke. markers of neurodegeneration linked to clinical dementia include brain volume loss-ie, hippocampal volume loss and entorhinal cortex and medial temporal cortical thinning-seen in structural imaging. the most studied molecular markers are in alzheimer's disease and are amyloid and tau, which pet and csf detect clinically. the prevalence of particular pathologies at different ages is important in interpretation of such studies. so, for example, population derived studies show increases in plaques in the population from less than 3% at age 50-59 years to around 40% at age 80-89 years. 182 amyloid imaging detects amyloid in the brain with high sensitivity and specificity in both cognitively normal and people with alzheimer's disease when the gold-standard comparison is either neuropathology or clinical diag nosis, distinguishing alzheimer's disease from other neurodegenerative conditions. 183 amyloid imaging is not a diagnostic test for dementia. a us study of randomly selected older people from the community recruited 1671 people (mean age of 71 years). 182 the prevalence of pet detected amyloid positivity increased from 2·7% (95% ci 0·5-4·9) of people without cognitive impairment aged 50-59 years to 41·3% (95% ci 33·4-49·2%) aged 80-89 years. 182 in 10-year follow-up pet positivity was associated with a higher probability of developing alzheimer's disease compared with those who were amyloid negative (hr 2·6, 95% ci 1·4-4·9). in participants with mild cognitive impairment who were amyloid positive the probability (hr 1·9, 95% ci 0·9-3·9) was not very different to those who were amyloid negative (1·6, 0·8-3·4). similarly, an 8-year follow-up study of 599 volunteers (average age 70 years) in australia found that cognitively normal pet amyloid-positive people had an elevated risk of developing alzheimer's disease compared with amyloid negative (17·7% vs 8·1%; or 2·4, 95% ci 1·5-4·0). 184 over 80% of the 266 people who were pet amyloid-positive did not go onto develop a cognitive impairment within 8 years, showing positive status does not predict impairment for most people in a timeframe that might be a useful prognostic window. follow-up at 5 years of amyloid-positive participants with normal cognition or mild cognitive impairment versus amyloid negative people found the same pattern of increased risk (2·6, 1·4-4·9). risk also increases per 1 year of age (hr 1·05, 95% ci 0·55-2·0/year), and apoeε4 status (2·6, 1·4-5·0). 184 most people who are amyloid positive with no other markers have not developed alzheimer's disease dementia during their lifetime. a model of lifetime risks of people who are amyloid positive without any other biomarkers finds it to be 8·4% for a 90-year-old woman who is cognitively normal at baseline, 23·5% for a 75-year-old woman and 29·3% for a 65-year-old woman. 185 the 10-year risk is considerably less, so a 65-year-old woman with only amyloid biomarkers but who is cognitively normal and has no neurodegeneration has a 10-year alzheimer's disease risk of 2·5% and a man 2·3%, but the risk is higher with accompanying neurodegeneration (table 2) . 185 overall, the knowledge of pet-measured amyloid and tau status and mri-derived cortical thickness in a general population derived sample, only adds a small improvement, which might not be clinically important for predicting memory decline over a model with clinical and genetic variables. 186 using amyloid pet in patients with cognitive impairment of uncertain causes, results in changes to the clinical diagnosis of alzheimer's disease 187 and sometimes to medication prescription. we do not know whether pet use improves patient care or decreases care costs. many people have a mixed cause of dementia and a positive result does not indicate only alzheimer's disease. pet imaging is very costly (us$3000 in the usa) and although used in some clinical settings remains the topic of research to understand its usefulness in broader populations. fluid biomarkers-ie, blood and cerebrospinal fluid tests-have become a more practical focus of interest since it has become possible to measure specific proteins linked to the proteins associated with the neuropathologies of alzheimer's disease. 188 a composite blood biomarker for amyloid tested in a discovery dataset and then a validation cohort of participants aged 60-90 years who were already taking part in studies in japan or australia had areas under the receiver operating risks are particularly high in more socially disadvantaged populations including in black, asian, and minority ethnic groups. • prioritise childhood education for all, worldwide • implement social public health policies that reduce hypertension risk in the entire population • develop policies that encourage social, cognitive, and physical activity across the life course for all (with no evidence for any specific activities being more protective) • scrutinise the risks for hearing loss throughout the life course, to reduce the risk of exposure to this risk factor • reduce the risk of serious brain trauma in relevant settings, including occupational and transport • national and international policies to reduce population exposure to air pollution • continue to strengthen national and international efforts to reduce exposure to smoking, both for children and adults, and to reduce uptake and encourage cessation • use hearing aids for hearing loss; we need to help people wear hearing aids as many find them unacceptable, too difficult to use, or ineffective • avoid or discourage drinking 21 or more units of alcohol per week • prevent head trauma where an individual is at high risk • stopping smoking is beneficial regardless of age • reduce obesity and the linked condition of diabetes by healthy food availability and an environment to increase movement • sustain midlife, and possibly late-life physical activity characteristic curves of 96·7% for discovery and 94·1% for validation. the blood biomarker had sensitivity and specificity above 80% against amyloid pet measurement 188 and correlated with csf concentrations of aβ1-42. these results are similar to other amyloid blood biomarkers 189, 190 and harmonisation to a common reference standard is now vital. although csf aβ1-42/1-40 ratio and amyloid pet are now considered interchangeable, 191 csf tau biomarkers have only correlated weakly with brain tau as currently measured by radioligands. 192 neurofilament light protein is measured in many cohorts; however, it is non-specific. people with huntington's disease, multiple sclerosis, mild cognitive impairment, and alzheimer's disease might have raised blood neurofilament light concentrations, which are a marker of neurodegeneration. [193] [194] [195] to be useful in clinical practice biomarkers must be well understood in the populations to which they are going to be applied, including the effects of age and sex on results. there is now reasonable evidence that amyloid and tau measured by pet or in fluid indicate increased risk for development of cognitive impairment in older adults but at the individual level prognostication is not possible as most cognitively normal people with these markers do not develop dementia within a clinically relevant timeframe. negative amyloid results can be useful for ruling out current alzheimer's pathology in people with cognitive impairment when the cause is uncertain and show an individual is unlikely to develop alzheimer's disease during the next few years. high neurofilament light concentrations indicate a neuro degenerative process but not its cause. the value of biomarkers, in terms of diagnostic value, has not been addressed in different representative populations and particularly not in those from lmic. the potential advantages of blood biomarkers are their low cost and their wider acceptability and applicability in many settings. in many areas of medicine more reliable diagnostic tests have improved research, including epidemiological and public health research and trials, to help distinguish cause from symptom (tuberculosis from a fever) or assess risk factor and disease (hyper cholesterolaemia and ischaemic heart disease). those biomarkers developed for the underlying biology of the dementia syndrome are subject to the same assessment of value. in the 2017 commission, we discussed that when concerns are raised by patients or family, an accurate diagnosis is helpful. such a diagnosis provides a gateway to intervention and services where available, for planning for possible futures, and support for family, as well as to research. unfortunately, these services are not always available. national plans for dementia support timely diagnosis and offer help to individuals and their families. we did not address screening of those not presenting with concerns but rigorous systematic reviews by the us task force on prevention have found an absence of evidence of benefit and harm. 196 the first trial of population screening took place in the usa, screening 4005 primary care patients aged 65 years or older. no clear benefit or harm in terms of quality of life, mood, or increasing diagnostic rates was found. 197 other strategies might become more valuable in time such as sensitive awareness of risk factors, when routine records suggest an individual might be deteriorating cognitively. 198 people with dementia have complex problems with symptoms in many domains. those providing support and any interventions must consider the person as a whole, as well as their context and their close carers, whether family or friends. individuals' medical, cognitive, psychological, environmental, cultural, and social needs must be given consideration. 2 in the context of under provision of services, this notion is and will continue to be a challenge. dementia, as an illness which affects cognition by definition, affects the ability to organise activities and people with dementia often need help to do what they enjoy-for example, listen to music, or go to gardens and parks. wellbeing is one of the goals of dementia care. data are relative risk (95% ci) or %. reproduced from brookmeyer and abdalla 185 by permission of elsevier. cholinesterase inhibitors have a useful, modest role in improving cognition and activities of daily living in patients with mild-to-moderate alzheimer's disease and memantine can be prescribed in combination or each drug used separately for moderate and severe alzheimer's disease. 2, 199, 200 however, although available in most countries these drugs are no longer remunerated in france because it is felt that they offer only a small benefit while shifting clinician's attention from other interventions. whether non-prescribing of this drug will help patients by removing an intervention with known benefit or be detrimental to them is unknown. 201 no advances have been reported in aβ therapeutics, with negative results from phase 3 trials of monoclonal antibodies (eg, solanezumab, crenezumab) and inhibitors of β-secretase, a protease involved in the production of aβ peptides. 202 aducanumab previously abandoned as futile now has further unpublished results. three 5ht6 antagonists and the calcium channel blocker nilvadipine 203, 204 have also been ineffective. these drugs also show substantial impact during treatments at socalled therapeutic concentrations on the leakiness of blood vessels. the long-term impact of such side-effects is unknown. anti-tau, anti-amyloid, and anti-inflammatory drugs continue to be in focus and some argue that pre-symptomatic interventions are necessary, especially if targeting aβ production, but no evidence of efficacy 205 and some evidence of worsening target symp toms currently exists. 206 a meta-analysis of 12 controlled trials of 389 people with mild dementia, completing 4 or more hours of group-based computerised cognitive training (mean age 66-81 years, 63·5% female participants), found a small, statistically significant beneficial effect on overall cogni tion, driven by two trials of virtual reality or video games (smd=0·3, 95% ci 0·0-0·5), one with a low and one with a high risk of bias. 55 a cochrane review 207 found 33 trials of cognitive training, only one of which over lapped with the study above, with around 2000 participants with mild-tomoderate dementia, most with a high or uncertain risk of bias. 207 people completing cognitive training, compared with usual treatment or non-specific activities, had small-to-moderate effects on overall cogni tion (smd 0·4, 95% ci 0·2-0·6) and specific cognitive abilities such as verbal fluency and improvements lasted for a few months to 1 year. no direct evidence was observed to suggest that cognitive training was better than cognitive stimulation therapy. the dementia and physical activity rct 208 found moderate-to-high intensity aerobic and strength exercise training did not slow cognitive impairment in people with mild-to-moderate dementia but improved physical fitness. the us reducing disability in dementia study 209 implemented an at-home multicomponent intervention including exercise education, training to increase pleasant events, and activator-behaviour-consequence problemsolving approach over 6 weeks by case managers in 255 community dwelling people with dementia older than 60 years and their family carer and were able to follow up 140 (54·9%). the study found increased physical activity; days of taking 30 or more minutes of exercise (effect size 0·6, 95% ci 0·4-0·8 after the treatment and 0·3, 0·1-0·5 at 13 months) in a before and after intervention comparison. neuropsychiatric symptoms are common and often clus tered in people with dementia. these symptoms might precede dementia and are associated with tau and amyloid neuropathology. 210 this suggests that underlying neurobiological mechanisms might underpin neuropsychiatric symptoms. however, other drivers relating to the personal history and the environment of the person with dementia are also likely to exist. neurodegeneration could lead to increased vulnerability to stressors or triggers. genetics, cognitive reserve, resilience, medical comorbidities, and environment including responses of carers might modify these relationships. needs and responses will also be individual and relate to a person's own social, cultural, and historical context. first-line assessment and management of neuropsychiatric symptoms should focus on basic health: describe and diagnose symptoms; look for causes such as pain (using validated pain assessments might help), illness, discomfort, hunger, loneliness, boredom, lack of intimacy and worry that could cause the behaviours and alleviate these while considering risks of harm. 2 no new evidence of medication effectiveness for these symptoms exists; risperidone in low doses (0·5 mg daily) and some other antipsychotics are sometimes effective but often ineffective and have adverse effects. 2 specific initiatives have led to a decrease in antipsychotic prescriptions for people with dementia, although often replaced with other psycho tropics (figure 8), such as benzodiazepines, antidepres sants, and mood stabilisers. 211 these psychotropics lack evidence of efficacy for neuropsychiatric symptoms but show clear evidence of possible harm; for example, trazodone and benzodiazepines increase fall-related injuries. 144 major policy changes should be assessed carefully, within and across countries for unintended consequences (and perhaps unexpected benefits) and their costs. evidence is slowly accumulating for the effectiveness, at least in the short term, of person-centred evidence-based psychosocial interventions. in germany, a 6-month cluster rct of nurse-delivered, supervised dementia care management used a computer-assisted nurse assessment to determine personalised intervention modules, then a multi-disci plinary team discussion and agreement with the physician for 634 people (mean age 80 years) with dementia living at home with a primary carer or alone. 212 the mean mini mental state examination (mmse) was 23, only 38% had a formal diagnosis of dementia; the majority of participants (51%) had mild dementia but some had moderate and some severe dementia. the intervention consisted of psychosocial management of treatment and care, medi cation management and carer support, and education and discussion with a psychiatrist or neurologist. the intervention, compared with care as usual, was associated with better outcomes for neuropsychiatric symptoms (neuropsychiatric inventory [npi] score −7·5, 95% ci −11·1 to −3·8), however this effect could be because of deterioration in care as usual (in the care as usual group npi increased from 7·2 to 15·2; in the intervention group npi increased from 7·6 to 8·2). this between-group reduction in neuropsychiatric symptoms was greater than that expected, extrapolating from other study results, with antipsychotic medication. effects on quality of life were only apparent for those people living with a carer. an eight-session home-based tailored activity programme rct, tailored both to the person with dementia living at home and to a family member compared with eight telephone-based education sessions, recruited 160 participants with 64% follow-up, imputing values for the rest. 213 the study reported a large reduction in overall neuropsychiatric symptoms immediately after the intervention, which were better in the group receiving home-based tailored activity programme on the neuropsychiatric inventory (mean difference in score 24·3, 95% ci 3·1-45·6), and on functional dependence and pain but this was not sustained 4 months later. noncompleters had more severe neuropsychiatric symptoms. since the 2017 commission two new systematic reviews of antidepressants to treat depression in dementia reported moderate quality evidence that antidepressant treatment for people with dementia does not lead to better control of symptomatology compared with placebo. 214, 215 agitation agitation is distressing for people with dementia and those around them, and contributes substantially to the overall costs as the level of agitation increases. 216 the body of evidence on this key behaviour is growing, mostly focused on care-home settings. these findings are valuable as these populations are most affected; however, because many people with dementia reside at home a major gap in knowledge remains. care home residents with agitation often find sitting still difficult and therefore might not be included in activities. 217, 218 two new cluster rcts of professionals delivering multicomponent, interdisciplinary, interventions in care homes successfully reduced agitation. the wheld study 219 included participants with or without neuropsychiatric symptoms and provided person-centred care, aiming to improve communication with people with dementia. it implemented social, sensory experiences or other activities; educated about antipsychotic review; and addressed physical problems, finding lower cohen mansfield agitation inventory (cmai) at 9 months (md −4·3 points, 95% ci −7·3 to −1·2). 219 the time study 220 for people with moderate-to-high levels of agitation consisted of a manual-based comprehensive assessment of the resident and structured case conference for the staff and doctor, to create a tailored plan, and then implement it. this intervention led to reduced agitation at 8 weeks (npi −1·1 points, 95% ci −0·1 to −2·1; cmai −4·7 points, −0·6 to −8·8) and 12 weeks (npi −1·6, −0·6 to −2·7; cmai −5·9, −1·7 to −10·1). 220 these effect sizes are similar to those seen for medications, but without harmful side-effects. 2,221 a further rct studied a six-session intervention with staff in groups, teaching staff to understand agitation as related to medical, psychological, or social unmet needs and to implement strategies to meet these needs, using the describe, investigate, create, and evaluate approach. 222 the intervention did not reduce agitation symptoms, although it was cost-effective, improving quality of life. 223 overall, the current evidence for agitation in care homes favours multi-component interventions by clinical staff, including considering if drugs might harm, and not drug interventions. thus a major gap remains in knowledge about people living at home who comprise the majority of those with dementia. people with dementia might be wrongly thought to have delusions when they misremember, and new psychotic symptoms are often due to delirium, thus thorough assessment of symptoms is essential. 2 management of psychosis in dementia should start with non-pharmacological interventions; however, evidence for effectiveness of these interventions for psychosis in dementia is weaker than for agitation. 224 antipsychotics for psychosis in dementia should be prescribed in as low a dose and for the shortest duration possible. 2 however, a cochrane review of antipsychotics withdrawal found two trials with participants with dementia who had responded to antipsychotic treat ment. these reported that stopping antipsychotics was associated with symptomatic relapse 225 suggesting the need for caution in any medication withdrawal in this group. there was lowquality evidence that, in general, discon tinuation might make little or no difference to overall neuropsychiatric symptoms, adverse events, quality of life or cognitive function. 226 apathy apathy might be conceptualised as the opposite of engagement, comprising reduced interest, initiative, and activity. like people without dementia, those with dementia engage more in preferred activities, but require additional support to do so. 227 a study in care homes observed engagement increased during activities in those who attended the groups. 228 a cochrane review of the few people who had been in drug rcts of methylphenidate versus placebo for apathy in dementia found small improvements on the apathy evaluation scale (md −5·0, 95% ci −9·6 to−0·4, n=145, three studies, low-quality evidence) but not on the npi apathy subscale (md −0·1, 95% ci −3·9 to 3·7, n=85, two studies). 229 there is no evidence that medication for sleep in dementia is effective 230 and considerable evidence for harm-ie, earlier death, increased hospitalisation, and falls-exists. 139, 144 test ing of non-pharmacological interventions is ongoing. 231 carer distress related to neuropsychiatric symptoms rather than the dementia symptoms was associated in one study with increased use and costs of health services, 232 high lighting the need for effectively identifying, educating, and supporting distressed carers. an rct 233 reporting 6-year follow-up after the eight session strategies for relatives intervention-manual-based coping intervention delivered by supervised psychology graduates-found continuing effectiveness for depressive symptoms in carers (adjusted md −2·00; 95% ci −3·4 to −0·6) and risk of case-level depression, with patient-related cost being approximately 3 times lower than those who did not receive the intervention (median £5759 vs £16 964 in the final year; p=0·07). 233 another us study 234 followed up 663 people, mean age 77 years, 55% women. caregiver depression rather than symptoms of people with dementia predicted emergency department use for people with dementia, with a 73% (rr 1·73, 95% ci 1·3-2·3) increase. 234 functioning a uk rct of 14 sessions of cognitive rehabilitation focused on individual goal attainment with therapy delivered at home by an occupational therapist or nurse to 475 participants with mild-to-moderate dementia (mmse ≥18 for inclusion; mean 24) and a family carer. 235 individuals had two or three goals; the most common was engaging in activities (21% of goals). the intervention group reported increased goal attainment over 3 and 9 months compared with usual treatment (effect size 0·8, 95% ci 0·6-1·0 at both 3 and 9 months). 235 the treatment did not improve participants' quality of life, mood, selfefficacy, cognition, carer stress, or health status and was not cost-effective. a systematic review 236 of rcts without meta-analysis for overall effect size, concluded that all interventions which had improved functioning in people living with dementia in the community have been individual rather than group interventions. these were: in-home physiotherapist delivered aerobic exercise (two studies, larger one positive, 140 people with alzheimer's disease; smaller study negative, 30 people with alzheimer's disease), individualised cogni tive rehabilitation (mild or moderate dementia; two studies; 257 cognitive reserve intervention groups and 255 controls), and in-home activities-focused occupa tional therapy (people with mild to moderate dementia, three studies, 201 intervention, 191 controls) reduced functional decline compared to controls but group-exercise and reminiscence therapies were ineffective. 236 multimorbidity is a huge challenge in dementia, not only because people with dementia have increased rates of other illnesses, but also because they often find it parti cularly difficult to organise care. people with dementia might forget to tell their family or health professionals of symptoms, struggle to understand or follow agreed plans, and are more likely to forget to drink and eat, increasing falling and infection rates. 237 people with dementia consult primary care less often 238 and have fewer dental visits 239 than those without dementia and their family members, if involved, often feel they lack knowledge to assist. 240 health-care professionals need education to be more comfortable, understanding, and positive in communicating with people with dementia. 241 around 70-80% of people diagnosed with dementia in primary care have at least two other chronic illnesses. 242, 243 people who are physically more frail are more likely to have dementia, but the relationship between pathology and symptoms in these people is comparatively weak suggesting that dementia might be from other causes. 22 compared to the general older population, people with dementia have increased rates of cerebro vascular disease, [243] [244] [245] [246] stroke, 247 parkinson's disease, 243, 245 dia betes, 245, 247 skin ulcers, anxiety and depression, 243,245 pneu monia, incontinence, and electrolyte disturbance. 245 multimorbidity in people with dementia is associated with faster functional decline 248 and worse quality of life for people with dementia and their family carers. 249 severe acute respiratory syndrome coronavirus 2, was first identified in patients with viral pneumonia in hubei province, china. 250 severity and mortality of the associated disease (covid-19) worsen with increasing age 251 and with pre-existing illnesses such as hypertension and diabetes, 252 and thus many people with dementia are at particular risk. death certificates from the uk indicate that dementia and alzheimer's disease were the most common underlying conditions, specified in 11 950 deaths (25·6% of all deaths involving covid-19) in march to may, 2020. 253 many charities, practitioners, and academics supporting people with dementia have issued guidance based on current evidence and best practice, including advance consideration of whether people would wish to be hospitalised if they develop severe covid-19. concern has been expressed that the illness and consequent distancing might increase family carer stress, loneliness, neuropsychiatric symptoms and use of psychotropic medication, and lead to complications, including future dementia. interventions delivered remo tely through technology have also been implemented in some places. [254] [255] [256] [257] people with dementia might struggle to adhere to measures to reduce virus transmission, as they might not understand or remember about required changes to behaviour, such as physical distancing and hygiene, leading to increased risk to themselves and their carers. 258 they might additionally be vulnerable if they depend on others for daily activities or personal care, as this necessitates close personal contact. this situation is particularly concerning in those care homes, where many residents have dementia and where many covid-19 deaths have occurred in many countries [259] [260] [261] with reports of more than half of residents being admitted to hospital. in us nursing homes, among 10 576 people with confirmed covid-19, residents living with dementia made up 52% of covid-19 cases; yet, accounted for 72% of all deaths (an increased risk of 1·7). 262 the number of people living together in care homes means that the infection of an individual, either staff or resident, could endanger more people than in traditional or family households. although evidence exists that if staff are sufficiently and rigorously protected they are unlikely to develop covid-19, many staff have become unwell and some have died. 263, 264 illness means that there are fewer people to care for residents at a time when they need particularly high levels of care. this situation is par ticularly relevant in the care of residents with dementia, if they are expected to remain in their own rooms, rather than eating and participating in activities with others. staff or residents might also be moved between care homes and increase risk in other homes. 261 restrictions on visitors to private homes, care homes, and hospitals might cause greater distress for people with dementia and they might not understand why people are wearing masks, recognise who is behind it, or understand speech when lips are covered. lack of restrictions means that the visitors might also be at elevated risk. 261 the impacts of covid-19 on people with dementia might be particularly severe in lmics, due to smaller health budgets for testing and protective equipment, capacity of health-care systems, quality of care home provision and patterns of workforce mobility. 264 thus, people with dementia are particularly vulnerable to covid-19 because of their age, multimorbidity, and difficulties in maintaining physical distancing. [250] [251] [252] we recommend rigorous public health measures of protective equipment and hygiene, including not moving staff or residents between care homes or admitting new residents when their covid-19 status is unknown, should mitigate impacts on people with dementia. it is also imperative that there is frequent and regular testing of staff in care homes for infection, ensuring staff have sick pay so that they do not come in when symptomatic and interim care is being set up for people discharged from hospital so that only those who are covid-19 free come to live in care homes. resident testing should encompass asymptomatic as well as symptomatic people, when there is exposure within the home to covid-19. in the future, many homes might be able to start to provide oxygen therapy so that those who do not want to be admitted to hospital are still able to access oxygen therapy. in addition, it is also important to reduce isolation by providing the necessary equipment and a brief training to relatives on how to protect themselves and others from covid-19; so that they can visit their relatives with dementia in nursing homes safely when it is allowed. further evidence is needed to inform responses to this and future public health emergencies. hospitalisation in people with dementia is associated with adverse, unintended consequences, including distress, func tional and cognitive decline, and high economic costs. [265] [266] [267] people with dementia have 1·4 to 4 times more hospital admissions than others with similar illnesses. 266, [268] [269] [270] a systematic review and meta-analysis including 34 studies of 277 432 people with dementia found that in the six studies which compared the two groups, people with dementia had increased hospital admissions compared with those without dementia, after adjusting for age, sex, and physical comorbidity (rr 1·4, 95% ci 1·2-1·7; figure 9 ). 271 hospitalisation rates in people with dementia ranged from 0·37 to 1·26 per person-year in high-quality studies. admissions are often for conditions that might be manageable in the community (potentially preventable hospitalisations). 268 people with dementia experience longer and more frequent admissions and readmissions; health-care expenditure for people with moderate-severe dementia is around double that of people without dementia. 269, 272, 273 early detection and management of physical ill-health in people with dementia, particularly of pain, falls, diabetes, incontinence, and sensory impair ment, is important. 199, 274, 275 however, no intervention has successfully reduced number of hos pital admissions of community-dwelling people with demen tia, 276 although education, exercise, rehabilitation, and telemedicine have reduced admissions for older people without dementia. 277 high-quality care for people with dementia takes longer than caring for others with the same condition. 278 recognition of dementia in hospital inpatients is necessary for optimum care, 279 but dementia is often undetected or unrecorded. 280 in the uk however, detection rates have increased over the past 10 years. 281 dementia and delirium frequently occur together. in one hospital inpatients' survey nearly 35% of those older than 80 years experienced delirium; those with prior cognitive impairment had 15 times the risk of devel oping delirium than those without (or 15·3, 95% ci 5·2-45·4). 282 people with delirium without known dementia are more likely to be diagnosed with dementia in the future than others, either because of pre-existing undiagnosed dementia or cognitive impairment, present in 20·7% (95% ci 11·9-29·5) and 37·8% (27·3-88·3) respectively of one cohort, or because delirium has neurotoxic effects and so precipitates dementia. 283 people with similar people diagnosed with alzheimer's disease had mixed causes of dementia. 299 although alzheimer's disease neuropathology was the commonest cause of dementia, alzheimer's disease changes rarely occurred on their own, so only 9% of people with dementia had pure alzheimer's disease pathology. 300 people who have alzheimer's disease patho logy without developing dementia tend to have fewer age-related health deficits than those who develop it with even low concentrations of plaques and tangles. 301 a moderation analysis showed that the relationship between alzheimer's disease pathology and dementia status differed according to level of frailty (adjusted for age, sex, and education) with increasing frailty weakening the relationship between alzheimer's disease pathology and dementia (figure 10). 22 as with delirium, some of this additional health risk might be modifiable. this approach suggests a new type of therapy focus on specific agerelated processes that underpin many diseases of late life might reduce the incidence or severity of dementia. the numbers of people dying with dementia are increasing but the evidence for the best end-of-life care is scarce. trends in age-standardised death rates (3·6%) for dementia increased slightly between 1990-2016, with pronounced increases in the usa and japan and decreases in western europe and central latin america. 4 dementia is more readily being included on death certificates, which accounts for some of the rise. the increase might be related to dementia manifesting at later ages, with higher physical frailty 22 leading to a faster decline. most people with dementia might die while still in the mild-to-moderate stages whereas only about a quarter of those dying with dementia have severe dementia. 302, 303 the trajectory of dementia is often unpredictable 304 and palliative care initiation should reflect need not prognosis. neuropatho logy show faster cognitive decline if they develop delirium than if they do not. 284 additionally, older people without dementia declined cognitively more than twice as fast after an emergency hospital admission for any cause, compared with those not admitted, suggesting any severe illness is associated with cognitive decline. 285 risk factors for delirium in dementia include sensory impairment, pain, poly pharmacy, dehydration, intercurrent illnesses, such as urinary tract infections or faecal impaction, and an unfamiliar or changing environment. 286 delirium in older people should prompt consideration of underlying dementia. most research on delirium prevention has been in people without dementia. it suggests targeting hydration, stopping medication predisposing to delirium, monitoring the depth of anaesthesia, and sleep promotion. however, no evidence for medication efficacy, including cholinesterase inhibitors, antipsychotic medication, or melatonin exists. [287] [288] [289] the hospital elder life program 290an intervention to prevent delirium in those admitted to hospital-reduces delirium incidence and includes people who are cognitively impaired. this multidisciplinary treatment consists of daily visits, orientation, therapeutic activities, sleep enhancement, early mobilisation, vision and hearing adaptation, fluid repletion, infection prevention and management of constipation, pain, and hypoxia, and feeding assistance. 290 a network meta-analysis of drugs for prevention and treatment of delirium did not include studies of people with dementia, thus we cannot use this to recommend drugs for people with dementia and delirium as this research might be inapplicable to them. 291 little high-quality research exists on managing delirium in dementia. one rct compared care at a specialist medical and mental health unit to usual care for 600 confused people older than 65 years, acutely admitted to hospital and found no difference in the primary outcome of days spent at home or in hos pital, but increased family satisfaction. 292 a further rct of cognitively stimulating activities for people with delirium in dementia did not improve the delirium. 293 no definitive evidence that any medication improves delirium in people with dementia exists: cholinesterase inhibitors, antipsychotics, and sedating benzodiazepines are ineffective and antipsychotics and benzodiazepines are associated with mortality and morbidity. 265, 288, [294] [295] [296] [297] given the risk of dementia in people who develop delirium, its prevention, and possibly advances in its management, might offer a means for dementia prevention. 298 the fastest growing demographic group in most advanced countries are people aged 90 years and older. one well characterised post-mortem cohort of the oldest old (n=1079; mean age 90 years) dying with dementia, found that neuropathological features of alzheimer's disease account for about half of the cognitive decline seen as decision making about end of life is complex and simple rules of thumb, co-designed with staff and carers, provided clarity in some small studies. 304 one rct testing decision-aids about families' and doctors' goals of care for people with advanced dementia led to increased palliative care content in care plans. 305, 306 in a 9-month uk prospective study, 85 care home residents with advanced dementia from 14 homes were likely to be living with distressing symptoms, specifically agitation (54%) or pain (61% on movement). 304 capacity to make abstract decisions, including about the future, might be lost early in dementia. 307 therefore, advance care planning, designed to empower people with dementia and improve quality of dying, might theoretically be something everyone should do before developing dementia. 308 however, people might not be able to predict their future wishes. this might explain why family carer proxies show only low-to-moderate agreement with stated end-of-life treatment preferences of people with dementia. 309 advance care planning might, however, reduce carers' uncertainty in decision making and improve perceptions of quality of care. 310 partners of people dying with dementia experience poorer mental health than those facing bereavement from other causes 311 possibly because of long and difficult caring responsibilities. this might be ameliorated through sensitive and timely information, particularly regarding the progression of dementia, 312 individually or through family and staff case-conferencing. 313, 314 conclusions knowledge about risk factors and potential prevention, detection, and diagnosis of dementia is improving although significant gaps remain. 315 in this commission report, we have specified policy and individual changes to delay the onset of cognitive impairment and dementia and better ways to support and treat people with dementia and their families and to improve their quality of life. interventions, including organisation of the 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specialist medical and mental health unit compared with standard care for older people with cognitive impairment admitted to general hospital: randomised controlled trial (nihr team trial) effect of cognitively stimulating activities on symptom management of delirium superimposed on dementia: a randomized controlled trial antipsychotics for treatment of delirium in hospitalised non-icu patients cholinesterase inhibitors for the treatment of delirium in non-icu settings benzodiazepines for delirium updated beers criteria for potentially inappropriate medication use in older adults challenges and opportunities in understanding dementia and delirium in the acute hospital attributable risk of alzheimer's dementia attributed to age-related neuropathologies person-specific contribution of neuropathologies to cognitive loss in old age relationship between frailty and alzheimer's disease biomarkers: a scoping review dementia severity at death: a register-based cohort study older people dying with dementia: a nationwide study living and dying with advanced dementia: a prospective cohort study of symptoms, service use and care at the end of life goals of care or goals of trust? how family members perceive goals for dying nursing home residents effect of the goals of care intervention for advanced dementia: a randomized clinical trial healthcare decisionmaking: past present and future, in light of a diagnosis of dementia advance directives for dementia: meeting a unique challenge advance care planning in dementia: do family carers know the treatment preferences of people with early dementia? effectiveness of advance care planning with family carers in dementia nursing homes: a paired cluster randomized controlled trial the mental health and mortality impact of death of a partner with dementia experiences of end of life amongst family carers of people with advanced dementia: longitudinal cohort study with mixed methods effects of facilitated family case conferencing for advanced dementia: a cluster randomised clinical trial a facilitated approach to family case conferencing for people with advanced dementia living in nursing homes: perceptions of palliative care planning coordinators and other health professionals in the ideal study a roadmap to advance dementia research in prevention, diagnosis, intervention, and care by 2025 we are partnered by university college london (ucl), the alzheimer's society, uk, the economic and social research council, and alzheimer's research uk, and would like to thank them for financial help. these organisations funded the fares, accommodation, and food for the commission meeting but had no role in the writing of the manuscript or the decision to submit it for publication. we would like to thank bernadette courtney, jacques gianino, and nuj monowari, from ucl, london, uk, for their administrative help, including managing finances, booking rooms and food, and setting up a website supported by the university college london hospitals national institute for health research biomedical research centre. we would like thank henrik zetterberg for advice on biomarkers and dementia. key: cord-300046-orlga9qf authors: gomes da silva, j.; sofia silva, c.; alexandre, b.; morgado, p. title: health literacy of inland population in the mitigation phase 3.2. of covid-19's pandemic in portugal a descriptive cohort study date: 2020-05-14 journal: nan doi: 10.1101/2020.05.11.20098061 sha: doc_id: 300046 cord_uid: orlga9qf background: covid-19 is a respiratory disease transmitted through respiratory droplets with a high transmission rate. there's still no effective and approved antiretroviral treatment or vaccine, thus, preventive measures are the main key to contain this pandemic. portugal is now in phase 3.2 of the mitigation of covid-19, being imperative to understand the health literacy of our country and how to prevent the lack of information, through community empowerment. material and methods: a cross-sectional study with a cohort from a primary care facility was conducted. we collected demographic and epidemiological data and carried out a questionnaire by phone call. descriptive statistics and nonparametric tests were used to assess associations between the independent variables and the level of health literacy. the level of significance was set at p<0.05. results: our cohort includes 222 subjects (median age: 62 years old), mostly females (131), undergraduate (193) and with at least one risk factor for covid-19 (144). globally, younger individuals, females, graduates and the non-risk group appear to have higher levels of health literacy, with some exceptions to this pattern. conclusions: we observe a well-informed population. however, being a pandemic situation, we intend to identify and correct outliers/misconceptions. this work allows a perspective of the current state/pattern of health literacy as well as its possible predictors. furthermore, this study makes aware of how relevant the specific communication approaches are. further studies to understand the predictors of health literacy are necessary. key-words: covid-19, pandemic, sars-cov2, portugal, health literacy. in december 2019, an outbreak of pneumonia with unknown etiology began to arise in the city of wuhan, china and the diagnosis of influenza and other coronaviruses (such as mers and sars) were considered but later excluded by laboratory tests 1,2 . on 7 th of january, 2020, china announced that the cause of that epidemic was a new coronavirus strain, later designated sars-cov-2 and proven to be present in wild bats 2, 3, 4 . the transmission mode of sars-ncov-2 is through respiratory droplets, and they are either a source of direct or indirect contamination 5, 6 . this strain presented a basic reproduction number (r0) within a range from 1.4 to 6.5: the highest infection rates in the elderly or in people with underlying pathologies 2, 7 . therefore, this means that this strain of virus has a high rate of human-to-human transmission and a person is much more contagious as more symptomatic 6, 8 . the median age of the symptomatic patients seems to be between 47-59 years even though it can affect individuals of all ages 2 . the clinical presentation of covid-19 has a wide spectrum that ranges from assymptomatic or slightly upper respiratory infection to septic shock 6, 9, 10 . the cardinal symptoms described by the world health organization and later integrated in the flowcharts issued by the direção geral de saúde (dgs) are "cough", "fever" and "dyspnea". however, other studies report myalgia, fatigue, headache and gastrointestinal symptoms as other symptoms to be taken into account 11, 12, 14 . in a study involving 1099 laboratory confirmed cases, zhong et al described that the most common clinical manifestations were fever (88.7%), cough (67.8%) and fatigue (38.1%), with sputum, dyspnea, sore throat and headache also being highly reported by the patients 13 . this study also mentions that there was a minor percentage of patients who showed gastrointestinal symptoms such as vomiting and diarrhea. despite the broad spectrum of the disease, huang et al described that the elderly or those with underlying pathologies such as hypertension, chronic obstructive pulmonary disease, diabetes mellitus and cardiovascular diseases had a faster progression of the disease, with a higher rate of acute respiratory distress syndrome, consequent multiorgan failure and higher rate of death 2, 10 . these pathologies, considered as risk factors for covid-19, were later included in the "norma de orientação clínica 004/2020" of dgs, as patients with a particular risk of infection and with higher care needs. at the moment, there is no effective and approved antiretroviral treatment or vaccine targeting sars-cov-2, with the treatment being mainly symptomatic and organ support 6, 10 . therefore, in the absence of effective specific treatment, there is a range of preventive measures to be taken, such as a correct handwashing, respiratory etiquette, disinfection of surfaces and social isolation and/or social distancing (> 2 meters) 2,3,6,14 . these measures are assumed as vital in the control of the mitigation of the pandemic 3, 14 . to raise public awareness of these measures and health promotion, community empowerment is necessary and the main key for this public health problem. this empowerment through health literacy programs and official campaigns using television, radio and other media has a positive impact, especially in this actual context -outbreaks and/or pandemics 15-17 . on the 18 th of march, 2020, the state of emergency was decreed in portugal, with a law decree regulating preventive measures to contain the pandemic mitigation in portugal. on the 26 th of march, 2020, phase 3.2 of the mitigation of covid-19's pandemic in portugal was declared, e.g., chains of community transmission of the virus in the national territory. thereupon, it arose the need for tighter control and application of preventive measures. regarding the positive impact of official campaigns and community empowerment with a strong health literacy, we considered it extremely important to study the health literacy of the population in this mitigation phase, in order to understand the flaws that may still exist as well as identifying possible predictors of health literacy concerning this matter. thus, and since as far as we're concerned this is the first study focusing on this subject, it will be possible to rectify possible wrong ideas through specific intervention strategies aimed at different populations. also, we hope that this study helps to identify possible errors/flaws of health literacy in a pandemic situation and to avoid them at the early beginning of a possible future pandemic. we conducted this cross-sectional study with a cohort of 222 subjects, with an age greater or equal to 15 years old -to avoid a misunderstanding bias of our questionnaire -covid-19's questionnaire (supplementary information). we excluded subjects codified with the icp-2 codes for "dementia", "mental retardation" or "presbycusis", -to exclude the inherent misunderstanding bias. we selected a cohort: individuals with a scheduled medical appointment in a primary care facility of unidade local de saúde de nordeste between 1st and 8th of april. we collected the demographic and epidemiological data (age, gender, education level and risk factor(s) for covid-19 codified by icp-2) and carried out covid-19's questionnaire by phone call with simultaneous registration of the data, between march 30 and april 3. for statistical analysis, we regarded "age" as a continuous variable. concerning the other variables, we categorized subjects according to their "gender" ("female" and "male"); education ("undergraduate group" -<4 years of schooling; 4, 6, 9 or 12 years of schooling; "graduate group" -graduate, master's degree and/or doctorate); "risk factor(s) for covid-19 codified by icp-2" ("risk group" -presence -and "non-risk group" -absence -as described in "norma de orientação clínica 004/2020" by direção geral de saúde (dgs) such as chronic obstructive pulmonary disease, asthma, cardiac insufficiency, diabetes mellitus, chronic liver disease, chronic renal disease, ative malignant neoplasm or immunosuppression state). we performed the statistical analysis of the collected data using microsoft office excel 2019 ® (microsoft, redmond, washington, usa) and the spss ® statistical package (standard version 22.0; spss, chicago, il, usa). exploratory analysis was conducted to demographically characterize our cohort as well as for the answers given for each question of our questionnaire. we used non-parametric tests (kruskal wallis h and fisher's exact test) to test whether significant associations between the variables and the answers given were observed or not, except for the last question. the level of significance for all statistical tests was set at p<0.05, with a 95% confidence interval. this study was submitted for approval and approved by the direction of department of primary health care of unidade local de saúde do nordeste, according to the declaration of helsinki of the world medical association. the confidentiality of the data was guaranteed, only accessible by the main investigator and the respective authors. 3 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 14, 2020. . this study comprises a cohort of 222 subjects, with an age range 15-94 years old and a median age of 62 years old. the majority registered an undergraduate level of education and had at least one risk factor for covid-19 codified by icp-2 (table 1) . globally, younger individuals, females, graduates and the non-risk group presented higher relative frequencies of the correct answer along covid-19's questionnaire. however, three exceptions were observed: the undergraduate group and the risk-group had a high relative frequency stating that covid-19 has a cure and in mentioning "social isolation" as an important preventive measure to adopt when compared to the graduate group and the non-risk group, respectively. males have higher relative frequency in answering the correct number of sns24 and in stating that children can get sick and transmit the infection by sars-cov-2 when compared to females ( table 2 -supplementary information). the use of non-parametric tests (kruskal wallis h and fisher's exact test) demonstrated several statistically significant associations between our variables and the answers given along covid-19's questionnaire (table 3) . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 14, 2020. when questioned about the symptomatology of covid-19, 96.85% of individuals stated that they know the symptoms of covid-19. indeed , analysing only the 215 individuals who answered "yes" in the first 5 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 14, 2020. . question, we observe that most of the individuals stated the cardinal symptoms of covid-19 described in several "normas de orientação clínica" from dgs (e.g. "fever", "cough" and "dyspnea") in relative frequencies >70.00% and that 36.28% stated "other" symptoms such as "myalgia", "headache" and "loss of smell and taste". nonparametric tests denote statistically significant associations: "other" reveal a significant association with "education", with individuals of graduate group stating more often other symptoms of the disease; "cough" reveal a significant association with "risk factor", with individuals from non-risk group stating more often this symptom. when questioned whether covid-19 only affects old people or not, 90.99% of individuals answered the correct answer. nonparametric tests reveal a statistically significant association regarding variable "gender", with females answering more often the correct answer. regarding the two questions about children, there's a good level of health literacy among our cohort. when questioned if children can get sick, there's a major dominance of the answer "yes" (88.74%). nonparametric tests reveal a statistically significant association regarding variable "risk factor", with individuals from "non-risk group" stating more often the correct answer. when we questioned about the possibility of children transmitting the disease, 83.78% of individuals answered "yes". no statistically significant associations were observed. regarding the question about the cure of covid-19, we found a great dispersion of the answers: 41.44% of the subjects refer that covid-19 has a cure, 33.33% deny it and 25.23% refer that they don't know whereas this disease has a cure or not. nonparametric tests reveal a statistically significant association regarding variable "education" and "risk factor", with individuals from "undergraduate group" and "risk group" stating more often the correct answer. when questioned about the correct procedure in case they have symptoms compatible with covid-19, 77.48% stated they should "stay home and call sns 24". nonparametric tests reveal a statistically significant association regarding variable "age", "gender" and "risk factor", with younger individuals, females and individuals from risk-group stating more often the correct answer. regarding the number of sns 24, only 24.77% of subjects knew the correct number. nonparametric tests reveal a statistically significant association regarding variable "gender" and "risk factor", with males and individuals from non-risk group answering the correct number. when questioned about the preventive measures to adopt, 77.93% of individuals stated "social isolation", 50.90% stated "other" preventive measures (e.g., the use of gloves, the use of mask, distance >2 meters from other people, leaving shoes at front door,...), 45.50% of individuals refer "washing hands" and lastly, only 8 subjects (3.60%) of all subjects mention "respiratory etiquette" as an important measure to adopt. nonparametric tests demonstrate several statistically significant associations: "other" has a statistically significant association with variable "risk factor" -individuals from "non-risk group" state this symptom more often -and "social isolation" has a statistically significant association with "education" and "risk factor" -individuals from "graduate group" and "risk group" state this preventive measure more often. regarding the use of gloves, a great dispersion of answers was observed, with 56.31% of individuals referring that the use of gloves does not always prevent the infection by the new coronavirus, 13.51% affirming "i don't know" and 30.18% answering "yes". nonparametric tests demonstrate that variables "gender" and "risk factor" have a statistically significant association with the answers given, with females and individuals from "non-risk group" answering correctly more often. regarding the use of masks, a great dispersion of answers was observed, with 59.91% of individuals referring that the use of gloves does not always prevent the infection by the new coronavirus, 15.32% affirming "i don't know" and 24.77% answering "yes". nonparametric tests show a statistically significant 6 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 14, 2020. . https://doi.org/10.1101/2020.05.11.20098061 doi: medrxiv preprint association between variables "risk factor" for this question, with individuals from "non-risk group" answering correctly more often. when we questioned our subjects about the possibility of visits of friends and/or family during social isolation, 83.33% stated "no", 12.16% stated "yes" and 4.5% affirmed "i don't know". nonparametric tests show no statistically significant associations. regarding the final question, and even though we have a slight dispersion of frequencies of answers, it is obvious that the major source of information about covid-19 is the television, with 74.77% of individuals reporting that fact. after television, the social networks (10.36%) and other (4.50%) -such as official websites (who, dgs and cdc), employers, town hall and guarda nacional republicana -have an important role in informing the population about the actual public health problem (fig. 1) . according to portugal's censuses, the population of our cohort comprises 23850 citizens, with a proportion >1 female per male and as well as an undergraduate and older population 18, 19 . the characterization of our cohort is compatible with these data. globally, our results demonstrate a relatively well informed population. furthermore, females, younger individuals, the "graduate" and the non-risk groups presented higher relative frequencies of the correct answer throughout our questionnaire. there are some exceptions to this pattern, which we are going to discuss later on this section. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 14, 2020. . in the literature, several studies support our results, reporting age, gender and education as predictors of health literacy. indeed, sørensen et al in their comparative study of the results of european health literacy survey (hls-eu) reported education, age and gender as predictors of low health literacy, along with social status and financial privation. according to their findings, males and older individuals tend to have slightly lower health literacy, while a higher level of education is a strong positive predictor of health literacy 20 . besides, regarding health literacy, several other studies state these gender, age and education significant differences, reporting that an increase in age, being male and lower levels of education usually implies a decrease in health literacy , [21] [22] [23] [24] [25] [26] [27] . regarding the presence/absence of risk factors for covid-19 as far as we're concerned, there's no literature available to support the results found in our study. however, we do know that the median age of the risk group is higher than the median age of the non-risk group and these differences stated in non-parametric tests along this study may be a consequence of an age bias. concerning the symptomatology, most of the population knows the cardinal symptoms of covid-19 related by dgs (high relative frequencies >70.00%). curiously, even though not being reported by dgs, there's a significant percentage of subjects relating. "other" symptoms such as "myalgia", "headache" and "loss of taste and smell", described in several articles 10, 12, 13, 14, 28 . this fact may suggest that people do not obtain their information by a single source of information and that they try to search for relevant information. the third question was thus constructed to capture the discord underlying the definition of "cure". according to portuguese lexicon, "cure" is defined as "act or effect of self-healing or healing somebody" or "health recovery" and "healing" being described as "restore health". however, the answers given along the phone calls highlighted the uncertainty in this definition, emphasizing the insecurity in answering this question. indeed, throughout this study, most of the people who answered "no", justified using sentences such as "there's no vaccine" or "there's not a medication targeting the virus". these findings underline some incongruences and misconceptions. a vaccine is a tertiary preventive measure administered in an individual to confer immunity to a certain infectious disease, which enables an asymptomatic/mild clinical manifestation of it, useful in controlling epidemics [29] [30] [31] . therefore, it is necessary to demystify the idea that a vaccine is a cure for an infectious disease. even though there's not a specific antiretroviral targeting sars-cov-2 efficiently approved, there are several reported cases of healed patients, matching with the portuguese definition of "cure" 6, 10, 28, 32 . interestingly, the undergraduate group presents a higher relative frequency of the answer "yes", yet, it wasn't possible to find any information in literature supporting this finding. regarding the preventive measures to adopt face to covid-19, overall, the subjects in our study were able to mention them, with the exception of respiratory etiquette. in the literature there are several studies that report the importance of handwashing, respiratory etiquette and social isolation in containing epidemics and in controlling sars-cov-2 transmission 28,33 . indeed, even though chao yang reports that there's no proven efficacy of handwashing in controlling sars-cov-2 transmission 34 , there are several findings that report the opposite. qing-xia et al , in a study involving 7 countries, alert to the fact that handwashing significantly slows the exponential spread of sars-cov-2 35 and several other studies showed that a correct handwashing is useful in controlling epidemics as well as sars transmission 21, 35, 36 . even though handwashing is an important preventive measure to adopt face to covid-19, unfortunately, there are findings that show that the correct procedure -as recommended by who -isn't always applied and that some mistakes are observed, as such low frequency in washing hands and not washing hands the enough time 37, 38 . also, zhang et al conducted a study in beijing's population as a post-pandemic assessment and verified that even though people knew the importance of handwashing, they did not apply it 14 . in their study, fung et al also observed a decline of practice of this preventive measure 14 . therefore, in order to avoid this decline and errors, we must implement methods to successfully achieve a correct preventive handwashing 39 . 8 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 14, 2020. . as well as for other respiratory viruses, respiratory etiquette has a preponderant role in controlling the transmission of an infectious respiratory disease [40] [41] [42] . looking at the numbers in our study, the absolute and relative frequencies of subjects who mentioned it as a necessary preventive measure was disappointingly low. thus, this must be a point to improve in health literacy. concerning "social isolation", being sars-cov-2 an extremely high contagious virus, an effective and important preventive measure to adopt and to contain the pandemic is social isolation 6, 43 . interestingly and contrary to the other questions, in this question the risk group has a higher relative frequency of the preventive measure "social isolation'' than the non-risk group. this fact may be explained by the fact that non-risk group is a younger group. thus, younger people belong to the proletariat more than older people, having the necessity to leave home for work, which can be a justification to this finding. regarding the answers obtained in question 7, there are still cases of people who believe it is possible to receive or visit family and/or friends at home. since this idea may promote the creation of new transmission chains, it is necessary to demystify it, across every single outlier. regarding the right procedure in case of having symptoms, most of the subjects stated that they must stay at home and call sns 24, as recommended by dgs. concerning the number of sns 24, interestingly, males report higher relative frequency of the right answer. this may be explained by the fact that in our population, males have higher rates of education with more educational opportunities 19 . recalling that the graduate group has a higher relative frequency of correct answers, this difference between females and males may be explained by this bias. also, along the phone calls, individuals that belong to the risk group -overall, older individuals -referred that they didn't know the number by heart because their caregivers knew or they had it pointed on a paper. besides suggesting the lower capacity of older people to memorize numbers, this draws our attention for the important role that caregivers may have in transmitting the proper information to older people. regarding the questions about the epidemiology of covid-19, there's a major consensus that this disease affects the elderly and that children either transmit and can get sick. indeed, concerning all the information already mentioned, the literature states that sars-cov-2 may infect individuals of all age ranges, with a more severe clinical manifestation in the elderly and/or people with underlying pathologies 6, 10, 44 . also, concerning the clinical manifestation and transmission in children, throughout this study, some people reported that "children can transmit the virus, that's why grandchildren and grandparents cannot be together". indeed, children can get sick and are an important vector of transmission of sars-cov-2 6,10 . this fact is especially because if infected they are mainly asymptomatic and have more difficulties in applying the correct procedures of the hygiene measures correctly 45, . interestingly, males reported higher relative frequencies than females in stating that children can get sick and transmit sars-cov-2. however, there's no literature supporting this finding. regarding the use of gloves and/or masks, it is visible a certain hesitation and some myths associated with them, which may be explained by the quantity of contradictory information transmitted concerning these equipment 46 . the use of gloves is recommended during procedures associated with aerosol production, in a clinical context 46 . regarding the global use of gloves, its general use is not recommended by who, cdc and dgs and may even constitute a false security if people don't discard them regarding the proper procedure 47 . the use of masks has been under constant study since the beginning of this pandemic, in order to understand whether it prevents the infection by sars-cov-2 or not and the literature regarding this matter is very controversial. however, in a recent study, greenhalgh et al advocate the general use of the mask, regardless of their material, even stating that a simple cotton mask will reduce the amount of transmitted virus by 36 times 48 . indeed, masks are gaining a major role as a community preventive measure and not as an individual preventive measure 35,44,48,49,50. concluding, even though we observe a relatively well informed population, this is a pandemic of a virus with an elevated transmission rate. thus, biological characteristics as well as individual and communitary behaviours have an impact in its course 10, 14, 20 and even a single error/mistake may have a 9 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 14, 2020. . negative impact, creating new transmission chains that could have been prevented 32, 33, 43, 44, 62 . following this thought, we are looking for the outliers of wrong answers/unfamiliarity of a concept and in order to promote a fruitful health literacy, towards an informed population and avoid an overwhelming unjustified panic, which may lead to more mistakes 51, 52, 53 . to pursue this objective, we must take in account the major sources of information and adapt our communication, creating programs/methods in order to reach each specific population 54 . this adjustment to different realities has a positive impact on the population and their behaviour, by promoting community empowerment 55 . on a final note, we safeguard that a correct health literacy does not always mean a correct behaviour and that some mistakes can still prevail 53,54 . health literacy is nowadays a critical issue and has an impact in controlling epidemics and pandemics 56, 57, 58 . in portugal we are now in phase 3.2 of mitigation of covid-19's pandemic and, even though we have a relatively well informed population, there seems to be some misconceptions of the guidelines 57 . as the actual public health situation is a pandemic by a highly infectious virus, every single deviant compliance matters and must be prevented. thus, our goals were to characterize the population regarding their covid-19's health literacy, in order to help create specific intervention strategies aimed at populations with different levels of health literacy. although our cohort has a small dimension, it highlights some aspects that can bridge gaps that still remain. we believe it also provides support for future studies and alerts to the necessity of new approaches of communication in order to control not only this pandemic but also possible future pandemics with human-to-human transmission. the main limitation of this work was the size of the database. also, besides comparison between groups, other tests or applying metrics could have been used, e.g., correlation coefficients such as spearman's rank and pearson's. also, a multinomial regression could have been carried out in order to predict the health literacy for an individual. likewise, a new index variable representing health literacy could have been created, in order to state the level of health literacy of an individual. in further studies, this new variable can be created based on who and dgs information, enabling a comparative study of various coefficients, considering criteria and quality adjustment metrics. all data confidentiality was guaranteed. all authors report no conflict of interest. no financial support was obtained for this study. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. 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of a public health campaign community matters -why outbreak responses need to integrate health promotion fair allocation of scarce medical resources in the time of covid-19 how will country-based mitigation measures influence the course of the covid-19 epidemic? at the epicenter of the covid-19 pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation key: cord-308648-bus3axay authors: he, shan; chen, siyu; kong, lingna; liu, weiwei title: analysis of risk perceptions and related factors concerning covid-19 epidemic in chongqing, china date: 2020-06-26 journal: j community health doi: 10.1007/s10900-020-00870-4 sha: doc_id: 308648 cord_uid: bus3axay objective: to assess perceptions of risk and related factors concerning covid-19 epidemic among residents in chongqing city, china. methods: with convenience sampling, a web questionnaire survey was conducted among 476 residents living in chongqing on february 13rd to 14th in 2020, when citizens just started to get back to work. results: residents’ estimated perceived risks were (4.63 ± 0.57), (4.19 ± 0.76), (3.23 ± 0.91) and (2.29 ± 0.96) for the infectivity, pathogenicity, lethality and self-rated infection possibility of covid-19, respectively. females (or = 4.234), people with income ≥ 2000 yuan (2000–4999 yuan: or = 5.052, 5000–9999 yuan: or = 4.301, ≥ 10,000 yuan: or = 23.459), the married status (or = 1.811), the divorced status, widows or widowers (or = 3.038), people living with families including children (or = 5.085) or chronic patients (or = 2.423) had a higher perceived risk level, as well as people who used free media websites (or = 1.756), community workers (or = 4.064) or community information platforms (or = 2.235) as main media information sources. the perceived risk increased by 4.9% for every one-year increase of age. people who used wechat contacts (or = 0.196) as the main media information source, reported a lower perceived risk. conclusion: residents reported a high level of risk perception towards covid-19 in chongqing and it was impacted by the population demographic characteristics. media information sources, including community information platforms and community workers may cause the increase of public risk perceptions. continuous and relentless attacks from emerging and reemerging pathogens create global challenges for public health [1] . in december 2019, some cases of severe pneumonia of unknown cause linked to a seafood wholesale market occurred in wuhan, hubei province, china [2] . this emerging infectious disease presented with fever, dry cough, fatigue, dyspnea, diarrhea even severe symptoms was later named coronavirus disease (covid-19) by the world health organization (who). till february, 2020, the basic reproductive number r 0 of covid-19 was 2.2 in china, and its fatality rate (2.9%) was lower than sars (10%) and mers (37%) [3, 4] . the rapidly increasing number of cases graved public's concerns about the future trajectory of the outbreak, especially with the approaching of chinese lunar new year, an estimated 3 billion travels would be made during the spring festival vacation this year, which increased the risk of transmission from person to person [5] . chinese health authorities and services acted immediately to characterize and control the disease. strategies for the control and prevention of covid-19 included travel restriction, epidemic surveillance, quarantining source of infection and lockdown of communities. on january 21st, 2020, the national health commission of the people's republic of china confirmed that chongqing had the first imported case from wuhan [6] . chongqing is one of the four province-level municipalities under the direct control of the state council. chongqing has a residential population of over 31.24 million and an outflow population of over 11.78 million [7] . its location is adjacent to hubei province. the big population and migration during the spring festival put chongqing at a greater risk facing the surveillance and control of covid-19. chongqing initiated level i response to major public health emergencies on january 24th. the local government of chongqing mobilized urban and rural communities to execute community-based control and prevention measures [8] . the precise and scientific community gridded management underlined epidemic monitoring, health campaign and health care for the vulnerable population including the elderly, people with underlying diseases, children and pregnant women. community workers were advised to deliver public health education through wechat groups and subscriptions, qq groups and smart community platforms (wechat and qq are both instant messaging apps widely used in china). residents were advised to stay at home, wear a mask outside, practice physical distancing, use cough etiquette, wash hands frequently, and report to community health service center when they were presented with suspected symptoms. previous studies have linked risk perceptions with individual behaviors. risk perceptions examine the judgments that people use to characterize and evaluate hazardous activities [9] . monitoring people's risk perceptions is part of emergency management in major public health emergencies. during the disease control and prevention, public risk perceptions are widely accompanied with the attitudes, emotional response and prevention behaviors, which have an impact on the evolution of emergencies [10] . the study of public risk perceptions towards covid-19 may help to understand public's attitudes towards the emerging disease and to predict their behaviors. the goal of this article is to measure what are the risk perceptions towards covid-19 among chinese residents in chongqing, and to explore what factors may influence their perceived risk. the survey was conducted in chongqing, using a convenience sampling method. inclusion criteria were: (1) chinese residents who stayed in china during the past 6 months; (2) citizens living in chongqing during the 2020 spring festival vacation; (3) use of smart phones. the questionnaire was developed based on the concept of public risk perceptions and the epidemiological characteristics of covid-19, by the first and correspondent authors, then piloted among co-authors to ensure its readability and content validity [9, 11] . domain 1 was citizens' demographics including gender, age, educational level and place of residence, et al. participants were asked whether they lived with family members including the elderly, chronic disease patients, the pregnant, the puerperant and children. in domain 2, we asked participants to choose the main channels to acquire information about covid-19 from january 23rd to february 9th (the spring festival vacation). options included new media, traditional media, community information platforms and community workers. options were showed randomly in the online questionnaire. participants were allowed to choose five items at most. this part aimed to explore the most commonly used information source by citizens during the spring festival vacation. domain 3 had four questions in 5-point likert-type scale. participants were asked to (1) estimate the risk of infectivity, pathogenicity and lethality of covid-19 from 1, 'very low', to 5, 'very high', with 3 being 'moderate'; (2) rate their likelihood of being infected with covid-19 from 1, 'extremely unlikely', to 5, 'extremely likely', with 3 being 'neither unlikely nor likely'. to help participants to understand the means of these scientific terms, annotations were added below the questions: 'infectivity differs across different infectious diseases. infectivity is a pathogen's capacity to spread from one host to another.' 'pathogenicity is the potential disease-causing capacity of pathogens. pathogenicity is related to virulence.' 'lethality is how capable of covid-19 is of causing death. we usually count dead cases among the patients.' online anonymous questionnaire survey was used in the study. the questionnaire was established using an online survey platform (wen juan xing, wjx.cn) developed by changsha ran xing technology company, then the questionnaire was forwarded and disseminated through wechat and qq from february13rd to 14th 2020. each respondent was limited to reply only once and allowed to submit after all items were filled. the inclusion criteria, purpose of the study and information confidentiality were illustrated at the beginning, to obtain respondent's informed consent. after the questionnaire was filled and submitted, the page automatically skipped to a thank-you letter with recommendation of authoritative information resources: wechat subscriptions 'health china' managed by the national health commission of the people's republic of china, 'latest news of the chinese center for disease control and prevention (cdc)' managed by the chinese cdc and some educational reading materials. ethical approval was obtained from the ethics committee of chongqing medical university. statistical software package ibm spss statistics 23.0 (ibm corp., armonk, new york, usa) was used for data input and analysis. descriptive statistics like frequencies, means and standard deviations (sd) were used to describe the data. chi-square test was used to examine the differences across categorical variables. binary logistic regression analysis was used to explore the effect of demographics and information sources on risk perceptions. p value of < 0.05 was considered as statistically significant. a total of 479 questionnaire were collected and exported to an excel file. then all data were checked by the place of residence to ensure that all samples met the inclusion criteria. three were excluded because these respondents did not stay in china during the spring festival vacation. a total of 476 questionnaires were input to the database and used for data analysis. of the 476 respondents, 465 resided in chongqing during the last 6 months, and 11 resided in other cities and stayed in chongqing during the spring festival. participants were mostly women (the ratio of male/female was about 1:2). participants' age was between 19 and 72 years of age. the median age was 34-year-old. the sample was highly educated. more than 80% had college degree or higher. the majority of the sample lived in the urban area of chongqing ( table 1 ). the percentage of family members living with participants included the elderly (274, 57.56%), chronic disease patients (210, 44.12%), children (157, 32.98%), the pregnant (16, 3.36%), and the puerperant (6, 1.26%). of all respondents, 56.93% used wechat contacts (including friends and groups), and 51.26% used television to acquire information about covid-19. wechat contacts ranked the first in the new media and television ranked the first in the traditional media among the most commonly used media sources. other most commonly used channels were authoritative websites (49.37%), wechat subscriptions (42.86%), sina weibo (40.76%), short messages sent by the government (32.98%), medical app ding xiang yuan (24.79%) and free media websites (23.95%). 15.97% of respondents used community information platforms (bulletin board services, posters and broadcasting), and 11.55% used community workers as the main information source. residents perceived the highest risk towards the infectivity of covid-19, followed by pathogenicity, lethality and selfrated infection possibility. 96.22% of respondents thought that the infectivity of covid-19 was very high or high. 83.41% thought the pathogenicity of covid-19 was very high or high. 34.45% perceived covid-19 to be very highly deadly or deadly, and 45.17% perceived it to be moderate. 39 (8.19% ) respondents rated their infection chance to be very likely or likely. among them, 38 lived in the urban area of the city (table 2) . to analyze the difference of risk perceptions towards covid-19 across demographic characteristics and information sources. the score of four and five was considered as high risk, and the score of 1-3 was considered as low risk. risk perceptions towards the infectivity, pathogenicity, lethality and self-rated infection possibility differed by demographic characteristics and commonly used information channels (table 3 ). respondents' demographic characteristics and commonly used information channels were independent variables in the binary logistic modeling analysis for public risk perceptions. (table 4 ). this survey was conducted on february 13rd to 14th, when the number of newly diagnosed cases and suspected cases was declining and the number of cured cases was increasing in china. work from home policy was gradually replaced by the routine condition. moreover, a large number of migration population would go in and out of chongqing. the city was faced with risk of possible rebound of epidemic after work resumption. in our study, residents in chongqing had a high level of risk perception towards the infectivity and pathogenicity of covid-19, and relatively lower risk of the lethality and self-rated infection possibility. the risk was perceived based on the information from all information channels, reflecting people's judgement of the characteristics and severity of covid-19 epidemic. it demonstrated that residents in chongqing had a rational understanding and attitude towards the disease. demographics impact on public risk perceptions during the covid-19 epidemic. in the study, females, highincome groups, the elderly, married residents or residents with marriage history, and people living with children or families with chronic diseases perceived a higher risk. people are all generally susceptible to covid-19. females, the elderly, residents with chronic diseases, and children are the vulnerable groups and need special attention in healthcare management. the elderly and patients with comorbidities are more prone to be infected and progressed to serious complications [3] . a small number of cases showed that the clinical characteristics of pregnant women confirmed covid-19 infection were similar to non-pregnant adults, however, pregnant women could also be more susceptible to covid-19 infection versus the general population [12] . the national health commission proposed strengthening health counselling, screening and follow-ups for pregnant women, to ensure maternal and fetal safety. epidemiological data from many countries reflected lower susceptibility among children compared with adults. most pediatric patients had mild or moderate type of covid-19, but large proportion of asymptomatic children may increase the difficulty of epidemic surveillance [2, 13] . moreover, children in europe were stricken by a novel severe kawasaki-like disease related to covid-19 [14] . authorities don't advise parents to put on mask for children younger than 1-year-old for the risk of suffocation, and active prevention measures like staying at home are more encouraged. for one thing, high risk perceptions may enhance the public's active response to the epidemic. in zika prevention, pregnant women's personal risk perception was increased after exposure to intervention provided by cdc [15] . their degree of concerning about zika, self-rated chance of being infected and confidence in ability to protect self and baby was significantly elevated, and self-protection behaviors like mosquito repellent use, long-pant wearing became more frequent. during the first wave of the 2009 h1n1 pandemic in hong kong, residents' lower perceived severity of h1n1 was associated with less use of hygiene measures [16] . therefore, the higher risk perceived by vulnerable groups may promote their self-protection behaviors, which is beneficial for infection control. for people who perceived low risk towards covid-19, they may underestimate the threat from the highly contagious disease and were less likely to adopt self-protective behaviors. this group of people are a prime target for public health education. for another, perceptions of risk could amplify the social, political, and economic impact of the epidemic well beyond its direct consequences [10] . people who perceived high risk towards covid-19 may suffer from strong negative emotions, resulting stress, panic and conformity to others' behaviors [10] . psychological and psychiatric services should be implemented to deal with the covid-19 crisis. to ensure effective and efficient disclosure of epidemic information, a daily press release system has been established by the national health commission. the local government of chongqing also released daily epidemic report. numbers of newly diagnosed cases, suspected cases, dead cases and close contacts, are announced by channels of television, websites, wechat subscriptions and apps like ding xiang yuan, et al. because of the lockdown of communities, these media became the main information sources for citizens to obtain information about the trajectory of covid-19 epidemic. at the initial stage of covid-19 transmission, the uncertainty of epidemic control effect, no vaccines and specific medicine, all gave rise to public's fear for the emerging disease. in our study, information channels including television, free media websites, community workers and community information platforms increased residents' risk perceptions. interestingly, people who used wechat friends and groups as main information source perceived a lower risk. wechat provided information exchange with personal contacts like families, friends and colleagues versus data disclosed by authoritative channels. social contacts during the epidemic seemed to decreased residents' judgement about the severity of covid-19. covid-19 is a highly contagious infectious disease. public awareness of dealing with covid-19 is important in limiting the spread of infection [17] . public risk perceptions may change with the trajectory of the disease [16] , and social networks amplify the spread of behaviors that are both beneficial and harmful during an epidemic [18] . in dealing with major public health emergencies, when individuals exchange information and opinions with institutions and organizations, the effective use of communication channels to rationally distribute information should be advocated, to meet the psychological needs of the population. because of community lockdown and regulations on disease control and prevention, this study did not perform on-site investigation on february. the online questionnaire survey accessed less sample of males, less-educated population and people living in rural areas of chongqing. in the future we should focus more on how these population perceive and respond to the risk of emerging infectious diseases. in conclusion, residents perceived a high risk towards covid-19 epidemic at the time close to the work resumption on february in chongqing, which demonstrated residents' rational understanding of the epidemic. perceptions of risk towards covid-19 were impacted by residents' demographic characteristics and main media sources used by them. in the management of public health emergencies, the level of risk perceptions should be monitored. it may be helpful in guiding how individuals and communities should prepare for and respond to the covid-19 epidemic, and helpful in the information disclosure and policy formulation in a timely, active and precise manner. from "a"iv to "z"ikv: attacks from emerging and re-emerging pathogens a novel coronavirus from patients with pneumonia in china early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical features of patients infected with 2019 novel coronavirus in wuhan china a novel coronavirus outbreak of global health concern health committee and civil affairs bureau mobilized urban and rural communities to carry out disease prevention work perception of risk risk perception and behaviors: anticipating and responding to crises the epidemological characteristics of an outbreak of 2019 novel coronavirus diease (covid-19) in china what are the risks of covid-19 infection in pregnant women? the lancet coronavirus infection in pediatric emergency departments research g. children with covid-19 in pediatric emergency departments in italy kawasaki-like disease: emerging complication during the covid-19 pandemic. the lancet influences of community interventions on zika prevention behaviors of pregnant women, puerto rico community psychological and behavioral responses through the first wave of the 2009 influenza a(h1n1) pandemic in hong kong attitude of egyptians towards the novel coronavirus disease (covid-19) using social and behavioural science to support covid-19 pandemic response the authors wish to thank all residents for participation in the study.author contributions all authors have made substantial contributions to (1) the conception and design of the study, the acquisition of data, analysis and interpretation of data, (2) the drafting of the article and by revising it critically for important intellectual content, (3) final approval of the version of the manuscript to be submitted.funding this study was funded by the covid-19 prevention and control emergency research project of school of public health and management, chongqing medical university (grant number 2020yj01). conflict of interest the authors declare that they have no conflict of interest. key: cord-293822-axr9qu58 authors: rolland, john s. title: covid‐19 pandemic: applying a multi‐systemic lens date: 2020-07-17 journal: fam process doi: 10.1111/famp.12584 sha: doc_id: 293822 cord_uid: axr9qu58 the covid‐19 pandemic has a pervasive effect on all aspects of family life. we can distinguish the collective societal and community effects of the global pandemic and the risk and disease impact for individuals and families. this paper draws on rolland’s family systems illness (fsi) model to describe some of the unique challenges through a multi‐systemic lens. highlighting the pattern of psychosocial issues of covid‐19 over time, discussion emphasizes the evolving interplay of larger systems public health pandemic challenges and mitigation strategies with individual and family processes. the paper addresses issues of coping with myriad covid‐19 uncertainties in the initial crisis wave and evolving phases of the pandemic in the context of individual and family development, pre‐existing illness or disability, and racial and socioeconomic disparities. the discussion offers recommendations for timely family oriented consultation and psychoeducation, and for healthcare clinician self‐care. the novel coronavirus-19 pandemic presents unique challenges for individuals and families. with the current lack of an effective treatment or a preventive vaccine, all aspects of life are affected (luttik et al, 2020) . stringent mitigation efforts, such as social distancing, household quarantine, facemasks, vigilant hand washing, and avoidance of public gatherings and transportation were instituted in the united states in march 2020 and are likely to continue in some form for the foreseeable future. the covid-19 pandemic has unmasked the stark reality and profound health and economic consequences of glaring socio-economic and healthcare disparities. risks for morbidity and mortality vary enormously by social location, in particular, race, social class, gender, age, ability, and geographic location (cdc, 2020; price-haywood et al, 2020) . with infection, the course, and recovery or fatality. with a pandemic individuals and families are continually dealing with developments at all levels. it is useful to inquire about and frame adaptation in those terms. most people focus on their local situation and risks in their daily lives, job, family, and social network -getting food, medicine, and other needs. this discussion will highlight the individual and family experience. also, this paper is written in the midst of the pandemic when some of the emerging issues, such as if and when of second or third waves/spikes of cases, the timing of a vaccine or economic recovery, and the ultimate scale of emerging mental health and psychosocial impact remain uncertain (amsalem, dixon, & neria, 2020; wanga et al, 2020) . how can we organize this complex covid-19 landscape in a manner helpful to families and clinical practice? the family systems-illness (fsi) model (rolland, 2016; 2018 ; 2019) provides a useful framework for assessment and treatment with families dealing with a range of serious and chronic illness and disability, including infectious disease. (see rolland [2018] for useful resources, practice guidelines and case examples). the fsi model is grounded in a strengths-orientation, viewing family relationships as a potential resource and emphasizing possibilities for resilience and growth (walsh, 2016) . seeing the family as the interactive focal point, this approach attends to the systemic interaction between an illness and family that evolves over time. the goodness of "fit" between the psychosocial demands of a particular condition over time and the family style of functioning and resources is a prime determinant of successful versus dysfunctional coping and adaptation. the fsi model focuses on three dimensions of experience: 1) a psychosocial typology of this article is protected by copyright. all rights reserved chronic conditions; 2) major time phases in their evolution; and 3) key family system components. in addition to communication processes and organizational/structural patterns, particular emphasis includes: family and individual life course development in relation to the time phases of a disorder; multigenerational legacies related to illness and loss; and belief systems (including influences of culture, ethnicity, race, spirituality, and gender) (figure 1 ). place figure 1 about here covid-19 is a novel coronavirus infectious disease. to create a normative context for the pandemic experience, families can benefit from a psychosocial map as they navigate overwhelming challenges. first, the psychosocial map offers an understanding of covid-19 in systems terms, which explicates the expected (or uncertain) pattern of practical and emotional demands of this disease over the course of the pandemic. second, such maps are helpful for families in understanding systemic processes. in the fsi model, illness patterning can vary in terms of type of: 1) onset (acute or gradual) 2) course (resolves versus progressive, constant, relapsing) 3) outcome (non-fatal to fatal) 4) type and degree of disability or complications 5) level of uncertainty about its trajectory. some diseases have clear-cut predictable patterns; such as als, which is gradual onset, progressive, disabling, and fatal. by contrast, covid-19 manifests in a variety of unpredictable ways. for most, it is not a chronic illness, but for some it has long-term health consequences. for some, it is fatal. despite significant risk differences related to social location, age, and health status, anyone can be infected and then can transmit covid-19; anyone may develop a severe case and may die. unlike other infectious diseases that run their course in known timeframes or are seasonal and/or regional, currently there is no known endpoint to the covid-19 pandemic. this uncertainty and indeterminate timeframe are particularly taxing in a cumulative way -pandemic fatigue. further, data is accumulating that recovery can be protracted and result in long-term medical complications this article is protected by copyright. all rights reserved cardiovascular, pulmonary, and neuropsychiatric are among the most common (long et al, 2020; varatharaj et al, 2020) . in the united states, six in ten adults have a chronic illness (nccdphp, 2020) , which medically heightens their risk of getting covid-19 and increases the risk, to varying degrees, of a severe case and mortality. one in four adults have a chronic disability. the pandemic magnifies longstanding prejudices toward those with disability, stigmatizing and treating them as inferior. many in the disability community fear that their lives would be expendable in circumstances of a shortage of adequate covid-19 testing, icu beds, respirators, and response resources. ageism contributes to attitudes that older persons are expendable. compared with younger and disease-free individuals, older adults and those with preexisting chronic conditions must grapple with higher risk of complications and deciding their acceptable social risk as covid-19 restrictions are relaxed. individuals and families with an already chronically ill or disability-challenged member may be far less able to absorb the added caregiving burdens if either an affected member or a primary caregiver develops covid-19. uncertainties and unknowns abound with covid-19. perhaps the most challenging are the facts that transmission is invisible and many individuals that carry the disease, maybe even most, are asymptomatic, yet contagious. these disease characteristics heighten the experience of living with risk and anticipatory loss (rolland, 1990; 2018) . for example, the ambiguity of being at risk versus an asymptomatic carrier would increase fears of transmitting covid-19 to an older or chronically ill at risk family member. the importance of viral load (the concentration of virus in saliva) in covid-19 severity is established, but the length of exposure and the level of viral load needed for infection to occur are still ambiguous. further, the incubation period, although on average five days, can vary from two to fourteen days. technically, this means that if someone wants to visit an individual at higher risk beyond the socially distanced visit they should consider self-quarantine for fourteen days beforehand. for many families this is not feasible or realistic. now the discussion is about safe "social pods" visiting with others who are practicing safe protections. this article is protected by copyright. all rights reserved 1) unpredictable course. some who are infected seem fine then progress rapidly to a lifethreatening state (see the case description below). some appear to be improving and then take a turn for the worse. this necessitates ongoing monitoring and vigilance by family members for a protracted period. 2) uncertainty regarding long-term complications (e.g. cardiac, respiratory, cns). recovery has proven slow and ongoing complications may occur, even in those who were asymptomatic. this puts the affected member and family members into a protracted period of limbo. they don't know what will be the eventual new normal. key questions for families include: "what caregiving and role functions may need longer-term reevaluation?" and "what additional economic strains would this create?" larger collective public health uncertainties include: 1) who has been infected? who has immunity and for how long? antibody status and degree and length of time of protection from antibodies are not yet well understood (robbiani, et al 2020) . 2) how long until an effective and widely available vaccine emerges or until herd immunity (roughly 70% of total population has developed antibodies) negate the impact of the disease? despite some horrific initial spikes, such as new york city, the proportion of individuals that have been infected with covid-19 in these hot spots is only 10% of the population. 3) incidence and fatality trends can improve in one region, but then spike in another region. a second or third wave of resurgence is very likely, unless widespread readily accessible testing and contact tracing are implemented, and the public adheres to ongoing and shifting precautions. as of july 2020, we are seeing the dire consequence of too rapid state-level relaxation of restrictions and resulting widespread disregard of key precautions (e.g. mask usage). 4) without strong national leadership, regulations, and guidelines, regional improvements and surges can occur independently. from a public health standpoint, often divergent and sometimes politically motivated state-based regulations are epidemiologically nonsensical. locally, individuals and their families lack clear, consistent information and guidelines. this chaotic process is both medically dangerous and psychologically exhausting. this article is protected by copyright. all rights reserved these myriad individual and population level uncertainties have significant impact on and implications for families. as this is written in july 2020, the cumulative mental and physical health consequences of this "pressure cooker" existence are just beginning to emerge (killgore et al, 2020; wanga et al, 2020) . living well with illness uncertainties and threatened loss (rolland, 1990; 2018) entails acknowledging the possibility of loss, sustaining hope, and building flexibility into planning that can accommodate changing circumstances. similar to living with chronic illness, the metaphor that living with the uncertainties of the pandemic is a marathon not a sprint is apt and clinically useful. systemic racism has a profound impact on covid-19 susceptibility. july 2020 cdc data reveals that latinx and african-americans are three times as likely to become infected with covid-19 as their white neighbors throughout urban and rural regions of the united states and across all age groups. and, they are twice as likely to die from the disease as white people. native american people also experience similar disparities. lower income families, disproportionately african-american, latinx, and immigrant, rely on income from members working in job conditions at high risk of infection. crowded multigenerational living conditions makes social distancing difficult in households (cdc, 2020). living with racial residential segregation, at a distance from healthcare facilities and grocery stores, makes it harder to get needed care or garner supplies for stay-at-home precautions. lower income families' livelihoods require leaving home and taking public transportation daily to work in the service sector, factories, and/or other crowded conditions, where personal safety is often compromised for the sake of a paycheck needed for family survival. these families live with the daily fear that covid-19 will be brought into the home from work settings and travel to and from work. the ability of most whitecollar desk jobs to be accomplished remotely has provided double protection -preventing covid-19 infection and keeping one's job. this is a huge advantage over jobs requiring physical presence. dr. anthony fauci, the director of the national institute for allergy and infectious diseases, stated at a us congressional hearing (june 23, 2020) that the coronavirus has been a "double whammy" for african-americans, because they are more likely to be exposed to the disease by way of their employment in jobs that cannot be done remotely. second, they are more vulnerable to severe illness this article is protected by copyright. all rights reserved from the coronavirus because they have higher rates of underlying conditions like diabetes, high blood pressure, obesity and chronic lung disease (bolin & kurtz, 2018; cunningham et al, 2017) . these individuals often lack health insurance or are under-insured, and lack access to adequate basic health care, including paid family and medical leave (bartel et al, 2019) . this leaves them and their families extremely vulnerable to severe illness and economic ruin if covid-19 strikes. almost twothirds of us bankruptcies are linked to illness and unaffordable medical bills (himmelstein et al, 2009 ). the need for an "improved medicare for all" national healthcare system could never be more urgent. covid-19 is a risk to all family members and prevention requires an understanding of mitigation strategies within the household and in the community. this necessitates ongoing effective communication amongst family members of all ages. children coping with chronic illnesses, such as diabetes or asthma, need to learn about their illness and aspects of self-management from an early age. the covid-19 pandemic warrants the same mindset, although here healthy children (and adults) may be introduced for the first time to a "new reality" of personal disease risk. it is valuable to inquire whether anyone is protected in or excluded from such discussions (e.g. children; or aged, frail, or vulnerable family members) and why. adults may feel reticent to share with children given the uncertain nature of covid-19, but communicating age-appropriate information about the disease supports psychological wellbeing for the child and the family (dalton, rapa, & stein, 2020) . the pandemic may reveal sharp differences between partners regarding beliefs about appropriate safety restrictions for children or each other (grose, 2020) . couples need to discuss these differences, which may warrant additional input from primary care providers. individual family members may process the same covid-19 information through very different historical, cultural, and political ideological filters, leading to conflicting views. it's crucial to understand beliefs about what can cause or prevent covid-19 and personal risk perception. research has repeatedly shown that the perception of risk is a more powerful behavioral motivator than actual risk (ferrer & klein, 2015) . given covid-19's highly transmissible nature, perceptions of relative invulnerability and disregarding precautions can put all family members at risk. teenagers this article is protected by copyright. all rights reserved and young adults often ignore social distancing and mask use out of a belief in personal invulnerability. it can be enormously helpful for families to hold regular family "meetings" to review daily life together during the pandemic and make any needed adjustments. where possible, tele-technology can enhance such pragmatic discussions by facilitating inclusion of family members living at a distance and separated by pandemic precautions. families at higher risk benefit from proactive discussions or consultations about role function flexibility and other potential extended family, community, or healthcare provider resources. this might include adult children (and their parent(s) conferring about shared responsibilities to protect an elder or tend to them if covid-19 strikes. another example is proactive discussions among parents and with their teenage children about any misguided sense of invulnerability. disagreements about appropriate safety precautions can occur among family members, between neighboring families, between states, and sadly often divide along political party lines. we need one data-driven and unified national public health mandate on precautions and adequate testing, which is separated from politicians and divergent political agendas. this would save countless lives. it must be well funded across socio-economic and minority group strata. compared to other countries strategies over time, us failings at a national level are increasingly and blatantly clear. a unified message would greatly help galvanize state, community, and family level buy-in and cohesion. although most contemporary couples and families strive toward flexible and equitable gender role relations, the influence of culturally based gender norms persist for caregiving roles. as a health crisis, covid-19 heightens the tendency to expect women to absorb the bulk of child and elder care and attend to the practical and emotional needs of an ill member. it is crucial to explore family expectations about caregiving roles. encourage flexibility and a shift from defining one female member as the caregiver to that of a collaborative caregiving team (walsh, 2016) . with the geographic dispersion of many families, members may need to accept not seeing loved ones for an indeterminate period. elders, especially those that are frail and chronically ill, this article is protected by copyright. all rights reserved consider that they may not see members living at a distance again. adult children and grandchildren might not see an older parent again. this possibility always is present, yet, is heightened with the pandemic. families can harness this fact to appreciate each other more fully, express caring, and use it as an opportunity to repair and heal relationship wounds. similar to many people living with the uncertainties of a life-threatening illness, the pandemic can stimulate a sense of urgency for family members to deal with unresolved relational issues. whether living near or far, adult sons and daughters have to weigh under what circumstances they would visit their elder parents. if their parents contract covid-19 or develop a different health crisis, would they accept the risk of seeing them and providing caregiving, thereby putting themselves and their own children at risk. conversely, adult children often fear bringing the infection to their older parents, who are at higher risk. these are profoundly difficult questions, warranting proactive family discussion and consultation with healthcare providers. adult children need to discuss these issues within their own nuclear family. a spouse or partner may have different views about acceptable risk as well as their own aging parents or kin to consider. as the pandemic continues to evolve, these discussions will need to be revisited -relating to new covid-19 data and to changing family circumstances, such as life cycle transitions or altered economic and health status. those living alone, especially seniors, are at increased mental health risk for anxiety, depression, even suicide during the pandemic (aronson, 2020) . they can experience despair that meaningful social contact and purpose will no longer occur within the timeframe of their remaining years. they typically lack the support and companionship provided by a spouse, partner, or sibling, for instance. other family members carry additional concerns about the vulnerability of an isolated member. social media and tele-technology options (e.g. zoom, facetime, skype) have provided ways for family members and friends to remain more connected. many families have actually had this option for several years, but are now discovering its utility for the first time. geographically dispersed members can gather for a weekly zoom meeting. grandparents can have a play date with grandchildren. despite the two-dimensional shortcomings and oft heard complaint that it's not the same as in-person, this technology enables clinicians to more easily convene family members for this article is protected by copyright. all rights reserved health and mental healthcare consultations and therapy. however, lower income families often lack the computer resources to avail themselves of this technology, adding another layer of disparity. long-term care facilities (ltcf) are a major challenge for safety during the pandemic. june 2020 data revealed that in most states a staggering 50 -80% of covid-19 related deaths occur in ltcf (d'adamo, yoshikawa, & ouslander, 2020). families may need to evaluate the relative safety of leaving a family member in a ltcf or bringing them to live with them. data shows that persons with cognitive impairment are four times more likely to die of covid-19 in a ltcf than other residents (cdc, 2020). lack of judgment, impulsiveness, and confusion with dementia all interfere with risk reduction behavior. those with dementia or intellectual disabilities may be particularly distraught and not comprehend why family members are not able to visit. a family caregiving for an elder with advancing alzheimer's disease, that is becoming unmanageable at home, may have to make a wrenching decision between their own limits and personally caring for a loved one. consultation with involved primary care, specialist, and family behavioral health providers can guide and support family decision-making. fortunately, use of technology through video conferencing allows persons who are hospitalized or in ltcf and their loved ones to sustain vital contact. this is especially important in situations of advanced chronic illness or covid-19 where death may ensue without loved ones physically present again. applying the fsi model time phases can help us understand two levels: 1) the course of the covid-19 pandemic; and 2) the experience living with personal covid-19 risk and infection over time. this section discusses the evolving challenges at both levels for individuals and families (rolland, 2018) . despite the uncertainty of the future pandemic unfolding, we can diagram a timeline for each level (figures 2 & 3) . the pandemic level phases (figure 2 ) are intended to clarify psychosocial challenges over time rather than emphasize covid-19 biological or public health incidence and prevalence. core psychosocial themes in the evolving course of the covid-19 pandemic can be conceptualized into this article is protected by copyright. all rights reserved three broad phases. the initial crisis phase is characterized by a wave of cases with varying course, indeterminate length, and potential spikes. for some countries this initial phase/wave subsided within a few months. in the united states, as of july 2020, with a rising spread of cases and regional spiking, it is unclear when the initial wave will end. in the next phase, a second wave is predicted with the potential for one or more following waves. in the final phase, the course of the pandemic spread diminishes as herd immunity is reached, with or without a vaccine. the pattern of the initial crisis wave has varied considerably in different regions. figure 2 illustrates several general patterns in the initial crisis wave and recurrent wave(s). place figure 2 about here with the current pandemic, the initial crisis phase involves adaptation to the societal risk for everyone. depending on social location, the entire population was presented with the medical risks of covid-19 as well as mitigation and prevention measures. families needed to reorganize family life, including roles and routines, and communicate about practical and emotional challenges of living with the pandemic. acknowledging risk is needed while maintaining hope. it is vital that families see the covid-19 pandemic as a shared challenge in "we" terms both at a community and family level. because this is a novel virus, our understanding of medical risks has been evolving as new and more population level data emerges. this changing landscape has been complicated by multiple scientific and political voices with different priorities and agendas. health care experts and policymakers often vehemently disagree about whether to prioritize disease prevention or immediate economic recovery strategies. the lack of a unified message in the face of a life-threatening illness is akin to multiple and divergent medical opinions that can leave families bewildered and frightened, often leading to opposing and conflicted viewpoints about what is needed. this pattern increases the likelihood that dysfunctional family patterns will emerge or pre-existing ones will be exacerbated. the economic consequences of the pandemic, stark witnessing and worsening of racial and socio-economic disparities, and the need for covid-19-related health precautions are all simultaneously important. yet, immediate priorities, such as continued vigilant covid-19 illness prevention and back-to-work imperatives in the face of massive unemployment has collided both at accepted article the macro societal level and among family members. the relative weighing of these different risks and options can vary enormously depending on social location. more affluent families can prioritize covid-19 risk management because of a more secure economic base. most working and middle class families, who live with economic strains, cannot afford to prioritize health unless protected economically by continued government subsidies. with persistence of the initial wave many individuals and families have shifted from a crisis reactive mode to a longer-haul mind-set. where the initial wave has subsided, others may hold onto hope that there will be no second wave. whenever this psychosocial transition occurs, it involves fuller acceptance of the ongoing nature of the pandemic and living with covid-19 uncertainty/risk and threatened loss. it is a period when families may consider modifying precautions and reorganizing to adapt to a more protracted coping with the pandemic. the emotional strain of living with covid-19 risk can feel heightened as they experience the realities of living with an ongoing pandemic. as discussed below, the enormous variation in timing and unfolding of covid-19 new case trajectories locally, regionally, and nationally adds ambiguity to when this transition is salient for a particular family or community. as with the initial crisis phase/wave, one can conceptualize a more indeterminate length recurrent wave phase in the covid-19 pandemic. this is distinct from an infected individual living with a chronic phase of covid-19. covid-19 is not the only threat to health and wellbeing. as aronson (2020) notes, the challenge for individuals and a society, is that two contradictory realities are simultaneously true. our approach to pandemic containment works, but our approach causes suffering, eroding physical and mental health, and causing economic dislocations. this affects everyone, but especially individuals with pre-existing chronic illness, disability, in later life, and/or subject to socio-economic and racial disparities. the key is to sustain daily structure and meaningful purpose. digital technology facilitates roles for elders, for instance, in connecting with grandchildren, volunteering to help the less advantaged, or political activism. increasingly with covid-19, many families struggle with the ongoing challenges of being this article is protected by copyright. all rights reserved confined at close range for extended and open-ended time. in the united states, many parents needed to negotiate more flexible childrearing roles to accommodate having their children home 24/7 without going to school, having after school activities, and depending on usual daycare. with special needs children (e.g. autism, cerebral palsy, intellectual disability) or adults (e.g. serious mental disorders, acquired brain injury), families are managing alone without the usual specialized supportive and educational services. communities are exploring innovative ways to provide in-person education and specialized services. also, increased substance use and family violence are emerging as the pandemic continues (bradbury-jones & isham, 2020). primary care based health and mental health clinicians can touch base periodically with families at known risk and provide some measure of prevention and early intervention. different geographic regions vary in their approach to transition (re-entry) from the initial crisis phase/wave to a more protracted phase for living with ongoing covid-19 risk. state-by-state stages of re-entry are akin to recovery and rehabilitation from an illness, where "vital signs" are monitored to guide timing of graduation to the next stage of recovery or retreat to a previous one. these larger system rules and recommendations inform and guide families. it is essential for families to discuss this step-wise transition as newer longer-haul covid-19 guidelines become available. families need to consider how these guidelines fit with their own beliefs and priorities. distinctions for members at different ages (e.g. children, elders) warrant discussion. again, consultation with a healthcare provider can offer clearer guidance, for instance with decisions about a college student or young adult losing a job and returning home to live with parents. with the covid-19 pandemic, relative risk may wax and wane with the alternation of periods of "flattening the curve" and decline in new cases with periods of resurgence, higher risk, and the need to resume more intensive case suppression/mitigation public health measures. like relapsing illnesses, communities and families need to maintain some measure of vigilance and preparedness for both, not knowing "if" and "when" a resurgence/flare-up may occur (rolland, 2018) . unlike a condition that is always symptomatically present, here families are strained both by the potential fluctuation of transition between covid-19 quiescent and resurgence periods and the ongoing uncertainty of when a spike may occur. good spirits in resuming more normal routines may be dashed by a new wave of cases. hunkering-down again after a period of greater freedom can be this article is protected by copyright. all rights reserved discouraging and anxiety provoking. the psychological shift between these two ways of living is a particularly taxing feature for this pandemic as it is for relapsing chronic illnesses. this fluctuating pattern may exact a huge psychological toll over time. public health media and primary care based psychoeducation supplemented by offering periodic individual or family mental health consultation and brief treatment can be beneficial. when living with personal risk and actual infection, shown in figure 3 , we can identify three phases: 1) at risk, 2) acute infection, which can be symptomatic (possibly fatal) or asymptomatic, and 3) a long-term phase that can lead to recovery, may involve complications/chronicity, or can be fatal. living at risk has been integrated into earlier discussion. place figure 3 about here if a family member becomes ill with covid-19, especially an elder, precautions often require isolation and self-care without direct caregiving support from family members. in severe life threatening situations that require hospitalization, family members are restricted from direct contact with the ill member. and, if the member dies in a hospital or skilled care facility, it is typically without loved ones present. the inability to be there physically for the dying member's final hours, say goodbye, or have a traditional funeral and burial service can burden family members with myriad complex feelings, such as guilt and anger, that complicate grief reactions. in one recent case, bill, who is 70 and in good health, with the covid-19 disease, the long-term phase for affected individuals and their families is influenced by an emerging wide range of complications and may be marked by constancy, progression, or episodic change. it is "the longer haul," involving day-to-day living with a potentially chronic condition and associated disruptions in lives and livelihood. salient family issues include: (1) pacing and avoiding burnout; (2) minimizing relationship imbalances between the affected individual and other family members; (3) maximizing autonomy and preserving or redefining individual and family developmental goals within the constraints of covid-19; and (4) sustaining connectedness in the face of threatened loss (rolland, 1990; 2018) . all major life course milestones and nodal events are impacted (rolland, 2016; 2018) . covid-19 risk has put a threatening cloud on the horizon of any event where family, friends, and community networks would gather. this includes: weddings, graduations, funerals and memorial services, family this article is protected by copyright. all rights reserved reunions, annual holiday or vacation traditions, and regular gatherings of community groups or religious congregations. improvisation and creative adapting of events and rituals are key responses fostering family and community resilience (imber-black, 2019). by example, one of our center trainees' wedding plans were modified to include only ten individuals present for the actual ceremony in their backyard, while other family and friends joined the ceremony via zoom. this adaptive response allowed family members, who live at a distance to join the celebration. while there are a number of important individual and family developmental phases, this discussion will highlight several especially salient ones. those over 65 and/or with a chronic illness (e.g. heart disease, diabetes, obesity, respiratory conditions, immune system compromise) are at much higher risk with more stringent and ongoing restrictions. many families have organized to protect elders and members with chronic conditions, such as limit entering their home or having close range contact. the lack of physical contact, such as hugging, is particularly difficult, contributing to feelings of isolation and disconnection (killgore et al, 2020) . with all older clients and those with chronic illness, it is important for clinicians to encourage them to have updated advance directives, a health care proxy, and wills. with life-threatening conditions, like covid-19, that can involve rapid progression, unresponsive state, or leave cognitive impairment, there is added incentive for preventive or early frank conversations. knowing family members' wishes concerning heroic medical efforts and life support can benefit everyone. despite the short-run challenge of having end-of-life discussions, it is important to keep in mind that many of the most wrenching end-of-life experiences for families occur when the wishes of a dying member are unknown or have been disregarded. since family members are typically not allowed to be present in the hospital with covid-19, it is particularly important that a health care proxy has been designated and identified to the healthcare team (rolland, emanuel, & torke, 2017) . the proxy can be proactive regarding limits of heroic measures or other important cultural and religious preferences. and, the healthcare team benefits in knowing whom to contact in dire circumstances, where urgent life and death decisions may be necessary. this article is protected by copyright. all rights reserved with colleges managing remotely on-line and unemployment staggering among younger adults, future plans are impacted and some put indefinitely on hold. for financial reasons, many young adults are returning home to live with their families-of-origin concurrent with increased economic hardships at home. covid-19 anxieties, pandemic fatigue, and evolving public health restrictions; along with economic and co-habiting stresses can easily lead to or heighten family tensions. regular family "check-in" meetings can help manage these inevitable strains. covid-19 and its economic fallout are causing young adults to encounter huge uncertainties about future hopes and dreams. this may be a significant undercurrent strain for adolescents, young adults, and their parents that can benefit from open discussion. it is worthwhile to ask individuals and family members about prior illness or life crisis/adversity experiences that they can draw on when facing the covid-19 pandemic. areas of vulnerability and resilience are important to identify. for instance, a family history of an untimely illness or death by infection, the succumbing of a robust family member, or a family member suffering alone, can signify particular sensitivity in the context of covid-19. a past experience of enduring well prolonged adversity (e.g. poverty) or an illness with high risk and uncertainty (e.g. heart disease) can inspire resilience in the face of covid-19. as the covid-19 pandemic continues, the enormous toll on frontline healthcare workers is emerging as exhaustion, anxiety, depression, insomnia, trauma, and suicide (schechter, et al, 2020; wong, et al, 2020) . this toll profoundly and severely impacts their own family relationships. at times, the relentless and largely untreatable nature of covid-19 confronts the core identity of healthcare professionals to save and cure patients. although healthcare providers often make decisions amid uncertainty, "we typically focus on the patient's risk, not our own. in an infectious disease epidemic, our calculus must incorporate our own exposure risk -and how exposure would limit our ability to care for future patients" (rosenbaum, 2020) . the sense of helplessness and witnessing waves of death is deeply and cumulatively disturbing, and can lead to a sense of failure and moral injury (griffin et al, 2019) . this has been compounded by restrictions barring patients' family members' physical this article is protected by copyright. all rights reserved presence to provide comfort as their loved one's life is threatened and often in their final hours. this leaves clinicians aware that they may be the last person that the covid-19 patient interacts with. as one anesthesiologist put it, "i could be the last person some of these patients ever see, or the last voice they hear. a lot of people will never come off the ventilator. that's the reality of this virus. i force myself to think about that for a few seconds each time i walk into the icu to do an intubation" (saslow, 2020) . working with illness and loss typically stimulates concerns related to our own and our loved ones' physical vulnerability and mortality. this is especially true with covid-19, where we are all at risk. a we-they mindset is impossible. there is an enormous need for debriefing with colleagues and the availability of individual and family mental health consultations. a multi-systemic lens and drawing on the family systems illness model can provide a psychosocial map to guide individuals, couples, and families meet the myriad challenges of covid-19. as a worldwide crisis, the covid-19 pandemic gives us a sense of belonging that can promote solidarity and increase global empathy and caring for each other. the coronavirus disease 2019 (covid-19) outbreak and mental health: current risks and recommended actions for older people, despair, as well as covid-19, is costing lives. the new york times racial and ethnic disparities in access to and use of paid family and medical leave: evidence from four nationally representative datasets accepted article this article is protected by copyright. all rights reserved race, class, ethnicity, and disaster vulnerability handbook of disaster research the pandemic paradox: the consequences of covid-19 on domestic violence covid-19 in racial and ethnic minority groups vital signs: racial disparities in age-specific mortality among blacks or african americans-united states protecting the psychological health of children through effective communication about covid-19 coronavirus disease 2019 in geriatrics and long-term care: the abcds of covid-19 u.s. house of representatives energy and commerce committee hearing on oversight of the trump administration's response to the covid-19 pandemic risk perceptions and health behavior moral injury: an integrative review when couples fight about virus risks medical bankruptcy in the united states accepted article this article is protected by copyright. all rights reserved rituals in contemporary couple and family therapy loneliness: a signature mental health concern in the era of covid-19 changing gender norms in families and society cardiovascular complications in covid-19 the covid-19 pandemic: a family affair hospitalization and mortality among black patients and white patients with covid-19 convergent antibody responses to sars-cov-2 in convalescent individuals anticipatory loss: a family systems developmental framework the expanded family life cycle: family and social perspectives helping couples and families navigate illness and disability: an integrated practice approach the family, chronic illness, and disability: an integrated practice model accepted article this article is protected by copyright. all rights reserved applying a family systems lens to proxy decision making in clinical practice and research the untold toll -the pandemic's effects on patients without covid-19 voices from the pandemic. the washington post psychological distress, coping behaviors, and preferences for support among new york healthcare workers during covid-19 pandemic neurological and neuropsychiatric complications of covid-19 in 153 patients: a uk-wide surveillance study. the lancet psychiatry strengthening family resilience a longitudinal study on the mental health of general population during the covid-19 epidemic in china healing the healer: emergency health care workers' mental health during covid-19 key: cord-300170-s2qthxx4 authors: aven, terje; zio, enrico title: globalization and global risk: how risk analysis needs to be enhanced to be effective in confronting current threats date: 2020-10-15 journal: reliab eng syst saf doi: 10.1016/j.ress.2020.107270 sha: doc_id: 300170 cord_uid: s2qthxx4 in the last 20-30 years, technological innovation has enabled the advancement of industry at a global scale, giving rise to a truly global society, resting on an interdependent web of transnational technical, economic and social systems. these systems are exposed to scenarios of cascading outbreaks, whose impacts can ripple to very large scales through their strong interdependencies, as recently shown by the pandemic spreading of the coronavirus. considerable work has been conducted in recent years to develop frameworks to support the assessment, communication, management and governance of this type of risk, building on concepts like systemic risks, complexity theory, deep uncertainties, resilience engineering, adaptive management and black swans. yet contemporary risk analysis struggles to provide authoritative societal guidance for adequately handling these types of risks, as clearly illustrated by the coronavirus case. in this paper, we reflect on this situation. we aim to identify critical challenges in current frameworks of risk assessment and management and point to ways to strengthen these, to be better able to confront threats like the coronavirus in the future. a set of principles and theses are established, which have the potential to support a common foundation for the many different scientific perspectives and ‘schools’ currently dealing with risk handling issues. currently the world is suffering as a result of the coronavirus, which among other catastrophic consequences has also led to the implementation of different forms of social isolation as measures of mitigation. this is affecting directly the fundamental element exposed to the health risk, which is also the principal actor in the globalized industrial, economic and social world: people. as a result of people's isolation, many industrial, social and cultural systems have suspended or significantly reduced their production and services, with future effects still to be seen. the coronavirus case demonstrates that the development of disastrous events has dramatically changed during recent years, because of globalization, pushed by technological innovation and strong industrialization. our society now relies on an interdependent web of transnational technical, economic and social systems, which has allowed the massive and wide transportation and distribution of people, materials, products, services, for an unprecedented improvement of welfare in most regions of the world. at the same time, however, the interconnected systems are inevitably exposed to potential scenarios of cascading outbreaks, whose effects can ripple to very large scales through their strong interdependencies. the vulnerabilities are massive and disturbing. the underlying systems have complex features, interactions among the system elements lead to complex dynamics, and surprises occur (turner and pidgeon 1997 , meadows 2008 , helbing 2013 , mcdaniel and driebe 2005 . classical risk assessments do not work in these situations, as a potential disaster in such complex systems cannot be foreseen by looking at the chain of events that may occur (leveson 2004) . the global financial crisis of a few years ago is an example: one bank, lehman brothers, filed for bankruptcy in 2008 (mishkin 2010) , with losses that extended far beyond its own financial value or its thousands of employees who lost their jobs; the effects rippled throughout the global financial system, bringing it to its knees and spreading to other major sectors like the car industry. the main lifeline systems today are all tightly connected in large and intricate networks of dependency and with interdependent links to other sectors and across national borders. with respect to the above , a major issue for risk analysts and managers is how to deal with hazards and threats with a potential for extreme consequences and large uncertainties. we know that in these cases, accurate predictions of what is coming cannot be made and, in fact, the coronavirus case has shown that the world's risk management and governance systems are not working as intended. we have not been effective in protecting people from this virus. as risk scientists, it is necessary to reflect on thisis the reason mainly about unfortunate circumstances or poor risk handling by authorities and agencies? do we, as a risk science community, also bear a responsibility for this failure? have we provided the proper concepts, principles, approaches, methods and models for adequately assessing, communicating, managing and governing the risk? in recent years, various perspectives and approaches have been proposed in the literature, to try to meet the challenges of assessing and handling risk in relation to such extreme situations and complex systems. these perspectives and approaches, which to a large extent can be viewed as scientific schools, include what we will refer to as 'safety science' (highlighting sociotechnical aspects, complexity theory, and resilience analysis), 'risk governance and systemic risk frameworks', 'post-normal science', quality management and 'risk science' (highlighting 'broad' perspectives on risk with an emphasis on uncertainties, knowledge and potential surprises (black swans)). these perspectives and approaches all produce knowledge relevant to the proper assessment, communication and handling of risks subject to large uncertainties. but is the message the same? is the separation between these schoolsas reflected by differences in scientific pillars and preferred journals, conferences, societies, etc. -hampering the development of authoritative guidance to help policy-makers, managers and decisionmakers to properly assess, communicate and handle risk? is there a potential for joining forces, to build a new generation of risk, safety and resilience frameworks for the benefit of society and us all? the present paper discusses all these issues, motivated by the pandemic outbreak that the whole world is experiencing and the consequences that it is suffering because of the coronavirus, covid-19. the main aim of the paper is to provide new reflections and knowledge on the proper assessment and handling of risk of the types addressed above, by critically reviewing current perspectives and approaches, and pointing to areas with the potential for enhancements, so that we can be better able to confront global, highly uncertain and large consequence threats like the coronavirus in the future. a key topic discussed is the tension between using scientific methods and models, on the one hand, and applying the precautionary principle, on the other, as we have seen also in the context of the scientific and political debates for the coronavirus. in fact, in relation to the coronavirus case, politicians have to a large extent referred to the precautionary principle (and still are), to justify the implementation of many specific measures. in this respect, we seek to bring new insights about this principle and associated ideas of risk handling, by relating it to the particular case of the global risk of coronavirus and the perspectives of the different scientific schools of risk assessment, management and governance mentioned above. the reminder of this paper is structured in the following way. first, in section 2, we discuss the general issues involved in preparing for and managing disasters. then, in section 3, we describe the coronavirus case from a risk assessment and management perspective, addressing relevant specific features and challenges. in section 4, we summarize and reflect on current perspectives and approaches (schools) for assessing and handling risks of this type, using the classification referred to above. from this basis, in section 5, we discuss what we can do to improve the way we assess, communicate and handle risks like those of the coronavirus type. finally, section 5 provides some conclusions. in general terms, a disaster is any occurrence that causes damage, destruction, ecological disruption, loss of human life, human suffering, or the deterioration of health and health services on a scale sufficient to warrant an extraordinary response from outside the affected community or area (who, 2007) . such situations may include natural disasters, such as droughts, earthquakes, floods or storms, and epidemics; or industrial accidents, such as nuclear or chemical ones (lehtveer and hedenus 2015 , lidskog and sjödin 2015 , and xu et al 2016 . the former are addressed within the concept of disaster management (akgün et al 2015) , but studies of epidemic disaster management are quite rare, compared to those of earthquakes, floods and other disasters, and are mostly focused on predicting the impact of an epidemic if one were to start. the latter (industrial disasters) are typically dealt with by formalized frameworks of technical risk assessment and management, to inform decisions on the design and operation of adequate preventive and mitigative barriers. the physical setting in which disasters may occur has dramatically changed over recent years, because of globalization pushed by technological innovation and strong industrialization. new factors are driving the occurrence and the consequences of disasters, among which population density, urbanization, globalization and climate change are perhaps the most evident. these factors are proving catalysts for the acceleration of pandemic disasters. for example, climate change might play a role in the birth and transmission of specific diseases; the huge trend of urbanization of the world's population, along with the substantial growth in population itself, is a factor that can accelerate epidemic outbreaks into pandemic disasters, through social globalization. all this renders our socio-technical-economic systems vulnerable to a pandemic like the one we are facing today, and more difficult the risk management of disasters and crises in general. disaster management comprises, in general, a set of activities that are performed before, during and after a disaster, with the goal of preventing loss of human life, reducing the impact of the disaster on the economy and re-establishing a normal, or even improved, state of affairs (altay and green iii 2006) . disaster risk management seeks to identify and adopt adequate measures of prevention, mitigation, preparedness, emergency response and recovery (pettit and beresford 2005) . various studies have shown that risk management of disasters can save lives and offer relief to those hit by the disaster (pettit and beresford 2005, akgün et al 2015) . the objectives of disaster preparedness for control and containment of an outbreak of an epidemic or pandemic relate, then, to reducing the rate at which vulnerable individuals become infected, reducing the mortality rate for those already infected and increasing the immunization capacity of the population. the preparation measures for control and containment must build the capabilities to launch quarantine programs over entire geographic regions, where possible. they must provide medical supplies and life commodities. they can be adopted both for prevention of the spread after the initiation of an infectious disease (pre-event measures) or for control and containment of a confirmed outbreak (post-event measures). in the former case, a predetermined amount of medical supplies should be kept in stock and ready to be used at the outbreak of the epidemic. for the specific case of the coronavirus, the european union (eu) has created a stockpile of medical equipment (such as ventilators and protective masks) to help eu countries fight the covid-19 pandemic. the stockpile includes medical items, such as intensive care medical equipment, for example ventilators, and personal protective equipment, such as reusable masks, and laboratory supplies; its current main aim is to help those eu states that face shortages of the equipment needed to treat infected patients and to protect health care workers (https://ec.europa.eu/commission/presscorner/detail/en/ip_20_476). in general, the management of the risk of disasters, such as epidemic/pandemic outbreaks, calls for preparedness and a prompt response to control them. certain protocols should be prepared and, then, followed; supplies and human resources (medical and other personnel, particularly in the case of epidemics and pandemics) should be adequately prepared and effectively made available and utilized, for the containment effort to be successful. for example, if a smallpox attack happens, vaccination of the affected population should take place within four days, while, in the case of an anthrax outbreak, the distribution of antibiotics should take place within two days of the event (lee, 2008) . this calls for an emergency supply chain (sometimes also called a humanitarian supply chain) that is properly designed, managed and operated, to successfully handle the many logistics issues that arise. this entails that financial resource allocation, vital commodities' and medical supplies' stockpiling capacities and locations be optimized, based on an a priori risk assessment, and the logistics operations during emergency for their management transportation and distribution be carried out in conjunction with the available information on the evolution of the disaster, in order to contain its spread and hopefully keep it below critical proportions. governmental agencies and health institutions must be prepared in advance for the control and containment of disasters of epidemic outbreaks. to prepare, they must take risk-informed decisions on contingency plans to be set up so as to ensure the availability of emergency medical stocks and well-trained personnel, their appropriate deployment, and the availability of different types of vehicles for the transportation of essential medical supplies and commodities, etc. an evident common ground and connection exists between the technical risk assessment & management and the disaster management, stemming from the four stages that meet their purpose: prevention/mitigation, protection/preparation, response, and recovery. prevention/mitigation comprises all activities for avoiding the occurrence of the accident/disaster and reducing its probability. protection/preparation relates to all safety measures and activities that are designed and planned to be put into action when the accident/disaster occurs, in order to reduce its impact and minimize losses. response is obtained through the activities of emergency and crisis management implemented during the aftermath of the accident/disaster, to prevent additional damage and loss. finally, recovery is the phase of restoring the back-to-normal situation after the accident/disaster. the four stages of disaster management, thus, match those of resilience management (zio 2018) or business continuity zio 2017, xing et al 2019) , typical of engineered systems and industrial companies, respectively. in spite of the importance of taking a risk-informed approach to disaster preparedness, and all the associated logistics operations for disaster control and containment, the scientific community has not yet produced well-established approaches that explicitly incorporate risk assessment as a systemic framework for holistically dealing with the problem of disaster preparedness. this paper is motivated by the pandemic outbreak that the whole world is experiencing because of the coronavirus, covid-19. as of april 2, 2020, 9.04 gmt, there are 938,373 confirmed cases of coronavirus globally. sadly, there have been 47,273 deaths. the current coronavirus pandemic has raised the importance of preparing for disasters, but, unfortunately, once again, only after the factonce the covid-19 epidemic outbreak in china had escalated to a global pandemic. and although some claim this event to be a black swan (a surprising, unforeseen extreme event), there are aspects that lead to a different perspective on the matter, which make it not surprising at all, in our globalized world, but actually very likely to occur in, say, a ten-year horizon, having in mind the rather high number of similar events in recent years. a set of characteristics defines the risk of global crises that we are exposed to, such as that due to the coronavirus outbreak, and these shape the way we address it. in the specific case of the current pandemic, the probability of and the risk related to the occurrence of the outbreak of such a crisis and of its severity have been judged too low in spite of clear evidence. large uncertainties and weak knowledge have partially caused this, leading to an insufficient level of preparedness in all countries and from all points of view: material, organizational, financial, political and cultural. what has not helped the preparedness is the individual and regionally collective "optimistic bias", which often determines the attitude to risk and the policy measures that follow. from the point of view of individual attitude, the optimistic bias leads people to ignore the risks: it is the superwoman/superman attitude of "it won't happen to me", in most cases supported by the illusion of having control over things. it has led some people to feel that they will avoid the covid-19 disease and, therefore, they can even ignore protective measures, including confinement (bako and zio 2020) . this is somewhat fed by certain erroneous, or incomplete at best, communication, e.g. that which fosters the belief that the virus is really only dangerous for old and sick people. communication should, instead, be clear on the fact that nobody can escape infection by the new coronavirus and that the physical reaction to the disease differs from individual to individual, as it is conditioned by a number of factors, mostly unknown. from the point of view of collective communities, it has again to a large extent been an "it won't happen to me" attitude, until it is suddenly revealed that the pandemic is real and there will be a high number of cases and also deaths in this region/country/area. another characteristic refers to the perception that people have of different risks. irrespective of whether there is more or less risk, tangible hazards like those arising from activities like car driving are perceived to be less severe than intangible hazards, like those related to epidemics or nuclear accidents. in the specific case of the coronavirus, the high speed at which it spreads makes it legitimate to feel worried and, so, legitimate questions arise: how does this novel pandemic compare to the "normal" or accepted risk of infectious death? what is the "worst case" scenario? should we panic and shun other people who may be carrying what might kill us? and, although it is rational to advocate that there is no need to become paranoid and fearful, but, on the contrary, there is a need to evaluate the risk and manage it scientifically, this is difficult to do in practice because:  the risk level depends on the characteristics of the virus, including how it spreads to people  a number of factors affect the behavior of the virus and of people, and all are highly uncertain because of lack of knowledge on the physics of the virus and uncertainty in the actions and reactions of people, at all levels  uncertainty affects the effectiveness of measures put in place to control the pandemic. so, the rational and logical approach to dealing with the risk of the occurring pandemic (as with any other risk, for that matter) is not to panic but to limit one's own personal and potential exposure and to minimize both the size and scale of the potentially exposed population. but the risk values produced to guide the decisions on how to do that cannot be exact, as they are based on weak and even potentially erroneous knowledge related to, for example, the spread of the virus and the actuation and respect of the measures implemented. and if risk were judged based on how it is perceived (also biased by "street" news and politics), then intangible hazards would receive the highest attention, as is the case for operating nuclear power plants and today's pandemic. so, professional risk numbers are not enough to deal with situations like the coronavirus crisis. policies crave to be science-based, but science does not have clear answers in cases like this, characterized by large uncertainties due to a weak knowledge base on the phenomenon and the factors involved. and the communication of the risk becomes difficult itself: how to explain what risk is in situations of large uncertainties and little knowledge? how can one say that it is small or large, relating it to uncertainties and knowledge? a risk professional may say that the risk is low (e.g. in the early phases of the outbreak), but the uncertainties are large: how can this be communicated, so that it is properly understood and used for decision making? in a case like this, when the stakes involved and uncertainties are so large, there are no alternatives but to give weight to the precautionary principle. the health experts have been crystal clear about the need for some type of societal lockdown, and politicians, faced with a potential for catastrophic events with thousands and even millions of deaths, have had no other choice than to follow the recommendations of the experts and even to take the precautionary measures some steps further. while trying to limit the spread and control of the pandemic, the healthcare systems have been pushed to the edge of their capacity. the expected economic and social costs are, however, enormous, and this brings strong pressure to lift the measures and reopen everything as soon as possible. in support to this, real-time tests are performed, and extensive research is conducted, to find ways of treating the patients and developing efficient vaccines against the virus, while some form of adaptive, learning-based risk management policy is applied in basically all countries (duffey and zio 2020a and b). we imagine that we are confronted with the coronavirus pandemic, in its early stages of development. authorities must make decisions and take countermeasures to control the pandemic. these decisions and countermeasures imply public investments and can be restrictive for people's activities. the potential impacts of the pandemic are huge and the uncertainties are large concerning the actual evolution of the outbreak and its consequences, as well as the effects of the possible interventions. predictions on the scenarios of the evolution of the spread of the virus are highly desirable, but the influencing factors are many and the models of the phenomena involved need to be based on many assumptions, for most of which there is no absolute justification. this is because the physical, medical, social and economic phenomena involved are not really understood, in spite of the fact that there is field experience and considerable knowledge on such types of viruses, in general, and also on how to best handle their spread and the risks they carry. for situations like this, characterized by large uncertainties, the traditional textbook approaches to risk assessment and management cannot be used. formal risk assessments cannot be applied as is, to accurately predict scenarios of evolution and estimate their consequences, accounting for the effects of alternative countermeasures. thus, the decision-making remains intrinsically dynamic and adaptation to the evolution of the situation is inevitable, as shown by the different decision strategies taken back and forth by the authorities of the countries affected by the covid-19 pandemic. this motivates a reflection on the approaches to risk assessment and management for different types of risk problems. there are, indeed, many ways of categorizing risk problems. many relate to the severity of the consequences (the stakes involved) and their degrees of uncertainty (e.g. funtowicz and ravetz 1993 , renn 2008 , aven 2020 . from the perspective of these two dimensions, the pandemic situation that we are addressing corresponds to a high risk problem (large consequences with high uncertainty), and the traditional approach to risk assessment and management just does not work. as mentioned in section 1, different 'schools' exist, to meet this type of situation. in the following, we briefly recall some of these, the main aim being to show that, in fact, they all provide useful perspectives for and approaches to how to meet the challenges of assessing and managing risk in relation to critical situations of the kind that we are experiencing due to the coronavirus pandemic. post-normal science ravetz 1993, ravetz 1999 ) acknowledges the need for an alternative and supplementary approach to science and policy making, when the stakes involved and the related uncertainties are largeand, typically, with different values in dispute and decisions urgently needed on which actions to take. this requires extending beyond the traditional perspective that science is not only certain but also value-free, calling for the need of new methods capable of going beyond numbers through different aspects of knowledge and information, dialogue and participation. the post-normal science emphasizes uncertainty and qualitative analysis, and a scheme for how to perform such analysis has been proposedthe nusap system (funtowicz and ravetz 1990 , 1993 , van der sluijs 2005 . nusap uses five categories for the management and communication of uncertainty in science for policy: numeral, unit, spread, assessment and pedigree. through nusap, a qualitative study of the quality and strength of the knowledge base behind the relevant scientific information and risk findings can be made, to inform policy making. . it is undoubted that pandemics, like the one we are experiencing, do pose systemic risk and, from this perspective, must be assessed and managed. system thinking, based on seeing wholes and interconnections, is, then, needed if we are to identify potential surprises and the unforeseenas stressed by many scholars of organizational theory, accident analysis, and the quality discourse (turner and pidgeon 1997 , deming 2000 , hollnagel et al 2006 , leveson 2011 )and effectively deal with their consequences. risk governance and systemic risk frameworks rely on three main categories of strategies for handling risk: risk-informed (based on risk assessments), robustness/resilience (based on the cautionary and precautionary principles) and discursive strategies (renn 2009 ). the strategy to apply in practice, to confront a systemic risk such as that brought by a pandemic, is normally a combination of these three types of strategies, with robustness/resilience as a main instrument for dealing with uncertainties (including potential surprises and the unforeseen), and dialogue for addressing differences in values. acknowledging complexity and dealing with uncertainties and the potential for surprises, through robustness and resilience-based approaches are key features of the risk governance school. this leads to safety science, and its roots in the 'sociotechnical perspectives on safety', which builds on three pillars (aven and ylönen 2018): i) a holistic view is needed to manage safety, using knowledge and experiential insights from different fields and disciplines (including technology and social sciences); ii) it is not possible to predict with sufficient accuracy and manage with sufficient control the behaviour of complex systems, their vulnerabilities and their response to accidents and disasters; and iii) robustness and resilience, thus, need to be accommodated, in addition to risk analysis. along these lines of thought, a rich body of literature on resilience has arisen in recent years, as a supplement to the traditional quantitative risk assessment approach, which has shown strong limitations when confronted with the analysis of complex systems and interconnected activities subject to large uncertainties regarding events' occurrences and consequences' evolution. the underlying idea is that, by strengthening the resilience of the system, the safety is improved without the need to calculate all probabilities and risks. we do not need to identify all eventshazards and threatsthat can occur as we have to do in traditional, quantitative risk assessments based on probabilistic methods. theories are developed providing a rationale for moving from 'safety-i', where the focus is on ensuring that 'as few things as possible go wrong', to 'safety-ii', where the aim is to ensure that 'as many things as possible go right' (hollnagel et al 2015) . in contrast somewhat to this perspective, the high reliability organizations (hros) tradition emphasizes the importance of failures, and that high performance and reliability can be achieved even in complex organizations if properly managed; five principles are highlighted therein: preoccupation with failure, reluctance to simplify, sensitivity to operations, ccommitment to resilience and deference to expertise (weick and sutcliffe 2007) . potential surprises are also a key focus of the quality discourse (deming 2000 , bergman 2009 ), with its distinction between 'common-cause variation' and 'special-cause variation'. the former variation relates to 'normal' system variation, whereas the latter is associated with the unusual variation, the surprises (the black swans). understanding the system causes is seen as the key to improving the system. risk science is the final school to be mentioned in this brief overview. it is based on the idea that the concepts, principles, approaches, methods and models for assessing, communicating, managing and governing risk form a distinct science (sra 2015 , 2017a ,b, aven 2018 . this science provides guidance for all types of situations, including those characterized by the potential for severe consequences and large (deep) uncertainties, like the one we are facing in the covid-19 pandemic. it provides knowledge about risk fundamentals, for example related to what risk is, how to characterize risk, what methods are suitable for analyzing risk, how to treat uncertainties in risk assessment, how to understand and use the precautionary principle, the difference between professional risk judgments and risk perception, how to best deal with risk related to potential surprises and the unforeseen (black swans), and how to understand the link between risk and resilience. all the other schools can be viewed as providing knowledge to this science. a broad perspective on risk is adopted (sra 2015, aven 2020), which sees uncertainty as a main component of risk and stresses the importance of knowledge and its strength when assessing and describing risk. the perspective allows for the inclusion of many safety, security, resilience and quality issues and is applicable to all domains (engineering, health, business, etc.). in addition, many different risk management frameworks have been developed to deal with specific issues and domains, for example enterprise risk management (erm) and business continuity management (bcm), in the case of commercial activities. bcm is of special relevance in this context, as it highlights disaster and crisis management, resilience and recovery planning (zeng and zio 2017) . as a final note on the perspectives taken above on risk, resilience, robustness, safety and security, these follow fundamental work by the society for risk analysis (sra), see sra (2015 sra ( , 2017a . there are other perspectives than these, as for example that by the us national academy of sciences which defines risk as part of resilience (see e.g. linkov and trump 2019 , linkov et al 2014 , galaitsi et al. 2020 . we also refer to ale et al (2020a,b) , jongejan (2011) and aven (2020) for discussions related to the nexus between risk and resilience. it is beyond the scope of the present paper to discuss the justification and rationale of the different perspectives, but one key point should be made clear: the difference is to large extent rooted in different conceptual understandings and terminology. there is a broad recognition of the importance of resilience to meet uncertain and unknown types of threats and disturbances. recent works on resilience and risk analysis and management in relation to covid-19 (e.g. hynes et al 2020, golan et al 2020, aven and bouder 2020) demonstrate this by their focus on system response measures and policies to prepare, absorb, recover and adapt. however, the resources are limited and what measures and policies to implement is challengingconsiderations of what will or can happen are needed, as well as overall judgments of what is acceptable levels of risk and vulnerabilities. risk science as referred to above provides one framework for conceptualising and understanding these phenomena; resilience analysis and management others, see the above references. for the purposes of the present paper, such differences in perspectives just underscore the point being made in the coming section: there are many 'schools' providing knowledge on how to handle risk when the uncertainties are large, which to varying degree work together. the overview in the previous section has shown that there are many perspectives and schools providing knowledge on how to understand, assess, communicate and handle risk, in relation to hazards and threats with the potential for extreme consequences, where the uncertainties are large. these perspectives and schools are founded on different scientific fields, developing in, to a large extent, separate activities, such as conferences, research activities, scientific journals and educational programs. yet, we argue here that the similarities and overlaps in the fundamental ideas are stronger than their differences. specifically, we highlight the following theses as common to all these perspectives and schools: a) uncertainty is a key element of all the relevant frameworks. b) an important source of uncertainty is potential surprises and the unforeseen. c) it is essential to distinguish between uncertainty and ways of measuring uncertainty. d) risk assessments provide knowledge about what type of events may occur, how often they may occur and what could be the consequences of these events if they were to occur. e) risk perception reflects aspects like fear and dread, but could also include conscious judgments of uncertainties. f) robustness and resilience are fundamental strategies to deal with the uncertainties. g) sciences about activities, events, processes developing in the world (for example, about the global spread of a virus) are supported by all perspectives and schools through their process of generation of knowledge on how to understand, assess, communicate and handle the risk (vulnerabilities, resilience, etc) and the uncertainties associated with these activities, events, processes. h) precautionary thinking is necessary in cases when the stakes involved are high and there are large (scientific) uncertainties, but the degree of precaution remains a political issue more than a science issue. as a matter of fact, scientific work can be regarded as a precautionary measure to reduce the uncertainties. i) adaptive, learning-based risk handling is suitable and advisable, given the occurrence of the hazard or threat. j) prevention of the occurrence of the potential crises-initiating hazards and threats remains a major priority. k) science informs decision-makers; it does not prescribe what is the best policy, arrangement or measure. l) openness, transparency, dialogue and participation are general features of prudent risk-handling frameworks. acknowledging uncertainty as a key component of risk is critical if we are to properly understand, assess and communicate risk. the traditional approaches to risk assessment and management jump more or less directly to the uncertainty measurement toolprobabilitythe result being that key aspects of uncertainty are not given the attention they require. all the schools discussed in section 4 see this challenge and provide broader frameworks for allowing the analysts to take some steps back from the operational measurement tool and look more deeply into the knowledge supporting the analyses and the uncertainty measures used. risk assessments cannot produce accurate predictions of what is coming; rather, they help us to see what we know and what we do not know. they report the knowledge we have and are used as instruments for gaining new knowledge by, for example, studying how assumptions and model parameters influence key risk metrics. in the current coronavirus case, we have seen a number of models used to estimate the number of deaths, with uncertainty intervals showing the dependencies on key assumptions. however, seldom or never have we seen communicated the actual meaning of these uncertainty intervals and their dependencies on the knowledge basis supporting the evaluation of these intervals. at an early stage of the development of the coronavirus epidemic, many people raised their concerns. however, some experts indicated that lay people's concerns were the result of risk perceptional factors and biases, well-known from the scientific literature on this topic (e.g. kahneman et al 1982 , kahneman 2011 . the point made was that coronavirus hits all the 'hot buttons': a risk situation which is characterized by features like unknown, new and delayed effects, lack of control and catastrophic potential, commonly summarized by the two dimensions: newness and dread. the implication is that the risk is amplified, and there is a potential for overreaction. but how can we conclude that the response is an overreaction? at the time of concern, we are still faced with considerable uncertainties, and overreaction is a human attitude which reflects that. there is no ground truth to be used as reference for what is or is not an adequate response in such uncertain situations. lay people's risk perception can also include conscious judgments of uncertainties, partly ignored by the professional risk judgments. the insights provided by the different schools referred to above acknowledge that the experts' assessments have limitations and other knowledge sources can also provide valuable input to the overall risk considerations and should be considered. when faced with uncertainties, robustness and resilience-based strategies are important, as we do not know what will happen next. we need to be ready to tackle different types of scenarios, also surprising ones. at the same time, we need to build on the available knowledge and strengthen it to better understand what is happeningwe adapt and learn. the schools discussed in section 4 support this approach to tackling risks, based on adaptation and learning, by providing concepts, principles, approaches, methods and models for how to do this. the perspectives differ partly on terminology and tools but remain similar on the fundamental ideas. inevitably, there is always a balance to be made between measures to create values, on the one hand, and measures to protect, on the other. science does not give us the formula for finding the right balance. it provides relevant knowledge and is, thus, informing the decision-maker, but it does not prescribe what should be done. the authorities in different countries have all labelled their policies "science-based", indicating that their policies are determined by the science findings. this type of notion is misleading, as the policies are at best science-informed. as we know, science produces justified claims about the world, but claims are not facts nor the truth. policies also reflect values, in particular related to how to give weight to uncertainties. in the case of large uncertainties, there is a considerable leap between insights provided by science and the considerations and policies derived by the political institutions. when faced with high stakes and large (scientific) uncertainties, precautionary measures will be and should be given weight in informing the decisions, as in the risk handling related to the coronavirus. the point is simply that we will avoid very high losses, and, given the uncertainties about the virus and the process of its spread, this leads to extraordinarily cautious policies. all governments now seem to have adopted such policies. some scholars are skeptical about the use of the precautionary principle/approach, indicating that it is not rational and scientific. however, the principle, as interpreted here as a guiding perspective, is in no way non-scientific: because of the uncertainties, there is not sufficient knowledge available to guide us differently on a solid basis. a key precautionary measure becomes, then, research to strengthen the knowledge base. it is acknowledged that different situations call for different approaches for assessing and handling risk -"simple" problems with no or very limited uncertainties require different strategies than those required by problems with high stakes involved and large uncertainties, as considered in this paper. all schools referred to in section 4 acknowledge this, although the different ways of classifying the "problems" vary. uncertainty is, however, a common feature in all classification systems used. these schools also highlight the importance of openness, transparency, dialogue and participation for dealing with situations of the kind discussed in this paper (high stakeslarge uncertainties). there are always some limitations to this in practice, for example on the extent of openness that one can really achieve/obtain, but in many ways these features characterize an ideal in our democratic societies and we should be concerned when they are threatened in any way. finally, we conclude this section with some reflections about the actual risk handling in the coronavirus case. today, the world is faced with an extreme crisis as a result of the coronavirus. thus, we can conclude that the risk handling has failed. the failure can be traced back to i) the origin of the virus, ii) the lack of early control, and iii) the mitigation measures adopted, given its spread. the first type of failure is difficult to analyze at this stage, but thorough investigations and efforts are needed to see whether there are some fundamental problems in our societies, creating this type of threat. openness and international cooperation are required to meet this challenge, but it could be difficult to obtain necessary changes in activities that are grounded in traditional and cultural practices. nonetheless, this issue is a major concern. is it possible to avoid such a virus occurring? nothing would be better than the solution to this question. secondly, it was a failure that the signals and warnings were not taken seriously, which led to a delay in actuating measures for the control of the spread. the health organizations have warned governments and politicians for years that a serious pandemic is likely to occur. national and global risk assessments all point to pandemics as a major risk. yet the signals and warnings were to a large extent ignored. as such, the coronavirus pandemic is not to be seen as a black swan; its occurrence is not a surprising event relative to our knowledge. maybe we could classify the event as a known unknown, indicating that there was knowledge that a serious pandemic could occur quite soon, but when it would occur was unknown to us. surely there is a need to improve the way the world deals with this type of alarms and warnings. international cooperation is needed to develop relevant tools and institutions to look into this. thirdly, governments struggle to justify investments in preparedness measures. there are many threats that we must be protected from and using a lot of public money for something that might happen requires a strong economy and strict prioritizations. however, for pandemic risks, the evidence has been strong and clear, but still the coronavirus spread has been enormous, whereas its mitigation has been weak in many respects. the problems that we are facing have demonstrated the extreme degree of vulnerability that our societies face today because of globalization. necessary equipment is not available locally. all countries now depend on deliveries from specific producers often far away. following the coronavirus case, fundamental pillars for how we have organized the world will be questioned. more decentralized systems will challenge the globalist perspective. one of the reviewers of the original version of this paper questioned the above conclusion that the risk handling in this case has failed. the point made was that some risks were taken and accepted, and the potential consequences were known, see also discussions in ale et al (2020a,b) . yes, decision-making about risk acceptance is an important task of risk management and governance, but it also makes sense to challenge this decisionmaking with respect to the outcomes and its rationale. we should question why many risk aspects where accepted and key vulnerabilities not reduced or eliminated. that is exactly what this paper and many others are doing. it is about scrutinizing the current risk handling in order to identify weaknesses and look for ways that it can be improved. the risk management and governance is not based on a destiny perspective, expressing that serious events will occur if we have calculated a probability for these events to occur. an ultimate goal of risk management and governance is to avoid disasters. above, we have pointed to some issues that we consider critical for being able to do this. it is about improving current approaches for risk handling. we also point to the need for the sciences and schools dealing with these challenges to do their job together, supporting the actual risk handling in the world. this is about risk analysts and scientists to make constructive reflections on systems and processes of the world, and on how to improve the handling of these and of their risks, in line with the ideas of science and quality management. in this paper, we have taken the dramatic world crisis of the coronavirus pandemic to reflect on the current frameworks for risk assessment and management and what they can offer in these situations of high stakes and large uncertainties. we have recognized that the contemporary frameworks struggle to provide authoritative unified societal guidance to adequately handle these types of risks. this is clearly shown by the coronavirus case, in which the risk handling has failed in the identification and prevention of the origin of the virus, in the lack of early control and in the efficacy of the decision-making about the mitigation measures to be adopted once the spread had started. we have highlighted that the existing scientific perspectives and schools related to risk share a number of fundamental principles and theses. they all consider uncertainty as a key element and view risk assessment as providing knowledge on what is known and what is not known about the occurrence and consequences of dangerous events, in the different risk situations. recognition is given to the fact that risk perception reflects human feelings, like fear and dread, but could also include conscious judgments of uncertainties different from those of the risk professionals. precautionary thinking, robustness and resilience are necessary approaches to develop adequate policies to address situations of high stakes and large uncertainties. the level of precaution, the decisions on how robust and resilient to be, remain political decisions, which can be informed by science and scientific knowledge: science does not prescribe the best policy of risk handling, but it can provide information for its definition by the decision-makers. it is time to initiate processes to obtain stronger integration of these perspectives and schools. only then, it is likely that we will be able to provide guidance for risk handling that really can have an impact. how to proceed is, however, difficult, given the way academic fields and societies work. the current crisis has been an eye-opener for many of us in different ways; perhaps it can also be that in relation to this challenge. we do hope so. certainly, prevention remains a main priority ("if you think that safety is expensive, try an accident", kletz, 2009) , and the capabilities for adaptive, learning-based risk handling are required in 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of risk assessment the authors are grateful to two reviewers for their useful comments and suggestions to the original version of this paper. the work has been carried out by terje aven and enrico zio, based on close collaboration on all aspects of the paper. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. key: cord-029253-03c9p7rk authors: lee, chien‐chiang; olasehinde‐williams, godwin; akadiri, seyi saint title: geopolitical risk and tourism: evidence from dynamic heterogeneous panel models date: 2020-07-07 journal: nan doi: 10.1002/jtr.2389 sha: doc_id: 29253 cord_uid: 03c9p7rk this paper provides an empirical insight into how geopolitical risks impact international tourism demand. an augmented tourism demand function was developed and empirically estimated in line with classical theory for a panel of 16 countries from 2005m1 to 2017m12 through the amg and ccemg estimation techniques that address underlying heterogeneity, non‐stationarity, and cross‐sectional dependence. the study further examines the potential moderating effect of covid‐19 outbreak on the relationship between geopolitical risk and tourism by investigating the interactive effect of past outbreaks and geopolitical risks on tourism demand. additional insight on causal relations between geopolitical risks and tourism demand was obtained using panel bootstrapping technique. the results show that geopolitical risk negatively impacts tourism demand, and that pandemic outbreaks aggravate the negative impact of geopolitical risks on tourism demand. panel causality outcomes further confirm that geopolitical risk is a significant predictor of tourism demand (captured by either tourism receipts or number of inbound tourists). our findings confirm that the dynamic attributes of both local and international political environments significantly impact the consumption decision of tourists and the economic performance of tourist destinations. our recommendation is that pre‐crisis, in proposing policy directions for tourism sector development, policy‐makers should establish crisis management plans to protect the tourism sector. post‐crisis, policy‐makers should initiate aggressive recovery marketing strategies to re‐establish the image of safety and attractiveness required to reassure potential tourists of the safety of the destination, thereby ensuring return to competitiveness and economic recovery. the study further examines the potential moderating effect of covid-19 outbreak on the relationship between geopolitical risk and tourism by investigating the interactive effect of past outbreaks and geopolitical risks on tourism demand. additional insight on causal relations between geopolitical risks and tourism demand was obtained using panel bootstrapping technique. the results show that geopolitical risk negatively impacts tourism demand, and that pandemic outbreaks aggravate the negative impact of geopolitical risks on tourism demand. panel causality outcomes further confirm that geopolitical risk is a significant predictor of tourism demand (captured by either tourism receipts or number of inbound tourists). our findings confirm that the dynamic attributes of both local and international political environments significantly impact the consumption decision of tourists and the economic performance of tourist destinations. our recommendation is that pre-crisis, in proposing policy directions for tourism sector development, policy-makers should establish crisis management plans to protect the tourism sector. post-crisis, policy-makers should initiate aggressive recovery marketing strategies to re-establish the image of safety and attractiveness required to reassure potential tourists of the safety of the destination, thereby ensuring return to competitiveness and economic recovery. covid-19, geopolitical risk, second-generation panel, tourism tourism business development is increasingly gaining attention across the world because of its associated direct, indirect, and induced economic effects. the tourism business generates foreign exchange income, leads to job creations, and boosts industry revenues, and empirical evidence shows that tourism development positively impacts the gross domestic product (gdp) of nations (lee & chang, 2008) . sequeira and campos (2005) confirm that while tourism development is not the sole determinant of economic growth, countries with well-developed tourism sectors generally exhibit higher economic growth rates than others. to maximize the economic benefits attainable from tourism business development, there is a need to adequately identify the risk factors affecting the tourism industry and advance possible means of mitigating the effects. the susceptibility of the tourism industry to external shocks such as geopolitical risks is key among such risk factors. balli, uddin, and shahzad (2019) posit that risks associated with wars, terrorism, tensions, ethnic, and political violence within and between states, generally referred to as geopolitical risks, heavily affect the socio-economic environment, and often lead to issues such as declining flow of tourism into affected regions. the tourism business is highly sensitive and very prone to panic. thus, events such as wars, terrorism, tensions, ethnic, and political violence can influence the behaviors of both investors and tourists. investors in the tourism industry, like most other investors, behave in a risk-averse manner. they channel their resources much more toward the industry when industry projections suggest limited risk and uncertainties. the presence of geopolitical risks is thus likely to cause reduction in tourism investment. geopolitical risks also have the capacity to influence tourists' destination choices. hall and o'sullivan (1996) claim that the presence or threat of occurrences of violent protests, social unrest, civil war, terrorist actions, and human rights violations are capable of altering the travel behaviors of tourists. international and/or local tourists mostly prefer to visit countries or locations with past and present records of social, economic, and political safety and security. moreover, tourism demanders display higher willingness to pay for goods and services in safer locations. the shortterm, mid-term, and long-term effects of geopolitical risks on tourism can therefore be detrimental to tourism industry gains and overall economic growth and development. geopolitical occurrences such as the us-turkey, us-russia, russia-ukraine, us-china, us-saudi-iran, syrian, north korean, and yemen conflicts as well as the struggle for european fragmentation have raised concerns and called increased attention to the direct and indirect economic effects of geopolitical risks (shahbaz, olasehinde-williams, & balcilar, 2018) . consequently, geopolitical risk is currently classified as one of the top five business threats in the world (pricewaterhousecoopers, 2018) . furthermore, the covid-19 crisis is one of the greatest problems currently plaguing the entire world. unlike other sources of global shocks, it is a health crisis with the capability to trigger all sorts of other crises, including those that are geopolitical in nature. the sudden advent of the covid-19 crisis is projected to have a multifaceted impact on how geopolitical risks affect tourism around the world. the outbreak has the potential to aggravate geopolitical risks by causing more havoc in fragile countries and regions and triggering series of unrests as the health and economic impacts of the outbreak put pressure on the relationship between citizens and governments and between countries. early signs of this are already visible in countries like brazil, italy, ukraine, venezuela, and colombia. it is also capable of providing political leaders with the opportunity to advance their objectives in ways that escalate domestic and international conflicts on the assumption that the world is too preoccupied to notice. evidence of how the disease outbreak is already fueling geopolitical risks includes the accusations made by the united states and other countries that china is responsible for the spread of the disease and the xenophobic sentiments being directed toward people of asian descent. this study contributes to the ongoing debate in empirical literature on the interaction between geopolitical risk and the tourism sector by evaluating the role of geopolitical risk in tourism industry development and by determining whether geopolitical risk is a useful predictor of tourism sector performance. the study further examines the potential moderating effect of covid-19 outbreak on the relationship between geopolitical risk and tourism by investigating the interactive effect of past outbreaks and geopolitical risks on tourism. to achieve this, we adopt the recently introduced geopolitical risk index in a panel-based study that proxies tourism demand with international tourism receipts and tourist arrivals from abroad, using monthly frequency panel-based data for 16 countries (brazil, china, columbia, india, indonesia, israel, malaysia, mexico, philippine, russia, saudi arabia, south africa, south korea, turkey, ukraine, and the united states) from 2005m1 to 2017m12. this paper thus establishes, within a panel framework, the degree of impact of geopolitical risk on tourism sector development, the moderating impact of pandemics on the relationship between geopolitical risk and tourism, and the direction of causality between geopolitical risk and tourism. the choice of panel data analysis is due to its superiority over cross-sectional data analysis and time series data analysis. the use of panel data series makes it possible for econometricians and/or researchers to construct and investigate more complex models than the time series or single cross-sectional data set would permit (baltagi, 2005; hsiao, 2007) . panel data combine time series and crosssectional characteristics for empirical analyses (baltagi, 2005; hsiao, 2007) . the ability of panel data to combine inter-cross-section differences and intra-cross-section dynamics leads to a series of benefits. first, it demonstrates superior capability for modeling complex human behavior (hsiao, 2007) . second, it is more efficient for modeling both common and individual behaviors of countries (hsiao, 2007) . third, it is more suitable for detecting dynamic relationships. lastly, it is more efficient in minimizing estimation biases that one might encounter in regression analyses (hsiao, 2007; saint akadiri, eluwole, akadiri, & avci, 2019) . two important issues need to be mentioned upfront. first, the different developmental progressions noticeable in the paneled countries are expected to be duplicated in the development of their various tourism sectors. also, the nature and intensity of geopolitical risks vary across the paneled countries. the possibility that the panel of countries is heterogeneous in nature is thus quite high. second, the flow of information about potential and existing geopolitical risks across international borders is capable of influencing international tourism demand. this suggests the possibility of cross-sectional dependence as shocks are transmittable between the paneled countries. to deal with potential heterogeneity and cross-sectional dependence, this study employs relatively new panel regression methodologies that are robust to these factors (common correlated effects mean group and augmented mean group estimators). for the direction of causal relationships among the panel series, we employ the panel bootstrap causality approach that is also robust to these factors. this study is one of the first studies to examine the connection between geopolitical risk and tourism in a multivariate panel-based empirical study that specifies a tourism demand function, which includes the traditional determinants of tourism demand. thus, we contribute to extant literature on tourism both empirically and methodologically. the remaining sections of this paper are structured as follows: section 2 highlights the conceptual perspectives on tourism and geopolitical risk from extant literature, section 3 discusses the data and panel-based methodologies adopted for empirical estimations, section 4 presents and discusses empirical findings, and section 5 provides the concluding remarks and possible policy recommendations. 2 | tourism and geopolitical risk lanouar and goaied (2019) , in their study, establish that global tourism is affected by political unrests, terrorism, and natural disasters. available literature on the interconnectedness of political risk and tourism reveals that geopolitical conflicts, tensions, or political risks generate uncertainties or fluctuations in economic and political scenes, and significantly impact tourism demand (haddad, nasr, ghida, & alibrahim, 2015; muzindutsi & manaliyo, 2016) . antonakakis, gupta, kollias, and papadamou (2017) , on the other hand, argue that the tourism sector responds to external shocks and adjusts to wider political and economic environments as it transforms and develops. fundamentally, the characteristic features of both domestic and foreign political and economic environments have a large effect on tourism, market agents as well as the economy as a whole. however, according to kozak (2007) , the choice of travel destination of tourism demanders is significantly affected by their risk perception. slevitch and sharma (2008) further show that tourism demanders display higher willingness to pay for goods and services in safer locations. no country has so far succeeded in shielding its tourism industry from the negative effect of geopolitical risks. therefore, if adequate policy is not put in place, geopolitical risk can exercise significant impact on the international tourist arrivals, number of overnight stays, tourism imports, and several significant measures of tourism development (drakos & kallandranis, 2015; lanouar & goaied, 2019; omar, wisniewski, & nolte, 2017; sönmez, 1998) . it is widely understood that personal safety is highly valued by everyone and that people naturally try to avert any form of threat to their personal safety. according to bassil, saleh, and anwar (2019) , the presence of danger in tourism-supplying locations can adversely affect the number of tourists received; even the perception of insecurity within a tourism-supplying country is able to create significant travel anxiety that could negatively impact tourist arrivals and length of stay. tourists may, however, be willing to accept the risk if the destination is exceptional enough to entice them (frey, luechinger, & stutzer, 2007; lepp & gibson, 2003) . in the same vein, a number of papers have shown that the effect of political instability/terrorism on tourism may be non-linear; that is, it starts adversely impacting tourism after reaching a certain threshold (harb & bassil, 2019; mitra, pham, & bandyopadhyay, 2018; saha & yap, 2014) . sharifpour, walters, and ritchie (2013) and morakabati and kapu sci nski (2016) opine that risk appetite varies across tourist groups, from allocentric to psychocentric, and is mainly determined by the personality traits of tourists and the uniqueness of the destination. das, kannadhasan, and bhattacharyya (2019) , in their study, infer that geopolitical risk is an influential indicator of economic market reaction to shocks or volatility. balcilar, bonato, demirer, and gupta (2018) further buttress this notion and assert that geopolitical risk is the major factor affecting business cycles, financial markets, and economic directions. lanouar and goaied (2019) argue that shocks and volatility have both transitory and permanent impacts on tourism demands. for instance, findings from the study of liu and pratt (2017) reveal that terrorism impacts tourism in the short run. similarly, agiomirgianakis, serenis, and tsounis (2017) posit that terrorist upheavals and political instability contribute* significantly to fluctuation in tourism demands in the short run. a limited body of literature argues that tourism is resilient to the adverse effect of geopolitical risks. for example, uriely, maoz, and reichel (2009) claim that geopolitical conflicts are often ignored in cases where there is an opportunity for both sides to benefit from tourism. the success of the israeli tourism industry in spite of constant conflict was put forward by krakover (2013) as a prime example. another group of authors such as jurkovich and gesler (1997) , smith (1998) and weaver (2011) argues that tourism and geopolitical risk are, as a matter of fact, complementary under certain conditions. it is claimed that elements of geopolitical risk often support tourism growth. the upsurge in war tourism demand in afghanistan by people visiting combat scenes and former terrorist camps was given as an example of this complementary nature by adams (2001) . overall, however, empirical evidence is skewed in favor of a negative relationship between elements of geopolitical risk and tourism. classical economic theory suggests that tourism demand is a function of income and relative prices (naudé & saayman, 2005; walsh, 1996) . where q t denotes tourism demand, y t represents per-capita income of countries of tourism demanders and p t represents relative prices. according to the theory, income of tourism demanders is the most important determinant of tourism consumption. the greater the purchasing power of potential tourism demanders, the higher the level of tourism consumption. another factor that strongly influences tourism demand is relative prices. relative price effects are mainly felt through the relative exchange rates and the cost of goods and services demanded by tourists. with regard to costs of goods and services, it is natural for tourists to be concerned about the costs of products and services such as transportation, accommodation, site fees, cost of feeding, and cost of souvenirs, among others. the lower the general price levels in the tourism-supplying country, the higher the demand for tourism, ceteris paribus. as for exchange rate, it measures the relative price differences between the home country of the tourism demander and the tourism-supplying country. a weakening of the domestic currency of the tourism-supplying country means that the costs incurred by foreign tourists will be lowered, ceteris paribus. the relatively lower prices will most likely be translated into either longer stays or increased expenditures by visitors. it will also likely lead to relatively increased inflow of tourists, compared to other tourist destinations. we extend the demand function expressed in equation (1) by augmenting it with geopolitical risk. this is in line with our earlier argument that geopolitical risk is a useful determinant of tourism demand. we thus re-specify equation (1) as follows: where g t refers to geopolitical risk. we thus adopt the tourism demand model from equation (2) and rewrite it in an econometric form: where l refers to natural log, i represents country (i = 1, …, 16), t stands for the monthly time period (t = 2005m1, …, 2017m12), β k (k = 1, 2, 3, 4, 5) is the country-specific parameter estimate for the regressors and e it is the error term which includes the following; group fixed effects (α i ) that account for time-invariant heterogeneity across cross-sections, common factor (f t ) with heterogeneous factor loadings (λ i ) that accounts for time-variant heterogeneity and cross-sectional dependence and the white noise component (ε it ). lq is tourism demand. it is most commonly measured either through tourism receipts (expenditures made by inbound international tourists) or through the number of inbound tourists (number of foreign visitors). as a form of robustness check, we use both variables as regressands in separate regressions. to convert the data from annual to monthly, an interpolation method based on constant-match sum as described in startz (2007) and chaiechi (2014) was used. the technique converts from low to high frequency by dividing each low frequency observation by the number of high frequency observations associated with that particular low frequency observation and then assigns the same value to all observations in the high frequency series. lg, which represents the variable of interest, geopolitical risks, is measured using the caldara and iacoviello (2018) lpi stands for the general price level of the tourism-supplying country. it is measured using the consumer price index of the countries included in the data series. its purpose is to serve as a control for the impact of the cost of goods and services on tourism demand. lti refers to the number of tourism industries available in each of the tourism-supplying countries. it is included to account for timevarying destination-specific factors. as defined by the world tourism organization, tourism industries refer to the industries that provide tourism characteristic products, such as (a) those that provide accommodation for visitors, (b) those that provide food and beverage serving activities, (c) those that provide railway passenger transport, road passenger transport, water passenger transport, air passenger transport, and transport equipment rentals, (d) travel agencies and other reservation services activities, (e) cultural activities, (f) sports and recreational activities, (g) retail trade of country-specific tourism characteristic goods, and (h) other country-specific tourism characteristic activities. to test the moderating effect of pandemics on the relationship between geopolitical risk and tourism, we further include a dummy variable for pandemic outbreaks (po). the dummy variable takes the value of one during years with pandemic outbreaks (swine flu, ebola, mers-cov, and zika virus) and the value of zero otherwise. po is then interacted with geopolitical risk as shown in equation (5). the data set used for the empirical analysis consists of monthly (pesaran, 2006) . the procedure involves the inclusion of the crosssection averages of the dependent and independent variables as extra regressors when applying ols to each unit. ccemg displays satisfactory small sample properties, accounts for possible structural breaks, unit roots, non-cointegrated common factors, certain serial correlation, and is a robust estimator of short-run dynamics (kapetanios, pesaran, & yamagata, 2011) . the long-run relations of the model specified in equation (5) obtained from the ccemg and amg estimation procedures are shown in tables 6 and 7. both estimation techniques record a negative long-run effect of geopolitical risk on tourism demand irrespective of whether tourism receipts or number of inbound tourists are used as the dependent variable. as shown in table 6 , 1% increase in geopolitical risk will lead to 0.011% decline in the size of tourism receipts based on the amg estimation, and 0.014% decline in tourism receipts based on the ccemg estimation. table 7 similarly shows that 1% increase in geopolitical risk will lead to 0.010% decline in number of inbound international tourists based on the amg estimation, and 0.001% decline in number of inbound international tourists based on the ccemg estimation. we are thus able to conclude that the conditional marginal impact of geopolitical risk on tourism demand is negative when there are no pandemics. this outcome emphasizes the importance of geopolitical stability to tourism and confirms our assertion that geopolitical risk is a non-traditional determinant of tourism demand. the finding agrees with the conclusions of kozak (2007) , slevitch and sharma (2008) , haddad et al. (2015) , and muzindutsi and manaliyo (2016) . note: (a) theδ andδ adj tests are the modified versions of the swamy (1970) test proposed by . (b) the null hypothesis in both cases is slope homogeneity. the results also indicate that the outbreak of pandemics generally has a negative conditional marginal impact on tourism demand. as shown in table 6 the interactions between geopolitical risk and pandemic outbreak are also negative in all cases. this confirms our suspicion that the outbreak of pandemics has a moderating effect on the relationship between geopolitical risk and tourism. the results indicate that pandemics aggravate the negative impact of geopolitical risks on tourism demand. as reported in table 6 , the negative impact of geopolitical risks on tourism receipts increases by approximately 2.1 and 2.4% according to the amg and ccemg outcomes, respectively. in table 7 , note: (a) amg: augmented mean group (amg) estimator of eberhardt and teal (2010) . (b) ccemg: common correlated effects mean group (ccemg) estimator of pesaran (2006) . the negative impact of geopolitical risks on the number of inbound tourists increases by 0.9 and 1.2% according to the amg and ccemg results, respectively. the amg coefficient is, however, insignificant, pointing to the absence of a moderating effect. with regard to the control variables, as expected, average global income positively contributes to tourism demand. as reported in table 6 , when average global income increases by 1%, the size of tourism receipts is expected to increase by 0.668% based on the amg estimation, and by 0.065% based on the ccemg estimation. in table 7 , when average global income increases by 1%, number of inbound tourists is expected to increase by 0.550% based on amg estimation, and by 0.026% based on the ccemg estimation. this finding suggests that rising purchasing power of tourism demanders promotes international tourism. the general price level has a negative long-run effect on tourism demand, while real exchange rate has a negative long-run impact on tourism demand. results reported in table 6 respectively. in table 6 , a percentage rise in exchange rate (currency appreciation) will cause tourism receipts to fall by 0.194 and 0.189% based on amg and ccemg, respectively. table 7 reports similar outcomes, a percentage rise in exchange rate leads to 0.025 and 0.097% rise in the number of inbound international tourists based on amg and ccemg, respectively. these outcomes suggest that tourism demand is positively related to price competitiveness as captured by the cost of goods and services and exchange rate movements. with regard to tourism industries, the findings show that demand for tourism is strongly correlated with the availability in the tourismsupplying country of industry-supporting facilities such as accommodation for visitors, food and beverage serving, passenger transportation, and travel agencies/reservation services. the estimation outcomes show that when a country is able to raise its tourismrelated facilities by 1%, we can expect to witness a rise of about 0.179 and 0.139% in tourism receipts according to the amg and ccemg estimations, respectively. we can also expect to experience an increase of about 0.132 and 0.053% in the number of inbound tourists based on the amg and ccemg estimations, respectively. the reported outcomes for the control variables are in consonance with claims that income, price level, exchange rates, and availability of tourism-related facilities are traditional determinants of tourism demand (divisekera, 2003; khadaroo & seetanah, 2008; lim, 1997; morley, 1998; okafor, khalid, & then, 2018 we examined the relationship between geopolitical risks and tourism demand within a multivariate panel-based model. based on the classical theory, we first developed a traditional demand function, which treats tourism demand as a function of income, exchange rate, and price level, and then augmented it with geopolitical risks. we also controlled for time-varying destination-specific factors by including the number of tourism-related facilities in each of the sampled countries t a b l e 8 summary of causal relations between tourism and geopolitical risk in the demand function. furthermore, we examined the potential moderating effect of covid-19 outbreak on the relationship between geopolitical risk and tourism by investigating the interactive effect of past outbreaks and geopolitical risks on tourism. we were thus able to create a useful model for empirical analysis based on the theory of demand. as a next step, the empirical model was estimated for a panel of 16 countries from 2005m1 to 2017m12 through the amg and ccemg estimation techniques that address underlying heterogeneity, non-stationarity, and cross-sectional dependence in the panel series. additional insight on the patterns of causal relationships between geopolitical risks and tourism demand was obtained through the aid of panel bootstrapping technique of kónya (2006) . empirical results from the adopted estimation techniques indicate a negative long-run impact of geopolitical risk on tourism demand. consequently, the dynamic attributes of both local and international political environments significantly affect the consumption decision of tourists and the economic performance of tourist destinations. this outcome emphasizes the importance of geopolitical stability to tourism and confirms our assertion that geopolitical risk is a non-traditional determinant of tourism demand. overall, we conclude that peace and stability are a key requirement for tourism sector growth. as tourism is an important driver of economic growth (akadiri, lasisi, uzuner, & akadiri, 2018; fahimi, akadiri, seraj, & akadiri, 2018; katircioglu, 2009; lee & chang, 2008; liu & song, 2018; wu & wu, 2019) , geopolitical risks can indirectly stifle economic growth through their adverse effect on tourism. the causality results, however, show that the relationship between geopolitical risks and tourism demand is heterogeneous as it varies across countries. in spite of this, geopolitical risk turns out to be a significant predictor of tourism demand in all the 16 countries sampled. the findings also confirm that the outbreak of pandemics has a moderating effect on the relationship between geopolitical risk and tourism. our findings indicate that pandemics aggravate the negative impact of geopolitical risks on tourism demand. this suggests that the sudden outbreak of covid-19 pandemic is likewise likely to amplify the negative relationship between geopolitical risk and tourism. concerning the control variables, as expected, average global income positively contributes to tourism demand. this finding suggests that rising purchasing power of tourism demanders promotes international tourism. also, currency appreciation lowers tourism demand, while increasing price levels lower tourism demand. this is an indication that tourism demand is positively related to price competitiveness as captured by the cost of goods and services and exchange rate movements. moreover, our findings indicate that tourism demand is more sensitive to price variations (price level and exchange rate movements) than it is to geopolitical risks. since countries experiencing geopolitical risks are often negatively portrayed internationally and this often leads to the lowering of prices in their tourism sector, less risk-averse travelers are bound to take advantage of cheaper holiday costs in such places. geopolitical risks may thus indirectly cause an upsurge in tourism demand. in summary, at first glance, the concept of geopolitical risk seems unrelated to tourism. a closer look taken by this study, however, reveals that rising geopolitical risks negatively impact the tourism industry. this stands to reason since tourists are often regarded as soft targets and ambassadors of their home countries and are thus deliberately targeted for their symbolic value during geopolitical conflicts such as wars and terrorist attacks. international tourists are also commonly targeted during periods of crises for ideological reasons such as punishment for the support given by the government of their home countries to other governments or ideologies. the high profile nature of international tourists coupled with the news value they are able to generate is thus often exploited by violent actors during geopolitical conflicts. overall, the tourism sector is extremely vulnerable to geopolitical risks. post-crisis, tourism-supplying countries should initiate aggressive recovery marketing strategies to re-establish the image of safety and attractiveness required to reassure potential tourists of the safety of the destination, thereby ensuring return to competitiveness and economic recovery. moreover, our findings indicate that tourism demand is more sensitive to price variations (price level and exchange rate movements) than it is to geopolitical risks. since countries experiencing geopolitical risks are often negatively portrayed internationally and this often leads to the lowering of prices in their tourism sector, less risk-averse travelers can be persuaded through aggressive marketing to take advantage of cheaper holiday costs in such places. it is important to point out two limitations of this study. the first is that the characteristics of vacation, business, and vfr (visiting friends and relatives) tourism can show marked variation, and seasonality plays an important role in the distribution of tourist numbers over the year. the second is that geopolitical risk data unavailability limited the number of countries covered in the study. as a direction for future research, we, therefore, suggest the use of disaggregated tourism data as they become available, and the expansion of the sample size as the geopolitical risk database grows. panel bootstrap causality between geopolitical risk and inbound tourists lg, log of geopolitical risk; 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hospitality comparative advantage: explaining tourism flows geopolitical risk and tourism: evidence from dynamic heterogeneous panel models the authors are grateful for the insightful comments and suggestions received from the editor and the anonymous referees on the earlier draft of this paper. key: cord-277210-xaj2623u authors: weinkove, robert; mcquilten, zoe k; adler, jonathan; agar, meera r; blyth, emily; cheng, allen c; conyers, rachel; haeusler, gabrielle m; hardie, claire; jackson, christopher; lane, steven w; middlemiss, tom; mollee, peter; mulligan, stephen p; ritchie, david; ruka, myra; solomon, benjamin; szer, jeffrey; thursky, karin a; wood, erica m; worth, leon j; yong, michelle k; slavin, monica a; teh, benjamin w title: managing haematology and oncology patients during the covid‐19 pandemic: interim consensus guidance date: 2020-05-13 journal: med j aust doi: 10.5694/mja2.50607 sha: doc_id: 277210 cord_uid: xaj2623u introduction: a pandemic coronavirus, sars‐cov‐2, causes covid‐19, a potentially life‐threatening respiratory disease. patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe covid‐19. community transmission of covid‐19 could overwhelm health care services, compromising delivery of cancer care. this interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. main recommendations: during the covid‐19 pandemic: in patients with cancer with fever and/or respiratory symptoms, consider causes in addition to covid‐19, including other infections and therapy‐related pneumonitis. for suspected or confirmed covid‐19, discuss temporary cessation of cancer therapy with a relevant specialist. provide information on covid‐19 for patients and carers. adopt measures within cancer centres to reduce risk of nosocomial sars‐cov‐2 acquisition; support population‐wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. measures should be equitable, transparent and proportionate to the covid‐19 threat. consider the risks and benefits of modifying cancer therapies due to covid‐19. communicate treatment modifications, and review once health service capacity allows. consider potential impacts of covid‐19 on the blood supply and availability of stem cell donors. discuss and document goals of care, and involve palliative care services in contingency planning. changes in management as a result of this statement: this interim consensus guidance provides a framework for clinicians managing patients with cancer during the covid‐19 pandemic. in view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. endorsed by: australasian leukaemia and lymphoma group; australasian lung cancer trials group; australian and new zealand children's haematology/oncology group; australia and new zealand society of palliative medicine; australasian society for infectious diseases; bone marrow transplantation society of australia and new zealand; cancer council australia; cancer nurses society of australia; cancer society of new zealand; clinical oncology society of australia; haematology society of australia and new zealand; national centre for infections in cancer; new zealand cancer control agency; new zealand society for oncology; and palliative care australia. • for suspected or confirmed covid-19, discuss temporary cessation of cancer therapy with a relevant specialist. • provide information on covid-19 for patients and carers. • adopt measures within cancer centres to reduce risk of nosocomial sars-cov-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. measures should be equitable, transparent and proportionate to the covid-19 threat. • consider the risks and benefits of modifying cancer therapies due to covid-19. communicate treatment modifications, and review once health service capacity allows. • consider potential impacts of covid-19 on the blood supply and availability of stem cell donors. • discuss and document goals of care, and involve palliative care services in contingency planning. this interim consensus guidance provides a framework for clinicians managing patients with cancer during the covid-19 pandemic. in view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. patients with cancer could be at elevated risk of severe covid-19, while delivery of cancer therapies could be disrupted by quarantines, social distancing measures, and interruption of routine health care delivery by the pandemic. pending more definitive evidence, this article presents interim guidance, based on expert opinion, to aid decision making for clinicians treating patients with cancers. the suggestions provided here may be relevant to both adult and paediatric patients. as recommendations may change in light of new evidence or experience, we encourage clinicians to refer to the official information sources regularly, and the website of the national centre for infections in cancer (https://cance randi nfect ions.org/) for updates to this guidance. the most frequent symptoms of covid-19 are fever (90-98%), cough (59-76%) and lethargy (38-70%) . 3,8-10 abnormalities on computed tomography scans of the chest have been reported in 80-100% of admitted patients, with bilateral ground glass opacities the most common finding. 3,8, [10] [11] [12] median time to development of dyspnoea is 5-8 days 3,9 with median hospital admission stay of 7-10 days. 3 in adults, intensive care admission has been reported in 26% of admissions at a median time of 12 days after illness onset, coinciding with onset of acute respiratory distress syndrome. 10 atypical clinical presentations of other infections are common among cancer patients receiving highly immunosuppressive therapies, 13 although whether this applies to covid19 is not yet known. the clinical impact of covid-19 in children with cancer or haematological malignancy is currently unknown. although the mechanism is not clear, children appear to be less frequently affected by sars-cov-2, representing only 2% of covid-19 presentations in a large wuhan series. 1,14 when symptomatic illness occurs in children, it is usually mild, with fever and cough most frequently reported. diffuse pulmonary infiltrates in an asymptomatic child were recently described. 15 however, while asymptomatic or mild illness following sars-cov-2 infection is the norm in otherwise well children, the risk of severe illness may be higher in the immunocompromised. this is highlighted by a report of severe covid-19 in a child receiving chemotherapy for acute lymphoblastic leukaemia. 16 diagnosis can be made by specific reverse transcription polymerase chain reaction assay of nasopharyngeal or oropharyngeal swabs and lower respiratory tract samples 3 with median viral shedding of 20 days (interquartile range, 17-24 days). 10 following infection, sars-cov-2 viral shedding might be more prolonged in patients with cancer: viral shedding of seasonal coronaviruses lasts up to 4 weeks in patients with cancer, 7 and shedding of other respiratory viruses is prolonged in immunosuppressed patients. 17 the sars-cov-2 virus can also be detected in stool samples. although the impact of this on virus transmission remains uncertain, this should be considered in patients with therapy-associated diarrhoea or with stomas. 18 clinicians must note that the coronavirus testing incorporated in routine respiratory virus polymerase chain reaction panels may not detect sars-cov-2, and should verify suitability of the assays in local use for covid-19 testing. established risk factors for severe covid-19 in adults include advanced age and medical comorbidities. 3 in-hospital death has been independently associated with higher age, higher sequential organ failure assessment score and elevated ddimer levels. 10 importantly, some laboratory findings associated with adverse covid-19 outcomes, such as lymphopenia, neutrophilia, elevated d-dimer levels and elevated lactate dehydrogenase levels, are frequent in patients with cancer. however, the applicability of these biomarkers of covid-19 severity to patients with cancer has not been established, and they should be interpreted with caution. in an early report of patients with covid-19 in china, receipt of chemotherapy or cancer surgery was a risk factor for severe complications. 20 patients with cancer were also reported to be at higher risk of severe complications including intensive care unit admission, invasive ventilation or death, 20 and deteriorated more rapidly (median, 13 days v 43 days). receipt of cancer therapy or surgery within the preceding month was associated with an increased risk of severe events after adjusting for other factors (odds ratio, 5.34; p < 0.01). 20 however, the number of covid-19 cases with cancer in this series was small and the contribution of confounding factors, including smoking, was not clear. 5 risk factors for severe covid-19 in children are currently unknown, although a study of seasonal coronaviruses in children found that co-infection, younger age and immunocompromise were associated with an increased risk of severe lower respiratory tract infection. 21 specific risk factors for severe respiratory viral infection in patients with solid tumours are poorly described in the literature. although many treatments for solid tumours do not cause prolonged severe lymphopenia or neutropenia, severe infection risk may be elevated due to disruption of mucosal barriers by chemotherapy-induced mucositis, or altered anatomy and reduced physiological reserve caused by the malignancy itself or as a consequence of surgery or radiotherapy. 22 this may be of particular relevance to patients with lung cancer, who made up the majority of cancer patients affected by covid-19 in an early report. 20 among adult haematology and hsct patients with seasonal coronavirus (not sars-cov-2) infections, the following risk factors for lower respiratory tract disease were identified: 2,7,23 age 50 years and above; receipt of corticosteroids; graft versus host disease; lymphopenia; neutropenia; and hypogammaglobulinaemia (igg < 4 g/l). until specific risk factors for severe covid-19 manifestations among patients with cancer have been identified, clinicians will need to use their clinical judgement, referencing established risk factors for severe manifestations of other respiratory viruses, to evaluate an individual patient's risk of severe covid-19. the consensus development process began with definition of the objectives, a review of evidence, and identification of key considerations for clinicians, by members of the australasian leukaemia and lymphoma group and the national centre for infections in cancer. the objective was to provide interim guidance for clinicians managing patients with cancer during the covid-19 outbreak. as clinical urgency and travel restrictions precluded face to face meetings, discussions were held by telephone conference consensus statements mja 212 (10) ▪ 1 june 2020 483 and email. draft guidance was circulated by email to clinicians with expertise in medical and radiation oncology, hsct, palliative care and indigenous health; comments and edits were integrated into the guidance by a core writing group. as well as circulating versions to all co-authors for comment, sequential versions were uploaded to the national centre for infections in cancer website in view of the clinical urgency. later versions were circulated to leads of cancer and infectious disease organisations across australia and new zealand for review and to consider endorsement; additional suggestions from these groups were incorporated into the text by the core writing group, and the document was recirculated for approval. the draft guidance was reviewed by the consumer representative group of the australasian leukaemia and lymphoma group, and their suggestions were incorporated. as the clinical urgency and paucity of clinical evidence precluded satisfaction of all advancing guideline development, reporting and evaluation in health care (agree) instrument items, 24 this document is presented as interim, rather than definitive, consensus guidance. at this time, indications for testing for sars-cov-2 in cancer patients remain the same as the general population, although some specialist societies have recommended screening of patients for sars-cov-2 before high risk procedures, such as stem cell transplantation. 25 as indications for sars-cov-2 testing are rapidly evolving, clinicians should defer to the latest jurisdictional or institutional guidelines. interim guidance for the treatment of covid-19 is available elsewhere. 19 antiviral therapies such as lopinavir-ritonavir and remdesivir are undergoing evaluation, and the role of anticytokine therapies such as tocilizumab for severe infections is under exploration. pending further information, we suggest that management of covid-19 should be similar for patients with and without cancer. immunocompromised patients with suspected or confirmed covid-19 should be discussed with an infectious disease or clinical microbiology specialist. however, clinicians should be aware of the following considerations for patients with cancer who develop symptoms of covid-19: • among immunocompromised patients, the differential diagnosis of fever and respiratory symptoms is broad, and clinicians should be alert to the possibility of alternative or secondary infections, including bacterial, fungal or other viral infections. early recognition and treatment of bacterial sepsis remains vital, particularly in severely neutropenic patients. • pneumonitis may occur following certain cytotoxic chemotherapies, immune checkpoint blockade or radiotherapy, and shares clinical and radiological features with covid-19. corticosteroids should be considered if therapy-related pneumonitis is suspected, acknowledging that a detrimental impact of corticosteroids on the risk of severe covid-19 has not been excluded. • temporary discontinuation of cancer therapies will be warranted for some patients with cancer who develop symptoms of covid-19, to minimise treatment-related immunosuppression or to reduce the risk of drug interactions. this should be undertaken in discussion with an oncologist or haematologist familiar with management of the malignancy, who can advise on the benefits and risks of pausing therapy. for each of the reasons above, community assessment and management procedures developed for healthy people with covid-19 may be less well suited for some patients with cancer. health care system and policy responses to covid-19 are evolving rapidly. haematologists and oncologists should regularly review and follow institutional, specialist college, state level and federal government recommendations. we encourage haematology and oncology representatives to engage with, and participate in, pandemic planning within their organisations. as many patients with cancer may be at increased risk of severe covid-19 manifestations, we suggest a proactive approach. in box 1, we propose actions to consider, phased according to the presence or absence of community spread of covid-19 locally, and the capacity of health care services to deliver routine care. the suggested actions will not be appropriate for all settings, and are not exhaustive, but are intended to prompt discussion among clinicians planning their service's covid-19 response. at each phase, clinicians should review actions they could take to prepare for the subsequent phase; some units may elect to initiate later phase actions at an earlier phase. the actions are cumulative -the measures in phases b and c are suggested in addition to those of phase a. measures should be reviewed regularly, and reversed once the situation allows. institutional, local, statewide and national policies and recommendations (including for social distancing, isolation, quarantine or personal protective equipment use) are likely to cover some or all of these actions, and should take priority. social distancing measures, quarantine and visitor limitations will limit opportunities for family support and advocacy, affecting an important sense of connection and source of strength and wellbeing, particularly for indigenous peoples. we recommend services recognise these impacts and seek to counterbalance them with measures to ensure safe non-physical contact and support, such as facilitation of video and telephone contact. refer to guidance for the delivery of culturally safe care. 26, 27 the spread of covid-19 can be rapid, and may overwhelm primary and acute care facilities. 1,28 this may be compounded by covid-19 infection of medical personnel, quarantine requirements and school closures, all of which may impact staffing levels, 3 and by disruption to supply chains, affecting medical supplies. if acute care facilities are overwhelmed, institutions might make alternative provisions for the care of patients with cancers. adaptive measures could include increased use of community care (including hospital-in-the home services) or private facilities. clinicians may need to work flexibly to facilitate safe service provision in alternative settings. resource constraints may mandate prioritisation or modification of patients' cancer therapies. while it is anticipated that institutions will develop their own plans, which will take priority, we suggest individual patient decisions should be the responsibility of clinicians who are familiar with the malignancy, its treatment, and other therapeutic options. clinicians will have to balance the relative risks of patients developing covid-19 while severely immunosuppressed, or of developing a severe treatment complication, against the risks of tumour progression, while considering the prevailing state of the health care service, and current or incipient medicine supply constraints. we suggest discussing risks and benefits of any treatment modifications among clinical peers. take particular account of the need to protect vulnerable populations, including indigenous peoples, who experience a higher burden of both cancer and infectious disease. 2933 we suggest clearly documenting any treatment modifications, and the reasons for them, in each patient's medical record, and communicating them to the patient and their primary care physician. consider reviewing treatment modifications once resource availability allows; in some circumstances it may be appropriate to resume a postponed treatment, or to complete an abbreviated treatment course. the ethical principles of equity, proportionality and transparency apply to resource allocation decisions. refer to relevant regulatory guidance, such as that provided by the medical council of new zealand's safe practice in an environment of resource limitation, 29 and to ethical frameworks, as outlined in the australian health sector emergency response plan for novel coronavirus . 30 if crisis standards of care replace normal standards, conflicts with and between other ethical principles including justice, non-maleficence, beneficence and autonomy may become acute, and need to be openly acknowledged and addressed. where available, objective national guidelines should be followed, and a fair decision-making process adopted and shared between appropriate senior medical staff. staff involved with such decisions should be supported during and after the crisis has resolved. many patients with cancer, and their families, will be concerned or distressed about the impacts of covid-19. a list of suggested messages for clinicians to communicate to their patients with cancer is outlined in box 2. as covid-19 recommendations are likely to change frequently, clinicians should direct patients towards the most upto-date resources from the department of health in australia (https://www.health.gov.au/news/health-alert s/novel-coron avirus-2019-ncov-health-alert) and the ministry of health in new zealand (https://www.health.govt.nz/our-work/disea sesand-condi tions/ covid-19-novel-coron avirus). patients with family members or other close contacts who have suspected or confirmed covid-19 should aim to remain isolated from these contacts, and should inform their cancer centre of any quarantine requirements. the recommendations of the relevant health department regarding quarantine and isolation should be followed. steps should be taken to reduce the risk of patients with symptoms of covid-19, or with a known sars-cov-2 contact, presenting unannounced to cancer centres or clinics. we suggest that cancer centres inform patients of the symptoms of covid-19, indicate criteria for seeking medical advice, and state the appropriate mode of presentation. this may include use of a triage line, assessment in an acute care setting with isolation and testing facilities, or use of a dedicated community assessment facility. advice should be consistent with institutional, state or federal guidance, and should be disseminated to receptionists, nursing and clinical staff, as well as to patients themselves. advice should take account of the possibilities that cancer patients presenting with fever may be at elevated risk of bacterial or fungal infection requiring prompt antimicrobial therapy, and that the differential diagnosis of fever should not be limited to covid-19 (see "management of covid-19" above). measures that might be widely implemented in a pandemic setting, and which may warrant modification for immunocompromised patients, include community-based assessment; home treatment of covid-19; cohorting with other infected patients in a non-specialist ward; and symptomatic covid-19 treatment without confirmatory investigations or without empiric antibiotics. during the pandemic, patients may be assessed and we recommend that patients with cancer review governmental advice and restrictions before undertaking domestic and overseas travel. patients should ensure they travel with a sufficient supply of their medicines, accounting for the risk of quarantine during or after their journey. patients must be aware that in addition to a higher risk of infection with sars-cov-2, access to medical services may be limited in regions where the covid-19 caseload has exceeded health care capacity. transfusion support for patients with cancer and blood disorders accounts for most outpatient red cell and platelet utilisation, and for a large proportion of inpatient transfusions. 34 transfusion requires close patient monitoring, placing demands on inpatient and outpatient cancer services, which could fall under strain during the pandemic. visits to acute care facilities for transfusions expose immunocompromised patients to other patients and staff, some of whom could be shedding sars-cov-2. community spread of covid-19 may reduce the blood donor pool and threaten blood supplies due to deferral of donors, blood service staff shortages, or shortages of consumables and reagents. finally, although there is no precedent for transfusion transmission of respiratory viruses, sars-cov-2 viral rna can be detected in the plasma of people with covid-19, and donor deferral is the only current mechanism in place to prevent transmission via blood components. 35 although pathogen reduction technologies for platelets and plasma are effective for other coronaviruses, these are not in routine use in australia or new zealand, and no licensed pathogen reduction technology is available for whole blood or red cells. 35 updated information on risk of transfusion transmission and donor deferrals is provided by australian red cross lifeblood (https://www.trans fusion.com.au) and the aabb. 36 the national blood authority response to covid-19 and the national blood supply contingency plan are available at https://www.blood.gov.au, 37 and the world health organization provides guidance for national blood services on managing blood supplies. 38 community spread of covid-19 has the potential to diminish the donor pool, to threaten the capacity of cancer services to provide routine transfusion support, and to increase the risks that transfusion-dependent patients will come into contact with other individuals with sars-cov-2. this may favour the adoption of more restrictive transfusion practices during the pandemic, especially when health care services experience capacity constraints. restrictive red cell transfusion strategies have been assessed in a variety of settings. although optimal thresholds for outpatient transfusion of patients with haematological malignancies have not been established, 39 and practice varies widely, 40 preliminary data suggest that more restrictive transfusion thresholds require fewer red cells. 41 red cell transfusion thresholds have been reviewed elsewhere, 42 and the most highly restrictive thresholds may be inappropriate in patients with cardiovascular disease. 43 for some patients, iron, folic acid, vitamin b12 or erythropoietin may present alternatives to red cell transfusion and should be considered, to limit transfusion need. due to their short shelf-life, platelets may be impacted by blood supply shortages early. while prophylactic platelet transfusion reduces risk of bleeding following intensive chemotherapy for haematological cancers, an impact on survival has not been demonstrated. 44 international guidelines recommend no prophylactic platelet transfusions for asymptomatic patients with chronic bone marrow failure (including during low dose oral chemotherapy or azacitidine), and to consider no prophylactic platelet transfusions for well patients without bleeding after autologous stem cell transplantation. 45 an ongoing trial is assessing efficacy and safety of prophylactic tranexamic acid during severe thrombocytopenia after intensive chemotherapy. 46 in the event of health care capacity constraints or a threat to the supply of platelets for transfusion, clinicians should consider transfusing only patients at highest risk of bleeding, and consider alternatives to platelet transfusion (such as tranexamic acid), restrictive platelet transfusion criteria and deferral of non-urgent therapies likely to require platelet transfusion support. both autologous and allogeneic hsct, and cellular cancer therapies, such as chimeric antigen receptor t cell therapies, present specific challenges, as they place recipients at high risk of infection, often for an extended period. moreover, if health care services are overwhelmed by demand, there is a risk that recipients will be unable to receive prompt intensive care therapy. regulatory and ethical considerations for modifying or deferring bone marrow transplants and cellular therapies mirror those for non-cellular therapies (see "cancer centre preparation and response" above). team-based discussion, application of the • severe covid-19 disease is possible in any individual, but patients with cancer may be at higher risk due to their disease and/or its treatment. • preventing transmission of infection should be a high priority for patients and carers. review, monitor and closely adhere to recommendations from the department of health (australia) or ministry of health (new zealand) regarding hand hygiene, social distancing and other measures to avoid covid-19. • reiterate smoking cessation advice. • no vaccine for covid-19 is available, but vaccination against influenza (and against other infections if appropriate) and adherence to other recommended measures to reduce infection risk (eg, prophylactic antimicrobials, limiting dusts and soil exposure if prolonged severe neutropenia) may reduce risk of other infections. • provide advice on when, how and where to present for assessment if patients have symptoms suggesting covid-19, or have had recent contact with a person with covid-19; and advise patients not to present unannounced to the cancer centre or clinic. • covid-19 is not the only potential cause of fevers or respiratory symptoms; patients must still follow febrile neutropenia recommendations if applicable, and be alert to other side effects of treatment (including pneumonitis, if applicable). • patients should communicate their cancer diagnosis and any current treatments to clinicians, or to telemedicine advice providers, if under assessment for possible or proven covid-19 or exposure. consider providing patients with a copy of a recent clinic letter to carry. • provide advice on how to contact the cancer centre in case of difficulty obtaining medications as a result of increased demand or supply constraints. • if considering domestic or overseas travel, patients should follow government advice, advise their clinician, and ensure they have sufficient medication for their journey, taking the risk of quarantine into account. • direct patients towards information resources regarding covid-19 specifically for cancer patients and their carers if available. mja 212 (10) ▪ 1 june 2020 principles of equity, transparency and proportionality, and clear documentation of decisions and their reasons, with subsequent review once capacity allows, are recommended. infection with respiratory viruses presents an increased mortality risk for hsct recipients, 47 and transplantation in recipients with active respiratory infections is often delayed where possible. community transmission of sars-cov-2 should be taken into account when considering risks and benefits of transplantation, which are likely to differ on a case-by-case basis. during community sars-cov-2 transmission, transplant recipients should be advised to self-isolate before the procedure. inclusion of sars-cov-2 in pre-transplant infectious disease screening of symptomatic recipients should be considered if community transmission is present, and some specialist societies are now recommending this for all recipients, 25 with a positive result prompting consideration of deferral. post-transplant care should be guided by the principles outlined in previous sections, with particular attention to the period before immune recovery. among adult hsct recipients, the immunodeficiency scoring index, initially developed for respiratory syncytial virus, might help evaluate the risks of lower respiratory tract disease and of mortality. 48 the immunodeficiency scoring index has been applied to hsct recipients with influenza virus infection, 49 but is not yet validated for sars-cov-2 infection. consideration should be given to early vaccination for respiratory pathogens (seasonal influenza and streptococcus pneumoniae). most unrelated donor stem cell products in australasia come from international donors. 50 the complex logistics of international stem cell donation are vulnerable to disruption by the covid-19 pandemic, which could affect donor availability, donor site staffing, border restrictions, international flight changes, courier availability, and specialist laboratory staffing. donor cancellation may occur at short notice between donor assessment and stem cell harvest, presenting a risk that recipients lack a stem cell product after myelosuppressive conditioning. contingency planning could include securing back-up donors if possible, or collection, transportation, cryopreservation and storage of stem cell products at the transplant unit before commencing recipient conditioning. it is unclear whether sars-cov-2 is transmissible by cellular therapy products. viral rna can be detected in plasma of covid-19 patients, but the presence of infectious virus has not been reported. 36 at present, no recommendation can be made for donor sars-cov-2 testing, owing to variable availability of polymerase chain reaction testing at donor collection centres and the lack of a serologic assay, but donor testing may be adopted in the future. donors in all regions should be assessed for risk based on current knowledge of local covid-19 prevalence, travel history, exposures and symptoms. position statements have been provided by a number of transplant organisations including the world marrow donor association. 51 donor registries and bone marrow transplant and cellular therapy societies have produced guidelines and position statements, 25, [51] [52] [53] which are frequently updated. the impact of covid-19 on international transport may also affect the supply chain for autologous chimeric antigen receptor t cells. as for stem cell recipients, patients awaiting chimeric antigen receptor t cell therapies should consider self-isolation to minimise the risk of sars-cov-2 exposure during the period of greatest vulnerability. provision of radiation therapy should be guided by the principles outlined above in "cancer centre preparation and response". the lead time between radiotherapy planning and treatment may be days to weeks, while cessation of radiation therapy partway through a treatment course may compromise outcomes. radiation oncology services should attempt to anticipate staffing and other capacity constraints, which will be difficult in a rapidly changing situation. consider use of shorter fractionation schedules where this is an option, 54 deferral of therapy, or omission of radiotherapy if the clinical benefit is low and the risk is high. radiation oncology services should screen patients for symptoms suggestive of covid-19, and adopt infection control measures. for some centres, this may include consideration of dedicating a linear accelerator for those with suspected or confirmed covid-19. 54, 55 the ich guideline (paragraph 2.3) states that the "rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society". 56 at phases b and c (see "cancer centre preparation and response" above and box 1), it may be necessary to reduce routine follow-up appointments, institute remote or telehealth reviews, or modify treatment plans and strategies for treatment delivery in the interests of the study participant. if this will lead to protocol deviations or violations, clinicians should contact the medical monitor or sponsor of their study, and contact the relevant human ethics committee. international travel restrictions could affect trial monitoring, start-up and investigator meetings, and distribution of investigational products and laboratory samples. when enrolling new participants, principal investigators should take reasonable steps to ensure that a trial is proceeding as usual, and consider the potential impact of covid-19 on the capacity of their own centre to conduct study procedures according to the trial protocol. consideration should be given to suspending accrual of new patients to ongoing trials and delaying opening of new trials based on availability of local resources. palliative care will play a critical role during the covid-19 pandemic, and will be a responsibility for all health care professionals. 57 cancer services should collaborate with specialist palliative care services when developing covid-19 contingency plans. palliative care will involve managing symptoms of cancers and covid-19 at all stages, including at the end of life. other roles include rapid reassessment of an individual patient's goals if treatment plans are changed, helping patients and families navigate end-of-life care decisions during a period of societal and economic disruption, supporting care in the community to avoid unnecessary hospitalisations, and delivering care in a culturally safe and responsive manner. 26, 27 at the same time as raising demand, covid-19 presents a threat to palliative care service staffing and capacity. palliative care delivery will frequently need to be undertaken by primary treating teams, under guidance of specialist palliative care services. throughout the pandemic, clinicians should proactively discuss goals of care with patients with advanced cancers, and clearly document enduring powers of attorney or advance care plans. visitor restrictions on wards, quarantine or isolation requirements, and travel restrictions or social distancing measures are likely to complicate the planning and delivery of palliative care and compete with cultural rituals and norms for end-of-life care and death. increased use of telephone or video consultation will become necessary. issues of trust, isolation, disconnectedness and worries about abandonment should be proactively addressed. 58 in particular, the impact of restriction or banning of hospital visitors on the presence of family and friends at life's end needs to be addressed with compassion and humanity. at all stages of the covid-19 pandemic, for all patients, clinicians should strive to follow the principle of non-abandonment. the covid-19 pandemic presents a challenge of global reach and significance which is unprecedented in the era of modern haematology and oncology. we present interim guidance for clinicians caring for patients with cancer who may be particularly vulnerable both to severe covid-19 and the potential impact of the pandemic on the provision of cancer investigations and treatment. this is a rapidly evolving situation, and we emphasise again that clinicians must regularly review and implement institutional, local, state and national policies, modifying or adapting the suggestions provided here as needed. finally, given the potential severe impact of covid-19 on people with cancer, we propose that oncologists and haematologists advocate for the timely application of public health measures, vaccines or treatments that might contain, delay or mitigate the 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trial (trial to evaluate tranexamic acid therapy in thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with rsv infections outcomes of influenza infections in hematopoietic cell transplant recipients: application of an immunodeficiency scoring index australasian bone marrow transplant recipient registry covid-19 -impact on registry operations national bone marrow donor program. response to covid-19 the impact of covid-19 on the provision of donor hematopoietic stem cell products worldwide: collateral damage covid-19: global radiation oncology's targeted response for pandemic preparedness hiding in the bunker: challenges for a radiation oncology department operating in the severe acute respiratory syndrome outbreak therapeutic goods administration. ich guideline for good clinical practice. canberra: tga educational fellows in care at the end of life. palliating a pandemic: "all patients must be cared for the challenge of providing holistic care in a viral epidemic: opportunities for palliative care we acknowledge the endorsing organisations, and the following manuscript reviewers: leanne berkahn, theresa cole, megan crane, nada hamad, eliza hawkes, mark hertzberg, marie malica, nick pavlakis, david ross, rachel wiseman and leeroy williams. we also thank the australasian leukaemia and lymphoma group consumer representative panel for its input. key: cord-293174-4ucqudn4 authors: sun, ziheng; di, liping; sprigg, william; tong, daniel; casal, mariana title: community venue exposure risk estimator for the covid-19 pandemic date: 2020-09-29 journal: health place doi: 10.1016/j.healthplace.2020.102450 sha: doc_id: 293174 cord_uid: 4ucqudn4 complexities of virus genotypes and the stochastic contacts in human society create a big challenge for estimating the potential risks of exposure to a widely spreading virus such as covid-19. to increase public awareness of exposure risks in daily activities, we propose a birthday-paradox-based probability model to implement in a web-based system, named cosre (community social risk estimator) and make in-time community exposure risk estimation during the ongoing covid-19 pandemic. we define exposure risk to mean the probability of people meeting potential cases in public places such as grocery stores, gyms, libraries, restaurants, coffee shops, offices, etc. our model has three inputs: the real-time number of active and asymptomatic cases, the population in local communities, and the customer counts in the room. with cosre, possible impacts of the pandemic can be explored through spatiotemporal analysis, e.g., a variable number of people may be projected into public places through time to assess changes of risk as the pandemic unfolds. the system has potential to advance understanding of the true exposure risks in various communities. it introduces an objective element to plan, prepare and respond during a pandemic. spatial analysis tools are used to draw county-level exposure risks of the united states from april 1 to july 15, 2020. the correlation experiment with the new cases in the next two weeks shows that the risk estimation model offers promise in assisting people to be more precise about their personal safety and control of daily routine and social interaction. it can inform business and municipal covid-19 policy to accelerate recovery. history repeats from pandemic to pandemic (ghendon, 1994) . reducing the impact of pandemics 25 relies on early detection and mitigation strategies that slow the spread to allow more preparation and 26 reduce impacts on patient care. however, as the covid-19 pandemic continues to spread, the burden 27 weighs heavy on all of us to control further spread and consequences through social distancing. lifestyles 28 leading up to this pandemic are capable of spreading disease further and faster than ever before. new and 29 more intense factors amplify disease transmission (dashraath et al., 2020) . the risks apply reasonably 30 well to nearly all densely populated areas. environmental changes such as disruptive climate, may also 31 contribute (ogen, 2020) . as coronavirus is monitored across the u.s., some communities see a 32 diminishing number of cases, while others have yet to see the peak. reporting errors and delays also play 33 a role in changes in disease incidence. an objective, publicly-accessible means to estimate risk of 34 infection is needed in order to cope safely with the consequences of social distancing and sequestration. 35 although various self-quarantine and self-isolation policies are in place in most of the u.s., the virus is 36 not universally contained. people need to visit grocery stores, pharmacies and hospitals. they wish to 37 attend sport, recreation and entertainment events, and community activities and family gatherings. 38 considering the peak in coronavirus cases might have passed, some states have started to reopen business 39 to restore the economy. risk assessment tools are essential in order to assist reopening with key 40 information, as to where and when it may be safest to return to places of need or interest. 41 reopening is a very daunting challenge for many businesses in the united states this year 42 (workplaces, 2020). the duration of the pandemic is uncertain and its influence could last for a long 43 time. the current guidelines for reopening are very general and not very customizable to accommodate 44 the real scenarios of life in different communities. communities differ in population, store types, average 45 visit time, patients, air quality, etc. there is no one-size-for-all solution to cope. a safer plan should be 46 able to flexibly fit each circumstance by considering specific factors like the locally confirmed cases, 47 potential asymptomatic patients, store space, layout, people density, local population composition, 48 commodities, age distribution, capacity limit, social distancing, temperature check, violation enforcement, 49 etc. however, precise recommendations are rarely available for business managers to use. very few 50 quantitative models can estimate the impact of varying these factors. thus, few individual businesses can 51 tailor their reopening policies to make smarter decisions in balancing life, safety, and economy. 52 to find a balancing point between a full lockdown in fear of the virus and a plan of reopening 54 businesses out of socioeconomic concerns, a mechanism to help assist that decision is urgent. the 55 decision-makers to be supported include municipal policymakers, business managers and customers. the 56 mechanism, or system, should provide a customized, real-time risk estimation for store managers, who 57 may then adapt their operations to the unpredictable pandemic. an estimation of risk will also give 58 potential customers the information necessary to assess their own risks of visiting businesses or other 59 venues in an area, with increased awareness and confidence about their decision. 60 to achieve that goal, this project proposes a straightforward social probability model based on the 61 birthday paradox theory (if n people are selected at random, what is the probability that at least r people 62 will have the same birthday?) (mckinney, 1966; wagner, 2002) to estimate the venue risk of people 63 meeting at least one covid case, either asymptomatic, pre-symptomatic or actively symptomatic, in 64 various public venues such as shopping centers, grocery stores, gyms, recreational areas, restaurants, 65 dmvs (departments of motor vehicles), and federal agency public field offices. a prototype web-based 66 system named cosre (community social risk estimator) (sun, 2020a) is implemented to take zip codes 67 as inputs and output a percentage value indicating the probability of acquiring the virus in the community. risk is calculated based on real-time data collected from public resources. the purpose of the tool is to 69 give people a reasonable quantitative estimate of their risks of exposure to the covid-19 virus in their 70 communities. 71 pandemics are large scale outbreaks of infectious diseases that can increase mortality significantly 73 over great geographic area and cause significant economic, social and political disruption (madhav et al., 74 2017). extensive global travels and long-distance contacts in human society raise the likelihood of 75 pandemics. one recent example, the 2003 severe acute respiratory syndrome (sars) pandemic, was a 76 critical threat to public health (ksiazek et al., 2003) . the world health organization compels member 77 states to meet specific standards to detect, report on, and respond to infectious disease outbreaks. this 78 international framework contributed to a more coordinated global response during the 2009 influenza 79 pandemic than in the previous 2003 event (katz, 2009 ). global public health departments look to improve 80 pandemic preparedness through refined standards and responding plans to flatten the time-incidence 81 curves and reduce the deaths. management of community risks in a pandemic needs to apply more 82 restrictive emergency management strategies than other hazards. the objectives of risk management are 83 to strengthen our responding capacities to contain the diseases, enable and promote linkage and 84 integration across the governments and societies. accurate estimation of risks is the first and fundamental 85 step in making an effective risk management plan. common responding practices are to limit the point of 86 entry to reduce the possibility of virus traveling. people, communities, states, and countries should 87 continue to communicate with information and advice. precise information provided early and often will 88 enable the community to correctly understand the health risks they face, and will make it easier to engage 89 in actions to protect themselves. (who, 2018) 90 the sars-cov-2 virus was first isolated from a patient with a pneumonia of unknown origin in 91 wuhan, china. genetic analysis revealed that it is closely related to sars-cov-1 and genetically clusters 92 within the genus betacoronavirus, subgenus sarbecovirus (cont, 2020) . although pathology studies have 93 been done for the covid-19 disease, as an ongoing pandemic few tools are available to evaluate the real-94 time social exposure risks. an accepted classification groups risk assessment into several levels: little, 95 lower, medium, high, very high, and severe. nicholas et al proposed a conceptual full-risk-spectrum, 96 comprehensive pandemic risk management system (cprms) to prevent, prepare for, respond to, and 97 mitigate the multisector impacts of severe pandemics (studzinski, 2020) . it contains six institutional 98 building blocks in the global domain: governance and leadership, sustainable financing, information and 99 knowledge systems, human capital resources, essential commodities and logistics, and operational service 100 delivery. but the detailed framework still needs refinement in order to implement in each geographical 101 area (studzinski, 2020) . in the covid-19 pandemic, there is still a long way to go to implement such a 102 framework. 103 the us centers for disease control and prevention (cdc) has developed an online tool called 104 influenza risk assessment tool (irat) to assess the potential pandemic risk posed by influenza a 105 viruses (cox et al., 2014) . the irat uses 10 scientific criteria to measure the potential pandemic risk 106 associated with each of the life scenarios mentioned previously. these 10 criteria can be grouped into 107 three overarching categories: "properties of the virus", "attributes of the population", and "ecology & 108 epidemiology of the virus". a composite score for each virus is calculated based on the given scenario. 109 the score gives the means to rank and compare influenza viruses to each other in terms of their potential 110 pandemic risks. it is an evaluation tool, not a predictive tool (cdc, 2020 cromley discussed how to use gis technology and related technologies to analyze the geography of 130 disease, the relationships between pathological factors and their environments (cromley, 2003) . to 131 develop a predictive risk mapping of leptospirosis, an environmentally-driven infectious disease using 132 j o u r n a l p r e -p r o o f spatial bayesian network was proposed (mayfield et al., 2018) . in a risk model developed for rift valley 133 fever, exposure was measured as the proportion of total outbreak years for each district in prior 134 epizootics, whereas the district's risk of outcome was assessed as severity of observed disease in humans 135 and animals ( extended hierarchical spatial models to create spatio-temporal maps of disease rates (waller et al., 1997) . the methods of assessing and mapping the potential economic and public health risks associated with 140 avian influenza outbreaks have been discussed (dudley, 2008) . olaf berke proposed an exploratory 141 approach to map spatial relative risk using the background risk in the unexposed population. the results 142 can reveal the importance and geographical distribution of unknown spatial risk factors (berke, 2005) . 143 another paper offered a critical review of the methods of disease mapping and spatial regression based on 144 male lip cancer incidence data in scotland (wakefield, 2007) . however, these existing models require 145 input data that are unavailable or require contact tracing, or the targeted risks are not venue-based 146 exposure risks. these researches have inspired and influenced our work, which proposes a new index to 147 measure the community venue risks in covid-19 pandemic, but without contact tracing data. 148 the idea of calculating birthday paradox probability (flajolet et al., 1992 ) is reused here. the 157 probability distribution is similar to the binomial distribution (altham, 1978) . the basic formula is: 158 where is the probability function of meeting someone with active disease; is the total community 159 population (town, village, city, county, region, country); and is the total number of potential 160 covid-19 cases in the area on day i and day i-d (defined as all accumulated covid hosts in the 161 community at the given time, to include asymptomatic, symptomatic, hospitalized and self-quarantined; d 162 is the average number of days that the disease takes for people to recover or die (~30 days for covid-19); 163 people who have recovered from the virus are assumed unable to infect others and are not counted in 164 potential cases); is the number of the people in the business venue, e.g. grocery stores, shopping centers, 165 gyms, restaurants, workplaces and recreational areas (sun, 2020b) . 166 first, we calculate the odds of not meeting any infected person and subtract those odds from 1 to 167 get the probability of meeting at least one infected patient in that specific group of people. 168 this model assumes that all the people in the population visit a store with equal chance. if the 169 chance is not equal for everyone, the values of and should be changed to represent their varying 170 probabilities. for example, the population of fairfax county, va is over one million (census, 2010 ). the calculations for the maps in may differ from those for the april maps, a change based on physician 176 discovery that most confirmed covid-19 cases will either recover or die within a 30-day window. the d 177 for covid-19 is set to be 30 days. for the may calculation, patient numbers for the same day in april 178 (one month ago) are removed because they are no longer susceptible. as may has 31 days and april only 179 has 30 days, we use april 30 data in the calculation of may 31. 180 this risk estimation model can help people to evaluate risk and react accordingly instead of panicking 182 or just being indifferent towards the virus. the formula takes three parameters as inputs and the output is 183 the probability of meeting at least one infected person in the store. the result ranges from 0 to 1. the risk 184 can be generally interpreted as the probability of exposure to another covid-infected person. besides, 185 for policy making, it may be useful to classify the probabilities into several levels. for example: the risk 186 less than 25% may be considered relatively low, 25-50% means the probability is medium, 50-75% 187 reflect the place has a high probability for meeting a sars-cov-2 carrier, >75% means the risk is very 188 high and people might think twice before taking actions. this is just an example and the classification 189 should be validated with real exposure data collected in businesses and public areas. based on the 190 correlation analysis results, policymakers and community members will have a better understanding of 191 the risk when going outside in the community and may take corresponding actions to avoid being exposed 192 in their specific county. 193 to evaluate the proposed risk score, we use several correlation methods to analyze its relationships 195 with new case data for the next two weeks. for non-spatial correlation analysis, spearman's correlation 196 coefficient (spearman's ρ) (spearman, 1961) , a statistical measure of the strength of a monotonic 197 relationship between two variables, is utilized. its interpretation is similar to pearson's r (pearson, 1895) 198 and can be used for analyzing non-linear relationships.. in addition, spatial autocorrelation analysis is 199 used to study the relationship between risk estimates in one county and those in neighboring counties. if 200 there is a significant correlation, a cluster will be generated to identify the hot spot regions (oster, 2020) . 201 moran's i is the most common indicator for spatial correlation estimation. moran's i ranges from -1 to 1. using the proposed algorithm, we calculated the risks for all counties of the contiguous united states 211 and generated a series of maps since apr 1, 2020. fig. 1 shows six of the maps on the dates of april 1, 212 april 15, may 1, may 15, july 1, july 15 2020, from which the trends of social exposure risks in the 213 pandemic can be observed. the maps for june are similar to those for may and are omitted for brevity. 214 the map of april 1 (fig. 1a) shows that new york city, albany ga, new orleans, denver, salt 215 lake city, and sun valley in idaho became the centers with highest exposure risks. on the contrary, the 216 two states, california and washington, where the very first covid-19 patients were found, have 217 relatively low risk. overall, the epidemic centers had emerged by april 1 and began to spread among 218 neighboring counties. at that time, from abundant news media accounts, most states had instituted social 219 distancing and stay-at-home orders. these orders required people to stay at least 6 feet apart and avoid 220 gathering in groups. most mass gatherings were canceled following cdc guidelines. however, somee 221 virus-affected people started to show symptoms and confirmed cases were reportedfrom coast to coast. as 222 fig. 1(a) displays, almost every county showed social risk, but risks were low compared to succeeding 223 months, with the exception of several states that exhibited outbreaks. on april 1st, risks were highest in 224 the metropolitan areas of new york city, new orleans, and denver, and in blaine county, idaho, and 225 summit county, utah. a potential outbreak could be foreseen from these areas as the time-incidence 226 curves began to rise. 227 the april 15 map (fig. 1b) it is important to note at this point that state-to-state and region-to-region comparisons of critical 235 parameters, such as confirmed cases or population-patient ratios, depend on consistency and calibration of 236 methods, tools, training and, in some cases, infrastructure. with such inter-comparability, the information 237 content of the raw data and model output increases in important ways, e.g., nation-wide priority allocation 238 of medical resources and emergency assistance. covid-19 cases make a very high case to population ratio. unlike metropolitan areas, navajo county has 243 fewer stores and public places, which would make it even risker if businesses reopen and people gather. 244 also, in mid-april, the detroit and chicago metropolitan areas show signs of spreadingincidence. other 245 regional differences appear. for example, risks of contagion in washington and california remain 246 relatively low compared to outbreak centers in the u.s. south and east. florida shows a pattern of 247 relatively high risk around miami and less risk elsewhere. 248 the map of may 1 (fig. 1c) shows that new york, pennsylvania, new jersey, and massachusetts are 249 at high exposure risk in their coastal counties. new york city and its associated counties are the areas of 250 highest risk. for these counties, the risk map highlights the importance of following health guidelines to 251 wear masks and maintain social distancing in public places. . 252 other east coast states, including maryland, virginia, washington d.c., north carolina, south 253 carolina all turn darker red. inland regions, such as western pennsylvania, west virginia, western 254 virginia, western north carolina, eastern tennessee, show relatively lower exposure risks. on may 1 255 (fig. 1c) , the populous counties in the midwestern states like iowa, nebraska, ohio, indiana, kentucky, 256 minnesota, have turned dark red. but there is less outward spread than in highly urbanized areas like new 257 york. the risks are restricted in certain counties and show no obvious signs of a state-wide outbreak. those red counties are scattered and isolated. one explanation is that the other less populous counties 259 intentionally reduced their contacts with the populous counties. the connections among different counties 260 in these regions are not as close as those in the east coast counties. the risk in washington, california, 261 nevada, texas, and florida, is rising slowly and remains lower than in the other outbreak states. 262 according to the map of may 15 (fig. 1d) , the riskiest areas are still along the east coast, however 263 with a sign that risks may be on the decline in some suburban counties in new york, pennsylvania and, 264 further south. in georgia, counties surrounding columbus county saw less risk, suggesting the new case 265 load may have peaked. new york appears to show a downward trend in new confirmed covid-19 cases. 266 high-risk areas on july 1 (fig. 1e) and july 15 (fig. 1f) include, high-populated counties in the 267 mississippi basin and the corn belt states, which have become darker, and western counties in oklahoma 268 and kansas show that coronavirus has spread further (fig. 1e) . also, risk across georgia, florida, texas, 269 and louisiana has turned more serious, as has risk in southern california which has become higher after missouri. none show downward trend of covid-19 case incidences. however, in many of these states, 277 stay-at-home rules were slackened in order to "reopen" and spur the economy. health experts warn that 278 without data and without proper assessment, decisions to reopen will likely result in a spike of 279 coronavirus cases. yet, the success of any reopening will depend on decisions made by each and every 280 citizen. our research helps inform everyone's individual, smart choices during reopening. to evaluate the reliability of the cosre risk score, we validate its accuracy by comparing the risk 297 score for a county with the number of new covid-19 cases confirmed in the following two weeks. a 298 two-week interval was used because symptomatic patients are normally detected within two weeks of 299 infection. fig. 2 shows the spearman correlation analysis results. in fig. 2 , the x axis is the cosre risk 300 score at time t, the y axis is new cases per thousand people in the next two weeks after t. each spot in the 301 plot represents a county. spearman's correlation coefficient is consistently above 0.6, which falls in the 302 "strong" category 1 . that means a large cosre score is strongly correlated to more new cases in two 303 weeks, and a small cosre score is strongly correlated to fewer new cases in two weeks. chances of 304 coincidence are diminished because all the time steps have the similar correlation. the results show that 305 the cosre risk scores well represent future exposure risks. specifically, the april results show that risks 306 for most counties are below 30% while the new cases per thousand in two weeks are less than 5. on april 307 1 the confirmed numbers surpass exposure risks in many counties (many dots are above the diagonal line). 308 this is probably caused by insufficient testing in the early stage and the risk is underestimated. in may, 309 the increase of risk scores doesn't correspond to obvious increase in new cases. the new cases per 310 thousand for most counties remain under 5. one reason is that people became concerned and most states 311 have stay-at-home orders in place. so even though the confirmed cases are climbing, the number of 312 people with confirmed cases in public places are actually much lower than expected, resulting in low 313 numbers of infections. things changed in july. stay-at-home orders in most states expired, and people 314 gradually returned to normal life routines.. the spearman's r values are higher in july than in may, 315 meaning that the increased new cases are more positively correlated to cosre risk score. in summary, 316 the spearman correlation results indicate that cosre risk has a strong positive correlation with the new 317 cases in the next two weeks, which suggests that the risk scores reflect real exposure risk when the 318 quarantine orders relax or expire and people start to go back to normal life. 319 figure 2 . correlation between cosre risk score and the new confirmed cases in the following two weeks 321 (14 days); spearman's correlation coefficients are added in the tiles, the x axis is cosre risk score, the y 322 axis is the new case per thousand people in the following two weeks. 323 (1) spatial autocorrelation and moran's i 325 we calculated the global univariate moran's i of all the semi-month cosre risk maps from april to 326 july. as shown in fig. 3 means that for each county the restriction on in-person activities in public places in late april, may and 342 june works to reduce risk. however, after entering july the correlation began to show significance 343 between two continuous time steps; the county with high confirmed cases will very likely have a similar 344 amount of confirmed cases at the next checkpoint. overall, correlation of the risk scores of two 345 continuous time steps is positive and will have higher significance when venue activities increase. 346 347 figure 3 . the trends of global univariate moran's i and bivariate moran's i 348 cluster maps based on local univariate moran's i between one county's cosre score and its 349 neighbor counties are also generated to extract those counties that share the same pattern of case spikes or 350 lower cases (as shown in fig. 4) . a p-value less than 0.05 (typically ≤ 0.05) is normally considered to be 351 statistically significant. we use 0.05 as p-value threshold to extract the significantly correlated counties; 352 they are plotted in fig 4. all the colored counties have a p-value smaller than 0.05, which means 353 significant correlation between the cosre score of the county and its spatial lags. the high-high hotspot 354 regions agree well with our observations in section 4.1. the new york, new orleans, detroit, denver 355 and seattle metropolitan areas and neighboring counties are the major hotspot clusters in april. in may, 356 the chicago metropolitan area joined the list while seattle and detroit drop off, along with many major 357 cities in the midwest states. the navajo nation became a hotspot and persists since then. in july, the new 358 york and the other northeastern states turn blue after consistent low risks are observed. values less than 0.05 are considered as significantly correlated regions, and colored in fig. 5 . the results 382 show that cosre risk scores can actually reveal those hotspot counties on april 1, like those in new 383 york, louisiana, and detroit; case increases in the next two weeks agree very well with model estimates 384 in those regions. in all cluster maps, those hotspot regions are very consistent with the high-high regions 385 identified in fig. 4 , which means that the correlation between cosre risks and the new cases in the 386 following weeks is significantly positive, especially in those hotspot regions and when little venue 387 activity restrictions are in place. overall, our cosre risk shows reliable performance, with stable risk 388 scores that indicate true exposure risks, from the early stage to the reopening stage. it should be clarified that exposure risk is not equal to the actual transmission risk. the community 395 risk of exposure is an important contributing factor to the risk of transmission. the relationship is 396 delineated using the following generalized equation: 397 where "# ! $ " is the exposure risk in community daily activities, &! & is the infection risk. the two risks come from two steps. the former risk estimates the possibility of people coming in contact 399 with virus hosts and sources. for example, people who stay home are at lower risk of exposure than 400 people who go to the grocery store. the latter risk estimates the possibility of being infected by the virus 401 after contact with a source. if people wear mouth and nose masks, safety glasses and disposable gloves 402 and footwear, their contracting risk will be much lower than for people who wear no protections. ' $ ( represents the ability of the person or the community to be immune to the virus. people with 404 antibodies could be immune to certain types of viruses and their immunity is higher. the transmission 405 risk is inversely proportional to the immunity of the person or the entire community. 406 the work reported herein gives a customized quantitative estimation on the social exposure risks of 408 people who show up in public places. the results are tailored for every community by considering local 409 at-risk population, store numbers, potential guest flow. the purpose is to help people increase awareness 410 of their risks and help u.s. businesses adjust their store policies. following this guidance should 411 accelerate the reopening of business while maintaining a low risk of virus contact for the wellbeing of 412 both employees and customers. successful application of tools from this project will give both customer 413 and business a clearer understanding of the risk of opening up and going to a place of business or 414 recreation venue. decisions can be made on the fly. the correlation evaluation has demonstrated that the 415 cosre risk score has a strong positive correlation with new cases for the following two-week period. 416 the rate of new cases is basically determined by regional transmission risks in which the venue exposure 417 risk is a preconditional factor. the positive correlation can be used as evidence to validate the accuracy 418 and effectiveness of the cosre risk score. we would expect the score will serve as a simple, stable and 419 reliable indicator to measure current risk and estimating new cases for the next two-week period. 420 a reliable model designed for real-world application must consider many factors. more refinement is 422 needed to improve accuracy of the three input parameters. for example, the model assumes that the 423 confirmed patients comprise all the existing patients and all are free to move about the community; in 424 reality, this is not entirely true. as an improvement, r 0 should be used to calculate new potential covid 425 patient numbers, as close to the real situation as possible. as official virus tests become more available, 426 the ability to monitor and predict community-level risks amid a pandemic will improve. for the 427 population, the model assumes that everyone in the population has the same chance of showing up in one 428 store, which is also not true. individual preferences exist for which grocery store, shopping center, coffee 429 shop or library to frequent. to make the model more realistic, one can obtain store visiting data from 430 safegraph (safegraph, 2020), which allows analysis of the age, gender, and other characteristics of a 431 store's customers. from this, a more accurate customer pool is possible based on the regional population 432 census. one may also remove people from the customer pool who will not show up from the population 433 used for calculation, as when data to populate the april and may maps of figure 1 were adjusted to 434 accommodate finding of physicians. further improvement will come by adjusting the real-time store 435 visitation based on popular hours, business density, county income level and real-time customer counts. 436 also, real-world exposure data are scarce. apple and google are among the exceptions with more 437 accurate and more extensive data, where smartphone bluetooth has been used to trace potential 438 coronavirus patients. based on patient tracing data such as this, the real probability of a venue with 439 covid patients present could be compared with the estimated risks derived from our formula. since the 440 pandemic is still ongoing, such a dataset is relatively sensitive and hard to retrieve at present. model 441 evaluation with real-world data is our next step of work. 442 public awareness of virus exposure risks is important. individual decisions will be made during a 444 pandemic as people decide to leave home sanctuaries and reengage in social activities. to inform and 445 assist, we propose a birthday-paradox-based probability model, coupled with a publicly-accessible web-446 based system to calculate community exposure risks in public gatherings. model derived risks are 447 generated based on the real-time potential covid-19 cases, the population in local communities, and the 448 number of people number in a given venue. with this web-accessed system, people may explore effects of 449 the pandemic through a geographical spatiotemporal view, moving through time, and testing different 450 venues and the expected numbers of people in them in order to assess changes in risk as the pandemic 451 unfolds. the system integrates the risk estimation model, computational tools, and the analysis of 452 evolutionary pathways, together with refinements to virus surveillance and to research-based, new 453 understanding of this novel virus. the model and system proposed is an improvement in assessing risks posed by the sars-cov-2 455 virus and other virus outbreaks, epidemics or pandemics. we are subsequently better equipped to prepare 456 and respond to the ongoing pandemic and to all future vector borne diseases. yet, caveat and caution are 457 advised. the application scenarios of the system are made to be set in the middle of an outbreak or pandemic, 459 after testing and tracking of patients are in place. today, without extensive and comparable national 460 testing, the estimated risks might be far from reality. an important objective of our study is to show what 461 can be accomplished with extensive testing and tracking, where methods, materials and objectives are 462 comparable-where apples are compared with apples, without regard to state or region. valuable 463 information can be drawn from the current web-based system. complex interactions among factors and 464 inaccuracy of any or all of the input parameters will distort model from reality. we will continue to work 465 to limit these distortions, improve accuracy and reliability through peer and crowd-sourced review. 466 467 the authors would like to thank the anonymous reviewers, professor dieter pfoser, professor andreas 470 zufle, and professor pat gillevet from george mason university, nasa project (17-haq17-0044) team 471 members, the mit datathon team for their valuable advice. thanks for the covid-19 dataset provided 472 by john hopkins university, the population data from u.s. census, and the foot traffic data kindly 473 provided by safegraph inc. thanks to all the developers of the python libraries and tools used in this 474 work. 475 476 two generalizations of the binomial distribution geoda: an introduction to spatial data analysis, handbook of 481 applied spatial analysis exploratory spatial relative risk mapping spatial relative risk mapping of pseudorabies-seropositive pig herds 484 in an animal-dense region 486 assessing real-time zika risk in the united states cdc, 2020. 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emerging infectious diseases 15 a novel coronavirus associated with severe acute respiratory syndrome pandemics: 518 risks, impacts, and mitigation, disease control priorities: improving health and reducing poverty predictive risk mapping of an environmentally-driven infectious disease using spatial bayesian 522 networks: a case study of leptospirosis in fiji generalized birthday problem notes on continuous stochastic phenomena predictive factors and risk mapping for rift valley fever 527 epidemics in kenya assessing nitrogen dioxide (no2) levels as a contributing factor to the coronavirus 529 (covid-19) fatality rate trends in number and distribution of covid-19 hotspot counties-united states notes on regression and inheritance in the case of two parents proceedings of the 533 pyshp: this library reads and writes esri shapefiles in pure python safegraph places patterns data the proof and measurement of association between two things comprehensive pandemic risk management: a systems approach. london: 539 visiting international research fellow policy institute, king's college; 2020 cosre: covid-19 community social risk estimator what is the chance of meeting a covid-19 infected person in grocery stores estimation of the percentages of asymptomatic patients 545 and undiagnosed patients of the novel coronavirus (sars-cov-2) infection in hokkaido, japan by using 546 birth-death process with recursive full tracing a generalized birthday problem disease mapping and spatial regression with count data hierarchical spatio-temporal mapping of disease the authors would like to thank the anonymous reviewers, professor dieter pfoser, professor andreas zufle, and professor pat gillevet from george mason university, nasa project (17-haq17-0044) team members, the mit datathon team for their valuable advice. thanks for the covid-19 dataset provided by john hopkins university, the population data from u.s. census, and the foot traffic data kindly provided by safegraph inc. thanks to all the developers of the python libraries and tools used in this work. j o u r n a l p r e -p r o o f highlights:• a birthday-paradox-based probability model is proposed for estimating the community exposure risks in pandemics.• a web-based system named cosre is implemented to calculate the daily risks of each u.s. county in the ongoing covid-19 pandemic.• the model successfully reflected the early sign of outbreaks in covid-19 serious counties, including the navajo nation, new york, georgia, and louisiana.• the spatial correlation analysis shows the proposed risk score has significant positive relationship with the new cases in the next two weeks.j o u r n a l p r e -p r o o f key: cord-280642-cvxni7cd authors: the opensafely collaborative,; williamson, e.; walker, a. j.; bhaskaran, k. j.; bacon, s.; bates, c.; morton, c. e.; curtis, h. j.; mehrkar, a.; evans, d.; inglesby, p.; cockburn, j.; mcdonald, h. i.; mackenna, b.; tomlinson, l.; douglas, i. j.; rentsch, c. t.; mathur, r.; wong, a.; grieve, r.; harrison, d.; forbes, h.; schultze, a.; croker, r. t.; parry, j.; hester, f.; harper, s.; perera, r.; evans, s.; smeeth, l.; goldacre, b. title: opensafely: factors associated with covid-19-related hospital death in the linked electronic health records of 17 million adult nhs patients. date: 2020-05-07 journal: nan doi: 10.1101/2020.05.06.20092999 sha: doc_id: 280642 cord_uid: cvxni7cd background establishing who is at risk from a novel rapidly arising cause of death, and why, requires a new approach to epidemiological research with very large datasets and timely data. working on behalf of nhs england we therefore set out to deliver a secure and pseudonymised analytics platform inside the data centre of a major primary care electronic health records vendor establishing coverage across detailed primary care records for a substantial proportion of all patients in england. the following results are preliminary. data sources primary care electronic health records managed by the electronic health record vendor tpp, pseudonymously linked to patient-level data from the covid-19 patient notification system (cpns) for death of hospital inpatients with confirmed covid-19, using the new opensafely platform. population 17,425,445 adults. time period 1st feb 2020 to 25th april 2020. primary outcome death in hospital among people with confirmed covid-19. methods cohort study analysed by cox-regression to generate hazard ratios: age and sex adjusted, and multiply adjusted for co-variates selected prospectively on the basis of clinical interest and prior findings. results there were 5683 deaths attributed to covid-19. in summary after full adjustment, death from covid-19 was strongly associated with: being male (hazard ratio 1.99, 95%ci 1.88-2.10); older age and deprivation (both with a strong gradient); uncontrolled diabetes (hr 2.36 95% ci 2.18-2.56); severe asthma (hr 1.25 ci 1.08-1.44); and various other prior medical conditions. compared to people with ethnicity recorded as white, black people were at higher risk of death, with only partial attenuation in hazard ratios from the fully adjusted model (age-sex adjusted hr 2.17 95% ci 1.84-2.57; fully adjusted hr 1.71 95% ci 1.44-2.02); with similar findings for asian people (age-sex adjusted hr 1.95 95% ci 1.73-2.18; fully adjusted hr 1.62 95% ci 1.43-1.82). conclusions we have quantified a range of clinical risk factors for death from covid-19, some of which were not previously well characterised, in the largest cohort study conducted by any country to date. people from asian and black groups are at markedly increased risk of in-hospital death from covid-19, and contrary to some prior speculation this is only partially attributable to pre-existing clinical risk factors or deprivation; further research into the drivers of this association is therefore urgently required. deprivation is also a major risk factor with, again, little of the excess risk explained by co-morbidity or other risk factors. the findings for clinical risk factors are concordant with policies in the uk for protecting those at highest risk. our opensafely platform is rapidly adding further nhs patients' records; we will update and extend these results regularly. keywords covid-19, risk factors, ethnicity, deprivation, death, informatics. results: there were 5683 deaths attributed to covid-19. in summary after full adjustment, death from covid-19 was strongly associated with: being male (hazard ratio 1.99, 95%ci 1.88-2.10); older age and deprivation (both with a strong gradient); uncontrolled diabetes (hr 2.36 95% ci 2.18-2.56); severe asthma (hr 1.25 ci 1.08-1.44); and various other prior medical conditions. compared to people with ethnicity recorded as white, black people were at higher risk of death, with only partial attenuation in hazard ratios from the fully adjusted model (age-sex adjusted hr 2.17 95% ci 1.84-2.57; fully adjusted hr 1.71 95% ci 1.44-2.02); with similar findings for asian people (age-sex adjusted hr 1.95 95% ci 1.73-2.18; fully adjusted hr 1.62 95% ci 1.43-1.82). we have quantified a range of clinical risk factors for death from covid-19, some of which were not previously well characterised, in the largest cohort study conducted by any country to date. people from asian and black groups are at markedly increased risk of in-hospital death from covid-19, and contrary to some prior speculation this is only partially attributable to pre-existing clinical risk factors or deprivation; further research into the drivers of this association is therefore urgently required. deprivation is also a major risk factor with, again, little of the excess risk explained by co-morbidity or other risk factors. the findings for clinical risk factors are concordant with policies in the uk for protecting those at highest risk. our opensafely platform is rapidly adding further nhs patients' records; we will update and extend these results regularly. on march 11th 2020, the world health organisation characterised covid-19 as a pandemic after 118,000 cases and 4,291 deaths were reported in 114 countries. 1 as of 30 april, cases are over 3 million globally, with more than 200,000 deaths attributed to the virus. 2 in the uk, cases have reached 171,253, with 22,791 deaths in hospital. 3 age and gender are well-established risk factors, with over 90% of uk deaths to date being in people aged over 60 years, and 60% of deaths in men, 4 consistent with global patterns. various pre-existing conditions have been reported to correlate with increased risk of poor outcomes. in a re-analysis of a large aggregated case series dataset from the chinese center for disease control and prevention (44, 672 patients, 1,023 deaths), cardiovascular disease, hypertension, diabetes, respiratory disease, and cancers were all associated with increased risk of death. 5 these factors often correlate with age, but correction for age was not possible in the available data. more recently, a large uk cross-sectional survey describing 16,749 patients already hospitalised with covid-19 showed higher risk of death for patients with cardiac, pulmonary and kidney disease, as well as malignancy, dementia and obesity (hazard ratios 1.19-1.39 after age and sex correction). 6 obesity has been reported as a risk factor for treatment escalation in a french itu cohort (n=124) and a new york hospital presentation cohort (n=3615). 7, 8 the risks associated with smoking are disputed: increased risks were initially reported; recent studies suggest that smokers are underrepresented among those with more severe disease; and a potential protective mechanism for nicotine has been suggested. 9 smoking prevalence among hospitalised patients was lower than expected in china (1,099 patients, 12.6% vs 28% in the general population), 10 and in a small french study (139 outpatients and 343 inpatients; standardized incidence ratios 0.197 and 0.246, respectively). 11 people from black and minority ethnic (bme) groups are at increased risk of bad outcomes from covid-19, but explanations for this association are unclear. 12, 13 we therefore set out to determine factors associated with risk of death from covid-19 in england using a very large sample of the adult population, with deaths data linked to longitudinal primary care electronic health records. this is the first iteration, based on the currently available data; further updates and additional outcomes will be released as more data become available through the opensafely.org platform. we conducted a cohort study using national primary care electronic health record data linked to in-hospital covid-19 death data (see data source). the cohort study began on 1st february 2020, chosen as a date several weeks prior to the first reported covid-19 deaths and the day after the second laboratory confirmed case; 14 and ended on 25th april 2020. the cohort explores risk among the general population rather than in a population infected with sars-cov-2. therefore, all patients were included irrespective of their sars-cov-2 test results. we used patient data from general practice (gp) records managed by the gp software provider the phoenix partnership (tpp), linked to covid-19 inpatient hospital death notifications (cpns) from nhse/x, and office for national statistics (ons) death data. cpns provides the most current information on deaths of inpatients . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 7, 2020. . https://doi.org/10.1101/2020.05.06.20092999 doi: medrxiv preprint with laboratory confirmed covid-19 occurring within nhs hospitals; 15, 16 whereas ons includes information on all deaths, including those due to non-covid-19 causes, and was used for censoring. the data were accessed, linked and analysed using opensafely, a new data analytics platform created to address urgent questions relating to the epidemiology and treatment of covid-19 in england. opensafely provides a secure software interface that allows detailed pseudonymised primary care patient records to be analysed in near realtime where they already reside, hosted within the ehr vendor's highly secure data centre, to minimise the re-identification risks when data are transported off-site; other smaller datasets are linked to these data within the same environment using a matching pseudonym derived from the nhs number. more information can be found on https://opensafely.org/. the dataset analysed with opensafely for this paper is based on 24 million currently registered patients (approximately 40% of the english population) from gp surgeries using the tpp systmone electronic health record system. it extends to 20 billion rows of structured data characterising (for example) pseudonymised patients' diagnoses, medications, physiological parameters, and prior investigations. data extracted from tpp systmone have previously been used in medical research, as part of the researchone dataset. 17, 18 study population and observation period our study population consisted of all adults (males and females 18 years and above) currently registered as active patients in a tpp general practice in england on 1st february 2020. to be included in the study, participants were required to have at least 1 year of prior follow-up in the gp practice to ensure that baseline patient characteristics could be adequately captured, and to have a recorded sex and age. 19 patients were observed from the 1st of february 2020 and were followed until the first of either their death date (whether covid-19 related or due to other causes) or the study end date, 25th april 2020. for this analysis, cpns death data were available up to 25th april 2020; ons death data (used for censoring individuals who died without the outcome) were available to 16th april 2020; patient censoring for deaths due to other causes was therefore not possible during the last 9 days of followup (see discussion, weaknesses; a sensitivity analysis is presented with all data censored at 6th april 2020 in appendix table a1 ). the outcome was in-hospital death among people with confirmed covid-19, ascertained from the covid-19 patient notification system (cpns). potential risk factors included: health conditions listed in uk guidance on "higher risk" groups; 20 other common conditions which may cause immunodeficiency inherently or through medication (cancer and common autoimmune conditions); and emerging risk factors for severe outcomes among covid-19 cases (such as raised blood pressure). age, sex, body mass index (bmi; kg/m 2 ), and smoking status were considered as potential risk factors. where categorised, age groups were: 18-<40, 40-<50, 50-<60, 60-<70, 70-<80, 80+ years. bmi was ascertained from weight measurements within the last 10 years, restricted to those taken when the patient was over 16 years old. obesity was grouped using categories derived from the world health organisation classification of bmi: no evidence of obesity <30 kg/m 2 ; obese i 30-34.9; obese ii 35-39.9; obese iii 40+. smoking status was grouped into current, former and never smokers the following comorbidities were also considered potential risk factors: asthma, other chronic respiratory disease, chronic heart disease, diabetes mellitus, chronic liver disease, chronic neurological diseases, common autoimmune diseases (rheumatoid arthritis (ra), systemic lupus erythematosus (sle) or psoriasis), solid organ transplant, asplenia, other immunosuppressive conditions, cancer, evidence of reduced kidney function, and raised blood pressure or a diagnosis of hypertension. disease groupings followed national guidance on risk of influenza infection, 21 therefore "chronic respiratory disease (other than asthma)" included copd, fibrosing lung disease, bronchiectasis or cystic fibrosis; chronic heart disease included chronic heart failure, ischaemic heart disease, and severe valve or congenital heart disease likely to require lifelong follow up. chronic neurological conditions were separated into diseases with a likely cardiovascular aetiology (stroke, tia, dementia) and conditions in which respiratory function may be compromised such as motor neurone disease, myasthenia gravis, multiple sclerosis, parkinson's disease, cerebral palsy, quadriplegia or hemiplegia, malignant primary brain tumour, and progressive cerebellar disease. asplenia included splenectomy or a spleen dysfunction, including sickle cell disease. other immunosuppressive conditions included hiv or a condition inducing permanent immunodeficiency ever diagnosed, or aplastic anaemia or temporary immunodeficiency recorded within the last year. haematological malignancies were considered separately from other cancers to reflect the immunosuppression associated with haematological malignancies and their treatment. kidney function was ascertained from the most recent serum creatinine measurement, where available, converted into estimated glomerular filtration rate (egfr) using the chronic kidney disease epidemiology collaboration (ckd-epi) equation, 22 with impaired kidney function defined as egfr <60 ml/min/1.73m 2 . raised blood pressure (bp) was defined as either a prior coded diagnosis of hypertension or the most recent recording indicating systolic bp ≥140 mmhg or diastolic bp ≥90 mmhg. asthma was grouped by use of oral corticosteroids as an indication of severity. diabetes was grouped according to the most recent hba1c measurement, where a measurement was available within the last 15 months, into controlled (hba1c < 58 mmols/mol) and uncontrolled (hba1c >= 58 mmols/mol). cancer was grouped by time since the first diagnosis (within the last year, 2-<5 years, >5 years). other covariates considered as potential upstream risk factors were deprivation and ethnicity. deprivation was measured by the index of multiple deprivation (imd, in quintiles, with higher values indicating greater deprivation), derived from the patient's postcode at lower super output area level for a high degree of precision. ethnicity was grouped into white, black, asian or asian british, mixed, or other. the sustainability and transformation partnership (stp, an nhs administrative region) of the patient's general practice was included as an additional adjustment for geographical variation in infection rates across the country. information on all covariates were obtained from primary care records by searching tpp systmone records for specific coded data. tpp systmone allows users to work with the snomed-ct clinical terminology, using a gp subset of snomed-ct codes. this subset maps on to the native read version 3 (ctv3) clinical coding system that systmone is built on. medicines are entered or prescribed in a format compliant with the nhs dictionary of medicines and devices (dm+d), 23 a local uk extension library of snomed. code lists for particular underlying conditions and medicines were compiled from a variety of sources. these include bnf codes from openprescribing.net, published codelists for asthma, [24] [25] [26] immunosuppression, [27] [28] [29] psoriasis, 30 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. . https://doi.org/10.1101/2020.05.06.20092999 doi: medrxiv preprint sle, 31 ra 32, 33 and cancer, 34, 35 and read code 2 lists designed specifically to describe groups at increased risk of influenza infection. 36 read code 2 lists were added to with snomed codes and cross-checked against nhs qof registers, then translated into ctv3 with manual curation. decisions on every code list were documented and final lists reviewed by at least two authors. detailed information on compilation and sources for every individual codelist is available at https://codelists.opensafely.org/ and the lists are available for inspection and re-use by the broader research community. 37 statistical analysis patient numbers are depicted in figure 1 . the kaplan-meier failure function by age group and sex are shown in figure 2. for each potential risk factor, a cox proportional hazards model was fitted, with days in study as the timescale, stratified by geographic area (stp), and adjusted for sex and age modelled using restricted cubic splines. violations of the proportional hazards assumption were explored by testing for a zero slope in the scaled schoenfeld residuals. all potential risk factors, including age (again modelled as a spline), sex, bmi, smoking, index of multiple deprivation quintile, and comorbidities listed above were then included in a single multivariable cox proportional hazards model, stratified by stp. hazard ratios from the age/sex adjusted and fully adjusted models are reported with 95% confidence intervals. models were also refitted with age group fitted as a categorical variable in order to obtain hazard ratios by age group. in the primary analysis, those with missing bmi were assumed non-obese and those with missing smoking information were assumed to be nonsmokers on the assumption that both obesity and smoking would be likely to be recorded if present. a sensitivity analysis was run among those with complete bmi and smoking data only. ethnicity was omitted from the main multivariable model due to 26% of individuals having missing data; hazard ratios for ethnicity were therefore obtained from a separate model among individuals with complete ethnicity only. hazard ratios for other risk factors, adjusted for ethnicity, were also obtained from this model and are presented in the sensitivity analyses to allow assessment of the potential for confounding by ethnicity in the primary model. all multivariable models excluded the very small number of patients (<1%) with missing imd. the c-statistic was calculated as a measure of model discrimination. due to computational time, this was estimated by randomly sampling 5000 patients without the outcome and calculating the c-statistic using the random sample and all patients who experienced the outcome, repeating this 10 times and taking the average cstatistic. nhs england is the data controller; tpp is the data processor; and the key researchers on opensafely are acting on behalf of nhs england. this implementation of opensafely is hosted within the tpp environment which is accredited to the iso 27001 information security standard and is nhs ig toolkit compliant; 38,39 patient data has been pseudonymised for analysis and linkage using industry standard cryptographic hashing techniques; all pseudonymised datasets transmitted for linkage onto opensafely are encrypted; access to the platform is via a virtual private network (vpn) connection, restricted to a small group of researchers, their specific machine and ip address; the researchers hold contracts with nhs england and only access the platform to initiate database queries and statistical models; all database activity is logged; only aggregate statistical outputs leave the platform environment following best practice for anonymisation of results such as statistical disclosure control for low cell counts. 40 the . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. to require organisations to process confidential patient information for the purposes of protecting public health, providing healthcare services to the public and monitoring and managing the covid-19 outbreak and incidents of exposure. 41 taken together, these provide the legal bases to link patient datasets on the opensafely platform. this study was approved by the health research authority (rec reference 20/lo/0651) and by the lshtm ethics board (reference 21863). data management was performed using python 3.8 and sql, with analysis carried out using stata 16.1 / python. all code for data management and analysis is archived online at https://github.com/ebmdatalab/opensafel y-risk-factors-research. all clinical and medicines codelists are openly available for inspection and reuse at https://codelists.opensafely.org/. patients were not formally involved in developing this specific study design. we have developed a publicly available website https://opensafely.org/ allowing any patient or member of the public to contact us regarding this study or the broader opensafely project. this feedback will be used to refine and prioritise our opensafely activities. 17,425,445 adults were included (figure 1 ). table 1 shows distributions of demographics and baseline comorbidities. the overall cumulative incidence of covid-19 hospital death at 80 days from the study start date was <0.01% in those aged 18-39 years, rising to 0.35% and 0.17% in men and women respectively aged ≥80 years, with a trend by age ( figure 2 ). associations between patient-level factors and risk of covid-19 hospital death are shown in table 2 and figure 3 . increasing age was strongly associated with risk, with the ≥80 years age group having more than 12-fold increased risk compared with those aged 50-59 years . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. figure a1 ), equivalent to risk increasing exponentially with age. male gender was associated with a doubling of risk (fully adjusted hr 1.99, 1.88-2.10). all non-white ethnic groups had higher risk than those with white ethnicity: hrs adjusted for age and sex only ranged from 1.83-2.17 for black, asian/asian british and mixed ethnicities compared to white; these attenuated to 1.62-1.71 on adjustment for all included risk factors. increasing risks were seen with increasing levels of deprivation, and with increasing levels of obesity (bmi >40 fully adjusted hr 2.27, 95% ci 1.99-2.58). both current and former smoking were associated with higher risk in models adjusted for age and sex only, but in the fully adjusted model there was weak evidence of a slightly lower risk in current smokers (fully adjusted hrs 0.88, ci 0.79-0.99). in post-hoc analyses we added individual covariates to the model with age, sex and smoking to explore this further: the change in hr appeared to be largely driven by adjustment for chronic respiratory disease (hr 0.93, 0.83-1.04 after adjustment) and deprivation (hr 0.98, 0.88-1.10 after adjustment). other individual adjustments did not remove the positive association between current smoking and outcome. we also explored confounding by ethnicity, which was not adjusted in the primary model: among those with complete ethnicity, the current smoking hr adjusted for all variables except ethnicity was similar to in the full study population (0.88, 0.78-1.01) but this moved towards the null on adjustment for ethnicity (hr 0.94, 0.82-1.07). . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. most comorbidities were associated with higher risk of covid-19 hospital death, including diabetes (with a greater hr for those with recent hba1c >= 58 mmol/mol), asthma (with a greater hr for those with recent use of an oral corticosteroid), respiratory disease, chronic heart disease, liver disease, stroke/dementia, other neurological diseases, reduced kidney function, autoimmune diseases (rheumatoid arthritis, lupus or psoriasis) and other immunosuppressive conditions, as per table 2 . those with a history of haematological malignancy were at >3-fold increased risk up to 5 years from diagnosis, and nearly double the risk thereafter. for other cancers, hrs were smaller and risk increases were largely observed among those diagnosed in the last year. there was no association between hypertension (defined as a recorded diagnosis, or high blood pressure at the last measurement) and outcome (hr 0.95, 0.89-1.01). however, in sensitivity analyses, diagnosed hypertension was associated with slightly increased risk (hr 1.07, 1.00-1.15) while high blood pressure (≥140/90 mmhg) at the most recent measurement was associated with lower risk (hr 0.61, 0.56-0.67) . . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. the average c-statistic was 0.78. sensitivity analyses are shown in table a1 (appendix). results were similar when restricted to those with complete bmi and smoking information, and when adjusted for ethnicity, among those with complete data. violation of proportional hazards was detected in the primary model (p<0.001), so a further sensitivity analysis was run with earlier administrative censoring at 6th april 2020, since social distancing measures introduced across the uk in late march 2020 would not have been expected to impact on mortality rates at that time. there was no evidence of non-proportional hazards in this analysis (p=0.56). the overall pattern of results was similar to the primary model, though most hrs were somewhat larger in magnitude in the analysis restricted to this earlier period, while the effect of increasing deprivation appeared to be smaller (appendix table a1 ). we have successfully delivered a secure analytics platform operating across almost 24 million patient records for the covid-19 emergency, and used this to identify, quantify, and further explore a range of risk factors for death in hospital from covid-19 in the largest cohort study conducted by any country to date. most comorbidities we studied were associated with increased risk, including cardiovascular disease, diabetes, respiratory disease including asthma, obesity, history of haematological malignancy or recent other cancer, kidney, liver, neurological and autoimmune conditions. people from asian and black groups had a substantially higher risk of death from covid-19, only partially attributable to co-morbidity, deprivation or other risk factors. deprivation is also a major risk factor, which was only partly attributable to co-morbidity or other risk factors. the greatest strengths of this study were speed and size. by building a secure analytics platform across routinely collected live clinical data stored in situ we have been able to produce timely results from the current records of approximately 40% of the english population in response to a global health emergency. this scale allowed us to work with more precision, on rarer exposures, on multiple risk factors, and to detect important signals as early as possible in the course of the pandemic. the scale of our platform will shortly expand further, and we will report updated analyses over time. another key strength is our use of open methods: we pre-specified our analysis plan and have shared our full analytic code and all code lists for review and re-use. we ascertained patients' demographics, medications and comorbidities from their full pseudonymised longitudinal primary care records, providing substantially more detailed information than is available in hospital records or data recorded at time of admission alone, and on the total population at risk rather than the selected subset presenting for treatment in hospital. linkage to ons allowed censoring of data in the control population for patients who had died outside hospital or from other causes. analyses were stratified by area to account for known geographical differences in incidence of covid-19. we also identify important limitations. using cpns data alone relies on hospitals completing a new return under emergency conditions; furthermore covid-19 deaths among people with false-negative tests and those untested may not have been included; we will validate cpns against ons data (which has a longer delay to reporting) as more cases arise. this initial analysis was focused on in-hospital death: our findings therefore reflect both an individual's risk of infection, and their risk of dying once infected. we will explore patient trajectories in future research using test results and a&e presentation data . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. . https://doi.org/10.1101/2020.05.06.20092999 doi: medrxiv preprint which are now being linked on the opensafely platform. censoring patients at date of death from other causes, or outside hospital, was only possible until 16th april 2020, 9 days prior to study end. rather than ending the study earlier, greatly reducing case numbers, we end at 25 april, acknowledging that censoring would be incomplete for the last 9 days. consequently a small number of the sickest individuals, who died after being discharged from hospital, will have remained in the "at risk" group over the last few days of study time when they should be censored. this would most likely apply to those with risk factors present, and therefore attenuate hrs, but any impact is likely to be small: a sensitivity analysis with all data censored at 6 april showed minimal differences. our analysis to date covers 40% of the population, but may not yet be fully representative as it currently includes only practices using the ehr software systmone: there is substantial geographic variation in choice of ehr system and in london, where many earlier covid-19 cases occurred, only 17% of general practices use systmone. additionally it has been shown that the user interface of electronic health records can affect prescribing of certain medicines 42-44 so it is possible that coding of conditions may vary between systems; again we will evaluate this further with more data. primary care records, though detailed and longitudinal, can be incomplete for data on risk factors and other covariates. in particular, ethnicity was not recorded in approximately 26% of patients included; prior research has shown that when ethnicity is recorded in ehr its distribution is very similar to that in census ethnicity data. 45 obesity and smoking were assumed absent if missing; patients with missing creatinine and blood pressure measurements were included in the categories denoting no evidence of reduced kidney function or high blood pressure respectively. we undertook a number of sensitivity analyses to assess robustness of these approaches, hazard ratios were similar across analyses. deprivation score may be inaccurate for any patients without an up-to-date address, but this is unlikely to introduce a strong bias in any particular direction. deviations from proportional hazards were detected. this could be partly or wholly due to the very large numbers included meaning small deviations are statistically significant, or due to unmeasured covariates. however, it may have been due to rapid changes in social behaviours following government advice on social distancing, shielding, and changes in the pattern and burden of infection across the uk, which may also have affected different patient groups differentially. a sensitivity analysis with early censoring at 6th april 2020 (before social distancing and shielding measures would be likely to affect mortality) showed no evidence of non-proportional hazards (p=0.56) and similar results to the primary model, but with larger hazard ratios for several risk factors. this is consistent with the hypothesis that the most at-risk patients may have been more compliant with social distancing and shielding policies introduced later. in contrast, the effect of increased deprivation appeared to be smaller in the earlier period, suggesting that the risk associated with deprivation may have increased over time. subsequent analyses will explore different analytical approaches, including fitting interactions with time, and using accelerated failure time models, to further explore changes before and after national initiatives around covid-19. our findings on age and gender are consistent with patterns observed worldwide in smaller studies on patients infected and/or dying from covid-19. compared to white people, people of asian and black ethnic origin were found to be at . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. . https://doi.org/10.1101/2020.05.06.20092999 doi: medrxiv preprint a higher risk of death. non-white ethnicity has previously been found to be associated with increased covid-19 infection and poor outcomes. 12, 13, 46 commentators and researchers have reasonably speculated that this might be due to higher prevalence of medical problems such as cardiovascular disease or diabetes among bme people, or higher deprivation. our findings, based on more detailed data, show that this is only a small part of the excess risk. other possible explanations for increased risk among bme groups relate to higher infection risk, including over-representation in 'front-line" professions with higher exposure to infection, or higher household density. addressing these questions will likely entail bespoke data collection on, for example, occupation among cases and controls. we also found a consistent pattern of increasing risk with greater deprivation, with the most deprived quintile having a hr of 1.75 compared to the least deprived, consistent with recent national statistics. 47 again, contrary to prior speculation, very little of the increased risk associated with deprivation was explained by pre-existing disease or clinical risk factors, suggesting that other social factors increase the risk of covid-19 infection or death from infection. we found increased risk for the major included co-morbidities. the isaric study describing 16,749 hospitalised uk patients with covid-19 also indicated increased risk of death among hospitalised patients with cardiac, pulmonary and kidney disease, malignancy and dementia. 6 cardiovascular disease, hypertension, diabetes, respiratory disease, and cancers were all associated with increased risk of death in a large chinese study describing 44,672 confirmed cases, but which lacked age-correction. 5 of particular note in our results is the association of asthma with higher risk of covid-19 hospital death, with the hr increasing further for those having a recent oral corticosteroid (indicating greater severity of disease). this contrasts with previous findings: in several countries, asthma and other chronic respiratory diseases are underrepresented in hospitalised patients; 48 and among the first few hundred cases in uk, a protective association with asthma was observed, although presence of asthma was ascertained differently for cases and controls which could be a source of bias. 36 the isaric study reported 14% of hospitalised patients having asthma but no increased risk of death. 6 however, in both the uk and china, copd did appear to confer increased risk of death among hospitalised or confirmed cases, respectively. 5, 6 our study design combines both risk of infection and risk of death once infected; it is also possible that our methodology captured more people with asthma and was better able to delineate more severe asthma than previous studies based on hospital records. we found no association between hypertension and death where hypertension was defined as a recorded diagnosis or high blood pressure at last measurement (hr 0.96, 0.9-1.02). however when separated out in sensitivity analyses diagnosed hypertension was associated with slightly increased risk, whilst a high blood pressure measurement was associated with slightly reduced risk. hypertension is very strongly associated with age and although we adjusted for this, disentangling the effects of each is difficult. we showed increasing risk of death with degree of obesity: fully-adjusted hr 1.27 for bmi 30-34.9 kg/m 2 , increasing to 2.27 for bmi >=40 kg/m 2 . previous studies have shown increased risk with obesity among hospitalised patients: isaric, based on hospital survey data (2,212 deaths), found a hr of 1.37 for death associated with clinician-reported obesity among 16,749 hospitalised patients, after age and sex correction (95% ci 1.16-1.63) 6 ; obesity was also reported as a risk factor for treatment escalation in smaller studies in france and new york. 7, 8 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 7, 2020. we found some evidence of increased risks in former smokers. in current smokers there was a slight protective effect, which was removed when fully adjusted for ethnicity. the risks associated with smoking have been disputed, with increased risks initially reported, but some more recent reports finding that smokers are under-represented in those with more severe disease, and a potential protective mechanism for nicotine has been suggested 9,49 : smoking prevalence was lower than expected among hospitalised patients in china, 10 france 11 and the usa. 50 even if smoking does have a small protective effects against covid-19, this would still be massively outweighed by the well-established adverse health effects of smoking. the uk has a policy of recommending shielding (i.e. minimising face to face contact) for groups identified as being extremely vulnerable to covid-19 on the basis of pre-existing medical conditions. we were able to evaluate the association between most of these conditions and death from covid-19, and confirm that people with these conditions do have substantially increased mortality risk, supporting the shielding strategy. we have demonstrated -for the first time -that only a small part of the substantially increased risks of death from covid-19 among nonwhite groups and among people living in more deprived areas can be attributed to existing disease. improved strategies to protect people in these groups from covid-19 need urgent consideration. the uk has an unusually large volume of very detailed longitudinal patient data, especially through primary care. we believe the uk has a responsibility to the global community to make good use of this data, securely, and to the highest scientific standards. opensafely demonstrates the value of this data in practice. we will enhance the opensafely platform to further inform the global response to the covid-19 emergency. the underlying causes of higher risk among those from non-white backgrounds, and deprived areas, require further exploration; we would suggest collecting data on occupational exposure and living conditions as first steps. the statistical power offered by our approach means that associations with less common risk factors can be robustly assessed in more detail, at the earliest possible date, as the pandemic progresses. we will therefore update our findings and address smaller risk groups as new cases arise over time. the open source re-usable codebase on opensafely supports rapid, secure and collaborative development of new analyses: we are currently conducting expedited studies on the impact of various medical treatments and population interventions on the risk of covid-19 infection, itu admission, and death, alongside other observational analyses. opensafely is rapidly scalable for additional nhs patients' records, with new data sources progressing. we report early data on risk factors for death from covid-19 using an unprecedented scale of 17 million patients' detailed primary care records in the context of a global health emergency; we will update our findings as new data arises. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 7, 2020. . https://doi.org/10.1101/2020.05.06.20092999 doi: medrxiv preprint who. who director-general's opening remarks at the media briefing on covid-19 -11 who. coronavirus disease 2019 (covid-19) situation report -101 number of coronavirus (covid-19) cases and risk in the uk covid-19 daily deaths clinical determinants for fatality of 44,672 patients with covid-19 features of 16,749 hospitalised uk patients with covid-19 using the isaric who high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission the association of smoking status with sars-cov-2 infection, hospitalisation and mortality from covid-19: a living rapid evidence review clinical characteristics of coronavirus disease 2019 in china low incidence of daily active tobacco smoking in patients with symptomatic covid-19 is ethnicity linked to incidence or outcomes of covid-19? are some ethnic groups more vulnerable to covid-19 than others? covid-19) cases in the uk supporting providers to record covid-19 patient notifications technical summary: public health england data series on deaths in people with covid-19 development and validation of an electronic frailty index using routine primary care electronic health record data estimating primary care attendance rates for fever in infants after meningococcal b vaccination in england using national syndromic surveillance data the relationship between time since registration and measured incidence rates in the general practice research database guidance on social distancing for everyone in the uk. gov uk immunisation schedule: the green book, chapter 11 a new equation to estimate glomerular filtration rate what is the dm+d? the nhs dictionary of medicines and devices validation of asthma recording in the clinical practice research datalink (cprd) safety of inadvertent administration of live zoster vaccine to immunosuppressed individuals in a uk-based observational cohort analysis rheumatoid arthritis and incidence of twelve initial presentations of cardiovascular disease: a population record-linkage cohort study in england medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a populationbased cohort study using multiple linked uk electronic health records databases opensafely codelists: cancer excluding lung and haematological covid-19 in great britain: epidemiological and clinical characteristics of the first few hundred (ff100) cases: a descriptive study isb1523: anonymisation standard for publishing health and social care data -nhs digital secretary of state for health and social care -uk government. coronavirus (covid-19): notification to organisations to share information impact of electronic health record interface design on unsafe prescribing of ciclosporin, tacrolimus and diltiazem: a cohort study in english nhs primary care. jmir preprints: accepted for publication quality of co-prescribing nsaid and gastroprotective medications for elders in the netherlands and its association with the electronic medical record ghost branded generics: why does the cost of generic atorvastatin vary? ebm datalab completeness and usability of ethnicity data in uk-based primary care and hospital databases ons. deaths registered weekly in england and wales, provisional: week ending 17 do chronic respiratory diseases or their treatment affect the risk of sars-cov-2 infection? smoking, vaping and hospitalization for covid-19 covid-19 testing, hospital admission, and intensive care among 2,026,227 united states veterans aged footnotes: models adjusted for age using a 4-knot cubic spline age spline, except for estimation of age group effects. *ethnicity effect estimated from a model restricted to those with recorded ethnicity. * 2 ocs = oral corticosteroids we are very grateful for all the support received from the tpp technical operations team throughout this work; for generous assistance from the information governance and database teams at nhs england / nhsx; and for additional discussions on disease all authors have completed the icmje uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare the following: cb jp fh jc sh are employees of tpp. no dedicated funding has yet been obtained for this work. tpp provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. bg's work on better use of data in healthcare more broadly is currently funded in part by: figure a1 . estimated log hazard ratio by age in years from the primary fully adjusted model containing a 4-knot cubic spline for age, and adjusted for all covariates listed in table 2 except for ethnicity. key: cord-297395-5r4fxcuq authors: rezende, leandro f. m.; thome, beatriz; schveitzer, mariana cabral; de souza-júnior, paulo roberto borges; szwarcwald, célia landmann title: adults at high-risk of severe coronavirus disease-2019 (covid-19) in brazil date: 2020-05-15 journal: revista de saude publica doi: 10.11606/s1518-8787.2020054002596 sha: doc_id: 297395 cord_uid: 5r4fxcuq objective: to estimate the proportion and total number of the general adult population who may be at higher risk of severe covid-19 in brazil. methods: we included 51,770 participants from a nationally representative, household-based health survey (pns) conducted in brazil. we estimated the proportion and number of adults (≥ 18 years) at risk of severe covid-19 by sex, educational level, race/ethnicity, and state based on the presence of one or more of the following risk factors: age ≥ 65 years or medical diagnosis of cardiovascular disease, diabetes, hypertension, chronic respiratory disease, cancer, stroke, chronic kidney disease and moderate to severe asthma, smoking status, and obesity. results: adults at risk of severe covid-19 in brazil varied from 34.0% (53 million) to 54.5% (86 million) nationwide. less-educated adults present a 2-fold higher prevalence of risk factors compared to university graduated. we found no differences by sex and race/ethnicity. são paulo, rio de janeiro, minas gerais, and rio grande do sul were the most vulnerable states in absolute and relative terms of adults at risk. conclusions: proportion and total number of adults at risk of severe covid-19 are high in brazil, with wide variation across states and adult subgroups. these findings should be considered while designing and implementing prevention measures in brazil. we argue that these results support broad social isolation measures, particularly when testing capacity for sars-cov-2 is limited. the world health organization (who) suggests that most people infected with the virus may develop mild or uncomplicated (80%) coronavirus disease 2019 , while the remaining 20% may develop its severe variation, requiring hospitalization (14%) or intensive care unit (6%) 1 . established risk factors for severe disease among inpatients with covid-19 in china included older age 2,3 and serious medical conditions such as cardiovascular disease 2-4 , diabetes [2] [3] [4] , chronic respiratory disease (in particular chronic obstructive pulmonary disease -copd) 2 , hypertension 2,4 , cancer 2,5 , and cerebrovascular disease 3, 4 . recent findings from united states (us) and europe confirmed these risk factors and proposed new ones, such as chronic kidney disease, obesity, asthma and smoking [6] [7] [8] [9] . the emergence of a highly transmissible pathogen 10 in a completely susceptible population has resulted in an exponential growth of new cases worldwide and a wide dissemination across the globe. as of april 12, 2020, the number of sars-cov-2 infections was above 1.8 million, reported in 185 countries/regions of the world 11 . high-and low-income regions are already facing overload of health facilities and facing scarcity of resources to fight the pandemic. in lower resource settings, countries have a short time to prepare prevention and management strategies, including the identification of high-risk populations and regions within countries. herein, we propose a calculation of the proportion and total number of the general adult population who may be at higher risk for severe covid-19, based on routinely collected data from a nationwide, household-based survey in brazil. we argue that this method could be easily and rapidly applied within and across countries in order to craft tailored prevention strategies such as social isolation. we obtained data from the most recent representative, household-based survey conducted in brazil, the national health survey (pns, 2013 -pesquisa nacional de saúde), carried out by the ministry of health in partnership with the brazilian institute of geography and statistics (ibge). the pns enrolled 62,202 adults who responded to a comprehensive questionnaire about several health-related issues. in this study, we included 51,770 participants who responded to the questionnaire about medical diagnosis and lifestyle risk factors, and had their weight and height measured. further details about pns have been described elsewhere 12 . we included risk factors for severe covid-19 based on currently available information from clinical studies and expertise [2] [3] [4] [5] [6] [7] [8] [9] , and for which exposure data were available in the pns 12 . age and medical diagnosis of cardiovascular disease, diabetes, hypertension, chronic respiratory disease, cancer, stroke, chronic kidney disease and asthma were assessed. we also obtained time (in years) since cancer diagnosis and treatment/medication use for chronic kidney disease (e.g. dialysis) and asthma to match definitions from the literature (e.g. moderate to severe asthma). information about age, smoking status and measured body mass index (bmi) were also obtained/estimated. prevalence of one or more risk factors for severe covid-19 was estimated using two criteria (table 1) . criterion 1 included first identified and established risk factors for severe covid-19 such as age ≥ 65 years or medical diagnosis of cardiovascular disease, diabetes, hypertension, chronic respiratory disease, cancer or stroke. although ≥ 60 years have been used to define older adults in brazil, herein we considered ≥ 65 years to match the definition of risk factors for covid-19 obtained from the literature and allow comparisons with other publications 2-9 . criterion 2 additionally included diagnosis of chronic kidney disease and moderate to severe asthma, smoking status (current smokers) and obesity (bmi ≥ 30 kg/m 2 ). criterion 2 was used to provide a higher sensitivity for the proportion of adults at risk of severe illness. denominator for both criteria 1 (n = 52,511) and 2 (n = 51,770) included all participants with complete questionnaires. we also estimated the sum of all risk factors for severe illness (0, 1, 2, 3 + risk factors). information on covariates including sex, race/ethnicity, educational level, and brazilian state (26 states and the federative district) were obtained to describe the proportion of adults at risk of severe covid-19 by population strata. we also retrieved the total projected number of the brazilian adult population (≥ 18 years) in 2020 by sex and state from the ibge 13 . we estimated the prevalence and 95% confidence intervals of adults at risk for severe covid-19 (criterion 1 and criterion 2) by sex, education, race/ethnicity and brazilian state. we performed sensitivity analyses for prevalence by considering two other definitions for older adults (≥ 60 years and ≥ 70 years). in order to obtain the total number of adults at risk of severe illness, we applied the prevalence to the number of adult's population (≥ 18 years) by sex and state. the sample design was considered for all analyses using the survey prefix command (svy) in stata version 15.0. participants characteristics and risk factors for severe illness are presented by age group (table 2) . compared with younger participants, older adults (≥ 65 years) were less educated, more likely women, white and presented higher prevalence of risk factors for severe covid-19, except for smoking. prevalence of one or more risk factors for severe illness was 47.3% in younger vs 75.9% in older adults. proportion and total number of adults at risk for severe covid-19 in brazil varied from 34.0% (53 million adults) to 54.5% (86 million adults) (table 3) . overall, 46% of the sample presented no risk factor, 30.0% with one, 15.0% with two, and 9% with 3 or more risk factors for severe illness. sensitivity analyses considering older adults ≥ 60 years and ≥ 70 years suggested that prevalence could vary from 36.7%-56.2% to 32.3%-53.3%, respectively (table 4 ). proportion of adults at risk for severe covid-19 was 2-fold higher in less educated participants compared with university graduated. we found no differences in prevalence estimates by sex and race/ethnicity (table 3) . estimates varied widely across states, with higher prevalence in the south and southeast regions of the country (figure) . the highest prevalence was 39.5%-58.4% in rio grande do sul, followed by 36.0-55.8% in rio de janeiro and 35.6%-58.2% in são paulo. the lowest prevalence was found in amapá (23.4%-45.9%), followed by roraima (25.0%-48.6%) and amazonas (25.1%-48.7%). the highest number of adults at risk of severe illness was found in são paulo (17-21 million), minas gerais (6-9 million) and rio de janeiro (5-7 million) ( in this study, we estimated that a third (53 million) to over a half (86 million) of brazilian adults present at least one risk factor for severe covid-19. our findings point to high prevalence of serious medical conditions in younger, but mostly, among older adults. less educated adults present 2-fold higher prevalence of risk factors compared with university graduated. são paulo, rio de janeiro, minas gerais and rio grande do sul were the most vulnerable states in absolute and relative terms of adults at high-risk. contrasts between south and southeast vs north and northeast regions might be due to different age structure, prevalence of health condition and/or access to medical diagnosis and care. estimating the proportion of the population at risk for severe covid-19 within and across countries is key to improve prevention measures. however, to our knowledge, these estimates are still sparse worldwide. in the us, it was estimated that four in ten (37.6%) adults ≥ 18 years may be at high-risk of severe covid-19 14 . during the pandemic, time is limited and hence the use of existing health information to support countries' response is imperative. these findings and methods to identify high-risk settings may be useful to plan and manage prevention strategies in brazil and other low-to middle-income settings with routinely collected data from population-based surveys, but limited testing capacity for sars-cov-2. the understanding of risk factors for severe covid-19 has so far supported the implementation of prevention strategies. it is interesting to note that non-communicable diseases such as cardiovascular disease, cancer, respiratory diseases, and diabetes, which accounts for most of deaths globally 15 , play a role on worsening the impact of the covid-19 pandemic. since isolation of infected cases and contact tracing alone will not likely suffice to control the pandemic 16 , countries have largely implemented social isolation measures. the combination of different interventions such as case isolation, social distancing of the entire population, household quarantine, school closure and, ultimately, complete lockdown is predicted to have significant impact on transmission 17 . protecting the groups that are most at risk 18 , such as older adults and people with comorbidities, by widely and temporarily refraining from engaging in social contact, remains imperative. as knowledge on the clinical course of covid-19 advances, the understanding of risk factors for severe disease will be improved, and so will the estimates of most-at-risk populations. our results have some limitations. prevalence of risk factors for severe covid-19 is likely underestimated due to self-reported medical diagnosis of comorbidities and smoking status. underlying diseases have been associated with poorer prognosis among inpatients with covid-19, but some people may have lower risk due to well-controlled blood pressure and serum glucose, for instance, which may have overestimated the proportion and number of adults at risk. undiagnosed, asymptomatic diseases such as diabetes and hypertension are concerns, especially in low-income settings. this may partially explain differences of adults at risk between brazilian states. estimates considered the same weight for all risk factors assessed, which may not be applicable. furthermore, other known risk factors for severe covid-19 such as living in a nursing home or long-term care facility, and immunosuppression could not be captured in our study. lastly, risk factors information date from 2013, the most recent representative, household-based health survey of brazilian adults. the proportion of older adults has increased in brazil in the past seven years, as well as the prevalence of obesity and other non-communicable diseases 19 , which may have underestimated our estimates. on the other hand, the prevalence of tobacco smoking has decreased, which may have overestimated the adults at risk of severe covid-19. in conclusion, proportion and total number of adults at risk of severe covid-19 is high in brazil, with wide variation across states and adult subgroups. these findings should be considered while designing and implementing prevention measures. we argue that these results support broad social isolation measures, particularly while testing capacity for sars-cov-2 is limited. novel coronavirus pneumonia emergency response epidemiology team characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention predictors of mortality for patients with covid-19 pneumonia caused by sars-cov-2: a prospective cohort study clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan cancer patients in sars-cov-2 infection: a nationwide analysis in china baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -united states rome (ita): istituto superiore di sanitá ace-2 expression in the small airway epithelia of smokers and copd patients: implications for covid-19 geneva: who; 2020 the novel coronavirus, 2019-ncov, is highly contagious and more infectious than initially estimated projeções da população: brasil e unidades da federação: revisão 2018 how many adults are at risk of serious illness if infected with coronavirus? updated data global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the global burden of disease study report 3: transmissibility of 2019-ncov report 9: impact of non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand centers for disease contol and preventiion. implementation of mitigation strategies for communities with local covid-19 transmission secretaria de vigilância em saúde, departamento de análise em saúde e vigilância de doenças não transmissíveis. vigitel brasil 2018: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico: estimativas sobre frequência e distribuição sociodemográfica de fatores de risco e proteção para doenças crônicas nas capitais dos 26 estados brasileiros e no distrito federal key: cord-276267-77903fld authors: al‐ani, aysha h.; prentice, ralley e.; rentsch, clarissa a.; johnson, doug; ardalan, zaid; heerasing, neel; garg, mayur; campbell, sian; sasadeusz, joe; macrae, finlay a.; ng, siew c.; rubin, david t.; christensen, britt title: review article: prevention, diagnosis and management of covid‐19 in the ibd patient date: 2020-05-26 journal: aliment pharmacol ther doi: 10.1111/apt.15779 sha: doc_id: 276267 cord_uid: 77903fld background: the current covid‐19 pandemic, caused by sars‐cov‐2, has emerged as a public health emergency. all nations are seriously challenged as the virus spreads rapidly across the globe with no regard for borders. the primary management of ibd involves treating uncontrolled inflammation with most patients requiring immune‐based therapies. however, these therapies may weaken the immune system and potentially place ibd patients at increased risk of infections and infectious complications including those from covid‐19. aim: to summarise the scale of the covid‐19 pandemic, review unique concerns regarding ibd management and infection risk during the pandemic and assess covid‐19 management options and drug interactions in the ibd population. methods: a literature review on ibd, sars‐cov‐2 and covid‐19 was undertaken and relevant literature was summarised and critically examined. results: ibd patients do not appear to be more susceptible to sars‐cov‐2 infection and there is no evidence of an association between ibd therapies and increased risk of covid‐19. ibd medication adherence should be encouraged to prevent disease flare but where possible high‐dose systemic corticosteroids should be avoided. patients should exercise social distancing, optimise co‐morbidities and be up to date with influenza and pneumococcal vaccines. if a patient develops covid‐19, immune suppressing medications should be withheld until infection resolution and if trial medications for covid‐19 are being considered, potential drug interactions should be checked. conclusion: ibd patient management presents a challenge in the current covid‐19 pandemic. the primary focus should remain on keeping bowel inflammation controlled and encouraging medication adherence. in december 2019, reports of a novel coronavirus, since named sars-cov-2, emerged from wuhan, central hubei province, china. 1-3 the virus causes the disease covid-19, which manifests as a severe acute respiratory illness that can be complicated by acute respiratory distress syndrome (ards), multiorgan failure and even death. 3 following rapid spread of the virus across the globe, the world health organisation (who) declared covid-19 a pandemic on 11 march 2020. 2 there are currently almost 2 million confirmed cases across more than 200 countries with a total death count greater than 100 000 at the time of writing. 2 as the pandemic expands, there has been increasing concern regarding the impact of covid-19 on patients with ibd. the primary management of ibd involves treating uncontrolled inflammation with a significant number of patients requiring immune-based therapies. 4 in the last decade, there has been a considerable expansion of the therapeutic armamentarium for patients with ibd to include immunomodulators, tnf antagonists, non-tnftargeted biologics and targeted small molecule therapies. 5 however, these therapies, in addition to malnutrition which can complicate ibd, may weaken the immune system and potentially place ibd patients at increased risk of infections and infectious complications. 6 consequently, there is a concern that ibd patients are at greater risk of developing covid-19 and at increased risk of progressing to a more severe clinical course or even death compared to the general population. in addition, if an ibd patient develops covid19, there is a lack of guidance on medication management and concern regarding drug interactions if trial medications are utilised to treat therefore the aim of this review is to summarise the evidence and discuss in detail the data regarding the risks of developing covid-19, strategies that can be implemented to reduce these risks and issues surrounding the treatment of covid-19, including potential drug interactions and ibd medication management, in the ibd patient cohort. coronaviruses (of the family coronaviridae) are a group of related single-stranded, positive sense, enveloped rna viruses. they are the largest known rna viruses, ranging from 26 to32 kilobases in size. 7 they are named after their appearance under electron microssyndrome coronavirus 2 (sars-cov-2). 9 these viruses are all known to cause respiratory symptoms ranging broadly in severity, both between the different viruses and in different hosts infected with the same virus. most spread easily and result in relatively mild illness in immunocompetent patients, with certain strains being responsible for almost 30% of the common cold. 10 other coronaviruses (covs), including the sars-cov and the mers-cov, have previously emerged as epidemics with significant mortality and socioeconomic impact. compared to sars-cov-2, mers-cov causes a much more severe illness, with a case-fatality rate (cfr) of up to 30%, but appears to have a lower person-to-person transmission, limiting its global impact. 5 there are still new cases of mers being reported today. 11 similarly, the sars-cov outbreak in 2002-2003 had a high cfr (9.6%), but its reduced infectivity compared with sars-cov-2 lessened its overall impact. 12 this outbreak appears to have been contained. 12 sars-cov-2 is the first pandemic coronavirus. therefore, it poses a threat of uncertain dimensions and represents uncharted territory for the public and global healthcare systems alike. 2,3 sars-cov-2, the virus previously known as novel 2019-coronavirus, causes the disease covid-19. it was first discovered following the reports of an outbreak of pneumonia in china, with initial infections linked to a single seafood market. 1, 13 genetic studies have shown its genetic sequence is 82% similar to sars-cov, and 89% similar to bat-sl-covzc45 and bat-sl-covzxc21, leading to the postulation that bats served as reservoir host for the new coronavirus' progenitor. 14 human transmission is thought to have been facilitated by an animal intermediate host, currently hypothesised to be a pangolin. 15 human-to-human transmission is believed to be predominantly via direct contact, exhaled droplets and fomites from an infected individual. 16 sars-cov-2 can also be detected in saliva, urine and the gastrointestinal tract in both biopsy specimens and stools, although their role in transmission remains unclear. [17] [18] [19] data suggest it is more easily transmitted than seasonal influenza based on a basic reproduction number (r 0 -the expected number of cases directly generated by one case in the population) of 2-2.5. 20 entry of coronaviruses into human target cells requires spike (s) protein binding to a cellular receptor followed by s protein priming by host proteases to facilitate cell entry. 21 sars-cov-2 human-to-human transmission is enabled by the interaction of the sars-cov-2 s-protein with the human angiotensin-converting enzyme 2 (ace2) receptor. 17, 18 transmission occurs when the virus enters the nose, mouth or eyes, and potentially the digestive system and attaches to cells that produce ace2. ace2 are found in multiple organs and are highly expressed in lung at2 cells, enterocytes of the small intestine and colon. 22, 23 once the virus is attached to ace2 it uses the host serine protease tmprss2 for s priming allowing fusion of viral and cellular membranes and viral entry into the cell. 21 once a person develops initial symptoms of covid-19, respiratory viral shedding occurs for a median of 20 days in survivors and is sustained until death in nonsurvivors. 24 of note, prolonged shedding has been demonstrated with other coronaviruses in immunocompromised patients 25 and in immunocompromised animals with mers-cov. 25 27 asymptomatic people are also potential sources of sars-cov-2 as transmission may occur in the pre-clinical period (2-14 days) or from an oligosymptomatic individual. 27, 28 furthermore the virus has been detected in up to 50% of stool specimens and can remain positive for viral rna following negative respiratory samples in more than 20% of sars-cov-2 patients. 19, 22, 29 these characteristics may have implications regarding isolation and decision-making for ibd patients who are infected with sars-cov-2 although there are no evidence-based guidelines on this currently. the major clinical manifestations of covid-19 are fever (44% on admission and 89% during admission), dry cough (68%), shortness of breath (19%), diarrhoea/vomiting/abdominal pain (20%), generalised myalgia/arthralgia (15%), headache (14%), malaise and bilateral interstitial pneumonia. 15, 19, 30 covid-19 pneumonia manifests with chest ct imaging abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progress to or co-exist with consolidations within 1-3 weeks. 15 while the mechanism of covid-19 induced gastrointestinal symptoms remains to be clarified, enteric symptoms may occur due to malabsorption secondary to direct damage of the invaded enterocyte in the setting of a viral infection. 18 furthermore, there is a recent case report of a possible sars-cov-2 gastrointestinal infection causing acute haemorrhagic colitis and signalling covid-19 disease. 31 it is not clear if gastrointestinal symptom rates secondary to covid-19 differ in patients with ibd but if an ibd patients presents with worsening gastrointestinal symptoms, covid-19 infection should be considered as a differential. the median age of an infected individual is 51 years old and the majority of infected individuals range from 30 to 69 years. 16 fifty-one percent of reported cases is male. healthcare workers may be at increased risk of infection secondary to close contact with infected patients and exposure to aerosolised virus from medical equipment and procedures including endoscopy. 32 in china healthcare workers made up 3.5% of covid-19 patients and italy have reported that 20% of its responding healthcare work force is being infected. 17, 33 current data suggest that children under the age of 18 years have a low infection rate (2.4%), with a large proportion being identified through contact tracing in adults rather than through symptomatology. 16 the median incubation period for sars-cov-2 is 4-5 days, with most patients having symptom onset before 14 days, but there have been cases with longer incubation. 34 a mean interval of 9.1-12.5 days between illness onset and hospitalisation has been documented highlighting the challenge in the identification and isolation of individuals at an early stage of disease. 35 in recovered cases, the median time from initial symptoms to discharge from hospital was 22 days and in those that succumbed the average time to death was 18.5 days. 35 overall cfr of covid-19 are estimated to be approximately 1%-2%, rising to more than 15% in patients aged 80 years and over. 36 current who data surmise that most cases of covid-19 have mild to moderate disease (80%) with 13.8% experiencing severe disease defined by the following signs and symptoms within 24-48 hours: shortness of breath; tachypnoea >30 breaths per minute; hypoxia <93%; hypoxaemia with pao 2 /fio 2 ratio < 300 and/or pulmonary infiltrates >50% of the lung field. 16 critical infections occur in 6. risk factors for contracting covid-19 have not been fully elucidated. healthcare professionals are at greater risk secondary to increased exposure 32 and it is thought that smoking may exacerbate contraction. 37 for all patients with covid-19, severity and mortality is associated with age (median age 66 years for critically ill vs 51 years in the overall patient population) and underlying cardiovascular disease, hypertension, chronic pulmonary disease, diabetes and cancer. 16, 17, 38 severe covid-19 is less common in children with reports suggesting approximately 5% develop severe disease and 0.6% become critical. 39 the crude fatality rate is higher in males (4.7%) vs females (2.8%) and smokers. 16 26, 40 for ibd patients, the greatest risk factor for general immunosuppression and infections remains pharmacological. 41, 42 nutritional status, co-morbidities, age and disease activity also contribute. 42 41, 42 furthermore, low vitamin d levels are prevalent in ibd patients and may be associated with an increased risk and/or severity of influenza and covid-19. 45, 46 vitamin d increases anti-inflammatory cytokines and lowers viral replication, which in turn may reduce pro-inflammatory cytokines that propagate lung injury and ards. [45] [46] [47] therefore assessment of vitamin d and supplementation when it is low is reasonable. as gastrointestinal tract permeability may be increased in ibd a diagnosis of covid-19 should be considered in patients who display fever, cough, anosmia, nausea, vomiting and diarrhoea. of note, a subgroup of patients may present with mild disease marked by the presence of diarrhoea initially and these patients often experience delayed diagnosis compared to those that present with respiratory symptoms. 51 biochemical markers of covid-19 include lymphopenia, thrombocytopenia and leukopenia as well as elevated c-reactive protein (crp), which may also correlate with severe disease. 17 less commonly, there may also be elevations in alanine aminotransferase (alt), aspartate aminotransferase (ast), creatine kinase (ck) and d-dimer. 17 recommendations on whom to test for covid-19 will vary depending on the local guidelines, availability of testing kits and regional transmission dynamics. in high-risk settings where an outbreak has occurred, all patients with clinical features consistent with covid-19 should be considered for testing. in non-outbreak areas, a case of covid-19 should be suspected and tested for if a patient has clinical features suggestive of covid-19 and fits epidemiologic criteria for example international travel or contact with a confirmed covid-19 case. a patient is also considered a suspect case of covid-19 regardless of their history if they are admitted to hospital with acute respiratory illness or unexplained fever. diagnosis of covid-19 is via nucleic acid testing of nasopharyngeal and oropharyngeal swabs. 52 serology testing is currently not widely available. it is important to ensure that routine local protocols for testing in acute pneumonia/pneumonitis are also followed, such as bacterial cultures, urinary antigen testing, acute and convalescent serology and respiratory virus panels. at this stage, faecal sampling is not standard; however, this may be indicated in those with gastrointestinal symptoms. a positive test for covid-19 must be immediately notified to the relevant communicable diseases agency. 52 despite a lack of evidence demonstrating any increased susceptibility to covid-19, 50 (table 2 ). however, theoretically, there may also be some beneficial effects seen with certain immunosuppressive medications, given the cause of death in covid-19 is a cytokine storm resulting in ards. overall, apart from corticosteroids, the risks of ibd therapies, particularly 5-asas and biologics, appear limited, and the importance of careful discussion regarding the risks versus benefits of medications with patients and among medical practitioners cannot be overstated. inappropriate cessation of effective agents due to unjustified fear of adverse events may lead to ibd relapse, which when requiring the use of steroids or hospitalisation may inadvertently strain medical resources and increase the risk of covid-19 exposure and infection. sulfasalazine and the 5-asa medications are used as first-line induction and maintenance treatment for uc. 5-asas have very mild immunosuppressive activity and they are often well tolerated with minimal side effects. there are no reports of these medications being associated with an increased risk of infection and studies of large cohorts evaluating the safety profile of 5-asas do not demonstrate an increased risk of serious or opportunistic infections. 53 sulfasalazine and 5-asa • treatment with 5-asa therapy should continue without concern for increased risk of contracting or developing severe covid-19. • if a patient is in contact with someone who has covid-19 or develops covid-19, treatment with 5-asa should continue. corticosteroids systemically reduce inflammation by turning off multiple inflammatory genes. in patients with covid-19, a systemic inflammatory response syndrome can perpetuate lung injury with persistent inflammation resulting in ongoing pulmonary damage even subsequent to viral suppression. 54 55 in sars, corticosteroid treatment was of no clinical benefit in regard to infection resolution but was associated with an increased risk of psychosis, 57 delayed clearance of viral rna, 58 diabetes 59 and avascular necrosis. 60 finally, in a systematic review on corticosteroid treatment in influenza patients, corticosteroids were associated with an increased length of stay in intensive care, an increased rate of secondary bacterial and fungal infections and an increase in mortality compared to those who did not receive corticosteroids. 56 however there is limited evidence that they increase the risk of either upper respiratory tract infections or pulmonary infections. 70, 71 in addition, mercaptopurine has been shown to inhibit one of the proteases essential to viral maturation of mers-cov in vitro, although no further animal-based models exist to suggest clinical efficacy. 72 methotrexate has variably been demonstrated to increase the risk of infections in patients with inflammatory diseases. reassuringly, a recent systematic review reassuringly found that in the nonrheumatoid arthritis inflammatory disease population, there was not an sulfasalazine and 5-asa • treatment with 5-asa therapy should continue without concern for increased risk of contracting or developing severe covid-19. • if a patient is in contact with someone who has covid-19 or develops covid-19, treatment with 5-asa should continue. increased risk of infection with methotrexate (1.03, 95% ci0.82-1.3). 73 this applied similarly to respiratory infections specifically. 74 anti-tnf agents have been shown to increase the risk of upper and lower respiratory tract infections, as well as serious and opportunistic pulmonary infections. 62, 75, 76 compared with anti-tnf monotherapy, risk of serious infections increases with combination of anti-tnf and an immunosuppressive agent or most significantly in combination with corticosteroids. 77 in a study that did not separate mono-or combination-anti-tnf therapies, the risk of pneumonia was only slightly increased in patients receiving a tnf antagonist of note, anti-tnf therapy has been employed in the management of severe sepsis, with a meta-analysis demonstrating reduced overall mortality when used in severe sepsis before shock, and improved survival at 30 days in patients with shock or high baseline levels of il-6. 78 there are no data on the incidence and severity of sars or covid-19 in patients on anti-tnf medications. anti-tnf agents were utilised in the initial phase of the sars epidemic, although the overall evidence for efficacy is lacking. 79 the main non-tnf antagonist biologics for ibd include the anti-il12/23 biologic ustekinumab and the anti-integrin therapy, vedolizumab. reassuringly, the risk of severe respiratory tract infections, severe infections in general or opportunistic infections does not appear to be increased in long-term follow-up studies of ustekinumab in both ibd and psoriasis. [80] [81] [82] similar data have also been reported for vedolizumab. [83] [84] [85] [86] there is a theoretical concern of an increased risk of respiratory infections, and hence covid-19, with vedolizumab treatment as vedolizumab binds the t-cell integrin receptor α 4 β 7, inhibiting its binding to madcam1 present on the small intestinal endothelium and vasculature. these receptors are also expressed in the t cells occupying the nares, although to a far lesser extent when compared to the intestine. 87 interestingly, baricitinib, a jak inhibitor used in rheumatoid arthritis, has a potential therapeutic role in the management of sars-cov-2 through both its anti-inflammatory action and numbassociated kinase (nak) inhibition. tofacitinib has no affinity for this particular kinase. naks are involved in the function of clathrin, which mediates endocytosis of sars-cov-2 into cells resulting in infection. 94 due to the anti-inflammatory effects of the jak inhibitors, it has also been speculated that they may be able to combat the elevated levels of cytokines observed in covid-19 which may potentially further decrease the severity of the infection. 94 if a patient is exposed to or gets infected with covid-19, the withholding of immunosuppressive medications should be considered where possible. it is important to note that many ibd medications may take months to be eliminated from the body so the utility of withholding these medications in the short term is likely to be limited. (see table 3 ). the response to covid-19 is rapidly evolving and gastroenterologists should regularly review local, institutional and international recommendations. despite limited data, patients with ibd are theoretically at increased risk of covid-19 due to proximity to medical facilities and immunosuppression. there are therefore several recommendations that clinics and patients can implement to reduce risks. nutrition should be optimised as malnutrition can disrupt the innate immune response, including complement and mucosal secretory antibody formation, and is associated with increased infection risk in ibd patients. 96 smoking has been associated with worse outcomes and increased mortality in covid-19 17 and therefore patients should be encouraged to quit smoking. immunisation: immunisation of patients should be strongly encouraged to reduce preventable co-infection with other viruses: patients should receive pneumococcus (pcv13 and ppsv 23) and influenza (quadrivalent inactivated vaccine) vaccination. therapies are summarised in table 4 . where interactions exist, it is possible for patients to cease their ibd medications and continue on trial medications. remdesivir is a prodrug of the adenosine nucleotide analogue gs chloroquine is a widely used anti-malarial and autoimmune disease drug. it has a broad spectrum anti-viral action that is exerted 109 chloroquine is not accessible in australia and it has been suggested that hydroxychloroquine could be an effective alternative given that it is an identical molecule to chloroquine apart from the addition of a hydroxyl group. 108 favipiravir, a guanine analogue, effectively inhibits the rnadependent polymerase of rna viruses. this anti-viral effect has efficacy on influenza (approved use), ebola, yellow fever, chikungunya, norovirus and enterovirus. activity against covid-19 has been reported. 112 it is currently being tested in japan and has no significant drug interactions. in a recent study it has 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=&regno =&regst atus= 0&count ry=&provi nce=&city=&insti tutio n=&insti tutio nleve l=&measu re=&inter code=&sourc eofsp ends=&creat eyear =0&isupl oadrf =&wheth erpub lic=&btngo =btn&verif ycode =&page=1 protecting healthcare workers during the coronavirus disease 2019 (covid-19) outbreak: lessons from taiwan's severe acute respiratory syndrome response clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study contact and self-contact patterns of healthcare workers: implications for infection prevention and control budesonide for the induction and maintenance of remission in crohn's disease: systematic review and meta-analysis for the cochrane collaboration oral beclometasone dipropionate in the treatment of active ulcerative colitis: a double-blind placebo-controlled study respiratory tract infections in patients with inflammatory bowel disease: safety analyses from vedolizumab clinical trials long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials clinical pharmacokinetic and pharmacodynamic considerations in the treatment of inflammatory bowel disease comparative effectiveness of azathioprine in crohn's disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients pharmacokinetics and immune reconstitution following discontinuation of thiopurine analogues: implications for drug withdrawal strategies subcutaneous absorption contributes to observed interindividual variability in adalimumab serum concentrations in crohn's disease: a prospective multicentre study clinical pharmacokinetics and pharmacodynamics of monoclonal antibodies approved to treat rheumatoid arthritis clinical pharmacokinetics and use of infliximab infliximab pharmacokinetics in inflammatory bowel disease patients clinical pharmacokinetics and pharmacodynamics of infliximab in the treatment of inflammatory bowel disease understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children review article: the pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment review article: prevention, diagnosis and management of covid-19 in the ibd patient key: cord-031696-gcduh13u authors: katsikopoulos, panagiotis v. title: individual and community resilience in natural disaster risks and pandemics (covid-19): risk and crisis communication date: 2020-09-10 journal: mind soc doi: 10.1007/s11299-020-00254-0 sha: doc_id: 31696 cord_uid: gcduh13u civil protection and disaster risk specific agencies legally responsible to enhance individual and community resilience, still utilize in their risk and crisis communication efforts, the “deficit model” even though its basic assumption and approach have been criticized. recent studies indicate that information seeking behavior is not necessarily a measure of enhanced individual preparedness. a qualitative change from “blindly” following directions to practicing emergency planning and becoming your own disaster risk manager is required. for pandemics, the challenge is even more complicated due to their unique characteristics. community based exercises (cbex), a framework concept encompassing a variety of interactive activities, have recently started being utilized to develop resilience amongst citizens. existing models of resilience can pinpoint to the required knowledge, skills and attitude. research in the factors influencing behavioral change could offer new understanding of the interplay between cognitive and demographic drivers/factors of resilience. such knowledge could be utilized for setting targeted objectives, developing appropriate activities and the corresponding training for the cbex facilitators. despite the importance of preparation, the current covid-19 crisis indicates that high levels of adaptive resilience can be displayed even in the absence of any risk communication effort beforehand by utilizing a pre-existing collective understanding of the system situation. one of the fundamental principles of emergency planning, that every student has been taught, is that it takes place in an environment of apathy, even resistance, and with limited resources (fema 2006) . this is even more valid for risk communication also termed "public preparedness education" in the emergency management field. governments and citizens (both faced with limited resources and attention) tend to consider prudent to focus on "frequently" occurring disaster risks at the national and/or local level, as these risks are naturally presumed to be of the highest priority (wilkinson et al. 2017) . it is an issue of risk assessment and management. the 34 countries participating in the union civil protection mechanism regularly submit to the european commission (ec) their national risk assessment. in the latest report available (european commission 2017), one finds listed as priority risk along earthquakes, floods, and forest fires, the biological threat/pandemics risk as well. only nine countries (cyprus, france, greece, italy, montenegro, north macedonia, portugal, spain, and turkey) have not included the latter. the risk and crisis communication mandate rests predominantly on civil protection authorities and disaster risk specific agencies (e.g. responsible for earthquakes, floods, public health, etc.) at central, regional, and local level. to fulfill their mandate they provide information about various disaster risks in order to enhance individual and community disaster preparedness. the staff of these organizations has, in general, limited knowledge of the state of the art in the relevant to risk communication scientific fields and lacks the necessary links with academia that could inform their effort (haddow et al. 2011) . as a result, the approach has been and is still based on the so-called "deficit model" even though its basic assumption (the public is an empty vessel to be filled with information) has been criticized (nisbet and mooney 2007; boersma et al. 2017) . a number of alternative two-way interaction models (also called engagement models) have been proposed (boersma et al. 2017 ). ec has funded relatively few programs to experiment with the so-called engagement models (boersma et al. 2017; musacchio and solarino 2019; yovkov et al. 2015) . in europe and the usa the assessment is that despite more use of various two-way communication approaches, the efforts still fall short of inducing the necessary changes in behavior (boersma et al. 2017 ; national academies of sciences, engineering, and medicine 2018). the conclusion is that more research is needed to determine how to motivate behavior change, as well as to identify what other factors contribute to successful public disaster education campaigns. the information provided to the public usually covers facts for a) basic understanding of specific disaster risks (e.g. earthquakes, floods, etc.), and b) directions to strengthen prevention, inform and educate about the actions and behavior to decrease personal exposure to each specific risk [e.g. for earthquakes: "stop, drop under or beside, and cover" against the natural tendency to flight -evacuate the building during shaking, for severe weather phenomena: having a stock of emergency supplies (water, canned food, etc)], and how to make an individual and/or household emergency plan. it is commonplace to specifically address certain vulnerable populations, like school students. the websites of the responsible authorities and of other organizations (ngos, professional associations, civil society) are full with information of that sort. nevertheless, the effectiveness of the means used (traditional, like pamphlets and contemporary, like social media) has not really been the subject of serious study. recent studies (maduz et al. 2019; kohn et al. 2012 ) have indicated that information seeking behavior is not necessarily a measure of enhanced preparedness. the actual challenge is to make the transition from the so-called "weak preparation" (like storing emergency supplies) to "hard preparation" (e.g. establishing an individual and/or household emergency plan). in a sense, what is required is a qualitative change from "blindly" following some directions to cooperating with others to practice emergency planning and even further, become your own emergency or even disaster risk manager. the concept of resilience with the abundance of definitions (alexander 2013) and the various numbers of dimensions (called domains, properties, or stages) that have been proposed to operationalize it, can be useful in informing that goal. especially, the definition of resilience as "the ability to prepare and plan for, absorb, recover from, or more successfully adapt to actual or potential adverse events" (national research council 2012), the proposition that it encompasses the properties of robustness, redundancy, resourcefulness, and rapidity (bruneau et al. 2003; tierney and bruneau 2007) , and the view (cutter et al. 2008 ) that it consists of inherent resilience and adaptive resilience (through improvisation and learning), when applied to individuals and groups can guide us. they help pinpoint to the knowledge, skills and attitude we need to focus on and communicate to the public in order to enhance its resilience level. in conjunction with individual disaster preparedness surveys that could help identify barriers and possible triggers for its enhancement, they can provide paths to research that could offer some interesting and useful insights for effective risk and crisis communication. depending on the application unit, we can talk about resilience of individuals, infrastructures, institutions, ecosystems and communities (kahan 2015) . it is important to realize that there is inherent, not well understood, interaction between them, e.g. when citizens know what to expect from the authorities then the latter's emergency plans have an increased effectiveness and efficiency and vice versa. pandemics risk, like covid-19, displays a number of characteristics differentiating it from natural disasters, namely: • relatively infrequent occurrence that "deprives" the public from firsthand experience (recent epidemics sars, mers were contained fairly easily). • pandemics risk and its management are surrounded by lots of unknowns and uncertainty, including variable positions by experts, sometimes even seemingly changing over time [adams (2003) considers that it belongs to the so-called "virtual risks"]. • early recognition of the forthcoming crisis is not (always) obvious, resulting in challenges in sense-making. • the guidelines (social distancing, wearing gloves, washing hands frequently, avoiding vulnerable friends and family, staying at home, not going to work, etc.) the public is "advised" -"ordered" to follow are "unnatural". they oppose people's tendency of wanting to spend even more time together when confront-ing a disaster situation. it is this very closeness and camaraderie that have been observed to build people's adaptive resilience in natural disasters. • emergency response lasts much longer (many months) as compared to natural disasters (days to weeks). in addition, as by definition emergency response ends when the situation stabilizes i.e. threat to life and property has fallen down to the pre-emergency level (fema 2006) , even the end is not straightforward but a matter of debate in pandemics. • in pandemics the public has an apparently passive role contrary to natural disasters where the public actively participates in response and recovery activities. it should also be pointed out that pandemics is probably the only disaster risk, that the protective measures bear the potential to cause individual and community resilience decreases in the future, as they negatively influence community competence factors (psychopathologies, health & wellness (brooks et al. 2020) ) of the population and especially of vulnerable groups (elderly, people with chronic sickness, etc.) as well as economic factors (cutter et al. 2008) . therefore, the main question is "how do you protect now, without negatively affecting long term resilience at the individual and community level?" more specifically, what should be the characteristics of the risk and crisis communication campaigns as far as message content and frequency of repetition, how is the effect of the unknowns on the message content managed, what are the possible shortcomings of "the war against an invisible enemy" model (adopted in many countries), what is an effective and viable mixture of coercion and persuasion, etc. all these together form a quite different and more complicated environment for the risk and crisis communication than the one we are used to in natural disasters. they superimpose on the general risk communication challenges referred to previously. besides specific disaster risk communication, risk communication efforts should be targeted to instilling to the public the emergency planning toolbox of knowledge, skills, and attitude, i.e. identifying and assessing disaster risks and vulnerabilities, understanding that preparation is key, and that key to preparation is planning together with others (family members, co-workers, neighbors, etc.), and finally acquiring the mindset for the implementation of a plan and the need to improvise if necessary. the traditional one-way communication approach is not an effective way to achieve these objectives. a framework concept encompassing a variety of two-way communication interactive activities on the above topics altogether in one event, is the so-called community based exercise (cbex). cbex have recently started being utilized with main objective to develop resilience amongst citizens (yovkov et al. 2015) . a cbex uses as trainers/facilitators experts and personnel of organizations that are part of the civil protection system and utilizes the participation of other stakeholders that are part of a community. the choice of the specific objectives, topics and the design of activities (facilitated work sessions, workshops, competitions, demonstrations, short exercises, games, etc.) for the various target groups of a community, are of great importance for the effectiveness of the effort. research in the factors that influence behavioral change could offer new and practical understanding of the interplay between cognitive and demographic drivers/factors of preparedness/resilience. subsequently, such knowledge could be utilized for setting clearly targeted objectives, developing appropriate activities and the corresponding training for the trainers/facilitators. in particular regarding the pandemics risk, it is necessary to understand how the specific characteristics listed before, affect and shape the risk communication effort regarding "hard preparations" as it is of a quite different nature as compared to natural disaster risks. it is also interesting to study the interplay between risk and crisis communication in pandemics as it is also defined by the pandemics' very characteristics. as a final point, we turn to the actual reason we care about all that, which is to see how individual, community, societal resilience is realized in time of crisis and identify ways to enhance it. for an effective crisis management effort, stern (2014) has emphasized the importance of early recognition of a forthcoming crisis, expedient sense-making and use of an appropriate narrative to guide crisis communication by the crisis management team. the distinguishing features of risk communication and crisis communication have been stated by reynolds and seeger (2005) . an underlying assumption is that the latter builds on the former. we would like to claim that, in the presence of early recognition and expedient sense-making, it is possible to display high levels of adaptive resilience even in the absence of any risk communication campaign beforehand by utilizing a pre-existing collective understanding of the system situation. specifically a, well known to all (crisis managers and public), weakness (e.g. the quite limited capacity of the health system) can, almost explicitly, serve as the critical element in the persuasion of the public to adhere to strict measures (movement restriction, etc.). in that way, a weakness is turned around, becoming instead an enabler for crisis communication success. unexpected allies can arise in dire situations. one should not rely on this possibility but it exists and sometimes can save even the ones that have not prepared but showed a particular type of vigilance in crisis. eur 28034 en, publications office of the european union the psychological impact of quarantine and how to reduce it: rapid review of the evidence a framework to quantitatively assess and enhance the seismic resilience of communities a place-based model for understanding community resilience to natural disasters commission staff working document, overview of natural and manmade disaster risks the european union may face, swd(2017) 176 final fema (2006) fundamentals of emergency management online textbook. fema higher education project introduction to emergency management resilience redux: buzzword or basis for homeland security. homeland security affairs 11 personal disaster preparedness: an integrative review of the literature individual disaster preparedness: explaining disaster-related information-seeking and preparedness behaviour in switzerland, risk and resilience report emergency alert and warning systems: current knowledge and future research directions. the national academies press, washington disaster resilience: a national imperative framing science crisis and emergency risk communication as an integrative model from warning to sense-making: understanding, identifying and responding to strategic crises conceptualizing and measuring resilience. a key to disaster loss reduction science for disaster risk management 2017: knowing better and losing less community-based emergency preparedness exercise (cbe) guide, funded by the eu civil protection financial instrument the author would like to acknowledge colleagues and students over the years and especially th. sfetsos (ncsr demokritos) and p. dimitropoulou (univ. of crete) for fruitful discussions. conflict of interest the author declares that he has no conflict of interest. key: cord-289003-vov6o1jx authors: burdet, c.; guégan, j.-f.; duval, x.; le tyrant, m.; bergeron, h.; manuguerra, j.-c.; raude, j.; leport, c.; zylberman, p. title: need for integrative thinking to fight against emerging infectious diseases. proceedings of the 5th seminar on emerging infectious diseases, march 22, 2016 – current trends and proposals date: 2018-02-28 journal: revue d'épidémiologie et de santé publique doi: 10.1016/j.respe.2017.08.001 sha: doc_id: 289003 cord_uid: vov6o1jx abstract we present here the proceedings of the 5th seminar on emerging infectious diseases, held in paris on march 22nd, 2016, with seven priority proposals that can be outlined as follows: encourage research on the prediction, screening and early detection of new risks of infection; develop research and surveillance concerning transmission of pathogens between animals and humans, with their reinforcement in particular in intertropical areas (“hot-spots”) via public support; pursue aid development and support in these areas of prevention and training for local health personnel, and foster risk awareness in the population; ensure adapted patient care in order to promote adherence to treatment and to epidemic propagation reduction measures; develop greater awareness and better education among politicians and healthcare providers, in order to ensure more adapted response to new types of crises; modify the logic of governance, drawing from all available modes of communication and incorporating new information-sharing tools; develop economic research on the fight against emerging infectious diseases, taking into account specific driving factors in order to create a balance between preventive and curative approaches. the objectives of the 5th edition of the val de grace school's seminar were to take a global, integrative approach to the emergence of new infectious disease agents, putting these in perspective relative to other types of risk, as well as studying crisis situations and the breaches brought on by the occurrence of emerging infectious diseases (eids). two key conferences respectively opened and closed this annual seminar; the first was given by dr. peter daszak (president of the ecohealth alliance and program director of usaid-ept-predict), the second by dr. patrick lagadec (former research professor at the é cole polytechnique, palaiseau). planned for an anticipated up to 200 participants, this seminar is designed for decision-makers, experts, medical doctors and scientists interested in human and animal health, social sciences, environmental sciences, prospective analysis, biosecurity and defense. this day of presentations and debates is presented under the auspices of the french social affairs and health ministries, as well as that of the environment, energy and marine affairs. peter daszak remarks today can be summed up in two primary messages, both personal and that of scientists from the ecohealth alliance. first, we must increase our research capabilities in order to understand the direct and less-direct causes of emerging infections if we hope to fight them once they become responsible for epidemics or pandemics. secondly, this presentation was illustrated with a few projects concerning the economics of eids which reveal the extraordinary costs they incur for national economies. there is at least one obvious reason to speak of this, which is that politicians and public decisionmakers are in fact quite sensitized when the economic damage engendered by the latest epidemics and pandemics are explained to them. if one takes, for example, the sars-cov pandemic, it led to a 1 to 2% decrease in gross domestic product in several southeast asian countries, for an estimated overall cost of 30 to 50 billion us dollars, relative to the total number of approximately 800 people worldwide who were affected. the appearance of new eids appears both more frequent and also vaster in terms of number of people affected these last years, many of these diseases appearing in developing or low-income countries. taking the case of the ebola virus (ebov) epidemic which broke out in west africa in 2014, it was much more widespread than any other epidemic to ever occur in central africa (400 people affected during an epidemic). it is very difficult in the united states -where peter daszak is working -to get public decision-makers interested, as is true with the population which feels very distant from such problems. ecohealth alliance has tried to draw the media and the public's attention to it, in vain! they only received one single email from the management of the boston airport, informing us that our work on the risk of ebola virus propagation via transcontinental air transport was unfounded and that the boston airport could not experience this type of threat. about a month later, when an american citizen was repatriated for treatment, the public began to panic; the media, particularly the tv channel cnn, exaggerated in broadcasting the issue, and the government took several decisions, notably regarding assistance and monitoring of international airports. these measures were decided upon no scientific basis in a moment of panic, and it seems that with every new worrisome eid, it is the same story! the measures taken are often disproportionate to the seriousness of the phenomenon. human demography has exploded in recent years, and populations today are concentrated in megalopolises. this tendency is even more marked in tropical areas in the south where there is also an important biodiversity of animal species. therefore, there exist today more opportunities for a virus or bacteria to pass from an animal to a human, then to propagate among the human population. international air transport makes possible the spread of these new infectious risks on a vast scale. what are governments doing faced with this type of threat when the demands on the part of the population are ever-increasing? vaccines are also considered by the former as a weapon of total destruction, and by the public as a widely-available miracle tool. neither is truly aware that it takes an average of 10 years to produce a vaccine. also, is it the right strategy in that it banks more on cure than on anticipation? in the u.s., president obama opted for a development aid policy through usaid favoring training and improvement of human and technical capacities to prevent future eids in the most needy countries. the american congress, however, did not follow this path, instead directing funds allocated to usaid towards research on a vaccine for and on epidemic management of the ebola virus crisis. recently, in collaboration with economists, ecohealth alliance modeled the risk of a new emergence in a situation identical to that of ebola in 2014-15 in west africa, estimating the economic damage caused, and attempted to deduce the economic cost of a health policy based on epidemic management as opposed to one favoring prevention and training. according to their estimates, a budget of 5 billion us dollars seems to suffice to prevent a new epidemic in west africa in opting for the second solution. their simulations obviously include many underlying hypotheses. all the same, this analysis indicates that if we were to quickly make available 1 billion of the 5 billion dollars for the purchase of equipment, the setting up of working laboratories on site, field hospitals, sending doctors and nurses to the area, training of our partners in affected countries -as military medical services know how to do -such a strategy would represent a real capital investment in managing epidemic propagation. unfortunately, this was not the option chosen by u.s. current governments, which we can only regret. now let us discuss the ecology of ebola virus transmission. the bat species pteropus are possibly the host reservoirs of ebola virus. as for the marburg fever virus, we are now certain that these bats are in fact the reservoir. the ebola virus is clearly present in a few giant bat species in africa. it can also circulate among primate species or indirectly through other infected mammals. we also know which species of bats are affected or not. even if the reservoir question is still under debate, we know a great deal about the rainforest circulation of this virus and the circumstances of its spreading in the human population with high-risk groups such as hunters. based on this, is it possible to prevent the virus' transmission to humans? although it poses a complex question, it is nonetheless possible to offer some avenues of reflection. william karesh, vicepresident of ecohealth alliance and instigator of the onehealth concept, carried out a research project in the democratic republic of congo, which consisted in educating villagers, and particularly hunters, regarding the danger of recovering primate corpses from the forest. this program was a real success, as the villagers changed their behavior and the eating of monkey meat. this represents a low-cost prevention approach, which in the end functions well if properly implemented. the only real solution when faced with this type of health threat is to work in conjunction with populations, and to treat questions of poverty, equality, and use and transformation of land together. these are arduous and complex tasks which must be carried out over the long-term. this type of message is extremely difficult to make heard among politicians and the public, and obviously more complex that announcing or clamoring for a vaccine. we are faced with primordial questions which are more or less difficult to answer. are we witnessing an increased frequency of eids appearance? are there more cases today? can we predict patterns, or rules, of emergence? are there geographic areas in which these emerging infections are more frequently or widely observed today? do we possess the scientific ability to predict exactly where the next infectious epidemic will start? evidently, if we were so able we might allocate the financial resources and technical and scientific support to suspected areas. at the moment, we do just the opposite, or we do nothing, and we are disconcerted at each new emergence. in order to convince governing bodies and public decision-makers, we must demonstrate to them that predictive approaches are less costly than curative ones. using approaches inherited from ecology and biogeography ecohealth alliance has adapted the same principles to understanding the ecology and spatial distribution of eid principles observed over the last decades. their work shows that of the nearly 400 new eids which have appeared, the so-called zoonotic ones originating in wild animals have been in net increase in the last 40 years; 3 out of 5 new infections which appear each year originate in wild fauna. what's more, the risk of infectious transmission is highly and doubly correlated with human density, as are these diseases of animal origin to the areas' biodiversity. they called these areas ''hot-spots'' for disease risks, mostly situated in intertropical regions. they are advocating for these specific zones to be those on which they concentrate our research efforts as well as international public aid for development. in fact, it is not only biological diversity in animals which must be taken into account, but also the evolution of natural ecosystems and their disappearance over recent years. deforestation and land use changes by populations are driving forces in the appearance in new eids. therefore, international politicians must better link economic strategies to those of habitat and biodiversity coordination if we wish to avoid new pandemics. in further use of the formalism of economic models, they have shown that a stable political strategy appears once joint simulations were conducted on economic damage due to a pandemic health crisis and preventive decision-making. even though the financial cost of preventive strategies may initially appear great, an optimal solution based on prevention shows itself over the mid-and long-term to be finally less costly than cure and control-focused strategies. we have need on an international level for the equivalent of the intergovernmental panel on climate change (ipcc) which, in the same way as does the ipcc on climate change scenarios and their impact, would concentrate on eids and their sociopolitical, economic and environmental consequences. the american development aid agency usaid did not originally give priority to eids, but the different public health crises brought on by the h5n1 bird flu virus in recent years have led usaid to modify their strategic orientation, notably with regard to the economic weight they bring to bear on regional economies. the fact that these epidemics appear first in countries situated in strongly species-rich intertropical areas which are developing or low-income, requires a reconsideration of our western policies on development aid in order to better include these notions. for ten years, usaid funded a program on new emerging infection threats, for a total of 1.3 billion u.s. dollars. at ecohealth alliance we have collaborated with this initiative through participation in the predict research project with funding of 45 to 50 million dollars. the goal of the predict program was to identify microorganisms potentially pathogenic for human populations, and which are hosted in animal reservoirs. we took particular interest in three animal groups, not only because it was impossible to work on all the animal groups present, but also because the three groups we choseprimates, rodents and bats -were recognized as being major reservoirs of agents which are pathogenic for humans. these three groups alone make up 75% of the world's mammal species. within the predict program we applied our knowledge of the high-risk emergence zones to draw samples from a large cohort of these three animal groups. over the first five years of the program we sampled 56,000 animals, trained 2500 scientists and medical and administrative personnel, and discovered more than 1000 new viruses belonging to families of viruses known not to be infectious to humans. this in itself represents a major finding! obviously, the discovery of a microorganism does not in and of itself indicates that a new eid might appear. their work in mexico on bat species demonstrated the existence of a dozen viruses which are very like the mers-cov responsible for the respiratory syndrome in the middle east. they therefore believe that the mers-cov is not hosted by dromedaries but rather by bats, as they found it in our work in mexico. some of these new coronaviruses may potentially be pathological for humans. it is clearly impossible to identify all viruses present on the planet. it would also be necessary to do the same for bacteria, parasitic fungi, and protozoa. as they are innumerable, it is preferable to make strategic choices regarding microorganism research and that on the highest-risk animal groups. based on our knowledge of currently known viruses in bangladesh bats, they extrapolated this data using species curve rarefaction, and capture-recapture techniques well known to ecologists, to estimate the total number of viruses to be expected in the totality of known mammal species in the world. they reached a value of 320,000 new viruses which remain to be discovered. were we to carry out biodiscovery research on these viruses, one could catalogue them, classify them in relation to already-known viruses, in particular those known to be pathogenic to humans, and through comparative genome studies assess their pathogenic potential. we are currently in the second phase of the us predict program, with an important accent on our manner of working. in fact we are currently concentrating more on factors involved in emergence and seek particularly to understand three such factors: habitat change and use, intensive agriculture, and the commerce of biodiversity. us development aid policy also focuses on three strategic areas: north africa, west africa, and continued research activity in saudi arabia. these geographic choices are shaped by recent events around the mers-cov and ebola viruses. especially in the case of mers-cov, dromedaries are certainly involved in the transmission cycle of the virus, but we believe that its true reservoir is the bat. thus using the many data at our disposal, we were able to show that the infectious risk of mers-cov for humans is not great in saudi arabia, but it is in other areas of contact between bat, dromedary and human populations, particularly in the horn of africa, especially in somalia. somalia is currently a politically disjointed country, where public health surveillance and care are greatly lacking or simply non-existent. for example, it is currently impossible to state how many mers-cov cases there are in somalia, or how many might exist. our scientific objectives are therefore to better understand the behaviors at the junction of wild or domestic fauna and human populations. for example, understanding human behaviors and practices at the interface of tropical forests and villages could help us to interpret how zoonotic transmission happens. through acting upon these behaviors and habits, we could lower this type of emerging risk. currently ecohealth alliance has research sites in uganda, malaysia and brazil; they are investigating the role played by habitat changes such as deforestation, human interaction with biodiversity through behavior and use. in manaus in brazil for example, the maximum risk of new infection is not in the heart of the city where the major markets are located, but in the peri-urban areas where agriculture and ranching are developing. these zones which ecologists call ''ecotones'', or transition zones, are located near strongly species-rich regions, with high concentrations of livestock which can come into contact with wild fauna, and which are furthermore inhabited by ranchers and farmers. these regions which are now located everywhere in the intertropical world for the purpose of feeding urban populations, are generally those where new infections appear, and where future pandemics will also most likely appear. at the heart of this research is the priority of understanding behaviors, habits and practices of populations with the goal of changing these factors. this is a long-term endeavor which requires developing approaches in the field for communicating with local populations, and for developing community participation in our own research, which we also consider an excellent means of education. o. borraz recalled the fact that we live in a society of risk. it is not that the dangers surrounding us are more numerous or more fearsome than before, but simply that the notion of risk plays a central role in public policies, in public and private organizational management, and in the controversies around new technologies. genetically modified organisms, mobile phones, nuclear waste, urban sanitation sludge; the activities now considered health or environmental risks are countless. this categorization puts public authorities in a position of having to ensure the safety of populations, even as the state itself sometimes represents a risk factor. it is therefore essential to understand how an activity becomes a risk, and how it is then managed by public authorities as well as by companies, associations and local conglomerates. risk from its identification to its management, from its highlighting to its instrumentalization becomes a tool linked to the emergence and expansion of a welfare state. it is used by politicians to justify on the one hand its lack of involvement in risk management, on the other the seizing of power over sectors from which they had previously disengaged. this political power seizure plays on politicians' selective dissemination within society of risk identification and the knowledge required for its management. two different processes exist by which risk represents an organizing principle for political power, a means to assist and contribute to the definition of the state's limits: ''putting at risk'' and ''regulation through risk''. ''putting at risk'' refers to all processes by which an event is described as or constitutes a real or predicted danger, and which thus is categorized as a risk [1] . there are many events, objects, and situations which have historically been categorized as ''putting at risk'' and which can be studied by sociologists (illness, divorce, food crises, unemployment, nuclear risk, chemical substances, technological risks. . .). this putting at risk can be a product of the state or of interest groups, under the influence of lobbying. this has been part of the organization of modern societies since the 20th century, and in particular following world war ii with the expansion of the welfare state which took advantage of different factors putting the population at risk in order to enlarge its sphere of activity and thus its power in the name of a protective mission. this welfare state built itself around risk management in creating and organizing agencies, action plans, drills, and monitoring mechanisms for their application through nationwide inspection bodies. the promotion of ''risk instruments'' and a ''risk-based regulation'' approach makes it possible to deal with risk-creating events. for the last two decades, in a context of decreasing means and in reaction to public-health crises which have led, according to some, to an overprotective state, a new tendency has emerged of governments using ''risk instruments'' to better allocate means and to decrease the state's hold. despite their differences, these two approaches are to the same end, which is to define -or perpetually re-define -the limits of the state. ''risk instruments'' contribute in each ''putting at risk'' situation to determining the state's involvement, the reason for its having competencies and resources, and therefore also the state's limits as opposed to that which concerns the private sector and individuals. the outcome of this defining as ''putting at risk'' and of the application of these risk instruments may be used by the state either to invest, or to disinvest; in the latter case for example entrusting risk management which formerly would have been the realm of institutions to local or private agents or to individuals. in the same way, risk instruments (or risk-based regulation or using risks to rationalize public intervention) may lead to state disinvestment or, on the contrary, be used by the state to seize back the reins in certain areas. paradoxically risk instruments serve in this instance to re-centralize or to ''remote-control'' areas to which the state had granted greater autonomy (universities or hospitals, for example). thus the way in which western societies manage risk, and the way in which these risks -their identification, how politicians and individuals perceive them, and their management -transform the links between the state (the political powers-that-be) and civil society are important to understand for those faced with risk management, especially in public-health risk management. what consequences these risk technologies have from one country to another thus greatly depends on institutions, state structure, professional organizations and their interrelationships, the balance of power and the forces involved, and the legal structurewhich may be more or less open to interpretation according to how it is drafted (more or less restrictive laws). risk management is, after all, at the core of the state and has always been central to its transformations. presenter: alfredo pena-vega (ehess, cnrs) climate change can be interpreted, according to a. pena-vega, as a complex system such as edgar morin defined it in his ''introduction to complex thought'' [2] . the stakes involved in it are multidimensional, and suppose at once the ideas of transformation, uncertainty and unexpectedness, unpredictability and crisis. . . it henceforth seems necessary to arm ourselves with instruments enabling us to understand this reality. the common denominator of such instruments is rationality. because climate change involves stakes which are climatological, economic, social and health-related, as well as questions of governance, ethics, biodiversity etc., cross-disciplinarity appears to be one form of rationality which allows us to avoid the dangers of ''fear-mongering''. a study was conducted among 12,000 high school students from 20 different countries, of which the objective was to understand how younger generations see climate change. the results are quite varied. if a minority of responders question the existence of climate change -with an argument largely based on a social construct communicated by the media -90% of responders claimed to be concerned and aware of the negative consequences of climate change. the vast majority consider it to be a threat to the survival of humanity, in particular due to the multiplication of natural disasters, dwindling biodiversity, the spread of new infectious diseases, notably those with vector-borne transmission, and the inequalities it fosters between humans. we are currently in the ''age of the unthinkable''. today's world constantly exposes us to new crisis situations which we must learn to confront. these situations are all the more difficult to manage in that they most often occur ''out of framework'', or within a framework in which it is difficult to define the outlines delimiting an increasingly ''volatile'' environment. whereas our benchmarks in terms of crisis management are structured according to typologies (natural/biological/social disaster), the boundaries of current crises are unclear, and their typologies intertwined. unexpected and unpredictable, they emerge within a context where uncertainty reigns and where the response is organized according to the logic of competitive leadership. information no longer follows a downward flow from the state to the public, but circulates in a collaborative manner via widespread connectivity, social networks, which compete with institutional media which are sometimes outdated. it is therefore difficult for decision-makers to circumscribe the areas of operation, to isolate causes, and to distinguish the components which permit specific, technical and successive interventions. good judgment thus becomes key. public health crises, and especially those concerning eids, have pointed up the difficulties in predicting their appearance and development. comparisons and connections between these and other types of crises (natural, technological, industrial. . .) and how they are interpreted can thus prove useful in public health crisis management. the unattainable goal of predicting such crises makes it necessary to prepare to meet with unexpected events during the ongoing management of the crisis; it is no longer a question of predicting the unpredictable, but preparing to deal with it. in the context of our intricate, complex society, coordination and communication are of course necessary, but it has also become imperative to have a thorough knowledge of the steering process. in ''out of framework'' situations, strategic thinking capability takes precedence over the quality of available technical expertise. this can take the form of an ''express thinktank'', a group made up of diverse members capable of and trained to work together in situations of uncertainty. whereas in a ''classic'' situation the command functions is a pyramid, in these ''out of framework'' situations, collaborative and flowing cooperation is required, without leadership's impeding the efficaciousness of the response. in the case of hurricane sandy in the u.s., in 2003, several work teams were set up in order to handle the unprecedented nature of the situation: ''real-time innovation'', ''immediate flaw detection'', ''emergency support functions''. these parallel work teams made it possible to optimize management of the disaster by limiting disastrous consequences. it seems essential to develop such networkbased crisis management in france. p. zylberman recalled to mind the definition of an eid as an unexpected infectious -or presumably infectious -phenome-non, affecting humans, animals or both. according to the definition used in the high council of public health's 2011 report [3] , this can entail an infectious clinical entity which has just appeared (''true'' emergence), one previously identified (known emergence) or a known infectious disease whose incidence has increased or whose characteristics have changed (re-emergence). the hiv epidemic in the 20th century or the sars-cov epidemic in the early 21st century are examples of true emergence. the emergence of hepatitis c corresponds to a known clinical entity whose etiological agent was identified at the end of the 1980s. the measles and west nile virus outbreaks on the american continent, in the 19th and end of the 20th centuries respectively, are examples of reemergence. nathan d. wolfe has defined five stages of transformation of an animal pathogen into a specifically human pathogen, resulting in a ''true'' emergence, with the possibility of an evolutionary interruption at each stage. stage 1 corresponds to a situation in which a known virus in animals has never yet been detected in humans in natural conditions. in stage 2, the virus known in animals is capable of infecting humans in natural conditions, but without the capability of person-to-person transmission. in stage 3, some cycles of secondary person-toperson transmission are possible. in stage 4, the virus circulates among humans through several secondary person-to-person transmission of varying duration. stage 5 is reached when the virus becomes exclusively human, and also contagious. on a population-wide scale an epidemic goes through four phases: introduction, propagation, amplification, and regression of the infectious phenomenon. the propagation phase is that during which there are the most widespread and frequent sites of infection. it corresponds (particularly for viruses) to the adaptation of the pathogen to its new host with person-toperson transmission taking effect little by little. it is often at this stage that the epidemic phenomenon is detected, sometimes with a considerable delay relative to the introduction of the pathogen. propagation can take place not only by contiguity but also across vast distances. humans thus play a role through their activities, and are what s. morse refers to as ''microbial traffic engineers'' [4] . what are the major factors in the emergence of new infectious pathogens in humans? a great deal of progress has been made in improving the rapidity in identifying new viruses, as j.-c. manuguerra points out. the time delay between the individualization of a new infectious nosological entity and the identification of the causal agent thus continues to shorten, from 14 years for hepatitis c in the 1970s to 2 years for hiv in 1983, and to 6 weeks for sars in 2003; even less for mers-cov. even so, the discovery or the knowledge of the pathogen's existence does not provide all the answers about the risks posed for or by a host species. various behaviors of pathogens can nonetheless be observed, in particular the pathogen's adaptation may require passing through several intermediary host species before adapting to its final host. moreover, the epidemic potential of a discovered virus is difficult to determine. among the very numerous known arboviruses, most are of anecdotal importance for human pathology, and little has been undertaken upon their discovery in preparation in case the pathogen were to become epidemic. this is true in the case of the zika virus, first isolated over 50 years ago, and currently responsible for a major epidemic in latin america and in the caribbean. the question of the time lapse between the beginning of an epidemic and identification of the pathogen is progressively slipping toward that between the beginning of the phenomenon and its detection by the health system. this period appears to be critical for eradicating the development of an epidemic. is it possible to narrow the time gap between the beginning of an epidemic and its detection by the healthcare services? early identification of an epidemic-level incident mobilizes all health services professionals, both in regards to human and to animal health, according to m. van kerkhove. human and animal health and the state of ecosystems are inextricably linked, and it is believed that nearly 60% of eids, including those re-emergent, are of zoonotic origin. it is through this exploration of the connections between animals and humans that the means of transmission and propagation of mers-cov within the human species could be revealed. this virus is an example of a potentially epidemic emergence. schematically, during the mers-cov epidemic, a limited number of person-to-person transmissions, and sporadic cases between dromedaries and humans, were observed, with a certain degree of increase seen in healthcare facilities, sometimes considerable, as was the case recently in korea. during the epidemic 75% of the mers-cov cases were reported in saudi arabia, and of 1600 cases reported to the who task force, 60% were considered to be primary cases, that is, contracted from an animal host source, and 40% to be secondary cases, or acquired through another human case. every primary case represents an opportunity to understand how the infection was contracted. it gradually seemed necessary to launch a veterinary investigation as soon as a case was diagnosed. this led to the development of animal surveillance, which made it possible to reveal the seropositivity of certain dromedaries, as well as active excretion of the virus in their environment, which made possible its transmission to humans. this improvement in detection of emerging pathogens and early epidemic detection calls for the improvement as well of the veterinary surveillance network, the so-called onehealth approach. in an area with limited resources, where all animals cannot be tested, it is imperative to concentrate on those areas with high concentrations of animals, such as slaughterhouses, and on areas in which humans come into close contact with animals and thus represent a high risk of transmission (see conference by p. daszak). the data collected in these areas of frequent contact between humans and animals can be utilized to issue recommendations for at-risk populations in order to reduce transmission. once the virus has acquired person-toperson transmission capability, its control is far more complex due to the rapidity of propagation following its introduction into the population. it therefore becomes difficult for the healthcare system to improve detection of the epidemic. establishing health policies to optimize the case reporting system is thus critical. how to provide care to patients in the case of new eids? in an epidemic situation, the treatment of affected patients usually is secondary to the need to control the disease, as a. mcgeer stated. nevertheless, an adapted patient care procedure can change the evolution of an epidemic, to varying degrees according to the pre-existing healthcare infrastructure in the given country. in north america, where the services for the monitoring and managing of infectious diseases and public health are separated from the healthcare system, the organization of care for infected patients is usually left to the physicians. the healthcare system is in fact organized around individual patient care, and not oriented toward an approach of global individual and collective care providing. in the case of eids, care of affected patients becomes a political issue in a country graced with a public health system. health is seen as a human right, and governments are judged not only by their ability to prevent and manage epidemics, but also according to their management of care provided to ill patients. the role of the public healthcare system is therefore to advise physicians and to develop recommendations for the detection of cases and their homogeneous treatment. these guiding principles make the physicians the kingpins between healthcare structures and the treatment of patients, and the public healthcare system. better patient care provision thus improves epidemic response. in fact, treating ill subjects also allows the risk of person-to-person transmission and propagation to be reduced. this treatment role attributed to physicians can be variously interpreted in countries in which the healthcare and public health system are underdeveloped or lacking. in fact, the arrival of healthcare personnel and the setting up of precautionary measures required to contain the epidemic may be experienced as an intrusion. the lack of comprehension and communication between medical staff and the affected community, as well as the potential lack of comprehension of the measures set in place can prompt affected individuals to hide, due to the uncertainty of their fate. this was the case for example in west africa during the ebola virus epidemic, during which affected patients were sometimes hospitalized far from their villages without care being taken to inform their families of their clinical progress and outcome. this led to sometimes-violent rejection of the healthcare personnel, which interfered with the measures meant to control the epidemic. another element to take into consideration in the care of affected patients is protection of the healthcare personnel, which has become a recurring problem. most of the microbial forms with epidemic potential propagate within the community. for a long time hospitals were not troubled over the risk of nosocomial transmission of eid agents. care providers were not aware at the time of the risk of contagion that they themselves ran when providing care to patients. this awareness happened during the recent sars, mers-cov and ebola epidemics, which shared certain physio-pathological characteristics different from those involved in previous epidemics. in fact the peak of virus excretion for measles, chicken pox and influenza generally occur before or upon the appearance of symptoms, and the risk of transmission is virtually nil when the patient arrives at hospital. sars, mers-cov and ebola virus have a different viral excretion rhythm: symptoms appear with a weak viral load, and their intensity increases with the level of viral excretion, which reaches its maximum just when the patient requires the most care. the hospital thus becomes a center for the propagation of the pathogen. the hospital system is therefore in danger of breakdown, as it is both the pole for patient care and the new center of the infection's transmission. these new pathogens therefore require a re-thinking of hospital design, in order to optimize both control of epidemics and patient care. what has been, or is, the extent of nosocomial infection's role in the transmission of sars-cov and mers-cov? the new pathogens require us to re-evaluate modes of prevention for nosocomial transmission, confirmed b. guéry. the 2003 sars-cov epidemic serves as a good example of what was learned about the intra-hospital transmission of these new pathogens. person-to-person transmission of sars occurs through droplets, physical contacts and airborne pathways. the sars-cov transmission rate to healthcare providers exclusive of invasive procedures has been estimated at 21%. the main risk factor identified was the lack of protection of the provider's airway through wearing a mask, with an odds ratio estimated at 13 . wearing scrubs and handwashing were also associated with lower transmission risk. sars is a disease which appeared in 2003 in guangdong province in china, then in hong kong, where numerous primary and secondary cases occurred. in total, according to the case index, 716 secondary and tertiary cases occurred, of which 52.3% among healthcare providers. beyond standard hygiene measures, studies conducted on affected healthcare providers revealed that certain categories of personnel, such as technicians and nurse's aids, show an infection rate twice that of the nursing staff, and 6 times greater than the medical personnel. these studies made it possible to identify infection risk factors generally not taken into account in the fight against nosocomial transmission of pathogens: a significantly, greatly increased risk (odds ratio 7.3) was noted in care providers having used precautionary measures against sars transmission for less than 2 hours, as was the case with those not having understood the protective measures (odds ratio 3.1). the factors identified as influencing transmission are patient viral load and patient index distance. the ideal conditions for transmission to occur are those of an infected patient excreting large quantities of virus, presenting with a certain number of comorbidities capable of masking the initial profile, and the existence of multiple close contacts with high-risk procedures such as oro-tracheal intubation, performing a fibroscopy, or the administration of treatments through nebulizers. the idea of a ''super-excreter'' patient was also identified during recent respiratory virus epidemics. this concept could play a crucial role. usually it concerns cases of very serious infection occurring in patients with several co-morbidities. in beijing in 2003, the sars case index was also associated with a large number of secondary cases (76 cases, of which 12 among healthcare personnel). as with mers-cov, despite a relatively low basal reproduction rate (r0), a large number of care providers were infected during the epidemic. this is what happened, for example, in abu dhabi, where 65 cases of mers-cov were diagnosed, of which 42% among healthcare providers. each case of provider infection was followed up through an epidemiological study, and each time an obstacle to the isolation of the patient and to the application of hygiene practices was noted. over 80% of the mers-cov cases identified in korea were thus traceable to 5 ''super-excreter'' patients. this notion remains questionable, as it is reductionist and could lead to the identification only of patients in this category, to the neglect of transmission risks associated with other patients. it is probably more fair to speak of ''hyperexcretion events'' which implies that each patient is at maximum risk, and should be treated using precautionary measures. in conclusion, the intra-hospital control and transmission of eids can only occur in connection with the development of precautionary standards, which should be ongoing over time, and should be applied by all healthcare providers. it is imperative to ensure that caregivers are adequately and regularly trained, and that they constantly keep in mind the importance of isolation of all infected patients. to achieve this, it is probably necessary to resort to specialized units, in reference hospitals, in conjunction with clear decisions at the national level. an integrated approach to health in face of the globalization of risk has been developing over the last few years. the ''onehealth/ecohealth'' concept, or global health, takes into account the fact that human health, animal health and environmental health are inextricably linked, especially in regards to eids, exposure to which is fostered by the multiplication of transcontinental travel, many instances of human-animal contact, and intensive farming and ranching. many recent examples have made it possible to establish the key role played by animal biodiversity in the introduction and transmission of pathogens within human populations. whether it be the role of bats in the 2014 ebola virus epidemic, or dromedaries in the 2012 mers-cov epidemic, the crucial role of animals and of human-animal contact -being wild or domestical animals -in triggering an epidemic has recently been emphasized. primates, rodents and bats are the three mammal groups most likely to be at the origin of future pandemics due to the high proportion of viruses which they share with humans. the inclusion of fields which appear quite unrelated (infectious diseases, animal health and ecological and environmental sciences) should thus be pursued and improved. it has been possible to establish models which allow the prediction of emergence tendencies in infectious diseases, and certain geographical areas at high risk for emergence have been identified: central africa and west africa, southeast asia, central america. these areas correspond to those at high risk of propagation due to underdeveloped or deficient public health systems, and to the absence of epidemiological surveillance. tools necessary for effective prevention of future epidemics are now available. these are all the more critical in that recent increasing tendencies raise fears of a multiplication of the number of emergent epidemics in future. beyond the fight against pathogen propagation, its introduction into the human population is in fact a key step against which ''battle plans'' can be drawn up. in order to perfect pandemic response, it is necessary to improve the coordination and interconnection between individual and institutional participants, such as healthcare providers and public health systems. a global response approach (oneresponse) should be reflected upon and developed. on an institutional level, a first step in bringing together the fields of environment and animal health occurred in 2010 in france with the creation of a national french agency for food, environmental and occupational health & safety (anses), originating in the french agency for food safety (afssa, which also includes the national agency for veterinary drugs) and the french agency for environmental and occupational health & safety (afsset). another case of bringing together the areas of surveillance, prevention and human health intervention occurred in 2016 with the creation of the french public health agency, with the merger of the health surveillance institute (invs), the national institute for prevention and health education (inpes), and the organization for preparedness and response to health emergencies (eprus). the relations between these two new institutions should be developed in order to provide a better-coordinated response to future health crises. the response to an eid should take into account not only factors linked to eids, but also to a constellation of political, economic and socio-cultural constraints. the decision to put in place such a battle is in fact a political decision which involves, beyond the scientific aspects, the intervention's impact upon the popularity of the acting political powers-that-be. if governments are judged according to their ability to prevent epidemic crises, they are equally judged on their ability to avoid expenditures deemed excessive given the existing risk. these political considerations can run counter to the scientific rationale behind the response. this is how, in the case of the 2014 ebola virus epidemic, the united states became involved: through the declaration by the liberian president on august 6, 2014, on the threat to national security posed by ebola, and the danger of the spread of the epidemic to the u.s. soil. in parallel with vaccine research and development, the actions of the u.s., the who and the united nations have focused on treatment of infected patients and the epidemiological securing of burials. in addition, despite a sometimes limited human impact, the economic impact of epidemics involving indirect costs (consequence for certain sectors of activity) has shown a marked increase. however, what characterizes modern epidemics is the duration of the economic ''shock'', in that it is temporary, as opposed to previous epidemics during which the shock tended to be drawn out in particular due to the persistence of infectious sources. there are many examples of this: among others, the ''spanish influenza'' of 1918, the effects of which (company closures, loss of revenue) faded out in 1921, or, more recently, the sars-cov epidemic, when the recession, that had been triggered by alerts against travel to southeast asian destinations communicated in march, ceased once these alerts were lifted two or three months later. it is of note that during the sars-cov epidemic only certain sectors (especially tourism) were affected in asia and in ontario, canada, and not the entire global economy. carrying out preventive measures such as staff training makes it possible to limit the number of crises at a lower cost. the costeffectiveness of such an approach has already been shown. it is henceforth necessary to raise awareness in decision-makers of the importance of prevention relative to risk. beyond these constraints, the decision to intervene is complicated by the heterogeneous nature of potential epidemics of the different pathogens. for this reason, and given the absence of technology permitting the prediction of the epidemic potential of a pathogen, prevention which targets the agent is impossible. prevention must therefore adopt other means, such as training locals in order to improve hygiene conditions. the improvement of transversal knowledge on infectious agents' transmission carries particular importance for the goal of preventing emergence. once an emerging agent is introduced into the human population, the pathogen propagation phase within the human population is the key phase in the development of the epidemic, and the one during which it is still possible to act in order to prevent the amplification of the pathogen in the population. the beginning of the propagation phase can be difficult to identify, and improvement in diagnostic techniques as well as the development of rapid diagnostic tests, and even on the field, makes it possible to accelerate detection of an epidemic signal. moreover, given the key role of certain animal species in the development of new epidemics, the development of animal health surveillance would allow us to further shorten the time lapse between the introduction of the pathogen and its propagation; however, this poses significant problems of wild animal monitoring particularly in southern hemisphere countries. better knowledge of states' operational modes in dealing with risk makes it possible to better understand their interventions and to better adapt the scientific response. the notion of risk has, little by little, become political, and the state uses risk to govern. risk management is therefore at the very heart of the state. recent public health crises have led to risk's taking on a new form, that of the unknown, by the fact of the unpredictability of its appearance and evolution. an interaction between scientific and political approaches to risk is absolutely necessary, in order to better evaluate at-risk situations according to modern methods such as structured decisionmaking, and to better handle risk-management tools. the changing nature of risks calls for the emergence of a new form of governance, which puts the individual back into the center of the state's action, as well as the confronting of arguments with expert committees. civil society's participation in risk management should be developed, and observation should once again play its part in crisis response. younger generations might also take greater part in responding to current crises. seven priority proposals can be outlined as follows: encourage research on the prediction, screening and early detection of new risks of infection; develop research and surveillance concerning transmission of pathogens between animals and humans, with their reinforcement in particular in intertropical areas (''hot-spots'') thanks to public support; pursue aid development and support in these areas of prevention and training for local health personnel, and to foster risk awareness in the population; ensure adapted patient care in order to promote adherence to treatment and to epidemic propagation reduction measures; develop greater sensitization and training among politicians and healthcare providers, in order to better prepare them to respond to new types of crises; modify the logic of governance, drawing from all available modes of communication and incorporating new information-sharing tools; develop economic research on the fight against eids, taking into account specific determining factors in order to create a balance between preventive and treatment approaches. the authors declare that they have no competing interest. introduction à la pensée complexe les maladies infectieuses émergentes : état de la situation et perspectives. available online: www global microbial traffic and the interchange of disease we are grateful to the speakers who generously brought their contributions to this seminar: peter daszak, olivier borraz, we thank corinne jadand for helpful organization and management support. key: cord-308184-w8ewm8ve authors: sarzi-puttini, piercarlo; marotto, daniela; antivalle, marco; salaffi, fausto; atzeni, fabiola; maconi, giovanni; monteleone, giovanni; rizzardini, giuliano; antinori, spinello; galli, massimo; ardizzone, sandro title: how to handle patients with autoimmune rheumatic and inflammatory bowel diseases in the covid-19 era: an expert opinion date: 2020-05-05 journal: autoimmun rev doi: 10.1016/j.autrev.2020.102574 sha: doc_id: 308184 cord_uid: w8ewm8ve • a correct patient risk stratification is of paramount importance for the proper management of economic and human resources. • it's fundamental to prioritize clinical trials evaluating dosing, prophylaxis, and treatment with immunosuppressant in covid-19 in order to avoid either an overuse and a treatment shortage. • future controlled studies may highlight in our patients a potential preventive role of immunosuppressant therapies in the development of severe forms of covid-19. • despite the overall risk of infection in rheumatic and gastroenterological diseases a conclusive association between these diseases and covid −19 remains questionable. since december 2019, the new coronavirus infections covid-19 has spread like a rising tide overwhelming the world. this unabated spread led the world health organisation (who) to classify it as a pandemic on march 11,2020 a global public health emergency that will also have serious social and economic repercussions [1] . the last time the who declared a pandemic was for h1n1 swine flu in 2009. at the time of writing, covid-19 has killed more than 30,100 people and, unfortunately, this number will continue to rise. while awaiting the development and distribution of a vaccine, scientists around the world are racing against time in the search for possible therapeutic strategies based on those used in previous health emergencies [2] . everyone, from governments to clinicians and entire populations, feels disoriented before this unknown enemy, and so scientific societies have been drawing up constantly updated guidelines in a bid to aid physicians caring for patients with autoimmune rheumatic and inflammatory bowel disease [3] [4] [5] [6] [7] [8] [9] . the highly contagious and phenotypically diverse sars-cov-2 virus has a direct impact on everybody's daily life, particularly in the case of already vulnerable patients [10] . preliminary recommendations regarding changes in the treatment of the patients with autoimmune diseases attending our rheumatology and gastroenterology units. patients with rheumatic and inflammatory bowel diseases (ibds) may be at higher risk of infection [6, 7, 11, 12] . disease activity, co-morbidities, immunosuppressive drugs including glucocorticoids (gcs), disease-modifying antirheumatic drugs (dmards), conventional synthetic (csdmards), biological (bdmards), targeted synthetic dmards (tsdmards), and the biological agents currently available for treating patients with ibd are all considered risk factors for infective complications. in addition, there are the risks inherent to the individual diseases and their treatments. the overall risk is increased if more than one of these drugs are taken, therefore preventing infections is a crucial part of the management of rheumatic and gastroenterological patients [13] [14] [15] [16] [17] . for example, before starting tumour necrosis factor (tnf)-α blocking agents or biological agents in general, quantiferon-tb is required for the diagnosis of latent or active tuberculosis, and it is rheumatological diseases and ibd are immune disorders that are associated with an increased risk of developing opportunistic and community-acquired infections such as respiratory virus infections. they are therefore also at risk of high co-morbidity and mortality rates, particularly those receiving immunosuppressive therapy [11, 12, 16] . this has raised concerns about the potential risk of covid-19 infection in ibd patients (particularly those who are taking immunosuppressants or biological drugs) because of the high morbidity and mortality rates observed in the old and frail with co-morbidities. however, to the best of our knowledge, the only data concerning the risk of sars-cov-2 infection in ibd patients come from just one study [19] , and there are no data concerning the risk in rheumatic patients. the observational study of ibd patients was carried out in wuhan, china, during the peak of the outbreak (between january 1,2020 and february 8,2020) involved 318 patients with a mean age of 39 years who answered a questionnaire covering concerns about their clinical condition and disease relapses. as a result of the early warning and strict preventive measures, none of the patients developed any significant clinical manifestation of covid-19 infection, not even those being treated with corticosteroids (12.6%), immunosuppressants (11%) and biological agents (6%), or those with co-morbidities. at the end of the study period, none of them reported any significant respiratory symptoms or other clinical manifestations attributable to viral infection, and none had a confirmed diagnosis of covid-19. an international pediatric and adult registry designed to monitor and report the outcomes of [ 24] . unfortunately, there are no data concerning the risk of relapse of ibd and related symptoms in patients with sars-cov-2 infection but, given that worsening symptoms or relapsing ibd are usually characterised by diarrhoea, nausea, vomiting and fever, these may mimic and hide a covid-19 manifestation. as this could be misinterpreted as a pure relapse, it would be appropriate to investigate other more specific symptoms of covid-19, such as headache, dyspnoea, or changes in smell and taste before planning an examination or treating such patients. at the time of writing, italy has the third highest number of covid-19 cases after usa and spain it is essential to promote the basic protective measures against covid-19 recommended by the who for everybody [25] :  stay at home and follow the directions of the local health authority;  maintain social distancing of at least two meters from anyone;  wash hands frequently and thoroughly with soap and water or clean them using an alcoholbased hand rub;  avoid touching the eyes, nose and mouth  practice respiratory hygiene by covering the mouth and nose with a bent elbow or tissue when coughing or sneezing (and immediately dispose of the used tissue);  seek medical care early if symptomatic. in addition, people should be educated to wear a mask in order to avoid infecting other people, avoid public toilets, and use gloves for shopping and all other outside activities. given the speed at which the pandemic is evolving, all of our patients have been asked to keep themselves informed and been told that our units would provide them with behavioural indications that will enable them to comply fully with all of the provisions issued by the italian government and regional institutions. all patients should be warned not to discontinue or reduce their treatment without consulting their rheumatologist unless they have specific symptoms. the first challenge for rheumatologists is to decide whether to interrupt or continue a treatment: although it is true that the treatment is designed to control disease activity, it is also undeniable that the same treatment may expose patients, such other infection, to an increased risk for covid-19. it is known that infections are a major concern in patients with overt inflammatory arthritis as they can contribute to disease flares [26] . one prospective cohort study of patients with inflammatory polyarthritis showed that the risk of hospitalisation because of infection is 2-4 times higher than in the healthy population [27] . similarly, an analysis by the us corrona registry of rheumatoid arthritis (ra) patients has shown that each 0.6 unit increase in the 28-joint disease activity score (das28) corresponds to a 25% increase in the rate of infections requiring hospitalisation and a 4% increase in the rate of outpatient infections [28]. j o u r n a l p r e -p r o o f although there are no published data supporting it, we prefer to discontinue the use of rituximab (rtx) infusions because of the related risk of infections. rtx is a monoclonal antibody that acts by binding the cd20+ surface antigen, thus leading to the depletion of cd20-positive b cells. it was originally approved for the treatment of a broad variety of hematological disease such as b-cell lymphoma, but it has been increasingly used in various autoimmune diseases in which b cells are thought to play a key role, and is now also approved for the treatment of severe active ra and granulomatosis with severe active polyangitis and microscopic polyangitis. in addition to infections. which remain a major concern for patients receiving rtx, another rare but potentially fatal complication associated with rtx infusion is cytokine release syndrome (crs), a life-threatening condition generated by uncontrolled immune activation that leads to multi-organ failure and eventually death [29] . covid-19 can induce such a "cytokine storm" [2, [30] [31] [32] of over-active effector t cells and the bulk production of pro-inflammatory cytokines, thus leading to acute lung injury (ali) and ards [33] . cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in autoimmune diseases. given its increased risk of opportunistic infections and potential haematological alterations such as leukopenia and thrombocytopenia we prefer to discontinue it although, at now, there aren't data supporting it [34, 35] . another important and much debated issue is how to deal with the use of corticosteroids, which do not seem to add any benefit in terms of the clinical outcome of covid-19, and may actually slow virus clearance. we therefore consider it appropriate to reduce their administration to the minimum effective dose, but not below 5-10 mg of prednisone per day. a great tumult arose about the use of nsaids after the french minister of health''s statement advising against the use of ibuprofen in patients with covid-19. the european medicines agency (ema) has reiterated that up to now there is no scientific evidence of a link between ibuprofen and the worsening of covid-19, although the situation will have to be monitored over time [36] . we believe that it is best to be prudent and that it is up to each individual rheumatologist to choose which nsaid or analgesic to use for each specific case. we therefore recommend their use on demand, albeit for as short a time as possible. a recent study found that chloroquine, a long used antimalarial drug, had a potent in vitro antiviral effect in a covid-19 assay by increasing the endosomal ph required for virus/cell fusion and j o u r n a l p r e -p r o o f interfering with the glycosylation of cell receptors, thus adding to its well-known immunemodulating action [37] . chloroquine is being considered for inclusion in the next versions of the guidelines for the prevention, diagnosis and treatment of covid. 19 [3] . although the available data do not suggest that there is a specific risk of sars-cov-2 infection and morbidity in ibd patients receiving immunosuppressive treatment, it is known that opportunistic infections have deleterious effects on such patients, which suggests that the risks and benefits of the treatment should be balanced before continuing its administration. there is evidence showing that ibd patients have impaired innate mucosal immunity, but they should not be considered as having altered immunocompetence per se. the current guidelines recommend screening patients who have to start immunosuppressive or biological therapy for some, but not all viruses: for example, screening for hbv, hcv and hiv is recommended, but screening for herpes simplex virus (hsv), patients should be vaccinated against vzv using inactivated vaccine before starting any immunomodulatory therapy because of the greater risk of developing severe viral infection [12] . given that there is no vaccine or specific treatment for covid-19, it seems that the only preventive measure that could be taken is to discontinued immunosuppressive treatment while bearing the associated risks in mind. there are no data that contraindicate the use of oral or rectal mesalazine, which can and should be continued if it is already being used. although the chinese experience suggests that the short-term use of low-dose steroids (≤0.5-1 mg/kg for seven days) may be beneficial in controlling overwhelming inflammation and cytokinerelated lung injury as much as possible, it is better to avoid systemic steroids, especially if they are any patient who develops symptoms of any infection such as fever, cough and/or shortness of breath should be tested (pharyngeal and/or nasal swab, sputum, bronchoalveolar lavage fluid) and given medical care. as sars-cov-2 preferentially proliferates in type ii alveolar cells, a higher positive rate of nucleic acids is found in the lower respiratory, and so a specimen taken from this area is to be preferred. however, an initial negative test should be repeated on subsequent days because peak viral shedding occurs 3-5 days after disease onset. in the case of a positive test, immunosuppressive treatment with traditional dmards other than chloroquine or hydroxychloroquine, biological dmards (bdmards), small molecules, and biological agents for ibd should be discontinued throughout the course of the infection. we believe that a temporary suspension of even one month does not worsen disease activity, whereas, at now, given the well-known infectious risk relating to these therapies, continuing immunosuppressive therapy would lead to the possibility of a rapid evolution of the infection. we resume biological agents after patients have undergone two negative tests and their full blood counts, creatinine, bilirubin, albumin, ldh, ast/alt, ck, crp, il-6, troponin t and ferritin levels, pro-thrombin (inr) and lipid profiles have normalized. our prudent attitude, guided by current scientific evidence on immunosuppressant infectious riskrelated, does not preclude the possibility that future data will instead highlight the protective role of these therapies in the development of severe forms of covid-19 [43] . in accordance with the provisions of the italian government and regional institutions, all deferred medical services were suspended except for those required for urgent clinical conditions (within three days) and those that could only be delayed for ten days. consequently, all of the scheduled clinical and instrumental evaluations of stable patients in regular follow-up were re-scheduled, although is still possible for patients to interact with their dedicated rheumatology and gastroenterology team via phone interviews and social networks, thus making it possible to monitor their clinical condition [44] . they can also send in the results of routine laboratory tests and report any problems with their clinical condition or current therapies. electronic intensive care unit (e-icu) monitoring programs, which allow nurses and physicians to monitor the status of sicker patients are ideal, but patients who report symptoms suggesting a recurrence are preferably assessed by means of a telephone interview in order to clarify the severity of the episode and make therapeutic decisions [45] . patients complaining symptoms suggesting a severe relapse are invited to visit the hospital (while strictly complying with all of the necessary procedures) with the aim of assessing the need for hospitalization, and the consequent diagnostic and therapeutic procedures. patients on the surgical list were contacted by our reference surgeon and re-scheduling was considered, while ensuring a non-covid path for urgent interventions. the following procedures were defined for patients enrolled in controlled clinical trials: -they can only be admitted to hospital if they are being treated with intravenously administered drugs; -if they are being treated with subcutaneous drugs and unpostponable visit is planned, the sponsor is asked to have the drug delivered to their home; -the possibility of carrying out laboratory tests at trusted laboratories close to each patient's home is verified. the de novo enrolment of patients with rheumatic disease and/or ibd is continued only if the study drug is the only therapeutic alternative. for the more than 1000 patients administered biological drugs at our rheumatology and gastroenterology units, the following general measures have been taken: -they are received by a nurse who provides them with an alcohol solution for hand cleansing, a mask and gloves; -they then undergo the planned outpatient examination by a doctor from the rheumatology or gastroenterology team; -infusions are administered in special rooms with armchairs separated by more than one meter (as mortality is higher among elderly patients [46] , they are allocated single rooms in order to avoid any other possible contact); -if necessary, the time interval between infusions is extended. in the case of subcutaneous biological therapies, lombardy's regional government has activated alternative means of delivering the medicines for home use in order to limit the need for patients lombardy but unable to attend a regional hospital for objective reasons, the ats schedules the collection of drugs from the hospital pharmacy and their delivery to each patient's home by a courier; in the case of patients resident, domiciled or simply present in the territory of the ats who are being treated at a hospital outside lombardy and for whom movement is not recommended, the ats coordinates with hospital facilities in lombardy in order to guarantee the continuation of the therapeutic program. some recent studies have reported that chloroquine has an antiviral effect on covid-19 assays, and chloroquine and its analogue hydroxychloroquine are well known to rheumatologists. the repositioning of old drugs to antiviral treatment is a remarkable strategy because the drugs have well-known safety profiles, side effects, schedules and drug interactions [37, 47] . recent findings have shown that hydroxychloroquine is three times more potent than chloroquine [48] .  despite the overall risk of infection in rheumatic and gastroenterological diseases a conclusive association between these diseases and covid -19 remains questionable. possible world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19) covid-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? simit vademecum available nhs clinical guide for the management of rheumatology patients during the coronavirus pandemic available from are my patients with rheumatic diseases at higher risk of covid-19? second european evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease infection and malignancy in rheumatic diseases update of eular recommendations for vaccination in adult patients with autoimmune inflammatory rheumatics diseases eular recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases protection of 318 inflammatory bowel disease patients from the outbreak and rapid spread of covid-19 infection in wuhan, china. the lancet mechanisms and management of chimeric antigen receptor t-cell therapy related toxicities epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (covid-19) with gastrointestinal symptoms manifestations of digestive system in hospitalized patients with novel coronavirus pneumonia in wuhan, china: a single-center, descriptive study review article: gastrointestinal features in covid-19 and the possibility of faecal transmission clinical characteristics of covid-19 patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study who -coronavirus disease (covid-19) advice for the public available from anti -tnf therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment british society for rheumatology biologics register with special emphasis on risks in the elderly risk and predictors of infection leading to hospitalization in a large primary-care-derived cohort of patients with inflammatory polyarthritis rituximab-induced cytokine storm in the absence of overt lymphoproliferative disease pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology how the sars coronavirus causes disease: host or organ-ism? preventing covid-19-induced pneumonia with anti-cytokine therapy. the lancet rheumatology dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in sars-covinfected mice risk of infection with different immunosuppressive drugs combined with glucocorticoids for the treatment of idiopathic membranous nephropathy: a pairwise and network meta-analysis int immunopharmacol infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies european drugs agency to review safety of ibuprofen remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro on the use of corticosteroids for 2019-ncov pneumonia potential benefits of precise corticosteroids therapy for severe 2019-ncov pneumonia clinical course of covid-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies ann rheum dis virtually perfect? telemedicine for covid-19 telehealth for global emergencies: implications for coronavirus disease 2019 (covid-19) case-fatality rate and characteristics of patients dying in relation to covid-19 in italy hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) hydroxychloroquine and azithromycin in patients with severe covid-19 infection natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing sars-cov-2 infectivity? infection and rheumatoid arthritis: faraway, so close! autoimmun rev scarpa r could sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects? autoimmun rev interferons at age 50: past, current and future impact on biomedicine what is the role of rheumatologists in the era of covid-19? key: cord-306008-kh4y44uy authors: khalatbari-soltani, saman; cumming, robert g; delpierre, cyrille; kelly-irving, michelle title: importance of collecting data on socioeconomic determinants from the early stage of the covid-19 outbreak onwards date: 2020-05-07 journal: j epidemiol community health doi: 10.1136/jech-2020-214297 sha: doc_id: 306008 cord_uid: kh4y44uy disadvantaged socioeconomic position (sep) is widely associated with disease and mortality, and there is no reason to think this will not be the case for the newly emerged coronavirus disease 2019 (covid-19) that has reached a pandemic level. individuals with a more disadvantaged sep are more likely to be affected by most of the known risk factors of covid-19. sep has been previously established as a potential determinant of infectious diseases in general. we hypothesise that sep plays an important role in the covid-19 pandemic either directly or indirectly via occupation, living conditions, health-related behaviours, presence of comorbidities and immune functioning. however, the influence of socioeconomic factors on covid-19 transmission, severity and outcomes is not yet known and is subject to scrutiny and investigation. here we briefly review the extent to which sep has been considered as one of the potential risk factors of covid-19. from 29 eligible studies that reported the characteristics of patients with covid-19 and their potential risk factors, only one study reported the occupational position of patients with mild or severe disease. this brief overview of the literature highlights that important socioeconomic characteristics are being overlooked when data are collected. as covid-19 spreads worldwide, it is crucial to collect and report data on socioeconomic determinants as well as race/ethnicity to identify high-risk populations. a systematic recording of socioeconomic characteristics of patients with covid-19 will be beneficial to identify most vulnerable groups, to identify how sep relates to covid-19 and to develop equitable public health prevention measures, guidelines and interventions. importance of collecting data on socioeconomic determinants from the early stage of the covid-19 outbreak onwards saman khalatbari-soltani, 1,2 robert g cumming, 1,2 cyrille delpierre, 3, 4 michelle kelly-irving 3,4,5 abstract disadvantaged socioeconomic position (sep) is widely associated with disease and mortality, and there is no reason to think this will not be the case for the newly emerged coronavirus disease 2019 (covid-19) that has reached a pandemic level. individuals with a more disadvantaged sep are more likely to be affected by most of the known risk factors of covid19 . sep has been previously established as a potential determinant of infectious diseases in general. we hypothesise that sep plays an important role in the covid-19 pandemic either directly or indirectly via occupation, living conditions, health-related behaviours, presence of comorbidities and immune functioning. however, the influence of socioeconomic factors on covid-19 transmission, severity and outcomes is not yet known and is subject to scrutiny and investigation. here we briefly review the extent to which sep has been considered as one of the potential risk factors of covid-19. from 29 eligible studies that reported the characteristics of patients with covid-19 and their potential risk factors, only one study reported the occupational position of patients with mild or severe disease. this brief overview of the literature highlights that important socioeconomic characteristics are being overlooked when data are collected. as covid-19 spreads worldwide, it is crucial to collect and report data on socioeconomic determinants as well as race/ethnicity to identify high-risk populations. a systematic recording of socioeconomic characteristics of patients with covid-19 will be beneficial to identify most vulnerable groups, to identify how sep relates to covid-19 and to develop equitable public health prevention measures, guidelines and interventions. the socioeconomic gradient in health is ubiquitous, 1 and has been described across pathologies, in life expectancy and mortality. it is characterised by a social patterning of health, where the most socially disadvantaged are more likely to be exposed, to get sick and to die compared to their advantaged counterparts. the most commonly used individual measures of socioeconomic position (sep) are occupation, income and education, 2 each one measuring different components and aspects of the social environment. all have well-established associations with numerous health outcomes and mortality, through various pathways such as behaviours, chemical and physical exposures or chronic stress exposures. 3 moreover, evidence has suggested a link between disadvantaged sep and increased risk of infectious disease in general 4 5 and immune response. people with disadvantaged sep should be considered as high-risk populations at the time of any infectious disease outbreak 6 since their social context could affect the occurrence and severity of an infectious disease via several pathways. 4 the outbreak of coronavirus disease 2019 (covid-19) caused by the novel coronavirus sars-cov-2 was first reported on 31 december 2019, in wuhan, china, and has since spread to 184 countries and regions globally. as of 9 april 2020, there were more than one million and half confirmed cases (n=1 511 104) and 88 338 deaths. so far, advanced age, being a man and having chronic conditions, such as obesity, diabetes, respiratory disease, kidney disease and cardiovascular diseases (cvd), have been linked with more severe covid-19 symptoms often leading to the development of acute respiratory distress syndrome (ards) and progression from ards to death. 7 other potential factors such as race/ethnicity and socioeconomic factors may also play an important role in the covid-19 epidemic. while the economic impact of the covid-19 outbreak and the resulting measures have been raised as an important issue, we should not neglect individuals' own sep and its effect on covid-19 incidence, transmission, severity and mortality. based on our previous knowledge of social and structural determinants of health, there is no reason to think that these factors are any less important in affecting who is exposed to covid-19, who gets sick, who is likely to need intensive care and who will die from it. without collecting data on these social factors and making them available, we are blind to how these factors affect the epidemic and how they may be used to inform public health prevention measures. here we attempt to briefly assess the extent to which the current data available on covid-19 take into account socioeconomic factors. we then make the case for why social factors are likely to be involved, both directly and indirectly, in the epidemiology of covid-19, and therefore why they need to be collected. we identified published studies through a rapid review of pubmed from inception to 03 april 2020, with the following search terms: ('covid-19', 'sars-cov-2') and ('characteristic', 'risk factors', 'socio', 'socioeconomic', 'occupation', 'education', 'income', 'wealth'). we also screened the reference lists of the eligible publications. we included studies that were written in english and reported descriptive characteristics of covid-19 cases or reported risk factors of covid-19 incidence, severity and mortality. the search identified 161 articles; after title, abstract and full-text screening, 16 publications were eligible for inclusion. we identified another 13 eligible publications through reference screening. most of the studies were from china (n=26; mostly in wuhan), two from singapore, one from europe and one from the diamond princess cruise, japan. all studies included cases of covid-19, and the sample sizes range from 18 to 72 314. of note, in the rush to publish covid-19 papers, it is highly possible that the same sample of patients have been reported in different articles. 8 while all included studies reported data on age, gender and comorbidities, only one study reported any indicator of sep. in this study, shi et al, using data on occupational position from 484 covid-19 patients in zhejiang province of china, reported that severe cases were more likely to be agricultural workers and less likely to be self-employed than mild cases. 9 to our knowledge, no study thus far has reported data on other sep indicators such as educational level, income and housing conditions. one of the reasons for this is that data on individual-level sep are not being collected. this could be due to the suggested world health organization standard covid-19 case report form 1 which only asks for each patient's age, sex/ gender, place where the case was diagnosed and usual place of residency. this could also be due to the fact that social measures are not considered as data of clinical interest by most clinicians. the consequence is that these data are absent from medical records, limiting the possibility of studying the evolution of diseases with regards to these determinants. however, it is critical to also consider socioeconomic factors at each phase of the epidemic to effectively interrupt humanto-human transmission chains, prevent further spread through appropriate equitable interventions, as well as to identify and better treat individuals who have greater susceptibility to becoming severe or even critically ill upon infection. the reasons why individual sep must become 'clinical' data in the same way as age are numerous: ► a person's occupation may expose them to risk by the nature of their job. work involving constant human contact, interaction with others or caring for people means that risk of infection spread through droplets of aerosol is higher. 10 with regards to covid-19, occupation is likely to be a direct determinant of infection and an indirect determinant of disease severity and mortality through the relationship between occupational social class and comorbidities. for example, the direct impact of occupation on the covid-19 incidence could be seen among workers such as retail staff, cleaners, teachers, healthcare workers or crew on board cruise ships. 11 people in disadvantaged sep categories are more likely to be exposed to job stress including high job strain, burnout and unemployment, which may lead to disrupted immune and inflammatory system responses 12 13 as well as an increased risk for cvd. 14 so far, both reduced immune function and the presence of cvd are known risk factors of covid-19 severity. ► low income might affect living conditions in many ways, such as residence in more deprived neighbourhoods and housing conditions, especially cramped or overcrowded housing, which has been associated with an increased risk of infection from numerous pathogens, such as tuberculosis 15 helicobacter pylori 16 or epstein-barr virus. 5 ► a lower education level is indirectly associated with a number of factors that may increase the risk of developing severe forms of covid-19, such as increased prevalence of smoking and poor nutrition, which could suppress the immune system. a recent systematic review of five retrospective or prospective studies reported that smoking is most likely associated with adverse outcomes of covid-19. 17 furthermore, known comorbidities for covid-19, such as cvd, diabetes, respiratory disease and kidney disease are more prevalent among socially disadvantaged individuals than in populations with higher sep. 18 health literacy, which is associated with education, may play an important role in covid-19 incidence and severity. effective public health communication to act appropriately during an infectious disease outbreak is contingent upon people being able to access and understand the information. individuals with limited health literacy may be more easily misguided by incorrect sources of information. 6 furthermore, we also know that screening measures are often overlooked by disadvantaged populations with low health literacy levels, which may lead to delay in seeking care when their sickness is worse. 19 thus, a whole-ofsociety approach must include appropriate language and accessible healthcare strategies. to be able to understand the complex and interrelated influence of socioeconomic factors on covid-19 transmission, incidence and its health outcomes, data sources with comprehensive socioeconomic measures are needed. some might argue that we can link people's addresses or postcodes to area-based sep through geolocalisation, which may offer some insight into the likelihood of exposure to certain health risks, including pollution or public transport. indeed, these variables are often used as proxies for individual sep; however, they are not an accurate reflection of individual circumstances, could underestimate the extent of social inequalities compared to individual social measures 20 and are best used in parallel with individuallevel variables to reflect geographical or aggregate-level exposures. other dimensions that interact with sep need also to be considered race/ethnicity ethnic minorities including indigenous peoples are subject to systematic and structural discrimination, which leads to them being more socioeconomically disadvantaged and less likely to be able to seek healthcare when they need it. 21 recent reports from health authorities and journalists suggest that covid-19 hospitalisation and mortality rates may be higher in geographical areas or neighbourhoods which are more socially disadvantaged or where ethnic minorities are more likely to live. the poorest department in mainland france, seine st. denis, with a high proportion of people from ethnic minorities living there, reported a 63% increase in mortality during the week of the 21st of march, a bigger increase than any other french department. reports emerging from the united states also suggest that african americans and possibly people from other ethnic minorities are over-represented among the covid-19 deaths. these are anecdotal and unscientific reports for the moment; however, they deserve to be taken seriously and met with scientific methods and analyses to examine them thoroughly. furthermore, within each country, attention should be paid to the specific cultural practices and needs of different populations; they may need support in sending appropriate prevention messages to their community about festivals, rituals and habits. thus, as previously suggested by the sendai framework, governments should engage with migrants, people from ethnic minorities and indigenous peoples in the design and implementation of policies during a pandemic. 22 gender is another important aspect that deserves serious attention in the covid-19 pandemic, 23 especially as it intersects with occupation, education and race/ethnicity. women are more likely to have jobs or roles where they are in contact with others, as teachers, nurses, carers or retail workers. when schools closed across different countries, women are most likely to have had to take on childcare and homeschooling responsibilities. on the other hand, men are more likely than women to present with severe forms of covid-19 and have a higher mortality rate. 7 24 the reasons for this remain to be understood and may vary between contexts; however, men tend to have a higher prevalence of the main covid-19 risk factors. when it comes to the mitigation policies put in place to curtail the spread of disease, such as confinement or quarantine, these intersecting factors including gender, class and race/ethnicity will affect how people cope with the social, economic and psychological consequences of such measures. 25 26 national and local contexts the impact of socioeconomic determinants on the covid-19 outbreak could vary in high-income-countries versus low-and middle-income countries (lmics). as observed across the world, once covid-19 cases appear initially from abroad, the community spread of disease will depend upon the specific local infrastructures and social inequalities in each context. current public health measures of social distancing including lockdowns, quarantine and self-isolation cannot be implemented or may carry consequences in lmics. in lowincome settings where absolute poverty is a major problem, access to basic needs such as water, sanitation and food will have a big impact on how easily people can practise any physical distancing measures. moreover, in lmics where people are more likely to live in overcrowded households or neighbourhoods, it would be impossible to isolate older adults or vulnerable people. in many parts of the world, health is not free at the point of need, and healthcare systems, which are stretched at the best of times, will become quickly saturated. furthermore, while children appear to be less severely affected by covid-19, they may be more vulnerable to the social, economic and psychological consequences of the disease and ensuing public health containment measures, especially in low-income settings. 27 in order to identify groups who are most likely to have poor outcomes, high-quality data on socioeconomic factors are urgently needed, which will have important implications in the development of public health measures. social measures should be considered as clinical variables, in the same way as age or gender, and should therefore be routinely recorded in medical records. pandemic recommendations and guidelines provided by international and national agencies need to recognise the collective contribution of the social determinants of health and their intersectionality to pandemic risk mitigation. contributors sks and mki drafted all versions of the manuscript, sks carried out the literature review, and rgc and cd drafted the manuscript and provided edits. funding sks is supported by the australian research council centre of excellence in population ageing research (project number ce170100005). the funder had no role in study design, data collection, decision to publish or preparation of the manuscript. this work was also part of a project funded by the agence national de recherche flash-covid grant and région occitanie. competing interests none declared. patient consent for publication not required. data sharing statement data are available upon reasonable request. provenance and peer review commissioned; internally peer reviewed. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is noncommercial. see: http://creativecommons.org/licenses/by-nc/4.0/. michelle kelly-irving http://orcid.org/0000-0001-5749-4791 putting the concept of biological embedding in historical perspective a glossary for social epidemiology the embodiment dynamic over the life course: a case for examining cancer aetiology the associations between socioeconomic status and risk of staphylococcus aureus bacteremia and subsequent endocarditis -a danish nationwide cohort study the role of the early social environment on epstein barr virus infection: a prospective observational design using the millennium cohort study from sars to pandemic influenza: the framing of high-risk populations risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china editorial concern: possible reporting of the same patients with covid-19 in different reports host susceptibility to severe covid-19 and establishment of a host risk score: findings of 487 cases outside wuhan healthcare personnel exposure in an emergency department during influenza season occupational risks for covid-19 infection psychosocial job stress and immunity: a systematic review multi-cohort study identifies social determinants of systemic inflammation over the life course work stress as a risk factor for cardiovascular disease role of socio-economic factors in tuberculosis prevalence relation between infection with helicobacter pylori and living conditions in childhood: evidence for person to person transmission in early life covid-19 and smoking: a systematic review of the evidence socioeconomic disparities in health: pathways and policies low health literacy and health outcomes: an updated systematic review using ecological socioeconomic position (sep) measures to deal with sample bias introduced by incomplete individual-level measures: inequalities in breast cancer stage at diagnosis as an example discrimination and health inequities united nations office for disaster risk reduction covid-19: the gendered impacts of the outbreak clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study the mind-body connection socioeconomic and racial/ethnic disparities in the incidence of bacteremic pneumonia among us adults the extent, nature and distribution of child poverty in india key: cord-292559-b21j9sf3 authors: karcher, nicole r.; barch, deanna m. title: the abcd study: understanding the development of risk for mental and physical health outcomes date: 2020-06-15 journal: neuropsychopharmacology doi: 10.1038/s41386-020-0736-6 sha: doc_id: 292559 cord_uid: b21j9sf3 following in the footsteps of other large “population neuroscience” studies, the adolescent brain cognitive development℠ (abcd) study is the largest in the u.s. assessing brain development. the study is examining approximately 11,875 youth from 21 sites from age 9 to 10 for approximately ten years into young adulthood. the abcd study® has completed recruitment for the baseline sample generally using a multi-stage probability sample including a stratified random sample of schools. the dataset has a wealth of measured attributes of youths and their environment, including neuroimaging, cognitive, biospecimen, behavioral, youth self-report and parent self-report metrics, and environmental measures. the initial goal of the abcd study was to examine risk and resiliency factors associated with the development of substance use, but the project has expanded far beyond this initial set of questions and will also greatly inform our understanding of the contributions of biospecimens (e.g., pubertal hormones), neural alterations, and environmental factors to the development of both healthy behavior and brain function as well as risk for poor mental and physical outcomes. this review outlines how the abcd study was designed to elucidate factors associated with the development of negative mental and physical health outcomes and will provide a selective overview of results emerging from the abcd study. such emerging data includes initial validation of new instruments, important new information about the prevalence and correlates of mental health challenges in middle childhood, and promising data regarding neural correlates of both healthy and disordered behavior. in addition, we will discuss the challenges and opportunities to understanding both healthy development and the emergence of risk from abcd study data. finally, we will overview the future directions of this large undertaking and the ways in which it will shape our understanding of the development of risk for poor mental and physical health outcomes. a number of large "population neuroscience" studies have been undertaken over the past two decades, both in the u.s. and internationally, ushering in an exciting new era in understanding the development of risk for negative physical and mental health outcomes. for example, the adolescent brain cognitive develop-ment℠ (abcd) study is currently underway and was devised to better understand the development of both healthy and disrupted brain and behavioral development [1] [2] [3] . the abcd study® was begun in the footsteps of several other studies pioneering open access techniques, non-convenience study samples, and including longitudinal and neuroimaging components (for e.g., see ref. [4] [5] [6] ). the abcd study is the largest study in the u.s. to date assessing brain development, examining youth from age 9 to 10 for approximately ten years into young adulthood. the abcd study dataset has a wealth of measured attributes of youths and their environment, which will be described below, including neuroimaging, cognitive, biospecimen, behavioral, youth self report and parent self-report metrics, and environmental measures. initial driving questions of the abcd study included examining risk and resiliency factors associated with the development of substance use [3, 7, 8] . however, the abcd study has expanded beyond this initial set of questions and will also greatly inform our understanding of the contributions of biospecimen-derived (e.g., pubertal hormones, genomic, and epigenetic factors), neural, and environmental factors to the etiology of mental and physical outcomes from middle childhood through early adulthood [9] . the abcd study provides many unique opportunities for understanding the development of both healthy behaviors and risk for mental health challenges. first, the abcd study utilized a school-based national recruitment strategy with limited exclusion criteria, helping to overcome challenges to previous general population studies that generally did not include neuroimaging [10] as well as attempts to understand the risk factors associated with negative outcomes that relied on convenience samples [11] . second, the abcd study also includes an embedded twin sample. this will allow researchers to better disentangle the influences of genetic versus environmental factors on development [12] . third, the abcd study has an unprecedented sample size (i.e., 11,875 youth at baseline). this enables the development of reliable standards of development across a number of metrics, including the brain, biospecimens (e.g., pubertal hormones), and cognition. fourth, the abcd study focuses on adolescence. adolescence is arguably a critical and unique period for understanding the evolution of risk and resiliency [13] . fifth, the abcd study will follow youth longitudinally throughout adolescence. this will enable examining which factors most strongly predict the emergence and progression of both positive and negative physical and mental health outcomes. the current review will describe how the abcd study was designed to elucidate factors associated with the development of negative mental and physical health outcomes. this review will also provide a selective overview of results already emerging from the abcd study. this review will discuss the challenges and opportunities to understanding the development of risk using the abcd study. lastly, we will discuss the future directions of this massive undertaking that will shape our understanding of the development of risk in adolescence. the abcd study has completed recruitment for the baseline study sample (n = 11,875; youth = 9-10-years-old; 47.8% female; 52.1% white, 15 .0% black, 20.3% hispanic, 2.1% asian, and 10.5% other [e.g., biracial]) and will be continuing to follow these youth for at least ten years. an important motivation for abcd study sampling techniques was to reflect the sociodemographic variation of the us population. the recruitment approach of the abcd study was generally through public schools, including charter and private elementary schools, though the embedded twin sample (described below) used a birth record approach. overall, the abcd study aimed to utilize a multi-stage probability sample of eligible youth, selecting a stratified, probability sample of schools across the u.s. in order to capture demographic diversity [14] . however, some participants (<10%) were recruited via other means, including through community events, non-targeted schools, and referral systems. further, the selection of collaborating sites was constrained by the requirement that engaged locations had to have both the research expertize and the neuroimaging equipment required by abcd study protocol [14] . the abcd study has 21 sites that are distributed nationally. for each site, the abcd study created a catchment area, defined as all schools within 50 miles of the research institution [14] . each school within the catchment area was coded according to several factors, including geographical location, racial, ethnic and sex composition, and percentage of students receiving free or subsidized lunches as an index of socioeconomic status (ses). based on this information, the abcd study used stratified sampling of schools within each site's catchment area, and a subset of schools was randomly selected from this list of potential schools within each catchment area. procedures were used to ensure that systematic sampling biases in recruitment at the school level were minimized [14] . the abcd study then recruited eligible children from each of the randomly selected schools within the catchment area. initial recruitment often involved the delivery of hard and electronic copies of recruitment materials to caregivers. in total, 11,875 children completed the baseline assessment. in the end, the abcd study sample is epidemiologically informed and designed to reduce selection bias that plagues convenience samples. however, the degree to which this sample is fully representative of the u.s. population will vary across outcome measure examined. the use of weighting methods that evaluate the distributions in relationship to u.s. demographic characteristics will be a helpful additional tool when attempting to make claims about representativeness [15] . in addition to this school-based approach, there are four abcd study sites that recruited samples of monozygotic and dizygotic twins (washington university in st. louis, university of minnesota, university of colorado at boulder, and virginia commonwealth university), resulting in~860 twin pairs in the baseline sample. these sites each have over 25 years of experiences in the recruitment of twin populations and therefore used existing recruitment processes [12] . for example, these sites used approved vital records approaches to capture a diverse set of twins generally representative of the demographics of their respective states [12] . each of these sites also recruited "singletons" using the school-based approach described above. the inclusion of twin samples was designed to enhance the ability to make causal inferences about factors contributing to both healthy and disordered brain and behavioral development. for more details on sampling strategy, recruitment, and retention, including twin sample recruitment, please see refs. [12, 14, 16] . the abcd study is a consortium composed of a coordinating center, a data analysis, and informatics center, and members from the 21 research sites (https://abcdstudy.org/study-sites/). work groups facilitate data collection and quality control for current and future abcd study data collection waves. all youth are asked to come for in-person assessment sessions once a year, with brief remote assessments at 6 months between in-person sessions. self-report, behavioral, and biospecimen collections occur yearly, while brain imaging occurs bi-annually (table 1) . below, measures collected for each of the assessment domains are briefly reviewed. many of these assessments are described in more detail in a special issue of developmental cognitive neuroscience published in 2018 [1, 7, 17, 18] . the abcd study assessments can be loosely grouped into seven domains: substance use, mental health, physical health and biospecimens, neurocognition, gender identity and sexual health, culture and environment, and brain imaging. each domain was designed to use instruments with documented reliability and validity, be developmentally sensitive, engage the most appropriate informant depending on the developmental stage and domain (e.g., parent versus youth), minimize participant burden, and be informed by previous relevant literature on both healthy and disordered brain and behavioral development. furthermore, the inclusion of multiple informants for certain measures, including obtaining information from youth, caregivers, and teachers regarding youth mental health at baseline (youth = 9-10-years-old), helps to mitigate potential unreliability of youth reports due to variability in language skills and retrospective reporting problems. for each domain, additional assessments have been added in follow-up years, which are described in the annual release notes of the abcd study data releases on the nih national data archive. additionally, abcd consortium members have added several sub-studies to the abcd study protocol for future waves of data collection. these sub-studies include adding measures to address reactions to hurricane irma and the covid-19 pandemic, and a sub-study focused on behavior in youth that might put them at risk for involvement in the justice system. substance use. for an overview of measures started at baseline and year 1 (youth = 10-11-years-old), please see ref. [7] . the goal of the substance use assessment was to start with the very earliest indicators of exposure to and knowledge about substances, and then to capture the onset, timing, and quantity of any substance use that emerges during the course of the abcd study data collection. a variety of measures collected from youth are used to accomplish this goal, with a central one being the timeline followback interview [19, 20] designed to establish the specifics of substance use onset and timing. factors impacting substance use are also assessed, including assessments about intentions to use, expectations about substance effects, curiosity, and motivations regarding substances, perceptions about peer beliefs regarding substances, assessment of sibling use, and community risk and protective factors. further, parents are asked about their youth's substance use, family rules about substance use, availability of substances in the environment, and a range of community risk and protective factors. lastly, biospecimens (saliva and hair) are assessed for exposure to alcohol and substances. mental health. for an overview of all measures that started at baseline and year 1, please see ref. [1] . the goal of the mental health assessments is capturing categorical and dimensional assessments of current and past mental health from the parent and youth perspective, as well as teacher perspective, and assessing traits and characteristics relevant to understanding risk trajectories for mental health. the core of the categorical assessment of youth mental health is the new computerized kiddie-structured assessment for affecitive disorders and schizophrenia (ksads), used to assess parent-report of youth mental health as well as youth's self-report [21] [22] [23] . this version of the ksads is not clinician administered, though youth are aided by research assistants. in early abcd study assessment waves, most modules are completed by a parent/caregiver (mood, psychosis, anxiety, externalizing, sleep, and suicidality), with a subset also completed by youth (mood, anxiety, sleep, and suicidality), with the number of modules completed by youth increasing across the course of the study as developmentally appropriate. a range of dimensional measures of mental health are completed by either or both the parent/caregiver and youth, and the core of these dimensional assessments is the achenbach system of emprically based assessment (aseba) system [24, 25] generously provided at no cost to the abcd study. the parent/ caregiver annually completes the child behavioral checklist as a broad dimensional assessment of youth mental health. the parent/caregiver also completes additional measures of early signs of mania and autism spectrum symptoms, youth temperament, life events, and emotion regulation abilities, the family's mental health history, and their own mental health and stress. the youth completes additional measures of psychotic-like experiences (ples), mania, and conduct disorder, as well as personality traits (e.g., impulsivity, behavioral activation and inhibition, and emotion regulation) and relevant experiences, including friendships, peer relationships, bullying, and life events. the youth completes the aseba brief problem monitor (bpm) every 6 months. lastly, teachers are also asked to report on youth mental health using the bpm for teachers. physical health and biospecimens/genetics. for an overview of all measures that started at baseline and year 1, please see ref. [1] . this assessment includes a lifetime medical, head injury, and developmental history for the youth provided by the parent/ = nih toobox; = "cold" cogn nitive e me easures; = "hot" c cogni itive mea asure es; = = geo ocode ed factor rs; = b brain imag ging the abcd study: understanding the development of risk for mental and. . . nr karcher and dm barch caregiver at baseline, along with annual updates about medical experiences, medications, and head injuries (including sports related). both the parent/caregiver and youth provide annual descriptions of their pubertal status and saliva assessments of pubertal hormones (including assessing levels of testosterone and dhea in males and females, as well as estradiol in females). parent/caregiver and youth also report on experiences with sleep and sleep disorders, including youth reports of sleep chronotypes, respiratory function, and pain experiences. the youth and/or their parent/caregiver provide annual information about diet, frequency of exercise, involvement in sports and other activities, and time spent using various types of electronic media, including tv, videos, social media, etc. further, in year 2 of data collection (youth = 11-12-years-old), all youth were asked to wear a fitbit for 2 weeks. fitbits provide data on heart rate, physical activity levels, and sleep. biospecimens are collected, including baby teeth, saliva, hair, and blood, for purposes of screening for and examining effects of drug use, assessing pubertal hormones, characterizing genetic and epigenetic factors, and assessing the presence and effects of exposure to environmental toxins [9] . youth who initially provided saliva for dna assessment are asked to provide blood in later years as they become more comfortable with blood draws. neurocognition. for an overview of all measures that started at baseline and year 1, please see ref. [8] . the base of the neurocognitive assessment for abcd study is the nih toolbox [26, 27] , with the complete cognitive toolbox administered at baseline, and the majority of tasks administered every 2 years. the toolbox measures were complemented at baseline by additional assessments of verbal learning, matrix reasoning, spatial processing, and delay discounting, with all of these measures other than matrix reasoning repeated approximately for every 2 years [8] . additional cognitive measures are administered in alternating years, including those that focus on more "hot" aspects of cognition, including an emotional stroop task, a monetary decision-making task, and a social influence task. assessments of math ability were introduced in year 3 (youth = 12-13-years-old). these assessments are contextualized by vision assessments for every 2 years, and a measure of hand dominance. gender identity and sexual health. the goal of the gender identity and sexual health assessments are to provide developmentally appropriate assessments of gender identity and expression, as well as sexual identity and communication about sexual health. both youth and parent complete a questionnaire about gender identity, including questions on gender identity and gender expression, with the youth also reporting on dimensional assessments of gender identity. for an overview of all measures that started at baseline and year 1, please see ref. [18] . the assessments of culture and environment include both youth and parent/caregiver's perspectives on family relationships, conflict, parent acceptance and rules, familial cultural experiences and values, pet ownership, and other aspects of the home environment such as the nature of home spaces and parent-youth interactions in the home around cognitive and emotional behaviors. this domain also assesses characteristics of the neighborhood from the perspective of the youth and/or parent/caregiver, including perceptions of crime and safety, community cohesion, and school attributes. data releases also include several variables geocoded based on the participant's address and derived from publicly available data such as the american community survey's metrics of socioeconomic characteristics. these variables include population density, neighborhood walkability, county-level crime exposure information, census-tract level estimates of area deprivation indices, air pollution exposure (estimated with a resolution of 100 km 2 of address), and lead exposure risk. brain imaging. for an overview of all measures that started at baseline, see ref. [17] and for processing approaches and information about released data, see ref. [28] . youth participate in a magnetic resonance imaging (mri) session for every 2 years. this mri assessment includes measures of brain structure, with both t1 and t2 weighted imaging and diffusion imaging for assessment of white mater integrity. the mri assessment also includes 20 min of resting state functional connectivity data and functional mri during three different task domains. these domains were designed to capture brain activity during numerous aspects of cognition and emotion function in as short a time as possible, including working memory, response inhibition, anticipation and receipt of rewards and losses, face processing (both neutral and emotional), and subsequent memory. processed data from each of these domains is released in tabular format as part of the abcd annual releases using a variety of brain atlases. raw mri data is available through the fast track release mechanism (https://nda. nih.gov/abcd/query/abcd-fast-track-data.html). the abcd study was begun in the footsteps of several other large population neuroscience studies. these studies include the sanguenay youth study (http://saguenay-youth-study.org; n = 1029) [29] , the national institutes of health pediatric mri database (n = 550) [30] , imagen (n = 2000) [6] , pediatric imaging, neurocognition, and genetics study (ping) (n = 1493) [31] , national consortium on alcohol and neurodevelopment in adolescence (ncanda) (n = 831) [4] , human connectome project (hcp) (n = 1200) [32, 33] , and hcp-development (hcp-d; n = 1350 [34] ), uk biobank (n = over 500,000) [35] , generation r (n = 9778) [5] , philadelphia neurodevelopment cohort (pnc) (n =~9498) [36] , and the dunedin multidisciplinary health and development study (n = 1037) [37] , among others. as can be seen in table 2 , in general these previous studies were large (sample sizes > 800), examined a range of ages from beginning prenatally (generation r) to adulthood populations (e.g., hcp, uk biobank). some followed the sample longitudinally (e.g., imagen, uk biobank, generation r, dunedin, ncanda), or followed a subset longitudinally (e.g., pnc). all included neuroimaging data (e.g., imagen, ping, ncanda, hcp; note the dunedin study did not collect neuroimaging data during childhood or adolescence), or included neuroimaging on a subset of participants (e.g., pnc, uk biobank). notably, several even included longitudinal imaging (e.g., ncanda, generation r, imagen). the abcd study complements and extends beyond these other studies by examining measures across development from middle childhood-adulthood at 21 different sites across the u.s. and conducting assessments for every 6 months and imaging for every 2 years. furthermore, a critical component of the abcd study is the open science framework, whereby the abcd consortium is releasing data collected from the study in annual data releases to the scientific community. this approach builds upon the open science framework of release while data is still being collected pioneered by a number of previous studies, including the hcp and uk biobank projects. overview of emerging findings from the abcd study the abcd study has submitted two data releases, and numerous investigators both within the consortium and from without have been utilizing these data to begin to address questions relevant to both healthy and disordered brain and behavioral relationships. here, we provide a selective review of some of this emerging research. notably, the majority of the published emerging work to date is cross-sectional and focused on the initial baseline data set. the abcd study: understanding the development of risk for mental and. . . however, several emerging studies have utilized the partial data available from year 1 [38, 39] . abcd release 3.0 is slated for release during august 2020, and will include the entire year 1 and part of year 2, which will include repeated neuroimaging assessments. these emerging studies vary in scientific rigor, including using appropriate analytic methods (e.g., nested models), using rigorous multiple comparison control, controlling for potential confounds (e.g., age, sex, race/ethnicity, and ses), and replicating findings. several of the emerging studies have implemented each of these rigorous inclusions [40] [41] [42] [43] , and 88% included at least one of these methodologies/techniques. emerging studies from the abcd study have been utilizing a variety of measures to examine an array of both adaptive and maladaptive aspects of cognitive, social, emotional, and neural correlates in middle childhood [1, 7-9, 17, 18] . many of the measures already have extensive psychometric data. however, in some cases, measures were shortened to reduce participant burden, adapted for use in a younger population, or created from items selected from various other scales. as such, several early emerging studies from the abcd study have examined psychometric properties and validity for several measures [44, 45] . further, emerging studies have begun to utilize the large sample to create short forms [38] . these emerging studies highlight several exciting avenues for examining the properties and novel uses of the abcd study measures. one of the first emerging studies to analyze abcd study baseline data examined the properties and conducted some initial validation analyses for a measure of ples entitled the prodromal questionnaire-brief child version (pq-bc) [44] , including conducting measurement invariance analyses and finding the pq-bc functioned similarly across sex and race/ethnicity. another recent emerging study conducted item response theory analyses on the pq-bc and used information gleaned from these analyses to begin the process of creating a short form that theoretically can be used for future clinical purposes [38] . similarly, another emerging study examined validity evidence for a novel, abbreviated measure of impulsivity in youth, the upps-p impulsive behavior scale [45] . the authors found adequate measurement invariance across gender, race/ethnicity, household income, and parental education, and examined convergent and discriminant validity across a number of relevant characteristics, including youth-reported and parentreported psychopathology and measures of cognition. lastly, researchers also used abcd study measures to create a 4-item measure of callous-unemotional traits [40] , finding evidence for good psychometric properties, including measurement invariance across age, sex, and race, and expected associations with related constructs such as conduct problems, attention deficit and hyperactivity disorder symptoms, and oppositional defiant disorder symptoms. importantly, these findings replicated in an independent sample. these studies provide important evidence that the abcd study sample can be leveraged to conduct rigorous research practices, including examining the psychometric evidence for using existing (or newly created) measures in a middle childhood sample, supporting the use of these measures to better understand the development of risk. prevalence and behavioral correlates of psychopathology. there has been great interest in understanding the prevalence and correlates of a range of forms of psychopathology using the abcd study's large-scale population-based data. several emerging studies have utilized the abcd study data to examine the prevalence of psychopathology in middle childhood, as well as behavioral and cognitive correlates of psychopathology. as previously mentioned, one of the first emerging studies published examining abcd study baseline data examined associations between ples and correlates of psychosis spectrum symptoms [44] . this emerging study found ples were associated with several expected associations, such as cognitive impairments (including working memory impairments), motor and speech developmental delays, higher internalizing and externalizing symptoms, greater family history of psychosis, and higher scores on other measures of psychosis spectrum symptoms. another emerging study found maladaptive guilt was associated with several expected correlates, including family ses, youth-reported family conflict, history of maternal depression, and parental rejection [46] . emerging research also examined prevalence of eating disorder diagnoses in middle childhood [47] , finding the prevalence of overall eating disorder diagnoses was 1.4%, and the prevalence of anorexia nervosa diagnoses was 0.1%. lastly, an emerging study examined the prevalence and associations with suicidality in middle childhood [48] , finding the prevalence of passive suicidal ideation (as reported by youth or parent) was 6.4%, active suicidal ideation (either non-specific or specific) was 6.8%, and suicide attempts were~1.3%. further, the prevalence of non-suicidal self-injury was~9.1%. low parental monitoring was associated with suicidal ideation, suicide attempt, and nonsuicidal self-injury, and as with maladaptive guilt, family conflict was associated with suicidal ideation and non-suicidal self-injury. importantly, the authors replicated these findings in a hold-out abcd study baseline sample (i.e., 30% of the baseline sample). together these emerging studies are beginning to provide an important additional information on the prevalence of various forms of psychopathology in a middle childhood sample, complementing the already existing epidemiological data that is more common in adolescence and adulthood. in particular, this novel data on rates of suicidal ideation and attempts starting in middle childhood is critically informative about the timing of emergence of such thoughts and behavior in relationship to the rates in adolescence already identified by the centers for disease control and prevention. associations between psychopathology and both physical health and the environment. in addition to examining prevalence and behavioral correlates, the abcd study baseline sample has also been utilized to assess associations between psychopathology and several environmental and health-related variables. these emerging studies point to several factors, including prenatal drug use, body mass index (bmi), and cognition already showing associations with psychopathology and other health-relevant variables in middle childhood. emerging work indicates that prenatal cannabis exposure after knowledge of pregnancy is associated with ples, but not internalizing, externalizing, or attention symptoms [49] . another emerging study examined associations between health and environment, including correlates of bmi in middle childhood [50] , finding attention problems, social problems, and screen time were all associated with higher bmi, with some evidence that demographic factors (e.g., hispanic ethnicity, lower income) were most strongly associated with greater bmi. other emerging research examined associations with sexual orientation and/or gender identity status [51] , finding that less than 1% of the sample identifies as a sexual orientation or gender identity minority, and that minority status was not a source of substantial family or school problems. however, further emerging research did show that sexual orientation minority status was associated with greater prevalence of mood disorders and suicidality than in heterosexual-identifying youth [52] . another emerging study examined the structure of cognition and found evidence for three broad factors representing general cognition, executive function and learning/memory [53] , additionally finding that while parent-reported psychopathology (perhaps especially externalizing symptoms and stress reactivity) was associated with cognition, the sizes of the effects were small in magnitude. furthermore, other emerging work found little evidence that learning a second language was associated with higher executive functioning [54] . another emerging study examined associations between global cognition and healthrelated variables, finding higher global cognition scores were associated with meeting recommendations for sleep, screen time, and physical activity [55] . these emerging studies provide important information that will be critical for understanding the development of risk for physical and mental health-related outcomes, as well as several potential avenues for the development of health-related resources and interventions. youth behavior and brain structure, function, and connectivity. research has begun to utilize the wealth of neuroimaging data available from the baseline sample (i.e., data releases 1.1 and 2.0.1) in novel and innovative ways to begin to analyze important questions about early neural markers of risk. emerging research examining resting state functional connectivity (rsfc) to delineate the functional architecture of the brain found rsfc networks were highly reproducible across two samples of abcd study data, shared many features of adult-level networks, and showed associations with cognitive functioning [42] . other emerging research found rsfc associations with general cognitive ability were generalizable across abcd study sites and that rsfc within and between task control networks were associated with variability in general cognitive ability [56] . other emerging work examining brain-cognition associations found that with higher risk of lead exposure, lower family income was associated with lower cognitive functioning, lower cortical volume, and lower surface area [57] . emerging findings also found higher screen media activity was associated visual brain areas (e.g., occipital cortex) [58] , with these associations showing mixed positive and negative relations to cognitive functioning. other emerging baseline research has found that higher bmi is associated with lower cortical thickness, especially in prefrontal regions, and lower executive functioning performance [59, 60] . interestingly, other emerging work found an association between sleep duration and both cognitive function and psychopathology in youth, as well as with variation in brain volume in a variety of regions in the prefrontal, parietal, and temporal cortices [39] . furthermore, hippocampal volume was associated with depressive symptoms in males and involvement in sports was associated with fewer depressive symptoms, with some evidence that hippocampal volume mediated the association between sports involvement and depressive symptoms [61] . other emerging research found risk for depression, as assessed by parental history of depression, was associated with lower putamen volume [43] . further, emerging research examining specifically anhedonia found associations with hypoconnectivity in several rsfc networks, as well as lower activation compared to a group not endorsing anhedonia during reward anticipation, including in cingulo-opercular (con) network regions and the striatum [62] . other emerging research found evidence that higher ples were associated with lower functional connectivity in several rsfc networks, including lower con and default mode connectivity [63] . another interesting emerging study found youth with disruptive behavior problems who also had callous and unemotional traits showed lower gray matter in the amygdala and the insula compared to typically-developing youth. further, youth with disruptive behavior problems with and without callous/ unemotional traits showed alterations in several regions including lower hippocampal volume, though it was limited to the left hippocampus in disruptive youth without callous/unemotional traits [64] . collectively such data begin to establish the early emergence of alterations in brain structure, function and connectivity associated with a range of forms of psychopathology and individual differences in cognitive function and behavior, as well as critical environmental influences that shape brain development. crucially, they also begin to identify both commonalities and dissociations in these relationships. for example, lower hippocampal volume has been associated with both depression and disruptive behavior, while lower amygdala volume has only been associated with disruptive behavior. in terms of connectivity, disruption in the connectivity of the con network has been associated with higher ples, while disrupted connectivity between the con and the striatum has been associated with anhedonia. it will be critical to determine whether these similarities and dissociations remain over the course of development or whether the patterns of disrupted brain structure, function and connectivity evolve throughout development. challenges and opportunities of the abcd study challenges. one challenge the abcd study has encountered is that given data is open access, multiple groups can publish the same or very similar articles. although members of the abcd consortium are encouraged to publish research proposals on the internal abcd study site, this information is not available to the public. other challenges for large-scale studies in general include retaining subjects followed across a decade and potential biases in drop-out rates (e.g., lower ses populations). the abcd study has attempted to mitigate these challenges by developing strategies to maintain rapport, keeping detailed current locator information, offering participation-related resources (e.g., travel assistance), and monitoring retention during bi-monthly meetings [16] . effect sizes: what to expect. as outlined in a recent paper [65] , large sample sizes are necessary to examine the earliest markers and mechanisms of disease processes, as these markers are likely to be more subtle early in the course of illness. an opportunity that also presents a challenge is these large data sets enable the detection of very subtle effects not generally detectable in smaller sample studies. the challenge of detecting small effects is determining whether very small effects (i.e., <1% of variance explained) are practically meaningful [65] . large well-powered samples enable the detection of the earliest subtle associations between predictor and outcome of small effect, prior to larger effect size associations that may emerge later in the disease process. for example, estimating the prevalence of major depressive disorder at 2% in middle childhood [66] , the abcd study's power = .90 to detect small effect (cohen's d = .30) differences between individuals with major depressive disorder and controls. additionally, it is entirely expected that many of these analyses will produce small effects. first, baseline abcd study analyses are examining early risk factors of negative mental and physical health outcomes in a generally high functioning non-clinical sample prior to entering the age range of highest risk for a number of negative outcomes (e.g., psychosis spectrum symptoms) [67] . furthermore, since the abcd study is an epidemiologically informed study with a demographically diverse sample [14] , rather than a convenience or clinical sample, it is expected that effect sizes will be more "diluted" as they are being examined in the context of a complex set of contextual and background variables. further, our expectations for effect sizes are likely biased, as it is known that underpowered studies overestimate effect sizes [68, 69] . thus, the field is in need of well-powered studies, especially in neuroimaging analyses, to better understand the expected effect sizes for these associations in the general population. robust exploratory analyses. another opportunity that the large sample size of the abcd study offers is the possibility of conducting exploratory analyses for questions with no strong a priori hypotheses. as the nimh has recently advocated [70, 71] , it will be critical to implement robust and rigorous practices for conducting exploratory analyses. first, we suggest utilizing discovery and replication datasets. researchers conducting exploratory analyses can conduct analyses on the discovery dataset, and examine whether results replicate in the replication dataset, a technique used to improve the replicability of gwas studies [72] . researchers can match these datasets on demographic variables, including sex, race, ethnicity, and age. given that exploratory analyses are prone to false positives, first examining analyses in a discovery dataset and then testing any findings in a replication dataset reduces the possibility of type i error. furthermore, to the extent that it is possible, researchers should specify hypotheses prior to conducting analyses. ideally, researchers would create a pre-registration or even a registered report detailing hypotheses and analyses prior to conducting analyses (https://cos.io/rr/). specifying even general hypotheses helps frame the results and can put unexpected results into context. further, preregistering analysis approaches even in the absence of specific hypotheses helps to avoid problematic analytic approaches resulting in enhanced false positives [73, 74] . correcting for multiple comparisons is also critical when conducting exploratory analyses. it is important to account for experimentwide increased false discovery rates, even when conducting multilevel modeling. further, especially for researchers conducting complicated interaction or genetic analyses, power analyses should be conducted in order to determine whether the analysis is sufficiently powered in the abcd study sample [75] . lastly, researchers should always use best practices in model specification (e.g., nesting abcd study site and family) [76] . the importance of replication. the importance of replication is increasingly highlighted as a part of robust research practices [71, 77] . accordingly, another opportunity that a large study such as the abcd study affords is within sample replication. the opportunity to conduct a within sample replication can come in several forms. one possibility is researchers can examine the first data release (data release 1.0.1; n = 4524) and then replicate findings on the remainder of the baseline sample (data release 2.0; remainder sample n = 7351). this was recently done examining associations with ples [41] . in subsequent data releases, researchers will be able to replicate results across waves, paying close attention to expected developmental alterations that may influence results. second, as previously mentioned in the exploratory analyses paragraph, researchers can divide the sample into discovery and replication datasets. third, researchers can also conduct k-fold (e.g., 10-fold) cross-replication [78] . k-fold cross validation is used in predictive modeling to test a model's ability to predict new data not used to create the original model. however, the gold standard in replication is to use an independent sample with differing methods and sampling techniques in order to ensure that effects are replicable and generalize across samples. as mentioned in the "overview of the abcd study" section, there are a number of large-scale studies that would be ideal for such a replication. for example, the generation r study is a prospective longitudinal study following individuals from prenatally to young adulthood ( table 2) . as with the abcd study, the generation r study is collecting a wide range of outcomes, including physical, behavioral, cognitive, biospecimens, and mri [5] . in addition, the hcp-d study is collecting data from children ranging from age 5 to 21 (table 2 ) [34] . although the focus of the hcp-d study is on the development of the brain, the study also collects data on puberty, physical activity, health, genetics, and other relevant mental health correlates such as stress [34, 79] . other studies that may be relevant for replication efforts can be found in table 2 . developmental specificity and evolution of risk. the abcd study will provide one of the first opportunities to examine a wealth of neuroimaging, genetics, cognition, psychopathological, and psychosocial factors in the same youth in middle childhood, adolescence, and early adulthood. it will be important for researchers to consider the developmental period in question in order to properly formulate hypotheses regarding risk in each age group, as each period is defined by a unique set of psychosocial and neurobiological alterations. for example, middle childhood is associated with several changes, including continued neuromaturational processes that began in childhood, such as increases in both gray and white matter [80] . adolescence is a period of often dramatic changes, including hormonal fluctuations and substantial pruning processes [80] [81] [82] [83] . lastly, young adulthood is associated with another set of changes, including in role functioning [84] . in terms of the development of risk, each stage has its own unique set of risk-related factors and developmental changes. for example, adolescence is associated with a spiked increase in risk-taking behaviors, including substance use [8, 13] . researchers interested in examining abcd study data should carefully tune their questions depending on the developmental period from which they are drawing their sample. for example, researchers interested in understanding the progression of risktaking behaviors, such as the initiation of cannabis use, would likely examine future waves of the abcd study (e.g., at year 4 youth = 13-14-years-old) to identify outcome measures and to evaluate response to substance use, but maybe using predictors from an earlier developmental stage. the developmental period in question will also be critical in terms of the covariates of interest in analyses. pubertal status will be an important covariate in later middle childhood/early adolescence. likewise, substance use will be an important covariate for many analyses in later adolescence/ early adulthood. the abcd study also will provide the opportunity to examine the evolution of risk, including how risk factors change across development and to determine whether there are important variations in the most relevant risk factors at different phases of development. in terms of defining factors that predict variation in developmental trajectories, life course [85] and developmental psychopathology [86] theories suggest that early negative experiences can alter a youth's developmental trajectory [87, 88] and the accomplishment of developmental milestones. however, research has not elucidated whether the consequences of negative life events in terms of mental health are stronger during different development periods, such as in middle childhood versus adulthood. this would have critical treatment and policy implications. it is also possible that the factors associated with risk may be qualitatively different during different developmental periods. for example, factors associated with risk for depressive symptoms in middle childhood, such as lower physical activity [89] , may not be associated with risk for depressive symptoms in young adulthood, as these factors become more normative. in contrast, other risk factors, such as chronic stress and poor social support, may be consistently associated with risk for depression across development [90, 91] , although the degree of severity may be different in different development periods. thus, it is possible that some risk factors first emerge, and then accumulate over time, versus others are only associated with risk during "critical periods" that may correspond with certain maturational changes. balancing large-scale studies with deep phenotyping. research is increasingly moving towards precision medicine efforts, aiming to tailor interventions for psychopathology to the individual [92, 93] . thus, one potential criticism of large-scale population neuroscience efforts is the value and utility of massive research efforts for precision medicine. it is possible that in advancing our understanding of the etiology of mental and physical illness, we could obscure the trees for the forest by examining large-scale efforts as opposed to deep phenotyping. deep phenotyping refers to gathering details about disorder manifestations in a fine-grained manner to more precisely define phenotypes [94] , as many phenotypes currently fall short of fully capturing the diverse manifestations of the disorder (e.g., schizophrenia, asd). however, deep phenotyping is typically only possible with smaller samples, due to the large amount of resources required. the abcd study varies in the depth of assessment across phenotypes. for alcohol and substance use, the abcd study uses deeper phenotyping, with finer-grained data on patterns of use, including biospecimen collection, youth and parent interviews of use, as well as reports of peer use, expectancies, and consequences of use. combined with collection of neuroimaging and genetic data, the abcd study poses the opportunity to create a nuanced phenotype of alcohol and substance use across adolescence and young adulthood. in contrast, other phenotypes assessed in the abcd study, including psychosis, are assessed with less fine-grained detail. nonetheless, the insights gained from the abcd study can be used to spur subsequent deep phenotyping studies that can examine promising risk factors and mechanisms identified in the abcd study data in a more finegrained fashion in more tailored populations. longitudinal analyses. given that the abcd study is following youth from age 9 to 10 into adulthood, one of the most important future directions is conducting longitudinal analyses. the fields of psychology and psychiatry have made few reliable advances in understanding causal mechanisms underlying the development of negative mental health outcomes, including substance use disorders and psychosis [95] . following a cohort of youth through a period of significant risk will provide important information about what trajectories of risk factors significantly predict transition to negative mental and physical health outcomes. through examining trajectories of neural, cognitive, social, emotional, school, and hormonal functioning, the abcd study will be able to isolate factors reliably predicting typical versus atypical development from middle childhood into young adulthood [3] . this ten-year study sets the stage for several potential avenues for longitudinal research, helping to answer fundamental questions about the effects of the onset and progression of symptoms of psychopathology [8] . a major aim of the abcd study is to longitudinally examine the neurodevelopmental and behavioral effects of substance use. by analyzing development both preexposure and post-exposure, researchers will be able to clarify associations between substance use and outcomes, including neurodevelopmental, neural, behavioral, and cognitive correlates [3, 7, 8] . another aim of the abcd study is to longitudinally examine factors, including social and neurobiological, that might contribute to resiliency either from engaging in substance use or from negative outcomes after initiation [3] . this information will be critical for intervention development, including offering potential avenues to mitigate risk. thus, longitudinal analyses in the abcd study will enable the examination of trajectories associated with the onset and progression of, as well as resiliency from, psychopathology and substance use. passive data sampling. several passive data collection methods, or data collection methods that do not require active responses from participants but instead collect data from the participant, will become available in future abcd study assessment waves [96] . passive data collection can be a critical tool for large-scale studies, as it enables additional data without additional burden. the abcd study is conducting passive data collection from mobile devices and wearables (i.e., fitbits). mobile and wearable technologies can capture information about participants that is unable to be adequately captured through self-report, including precision regarding social interactions, sleep quality, and activity levels. one exciting avenue for passive data sampling is understanding the role of social media usage as either risk or resilience markers for physical and mental health outcomes, including substance use. social media use has been linked to psychopathology in adolescents, including higher symptoms of depression and anxiety [97] . however, previous research has not established screen time as a causal factor in the development of mental health outcomes, or whether altered social media use and screen time are a correlate or consequence of the development of psychopathology [98] . as noted above, starting at year 2, the abcd study is also using accelerometers (i.e., fitbits) to examine sleep quality and activity levels. a wealth of research links poor sleep quality to negative physical and mental health outcomes [99, 100] . the examination of variables such as sleep quality over time will begin to disentangle causality, such as whether poor sleep is a cause or a consequence of negative mental and physical health outcomes. likewise, increased physical activity is a protective factor for a number of positive physical and mental health outcomes, including maintaining a healthy weight and lessened risk of depressive symptoms [89, 101] . starting in year 4 of data collection, the abcd study will also be using an app to assess phone and app usage with youth and parent permission. using passive data sampling, the abcd study will begin to understand the contributions of physical activity level, sleep quality, and social media use to the development and maintenance of negative physical and mental health outcomes. examining complex patterns of interactions. another future direction for abcd study data is examining complex interactions. these examinations will likely take several forms, so the current review will focus on two: modeling moderating influences and examining gene × environment interactions. for the first example of complex interactions, researchers will be able to examine the moderating influences of a multitude of factors including mental health (e.g., internalizing and externalizing symptoms [102] ); and psychosocial (e.g., parental influences, social support) factors on the initiation of substance abuse. further, questions remain about how different types of substance use, such as drugs, alcohol, and nicotine use interact, including their interactive effects on cognition and neurobiology [3] . research using the abcd study will also be able to examine how patterns of use interact with psychopathology and psychosocial variables to predict trajectories. for example, it is possible that substance use interacts with poor social support to predict impairments in social and occupational functioning [103] . the abcd study sets to stage the begin to uncover the complex patterns of interactions among psychopathology, psychosocial factors, and neurobiology, as well as their interactive effects on long-range outcomes. further, the abcd study has oversampled for twins (i.e., the study has approximately 860 twin pairs at baseline). this will allow researchers to leverage this data to examine gene × environmental interactions. briefly, bivariate twin models can be used in order to examine gene × environment interactions [104, 105] , including parsing out how variance associated with additive genetic (heritable) and individual-specific environmental factors contribute to the covariance between indices of interest. discordant twin study designs can be used to examine whether one twin who was exposed to a certain environment (e.g., an adverse childhood event) has a different trajectory of psychopathology (e.g., ples) compared to the twin who was not exposed to this environment. this would provide evidence that in the context of certain genetic constitutions, the exposure to negative environments may alter one's trajectory. further, researchers will be able to examine polygenic risk scores, scores created to reflect the weighted effect of individual single nucleotide polymorphisms associated with risk for an outcome, to examine how heightened the genetic risk for disorders interacts with environmental factors to predict development of disorders [106] . for example, researchers will be able to examine how schizophrenia polygenic risk interacts with factors such as cannabis use to predict the development of schizophrenia spectrum symptoms. thus, researchers can use the abcd study to begin to tease apart complex genetic versus environmental contributions to psychopathology. the current review provided an overview of the goals, methods, initial results, and future directions for the abcd study for understanding the development of risk. the abcd study is a historic study following youth from ages 9 into early adulthood and is currently in its fourth year of data collection. the study operates under an open science framework and therefore annually releases data to the public. it is a large-scale population neuroscience study examining a heterogenous population recruited to reflect u.s. national sociodemographic proportions. the study is collecting data across a spectrum of domains, including mental and physical health, culture and environment, biospecimens, and neuroimaging. emerging cross-sectional results published from this study have already contributed to novel insights regarding psychopathology and brain and behavior correlates in middle childhood. the abcd study aims to better understand both normative and non-normative trajectories of development, examining risk for the development of many mental and physical health outcomes, including substance use. the characteristics of the abcd study, including a large heterogeneous sample longitudinally following youth across development, pose unique opportunities for understanding the development of risk. the heterogenous sample combined with examining a middle childhood sample, years prior to the period of greatest risk for many disorders, often results in finding smallmoderate effects. further, researchers have the opportunity to conduct exploratory analyses that incorporate rigorous best practices for data analysis including conducting power analyses. it will be crucial for researchers to replicate findings either using the abcd study sample (i.e., using discovery and replication samples or using additional data collection waves) or using an independent sample ( table 2) . as the abcd study makes advances in our understanding of risk and resiliency factors associated with psychopathology, it will be critical for researchers to begin to translate these findings into screening and intervention advances. this work was supported by national institute on drug abuse grant u01 da041120 (dmb) and national institute of health grants t32 mh014677 and l30 mh120574-01 (nrk). 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variability of objective sleep markers physical activity and weight gain prevention childhood externalizing and internalizing psychopathology in the prediction of early substance use peer network drinking predicts increased alcohol use from adolescence to early adulthood after controlling for genetic and shared environmental selection gene-environment interaction in psychological traits and disorders the impact of gene-environment interaction on alcohol use disorders polygenic risk scores in clinical psychology: bridging genomic risk to individual differences key: cord-318933-09ym98hx authors: betsch, cornelia; wieler, lothar h; habersaat, katrine title: monitoring behavioural insights related to covid-19 date: 2020-04-02 journal: lancet doi: 10.1016/s0140-6736(20)30729-7 sha: doc_id: 318933 cord_uid: 09ym98hx nan time, assessment of the relations between them, and randomisation of answer options where suitable. among others, included variables relate to demographics, protective behaviours, knowledge, perceptions, and trust. changes in risk perceptions or knowledge can be assessed over time; data on acceptance of new response measures can be made rapidly available; and misinformation or possible stigma can be identified as they emerge. immediate data analysis by means of an automated data analysis website provides fast access to the results. who materials contain commented code (free r studio online software) for data analysis and a website for rapid data presentation. the insights unit and health emergencies programme in the who regional office for europe are offering support to countries for implementation. national teams using the tool are urged to work in partner coalitions to discuss insights gained and implications for outbreak response interventions, policies and messages. making results rapidly available to journalists is also suggested to support high quality and responsible media reporting. journalists need timely knowledge about developing audience behaviour and habits to rapidly tailor information sharing and to develop narrative tools that encourage behaviour changes according to evidence from risk communication research. in sum, rapid data collection and sharing could support effective interaction between authorities, health workers, journalists, and the public to encourage appropriate behavioural change, to manage the crisis, and to protect the most important asset in a crisis: public trust. we declare no competing interests. the authors alone are responsible for the views expressed in this manuscript and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. the rapidly evolving coronavirus disease 2019 (covid-19) pandemic is placing an overwhelming burden on health systems and authorities to respond with effective and appropriate interventions, policies, and messages. a critical element in reducing transmission of the virus is rapid and widespread behavioural change. evidence shows that a perceived lack of consistency, competence, fairness, objectivity, empathy, or sincerity in crisis response in the public could lead to distrust and fear. 1 conversely, when the public perceives measures as having these characteristics, as well as being easily understood and communicated through trusted and accessible channels, and when the necessary services are available, people are able to make informed choices, protect themselves, and comply with recommended practices. 2, 3 risk perceptions influence individual protective behaviours 4 but paradoxically, how people perceive risk is not necessarily correlated with the actual risk. this was seen during the influenza pandemic in 2009-10, 5 where uncertainty and perceived exaggeration were also associated with a reduced likelihood to implement the recommended behaviours. 6 models of crisis and risk communication thus suggest that understanding risk percep tions is critical for an effective and appropriate crisis response. 7 at the same time, not enough is known about the complex interplay of changing epidemiology, media attention, pandemic control measures, risk perception, and public health behaviour. 5 behavioural insights for covid-19 are, therefore, of critical importance. this includes knowledge about what drives behaviour and awareness of changes in these drivers. 1, 3 other psychological challenges, such as misinformation, stigmatisation, or herd behaviour (such as hoarding of food or toilet paper) can be monitored to help estimate their prevalence and to identify sources. national authorities and other stakeholders, such as the media, can gain valuable insights into information needs, contextualisation of certain phenomena (eg, stigma tisation), and which target groups need additional attention. a few countries have rapidly initiated studies to gain such insights, and more countries are urged to prioritise such efforts, not in lieu of, but as a necessary supporting mechanism for other response measures. faced with overwhelming response requirements and cost, countries need opportunities to gain such insights through tools that: (1) are evidencebased; (2) can be rapidly applied; (3) can be regularly applied; (4) are simple and flexible enough to adjust to the changing situation; and (5) are low cost and cost-effective, particularly for low-income and middle-income countries. who and international partners can share such tools allowing countries to do this. shared tools offer the additional opportunity of preparing syntheses analysis across contexts, providing invaluable insights for the continued response effort as well as for the post-outbreak evaluation, sharing of lessons learnt, and the continued effort to better understand effective mechanisms of crisis response. weekly covid-19 snapshot monitoring (cosmo) was initiated in germany on march 3, 2020. 8 and needs to be expanded, and risk assessment frameworks also need to be refined further. preventing global spread of infectious diseases from mass gathering events and protecting global health security require public health decisions based on evidence and an agreed rational framework for decision making. a systematic process to assess the event encourages us to consider explicitly the reasoning behind the decision, what we expect the decision to achieve, and what evidence exists to support that reasoning. this, in turn, helps us evaluate whether the decision achieves what is expected and so informs future decisions. it also requires consideration of the negative impacts of a decision to cancel an event (jobs, mental health, the economy) and to look for ways to mitigate the adverse effects. crucially, we must look to the future. whatever the course of the covid-19 pandemic, countries, individually and collectively, will reach a point when they want to start removing restrictions and rebuild communities and economies. this will include decisions on re-starting mass gatherings. these decisions will need to be carefully reviewed and phased to ensure that the covid-19 pandemic is not reignited; here, we advocate our risk-based approach as a sensible and rational way forward to consider those decisions. mass gatherings to be considered in context, including the prevailing advice on physical distancing and movement restrictions. an open and transparent process to explicitly consider the risks of a mass gathering can, in fact, promote public confidence in the decision. the validity of our approach is exemplified by the emergence of the novel middle east respiratory syndrome coronavirus (mers-cov) in saudi arabia in 2012. 3 mers has a fatality rate 10-15 times greater than covid-19, and has spread globally; it has significant epidemic potential (as illustrated by the mers-cov outbreak in south korea 4 ) and remains on the who blueprint list of priority pathogens, yet we have never advocated cancelling the annual hajj pilgrimage in the epicentre of mers activity. this was because we adopted a risk-based approach and concluded that the risks were manageable in the context of the mitigation measures that saudi arabia had put in place; 7 years of safe and successful hajj since mers-cov emerged suggests that the decision was correct. we have not yet seen what decisions might be made by the saudi government about the impending hajj in 2020, in the context of covid-19, but we urge that those decisions are made on the basis of an evidence-based risk assessment process such as the one we describe in our comment. 2 any risk assessment and risk management framework for a mass gathering might inherently result in cancellation or postponement, as in the recent decision by the international olympic committee and japanese government to postpone the 2020 olympic games. 5 in the current covid-19 pandemic, it is inevitable in many countries that the outcome will be to cancel or postpone events, either because the risk is too great or because the capacity for mitigation measures is not available, or both. that is an appropriate and valid use of a risk assessment tool. the evidence base for mass gathering health is still evolving †cosmo group members are listed in the appendix. university of erfurt, 99089 erfurt, germany (cb); robert koch institute, berlin, germany (lhw); and who regional office for europe, copenhagen, denmark (kh) memish and colleagues, 1 in their response to our comment, 2 perceive conflict between the current bestpractice risk management advice on physical distancing and the scientific evaluation of cancelling or continuing mass gathering events during the coronavirus disease 2019 (covid-19) pandemic. although we have already acknowledged the need to balance these two considerations in order to maintain public understanding and trust, we do not accept that conflict is inevitable as our approach requires all vaccination and trusthow concerns arise and the role of communication in mitigating crises risk communication for public health emergencies communicating risk in public health emergencies: a who guideline for emergency risk communication (erc) policy and practice risk perception and self-protective behavior pandemic public health paradox": time series analysis of the 2009/10 influenza a/h1n1 epidemiology, media attention, risk perception and public reactions in 5 european countries public perceptions, anxiety, and behaviour change in relation to the swine flu outbreak: cross sectional telephone survey crisis and emergency risk communication as an integrative model covid-19 snapshot monitoring (cosmo): monitoring knowledge, risk perceptions, preventive behaviours, and public trust in the current coronavirus outbreak az is co-principal investigator of the pan-african network on emerging and re-emerging infections and is in receipt of a uk national institutes of health research senior investigator award. all other authors declare no competing interests. key: cord-303402-gxz2l8e4 authors: pereira da silva, alda; costa, maria do céu; aguiar, laura; matos, andreia; gil, ângela; gorjão-clara, j.; polónia, jorge; bicho, manuel title: impact on longevity of genetic cardiovascular risk and lifestyle including red meat consumption date: 2020-06-30 journal: oxid med cell longev doi: 10.1155/2020/1305413 sha: doc_id: 303402 cord_uid: gxz2l8e4 background: cardiovascular risk (cvr) underlies aging process and longevity. previous work points to genetic and environmental factors associated with this risk. objectives: the aim of this research is to look for any cvr gene-gene and gene-multifactorial/lifestyle interactions that may impact health and disease and underlie exceptional longevity. methods: a case-control study involving 521 both gender individuals, 253 centenarians (100.26 ± 1.98 years), and 268 controls (67.51 ± 3.25 years), low (lcr, n = 107) and high (hcr, n = 161) cvr. hypertension, diabetes, obesity (bmi, kg·m(−2)), and impaired kidney function were defined according to standard criteria. cvr was calculated using q risk®. dna was genotyping (ace-rs4646994, agt-rs4762, agr1-rs5182, grk4-rs2960306, grk4-rs1024323, nos3-rs1799983, and slc12a3-rs13306673) through iplex-massarray®, read by maldi-tof mass spectrometry, and analyzed by eartdecode®. results: antilongevity factors consisted (or 95% ci, p < 0.05) bmi 1.558 (1.445-1.680), hypertension 2.358 (1.565-3.553), smoking habits 4.528 (2.579-7.949), diabetes 5.553 (2.889-10.675), hypercholesterolemia 1.016 (1.010-1.022), and regular consumption of red meat 22.363 (13.987-35.755). genetic aspects particularly for hcr individuals ace ii (or: 3.96 (1.83-8.56), p < 0.0001) and nos3 tt (or: 3.11 (1.70-5.70), p < 0.0001) genotypes were also risk associate. obesity, smoking, hypercholesterolemia, and frequent consumption of red meat have an additive action to hypertension in the longevity process. there was a synergistic interaction between the endothelial nos3 genotypes and the severity of arterial hypertension. an epistatic interaction between functional genetic variants of grk4 and angiotensinogen was also observed. conclusions: cardiovascular risk-related genetic and multifactorial or predominantly lifestyle aspects and its interactions might influence the aging process and contribute to exceptional longevity in portuguese centenarians. besides lifestyle, the activity of nitrite oxide synthase may be one of the main physiologic regulators of cardiovascular protection in the path of longevity. the lifespan has been increasing in most countries, including portugal. particularly, the number of centenarians (cent) in portugal has almost tripled over the last 10 years from 589 in 2001 [1] to 1526 in 2011 [2] , according to the last census. this value is estimated to be increasing in mainland portugal, a number of individuals aged 100 years or over of 3342 in 2050 and 21177 individuals in 2080, mostly female, according to a central scenario [3] . although in 2019 there were more cent individuals and life expectancy has increased before covid-19 pandemics, the estimated 65-year-old prospect of reaching 100 years old is still extremely low, i.e., over 17.6 years for men and 20.9 years for women, not reaching, in any case, the 100year-old [4, 5] . environmental factors, as well as genetic factors, all contribute to exceptional or extreme longevity that means over 99 years [6] or above 95 years, namely, in the case of male gender [7] [8] [9] . the contribution of genetic factors for longevity seems no higher than 35% [10] . this presupposes an epigenetic and lifestyle influence that has to be considered. there are many theories that try to explain the phenomenon of longevity and why an individual grows old. nowadays, the combined theories have stood out and there is full awareness that biophysical, biochemical, and genetic factors may interact in the process [11, 12] , in a highly complex matrix, regulated through systems and levels of organization of different complexities, which are intercommunicated through feedback systems [13] . environmental and genetic agents, as well as their interaction, may lead to mechanisms related to oxidant stress and gene expression and influence the longevity process [14] . it is known that cardiovascular diseases have a great impact on achieving longevity since they constitute a risk for the shortening of life expectancy. the lifestyle associated with extreme longevity has been investigated; the hypothesis being raised of the influence of epigenetic factors on longevity and that genetic factors related to longevity may protect against the harmful effects of poor lifestyle choices [8] . some genes linked to the aging process have been studied. polymorphic genetic variants, related to the pathways involving aging and atherosclerosis [15] , such as the renin-angiotensin-aldosterone system (raas), message transduction, and oxidative stress, may affect the aging process, being susceptible to epistatic interactions, likewise with environmental factors. the insertion (i)/deletion (d) polymorphism of angiotensin-converting enzyme (ace) has been associated with longevity [16] and chronic diseases, such as cvds and alzheimer's dementia [15] . other genes, such as angiotensinogen (agt), specifically the agt m235t polymorphism, may be associated with chronic age-associated cvds [15] . as for nos3, this is a determinant polymorphism for the production of nitric oxide, with consequent implications for the development of atherosclerosis, hypertension [16, 17] , and alzheimer's, with impact on cardiovascular risk and longevity [16, [18] [19] [20] . variants of the at1 receptor of angiotensin ii (agtr1) [21] and other genetic polymorphisms such as the g protein-coupled receptor kinase 4 (grk4) [22, 23] and solute carrier family 12 member 3, slc12a3 [24] , have been related to arterial hypertension and atherosclerosis. cardiovascular risk (cvr) underlies aging process and longevity. arterial hypertension (ht) and its severity are one of the main factors associated with cardiovascular risk. previous work has shown that prevalence of ht in portuguese centenarians (64.4%) is lower than among portuguese population aged ≥65 years (74.9%) (p < 0:001) [25] and that portuguese centenarians, when hypertensive, have arterial pressure values from low to moderate, majority of grade 1 and only 4.7% grade 3 [16] . on the other hand, there were also found differences in frequency genotype distribution between centenarians and controls concerning ace-i/d-rs4646994 (p = 0:001) and nos3-gt-rs1799983 (p < 0:0001) polymorphisms [16] . the aim of the present study is the analysis of genetic variables associated with longevity and their interaction with cardiovascular risk variables and lifestyle, contributing to the understanding of the phenomenon of aging and its prevention, to delay its process. arterial hypertension and grade classification criteria were defined according to the european society of hypertension (esh)/european society of cardiology (esc) [26] and determined using a validated colson mam bp3aa1-2 device [27] . pulse pressure abnormal was considered when above 62.5 mmhg [28] . diabetes and obesity (body mass index, bmi, kg·m -2 ) were established in agreement with who criteria: diabetes for hgb a1c ≥ 6:5%, or fpg < 126 mg/dl; obesity classifications: underweight < 18:5 kg·m -2 , normal weight 18.5-24.9 kg·m -2 , preobesity 25.0-29.9 kg·m -2 , and obesity ≥ 30 kg·m -2 [29, 30] . impaired kidney function was considered when blood urea nitrogen > 60 mg/dl and/or serum creatinine concentration ≥ 1:5 mg/dl [31] . the control group was subdivided into low (lcr) and high (hcr) cardiovascular risk, according to the results obtained, by inserting the personal data of each individual in a program, q risk® 2-2016 [32] , consisting in a prediction algorithm based on age, gender, ethnicity, body mass index (bmi), past and present smoking habits, hypertension criteria, systolic blood pressure, total cholesterol/hdl-c ratio, presence of diabetes, atrial fibrillation, rheumatoid arthritis, chronic kidney disease (stage 4 or 5), atrial fibrillation, and a family history of angina or heart attack in a first-degree relative aged <60 years [33, 34] . a high cardiovascular risk (hcr) score was considered if q risk® ≥20% or in case of a history of acute myocardial infarction, stroke, peripheral arterial disease, congestive heart failure, or acute pulmonary edema. q risk, predicts predicts a risk of developing cardiovascular disease in the next ten years as a stroke or heart attack. the number of centenarians in the family until the 3rd generation was questioned. food consumption data were collected by applying a semiquantitative food frequency questionnaire, based on a validated ffq for a portuguese population [35] . regular consumption of red meat was considered weekly consumption and up to three times a day. dna extractions were performed from the buccal epithelium sample using the commercial citomed kit: "citogene®buccal kit" ref. buc-100. the evaluation of dna concentration and quality was done using the multiskan go microplate spectrophotometer (thermo scientific®). genotyping was performed using a microchip dna on a high-throughput platform using iplex massarray® technology from agena bioscience. the genotypes obtained were read 2 oxidative medicine and cellular longevity by maldi-tof mass spectrometry. the different mass values of each generated pcr product were converted into genotype information. genotyping data were analyzed using the eartdecode® software system from heartgenetics. the following genetic variants were studied: angiotensin-converting enzyme (ace) i/d, (-/(289pbalu) intr16; cr 17), (rs4646994); angiotensinogen (agt; cr 1) (rs4762); angiotensin ii receptor 1 (agr1; cr 3) (rs5182); endothelial nitric oxide synthase (nos3; cr 7) (rs1799983); g protein-coupled receptor kinase (grk4; cr 4) (rs2960306) and (rs1024323); member 3 solutes carrier of the family 12 (slc12a3; cr 16) (rs13306673). 2.1. statistical analysis. the pearson χ 2 test was used for comparisons between groups. the logistic regression method was conducted to model the probability of an existing event such as centenarians or controls, centenarian or low-or high-risk controls. in this logistic regression model, a binary dependent variable (categorical) was considered. the independent variables were binary with two classes, coded by an indicator or continuous variables. for the study of genegene or epistatic and gene-environment interactions, the multifactor dimensionality reduction (mdr) method was used through the mdr software package [36] . this methodology allows to perceive interactions between genes or between these and environmental factors, which interact for a given phenotype. the results are presented in the form of dendrogram and circle graphs, with visualization of additive and nonadditive connections or interactions in the phenotype. positive entropy values indicate synergistic or nonadditive interaction, and negative values indicate redundancy. the red and orange connections indicate synergistic interactions, the green and brown connections indicate independence or additivity, and the blue ones indicate redundancy [37] . data were analyzed throughout mdr 3.0.2 (available at http://www.multifactordimensionalityreduction.org/) and ibm spss statistics version 24.0 being statistical significance defined as a p value < 0.05. 3.1. sample. the sample consisted of 521 centenarians (cent) and controls (cont), from both genders. centenarians from all the regions of portugal were identified, enrolled, and evaluated at their usual place of residence, having their recruitment been previously described [38] . regarding centenarian's sample individuals, 58.1% presented blood pressure levels within the normal range and the others, ht, being 27.3% grade 1, 12.6% grade 2, and 2% grade 3. from control sample individuals, 49.3% presented blood pressure levels within the normal range and the others, ht, being 31.7% grade 1, 13.4% grade 2, and 5.6% grade 3. there were no significant differences in the distribution of levels of blood pressure among genders in both subgroups (p = 0:336 and p = 0:720 cent and cont, respectively). it should be noted that these values refer to the observed blood pressure and include normotensive and hypertensive individuals, whether controlled or not. table 1 shows the results of sex-adjusted empirical analysis of covariates involved in cardiovascular risk and longevity, except for genetic variables. in this table, the or and confidence intervals and their p value are compared, either taking as dependent variable cent vs. lcr controls, either cent vs. hcr controls, or cent vs. cont (control overall sample). the variables significantly (p < 0:001) most associated with the risk of not achieving exceptional longevity, considering cent vs. cont, expressed in or (95% ci) were, in ascending order of risk, hypercholesterolemia 1. 3.3.1. centenarians in the family. considering the number of centenarian individuals in the family, it was verified that this prevalence is greater for the centenarians of the study sample, relative to the control group. thus, while 34.6% of cent have one or more centenarians in the family, the same occurs in only 19.9% of the controls (p = 0:015, χ 2 = 10:450 gl = 3). considering the linear-by-linear association, we find cent vs. cont (p = 0:002) with a centenarian relative: 27.9% vs. 17.3%, with 2 centenarians: 5.1% vs. 1.8%, and with 3 centenarian relatives: 1.5% vs. 0.9%. the sex-adjusted empirical analysis of the genetic polymorphisms studied using different models (additive, recessive, and dominant) can be observed in table 2 . when considering the studied genotypes, significant differences were observed only in relation to ace and nos3 genotypes, considering dependent variable centenarian's vs. controls (total, low risk, and high risk), being the referent and the covariates, the different genotypes depending on the model (table 2 ). it was found that having the ace ii genotype increased 3.2 times the risk of not achieving longevity in low-risk controls (p = 0:004) and about 4 times in high-risk controls (p < 0:0001). similarly, having the nos3 tt genotype increases 2.1 times the risk of not achieving longevity in low-risk controls 3 oxidative medicine and cellular longevity (p = 0:021) and 3.1 times in high-risk controls (p < 0:0001) ( table 2) . through the reduction of multifactorial dimensionality, it can be verified that there is a close and strong genotype interaction between ace and nos3 that in turn relates to hypertension as well as to hypercholesterolemia, smoking, and red meat intake ( figure 1) . when considering the interactions of the genetic variants studied with multifactorial parameters related to cardiovascular risk isolated or determined as q risk, there is a predominant interaction between this marker and genetic polymorphisms nos3 gt and ace i/d related to exceptional longevity (figure 2 ). since the grade of hypertension is one of the most prominent cardiovascular risk factors, we looked to see if the genetic variants studied could interact with hypertension severity. although there were no differences in nos3 genotype distribution according to the levels of blood pressure in both subgroups cent p = 0:554 and cont p = 0:069, a high degree of synergy was detected between hypertension grade and nos3 genotype and also, an epistatic interaction although less strong than the latter was observed between ang and grk4 genotypes for longevity (figure 3(a) ). when including q risk in the model, the same observations are verified (figure 3(b) ). the underpinnings underlying the natural aging process are complex, given their multifactorial nature. this work is aimed at contributing to understanding the relative impor-tance of some cvr genetic as well as lifestyle aspects in the approach to exceptional longevity. it was not surprising that aspects such as diabetes, obesity, hypercholesterolemia, hypertension, and smoking contradict extreme longevity (table 1) . moreover, it was noticed how these aspects interact with each other and with the genotypes. when analyzing the graphs, it is noticed that there is a redundant or additive interaction between variables such as red meat consumption, hypercholesterolemia, obesity, smoking, and high blood pressure, which adds to the genetic aspects along the path of longevity (figure 1 ). smoking has been associated with all major dead causes as cardiovascular and respiratory diseases and has been associated with more than 7 million deaths per year [40] , a value far superior than diabetes, which has been related to 1.6 million deaths worldwide [41] . our findings support this because the frequency of smoking habits in centenarians was low (8.7%) and diabetes (4.7%) was rare, which differed significantly from those in the control group (heavy smokers 20.3% and diabetics 22.0%). the majority of centenarians (91.3%) never smoked, and when they did, it was in the amount of less than one pack per year, which did not happen in the control group in which 20.3% of individuals reported smoking more than one pack per day. hypertension is the main risk factor for cv disease. it was therefore named "the number one killer" by the who [42]. however, there are hypertensive centenarians and ht per se does not seem to prevent reaching a well above average age [43, 44] . thus, the interference of factors other than ht may contribute to longevity. the present study shows a frequency of ht in the portuguese centenarians (64.4%), similar to that found among centenarians in other european countries such as poland (65.0%) [44] and spain (64.0%) [45] . it should be pointed out that the prevalence of [25] . in another study conducted in the portuguese population over 55 years of age, the prevalence of ht was 67.6% according to the jnc vi criterion [46] . oxidative medicine and cellular longevity the probable justification for hypertensive individuals to reach the age of 100 years may be the fact that, although hypertensive, they have controlled arterial pressures. in fact, there were significant differences regarding the control of hypertension: while the frequency of controlled hypertensive individuals verified in the study concerning the portuguese hypertensive population was 42.5% [25] , in relation to the studied centenarians, the frequency of controlled hypertension was higher (58.9%) (χ 2 = 16:03, p < 0:0001). in addition, centenarians, when hypertensive, have low to moderate blood pressure values and most have grade 1 hypertension [16] . increased pulse pressure has been shown to be an independent cardiovascular risk factor, especially for very elderly individuals [47] . our data show that pathological pulse pressure was prevalent in the cent in relation to cont (p < 0:030) although the mean pp found in individuals at hcr did not differ significantly from those found in the studied cent. this means that hcr individuals approach centenarians in terms of cardiovascular aging (table 1) . individuals in the centenarian group had lower total cholesterol, ldl-c, non-hdl cholesterol, and total cholesterol/hdl-c ratio [35] . ldl-c and non-hdl are atherogenic factors. non-hdl cholesterol includes triglyceride-rich lipoproteins, remaining tg-rich lipoproteins enriched with cholesteryl esters and also lipoprotein (a), and has a high cv risk predictive value [48] . in relation to the cholesterol/hdl-c ratio, one of the cvr parameters, the centenarians had a better profile in particular when compared with the subjects in the high-risk subgroup of the control group [35] . in addition, centenarian individuals showed a significantly lower ldl mean value relative to the control group [35] . these aspects may be associated with their longevity success, and eating habits underlie this profile. in fact, membrane-rich cholesterol domains (lipid rafts) in which the receptors aggregate play an important role in signaling mechanisms, and activation of nadph oxidase leading to an increase of oxidant stress in the cell which may induce ldl-c modification [49] . in addition to the lowest ldl-c, the centenarians present the total cholesterol/hdl-c indicator (used to calculate q risk), which is significantly lower in relation to the high-risk subgroup of the control group [35] . this aspect is relevant since hdl particles remove fat molecules from cells such as cholesterol (especially oxidized), phospholipids, and triglycerides protecting arteries' walls [50] . moreover, hdl receptors, such as abca1 and sr-bi, may act as antiinflammatory receptors [51] . the inflammatory process, by stimulating the production of the acute phase protein hepcidin, leads to the internalization of its receptor, the ferroportin channel, in macrophages, preventing iron exporting from these cells, with resultant accumulation of iron. this phenomenon will contribute to the production of reactive intracellular oxygen species, leading to lipid oxidation preventing their efflux from inside the cell, facilitating the process of lipoperoxidation and modification of ldl, contributing to atheroma formation in a vicious cycle. this inflammatory condition generates more radicals that perpetuate this vascular process generalizing atherosclerosis [52] . not only diet [53] but obesity [54] may accelerate the aging process. low red meat intake was, in the present work, also checked for longevity impact (table 1) . our results agree with that observed by other authors suggesting that the highest cvr were associated with the highest frequencies of red meat consumptions [35, 55, 56] . particularly, processed red meat is associated with a higher incidence of cv diseases such as coronary heart disease, heart failure, and stroke in addition to other pathologies [56] . red meat is a source of heme-iron [57] which, besides carcinogenesis pathology [58, 59] in the presence of an inflammatory process, facilitates ldl lipoperoxidation and atherogenesis [52] . as the low consumption of red meat throughout life, the normal weight and the healthy level of visceral fat [38] were prevalent among portuguese centenarians; the results of the present study confirm the evidence that the lifestyle certainly contributed to their low cardiovascular risk and longevity (table 1) . regarding the genetic aspects, the contribution of genetics for longevity is estimated as 5 to 35% [10] , thus paving the way to a wide range of environmental factors [6] . actually, considering the number of centenarian individuals in the family, it is verified that this prevalence is greater for the cent of the study sample, relative to the cont group. thus, while 34.6% of cent have one or more centenarians in the family, the same occurs in only 19.9% of the controls. the genetic influence, minimum before age 60, increases thereafter, becoming genetic factors increasingly important to achieve longevity [60] . exceptional longevity may be influenced by polymorphisms in specific genes, coupled with superior genomic stability and homeostatic mechanisms [6] . despite a genetic association to longevity, the environment can influence gene expression through possible epigenetic mechanisms [61] , with lifestyle factors being a major contributor to longevity. the fact that the number of centenarians increases, according to the demographic statistics unit of the portuguese national statistics institute [3] , corroborates the environmental influence in contributing to longevity, which is in line with other authors [6, 55, 62] . studies indicate the existence of genetic interactions between renin-angiotensin system loci [63, 64] and endothelial nitric oxide synthase polymorphisms [65] . in the present work, interactions of different types and intensity were verified, among grk4, ace, nos3, agt, and agr1 gene polymorphisms (figures 1 and 2) . the grk4 gene polymorphism may, in synergy with that of the angiotensinogen gene, influence cvr (figure 2 ). polymorphic variants of angiotensinogen gene (m235t, rs699, and t174m, rs4762) could be associated with angiotensinogen levels, ht, left ventricular hypertrophy, and survival in heart failure [66] . polymorphisms of this protein may be on the basis of susceptibility to hypertension, including during pregnancy [67] . it is reported genetic interaction of genes related to the raas, namely, angiotensinogen with environmental factors, affecting longevity by conditioning susceptibility to ht [68] . an angiotensinogen derivative, i.e., angiotensin ii, in turn, throughout renin and ace activities, acts through angiotensin ii type 1 receptor that plays an important role in vasoconstriction and retention of salts 9 oxidative medicine and cellular longevity and water, which action is modulated by the associated agr1 ct genotype [69] . the strong redundant interactions of red meat consumption, smoking, bmi, and hypercholesterolemia are additive to high blood pressure, ace, and nos3 genotype polymorphisms, all being able to contribute to cardiovascular risk. the question that arises is to what extent can the genotypic variants of these enzymes condition the harmful effects of these variables obstacle to longevity? it should be noted that ace plays a critical role in sodium and erythrocyte homeostasis. this enzyme catalyzes the formation of angiotensin ii from angiotensinogen and inactivation of bradykinin, and goralatide, an inhibitor of hematopoiesis n-acetyl-seryl-aspartyl-lysyl-proline, resulting in increased vasoconstriction and blood pressure and appropriate erythropoiesis [70] . the insertion/deletion polymorphism (id) has been studied in hypertensive individuals; the d allele is associated with higher plasma levels of ace. the dd genotype is significantly associated with higher systolic and diastolic blood pressure [71] [72] [73] . however, the dd genotype may be advantageous in this group of centenarians in the absence of cv environmental risk factors (table 2) , leading to a favorable gene-environment interaction which may have contributed to longevity. it is understood that genetic variants of grk4 (rs2960306 and rs1024323) may, in synergistic interaction with the angiotensinogen gene, influence cvr (figures 2 and 3) . the polymorphisms in the grk4 gene are associated with the etiology of arterial hypertension by regulating phosphorylation and the function of dopamine receptors in proximal renal tubule cells which may lead to a decrease in sodium elimination and a consequent increase in blood pressure [74] [75] [76] . studies indicate that grk4 gene polymorphisms are associated with susceptibility to hypertension in the european population [22] and caucasians [77] . both angiotensinogen and g protein-coupled receptor kinase are ultimately related to sodium retention, so their epistatic relationship makes sense. the human endothelial nitric oxide synthase has a heme domain [78, 79] . it is constitutively expressed, being a mediator of age-related phenotypes and longevity [80] . nitric oxide (no) product of the oxidation of l-arginine by nos3 is a gaseous free radical, which can function as a signaling molecule that, through a process of nitrosylation, regulates a series of physiological responses such as oxygen consumption, insulin secretion, apoptosis, neurotransmission, immunity, vasodilation, and angiogenesis. for its vasoprotective and antiatherosclerotic proprieties, it regulates smooth muscle relaxation and interacts with mitochondria, triggering mechanisms of cell survival or death [17, 80, 81] . the endothelial nos3 (snp rs1799983) (cr.7q36.1) have a gt polymorphism guanine to thymine change in position 894 of the nos3 gene leading to glu298asp [82] . this polymorphism allows the generation of two isoforms of endothelial nos3: nos3 glu298 (allele g) and nos3 asp298 (allele t) [83] . it is a functional polymorphism, which influences the activity of the enzyme, no production, blood pressure [17, 84] , lipid levels [85] , and angiogenesis [86] with people with the t allele being particularly homozygous, associated with less enzyme activity [84] and the highest cardiovascular risk [18, 19, 85] , reduced no bioavailability engaging in the initiation, progression, and complications of atherosclerosis [87] less likely to achieve longevity [16] . these mechanisms can explain what was observed in the present study of the synergistic interaction of nos3 genotypes with the degree of ht in longevity (figures 2 and 3) as well as the potentially additive effect of smoking, hypercholesterolemia, obesity, and frequent consumption of red meat (figure 1) . the risk associated with this consumption (table 1 ) has been neglected in longevity studies, but it is important that it be deepened because red meat increases heme-iron levels, inducing lipid peroxidation products, generating an inflammatory process and endogenous formation of abnormal no radical derivatives as nitration compounds, endogenous nitrosamines, also induced by tobacco, responsible for the known harmful effects of no [88, 89] . several studies have demonstrated that nonhemodynamic factors such as chronic inflammation and oxidative stress may contribute to early vascular aging (eva). on the other hand, caloric restriction may reverse this process and promote healthy vascular aging (hva) or even super normal vascular aging (supernova) [90] . these data may lead to a reflection on the importance of eating habits such as caloric overload and in particular that associated with red meat ingestion in longevity [35] . this study realized and confirmed some of the cardiovascular risk factors, both genetic and related to lifestyle, and their interaction, in longevity. it concludes that obesity, hypercholesterolemia, and hypertension, according to their severity and smoking and consumption of red meat according to their frequency of consumption, are aspects to control when trying to follow the path of longevity. these factors interact with each other, in a redundant and additive way to genetic factors, creating the long-lived phenotype. genetic polymorphisms associated with increased cardiovascular risk, such as ace and nos3, can modulate lifestyle aspects. being centenarian, it is a result of a set of life circumstances, environmental factors in their broadest concept associated with a genetic context that converged in the prevention of cardiovascular risk factors, translating into a phenotype of exceptional longevity. according to our results, being centenarian is strongly determined by environmental/lifestyle factors, specifically lack of smoking and nonregular red meat consumption habits and, to a lesser extent, eutrophic phenotype, low grade, and controlled hypertension when existent, adequate lipid profile. thus, interactions between genetic variants of polymorphisms with hemodynamic regulation in particular of ace and nos3 with environmental factors may contribute to exceptional longevity. functional genetic variants of the grk4 enzyme may, as evidenced, in synergy with those of the angiotensinogen gene, influence cvr and longevity. this synergism shows the relevance of the coordinated hepatorenal action in longevity. also, the synergistic interaction of the nos3 endothelial enzyme genotypes, conditioning the activity of this enzyme, with the degree of arterial hypertension, denotes to be one of the relevant mechanisms in the microcirculatory preservation in longevity. future studies may see the extent to which individuals have protective factors, either genetic or lifestyle, that allow longevity and healthy aging. in this study, the group of centenary individuals is compared to a control group of elderly, but younger, in order to ensure control of risk factors, assuming that the probability of reaching 100 years is remote, according to the bank contemporary database of portugal [4] . in addition, it is assumed that the cardiovascular risk of centenarians is small compared to the high-risk group in the control group. in fact, otherwise, they would not have reached such a high age. angiotensin-converting enzyme agt: angiotensinogen agr1: angiotensin ii receptor 1 bmi: body mass index cent: centenarians cont: controls cvr: cardiovascular risk dbp: systolic blood pressure esc: european society of cardiology esh: european society of hypertension grk4: g protein-coupled receptor kinase hcr: high cardiovascular risk ht: arterial hypertension lcr: low cardiovascular risk mbp: mean blood pressure mdr: multifactor dimensionality reduction nos3: endothelial nitric oxide synthase raas: renin-angiotensin-aldosterone system sbp: systolic blood pressure slc12a3: member 3 solutes carrier of the family 12. the data that support the findings of this study are available from the corresponding author upon request. this research work was approved by the ethics committee of the lisbon academic medical centre (faculty of medicine of the university of lisbon and santa maria hospital) and by the national commission for data protection and was conducted in agreement with the helsinki declaration [91] . all the participants gave their informed consent in order to be included in the study. oxidative medicine and cellular longevity population projections disclosed on june 14 life expectancy at 65 (indicator)," health status genetics, lifestyle and longevity: lessons from centenarians where are supercentenarians located? a worldwide demographic study lifestyle factors of people with exceptional longevity four genome-wide association studies identify new extreme longevity variants longevite et vieillissement. mecanismes et perspectives the fading electricity theory of ageing: the missing biophysical principle? modern biological theories of aging systems approaches to the networks of aging environmental factors of longevity genetic 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study from calcutta, india angiotensin converting enzyme gene polymorphism and hypertension in north coastal andhra pradesh g proteincoupled receptor kinase 4 (grk4) regulates the phosphorylation and function of the dopamine d3 receptor mechanisms of disease: the role of grk4 in the etiology of essential hypertension and salt sensitivity desensitization of human renal d1 dopamine receptors by g protein-coupled receptor kinase 4 genotyping of essential hypertension single-nucleotide polymorphisms by a homogeneous pcr method with universal energy transfer primers structure of human endothelial nitric oxide synthase heme domain with l-arg bound structures of human constitutive nitric oxide synthases common polymorphisms in nitric oxide synthase (nos) genes influence quality of aging and longevity in humans the discovery of nitric oxide and its role in vascular biology structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene a missense glu298asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the japanese in-vivo effects of glu298asp endothelial nitric oxide synthase polymorphism associations of thenos3rs1799983 polymorphism with circulating nitric oxide and lipid levels: a systematic review and meta-analysis angiogenesis related genes nos3, cd14, mmp3 and il4r are associated to vegf gene expression and circulating levels in healthy adults nitric oxide bioavailability dysfunction involves in atherosclerosis tobacco nitrosamines as culprits in disease: mechanisms reviewed heme iron from meat and risk of colorectal cancer: a meta-analysis and a review of the mechanisms involved concept of extremes in vascular aging world medical association declaration of helsinki: ethical principles for medical research involving human subjects the authors acknowledge dr. sara cardoso's (social researcher and writer, lisbon, portugal) valuable assistance in the establishment of contacts for the recruitment of centenarians and césar oliveira for operational collaboration in the fieldwork. the authors would also like to thank prof. doctor fausto pinto, dean of faculdade de medicina da universidade de lisboa and of the heart and vessels department of santa maria hospital, for the given support. finally, we acknowledge the funding support of fundação para a ciência e a tecnologia (fct), uidb/04295/2020. the authors declared no conflicts of interest. aps, mcc, jgc, and mb contributed to the conception and design of the work. aps held the investigation and data acquisition. aps drafted the manuscript. am and ag contributed to the laboratory work. aps, mcc, jgc, and mb contributed to the analysis and interpretation of data. aps, mcc, la, zm, jp, jgc, and mb critically revised the manuscript. all gave final approval and agreed to be accountable for all aspects of work, ensuring integrity and accuracy. key: cord-309122-9dfyjpid authors: sato, akiko; honda, kaori; ono, kyoko; kanda, reiko; hayashi, takehiko i.; takeda, yoshihito; takebayashi, yoshitake; kobayashi, tomoyuki; murakami, michio title: reviews on common objectives and evaluation indicators for risk communication activities from 2011 to 2017 date: 2020-08-25 journal: peerj doi: 10.7717/peerj.9730 sha: doc_id: 309122 cord_uid: 9dfyjpid background: risk communication is widely accepted as a significant factor for policy makers, academic researchers, and practitioners in diverse fields. however, there remains a lack of comprehensive knowledge about how risk communication is currently conducted across fields and about the way risk communication is evaluated. methodology: this study systematically searched for materials from three scholarly search engines and one journal with a single search term of “risk communication.” the eligibility assessment selected peer-reviewed articles published in english that evaluated risk communication activities. emphasis was placed on articles published in recent years accounting for about half of the pre-selected ones. data on field of study, intervention timing, target audience, communication type, and objectives/evaluation indicators was extracted from the articles. patterns of objectives/evaluation indicators used in risk communication activities were compared with those of the definitions and purposes of risk communication stated by relevant organizations. association analysis was conducted based on study fields and objectives/evaluation indicators. results: the screening process yielded 292 articles that were published between 2011 and 2017 in various fields, such as medicine, food safety, chemical substances, and disasters/emergencies. the review process showed that many activities were performed in the medical field, during non-/pre-crisis periods. recent activities primarily targeted citizens/non-profit organizations (npos), and was disseminated in the form of large group or mass communication. while “knowledge increase,” “change in risk perception and concern alleviation,” and “decision making and behavior change” were commonly addressed in practice, “trust-building” and “reduction in psychological distress” were rarely focused. the analysis also indicated that the medical field tends to perform risk communication at the individual or small group level, in contrast to the food safety field. further, risk communications in the non-/pre-crisis period are more likely to aim at “changes in risk perception and concern alleviation” than those in the crisis period. risk communications that aim at “changes in risk perception and concern alleviation” are likely to be presented in a large group or mass communication, whereas those that aim at “decision making and behavior change” are likely to be conducted at the individual or small group level. conclusion: an overview of recent activities may provide those who engage in risk communication with an opportunity to learn from practices in different fields or those conducted in different intervention timings. devoting greater attention to trust building and reduction in psychological distress and exploring non-citizen/npo stakeholders’ needs would be beneficial across academic and professional disciplines. the covid-19 pandemic made the world-from politicians, scholars and practitioners to individual citizens-desperate for accurate, timely information. as of june 2020, there is no single day during which one does not hear updates or stories related to covid-19. not only reliable information, but myths and false messages have also spread rapidly, causing great confusion. such incorrect information sometimes results in unnecessary fear or unrealistic hope among people (world health organization, 2020a; shiloh vidon, 2020) . in response to the upsurge in demand from affected nations, the international federation of red cross and red crescent societies (ifrc), the united nations children's fund (unicef), and the world health organization (who) jointly issued the strategy (international federation of red cross and red crescent societies, united nations children's fund & world health organization, 2020) . the world is now keen on effective risk communication. although risk communication is now gaining tremendous attention, it is not new. in 1989, the united states national research council published improving risk communication (national research council, 1989) and introduced an influential concept of risk communication by calling it: an interactive process of exchange of information and opinion among individuals, groups, and institutions. it involves multiple messages about the nature of risk and other messages, not strictly about risk, that express concerns, opinions, or reactions to risk messages or to legal and institutional arrangements for risk management (national research council, 1989) . the concept has been ardently applied to avert the occurrence of different risks in life and reduce their impacts on human health, property and the environment (fischhoff, 1995; covello & sandman, 2001; international risk governance center, 2017) . apart from public health emergencies such as covid-19, risk communication can take place in other areas, involving health care, food safety, and chemical substances (glik, 2007; lopez-gonzalez the inclusion criteria used to select empirical studies were (1) that the study evaluates risk communication activities in any field, and (2) that the study is written in english. this study also included previous research that did not directly evaluate risk communication but did ask implementers, such as medical professionals, about the objectives and effects of their activities relevant to risk communication. these studies were included because they chemical substances organization for economic co-operation and development (renn & kastenholz, 2000) (cited covello, von winterfeldt & slovic (1986) ) the act of conveying or transmitting information between interested parties about (a) levels of health or environmental risks; (b) the significance or meaning of health or environmental risks; or (c) decisions, actions, or policies aimed at managing or controlling health or environmental risks. helping to build trust among organizations that risks are being adequately assessed and managed; assisting with making better decisions on how to address risks; helping to ensure smoother implementation of risk management policies; helping to empower and reassure the general public; helping to bridge the gap between real risks and perceived risks ; and helping to prevent crises from developing and managing them when they do occur. the process of informing people about potential hazards to their person, property, or community. to help residents of affected communities understand the processes of risk assessment and management, to form scientifically valid perceptions of the likely hazards, and to participate in making decisions about how risk should be managed. the exchange of information and opinions concerning risk and risk-related factors among risk assessors, risk managers, consumers and other interested parties. to enable people to protect their health from food safety risks by providing information that enables them to make informed food safety decisions , to facilitate dialogue and understanding among all interested stakeholders, and to improve the overall effectiveness of the risk analysis process. the interactive exchange of information and opinions throughout the risk analysis process concerning risk, riskrelated factors and risk perceptions, among risk assessors, risk managers, consumers, industry, the academic community and other interested parties, including the explanation of risk assessment findings and the basis of risk management decisions. risk communication should: (i) promote awareness and understanding of the specific issues under consideration during the risk analysis; (ii) promote consistency and transparency in formulating risk management options/recommendations; (iii) provide a sound basis for understanding the risk management decisions proposed; (iv) improve the overall effectiveness and efficiency of the risk analysis; (v) strengthen the working relationships among participants; (vi) foster public understanding of the process, so as to enhance trust and confidence in the safety of the food supply; (vii) promote the appropriate involvement of all interested parties ; and (viii) exchange information in relation to the concerns of interested parties about the risks associated with food. european food safety authority (european food safety authority, 2017) to assist stakeholders, consumers and the general public to understand the rationale behind risk-based decisions and, to help them make balanced judgements about the risks that they face in their own lives. (continued on next page) effective risk communication can contribute to the success of a risk management program by: (1) ensuring that consumers are aware of the risks associated with a product and thereby use or consume it safely; (2) building public confidence in risk assessment and management decisions and the associated risk/benefit considerations; (3) contributing to the public's understanding of the nature of a risk or risks; and (4) providing fair, accurate, and appropriate information , so that consumers are able to choose among a variety of options that can meet their own ''risk acceptance'' criteria. (1) improved understanding of the risks and benefits of regulated products by the multiple audiences with whom fda communicates, including relevant international audiences; (2) increased public awareness of crisis events and the increased likelihood that affected individuals or groups will take recommended actions; (3) increased public satisfaction with fda as an expert and credible source of information about regulated products; and (4) increased confidence that target audiences are getting useful, timely information as it becomes available, to help them make informed choices. world health organization (gamhewage, 2014; world health organization, 2019) the two-way and multi-directional communications and engagement with affected populations. to share information vital for saving life, protecting health and minimizing harm to self and others; to change beliefs ; and/or to change behavior . (continued on next page) the exchange of real-time information, advice and opinions between experts and people facing threats to their health, economic or social well-being. to enable people at risk to take informed decisions to protect themselves and their loved ones. united states nuclear regulatory commission (persensky et al., 2004) an interactive process used in talking or writing about topics that cause concern about health, safety, security, or the environment. (examples listed:) (1) providing information to the public about numerous issues, including inspection findings and their significance, changes to regulatory requirements, security and safeguards issues, or how the decisionmaking process works; (2) to learn about stakeholder concerns, perceptions about risks, expectations about involvement in risk management decisions, or local information that will assist in risk analysis; (3) building/restoring trust and relationships ; (4) to ask stakeholders for input in a decision-making process ; and (5) influencing people's behavior and perceptions about risk. risk communication provides the community with information about the specific type (good or bad) and magnitude (strong or weak) of an outcome from an exposure or behavior. typically, risk communication is a discussion of a negative outcome and the probability that the outcomes will occur. risk communication can be employed to help an individual make a choice about a behavior such as smoking, getting vaccinated, or undergoing a medical treatment. underlined parts correspond to indicators identified in this study. a 1 = knowledge increase, 2 = communication satisfaction, 3 = change in risk perception and concern alleviation, 4 = reduction in psychological distress, 5 = trust building, 6 = decision making and behavior change, 7 = self-efficacy improvement. b translated by an author of this article (as). this study conducted two rounds of eligibility assessment. as it is briefly stated above, the first round was a review of only titles and abstracts of articles that were identified through the search engines and the journal of risk research. this initial assessment was to pre-select materials from which to derive the eligibility criteria for this study and to obtain a broad picture of recent risk communication activities in order to finalize a plan for subsequent analysis. the second round involved a review of full texts of pre-selected articles to confirm their eligibility. for the first round of eligibility assessment, the team established groups consisting of two researchers. each researcher independently assessed assigned articles and determined whether the study (1) evaluated risk communication activities quantitatively, (2) assessed the objectives and/or effects of risk communication activities qualitatively, and (3) discussed the objectives and/or effects of risk communication activities based on prior experiences and/or existing scientific knowledge. for the second round, researchers were re-grouped, and a pair of researchers independently read assigned articles that they had not checked during the first round to confirm the eligibility of the articles and finalize the material selection. the principal investigator of the research project (mm) coordinated this evaluation and selection process. mm checked all articles and developed a basic protocol for the eligibility assessment. in general, if both reviewers who checked a particular article agreed in their evaluation of its eligibility, the decision was accepted. when there was a disagreement, mm facilitated discussions between the researchers to achieve consensus. when necessary, mm reflected the points of agreement in the protocols to ensure consistency in evaluation. after completion of the first round of eligibility assessment, the research team discussed what data should be extracted and how the information should be labeled and coded. the team made decisions based on characteristics of risk communication activities learned from the first round of eligibility assessment, the international and national organizations' statements on risk communication (table 1) and other relevant literature, as well as individual researchers' experience and expertise. researchers remained in the same group formed for the second round of eligibility assessment, and separately extracted data from each assigned article and coded it as follows: • evaluation approach: (1) quantitative, (2) qualitative, and (3) based on prior experience and/or existing scientific knowledge (see the criteria in ''eligibility assessment''). • study field: (1) medicine, such as health and pharmaceutical realms, (2) food safety, (3) chemical substances (other than food safety matters), (4) nuclear and radiological disasters/emergencies, (5) other disasters/emergencies, (6) climate change, and (7) other. • timing when a risk communication intervention was implemented in line with the phases in the disaster management cycle: (1) non-crisis or pre-crisis, including nonspecified, (2) crisis, and (3) post-crisis, including recovery phase. • target audience: (1) citizens (e.g., individual citizens, residents, unspecified persons, and citizen groups) or non-profit organizations (npos), and (2) other (e.g., government, professionals, and companies). • objective/indicator: (1) knowledge increase, (2) communication satisfaction, (3) change in risk perception and concern alleviation, (4) reduction in psychological distress, (5) trust building, (6) decision making and behavior change (e.g., risk acceptance, risk avoidance, and risk management, such as avoidance of unhealthy foods, seeking healthcare, disaster mitigation and preparedness, and community partnerships; attitude toward behavior and behavioral intention were also included in this category), (7) self-efficacy improvement, and (8) other. with regard to ''intervention timing'', this study employed the three-stage approach proposed by coombs (2012). the term ''crisis'' in this study refers to the definition proposed by the same scholar (coombs, 2007) as, ''a significant threat to operations that can have negative consequences if not handled properly.'' the pre-crisis period involves the detection of warning signs relating to such crisis and prevention and/or preparedness. the crisis period concentrates on identifying the onset of a crisis, controlling the situation, and minimizing negative impacts. the post-crisis period concerns rehabilitation and full recovery from the crisis, evaluation of crisis management, and better preparation for future crisis (coombs, 2012) . with regard to ''objective/evaluation indicator'', the researchers jointly determined how indicators should be classified by referring to the definitions and purposes of risk communication stated by the selected international and national organizations (table 1) . where applicable, multiple response categories were selected. if both reviewers who checked a particular article classified it the same way, the decision was accepted. when the two researchers differed, discrepancies were evaluated by a third researcher. when needed, the issues were discussed with mm until all concerned researchers reached an agreement on the article's classification. examples of evaluation indicators were drawn for this paper. specifically, one example for each indicator was taken from the field of medicine, and another was from other fields due to the generally large number of relevant medicine-related articles. examples were chosen based on the frequency of citation assessed on may 10, 2019 through google scholar and the clarity of applied methods. even if some frequently cited studies targeted multiple indicators, they were referred to for only one indicator among all the applicable indicators. data was entered into a microsoft office excel spreadsheet. excel was used to compute descriptive information on the collected data. additionally, sets of pearson's chi-squared test with yates's continuity correction and fisher's exact test were conducted to examine the associations by study field and by objective/evaluation indicator. the statistical analyses were performed with studies that belonged to a single category of all the variables except for the variable of ''objective/evaluation indicator''. ''nuclear and radiological disasters/emergencies,'' ''climate change,'' and ''other'' from the study field variable were excluded because of their small size. for the same reason, the ''crisis'' group and ''post-crisis'' group were combined in the analysis on the associations by study field, and the ''crisis'' group was excluded in the analysis on the associations by objectives/evaluation indicators. for analyses involving study field, post hoc test (aoki, 2010) was conducted to determine where differences occurred if an initial analysis identified a significant difference between study field and other variables. r (r development core team, 2020) was used for the statistical analyses. test results were considered significant at p < 0.05. p-value adjustment by holm's method was applied for multiple comparisons. the data generated for this study is provided in table s1 . the table contains basic information from all 292 articles. figure 2 shows a descriptive summary of the data. more than 80% of the studies quantitatively evaluated own risk communication practices. over 60% were related to medicine. studies classified as ''other'' included those addressing human-wildlife conflicts (lu et al., 2018) and traffic safety (feenstra, ruiter & kok, 2014 ; wu & weseley, 2013), as well as studies that used a risk scenario or involved multiple risk domains to investigate effective means or to assess intrapersonal and other factors of risk communication (dawson, johnson & luke, 2017; poortvliet & lokhorst, 2016) . five studies (2%) fell in multiple study fields. the vast majority of activities were implemented during a non-/pre-crisis phase (93%), and one study involved multiple phases. over 90% of the studies targeted citizens/npos. of those, 15 studies or 5% also approached other target groups, such as medical professionals and farmers. as for communication type, more than 60% were communications to a large group audience or the public. of those, seven studies or 2% were also conducted in the form of individual/small group communication. frequently-used objectives/evaluation indicators were ''decision making and behavior change,'' ''change in risk perception and concern alleviation,'' and ''knowledge increase'' (61%, 44%, and 39%, respectively). examples of objectives/evaluation indicators are shown in table 2 . the authors of this study identified ''knowledge increase,'' ''change in risk perception and concern alleviation,'' and ''decision making and behavior change'' as areas of focus in all fields; these objectives are also discussed in the definitions and purposes of most organizations and agencies (fig. 2, table 1 ). here, ''knowledge'' is about the risks of concern and related risk management policies and actions. ''change in risk perception'' primarily focused on guiding individuals' subjective judgment of risk to align with available scientific evidence. this study assessed the relationships between health literacy, numeracy, and the ability to interpret graphs. participants were asked to interpret different types of graphs in the context of breast cancer risk and make hypothetical treatment decisions. interpreting the risk of a new breast cancer occurring in the other breast following preventive surgical options based on the hypothetical information from the provided graphs, making a surgical option, and describing differences in remaining risk between surgical options. chemical substances this study analyzed social transmission of risk information by examining how messages on the risk of a controversial antibacterial agent changed when being passed from one person to another in a chain of up to 10 persons. information diversions and defects occurred while being transferred from one person to the next. this study evaluated the effectiveness of gain-and lossframed messages and visual aids about sexually transmitted diseases (stds) on participants' reactions to intervention material and their std-related risk perception, attitude, behavioral intention, and behaviors. participants' evaluation on how interesting, involving, and informative the intervention material was. food safety this study evaluated the effectiveness of a campaign on salmonellosis on public risk awareness and knowledge on risk and prevention behavior. participants' evaluation of the usefulness of the campaign material. nan et al. (2015) medicine this study investigated the impact of evidence-oriented messages and narrative-type messages about human papillomavirus (hpv) on recipients' risk perception and vaccination intentions. participants' perceived susceptibility to hpv. other disasters/ emergencies this study analyzed the influence of interpersonal discussions on residents' perceptions about the risks and benefits of the planned us national bio-and agro-defense facility. residents' perceived risk of negative impacts associated with the facility on their safety, health, and the environment. henneman et al. this study assessed the effects of the provision of graphs in addition to frequency information about breast cancer on at-risk women's risk understanding, psychological wellbeing, and intention to have breast screening. psychological wellbeing measured by an adapted version of the lerman cancer worry scale (cws) and the dutch version of the six-item version of the state scale of the spielberger state-trait anxiety inventory. macdonald gibson et al. (2013) chemical substances this study explored how probabilistic information influences risk understanding, opinions regarding risk/site management, risk perception, and concerns of residents who live nearby a closed site contaminated with unexploded ordnance. negative emotional reactions to the provided information: ''how (worried, afraid, anxious) would you be about (getting hurt if you worked at the site, letting children play near the site, living near the site)?'' trust building besser, anderson & weinman (2012) medicine this study conducted interviews with patients with osteoporosis and collected their drawings to assess their views on the illness and treatment, as well as their conditions. doctor-patient relationship was reported as one motivation to adhere to medication regimen. other (genetic engineering) this study introduced ''issues mapping'' to facilitate dialogues between different stakeholders, clarify different perspectives, and promote mutual understanding. it applied the techniques to social conflicts relating to genetic engineering issues. perceptions of genetic engineering including participants' trust in other stakeholders and their views on current debate in society. (continued on next page) medicine this was an intervention study to see if communicating to people about cardiovascular diseases (cvds) by using risk assessment tools (framingham regicor and heart age) would lead to improvement in their cvd risk factors. changes in physical activity (number of sessions of physical activity per week), smoking behavior, and other modifiable risk factors, involving anthropometrical and blood pressure data. climate change this study assessed the effect of people's beliefs about nature and science on their perspective about uncertainty in relation to climate change. participants' willingness to carry out positive environmental behaviors (e.g., reducing water use) and agree on a household carbon budget. self-efficacy improvement harris, sutherl & hutchinson (2013) medicine this study analyzed the influence of parents' marital status, and parent-child sexual communication and relationship on male adolescents' knowledge regarding hiv and stds, and their intentions and their implementation of preventive behaviors. six-item condom use self-efficacy scale (e.g., ''i am confident that i know how to use a condom.'') feenstra, ruiter & kok (2014) other (traffic safety) this study assessed the impacts of a school-based road safety program on risk perception, attitude, intention, and behaviors in relation to risky cycling among 9th-11th-grade students. perceived self-efficacy for safe cycling (e.g., controlling the bicycle and applying traffic rules) in comparison with peers. in contrast, ''trust building'' is frequently included among the proposed purposes of risk communication, whereas it was rarely addressed in the studies assessed in this research (8%). further, while the organizations extended the target of risk communication in their statements to non-citizen parties, such as industries and media, those groups were rarely targeted in risk communication activities in the studies assessed in this research. consequently, relevant indicators were not discussed in the study articles. table 3 shows the frequency data, which is cross-tabulated with study field and other variables. in most fields of study, risk communication activities were conducted in a non-/pre-crisis phase, whereas nearly half of the risk communications in the field of nuclear and radiological disasters/emergencies were conducted in a non-/pre-crisis phase, and the remaining were in a post-crisis phase. the table shows that the majority of risk communication targets citizens/npos. at the same time, 29% in the field of chemical substances targeted other groups. in the medical field, half of the risk communications were conducted at an individual level or in a small group, whereas risk communication in other fields was conducted mainly in a larger group or to an entire population of interest. table s2 shows the results of the analyses between study field and other variables. the series of analyses found significant associations between study field and communication type (p < 0.01). multiple comparisons suggested a significant difference pertaining to communication type between risk communications in the field of medicine from those in food safety (p < 0.05). table 4 highlights the diversity in objectives and indicators of risk communication activities. for instance, the fields of food safety and other (i.e., non-nuclear/radiological) disasters and emergencies had a higher percentage in terms of risk communications aiming or addressing ''trust building'' (22% and 19%, respectively) than other fields, especially compared to the field of medicine (5%). the chemical substance field had a higher percentage (76%), and the field of nuclear and radiological disasters/emergencies had a lower percentage (33%) compared with other fields with regard to risk communications focusing on ''decision making and behavior change.'' table 4 also suggests some percentage differences in intervention timing, target audience, and communication type by objective/evaluation indicator. the main objectives and indicators of risk communications conducted in a non-/pre-crisis period were ''knowledge increase,'' ''change in risk perception and concern alleviation,'' and ''decision making and behavior change'' (39%, 45%, and 62%, respectively). ''decision making and behavior change'' was a main indicator for risk communications conducted in a crisis period (57%). ''knowledge increase,'' and ''change in risk perception and concern alleviation'' were the main indicators for risk communications conducted in a post-crisis period (83%, 50%, respectively). there was over 15% difference in ''change in risk perception and concern alleviation'' between risk communications targeting citizens/npos compared to although the total number of studies included in the analysis was 292, the total number of each variable varies owing to the allowance of multiple responses. the percentages were based on the total number of each study field. (5) 115 (63) 10 (5) 8 (4) food safety (n = 18) 7 (39) 5 (28) 10 (56) 0 (0) 4 (22) 8 (44) 0 (0) 1 (6) chemical substances (n = 17) 9 (53) 1 (6) 7 (41) 1 (6) 0 (0) 13 (76) 0 (0) 0 (0) nuclear and radiological disasters/emergencies (n = 6) 3 (50) 1 (17) 3 (50) 0 (0) 1 (17) 2 (33) 0 (0) 0 (0) other disasters/emergencies (n = 27) 7 (26) 1 (4) 16 (59) 0 (0) 5 (19) 16 (59) 1 (4) 2 (7) climate change (n = 5) 1 (20) 0 (0) 3 (60) 0 (0) 0 (0) 2 (40) 0 (0) 0 (0) (7) 168 (62) 13 (5) 12 (4) crisis (n = 14) 3 (21) 1 (7) 2 (14) 0 (0) 3 (21) 8 (57) 0 (0) 1 (7) post-crisis (n = 6) 5 (83) 2 (33) 3 (50) 0 (0) 1 (17) 2 (33) 0 (0) 0 (0) target audience citizens/npos (n = 267) 106 (40) 46 (17) 119 (45) 6 (2) 20 (7) 163 (61) 13 (5) 12 (4) other ( the total number of each variable varies because of the allowance of multiple responses. percentages were based on the total number of each value. while risk communication has been implemented in a variety of ways for diverse objectives, this study revealed some overall trends in the objectives, approaches and evaluation indicators applied for recent risk communication activities. at the same time, the results of analysis also suggest that there are some patterns in implementation; associations exist between the study field and the communication type, and between the objectives/evaluation indicators and the intervention timing and communication type. these facts may provide useful insights to those who are involved in risk communication in designing and evaluating their activities. this study also identified the limited attention in current practices to cultivating trust building and reduction in psychological distress, as well as targeting noncitizen/npo groups. addressing these gaps is an important way forward for a sustainable path toward effective risk management and better resilience. hiritsu no sa how do osteoporosis patients perceive their illness and treatment? implications for clinical practice interpersonal amplification of risk? 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department of health and human services united states department of health and human services this article was prepared after the authors added analyses, results, and discussion to a report for the research on the health effects of radiation organized by the ministry of the environment, japan (http://www.env.go.jp/chemi/chemi/rhm/r0104e_3.pdf). we thank our colleagues who are in charge of other parts of the larger research project that encompasses this study. they provided valuable input during the preparation and implementation of this study. the views discussed in this paper are those of the authors and do not necessarily reflect the positions of those colleagues, the affiliated institutions, or the funding agency. the following grant information was disclosed by the authors: the research project on health effects of radiation organized by the ministry of the environment, japan. the authors declare there are no competing interests. • akiko sato performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft.• kaori honda, kyoko ono, reiko kanda, takehiko i. hayashi, yoshihito takeda, yoshitake takebayashi and tomoyuki kobayashi performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft.• michio murakami conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. the following information was supplied regarding data availability:the raw data are available as a supplemental file. supplemental information for this article can be found online at http://dx.doi.org/10.7717/ peerj.9730#supplemental-information. key: cord-299797-s1zdmf2u authors: dettori, marco; pittaluga, paola; busonera, giulia; gugliotta, carmelo; azara, antonio; piana, andrea; arghittu, antonella; castiglia, paolo title: environmental risks perception among citizens living near industrial plants: a cross-sectional study date: 2020-07-06 journal: int j environ res public health doi: 10.3390/ijerph17134870 sha: doc_id: 299797 cord_uid: s1zdmf2u the present work is a cross-sectional study aimed at assessing the risk perception and evaluating the community outrage linked to environmental factors among a self-selected sample of citizens living in an area characterized by the presence of industrial structures of high emotional impact. an anonymous questionnaire was administered to the population by publishing a google form url code in local and regional newspapers and via social media. the resulting data were entered on excel and analyzed. qualitative variables were summarized with absolute and relative (percentage) frequencies. the results showed that the event that causes the greatest worry was air pollution, with 92.6% of the respondents stating that they perceived the problem as “very” or “quite” worrying. furthermore, all the health problems investigated in relation to environmental quality aroused concern among the interviewees, with 93.1% believing there was a cause-effect relationship between environmental quality and health. overall, as other studies had previously underlined, the survey shows that the perceived risks are not always in line with the real ones, thus, it is imperative to articulate interventions aimed at offering the population objective tools to enable them to interpret the risks themselves. in this regard, a fundamental role is played by adequate communication between the competent bodies and political decision-makers and the population. the relationship between environment and health is of extreme relevance in public health. according to the world health organization (who) [1] , 23% of all deaths globally are attributable to environmental factors, and several diseases could be avoided if we lived in healthier environments. in particular, according to the european environmental agency [2] , poor air quality causes 6.5 million premature deaths worldwide, 620,000 of which are in the who european region. indeed, the european environment agency [3] also certifies that noise and air pollution continue to have a serious impact on the health of the population, and human activities (mainly the key sectors of industry, energy, transport, agriculture) are a source of strong environmental pressure [4] [5] [6] [7] . the growing awareness of the health impacts caused by the alteration of environmental conditions by anthropic activities, such as industrial expansion near urban areas, atmospheric pollution, and climate change, plays a key role in the judgment and acceptability of the risks related to environmental owing to its insularity, the region lends itself very well to observational investigations and represents an excellent test case in relation to the reported social dynamics. in fact, the island has already proven to be well suited to epidemiological studies as it preserves the region from interferences caused by territorial contiguity. as such, it can act as an excellent exercise for the reported social and epidemiological dynamics. in particular, the present study was conducted in the marghine area, a historical region in central sardinia which covers an area of 475.42 km 2 and includes 10 municipalities: birori, bolotana, borore, bortigali, dualchi, lei, macomer, noragugume, silanus, and sindia [31] [32] [33] [34] . figure 1 shows the study area's territorial framework and the population of each municipality in 2018, the year in which observation was carried out, whereas table 2 as shown in figure 2 , several industrial plants (mostly dedicated to the management of solid waste from the entire region) are situated in marghine, located near urban areas, in particular in the municipality of macomer, the main town in the area, with a population of 10,019 in 2018. as shown in figure 2 , several industrial plants (mostly dedicated to the management of solid waste from the entire region) are situated in marghine, located near urban areas, in particular in the municipality of macomer, the main town in the area, with a population of 10,019 in 2018. [35, 36] . in the same industrial zone there is also a purifier that treats the waste water from the waste-toenergy process [36] [37] [38] . finally, the production cycle also includes the management of the controlled landfill, again serving the tossilo plant, located in monte-muradu, in the area north of macomer. although the area is heavily industrialized, the official data published by the health authority and the environmental protection agency have always highlighted parameter values that comply with the regulatory limits, the absence of pollution from the environmental matrices, and excluded an excesses of pathologies in the area of study [39-41]. [35, 36] . in the same industrial zone there is also a purifier that treats the waste water from the waste-to-energy process [36] [37] [38] . finally, the production cycle also includes the management of the controlled landfill, again serving the tossilo plant, located in monte-muradu, in the area north of macomer. although the area is heavily industrialized, the official data published by the health authority and the environmental protection agency have always highlighted parameter values that comply with the regulatory limits, the absence of pollution from the environmental matrices, and excluded an excesses of pathologies in the area of study [39-41]. an anonymous questionnaire was built, tested, adjusted, and validated through a pilot study, carried out on a convenience sample of 20 experts in public health (data not published). the internal consistency was assessed with cronbach's alpha test. the questionnaire consisted of 14 close-ended questions divided into two areas of investigation: 6 personal data questions; 8 questions related to health concerns and risk perception. to complete the questionnaire it was required to answer each question. only one question (item no. 13) allowed for more than one answer. the questionnaire was administered by publishing a google form url code in the local and regional newspapers (i.e., "il marghine" and "la nuova sardegna"), and via social media (i.e., facebook public profiles of the same newspapers). the questionnaire was to be completed in the period between 1st september 2018 and 31st december 2018. the full questionnaire is shown in tables 2 and 3 (results section): table 2 reports 6 questions related to the respondents' general information; table 3 shows 8 questions (numbers 7 to 14) related to health concerns and risk perceptions, together with their close-ended answers. questions and answers are reported in the first and second columns of the tables, respectively. data were entered on excel (microsoft office, microsoft corporation, redmond, wa, usa) and analyzed using the stata software 16 (statcorp., austin, tx, usa). qualitative variables were summarized with absolute and relative (percentage) frequencies. the differences between mean values for quantitative variables were tested applying the student t-test, whereas for proportions, z test was applied. the independence for qualitative variables was tested applying the x 2 test. in order to evaluate the equality of distributions, kolgomorov smirnov test for two samples was performed. a p-value less than 0.05 was considered statistically significant. with regard to the internal consistency, the questionnaire showed a cronbach's alpha reliability test global value of 0.9044, which highlights a very good internal consistency. no missing data were managed. during the observation period, 651 residents in the study area voluntarily answered the questionnaire. the respondents' general information related to the first six questions is shown in table 3 . of the 651 respondents, 500 were from macomer, whereas 151 lived in the other municipalities in marghine. as regards the age and gender of the respondents, the average age was 38.7 years (±13.8), without statistically significant differences between gender, and more than half of the self-selected sample were between 18 and 39 years old. as regards the equality of the distribution by age groups, no differences were observed between genders (combined kolmogorov-smirnoff k-s = 0.05; p = 0.82). moreover, 64.4% were female. as regards marital status, most of the respondents were unmarried, and this percentage was in line with that of the general population (45.3% and 45.0%, respectively). all age groups had at least one respondent. over 80% of the sample interviewed had a high school diploma or a university degree, while more than half said they were in employment. finally, 89.9% of the respondents had resided in the study area for over 10 years. the results of the descriptive analysis are shown in table 4 (questions 7 to 14). as regards the respondents' perception in relation to the environmental problems reported in question 7, the results are shown graphically in figure 3 . in particular, the interviewees showed quite a high level of concern regarding all the environmental problems investigated. as the graphic shows, the events that cause the greatest worry are air pollution, with 95.3%, and hazardous waste, with 92.7% of the respondents stating that they perceived the problem as "very" or "quite" worrying, respectively. these latter two figures (air pollution and hazardous waste) seem to significantly differ between genders, with a concern proportion, from quite to very high, of 91.8% vs. 97.1% and 88.8% vs. 95.0%, for males and females, respectively. statistically significant differences for the same two figures were also observed among age groups (p < 0.001). in particular, the concern seems to grow according to age, ranging from 75.0% in <18 years old to 98.4% in 60-69 years old. in particular, the interviewees showed quite a high level of concern regarding all the environmental problems investigated. as the graphic shows, the events that cause the greatest worry are air pollution, with 95.3%, and hazardous waste, with 92.7% of the respondents stating that they perceived the problem as "very" or "quite" worrying, respectively. these latter two figures (air pollution and hazardous waste) seem to significantly differ between genders, with a concern proportion, from quite to very high, of 91.8% vs. 97.1% and 88.8% vs. 95.0%, for males and females, respectively. statistically significant differences for the same two figures were also observed among age groups (p < 0.001). in particular, the concern seems to grow according to age, ranging from 75.0% in <18 years old to 98.4% in 60-69 years old. the answers to question 8 are shown in figure 4 . in particular, the interviewees showed quite a high level of concern regarding all the environmental problems investigated. as the graphic shows, the events that cause the greatest worry are air pollution, with 95.3%, and hazardous waste, with 92.7% of the respondents stating that they perceived the problem as "very" or "quite" worrying, respectively. these latter two figures (air pollution and hazardous waste) seem to significantly differ between genders, with a concern proportion, from quite to very high, of 91.8% vs. 97.1% and 88.8% vs. 95.0%, for males and females, respectively. statistically significant differences for the same two figures were also observed among age groups (p < 0.001). in particular, the concern seems to grow according to age, ranging from 75.0% in <18 years old to 98.4% in 60-69 years old. the answers to question 8 are shown in figure 4 . the events that respondents found less likely are war, terrorism, nuclear risk, and addiction, while diseases were considered to be the most likely event. figure 5 shows the results of the answers given to question no. 9, concerning worries about one's own health regarding environmental determinants. as the figures show, all the health problems investigated in relation to environmental quality aroused concern among the interviewees, in particular tumors and (temporary or permanent) damage to the respiratory tract, without statistically significant differences between gender and age groups. finally, the results of the questionnaire show that 93.1% believed there was a cause-effect relationship between environmental quality and health (question no. 10), 60.3% believed that the environmental situation in the area was serious (question no. 11) and 63% believed that citizens do not have an influential role in decisions made by the municipal administration (question no. 12). question number 13 revealed the respondents' main sources of information (more than one answer was allowed) and the answers are shown in figure 6 . as can be seen from the graph, the internet was found to be the most widely used source of information, as opposed to consulting political decision-makers, municipalities, and the regional agency for environmental protection agency (arpas). finally, question number 14 highlighted the willingness of over 40% of the interviewees to relocate away from their place of residence. the events that respondents found less likely are war, terrorism, nuclear risk, and addiction, while diseases were considered to be the most likely event. figure 5 shows the results of the answers given to question no. 9, concerning worries about one's own health regarding environmental determinants. as the figures show, all the health problems investigated in relation to environmental quality aroused concern among the interviewees, in particular tumors and (temporary or permanent) damage to the respiratory tract, without statistically significant differences between gender and age groups. finally, the results of the questionnaire show that 93.1% believed there was a cause-effect relationship between environmental quality and health (question no. 10), 60.3% believed that the environmental situation in the area was serious (question no. 11) and 63% believed that citizens do not have an influential role in decisions made by the municipal administration (question no. 12). question number 13 revealed the respondents' main sources of information (more than one answer was allowed) and the answers are shown in figure 6 . as can be seen from the graph, the internet was found to be the most widely used source of information, as opposed to consulting political decision-makers, municipalities, and the regional agency for environmental protection agency (arpas). finally, question number 14 highlighted the willingness of over 40% of the interviewees to relocate away from their place of residence. the survey enabled an evaluation of environmental risk perception in a self-selected sample of a population living near industrial plants with a high emotional impact. the strengths and weaknesses presented in the study are discussed in this section. during the observation period, 651 people responded to the survey, with female respondents more numerous. this figure is attributable to the fact that in the region, and in the area subject to observation, the female population outnumbers the male. furthermore, as is known, the female population is more sensitive than the male to environmental issues. for this reason, the greater frequency of female respondents is in line with what has been reported in other similar surveys [42] . of the 651 respondents, 500 claimed to reside in macomer. this, on the one hand, is attributable to the fact that the municipality counted almost a half of the population of the entire area observed at the time of the investigation; on the other, the fact that the main industrial plants in the area (i.e., the survey enabled an evaluation of environmental risk perception in a self-selected sample of a population living near industrial plants with a high emotional impact. the strengths and weaknesses presented in the study are discussed in this section. during the observation period, 651 people responded to the survey, with female respondents more numerous. this figure is attributable to the fact that in the region, and in the area subject to observation, the female population outnumbers the male. furthermore, as is known, the female population is more sensitive than the male to environmental issues. for this reason, the greater frequency of female respondents is in line with what has been reported in other similar surveys [42] . of the 651 respondents, 500 claimed to reside in macomer. this, on the one hand, is attributable to the fact that the municipality counted almost a half of the population of the entire area observed at the time of the investigation; on the other, the fact that the main industrial plants in the area (i.e., waste-to-energy plants, landfills, and purifiers) were in close proximity to the town center could explain the citizens' greater sensitivity toward this investigation. as far as the self-selected sample's general information is concerned, over half of the respondents were aged between 18 and 39 years, with an average age of 38.7 years. in particular, with regard to the population of sardinia (average age of 45.9 years), and of marghine (average age of 47.9 years), the respondents were younger. nevertheless, approximately 90% of those surveyed said they had lived in the area for more than 10 years. although, on the one hand, the way the questionnaire was administered may have favored a response by people more inclined toward the use of it tools, on the other hand, all age groups are represented in the survey. another interesting result, in line with what has been described on the international scene, was the link between educational qualifications and perception of environmental risks. looking at the sample of respondents to the survey, over 80% of them had a high school diploma or university degree. as previously stated by carducci et al. and by ozdemir et al. [43, 44] , subjects with a higher level of education perceive environmental risks to be higher. in general, there was a clear concern among respondents toward environmental determinants, both in relation to the perception of risks and possible effects on health, with 93.1% of respondents claiming the existence of a clear cause-effect relationship between the state of the environment and health status. consequently, all of the environmental problems investigated worried the majority of respondents. in particular, percentages equal to or even greater than 90% were observed in relation to the presence of hazardous industries, particularly landfills and incinerators/waste-to-energy plants. as recently observed by other authors [11, 45] , these structures play an important role in environmental risk perception in populations exposed to them, and could explain the consequent high level of concern regarding food and aquatic environment pollution, hazardous material transportation, noise, and air pollution, and hazardous waste. as can be expected, these latter are closely related to the presence of industrial plants and may explain the citizens' apprehension about possible industrial catastrophes and long-term damage to health that emerged from this survey. in particular, a very high concern was observed among females and older age groups. these figures confirm the aforementioned statement that females are more sensitive than males to environmental issues. moreover, it seems interesting to point out the higher concern among older individuals. considering the younger mean age of our respondents compared to the general population, this aspect could imply that the real concern could be even greater. moreover, the self-selected respondents were concerned by severe weather phenomena (44.1%) and fires (45.0%). on the one hand, the catastrophes caused by extreme weather events that have hit italy [46] and sardinia [47] in recent years have certainly influenced the current fear of such an event. on the other hand, the concern about fires is not surprising, given that these events are frequent in the region [48] . it is also interesting to note two peculiar conditions declared by the interviewees. first, although sardinia is a region with moderate seismic hazard [49] , more than half of the respondents (54.6%) said they were worried by earthquakes. this particular fact could be traced back to the seismic events occurring in central italy starting from 2016 [50] which were most likely, according to the dynamics of availability bias, responsible for people's tendency to base their judgments on recent information, forming opinions conditioned by the latest news acquired [51, 52] . second, a factor that caused little concern was terrorism. in this case, contrary to what was described above, a terrorist cell had been uncovered in macomer shortly before the present investigation [53] , proving the gap that can be found in a population between the perception of a risk (outrage) compared to the real danger (hazard) [16, 54] . with regard to road or work accidents, however, a mixed feeling of exposure emerged from the investigation. on the one hand, in fact, respondents showed a high perception of the risk inherent in road accidents. in this case, as found in accordance with the investigations proposed by the italian national statistics institute and by congiu et al. [55, 56] , this phenomenon not only represents a known public health problem, but is also increasing if we take fragile categories into consideration. on the other hand, however, the scant perception of the danger inherent in accidents at work could be attributed to the fact that almost 50% of the volunteer participants were unemployed, students, housewives, or occasional workers. as for the perception of the environmental quality of the area of residence, although the official analyses carried out by the regional environmental protection agency of sardinia excluded the presence of pollutants in the environmental matrices at the time of investigation [39], and excessive numbers of disease cases have not been reported by health authorities [41], the concern of respondents is tangible. nevertheless, a possible determinant of the outrage could be identified in a controversy that arose in the territory understudy at the end of 2015. in fact, at that time the conversion of the incinerator into a waste-to-energy plant had started and an environmentalist association was in opposition to this transformation. this association claimed that there was an excess of pathologies and specific mortality caused by tumors in that territory. the data on which this position were based derived in part from some incorrect health statistics that had been published in that period [57] , in part from an incorrect reading and interpretation of available epidemiological data. not even the subsequent correction and publication of correct data [41, 58] was able to quell the controversy and judicial investigations were also initiated which had no effect and the waste-to-energy plant was set up. even some time later, the sense of bewilderment so clearly raised by the numerous newspaper articles that appeared in the local media for several months still remains strong. this fact could explain why the concern for an excess of tumors was high in both sexes, without significant differences. as jonathan swift said, "falsehood flies and truth comes limping after; so that when men come to be undeceived it is too late; the jest is over and the tale has had its effect" [59] . this situation is aggravated by the fact that most respondents (over 60%) believed that citizens do not play an influential role in the decisions made by the municipal administration. in fact, as highlighted by peter sandman himself [27] with the aforementioned outrage theory, the perception of a risk increases when the situation that generates it is independent of one's will and is attributable to third parties. furthermore, over 40% of respondents declared the will to relocate. this figure appears to be in contrast with the sardinian people's well-known sense of belonging and attachment to their land, as well as antithetical to the fact that almost 90% of the replies had been residing in the area for more than 10 years. nevertheless, since the question referring to the will to relocate in relation only to the perceived environmental risks is not explicitly asked, there could be social, economic, and cultural dynamics behind this desire to move away. the present study has evaluated the role of environmental risk perception among a self-selected sample of citizens living in an area where industrial plants with high perceptual and emotional impact are situated. in particular, as other studies had previously underlined, the study shows that the perceived risks are not always in line with the real ones, if we think of how, for example, the respondents answered regarding fear of earthquakes, highly unlikely events in the territory under observation. thus, it is imperative to articulate interventions that are aimed at offering the population objective tools to enable them to interpret the risks themselves. in this regard, a fundamental role is played by adequate communication between the competent bodies and political decision-makers and the population. moreover, the study also revealed how the process of participation in decision-making is one of the determining aspects that influences a person's environmental risk perception, and promoting citizens' involvement in decisions can strengthen their sense of belonging, attachment to the territory, and empowerment. in fact, any action on the territory and even more so its protection (and consequently the perception of the risk linked to the action) that does not stem from an involvement of the local community, is in vain, as it is not legitimized by the context [60] . starting from the results of the survey, although the study is descriptive in nature and, therefore, requires further investigation in order to better understand the dynamics underlying the high outrage found, some practical actions could be implemented. these should not only concern informing and educating citizens, but should also be addressed to health authorities and institutions (municipalities). in particular, the results of this survey could be very useful for the launch of projects in the area that see the active participation of citizens in decision-making. for this reason, it will be necessary to bring into play multiple professional skills, not only public health professionals and sociologists, but also designers, planners, and urban planners. in addition, an important role is played by journalists, who are responsible for informing citizens. as known, the mass media are often responsible for riding the wave of news stories that attract the attention of readers as they are fueled by an emotional component [15] . for this reason, it would be appropriate to implement a training project that also involves this category of professionals. finally, a reflection in light of the pandemic that the world is currently experiencing opens up interesting prospects for this study. indeed, it is worth questioning whether the desire to leave the territory studied in this paper is not quenched precisely because low population density is 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in the elderly in sardinia, italy, with a focus on the sassari municipality incidenti stradali in sardegna built environment features and pedestrian accidents: an italian retrospective study nuovi dati aggiornati sulla mortalità per tumore aree industriali the examiner no. 14 tutela ambientale e progetto del territorio: integrare, incrementare, interagire why italy first? health, geographical and planning aspects of the covid-19 outbreak deaths in sars-cov-2 positive patients in italy: the influence of underlying health conditions on lethality this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors would like to thank emma dempsey for the english language revision. the authors declare no conflict of interest. key: cord-318004-r08k40ob authors: raina macintyre, c.; engells, thomas edward; scotch, matthew; heslop, david james; gumel, abba b.; poste, george; chen, xin; herche, wesley; steinhöfel, kathleen; lim, samsung; broom, alex title: converging and emerging threats to health security date: 2017-11-27 journal: environ syst decis doi: 10.1007/s10669-017-9667-0 sha: doc_id: 318004 cord_uid: r08k40ob advances in biological sciences have outpaced regulatory and legal frameworks for biosecurity. simultaneously, there has been a convergence of scientific disciplines such as synthetic biology, data science, advanced computing and many other technologies, which all have applications in health. for example, advances in cybercrime methods have created ransomware attacks on hospitals, which can cripple health systems and threaten human life. new kinds of biological weapons which fall outside of traditional cold war era thinking can be created synthetically using genetic code. these convergent trajectories are dramatically expanding the repertoire of methods which can be used for benefit or harm. we describe a new risk landscape for which there are few precedents, and where regulation and mitigation are a challenge. rapidly evolving patterns of technology convergence and proliferation of dual-use risks expose inadequate societal preparedness. we outline examples in the areas of biological weapons, antimicrobial resistance, laboratory security and cybersecurity in health care. new challenges in health security such as precision harm in medicine can no longer be addressed within the isolated vertical silo of health, but require cross-disciplinary solutions from other fields. nor can they cannot be managed effectively by individual countries. we outline the case for new cross-disciplinary approaches in risk analysis to an altered risk landscape. few precedents or analytical tools. these technologies are increasingly available to hostile states and non-state terrorist groups. the rapidly evolving landscape of dual-use risks illustrates how societal preparedness for new challenges in health security can no longer be addressed within isolated vertical siloes. nor can they cannot be managed effectively by individual countries. well-recognised threats in the areas of biological weapons, surveillance for bioterrorism, laboratory security and antimicrobial resistance are discussed. we also highlight emerging new areas of threat in the intersection of health security and cybersecurity and enabling of precision harm through big data in medicine. against this backdrop, we outline below the need for new governance and risk analysis approaches that are global and cross-disciplinary. it has been possible since 2002 to create synthetic viruses in a laboratory, when researchers at the state university of new york at stony brook published the synthesis of the poliovirus in science (cello et al. 2002 ). there are now over 140 private companies in synthetic biology (global engage 2017), which are self-regulated with voluntary codes of conduct (samuel et al. 2009 ). whilst prior biosecurity efforts focused on the biological materials themselves and the inherent challenges of securing and accounting for these materials within laboratories, genetic code can now be transmitted rapidly and used to create new or modified infectious pathogens (kelle 2009 ). in the specific case of synthetic infectious agents, the unique characteristic of transmissibility from person-to-person raises special concerns about health security. a virus manufactured in one location may spread worldwide and has a major population impact, thus requiring a global risk mitigation approach. the global regulation of synthetic biology pertaining to communicable diseases is challenging, with many models proposed . the tapic (transparency, accountability, participation, integrity and policy capacity) framework provides a guide to good governance (trump 2017) , but there is no enforceable global governance system in place as yet. the many private synthetic biology companies worldwide remain self-regulated, with voluntary guidelines about reporting of suspicious orders. a case in point is smallpox, for which the genome is fully sequenced and publicly available. in a 2017 report, the who (world health organization 2017d) concluded that destroying existing stocks of smallpox in the usa and russia would serve no purpose because the virus can be created using synthetic biology. whilst it is theoretically possible for smallpox to be synthesised in a laboratory, experts have believed this to be a complex task. however, in 2017, canadian scientists synthetically created an extinct poxvirus, closely related to smallpox, for $100,000 in a laboratory using mail-ordered genetic sequences (koblentz 2017) , illustrating the very real risk of synthetic smallpox emerging as the cause of a pandemic. in addition to synthetic biology, viruses and bacteria can be engineered for enhanced pathogenicity. a revolutionary new precision tool for gene editing, clustered regularly interspaced short palindromic repeats (crispr cas9) associated nuclease cas9, raises concerns about dual-use potential (ran et al. 2013) . whilst crispr cas9 offers the prospect of cures to major diseases, it also enables the precision design and construction of engineered microorganisms as potential weapons of mass destruction. in 2016, the us director of national intelligence rated crispr cas9 as a leading weapon of mass destruction threat (mit technology review 2016). yet global planning for bioterrorism preparedness is still largely framed by cold war concepts and is largely limited to scenarios involving agents such as smallpox and anthrax in a twentieth-century context. however, contemporary biology presents an expanded threat spectrum with an unlimited array of possible engineered agents that transcend the scope of traditional concepts of biosecurity surveillance, preparedness and counter-measures. the convergence of security threats is illustrated by the use enabling technologies such as the dark web for trade in biological weapons and planning of bioterrorist attacks (macintyre 2015). a natural epidemic is one which arises in nature, without intervention by humans. unnatural epidemics are those which are caused by human intervention and may be deliberate or accidental release of either naturally occurring or altered pathogens. bioterrorism is the deliberate release of such pathogens to cause harm (venkatesh and memish 2003) . bioterrorism differs from other forms of terrorism in that a bioweapon is microscopic and invisible, and release of a bioweapon is not always recognisable as a deliberate attack (macintyre and engells 2016). all category a bioterrorism agents except smallpox also occur in nature. for example, anthrax occurs more frequently in nature (such as through humans handling infected animal carcasses) than as a bioterrorism attack (fong and alibek 2010) . planning for bioterrorism is underpinned by the assumption that attacks will be recognised as unnatural, but no public health systems exist to differentiate the aetiology of epidemics. tools such as the grunow and finke (2002) criteria are not well known in public health and have low sensitivity for detecting unnatural epidemics when tested against historical events (chen et al. 2017; macintyre and engells 2016) . public health agencies do not routinely use such tools and default to the assumption that they all epidemics are natural (macintyre 2015). there has been an unprecedented increase in the frequency of serious global epidemic risks such as ebola, avian influenza, mers coronavirus and zika virus in recent years (sands et al. 2016 ). this cannot be explained solely by environmental and ecological factors, which have changed at a slower rate than the increase in emerging infections. in a recent analysis , we documented that the rate of emergence of new strains of influenza virus infecting humans is escalating at an unprecedented rate, thereby increasing the probability of a pandemic. changes in climate, urbanisation and agricultural practices as well as improved global surveillance may have some role in this phenomenon, but have not changed at the same rapid rate as virus evolution. whether some of these new outbreaks involve engineered agents is unknown and has not been publicly analysed. historically, unnatural epidemics have not always been recognised at the time. for example, the rajneesh salmonella attack in oregon in 1984 was not only undetected as a bioterrorist attack, but when a local politician suggested bioterrorism, he was ridiculed by public health officials (mac-intyre 2015; török et al. 1997) . operation seaspray, which caused a serratia marcescens outbreak in san francisco in 1950, was not recognised at the time as an open-air test by the us military, which was later disclosed in 1976 (wheat et al. 1951) . the accidental anthrax release in sverdlovsk, soviet union, 1979, was investigated by us experts, who initially incorrectly believed the soviet explanation that it was a natural outbreak (the atlantic 2016). there are many other examples of failure to correctly identify unnatural epidemics (tucker and zilinskas 2002) . at a time when genetic engineering and synthetic biology contribute to increased risk of biological attacks, there is a need for new tools and risk analysis methods to rapidly identify unnatural epidemics. yet the grunow-finke criteria despite low sensitivity (macintyre and engells 2016) remain the best available tool. other tools have been developed but are even less known and used than the grunow-finke criteria (chen et al. 2017 ). in addition to risk analysis tools, rapid surveillance methods are required to detect unnatural epidemic signals. new methods for data mining of opensource unstructured data such as social media show promise for rapid epidemic intelligence (the conversation 2016) but have not yet been utilised for biosecurity (yan et al. 2017 ). laboratory safety has been highlighted as a key area of concern, with multiple breaches involving security sensitive pathogens in leading laboratories occurring in recent years (science 2014). research staff have the unique privilege of working with biological select agents and toxins and possibly the broader group of valuable biological materials (world health organization 2013), yet insider threat and laboratory accidents are known risks. a related issue is practical impacts of the emerging field of biorisk management in which the previously separate disciplines of biosafety and biosecurity are merged into a singular approach of laboratory biorisk management (cook-deegan et al. 2005; salerno and gaudioso 2015) so as to achieve the mutual goal of keeping these materials safe and secure within those areas designated for use and storage. several entities are proposing this combined approach to enhance the risk management process and produce safer laboratories and more secure practices for these materials (association of public health laboratories 2016). a far too common situation at advanced biomedical research laboratories is a problematic relationship between the researchers and security staff. those relationships must change to reflect a new reality-one in which the research scientist and the law enforcement official are considered members of the same team striving for a mutual goal. those working in laboratories should monitor each other to create a rigorous form of professional self-governance (garrett 2013) . the implementation of that change will be strategic, for it changes the focus from the substances (biological materials), which because these are alive can be freely found outside the laboratory and continue to defy accurate longterm measurement, to a focus on the behaviours of those who work with these substances-biomedical research scientists, public health officials, clinical laboratorians and others (aquino 2016) . another threat is a new facet to the insider threat-the potential for radicalisation of health care workers and researchers, for violent extremists continue to defy precise categorisation or predictable profiles and to infiltrate research institutions (macintyre and engells 2016). in the current age, we must move past our previous solutions dominated by guns, gates and guards and move to a new age in which enhanced personnel security practices through innovative uses of psychology and organisational dynamics will enhance individual and small group accountability and produce a safer laboratory and community at large. doit-yourself biology and biohacker labs fall outside of such systems of governance and are presently self-regulated, but the technology is easily accessible for terrorist groups to establish clandestine labs. no systems exist to detect such laboratories. the risk of emerging infections is increasing, whilst our ability to treat infections with antibiotics is decreasing. antibiotics represent one of the major public health achievements of the twentieth century, which together with vaccines are responsible for the dramatic reduction in morbidity and mortality caused by infections. whilst antimicrobial resistance is not new, its cascading global impact and threat to national and global security are considerable. within a decade, antimicrobial resistance, driven by prolific misuse in animals, humans and food production, and limited development of new antimicrobial options, will present a significant threat to humanity in the twenty-first century. a key solution is to judiciously use our remaining antibiotic options, yet even in relatively well-off organisation for economic cooperation and development (oecd) nations, antibiotic misuse continues virtually unabated in both the human and veterinary sectors (world health organization 2017b). the world health organization (2017b) and other key stakeholders have indicated the critical need for immediate global antimicrobial optimisation, reduction in unnecessary usage, and the roll-out of stewardship across health and agriculture sectors. for example, there has been a 40% global increase in use of last resort antimicrobials (carbapenems) over the last 10 years, and both low-income countries and high-income countries are using substantially more antibiotics per capita than in previous decades (review on antimicrobial resistance 2016). as with other infectious diseases threats, a global response to this threat is urgently required, with human movement across national borders, threatening antimicrobial viability, even in countries with active surveillance and control programmes. the vertical management of antibiotic use in the human and animal sectors as well as in agriculture and food production must also be addressed in an integrated way, as the volume of use is much higher in these other sectors. a key strategy, in terms of policy, will be the adoption of the one health model for amr supported by who (2017a), the eu, and the usa (centers for disease control and prevention 2017). whilst policy and regulation have progressed considerably in health care environments, a parallel set of strategies will need to be implemented in farming, agriculture and veterinary medicine, which account for around 80% of antibiotic use (food and drug administration 2010). thus far, strategies utilised across contexts have largely failed to set national targets to reduce antibiotic use in animal agriculture and nor mandate the collection of antibiotic usage data (martin et al. 2015) . consumer-led strategies-for example, the marketing of antibiotic free products-are one such strategy that may be used to promote sustainable use of antibiotics in the non-health sector (doyle et al. 2016) . increasing public awareness of the connections between animal and human health-a cornerstone of the one health approach-will be central to this strategy. there is growing recognition of the costs and significance of amr. multi-resistant organisms are emerging at much higher rates than seen previously, with urgent attention needed to mitigate a risk which is predicted in one report to be the greatest global burden of disease (review on antimicrobial resistance 2016). one recent estimate indicates that by 2050, infections from resistant bacteria may overtake cancer as the leading cause of death in the world and cost us$100 trillion. this estimate has been questioned and likely an overestimate, but amr nonetheless causes a significant burden of disease (de kraker et al. 2016 ). the world is in urgent need of new strategies in the human, animal, agricultural and food industries. this includes reviewing how we price/value antimicrobials, incentives for new antimicrobial development and judicious use, and restrictions around use across sectors. in addition, serious amr could be engineered and released as an act of bioterrorism, given the availability of technology such as crisp cas9 (macintyre and bui 2017). a longer-term model of population risk (versus immediate individual risk of often minor infection) is required to guide everyday use and mitigate this global threat. whether a bioterrorist attack, pandemic or infections complicated by amr, the risk is increasing as outlined above. infectious diseases do not respect international borders and can spread rapidly around the world. the continued growth in large urban areas, and megacities in particular, in which high population densities represent optimum conditions for spread of infection merits significant attention in biosecurity. this risk is heightened for megacities in developing countries in which serious gaps exist in public health surveillance for early detection of epidemic threats, together with inadequate critical infrastructure and other preparedness resources. prevention, mitigation and control of these threats, therefore, require efforts at local, national and global levels. despite the call for a one health approach (rabinowitz et al. 2013) , there is no suitable system for governing use of antimicrobials across human health, animal health and food production, and often no coordination of efforts across these sectors. in considering new technologies such as crispr cas9 (bulletin of the atomic scientists 2016). the cartagena protocol was developed to address regulation of movements of living modified organisms (lmos) resulting from biotechnology from one country to another, but has focused on ecology and biodiversity and has not been utilised for human biosecurity. the tapic framework (trump 2017 ) is a good starting point for considering how existing regulations can be improved and enforced and how new ones could be developed globally. the key needs in risk analysis for biosecurity are timely surveillance and identification of biosecurity threats, risk analysis of impacts and differentiation of natural versus unnatural outbreaks. traditional disease surveillance lacks the timeliness required for rapid detection of emerging and re-emerging pathogens. current public health systems rely on validated data from sources health systems, such as hospital and laboratory data, which are important for analysing trends over time, but do not meet rapid epidemic intelligence needs for early detection of epidemics (yan et al. 2017 ). epidemics, defined by a reproductive number greater than one (macintyre and bui 2017), grow exponentially, so every day of delay in detection could substantially increase the morbidity and mortality burden. mathematical models, typically of the form of deterministic systems of nonlinear differential equations, are often used to gain insight into the transmission dynamics and impact of natural and unnatural emerging and re-emerging infectious diseases that threaten health security, such as disease pandemics (nuno et al. 2007; nuño et al. 2008; sharomi et al. 2011 ) and the deliberate release of agents of bioterrorism, such as anthrax (brookmeyer and blades 2003; mushayabasa 2016; pantha et al. 2016 ) and smallpox (banks and castillo-chavez 2003; del valle et al. 2005; kaplan et al. 2003; meltzer et al. 2001 ). these models, combined with robust health data analytics, computational and data visualisation techniques and numerical simulations provide a realistic, rapid real-time assessment of threats to public health security. furthermore, informing these models with data generated from modern diagnostic tools that are capable of detecting asymptomatic cases with high degree of sensitivity and specificity (such as peptide-based immune-signaturing or low-cost paper-based rna sequencing) (legutki et al. 2014; navalkar et al. 2014; pardee et al. 2016; stafford et al. 2014) , and using knowledge of prior bioterrorism attacks and natural disease outbreaks allow for a realistic proactive prediction of future threats before they are detected by the public health system. these approaches allow for a more proactive disease surveillance for human diseases as well as veterinary surveillance for zoonotic pathogens that can mutate and cause major burden in human populations. other modelling paradigms, such as agents-based and other datadriven statistical and stochastic modelling approaches (halloran et al. 2002; hu et al. 2014; kaplan et al. 2003; nuño et al. 2008) , are also being used for this purpose. a stochastic approach to risk analysis allows model inputs to exhibit a degree of uncertainty. in contrast to deterministic models, the inputs follow various forms of probability distributions. risk is computed by sampling these input distributions many times. therefore, the outcome of a stochastic risk model is a distribution of risk-rather than a single value. the key advantage is that in addition to analysing outcomes, it allows for an analysis of the probability of these outcomes. it also allows for easy scenario analysis and sensitivity analysis. these can all assist decision-makers in taking intervention measures and allocating resources. one such example is a stochastic risk model (hill et al. 2015) of zoonotic and pandemic influenzas, with a focus on human infection with avian influenza. however, there are few real-time models with applicability in operational public health, with most modelling occurring in academia without real-time applicability for disease control . end-users in the public health system do not have much knowledge or nor trust in modelling, and do not use it widely for disease control (muscatello et al. 2017) . availability of simple, transparent tools that can assist with pressing questions such as surge capacity planning during the influenza season is what stakeholders value (muscatello et al. 2017) . although mathematical modelling has enjoyed widespread popularity within the academic public health community in terms of using it to predict epidemics as well as to assess and propose effective containment strategies (newall et al. 2007) , the use of genetic data (despite its huge potential to provide much deeper insight) for predictive purposes has not yet become a mainstream tool in public health practice (dudas et al. 2017) . virus phylogeography and phylodynamics are methods developed to utilize viral dna sequences to explore the evolution of pathogens by estimating their ancestry. these methods also show promise for public health surveillance, but are not as well developed or used in public health practice. it has only been somewhat recent that more focus has been on combining descriptive phylogenetic approaches with other modelling methods that attempt to predict epidemics. phylogenetic and phylogeographic analyses can be combined with methods for epidemic modelling to analyse risk factors and predictors of risk in a geospatial and genetic context. geographic information systems (gis) provide a further platform for public health researchers to take a map of an area and add layers of information regarding demographics, disease prevalence and socio-economic status (mondini and chiaravalloti-neto 2008; rushton 2003) . when overlaying multiple types of information, relationships and correlations can be discovered, adding analytical value beyond traditional descriptive approaches (doku and lim 2009) . patient data distributions and timestamps are significant factors in determining the specifics of an epidemic disease. hence, gis techniques such as emerging hot spot analysis and grouping analysis (van steenwinkel et al. 2011 ) allow for risk analysis of healthrelated concerns as correlated to location. for example, emerging hot spot analysis (wang et al. 2008) can help monitor changes and trends of an epidemic disease, such as identifying locations representing new or intensifying hot spots. new risk analysis methods are required to flag epidemics for urgent intervention, as illustrated by the catastrophic consequences of inaction with the 2014 ebola epidemic in west africa (world health organization 2015). we have shown that a simple risk prediction tool can be developed which identifies regions at high risk of severe outcomes of epidemics (argisiri et al. 2017) . such a tool, which considers disease specific, geographic, political, social, situational and contextual factors, could be used to prioritise epidemic response in situations of limited resources and reduce the impact of serious events. finally, the vast quantities of publicly available, unstructured data such as news feeds, social media and other public information offer potential for rapid epidemic intelligence and early detection, but are not yet accepted in public health (yan et al. 2017) . google, twitter and other sources have shown early promise for rapid disease detection by using algorithms and natural language processing to detect signals for epidemics, but are still eschewed by traditional public health systems (schmidt 2012) . rapid epidemic intelligence tools based on social media and news feeds could supplement traditional health system based, validated surveillance systems by providing more timely signals for epidemics of concern (yan et al. 2017) . we have shown that the ebola epidemic of 2014 could have been detected months earlier than it was using a novel twitter-based tool (yan et al. 2017 ). in addition, risk analysis frameworks play an important role in biosecurity decision-making and policy. using the approach of multiple criteria based upon emerging biotechnologies such as synthetic biology, traditional risk assessment such as health and environmental data, and other characteristics such as the uncertainty, reversibility, manageability of risk and levels of public concern (cummings and kuzma 2017; trump et al. 2017) , can be integrated to provide evidence-based information to government, academia and non-governmental organisations. such risk analysis methods could assist decision-makers to rank policy priorities and to improve the governance of biosecurity. whilst new risk analysis methods and tools are continually developed, many of the established methods for risk analysis of emerging infections are used separately and in different contexts. with increasing biothreats in society, these methods could be better integrated to add value improve the capacity to predict and mitigate risk. biosecurity is affected by cybersecurity concerns, but planning for biosecurity often fails to consider critical dependencies with information technology and computing. for example, mitigation and prevention of bioterrorism require surveillance for trade in bioweapons. the dark web offers terrorists a platform for trade in weapons, including bioweapons. numerous dark web marketplaces such as silk road and alphabay have been shut down by us law enforcement in recent years, but new ones continue to emerge (business insider australia 2017). whilst such market places are better known for trading in drugs and weapons, in 2015 a new york university student was arrested for attempting to purchase a category b bioterrorism agent, ricin, on the dark web (new york post 2016) . this highlights the need for integration of cybertechnology as a tool in prevention and surveillance for bioterrorism. surveillance for planned bioterrorism is not as well advanced in this realm as it is for traditional forms of terrorism. law enforcement agencies employ surveillance of the dark web and social media to detect chatter about planned terrorism, but the focus has been far less on bioterrorism. for example, surveillance for purchase of genetic code to create dangerous viruses failed to pick up the canadian scientists who created an extinct poxvirus in the laboratory using mail-order dna (science 2017). the world first knew about this experiment only when the scientists announced it. whilst this group was legitimate and not engaged in bioterrorism, the same methods for procurement which they used could well be used by terrorist groups. therefore, surveillance is required to detect such activity and prevent bioterror attacks. it was reported in 2017 that the unique health records of all australians are available for sale on the dark web, a fact uncovered by a reporter, not by law enforcement or government, exposing authorities as completely unprepared (bickers et al. 2017) . cyberattacks and cybertheft affect all facets of society, from banking and health to critical infrastructure (the age 2017). in many cases, the outcome of a cyberattack is loss of money or assets. however, if critical infrastructure or health systems are attacked, human lives may be lost. for example, if the power grid of a city is compromised, this has many flow-on effects on health systems, such as loss of functioning of critical equipment in intensive care units or operating theatres, or even for home interventions that rely on power such as nebulisers or oxygen (lee et al. 2016) . hospitals rely on generators as backup, but these can fail in the event of a disaster (parson 2002; sifferlin 2012) . the escalation of ransomware attacks on hospitals, which are poorly prepared and easy targets, can bring whole health systems to standstill, as seen within the uk nhs and us hospitals (deane-mckenna 2017; gillett 2017; landi 2017) . the goal of most health systems is to achieve paperless operations, to which the electronic patient medical record is central. yet the zeal for electronic health (e-health) has progressed with very little consideration of cybersecurity, leaving hospitals vulnerable to ransomware attacks (cbsnews 2016). the aspiration of health systems towards the e-health record is driven by the desire to improve care, protect patient safety and reduce medical errors (australian digital health agency 2016). the e-health record (ehr) has also been embraced by researchers as a means to efficient health research through data linkage of large administrative databases (powell and buchan 2005) . for example, data linkage was used to show that ct scans are associated with childhood cancer (mathews et al. 2013) . whilst big data allows new ways of conducting medical research, the risk of hacking of the ehr has not been adequately mitigated in health care. education and training in hospital and health management does not routinely offer courses in cybersecurity, leaving health planners and hospital managers unaware of the risk and underprepared. participants in the us federal medicare ehr incentive program have to attest that they have a fundamental cyber security programme and have adopted certified ehr technology (the office of the national coordinator for health information technology 2015). hospitals attesting meaningful use are legally bound to meet specific standards, including protection of the her, and can be audited. however, even this system has not protected us hospitals from cyberattacks (cbsnews 2016), and many countries do not have any such safeguards. precision medicine has revolutionized medicine, with the ability to tailor treatments for individuals by combining detailed medical, genetic and other patient information. this, however, also leads to the possibility of the same information being used to tailor "precision harm". it is well recognised that individuals can be targeted by biological weapons (macintyre and engells 2016), but convergence of technology opens new avenues for precision harm of individuals. the catastrophic hacking of the us office of personnel management (opm) in 2014 (mukherjee 2017) exposed data on over 20 million us federal employees. at the same time, anthem health, the largest provider of health insurance to these employees, was also hacked (tuttle 2016) . data linkage would allow the perpetrators to access the sensitive personal medical information of employees, identify their medical vulnerabilities and plan targeted attacks, such as medication tampering or hacking of digital medical devices. the risks posed by hacking digital medical devices such as pacemakers and insulin pumps are also cause for concern (francies 2017) . this includes more extreme scenarios in which individuals with high political profiles or other strategic value could be assassinated by manipulation of their medical devices, tampering with their medication regimen or the design of microbial agents matched to their individual genetic profile. former us vice president dick cheney had his pacemaker wireless function disabled to mitigate such risk (peterson 2016) . if hostile states, organised crime groups or terrorist gain digital medical information on defence or security professionals, government officials or judges, it may become a more attractive option to more obvious methods for causing harm. figure 1 illustrates the potential for precision harm targeting high profile individuals, enabled by convergence of technologies. in the example provided, a federal judge could be targeted in several different ways, including biological weapons, hacking of digital medical devices, medication tampering, interference with scheduled medical procedures or use of toxins or immune modulators, once a roadmap for precision harm is created. this example could apply to linkage of data from the opm and anthem health hacks to create personalised medical profile for federal employees. these examples illustrate the convergence of cybersecurity and health security and the need for more integrated approaches to prevention and mitigation of emerging risks in health care. in summary, we face rapid advances in science and technology, a corresponding escalation of risk to biosecurity, and convergence of multiple security threats which have traditionally been addressed separately. the changing landscape in biothreats and convergence with other areas of security can no longer be addressed in the traditional narrow, healthcentric way. the solution requires a multidisciplinary, global approach to security, whilst meeting local government regulatory requirements. we need new methods to prevent, identify and mitigate threats to biosecurity, which require cooperative thinking across national and professional boundaries. globally, health, law enforcement, defence and intelligence agencies will need to collaborate and pool their information and expertise. new risk analysis methods and surveillance tools need to be developed, and old methods may need to be used in new ways. this must be addressed in a coordinated global way to ensure risk is minimised. radicalized health care workers and the risk of ebola as a bioterror weapon a risk analysis approach to prioritising epidemics-ebola virus disease in west africa as a case study biorisk management for clinical and public health laboratories benefits of having a my health record hackers are offering to sell the medicare details of australians on the dark web statistical models and bioterrorism: application to the us anthrax outbreak an overview of the epidemiology and emergence of influenza a infection in humans over time can the bioweapons convention survive crispr? authorities just took down alphabay, an online black market 10 times bigger than silk road hack on d.c.-area hospital chain reverts them to paper chemical synthesis 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hundreds of speeding fines after wannacry virus attack how dna evidence confirmed a soviet coverup of an anthrax accident social media for tracking disease outbreaks-fad or way of the future? https://theconversation.com/ social-media-for-tracking-disease-outbreaks-fad-or-way-of-thefuture-66401 the office of the national coordinator for health information technology (2015) guide to privacy and security of electronic health information a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars synthetic biology regulation and governance: lessons from tapic for the united states a decision analytic model to guide early-stage government regulatory action: applications for synthetic biology the 1971 smallpox epidemic in aralsk, kazakhstan, and the soviet biological warfare program cyberdisaster: how the government compromised our security assessing biosecurity practices, movements and densities of poultry sites across belgium, resulting in different farm riskgroups for infectious disease introduction and spread bioterrorism-a new challenge for public health measuring the deconcentration of housing choice voucher program recipients in eight us metropolitan areas using hot spot analysis infection due to chromobacteria; report of 11 cases who, geneva world health organization (2015) report of the ebola interim assessment panel antimicrobial resistance world health organization (2017b) global action plan on antimicrobial resistance world health organization (2017c) international health regulations (ihr) world health organization (2017d) who advisory committee on variola virus research: report of the eighteenth meeting utility and potential of rapid epidemic intelligence from internet-based sources the authors are affiliated with global security key: cord-303137-g2pe3ad8 authors: moss, emanuel; metcalf, jacob title: high tech, high risk: tech ethics lessons for the covid-19 pandemic response date: 2020-10-09 journal: patterns (n y) doi: 10.1016/j.patter.2020.100102 sha: doc_id: 303137 cord_uid: g2pe3ad8 the covid-19 pandemic has, in a matter of a few short months, drastically reshaped society around the world. because of the growing perception of machine learning as a technology capable of addressing large problems at scale, machine learning applications have been seen as desirable interventions in mitigating the risks of the pandemic disease. however, machine learning, like many tools of technocratic governance, is deeply implicated in the social production and distribution of risk and the role of machine learning in the production of risk must be considered as engineers and other technologists develop tools for the current crisis. this paper describes the coupling of machine learning and the social production of risk, generally, and in pandemic responses specifically. it goes on to describe the role of risk management in the effort to institutionalize ethics in the technology industry and how such efforts can benefit from a deeper understanding of the social production of risk through machine learning. and technological structures that seem to operate autonomously. these structures are pervasive and deeply intertwined with technologies of bureaucratic control in vivid (as automated decision systems for welfare services 6 and predictive policing) 7 and banal forms (as accounting norms, quarterly shareholder dividends, and unscalable unemployment insurance portals running on cobol). 8 the risks that define contemporary life are not just socially produced, but are actively managed by technocrats and technologies that calculate risk thresholds for pollutants and automotive safety, by a financial system that creates a market for risk so that it can be hedged against, and by business managers who offer customers the ability to outsource infection risk by arbitraging weak and outdated labor laws. caitlin zaloom, an anthropologist who studies risk, identifies two modes of understanding risk from a sociocultural perspective-how groups understand risk as a threat or vulnerability, and how groups attempt to exert control over an uncertain future by limiting exposure to risk. 9 we apply those understandings of risk to applications of machine learning in the covid-19 pandemic to ask how those who build machine learning applications construct and act upon risk. this necessarily leads us to also ask how they maintain and build socioeconomic power by exerting control over the distribution of risk. this framing extends ongoing conversations about the social implications of machine learning beyond those of algorithmic bias 10, 11 to point to a type of harm that occurs not when machine learning ''gets it wrong'' due to various forms of bias. rather, we interrogate what happens when machine learning ''gets it right'' by acting as expected but doing so while reinforcing and exacerbating social and economic inequity. 12 despite recent debates within the machine learning community showing how resistant some quarters are to acknowledging the social, cultural, and economic dimensions of the field (against the ample evidence from others), 13 the question of how to properly bound which aspects of sociotechnical systems machine learning practitioners have agency upon and responsibility for has become vitally important. pandemics are not strictly a microbial phenomenon, they follow the contours of society the contagion encounters, 14 some of which shift medical risk toward the impoverished or oppressed. as each of us are made responsible to minimize our own risk of spreading the coronavirus, it becomes all too clear that ''responsibility'' is, to some extent, coterminous with a social and economic status that allows us to externalize risk onto others. in recent years, this capacity for nearly autonomous, unquestioned risk externalization has been mediated through machine learning applications to a remarkable extent. machine learning, because of its versatility in dealing with problems across domains, because of the wealth of financial and computing resources at its practitioners' disposal, and because teams of machine learning engineers can collaborate remotely, has found no shortage of potential applications to the current crisis. therefore, we suddenly find our personal and societal responses to the pandemic emerging through machine learning applications that act as a ubiquitous tool for distributing societal, health, and economic risks. machine learning applications already shape the distribution of risk across the labor, health, and surveillance landscapes that are central to distributing risk as part of our pandemic response. gig worker platforms, instant delivery, supply chain management, and automated scheduling applications determine who is exposed to how much risk from the disease, while the workers themselves attempt to navigate continually shifting affordances on those platforms. 15 the machine logics of these systems are determinative of risk, whether human technocrats could have orchestrated these processes in identical ways or not, and early evidence suggests some of the ways that such applications are proving brittle in their response to the covid-19 pandemic. 16 these applications financialize and arbitrage risk from app users (whether individual consumers or enterprise users) to gig workers, waged staff, and warehouse laborers, with stockholders reaping the difference. the tech companies that are driving the technological response to the covid-19 pandemic have arranged their business models and organizational practices around building products that distribute upsides and downsides according to socio-historical patterns, as interpreted by machines, yet lack the capacity to ''understand just how pervasively. technology is being used to marginalize many groups of people,'' as leading machine learning researcher timnit gebru and colleagues have observed. 13, 17 machine learning applications are ultimately exercises in distributing attention and resources, both in how we understand the risks we face and how those risks are distributed across society. increasingly, the calculation, production, and management of risk has been accomplished through the application of machine learning techniques. machine learning is used to understand threats and vulnerabilities, and also as a means of exerting control over such threats. indeed, risk is foundational to machine learning. loss functions, central to the applied power of machine learning, were developed to analyze and minimize risk. all objective functions can be thought of as minimizing the risk of a prediction being wrong, but machine learning has been applied to more ''human readable'' understandings of risk across a vast array of domains. these include predicting cardiovascular risk, 18 estimation of genetic risk factors, 19 consumer credit risk, 20 and risk of individuals attempting suicide. 21 machine learning is used not only to understand the nature of threats to health, safety, and finance but also to intervene in these threats by allocating scarce resources toward interventions that minimize risk the most for those who control or own the algorithmic tools. in this way, a rideshare platform produces risk for drivers who take on the liability of car payments and vehicle maintenance, while minimizing risk for the platform itself through its freedom from maintaining a fleet of vehicles for the service it ostensibly offers. 22 machine learning, then, is deeply implicated in the social production of risk that beck and zaloom describe above. by seeing machine learning as productive of risk, it becomes possible to recognize the responsibilities machine learning practitioners hold for the ways they produce risk. in constructing representations from data, in crafting classifiers and evaluating their utility, and in optimizing for desired performance behaviors, machine learning shapes and distributes risk across society. 23 machine learning can identify for bankers which individuals are at the ll open access greatest risk of not repaying loans, for police which neighborhoods are at the greatest risk of certain kinds of criminal activity, and for doctors (and insurers) patients who are at the greatest risk of diabetes, heart disease, cancer, pneumonia, or covid-19. and in all too many cases, machine learning actively produces risk while also distributing it unevenly across society, as predictive policing algorithms focus police attention on already over-policed (largely black and latinx) neighborhoods. 24 algorithmic methods for deciding where risk lies would be a purely academic exercise if not for the real-world impacts to people's lives that this entails. machine learning applications operate upon theoretical constructs that are not directly observable-creditworthiness, health, and recidivism cannot be directly measured-but rather are inferred from proxies for such constructs. 25 models built from such proxies, because they are operationalized as part of algorithmic decision-making systems, often seem like a concrete instantiation of the theoretical constructs they purport to represent but may instead become like self-fulfilling prophecies, actually producing the phenomena they purport to measure. and they are often used in ways that produce concrete negative impacts to people's lives. individuals classified as risky loan applicants have trouble buying homes and building wealth. neighborhoods classified as high-risk crime areas get policed more heavily and see more arrests for petty crimes. 26 over time, heavily policed neighborhoods see more re-arrests, and therefore steeper penalties for residents who become re-offenders. 27, 28 patients classified as being at high risk of certain diseases may receive life-saving early testing and have better long-term outcomes, but may also see higher healthcare costs and dangerous side effects from maintenance medications, 29 be seen as having pre-existing conditions by their insurers, or be triaged to a lower degree of medical urgency by a racially biased algorithm trained to seek price efficiency. 30 to be clear, these impacts are not a first-order result of machine learning but neither are they entirely external to machine learning. rather, they are the result of complex sociotechnical responses to risk in specific domains. the role of machine learning in producing ''risk'' as an actionable construct for some and not for others cannot be ignored, as machine learning practices rely on, recreate, and often amplify already-existing patterns of how risk is distributed across society, irrespective of whether that risk is fairly or justly distributed. this is particularly apparent in how racial disparities are algorithmically encoded in many machine learning applications, as when overrepresentation of non-white inmates in criminal justice records leads to the over-estimation of risk for non-white defendants in pretrial detention models. 31 however, it is also evident in how such applications themselves participate in the perpetuation of unjust institutions, such as the carceral system. 7 on top of this, the role that machine learning plays in producing crime, for some and not for others, 32 cannot be ignored. machine learning practitioners have invested significant effort in adjusting technical systems to blunt downstream risks, but the role machine learning might play in the reproduction of patterns of risk is also operative in less-apparent ways as well. even when datasets are balanced, 33 optimization functions are constrained to minimize bias for disadvantaged groups, 34 and instances of algorithmic bias are measured and mitigated, 35 a long tail 36 of social effects remain embossed on the data creation and collection processes that underlie the machine learning economy. given the profound threat of covid-19, it is crucial to consider how the application of machine learning to the social challenges of a global pandemic can produce and distribute risk across society. these risks are socially constructed, as are specific harms produced by machine learning systems, and so we must ask what is being done to make sure that one is not amplifying the other. since the pandemic was declared in early march of 2020, 37 hundreds of articles have been published to pre-print archives, such as arxiv, biorxiv, and medrxiv reporting potential advances in machine learning applications for combatting the pandemic. these applications include natural language processing for combing through the existing literature on covid-19, 38 machine learning models that attempt to infer the asymptomatic spread of the virus, 39 models of the effect of quarantine policies on viral transmission, 40 facial recognition applications for use in emergency room triage, 41 and deep learning for covid-19 diagnoses through medical imaging. 42 these studies point to the ways machine learning participates in how risk is both understood and managed, through attempts to understand the nature of the threat and to respond to it. more recently, a host of machine learning applications have been developed to track, treat, and limit the spread of the virus. 43, 44 these applications include automated contact tracing used to notify those who have been exposed that they ought to self-quarantine (for which machine learning algorithms assist in estimating the strength of contacts between people based on bluetooth signal strength), 45, 46 but also natural language processing-based early warning systems (available on a subscription basis) for outbreaks, 47 and computer vision systems that detect mask-wearing and crowding on public transportation systems to inform potential riders that they may want to choose alternate modes of transportation during busy times. 48 while these efforts are doubtless well intentioned, each suggests a machine learning intervention into the already-existing distribution of risks and potential harms for society. 49 in the us we are seeing the most severe cases of covid-19 striking black and latinx communities in drastically disproportionate ways, 50 and it is clear that this is in large part because of how risk and inequality map onto each other along racial dimensions. 51 this is in part because of long-standing disparities in health outcomes for black and latinx communities, environmental racism that places environmental determinants of health near black and latinx communities, 52 as well as the disproportionate number of black and latinx workers in job roles that cannot be filled at home and do not have adequate sick leave or healthecare. 53 for contact tracing, the ability to make use of a notification to minimize one's own risk by self-quarantining is far too dependent on one's personal wealth and capacity to afford to stay home (either because of a generous workplace sick leave policy, the ability to work from home, or one's own savings). any contract tracing is a sociotechnical system that depends on how different parts of social life fit together-telling people they should stay home does not mean that they will be able to stay home. for contact tracing to work at all, its designers must be attuned to the context of social life in which such systems can produce harmful, difficult-to-foresee effects 54 that replicate or amplify inequalities already present in society. rather than individualizing the risk through contact tracing systems currently being proposed, attending to the contextual use of such a system could collectivize risk by identifying and emphasizing the necessary forms of social support for self-quarantine and medical care: adequate sick leave and quarantine leave policies, robust testing, and economic relief that targets individual workers over large companies. automated contact tracing notifications are useful to those who already possess the means to work from home and are less useful to those who cannot self-quarantine without losing their job. an automated update about a crowded subway car will not help someone who has no other means of transportation and cannot be late to return home to care for a child. others, meanwhile, will maintain their freedom of movement-the delta between who can move about freely and who cannot will have profound consequences for those who have and those who do not have compatible mobile devices, or who lack the resources to maintain their income or care for their dependents while unable to work or cohabitate with others. 55 in this way, automated technologies that construct and manage the shared risks of the pandemic can perniciously codify and reinforce unjust social and economic dynamics that are the context in which the infectious disease spreads. machine learning applications may construct risk such that individuals can act upon it to their own advantage without addressing the social conditions that make such risks unevenly distributed, thereby presenting a false sense of risk reduction. those who build and deploy automated tools to track and treat the pandemic should not treat risk as if it were flat across the population, but as something that they are actively engaged in constructing and distributing and are responsible for doing so justly. understandings of how the production and distribution of risk through algorithmic technologies leads to sociotechnical impacts of machine learning are still in their infancy, and such technologies are only just beginning to be thought of as capable of being brought under any sort of governance regime. [56] [57] [58] [59] professional organizations have attempted to mitigate harmful impacts from applying data-driven and machine learning solutions to the problems of the covid-19 pandemic. some of these are quite robust, if non-binding, sets of recommendations, 60 while others attend to a limited definition of privacy rights without attending to the range of sociotechnical impacts discussed above. 61 over the past 2 years, we have been studying how those inside of silicon valley tech companies, which build the machine learning models that are most likely to directly affect people, go about understanding the impacts of machine learning and developing organizational practices to manage the effect they have on how risk is distributed across society. 62, 63 under the mantle of ''ethics,'' silicon valley companies manage the emerging risks their products and services pose for individuals, society, and for their own firms. in response to the unprece-dented public health challenges represented by the covid-19 pandemic, many of these companies are rushing to play a role in producing technological solutions. in the rush to produce solutions, however, it is even more important to think through the lessons the tech industry has learned from managing organizational risk in the years leading up to the current crisis, and not to jettison those lessons out expediency. reading the potential applications of technology to the current crisis through the recent history of tech ethics, several lessons stand out: context is key, the upside benefits of technology are in tension with downside risks, and leadership and organizational culture matters. these lessons are made explicit through the applications of machine learning to the covid-19 pandemic, but can also be extended to examining how machine learning, and digital technologies more broadly, produce and distribute risk across society. any framework to identify and manage risk within an organization must deliberately and methodically consider the context in which it operates. context includes not just the social milieu at which a product is targeted, but also the intentions, worldview, and the necessarily partial knowledge of those who build the product. 64 including producers of technology in any consideration of context is important because the way they are positioned in the world can have an outsized influence on what are chosen as problems to be solved, 65 what data are selected to serve as proxies for unobservable phenomena, 25, 66 and what forms of risk are visible. this is particularly true for the use of technology to manage the risks covid-19 presents to society. technological applications for the pandemic offer a compelling set of technical challenges for engineers and designers, but not all technical challenges present opportunities to improve outcomes. a deep learning tool for hypoxia detection intended for use in emergency room triage sounds useful, but given the speed at which health professionals can visually detect hypoxia (by noting pallor of complexion or blue lips), 41 such a technological intervention is an additional step on top of what needs to happen in triage already, not necessarily a time-saving tool for busy hospital workers. recent research demonstrates the importance of recognizing the additional work integrating new tools into the existing practices of workplaces they are intended for requires from all those who interact with them. 67 given the enthusiasm for using covid to accelerate the adoption of artificial intelligence (ai) in healthcare settings, 47 it is reasonable to ask whether solving relatively simple diagnostic (but scientifically interesting) tasks is really as useful as predicting and managing resources that vulnerable human caretakers truly need, such as adequate personal protective equipment. 68 perhaps diagnostic applications of ai receive so much attention because diagnosing is a type of activity that powerful and economically valued physicians do, whereas supply chain management that keeps the nurses, janitors, and technicians-who have far more contact with patients than physicians-safe is mundane and less economically valued. there is less money to be had in keeping nurses alive than in displacing physician labor, for no reason other than how risk has been financialized and distributed. technologists should ask themselves: if an automated tool for tracking and treating a pandemic is not useful ll open access for the most vulnerable, then in what sense is it useful enough to merit investment and justify the effort of integrating it into existing practices? 67 upsides and downsides inside product and legal teams at tech companies, it has often been easier to argue for limiting the risk of a product that might harm users than it is to argue for changes to a product that benefit users. this is particularly true if those positive outcomes for users or society cannot be straightforwardly accounted for in the company's bottom line. this is at least in part because limiting the riskier aspects of a product aligns with mechanisms companies already have to limit their liabilities. conversely, additional investment in a product ''merely'' to generate a social good is seen as reducing the return on investment because it raises the cost of investment without raising the financial return in a manner that can be booked. amid the current pandemic, however, this tendency is inverted, and within the closed loop of technology vendors and enterprise clients, it may appear there is only upside to adapting the ad-serving and data brokerage surveillance apparatus to the purpose of contract tracing or epidemiological modeling. however, this upside comes with significant downside risks that covid-19 tracking systems might pose to individuals and groups outside that closed loop in the near and distant future. 69 these risks are often framed as threatening privacy, and there are various technical methods for limiting such risks for individuals, including differential privacy, encrypted computation, and decentralized computation (particularly for contact tracing and other diagnostic applications). yet such technical methods have trade-offs in terms of accuracy and time-to-market-a not insignificant issue given the urgent demand and short contracting windows for such systems. but ''privacy'' is an inadequate frame for these risks, because it individualizes responsibility to manage one's own data without attending to how these risks are produced through the design of technical systems and their integration into society. furthermore, privacy unburdens the legal system from adequately protecting the rights of those who might be harmed by the systematic misuse of personal data, and forestalls any possibility of ''collective determination over the infrastructures and institutions that process data and that determine how it will be used.'' 70 having a framework in place to work through the internal and external risks to the firm, and to society, is crucial for maximizing the upside benefits of any machine learning applications. to accomplish these aims, such a framework would need to be supported by the necessary resources to achieve the substantive outcomes that are desired. for a company building an intervention as sweeping as contact tracing, success depends on having financial, social, emotional, and medical resources already in place to enable people to deal with the risk a digital contact tracing app assigns to them. a smartphone alert is useless if people do not have the ability to isolate themselves without suffering or failing those who depend on them, which means that the distribution of those capacities also determines the distribution of the upsides and downsides of a contract tracing interventions. 71 machine learning applications are (thus far) not useful for rectifying this type of risk distribution despite that there are plenty of data proxies for economic inequity. because so many machine learning applications are built around arbitraging risk from an advantaged to a disadvantaged party we should expect the same from pandemic solutions that are not subject to critical interrogation. therefore, product managers, engineers, policy teams, legal consuls, executive boards, marketing teams, and user experience researchers need to ask themselves if the necessary social support is in place where their product is intended to be used. they also would need to ask themselves if their product will conceive of and distribute risks in a manner that is just, and what measures, metrics, and other signals they would need access to know that such questions have been answered adequately. while some companies have begun to invest in the capacity to ask such questions, 62,63 the industry as a whole does not yet have such frameworks in place. approaches that can identify and redistribute risk so that it does not fall disproportionately on those least able to bear its burden exist, 72 but are often not required to be brought into practice. inside tech firms, choices about investing in upside benefit over limiting downside risk get made at the top, as are decisions about how much time, energy, and cost to invest into context alignment. as our research indicates, without clear signals from the ceo that efforts to enact good governance, build products with responsible safeguards, and prioritize users' rights would not be scrapped for a bottom-line calculation, those efforts cannot amount to much. 62 in recent years, activist employees and a vigilant public have provided a check 73 on some companies when their ceos pursue contracts with repressive regimes or military applications. however, not all companies have experienced this kind of pressure internally (the possible reasons for this run the gamut from a lack of diversity inside to an environment in which such dissent is actively discouraged), and others have not proven responsive when faced with pressure. some of the most recalcitrant of these companies are in the running for contract tracing application contracts, and will require a different form of pressure to conform to expectations for the responsible deployment of such a system (if this is even possible). leadership matters when it comes to the government response to pandemic disease, and when it comes to provisioning contact tracing algorithmic systems from tech companies, too. many companies, big 74 and small, 75 are racing to build contact tracing applications and related infection tracing tools for governments to use. some will be safer for users, in terms of digital rights, than others. having options is great, but there is little obligation for federal, state, or local governments to choose the option that is best able to preserve digital rights. as it stands in the us, there are very few legal protections for civil rights and liberties that might be harmed by the misuse of the kind of data contract tracing systems depend on. draft legislation, like the ny state geolocation tracking ban 76 would provide a modicum of protection from unreasonable police use of such data, but government contracts for contract tracing systems will be written under the legal frameworks we have now, not the ones we wish we had. trust in those at the very top-of companies, of public health institutions, and (perhaps most importantly) national governments-to do what only leadership can do is paramount. only those who hold final authority can prioritize alternatives that distribute risk equitably rather than toward those who are most vulnerable. in practice this can mean only building in contexts where the necessary social infrastructure for product goals to be met can be ensured. it can also mean refraining from turning the tools of emergency response to covid-19 toward other, more nefarious purposes. in the absence of regulation, or other forms of social pressure, the incentives for pursuing opportunities to squeeze additional profit by selling data or licensing a machine learning product to unsavory actors can be difficult to resist. similarly, the resolve needed to dismantle emergency tools when the crisis passes is currently the limiting factor for leadership in determining how the risks we all face of getting sick, losing loved ones, and losing our livelihoods unfolds. historically, risk distribution is a key conceptual and economic feature of machine learning applications. this type of risk is not a natural phenomenon, such as where lightning might strike, but a social construction of technocratic systems through which people must pass to have access to the economy, justice system, and health care. machine learning has already shaped the landscape on which our society is responding to the covid-19 pandemic by distributing risk, and the pandemic has accelerated the role that data-driven technology has in directly determining the conditions of our lives. however, despite the efficiency and utility promised by machine learning applications, there lurks a fundamental challenge: are machines good for distributing risk in the ways we actually should distribute it? consider for a moment, whether it is possible to build machine learning applications that distribute risk up the socioeconomic ladder rather than down. not just ''is it conceivable,'' but would those of us involved in the research and development of these technologies know what that looks like and how to get there? this would, in part, look like subverting existing power hierarchies, as demonstration projects tracking white-collar crime zones have done. 32 it would also look like reconfiguring who builds machine learning applications (machine learning teams in industry, and corporate ethics teams, have had notorious difficulties retaining black and latinx team members) 77 and how they are governed. if not, then is it just to build high-tech pandemic solutions that distribute risk only downward? approaches that can identify and redistribute risk so that it does not fall disproportionately on those least able to bear its burden exist, 72 but are not required to be brought into practice. inside tech firms, choices about investing in upside benefit over limiting downside risk get made at the top, as do decisions about how much time, energy, and cost to invest into context alignment. as our research indicates, without clear signals from the ceo that efforts to enact good governance, build products with responsible safeguards, and prioritize users' rights would not be scrapped for a bottom-line calculation, those efforts cannot amount to much. 62 in recent years, activist employees and a vigilant public have provided a check 73 on some companies when their ceos pursue contracts with repressive regimes or military applications. but not all companies have experienced this kind of pressure internally, and others have not proven response when faced with it. some of the most recalcitrant of these companies are in the running for contracts applying machine learning to the covid-19 pandemic, and will require a different form of pressure to conform to expectations for the responsible deployment of such a system-if this is even possible. risk society: towards a new modernity (sage publications), p. 260, theory, culture & society blaming china for coronavirus isn't just dangerous. it misses the point | andrew liu (the guardian where's the data? we need to know how many black people are dying from covid-19 (essence) the complexity and cost of vaccine manufacturing -an overview paid sick leave flattens the curve -data & society: points [internet automating inequality: how high-tech tools profile, police, and punish the poor captivating technology: race, carceral technoscience, and liberatory imagination in everyday life unemployment checks are being held up by a coding language almost nobody knows (the verge the productive life of risk algorithmic bias: from discrimination discovery to fairness-aware data mining gender shades: intersectional accuracy disparities in commercial gender classification algorithmic injustices: towards a relational ethics ai weekly: a deep learning pioneer's teachable moment on ai bias (venturebeat) pandemic: tracking contagions, from cholera to ebola and beyond (farrar, straus and giroux) gig work used to be a recession-proof safety net our weird behavior during the pandemic is messing with ai models (mit technology review consumer credit-risk models via machine-learning algorithms predicting risk of suicide attempts over time through machine learning uberland: how algorithms are rewriting the rules of work a few useful things to know about machine learning race after technology: abolitionist tools for the new jim code measurement and fairness race, homeownership and wealth runaway feedback loops in predictive policing dirty data, bad predictions: how civil rights violations impact police data, predictive policing systems, and justice drugs for life: how pharmaceutical companies define our health dissecting racial bias in an algorithm used to manage the health of populations machine bias (propublica) white collar crime risk zones (the new inquiry magazine inclusivefacenet: improving face attribute detection with race and gender diversity measuring discrimination in algorithmic decision making bored techies being casually racist: race as algorithm virtual press conference on covid-19 applying lexical link analysis to discover insights from public information on covid-19 machine learning the phenomenology of covid-19 from early infection dynamics neural network aided quarantine control model estimation of global covid-19 spread au-totriage -an open source edge computing raspberry pi-based clinical screening system improving coronavirus (covid-19) diagnosis using deep transfer learning infectious diseases (except hiv/aids) artificial intelligence systems aim to sniff out signs of covid-19 outbreaks how ai and machine learning are helping to tackle covid-19 information technology-based tracing strategy in response to covid-19 in south korea-privacy controversies we need an ''army'' of contact tracers to safely reopen the country covid-19 will accelerate the ai health care revolution (wired) mta wants startups to help solve its coronavirus problem (csny) risk for early data shows african americans have contracted and died of coronavirus at an alarming rate (propublica) historical insights on coronavirus disease 2019 (covid-19), the 1918 influenza pandemic, and racial disparities: illuminating a path forward anatomy of environmental racism and the environmental justice movement for us, covid-19 is personal the long tail of contact tracing'' (societal impact of ct) $ issue #118 (github) contact-tracing apps are political (brookings) disparate impact in big data policing algorithmic impact assessments: a practical framework for public agency accountability algorithmic impact assessments under the gdpr: producing multi-layered explanations. ssrn electron governing with algorithmic impact assessments: six observations. ssrn electron statement regarding the ethical implementation of artificial intelligence systems (ais) for addressing the covid-19 pandemic -ieee spectrum on the responsible use of digital data to tackle the covid-19 pandemic owning ethics: corporate logics, silicon valley, and the institutionalization of ethics ethics owners: a new model of organizational responsibility in data-driven technology companies translation tutorial: positionality-aware machine learning the science question in feminism fairness and abstraction in sociotechnical systems the human body is a black box'': supporting clinical decision-making with deep learning strategies to optimize the supply of ppe and equipment today's covid-19 data will be tomorrow's tools of oppression (the daily beast privacy versus health is a false trade-off we need to talk about digital contact tracing data-driven responses to coronavirus are only as good as the trust we place in them google the latest company to face worker revolt over immigration policy apple and google are building a coronavirus tracking system into ios and android (the verge a facial recognition company wants to help with contact tracing. a senator has questions welcomes introduction of ny geolocation tracking ban five years of tech diversity reports-and little progress (wired) about the authors emanuel moss is a doctoral candidate in anthropology at the cuny graduate center and researcher for the ai on the ground initiative at data & society. he is also a research assistant for pervade, an nsf-funded multisite project jacob metcalf is a researcher for the ai on the ground initiative at data & society. he is a pi for pervade, an nsf-funded multisite project and also serves as the ethics subgroup chair for the ieee p7000 standard key: cord-301479-dc1oyftd authors: koehlmoos, tracey pérez; anwar, shahela; cravioto, alejandro title: global health: chronic diseases and other emergent issues in global health date: 2011-09-30 journal: infectious disease clinics of north america doi: 10.1016/j.idc.2011.05.008 sha: doc_id: 301479 cord_uid: dc1oyftd infectious diseases have had a decisive and rapid impact on shaping and changing health policy. noncommunicable diseases, while not garnering as much interest or importance over the past 20 years, have been affecting public health around the world in a steady and critical way, becoming the leading cause of death in developed and developing countries. this article discusses emergent issues in global health related to noncommunicable diseases and conditions, with focus on defining the unique epidemiologic features and relevant programmatic, health systems, and policy responses concerning noncommunicable chronic diseases, mental health, accidents and injuries, urbanization, climate change, and disaster preparedness. prevailing concerns and expected future trends, as seen clearly in the reemergence of tuberculosis and malaria as key health problems that have become global and individual country health priorities. infectious diseases have always had a decisive and rapid impact on shaping and changing health policy with global pandemics such as severe acute respiratory syndrome (sars) and h1n1, emerging without warning and challenging approved priorities within days if not hours. however, it is important not to lose sight of other areas of health and to maintain a close and watchful eye on trends and developments in those diseases that do not generate the immediate impact that some infectious diseases have been able to do. noncommunicable diseases fall into this group; they may not have garnered as much interest or importance over the past 10 or 20 years, but in fact have been affecting public health around the world in a very steady and critical way, becoming the leading cause of death in both developed and developing countries. 1 this article discusses emergent issues in global health related to noncommunicable diseases and conditions. trying to offer an in-depth discussion on such a wide range of issues in just one article is clearly not possible, and therefore focus and emphasis is given to defining the unique epidemiologic features and relevant programmatic, health systems, and policy responses concerning noncommunicable chronic diseases (ncds), mental health, accidents and injuries, urbanization, climate change, and disaster preparedness. in the shadow of global efforts to achieve the millennium development goals (mdgs), by far the largest killer on the planet has continued to advance in low-income and middle-income countries. ncds cause 60% of all global deaths but receive just 2.3% of international development assistance for health. approximately 80% of deaths caused by ncds occur in developing countries, generally in a younger population than those in high-income countries. 1, 2 over the next 10 years, the world health organization (who) predicts that ncd deaths will increase by 17% globally with the greatest increases in the african (27%) and the eastern mediterranean (25%) regions. in terms of the highest absolute number of deaths, the western pacific and south-east asia are projected to lead the field. 3 noncommunicable diseases are a group of illnesses and include those conditions that have been identified as the leading causes of death around the world: heart disease, stroke, cancer, chronic respiratory diseases, and diabetes. these diseases are characterized by their long latency period often influenced by exposure to risk factors for extended periods over a patient's lifetime. the situation becomes more acute with the addition of the word "chronic," indicating that these diseases are mostly incurable and the duration of treatment may cover decades of a person's life. cardiovascular disease (mainly heart disease and stroke) is the biggest killer worldwide, contributing to 30% of global deaths each year. 1 the importance of such a high figure can be seen in the 47 countries that make up latin america and the caribbean, where cardiovascular disease alone accounts for 35% of the total mortality burden while aids, tuberculosis, malaria, and all other infectious diseases combined are responsible for only 10% of that burden. 4 globally, chronic disease deaths have been predicted to increase by 17% between 2005 and 2015. 1 although research on multimorbidity has been based primarily on high-income countries, experts estimate that around 50% of the population living with chronic disease may actually be living with multiple chronic conditions. 5 sometimes erroneously referred to as "lifestyle diseases," ncds are affected by a variety of risk factors that are often outside the control of the individual. there is very little that can be done about some risk factors, such as age and genetic inheritance, and increasing evidence suggests that what happens before a person is born and during early childhood plays a key role in the onset of adult chronic disease, demonstrated by the proven association between low birth weight and increased rates of high blood pressure, heart disease, stroke, and diabetes. 6 however, the most common chronic diseases share some of the same highly preventable or avoidable risk factors including physical inactivity, tobacco use, and obesity, leading researchers to study mortality for ncds by risk factor. the who estimates that each year approximately 4.9 million people die from tobacco use, 2.6 million from being overweight or obese, 4.4 million as a result of raised cholesterol levels, and 7.1 million as a result of raised blood pressure. 1 raised cholesterol and raised blood pressure (hypertension) are particularly dangerous risk factors because they can exist in an individual for a long time without presenting any obvious symptoms. in its seminal book preventing chronic disease: a vital investment, the who presents what it defines as effective and feasible interventions to reduce the threat of ncds, with low-income and middle-income countries being specifically targeted. 1 the who seeks ideally to reduce the burden of ncd mortality by 2% per year through the implementation of the who framework convention on tobacco control (fctc), which was the first global treaty negotiated by the who in 2003. as of 2010 it had been signed by 168 nations, although stages of ratification vary. the fctc contains guidelines for implementing demand-reducing policies toward tobacco including health policies aimed at protecting the public with respect to commercial and other vested interests of the tobacco industry, protection from exposure to tobacco smoke, packaging and labeling of tobacco products; and limits or bans on tobacco advertising, promotion, and sponsorship. 7 tax increases for tobacco control are considered to be clinically effective and very cost-effective relative to other health interventions, 8 while the implementation of smoking bans in public areas appears to reduce the risk of heart attacks significantly, particularly among younger individuals and nonsmokers, according to a study published in the journal of the american college of cardiology (september 29, 2009 issue). researchers reported that smoking bans can reduce the number of heart attacks by as much as 26% per year. 9, 10 policy level programs are also being discussed for reducing salt and sugared beverages 11, 12 in the diet, consumer products, and food outlets. the who report also encourages screening for which there are clear public health benefits and cost benefit, and in situations in which the ability to treat the condition (such as raised blood pressure and cervical cancer) exists. 1 however, at present the quality and quantity of research investigating the actual benefits of different intervention programs to prevent noncommunicable diseases in developing countries is sparse and exists primarily as case studies. 1, 11 low-income and middle-income countries have developed their health provision and policies according to a primary care or alma ata model, focused on meeting the needs of pregnant women and children younger than 5 years, and developing services for a variety of high-impact communicable diseases such as human immunodeficiency virus (hiv)/aids, tuberculosis, and malaria. the health systems in these countries are unprepared to deal with risk-factor education and behavior modification for the prevention, diagnosis, and treatment of ncds, or the long-term management of these conditions. despite growing interest among the population and health system leadership, one high-ranking health official pointed out that currently, donor countries are operating a policy ban on funding ncds, thereby starving low-income governments of the financial and technical assistance needed to turn around the ncd epidemic. this policy has to change, with overseas development assistance aligned to the priorities of recipient countries. 3 this situation continues to be an issue for developing countries despite numerous calls for action in the area of ncds and funding. 4, 11, [13] [14] [15] furthermore, there is a clear inequity inherent in noncommunicable diseases, as the poor and less educated are more likely to be exposed to several preventable risk factors including tobacco use, high-fat and energy-dense food consumption, physical inactivity, and obesity. 16 there is no denying that noncommunicable diseases are linked to economic loss, and the who highlighted this in 2005, predicting that national income loss due to heart disease, stroke, and diabetes for china, india, and the united kingdom are expected to be $558 billion, $237 billion, and $33 billion, respectively, with part of the losses being the result of reduced economic productivity. 1 the global burden of disease (gbd) project began in 1990 and since then chronic diseases have exceeded the burden of infectious diseases. 17 despite this, the international community has yet to display a sense of urgency toward reducing ncds or supporting ncd-focused interventions in developing countries, even though they are threatening development and economic progress. 3 perhaps the situation will change in the near future with the participation of united nations (un) member states in a highlevel summit on noncommunicable diseases scheduled to take place in new york in september 2011. although nothing can be guaranteed, similar un summits have provided the catalyst for change, as seen following the summit on hiv/aids in 2001 that resulted in significant funding and political commitment to a coordinated action plan. 3 since 1946, the who has defined health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." 18 however, mental illness and related conditions have never received the same importance or consideration as other areas of health despite their enormous burden on the population. this fact is exemplified by the routine exclusion of mental health services from primary health care (phc) and the absence of any mental health-related objectives in the mdgs. 19, 20 mental illnesses, including behavioral, neurologic, and substance use disorders, affect a significant number of the world's population. in 2002, the who estimated that globally 154 million people suffered from depression, 25 million from schizophrenia, and 15 million from substance use disorders, with around 877,000 people committing suicide every year. 21 in the same year, unipolar depressive disorders were ranked as fourth in terms of burden of disease, 22 well on the way to prove the 1990 prediction of the gbd analysis that estimated mental illness, specifically unipolar major depression, would become the second leading cause of burden of disease by 2020, second only to ischemic heart disease. 17 studies in phc settings in turkey, the united arab emirates, france, vietnam, and zimbabwe revealed that the prevalence of mental illness ranges between 10% and 60% among adults, [23] [24] [25] [26] [27] [28] [29] [30] with depression being the most common ranging from 5% to 20%, followed by generalized anxiety disorders (4%-15%) and dependency on addictive substances (5%-15%). [31] [32] [33] children are not immune to mental health problems, with those aged between 6 and 14 years exhibiting a prevalence of mental illness of between 20% and 30%, 34,35 the most common diagnoses being anxiety disorders, major depression, behavioral disorders, and attention-deficit/hyperactivity disorder. 28, 35 mental illness has an effect on other family members, which is seen clearly in a study looking at growth rates of children with mothers suffering from mental illness. the study showed that 20% of these children suffered from stunted growth, which could have been averted if interventions to treat the maternal depression had been performed. 28, 35 individuals suffering from severe form of depression are at increased risk of attempting suicide, 36 as are women who experience abuse. 37 meanwhile, the prevalence of mental health problems among elderly people is 33%, the majority of whom suffer from depression. 38, 39 cost-effective treatment for most mental illnesses exists and, if correctly applied, most patients become functioning members of society, leading normal lives even in low-resource areas, and suicide risk is reduced. 40 of interest, poverty indicators are related to mental disorders 41-44 with low education level being the most influential determinant. 45 extrapolating these data, it is feasible to suggest that developing countries with low education levels will tend to have a higher proportion of the population suffering from mental health problems. despite this, however, most low-income and middle-income countries spend less than 1% of their health expenditure on mental health. explicit mental health policy, legislation, mental health treatment facilities, and community care are all lacking. 21 injuries as a global health issue include many types that are routinely reported to and published by the who, such as poisoning, falls, drowning, burns, and intentional injuries including interpersonal violence such as elderly, partner, or child abuse, and collective violence such as war. however, two of the most important injuries that contribute to high global death rates are road traffic accidents and occupational injuries. in 2005, an estimated 9% of all global deaths were the result of an injury. 46 injuries not only affect morbidity and mortality rates but also have a tremendous effect on the individual, the family, and the community. box 1 presents the scope of injuries and their importance as a national health issue. it is predicted that by 2030, road traffic injuries will be the fifth leading cause of death. 47 already, approximately 1.3 million people die due to road traffic accidents each year, and an additional 20 to 50 million are injured or disabled. 47 despite being home to fewer than 50% of the world's motor vehicles, low-income and middleincome countries have 90% of the mortality burden for road traffic accidents. 47 one injuries prove to be the largest killer of children between 1 and 17 years of age, accounting for 38% of all classifiable deaths. this means that 83 children per day die of injuries or 3 children per hour. the leading cause of injury-related deaths among children is drowning (59.3%) followed by road traffic accidents (12.3%), animal bites (9.3%), and suicide (8.0%). it is estimated that injuries permanently disable around 13,000 children per year in bangladesh. nonfatal injuries occur in approximately 1 million children per year or 2 per minute (institute of child and mother health, 2005). when injury-related deaths are broken down by type and by age group, children aged 1-4 and 5-9 years are most likely to die from drowning with a mortality rate of 86 per 100,000 and 26 per 100,000 child deaths, respectively. in the 10-14year age group, road traffic accidents account for 8 per 100,000 child deaths, and in the 15-17year age group, suicide accounts for 24 per 100,000 child deaths. of the most important reasons for this apparent discrepancy is the high number of vulnerable road users in developing countries. vulnerable road users include pedestrians, cyclists, and both the rider and passenger of motorcycles and scooters. vulnerable road users account for 46% of deaths, and in low-income countries pedestrians account for nearly half of all road accident-related deaths. 48 there are proven interventions that can lead to a reduction in the amount of road traffic deaths and injuries. such measures include controlling or reducing the speed of traffic with speed bumps or low-speed zones in urban areas, establishing and enforcing blood alcohol concentration limits, enforcing the use of helmets for both riders and passengers on motorcycles, and enforcing the use of seat belts, infant seats, and child booster seats. 47 the wearing of seatbelts in automobiles can reduce front-seat passenger deaths by 40% to 65% and rear-seat passenger deaths by 25% to 75%; however, only 57% of countries require the wearing of seat belts by all passengers. 47 the problem is that because of the high numbers of both people and different types of vehicles in developing countries and the lack of resources to police traffic effectively, traffic laws are not easily enforced, despite evidence showing the benefit of specific interventions in the reduction of traffic-related morbidity and mortality. 49 occupational injuries are a significant problem in global public health, contributing to between 312,000 and 334,000 deaths worldwide each year. with great shifts in industrialization from the developed to the developing countries, it is logical that the highest number of occupational injuries is shifting in the same way toward the developing world. however, it is very likely that published figures are underestimated, with numbers probably being 10% below the actual figure for the united states and as much as 85% for some locations such as rural africa. 50, 51 although several factors come into play when analyzing the causes of underreporting in developing countries, one of the main reasons is the lack of adequate data. 52 determining the actual prevalence of occupational injury is critical for several reasons: (1) to provide accurate data to health providers, policy makers, nongovernmental organizations (ngos), and the public; (2) to provide baseline data against which to measure interventions; (3) to aid priority setting and targeting for policy change and interventions; and (4) to estimate societal costs of rising occupational injuries. tools to capture occupational injury have been designed and widely circulated by the un's specialized agency, the international labour organization. however, field testing of the tools has been limited to small-scale surveys in diverse settings such as vietnam, ghana, and bangladesh, 53-56 and larger, nationally representative studies are needed. in many developing countries, there is a lack of policy for or enforcement of safe working environments, which naturally means that wood cutting, mining, agriculture, construction, and manufacturing are more hazardous than in developed countries. the developed world has accepted that poor working conditions and practices are unacceptable and has legislated against them, leading to a reduction in occupational injuries over the past century. however, it seems that globally the same care has not been forthcoming, and developing countries have taken on the burden of heavy industry and poor working conditions that generate increases in occupational injuries. this trend is perfectly exemplified by the phrase "export of hazard" to describe when an outdated and dangerous technology is relocated from a high-income country to a developing country, despite the knowledge that the risk of injury with this technology is high. 57 cost of production plays a key role in maintaining poor working conditions, and many industries in developing countries manage cost control through the use of manual labor, which is cheaper than the infrastructure and equipment needed to upgrade a process that produces the same amount of product at a much safer level. manual labor is particularly exploited in the construction industry in developing countries, which have a disproportionate number of deaths from workers falling and injuries from falling objects. working conditions at all levels of commerce are also full of risk factors to health, from the lack of ergonomically designed offices to avoid back injuries and repetitive stress disorders, to building materials used in construction, which may offer a long-term risk of health problems. the latter is of particular concern in many low-income and middle-income countries, with construction still making use of asbestos despite the documented links to lung cancer. 58, 59 urbanization urbanization is a major public health challenge for the twenty-first century, with significant changes in our living standards, lifestyles, social behavior, and health. previously more of a phenomenon in developed countries; it is now taking hold and being seen at a greater level in developing countries. 60 the united nations population fund (unfpa) predicts that over the next 2 to 3 decades, almost all the world's population growth will be in urban areas in developing countries. 61 who figures for the period 1995 to 2005 already show an alarming increase in urban population growth, with developing countries' urban areas growing at an average of 1.2 million people per week or around 165,000 people every day. 60 while urban settings offer many opportunities including access to better health care, they can affect existing health risks and introduce new health hazards. the living and working conditions of those living in rapidly expanding and poorly planned urban areas often experience risks to health in some of the most basic areas such as unsafe drinking water, unsanitary conditions, poor housing, overcrowding, hazardous locations, and exposure to extremes of temperature. these increases in health risks are particularly critical for those most vulnerable: children younger than 5 years, infants, and the elderly. 60, 62 the rapid growth of urban settlements is often due to poor economic performance of the area in question and lack of urban planning and regulation, which has resulted in an increase in the number and size of informal settlements or slums in many cities. it is estimated that in the developing regions, more than 70% of urban residents live in slums. 61 the urban health situation the current pattern of urban growth is expected to have a multiplier effect on many dimensions of illness and disease. child mortality is already high in the urban areas of developing regions. in nairobi, where 60% of the city's population lives in slums, child mortality in these slums is 2.5 times greater than in other areas of the city. 63 evidence from various surveys and studies points to a heavier burden of diseases such as diarrheal diseases, acute respiratory diseases, malnutrition among children, hiv/aids, tuberculosis, malaria, diabetes, and obesity on the urban poor. 60, 61, 64 migration, increased mobility, changes in the ecology of urban environment, high population density, poor housing, and poor provision of basic services all act as pathways for emerging and reemerging communicable diseases. 61, 62 the consequence of these changes is evident in the spread of multidrug-resistant strains of tuberculosis that is placing the urban poor of india, indonesia, myanmar, and nepal at a higher global health risk. vector-borne diseases such as dengue and malaria are also increasing in many urban areas, due to migration, climate change, stagnant water, insufficient drainage, flooding, and improper disposal of solid waste. 61, 62 unhealthy lifestyles characterized by unhealthy nutrition, reduced physical activity, and tobacco consumption due to rapid and unplanned urbanization are associated with common modifiable risk factors for chronic diseases such as hypertension, diabetes mellitus, and obesity. 60 urban environments tend to discourage physical activity and promote unhealthy food consumption. overcrowding, heavy use of motorized transport, poor air quality, and lack of safe public spaces are some urban factors that restrict participation in physical activities. in the larger populated cities of asia obesity is becoming a significant problem, and the rapid transition of diets in developing countries is typified by the coexistence of child malnutrition and maternal obesity in the same household. one of the main factors identified as causing an increase in diabetes worldwide is the change in traditional diets caused by urbanization. 65 urbanization is exacerbating the health risks in terms of traffic accidents, injuries on the street or in the home, and mental health problems. the changes in climate and rising sea levels work toward increasing urbanization, with 600 million people living in the low-elevation coastal zones being at heightened risk of flooding, which will lead to migration to higher elevations and larger cities. 61 adopting preventive measures to control communicable diseases, upgrading the infrastructure of existing health facilities, increasing human resource capacity, and taking appropriate measures for providing equitable health services to all, especially the most vulnerable groups, are vital for improving urban health. recently, the who identified 5 key areas of action for improving urban health: 1. promote urban planning for healthy behaviors and safety 2. improve urban living conditions, including access to adequate shelter and sanitation for all 3. involve communities in local decision making 4. ensure cities are accessible and age-friendly 5. make urban areas resilient to emergencies and disasters. 60 however, these actions will only be effective if there is strong collaboration between health authorities, urban planning agencies, environmental agencies, energy providers, and the transportation systems. climate change is an emerging threat to global public health. it is now widely accepted that climate change is occurring as a result of emission of greenhouse gases, especially from fossil-fuel combustion. 66 climate change is predicted to affect many natural systems and habitats, for example, increasing the frequency and intensity of heat waves, increasing the number of floods and droughts, altering the geographic range and seasonality of certain infectious diseases, and disturbing food-producing ecosystems, 67 which in turn will affect human health both directly and indirectly. direct health effects include changes in mortality and morbidity, and changes in respiratory diseases from heat waves. in terms of indirect health effects, these are much more extensive and include changes in the distribution of vector-borne diseases, the nutritional and health consequences of regional changes in agricultural productivity, and the various consequences of rising sea levels, flooding, and droughts. [66] [67] [68] climate change is highly inequitable, and the paradox is that those at greatest risk are the poorest populations in developing countries who have contributed least to koehlmoos et al greenhouse gas emissions. however, the rapid economic development and concurrent pollution means that developing countries are now vulnerable to adverse health effects from climate change and, simultaneously, are becoming an increasing contributor to the problem. 67, 69 although the effects of climate change affect all levels and ages of any single population, the elderly and those with preexisting medical conditions are seen as being the most vulnerable. conversely, major diseases that are most sensitive to climate change such as diarrhea, malaria, and infection associated with malnutrition are most serious in children living in poverty, making them highly vulnerable to the resulting disease burden. 67 heat waves are expected to increase the occurrence of heat-related illnesses such as heat exhaustion and heat stroke, and aggravate existing conditions related to circulatory, respiratory, and nervous system problems, especially among the elderly. 67, 68 in 2003, a major heat wave affected most of western europe and caused 2000 additional deaths in england and wales. 68 another consequence of high temperatures is that they raise the levels of ozone and other air pollutants, which in turn aggravate respiratory diseases such as asthma. meanwhile, health impacts due to natural disasters, such as floods, droughts, and storms, range from immediate effects that include physical injury, mortality and morbidity, and communicable diseases, to possible long-term effects such as malnutrition and mental health disorders. from 1992 to 2001, flooding was the most frequent natural disaster (43%), killing almost 100,000 people and affecting over 1.2 billion people worldwide. 70 droughts increase the risk of food shortages and malnutrition, and increase the risk of diseases spread by contaminated food and water, because viral load increases in water sources when levels drop dramatically. rising temperatures, irregular rainfall patterns, and increasing humidity affect the transmission of many vector-borne and water-borne diseases such as malaria, dengue, cholera, and other diarrheal diseases. vector-borne diseases currently kill approximately 1.1 million people each year while 2.2 million die from diarrheal diseases. 71 studies suggest that by 2030, climate change may put 170 million people in africa at risk of malaria, 67, 72 and by the 2080s the global population at risk of dengue is likely to increase to 2 billion. 67, 73 recent published data provides evidence of an association between the el niñ o and la niñ a phenomena, which are major determinants of global weather patterns, and some infectious diseases. evidence shows that there is an association between el niñ o and malaria epidemics in parts of south asia and south america, and with cholera in coastal areas of bangladesh. 68, 74 studies of malaria have already revealed the health impacts of climate variability associated with el niñ o, including large epidemics on the indian subcontinent, colombia, venezuela, and uganda. 75 one of the most immediate problems related to changes in climate and climate patterns is that on food production and availability. each year approximately 3.5 million people, mostly children from developing countries, die from malnutrition and related diseases. it is projected that climate change will decrease agricultural production in many tropical developing regions, thus putting tens of millions more people at risk of food insecurity and adverse health consequences of malnutrition. 67 disasters in certain areas of high food production will also affect global prices, thereby affecting not only those people living in the affected region but others around the world who depend on food produced from that region. the who gbd study in 1990 indicated that the climatic changes that have occurred since the mid-1970s would be having an effect by the year 2000, with 150,000 deaths (0.3% deaths globally each year) and 5.5 million lost disability-adjusted life years (dalys) per year (0.4% global dalys lost per year). the estimated effects are predicted to be most severe in those regions that already have the greatest disease burden of climate-sensitive health outcomes, such as malnutrition, diarrhea, and malaria. 17, 67, 71 many of the projected impacts on health are avoidable, and public health policy makers need to act to reduce or negate the impact caused by climate change through a combination of short-term public health interventions that aim to adapt measures in health-related sectors, such as agriculture and water management, and long-term strategy. the most effective responses are likely to be strengthening of the key functions of environmental management, surveillance and response to protect health from natural disasters and changes in infectious disease patterns, and strengthening of the existing public health systems. 67, 68 however, countries need to assess their main health vulnerabilities and prioritize adoptive action accordingly, keeping in mind the costs involved. natural disasters know no boundaries, and any nation or population can be subject to a catastrophic disaster at any time. however, some nations and populations are more at risk of disasters than others due to geographic location, poverty, and several sociopolitical factors. this issue of disaster risk reduction (drr) rose to global prominence in the aftermath of the tsunami in the indian ocean in december 2004. following a disaster, some populations suffer more acutely than others. it is worth considering the complex issues of how societies organize themselves in terms of risk and actual prevention and care, for access to clean water and sanitation, and how they communicate and initiate behavioral change among the displaced or fragile populations. at the forefront of most discussions when planning post-disaster management and action is the priority placed on certain elements of disaster relief, such as the building of embankments, the distance to clean water, or the time from incident to response. recent examples of varying responses and outcomes were seen following the two cyclones in south asia. there was a relative success in bangladesh in terms of lives saved and response coordination after cyclone sidr in november 2007, compared with the devastating loss of more than 100,000 lives after cyclone nargis in myanmar in may 2008, not to mention the loss of draft animals and dykes, and the flooding of fields during planting season. 76 bangladesh reverted to its welldeveloped program for drr that includes national-level coordination, whereas in myanmar there was no national platform for disaster preparedness, and delays occurred in the coordination of international response to the disaster. in addition to the immediate and obvious impact of natural disasters, conditions often worsen in poorly coordinated settings, as evidenced in 2010 when vibrio cholerae emerged in post-flood pakistan, and for the first time since the 1960s in post-earthquake haiti. 77 in general, there are 7 factors that can turn a natural disaster into a complex disaster regardless of the severity or magnitude of the initiating event such as a hurricane, earthquake, or tsunami. according to the un department of humanitarian affairs, the 7 factors are: poverty, ungoverned population growth, rapid urbanization and migration, transitional cultural practices, environmental degradation, lack of awareness and information, and war and civil strife. 78 poverty is by far the single greatest factor that contributes to the vulnerability of a population to complex disasters. in addition to lacking financial resources to prepare for or recover from a disaster, impoverished people are also more likely to have low levels of education and low amounts of political influence to properly deal with a disaster situation. in addition to increases in birth rates, rapid population growth can be the consequence of urbanization or migration. population growth without limits produces a population that is more likely to settle in areas that are unsuitable or at risk for natural disasters, meaning that more people are at risk of disease and, most importantly, are more likely to undergo civil strife while competing for scarce resources. as mentioned previously, rapid urbanization and migration lead to impoverishment. former rural populations make themselves more vulnerable to disaster by settling in less developed or high-risk city environs, often leading to homelessness or living in urban slums that have circumvented any planning controls or regulations. such populations therefore are made more vulnerable to floods, landslides, and the destruction of their dwelling during a hurricane or earthquake. transition of cultural, economic, or government practices such as the increase in migration from rural to urban areas, economic advancements, families moving away from traditional support networks and to unfamiliar surroundings, and the shift from an agrarian to an industrialized society leave certain societies vulnerable to natural disasters. environmental degradation can play a role by either causing or exacerbating a disaster. for example, deforestation can work in two ways: firstly enabling runoff or secondly, making landscapes vulnerable to storms, due to lack of natural wind breaks. everyone is aware of the natural conditions that provoke droughts, but through the construction of dams, unchecked urbanization, implementation of poor cropping patterns, and the depletion of water supplies, man-made droughts are becoming more widespread. it is clearly of upmost importance to ensure that populations are informed about what to do to prepare in advance of a natural disaster such as a hurricane, and also are able to fend for themselves following the event. a lack of awareness and the dissemination of accurate information is a major factor that can turn one disaster into a multiple or complex disaster involving, for example, subsequent outbreaks of cholera, malnutrition, and physical injury. war and civil strife are extreme events that can both produce disasters or be caused by disasters, normally as a result of the preceding 6 factors. 78 the phrase for disasters that specifically strike war-torn populations is complex humanitarian emergencies. 79 global efforts to address and capture the importance of disaster risk and poverty have been hampered by a lack of data, especially from asia, latin america, and the caribbean. empirical evidence linking disaster risk to poverty tends to come from microstudies within one community, making it impossible to generate generalized findings across regions or entire countries. 80 prompted by the devastation that followed the tsunami on 26 december, 2004, there was widespread acceptance that an early-warning system should be installed and other actions taken to prevent loss of life where possible. the world conference on disaster reduction was held in japan in january 2005, and resulted in the creation of the hyogo framework for action 2005-2015 (hfa), which was endorsed by 168 un member states and urges all countries to make major efforts to reduce their disaster risk by 2015. the hfa outlines the need to increase awareness and understanding about drr, the importance of knowing the real and potential risks, and taking action against them. specific recommendations included the need to create or enhance early-warning systems, build drr into education, and reduce risk factors such as deforestation, unstable housing, and the location of communities in risk-prone areas. although different areas of the planet experience different risks, the one common factor is that drr "concerns everyone, from villagers to heads of state, from bankers and lawyers to farmers and foresters, from meteorologists to media chiefs." 81 to support common needs within regions, associations and networks have been established to support drr, such as the south asian saarc disaster management center and the caribbean disaster emergency response agency. types of activities that can feature in a national or regional drr program can include: establishing early-warning systems; using local knowledge of events; building an awareness of risk and risk preparedness through community activities; building flood-resistant buildings and safe homes; developing contingency plans; helping communities and individuals develop alternative sources of income; and establishing insurance or microfinance programs to help transfer the risk of loss and provide additional resources to the community. 82 in addition to chronic diseases, mental health problems, injuries, and complex disasters, communities should consider increasing risks from more than 30 new or reemerging diseases that have appeared since the 1970s: liver disease due to the hepatitis c virus; lyme disease; food-borne illnesses caused by escherichia coli o157:h7; cyclospora, a water-borne disease caused by cryptosporidium; hantavirus pulmonary syndrome; and human disease caused by the avian h5n1 influenza virus. 83 the increasing number of new and reemerging diseases is not the only risk factor that should be added to the planning processes for developing a drr program. drug resistance in treating many diseases and illnesses is a major concern, as witnessed in malaria and tuberculosis, and with a highly mobile world population, global pandemics such as sars, h5n1, and h1n1, for which treatments either are not available or levels of suitable drug are clearly not sufficient for a worldwide epidemic, are proving to be very challenging. this clear inability to predict and maintain sufficient levels of treatment for potential threats makes health risk reduction extremely difficult, and in developing countries where resources are already stretched to cope with existing health issues, creating effective programs will require intervention from social partners, global support organizations, and aid from the developed world. an ever quickening pace of globalization means that public health-related problems in one area of the world will have an impact on those living in another area and therefore, it is in everyone's interest to ensure that all countries, irrespective of their economic development and available resources, are sufficiently supported to maintain and review strategies that will effectively reduce morbidity and mortality rates in all spheres of public health. preventing chronic diseases: a vital investment a race against time: the challenge of cardiovascular disease in developing economies non-communicable diseases: time to pay attention to the silent killer. press release missing in action: international aid agencies in poor countries to fight chronic disease when people 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and associated characteristics prevalence and determinants of depressive disorders in primary care practice in spain prevalence of anxiety, depression, and substance use disorders in an urban general medicine practice prevalence of mental disorders in childhood in pediatric primary care psychiatric disorders in a paediatric primary care clinic depression in deliberate self harm patients paramedic conducted mental health counselling for abused women in rural bangladesh: an evaluation from the perspective of participants mental disorders among elderly people in primary care: the linkö ping study psychiatric morbidity among the elderly in a primary care setting-report from a survey in sã o paulo, brazil psychiatric morbidity in cancer patients poverty and mental health: a qualitative study of residential care facility tenants poverty and mental health in aboriginal australia links between social class and common mental disorders in northeast brazil mental illness and exclusion: putting 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settings. kobe (japan): who centre for health development urbanization and health mortality trends and setbacks: global convergence or divergence? emerging disease burdens and the poor in cities of the developing world world health organization. diet, nutrition and the prevention of chronic diseases global climate change: the potential effects on health protecting health from climate change: connecting science, policy and people climate change and human health: impacts, vulnerability and public health climate change and developing-country cities: implications for environmental health and equity climate change and human health: present and future risks the global burden of disease: 2004 update scenario review paper prepared for the detection and identification of infectious diseases project (diid), foresight project, office of science and innovation potential effect of population and climate changes on global distribution of dengue fever: an empirical model el nino and health impact of regional climate change on human health burma death toll jumps to 78,000 haiti cholera outbreak causes not clear, experts say united nations, department of humanitarian affairs [un-dha] the use of military and civil defence assets in relief operations. mcda reference manual evolution of complex disasters united nations-international strategy for disaster reduction united nations-international strategy for disaster reduction [un-isdr] living with risk. a global review of disaster reduction initiatives disaster risk management and climate change adaptation in south asia. dhaka: portfolion new and reemerging diseases: the importance of biomedical research key: cord-280060-gzby85u9 authors: rello, jordi; manuel, oriol; eggimann, philippe; richards, guy; wejse, christian; petersen, jorgen eskild; zacharowski, kai; leblebicioglu, hakan title: management of infections in critically ill returning travellers in the intensive care unit—ii: clinical syndromes and special considerations in immunocompromised patients() date: 2016-04-28 journal: int j infect dis doi: 10.1016/j.ijid.2016.04.020 sha: doc_id: 280060 cord_uid: gzby85u9 this position paper is the second escmid consensus document on this subject and aims to provide intensivists, infectious disease specialists, and emergency physicians with a standardized approach to the management of serious travel-related infections in the intensive care unit (icu) or the emergency department. this document is a cooperative effort between members of two european society of clinical microbiology and infectious diseases (escmid) study groups and was coordinated by hakan leblebicioglu and jordi rello for esgitm (escmid study group for infections in travellers and migrants) and esgcip (escmid study group for infections in critically ill patients), respectively. a relevant expert on the subject of each section prepared the first draft which was then edited and approved by additional members from both escmid study groups. this article summarizes considerations regarding clinical syndromes requiring icu admission in travellers, covering immunocompromised patients. over the last 20 years, the increase in international travel, which has been intensified by the availability of low-cost flights, has facilitated the movement of an increased number of patients from areas with endemic diseases to distant regions. as a consequence, cities around flight hubs have been and are exposed to the rapid dissemination of imported infections, as was reported in the initial dissemination of hiv infection in north america, and more recently in the 2009 influenza pandemic. similarly, outbreaks of cholera have been reported in travellers after long distance flights, and tourism has also been associated with the dissemination of infections such as measles, rubella, diphtheria, typhoid fever, and chicken pox, in addition to malaria and haemorrhagic fevers. poor health conditions and crowding are associated with tuberculosis (tb), diarrhoea, tetanus, and other infectious events, which may be imported by migrants from areas devastated by war. immunocompromised patients encompass a growing population with increased susceptibility to infectious complications. because they live longer and have a better quality of life than ever before, they may have more opportunity to travel and potentially encounter travel-associated infections. it has been estimated that up to one third of solid-organ transplant (sot) recipients may travel to resource-limited countries within the first year post-transplant. 1 in a survey in north american transplant centres, up to 44% of haematopoietic stem cell transplant (hsct) recipients reported travel outside the usa and canada after transplantation. 2 a international journal of infectious diseases 48 (2016) 104-112 significant number of immunocompromised patients may also be migrants who may return to their countries of origin to visit friends and relatives, and may acquire travel-associated infections. the increased use of monoclonal antibodies for therapy in immunological and oncological diseases has created another at-risk population, although the actual risk of travel-associated infection in these patients is not well established. 3 data on the real risk of infection in immunocompromised travellers relative to the general travel population are scarce, 4 and particularly the risk of developing an illness severe enough to warrant admission to an intensive care unit (icu). the repatriation of immunocompromised patients from hospitals in destination countries also carries the risk of contamination of the receiving hospital with multidrug-resistant (mdr) microorganisms, which requires specific infection control measures. 5 this article also addresses certain specific syndromes, such as pneumonia and acute respiratory distress syndrome (ards) occurring after travel. this position paper is the second escmid consensus document on this subject and aims to provide intensivists, infectious disease specialists, and emergency physicians with a standardized approach to the management of serious travel-related infections in the icu or emergency department. this document is a cooperative effort between members of two european society of clinical microbiology and infectious diseases (escmid) study groups and was coordinated by hakan leblebicioglu and jordi rello for esgitm (escmid study group for infections in travellers and migrants) and esgcip (escmid study group for infections in critically ill patients), respectively. a relevant expert on the subject of each section prepared the first draft, which was then edited and approved by additional members from both escmid study groups. this article summarizes considerations regarding clinical syndromes requiring icu admission in travellers, covering immunocompromised patients. (table 1) the risk of infection in sot recipients varies according to multiple factors, namely the type of organ transplanted, the time from transplantation, and the type and dose of immunosuppressive drugs received. 6 during the first month post-transplant, infectious complications are mainly healthcare-associated. the most profound immunosuppression occurs between months 2 to 6; historically, this is the period in which most opportunistic infections were diagnosed, including herpesvirus infections (cytomegalovirus), pneumocystis jirovecii pneumonia, and invasive fungal infections. 7 however, with the use of universal antiviral preventive strategies and long-term co-trimoxazole prophylaxis, opportunistic infections are currently rarely seen. after 6-12 months, the risk of infection decreases significantly and infections over this period are usually community-acquired, except in the case of increased immunosuppression (due to allograft rejection or dysfunction) or in the case of chronic surgical complications. because the incidence of infection is higher early after transplantation, it is recommended to avoid travel during the first year. 8 hsct recipients are at increased risk for bacterial and fungal infections during the engraftment period in the first month posttransplant. in the case of graft-versus-host disease, cellular immunosuppression is the mechanism responsible for the development of viral infections (particularly cytomegalovirus, adenovirus, and bk virus) and invasive fungal infections. 9 after the second year post-transplant it is considered that the degree of immunosuppression is non-significant if the patient has not developed chronic complications. while the use of biological agents for the therapy of rheumatological and autoimmune diseases has increased considerably over recent years, data on the risk of infection are mainly limited to the use of anti-tumour necrosis factor (tnf) agents. several large cohort studies found patients receiving anti-tnf therapy to be at greatest risk of developing skin infections, although the overall risk of severe infections was similar to that of patients receiving other non-biological therapies. 10 a study from the netherlands assessed the risk of infection in 75 travellers receiving biological agents relative to their travelling companions. 4 immunocompromised patients were at significantly higher risk of developing skin infections, fatigue, and abdominal pain, but not fever, diarrhoea, or respiratory infections. of note, no serious infection developed during or after the trip in these patients. patients on anti-tnf therapy have an increased risk of developing mycobacterial infections, with several cases of disseminated tb with a fatal outcome reported in the literature. 11 cutaneous leishmaniasis has also been reported in patients on anti-tnf treatment. 12 the risk of bacterial and fungal infections in patients with an oncological condition is increased during the administration of chemotherapy and/or radiotherapy and/or immunotherapy, particularly during the period of neutropenia. 13 in contrast, the risk of infection is generally considered not to be increased some months after the conclusion of chemotherapy and in patients receiving hormone therapy. patients with haematological conditions, such as lymphoma or hodgkin disease, may, however, have some degree of cellular immunosuppression even months after the remission of the disease. asplenic patients are at significantly higher risk of infection with encapsulated bacteria, namely streptococcus pneumoniae, neisseria meningitidis, haemophilus influenzae, and capnocytophaga canimorsus. 14 thus, appropriate vaccination with conjugated vaccines is an essential preventive strategy in these patients. other potentially life-threatening infections that are more common in asplenic patients include salmonellosis, babesiosis, and malaria. while the risk of infection is higher during the first month following splenectomy, the increased risk persists for years. the risk of infection in asplenic patients depends on the underlying condition, being higher in patients with haematological diseases and in those in whom immunization may not be fully successful or is associated with suboptimal protection over long periods of time. such patients may be instructed to start empirical antibiotics targeted at encapsulated bacteria immediately if any clinical signs or symptoms of infection ensue. 15 there are few studies that have addressed the epidemiology and clinical manifestations of malaria in immunocompromised patients. the incidence of malaria was reported to be less than 1% in hsct recipients in an endemic country (pakistan); however, data on other immunosuppressive conditions and in travellers are missing. 15 despite the lack of prospective studies, it appears that malaria is associated with more severe outcomes in immunocompromised patients than in the general population. a recent systematic review found that up to 45% of published cases of malaria in sot recipients had at least one criterion for severe malaria (o. manuel, personal communication). importantly, malaria may develop through transmission from the organ donor, and as such there may not be a travel history. 16 a case of cerebral malaria with >50% parasitemia has been reported in a patient receiving infliximab; 17 however such severe disease can occur in patients not on biologicals as well. malaria can also be more severe in splenectomized patients due to the lack of clearance of intraerythrocytic parasites. the successful treatment of severe malaria in immunocompromised patients has been reported with the use of erythropheresis and artesunate. 18 the choice of the preventive strategy for malaria in immunocompromised travellers should be individualized, favouring antimalarial prophylaxis in patients travelling to intermediate-risk and high-risk regions. several cases of severe dengue in immunocompromised patients have been reported, mostly in patients in endemic countries. in a series of kidney transplant recipients in india, up to 37% of patients diagnosed with dengue had a severe course and died. 19 all presented with fever, thrombocytopenia, myalgia, and retro-ocular pain. in contrast, in a series of eight patients receiving biologicals who were diagnosed with dengue, none developed severe infection. 20 dengue fever was reported to be a frequent cause of febrile neutropenia in haematological patients in india, but this was not associated with worse outcomes. 21 early diagnosis is essential in immunocompromised travellers with clinical manifestations suggestive of dengue in order to initiate early appropriate supportive therapy. aggressive volume replacement within the first 24 h of icu admission is important to limit the development of multiple organ dysfunction syndrome and increase the probability of survival. travel-related fungal infections in immunocompromised patients are uncommon, but potentially associated with a severe course and increased mortality. 22 invasive travel-related fungal infections that have manifested with a severe course in sot recipients and hiv-infected individuals include disseminated penicillium marneffei infection, aspergillosis, histoplasmosis, and coccidioidomycosis. 23 in patients receiving monoclonal antibodies, severe travel-associated histoplasmosis has been associated with a 50% mortality rate, and in another report, malignancy was a risk factor for acquiring a cryptococcus gattii infection. 24 importantly some of these infections may have a long incubation period so the travel history may be underreported. as such, a detailed travel history should be sought in immunocompromised travellers who develop fever associated with pulmonary lesions and/or localized cutaneous or subcutaneous disease, and these patients should be investigated promptly and aggressively for the diagnosis of invasive fungal infections. 22 the risk of tb is increased in transplant patients, hiv-infected individuals, and in patients receiving biologicals, but the risk of travel-acquired tb in immunocompromised patients is not well established. screening for latent tb infection after travel to endemic regions in these patients might, however, identify patients at risk of developing active tb. leptospirosis is a common cause of fever in returning travellers, and can be associated with severe complications. in a series of nine hiv-infected patients with leptospirosis, 67% presented with severe sepsis and the mortality was 22%. 25 data on the severity of leptospirosis in other immunocompromised populations are lacking. nocardiosis in sot recipients is associated with a high incidence of disseminated disease, particularly with central nervous system involvement. strongyloidiasis in immunocompromised patients is a rare but potentially life-threatening condition. donor-derived or travelacquired infestation with strongyloides stercoralis is associated with a high mortality. 26 cases of chagas disease (trypanosoma cruzi) either as a consequence of reactivation of a latent infection not identified at the time of transplant (because an unrecorded travel history or stay in an endemic area) or by transmission through the organ donor, can also be associated with a high mortality. 27 furthermore, immunocompromised patients may be particularly susceptible to severe forms of west nile virus infection and tick-borne encephalitis, all of which should be actively sought in the workup of patients with central nervous system symptoms after returning from endemic areas. there have also been case reports of severe disease from other travel-associated infections, such as salmonellosis, vibrio parahaemolyticus, and visceral leishmaniasis in immunocompromised patients. there are many causes of respiratory failure and of ards. those that are specific to certain geographic regions and that may appear unexpectedly in travellers are less common, but are nevertheless extremely important because appropriate therapy requires a correct diagnosis, and some infections may have epidemic potential. the infectious causes in particular may not be recognized immediately because they may be out of their usual geographical context. those that can cause ards will be discussed briefly below. table 2 summarizes the main recommended antimicrobial regimens for specific organisms involved in ards in returning travellers. cap is the most likely cause of acute respiratory failure in returning travellers. the usual pathogens, such as s. pneumoniae, h. influenzae, mycoplasma pneumoniae, chlamydophila pneumoniae, legionella pneumophila, and viruses such as influenza and respiratory syncytial virus, are the most common culprits. however aspiration must be considered in the elderly and in those who have become inebriated whilst on holiday. less common pathogens such as staphylococcus aureus, avian influenza viruses such as h7n9 and h5n1, the middle east respiratory syndrome coronavirus (mers-cov), and gram-negative rods such as burkholderia pseudomallei must also be considered, as well as a few other pathogens that do not usually cause pneumonia, such as malaria. influenza viruses such as h1n1 and h3n2, which are currently circulating, are perhaps the most common travel-related infections, particularly in the unvaccinated, those travelling across hemispheres, and where the available vaccine does not cover a particular strain effectively. influenza is an acute illness manifested by pyrexia, cough, chills, myalgia, and fatigue. there can, however, be more severe complications, specifically pneumonia, especially in pandemic years. in the 2009 influenza a(h1n1)pdm09 pandemic, more than 18 500 deaths were reported, with global estimates 15 times higher. the primary risk factors were age (young to middle age; >60% were aged <65 years), morbid obesity, pregnancy, and an immunocompromised status. influenza also increases the risk of bacterial pneumonia, particularly that caused by s. pneumoniae and s. aureus. those with severe disease deteriorate acutely after 4-5 days, with profound hypoxemia, shock, and often multiple organ dysfunction syndrome. the pathological findings are of an intense inflammatory/ haemorrhagic pneumonia, the severity of which seems to be influenced by the presence or absence of associated bacterial cap. 28 any patient with the above features, particularly if unvaccinated or having travelled to another hemisphere during the winter season, should be investigated for influenza, with diagnosis based on throat swab or nasal wash and a commercial kit based on antigen or rt-pcr. 29 unfortunately there is very low uptake of influenza vaccine even amongst healthcare workers, and as such there remains a large pool of susceptible individuals. although not yet reported to have been transmitted from humans, avian influenza h5n1 and h7n9 remain a potential threat, particularly in southeast asia. travellers who have had contact with birds in the affected areas and who present with otherwise unexplained ards should be screened. h5n1 has been reported from 17 countries and is currently most prevalent in egypt. 30 staphylococcus aureus pneumonia is usually a fulminant disease associated with rapid onset respiratory failure, frequently progressing to multiple organ dysfunction, shock, and death. complications are frequent and include pulmonary necrosis and abscess and empyema formation, particularly if the strain is a producer of panton-valentine leukocidin (pvl) toxin, a cytotoxin responsible for leukocyte destruction and tissue necrosis. risk factors are colonization or infection with s. aureus and a preceding influenza-like illness (ili). leucopenia (2.5 â 10 9 /l) is characteristic and may be an inverse biomarker of pvl burden. 31 both methicillin-sensitive s. aureus (mssa) and methicillinresistant s. aureus (mrsa) can cause cap. the latter is primarily a problem of recognition, as the organism is not prevalent in all countries and standard guideline-based therapies for pneumonia do not cover mrsa. the sensitivity profile of community-acquired mrsa differs from that of hospital-acquired mrsa in that it may be susceptible to macrolides, quinolones, clindamycin, and trimethoprim-sulfamethoxazole. therapy consists of appropriate antimicrobial therapy such as linezolid (possibly in preference to vancomycin, particularly if the strain is a pvl-producer), vancomycin, or ceftaroline. 32 pneumonia is the most common presentation of legionnaire's disease or legionellosis, and it may be severe, leading to multiorgan failure and death. characteristic clinical findings are relative bradycardia, hyponatremia, elevation in serum creatinine kinase, diarrhoea, confusion, and impaired liver and kidney function. 33 the recommended treatment regimen is macrolides or fluoroquinolones. 34 ten years after the severe acute respiratory syndrome (sars) epidemic that affected almost 8000 people and caused 775 deaths, mers-cov, a new coronavirus of the same family, appeared in saudi arabia and subsequently spread to nine countries in or near the arabian peninsula and 14 countries elsewhere. 35 on march 10, 2015, the world health organization global case count was 1060 laboratory-confirmed cases with 394 deaths (37%). all cases were resident in or had travelled to the middle east, most to saudi arabia, or had been in contact with travellers returning from these areas. mers-cov differs from sars-cov in that it binds to different receptors, and camels are thought to be the primary reservoir host, although the means of transmission from these animals is poorly understood. whereas transmission can occur between humans, the epidemic potential appears to be less. the disease is not always severe and symptoms range from an ili to severe pneumonia requiring mechanical ventilation. the most severely affected patients have mostly had comorbidities such as diabetes, renal failure, and chronic lung disease, or have been immunocompromised. 36 there is no specific antiviral treatment available for mers-cov infection. management is primarily supportive, directed towards the prevention of respiratory complications and infection control. corticosteroids are not currently recommended in this setting. it is still advised that those travelling to the middle east and who are at increased risk of severe disease should avoid contact with camels and their secretions, and avoid drinking raw camel milk (which will also prevent infection with brucella). all travellers should practice good hand and food hygiene, particularly where camels are present. a number of gram-negative pathogens may cause pneumonia and ards, in particular in relation to aspiration, or in association with ventilation where pathogens such as pseudomonas aeruginosa, acinetobacter baumannii, klebsiella pneumoniae, escherichia coli, and other enterobacteriaceae are of concern. 37 the latter include the extended-spectrum beta-lactamase (esbl)-and carbapenemaseproducers (such as those producing new delhi metallo-blactamase 1 (ndm-1)), which may be acquired during 'medical tourism'. 38 diagnosis requires a high index of suspicion and testing for the specific genes responsible for enzyme production. treatment remains a challenge due to deficiencies in the antibiotic pipeline. burkholderia pseudomallei is also a gram-negative bacillus endemic in southeast asia, northern australia, and possibly the indian subcontinent, southern china, hong kong, and taiwan. infection results from inoculation of contaminated soil and surface water through skin abrasions, with subsequent haematogenous spread. horizontal transmission also occurs, as well as transmission through the inhalation of polluted water. it is the most common cause of fatal community-acquired bacteraemia and pneumonia in certain areas of north-eastern thailand, as well as in darwin, australia. 39 travellers from endemic areas, especially in the wet season and particularly if there are comorbidities, are at risk. variable disease severity and the range of presentations (pneumonia, abscesses, osteomyelitis, and arthritis) make diagnosis a challenge. about 50% of patients present with pneumonia (which may appear as nodular infiltrates or air space consolidation), often with septic shock. the diagnosis is made when b. pseudomallei is cultured, but specific media are required. ceftazidime or meropenem with or without high-dose co-trimoxazole are the drugs of choice. although tb may occur in any patient, it seldom causes respiratory failure over a short period of time. yet, a recent prospective study from south africa reported that 1.5% of adults with active tb may require mechanical ventilation because of refractory hypoxemia, which in high tb prevalence countries translates into a significant burden of disease. 40 in this setting, 15% of tb suspects had confirmed tb, and it should be considered if the travel history involves relevant exposure. standard smear microscopy or culture are used for diagnosis, or rapid pcr if available (genexpert mtb/rif), which has been shown to have increased sensitivity and shorten the time to treatment. 41 where there is a high clinical suspicion of tb, empiric therapy should be initiated after adequate sampling has been obtained, particularly in the case of life-threatening or disseminated infection. initial therapy with four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) is generally recommended where there is a low prevalence of resistance, and depending on the patient's origin and the results of the rapid detection of rpob gene mutations. patients with mdr-or xdr-tb need to be treated with second-line agents including aminoglycosides, quinolones, para-aminosalicylic acid, cycloserine, and clofazimine, and new drugs such as bedaquiline, linezolid, and delamanid. malaria, which is a frequent travel-related disease, may also lead to ards in severely affected patients. 41 increased alveolar capillary permeability may result in pulmonary oedema and respiratory failure either at presentation or after treatment. pregnant women are particularly at risk. slide microscopy and rapid antigen tests are the standard diagnostic tools, and the treatments of choice are the parenteral artemisinins, although resistance is emerging. non-infectious causes of bilateral pulmonary infiltrates with respiratory failure must be differentiated from infectious causes. these include cardiogenic pulmonary oedema, inflammatory pulmonary diseases such as cryptogenic organizing pneumonia (cop) and fibrosis, alveolar haemorrhage (including idiopathic granulomatous polyangiitis, lupus, and vasculitis), and ards from conditions such as eosinophilic pneumonia, pancreatitis, inhalational injury, and trauma. to identify these, clinical expertise is critical, along with the use of biomarkers (such a c-reactive protein, procalcitonin, and pro-b-type natriuretic peptide), serology to exclude autoimmune diseases, and imaging including echocardiography. if mechanical ventilation alone is inadequate, the use of neuromuscular blockade, recruitment techniques including prone ventilation, and veno-venous extracorporeal membrane oxygenation (ecmo) may improve oxygenation and the outcome. the berlin classification of ards severity is universally accepted and should be utilized to determine the site of therapy. 42 the acute physiology and chronic health evaluation (apache) score provides additional information regarding icu and hospital outcomes. 43 for pneumonia, the most frequently used scores are the pneumonia severity index (psi) and curb-65. to evaluate mortality risk in tb patients, the tbscore is useful and has been shown to predict the outcome. 44 haemorrhagic symptoms and fever can be caused by many infections due to bacteria, viruses, and parasites. disseminated intravascular coagulation (dic) may be a manifestation of severe septicaemia and can be caused by almost all gram-positive and gram-negative bacteria. dic is particularly present in septicaemia with n. meningitidis (figure 1 ), but is also seen in patients with s. aureus and s. pneumoniae bloodstream infections (figures 2 and 3 ). numerous viruses may also cause haemorrhagic symptoms, and these include dengue virus, crimean-congo haemorrhagic fever virus, ebola virus, yellow fever virus, hanta virus, and others (table 3) . it is most important to establish whether the patient has a history of travel within the past 4 weeks to areas where viral haemorrhagic fevers are endemic immediately at admission (table 3 ). if the history and the clinical features are suggestive, further details should be obtained, as shown in table 4 , and the patient should be evaluated as to whether isolation is necessary. in most countries where haemorrhagic fever viruses occur, malaria is also endemic, and a malaria test (rapid diagnostic test or microscopy) should be performed immediately and at the same time as blood cultures for bacterial infections are obtained. once malaria has been excluded, treatment should be started to cover a broad range of bacterial infections until such time as the diagnosis is confirmed. an example of gangrene related to severe staphylococcal septicaemia is shown in figure 2 . rapid assessment of the patient and isolation are key to limiting healthcare-associated transmission. the mers-cov outbreak in south korea illustrates how rapidly infections can spread in overcrowded hospitals. 45 most mers-cov cases in saudi arabia have also been linked to transmission in hospitals, 46 as was the case with sars-cov 47 and with crimean-congo haemorrhagic fever. 48 training of paramedical staff, nurses, and physicians, as well as guidelines for the recognition and rapid assessment of febrile patients at the initial point of contact, are essential, as is an isolation area for febrile patients with a relevant travel history. dic is an acquired condition of the vascular system leading to an uncontrolled systemic activation of the coagulation pathway. the generation of thrombin and fibrin may cause thrombotic occlusions of blood vessels, and hence organ injury and failure. 49 this is accompanied by an inflammatory reaction, further augmenting the coagulation process. dic frequently accompanies systemic inflammatory response syndrome (sirs), severe sepsis, trauma, and other conditions as diverse as anaphylaxis and heat stroke. [49] [50] [51] [52] [53] [54] the systemic activation of the clotting system is associated with the consumption of both coagulation factors and platelets, and as such, various combinations of platelet count, prothrombin time, activated partial thromboplastin time (aptt), a decrease in anti-thrombin (at) and protein c, as well plasma levels of fibrin and d-dimers have been used for the diagnosis. 55 a more standardized approach can be achieved by using the scoring system of the international society of thrombosis and haemostasis. 56 the successful therapy of dic is only possible when the underlying cause is identified and treated. the substitution of coagulation factors is currently unclear due to the lack of appropriate randomized placebo-controlled trials. the use of antifibrinolytics during dic should be avoided, as this drug class may lead to the deposition of fibrin in the vascular walls. 57 overall, the prevalence of dic during viral haemorrhagic fever is high and contributes to morbidity and mortality. early and effective treatment against the viral infection, if available, reduces the detrimental complications of dic. parameters for assessing dic and haemolysis are provided in table 5 . questions to be asked if the patient has travelled in an area where haemorrhagic fever occurs does the patient have a fever (>38 8c) or history of fever in the previous 24 hours? and has the patient cared for/come into contact with body fluids of/handled clinical specimens (blood, urine, faeces, tissues, laboratory cultures) from a live or dead individual or animal known or strongly suspected to have vhf? has the patient received a tick bite and/or crushed a tick with their bare hands and/or travelled to a rural environment where contact with livestock or ticks is possible in a cchf endemic area? has the patient lived or worked in basic rural conditions where lassa, ebola, or marburg fever is endemic, i.e., west/central africa or south america? has the patient travelled to any local area where a vhf outbreak has occurred? cchf, crimean-congo haemorrhagic fever; vhf, viral haemorrhagic fever. patients with suspected severe sepsis should be managed according to standard guidelines. 58 these include broad-spectrum antibiotics, aggressive initial fluid replacement, blood pressure support if needed, the correction of acidosis, and oxygenation by intubation and mechanical ventilation as needed. echocardiography is essential to evaluate cardiac function and any vegetations on the cardiac valves. in the initial stages it is difficult to differentiate between a viral haemorrhagic fever, severe bacterial sepsis, and severe malaria. travel patterns and risk behavior in solid organ transplant recipients international travel patterns and travel risks for stem cell transplant recipients international travel in the immunocompromised patient: a cross-sectional survey of travel advice in 254 consecutive patients symptoms of infectious diseases in immunocompromised travelers: a prospective study with matched controls multidrug-resistant bacteria without borders: role of international trips in the spread of multidrug-resistant bacteria infection in solid-organ transplant recipients impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients travel medicine and transplant tourism in solid organ transplantation hematopoietic stem cell transplantation: an overview of infection risks and epidemiology rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the british society for rheumatology biologics register tuberculosis associated with infliximab, a tumor necrosis factor alphaneutralizing agent anti-tumour necrosis factor-induced visceral and cutaneous leishmaniasis: case report and review of the literature bacterial infections in low-risk, febrile neutropenic patients post-splenectomy and hyposplenic states the stem cell transplant program in pakistan-the first decade posttransplant malaria: first case of transmission of plasmodium falciparum from a white multiorgan donor to four recipients overwhelming parasitemia with plasmodium falciparum infection in a patient receiving infliximab therapy for rheumatoid arthritis donor-transmitted malaria after heart transplant managed successfully with artesunate dengue virus infection in renal allograft recipients: a case series during 2010 outbreak dengue fever in patients under biologics dengue fever as a cause of febrile neutropenia in adult acute lymphoblastic leukemia: a single center experience fungal infections in immunocompromised travelers donorderived fungal infections in organ transplant recipients: guidelines of the american society of transplantation, infectious diseases community of practice risk factors for cryptococcus gattii infection leptospirosis and human immunodeficiency virus co-infection among febrile inpatients in northern tanzania donor-derived strongyloides stercoralis infection in solid organ transplant recipients in the united states trypanosoma cruzi fatal reactivation in a heart transplant recipient in switzerland critically ill patients with influenza a(h1n1)pdm09 virus infection in 2014 rapid diagnostic testing for influenza: information for health care professionals avian influenza a(h7n9) virus. geneva: who severe community-onset pneumonia in healthy adults caused by mrsa carrying the panton-valentine leukocidin genes ceftaroline fosamil for the treatment of staphylococcus aureus bacteremia secondary to acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia clinical features and predictors of mortality in admitted patients with community-and hospitalacquired legionellosis: a danish historical cohort study legionnaires disease and the updated idsa guidelines for community-acquired pneumonia middle east respiratory syndrome (mers) interhuman transmissibility of middle east respiratory syndrome coronavirus: estimation of pandemic risk aetiological agents of ventilator-associated pneumonia and its resistance pattern-a threat for treatment risk factors for infections with extended-spectrum beta-lactamase-producing escherichia coli and klebsiella pneumoniae at a tertiary care university hospital in switzerland melioidosis: a review a randomised controlled trial of the impact of xpert-mtb/rif on tracheal aspirates nested within a burden of disease study in south african intensive care units managing malaria in the intensive care unit acute respiratory distress syndrome: the berlin definition. ards definition task force severity scoring in the critically ill: part 1-interpretation and accuracy of outcome prediction scoring systems tbscoreii: refining and validating a simple clinical score for treatment-monitoring patients with pulmonary tuberculosis middle east respiratory syndromeadvancing the public health and research agenda on mers-lessons from the south korea outbreak mers-cov outbreak in jeddah-a link to health care facilities cluster of severe acute respiratory syndrome cases among protected health-care workers-toronto, canada probable crimean-congo hemorrhagic fever virus transmission occurred after aerosol-generating medical procedures in russia: nosocomial cluster disseminated intravascular coagulation prospective validation of the international society of thrombosis and haemostasis scoring system for disseminated intravascular coagulation disseminated intravascular coagulation in trauma patients disseminated intravascular coagulation (dic) in cancer the obstetric patient and disseminated intravascular coagulation disseminated intravascular coagulation guidelines for the diagnosis and management of disseminated intravascular coagulation. british committee for standards in haematology towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation prevention and treatment of major blood loss surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 the authors declare no conflicts of interest. jr and hl designed the manuscript: om and pe wrote the immunocompromised host section, gr and cw wrote the ards section, and cw, ep and kz wrote the haemorrhagic fever section. om and jr assembled the final version. all authors read and approved the last version of the manuscript. key: cord-318852-gouz6tth authors: lee, j.s.e.; goy, r.w.l.; sng, b.l.; lew, e. title: considerations and strategies in the organisation of obstetric anaesthesia care during the 2019 covid-19 outbreak in singapore date: 2020-04-20 journal: int j obstet anesth doi: 10.1016/j.ijoa.2020.04.003 sha: doc_id: 318852 cord_uid: gouz6tth • identifying ‘high-infection risk’ parturients is challenging in the covid-19 outbreak. • a multidisciplinary approach is required to provide obstetric anaesthesia services. • protocols for labour analgesia and caesarean delivery allow safe provision of care. • infection control resource management allows for the allocation of finite resources. • organisational changes are required to respond to the covid-19 outbreak. since the outbreak of the coronavirus disease in 2019 (covid-19), singapore has seen the emergence of 1309 cases with six mortalities (as of 5 april 2020). 1 the 'disease outbreak response system condition' (dorscon) orange alert was declared by our local health authorities in early february, signifying a severe disease of limited community spread. 2 the kk women's and children's hospital provides tertiary obstetric care for approximately 11 000 deliveries a year. even in a global pandemic, we need to maintain essential obstetric services at our institution. here we share our experience in the provision of an obstetric anaesthesia and analgesia service, through careful re-organisation and resource planning, aimed to prevent disease transmission amongst our patients and healthcare staff. a multidisciplinary task force comprising of obstetricians, obstetric anaesthesiologists, neonatologists, infectious disease physicians and operating theatre and delivery suite nursing managers was formed before the first covid-19 case was identified in singapore. there was an urgent need to review pre-existing institutional infection control protocols that were established during the outbreaks of sars and mers-cov, in keeping with emerging evidence from the current global outbreak. 3 as the epidemiologic and infectious characteristics of the virus were initially unknown, the task force reviewed and revised infection control protocols based on emerging information. specific challenges were, firstly, the problem associated with making evidence-based clinical decisions given the lack of published information. there was a need to establish communication channels with staff to facilitate frequent updates. good communication among medical staff, taskforce stakeholders, institutional senior leadership and health ministry officials is pivotal if ground staff are to obtain timely information, updates and clarifications in a rapidly-evolving situation. our major considerations included: 1. identification of the 'high infection-risk' parturient. 2. clinical management of the 'high infection-risk' parturient, presenting for labour epidural and delivery. 3. organisational changes to respond to the crisis. because of the rapidly changing risk criteria for covid-19 'cases', identifying the 'high infection-risk' parturient was a challenge. prompt identification was needed so that these women could be isolated and treated appropriately, minimising the infection risk to healthcare staff and other patients. this problem arose for several reasons. firstly, infected patients may be infectious during the incubation period but do not exhibit symptoms or signs of acute infection. 4 secondly, viral shedding can occur 8-37 days from the onset of symptoms in infected patients. 5 thirdly, patients may have nonspecific symptoms that are similar to the 'common flu'. 6 these characteristics limit the usefulness of temperature screening prior to admission for labour or caesarean delivery. screening for travel history may also be unreliable, not only because of under-reporting in some countries, but because as the infection spreads globally, local community transmission occurs. consequently, all parturients with an acute respiratory tract infection or a positive travel or contact history were considered of high infection-risk and isolated until they tested negative for the virus. it is in this context that local health authorities mandated that healthcare staff performing aerosol-generating procedures (agp) such as tracheal intubation and extubation, bag-mask ventilation, orogastric tube insertion and bronchoscopy, don full personal protective equipment (ppe) regardless of risk status. protective equipment includes a splash-resistant gown, double-gloves, goggles or face shield with national institute for occupational and safety health (niosh) n95 mask, with or without a powered air purifying respirator (papr). 7 management in the labour ward 'high infection-risk' parturients are placed in negative pressure ( -2.5 pa) rooms and are asked to wear a surgical mask. to minimise infection risk, no visitors are allowed. early labour epidural analgesia is encouraged to reduce the use of nitrous oxide/oxygen inhalation analgesia and also general anaesthesia with airway instrumentation for intrapartum caesarean delivery, both of which are associated with aerosolization of the virus. high-flow oxygen administration via face mask was identified as a factor causing hospital ward outbreaks during the sars epidemic and should be avoided. 8 however, nitrous oxide/oxygen inhalation, where appropriate, is provided to the parturient while awaiting epidural catheter insertion. an experienced anaesthesiologist, donned in ppe against possible aerosol generation from nitrous oxide/oxygen use, should perform the neuraxial procedure to improve the chances of success. goggle design may limit peripheral vision and visual acuity, hampering the ability to successfully perform the procedure to a greater degree in a novice anaesthesiologist. the decision whether to provide combined spinal-epidural analgesia or epidural analgesia is left to the discretion of the anaesthesiologist. when possible, we prefer to proceed with caesarean delivery in the 'high infection-risk' patient only after she has been de-isolated or has tested 'negative' for covid-19 from the first nasopharyngeal swab. however, should an emergency caesarean delivery be required, it is performed in a dedicated negative-pressure operating room with staff donning full ppe. should this type of room be in use, we proceed with surgery in another operating room, adopting the necessary precautionary measures when accommodating a patient with covid-19. 9 for cesarean delivery the anaesthetic technique of choice remains neuraxial anaesthesia as this minimises the risk of aerosolisation associated with airway intervention. 10 the authors also prefer a combined spinal-epidural technique if surgery is expected to be prolonged, in order to minimise the risk of a mid-procedure conversion to general anaesthesia. if the risk of a failed neuraxial anaesthetic is anticipated to be high or general anaesthesia is planned, the papr should be worn over the n95 mask from the outset. after rapid-sequence induction, intubation by an experienced anaesthesiologist is performed with a video-laryngoscope to maximise the chances of rapid successful intubation. face mask-ventilation is avoided when possible, and if rescue maskventilation is needed in the setting of failed intubation, small tidal volumes used until the cuff on the tracheal tube has been inflated. we advocate the use of disposable equipment (e.g. disposable laryngoscope blades) and consumables. an anaesthetic nurse runner is stationed in the anteroom should further drugs or equipment be required. a difficult airway cart is placed either in the operating room or anteroom. depending on the pathological lung changes present, patients with pneumonia may need sophisticated ventilators capable of delivering varied ventilatory settings and lung recruitment manoeuvres. after delivery, the neonate should be isolated as a precautionary measure. no skin-to-skin contact with the mother is allowed, to minimise infection risk. after surgery, patients are monitored in the operating room until ready for discharge to the postpartum ward, with the patient wearing a surgical mask en route. the operating room and the transportation route to the ward are disinfected. patients who need the postoperative intensive care unit (icu) for indications such as ventilatory support and/or management of obstetric-related complications should be transferred there directly, accompanied by healthcare staff donned in full ppe. all soiled consumables, used gloves, masks and gowns should be discarded in biohazard bags and sealed. we generally avoid activating a category 1 caesarean delivery in 'high infectionrisk' parturients by encouraging our obstetric colleagues to perform frequent surveillance of their fetal status and cardiotocography tracings, and to forewarn operating theatre staff of impending likely caesarean delivery. this allows the operating room team to prepare in advance, to allow expedient delivery having undertaked precautionary measures for staff protection. with collaborative teamwork and communication, we believe it is possible to achieve decision-to-delivery intervals of 30 min, even for category 1 cases. since the implementation of this workflow pattern in early february 2020, we have managed 11 'high infection-risk' parturients for caesarean delivery as of 25 mar 2020. although none eventually tested positive for the covid-19 virus, the surgeries were still performed in a negative pressure operating room with staff dressed in full ppe. two patients had general anaesthesia and were transported postoperatively to the icu while still intubated; spinal anaesthesia was initiated for eight patients, and one patient had extension of labour epidural analgesia. to increase the availability of isolation beds, all elective surgical procedures were postponed and only operations deemed essential or urgent allowed to continue. a prudent approach to the use of protective face masks is necessary to balance the need to conserve a finite resource against the overwhelming need to protect healthcare staff from the disease. while staff are advised to wear surgical masks in all clinical areas, only frontline staff who come into close contact with 'high infection-risk' patients (e.g. screeners and those who perform agps) need to wear n95 masks. all staff should undergo n95 mask fitting. guidance on the use of ppe was formulated and disseminated. all leave applications were rescinded and approved only on an 'as needs' basis, to ensure everyone is available to deal with the crisis at hand. to mitigate the risk of service disruption due to disease transmission among staff, we organised the department into modular teams segregated by physical location. bedside handovers are done via focused clinical summaries, with the staff donning the appropriate protection. as the sars-cov-2 virus is transmitted through close contact, good hand hygiene and social distancing are reinforced. advances in information technology are fully exploited, with department meetings and educational activities being conducted via video-conferencing platforms. we also use secure communication applications on mobile devices to build channels of communication among working teams for the rapid dissemination of information. all healthcare staff monitor and log their temperatures twice daily. a staff clinic manages staff with fever (>37.5°c) and/or respiratory symptoms and facilitates the prompt identification of institutional nests of outbreaks. with the implementation of modular teams and the consequent increase in overnight duties, we recognise that more staff may experience acute stress, fear of infection and burn-out. 11, 12 hence, we are working with hospital support groups to provide further support and feedback channels. in order to provide sustainable and safe obstetric anaesthesia during an infectious disease pandemic, a collaborative effort among anaesthesiologists, intensivists, obstetricians, neonatologists, nursing, infectious disease physicians and environmental services is required to minimise infection risks to both patients and healthcare workers. constant review of the criteria of the 'high infection-risk' patient, aligned to the evolving global situation, facilitates effective screening, isolation, and management. protocols and workflows for the management of such patients in labour and operative deliveries also need frequent revision to enhance efficiency while optimising the use of finite resources. lastly, establishing good communication channels among health officials, institutional leadership and ground staff is pivotal for the timely dissemination of updated information and obtaining feedback. updates on covid-19 (coronavirus disease 2019) local situation what do the different dorscon levels mean? available at a pneumonia outbreak associated with a new coronavirus of probable bat origin a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical features of patients infected with 2019 novel coronavirus in wuhan, china protecting health-care workers from subclinical coronavirus infection why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? what we do when a covid-19 patient needs an operation: operating room preparation and guidance expert recommendations for tracheal intubation in critically ill patients with novel coronavirus disease 2019 risk perception and impact of severe acute respiratory syndrome (sars) on work and personal lives of healthcare workers in singapore healthcare workers emotions, perceived stressors and coping strategies during a mers-cov outbreak highlights identifying 'high-infection risk' parturients is challenging in the covid-19 outbreak a multidisciplinary approach is required to provide obstetric anaesthesia services protocols for labour analgesia and caesarean delivery allow safe provision of care infection control resource management allows for the allocation of finite resources organisational changes are key: cord-315367-e0frkhe6 authors: du, houwei; pan, xiaobin; liu, nan; chen, junnian; chen, xiaoling; werring, david j.; ambler, gareth; li, xiaoqing; chen, ronghua; zhang, yixian; huang, huayao; lin, feifei; xia, pincang; chen, chao; zheng, zhenyang; wu, sangru; lei, hanhan; gao, lei; huang, mingxu; lin, kexu; xu, xiaoping; luo, yukun; zhao, ziwen; li, chen; lin, hailong; lin, yu; huang, zhenghui; cao, rongxiang; chen, limin title: the effect of vascular risk factor burden on the severity of covid-19 illness, a retrospective cohort study date: 2020-09-21 journal: respir res doi: 10.1186/s12931-020-01510-0 sha: doc_id: 315367 cord_uid: e0frkhe6 background: patients with cardiovascular comorbidities are at high risk of poor outcome from covid-19. however, how the burden (number) of vascular risk factors influences the risk of severe covid-19 disease remains unresolved. our aim was to investigate the association of severe covid-19 illness with vascular risk factor burden. methods: we included 164 (61.8 ± 13.6 years) patients with covid-19 in this retrospective study. we compared the difference in clinical characteristics, laboratory findings and chest computed tomography (ct) findings between patients with severe and non-severe covid-19 illness. we evaluated the association between the number of vascular risk factors and the development of severe covid-19 disease, using a cox regression model. results: sixteen (9.8%) patients had no vascular risk factors; 38 (23.2%) had 1; 58 (35.4%) had 2; 34 (20.7%) had 3; and 18 (10.9%) had ≥4 risk factors. twenty-nine patients (17.7%) experienced severe covid-19 disease with a median (14 [7–27] days) duration between onset to developing severe covid-19 disease, an event rate of 4.47 per 1000-patient days (95%ci 3.10–6.43). kaplan-meier curves showed a gradual increase in the risk of severe covid-19 illness (log-rank p < 0.001) stratified by the number of vascular risk factors. after adjustment for age, sex, and comorbidities as potential confounders, vascular risk factor burden remained associated with an increasing risk of severe covid-19 illness. conclusions: patients with increasing vascular risk factor burden have an increasing risk of severe covid-19 disease, and this population might benefit from specific covid-19 prevention (e.g., self-isolation) and early hospital treatment measures. the coronavirus disease 2019 (covid-19) is a highly infectious viral respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which was first reported in december 2019 in wuhan, china [1] . covid-19 rapidly became a worldwide pandemic, affecting more than 28 million people [2] . cardiovascular risk factors, including ischemic heart disease, hypertension and diabetes, are common in patients with covid-19 infection, and associated with mortality [3, 4] . cardiovascular diseases are a major public health challenge worldwide. for example, a population-based study with a large sample size showed that 6.63% (3070/46,285) of people had at least one major cardiovascular disease [5] . a global cohort study showed that 57,303 (39.4%) people had hypertension, 15 ,900 (10.2%) had diabetes and 26,691 (18.5%) reported low physical activity, and that mean body-mass index (bmi) was 25.7 (sd 5.3) kg/m 2 [6] . given the vast number of people living with prevalent vascular risk factors and the rapid global spread of the covid-19 pandemic, it is essential to know how vascular risk factors influence the risk of developing severe covid-19 disease. most previous studies showed an association between vascular risk factors (such as hypertension and diabetes) and covid-19 severity [7] . however, little is known about how patients stratified by burden of vascular risk factors differ from each other, and whether the number of vascular risk factors is associated with covid-19 disease severity. we hypothesized that in patients infected with sars-cov-2 increasing vascular risk factor burden increases the risk of developing severe illness. we therefore investigated the association between the number of vascular risk factors and severe covid-19 disease in this observational retrospective study. this is a single-center, retrospective, observational study done at tumor center of union hospital, tongji medical college, huazhong university of science and technology (wuhan, china), which is a designated hospital to treat patients with covid-19 disease by national medical teams to support wuhan. we analyzed admitted patients between 15 february and 14 march 2020, who had been diagnosed with covid-19 disease based on world health organization interim guidance [8] . laboratory confirmation of covid-19 infection was performed by the local health authority as previously described [9] . we retrospectively reviewed the electronic medical records of 164 consecutive eligible patients with covid-19 using a digital database. two physicians (j.c and x.c) extracted the epidemiological, demographic, clinical, laboratory data on admission, and treatment data using a standardized data collection form. data on the most intense level of oxygen treatment during hospitalization (nasal cannula, medical mask, high solution and invasive mechanical ventilation) was also collected. two physicians (k.l and x.p) collected the outcome data, which was adjudicated by two senior physicians (h.d. and y.l.) blinded to baseline demographics. two physicians (g.l and r.c) reviewed the chest ct images blindly. in cases of disagreement, a consensus was reached after discussion with a senior respiratory physician (l.c.) and a radiologist (h.l). if data were missing or uncertain from the medical records, we obtained and clarified data by direct communication with attending doctors and other healthcare providers. definitions of vascular risk factors were based on previous literature [6, [10] [11] [12] [13] as follows. hypertension was defined as documented systolic blood pressure ≥ 140 mmhg and/or diastolic blood pressure ≥ 90 mmhg, or by patients' self-reported diagnosis of hypertension and/ or by the treatment of antihypertensives [10, 11] . diabetes was defined as fasting blood glucose ≥7.0 mmol/l and/or a previous diagnosis of diabetes and/or by the treatment of antidiabetic drugs [10] . dyslipidaemia was defined as tc ≥6.22 mmol/l and/or tg ≥2.26 mmol/l and/or hdl-c < 1.04 mmol/l and/or ldl-c ≥ 4.14 mmol/l [10] . we classified patients as having atrial fibrillation (af) if they had been diagnosed with af by electrocardiogram at admission or during hospital stay [11] . current smoking (≥1 cigarette per day) and regular drinker (any dose of alcohol, ≥1 time per week) were defined by patients' self-report [12] . physical inactivity was defined as less than 150 min per week of moderate activity or less than 75 min per week of vigorous activity [13] , and overweight as body mass index (bmi) ≥25 kg/m 2 [10] . we counted and aggregated the following vascular risk factors to construct a vascular risk factor score in each patient: hypertension, diabetes, dyslipidemia, atrial fibrillation, current smoker, overweight and physical inactivity. these factors are considered well-documented risk factors for cardiovascular diseases, including cerebrovascular disease [6, [10] [11] [12] [13] [14] . our primary outcome was severe covid-19 disease defined as fever or suspected respiratory infection, plus one of: respiratory rate > 30 breaths/min; severe respiratory distress; or spo 2 ≤ 93% on room air based on the interim guidance of the world health organization [8] . our secondary outcome was death, which was limited by the duration of our observation period. all the authors agreed on the study protocol and reviewed the manuscript. continuous data were summarized using means with standard deviations or medians with interquartile ranges (iqr), and categorical data were summarized as counts with percentages. we used the t-test or mann-whitney test to compare differences in continuous variables, and the chi-square test or fisher's exact test to compare differences in categorical variables. we calculated the absolute event rate per 1000 patient-days for severe covid-19 illness and death during our observation period. we also compared event rates during our observation period stratified by the number of vascular risk factors (none, 1, 2, 3, or ≥ 4 risk factors). kaplan-meier curves depicted the risk for outcome events stratified by the number of vascular risk factors (none, 1, 2, 3, or ≥ 4 risk factors). we used univariable cox regression analysis to evaluate the association between vascular risk factor burden and severe covid-19 pneumonia. for multivariable analysis, we chose variables based on previous findings and clinical constraints to avoid overfitting the cox regression model [15] . we therefore included chronic obstructive pulmonary disease (copd), cardio-cerebrovascular disease, tumor, renal impairment, decreased leucocytes, decreased lymphocytes, increased lactate dehydrogenase (ldh) and chest ct findings separately as potential confounders, in addition to age and sex in the regression model. we also performed sensitivity analyses using the e-value approach, where the e-value is defined as the minimum strength of association on the risk ratio scale that an unmeasured confounder would need to have with both the exposure and the outcome, conditional on the measured covariates, to fully explain away a specific exposure-outcome association [16] . we calculated the e-value using an online e-value calculator (https:// mmathur.shinyapps.io/evalue/). all analyses were performed using stata 12.0 (statacorp lp, college station, tx) and spss for windows (spss 25.0, ibm, inc., chicago, il, usa). in this analysis, we included 164 consecutive patients (61. 8 days) duration between symptom onset to developing a severe disease, an event rate of 4.47 per 1000patient days (95%ci 3.10-6.43). six patients (3.7%) died during hospitalization, an event rate of 0.84 per 1000patient days (95%ci 0.38-1.88). kaplan-meier curves showed that the risk of severe covid-19 illness tended to increase with the number of vascular risk factors (log rank p < 0.001, fig. 1 ). in univariable analysis, the risk of severe covid-19 increased with increasing vascular risk factor burden (unadjusted hr 2.06, 95%ci 1.51-2.80). after adjustment for age and sex, the vascular risk factor burden remained significantly associated with severe covid-19. (adjusted or 1.55 95%ci 1.09-2.21, table 3 ). this relationship did not change after additional confounder adjustment for, separately, copd, cardiocerebrovascular disease, tumor and renal impairment, in addition to age and sex (table s1 ). separate adjustment for routine blood examinations and chest ct findings, in addition to age and sex, did not alter our results (table s2 ). sensitivity analyses revealed that it would need moderately robust unobserved confounding to render the exposure-outcome association null. (table 3, table s1 and table s2 ). for example, an e-value of 2.12 for the estimate (table 3 , and figure s1 ) indicates that the observed risk ratio of 2.12 could only be explained away by an unmeasured confounder that was associated with both the exposure and the outcome by risk ratios of more than two, above and beyond the measured confounders, but weaker confounding could not do so [16] . our most important finding is that in covid-19 patients increasing vascular risk factor burden is associated with an increasing risk of experiencing severe covid19 illness. the seven included vascular risk factors are generally readily available at hospital admission, which may help clinicians to identify patients with poor prognosis at an early stage. previous studies suggested patients with mild covid-19 disease were at low risk for an unfavorable outcome than those with severe covid-19 disease [4, 15] . therefore, identifying risk factors for severe covid-19 illness is essential to ensure timely management. in our cohort, symptoms at covid-19 onset were not significantly different between patients with and without severe covid-19 illness, suggesting that onset symptoms were not of prognostic relevance. the association between total baseline vascular risk factor burden and severe covid-19 illness in our cohort may inform the development of future risk stratification models. our data showed that patients with severe covid-19 illness were more likely to have a baseline ischemic cardiac or cerebrovascular disease (8 [27.6%] vs 15 [11.1%] ). this result is line with findings of previous descriptive studies [3, 17] . previous studies also showed individual vascular risk factors such as hypertension and diabetes were more frequent in severe covid-19 patients [3, 14] . moreover, data from italy and the united states confirmed increased mortality rates in patients with comorbidities, particularly the older population with pre-existent cardiovascular conditions [18, 19] . our findings showed vascular risk factors were prevalent among covid-19 patients. only sixteen (9.8%) patients had no vascular risk factor, whereas twothirds of patients had more than one risk factor. patients with increasing vascular risk factor burden in our cohort were older (p < 0.001), having a high risk for the severe covid-19 disease, and consequently underwent more aggressive ventilation. to the best of our knowledge, the association between total vascular risk factor burden and the severity of covid-19 has not been systematically investigated before. our data therefore expands upon previous findings of individual comorbidities as risk factors for severe covid-19 disease and may be relevant for important public health and clinical decisions regarding the management of the current covid-19 and future pandemics. death, n (%) 6 (3.7) 6 (20.7) 0 < 0.001 tumor was defined by patients' self-report of having a history of a malignant tumor. decreased means below the lower limit of the normal range and increased means over the upper limit of the normal range among the vascular risk factors associated with severe covid-19, being overweight showed a strong association [20] . people with obesity around the world are at high risk for severe covid-19 illness [21] . for example, a previous study has shown that overweight patients had a 1.84-fold higher risk of developing severe covid-19 (95% ci 0.99-3.43) than normal-weight patients [22] . moreover, our data indicate that patients with physical inactivity are more likely to have severe covid-19 illness. the relationship between these lifestyle factors and covid-19 severity warrants further studies for clarification, but in the meantime our findings further strengthen the idea that the population at risk of covid-19 should keep exercising at home during the quarantine. moreover, considering the strict isolation strategies to curb virus spreading, the effect of physical inactivity on the potential risk of the cardiocerebrovascular events needs further urgent investigation worldwide. whether some antihypertensives could increase the susceptibility to developing severe forms of covid-19 remains uncertain. sars-cov-2 is linked to the renin-angiotensin system (ras), which plays an essential role in regulating blood pressure and the pathophysiology of cardiovascular disease [23] . patients with pre-existing vascular risk factor burden such as hypertension and diabetes were likely to be treated with angiotensin-converting enzyme inhibitors (acei) or angiotensin receptor blockers (arb). both acei and arb can upregulate ace2, facilitating the sars-cov-2 entry into pneumocytes, and might cause exacerbation of the underlying disease [24] . however, available clinical evidence does not confirm an association between the use of acei or arb and the poor outcomes of covid-19 [7, 25, 26] . long-term studies in larger numbers of hospitalized covid-19 patients receiving acei and arb therapy are needed to address this question. the underlying mechanisms of the association between vascular risk factor burden and covid-19 severity remain unclear. immobilization and high body mass were found to be risk factors for pulmonary embolism [27, 28] , which were prevalent in severe covid-19 disease [29, 30] . other possible explanations might include exaggerated systemic inflammation or a "cytokine storm". for example, metabolic risk factors such as obesity may increase the inflammation of the lung parenchyma and compromise the pulmonary function [31, 32] . our findings suggest that clinicians should pay close attention to the warning signs and symptoms of cardiac or cerebrovascular events in covid-19 patients with high vascular risk factor burden. establishing a multidisciplinary medical team of cardiologists, neurologists, respiratory specialists, and infectious disease specialists to offer rapid evaluation and acute treatment in covid-19 is urgently needed. we acknowledge limitations. first, this is a retrospective study conducted at a single-centered hospital with limited sample size. our findings need to be validated in further large sample-sized studies. second, some vascular risk factors were self-reported, so their prevalence may be underestimated. however, previous studies showed that selfreports and hospital records were highly consistent for vascular disease [5, 33] . lastly, lack of information on some other vascular risk factors (i.e., air pollution, depression, and sleep disorder) may cause inaccuracy in risk estimates based on the number of these risk factors. vascular risk factor burden is associated with the course of covid-19 infection; patients with an increasing number of vascular risk factors have an increasingly high risk of severe covid-19 disease and might benefit from specific covid-19 prevention (e.g., self-isolation) and early hospital treatment measures. a better understanding of the pathophysiological mechanisms causing severe covid-19 disease is needed to develop new treatment strategies for improving outcomes and reducing mortality in this high-risk population. supplementary information accompanies this paper at https://doi.org/10. 1186/s12931-020-01510-0. additional file 1: table s1 . association between vascular risk factor burden and severe covid-19 illness adjusted for comorbidity, and sensitivity analyses using the e-value approach. table s2 . association between vascular risk factor burden and severe covid-19 illness adjusted for laboratory and chest ct findings, and sensitivity analyses using the evalue approach. epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study novel coronavirus (2019-ncov) advice for the public clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: 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cardiovascular considerations for patients, health care workers, and health systems during the covid-19 pandemic self-reported stroke and myocardial infarction had adequate sensitivity in a populationbased prospective study jphc (japan public health center)-based prospective study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all the patients with their data for this analysis and the medical workers who are on the front line of caring for patients. we thank dr. liming lin (xiamen university) for his assistance in statistical analysis. drs h du and n liu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. drs h du, n liu, x pan, j chen and x chen contributed equally to this work. study concept and design: drs h. du, n. liu, and d.j.werring. acquisition, analysis, or interpretation of data: drs h du, n liu, x pan, j chen, x chen, dj werring, g ambler, x li, z zheng, s wu, h lei, p xia, lei gao, k lin, m huang, x xu, c chen, y luo, z zhao, c li, r cao, yu lin. drafting of the manuscript: drs h du, n liu, x pan, j chen, x chen. critical revision of the manuscript for important intellectual content: drs. r chen, y zhang, h huang, f lin, c li, h lin, z huang, g amber, d.j.werring and l chen. the authors read and approved the final manuscript. this study was supported by the fujian provincial special foundation for natural science innovation project (2016b014) and the fujian science and technology innovation joint fund project (2019y9099). the funders had no role in the study design and the collection, analysis, and interpretation of data or drafting of the article and the decision to submit it for publication. the researchers confirm their independence from the funder. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request (email: houweidu@fjmu.edu.cn). the ethics committee of fujian medical university union hospital approved the study protocol (no.2020gfky005). all clinical investigations were conducted according to the principles expressed in the declaration of helsinki. written informed consent was waived due to the nature of our retrospective study of routine clinical data. not applicable. none.author details 1 18 department of respiratory medicine, fujian medical university union hospital, fuzhou, china.received: 23 july 2020 accepted: 14 september 2020 key: cord-314423-6kuefmol authors: experton, b.; tetteh, h.; lurie, n.; walker, p.; carroll, c.; elena, a.; hein, c.; schwendiman, b.; burrow, c. title: a multi-factor risk model for severe covid-19 for vaccine prioritization and monitoring based on a 15 million medicare cohort date: 2020-11-03 journal: nan doi: 10.1101/2020.10.28.20219816 sha: doc_id: 314423 cord_uid: 6kuefmol background: public health interventions to slow the spread of the covid-19 pandemic focus on protecting individuals at risk for severe disease. risk categorization is essential to effective pandemic response. however, existing risk models for severe covid-19 lack needed integration of both socio-demographic and clinical risk factors, and geographic characteristics. methods: we present an integrated multi-factor risk model for severe covid-19 using de-identified medicare claims from which we extracted demographic and clinical data for a cohort of 15 million medicare beneficiaries with 770,000 covid-19 cases, and socio-economic data at the county and zip code level from the cdc social vulnerability index. the model and associated digital maps were developed as part of project salus of the department of defense joint artificial intelligence center, for use by the national guard and other military personnel in their support mission to hospitals and local jurisdictions impacted by the pandemic. results: the model affirms ethnicity (black: or 1.64; 95% ci 1.61-1.68, american indian: or 2.21; 95% ci 2.01-2.42), age over 85 (or 1.75, 95% ci 1.69-1.81), the socio-economic factor of residing in a zip code in the lowest quartile of income (or 1.23; 95% ci 1.21-1.26), esrd (or 2.35; 95% ci 2.25-2.45) and chronic lung disease (or 1.95; 95% ci 1.90-2.00) as leading risk factors for covid-19 hospitalizations, but reveals low risk for copd (or 1.15; 95% ci 1.13 -1.17) and minimal or no risk for diabetes (or 1.03; ci 1.01-1.05), chf (or 1.10, 95% ci 1.08-1.12) or hypertension (or 0.96; 95% ci 0.94-0.98), and demonstrates an association between prior herpes zoster immunization (or 0.74; 95% ci 0.71-0.77), and to a lesser degree prior influenza and pneumococcal vaccines with less severe covid-19. conclusions: this multi-factor risk model and derived digital maps can be applied for use by national and local health authorities to augment existing tools for pandemic response, including monitoring of post covid-19 sequelae, prioritization of covid-19 vaccine, and vaccine monitoring for both safety and efficacy. over eight million people in the united states have been infected with sars-cov-2, with more than 225,000 deaths of whom 80% are over the age of 65. 1, 2 public health interventions to slow the spread of the pandemic have focused on protecting individuals most at risk for exposure to sars-cov-2, or at risk for severe covid-19. the centers for disease control (cdc) has identified people of color, individuals with certain comorbidities and those over the age of 65 at highest risk. 3 this risk-based approach to pandemic response is now directing covid-19 vaccine prioritization to allocate the first available vaccine doses to individuals most at risk. all covid-19 vaccine prioritization frameworks reviewed by the advisory committee for immunization practices (acip) are risk-driven with a time-phased approach. 4 the national academies of science, engineering and medicine recommend a four-phase equitable plan determined by risk categories. 5 the "jumpstart phase 1a" allocates the first vaccine doses to front line healthcare professionals and emergency responders, followed by phase 1b for high risk individuals with comorbidities or older individuals living in congregate or overcrowded settings. in addition, the national academies recommend special efforts to deliver vaccines to residents of high-vulnerability areas by using the cdc's social vulnerability index (svi) 6 or the covid-19 community vulnerability index (ccvi). 7 multiple-factor risk categorization is needed for vaccine allocation schemes to simultaneously include individual demographics, comorbidities, and socioeconomic characteristics. integration of these various data should also consider overlap of risk categories, as the cdc highlighted during the acip october meeting. 8 this is important when considering that more than half of the 53 million americans over age 65 suffer from two or more chronic conditions, 9 qualifying them for phase 1b vaccine allocation. at a population level, both clinical and sociodemographic risk need to be considered in tandem. the current cdc listing of risk factors for severe covid-19 10 is derived from single hospital-based studies with limited sample sizes, 11, 12 or hospital reporting, both of which lack nationwide representation. 13 the center for medicare and medicaid services (cms) issues monthly medicare covid-19 data snapshots that include national demographic characteristics and prevalence of common chronic conditions of hospitalized fee-for-service (ffs) medicare beneficiaries, but lack more detailed diagnosis, medication, and procedure data as well as socio-economic data needed for identifying risk factors for severe covid-19 at the individual and population levels. 14 there are no analyses that fully support operationalization of the national academies recommendation to use both clinical and svi or ccvi risk factor data. the ccvi provides an integrated risk model of both cdc identified risk factors for severe covid-19 and svi data, at the state and county, but not at the local zip code level. this and other models of this type, such as the pandemic vulnerability index, 15 have further limitations. they offer population (not individual) based risk data, include limited clinical data with certain chronic conditions with their geographic distributions, and use dissociated geographic data sources (national data for comorbidities, and census tract level data for svi socio-economic risk factors). this study integrates multiple factors in its risk models for severe covid-19 in the medicare population, based on de-identified medicare claim data from which detailed clinical and past medical history data were extracted, the cdc svi and other public datasets. the risk models were developed in part based on prior analysis of medicare patient outcomes in the frail elderly population, 16 and the medicare claim data processing conducted by humetrix with our cms approved technology as part of the cms blue button program since 2011. 17 the resulting risk models are both individual and population based and has been used to create an interactive dashboard currently hosted on a secure government intranet, enabling visualization of calculated population risk at national, county and zip code levels. the risk models and associated mapping were developed as part of a department of defense (dod) joint artificial intelligence center (jaic) covid-19 related data analytics project named salus (the roman goddess for safety and health), to provide predictive visualization tools to the national guard and other military personnel in charge of resourcing covid-19-related healthcare and other vital sector supply and personnel assets, especially serving local hospitals and health departments affected by the pandemic. 18 following on the national academies recommendation for use of existing systems across all levels of government, we discuss the possible use of the salus medicare risk models and its derived dashboard as a tool for supporting equitable allocation, distribution of covid-19 vaccine and vaccine monitoring, as well as for covid-19 surveillance in the higher risk medicare population. the salus medicare risk models are based on an observational study of all ffs medicare beneficiaries who since january 1, 2020, either had a covid-19 test or diagnosis, or for any medical reason had an emergency department, urgent care, or telehealth visit, or were hospitalized. the cms office of enterprise data and analytics provides for this cohort weekly medicare claim outputs from the cms chronic condition warehouse with project salus specified outpatient and inpatient institutional, part b professional, skilled nursing facility, and hospice claims extending back to october 1, 2019, and part d claims starting january 1, 2020. de-identified claims are received in the ecs federal secure unclassified network (sunet) for processing and analysis by salus partner humetrix to build risk models for severe covid-19. in addition to the clinical and demographic data generated from medicare claims, the models used selected socio-economic variables from the cdc svi. the humetrix enterprise platform with its claim and other health data analytics software provides weekly data processing of over 100 million cms de-identified medicare claim records in its secure jaic sunet enclave, including data upload into a database to generate covid-19 outcome datasets for: covid-19 confirmed cases and related hospitalizations, icu and ventilator use, outpatient care only, and death. medicare claim-generated clinical, demographic and outcome variables are then merged with cdc svi variables for the residential zip codes of individuals in the cohort. the independent variables included in our severe covid-19 risk models are: beneficiary age, sex, ethnicity, insurance coverage and residential zip code, prior health care utilization (prior hospitalization(s), skilled nursing home admissions, etc.) as a measure for disease severity and frailty, the individual's multiple chronic conditions with in addition to the cms chronic condition flags, humetrix compiled diagnostic categories using specific icd-10 code algorithms, medications grouped by pharmaceutical class, vaccinations before covid-19 diagnosis, and other variables starting october 1, 2019 (see supplemental methods in the appendix). socio-economic variables (e.g., income quartile, education, residential density, and other factors) were defined at the individual residential zip code level, after conversion from the census track based data found in the cdc social vulnerability index. to determine significant predictors of covid-19 related hospitalization, icu admission and death outcomes, we used logistic regressions (r statistical software, version 3.6 with rms, glmnet and proc packages). for these regressions, we defined the following groups of covid-19 cases: those who received all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint outpatient care only (defined as cases that did not require hospitalization or didn't die at least thirty days after diagnosis), hospitalizations attributed to covid-19, and deaths (defined as cases who died of sars-cov-2 infection within 60 days of diagnosis). the logistic regression models were built on 60% training and 40% validation sets obtained by random selection of covid-19 confirmed cases. we used a 50:50 ratio of covid-19 cases who required either hospitalization, or who only received outpatient care for training the hospitalization model, and a 50:50 ratio for covid-19 survivors versus deceased cases, for training the death model. determination of correlation coefficients between independent variables, as well as lasso regression, were used to eliminate independent variables which demonstrated significant correlations and collinearities in both models. a stepwise backward variable selection procedure based on the akaike information criterion (aic) was also used to remove non-significant variables, verifying that independent variables discarded by the lasso regression corresponded with variables identified by the stepwise backward selection procedure. computation of the 95% confidence intervals for the coefficient estimates were generated by bootstrapping (2000 repetitions) on the training set. model performance was measured by the area under the receiver operating characteristics (auroc) curve value. the hospitalization risk model auroc was computed on a validation set composed of cases that were not used in the training set, with adjustments to give a 60:40 ratio of outpatient to hospitalized cases (which is the observed ratio for hospitalization in the covid-19 study population). for the death model auroc we used an 85:15 ratio (which is the observed case fatality ratio in the covid-19 study population). logistic regression coefficients were used to compute individual predicted probabilities of hospitalization in the event of sars-cov-2 infection for the entire salus medicare cohort of 15 million beneficiaries. the regional percentage of the cohort population over a predicted probability of 0.55, is displayed on a digital risk map at the county and zip code levels. additional mapping data was also produced to display covid-19 confirmed cases and their outcomes at the national and local level, with recent, cumulative and times series displays. socio-demographic and clinical characteristics of the 15 million study population, as of september 16, 2020, and its subsets of covid-19 cases (n=770,000) who were either hospitalized with severe disease (n=264,000) or who only required outpatient covid-19 care (n=299,000), or who died (n=105,000) are summarized in table 1 . table 1 displays comparisons between non-sars-cov-2 infected ffs medicare beneficiaries and covid-19 cases, and among them, hospitalized vs. non-hospitalized and deceased cases. among covid-19 cases, the severe disease groups of hospitalized and deceased patients show higher frequencies of diabetes, copd, esrd, hypertension, ischemic heart disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, chronic liver disease, and congestive heart failure although the effect sizes for these differences are small (see supplemental appendix). we used logistic regression analysis to determine the relative importance of significant predictors of severe covid-19. the predictor variables for hospitalization are shown on figure 1 and for death in figure 2 . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the regression analyses indicate that prior herpes zoster immunization (with the recombinant glaxosmithkline shingrix ® vaccine) is also associated with lower odds of covid-19 hospitalization or death (hospitalization or 0.74; 95% ci 0.71-0.77; death or 0.71; 95% ci 0.66-0.77). use of this vaccine was not correlated with any other demographic, socioeconomic or other variable in the model. we observed a smaller association of prior influenza vaccination on hospitalization (or 0.89; 95% ci 0.88-0.91), but none against death. pneumococcal vaccination is associated with reduced odds of death (or 0.87; 95% ci 0.84-0.91), as recently proposed, 19 but not hospitalization. to test the hypothesis that these vaccinations simply represent preventive behaviors that are also associated with less hospitalization and death, we created a preventive behavior variable based on the use of preventive screenings (colonoscopy and mammography) as well as vaccinations. indeed, these preventive behaviors were associated with lower odds of developing severe covid-19 (hospitalization or 0.73; 95% ci 0.71-0.74, death or 0.65; 95% ci 0.63-0.67). however, the use of shingrix was poorly correlated with these other behaviors (preventive screenings and other vaccinations), and vaccination with shingrix retained a significant reduction in odds ratio, even when preventive behaviors were accounted for in the models. this raises the intriguing hypothesis that this recombinant adjuvanted vaccine may have an unrecognized biological effect which reduces the probability of severe covid-19. the hospitalization model logistic regression coefficients were used to calculate the predicted probability for hospitalization in the event of sars-cov-2 infection, at the individual level, for the entire 15 million cohort. we mapped areas in which the percentage of this cohort with a predicted probability of hospitalization was greater than 0.55 for every residential zip code in the u.s. figure 3 shows a portion of the los angeles metropolitan area with zip codes displaying a wide range of population percentages over this threshold which were positively correlated with the cumulative percentage of covid-19 patients requiring hospitalization in these zip codes (pearson correlation coefficient 0.65 p < 0.001). we further conducted the same correlation analysis in a set of zip codes drawn from other metro areas shown in figure s1 in the appendix. all correlation coefficients in these regions (washington d.c., 0.61; houston, 0.66; miami, 0.72; phoenix, 0.72; and new york city, 0.52) had p values < 0.001. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint the severe covid-19 risk models and the mapping of their outcomes are based, to our knowledge, on the largest covid-19 dataset assembled to date for this purpose. all members of the study cohort are active users of healthcare services, presenting on average a frailer clinical profile than the general medicare population, 20 as shown by their clinical characteristics in table 1 . while our observed 770,000 medicare ffs cases represent a little more than 10% of the total number of covid-19 cases in the u.s., they contribute close to 50% of all cdc estimated covid-19-related hospitalizations and a majority of medicare hospitalizations. 21 the scale of this dataset has allowed us to quantitively and qualitatively validate our hospitalization risk model with actual hospitalizations in multiple geographic areas. the countrywide distribution, and local representation of the salus medicare cohort also enabled project salus to offer the first county and zip code level mapping for this population at higher risk for severe covid-19 and related hospitalizations. beyond its use for epidemic mapping, the salus medicare covid-19 platform provides a disease surveillance tool for covid-19, which can be extended to influenza to evaluate the potential compounding effect of these two respiratory diseases on hospitalizations as influenza undergoes its seasonal progress in the coming months. our logistic regression analysis, as applied to this very large medicare population, allowed us to test the current cdc listing of risk factors for severe covid-19. our analysis affirms the critical risk factors of ethnicity and older age but reveals the lack of or more modest effect of hypertension, diabetes, copd, asthma, and cardiovascular diseases. the new findings of the significant and independent association of less severe covid-19 with prior use of a recombinant herpes zoster vaccine calls for further investigation. if the effect of herpes zoster vaccination is confirmed, use of this vaccination may be even more beneficial than previously recognized. the independent association of prior use of preventive screenings, a possible marker for a higher rate of covid-19 preventive behavior (social distancing, hand washing, mask wearing), with less severe covid-19, is a reminder of the importance of such behaviors. in preparation for a covid-19 immunization campaign, the models we have developed integrate both socio-economic factors and individual clinical data, and thus respond to the recommendations of the national academies for prioritization and allocation of covid-19 vaccines when they will become available. they could be used by the medicare program, in collaboration with local health officials to affirmatively invite or encourage highest risk beneficiaries to seek early vaccination and can be used as a tool for vaccine allocation. in figure 4 , we show on a histogram the distribution of the predicted probabilities of hospitalization for sars-cov-2 infected patients in the 15 million salus medicare population which can identify priority groupings for covid-19 vaccination, according to the quantities of vaccine doses available. further, once receipt of vaccination is linked to medicare claims, the system could be used to support post-licensure pharmacovigilance and effectiveness studies. these are of paramount importance, especially in the early phases of a vaccination campaign. to conclude, we believe that this quantitative analysis of risk for severe covid-19 provides important new insights which should be considered before finalization of acip covid-19 vaccine recommendations. state and local governments could consider asking the dod, through the mission assignment process, to provide the salus medicare risk mapping to their jurisdictions. the data rich salus medicare dataset, which underscores the value of medicare claim data for epidemiologic surveillance, with its size and nationwide representation, can also augment both the ilinet and covid-net disease surveillance systems and complement the existing vaccine monitoring systems for tracking both the safety and efficacy of covid-19 vaccination in the high risk medicare population. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. the views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the department of defense, nor the u.s. government. authors are military service members (or an employee of the us government). this work was prepared as part of their official duties. title 17 usc §105 provides that copyright protection under this title is not available for any work of the us government. title 17 usc §101 defines a us government work as a work prepared by a military service member or employee of the us government as part of that person's official duties. the independent variable odds ratios were determined by binary logistic regression analysis of confirmed covid-19 cases that required hospitalization for the disease and for those that were managed with outpatient care only. in addition to the thirty nine variables shown, hiv (or 0.90; 95% ci 0.83 -0.96), a past history of anemia (or 0.87; 95% ci 0.86 -0.89); a prescription for azithromycin overlapping the date of covid-19 diagnosis (or 1.18; 95% ci 1.15 -1.22), medicare-medicaid dual coverage and the medicare defined ethnicity of "other" were included in the model based on the criteria described in the methods section. variables excluded from the model on the basis of these criteria (or for a regression coefficient p value of > 0.05) included prescriptions for chloroquine or hydroxychloroquine overlapping the time of covid-19 diagnosis; the medicare defined "unknown" ethnicity, a history of ischemic heart disease, cerebrovascular disease, breast cancer, endometrial cancer; or a history of prescribed immunosuppressive drugs, histamine type-2 receptor antagonists, inhaled corticosteroids or opioids. the auroc for the model was 0.65. the independent variable odds ratios were determined by binary logistic regression analysis of confirmed covid-19 cases that survived and those that died within 60 days of covid-19 diagnosis. in addition to the thirty nine variables shown, a prescription history which included immunosuppressive drugs (or 0.93; 95% ci 0.89 -0.98), and the medicare defined "other" ethnicity were included in the model based on the criteria described in the methods section. variables excluded from the model on the basis of these criteria (or for a regression coefficient p value of > 0.05 ) included the medicare defined ethnicity of "unknown"; a history of prescribed histamine type-2 receptor antagonists, anticoagulants, inhaled corticosteroids or opioids; a past history of endometrial cancer, colorectal cancer, breast cancer, hypertension, ischemic heart disease, acute myocardial infarction in 2019 or hiv. the auroc for the model was 0.71. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint medicare claim data processing; the humetrix saas platform installed in the sunet secure classified government network provides automated pre-processing of weekly updates downloaded to the humetrix sunet enclave of medicare part a inpatient and outpatient, hospice and snf, part b carrier claims and part d (pde) claims data to generate output files containing derived variables used to train logistic regression models as described below. the platform's medical terminology service includes a complete collection of ama cpt-4, fda ndc, nnpes npi, icd-10-cm, cms level ii hcpcs, and nlm rxnorm codes and provides automated identification grouping of icd-10-cm codes to identify chronic condition categories and ndc drug code to rxnorm ingredient code mappings to identify pharmaceutical classes of active pharmaceutical ingredients from medicare claim data. demographic and coverage variables: weekly updates of cms "master beneficiary summary 2020 file" (mbsf_2020) data were processed, extracting variables: orig_reason_for_entitlement (disability), zip_cd (residential zip code), yob, sex_code, race_code, and dual_stus_cd 01-12 (dual medicare-medicaid insurance). social vulnerability index (svi) variables associated with zip codes: these were derived from cdc data, which are categorized by census tract. the variables analyzed using binary logistic regression to determine significant predictor variables for hospitalization or death due to covid-19 included the following svi variables: epl_pci, epl_pov, epl_nohsdp, rpl_theme1, epl_crowd, epl_groupq, epl_munit, epl_theme4, rpl_themes. chronic condition summary variables: chronic conditions in the mbsf_2019 chronic condition segment file was extracted, including variables: or 10 days before the covid-19 diagnosis date, or by finding part a inpatient claims where the data of admission no more than 14 days after or 10 days before the covid-19 diagnosis date. 2. covid-19 cases managed by outpatient care only were defined as cases who were not hospitalized in the 30 days after the covid-19 diagnosis date and who did not die within 60 days of the diagnosis date. 3. deaths due to covid-19 were defined as either deaths which occurred during a covid-19 hospitalization using the inpatient ptnt_dschrg_stus_cd code, or a death which occurred within 60 days of the covid-19 diagnosis as reported in the death_dt field of the mbsf_2020 file. effect size calculation ( all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint figure s1 : metropolitan region risk maps for severe covid-19 (a) los angeles county, (b) new york city, (c) houston, (d) miami dade, (e) phoenix arizona, (f) washington dc. in each metropolitan region, zip codes with the higher predicted probabilities of hospitalization with covid-19 based on the logistic regression hospitalization model are shown in darker shades of lavender. circles denote observed cumulative hospitalizations due to covid-19 extracted from claims data with the size of the circles scaled to the number of hospitalizations. the percentage of cases requiring hospitalization is displayed by the color of the circles on a beige to dark orange-red color scale with the darker circles indicating higher zip codes with higher percentages of cases requiring hospitalization for covid-19. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 3, 2020. ; https://doi.org/10.1101/2020.10.28.20219816 doi: medrxiv preprint people at increased risk acip covid-19 vaccines work group national academies release framework for equitable allocation of a covid-19 vaccine for adoption by hhs, state, tribal, local, and territorial authorities surgo foundation. the covid-19 community vulnerability index (ccvi centers for disease control and prevention. acip covid-19 vaccines work group preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -united states covid-19 in older people: a rapid clinical review hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 -covid-net, 14 states centers for medicare & medicaid services. preliminary medicare covid-19 data snapshot the covid-19 pandemic vulnerability index (pvi) dashboard: monitoring county-level vulnerability using visualization, statistical modeling, and machine learning the impact of payor/provider type on health care use and expenditures among the frail elderly ai in defense dod's artificial intelligence blog. the jaic forges ahead possible cross-reactivity between sars-cov-2 proteins, crm197 and proteins in pneumococcal vaccines may protect against symptomatic sars-cov-2 disease and death prevalence of chronic conditions among fee-for-service beneficiaries covid-19 laboratory confirmed hospitalizations ami) 2. chronic kidney disease (chronic_kidney_ever) diabetes mellitus (diabetes_ever) ischemic heart disease (ischemicheart_ever) stroke/transient ischemic attack (stroke_tia_ever) cancer_lung) 11. recent endometrial cancer hypertension (hypert_ever) end stage renal disease (esrd) was identified by finding a "y humetrix saas platform identification of additional chronic conditions: the following chronic condition variables were identified by analyzing icd10 codes in these cms claim files: (beneficiary part a institutional inpatient and outpatient claims, part b carrier claims, snf and hospice claims) from october 1 chronic liver disease (includes alcoholic cirrhosis, primary biliary cirrhosis, chronic viral hepatitis due to hepatitis b and c, alcoholic fatty liver hiv/aids 5. organ transplant (includes following transplants: lung, bone, heart, liver, pancreas, intestine, kidney, bone marrow bmi over 40 note coding of non-chemotherapy drugs as "true" signifies at least one applicable prescription fill was identified in 2020. these variables were all identified by mapping ndc drug product codes to rxnorm ingredient codes for these pharmaceutical classes of drugs: 1. chemotherapy: a value of "true" signifies that a beneficiary at any time in 2020 either had an icd10 code for chemotherapy in part a institutional or part b carrier claims, had a cpt-4 code indicating administration of parenteral chemotherapy in a part b claim, or had a pharmacy (pde) claim with an ndc code which mapped to an rxnorm ingredient code for an active pharmaceutical a value of "true" was assigned if a sufficient quantity of these drugs was filled to extend up to immunization variables: influenza and pneumococcal vaccinations were identified using their respective cpt-4 codes found in part b claims from october 1 covid-19 hospitalizations were identified either by part b carrier claims with place of service code and cpt codes indicating inpatient care with a date of service no more than 14 days after key: cord-309563-3cuzmsll authors: duprex, w. paul; fouchier, ron a. m.; imperiale, michael j.; lipsitch, marc; relman, david a. title: gain-of-function experiments: time for a real debate date: 2014-12-08 journal: nat rev microbiol doi: 10.1038/nrmicro3405 sha: doc_id: 309563 cord_uid: 3cuzmsll according to the who, dual use research of concern (durc) is “life sciences research that is intended for benefit, but which might easily be misapplied to do harm”. recent studies, particularly those on influenza viruses, have led to renewed attention on durc, as there is an ongoing debate over whether the benefits of gain-of-function (gof) experiments that result in an increase in the transmission and/or pathogenicity of potential pandemic pathogens (ppps) are outweighed by concerns over biosecurity and biosafety. in this viewpoint article, proponents and opponents of gof experiments discuss the benefits and risks associated with these studies, as well as the implications of the current debate for the scientific community and the general public, and suggest how the current discussion should move forward. w. paul duprex. first, we must recognize that the term 'gof experiment' is being used somewhat pejoratively to describe a small number of recent studies using avian influenza virus that led to increased viral transmission in mammals. rather like the viruses we work with, the term has taken on a 'life' of its own, 'infecting' debates and 'muddying the waters' for scientists, governments, policy makers, journalists and the public. although à la mode, it is totally imprecise to equate gof studies only with influenza transmission experiments. virology is founded on adaptation approaches, and these have broad utility because they provide phenotypic evidence of a genotypic change when combined with a discriminatory biological assay. phenotypes include resistance to a drug, alteration of host range, enhanced stability and replication, and not only transmission. dissecting the underlying genotype drives mechanistic studies, which in turn facilitate the study of host-pathogen interactions. virologists will be deprived of a powerful tool of human inquiry if they are unable to perform adaptation experiments. second, it is critical to realize that the benefits of basic research are often unanticipated and accrue over time. considering that these influenza transmission studies were performed relatively recently 1,2 , it is impressive that translatable benefits are already apparent, including the identification of mutations that increase virus replication (which is applicable to vaccine production) and changes that enhance stability of receptor-binding proteins (which is useful for surveillance). ron a. m. fouchier. we need gof experiments to demonstrate causal relationships between genes or mutations and particular biological traits of pathogens. in most cases, there are no alternative approaches that would provide similarly strong evidence as gof experiments. for example, loss-of-function approaches will show that modification or deletion of almost every gene of a pathogen can result in a reduction of replication, pathogenicity or transmission. bioinformatics and modelling approaches may be used to identify associations between genotypic and phenotypic traits, but will very rarely prove causality. in vitro experiments on genes in isolation and studies with attenuated strains may identify causal relationships between genes and some biological traits, but many phenotypes can only be investigated in the context of the wild-type pathogen. therefore, gof approaches are absolutely essential in infectious disease research; although alternative approaches can be very useful, these can never replace gof experiments. michael j. imperiale. gof experiments using these types of pathogens allow investigators to ascertain whether certain new phenotypes, such as the ability to transmit more efficiently, can be acquired by the pathogens. in my opinion, there are two main reasons for performing such experiments. first, it is possible that the information gained from these studies can be used to improve surveillance or to develop therapeutics. second, these studies often teach us interesting biology. there may be alternative approaches available for some studies, but that would need to be determined on a case-by-case basis. there are also ways to build in safety features, such as the incorporation of a microrna target sequence into the influenza virus genome that results in inhibition of replication outside the laboratory setting 3 . all of us share the goal of preventing and mitigating pandemics. biologists and public health specialists have a portfolio of approaches to do that; these include working with viral subunits to understand molecular and biochemical interactions in detail, studying sequences of animal and human viral strains, developing therapies that improve the host response or kill the virus, developing universal vaccines, improving technology for faster vaccine production and many more 4 . creating ppps -a subset of gof experiments involving creation of novel, virulent, transmissible viruses -is one of these approaches. unlike other gof experiments, the creation of ppps entails a unique risk that a laboratory accident could spark a pandemic killing millions. the question is not whether to carry out research on ppps or to do nothing; it is whether to have a portfolio of approaches to defeat viruses without creating a pandemic risk, or whether to include ppp experiments in that portfolio. for example, we should decide whether devoting our limited resources for flu research towards ppp creation experiments -which are expensive, often underpowered, low-throughput and often poorly generalizable 5 , and which create pandemic risk -is better than using those resources to enhance the rest of the portfolio for flu preparedness. similarly, it has been suggested that we need to enhance pathogenicity of coronaviruses in order to develop a valid animal model for corona viruses. this might be true, and we need to examine that assumption, but perhaps we can modify the animal to reproduce the human disease (as has been done, for example, by developing an animal model of meningococcal disease 6 ) rather than making a novel virus. amazingly, abstract | according to the who, dual use research of concern (durc) is "life sciences research that is intended for benefit, but which might easily be misapplied to do harm". recent studies, particularly those on influenza viruses, have led to renewed attention on durc, as there is an ongoing debate over whether the benefits of gain-of-function (gof) experiments that result in an increase in the transmission and/or pathogenicity of potential pandemic pathogens (ppps) are outweighed by concerns over biosecurity and biosafety. in this viewpoint article, proponents and opponents of gof experiments discuss the benefits and risks associated with these studies, as well as the implications of the current debate for the scientific community and the general public, and suggest how the current discussion should move forward. these types of experiments were commenced without asking that question in quantitative terms, and no quantitative case has been made for why the unique risks are justified by unique benefits. david a. relman. i view gof as a generic label for a broad class of experiments that lead to a genetically altered biological agent with new or enhanced functions. these experiments help to link genotype with phenotype and can therefore be valuable, although they can entail risk and are by no means the only approach for linking sequence with function. my early research career was dedicated to the study of pathogens. i continue to believe that naturally occurring pathogens, including those that have the potential for causing pandemics, deserve detailed investigation in order to understand their behaviour and interaction with hosts, as this can inform drug design, vaccine development, diagnostics and surveillance. however, gof experiments are just one of several approaches for studying pathogens. inactivating mutations and the manipulation of key functional domains in attenuated genetic backgrounds are alternative approaches that may be slightly less informative, but are much less risky. because there are alternatives, gof strategies should be used cautiously and only to achieve critical benefits when they clearly outweigh the risks and are realizable in the near-term. in general, it is unnecessary and inappropriate to create new infectious agents that are capable of causing widespread harm. genetic and biological contexts are important. as an example, genetic engineering that is intended and likely to endow a low-patho genicity, low-transmissibility agent with either enhanced pathogenicity or enhanced transmissibility may be appropriate if the benefits are substantial. conversely, creating a highly pathogenic, highly transmissible organism that does not already exist in nature is unnecessarily risky and potentially irresponsible. in the debate over whether or not to allow durc, the main concerns seem to be over biosecurity and biosafety. however, research on pathogenic organisms that are major health threats already happens worldwide and is deemed safe. are there reasons to believe that the current requirements for biocontainment are insufficient for gof experiments? and what is your reaction to the recent announcement of a "pause on funding" for gof studies by the us government? w.p.d. i am confident that biomedical research on potentially dangerous pathogens can be performed safely and is essential for a comprehensive understanding of microbial disease pathogenesis, prevention and treatment. from the moment scientists brought clinical samples into the laboratory and isolated wild-type viruses, they have developed biocontainment procedures to mitigate risk. in my opinion, self-interest spurs a keen interest in biosafety, and virologists have no wish to endanger their colleagues or themselves. pioneer virologists would probably be amazed to see the advances in biocontainment infrastructure, and how developments in engineering and technology have changed working practices. trust, good communication and transparency are vital between scientists, facilities staff and security personnel. every time i wear my training suit in the biosafety level 4 (bsl-4) laboratory, i am secure knowing that there are multiple reasons why, if there is a malfunction in the air, if the electricity supply fails or if there is a fire, i will still be able to breathe, pipette or exit the building safely. i trust the highly professional team of security guards, electricians, research safety experts, occupational health professionals and external inspectors from the us centers for disease control and prevention (cdc) and the us department of agriculture (usda), as this underpins everything i do. likewise, i am confident that they trust me to perform experiments responsibly and, if an accident occurs, to adhere strictly to standard operating procedures that are in place to minimize risk. working with dangerous pathogens is already highly regulated, and i believe that the current requirements for biocontainment are fit for purpose. therefore, i am convinced that limiting virus phenotype adaptation experiments by means of an ambiguously worded 'pause' is not the answer. in laboratories (and elsewhere), people make errors and machines occasionally stop working properly. as a consequence, biocontainment measures are designed in multiple layers, such that if some layers fail, others exist to mitigate the risks. furthermore, the layers of biocontainment measures increase in number and stringency with the increasing risk of the experiments. for example, in the case of our h5n1 virus transmission studies, if initial biocontainment measures fail, our personnel is vaccinated against h5n1, can be treated prophylactically with antivirals and can be quarantined in specialized wards to prevent potential onward transmission. there is no evidence that current biocontainment measures are insufficient; major laboratory-derived human outbreaks have not occurred during more than a century of scientific research on dangerous pathogens, even at times when biosafety measures were largely non-existent. recent inferences of the likelihood of pandemics occurring as a consequence of laboratory incidents are misleading; all laboratory incidents were interpreted as accidents with potential onward human transmission, which is incorrect. historical evidence has shown that even when there were human transmission events after laboratory accidents (such as the cases of severe acute respiratory syndrome (sars) in beijing, china), human cases were limited. some people have argued that the 1977 russian influenza epidemic was the result of a laboratory accident, but in 1977 influenza research was done on the bench (under conditions of limited biocontainment), and attenuated and wild-type strains were tested in humans; we do not know what happened in 1977, but we cannot conclude that the virus escaped a laboratory that met biosafety standards. finally, the influenza field voluntarily paused h5n1 gof transmission research in 2011-2012 to facilitate deliberation and checking of the facts on safety and security. in 2012, the us government concluded that the work could continue in specialized laboratories, but with additional governmental oversight. as the facts have not changed since then, i am hopeful that the same conclusion will be reached in response to the current moratorium. m.j.i. laboratory accidents happen, even in high containment settings. the recent events at the cdc in the united states, in which a strain of highly pathogenic avian influenza was accidentally shipped to another laboratory and in which a pathogen was taken out of a laboratory without proper inactivation, are just two examples. theoretically, the cdc has some of the best biosafety protocols in the world. one can only imagine what might happen if gof experiments are performed in laboratories with lower biosafety standards. however, the possibility that additional rules and regulations might end up slowing down the exact research that we require to protect ourselves from these pathogens is a real concern. i think that the wording of the announcement by the us government of a "pause on funding" for gof studies serves as an example. the office for science and technology policy published the following statement. "specifically, the funding pause will apply to gain-of-function research projects that may be reasonably anticipated to confer attributes to influenza, mers [middle east respiratory syndrome], or sars viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route ... the funding pause will not apply to the characterization or testing of naturally occurring influenza, mers, and sars viruses unless there is a reasonable expectation that these tests would increase transmissibility or pathogenicity. " what do "reasonably" and "reasonable" mean in this context? this is too subjective, and the open-ended timeframe of the pause also troubles me. m.l. the pause on funding for gof experiments for quantitative deliberation on risks and benefits is long overdue. the pause covers not all research on pathogenic organisms but only research that enhances pathogenicity or transmission of flu, sars or mers. ultimately, after deliberation some of that research may resume, and that may be appropriate if the weighing of risks and benefits has been done well. what we consider as 'safe' must depend on what the impact of an accident would be. more than twice a week in us laboratories, there is a 'possible release event' or a 'possible loss event' , even if we look only at select agents -some of the most dangerous pathogens 7 . for every 1,000 lab-years of work in bsl-3 laboratories in the united states with select agents, there are at least 2 accidental infections 7 . this level of safety may be acceptable if the risk is to the laboratory workers only, as it is with most pathogens that are not readily transmissible. however, the same probability of an accident that could spark a global pandemic cannot be called acceptably safe. although most advocates of ppp experiments have been responsible in their discussion of the issue, a few have inappropriately caricatured those of us who express concern. we do not advocate curtailing research on dangerous pathogens in general, but we support replacing a very specific category of work that is small in extent (the funding pause affects about 18 projects 8 ) but that is exceptional in its level of risk with safer approaches. the current debate is not about whether durc in general should be allowed; it is about whether there is a tiny subset of durc with unusual risks that ought not to be allowed. for this tiny subset, there are additional main concerns besides biosecurity and biosafety -namely, concerns about the moral and ethical responsibilities of scientists to the general public 9 , and concerns about justice. furthermore, research on pathogens is not always safe; on the contrary, it always carries risks. in fact, recent accidental releases of dangerous pathogens by some of the most-respected laboratories in the world have demonstrated to the public that the risks may be greater than previously assumed and are due to the inherent failings of humans. nevertheless, this reality should not prevent research on pathogens from taking place. gof experiments that seek to create new, highly transmissible, highly pathogenic infectious agents pose special risks because of the greater likelihood that these agents will escape from the laboratory through either accidental or deliberate means and will lead to much greater harm than their naturally occurring counterparts. from a biosafety perspective, i believe that some of the work performed so far with highly pathogenic influenza viruses that have enhanced transmissibility in mammals has not been conducted at a sufficiently high enough biosafety level. from a biosecurity perspective, the unfettered dissemination of the complete genome sequence of a new, highly transmissible, highly pathogenic agent enables anyone skilled in the art to produce the agent de novo if a reverse genetics system for that class of agent is available, which could occur at locations that lack even basic biocontainment measures. i strongly support a funding pause for a narrow subset of experiments that entail unusual risks. the pause focuses attention on risk, benefit, governance and responsibility, and begs for seriousness and breadth of discussion that have been lacking so far. woefully insufficient input has been obtained from a wide variety of scientists and from many other stakeholders among the general public. it is unethical to place so many members of the public at risk and then consult only scientists -or, even worse, just a small subset of scientists -and exclude others from the decision-making and oversight process. a parallel debate has focused on how and when to report the results of studies involving durc. in your opinion, how should journals deal with these concerns? should sensitive information be redacted for publication, should publication be halted until safety concerns are addressed, or should all experimental details be made available at the time of publication? who do you think should be responsible for making these decisions? w.p.d. the scientific continuum can be divided into four steps: conceive an idea, conduct the experiments, present the data and publish a manuscript; the number of people involved in this pipeline increases with each step. nevertheless, even conception usually involves more than one person and, in an academic setting, strict confidentiality is difficult to achieve, as colleagues tend not to request that non-disclosure agreements are signed before going to lunch and discussing an idea. at the other end of this pipeline are editors and publishers and, in response to the recent influenza transmission studies, journals and professional societies have established internal review processes to evaluate papers containing potential durc. journals could be considered as the ultimate 'gatekeepers' , but redaction is a blunt instrument that rarely, if ever, should be used to limit access to publically funded, non-classified research; all details should be published. similarly, i find it impossible to imagine how laboratory meetings, seminars, poster sessions and conference presentations could be regulated. conducting the research, a step that requires institutional facilities and external funding, seems to offer the best opportunity for some oversight. universities have developed policies and established durc committees that can work with scientists who have conceived studies that are flagged during institutional review. funders could request that applications with a durc component be presented for review to a standing committee of scientific experts. in both cases, the responsibility would be on institutions and funders to ensure expeditious review, and the scientists who conceived the study should be intimately involved. with public funds, exchange (international) personnel extensively, are expected to act with maximum transparency and do not operate in highly secretive environments. as a consequence, unless research is done in a 'classified' environment from the beginning, academic research is considered to be already in the public domain by the us legal courts, and redaction of manuscripts would thus be ineffective. therefore, the default decision should be to make all experimental details available at the time of publication. scientists, along with their host institutions, have a huge responsibility in this decisionmaking process. when in doubt, scientists should seek advice from their peers. funding bodies can decide not to fund particular work, but this does not necessarily prevent scientists from doing and publishing the research, or from seeking alternative funding mechanisms. publishers have a moral obligation to publish responsibly, but because they are at the end of the chain and because scientists can disseminate results via alternative channels, this is not where the primary response to durc issues should be. in my view, the best option is to leave the primary responsibility with scientists and their institutions, with oversight and advisory roles for governments. m.j.i. i think that the life sciences research community has to accept the fact that we live in a very different world today than even 10-15 years ago, a world in which individuals and groups will engage in unethical behaviours that we would not have imagined in the past. taken together with the fact that the technologies required to produce dangerous pathogens are relatively easy to acquire, i believe that we are going to be faced with more and more examples of data that could enable those wishing to do harm to do so. i believe that we must develop a system that will allow selective sharing of information that has a high likelihood of being misused. i am not trying to be a 'fear-monger' by asking us to think about potential misuse. rather, i am stating that we cannot ignore the possibility. however, this is a complicated issue because ascertaining the likelihood of misuse is incredibly difficult. the question of who gets to make these decisions is also a tough one to answer because of the complexity. arguably, authors themselves are in the best position to realize the potential risks of publishing certain details; this was the opinion of the us national science advisory board for biosecurity (nsabb) before the submission of the manuscripts describing gof experiments that resulted in increased transmission of h5n1 influenza virus in mammals. however, there is great pressure to publish, any given individual may not think that the risks are more than negligible, and the risks and benefits of scientific research are not always immediately evident. at the journal level, similar concerns apply. are reviewers and editors in a knowledgeable enough position to be aware of and to analyse the risks and benefits associated with such publications? given the international nature of research, do we get governments involved and, if so, which ones? i think one approach to consider is to have a committee, similar to the recombinant dna advisory committee in the united states, that acts nimbly; as it accumulates experience, it can delimit what needs review and what does not, similar to the way the governance of recombinant dna research has evolved. m.l. i think the concern about publication has two issues: do we make it easier for well-meaning scientists with poor biosafety standards to do unsafe experiments, and do we make it easier for potential bioterrorists to create novel bioweapons? both are important concerns but, in my mind, for experiments that create novel, virulent, transmissible ppps, the accident concern alone is enough to outweigh any of the purported benefits that have been mentioned to date, especially if we appropriately compare the resources allocated to ppp experiments with the alternatives we could fund with the same resources. a proper discussion about risky research is far more effective if it is held before the initiation of such research, rather than after the results have been obtained. however, unanticipated discoveries happen, and some will produce information that creates risks and vulnerabilities. meanwhile, research takes place in an increasingly interconnected global society, in which all deserve to share in the benefits and all rightfully expect to be protected from undue risk. the moral and social obligations of all scientists include the duty to first do no harm. when research findings directly pose potential risks of such magnitude that they greatly outweigh the associated benefits of these findings, scientists and those that oversee their research and its dissemination are obligated to minimize these risks, which might include temporarily limiting the dissemination of data. the important general principle that supports the free and open sharing of scientific knowledge does not trump our obligation to prevent undue harm in those unusual circumstances where direct misapplication of information can be reasonably anticipated to cause grave and widespread consequences. of note, restrictions on communication of research findings need only to be temporary; they should and can be lifted as soon as risks have been mitigated, for example, by creation of countermeasures against the newly identified threat. we need standardized and widely accepted mechanisms for identifying these rare circumstances where research findings ought not to be freely disseminated, as well as legally validated mechanisms for limiting information dissemination 10 . such mechanisms, aside from national security classification, are not currently available. the role for limited dissemination was discussed in the corson report issued in 1982 by the us national academy of science 11 . in fact, there are plenty of circumstances today in which experimental results or details are not fully disclosed, such as situations involving intellectual property, commercial secrets and privacy. concerns about security and safety should be at least as compelling as these other concerns. such decisions are most appropriately made jointly by the relevant investigator (or investigators) and local institutions, with guidance by national and international experts within and outside governments. the current debate has made headlines in the press. in your opinion, has the debate been beneficial, as it has raised public awareness and has the potential to make scientists work towards a consensus, or has it been harmful, owing to its potential to alarm the general public, which could result in additional regulatory guidelines that many microbiologists fear could hinder future research? w.p.d. what concerns me greatly is that owing to the use of imprecise definitions, rhetorical language and a paucity of personal engagement between individuals who disagree, no meaningful debate has occurred about the merits and risks of the adaptation of pathogens towards enhanced transmission or any other durc phenotype. opinions have been reactionary, and arguments have been played out in the media, on blogs and in podcasts, augmented by twitter discussions and op-ed pieces, in a process that seldom involves peer review. selfishly, i believe my discipline deserves better, and the efforts of arturo casadevall and michael j. imperiale to raise the level of debate are to be applauded [12] [13] [14] . however, on the whole, communication has been poor. this is exacerbated by the fact that the groups with differing opinions (on microbiology, public health and bioethics) largely inhabit very different worlds, meaning that individuals with opposing opinions rarely meet. additionally, the media feels the need to frame the debate as a fight, which is also counterproductive and harmful, and is doing little to help the public to understand the key issues. the least beneficial outcome is the current moratorium which, from a virologist's perspective, also seems reactionary. invoking the apocalypse should not be used to drive debate, set agendas, decide policy or regulate experiments with dangerous pathogens out of existence. there has hardly been a real debate. i have participated in several public meetings, but opposition against gof research has been minimal in most of these cases. instead of a real debate, we have seen the sharing of tweets and one-liners that are copied by press outlets in search of sensation. the lay press and some scientific journals have blindly placed opinion pieces without checking the facts or seeking alternative opinions. the problem here is that much of the press and the public are interested in sensational news but are less interested in careful explanations of the (boring) facts related to the regulatory frameworks that are in place, the safety and security procedures that are in use, the purpose of particular research projects, the weighing of risks and benefits of research, and so on. while ringing the alarm bell is fast and easy, communicating the fact that the bell may have sounded a false alarm will take considerable efforts. i am worried that new regulatory guidelines may not contribute to what they were designed for, which is to make the world a safer place. extensively recently about the complicated nature of the debate and the dangers of the manner in which it is being conducted [12] [13] [14] . i think the debate has been both harmful and beneficial. it has been harmful in that, as in any debate that becomes public, people will draw conclusions without necessarily learning all the facts or understanding all the nuances of the issue. it has been beneficial in getting the disparate views out, but not as beneficial as it could be because the discussion has largely been in print, in social media or on the internet without people actually sitting down in a room and discussing the issues. it is common sense that before embarking on a course of research that has even a low risk of sparking a global pandemic, there should be very careful consideration given to the risks and benefits. both risks and benefits of performing gof experiments on influenza viruses apply to human beings in general, as we are all susceptible to flu infection. therefore, this must be a discussion that moves beyond flu researchers, some of whom have personal interests at stake, and beyond microbiologists, to the whole scientific and medical community and others who would be directly affected -the general public. the natural order of events is deliberation, risk and benefit analysis, evaluation of the results of that analysis, and then a decision to go forward or not with each type of research. unfortunately, the initial discussions of this topic fizzled a decade ago 15 . research on ppp creation went forward and was reported publicly in 2011, then published in 2012. the public debate is long overdue and necessary. an admirable example of how such work might have proceeded is given by the scientific leaders of work on gene drives, another area of biological research with good intentions but that also poses danger to human and animal populations. the leaders of that field have publicly announced what they are doing, how they are mitigating risks, and how the public can get involved in discussing risks and benefits 16 . when scientific research potentially endangers large numbers of lives, the public (in this case, the global public) should know and have input. the debate has been largely beneficial for raising awareness of and clarifying the issues. if the discussion has been flawed, it is because the pros and cons of the work have both been slightly exaggerated, the tone of the discussion too personalized and emotional, and the diversity of participants too narrow. in many cases, conversations have only involved infectious-disease researchers, and conflicts of interests among participants have not been adequately acknowledged or addressed. as discussed above, it is unethical to put the general public at risk, as one does with the creation of new ppps, and then minimize inclusion of the public in discussions about the appropriateness and oversight of such research. it is our responsibility as scientists to explain the rationale behind our work, including its benefits and risks, to the general public in terms that are accessible to those with an average level of education, rather than to be dismissive. this is especially important when the work has important consequences for the whole of society. flexible, agile and adaptive oversight mechanisms are critical because of the rapidly evolving nature of this field of science and technology. several scientists have argued that one of the positive aspects of the controversy has been the initiation of a debate on the pros and cons of durc. however, a consensus on how, when and where to allow this type of research, and how to handle the release of sensitive data, has not been reached. how do you think the debate should move forward? in your opinion, can the two sides come to an agreement? w.p.d. scientists have the responsibility to engage and inform, not to entertain or scare. this led to the foundation of scientists for science, a group of international scientists who are convinced that only by engaging in open, constructive dialogue can we learn from one another's experience, understand genuine concerns and move from dogmatism to consensus. transparency and good communication are important in articulating why working with potentially dangerous pathogens is critical for society, and we will continue to argue for safe and sound science. this debate goes far beyond the single issue of influenza transmission studies and has implications for all of microbiology; therefore, it must be inclusive. policy makers, national academies, international organizations and governments should recognize that although influenza virologists have been at the forefront of this debate, as the recent studies involved altering the transmission and host range of influenza viruses, many other microbiologists perform comparable in vitro and in vivo evolution and adaptation studies. colleagues working on sars and mers viruses are acutely aware of this following the us government's call for a "pause in funding" and instructions to stop certain ongoing experiments. a wide net should be cast when meetings and symposia are arranged by scientific societies and national academies. furthermore, a substantial amount of resources have been invested globally to build and operate bsl-3 and bsl-4 facilities and to mitigate risk and share good practice, so that risk is minimized; this is our most important line of defence. i am convinced that limiting certain types of experiments is not the answer. however, neither is completely resisting the use of appropriate quantifiable risk-benefit analyses. i am optimistic that dialogue will help and that building a consensus is not impossible. supportive of open debates about durc, biosafety, biosecurity and policies on scientific publishing. i participated in many of these and will continue to do so. however, we should be realistic in that we may not reach consensus on some of these topics. for instance, in durc discussions there will be debates about weighing risks and benefits of research. since neither the risks nor the benefits are truly quantifiable, the weighing will remain a judgment call. for example, in the debate about release of sensitive data, bioterror risks as perceived by intelligence experts are weighed against the scientific benefits as perceived by scientists; this is like comparing apples to oranges. furthermore, trying to address the question of whether we should do a particular kind of gof research may be aiming a bit too high. perhaps we should address some more tractable questions initially, such as how has biocontainment improved from the asilomar conference to the present day, with the introduction of purpose-built biosafety laboratories? how should we interpret laboratory incident reports in light of public health risks? what is the relative likelihood of dangerous human pathogens emerging in nature versus in the laboratory? what is the value of basic scientific research on dangerous pathogens? what is the risk of abuse of scientific research by 'lone wolves' , terrorist organizations and rogue states? and how effective and feasible is redaction, classification and export control of manuscripts produced within academic institutions? answers to these simpler questions may help to move the debate forward. m.j.i. since the gof issue came to the forefront in 2011, i have been of the belief that there has not been the type of discussion there ought to have been -one in which the scientific, biosafety, biosecurity and ethical issues are all on the table. i am therefore one of those who welcome the recent movement to have these discussions. i think that not only can the two sides come to an agreement, but they must do so. these are important issues with large implications for human, animal and plant health. i think that individuals who hold extreme viewpoints on either side may not be able to compromise, but that a vast majority of stakeholders will be able to agree on the best way forward. m.l. there may never be complete agreement. quantifying risks and benefits has the effect of taking the discussion away from personal comments -such as "this person's laboratory is safe" or "this person's science is important" -and looking at it objectively. i have argued that the risks for creating novel flu strains are so large (low probability but very high potential consequence) that we cannot justify such work when there are safer alternatives 4, 5 . the answer might turn out to be different for other viruses. furthermore, scientists are ingenious and may be able to find ways to do the science in which they are interested with less or no risk. the previous regime of not properly accounting for risk is clearly not sustainable, and i expect that a lot of new approaches to risk mitigation and alternative methods will come to light during this period of deliberation. a.r. i agree that there have been positive aspects of the controversy, in so far as attention has been drawn to important issues that deserve careful and deliberate discussion, and i do believe that agreements can be achieved on important aspects of this issue. moving forward, leadership of the discussion process should be shared by governments and by key stakeholders, including domestic and international science organizations (for example, national academies of science); highly respected, dispassionate and trusted representatives of the general-science communities; key non-scientist thought leaders; and representatives of the security communities. principles of deliberative democracy should be incorporated. goals of this process should include establishment of a credible, objective and balanced governance scheme for the life sciences; establishment of norms and an understanding of the relationship of the scientific community with governments and with the general public; articulation and acceptance of responsibilities by the scientific community towards the general public and the ecosphere; and development of a consensus on whether and how risky work should proceed. we will also need ongoing review and oversight of risks in the life sciences and associated technologies, as well as ongoing engagement of life scientists across all sectors on these issues. these are challenging goals for which the life sciences research community has so far failed to demonstrate broad commitment, but goals that are more than deserving of serious effort. experimental adaptation of an influenza h5 ha confers respiratory droplet transmission to a reassortant h5 ha/h1n1 virus in ferrets airborne transmission of influenza a/h5n1 virus between ferrets microrna-based strategy to mitigate the risk of gain-of-function influenza studies ethical alternatives to experiments with novel potential pandemic pathogens can limited scientific value of potential pandemic pathogen experiments justify the risks? cd46 in meningococcal disease monitoring select agent theft, loss and release reports in the united states moratorium on risky virology studies leaves work at 14 institutions in limbo the increasingly compelling moral responsibilities of life scientists inconvenient truths" in the pursuit of scientific knowledge and public health the apocalypse as a rhetorical device in the influenza virus gain-of-function debate an epistemological perspective on the value of gain-of-function experiments involving pathogens with pandemic potential risks and benefits of gain-of-function experiments with pathogens of pandemic potential, such as influenza virus: a call for a science-based discussion tiptoeing around pandora's box regulating gene drives scientists for science: www.scientistsforscience.org key: cord-009481-6pm3rpzj authors: parnell, gregory s.; smith, christopher m.; moxley, frederick i. title: intelligent adversary risk analysis: a bioterrorism risk management model date: 2009-12-11 journal: risk anal doi: 10.1111/j.1539-6924.2009.01319.x sha: doc_id: 9481 cord_uid: 6pm3rpzj the tragic events of 9/11 and the concerns about the potential for a terrorist or hostile state attack with weapons of mass destruction have led to an increased emphasis on risk analysis for homeland security. uncertain hazards (natural and engineering) have been successfully analyzed using probabilistic risk analysis (pra). unlike uncertain hazards, terrorists and hostile states are intelligent adversaries who can observe our vulnerabilities and dynamically adapt their plans and actions to achieve their objectives. this article compares uncertain hazard risk analysis with intelligent adversary risk analysis, describes the intelligent adversary risk analysis challenges, and presents a probabilistic defender–attacker–defender model to evaluate the baseline risk and the potential risk reduction provided by defender investments. the model includes defender decisions prior to an attack; attacker decisions during the attack; defender actions after an attack; and the uncertainties of attack implementation, detection, and consequences. the risk management model is demonstrated with an illustrative bioterrorism problem with notional data. toward risk-based regulations, specifically using pra to analyze and demonstrate lower cost regulations without compromising safety. (7, 8) research in the nuclear industry has also supported advances in human reliability analysis, external events analysis, and common cause failure analysis. (9−11) more recently, leaders of public and private organizations have requested risk analyses for problems that involve the threats posed by intelligent adversaries. for example, in 2004, the president directed the department of homeland security (dhs) to assess the risk of bioterrorism. (12) homeland security presidential directive 10 (hspd-10): biodefense for the 21st century, states that " [b] iological weapons in the possession of hostile states or terrorists pose unique and grave threats to the safety and security of the united states and our allies" and charged the dhs with issuing biennial assessments of biological threats to "guide prioritization of our on-going investments in biodefense-related research, development, planning, and preparedness." a subsequent homeland security presidential directive 18 (hspd-18): medical countermeasures against weapons of mass destruction directed an integrated risk assessment of all chemical, biological, radiological, and nuclear (cbrn) threats. (13) the critical risk analysis question addressed in this article is: are the standard pra techniques for uncertain hazards adequate and appropriate for intelligent adversaries? as concluded by the nrc (2008) study on bioterrorism risk analysis, we believe that new techniques are required to provide credible insights for intelligent adversary risk analysis. we will show that treating adversary decisions as uncertain hazards is inappropriate because it can provide a different risk ranking and may underestimate the risk. in the rest of this section, we describe the difference between natural hazards and intelligent adversaries and demonstrate, with a simple example, that standard pra applied to attacker's intent may underestimate the risk of an intelligent adversary attack. in the second section, we describe a canonical model for resource allocation decision making for an intelligent adversary problem using an illustrative bioterrorism example with notional data. in the third section, we describe the illustrative analysis results obtained from the model and discuss the insights they provide for risk assessment, risk communication, and risk management. in the fourth section, we describe the benefits and limitations of the model. finally, we discuss future work and our conclusions. we believe that risk analysis of uncertain hazards is fundamentally different than risk analysis of intelligent adversaries. (14, 15) some of the key differences are summarized in table i . (16) a key difference is historical data. for many uncertain events, both natural and engineered, we have not only historical data of extreme failures or crises, but many times we can replicate events in a laboratory environment for further study (engineered systems) or analyze using complex simulations. intelligent adversary attacks have a long historical background, but the aims, events, and effects we have recorded may not prove a valid estimate of future threat because of changes in adversary intent and capability. both uncertain hazard risks of occurrence and geographical risk can be narrowed down and identified concretely. intelligent adversary targets vary by the goals of the adversary and can be vastly dissimilar between adversary attacks. information sharing between the two events differs dramatically. after hurricanes or earthquakes, engineers typically review the incident, publish results, and improve their simulations. sometimes after intelligent adversary attacks, or near misses, the situation and conduct of the attack may involve critical state vulnerabilities and protected intelligence means. in these cases, intelligence agencies may be reluctant to share complete information even with other government agencies. the ability to influence the event is also different. though we can prepare, we typically have no way of influencing the natural event to occur or not occur. on the other hand, governments may be able to affect the impact of terrorism attacks by a variety of offensive, defensive, and recovery measures. in addition, adversary attacks can take on so many forms that one cannot realistically defend/respond/recover/etc. against all types of attacks. although there have been efforts to use event tree technologies in intelligent adversary risk analysis (e.g., btra), many believe that this approach is not credible. (19) the threat from intelligent adversaries comes from a combination of both intent and capability. we believe that pra still has an important role in intelligent adversary risk analysis for assessment of the capabilities of adversaries, the vulnerabilities of potential targets, and potential consequences of attacks. however, intent is not a some cities may be considered riskier than others (e.g., new york city, washington), but terrorists may attack anywhere, any time. information sharing: asymmetry of information: new scientific knowledge on natural hazards can be shared with all the stakeholders. governments sometimes keep secret new information on terrorism for national security reasons. natural event: intelligent adversary events: to date, no one can influence the occurrence of an extreme natural event (e.g., an earthquake). governments may be able to influence terrorism (e.g., foreign policy; international cooperation; national and homeland security measures). government and insureds can invest in well-known mitigation measures. attack methodologies and weapon types are numerous. local agencies have limited resources to protect potentially numerous targets. federal agencies may be in a better position to develop better offensive, defensive and response strategies. modified from kunreuther. (17, 18) 431-461. (18) factor in natural hazard risk analysis. in intelligent adversary risk analysis, we must consider the intent of the adversary. the adversary will make future decisions based on our preparations, its objectives, and information about its ability to achieve its objectives that is dynamically revealed in a scenario. bier et al. provides an example of addressing an adversary using a defender-attacker game theoretic model. (20) nrc provides three examples of intelligent adversary models. (16) we believe it will be more useful to assess an attacker's objectives (although this is not a trivial task) than assigning probabilities to their decisions prior to the dynamic revelation of scenario information. we believe that modeling adversary objectives will provide greater insight into the possible actions of opponents rather than exhaustively enumerating probabilities on all the possible actions they could take. furthermore, we believe the probabilities of adversary decisions (intent) should be an output of, not an input to, risk analysis models. (16) this is a principal part of game theory as shown in aghassi et al. and jain et al. (21, 22) to make our argument and our proposed alternative more explicit, we use a bioterrorism illustrative example. in response to the 2004 hspd, in october 2006, the dhs released a report called the bioterrorism risk assessment (btra). (19) the risk assessment model contained a 17-step event tree (18 steps with consequences) that could lead to the deliberate exposure of civilian populations for each of the 27 most dangerous pathogens that the center for disease control tracks (emergency.cdc.gov/bioterrorism) plus one engineered pathogen. the model was extremely detailed and contained a number of separate models that fed into the main btra model. the btra resulted in a normalized risk for each of the 28 pathogens, and rank-ordered the pathogens from most risky to least risky. the national research council (nrc) conducted a review of the btra model and provided 11 specific recommendations for improvement to the model. (16) in our example, we will use four of the recommendations: model the decisions of intelligent adversaries, include risk management, simplify the model by not assigning probabilities to the branches of uncertain events, and do not normalize the risk. the intelligent adversary technique we developed builds on the deterministic defenderattacker-defender model and is solved using decision trees. (16) because the model has been simplified to reflect the available data, the model can be developed in a commercial off-the-shelf (cots) software package, such as the one we used for modeling, dpl (www.syncopation.org). other decision analysis software may work as well. 4(23) event trees have been useful for modeling uncertain hazards. (24) however, there is a key difference in the modeling of intelligent adversary decisions that event trees do not capture. as norman c. rasmussen, the director of the 1975 reactor safety study that validated pra for use in nuclear reactor safety, states in a later article, while the basic assumption of randomness holds true for nuclear safety, it is not valid for human action. (25) the attacker makes decisions to achieve his or her objectives. the defender makes resource allocation decisions before and after an attack to try to mitigate vulnerabilities and consequences of the attacker's actions. this dynamic sequence of decisions made by first the defender, then an attacker, then again by the defender should not be modeled solely by assessing probabilities of the attacker's decisions. for example, when the attacker looks at the defender's preparations for their possible bioterror attack, it will not assign probabilities to its decisions; it chooses the agent and the target based on perceived ability to acquire the agent and successfully attack the target that will give it the effects it desires to achieve its objectives. (15) representing an attacker decision as a probability may underestimate the risk. consider the simple bioterrorism event tree given in fig. 1 with notional data. using an event tree, for each agent (a and b) there is a probability that an adversary will attack, a probability of attack success, and an expected consequence for each outcome (at the terminal node of the tree). the probability of success 4 a useful reference for decision analysis software is located on the orms website (http://www.lionhrtpub.com/orms/surveys/das/ das.html). involves many factors, including the probability of obtaining the agent and the probability of detection during attack preparations and execution. the consequences depend on many factors, including agent propagation, agent lethality, time to detection, and risk mitigation; in this example, the consequences range from 0 or no consequences to 100, the maximum consequences (on a normalized scale of consequences). calculating expected values in fig. 1 , we would assess expected consequences of 32. we would be primarily concerned about agent b because it contributes 84% of the expected consequences (30 × 0.9 = 27 for b out of the total of 32). looking at extreme events, we would note that the worst-case consequence of 100 has a probability of 0.05. however, adversaries do not assign probabilities to their decisions; they make decisions to achieve their objectives, which may be to maximize the consequences they can inflict. (26) if we use a decision tree as in fig. 2 , we replace the initial probability node with a decision node because this is an adversary decision. we find that the intelligent adversary would select agent a, and the expected consequences are 50, which is a different result than with the event tree. again, if we look at the extreme events, the worstcase event (100 consequences) probabilities are 0.5 for the agent a decision and 0.6 for the agent b decision. the expected consequences are greater and the primary agent of concern is now a. in this simple example, the event tree approach underestimates the expected risk and provides a different risk ranking. furthermore, the event tree example underestimates the risk of the extreme events. however, while illustrating important differences, this simple decision tree model does not sufficiently model the fundamental structure of intelligent adversary risk. this model has a large number of applications for homeland security. for example, it would be easy to see the use of this canonical model applied to a dirty bomb example laid out in rosoff and von winterfeldt (27) or any other intelligent adversary scenario. in this article, we show a use of a bioterrorism application. we believe that the canonical risk management model must have at least six components: the initial actions of the defender to acquire defensive capabilities, the attacker's uncertain acquisition of the implements of attack (e.g., agents a, b, and c), the attacker's target selection and method of attack(s) given implement of attack acquisition, the defender's risk mitigation actions given attack detection, the uncertain consequences, and the cost of the defender actions. from this model, one could also conduct baseline risk analysis by looking at the status quo. in general, the defender decisions can provide offensive, defensive, or information capabilities. we are not considering offensive decisions such as preemption before an attack; instead, we are considering decisions that will increase our defensive capability (e.g., buy vaccine reserves) (28) or provide earlier or more complete information for warning of an attack (add a bio watch city). (29) in our defenderattacker-defender decision analysis model, we have the two defender decisions (buy vaccine, add a bio watch city), the agent acquisition for the attacker is uncertain, the agent selection and target of attack is another decision, the consequences (fatalities and economic) are uncertain, the defender decision after attack to mitigate the maximum possible casualties, and the costs of defender decisions are known. the defender risk is defined as the probability of adverse consequences and is modeled using a multiobjective additive model similar to multiobjective value models. (30) we have assumed that the defender minimizes the risk and the attacker maximizes the risk. 5 we implemented this model as a decision tree (fig. 3 ) and an influence diagram (fig. 4) using dpl. the mathematical formulation of our model and the notional data are provided in the appendix the illustrative decision tree model (figs. 3 and 4) begins with decisions that the defender (united states) makes to deter the adversary by reducing the vulnerabilities or be better prepared to mitigate a bioterrorism attack of agents a, b, or c. we modeled and named the agents to represent notional bioterror agents using the cdc's agent categories in table ii . for example, agent a represents a notional agent from category a. table iii provides a current listing of the agents by category. there are many decisions that we could model; however, for our simple illustrative example, we chose to model notional decisions about the bio watch program for agents a and b and the bioshield vaccine reserve for agent a. bio watch is a program that installs and monitors a series of passive sensors within a major metropolitan city. (29) the bioshield program is a plan to purchase and store vaccines for some of the more dangerous pathogens. (28) the defender first decides whether or not to add another city to the bio watch program. if that city is attacked, this decision could affect the warning time, which influences the response and, ultimately, the potential consequences of an attack. of course, the bio watch system does not detect every agent, so we modeled agent c to be the most effective agent that the bio watch system does not sense and provide additional warning. adding a city will also incur a cost in dollars for the united states. the second notional defender decision is the amount of vaccine to store for agent a. agent a is the notional agent that we have modeled with the largest probability of acquisition and potential consequences. the defender can store a percentage of what experts think we would need in a largescale biological agent attack. the more vaccine the united states stores, the fewer consequences we will have if the adversaries use agent a and we have sufficient warning and capability to deploy the vaccine reserve. however, as we store more vaccine, the costs for purchasing and storage increase. for (31) category definition a the u.s. public health system and primary healthcare providers must be prepared to address various biological agents, including pathogens that are rarely seen in the united states. high-priority agents include organisms that pose a risk to national security because they: can be easily disseminated or transmitted from person to person; result in high mortality rates and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness. b second highest priority agents include those that: are moderately easy to disseminate; result in moderate morbidity rates and low mortality rates; and require specific enhancements of cdc's diagnostic capacity and enhanced disease surveillance. c third highest priority agents include emerging pathogens that could be engineered for mass dissemination in the future because of: availability; ease of production and dissemination; and potential for high morbidity and mortality rates and major health impact. simplicity's sake, each of the defender decisions cost the same amount; therefore, at the first budget level of us$ 10 million, the defender can only choose to one decision. after the defender has made its investment decisions, which we assume are known to the attacker, the attacker makes two decisions: the type of agent and the target. we will assume that the attacker has already made the decision to attack the united states with a bioterror agent. in our model, there are three agents it can choose, although this can be increased to represent the other pathogens listed in table iii . as stated earlier, if we only looked at the attacker decision, agent a would appear to be the best choice. agents b and c are the next two most attractive agents to the attacker, respectively. again, agents a and b can be detected by bio watch whereas agent c cannot. the attacker has some probability of acquiring each agent. if the agent is not acquired, the attacker cannot attack with that agent. in addition, each agent has a lethality associated with it, represented by the agent casualty factor. finally, each agent has a different probability of being detected over time. generally, the longer it takes for the agent to be detected, the more consequences the united states will suffer. the adversary also decides what size of population to target. generally, the larger the population targeted, the more potential consequences could result. the attacker's decisions affect the maximum possible casualties from the scenario. however, regardless of the attacker's decisions, there is some probability of actually attaining a low, medium, or high percentage of the maximum possible casualties. this sets the stage for the next decision by the defender. after receiving warning of an attack, the defender decides whether or not to deploy the agent a vaccine reserve. this decision depends upon how much of the vaccine reserve the united states chose to store, whether the attacker used agent a, and the potential effectiveness of the vaccine given timely attack warning. in addition, there is a cost associated with deploying the vaccine reserve. again, for simplicity's sake, the cost for every defender decision is the same, thus forcing the defender to only choose the best option(s) for each successive us$ 10 million increase in budget up to the maximum of us$ 30 million. in our model (fig. 4) , we have two types of consequences: casualties and economic impact. given the defender-attacker-defender decisions, the potential casualties and the economic impact are assessed. casualties are based on the agent, the population attacked, the maximum potential casualties, the warning time given to the defender, and the effectiveness of vaccine for agent a (if the agent a is the agent and the vaccine is used). economic effects are modeled using a linear model with a fixed economic cost that does not depend on the number of casualties and a variable cost of the number of casualties multiplied by the cost per casualty. of course, the defender would like potential consequences (risk) given an attack to be low, whereas the attacker would like the potential consequences (risk) to be high. our economic consequences model was derived using a constant and upper bound from wulf et al. (34) the constant cost we used is $10 billion, and from the upper bound, also given in wulf et al., we derived the cost per casualty. (34) we believe this fixed cost is reasonable because when looking at the example of the anthrax letters of 2001, experts estimate that although there were only 17 infected and five killed, there was a us$ 6 billion cost to the united states. (35) in this tragic example, there was an extremely high economic impact even when the casualties were low. each u.s. defender decision incurs a budget cost. the amount of money available to homeland security programs is limited by a budget determined by the president and congress. the model will track the costs incurred and only allows spending within the budget (see the appendix). we considered notional budget levels of us$ 0 million, us$ 10 million, us$ 20 million, and us$ 30 million. normally, a decision tree is solved by maximizing or minimizing the expected attribute at the terminal branches of the tree. in our model however, the defender risk depends on the casualty and economic consequences given an attack. we use multiple objective decision analysis with an additive value (risk) model to assign risk to the defender consequences. 6 the defender is minimizing risk and the attacker is maximizing risk. we assign a value of 0.0 to no consequences and a value of 1.0 to the worst-case consequences in our model. we model each consequence with a linear risk function and a weight (see the appendix). the risk functions measure returns to scale on the consequences. of course, additional consequences could be included and different shaped risk curves could be used. some of the key assumptions in our model are listed in table iv (the details are in the appendix) along with some possible alternative assumptions. given different assumptions, the model may produce different results. we model the uncertainty of the attacker's capability to acquire an agent with a probability distribution and we vary detection time by agent. clearly, other indications and warnings exist to detect possible attacks. these programs could be included in the model. we model three defender decisions: add a bio watch city for agents a and b, increase vaccine reserve for agent a, and deploy agent a. we assume limited decision options (i.e., 100% storage of vaccine a, 50% storage, 0% storage), but other decisions could be modeled (e.g., other levels of storage, storing vaccines for other agents, etc). we used one casualty model for all agents. other casualty and economic models could be used. finally, our model makes some assumptions about objectives. in the first of these we assume that the risks important to the defender are the number of casualties and the economic impact, but additional measures could be used. second, we assume defenders and attackers have a diametrically opposed view of all of the objectives. clearly, we could model additional objectives. in addition, we made some budget assumptions, which could be improved or modified. we assumed a fixed budget, but this budget could be modeled with more detailed cost models (e.g., instead of a set amount to add a city to the bio watch program, the budget could reflect different amounts depending upon the city and the robustness of the sensors installed). finally, our model results in a risk of a terrorist attack; the same methodology for a defender-attacker-defender decision tree can be used to determine a utility score instead of a risk; an example of this is in keeney. (15) one thing to consider when altering or adding to the assumptions is the number of strategies the model evaluates. currently, the canonical model has 108 different strategies to evaluate (table v) . with more complexity, the number of strategies that would need to be evaluated could grow significantly. largescale decision trees can be solved with monte carlo simulation. after modeling the canonical problem, we obtained several insights. first, we found that in our model economic impact and casualties are highly correlated. higher casualties result in higher economic impact. other consequences, for example, psychological consequences, could also be correlated with casualties. second, a bioterror attack could have a large economic impact (and psychological impact), even if casualties are low. the major risk analysis results are shown in fig. 5 . risk shifting occurs in our decision analysis model. in the baseline (with no defender spending), agent a is the most effective agent for the attacker to select and, therefore, the agent against which the defender can protect if the budget is increased. as we improve our defense against agent a, at some point the attacker will choose to attack using agent b. the high-risk agent will have shifted from agents a to b. as the budget level continues to increase, the defender adds a city to the bio watch program and the attackers choose to attack with agent c, which bio watch cannot detect. we use notional data in our model, but if more realistic data were used, the defender could determine the cost/benefit ratios of additional risk reduction decisions. this decision model uses cots software to quantitatively evaluate the potential risk reductions associated with different options and make cost-benefit decisions. fig. 5 provides a useful summary of the expected risk. however, it is also important to look at the complementary cumulative distribution (fig. 6) to better understand the likelihood of extreme outcomes. for example, the figure shows that spending us$ 0 or us$ 10 million gives the defender a 10% chance of zero risk, whereas spending us$ 20 or us$ 30 million gives the defender an almost 50% chance of having zero risk. the best risk management result would be that option 4 deterministically or stochastically dominates (sd) option 3, option 3 sd option 2, and option 2 sd option 1. the first observation we note from fig. 6 is that options 2, 3, and 4 stochasically dominate 1 because option 1 has a higher probability for each risk outcome. a second observation is that while option 4 sd option 3, option 4 does not sd option 2 because option 4 has a larger probability of yielding a risk level of 0.4. along the x-axis, one can see the expected risk (er) of each alternative. this expected risk corresponds to the expected value of risk from the budget versus risk rainbow diagram in fig. 5 . this example illustrates a possibly important relationship necessary for understanding and communicating how the budget might affect the defender's risk and choice of options. risk managers can run a value of control or value of correlation diagram to see which nodes most directly affect the outcomes and which are correlated (fig. 7) . because we only have two uncertainty nodes in our canonical model, the results are not surprising. the graphs show that the ability to acquire the agent is positively correlated with the defender risk. as the probability of acquiring the agent increases, so does defender risk. in addition, the value of control shows the amount of risk that could be reduced given perfect control over each probabilistic node, and that it is clear that acquiring the agent would be the most important variable for risk managers to control. admittedly, this is a basic example, but with a more complex model, analysts could determine which nodes are positively or negatively correlated with risk and which uncertainties are most important. using cots software also allows us to easily perform sensitivity analysis on key model assumptions. from the value of correlation and control above, the probability of acquiring the agent was highly and positively correlated with defender risk and had the greatest potential for reducing defender risk. we can generate sensitivity analysis such as rainbow diagrams. the rainbow diagram (fig. 8) shows the decision changes as our assumption about the probability of acquiring agent a increases. the different shaded regions represent different decisions, for both the attacker and the defender. this rainbow diagram was produced using a budget level of us$ 20 million, so in the original model, the defender would choose not to add a city to bio watch, store 100% of vaccine for agent a, but not choose to deploy it because the attacker chose to use agent b. if the probability of acquiring agent a was low enough (in section a from fig. 8) , we see that the attacker would choose to use agent c because we have spent our money on adding another city to bio watch, which is the only thing that affects both agents a and b, but not agent c. as the probability of acquiring agent a increases, both the attacker's and the defender's optimal strategies change. our risk management decision depends on the probability that the adversary acquires agent a. risk analysis of intelligent adversaries is fundamentally different than risk analysis of uncertain hazards. as we demonstrated in section 1.3, assigning probabilities to the decisions of intelligent adversaries can underestimate the potential risk. decision tree models of intelligent adversaries can provide insights into the risk posed by intelligent adversaries. the defender-attacker-defender decision analysis model presented in this article provides four important benefits. first, it provides a risk assessment (the baseline or status quo) based on defender and attacker objectives and probabilistic assessment of threat capabilities, vulnerabilities, and consequences. second, it provides information for risk-informed decision making about potential risk management options. third, using cots software, we can provide a variety of very useful sensitivity analysis. fourth, although the model would be developed by a team, the risk analysis can be conducted by one risk analyst with an understanding of decision trees and optimization and training on the features of the cots software. the application of risk assessment and risk management techniques should be driven by the goals of the analysis. in natural hazard risk analysis, there is value in performing risk assessment without risk management. some useful examples are "unfinished business," a report from the epa and the 2008 u.k. national risk register. (36, 37) in intelligent adversary risk analysis, the defender-attacker-defender decision analysis can provide essential information for risk management decision making. in our example, risk management techniques are important, and this type of model provides insights about resource allocation decisions to reduce or shift risk. in addition, with budget set to us$ 0, the model can be used to assess the baseline risk. as the budget increases, the model clearly shows the best risk management decisions and the associated risk reduction. this model enables the use of cots risk analysis software. in addition, the use of cots software enables the use of standard sensitivity analysis tools to provide insights into areas in which the assumptions are critical or where the model should be improved or expanded. currently, many event tree models including the dhs btra event tree require extensive contractor support to run, compile, and analyze. (16) although one would still need a multidisciplinary team to create the model, once completed the defenderattacker-defender decision analysis model is usable by a single risk analyst who can provide near realtime analysis results to stakeholders and decisionmakers as long as the risk analyst understands the risk management options, decision trees, optimization, and has training in the cots tool. the technique we advocate in this article has limitations. some of the limitations of this model are the same as those of event trees. there are limitations on the number of agents used in the models. we easily modeled 28 bioagents with reasonable run times, but more agents could be modeled. in addition, there are challenges in assessing the probabilities of uncertain events, for example, the probability that the attacker acquires agent a. next, there is a limitation in the modeling of the multiple consequences. another limitation may be that to get more realistic results, we may have to develop "response surface" models of more complex consequence models. these limitations are shared by event trees and decision trees. however, decision trees also have some limitations that are not shared by event trees. first, only a limited number of risk management decisions can realistically be modeled. therefore, care must be used to choose the most appropriate set of potential decisions. (15, 18) in addition, there may be an upper bound on the number of decisions or events that can be modeled in cots software. it is important to note that it may be difficult to determine an objective function for the attacker. as mentioned before, there is a tradeoff in replacing the probabilities assigned to what an attacker might do (event tree approach) with attacker objectives (decision tree approach). we believe it is easier to make informed assessments about the objectives of adversaries than to assess the probabilities of their future actions. however, we need more research on assessing the robustness of risk management decisions to assumptions about adversary objectives. finally, successful model operation and interpretation requires trained analysts who understand decision analysis and defenderattacker-defender optimization. this article has demonstrated the feasibility of modeling intelligent adversary risk using defenderattacker-defender decision analysis. table iv and section 2.7 identified several alternative modeling assumptions that could be considered. we can modify and expand our assumptions to increase the complexity and fidelity of the model. the next step is to use the model with the best data available on the agents of concern and a proposed set of potential risk management options. use of our defender-attacker-defender model does not require a major intelligent adversary research program; it requires only the willingness to change. (16) much of the data used for event tree models can be used in the decision analysis model. assessing probabilities of attacker decisions will not increase our security but defender-attacker-defender decision analysis models can provide a sound assessment of risk and the essential information our nation needs to make risk-informed decisions. g.s.p. is grateful for the many helpful discussions on intelligent adversary risk analysis with his colleagues on the 2008 nrc committee and the defender-attacker-defender research of jerry brown and his colleagues at the naval postgraduate school. the authors are grateful for the dpl modeling advice provided by chris dalton of syncopation. the authors thank roger burk at the united states military academy for his useful reviews and suggestions. finally, the authors thank the area editor and reviewers for very detailed comments and suggestions that have helped us improve our article. this model is a multiobjective decision analysis/game theory model that allows for risk management at the u.s. governmental level in terms of budgeting and certain bioterror risk mitigation decisions. the values for probabilities as well as factors are notional and could easily be changed based on more accurate data. it uses the starting u.s. (defender) decisions of adding a city to the bio watch program (or not) and the percent of storing an agent in the nation's vaccine reserve program to set the conditions for an attacker decision. the attacker can choose which agent to use as well as what size of population to target. there is some unpredictability in the ability to acquire the agent as well as the effects of the agent given the defender and attacker decisions. finally, the defender gets to choose whether to deploy the vaccine reserve to mitigate casualties. the model tracks the cost for each u.s. decision and evaluates them over a specified budget. the decisions cannot violate the budget without incurring a dire penalty. the objectives that the model tracks are u.s. casualties and impact to the u.s. economy. they are joined together using a value function with weights for each objective. we outline our model using a method suggested by brown and rosenthal. 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zhu, wei; pei, xi; cui, xueting title: hedging crash risk in optimal portfolio selection date: 2020-07-28 journal: j bank financ doi: 10.1016/j.jbankfin.2020.105905 sha: doc_id: 290708 cord_uid: hv1um2ln when almost all underlying assets suddenly lose a certain part of their nominal value in a market crash, the diversification effect of portfolios in a normal market condition no longer works. we integrate the crash risk into portfolio management and investigate performance measures, hedging and optimization of portfolio selection involving derivatives. a suitable convex conic programming framework based on parametric approximation method is proposed to make the problem a tractable one. simulation analysis and empirical study are performed to test the proposed approach. in this paper, we propose an approach for optimal portfolio choice, taking into account a crash, that combines the ideas of hedge and measure of crash risk. our strategy and research roadmap are illustrated by figure 1 . we propose a general nonlinear portfolio optimization model involving both, normal risk and crash risk, which can deal with risk in a more flexible way. the crash risk is hedged by derivatives and the model is formulated as a tractable one via parametric approximation. we then demonstrate that even if the return of derivative is usually asymmetric, the proposed model is reasonable when the portfolio is relatively diversified. we further derive an efficient convex programming approach to solve this general nonlinear portfolio problem. a common belief in financial literature is that asset returns are distributed with heavy tails. consequently, several tail risk measures have been proposed. var (see jorion (2007) ), conditional var (cvar) (see rockafellar and uryasev (2000) ), lower partial moments (lpm) (see fishburn (1977) ) are among the most popular ones. time-varying tail risks defined as the average logarithmic shortage with respect to a prescribed threshold are discussed by kelly and jiang (2014) and faias and a. zambrano (2017) . however, with the exception of the extreme returns associated with market crashes or booms, we find that the returns closely follow normal distributions. therefore, estimating risk using traditional risk measures while falling to distinguish return data sets between normal situations and crash situations, we will overestimate risk in a normal market and underestimate it in a crash situation. thus, measuring risk under normal versus extreme conditions separately is critical in portfolio decision-making. wilmott (2007) introduced a risk measuring system called crashmetrics to deal with risk problems during a crash. it parallels riskmetrics (j. p. morgan (1996) ) for market risk and creditmetrics (j. p. morgan (1997) ) for credit risk in normal market conditions. whereas these latter systems based on var work well in normal market conditions, crashmetrics addresses risk management in extreme market conditions. in crashmetrics (wilmott (2007) ), the portfolio risk under crash conditions, i.e., crash risk, is defined as the worst-case realized return of the portfolio where uncertain asset returns are modeled as a suitable set containing all possible returns. this measure of crash risk makes sense since it is approximately the loss of the portfolio in the situation where all the assets fall more or less simultaneously. managing crash risk is an issue even more important than how to measure it. since diversification does not work in a crash, hedging using options and/or other derivatives is a natural choice (see, e.g., wilmott (2007) ; hull (2009) ). although much literature has investigated the hedging of portfolio risk using derivatives, there is relatively little research on portfolio optimization involving derivatives. isakov and morard (2001) and liang et al. (2008) discuss the mean-variance portfolio selection using options. investigate the conditional value-at-risk (cvar) model based portfolio optimization problem considering only derivatives. also based on cvar risk measure, a stochastic portfolio model incorporating options is studied by topaloglou et al. (2011) , and the model is solved by its corresponding deterministic linear programming form with scenario generation techniques. cui et al. (2013) propose a general hedged portfolio optimization approach based on risk measure calculated by the approximate parametric var. zymler et al. (2013) use a robust optimization approach to investigate the var based derivative portfolio optimization problem when the required complete distribution information is unavailable. faias and santa-clara (2017) note that the option returns are asymmetrically distributed and propose a utility maximization framework for the portfolio selection involving european options held to maturity. they conclude that the effective performance of the approach is mostly obtained by exploiting mispricing between options. research on portfolio optimization tends to focus on normal risk even for those on the derivative portfolio optimization. there seems to be no research directly addressing the issue of portfolio optimization using derivatives to hedge the disaster caused by a market crash. the rest of the paper is organized as follows. in section 2, we propose a tractable formulation of the hedged portfolio with crash risk control. in section 3, we conduct a simulation analysis and an empirical study to test the proposed approach. concluding remarks are given in section 4. in this section, we discuss parametric approximation of the value change of a hedged portfolio and investigate the problem of measuring risk of a hedged portfolio in normal market conditions and in a crash, respectively. we then propose a tractable convex conic programming approach to solve the hedged portfolio optimization problem with crash risk control. we suppose there are m risky underlying assets and based on this there are n derivative assets. denote d t = (d t 1 , d t 2 , · · · , d t n ) and u t = (u t 1 , u t 2 , · · · , u t m ) as the value vectors of the derivative assets and their underlying assets at time t, respectively. let x = (x 1 , x 2 , · · · , x n ) ∈ r n and y = (y 1 , y 2 , · · · , y m ) ∈ r m denote the vector of holding amount of derivative assets and their underlying assets, respectively. then the value change of portfolio (x, y) over time period [0, ∆t] , the investment period we consider, can be expressed as where ∆d i and ∆u i denote the value change of derivative i and its underlying asset over time period [0, ∆t], respectively. generally, the price of a derivative is a function of factors, such as the prices and volatilities of the underlying assets, the risk-free interest rate and the time interval. we reasonably assume that derivative price is a sufficiently smooth function of some corresponding factors. recall some definitions of "greeks" (see, e.g., glasserman (2004) ; hull (2009)): where we omit the notation of time t for simplicity when it is unnecessary. then we can reasonably approximate the value change of derivative i over time period [0, ∆t] by taylor expansion using greeks as follows (see, e.g., glasserman (2004) ; hull (2009)): where the greeks are all calculated at time 0. of course, we can use additional terms of taylor expansion with respect to volatility of underlying asset and/or risk-free interest rate to produce a more accurate approximation, but the most influential factor is the price of the underlying asset. approximation (2) could be accurate enough (see cui et al. (2013) and the reference therein). combining (1) and (2), we can approximate the value change of portfolio (x, y) as x i θ i . in the sequel, the value change of portfolio (x, y) is defined by (3). remark 1 since the "more accurate approximation" of v(x, y) with additional terms associated with volatility of underlying asset or/and risk-free interest rate remains a quadratic form in u and a linear form in x and y, just as same as approximation (3), the problem reformulation done in the following according to approximation (3) can be similarly applied to "more accurate approximation". that is to say, the following derivation does not lose its generality in deriving a "more accurate approach". because of the unusual nature of a crash, traditional risk measures are not suitable for portfolio management. in this subsection, we discuss the measure and calculation of hedged portfolio risk in a normal market and in a crash, respectively. figure 2 , an example of a jointed distribution of value changes of two assets, illustrates the intuitive idea of distinguishing these two types of measures of risk. one thing deserving special mention is that a market boom can also cause large losses in a portfolio with a large short position. actually, a portfolio involving derivatives, such as the butterfly strategy, may encounter large loss even when there is no crash or boom. thus the concept of "crash risk" in this paper is best interpreted in the broader sense according to crashmetrics (wilmott (2007) ): the worst-case loss, not only the loss occurred in a real market crash. in a normal market, there are no extreme asset price movements and therefore the value changes of underlying assets can be effectively modeled with a normal distribution. in such a market, we can assume that the value change vector ∆u follows a multi-normal distribution, i.e., where µ and σ denote the mean vector and the covariance matrix, respectively. this assumption will be verified by empirical tests in section 3. the following useful results can be obtained on calculation of mean and variance of the value change of hedged portfolio ∆v(x, y). proposition 1 suppose ∆u ∼ n (µ, σ) and σ is nonsingular. then the mean and variance of ∆v(x, y) are given as here, tr(·) denotes the trace of a matrix and i denotes the m-dimensional identity matrix. with the results of proposition 1, we can analyze portfolios under the mean-variance framework. although variance might be the most popular risk measure adopted in portfolio management, it is only regarded as suitable for symmetrical return distributions. usually return of a derivative such as an option is asymmetrical. whether variance is a suitable risk measure for hedged portfolio with derivatives will be addressed in the following. denote ξ = σ −1/2 ∆u, where σ −1/2 is the inverse of σ 1/2 satisfying σ = σ 1/2 σ 1/2 . recall that ∆u ∼ n (µ, σ), which implies ξ ∼ n σ −1/2 µ, i , then we can reformulate (3) as: ∆v(x, y) = δ σ 1/2 ξ + 1 2 ξ σ 1/2 γς 1/2 ξ + θ∆t. defining a = σ 1 2 γς 1 2 , we can decompose the symmetrical matrix a as a = c λc, where λ is the diagonal matrix constructed by the eigenvalues λ 1 , · · · , λ m of a, and c is an orthogonal matrix consisting of the corresponding eigenvectors. denoting η = cξ, we have η ∼ n cς −1/2 µ, i . we can then express the change of portfolio value as ∆v(x, y) = c η + 1 2 η λη + θ∆t where c = (c 1 , . . . , c m ) = cς 1/2 δ. and by assuming λ 1 , . . . , λ h = 0 and λ h+1 , . . . , λ m = 0, h ≤ m without loss of generality, we can have then the first part of the right side of above equation can be written as from the above discussion, it can be seen that ∆v(x, y) is actually the sum of a linear combination of some independent χ 2 1 random variables, an independent normal random variable and a constant. now to clarify the normality of ∆v(x, y), we only need to verify the normality of a linear combination of independent χ 2 1 random variables. we can prove the following result: proposition 2 suppose z 1 , . . . , z n are independent normal random variables with means ζ i , i = 1, . . . n and unit variances, i.e., where e(z n ) and v (z n ) denote the mean and variance of z n , and the symbol " " means convergence in distribution. proof. see appendix b. for a clear understanding of the condition of proposition 2, let's consider the special case with λ i = λ and ζ i = 0 for i = 1, · · · , n. the condition holds for this special case since essentially, except for the assumption of normal distribution on the returns of underlying assets, the condition of proposition 2 indicates that there are two key points for z n = n i=1 λ i z 2 i to be close to a normal distribution: sufficiently large n and no dominant λ i . intuitively, these two points can be satisfied for a sufficiently diversified portfolio. in plain language, proposition 2 says that the return of a sufficiently diversified hedged portfolio is close to a normal distribution if the returns of underlying assets are normally distributed. now assume that ∆v(x, y) is normally distributed. then several other well-known risk measures, such as mad (mean-absolute deviation, see konno and yamazaki (1991) ), var (see jorion (2007) ), cvar (see rockafellar and uryasev (2000) ), can be uniformly defined as follows: ρ risk (x, y) τ 1 µ(x, y) + τ 2 σ 2 (x, y) where τ 1 and τ 2 are two constant parameters independent of decision variables x and y. thus, portfolio optimization using these risk measures is equivalent to that using variance as a risk measure (some mild condition is needed for var and cvar model, see rockafellar and uryasev (2000) ). artzner et al. (1999) proposed four axioms to qualify risk measures and called any risk measure satisfying these four axioms a coherent risk measure. of the four popular risk measures mentioned above, only cvar qualifies as a coherent risk measure. fortunately, in the situation of a normal distribution, portfolio optimization under a return-risk framework with risk measures other than variance is almost equivalent to that under the mean-variance framework. we can conclude from the above discussion that, under a normal market condition, variance is a suitable risk measure for diversified hedged portfolios. but downside risk measures, such as var and cvar, are better choices for non-diversified hedged portfolios even in a normal market. while could include downside risk measures in the model, we will focus on the mean-variance formulation as it is sufficient for diversified hedged portfolios. in this paper, a crash is identified as the situation where almost all asset prices fall suddenly. in such a situation, almost all asset returns are corrected perfectly and the change in portfolio value can not be well modeled as a random variable. since a risk measure is usually defined as a moment (e.g., variance and mad), a quantile (e.g., var) or a quantile-based moment (e.g., cvar) of the random return/loss, it is not suitable for measuring crash risk. when a crash happens, loss of a portfolio is almost an inevitable and can be interpreted, to a large extent, as the realization of portfolio return in the worst-case market condition. noting its speciality, we following wilmott (2007) and define the crash risk measure as where u is the set that contains all possible realizations of ∆u in an extreme market condition. intuitively, crash risk is measured by the worst-case realization of value change of a portfolio. actually, the above idea used to measure risk is not new. for example, it was employed for portfolio management by young (1998) , where the worst-case historical return is adopted as risk measure. although, worst-case return is too conservative to quantify risk under a normal market condition, it is obviously a proper risk measure for counting loss in a crash. the crucial issue left for computing crash risk is the determination of set u. as suggested by wilmott (2007) , a suitable choice of u is an ellipsoid defined as where · denotes the euclidean norm, λ 1 is an invertible matrix that scales the ellipsoid with respect to ∆u and λ −1 1 ∆u 0 is the ellipsoid center. since factor model is widely used in practical applications, computing crash risk according to a factor model will facilitate a realworld application. generally, a factor model is given as: where f j 's are factors driving the changes of asset values, β i0 is a constant, β ij 's are coefficients representing the sensitivities to factors, and ε i is the random residual error with zero mean. we assume that residual errors are independent with each others and also independent of all the factors, which implies cov(ε i , ε j ) = 0 for i = j and cov(ε i , f j ) = 0 for all j = 1, · · · , l. since ε i 's are the independent random residual errors with zero means, they shall have a small impact on the value of sufficient diversified portfolios. we can reasonably measure the crash risk according to factors f = (f 1 , · · · , f l ) as where ∆ṽ(x, y) is calculated according to (3) and (11) by omitting ε i 's andũ is defined as here, λ 2 is an invertible matrix that scales the ellipsoid with respect to f and λ −1 2 f 0 is the ellipsoid center. another advantage of using (12) as a measure of crash risk is that it can reduce the dimensionality of the problem. since the dimension of ∆u is usually high for a sufficient diversified portfolio, it is time-consuming to solve the corresponding optimization problem using crash risk defined by (9). the dimension of f is usually much lower than that of ∆u, hence formulating the problem with crash risk defined by (12) can significantly improve the computational efficiency. generally, how to choose λ 1 /λ 2 and ∆u 0 /f 0 should be problem-oriented. in this paper, we suggest an optimization approach to determine these parameters. more specifically, we can determine them by solving an ellipsoid covering problem, which can be equivalently formulated as a semidefinite program. the details will be discussed in empirical test in section 3. as we have noted above, crash risk is completely different from the normal risk. we propose a portfolio analysis framework that takes crash risk into account as this can help investor avoid large losses. such an analysis can be used to deal with portfolio risk more flexibly and effectively. letx denote the set of all admissible portfolios: where p x and p y are the prices of the derivative assets and their underlying assets at time 0, l x , l y and u x , u y are the lower and upper bounds of the investment amount of the derivative assets and the underlying assets, respectively. the price of an option is different when it is bought and sold. the difference between the two prices is exactly the ask-to-bid spread which is a nonnegligible transaction cost in derivative market. incorporating the ask-to-bid spread, the portfolio setx has the following form: where p ask x and p bid x are vectors of the ask and bid prices, respectively, and x + and x − are the vectors with max{x i , 0} and min{x i , 0} being the ith element, respectively. for the ask-to-bid spreads in option strategies, please refer to santa-clara and saretto (2009), eraker (2013) and faias and santa-clara (2017). following the framework of mean-variance analysis (markowitz (1952) ), we propose a meanvariance model with crash risk control as follows: whereσ andρ are pre-determined risk tolerance parameters with respect to the risk under normal condition and the crash risk under extreme condition. remark 2 in accordance with wilmott (2007) , the crash risk is defined as the "worst-case return". thus crash risk constraint is defined as ρ crash (x, y) ≥ρ in (p ) to control the extreme loss under a crash. as compared to the bicriteria mean-variance model, problem (p ) is a tricriteria decision model integrating crash risk. the model (p ) we propose is different from the existing tri-criteria portfolio selection models, such as mean-variance-skewness model (briec et al. (2007) ) and mean-variance-cvar model (gao et al. (2016) ). in our model, the two risk criteria are defined according to portfolio value distributions under normal v.s. crash market situations whereas in other models risks have been defined in terms of a common portfolio value distribution. optimizing a utility function, for example, constant relative risk aversion (crra) function, is also a method widely used for portfolio construction, especially for option strategies (bliss and panigirtzoglou (2004) ; faias and santa-clara (2017)). the expected utility maximization framework integrates all distribution information in a clear way. however, it is inconvenient for investors to specify their utility functions. even if the utility function is determined, the limitation may remain. as for the crra utility, the existence of expectation of crra utility is extremely fragile with respect to distribution assumption (geweke (2001) ). in contrast, the return-risk framework does not take into account all the distribution information. but it captures the key point of return-risk tradeoff and facilitates the practical application. in problem (p ), we can use (9) or (12) to define crash risk ρ crash (x, y), and regardless of which definition of crash risk is adopted, it can be translated into a semidefinite program. in the following, to avoid unnecessary repetition, we only show the details of reformulation of problem (p ) with crash risk defined by (9) and the details of using (12) is proposed in appendix b. first, we show that the first constraint on normal risk in (p ) can be formulated as a secondorder cone constraint. following cui et al. (2013) , we give the derivation below. attention needs to be paid to the fact that we can rewrite the second term in the right side of equation (5) as since σ is a covariance matrix, it is positive semidefinite and can be decomposed as σ = σ where σ 1 2 is symmetrical. notice that tr(abc) = tr(bca) = tr(cab). then we further have where the last inequality is from the fact that tr(a 2 ) ≥ 0 holds for any real symmetrical matrix a. thus, φ in (14) is a positive semidefinite matrix. since both φ and σ are positive semidefinite, we can decompose them as φ = m m and σ = l l. denote by (5), we can rewrite σ(x, y) ≤σ as the following second-order cone constraint which means that (x , y ) h ≤σ. second, we show that the constraint on crash risk defined by (9) can be reformulated as a semidefinite constraint. notice the constraint is defined as now we invoke the following well-known s-lemma (see, e.g., boyd et al. (1994) ) to demonstrate that constraint (16) can be equivalently formulated as a semidefinite constraint. then, according to the notations of lemma 1, δ ∆u + 1 2 ∆u γ∆u + θ∆t ≥ρ and ∆u ∈ u are f 0 (∆u) ≤ 0 and f 1 (∆u) ≤ 0, respectively. noting that f 1 (λ −1 1 ∆u 0 ) < 0, by lemma 1, the crash risk constraint is satisfied if and only if there exists a real number λ ≥ 0 such that note that a 0 (x), b 0 (x, y) and c 0 (x) are linear in x and/or y. turning to the portfolio set x , we notice that the term (p bid x ) x − in the budget constraint in x is not convex with x. we rewrite the budget constraint: due to the fact that the ask price is not lower than the bid price for an option, the constraint above can be transformed in the form: which is equivalent to a group of linear constraints thus, portfolio set x is a polyhedral set formed by linear constraints. using (4), (15), (17) and (18), we get the following proposition which means that the portfolio optimization problem with crash risk control can be solved by a tractable convex programming approach. proposition 3 problem (p) with crash risk defined by (9) can be transformed to the fol-lowing equivalent semidefinite program (sdp): if we omit the second constraint in (p 1 ), then it is referred as a second-order cone program (socp). socp and sdp are both instances of linear conic program, as they are a linear optimization problem under constraints represented by second-order cones or constraints represented by cones of positive semidefinite matrices. both of them can be regarded as an extension of linear program (lp). the interior point methods applied in lp can be easily extended to socp and sdp, which has been extensively investigated over the last two decades. lp is in fact a special case of socp, and socp is a special case of sdp, i.e., lp ⊂ socp ⊂ sdp. the reader is referred to lobo et al. (1998) and alizadeh and goldfarb (2003) for details of socp problems, and vandenberghe and boyd (1996) for details of sdp problems. the wide applications of conic programming in finance can be found in cornuejols and tütüncü (2006) . the portfolio optimization problem (p ) can also be defined as one of minimizing normal risk (under constraints placed on expected returns) as well as crash risk, and in this way can also be reformulated as an sdp. reformulation (p 2 ) of (p ) in terms of sdp with crash risk defined by (12) using a factor model is given in appendix c. in this section, we mainly conduct the simulation/empirical test to compare the performance of portfolio strategies generated by different models. the following four portfolio strategies are considered: 1) crash strategy without factor generated by model (p 1 ) without using factor model; 2) crash strategy generated by model (p 2 ) using factor model; 3) no crash strategy generated by model (p 2 ) without crash risk constraint; 4) no option strategy generated by model (p 2 ) without options. simulation/empirical test is based on historical data related to the index of dow jones industrial average (djs), the constituent stocks of djs and the options written on these stocks and index. in the following, we first investigate the characteristics of value/price change of djs constituent stocks, which is used to verify the motivation of this paper. we then conduct simulation and empirical analysis to compare in-sample efficient frontiers and outof-sample performance of different strategies by using data sets of the djs constituents and options written on them. finally, we conduct empirical test on the performance of different strategies based on data sets of djs index and the associate index options in subsection 3.3. all the calculations are conducted on a personal computer using matlab r2015b and stata 11.0, and the sdp problem is solved via cvx, which is a matlab-based modeling package for convex optimization problems. in this subsection, we investigate the characteristics of the value/price change of djs constituent stocks. we perform a test for one dimensional normality of stock returns using samples from january 2000 to december 2018. after deleting 2 constituents with missing data, 28 constituents are retained in the empirical study. notice that ∆u i = u ∆t i − u 0 i = r i u 0 i where r i denotes the return over time period [0, ∆t] . thus it can be inferred that the properties of ∆u i are characterized equivalently by r i since u 0 i is a pre-given parameter. we perform statistical test on the normality of stock returns by using different data samples associated with different time frequencies . since the test of joint normality in a highdimensional case is a hard thing, we just perform the test for one-dimensional case in this paper. we apply both kolmogorov-smirnov (k-s) test and jarque-bera (j-b) test of the normality of price change for each constituent of djs index. the data samples are divided into three categories: (i) full samples, (ii) full samples after removing those three times standard deviation above or below the mean and (iii) full samples after removing those two times standard deviation above or below the mean. confidence levels for statistical tests are set as α = 5% and 1%. the results of the test are summarized in table 1 . from the table, we can see that for daily data with relatively high frequency, price changes of a large part of stocks are non-normal whether or not the extreme data has been removed. but for weekly data and monthly data, after removing extreme cases with two standard deviations above or below the mean, the normality assumption on the price changes cannot be rejected for more than 95% of the stocks. based on the results of normality test, we cluster the historical returns of the corresponding index as follows: returns with two standard deviations above the mean, returns with two standard deviations below the mean, and the rest. accordingly, we classify the individual stock data samples as boom samples, crash samples and normal samples, respectively. factor model is usually used to describe the common features of a group of stocks. by statistical analysis, two-factor models are enough to model the returns of the constituents of djs index. figure 3 illustrates the distribution of two standardized factors for the historical daily returns of djs constituents. typically, the most typical characteristic is that the factor values during both a boom and a crash scatter near the two poles of the ellipsoid which covers all the realizations of factor values. this finding confirms that it is reasonable to use the worstcase realization of the portfolio returns within an ellipsoid covering all the possible returns to measure the crash risk. the details of data sets used in the analysis and test in this subsection are as follows: all the data for stocks and options are from bloomberg database. we divide the time period of each data set into in-sample period and out-of-sample period. for each data set, the out-of-sample period is the same as the time period of option data, while the in-sample period is the time period of the stock data after removing the out-of-sample period. for problem formulation related to data sets 1 and 2, we use lsm (least-square monte carlo simulation) method given by longstaff and schwartz (2001) to calculate or estimate the prices and "greeks" of american options. specifically, we simulate 20000 different 5-period paths of the underlying stock price under the risk-neutral measure. by the end of last period, the option will be exercised if it is in the money. the option will be exercised prior to the last period if the value of immediate exercise is more than the expected value of continuation. lsm uses least-square method to calculate the expected value of continuation which can sharply decrease the scale of simulation. when the exercise time has been determined on each path, we can calculate the price of the american option using the mean of the discounted exercising value on these paths. the "greeks" of american option can be calculated using finite difference method. for example, to calculate δ, we change the price of the stock for one unit and calculate the difference of the option price as an approximation of δ. γ can be similarly calculated by using second order difference. normal risk in the model is estimated only by normal samples. as to the ellipsoid involved in (10) or (13), we adopt the löwner-john ellipsoid, i.e., the minimum volume ellipsoid containing all the samples, as illustrated in figure 2 . calibrating this ellipsoid is a convex optimization problem (see, e.g., boyd et al. (1994) ), which can be solved by cvx when the number of data points is relatively small. we first calculate the center (mean) of the samples, then pick out the top ten percent data farthest from the center and reconstruct the minimum volume ellipsoid containing these data. finally, we add the data out of the ellipsoid and reconstruct the minimum volume ellipsoid containing all the samples. all the portfolio optimization models are constructed with the weekly data facilitating description and comparison. in this subsection, we compare the efficient frontiers of crash strategy without factor, crash strategy, no crash strategy and no option strategy. investment period is set as one week, the risk free interest rate r is set to be 5% per year, the total amount of derivatives is restricted within 30%, the upper and lower bounds for holding any assets are 10% and −10%, respectively. to calculate the efficient frontier of crash strategy without factor by model (p 1 ), we first determine the lower and upper bounds of parameterσ by minimizing and maximizing σ(x, y) under the constraint (x, y) ∈ x , respectively. then we choose 10 values ofσ uniformly in this interval. for each choice ofσ, we set the lower and upper bounds of parameterρ by minimizing and maximizing ρ crash (x, y) with constraints σ(x, y) ≤σ and (x, y) ∈ x . again we choose 10 values ofρ uniformly in this interval. finally, for each pair of (σ,ρ), we solve the optimization problem (p 1 ) to get the maximum µ, denoted byμ, and consequently we get the efficient frontier of crash strategy without factor sketched by the triples of (μ,σ,ρ). the calculations of efficient frontiers of crash strategy and no option strategy according to model (p 2 ) are basically the same as that according to model (p 1 ). it should be mentioned that the efficient frontier of no crash strategy is with some speciality since it does not consider the parameterρ. however, it can be regarded as the one generated by the model with crash risk control where the parameterρ is set sufficiently small. as no crash strategy does not take into account the constraint on crash risk, the corresponding efficient frontier is a two-dimensional curve lying exactly on the boundary (associated with highest crash risk) of the three-dimensional efficient frontier corresponding to crash strategy. thus, when an extreme event happens, the possible loss of a strategy without considering the crash risk could be very large. another interesting finding from these figures is that crash risk is positively correlated with normal risk. hence, the traditional minimum variance strategy is usually accompanied by a relatively small crash risk, which might be the reason why the minimum variance strategy performs well in practice. figure 4 show the efficient frontiers corresponding to no option strategy. we find that the efficient frontier of no option strategy is much narrower than that of crash strategy using options. furthermore, the former is totally dominated by the latter. this means that using option can not only bring a more flexible control on crash risk, while also enhancing the portfolio performance. using the leverage of option can nonetheless increase risk. in this subsection, we test the performance of different strategies in different market scenarios ranging from a crash to a normal and a boom market simulated using data set 1 and 2. we first generate the optimal crash strategy and no crash strategy with different parameters. then we simulate 100 different market scenarios, which gradually change from crash scenarios to normal and boom scenarios. specifically, we calculate the ellipsoid associated with factors defined by (13) the subfigures show that when an extreme crash happens, no crash strategy suffers a large loss, while high risk strategy bears a relatively small loss and low risk strategy basically maintains its initial value. in a normal market, the performance of crash strategy and no crash strategy are similar. in a boom market, no crash strategy performs better than crash strategy. these results suggest that crash strategy helps to avoid losses in a market crash but only at the cost of losing opportunities under a boom market. in this subsection, we compare the out-of-sample performance of crash strategies with no crash strategy in a rebalancing manner with real data. the data sets described in subsection 3.1 are used to construct portfolio strategies. note that the out-of-sample period is the same as the time period of option data. for two data sets, we setρ = −0.05, −0.15 andσ = 0.15. the portfolio strategies are denoted as low risk and high risk according to different choices of crash risk parameterρ, respectively. the other parameters required by model (p 2 ) are set the same as in subsection 3.2.2. we start with an initial wealth p 0 = 1 and update the portfolio strategies every week. we estimate the required parameters at the beginning of each week using the samples taken prior to the portfolio rebalance, and reconstruct the portfolio strategies with the updated parameters. we calculate the portfolio value at the beginning of every week during the out-of-sample period using the real data. as trading costs have a significant influence on the performance of option portfolios during the rebalancing strategy we take them into account in the form of ask-to-bid spreads in the rebalance process. the detailed process is described as follows. at the initial time, we solve the problem (p 2 ) and generate an initial portfolio (x 0 , y 0 ). denote the cash k 0 = 1 − p ask assume that (x t , y t ) and k t are the portfolio and cash amount generated at the beginning of week t. the total value of the strategy at week t + 1 is calculated by where p ask x and p bid x are the ask and bid prices of options, p y is the constituent price at week t + 1, and r is the riskfree rate. at the beginning of week t + 1, we rebalance the portfolio strategy based on the existing portfolio (x t , y t ) and the cash k t . here, the admissible portfolio where p ask x , p bid x are the ask and bid prices of options at week t + 1, p y is the stock price at week t + 1, and a + , a − are the vectors with max{a i , 0} and min{a i , 0} being the ith elements, respectively. solving problem (p 2 ) with setx generates portfolio x t+1 , y t+1 , and the cash we also calculate the weekly returns of these strategies during out-of-sample period. tables 2 summarizes the results: mean return (meanret), standard deviation (std), minimum return (minret), average drawdown (add), upside potential ratio (up ratio) and downside sharpe ratio (ds ratio). here, we just recall the details of the average drawdown and upside potential ratio, because they are not as common as others in the literature. the average drawdown is defined as (alexander and baptista (2006) ; chekhlov et al. (2005) ): where w t is the portfolio value at time t during the out-of-sample period. the upside potential ratio (see sortino and van der meer (1991) ) measures the ratio of higher partial moment of order 1 with the lower partial moment of order 2 under a target return level τ : where r 1 , · · · , r n are weekly returns during the out-of-sample period. here, we set τ the mean return of djs index. the downside sharpe ratio (see ziemba (2005) ) is defined as the ratio of the mean return to the square root of lower semivariance. according to the listed 6 performance measures, among the three type of strategies, the low risk strategies have slight outperformance when compared with high risk strategies and no crash strategies. to detect the performance of the strategies during the 2007 -2008 crisis, we also conduct an analysis over a time period from january 2007 through december 2018. unfortunately, we cannot obtain real option data during the crisis. thus, we simulate a series of european options based on the constituents of djs index. in the test , the set of candidate assets contains the constituents of the djs index and simulated european options based on these constituents. we use the historical prices of the constituents of the djs index from january 2000 through we construct 4 one-month-to-maturity options for each constituent including four options: an atm call, an atm put, a 5% otm call and a 5% otm put. all the prices and "greeks" of these options are calculated under the black-scholes pricing formula. we can see that, during 2007 to 2009, the strategy with low crash risk could resist a crash and gain the best portfolio value. on the other hand, during the boom period, no crash strategy has an evident advantage of portfolio value when compared with crash strategies at both required risk levels as well as djs index. table 3 summarizes the monthly returns of these strategies from 2007 to 2018. the strategy with low crash risk has the minimum standard deviation, the highest minimum return, the best downside sharpe ratio and the minimum average drawdown among these three strategies. in this subsection, we analyze the performance of different portfolio strategies constructed using index and index options, including no crash strategy and two crash strategies with two different required crash risk levels. compared with the data set related to constituents of djs index , we can collect more real data of the djs index related options, so we can conduct relatively long-term test. here, the upper and lower bounds for option are 0.5 and -0.5, respectively. we start with an initial wealth of 1 in may 2019, and rebalance the strategies every week. the portfolio value are evaluated the same way as before, and the only difference is that we evaluate the portfolio value by delivering the options in the third friday of every month. in the model, we setσ = 0.02 andρ = −0.05, −0.15. other parameters are set in a same way. figure 9 displays the portfolio value of these strategies from may 2019 to may 2020. it is obvious that the low risk strategy performs better than other strategies, especially during the volatile months. table 5 list the different performance measures of these strategies. the strategy with low crash risk performs best in average return, upside potential ratio, downside sharpe ratio and average drawdown among the six performance measures. from these results, it seems that the model with crash risk control can generate a stable strategy by reducing the opportunities of a boom market. this is not, however, the case in practice. in the test, call and put options are both used in portfolio construction, and crash and boom data samples are both covered by the ellipsoid adopted to measure crash risk. in this setting both crash and boom could cause heavy losses. therefore only stable strategies can satisfy the crash risk constraint. the model allows for flexibility to suit different purposes. if one wants to hedge the risk resulting from a crash but also wants to avoid losing the opportunities of a rising market, then it is possible, for example, to hold a put option while shrinking the ellipsoid for measuring crash risk covering only the crash down data samples. in this paper, we have investigated performance measures, hedging and optimization of portfolio selection involving crash risk. the basic idea for dealing with crash risk has been to distinguish the modeling of return in normal market conditions from that in the extreme situation of a market crash. following wilmott (2007) , we define the crash risk as the maximum potential loss in an extreme situation and show that it is reasonable to use an worst-case realization of the portfolio return within an ellipsoid to measure it. we have also clarified that the return (value change) of a sufficiently diversified hedged portfolio in normal market conditions approximated with "greeks" is close to a normal distribution, thus its risk can be well captured by variance. we have further revealed that the optimal portfolio selection problem with crash control can be translated into an efficiently solvable semidefinite program. in addition, we have compared the performance of a crash strategy with that of a no crash strategy via both a simulation analysis and an empirical test. the results have shown that the crash strategy can resist crash, while the no crash strategy cannot. nonetheless the crash strategy may lose its opportunity in certain situations, for example, a stable strategy with crash control in any market conditions will bear heavy losses in a boom market. this is to be expected as the crash strategy cannot completely dominate the no crash strategy. in fact, the two-dimensional efficient frontier of no crash strategy lies exactly on the boundary of the three-dimensional efficient frontier of the crash strategy. that's to say the no crash strategy can be regarded as a crash strategy with a sufficiently loose parameter for crash risk control. finally, it should be mentioned that the simulation analysis and empirical test done in section 3 exhibit only the outcomes for the case that the ellipsoid used to measure crash risk is selected as the one covering all the historical returns, which is clearly the most conservative but not the necessary choice. investment is not only a "science", but also an "art". although our focus has been on the science aspect, the art aspect (e.g., predicting the future and determining the location and size of the ellipsoid used to capture the crash risk) is critical to successful practice and should be problem-oriented, and to this end we suggest that the model with crash risk control offers greater flexibility. appendix a: proof of proposition 1 recall that ∆u ∼ n (µ, σ) and ∆v(x, y) δ ∆u + 1 2 ∆u γ∆u + θ∆t since σ is a covariance matrix, thus it is positive semidefinite and can be decomposed as σ = σ then the change of portfolio value can be further reformulated as where ξ ∼ n σ − 1 2 µ, i . we can decompose the real symmetrical matrix ω as ω = cλc , where λ is the diagonal matrix constructed by the eigenvalues λ 1 , · · · , λ m of ω, and c is an orthogonal matrix consisting of the corresponding eigenvectors. let z = c ξ, we can express 1 2 ξ ωξ as a linear combination of independent χ 2 1 random variables: recall the fact that if ζ is a normally distributed random variable with mean µ and variance σ 2 . then we have that the random variable ( ζ σ ) 2 follows noncentral χ 2 -distribution with mean 1 + ( µ σ ) 2 and variance 2 + 4( µ σ ) 2 . by (20) and (21), we have that µ(x, y) = e (∆v(x, y)) by (20), the variance of ∆v(x, y) is given as σ 2 (x, y) = var (∆v(x, y)) = var δ σ 1 2 ξ + var 1 2 ξ ωξ + 2cov δ σ 1 2 ξ, 1 2 ξ ωξ . it is easy to see that the first term of (22) equals δ σδ. let's consider the second and the third terms in the sequel. where the third equation is based on the fact that cov δ σ 1 2ξ , 1 2ξ ωξ = 0 due to the the expectation ofξ equals zero (see lemma 2 of stein (1981) and page 175 of britten-jones and schaefer (1999)). by (22), we have that σ 2 (x, y) = δ σδ + 1 2 tr (γς) 2 + µ γσγµ + 2δ σγµ the proof is completed. remark 4 britten-jones and schaefer (1999) derive the similar results for the special case of ∆u ∼ n (0, σ). cui et al. (2013) derive the the same results under the additional condition that γ is nonsingular. we first introduce the following lévy's continuity lemma (van der vaart (1998) . since the characteristic function of standard normal distribution is e − 1 2 t 2 , according to lemma 2, to prove y n n (0, 1), we only need to prove lim n→+∞ e e ityn = e − 1 2 t 2 or equivalently lim n→+∞ ln e e ityn = − 1 2 t 2 . recall that the mean and variance of z 2 i are 1+ζ 2 i and 2+4ζ 2 i . let m = n j=1 λ 2 j 1 + 2ζ 2 j . notice the fact that the characteristic function of z 2 j is (1 − 2it) − 1 2 e it 1−2it ζ 2 j , then we have . denoting a j = by using (4), (15) and (25), we get the following equivalent sdp reformulation of portfolio selection with a drawdown constraint minimizing cvar and var for a portfolio of derivatives second-order cone programming coherent measures of risk option-implied risk aversion estimates linear matrix inequalities in system and control theory mean-variance-skewness portfolio performance gauging: a general shortage function and dual approach non-linear value-at-risk drawdown measure in portfolio optimization optimization methods in finance nonlinear portfolio selection using approximate parametric value-at-risk an overview of value at risk the performance of model based option trading strategies equity premium predictability from cross-sectoral downturns. available at ssrn 2617242 optimal option portfolio strategies: deepening the puzzle of index option mispricing mean-risk analysis with risk associated with below-target returns dynamic mean-risk portfolio selection with multiple risk measures in continuous-time a note on some limitations of crra utility monte carlo methods in financial engineering options, futures and other derivatives improving portfolio performance with option strategies: evidence from switzerland value at risk: the new benchmark for managing financial risk tail risk and asset prices mean-absolute deviation portfolio optimization model and its applications to tokyo stock market optioned portfolio selection: models and analysis applications of second-order cone programming valuing american options by simulation: a simple least-squares approach portfolio selection optimization of conditional value-at-risk option strategies: good deals and margin calls downside risk estimation of the mean of a multivariate normal distribution. the annals of statistics optimizing international portfolios with options and forwards asymptotic statistics semidefinite programming paul wilmott introduces quantitative finance a minimax portfolio selection rule with linear programming solution the symmetric downside-risk sharpe ratio worst-case value-at-risk of non-linear portfolios this research is supported by national natural science foundation of china under grants 71471180, and 71721001. we authors would like to thank the reviewers of the paper for their insightful comments. appendix c: semidefinite programming reformulation of (p ) with crash risk defined by (12) we just need to show that the constraint on crash risk defined by (12) can be reformulated as a convex semidefinite constraint similar to that defined by (9). according to (12), we havewhere β 0 = (β 10 , · · · , β m0 ) and b = (β ij ) m×l and f = (f 1 , . . . , f l ) . then the constraint on crash risk is equivalent tonow we use lemma 1 to demonstrate that (24) can be reformulated as a semidefinite constraint.according to the notations of lemma 1, δ (β 0 + bf ) + 1 2 (β 0 + bf ) γ(β 0 + bf ) + θ∆t ≥ρ is actually f 0 (f ) ≤ 0, and f ∈ũ is actually f 1 (f ) ≤ 0. noting that f 1 λ −1 2 f 0 < 0, by lemma 1, the crash risk constraint is satisfied if and only if there exists a real number λ ≥ 0 such that the values of european call and put options in terms of black-scholes formula are given as:s − the underlying asset price at current time t;k − the exercise price;t − the expiry time;σ − the volatility of the underlying asset return;r − the riskless return;n (x) − cumulative probability distribution function of standard normal distribution.the "greeks" under black-scholes pricing formula are summarized in table 6. key: cord-308169-a0ft6wdy authors: custovic, a.; johnston, s. l.; pavord, i.; gaga, m.; fabbri, l.; bel, e. h.; le souëf, p.; lötvall, j.; demoly, p.; akdis, c. a.; ryan, d.; mäkelä, m. j.; martinez, f.; holloway, j. w.; saglani, s.; o'byrne, p.; papi, a.; sergejeva, s.; magnan, a.; del giacco, s.; kalayci, o.; hamelmann, e.; papadopoulos, n. g. title: eaaci position statement on asthma exacerbations and severe asthma date: 2013-11-06 journal: allergy doi: 10.1111/all.12275 sha: doc_id: 308169 cord_uid: a0ft6wdy asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. this position paper, from the european academy of allergy and clinical immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult‐to‐treat asthma and severe treatment‐resistant asthma. it reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment‐resistant asthma. there is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult‐to‐control asthma. appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult‐to‐control asthma. further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma. and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma. at a recent summit organized by the european academy of allergy and clinical immunology (eaaci), a group of experts discussed current issues of concern and unmet needs in regard to the treatment of asthma. most attendees presented evidence that the current guideline-driven treatment strategies fail in two vital aspects of asthma. there was a general consensus that the needs of patients with severe asthma or frequent asthma exacerbations are not being adequately covered by the current treatment guidelines and are of major health and socio-economic concern. such patients suffer from significantly reduced quality of life and incur disproportionately higher costs on health service resources. this report summarizes the current data that indicate the need for a more rational approach to the treatment of asthma and one that takes into account the emerging evidence for pathophysiological heterogeneity of the disease, including its more severe forms. a significant outstanding problem in the clinical management of asthma is the failure to prevent and/or efficiently treat asthma exacerbations, which are associated with significant morbidity, risk of death and high treatment cost (1) (2) (3) . generally, an asthma exacerbation is considered to be an increase in a patient's asthma symptoms with increasingly impaired lung function that require increased medication, an unscheduled visit to a physician or hospitalization. a single asthma exacerbation requiring extra medication and possibly emergency treatment and hospitalization can increase the annual treatment costs by more than threefold (3) . recurrent asthma exacerbations lead to a progressive decline in lung function (4) , and the risk of an exacerbation doubles in children who have had one or more in the previous year (5) . a rare but distinct phenotype of asthma exacerbation is characterized by the development of sudden severe asthma symptoms in an otherwise mild or asymptomatic asthmatic subject, which may be triggered by an allergen, drug (e.g. aspirin), food, air pollutant, occupational agent, virus infection or, in many cases, an unknown (or unidentified) trigger (6) . it has been proposed that within the group of patients with recurrent exacerbations, detailed phenotyping in terms of clinical symptoms, lung function, inflammatory and other biomarkers is warranted (7, 8) . there is a significant unmet need for identifying and characterizing the factors that increase the risk of asthma exacerbations and the therapeutic and preventive options that reduce these risks. patients with severe asthma have high morbidity and mortality, often require hospitalization and are expensive to treat. they have diverse clinical profiles, which probably reflect diverse disease mechanisms, and, for many of them, standard treatment is not sufficiently effective (9) (10) (11) . severe asthma comprises a highly heterogeneous group of patients, which is defined in various ways in the published literature and in the national and international guidelines. a consensus is emerging that patients should be considered to have a 'difficultto-control asthma' if they have persistent symptoms and recurrent exacerbations despite being prescribed therapy at the highest steps of the guidelines' pharmacological management (12) . however, it is worth emphasizing that the guidelines also make clear that 'difficult-to-control asthma' is multifactorial, and issues such as incorrect diagnosis, comorbid conditions, nonadherence to prescribed medication, psychosocial morbidity and a number of other factors discussed later in this manuscript are major causes of 'difficult' asthma (12) . patients should be considered to have severe asthma that is resistant to currently available therapies only following a detailed analysis and appropriate management of all these background problems that are amenable to intervention. a recently published consensus statement on severe asthma broadened the concept of 'difficult asthma' to reflect the situation in less developed countries, where access to medications and appropriate care is a major issue, by defining three different patient groups including un(der)treated symptomatic patients, patients with low treatment adherence or unconventional therapies, and those remaining symptomatic despite high doses of anti-asthmatic therapies (13, 14) . nonadherence to prescribed medication has been identified in a number of studies in the developed countries as the most common clinical problem amongst adults (15) and children (16) with asthma, including those with difficult-to-control asthma (15, 17) . appropriate assessment of adherence (18) and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors, etc.) (19) has to be a priority in clinical assessment of all patients with difficult-to-control asthma, before any decision about increasing the treatment is made (including possible prescription of an expensive biological therapy) (17) . the clinical diversity and the underlying pathophysiology of severe treatment-resistant asthma need to be characterized, so that rational therapeutic targets can be identified and relevant biomarkers validated (20) . in addition, there is a need for controller as well as noninterventional studies in this patient population. although inhaled corticosteroids may protect against asthma exacerbations due to allergen exposure, they are reported to be relatively ineffective in children with virus infectioninduced wheezing (21) . this suggests the existence of different types of childhood asthma with different underlying pathophysiologies (22, 23) . recent joint modelling of longitudinal observations on wheezing from parental reports and medical records identified a novel phenotype of persistent troublesome wheeze with high rates of severe asthma exacerbations and healthcare utilization (24) . despite having phenotypic markers commonly considered to be indicators of good therapeutic response (atopy and eczema), these children had relatively poor response to currently available antiinflammatory treatments (24) . an atopy-related phenotype of children with high risk of asthma exacerbations has recently been identified by bayesian inference in two birth cohort studies in which multiple skin and ige tests were collected throughout childhood (25, 26) . the analysis revealed several different atopic vulnerabilities, only one of which had a much higher risk of asthma exacerbations (25, 26) . however, this group of children with a significant risk of asthma exacerbations was identified only using longitudinal data, and cross-sectional biomarkers allowing their identification in clinical practice are still lacking. several attempts have been made to identify predictors of asthma exacerbations. several comorbidities associated with recurrent asthma exacerbations have been identified in adult patients (27) , including severe nasal sinus disease, gastrooesophageal reflux disease, recurrent respiratory infections, psychological dysfunction and obstructive sleep apnoea. psychological dysfunction (28) and treatment nonadherence are separate psychosocial factors that may significantly contribute to the risk of asthma exacerbations. a significant number of patients with high rates of asthma exacerbations, and increased airway eosinophilia, were found to have a low perception of their lung dysfunction (29) . asthma exacerbations are frequent in asthma patients with poor treatment adherence, and poor adherence remains one of the major challenges in the treatment of severe asthma (15, 18) . the basis of asthma treatment guidelines is the use of clinical symptoms or impaired lung function to guide treatment of airway inflammation. however, there is a strong rationale for using direct measurement of airway inflammation as an additional means to guide treatment in severe asthma. green et al. (30) reported that titrating treatment to sputum eosinophil counts was more successful in reducing asthma exacerbations than treatment in accordance with guidelines. this was confirmed in a larger, multicentre study (31) , which also reported that the frequency and severity of eosinophilic exacerbations were reduced without increasing the dose of inhaled corticosteroids (ics) (the severity but not the frequency of noneosinophilic exacerbations was also reduced). the treatment strategy of these authors was to (i) treat patients with sputum eosinophil counts of >2% with the minimal ics dose required to reduce sputum eosinophil counts to normal and (ii) consider other treatment options in patients with normal sputum eosinophil counts, such as treatment of airway obstruction with long-acting beta-agonists (labas) or a leukotriene receptor antagonist, or treatment of neutrophilic inflammation with antibiotics. of interest, a treatment approach aimed at specifically reducing airway eosinophils using a monoclonal antibody directed against interleukin (il)-5 reduced the risk of asthma exacerbations in patients with severe asthma and persisting airway eosinophilia (32, 33) . however, it is of note that even after using this targeted approach, approximately 50% of severe exacerbations remained unaffected by the treatment. attempts to identify clinical biomarkers for predicting the risk of asthma exacerbation have so far failed. however, some small studies have identified possible candidate biomarkers. for example, gelb et al. (34) evaluated the use of spirometry and exhaled nitric oxide (f e no) in predicting the risk of asthma exacerbations in 44 stable, mild-to-severe patients with asthma over 18 months. those patients with a baseline fev 1 < 76% of predicted plus an f e no >28 ppb had a probability of an asthma exacerbation in 18 months of 85%, while those with fev 1 > 76% of predicted plus a f e no <28 ppb had zero probability of an asthma exacerbation in the same period. the f e no parameter may be a robust measure of the degree of eosinophil airway inflammation (35, 36) . numerous epidemiological studies indicate that asthma exacerbations are associated with upper respiratory viral infections, mostly with rhinoviruses, and to a lesser degree with respiratory syncytial virus or coronavirus, with frequency estimates of 85% and 60% for childhood and adult asthma, respectively (37, 38) . this was confirmed by the ga 2 len-dare systematic review (39) that reviewed data from 98 published epidemiological studies. the data for childhood asthma are more extensive than that for adult asthma and reveal the absence of geographical influence. the same review indicated that high rates of respiratory bacterial infections are also associated with asthma exacerbations, but the data are inconsistent. however, bisgaard et al. (40) provided evidence that bacterial infection and viral infection were independently associated with wheezing episodes in infants (<3 years old), with odds ratios of 2.9 and 2.8, respectively. although confirmatory studies need to be performed, current data strongly suggest that respiratory infections are the major cause of asthma exacerbations. case-control studies have revealed a synergism between viral infection and allergen exposure in increasing the risk of asthma exacerbation requiring hospitalization in children (41) and in adults (42) . atopic asthmatic patients have more severe and prolonged lower respiratory tract symptoms during rhinovirus infections than nonatopic healthy controls (43) . this may be explained by impaired innate and acquired immunity of the airways in asthma, as indicated from the studies of experimental and clinical viral infection (37, 44) . such impairments in airway immunity correlate with the in vivo severity of the infections and with the viral load (45, 46) . consequently, specific and nonspecific antiviral strategies may have great potential as therapeutic and preventative strategies for asthma exacerbations, a hypothesis that is supported by preliminary clinical studies (37) . patients with asthma also have deficient interleu-kin-12 and type iii interferon responses to bacterial stimuli, suggesting that inadequate host defence mechanisms and mechanisms specific to the infectious agents are the underlying factors for increased susceptibility (45, 46) . rhinovirus and enterovirus infections are more likely to cause an asthma exacerbation than most other viruses in patients of any age, with the exception of rsv in infants (39) , while virus load and virus co-infection rates correlate with symptom severity (47) . case-control studies indicate that asthma subjects are at greater risk of invasive pneumococcal infections than patients without asthma, with reported ors ranging from 2.5 to 12.0 (48-50). for example, the population-based case-control study by klemets and colleagues (49) assessed the risk of invasive pneumococcal (streptococcus pneumoniae) infection (ipi) amongst adult patients with asthma. using a national population-based laboratory surveillance, 1,282 cases of ipi were selected in patients aged 18-49 years (thus largely excluding copd patients) along with 10 noninfected controls per ipi case, matched for age, sex and health district. asthma cases were categorized as high (≥1 hospitalization within the previous 12 months) and low risk (with prescription drug entitlement and no hospitalization within the previous 12 months). overall, 7.1% of cases had asthma (6.0 and 2.4% with high-and low-risk asthma, respectively) vs 2.5% of controls (1.0 and 1.1% with high-and low-risk asthma, respectively), indicating that adults of working age with asthma are at substantially increased risk of ipi. impaired immune responses may be associated with exacerbations in asthmatic children with reduced lung function, but not in those with normal lung function (51) . specifically, at the time of an asthma exacerbation, a lower expression of th1 response genes was observed in children with reduced lung function than in children with normal lung function. other studies have shown that genetic factors such as vitamin d (52) or particulate matter (pm 10 ) (53) can modify the effect of environmental exposure on exacerbation frequency. the advent of genomewide association studies in populations with severe asthma (54) and asthma exacerbations (55) may aid in better prediction of exacerbation phenotypes and the subclassification of patients into subphenotypes that may reflect the differing aetiopathogenesis and response to treatment and so allowing better targeting of treatment. attempts to characterize severe asthma in childhood in childhood asthma, guidelines that outline stepwise treatment escalation with increased disease severity or impaired symptom control fail to adequately deal with nonresponders (56) (57) (58) . in particular, the stepwise treatment appears not always to be appropriate for children younger than 4 years, particularly those with mainly virus-driven asthma, who often do not respond to inhaled corticosteroids (57) . severe asthma in children is complex, with the asthma phenotype changing during development and requiring continual reassessment (56, 58, 59) . this makes cross-sectional analyses of childhood asthma less useful, as any apparent phenotypic stability within a population will obscure the significant individual instability of disease expression. one of the characteristics of severe treatment-resistant asthma in childhood is the large size of skin test wheal to inhalant and food allergens (60) . furthermore, in this patient group, the results of skin tests and ige measurements for individual allergens are not always concordant; as a consequence, both tests should be carried out and quantified (61) . similar quantitative relationship between skin tests (and sige levels) has also been reported in relation to severity of airway hyper-reactivity in adults (62) . rhinovirus infection in infants induces wheeze and, in a longitudinal study, was shown to be significantly associated with the development of childhood asthma (63) . in another 11-year prospective study, teenage asthma was strongly associated with infant wheezing requiring hospitalization (64) . this study identified eczema and allergen-specific ige as early asthma-predictive factors and the risk of developing teenage asthma to be increased fivefold after respiratory syncytial virus-induced wheezing in infants and >10-fold after rhinovirusinduced wheezing. rhinoviruses are frequently found in the lower airways in infants with recurrent respiratory symptoms, with the majority of these rhinovirus-infected infants exhibiting increased airway resistance (65) . in infants with wheezing requiring hospitalization, sole rhinovirus infection, but not sole infection with any other common airway viruses, was associated with atopy (66) . a recent study has demonstrated that a cardinal feature of bronchial epithelial cells from children with severe treatment-resistant asthma is impaired interferon-b and ifn-k induction by rhinovirus (67) . although this patient group was highly atopic, no relationship was observed between atopy, allergy or th2-mediated inflammation with impaired interferon (67) . a longitudinal study of an unselected birth cohort, which monitored lung function from the age of 3-26 years (68), reported that persistent wheezing, starting early in life, was associated with a decline in lung function in adult life and increased risk of exacerbations. a decline in lung function has also been associated with severe asthma exacerbations in adult asthma (4) . a german birth cohort of more than 900 children showed that the risk of development of persistent asthma at age 13 years was significantly increased by early allergen sensitization in combination with exposure to high levels of perennial allergens early in life (69) . in a recent study, predictors of subsequent troublesome symptoms amongst 3-year-old children with wheezing were large skin test responses to allergens and history of previous exacerbations and eczema (24) . attempts to identify phenotypes of adult asthma include the use of unsupervised cluster analyses (70, 71) aiming to group patients who share key features of asthma and airway inflammatory disease. haldar and colleagues (70) grouped patients according to clinical symptoms and evidence of airway inflammation (based on sputum eosinophil count) and found that symptom-led treatment of airway inflammation was appropriate in patients with mild and moderate asthma, but failed in more severe forms. they identified two discordant groups of patients who were refractory to standard treatment approaches and represented about 25% of all patients. one discordant group of patients were characterized as an obese, symptom-predominant, noneosinophilic phenotype, while the other group had few asthma symptoms, but a high degree of airway inflammation. using symptom-driven asthma treatment in these two discordant groups would lead to overtreatment of the former and undertreatment of the latter group. one difficulty with attempts to use clustering techniques to define disease mechanisms is defining cause and effect. in other words, 'are the pathophysiological features a consequence or an underlying cause of the disease?' a further confounding factor is the influence of treatment or lack of it (nonadherence). defining groups of patients with chronic diseases according to different personality traits (72) has identified personality traits that govern treatment adherence. there was a significant overlap between the phenotypes identified by haldar et al. (70) and those identified by moore et al. (71) . other similar initiatives included the eu-sponsored unbiased biomarkers for the prediction of respiratory disease outcomes (u-biopred) consortium that has published a consensus-based systematic algorithm approach to differentiate between 'problematic', 'difficult' and 'severe refractory' asthma in the evaluation of patients with chronic severe asthma symptoms for use in clinical research and specialized care (73) . the published practal consensus report on 'endotypes' (74) attempts to assign patients with asthma to groups sharing specific pathophysiological features, with the aim of identifying a basis for rational treatment of heterogeneous groups. patients with severe asthma are found in each of these groups. three recognizable clinical phenotypes of severe asthma emerge from these various analytical studies (see table 1 ): (i) a severe atopic form, (ii) severe 'intrinsic' asthma (the most malignant severe asthma phenotype (75)) and (iii) severe asthma with obesity. however, it has to be emphasized that distinct pathophysiological mechanisms underpinning these different clinical phenotypes of severe asthma have not as yet been identified. one potential problem of the cross-sectional approach to unbiased clustering is that the analysis does not include the important dimension of time, which may be essential to take into account potentially crucial longitudinal changes. furthermore, while unsupervised learning may be a useful tool to generate new hypotheses, using these techniques to find an association with predefined outcomes such as severe asthma can be misleading if asthma severity is derived using the same variables that are used for clustering. there is mounting evidence to demonstrate a close association between sensitisation to fungi and asthma severity (76) , and the term 'severe asthma with fungal sensitization' (safs) has been proposed for patients with persistent severe asthma and fungal sensitization (77) . proof-of-concept pilot studies have suggested an improvement in asthma after antifungal treatment in this patient group (78) . several studies have shown that the standard guideline treatment of persistent asthma with ics provides a variable response, with 25-35% of asthmatic subjects showing little improvement in fev 1 and/or bronchial hyper-responsiveness (9) (10) (11) . in the gaining optimal asthma control ('goal') study (79) , bateman and colleagues used 1 year of increasing doses of combined ics and laba treatment in patients with persistent asthma and reported that about 30% of patients, with varying degrees of disease severity, did not achieve 'well-controlled asthma'. asthma exacerbation risk may be further reduced using the same medication (i.e. an inhaled combination of a rapid-acting beta-2 agonist and corticosteroid (80)) as a controller and as a reliever of the disease. the price trial (81) aimed to identify predictors of short-term (6 weeks) response to ics. although several baseline biomarkers and asthma symptoms correlated with short-term improvements, only greater bronchodilator (short-acting b2agonist) reversibility showed a strong (p < 0.001) correlation. differentiating between responders (>5% fev 1 improvement) and nonresponders (<5% fev 1 improvement) revealed that asthma control in responders was maintained only with continued ics, while, in nonresponders, no improvement was observed with or without ics. interestingly, tiotropium, a long-acting antimuscarinic agent, still approved only for copd, has been recently shown to further improve lung function in patients with severe uncontrolled asthma (82) . of the four clinical phenotypes of severe asthma described in table 1 , the severe atopic form partially responds to standard treatment. table 2 indicates possible treatment approaches in the two groups of patients with severe asthma, which were described by haldar et al. (70) , that are less responsive to standard treatment. these treatment options for patients with severe asthma who remain symptomatic despite adhering to standard medical care include novel anti-inflammatory drugs that have been shown in preliminary studies to be effective in treating airway inflammation in asthma and so warrant further investigation (32, (83) (84) (85) (86) , and other novel approaches such as bronchial thermoplasty (87) . it is important to note that, for a more effective use of these novel treatment options, a better understanding of the pathophysiology and of the inflammatory mechanisms of the severe asthma subtypes are required in order that studies can delineate specific response patterns. as previously noted, antifungal treatments may be of benefit in patients with severe asthma with fungal sensitization (78, 88) , but large studies are needed to support these initial findings. current treatment of asthma exacerbations is inadequate, and new approaches to treatment are needed. these may include interferon-based treatments, treatments that aim to boost deficient antiviral immune responses and/or specific antiviral treatments. there may be patients with severe asthma who could benefit from treatments that target neutrophilic inflammation without further suppressing anti-infective immunity. another question that needs to be addressed is the possible benefit in asthma exacerbations of antibacterial treatments that are widely used (89), despite not being recommended in guidelines. the advances in molecular biology and immunology are being used to develop novel biological drugs for asthma treatment. these include therapeutic antibodies, soluble receptors, cytokines, small molecules and combinations thereof that target different effector molecules that influence the underlying immune and inflammatory processes. some biological drugs are currently in clinical trials in asthma (90) . however, there are major difficulties in developing novel drugs to treat asthma. these include (i) the complexity of the disease (in terms of the different disease phenotypes and the underlying molecular mechanisms), (ii) the limited number of biomarkers that have been identified for disease classification, (iii) the effectiveness of the current standard treatment approaches (combined inhaled steroid and beta-adrenergic agonist is not only effective but cheap) makes any comparative improvement difficult to identify in multicentre clinical trials, (iv) low patient adherence, which is characteristic of treatments of chronic disease, and (v) preclinical animal models may be poorly predictive of clinical efficacy (90) . importantly, future clinical trials will need to identify the patient groups that respond to novel treatment to provide evidence for the stratified, personalized approach to asthma management. in primary care, recognition of the clinical heterogeneity of asthma and the existence of different forms of severe asthma is obscured by a number of general deficiencies, including limited available time and clinical resources and lack of capacity and clinical capability. nonguideline treatment of asthma is high, and provision of treatment to patients with asthma varies greatly, for example, in the use of ics across european countries (91) . the influence of comorbidities and of asthma exacerbations on asthma symptoms, in both children and adults, are not sufficiently recognized (92, 93) . most patients with asthma in primary care have been found to have uncontrolled disease (94) . furthermore, it is becoming increasingly clear that many patients diagnosed as asthmatic, even after full evaluation at tertiary centres, do not have asthma, but various other diagnoses (95, 96) , which indicate a fundamental need to establish improved diagnosis as a basis of appropriate management (97) . the resources needed to review patients frequently until disease control is achieved vary between healthcare systems. the finnish national asthma programme (98) , predicated on a systematic approach to disease management and underpinned by educational and skills training in primary care, demonstrates that investment in the structure of the health system that delivers asthma care reduces morbidity significantly and at a lower overall cost. the above discussion aims to highlight the prominent issues and the attempts to acquire a better understanding of asthma exacerbations and severe asthma. however, there are several additional clinical and pathophysiological issues of importance for improving our understanding of asthma as a complex disease. these have not been highlighted here partly because there is no scientific consensus of their exact relevance. however, two examples are briefly reviewed here. airway remodelling is associated with poor clinical outcomes amongst asthmatic patients, but the pathophysiological relevance of, and the effect of treatment on, airway remodelling is unclear (99) . airway remodelling is a feature of adult asthma and is found to a similar extent, and quite early, in children with difficult-to-treat asthma (100). using epithelial reticular basement membrane thickening as a marker for airway remodelling, no association between airway remodelling and age, symptom duration, lung function and concurrent eosinophilic airway inflammation was found (100) , albeit in a small number of patients. inflammatory and structural changes typical of asthma, such as airway eosinophilia and angiogenesis, have been observed not only in children with asthma but also in atopic children without asthma, raising the possibility that some of these pathological lesions may be associated with atopy even in the absence of asthmatic symptoms. reticular membrane thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in the wheezing infants with reversible airflow obstruction, even in the presence of atopy (101, 102) . it was proposed that this lack of rbm thickening in wheezy infants was due to the apparent paucity of eosinophilic inflammation (102) , which may have a role in driving allergic airway remodelling (103) . based on the data from many population studies, it is generally considered that the environment has an important influence on the development of asthma and other allergic diseases. however, the proposed mechanisms, particularly the role of atopy, that underlie the effects of environment on asthma aetiology need to be revised in the light of recent findings (104) , such as the evident increase in prevalence of severe asthma in developing countries and its parallel decline in several developed countries (105) . the interaction of environment and asthma disease mechanisms is complex, and genetic variants that are protective in one environment may be associated with increased risk in another environment (106) . • although clinical guidelines improve patient treatment by bringing treatments to groups of patients who best benefit from them, they fail many patients who fall outside of the 'mean' clinical characteristics on which clinical guidelines are based. labas is insufficiently effective in many patients with severe asthma. • young children, particularly those with virus-driven asthma, are often poorly managed with currently available medications. • in asthma, there is a need to focus more on the individual patient, particularly those with severe asthma. • there is a need to recognize asthma as a heterogeneous disease and to properly identify the different disease mechanisms involved in patients with severe asthma. only in this way, we will begin to understand what is 'driving' severe asthma and identify novel therapeutic targets. • in childhood asthma, expression of atopy varies over time and in different characteristic ways that suggest differences in underlying pathophysiological mechanisms in relation to exacerbation-prone asthma phenotype. • in adult asthma, several forms of severe asthma have become recognized, and different treatment approaches to these forms of severe asthma are proposed. • there is a need for a consensus definition of asthma exacerbation that could usefully guide treatment. we need to better understand the mechanisms of asthma exacerbation, develop novel treatments for exacerbations and carry out studies of existing and new treatments to better guide their use. • as in copd, asthma diagnosis and treatment decisions should include consideration of future risk of exacerbations. • current data strongly link impaired innate immune responses and consequent increased risk of infection with increased risk of asthma exacerbations. this provides a sound basis for the development of novel treatments. • there is general concern that patients with asthma are not being sufficiently alerted to the risk of asthma exacerbations and that another term be considered other than 'asthma exacerbation' when describing these events to patients (such as 'lung attack' or 'asthma attack' to equate the seriousness of such an event with a heart attack). • development of diagnostic procedures accessible within primary care to ensure correct diagnosis. • an acceptance of the need for iterative review to gain control of the disease; patients, in whom asthma fails to become controlled, need further evaluation to confirm that asthma is the correct diagnosis and what further evaluations are required. • improved tools for 'scoring' the asthma patient in terms of disease severity, and future risk needs to be developed for use in primary care (97, 107) . • future studies should aim to establish whether serum ige, f e no and induced sputum eosinophil counts are valuable biomarkers of the severity of asthmatic airway inflammation. • new biomarkers are needed to predict the severity of asthma, the risk of exacerbation and the response to treatments. • there is a need for a more objective definition of childhood asthma, with broader use of lung function tests, especially in preschoolers, and so obtain more uniform criteria for diagnosis before initiating treatment to control the disease. • in both childhood and adult asthma, expression of atopy varies over time and in different characteristic ways that reveal differences in underlying pathophysiological mechanisms, including a severe asthma-prone phenotype. • observational longitudinal studies should be performed in a standardized way with patient and biological data sampling (using an asthma register) to allow a better characterization of the epidemiology, current healthcare utilization, risk factors (including genetic susceptibility) and comorbidities that are linked to exacerbations and severity. • the future task is to devise studies that differentiate between patient phenotypes, use robust clinically relevant biomarkers, include longitudinal outcomes (such as time to exacerbation and increase in airway remodelling) and identify relevant environmental factors, including the influence of current and prior medication. to facilitate the identification of new asthma endotypes, such studies should contribute to a repository (or biobank) of biological samples from the asthma population. • for characterization of the heterogeneity of severe asthma, more and improved clinical studies are needed to improve the evidence base. • randomized, controlled trials in asthma include highly selected patients, who are, almost exclusively, 'healthy asthmatics' with ß 2 -agonist reversibility. • cohort studies may complement clinical trials. • there are still insufficient longitudinal data in adult asthma, and cohort studies in this age group need to be established. • improving primary care of the asthmatic patient is in need of urgent attention and requires radical changes. • the ideal approach to dealing with the asthmatic patient in primary care is to (i) characterize the patient, (ii) confirm diagnosis, (iii) confirm whether a new or existing patient gains control by the iterative application of a structured review (108) and consider reducing treatment when control is achieved, while undertaking appropriate monitoring, (iv) maintain control by teaching the patient about asthma and developing the patient's self-management skills (109) according to the model developed by glasziou (110) , (v) attempt to understand the patient's perspective; this may be the key to improving patient compliance (111) , (vi) consider the risk of exacerbations (which is separate from controlling everyday symptoms) and factors that may increase the risk of exacerbations (93) and (vii) realize that nonsymptomatic patients are also at risk of exacerbations. • the complexity of the multifactorial nature of asthma and the resource limitations in primary care needs to be better characterized in order to address the wide variability of care delivered in this environment (98) . • support mechanisms that enable readily accessible means for patient self-management and self-education, having already met with varying degrees of success (112) (113) (114) (115) , need to be further developed. • primary clinicians have themselves recognized the research agenda that is needed to direct improvement in asthma care (97). • whether seen in primary care or secondary care, patients with uncontrolled asthma either (i) have treatment-resistant disease, (ii) are not fully compliant with treatment, (iii) are unable to appreciate deterioration in their disease, (iv) have a physician who is underestimating the degree of disease control, is undertreating or not recognizing the effect of comorbidities, or (v) do not have asthma. l. m. fabbri has received consultancy fees from: boehringer ingelheim, chiesi, glaxosmithkline, msd, nycomed, pearl therapeutics, sterna, peer voice europe, om pharma sa, kyorin pharmaceutical, boston scientific and bayer. readings, advisory board or reimbursement of expenses: astrazeneca, novartis, sigma-tau, roche, deutsches zentrum f€ ur luft und raumfahrt, german aerospace center, mundipharma int., genetech inc., elevation pharmaceutical, ferrer group, nycomed, dynamicon and laboratori guidotti. e. bel has received consultancy fees from novartis, gsk and sanofi-regeneron, and fees for speaking from gsk. p. le sou€ ef has received speaker fees from glaxo smith kline and astrazeneca and has received research funding from astrazeneca and pharmanet ag. he has received research grants from the national health and medical research council of australia and the australian research council. j. l€ otvall has over the last five years been a consultant and/or given lectures for gsk, astrazeneca, aerovant, novartis, ucb, oriel and merck, for which he has received honoraria. he has also received research grants and participated in clinical trials for novartis, gsk, astrazeneca and actelion under the full organization of the university of gothenburg. p. demoly is a consultant and a speaker for stallergenes, alk, circassia and chiesi and is a speaker for merck, astrazeneca, menarini and glaxosmithkline. c. akdis serves in the scientific advisory boards of novartis, actellion, circassia, allergopharma and stallergenes. he received research grants from novartis, swiss national science foundation, swiss-polish research grant. d. ryan has been supported to attend conferences, provide consultancy services to or lectured on behalf of az, novartis, chiesi, mundipharma, msd and aerocrine. mika m€ akel€ a has received speaker fees from berlin-chemie menarini, glaxosmithkline, msd and orion pharma. he serves as a consultant for orion pharma. he from bronchoconstriction to airways inflammation and remodeling risk factors and costs associated with an asthma attack an international observational prospective study to determine the cost of asthma exacerbations (coax) severe exacerbations and decline in lung function in asthma the origins of asthma and chronic obstructive pulmonary disease in early life near-fatal asthma phenotype in the enfu-mosa 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outcomes in taiwan clinical and cost effectiveness of mobile phone supported self monitoring of asthma: multicentre randomised controlled trial slj is funded by the asthma uk clinical professorship (ch11sj). we acknowledge the editorial support of gerard p mcgregor, of omniscience sa, who was financed by a grant from the eaaci. the authors wish to thank professor christian virchow, universit€ at rostock medizinische fakult€ at, klinik & poliklinik f€ ur innere medizin, abteilung pneumologie, ernst-heydemann-str. 6, rostock, germany, for reviewing the manuscript and extremely useful comments. a. custovic serves as a consultant for circassia. he received speaker fees from glaxo smith kline, thermo fisher scientific, airsonet, novartis, msd and alk. he received research grants from the uk medical research council, moulton charitable foundation national institute of health research.in the past five years s. l. johnston has had research grants from astra zeneca, centocor, glaxosmithkline, med-immune, sanofi-pasteur and synairgen. s. l. johnston holds share options in synairgen. s. l. johnston does some consultancy work for astrazeneca, centocor, glaxosmithkline, medimmune, sanofi-pasteur and synairgen.in the last five years, i. d. pavord has received speaker's honoraria for speaking at sponsored meetings from astra zeneca, boehringer inglehiem, aerocrine and gsk. he has received honoraria for attending advisory panels with almirall, astra zeneca, boehringer ingelheim, gsk, msd, schering-plough, novartis, dey and napp. he has received sponsorship to attend international scientific meetings from boehringer ingelheim, gsk, astra zeneca and napp.m. gaga received research grants from novartis, bi, cephalon, teva and gsk. the other authors of the paper declare no conflicts of interest. key: cord-306741-3ibprszo authors: fitchett, jennifer m; swatton, deryn-anne title: exploring public awareness of the current and future malaria risk zones in south africa under climate change: a pilot study date: 2020-11-11 journal: int j biometeorol doi: 10.1007/s00484-020-02042-4 sha: doc_id: 306741 cord_uid: 3ibprszo although only a small proportion of the landmass of south africa is classified as high risk for malaria, the country experiences on-going challenges relating to malaria outbreaks. climate change poses a growing threat to this already dire situation. while considerable effort has been placed in public health campaigns in the highest-risk regions, and national malaria maps are updated to account for changing climate, malaria cases have increased. this pilot study considers the sub-population of south africans who reside outside of the malaria area, yet have the means to travel into this high-risk region for vacation. through the lens of the governmental “abc of malaria prevention”, we explore this sub-population’s awareness of the current boundaries to the malaria area, perceptions of the future boundary under climate change, and their risk-taking behaviours relating to malaria transmission. findings reveal that although respondents self-report a high level of awareness regarding malaria, and their boundary maps reveal the broad pattern of risk distribution, their specifics on details are lacking. this includes over-estimating both the current and future boundaries, beyond the realms of climate-topographic possibility. despite over-estimating the region of malaria risk, the respondents reveal an alarming lack of caution when travelling to malaria areas. despite being indicated for high-risk malaria areas, the majority of respondents did not use chemoprophylaxis, and many relied on far less-effective measures. this may in part be due to respondents relying on information from friends and family, rather than medical or governmental advice. malaria is a dangerous and potentially fatal vector-borne disease caused by the plasmodium parasite, transmitted to humans through the bite of an infected female anopheles mosquito (cohuet et al. 2010; cella et al. 2019) . in 2018, an estimated 228 million cases of malaria were reported globally, similar to 231 million cases for 2017, with a death toll of4 35,000 in 2017 and 405,000 in 2018 (alonso and noor 2017; who 2019a,b) . the burden of malaria was disproportionately borne by developing nations, particularly in the african continent, which accounted for 92% and 93% of the malaria cases and deaths recorded in 2018, respectively (alonso and noor 2017; who 2019b) . in 2016, in an effort to combat malaria, the world health organization launched the e-2020 initiative in which it identified 21 countries with the potential to eliminate malaria within their borders by the year 2020 (who 2018). south africa was one of those countries, with an additional local objective of elimination by 2018 (baker 2018) . however, in 2017, south africa experienced a severe setback in achieving both objectives, reporting 7897 imported and 19,706 indigenous cases of malaria-the highest number of cases reported by any of the 21 identified countries, and more than four times the number of indigenous cases reported in the country in 2016 (who 2018; maharaj et al. 2019; abiodun et al. 2020) . this increase in numbers was due to a range of factors, including an increase in rainfall, temperature, and humidity following an abnormally mild winter (baker 2018) . as a result, the world health organization has classed south africa as "off-track" and has made a number of recommendations as to how the country can steer itself back on course (who 2018) . among these are efforts to refine malaria risk maps, to improve public awareness, and to revisit malaria strategies (who 2018) . due to the unlikelihood of achieving malaria elimination within south africa by 2020, the south african government has now adopted the self-mandated goal of zero malaria transmission by 2023, which it announced in the malaria elimination strategic plan for south africa 2019-2023 (national department of health 2019). one of the primary objectives of the malaria elimination strategic plan is to "ensure that 90% of the population affected by malaria receives information and education communication messaging by 2023" (national department of health 2019: 25). this objective speaks directly to the recommendations given by the world health organization (who 2018) . the national guidelines for the prevention of malaria in south africa comprise five key components which are summarized as the "abc" of malaria prevention, namely awareness and assessment of malaria risk, avoidance of mosquito bites, compliance with chemoprophylaxis when indicated, early detection of malaria disease, and effective treatment (ndoh 2018a; baker 2018; schmidt 2019a, b) . adding fuel to the fire, climate change is resulting in both an increase in the extent of the south african malaria risk area and the incidence of malaria transmission due to increases in temperature and changes in rainfall patterns (morris et al., 2013; abiodun et al., 2020) . the spatial distribution of malaria globally is strongly determined by climate (caminade et al. 2014; cella et al. 2019) . by 2050, a 50% increase in the probability of malaria incidence is projected globally due to increases in temperature and changes in rainfall patterns (cella et al. 2019) . temperature has been found to affect both the extent of malaria areas and malaria transmission incidence across the african continent (eikenberry and gumel 2019) . for south africa, both temperature and rainfall have been found to affect the malaria rate, with a notable increase in cases following flood events induced by strong tropical storms (adeola et al. 2019; makinde and abiodun 2019) . a change in malaria area extent is documented in the frequent updating of the national department of health malaria risk maps for south africa (coetzee et al. 2013; morris et al. 2013) . mathematical models have been developed to explore the role of climate in malaria incidence and to aid in projecting future changes in malaria risk distribution, and the risk of transmission (cella et al. 2019; eikenberry and gumel 2019) . at a local scale, seasonal malaria forecast models are being developed for south africa (kim et al. 2019; landman et al. 2020) . the modelling of the climate impact on malaria distribution and incidence and projections for future incidence are valuable in developing public health policies, and in communication to the public. however, the increased incidence of malaria cases in south africa in recent years would suggest that effectiveness of the distribution of these maps, particularly with regular updates, remains limited. a range of studies relating to disparate diseases have revealed the importance of public awareness and understanding of disease risk in determining the precautionary measures that they will adopt (cf. erhardt and hobbs 2002; glik et al. 2004; goldman et al. 2006; young et al. 2008 seale et al. 2010 . the role of sources of information, and the level of frequency of communication regarding diseases, is key in the veracity of public awareness (young et al. 2008 ). this has been widely understood in south african malaria control efforts (blumberg et al. 2014) , with malaria risk maps for the public dating back to 1938 (coetzee et al. 2013) . however, the efforts in assessing communities' awareness and understanding of malaria risk have largely been limited to regions within the high-risk zone, due to resource scarcity (maartens et al. 2007; cox et al. 2018) . in line with the who (2018) recommendations, this pilot study seeks to expand on previous work to explore public understanding of the location of the contemporary high-risk malaria zone, the anticipated future expansion of the high-risk malaria zone under climate change, and public behaviour regarding malaria precaution and prophylaxis, among those who reside outside of the malaria risk area, but travel into the high-risk zone on vacation. the aim of this study is to develop a methodology to explore any disconnects between reported and demonstrated awareness and behaviour regarding malaria for gaps in understanding to be addressed more effectively through government intervention, and for targeted awareness campaigns to be developed. malaria can be found in each of south africa's neighbouring countries, barring lesotho, where the altitude and consequent colder temperatures make it inhospitable to the malariacarrying anopheles mosquito (blumberg et al. 2014) . within south africa itself, malaria is confined to the north-eastern reaches of the country, where it is endemic to three of south africa's nine provinces, namely limpopo, mpumalanga, and northern kwazulu-natal (maharaj et al. 2019; adeola et al. 2019 ; fig. 1 ). according to the latest malaria risk map produced by the south african national department of health in december 2018, areas of moderate risk (where chemoprophylaxis is indicated for all travellers from september to may) are concentrated along the border between south africa and mozambique and zimbabwe (fig. 1) . these areas of moderate risk can be found in the mpumalanga municipality district of ehlanzeni and in limpopo in the mopani and vhembe municipality districts (fig. 1 ). areas of low risk (where malaria is still present, but only non-drug preventative measures are indicated), however, extend as far west as limpopo's waterberg district and as far south as the umkhanyakude district in kwazulu-natal province ( fig. 1 ). at present, the regions of highest malaria risk in south africa have relatively low population density, with no major cities and a large proportion of the high-risk area limited to the kruger national park. this does however pose a threat to both local and international tourists visiting the kruger national park and nearby game farms and nature reserves, who may be unaware of the risk levels within south africa. this research explores respondents' malaria awareness and self-reported behaviours. therefore, questionnaires were selected as the most appropriate instrument for data collection. types of questions ranged from multiple choice and likert scale questions to more open-ended, paragraphstyle questions (bird, 2009) . topics included respondents' demographics and travel histories, awareness and perception of malaria distribution and risk in southern africa, understanding of climate change, and attitudes towards malaria prophylaxis-both in terms of bite prevention and chemoprophylaxis. the closing question of the questionnaire required respondents to draw two lines, in different colours, on a map of southern africa: a blue line indicating where they understand the boundary of the present malaria risk zone to be located and a red line indicating where they think the boundary of the malaria risk zone will be located in 20 years' time. the map was created using arcmap and displayed national and provincial borders, but contained no other information to avoid leading respondents. questionnaires were distributed in hard copy. respondents were identified through a combination of purposive and snowball sampling (bernard 2013) . to ensure a degree of standardization throughout the study sample for this initial pilot study, a target population was identified and a number of parameters were defined. in order to qualify for the study, respondents had to live within the gauteng province of south africa (currently not a malaria area), have at least an undergraduate university degree, and have travelled to a malaria risk area within southern africa within the last 5 years for leisure purposes. this ensured that the data gathered were relevant and that all respondents were middle-to upper-class leisure tourists with financial means to access to a wide range of precautionary measures to avoid contracting malaria when travelling to malaria areas, and have a reasonable level of education and understanding of health risks. this sample is not intended to be representative of the population of south africa nor the gauteng province. rather, this subgroup is used to determine whether any issues in awareness, behaviour, or use of chemoprophylaxis may warrant further, more extensive investigation. ethics clearance was obtained from the university of the witwatersrand's human research ethics committee (non-medical) prior to entering the field (ethics clearance: gaes-2019-06-01). given the target population and the minimum requirement of a completed undergraduate degree, no individuals under the age of 18 were approached. finally, it is important to note that this research dealt exclusively with the data collected from the completed questionnaires and no medical records were accessed or used in this study. responses to closed-ended questions from the questionnaire were analyzed using descriptive statistics, while responses to open-ended questions underwent thematic coding and content analysis (bernard 2013) . the hand-drawn maps generated in the last question of the questionnaire were digitized and layered over one another to create composite maps showing areas of consensus/disagreement among respondents. this particular methodology was adapted from a study conducted by roffe et al. (2019) which mapped agreement among experts regarding rainfall seasonality in south africa. finally, the composite maps were compared to the official malaria risk map created by the south african national department of health in 2018 to assess their accuracy. a total of 38 questionnaires were completed. of these, six questionnaires were excluded from analysis as the respondents did not fall within the defined parameters of the target population, in most instances as a result of not having visited a malaria area within the past 5 years. four maps were deemed unusable as the lines drawn could not be digitized as a contiguous vector line and/or what was drawn could not be meaningfully interpreted. neither the excluded questionnaires nor the unusable maps were used in the creation of the composite maps. in the cases where maps were unusable, but respondents met the selection criteria, the questionnaire responses were captured and included in descriptive statistics and content analysis. while the intention was to obtain a relatively even distribution of respondents across age groups, due to difficulty accessing people within the older age brackets who met the selection criteria (specifically the criterion relating to tertiary education), a skewed age distribution resulted. of the 32 respondents who submitted admissible questionnaires, the highest number (n = 14) fell into the 20-29 age group. the remaining age groups were comparatively poorly represented, with the 30-39 and 40-49 age categories comprising five respondents each, and the older age groups (50-59 and 60+) each representing one-eighth (n = 4) of the sample group. the majority (n = 17) of respondents held only a bachelor's degree, while nine held honours degrees (a postgraduate qualification in south africa), one held a master's degree, and two held a phd. the remaining three respondents selected "other" qualifications, in two cases citing university qualifications in the medical or nursing field. this last group, however, cannot be read independently, as respondents with medical or similar degrees may equally have chosen the equivalent qualification to their degree-type from the list provided. the overall spread of tertiary qualifications indicates a well-educated subset of the population. it is worth noting that the various levels of education were spread across the age groups, and it was not simply a case of the older the respondent, the higher their qualification. for example, all respondents in the 40 to 49year-old age group (n = 5) reported only holding a bachelor's degree, whereas of the two respondents in possession of a phd, one fell into the 30-39 age group and the other into the 60+ age group. this distribution is important, as it means that age and highest qualification are not collinear, but are rather independent factors each of which could be possible determinants of perception, risk assessment, and behaviour. we reiterate that the results of this small group cannot be read as representative of any sub-population, but rather the variety of results indicates a heterogeneity which reveals the importance of further, extensive, investigation. the questionnaire included a mapping exercise in which respondents were required to draw a line across a map of southern africa indicating where they understood the boundary of the present malaria risk zone to be located. in this question, respondents were instructed to include the entirety of the southern african region in the drawing of their malaria zone boundaries. however, eight of the 28 respondents who created usable maps only drew lines across south africa. therefore, for the sake of consistency, only the portion of the drawn risk areas which fell within the borders of south africa was digitized. overall, the composite map created from all 28 usable maps reveals a fairly high degree of awareness among respondents regarding the general location of malaria risk areas in south africa (fig. 2) . darker blue areas, which show a higher degree of consensus among respondents, can be found in the north-east of the country, concentrated along the border between south africa and mozambique and zimbabwe (fig. 2) . the majority of respondents have also included eswatini, northern kwazulu-natal, and more westerly parts of limpopo and mpumalanga in their assessment of malaria risk areas (fig. 2) . this is consistent with the official south african malaria risk map produced by the national department of health in 2018 (fig. 1) . however, the composite map also shows that many respondents believe that the malaria risk zone extends further west and south than is indicated on the governmental malaria risk map, with one respondent including the entirety of south africa in their rendering of the malaria risk zone. another respondent included the west coast of the northern cape, and many drew lines which either dissected or encompassed lesotho. this indicates a poor awareness of the government-communicated malaria risk maps of south africa, and moreover a limited understanding of the relationship between climate and malaria distribution, or at least limited awareness of the climate in these areas. in addition to instructing respondents to map their understanding of malaria risk areas in southern africa, the study also sought to assess the accuracy of respondents' selfreported awareness. respondents were asked whether, prior to taking the questionnaire, they were aware of malaria risk areas in the region. of the 32 respondents, the vast majority (n = 25) indicated that they were aware, while one respondent answered that they were not, and one did not respond. the remaining five respondents stated that they had limited awareness. with such a high degree of self-reported awareness, one would expect more accurate maps than were captured (fig. 2) . respondents were aware of the general location of malaria risk areas, but could not reliably recount their extent. this indicates a general, and perhaps intuitive, awareness among respondents, but little true, informed awareness. interestingly, despite the majority of respondents indicating that they were aware of malaria risk zones, only six felt that there was enough information available to the general public regarding malaria distribution, precautions to take against contracting malaria, and how to identify and treat malaria. respondents who indicated that they were either aware of malaria risk areas prior to taking the questionnaire, or who indicated that they had some degree of awareness, were then asked to stipulate where they accessed this information. importantly, government or official publications/websites were the least consulted (n = 2) source of information, while family, friends, or colleagues were the most frequently cited (n = 15) sources (fig. 3) . many of the 11 respondents who selected "other" indicated that they had accessed their information at school, through the media/news, or had been advised by a medical professional (fig. 3) . this could explain the lack of convergence between the government malaria map and those drawn by respondents. respondents were asked to rate the level of risk posed by malaria to south african citizens on a likert scale of 1 to 5, with 1 being low risk, 3 being moderate risk, and 5 being high risk. respondents most commonly (n = 11) rated the level of risk as moderate (as can be seen by the single peak), with a slight bias towards higher risk (fig. 4) . approximately three quarters (n = 23) of respondents indicated that they had taken precautions against contracting malaria during their most recent trip to a malaria risk area in southern africa, while eight reported taking no precautions and one declined to answer the question. among the eight respondents who did not take precautions, the most commonly reported reasons were issues around risk assessment and lack of awareness. interestingly, two respondents indicated that their risk assessment was informed by the advice of locals, with respondent 18 stating: i heard from people who live there that it was not a risk. similarly, respondent 30 reported: been travelling to mozam[bique] for a few years and nothing happened. locals there also say they moved there and lived there for yearsnothing happened. a further two respondents stated that they were not aware that their destination was a malaria area before departing, and only found out once they returned. for one of these respondents, their destination was mozambique, a country classified as high risk in its totality. of the eight respondents who did not take precautions, only one quarter (n = 2) indicated that they would change their behaviour and employ preventative measures on future trips. for the 23 respondents who did take precautions, insect repellent was the most popular (n = 18) preventative measure used (fig. 5) . insect repellent, along with travelling outside of the rainy season, were the two most common precautions used in isolation, each with four respondents. only 12 respondents used more than one method simultaneously. both respondents who selected the "other" option (fig. 5 ) cited wearing long trousers and long-sleeved shirts in the evenings. while this would minimize the chances of mosquito bites to the arms and legs, and is effective in reducing the irritation of mosquito bites, the efficacy of clothing worn in the evenings as a method of significantly reducing the risk of contracting malaria remains uncertain (nakazawa et al. 1998; del prete et al. 2019) . long clothing worn throughout the day and night (baker, 2018) , and impregnated with insecticides (shellvarajah et al. 2017) , shows more promise, but this is not the approach indicated by the respondents. in this context, wearing long clothing only in the evenings is less effective than these alternatives, and their combined use with chemoprophylaxis (baker, 2018) . of the 23 respondents who did take precautions against contracting malaria, five indicated that they would only do so again on their next trip to a malaria area if it was in the rainy season/summer. one respondent (respondent 11) stated that they would not take any precautions, as they believed that: risk is not significantly high when travelling for short time periods this is a misconception, and studies of imported cases of malaria in europe and the middle east resulting from tourists' short trips to southern africa underscore this (see ben-ami et al. 2005; baranova et al. 2019) . these erroneous sentiments are particularly concerning given the large proportion of respondents who obtain information on malaria risk from family, friends, and colleagues instead of government publications (fig. 3) . chemoprophylaxis is indicated for travel to all malaria areas considered moderate to high risk (schmidt, 2019a, b) . these areas can be found in all of south africa's neighbouring countries, and within south africa in limpopo and mpumalanga (fig. 1) . of the 32 respondents who submitted usable questionnaires, almost all (n = 30) indicated that they had travelled to malaria areas considered moderate or high risk. however, only one-third (n = 10) of these respondents reported that they had taken antimalarial drugs on their most recent trip to one of the areas. even more alarmingly, of the 10 respondents who had only travelled locally within south africa, to either limpopo or mpumalanga, only one-fifth (n = 2) had taken chemoprophylaxis. this indicates a very low level of compliance with chemoprophylaxis in indicated settings, which is particularly concerning among a sample group who have the level of education and socio-economic status to enable compliance. climate change awareness and impact on future malaria risk zones all 32 respondents indicated they understood what was meant by the term "climate change". respondents were then asked whether they thought climate change would impact malaria risk and distribution in southern africa, and if so, how. almost all respondents (n = 28) indicated that they believed that climate change would increase malaria risk in southern africa, while the remaining four indicated that they did not know. no respondents answered that climate change would decrease malaria risk in southern africa or have no effect. respondents also drew a line across indicating where they thought the boundary of the malaria risk zone would be located in 20 years' time. the composite map produced shows a far greater extent of malaria distribution than the composite map produced for current malaria risk (fig. 6) . respondents indicated that they believed the malaria risk zone would extend further west and south into the country's interior, with the majority of respondents including large parts of limpopo and mpumalanga (fig. 6) . this is consistent with the trend shown by the malaria risk maps produced by the government over the past century (coetzee et al. 2013; morris et al. 2013 ). the composite map indicates that respondents are cognizant of the increased risk of malaria projected for south africa in future decades, and significantly aware of the spatial patterns projected for the increase in the distribution of malaria risk. however, many respondents indicated an expansion of the malaria risk zone 20 years from now which is geographically impossible, and exceeds the model outputs for malaria projection. notably, the expansion into the mountainous highlands of lesotho, the temperate climates of the southern coast of south africa, and the arid west coast of south africa are unlikely in the next 20 years, if ever. these exaggerated perceptions of future risk, when not realized, may result in further complacency among respondents, particularly as relates to chemoprophylaxis. efficacy of the "abc" of malaria prevention in increasing public awareness the first tenet of the "abc" of malaria prevention relates to public awareness and the accurate assessment of malaria risk (ndoh 2018a). this emphasis on awareness and perception is further echoed in the malaria elimination strategic plan for south africa 2019-2023 which aims to "ensure that 90% of the population affected by malaria receives information education communication messaging by 2023" (national department of health 2019:25). when respondents were surveyed, it was found that while there is a relatively high level of self-reported awareness regarding the general location of malaria risk areas in south africa, the majority of respondents were unable to reliably recount the extent of these areas. the behaviour of the population regarding malaria avoidance similarly was not in line with governmental advice and scientifically determined best practice. this indicates that at least a proportion of the south african population are unaware of the precise location of the malaria risk zone, and their perceived awareness is incongruous with the demonstrated awareness or reality. this is consistent with prior research in kwazulu-natal (maartens et al. 2007 ). further research is needed to determine whether this lack of awareness in a statistically representative population amounts to greater than 10%. within the existing medium to high-risk malaria zones (fig. 1) , targeted governmental efforts at increasing awareness have been conducted actively at the community level, rather than solely passively through websites and risk maps in clinics which is the case for the respondent group from gauteng province (govere et al. 2000; cox et al. 2018) . for example, members of communities in the vhembe district in largely rural limpopo province who have been involved in the governmental malaria awareness programme (map) are found to have a 3.3 times greater knowledge on malaria transmission risk and 2.8 times higher awareness of prevention methods than those who had not been involved in these programmes (cox et al. 2018) . the perceptions of residents living in current malaria risk zones regarding the boundary of these zones would be a valuable avenue of future research. it is notable that among the respondents, government and official publications/websites were the least consulted sources of information, while family, friends, and/or colleagues were the most frequently consulted. as only six of the 32 respondents believed that there was enough information available to the general public regarding malaria distribution, precautions to take against contracting malaria, and how to identify and treat malaria, this suggests a weakness in policy's strategies regarding modes of delivery of malaria education and highlights the possibility of the transmission of misinformation from person to person. while targeted initiatives in high-risk malaria regions are of course imperative in addressing the epicentre of the problem, the significant tourism sector in south africa, and the large proportion of people migrating back to their homes in malaria areas during holiday periods, does necessitate a broader geographic reach of these activities (blumberg et al. 2014; raman et al. 2016) . following discrete epidemics, this has been facilitated through tourism operators distributing information (maartens et al. 2007 ), but this would not address tourists staying in less formalized accommodation. the incorrect perceptions that malaria risk is not high when travelling for short periods (see ben-ami et al. 2005; baranova et al. 2019) , or can be mitigated through wearing long clothing only in the evenings, reveal the dangers of relying on non-official sources of information when planning precautionary measures to avoid malaria (raman et al. 2016 ). these respondents appear to have misunderstood that while the longer the visit to a malaria-prone region, the greater the risk, short stays do not carry no or low risk; likewise, while long clothing is advised at all times, wearing it for short periods is not sufficient in preventing the risk of bites or malaria (baker 2018) . this misconception appears relatively unique to this study; an investigation into foreign tourists' awareness of malaria while at or tambo international airport in gauteng indicated that medical practitioners and travel agents were by far the greatest source of information on malaria (waner et al. 1999) . the low rates of use of chemoprophylaxis among respondents warrant particular concern. for persons with no immunity to malaria, which includes our study sample group, but also much of south africa (fig. 1) , chemoprophylaxis is indicated for the period of travel (freedman 2008; morris et al. 2013; schmidt, 2019a, b) . doxycycline, atovaquone-proguanil, and mefloquine are currently recommended for use in south africa, with an efficacy of~90% when taken correctly (baker, 2018; schmidt, 2019a, b) . the former two drugs have recently been downscheduled to s2, allowing for pharmacists to dispense these without prescription (baker 2018) , thus increasing access and reducing costs slightly through eliminating the necessity for a consultation with a doctor . while there are medical uncertainties regarding the safety of certain antimalarials, particularly mefloquine, in terms of neuropsychiatric adverse effects fig. 6 overlaid map of respondents' perceptions of future malaria risk boundaries in south africa in 20 years' time (n = 28) (freedman 2008; baker 2018) , these were not cited by the respondents as the reasons for non-compliance. more minor side effects, by contrast, were indicated as a reason for non-compliance, a theme which is echoed in studies of international tourists (waner et al. 1999) . a lack of awareness of the need for chemoprophylaxis, due to poor knowledge of the malaria areas, or to a lack of understanding of the severity of the risk may explain some of respondents not having used this precaution (leggat et al. 2002; maartens et al. 2007 ). however, as the majority of respondents over-estimated the expanse of the south african malaria risk area, this seems unlikely. a significant barrier to the use of chemoprophylaxis is the cost (leggat et al. 2002; ukpe et al. 2013) . even among more affluent travellers, the large cost of the antimalarial drugs serves as disincentive, particularly for trips of short duration or outside of the rainfall season (leggat et al. 2002) . greater medical aid coverage for antimalarials and a reduction in the cost of the drugs would be important in addressing this component. despite a relatively low sample size, this study reveals notable gaps in the awareness and risk-taking decision-making among persons who travel into malaria areas, who are resident in a country in which some but not all areas carry a high malaria risk (blumberg et al. 2014) . this is distinct to the majority of studies for south africa which either assess the awareness and behaviour of international tourists visiting malaria areas (cf. waner et al. 1999; freedman 2008) , or of local communities within high-risk malaria areas (cf. govere et al. 2000; morris et al. 2013; cox et al. 2018 ). this group is important because they do not receive the same level of travel advice as international tourists (waner et al. 1999 ), yet frequently travel into and through high-and medium-risk malaria areas (maartens et al. 2007 ), often through self-booking (de jager and ezeuduji 2015). the greatest awareness among local tourists has been found to directly follow major malaria epidemics, which is coupled with booking cancellations for accommodation establishments in malaria-prone regions (maartens et al. 2007) . the changes in the methods of malaria risk mapping, and the extent of the risk areas in these maps, particularly under climate change, further yield much of the information that regular travellers might have outdated (coetzee et al. 2013; morris et al. 2013) . policy improvements therefore need to be aware of both the limitations in knowledge and shortfalls in risk-aversion behaviour, and the potential for these factors to worsen under climate change. for effective policy adaptation, however, a much larger sample group with greater socioeconomic heterogeneity would be valuable. while the regularly shifting extent of the malaria risk zone is posited as one of the reasons for a poor awareness among respondents, it could be argued that under climate change, an even more frequent updating and reporting of risk may be beneficial. seasonal malaria forecasts are being produced for south africa by local researchers (kim et al. 2019; landman et al. 2020) , which could be presented to the public biannually to refine malaria prevention behaviour. frequent and standardized government publication of season-specific information would potentially result in a greater reliance on these resources over word-of-mouth based on travel which occurred less recently. the avenues of the dissemination are also an important consideration in effective communication of malaria information (blumberg et al. 2014 ). finally, this study was conducted during 2019, prior to the covid-19 pandemic (gilbert et al. 2020) . this pandemic has, both globally and in south africa, revealed an unprecedented public engagement with disease epidemiology and risk-aversion, and the extensive use of social media in government communication (gao et al. 2020) . south africa has been ranked second in the world for the most reliable covid-19 information, due in part to the conditions of the national lockdown which prohibit the dissemination of fake news (ryklief 2020) . announcements directly from the national institute for communicable diseases and the minister of health, each of which distributed both to the press and via social media, have allowed the public to follow both case numbers and the state of knowledge on precautionary measures. this provides valuable insight into methods of effective communication with the national populace involving disease prevention (young et al. 2008 ). this pilot study explores the self-reported risk behaviour and awareness of malaria area boundaries among south africans who are resident outside of the high-risk malaria area. while respondents in this study claim to have a high level of awareness relating to malaria, the vast majority overestimate the spatial extent of both the current and future malaria areas and do not practice the indicated precautionary measures when visiting regions that they report to understand to be malaria-prone. part of this disjunct between their understanding of the malaria areas and their behaviour appears to relate to their sources of information, with a considerable reliance on friends and family, rather than official sources. while this pilot study involves a small target group who cannot be considered representative of any broader sub-population, we provide insight as to avenues for more comprehensive research, and a methodology which could be used. this more extensive research would provide valuable insight to improve policy and intervention. investigating the 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perceptions of disease publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-296607-h2zwlyz7 authors: watson, ryan a.; johnson, drew m.; dharia, robin n.; merli, geno j.; doherty, john u. title: anti-coagulant and anti-platelet therapy in the covid-19 patient: a best practices quality initiative across a large health system date: 2020-06-09 journal: hospital practice doi: 10.1080/21548331.2020.1772639 sha: doc_id: 296607 cord_uid: h2zwlyz7 the coronavirus disease 2019 (covid-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has challenged health-care systems and physicians worldwide to attempt to provide the best care to their patients with an evolving understanding of this unique pathogen. this disease and its worldwide impact have sparked tremendous interest in the epidemiology, pathogenesis, and clinical consequences of covid-19. this accumulating body of evidence has centered around case series and often empiric therapies as controlled trials are just getting underway. what is clear is that patients appear to be at higher risk for thrombotic disease states including acute coronary syndrome (acs), venous thromboembolism (vte) such as deep vein thrombosis (dvt) or pulmonary embolism (pe), or stroke. patients with underlying cardiovascular disease are also at higher risk for morbidity and mortality if infected. these patients are commonly treated with anticoagulation and/or antiplatelet medications and less commonly thrombolysis during hospitalization, potentially with great benefit but the management of these medications can be difficult in potentially critically ill patients. in an effort to align practice patterns across a large health system (jefferson health 2,622 staffed inpatient beds and 319 intensive care unit (icu) beds across 14 facilities), a task force was assembled to address the utilization of anti-thrombotic and anti-platelet therapy in covid-19 positive or suspected patients. the task force incorporated experts in cardiology, vascular medicine, hematology, vascular surgery, pharmacy, and vascular neurology. current guidelines, consensus documents, and policy documents from specialty organizations were used to formulate health system recommendations. objective: our goal is to provide guidance to the utilization of antithrombotic and antiplatelet therapies in patients with known or suspected covid-19. covid-19; anti-coagulation; anti-platelet; thrombosis; acute coronary syndrome; venous thromboembolism; stroke; peripheral arterial disease; left ventricular assist device; extracorporeal membrane oxygenation coronavirus 2019 (covid-19) due to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is a global pandemic with over 4.3 million confirmed cases worldwide and over 297,000 deaths as of 15 may 2020. currently, the united states leads all countries with over 1.3 million confirmed cases and over 82,000 deaths [1] . disease severity ranges from asymptomatic to critical illness resulting in fatality. early studies revealed an increased prevalence of acute cardiovascular events leading to a higher risk of mortality [2] [3] [4] [5] . covid-19 patients may present with hemodynamic instability and increased biomarkers of cardiac injury, specifically troponin and b-type natriuretic peptide. this may be due to an acute coronary syndrome (acs), myocarditis, type 2 myocardial infarction, coronary vasospasm, or stress-induced cardiomyopathy. the specificity of these biomarkers in this setting is uncertain. additionally, markedly elevated d-dimer levels are associated with severe illness and high mortality. this has been postulated to be due to micro thrombosis but alternatively may be due to disseminated intravascular coagulation (dic) secondary to an increased inflammatory state. patients also appear at higher risk of venous thromboembolism (vte) due to critical illness, immobility, and inflammation. managing patients acute antiplatelet and anticoagulant regimens can be difficult without clear consensus on diagnosis and treatment. many patients are on antiplatelet and anticoagulants for preexisting conditions when they present to the hospital and thus the balance of further ischemic/thrombotic events vs. bleeding events must be weighed. the margin of error appears to be narrower in patients with multi-system failure where fluctuating organ function can impact drug metabolism. we aim to provide guidance for the management of various clinical scenarios encountered in covid-19 infected patients recognizing that these recommendations may change given the rapidly evolving understanding of covid-19 pathophysiology. the diagnosis of acs in the covid-19 patient can be challenging given that patients often have elevated troponin levels. biomarkers are nonspecific measures of cardiac injury and may represent a myriad of cardiac conditions including myocardial ischemia secondary to either plaque rupture or demand ischemia,, myocarditis, stress cardiomyopathy, or coronary spasm. in order to assist with diagnosis and treatment, it is important to take into consideration the patient's clinical presentation, electrocardiogram (ecg), and point of care ultrasound to evaluate ventricular wall motion. typically, with acs there is a characteristic rise and fall in troponins which represents myocardial tissue necrosis due to hypoperfusion, as opposed to myocarditis which can often lead to elevated but relatively stable troponin levels that represent ongoing myocardial inflammation and injury. a recent report demonstrated that st-elevation myocardial infarction (stemi) activation is down 38% in the united states [6] with growing concern that patients do not seek immediate medical attention due to fear of exposure to covid-19 leading to missed events. we recommend in all patients with concern for acs, nonenteric coated aspirin 162-325 mg should be given immediately if no contraindication exists followed by daily low dose aspirin (81 mg) indefinitely. p2y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) should be considered in these patients with guidance from cardiology with a length of therapy for 1 year in most patients [7] [8] [9] . for patients on anticoagulation prior to acs, triple therapy should be used for the shortest duration possible. a regimen of a direct oral anticoagulant (doac) with clopidogrel with short duration of aspirin is now considered the standard of care and triple therapy with warfarin should be avoided [10] [11] [12] [13] [14] [15] . all stemi patients should receive standard medical therapy including full dose aspirin, high-intensity statin, unfractionated heparin (ufh), and nitrates for chest pain if hemodynamics allow. there has been considerable discussion regarding best practices for patients who present with stemi in the covid-19 era with the debate over fibrinolytic therapy versus primary percutaneous coronary intervention (pci). based on early experience out of peking union medical college hospital in china, it was recommended that all stemis be treated with thrombolytic therapy given its efficacy and ease of administration and to limit health-care worker exposure [16] . in the united states, approximately 13% of stemis prior to the covid-19 era had fibrinolytic reperfusion strategies due to the inability to access hospitals with pci capabilities within 120 minutes [17] . to ensure staff safety, there can be considerable system delays in patients who present with stemi and have concern for covid-19. these delays may cause patients to no longer receive standard of care primary pci within the designated door to balloon time of 90 minutes, and the mortality benefit of primary pci may no longer be significant compared to fibrinolytic therapy [18] . finally, there is concern about transmission of infection from patient to staff and resources needed for these patients that fibrinolytic therapy may be considered in the covid-19 patient population [19] . despite the initial push for fibrinolytic therapy, there is hesitation with this strategy as it can lead to unnecessary use of thrombolytics in the case of 'stemi-mimicker,' patients with covid-19 who have non-obstructive coronary artery disease on coronary angiography despite stemi on ecg [20, 21] . the use of fibrinolytics in this population would lead to no clinical benefit and potential significant harm. even in those patients who receive thrombolytics for stemi, approximately 50% require rescue pci and thus the benefit of thrombolytics seems to be low in patients where pci can be performed. due to these concerns, the current society for cardiovascular angiography and interventions (scai) consensus document suggests continuing primary pci for stemi patients as the treatment of choice with the use of fibrinolytic therapy only for selected lower-risk patients (those with inferior stemi without rv involvement and those with lateral stemi without hemodynamic compromise) [20] . the recommendation for primary pci in the covid-19 patient was reiterated in a consensus statement from scai, american college of cardiology (acc) and the american college of emergency physicians (acep) and a pharmacoinvasive approach should only be considered if primary pci is not feasible [22] . we agree that primary pci should remain standard of care if a patient is at a pci capable hospital. the lack of familiarity with fibrinolytics dosing for many providers, their increased risk of significant bleeding, and the possibility of treating patients without coronary thrombosis makes this a less attractive first-line therapy. in patients with whom primary pci is not possible due to access to a cardiac cath lab, we recommend a pharmacoinvasive approach with fibrinolytic therapy followed by transfer to a pci capable hospital for possible intervention [23] . if pci is performed, dual antiplatelet therapy with aspirin and p2y12 should ideally be continued for 1 year. the diagnosis of type 1 nstemi (plaque rupture) is difficult in the covid-19 era due to the elevated troponin levels in a significant proportion of patients [4] . the true incidence of type 1 myocardial infarctions is not well known and thus covid-19 positive patients with elevated troponins should be risk stratified to determine the most appropriate management. all patients should receive medical therapy with full dose aspirin, high-intensity statin, parental anticoagulation (heparin or low molecular weight heparin (lmwh)), beta blocker if hemodynamics allow, and possible nitrate therapy if ongoing chest pain [7] . in patients undergoing early invasive strategy, we recommended using heparin over lmwh as an anticoagulant of choice due to the ability to titrate the medication and to measure the degree of anticoagulation in the cardiac catheterization lab with activated clotting times. patients who are covid-19 negative should be considered for early invasive therapy [20] . in patients who are covid-19 positive or still under investigation, we recommend invasive strategy in patients who have grace score > 140 [24] or those with high-risk clinical features such as refractory chest pain, unstable arrhythmias, heart failure, or hemodynamic instability. in covid-19 positive patients with low-risk nstemi, we recommend a delayed invasive approach and upfront medical management [7] . these patients receive less benefit from early-invasive primary pci compared to high-risk nstemi. we believe that the risks of resource utilization, risk of virus transmission to hospital workers, and lack of definitive diagnosis is higher than the potential benefit of invasive angiography and potential pci in this population. we recommend lmwh preferentially over ufh due to the ease of administration, lack of medication titration, and fewer lab draws that could lead health-care professionals to unnecessary exposures. in medically treated nstemi patients, aspirin (81 mg) with either clopidogrel (75 mg) or ticagrelor (90 mg bid) should be given if no contraindication exists. prasugrel is not indicated for patients being treated medically for nstemi [25] . consideration for outpatient testing and coronary angiography can be considered in these patients in the future once their infection has resolved in accordance with scai/acc/ acep recommendations [22] . patients with covid-19 may present on therapy from previous coronary intervention irrespective of their current hospital admission. data is limited in this patient population, and we, therefore, rely on established guidelines for antiplatelet recommendations [8] . patients with covid-19 may have thrombocytopenia and other coagulopathies similar to dic which can make the use of anti-platelet agents more challenging. it is important for providers to understand the indication for the patient's antiplatelet therapy in sihd as it can help guide therapy in those patients at higher bleeding risk. all patients with previous stent placement should be continued on single antiplatelet therapy regardless of indication unless at very high bleeding risk. in patients on therapy with platelet count > 50,000 mm 3 and at a low risk of bleeding, we recommend continuing outpatient anti-platelet therapy for the duration recommended in the acc/ aha guidelines [8] . in patients with a platelet count between 25,000 mm 3 to 50,000 mm 3 we recommend continuing aspirin therapy and if platelet count <25,000 mm 3 discussion with cardiology regarding the ongoing benefits of aspirin therapy (i.e. location of stents, previous ischemic history, size of stents, timing of stent) with the risk of bleeding. acute and chronic respiratory illnesses are risk factors for atrial fibrillation [26, 27] . covid-19 patients, commonly present with shortness of breath secondary to viral pneumonia with critically ill patients progressing to acute respiratory distress syndrome (ards). unfortunately, the rate of new atrial fibrillation in these patients is unknown. management of patients with atrial fibrillation includes oral anticoagulation which is recommended for patients with cha 2 ds 2 -vasc score of 2 or more in men or 3 or more in women as long as the benefit of anticoagulant outweighs the risk of bleeding [28] . in most scenarios, direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin due to large randomized controlled trials showing noninferiority or superiority for stroke reduction and superiority for bleeding risk in patients with non-valvular atrial fibrillation [29] [30] [31] [32] . in the inpatient setting, there is less guidance on the initiation of anticoagulation for new onset atrial fibrillation and decisions to continue outpatient oral anticoagulation can be more difficult due to rapid fluctuations in clinical status, need for invasive procedures, and renal/liver function changes. the risk of endothelial damage, vascular inflammation, and vascular thrombosis appears heightened in severe covid-19 patients and thus could pose an increased risk of arterial thrombosis in this patient population. the use of ufh or lmwh may be considered in patients with high potential stroke risk and new onset atrial fibrillation; however, heparin drips require constant monitoring and titration of dosing during hospitalization leading to increased nursing exposure to potential covid-19 patients. in this group, therapeutic enoxaparin 1 mg/kg every 12 hours could be used instead of unfractionated heparin. inpatient anticoagulation will be recommended for de novo af based on the risks of benefits of the individual patients with men with cha 2 ds 2 -vasc ≥2 and women ≥3 being most likely to benefit from anticoagulation. in this context, the annual stroke risks are between 5% and 10% in patients with cha 2 ds 2 -vasc 5 or 6, and >10% in patients with cha 2 ds 2 -vasc ≥7 [33] . we would recommend lmwh over heparin as long as creatinine clearance (crcl) ≥ 30 and no need for invasive procedures. in patients who are established on anticoagulation due to previous diagnosis of atrial fibrillation, continuing oral anticoagulation should be considered in patients at low risk of clinical decompensation or bleeding. in patients who are critically ill, we recommend holding outpatient oral anticoagulation and consideration of using a parenteral agent (heparin/ lmwh). the risks and benefits of stroke vs. bleeding as well as duration of time without oral anticoagulation should be considered in all cases. for patients who do not have prohibitive bleeding risk and cha 2 ds 2 -vasc score ≥ 5 or previous thromboembolic event, we would recommend a parental agent with lmwh considered first-line therapy if crcl ≥ 30 [34] . patients with mechanical heart valves and atrial fibrillation who require invasive procedures should be bridged with heparin or lmwh [33, 35] . the acc manageanticoag app can be used to help providers determine the need for anticoagulation interruption and bridging in case by case scenario (figure 1 ). despite the concern for increased thrombotic risk in covid-19 patients, there are no published reports of prosthetic valve thrombosis in this patient population. as such, we recommend anticoagulation in accordance with the latest acc/aha valvular guidelines. all patients with a mechanical heart valve should continue anticoagulation with a vitamin k antagonist (vka) with their previously recommended goal international normalized ratio inr [36, 37] . all patients with mechanical valve prostheses should also be continued on 81 mg aspirin daily [38] , and it is reasonable for patients with bioprosthetic valve prostheses to be continued on asa 81 mg daily [38] . anticoagulation with doacs should be avoided in patients with mechanical valve prostheses [39] . in patients on anticoagulation due to mechanical valve, anticoagulation should not be interrupted for low bleeding risk procedures. if, for a procedure, anticoagulation needs to be interrupted, then bridging with lmwh or heparin is reasonable for patients with mechanical mitral valve, mechanical aortic valve with risk factor(s) (atrial fibrillation, low ef, hypercoagulable state, or previous vte), or older generation mechanical aortic valve [40] . we suggest that warfarin only be continued upfront in those patients who are not critically ill or at high bleeding risk. in all others, suggest transition to a parental agent with a bridge until warfarin can be resumed. currently, the most common neurologic manifestations of covid-19 that should prompt strong consideration of an acute cerebrovascular event include dizziness, headache, focal neurologic deficits, and encephalopathy [41] . in four early studies, ischemic and hemorrhagic stroke complicated covid-19 infection in about 6% of patients at a median 10 days after symptom onset and the incidence, particularly of stroke due to large vessel occlusion, continues to rise in the united states [42] [43] [44] [45] . in addition to common cardiovascular comorbidities in the elderly covid-19 positive population, mechanisms for ischemic stroke in infected patients of all age groups include hypercoagulability from proinflammatory state, embolism from virus-related cardiac injury, and infection-induced disseminated intravascular coagulation. intracerebral hemorrhage and hemorrhagic conversion of ischemic stroke may also occur due to possible coagulopathy, specifically thrombocytopenia, in the severely ill, fluctuating blood pressures due to viral-binding to ace 2 receptors [46] , and potential interactions between anticoagulants and medications now commonly used for covid-19 patients (table 1) . non-contrast computed tomography (ct) head is the appropriate initial imaging in covid-19 patients with neurologic symptoms particularly prior to initiation of antithrombotic agents. while most serum studies are not required prior to emergent iv-tpa use based on guidelines, it may be reasonable to await results of coagulation studies and complete blood count in critically ill covid-19 suspected or positive patients prior to thrombolytic administration. patients with large vessel occlusion remain eligible for endovascular therapy despite infection. antithrombotic recommendations for secondary prevention of stroke in the suspected or positive covid-19 patient are currently unchanged from the general population assuming the absence of coagulopathy and prothrombotic state. for ischemic stroke due to small and large vessel atherosclerotic disease as well as embolic strokes of undetermined source, antiplatelet therapy with aspirin, clopidogrel, or aspirin/dipyridamole remains the appropriate first-line therapy [47, 48] . dual antiplatelet therapy should be reserved for symptomatic intracranial atherosclerotic disease [49] , certain carotid cases, recent stenting, and patients with recent minor stroke or highrisk tia [50] . outcomes in available covid-19 patient data do not suggest clear benefit over risk of therapeutic anticoagulation for primary stroke prevention. however, assuming low risk of hemorrhagic conversion, therapeutic anticoagulation with lmwh is frequently initiated for secondary stroke prevention in the critically ill with significantly elevated d-dimer and no other clear etiology of ischemic stroke. in addition to patients with atrial fibrillation, consider anticoagulation with ufh/ lmwh, warfarin, or doacs in patients with ischemic strokes that are embolic appearing with cardiac etiology, nonocclusive thrombi, recurrent ischemic strokes, atypical intracranial stenosis, venous sinus thrombosis, extracranial dissection with ischemia, and pro-thrombotic state [51] . minimize the use of triple therapy to avoid intracranial hemorrhagic complications. the appropriate timeframe to initiate anticoagulation in the ischemic stroke patient remains heavily individualized based on age, comorbidities, stroke size and location, imaging characteristics, and medication choice. the decision to initiate antithrombotic therapy in covid-19 positive patients with acute neurologic symptoms should be made in conjunction with a neurologist. peripheral arterial disease is a common cardiovascular disorder that is highly under-recognized with significant cardiovascular morbidity, mortality, and quality of life impairment. in patients with symptomatic peripheral arterial disease, anti-platelet medication with either aspirin (75-325 mg per day) or clopidogrel (75 mg per day) is recommended as first-line therapy [52] . the use of dual antiplatelet therapy is beneficial only in those patients who have undergone revascularization [52] . patients should remain on these medications throughout their hospitalization unless high bleeding risk. acute limb ischemia (ali) is associated with significant morbidity and mortality and is defined as <2 weeks of severe hypoperfusion of the limb characterized by features of pain, pallor, pulselessness, poikilothermia, paresthesias, and paralysis [53] . patients who present to the hospital with ali should be emergently evaluated to assess limb viability and systemically anticoagulated with heparin unless contraindicated. in early single-center retrospective studies, the incidence of ali in covid-19 patients appears to be higher than the general public and includes patients with no traditional risk factors [54, 55] . the success of revascularization was also decreased felt to be secondary to the virus-induced hypercoagulable state [54] . in patients with covid-19, it is important to remain hypervigilant for signs and symptoms of ali. emergent consultation with vascular surgery should be obtained and early initiation of parental anticoagulation is paramount due to the hypercoagulable state observed in some patients. we suggest that patients undergo limb salvage procedures in accordance with standardized guidelines due to the high risk of morbidity and mortality without acute intervention. acro-ischemia has been described in patients who are critically ill with covid-19 pneumonia and, despite treatment with lmwh, there was no clinical improvement and there was a high rate of mortality [56] . in these patients, a palliative approach should be considered. recent data suggests a high rate of vte in the hospitalized, critically ill covid-19 patient [57, 58] . the mechanism by which these patients are developing vte at significant rates have been hypothesized including immobility, severe inflammatory response, and coagulopathy including dic. decision algorithms of testing patients for asymptomatic and symptomatic vte as well as treatment of vte are not well defined. patients should be risk stratified (high, intermediate, or low risk) on presentation to help guide therapy [59, 60] . for covid-19 patients who present with or develop acute vte during hospitalization, we recommend treating with anticoagulation if no contraindication exists. for all patients with symptomatic pe, we recommend activating the pulmonary embolism response team (pert) to provide interdisciplinary care and make individualized decisions based on the patient's clinical status, co-morbidities, and hospital factors [60, 61] . in patients with high-risk pe, we recommend systemic or catheter-directed thrombolysis in patients with low bleeding risk or those who deteriorate after initial anticoagulation (i.e. development of worsening hypoxia, tachycardia, rv failure) [60, 62, 63] . in patients at high bleeding risk, the use of catheter-directed mechanical thrombolysis or surgical removal should be considered in consultation with the pert team [64] . in the intermediate-risk patient, debate remains over the best treatment. risk calculators such as the pesi or bova score can help further risk stratify these patients to help guide therapy [65, 66] . anticoagulation remains the mainstay of treatment for this population and we suggest the use of parental anticoagulation with heparin or enoxaparin instead of a doac due to potential decompensation [60, 67, 68] . enoxaparin is preferred if crcl is ≥ 30. the use of catheter-directed thrombolysis or thrombectomy for intermediate-risk pe should be made on a case by case basis with guidance from the pert team. due to the risk of infectivity, there should be a higher threshold to perform invasive procedures that have not been shown to improve mortality [64] . once patients have stabilized, we recommend the use of doac over the use of warfarin or lmwh therapy [60, 62] . in the low-risk patient, we recommend treatment with a doac without the need of parental anticoagulation (apixaban or rivaroxaban) to avoid increasing length of stay. the use of inferior vena cava filters should not be considered for routine use and only considered in those patients who have absolute contraindications for anticoagulation with clinically relevant vte [62] . in a patient who requires an ivc filter, anticoagulation should still be restarted once the bleeding risk has passed. the incidence of thrombotic complications in critically ill covid-19 patients in the icu has been shown to be at least 25-40% in observational studies [57, 58] . this increased rate of thrombotic complications appears to be related to a hypercoagulable state similar to dic or thrombotic microangiopathy yet with unique differences including the appearance of a positive lupus anticoagulant in patients [51, 69, 70] . in order to attempt to decrease the rates of thrombotic complications, preventative measures should be used whenever possible [71] . heparin, enoxaparin, and fondaparinux are all recommended for vte prophylaxis by the american college of chest physicians [72] . one retrospective study of critically ill covid-19 patients with d-dimers > 6x uln compared ufh or lmwh plus antiviral therapy versus no pharmacologic prophylaxis plus antiviral therapy. the combination therapy of pharmacologic plus antiviral group had a significantly decreased 28-day mortality [73] . lmwh was preferentially used in this study due to its previously reported anti-inflammatory effect. another retrospective trial in critically ill patients in china confirmed lower mortality in those patients who were treated with pharmacologic prophylaxis, yet stated that asian populations have a low incidence of vte and thus higher doses of anticoagulation may be necessary in other populations [74] . there remains concern throughout the medical community that in the most critically ill patients, pharmacologic prophylaxis is not enough to reduce the risk of thrombosis. a french cohort of icu patients on pharmacologic prophylaxis found a high prevalence of thrombotic complications including pe, stroke, circuit clotting of continuous renal replacement therapy or extracorporeal membrane oxygenation (ecmo) with minimal bleeding risk suggesting the need for higher doses of prophylactic anticoagulation in this patient population [70] . in another retrospective study, mechanically vented patients were found to have a significantly decreased risk of mortality if treated with fulldose anticoagulation compared to those not on anticoagulation, yet this mortality benefit was not seen in all covid-19 patients admitted to the hospital [75] . the use of higher dose thromboprophylaxis or full-dose anticoagulation is currently being investigated in multiple randomized control trials (nct04372589, nct04367831, nct04345949, and nct04366960). we recommend that all patients on admission be assessed for the risk of vte. for patients with platelet counts greater than 25,000, we recommend using pharmacologic prophylaxis for all covid-19 positive patients if no contraindication exists. while anecdotal and retrospective data may support higher doses of pharmacologic prophylaxis in critically ill patients, there is considerable risk of bleeding in these populations and thus without higher-level evidence, we remain hesitant to adopt these practices. as such, we continue to recommend standard dose pharmacologic prophylaxis with an understanding that our recommendations may change as data continues to evolve. enoxaparin is the preferred agent for patients with a crcl ≥ 30 ml/min. for those with impaired renal function, heparin can be used as an alternative agent with a dosing regimen based on patient weight. for heparin dosing, patients <50 kg use 5,000 units q12 hours, for patients 50-120 kg we recommend 5,000 units q8 hours, for >120 kg we recommend 7,500 units q8 hours. for enoxaparin dosing, we recommend 30 mg qday for those <40 kg, 40 mg qday for patients 40-120 kg, and 40 mg twice a day for patients >120 kg. we recommend mechanical prophylaxis in addition to pharmacologic prophylaxis for all icu patients without contraindication. for patients that are unable to be on pharmacologic prophylaxis due to low platelets or active bleeding we recommend mechanical prophylaxis (figure 2 ). critically ill patients who survive to discharge are still at increased risk of thromboembolic events [76] . given that thromboembolic events seem to be elevated in the covid-19 population, this risk may be even higher. we recommend that all patients be assessed for vte risk at discharge for consideration of extended vte prophylaxis. multiple studies pre-covid-19 have shown the benefit of extended prophylaxis for high-risk patients following discharge. the decreased incidence of thrombotic events is at the expense of a slight increase in bleeding. multiple agents have shown efficacy with extended prophylaxis including enoxaparin, rivaroxaban, and betrixaban [77] [78] [79] . we recommend that patients should be risk assessed for vte and bleeding on discharge for extended prophylaxis using the improved for vte and improve bleeding risk indices [80] [81] [82] [83] . the patient should have a creatinine clearance and liver function panel in addition to platelet count (>25,000 mm 3 ) prior to the initiation of extended prophylaxis. we preferentially recommend rivaroxaban 10 mg daily for 6 weeks for extended prophylaxis. enoxaparin 40 mg qday subcutaneously can be used as an alternative agent if the crcl ≥ 30 ml/min. if patients are unable to receive pharmacologic prophylaxis, we recommend knee high compression stockings (15-20 or 20-30 mmhg) and encourage ambulation. patients should be educated on the symptoms and signs of dvt/pe and report such events to their primary care provider. dic can be seen in hospitalized patients with severe illness [84] . it can accompany the acute respiratory failure and multiorgan failure from covid-19 and is associated with poor prognosis [85] . yet, further studies suggest that while similar to dic, the coagulopathy of covid-19 has distinct features with only mild thrombocytopenia and normal fibrinogen levels early in the course [2, 86] . there also appear to be similarities to thrombotic microangiopathy with elevated ldh and ferritin levels [87] . these coagulation abnormalities appear to promote the hypercoagulable hypothesis of covid-19 which has been further suggested by autopsy reports showing micro thrombosis of the lungs and various other organs [69] . the optimal initial approach to dic or dic like coagulopathy is to treat underlying causes, and in this case to support o 2 and co 2 exchange, metabolic functions, and possibly use antiviral agents and anti-cytokine release syndrome agents. clinically, close attention for these patients should be directed to unexpected bleeding or thrombosis. in addition to clinical monitoring, lab tests to monitor for the development and progression of dic are the cbc, pt and aptt, and fibrinogen. serial comparisons of the labs are essential as the development of dic during hospitalization is a poor prognostic indicator [85] . d-dimer, while not specific for dic has also been shown independently to be a predictor of morbidity and mortality when significantly elevated [2, 85, 86] . despite the incidence of dic being a poor prognostic indicator, the treatment of these patients remains the previous standard of care. in accordance with the guidance from the international society of thrombosis and hemostasis (isth), these patients should be treated with prophylactic dose enoxaparin if no contraindication exists [88] . there is no role for therapeutic anticoagulation in dic, in the absence of an acute thrombotic event. while bleeding in covid-19 patients remains less common than thrombosis, bleeding risk increases as the platelet count goes below 50,000 mm 3 , the pt and ptt rise to > 1.4 x uln, or when fibrinogen falls below 100 mg/dl. there is no role for giving blood products to correct lab abnormalities in the absence of bleeding [89] . if bleeding occurs, blood product(s) should be given to replace the depleted components. factor viia and prothrombin complex concentrate use are discouraged, as the risk of serious thrombosis is high. in the covid-19 era, there is an influx of drugs aimed to improve patient's morbidity and mortality. the only fda approved therapy at this time for covid-19 is remdesivir, and there remains over 100 pharmacological trials on clinicaltrials.gov attempting to find further treatment for this disease [90] . the effect of these medications on anti-platelet agents and anticoagulants is important for the individualized patient and the prescriber. pathways that are most important for identifying drug-drug interactions appear mediated via cytochrome p450 (cyp450) and/or transporter permeability glycoprotein (p-gp). the most common medications being used include hydroxychloroquine/chloroquine, azithromycin, remdesivir, lopinavir/ritonavir, and tocilizumab which may affect the efficacy of antiplatelets and anticoagulants. p2y12 inhibitors are commonly used in a wide spectrum of cardiovascular disease states as described above. their interactions with treatments for covid-19 are not well known and rely on package inserts and anecdotal experience. the only medication with significant known interactions with p2y12 inhibitors is lopinavir/ritonavir, a protease inhibitor previously used for the treatment of hiv. early studies in patients with covid-19 have found no decrease in morbidity or mortality with this medication combination [91] , yet ongoing trials continue to look at the impact of this combination on patients with covid-19. it is a known inhibitor of cyp3a4 metabolism and has significant effects on clopidogrel and ticagrelor, yet no significant effect on prasugrel. inhibition of cyp3a4 in patients taking clopidogrel can decrease its efficacy; however, inhibition of cyp3a4 leads to increased effects of ticagrelor and thus neither is recommended to be administered in patients on lopinavir/ritonavir [92, 93] . despite advances in doacs for reducing systemic thromboembolism and systemic bleeding compared to warfarin, doacs have drug-drug interactions that must be considered in all patients. cyp3a4 is important for the metabolism of apixaban (20-25%) and rivaroxaban (18%) with no significant effect on dabigatran and edoxaban while p-gp is an important mediator for apixaban, dabigatran, and rivaroxaban. the fda recommends avoiding concurrent use of apixaban and rivaroxaban with inducers of p-gp or cyp3a4 [94] . there is limited data on the in vivo effects of these medications with doac concentrations and unless explicitly known we do not have recommendations regarding avoiding or dose changes of these medications. table 1 summarizes the interactions between the investigational drugs and commonly prescribed doacs. further drug-drug interactions between doacs and commonly used medications can be found in the ehra practical guidelines [95] . hydroxychloroquine, used primarily in auto-immune disease, has not been found to interact with cyp3a4 or p-glycoprotein. azithromycin is an inhibitor of p-gp and thus could increase the serum concentration of dabigatran especially in conjunction with other cardiac p-gp inhibitors such as amiodarone. it is not recommended to decrease dabigatran dosing. however, patients on edoxaban should only be prescribed the 30 mg dose for vte. lopinavir/ ritonavir is known strong inhibitors of both cyp3a4 and p-glycoprotein and thus could have significant effects on the pharmacokinetics of all doacs leading to increased concentration and potential bleeds. the european heart rhythm association practical guidelines suggests that doacs should not be given in patients taking ritonavir [95] . however, the package insert of apixaban recommends dose reduction by 50% and should not be co-administered if patient is on low dose apixaban (2.5 mg bid). we suggest to avoid doacs in patients with whom lopinavir/ritonavir is being prescribed. tocilizumab is known to decrease serum concentrations of cyp3a4 substrates and thus could decrease the effectiveness of apixaban or rivaroxaban. finally, remdesivir has little pharmacokinetic data available although it is believed that there are no significant clinical interactions with cyp3a4 enzyme. (table 2) conclusions covid-19 has challenged our thinking about the management of critically ill patients. the mechanisms of this disease and its complications' continue to be elucidated. that being said the principles of managing these patients are built on the foundations of evidence-based medicine in severely ill patients. there is a narrow therapeutic index between prevention and treatment of venous and arterial thrombosis in these patients and the risk of bleeding. this document can be used to help guide providers to treat cardiovascular patients at high risk during this pandemic (figure 2 ). only by adhering to the principles of practicing what we know and maintaining openness to what we don't can we stand up to the greatest challenge of our professional lives. the contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. the authors report no conflicts of interest for their manuscript. a reviewer on this manuscript has disclosed that their institution has received research grants, and they have received honoraria for cme programs and consulting for companies developing novel antithrombotic therapies. the other peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose. table 2 . takeaway points from paper. 1. covid-19 patients have much in common with other critically ill patients where there may be a narrow margin for ac and apt of benefit (preventing thrombotic events) and risk (bleeding). 2. the rationale for ac should be carefully examined in all inpatients, balancing risk and benefit. for example: a patient on ac with cha 2 ds 2 -vasc of 1 for men and 2 for women. point of care risk calculators and apps to assist in evaluating the risk and benefit should be used when available. 3. in covid-19 confirmed or expected patients, it is reasonable to continue outpatient anticoagulation unless they become critically ill in the icu or if they have invasive procedures planned. 4. if interrupted, bridging should not be offered in low risk thrombosis patients. 5. routine use of aspirin increases bleeding risk by as much as 50% and benefit should be carefully assessed. 6. prolonged dapt beyond 6 months for elective stenting and beyond a year for acs should be examined, balancing risk and benefit. 7. warfarin based triple therapy for patients with stenting and af is inferior to doac based regimen with p2y12 and short duration aspirin. 8. decision to bridge either with ufh or lmwh in a covid-19 patient exposes nursing to a greater degree. this is not worthwhile in a low thrombotic risk patient. 9. when there is the potential for significant drug-drug interactions, consultation with pharmacy is invaluable. 10. careful consideration is required in weighing the risks and benefits of any intervention not only to the covid-19 confirmed or expected patient, but also to the health care workers who are directly involved in patient care. special consideration should be given when possible to limiting health care worker exposure to covid-19. references 1. world health organization. coronavirus disease. 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course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort isth interim guidance on recognition and management of coagulopathy in covid-19 guidelines for the diagnosis and management of disseminated intravascular coagulation. british committee for standards in haematology pharmacologic treatments for coronavirus disease 2019 (covid-19): a review a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 prescribing information. brilinta (ticagrelor) impact of booster antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites select drug-drug interactions with direct oral anticoagulants: jacc review topic of the week european heart rhythm association practical guide on the use of non-vitamin k antagonist oral anticoagulants in patients with atrial fibrillation we want to acknowledge the following people who helped with formulation of our best practice initiative for our institution: key: cord-291083-nd7cew7v authors: vargas-medrano, javier; diaz-pacheco, valeria; castaneda, christopher; miranda-arango, manuel; longhurst, melanie; martin, sarah l.; ghumman, usman; mangadu, thenral; chheda, sadhana; thompson, peter m.; gadad, bharathi s. title: psychological and neurobiological aspects of suicide in adolescents: current outlooks date: 2020-08-05 journal: brain behav immun health doi: 10.1016/j.bbih.2020.100124 sha: doc_id: 291083 cord_uid: nd7cew7v suicidality is one of the leading causes of death among young adults in the united states and represents a significant health problem worldwide. the suicide rate among adolescents in the united states has increased dramatically in the latest years and has been accompanied by considerable changes in youth suicide, especially among young girls. henceforth, we need a good understanding of the risk factors contributing to suicidal behavior in youth. an explanatory model for suicidal behavior that links clinical and psychological risk factors to the underlying neurobiological, neuropsychological abnormalities related to suicidal behavior might predict to help identify treatment options and have empirical value. our explanatory model proposes that developmental, biological factors (genetics, proteomics, epigenetics, immunological) and psychological or clinical (childhood adversities) may have causal relevance to the changes associated with suicidal behavior. in this way, our model integrates findings from several perspectives in suicidality and attempts to explain the relationship between various neurobiological, genetic, and clinical observations in suicide research, offering a comprehensive hypothesis to facilitate understanding of this complex outcome. unraveling the knowledge of the complex interplay of psychological, biological, sociobiological, and clinical risk factors is highly essential, concerning the development of effective prevention strategy plans for suicidal ideation and suicide. long been implicated in the genesis of psychiatric disorders, but the role such factors play in the causal pathway is less well understood (monk et al., 2011) . several reports from the literature have shown that newborns with low birth weight (<2500g) have significantly increased risk of major depression with suicidal ideation, anxiety disorders, phobias, and impaired functioning compared to those with normal birth weights (nomura et al., 2007) . ii. girls born late preterm and early term show an increased risk of emotional problems at 36 months of age. these finding suggests that gender should be taken into account when evaluating children who are born at these gestational ages (stene-larsen et al., 2016) . iii. despite elevated rates of psychiatric disorders is associated with childhood among preterm children, it must be emphasized that most are found with other co-morbid conditions, and later environmental factors may also trigger the manifestations of these mental health disorders (monk et al., 2011) .. iv. in the past few years, the number of suicidal adolescent deaths has increased dramatically in the united states. adolescent males 15 to 19 years old were six times greater than the rate for females. the number of attempted suicides to completed suicides among adolescents is estimated to be higher among females than among males (miron et al., 2019) . v. alcohol use and alcoholism are also one of the potential risk factors for suicide in adolescents. alcohol use has been strongly associated with 50% of suicides. gay and bisexual adolescents are reported to display higher rates of suicidal ideation and suicidal behavior, also have major depression, suicidal attempts are 3 times higher than other adolescents. hopelessness is considered as one of the risk factors for suicidality; however, it is also known to be associated with major depression; therefore hopelessness can be a contradictory factor when determining suicide risk by itself (efstathiou et al., 2018; wolfe et al., 2019; young et al., 1996) . additionally, when looking at personality traits, this factor can itself be considered a risk for suicide. in other cases, it can be a co-risk paired with other influencing factors. studies from the literature have shown that difficulties and during childhood will lead to hopelessness (gaskin-wasson et al., 2017) . impulsivity is strongly associated with risky behavior management, psychopathology, and suicidality (gvion, 2018) . several cross-sectional and longitudinal studies have been linked to suicide attempts with both self-reported and performance-based impulsivity in the adolescent population. impulsivity has a positive correlation (gvion, 2018) . it is considered to be a promising risk factor for suicide (coryell et al., 2018; lewitzka et al., 2017; singh and rao, 2018; wang et al., 2017) . aggression, though a complex construct-is often associated with disruptive behaviors such as anger, victimization of peers, homicide isolation, and suicidal thoughts (buchmann et al., 2014; gvion, 2018) . aggression, commonly seen in adolescents (buchmann et al., 2014) is one of the important risk factor for suicide, (zhang et al., 2018) when it coexists with bullying (shain and committee on, 2016) (klomek et al., 2009) . buchmann et al., (2014) have observed that impulsive aggression might be associated with suicidal behavior, as it relates to the stressdiathesis model of behavioral dysregulation during states of the strong negative effect that is common during the aggression (buchmann et al., 2014) . high levels of perfectionism are positively associated with the increase risk of suicidal ideation and suicide attempts. based on the literature, smith et al., (2017) conducted a meta-analyses based on 45 different studies, that includes undergraduates, medical students, community adults, and psychiatric patients (n = 11,747) to understand the association between correlates of suicide and perfectionism (smith et al., 2018) . a total of 13 out of 15 perfectionism dimensions were positively associated with suicidal ideation (beevers and miller, 2004; smith et al., 2018) . cognitive rigidity is one of the positive characteristic risk factor for suicidal attempts and behavior (neuringer, 1964; perrah and wichman, 1987) . cognitive rigidity leads to dichotomous thinking and categorizing all life experiences to either "good/bad", "success/failure" according to perrah and wichman (1987) these two processes leads to nuances in acknowledging leads to problem-solving deficits and cognitive rigidity (perrah and wichman, 1987) . further, j o u r n a l p r e -p r o o f neuropsychological studies have also shown that cognitive rigidity as a predictive cue for suicidal behavior (neuringer, 1964; perrah and wichman, 1987) . ii) thought suppression: thought suppression is a potent mediator of emotional reactivity and self-injury (pettit et al., 2009 ). tucker et al. (tucker rp, 2017 have shown that thought suppression unambiguously is strongly associated with suicidal behavior. further studies from najmi, wegner, and nock (2007) have shown suicide ideation, and at least one suicide attempt in adolescents reveal an increased propensity to suppress unwanted thoughts. per the prior studies reported, pettit et al. (2009) found a positive correlation between suicide ideation and thought suppression in subjects of undergraduate students and adolescent in-patients (pettit et al., 2009) . iii) fearlessness and pain sensitivity: in suicidal adolescents, self-injury is more common than in adults, and it can be due to an increase in pain tolerance . this increase has yet to be determined as either the source or the consequence of suicidal behavior (o'connor and nock, 2014; orbach et al., 1997) . iv) agitation and implicit associations: agitation and implicit cognitions are known to be projective behavior for suicide in people with suicidal ideations (fawcett et al., 1997) . agitation is strongly linked to suicidal behavior in correlation to certain mental illnesses and medication as it can amplify negative symptoms and side effects. close associations between the individual and death can be indicative of future suicide attempts in adolescents (fawcett et al., 1997) . recent research examining trends of suicidal behaviors among adolescents of different racial and ethnic groups in the united states has shown an increase in suicide attempts among black youth with a significant increase in injury by attempts among black males (lindsey et al., 2019, pediatrics) . the rise in the number of suicidal attempts is thought to be related to mental health and socio etiologic factors incommensurately experienced by black youth, including poverty and racial discrimination (lindsey et al., 2019, pediatrics) . stress-related to the aforesaid ethnicity groups including victimization is expected to account for their increased risk of suicidality (thoma et al. 2019, pediatrics) . i) social transmission: social or familial transmission occurs when a close family member attempted or committed suicide (qin et al., 2002) . exposure to suicidal behavior can increase tendencies, especially if it comes from a maternal aspect. parental suicide has a more detrimental effect on children rather than in adolescents or adults (qin et al., 2002) . ii) social isolation: social isolation can be indicative of suicidal behavior because of the lack of support and the vulnerability of the individual to negative factors such as stress (haw and hawton, 2011) . besides, social media and networking have also shown a negative effect on adolescents and have led to self-harming and suicidal ideations. this factor is critical when analyzing suicidal behavior (haw and hawton, 2011; . social isolation and social distancing during the covid-19 pandemic have also shown increased risks for mental health issues such as fear, anxiety and increased suicidal risk (ahorsu et al., 2020) . hirsch and conner et al., (2006) revealed that individuals with high confidence had a lower risk of developing suicidal behavior even when experiencing adverse life events. it is believed that optimism is a protective factor in lowering suicidal ideations (hirsch and conner, 2006) . iii) problem solving and coping: problem solving appraisal factors such as confidence, approach-avoidance style, and personality control are the most strongly related to suicide ideation and hopelessness (pollock and williams, 2004) . however, problem solving confidence might be associated with resilience which is important in coping with hopelessness and suicide (guerreiro et al., 2013; pollock and williams, 2004) . problem-solving and coping have shown to have significant impact on suicidal behavior. while the direct relationship has yet to be described, changes in neurobiology are known to strongly influence this factor (guerreiro et al., 2013; pollock and williams, 2004) . negative life events a. childhood adversities: early-life stress can lead to suicidal behavior. while the type of adversity affects the individual, the extent may vary according to the kind of stress j o u r n a l p r e -p r o o f experienced. in other words, inevitable difficulties may be more detrimental than others, such as sexual and physical abuse. suicidal behavior is significantly high in adolescents who experienced childhood adversities, and this behavior tends to decrease as age increases (bruffaerts et al., 2010) . b. traumatic life events during adulthood: while childhood adversities tend to increase suicidal behavior during adolescence, traumatic experiences can affect any individual at any age and could potentially lead to suicidal ideations (stein et al., 2010) . c. physical illness: physical illness has been associated with suicidal behavior; however, the system of how it can influence the behavior has not been identified. it is hypothesized that physical illness can cause depression and therefore lead to suicide however, this has not been proven (webb et al., 2012) . dopamine (da), a catecholamine synthesized in a two-step reaction process that involves the conversion of tyrosine into l-dopa, a reaction catalyzed by the tyrosine hydroxylase, the rate-limiting enzyme in da synthesis (nagatsu, 1991) . in recent years, several reports describe a good correlation between dysfunction of dopaminergic functioning and suicide (fitzgerald et al., 2017; ho et al., 2018; oquendo et al., 2014; pizzagalli et al., 2019) . the analysis of key dopaminergic markers such as the dopamine transporter (dat) and dopamine receptors d1 and d2 revealed an imbalance in the d1 and d2 abundance in the dorsal striatum in suicide compared to controls, and a clear reduction in the amount of dat and d1 appeared with age. nonetheless, the mean receptor binding in the striatum was unchanged between suicide and controls (fitzgerald et al., 2017) . interestingly, a reduction in dorsal striatal gray matter was observed in a group of adolescents with suicidal behavior, pointing to an important role of the dorsal dopaminergic system in vulnerability to suicide (ho et al., 2018) . the serotonin or 5-hydroxytryptamine (5-ht) is a monoamine synthesized by the ratelimiting enzyme tryptophan hydroxylase (tph1 and tph2) from the amino acid tryptophan (walther et al., 2003) . it is implicated in a variety of functions in the nervous system such as mood and anxiety, sleep, aggressiveness, circadian rhythm, feeding, and social behavior, among many others. not surprisingly, the serotonergic deficit is directly implicated in depression and compulsivity, leading to increased vulnerability to suicidal behavior in adolescents and j o u r n a l p r e -p r o o f adults (braquehais et al., 2012; oquendo et al., 2014; picouto et al., 2015) . there is compelling clinical and genetic evidence that the serotonin transporter (sert) plays a critical role in suicide. pet imaging in individuals with depression and who attempted suicide had a low abundance of sert in the midbrain and higher serotonin 1a receptor in the raphe nuclei oquendo et al., 2016) . likewise, postmortem brain tissue biochemical analysis has shown a reduction of sert in the frontal cortex, hippocampus, and putamen; however, contradictory outcomes have been observed depending on the brain region analyzed (purselle and nemeroff, 2003; steinberg et al., 2019) . besides, polymorphism at the transporter gene, particularly the polymorphism 5-httlpr predicts a three times higher-risk suicide compared to noradrenaline also called norepinephrine (ne) is another catecholamine synthesized from tyrosine by th and ddc enzymes and a final hydroxylation step of da to produce noradrenaline by the enzyme dopamine β-hydroxylase (dβh) (gonzalez-lopez and vrana, 2020). ne functions as a neurotransmitter in the central and peripheral nervous system, where it plays a role in regulating a variety of cognitive functions, motivation, and impulsivity, among others. similar to serotonin, noradrenergic neurotransmission dysfunction is well established to contribute to depression and suicide, conforming the monoamine hypothesis (benn and robinson, 2017; moret and briley, 2011; sasamori et al., 2019) . several polymorphisms have been identified at key components of the noradrenergic system such as dβh, norepinephrine transporter and ne receptors strongly associated to depression, addiction and suicide, either insertions, deletions or amino acid changes (cao et al., 2018; gonzalez-lopez and vrana, 2020; hamner and gold, 1998; ueda et al., 2016; zhou et al., 2015) . changes in the levels of the hormone are crucial for some individuals during suicidal behavior, especially in females. there is very interesting research regarding the menstrual cycle studying how feminine hormones fluctuate, thus affecting female behavior, which increases the risk for suicide (owens and eisenlohr-moul, 2018) . association between premenstrual dysphoric disorder and suicide (shams-alizadeh et al., 2018) had been associated, and levels of some hormones in the reproductive cycle of females are risk factors for suicide. other studies have shown that females with high levels of progesterone increase suicidal attempts (mousavi et al., 2014) . in adolescences, females that were under hormonal contraception had shown a positive j o u r n a l p r e -p r o o f association between hormonal contraception and suicide. it concerns that conclusion from several studies indicated that adolescent females would have the highest risk of commit suicide under this hormonal contraception (hughes and majekodunmi, 2018; owens and eisenlohr-moul, 2018; skovlund et al., 2018) . we reviewed research studies that concentrated on identifying certain proteins as biomarkers in adolescents that had committed suicide or with suicide ideations. one of the most accepted ideas is the dysregulation of the immune system, which was found in people with suicide attempts. dysregulation of the immune system led to the hypothesis that cytokines are a risk markers for suicide in adolescence as early evidence suggested (gabbay et al., 2009) . following this thought, data has shown that certain pro-inflammatory cytokines are risk markers for suicide (pandey et al., 2012) . a study conducted by amitai (amitai et al., 2019), measured cytokines in adolescent suicide victims and found elevated levels of cytokines in comparison to the control group (amitai et al., 2019). the probable mechanism for an increase in the levels of inflammatory cytokine levels might be due to the activation of the toll-like receptors (tlr) (pandey et al., 2014) . the toll receptors are known to play an essential role in regulating innate immune response and facilitating immune function in. so far, pandey et al. (2014) , have found that mrna and protein levels of tlr3 and tlr4 were consistently dysregulated in suicidal subjects (pandey et al., 2014) . based on the literature published so far, inflammatory cytokines are interlinked with suicidal behavior by several mechanisms (pandey et al., 2014) . inflammatory cytokines, like ifn-γ, il-6, il-1β, and tnf-α, are known to be affected by suicidal victims in adolescents. apart from the cytokines involvement in contributing to the pathophysiology of suicidal behavior include activation of the kynurenine pathway, dysregulation of the hpa axis, and alterations in monoamine metabolism. quin, an n-methyl-d-aspartic acid receptor agonist and acts via activation of the nr1, nr2a, and nr2b nmda receptors ( (jollant et al., 2020) . further, tonelli et al. (2008) have reported that elevated mrna transcripts of il-4 and il-13 in the orbitofrontal cortex of suicide victims (tonelli et al., 2008) . besides, steiner et al. (2008) demonstrated increased microgliosis is indicative of an enhanced inflammation in suicidality of the adolescent population (steiner et al., 2008) . although there is limited data on postmortem data on teenage suicide victims also points to the association between inflammation and suicide. pandey et al. (2010) reported that postmortem brain tissue from teenage suicide victims had increased mrna and protein levels of il-1β, il-6, and tnf-α in cortical regions of brodmann area 10 (pandey and dwivedi, 2010) . additional studies are j o u r n a l p r e -p r o o f needed to support the relationship between inflammation and suicidality in youth either by metaanalyses. together, these studies suggest that suicidality in adolescents might have an inflammatory signature irrespective of their primary diagnoses and other underlying conditions. steiner et al. (2006) first found the link between suicide and microglial activation, with hla-dr as a microglial marker in suicidal victims (steiner et al., 2006) . no significant changes were observed in the cell-density of microglia; however, a substantial increase in the microglial density was found in the dorsolateral prefrontal cortex (dlpfc) and anterior cingulate cortex (acc) of suicide victims (steiner et al., 2008; steiner et al., 2006) . schnieder et al. (2014) analyzed the microglial morphology with ionized calcium-binding adapter molecule 1 (iba-1) and cd68 as microglial markers, interestingly, the density of iba-1 activated microglia revealed significant effects in suicidal victims (schnieder et al., 2014) . torres-platas et al. (2014) conducted a case-control study using postmortem brains of suicide victims with major utilizing11c pet imaging study, holmes et al. (2018) conducted a case-control study to compare tspo in acc, pfc, and insula brain regions of mdd (n=14), controls (n=13) with moderate to severe depression severity (holmes et al., 2018) . they further conducted post hoc analysis to compare the tspo availability between patients with and without suicidal thoughts (holmes et al., 2018) . interestingly, tspo was significantly increased in suicidal compared to non-suicidal subjects, most robustly in the acc and insula (holmes et al., 2018) . (nagy et al., 2018) . both cx30 and cx43 were down-regulated across several brain regions and that pfc tissue and repression of astrocytic connexins in cortical and subcortical brain regions and prefrontal enrichment were observed with h3k9me3 in mdd and suicide (nagy et al., 2018) . these outcomes suggest a strong interlink between microglial and astrocyte activation and suicide. however, furthermore extensive studies, including various, are needed to elucidate the relationship between microglia and astrocytes with suicide using novel methodologies and techniques, also beyond the psychiatric diagnostic boundaries. suicidal behavior in adolescences has not been thoroughly studied, and not many factors have been identified in this developing stage (miron et al., 2019) . identifying markers can be useful in the prevention of suicide as they can serve as warning signs. different factors can influence depression and suicidal behavior; the way the body responds to stress, genetics, epigenetics, and environmental factors are the most influential ones (essex et al., 2013) . dysregulation of serotonin, hpa axis genes, and immune system in the human brain, especially in the frontal cortex, can affect human behaviors such as impulsivity, decision-making and mood and they have been strongly associated with the risk of suicidal behavior as they all play an important role in the body's response to stress (roy et al., 2012) . also, childhood trauma can affect the normal function of some genes associated with the risk of committing suicide (roy et al., 2012) . genetics plays an important role in everyday behavior, and there is no exception when it comes to suicidal behavior. all of the studies reviewed included childhood abuse and its correlation with altered genes. dysregulation of the serotoninergic system, which combined with childhood abuse, can lead to suicidal behavior. in suicide victims, low levels of brain-derived neurotrophic factor (bdnf) in the prefrontal cortex have been reported; impaired serotonin levels in this area can influence behaviors such as impulsivity, decision-making, and mood (martinowich and lu, 2008; perroud et al., 2008) . according to roy (2012) , the serotonin transporter 5-htt is responsible for the absorption of serotonin back to the cell (roy et al., 2012) . in the serotonin transporter gene, the polymorphic area 5-httlpr can be influenced by environmental stressors and lead to suicidal behavior. this polymorphic region has two alleles that regulate gene transcription, s-allele, and l-allele. the s-allele decreases 5-htt transcription efficacy as opposed to the l-allele. according to lin and tsai, 5-httlpr s-allele was more common in individuals that had attempted suicide. decreased levels of bdnf, altered crh and polymorphism in 5-httlpr influence decision making behavior in adulthood. these factors combined with childhood abuse can be directly linked to suicide in adolescents and they are summarized on table 1 (guillaume et al., 2013; martinowich and lu, 2008; perroud et al., 2008; sarmiento-hernández et al., 2019; shinozaki et al., 2013) . the dna and proteins in the chromatin can be modified to change the expression profile of genes in a very sophisticated process called epigenetics. one of the most studied and known modification is methylation and which is the addition of the methyl group(s) to either dna or a protein in the chromatin, thus affecting gene expression (greenberg and bourc'his, 2019) . methylation in epigenetics has gotten significant attention because childhood stress/trauma exposure can result in changes in methylation of some genes involved in suicidal behavior in adolescences (essex et al., 2013) . data has shown that corticotropin-releasing hormone (crh) can have changes in methylation in adolescents with suicide attempts (jokinen et al., 2018) . other non-adolescent research findings support this idea, as it states that there is an existing dysregulation on methylation in the prefrontal cortex in suicide human adult brains (schneider et al., 2015) . changes of methylation of some genes could be used as a biomarker that can help determine which adolescences are at risk of committing suicide and therefore be able to prevent it. regulation of gene expression at dna levels due to chromatin remodeling and post transcriptional mechanisms are strongly linked to suicidality (autry and monteggia, 2009). early life trauma has been associated with suicidal risk, and there is a strong association of epigenetics, which affects the functioning of several genes in the brain (labonte et al., 2012) . the vast amount of research in this area has been conducted in the adult brain, but in adolescences is rare. the hypothalamic-pituitary-adrenal (hpa) axis genes and proteins have being implicated to be dysregulated during childhood abuse/trauma, and genes for hpa-axis may be altered in suicidal idealization (labonte et al., 2012) . several genes have been associated with risk for suicide in the hpa-axis, such as crhbp and fkbp5 (roy et al., 2012) . therefore, there has been an effort to understand the process involved in epigenetic on the hpa-axis genes. indeed, jokinen et al., (2018) they were able to identify a loci cg19035496 at the promoted region of the crh gene (jokinen et al., 2018) . cg19035496 was hypermethylated in adolescents with a high psychiatric risk score, but in the same study with adults, they found that hypermethylation is associated with a high risk of suicide (jokinen et al., 2018) structural neuroimaging studies have shown that prefrontal cortex (dorsal and ventral) changes are associated with suicidal thoughts and behavior; changes include reduced volumes and serotonergic dysfunction. anterior cingulate cortex (dorsal and ventral) volumes are decreased in both adult and adolescents with a history of suicide attempts with major depressive disorder and bipolar disorder (schmaal et al., 2020) . middle and superior temporal gyri volumes are lowered in high lethality suicidal attempters with high impulsive behavior across various mental disorders. default network mode of the brain changes are associated with suicidal behavior in both adults and adolescents; changes are lower resting functional connectivity (schmaal et al., 2020) . adolescents with suicidal attempts and bipolar disorder showed a decrease volume in the lateral orbitofrontal cortex, low 5-ht1a receptor binding and an increased lateral orbitofrontal cortex activation when regulating negative memories . low volume of the dorsal and ventral anterior cingulate cortex in combination with mental disorders was associated with a higher attempt of suicide in adolescents (wagner et al., 2011; wagner et al., 2012) . suicidal ideations in adolescents showed an increase in activation in both the dorsal anterior cingulate cortex and dorsal lateral prefrontal cortex; this dysregulation can be due to the dorsal area of the brain being in charge of decision making and the control of emotions and behavior. dolsen (2017) conducted a study in which it was hypothesized that hyperarousal during sleep correlated with suicidal ideations as well as a major depressive disorder (dolsen et al., 2017) . neurophysiological hyperarousal occurs when the brain is at a constant state of high alert, which can lead to long-lasting stress. during sleep, hyper arousal can be reflected by an increased alpha and beta activity, as well as a slow frequency in delta activity (dolsen et al., 2017) . eeg studies on sleeping patterns have shown that neurophysiological hyper arousal during sleep may contribute to suicidal behavior when paired with major depressive disorder (dolsen et al., 2017). in figure-1 , we outline all the above sections into a integrative model to unravel the key target that needs to addressed in suicide research. an explanatory model that delineates neurodevelopmental, neurochemical, neuropsychological, clinical risk factors that are identified to be involved in suicidality. these biological (genetic, proteomics and epigenetics) and environmental factors might serve as endophenotypes and hold a strong interlink between them. developing such putative models are highly important to understand the screening, j o u r n a l p r e -p r o o f identifying targets that need further investigation to improve the process for prevention and treatment. based on the reports from clinical trials.gov, we have tried to list the active clinical trials, the ones that are in progress, and completed. according to the clinicaltrials.gov database, there are 112 studies so far on suicidal ideation, attempts, and suicidality. among those 42 studies are specific for suicidality in adolescents with youth (n=22 trials); teens (n=8 trials); adolescence in essence, the purpose of this trial was to evaluate a set of interventions derived from a theory of suicide and compare their effects on outcomes (jha et al., 2020) . also, it evaluates the effect of these interventions on reducing specific negative cognitions associated with depression and suicide ideation in an intensive outpatient program for suicidal youth. effective mental health preventions, interventions may reduce the impact that mental health problems have on young people's well-being. cultural considerations are warranted in the design of preventative interventions. research has found substantial gender and racial/ethnic differences in suicide risk factors among youth underscoring the need for this (lee and wong, 2020) . recommendations for interventions tailored to the black community include efforts to increase access to mental health care by reducing stigma and increasing help-seeking behavior (lindsey et al., 2019) . researchers examining risk and protective factors related to adolescent suicide attempts recommend psychotherapy aimed at treating persistent depression and increasing productive coping skills (mirkovic et al., 2020) . is also known that cognitive-behavioral sleep interventions might improve mental health in adolescents (particularly anxiety and depression) by improving sleep problems, since sleep is also a major risk factor for suicide. • dbt for adolescents there have been multiple studies examining dbt adapted for adolescents (dbt-a) for the prevention of suicide and self-harm. a one-year randomized control study of dbt-a vs enhance treatment as usual noted a significant reduction in self-harm (which includes suicide attempts and nonsuicidal self-injury) during the study and at one year of follow-up. there was also a significant reduction in suicidal ideation in the intervention group, though this result did not carry through in the follow-up period (mehlum et al., 2016) . motivational interviewing has been postulated as a way to encourage behavioral change concomitantly with safety planning. a pilot study tested the feasibility of randomizing and using this technique (czyz et al., 2019) . participants included adolescents between the ages of 13 and 17 who were hospitalized due to suicide risk. motivational interviewing was used in addition to safety planning at discharge. proximal outcomes in the mi group included greater likelihood in using coping and higher self-efficacy to refrain from suicide attempts. at 3 month follow-up however, it appears the intervention group had two more patients with suicide attempts compared to the control group. four more patients in the intervention group were hospitalized compared to controls (grupp-phelan et al., 2019) . demonstrated an nnt of three, although there were no significant differences in non-suicidal self-injurious behaviors, and there were statistically significant higher ed visits in the safety group. in 2019, godoy garraza, kuiper, goldston et al examined data from counties that received grants for suicide prevention in youths as part of the garrett lee smith youth suicide prevention program (godoy garraza et al., 2019) . previous analyses had found this program, which involves training, outreach programs, and early intervention programs aimed at youths aged 10-24, was associated with a significant decrease one year after implementation of the program in counties compared to matched controls. however, this effect was not sustained 2 years or more after implementation (godoy garraza et al., 2015) . this 2019 observational study further stratified counties into groups that used the programs for 1 years vs 2 years vs 3 years vs 4 years. they noted a greater association in the reduction of suicides in those counties that received gls programs for a longer period. this association was statistically significant at the 1 and 2 year follow-up mark after programs had ended in those counties, with 0.893 fewer expected deaths by suicide per 100,000 and 1.095 fewer expected deaths by suicide per 100,000 respectively. this association was greatest in rural counties (where there were 2.4 fewer expected deaths). one limitation is that larger metropolitan counties in new england were excluded as adequate matched-controls were not available (godoy garraza et al., 2019) . one large, multicenter, cluster-randomized controlled trial did find that a manualized, universal school-based intervention for pupils known as the youth aware of mental health program (yam) involving role-play with interactive workshops, booklets, and lectures about the risk of suicide and importance of mental health had a significant decrease in suicide and suicide ideation at 12-month follow-up with an odds ratio of 0.45 and 0.50 respectively (wasserman et al., 2015) . an open-label, single-arm study in adolescents aged 13-21 evaluated if n-acetylcysteine (nac) affected nonsuicidal self-injury (nssi) (cullen et al., 2018) . its exact mechanism is unknown; however, it has shown some utility in addiction and mood disorders. while (mahableshwarkar et al., 2020) . further, their detailed evaluations indicated that vortioxetine was not associated with an increased risk of suicidal ideation and behavior in adult patients with mdd (mahableshwarkar et al., 2020) . esketamine and ketamine are utilized as possible treatments for acute suicidal ideation (lengvenyte et al., 2019) . intranasal esketamine is typically used for treatmentresistant depression, and intravenous ketamine is a standard anesthetic drug (lengvenyte et al., 2019) . ketamine, an n-methyl-d-aspartate glutamate antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action (de berardis et al., 2018; lengvenyte et al., 2019) . clozapine, an j o u r n a l p r e -p r o o f antipsychotic drug, is approved for the treatment of suicidal ideation in patients who have schizophrenia (wilkowska et al., 2019) . although there is substantial evidence of these effects, to date, the mechanisms of anti-suicidal properties of clozapine are still elusive. clozapine with its unique pharmacology, anti-aggressive and anti-impulsive properties reduces the suicidal ideation properties in bipolar patients (wilkowska et al., 2019) . overall, ketamine in the treatment of suicidal patients involves several pathways, most importantly, the glutamatergic system seems to play a pivotal role, and its dysregulation may be the basis of suicidal cognitive biases, explaining the benefits of ketamine treatment (de berardis et al., 2018; lengvenyte et al., 2019) . there was one exploratory study to see if there is an effect on suicidal ideation (si)in 19 patients aged 13-19 with a 30 treatment-course of acute repetitive transcranial magnetic stimulation (croarkin et al., 2018) . initially, there was a response for decreased si, though further analysis adjusting for depressive symptoms severity found no statistically significant decrease in columbia suicide severity scale intensity of ideation score, nor in the "suicidality" item on the children's depression rating scale, revised. • ect: one observational follow-up study examined the effects of ect on adolescents at an academic medical center (mitchell et al., 2018) . packets of questionnaires were sent to 117 patients who were less than 18 years of age at the time of receiving ect, and of these, 25 returned the packets to the research team. using the self-assessment suicide rating scale, 78.3% of participants indicated they had none or mild suicidality after treatment (mitchell et al., 2018) . while these findings are encouraging, there are no baseline measurements as to the patient's suicidality prior to starting treatment. the safety planning intervention is a structured intervention that utilizes a variety of techniques including prioritized coping strategies for individuals and social contacts, and when combined with structured follow-up, a randomized controlled trial found an association with a decrease in suicidal behaviors in an adult population in va emergency departments (stanley et al., 2018) . future studies could look at an adolescent population. studies utilizing technology, such as smartphone application-based interventions, have shown promising, albeit limited j o u r n a l p r e -p r o o f results. in 2018, the smartphone app brite was used in inpatient adolescents at discharge, however, while this rct showed a trend towards a decrease in the occurrence of suicide attempts, these results were not significant, and there was no effect on suicidal ideation (kennard et al., 2018) . this does show promise for future studies aimed at using smartphone apps, particularly as according to the pew research center, 95% of adolescents have access to a smartphone, and 45% surveyed noted they use them often (monica anderson, 2018) . some studies are currently underway looking at using apps in patients who may be a risk for suicide or self-harming behavior in participants receiving mental health treatment (health, 2020 (hospital, 2020) . additional studies are looking at strategies that can be implemented at schools, in particular, to reduce suicide in those who identify as lgbtq (willging, 2019) . there is currently a study examining the effects of single-dose ketamine in adolescents with depression and anxiety (bloch, 2019). as there is some evidence that it can decrease suicidality in adults, if proven safe and effective for adolescents, this opens another treatment modality to prevent suicide ideation and attempts in children. j o u r n a l p r e -p r o o f sociobiological, and clinical risk factors is highly essential, concerning the development of effective prevention strategy plans for suicidal ideation and suicide. another focus of our review is the discussion of possible similarities and differences in the neurobiological abnormalities between adults and suicidality in adolescents. studies of the brain or postmortem brain are more appropriate for studies of suicide neurobiology, even though they may have many limitations. future research should emphasize on identifying the underlying mechanisms of suicidal thoughts and behaviors that are specific to adolescent populations. this knowledge would greatly help us in understanding the progression of the disease, early diagnoses, interventions that specifically address issues like impulsivity, aggression, reduced positive affect, lack of social interaction, increased negative thoughts, poor distress tolerance, and family interactions in suicidal adolescents. this information will facilitate generating treatment strategies that are more effective in reducing suicidal thoughts and behaviors in adolescents. the il-6 elisa high levels of il-6 were found to be a risk factor for fluoxetine-associated suicidality. subjects in this study were with an average age of 13.9 years. protein (pandey et al., 2013) gr-α western blot gr-α, protein, and mrna were low in the prefrontal cortex and amygdala of adolescent suicide victims. protein (pandey et al., 2012) il1-β, il-6, and tnf-α real-time pcr and elisa levels of mrna and protein for il1-β, il-6, and tnf-α were high in postmortem brains from suicide subjects. subjects in this study were aged from 13-20 years. the prefrontal cortex (human brain) protein (gabbay et al., 2009) the author proposed, based on their data, an association between adversities in early childhood and dna methylation. genetics (sarmiento-hernández et al., 2019) polymorphism 5-httlpr pcr this study was conducted in a mexican population of adolescents who found a high prevalence of "ss" and "s" genotype for 5-httlpr in a population with history of depression and suicide. genetics (guillaume et al., 2013) polymorphism of the genes crhr1 and crhr2 polymorphism in genes crhr1 and crhr2 may be implicated in suicide. genetics (roy et al., 2012) polymorphism of crhbp childhood trauma increases the risk of suicide as well as variation in the crhbp gene blood genetics (perroud et al., 2008) polymorphism of bdnf: val66met genotyping by pcr based on their data, they concluded that childhood abuse, besides with bdnf val/val genotype, is a 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back-testing risk evaluation date: 2020-07-24 journal: nan doi: nan sha: doc_id: 224491 cord_uid: qq9hdtww a new test for measuring the accuracy of financial market risk estimations is introduced. it is based on the probability integral transform (pit) of the ex post realized returns using the ex ante probability distributions underlying the risk estimation. if the forecast is correct, the result of the pit, that we called probtile, should be an iid random variable with a uniform distribution. the new test measures the variance of the number of probtiles in a tiling over the whole sample. using different tilings allow to check the dynamic and the distributional aspect of risk methodologies. the new test is very powerful, and new benchmarks need to be introduced to take into account subtle mean reversion effects induced by some risk estimations. the test is applied on 2 data sets for risk horizons of 1 and 10 days. the results show unambiguously the importance of capturing correctly the dynamic of the financial market, and exclude some broadly used risk methodologies. the evaluation of financial risk is an important part of any investment activity, and the regulators are imposing ever stricter rules over all participants. the overall financial risk can be classified along several categories, and this paper concerns market risk (together with credit risk). it is a major component of the financial risk, and it can be quantified efficiently. in this context, a difficult issue is the validation of the quantitative figures provided by a risk evaluation. a validation of a risk computation is done using back-testing. the core idea of a back-test is fairly simple: using a long sample of historical data, evaluate the risk at different dates, and check over the following days that the risk has been correctly computed. in details, the scheme is more complex. the primary outcome of a risk evaluation is a probability distribution for the returns over a selected risk horizon ∆t . from this distribution, the usual risk measures can be computed like standard deviation, value-at-risk (var) or expected shortfall (es, also called cvar). with the new information obtained each day, this distribution is changing in time. as attested by the large body of literature on the volatility dynamics and the heteroskedasticity, the dynamics is quantitatively large and the volatility can change easily by a factor 5 over different periods (quiet, volatile or crisis) . hence, we are dealing with a clearly non stationary system, with widely changing distributions. the core of the back-test algorithm is better explained at a one-day risk horizon. each day, a forecast of the probability distribution of the returns is made, an ex ante evaluation. the next day, the actual return realized by the market becomes available, an ex post value. this single return should be drawn from the distribution computed on the previous day. the goal of the back-test is to assess if the sequence of ex post draws is coming from the sequence of ex ante probability distributions. this is clearly not an easy problem, quite different from the usual test with repeated draws from a fixed distribution. a simple possible test is provided by var: since it is defined as the α quantile of the loss distribution, the fraction of exceedances should be 1 − α. this reduces the back-test to a simple counting exercise. the weaknesses of this simple test are to check only one level for α, and to ignore the dynamical aspect of the risk evaluation. better tests using the whole distribution of exceedances and/or the independence of the exceedances where proposed and improved in many contributions [kupiec, 1995] , [crnkovic and drachman, 1996] , [diebold et al., 1998 ], [barbachan et al., 2006] , [christoffersen, 1998] , [christoffersen and pelletier, 2004] , see also the reviews by [campbell, 2006] , [christoffersen, 2010] and the master thesis of [roccioletti, 2016] . better tests can be built using a probability integral transform (pit): given a probability distribution and a return, compute the cumulative probability associated to the return. we named "probtile" this realized p-value, since it corresponds to the cumulative probability of a quantile. if the forecast for the pdf is correct, the probtiles should be iid with a uniform distribution. after the pit transformation, the backtest problem becomes a standard statistical exercise for which numerous tests can be used, say for example a kolmogorov-smirnof test. this testing strategy is known for a long time by statisticians, going back at least to [rosenblatt, 1952] , and has been rediscovered several times in finance [christoffersen, 1998; zumbach, 2007] . its main advantage is to test the whole distribution, and tests can be constructed to emphasize the tails which are the focus point for risk evaluation. the dynamical aspect of the risk evaluation can also be tested, for example using lagged correlations of the probtiles. an interesting recent development concerns scoring functions, elicitability and the direct comparison of risk methodologies. the set-up is to have a fixed distribution for a random variable, playing the role of the returns. the idea is to have some functions that attribute a score to the set (confidence level α, tentative risk measure(s) , realized return). for some selected scoring functions, the minimum of the expectation of the scoring function is given by the actual risk measure, say var α . a risk measure for which such a scoring function exists is called elicitable. an interesting property of the scoring function is to allow for a direct comparison of risk methodologies, essentially using the expected difference of the scores for the respective methodologies (see e.g. [nolde and ziegel, 2017] and references therein). with this approach, various risk methodologies can be compared pairwise in order to decide which one is better. yet, the application of this approach to empirical data requires the distribution to be stationary, a hypothesis which is invalid in finance. given this limitation, we have to use an absolute approach, where each risk methodology is assessed independently for its qualities. so far, most of the literature about financial risk is to check the distributional aspect of the forecast, and the dynamical aspect of risk evaluation has been much less discussed. we find this bias quite odd, since having the dynamic right is quantitatively more important for actual decision-making than having the asymptotic distribution right. we will first present a simple illustrative example for one stock, showing visually the key role of the dynamic. then, we introduce the tile test that gives a joint test for the dynamics and the distribution. the price for the ubs stock (green line, right axis), the daily returns (black square) and the 5 and 95% var, computed with the historical return methodology (blue line) and the historical innovation methodology (red line). the example uses the ubs stock price (a major swiss bank), with a quite eventful history over the last 20 years related to the major crises and to events specific to ubs. this choice provides for spectacular figures, but all stocks, indexes or fx show similar properties. the figure 1 shows the ubs prices, the daily returns, and the 5 and 95% var computed with two methodologies. the daily returns are marked with black squares, and clearly the width of the return distribution changes with time. clear periods can be seen where the distribution is narrow or wide, a property called heteroskedasticity, namely the variance (skedasticity) of the return time series is not constant in time (hetero). accordingly, the risk is changing, and this should be reflected on the risk measures. on fig. 1 , the blue line corresponds to the widely used historical return methodology, namely the distribution for the next return is spanned by the daily returns in a moving 2 years window. the red line is based on a long-memory arch process, with a historical distribution for the innovations (details about the risk methodologies are given below in sec. 5). the dynamics is quite different between both models, with a slow (fast) adaptation to the market conditions for the blue (red) line. if the risk computation is correct at the 5 and 95% level, 5% of the daily returns should be below and above the var lines. this property should be verified not only asymptotically on a long sample, but at all times. with naked eyes, we see that the red line is about right, but the blue line shows clear periods with too many or too little exceedances. the difference can be large, see for example the covid crisis on the right of the graph. let us emphasize that the blue line can be wrong during extended periods, yet be correct on a long enough sample (i.e. asymptotically). this figure gives the gist of this paper, namely that the dynamics of the exceedances, or of the probtiles, should be tested thoroughly. the probtiles for the ubs stock, computed using the historical return methodology. the non uniformities during some periods are clearly visible, corresponding to a clear over-or under-estimation of the risk. the figure 1 is important since giving the key message in bare form, without any statistics. these time series are obviously not stationary, and therefore not amenable easily to statistics. as explained previously, the key idea to obtain a stationary problem is to use a pit to transform the realised returns into probtiles, using the forecasted distributions. the figures 2 and 3 show the realized probtiles using respectively the blue and red risk methodologies. if a risk methodology is correct, the probtiles should be iid with a uniform distribution. visually, the points should be uniformly spread in the figure. this is obviously not the case with the blue methodology, based on historical returns, where clusters are observed. even though, the asymptotic distribution, measured on the whole sample, could be uniform. hence, testing only the marginal distributions is a fairly weak test of the adequacy of a risk methodology. let us emphasize that the blue risk methodology can be off for periods up to years, during which the risk is systematically under-or over-valued. the core idea for the tile test is to check the number of points on sub-tiles of the whole sample. the whole sample is divided regularly in t t intervals along the t-axis, and t z intervals along the probtile z-axis, creating t = t t t z tiles with an equal area. in each tiles, n/t points are expected, with n the total number of points in the sample, and t the number of tiles. the actual number of points on a given tile is n i , and dn i = n i − n/t should be a random variable with zero mean. if the risk model is perfect, the variance of dn i should be in line with the theoretical model of random points. if not, the risk model can be rejected. in the literature, similar tests have been used to test random generators, to check that, in a sequence of draw x i , the vectors (x i , x i+1 , · · · , x i+n ) are uniformly spread in a unit cube [0, 1) n [knuth, 1998 ]. this test is of interest in finance since it is sensitive to both the uniformity in z and to the time dynamics. when applied on fig. 2 , the fluctuations between tiles are larger than with fig. 3 , and the hypothesis of uniformity should be rejected for the first methodology. a slight complication is that the points are deterministic in time with one point per business day, and random in the z direction. this is important to derive an analytical benchmark, but for several reasons detailed in this paper, we will only use numerical benchmarks. this test is used with empirical time series in order to check some major methodologies used to compute financial risk. a main outcome is that the dynamical part is crucial in delivering a good risk evaluation, then the distributional model is important. this conclusion is in-line with [zumbach, 2007] , where the lagged correlations of the probtiles were tested, yet the tile-test gives a clearly more powerful assessment of the dynamics. interestingly, the bulk of the literature on back-testing focusses on the marginal distributions computed with the full sample, a quantity that is indirectly sensitive to the dynamics through the choice of the sample time boundaries. this also contradicts the belief of many practitioners who are using long samples of historical returns, inducing a very slow dynamics for the volatility. the resulting lack of reactivity cost dearly to some banks during the sub-prime crisis in fall 2008, whereas the volatility started to raise already at the end of 2007, following a long period of decreasing volatility. not able to evaluate properly the risks with its dynamics, they kept their positions until september 2008, then made the headlines of newspapers. the plan of this paper is as follows. the notation and definition of the tile test is presented in the next section. section 3 defines the benchmark following the idea that the probtiles z should be iid in u (0, 1). the motivation for the tilings used in this work are presented in sec. 4, the risk methodologies in sec. 5, and the empirical data sets in sec. 6. the problems related to the benchmark are addressed in sec. 7, first by using the usual benchmark, then by introducing 3 benchmarks appropriate for different risk methodologies. the properties of these benchmarks are analysed in sec. 8, showing why some test results are too good to be true. equipped with the appropriate benchmarks, an empirical study is done for the 1 day and 10 days risk horizons in section 9 and 10 respectively. finally, the conclusions are presented, on the tile test and on the components required to construct a risk evaluation. 2 general set-up for the tile test the notation is as follows. the risk horizon is ∆t . the total number of points in the sample is n . the number of tiles in the probtile z and time t directions are t z and t t respectively, with the total number of tiles t = t z t t . the number of points in one given tile i is n i . the time axis is divided regularly from the start to the end of the sample. the length of the tiles in the t-direction is denoted with ∆t tile = ∆t sample /t t , with ∆t sample the sample length in year. consider now a column of tiles, spanning some time interval. the probability for one point to fall in one given tile in the z direction at a given time t is p = 1/t z . the statistical tests involve the total number of points in the column of tiles. due to holidays, the number is slightly changing, and should be counted from the number of valid data points in each column. the total number of points in a column of tiles, in the time span for these tiles, is n t with n t n/t t . the general idea for the tile test is that the points should be uniformly spread in the tiles, and we want to measure the deviation from uniformity. on a given tile indexed by i, the number of points is n i , with the expected mean µ t = n t /t z . the random variable measures the difference between the actual number of points in the tile i and the mean. its sample standard deviation σ δn is given by and measures the fluctuations of the point's count between tiles. the point's count standard deviation σ δn is our base random variable, depending on the number of tile t , on the time series, on the risk horizon ∆t , and on the risk methodology used to compute the ex ante probability distribution. our goal is to construct a statistical test based on σ δn . our null hypothesis is that the probtiles are iid with a uniform distribution, and this induces the null distribution for σ δn . following the standard statistical testing procedure, a methodology can be rejected if the fluctuations are too large compared to the theoretical distribution obtained with the null hypothesis. the usual approach is to demonstrate (or assume) an asymptotic distribution with the null hypothesis, then to compute the mean and standard deviation of σ δn . yet, this usual standardization strategy has the following limits. • it is more natural to take σ δn as the base random variable to construct a test, but analytical computations can be done only on σ 2 δn . • for the risk horizon ∆t larger than 1 day, the one-day sampling of the probtiles is correlated. unfortunately, the theoretical distribution for σ δn or σ 2 δn is then unknown. a possible remedy is to sub-sample the data every ∆t -points, but this reduces the sample size by the same factor. as the back-test gets increasingly difficult for growing ∆t , we would like to keep as many data points as possible. • stocks with low liquidity have many days with zero return, essentially due to no trading. many stocks have also quite low prices, making the minimal price increment apparent for small price changes. both effects are often compounded. for such case, the return distributions become singular, with peaks at zero and at the price increments, and the subsequent probtile distributions are not uniform in the neighbourhood of z = 1/2. unfortunately, many stocks are in this case, and it is important to validate risk evaluations also in such cases, and not only for indexes or major stocks. • depending on the algorithm used to compute the risk forecast, a subtle small negative autocorrelation makes the results better than the benchmark. this point is important to interpret the statistical test results, and is discussed extensively in sec. 7 for these reasons, we decided to use exclusively a monte carlo approach, simulating σ δn as computed from random walks with constant volatility and with normal iid returns, in order to have a reference distribution for the null hypothesis. then, the value for σ δn is computed for actual data and risk methodology, and the rejection probability is computed numerically with a probability integral transform (pit) using the null distribution for σ δn . for stocks, in order to deal with the slow trading and price granularity, we censor the tiles around z = 1/2 which can be easily done in a numerical scheme. these computations are explained in more details is the following section. the rejection test using a base monte carlo benchmark is build as follows, described for ∆t = 1. a sample of random probtiles is drawn from a uniform distribution, one per day along the time axis, and with the same sample length as in the empirical data size n . the tile test statistics σ δn,mc is computed on this sample, possibly including a censorship around z = 1/2 if used on the empirical data (i.e. for stocks). this is done for the range of tile numbers t that we want to use. the procedure is repeated n mc = 500 times in order to obtain a numerical estimate of the cumulative distribution cdf mc (σ δn ) for σ δn,mc . for an empirical value σ δn,emp , the tile test statistics is given as this quantity measures the probability that a value as large as σ δn,emp or larger is observed according to the null hypothesis that the probtiles are independent with a uniform distribution. if p is smaller than a threshold, say 5%, then the null hypothesis can be rejected. essentially, p measures the probability that a risk methodology is correct, and a small p indicates that the risk is incorrectly estimated (or equivalently that σ δn,emp is too large compared to a uniform sampling). this computation is done for a given time series with index α, and the corresponding probability p α is obtained. in order to have an overall measure for a risk methodology, the values p α are computed for a set of series, and the simple mean gives the probability that the methodology evaluates correctly the risk for this sample when sampling daily a risk computation at a risk horizon ∆t larger than one, the points separated by less than ∆t are correlated due to the overlap. thus, the monte carlo simulation needs to be adapted to include the correlations induced by the overlap. yet, another subtle problem occurs with this test, which need an extension to be based on normal random walks. this is discussed in sec. 7, and this extension provides naturally for a benchmark at ∆t larger than 1 day, while being equivalent to this one for ∆t = 1. the choice for the tiles are free, but the overall idea is to get a sequence of coarse to fine tiles, in order to test risk methodologies at various scales. we have tried a few tilings, in particular increasing simultaneously the division in the z and t directions. yet, the most interesting test is in t, since depending on the dynamics of the market and of the risk methodologies. after several exploratory studies, we singled out the following tiling: a fixed division in the z direction with t z = 8 tiles, and an increasing number of tiles in the t direction. the number of tiles in t follows a geometric progression with a factor √ 2. the number of tiles goes from t t = 1 (i.e. no division, or the full sample in t) to a maximal number of tiles corresponding to have no less than 2 points per tiles (so roughly 1 month). for the figures, the horizontal axis is the time length of the tiles, expressed in year. this tiling and representation allow to have a diagnostic of a risk methodology as function of the characteristic time length for the test. in the figures below for the tile test, the left side of the graph, corresponding to short tiles, is mainly sensitive to the dynamic, while the right side for the graph, corresponding to long tiles, is mainly sensitive to the asymptotic distribution of the probtiles. many risk evaluations used in the following empirical study use a 2 year trailing window, which is apparent in the graphs at the centre. the users typically focus on var or es, but the core object produced by a risk methodology is the (forecast for the) probability distribution for the losses (or for the returns, up to a trivial sign). a risk methodology is a recipe to construct this forecast, in practice in a multivariate setting, albeit we will investigate only the univariate case. at the core level, the risk methodologies can be based on the returns or on the innovations. since the ones based on the returns are simpler, let us present them first. the methodologies based on the returns typically "just" resample past returns, using a sample of length n hist . over the last n hist days, the daily returns are computed, and they are spanning the forecasted distribution. for a risk horizon ∆t , the daily returns are scaled by √ ∆t . a variation is to compute the returns over ∆t (using a sample of n hist + ∆t past prices), and no scaling. we have investigated these 2 methodologies. • historical returns @ 1d (with a √ ∆t scaling) • historical returns @ ∆t (without scaling) for the empirical investigation, we have used n hist = 500 days, corresponding roughly to 2 years. the algorithm simplicity is very appealing, and is the reason for its wide usage. since it is so simple ("it just resamples past returns"), it seems void of hypothesis. this argument is often used, but is wrong. the key hypothesis is that the returns have a stationary distribution. but this is incorrect because of the heteroskedasticity. the figures given in the introduction display the important dynamics of the volatility and of the return distribution. to be sure: in finance, the return distributions are time dependent for all time series, hence not stationary. the related volatility forecast is given by the standard deviation of the return sample. accordingly, the variance is an equal weighted sum of squared returns over the last n hist days. a large return entering the sample has a weight 1/n hist , and the weight is constant over the n hist subsequent days. then, this information is abruptly forgotten when the point leaves the trailing sample, possibly leading to an "echo" behaviour with a step down in the volatility. the methodologies based on the innovations use a process structure to model the volatility dynamics [zumbach, 2006] . at the time t, the base equation is where µ(t) and σ(t) are the forecast for the mean and standard deviation, computed using the information up to t. this equation can also be viewed as a location/size/shape decomposition of the return distribution, with the location and shape considered as predictable, while the shape is stationary. in a process, the innovations (t + δt) are assumed to have a fixed distribution p( ), typically normal or student (with zero mean and unit variance). in this setting, the predictable and time dependent parts are in µ(t) and σ(t), while the 's are random and have a time independent distribution p( ). since the expected returns are difficult to predict and small, the default µ(t) = 0 is often used. using historical data and given the returns and the forecasts for the mean and volatility, this equation can be expressed for the innovations with the innovations computed from historical data, the stationary assumption for the distribution and its shape can be studied. depending on the form for µ, σ and p( ), many methodologies can be constructed. for all methodologies used in this empirical study, a null mean return is assumed µ = 0. the remaining components are the volatility forecast, characterized by the shape of the memory kernel, and the probability distribution for the innovations. • risk metrics '94: this is the original proposition based an exponential moving average for the volatility and a normal distribution for the innovations [mina and xiao, 2001 ]. • lm-arch + student: this is the methodology proposed by riskmetrics [zumbach, 2006] , using a long memory arch (lm-arch) process for the volatility forecast and a student distribution for the innovations. in this model, the volatility forecast is inferred from a daily process using conditional expectations for the squared returns [zumbach, 2004] . since derived from a process, the forecasts are consistent for increasing ∆t , have a non-trivial term structure, and do not involve new parameters or adjustments. the forecast is a weighted sum of past squared returns, with weights that decay smoothly with increasing lags. this property captures the progressive decay of the information as it recedes into the past. the original distribution is a student with 5 degree of freedoms (dof), regardless of ∆t . we report in this study the same model but for dof = 6, which provides slightly better results. • lm-arch + normal: the same volatility model, with a normal distribution. • lm-arch + historical innovations: the volatility forecast is based on the same lm-arch process, and the distribution for the innovations corresponds to the empirical distribution of the historical innovations using a sample of length n hist . for the empirical investigation, we have used n hist = 500 days, as for the historical return methodologies. this methodology has a nontrivial mean in the returns distribution, corresponding to the mean of the historical innovations multiplied by the volatility forecast. as for the historical return methodologies, two variants can be studied, first with innovations at 1 day, second with innovations at the risk horizon ∆t . more methodologies can be crafted along these lines, but the main issue is to validate, or to invalidate, the various ingredients entering the computations. beyond a sound mathematical structure and extensive statistical studies of the stylized facts, back-tests become crucial at this point. two data sets are used for the empirical investigations below. • stock indexes a set of major stock indexes. number of time series 10, from 1.1.1993 to 29.4.2020, data length 6614 days. • fx major foreign exchange rates, all against usd. number of time series 6, from 1.1.1990 to 4.5.2020, data length 7654 points. the results have also been verified on a set of commodities indexes and on a random selection of large and small stocks from the swiss market. all the results and conclusions are consistent between the various sets. 7 benchmarks based on normal random walks for the sample of indexes, the figure 4 shows the results of a tile test using the iid uniform benchmark. the horizontal axis gives the time length of the tile in the t direction, the vertical axis is the probability to observe a value as large or larger than the empirical ones compared to an iid uniform benchmark. using the historical return methodology leads to the left figure. the values close to zero for the test show that this algorithm can be rejected at almost all time scales. it is only for very long samples, say more than 5 years that it is not rejected for some indexes. this shows that asymptotically this methodology could be correct, but a very long sample is required. notice that actual risk management operates in the days to months regimes, on the left of the figure, where this methodology is rejected. using the lm-arch + historical innovation methodology leads to the right figure. at first sight, it shows that this algorithm is excellent. on second sight, the probabilities close to one for long time intervals show that it is always better than a uniform distribution. to say it otherwise, the probtiles are distributed systematically more uniformly compared to random uniform points! something is wrong, since a perfect model should have values randomly distributed over the [0, 1] interval, and with a mean over many realizations around 1/2. here, all empirical time series would reject the theoretical model (using other data sets lead to the same conclusion). a plot of the probtiles shows nothing special, just random uniform dots. we checked very carefully our software, to no avail. but it is clearly not obvious how an actual risk computation can induce probtiles that are more uniform than a theoretical uniform distribution. such a subtle effect is indeed introduced by the trailing sample of historical innovations (and similarly for the historical return algorithm). in order to understand intuitively the cause, let us assume that one or a few large innovations do occur out of sample. they are associated with z values close to one. these innovations get incorporated into the trailing sample, for the next 500 days in our case. subsequently, small and normal innovation values will have z values slightly smaller compared to a theoretical distribution, as long as the large innovations are in the trailing sample. the same argument applies for large negative innovations, with slightly larger values for the subsequent probtiles. an excess of realized returns around zero produces an excess of probtiles around z = 1/2 in the trailing sample, then the following returns will be mapped to more extreme values for z (closer to z = 0 or z = 1), pushing the distribution toward uniformity. this is a type of "mean reverting" effect, that produces a slightly different dynamics for the probtiles, while still with a uniform distribution. the subtle point is that the asymptotic distribution is still a uniform one, but a sequence of such random variables has less variability than independent draws. hence, the values returned by the tile test are smaller compared to the ones obtained by iid uniform draws. the benchmark needs to be adapted in order to include the possible negative lagged correlations induced by an algorithm based on a "trailing" sample. this is done by monte carlo simulations using a normal random walk with constant volatility, followed by a part that compute the probtiles using a simple algorithm that reproduces the key parts of the actual risk algorithm. in this form, it is very simple to modify the benchmark to support risk horizons longer than 1 day, while still using the full sample (i.e. not decimating by taking one point every ∆t days). the random sample of returns is computed as follows, for a final sample length of n . a random sample of normal innovations is drawn. a moving sum of length ∆t is performed, with the sum normalized by 1/ √ ∆t . the resulting random variables correspond to the (scaled) return at ∆t , have a normal distribution, a unit variance, a correlations when separated by less than ∆t , and a sample length reduced by ∆t − 1. on these paths, three benchmarks are computed that reproduce the key parts of the main risk evaluation algorithms. • benchmark 1: a mapping of the returns with a normal cdf leads to iid uniform random variables with the desired correlation. for this benchmark, the raw monte carlo sample length is n mod = n + ∆t − 1. this benchmark is appropriate when the distribution for the returns or innovations is fixed, for example using a normal distribution. • benchmark 2: a trailing sample of 500 daily returns is used to obtain an empirical realisation of the cdf. this cdf is used to map the next out-of-sample return (computed at scale ∆t and scaled by 1/ √ ∆t ) to the corresponding probtile z. then, the oldest point in the trailing sample is dropped, the next 1 day return is added in the trailing sample, and the date is moved by 1 day. for this benchmark, the monte carlo sample length is n mod = n + n trailing + ∆t − 1 (with n trailing = 500). this benchmark is appropriate when the distribution for the returns or innovations is based on a trailing sample computed at 1 day. • benchmark 3: this benchmark is identical to benchmark 2, but returns at the scale ∆t are used in the trailing sample. for this benchmark, the monte carlo sample length is n mod = n + 500 + 2(∆t − 1). this benchmark is appropriate when the distribution for the returns or innovations is based on a trailing sample of returns or innovations computed at ∆t days. finally, this 1 path algorithm is repeated n mc = 500 times in order to obtain the desired statistics for σ δn . for the present tile test, the tile statistics for the desired tilings are computed on each random path, and the n mc values are used to build cdf mc (σ δn ) and to compute the corresponding mean µ mc and standard deviation σ mc . these statistics are obtained for each tilling. these monte carlo cumulative distributions are the final benchmarks for the actual algorithms used with empirical data, and the benchmark 1, 2 or 3 should be chosen according to the algorithm. we denote by 'adapted benchmark' one of those benchmarks appropriate for a risk methodology. a few points should be emphasized. first, at a risk horizon of 1 day, the benchmark 1 is drawing iid normal variables followed by a mapping with the normal cdf, hence uniform iid variables are obtained. therefore, the benchmark 1 at 1 day corresponds to the usual uniform benchmark, namely to iid uniform probtiles. for longer risk horizon, it is similar but with correlations for values separated by less than ∆t . for a 1 day risk horizon, the benchmark 2 and 3 are identical,but they are different for ∆t > 1. second, because the volatility of the random walk is constant and the distribution is fixed to a normal, there is no heteroskedasticity and no fat-tails. it is clearly much simpler to forecast risk in this theoretical bachelier world, whereas real life includes heteroskedasticity and fat-tails. consequently, the benchmarks are tough for actual algorithms operating on empirical time series. also, because the volatility is constant, there is no difference in the benchmarks between a methodology based on the returns or on the innovations. third, other statistics can be computed on the monte carlo paths, say for example lagged correlations or kolmogorov-smirnoff statistics. as for the tile test, the values returned by the 3 benchmarks can be noticeably different. fourth, more complex algorithms can be designed for risk evaluation, say for example a parametric distribution is estimated on the moving sample of 500 returns. such algorithms induce also a dependency on a trailing sample, and the benchmark should be computed accordingly. using the base set-up, the probability distribution for σ δn is investigated. the sample length is n = 5052 business days, corresponding approximately to 20 years of data. the number of tiles in the z direction is constant t z = 8, in the t direction is ranging from 1 to 256 (at which there is in average 2.5 points per tiles). the number of tiles increases with a geometric progression in the t direction with reason √ 2. the results are better presented using a folded-cdf, namely the cdf for cdf < 0.5 and 1-cdf for cdf > 0.5. this representation gives a truthful representation for an empirical or monte carlo sampling, without using a smoothing kernel. furthermore, a logarithmic vertical scale can be used, focusing on both tails of the cdf. the figure 5 gives the folded cdf for benchmark 1 and 2 fot ∆t = 1, with a low number of divisions in the t direction. both distributions have an almost disjoint supports, with the benchmark 2 displaying markedly lower values for σ δn , namely fewer fluctuations than the usual iid uniform benchmark corresponding to benchmark 1. depending on the tilling, the displacement of the distributions shows the very strong effect induced by the trailing sample for the empirical return distribution. this difference is the cause for the too good empirical results reported in fig. 4 . the core of the distributions is plotted in fig. 6 as function of the tile length in the t direction. for increasing tile lengths, the differences between both benchmarks increase, showing the importance of selecting an appropriate benchmark. the difference becomes large when the tile length is of the order of the trailing sample, in our case 500 business days equivalent to 2 years. this difference explains the figure 4 where the historical innovation algorithm is better than the benchmark for tile length longer than 2 years. figure 7 displays the scaled mean of the tile statistics σ δn for increasing risk horizons, for the benchmarks 1 and 3. this graph shows clearly the different behaviours when the tile length is shorter or longer than the memory length of 500 days 2 years used in the benchmark 3. this effect is persistent for increasing risk horizon ∆t . the reduction of the mean for large ∆t tile originates in the mean reversion induced by the trailing windows, and it occurs regardless of the risk horizon. the curves are moving upward with increasing ∆t . this is due to the reduction of the effective sample length induced by the correlations of the overlapping returns. as a first estimate, the effective sample length goes as 1/ √ ∆t , hence the mean of the fluctuations increases as √ ∆t . the actual increase is smaller, of the order of ∆t 0.25 to ∆t 0.3 . this smaller increase is the gain due to the overlapping sample, namely to sample every day even when the risk horizon is longer. the standard deviation shows a very similar behaviour when scaled as σ mc /∆t tile , both in term of the reduction of the variance for the benchmark 3 with increasing tile length, and for the slower increase in ∆t than a square root. these features, for the mean and the standard deviation, lead to a more powerful test, including for risk horizon larger than 1 day. indeed, most applications of risk evaluation are for medium to long risk horizons, say 5 days to a few months. this domain is increasingly difficult to test, and most of the numerical tests are inconclusive. the above gains are therefore instrumental at extending risk validation above 1 day. this section analyses the benchmarks for the tile test statistics, and its dependency on the risk algorithm. but a similar problem occurs for all statistics applied on a back-test: depending on the risk methodology, the simple benchmark can be (strongly) biased toward accepting a methodology. hence, for all statistics, a similar approach should be used, namely to compute a benchmark from the statistics evaluated on random paths with constant volatility and normal returns. 9 empirical results for ∆t = 1 day the fig. 8 is identical to fig. 4 , but with the benchmark 3, namely taking into account that both algorithms use a trailing sample of returns or innovations. against this benchmark, the historical return methodology is rejected strongly, at all time lengths, and for all series in this sample. the rejection of this model demonstrates the importance of the dynamics. even with a tile length using the full sample (more than 25 years), this algorithm is strongly rejected. this means that 2 decades is not long enough to reach an asymptotic regime where the return distributions converge to their long term limits. by contrast, the historical innovations cannot be rejected for most time series. it should be emphasized that the test is comparing a normal random walk with constant volatility against real data with heteroskedasticity and fat-tails. the brutal difference between both methodologies shows that it is important to understand the stylized facts of the financial markets, to have good mathematical models for the time evolution, and only then sound risk evaluation algorithms can be designed. now that we have a good understanding of the interactions between the risk methodologies and the benchmarks, a performance analysis of the main methodologies can be made using the tile test. the main ingredients we want to explore are returns or innovations based methodologies, the model for the volatility forecast, and the probability distribution for the returns or innovations. on this basis, a few risk methodologies have been chosen, see the sec. 5 for more details. the figures 9 and 10 present the tile test p-value as function of the tile length in the t direction for both data sets. the salient results for both data sets are the following. first, the historical return methodology is unable to get the short term dynamic, and is rejected for tile lengths up to a few years, or is rejected for all tile lengths. this is a particularly strong result, and a clear warning for its supporters. the core reason can be anticipated from our analysis of the ubs stock in the introduction, the tile test places clean statistics on the deficient model for the market dynamics. : tile test for several risk methodologies, for the 'indexes' sample, at ∆t = 1 day, using the benchmark 1 (left column), and the adapted benchmark (right column). the left column allows comparing directly the methodologies using the same benchmark, while the right column allows to compare a methodology against its adapted random walk benchmark. parable performances, which are not very good. other statistics are needed to understand the core reason, but essentially, a fixed distribution is not able to get the peculiarities of each instrument. for example, the indexes have positive mean values for the innovations, related to their long term upward trends. consequently, the innovations should have a positive mean value, whereas the normal and student distributions used in the present computation are centred. third, a methodology using the empirical innovations on a trailing window is very good. using the benchmark 1 (left column) shows the clear superiority of this model, while using an adapted benchmark shows that there is still space for improvements against a perfect model. the volatility forecast seems less important when using an empirical distribution. the reason lies likely in the structure of the risk forecast based on the historical innovations = r/σ (more precisely on (t ) = r(t )/σ(t − ∆t )) and the risk scenarios for the returns r =σ (more preciselyr(t) (t ) =σ(t) (t ) with t indexing the scenarios). since the algorithm contains both a multiplication and a division by the volatility (at different times), the defects of a volatility model become less important. 10 empirical results for ∆t = 10 business day in the back-test literature, the results beyond one day are very scarce. the reason is the shrinking samples, with the effective sizes going down as 1/∆t , and an effective test size growing as √ ∆t . notice that in our implementation, the computations are always done with the full sample, and the monte carlo benchmark have an increasing size, albeit growing as a smaller pace than a square root (see sec. 8). interestingly, the original bis requirements is to back-test risk evaluations at the 95% level, for a 1 and 10 days risk horizon. in order to tackle this challenge, both very long samples and powerful statistical tests are needed. in this section, we analyse the same methodologies, but for a risk horizon ∆t = 10 business days. such validations are very important for practical applications with medium to low turnover, and with an investment horizon ranging from a few weeks to several months. two methodologies are added to the panel. when computing a historical sample of returns, the time interval to compute the returns must be chosen. two choices are natural, namely to compute returns at 1 day or at the risk horizon ∆t . both choices have advantages, namely returns at 1 day lead to the largest sample of independent values, while returns at the risk horizon incorporate possible effects beyond a simple random walk. at priori, it is not clear which argument is better between the statistical sample and the financial time series model. this argument can be used for the returns and for the innovations, hence the 2 methodologies added to the panel. the results are given in figures 11 and 12 for the same empirical samples. overall, the results are consistent with the analysis done for a 1 day risk horizon, up to an overall loss of statistical power due to the shrinking samples. in particular, the historical return methodologies cannot get correctly the short term dynamic, the methodologies with a fixed (centred) distribution have difficulties capturing the peculiarities of time series, and the empirical innovations show the best performances. on the question raised in the previous paragraph, the analysis shows unambiguously that using innovations (and returns) at the risk horizon is better (in particular for indexes). this clear-cut answer points to possible specificities of the time series model beyond the heteroskedasticity using an ema or a lm-arch volatility model. a similar analysis has been done on a set of commodity indexes (agricultural, corn, soybeans, energy, non-precious metal, gold...) and on a panel of swiss equity (including large, medium and small caps). all the results are consistent with the above graphs and analysis, showing the robustness of our conclusions. we propose a novel statistical test for the back-test of risk methodologies. it is based on the fundamental object that a risk evaluation produces, namely a forecast for the probability distribution for the expected returns (or losses), and the properties that a correct forecast should have, namely the probability integral transform of the realized returns should be iid with a uniform distribution. since these properties should be valid for any sub-sample, a test of uniformity on a tiling allows to probe a risk methodology at various scales. because the dynamics of a risk methodology is a crucial feature to capture risk correctly, we choose a tiling with an increasingly fine divisions in the t direction, and a fixed number of tiles in the probtile z direction. this tiling allows to probe a risk computation from the short term dynamic (short tiles, on the left of the graphs) to the asymptotic long term behaviour (long tiles, on the right of the graphs). a first application of this test using a uniform benchmark leads to a paradox, that is a risk methodology applied on real financial data shows better uniformity that a uniform distribution. this paradox is resolved by realizing that a risk computation based on historical data induces negative correlations, creating a "return to uniformity" for the probtiles. consequently, many risk methodologies based on trailing distributions have too good statistical results when gauged with the natural benchmark. in order to take this effect into account, a benchmark based on random walks with constant volatility and normal returns is used. on the random paths, the algorithms used for the risk forecast is applied, possibly including a trailing sample of returns. this strategy leads to three benchmarks, whether the return distribution is fixed (benchmark 1), is based on a trailing sample of daily returns (benchmark 2), or is using a trailing sample of returns at the risk horizon (benchmark 3). the quantitative surprise is that the "return to uniformity" effect can be strong, leading potentially to distribution with disjoint supports for the benchmarks. as a side benefit, the benchmarks can be used for any risk horizon and with the full sample, without the need to decimate the sample by a factor ∆t . a censoring can also be used for stocks, in order to eliminate spurious effect due to low liquidity. the benchmark evaluations are purely based on monte carlo simulations, and unfortunately an analytical approach seems quite difficult. equipped with a powerful test and with a good understanding of the benchmarks, a panel of typical risk methodologies can be investigated. the key results are that methodologies based on historical returns do not behave correctly at scales up to a few years, since they do not capture correctly the multi-scales dynamic of the financial markets. methodologies based on innovations perform better, with a clear advantage to the methodologies using an empirical distribution for the innovations at the risk horizon. the figures presented in the paper are based on two data set and two risk horizons, but the empirical results are consistent with other data sets and other risk horizons (1, 2, 5, 10 and 30 days). so far, most statistical tests applied on risk evaluation are based on the asymptotic distribution of the returns, the simplest one being counting the number of exceedances at a given probability α. the test proposed in this paper is a significant improvement over the existing tests, in particular since it is a joint test of the dynamics and the distribution. on the down-side, the test does not provide for a diagnostic of what is right or wrong in a methodology, and other diagnostics should be used in parallel. in particular, the asymptotic distributions of the returns, probtiles and innovations, as well as lagged correlations for these quantities, give good complementary diagnostics to the tile test. finally, the tile test is only based on a forecast in the form of a probability distribution. hence, it can be applied to other fields, say for example weather forecast. goodness-of-fit tests focuses on var at risk estimation. brazilian review of economics a review of backtesting and backtesting procedures evaluating interval forecasts backtesting value-at-risk: a duration-based approach evaluating density forecasts with applications to financial risk management the art of techniques for verifying the accuracy of risk management models. risk measurement and systemic risk: proceedings of a joint central bank research conference return to riskmetrics: the evolution of a standard elicitability and backtesting: perspective for banking regulation backtesting value at risk and expected shortfall remarks on multivariate transformation volatility processes and volatility forecast with long memory the riskmetrics 2006 methodology back testing risk methodologies from one day to one year the author thanks samuel quinodoz and gwenol grandperrin for their help with the software development part of this project. key: cord-329770-tz8dwgzm authors: hamer, mark; kivimäki, mika; gale, catharine r.; david batty, g. title: lifestyle risk factors, inflammatory mechanisms, and covid-19 hospitalization: a community-based cohort study of 387,109 adults in uk date: 2020-05-23 journal: brain behav immun doi: 10.1016/j.bbi.2020.05.059 sha: doc_id: 329770 cord_uid: tz8dwgzm we conducted the first large-scale general population study on lifestyle risk factors (smoking, physical inactivity, obesity, and excessive alcohol intake) for covid-19 using prospective cohort data with national registry linkage to hospitalisation. participants were 387,109 men and women (56.4 ±8.8 yr; 55.1% women) residing in england from uk biobank study. physical activity, smoking, and alcohol intake, were assessed by questionnaire at baseline (2006-2010). body mass index, from measured height and weight, was used as an indicator of overall obesity. outcome was cases of covid-19 serious enough to warrant a hospital admission from 16-march-2020 to 26-april-2020. there were 760 covid-19 cases. after adjustment for age, sex and mutually for each lifestyle factor, physical inactivity (relative risk, 1.32, 95% confidence interval, 1.10, 1.58), smoking (1.42;1.12, 1.79) and obesity (2.05 ;1.68, 2.49) but not heavy alcohol consumption (1.12; 0.93, 1.35) were all related to covid-19. we also found a dose-dependent increase in risk of covid-19 with less favourable lifestyle scores, such that participants in the most adverse category had 4-fold higher risk (4.41; 2.52 –7.71) compared to people with the most optimal lifestyle. c-reactive protein levels were associated with elevated risk of covid-19 in a dose-dependent manner, and partly (10 – 16%) explained associations between adverse lifestyle and covid-19. based on uk risk factor prevalence estimates, unhealthy behaviours in combination accounted for up to 51% of the population attributable fraction of severe covid-19. our findings suggest that an unhealthy lifestyle synonymous with an elevated risk of non-communicable disease is also a risk factor for covid-19 hospital admission, which might be partly explained by low grade inflammation. adopting simple lifestyle changes could lower the risk of severe infection. for non-communicable disease outcomes, lifestyle risk factors have been consistently associated with morbidity, mortality and loss of disease-free years of life. [1] [2] [3] [4] there are also population cohort data on possible adverse effects of poor lifestyle on serious respiratory infections. for example, physical inactivity and smoking appear to be independently associated with higher risk of community-acquired pneumonia and pneumonia mortality. [5] [6] [7] [8] [9] evidence for alcohol intake and diet on risk of respiratory infection are less clear. 8, 9 a better understanding of the links between lifestyle risk factors and covid-19 has obvious implications for prevention of severe outcomes and also in identifying characteristics of those people most at risk. we are, however, unaware of any existing data on the relation of lifestyle risk factors with covid-19. accordingly, we examined the association of lifestyle risk factors with new cases of covid-19-hospitalisations in a general population-based cohort study. we used data from uk biobank, a prospective cohort study, the sampling and procedures of which have been well described. 10 baseline data collection took place between 2006 and 2010 across twentytwo research assessment centres in the uk giving rise to a sample of 502,655 people aged 40 to 69 years (response rate 5.5%). 10 ethical approval was received from the north-west multi-centre research ethics committee, and the research was carried out in accordance with the declaration of helsinki of the world medical association, and participants gave informed consent. no specific ethical approval was required for the present analyses of anonymised data. physical activity, smoking, and alcohol consumption were assessed by questionnaire at baseline. these characteristics have demonstrated face validity in the uk biobank sample through their associations with mortality and cardiovascular disease. 11 participants were categorised into never, previous, and current smokers. from information on the weekly intake of beer and cider (1 pint =2 units), wines (1 standard glass = 2 units) and spirits (1 shot = 1 unit), we aggregated units of alcohol intake per week. heavy alcohol intake was defined as ≥14 units in women and ≥21 units in men. 3 physical activity was assessed using the international physical activity questionnaire (ipaq) short form 12 that measures duration and frequency of moderate-to-vigorous physical activity (mvpa) from all domains in the last week. meeting activity guidelines was defined as ≥150 min/week mvpa or ≥75 min/week vigorous pa. 3 body weight was measured using tanita bc418ma scales and standing height using a seca height measure. body mass index (bmi) was calculated [weight (kilograms)/height 2 (meters 2 ) squared] and categorised into standard groups: healthy weight < 25; overweight 25 -< 30; obese ≥ 30 kg/m 2 . during the clinic visit, data were collected via self-report for ethnicity (white, south asian, black, chinese, other), educational attainment (college/degree; a-level; o-level; cses or equivalent; national vocational qualifications/ higher national diploma or equivalent; other professional qualification; none), and self-reported physician diagnosed cardiovascular diseases (heart attack, angina, stroke) and diabetes. hypertension was defined as elevated measured blood pressure (≥140/90 mmhg) and /or use of anti-hypertensive medication. provided by public health england, data on covid19 testing results up to 26 th april 2020 were included. these data can be regarded as a proxy for hospitalisations for severe cases of the disease for england only; study members from scotland and wales were therefore omitted from our analytical sample. covid-19 disease tests were performed on samples from combined nose/throat swabs, using real time polymerase chain reaction (rt-pcr) in accredited laboratories. 13 analyses were performed using spss version 26. we assigned points to different levels of each lifestyle behaviour: smoking history (0=never; 1=past; 2=current), physical activity (0=meeting guidelines; 1= active but below guideline; 2=inactive), alcohol (0= moderate intake within guidelines; 1= never or very occasional; 2= heavy intake exceeding guidelines), obesity (0=healthy weight; 1=overweight; 2 = obese). thus, scores ranged from 0 (optimal) to 8 (worst). we fitted regression models to estimate relative risk (rr) and 95% confidence intervals for associations between lifestyle scores and covid-19. relative risks were first adjusted for age and sex, followed by education, where pi = proportion of the population in group i; rri = rate ratio in group i; k = number of nonreference risk groups the there was a dose-dependent association between the risk of covid using the health survey for england prevalence estimates (17% for current smoking, 25% for exsmoking, 27% for physical inactivity, 35% for overweight and 28% for obesity), the paf for the three unhealthy lifestyle factors in combination was 51.4% (13.3% for smoking, 8.6% for physical inactivity, and 29.5% for overweight and obesity). we further explored potential mechanisms, specifically if low grade inflammation might partly explain associations between adverse lifestyle and risk of covid-19. data on high sensitivity c-reactive protein (hscrp), measured at baseline at least 10 years before possible infection, 16 were available in a sub-sample of participants (n=363,263). we observed an association between adverse lifestyle score and higher hscrp levels (b= 0.10, 95% ci, 0.09, 0.11) after adjustment for age, sex, education, ethnicity, diabetes, hypertension, cardiovascular disease. hscrp levels were associated with elevated risk of covid-19 in a dose-dependent manner (table 3) . when the association between lifestyle score and covid-19 was adjusted for hscrp, the effect estimates were attenuated by 10 -16 % suggesting a possible mediating effect (table 3 ). the present study demonstrates associations between adverse lifestyle and higher risk of covid-19 in a large community-dwelling cohort. the associations were not explained by taking into account covariates such as education, ethnicity and self-reported cardiometabolic diseases, although further adjustment for hscrp did partially attenuate the association. based on uk risk factor prevalence estimates, unhealthy behaviors in combination accounted for up to 51% of the population attributable fraction of severe covid-19. physical activity has been previously shown to protect against serious community acquired infections in population cohort studies. [5] [6] [7] [8] [9] other studies 17-20 in athletic populations have described a "j" shaped association between exercise volume and infection with optimal protection at moderate levels of activity. in the present study, protective associations of physical activity on covid-19 were observed even at relatively low levels of activity below the current guidelines (i.e., < 150 min moderate to vigorous activity) and no dose-response effect was observed for higher levels. there are plausible biological mechanisms explaining the immunological benefits of exercise, 17 for example, antiinflammatory effects and beneficial effects on adaptive immune responses. 21 the existing evidence on obesity and infection have been mixed. some data suggested bmi above 25 kg.m -2 was protective against pneumonia mortality 7,8 whilst others have suggested that overweight and obesity was associated with higher risk of respiratory and skin infections whilst protective against viral and fungal infections. 22 in a large norwegian cohort, overweight and obesity were associated with higher 30 day mortality risk after detection of blood borne bacterial infection. 9 our results suggested both overweight and obesity were risk factors for severe covid-19 infection, consistent with emerging data in small clinical studies. 23 the potential mechanisms have been linked to immune hyper-reactivity, impaired metabolic responses, and the adverse effects of obesity on lung function, diminishing forced expiratory volume and forced vital capacity. 23 we found only weak evidence for a link between excessive alcohol intake and covid-19, which was attenuated to the null in models mutually adjusted for other behavioral risk factors. this is largely consistent with our previous work on alcohol and infectious disease mortality. 8 interestingly, 'none drinkers' were at greater risk of covid-19, which is likely non-causal as this group have often stopped drinking due to prescribed medication and underlying health conditions. the role of low-grade inflammation in susceptibility to severe covid-19 infection remains poorly understood. our data suggests low grade inflammation was a risk factor for severe covid-19, and partially explained links between lifestyle behaviors and infection. c-reactive protein is known to play an important role in immune function 24 thus the findings are plausible. there are several caveats to our work. some cases of covid-19 could have been captured in patients originally hospitalized for reasons other than the infection. we did not capture covid-19 infections treated outside hospital settings; rather, our outcome was people with the infection of sufficient severity to warrant in-patient care. the response rate to the original baseline survey in uk biobank was 5.5%. as such, this is a select group: relative to the general population, the study sample is healthier and better educated. while this means that estimates of the occurrence of disease, including covid-19, have little utility, because exposures range is wide and the study sample is large, risk factors associations are not affected. 25 paf reflects the prevalence of the risk factor in the population and the strength of its association with the outcome being considered; the core assumption is that the risk factor has a causal link to the outcome. as our results are based on observational data rather than an intervention, the present paf-findings may overestimate of the proportion of covid-19 hospitalisation that could be been prevented by lifestyle change. in conclusion, these data suggest that adopting simple lifestyle changes could lower the risk of severe covid-19 infection. results are expressed as percentage or mean ± sd. lifestyle factors, cardiovascular disease and all-cause mortality in middle-aged and elderly women: a systematic review and meta-analysis adherence to healthy lifestyles and incidence of diabetes and mortality among individuals with diabetes: a systematic review and meta-analysis of prospective studies association of healthy lifestyle with years lived without major chronic diseases healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study physical inactivity and long-term rates of communityacquired sepsis a prospective study of age and lifestyle factors in relation to community-acquired pneumonia in us men and women risk and protective factors related to mortality from pneumonia among middle aged and elderly community residents: the jacc study lifestyle risk factors, obesity and infectious disease mortality in the general population: linkage study of 97,844 adults from england and scotland associations of obesity and lifestyle with the risk and mortality of bloodstream infection in a general population: a 15-year follow-up of 64 027 individuals in the hunt study uk biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age associations of combined genetic and lifestyle risks with incident cardiovascular disease and diabetes in the uk biobank study international physical activity questionnaire: 12-country reliability and validity covid-19 virus testing in nhs laboratories adult's health-related behaviours project: companion document to accompany serum biomarker data accessed 5/5/20 how much is too much? (part 2) international olympic committee consensus statement on load in sport and risk of illness incidence, etiology, and symptomatology of upper respiratory illness in elite athletes moderate to vigorous physical activity and risk of upper-respiratory tract infection upper respiratory tract infection is reduced in physically fit and active adults the effects of exercise on vaccination responses: a review of chronic and acute exercise interventions in humans body mass index and risk of infections among women in the danish national birth cohort obesity a risk factor for severe covid-19 infection: multiple potential mechanisms. circulation rethinking il-6 and crp: why they are more than inflammatory biomarkers, and why it matters comparison of risk factor associations in uk biobank against representative, general population based studies with conventional response rates: prospective cohort study and individual participant meta-analysis model 2 adjusted for age, sex, education, ethnicity, diabetes, hypertension, cardiovascular disease (heart attack, angina contributions: mh and gdb generated the idea for the present paper, and with mk formulated an analytical plan; crg prepared the data set; mh carried out all the data analyses and wrote the manuscript; all authors commented on an earlier version of the manuscript. mh will act as guarantors for this work. the corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.role of the funding source: the funders of the studies had no role in study design, data collection, data analysis, data interpretation, or report preparation. crg/mh had full access to uk biobank data. mh takes responsibility for the decision to submit the manuscript for publication. key: cord-315412-fm928vq1 authors: haas, charles title: coronavirus and risk analysis date: 2020-04-08 journal: risk anal doi: 10.1111/risa.13481 sha: doc_id: 315412 cord_uid: fm928vq1 nan george santayana wrote "those who cannot remember the past are condemned to repeat it." the coronavirus disease pandemic has revealed many failures in different countries and systems that have combined to yield lethal consequences. such failures, as well as actions in ongoing responses, contain elements that many members of the society for risk analysis comprehend and that have been well researched and understood in the risk analysis field, but that have not yet been assimilated into the institutional responses. some of these key concepts from risk analysis include the following: r perceptions of risk can be amplified or attenuated by a variety of factors including perceived dreadfulness, lack of controllability or unfamiliarity, as well as social and news media (renn, burns, kasperson, kasperson, & slovic, 1992; slovic, 1987) . r covid-19 is novel, unfamiliar, and dreaded, and therefore, strong social amplification of perceived risks was not unanticipated. however, formal analysis and training in risk assessment, disease modeling, and risk communication can and should be used to help promote accurate assessments of risks, effects, and uncertainties. r communications have sometimes been in absolutes with a message of certitude (e.g., that transmission is only by droplet). r some have compared the risks of covid-19 to other, more familiar, risks, for example, number of automobile fatalities or the seasonal flu. risk comparisons may be useful, but should be carefully done to convey accurate information without misleading. a risk that people perceive to be relatively controllable (e.g., car accident or seasonal influenza) should not be used to put an involuntary hazard in perspective. similarly, using the seasonal flu for comparison may evoke the wrong mental models (morgan, fischhoff, bostrom, & atman, 2002) , because there is no immunity against sars-cov-2 and the mortality rate seems to be higher for some subpopulations. r while sars-cov-2 (the agent responsible for covid-19) appears to be newly emergent, risk assessment has been applied to the related sars-cov and mers viruses (watanabe, bartrand, weir, omura, & haas, 2010) . undoubtedly, there are differences, but the data and conclusions that risk assessment has developed (including quantitative exposure assessment and dose response) are complementary to insights from epidemiology and medicine. integrating these different approaches could support more robust decision-making. initial high illness and mortality rates in many countries-and highly variable rates across and within countries-will eventually decrease, although resurgences may follow. risks of relaxing stringent mitigation must be balanced against costs to societal infrastructures and economic impacts. decision and risk analysis skills in formulating and assisting these decisions at different levels of government and on different time scales will be important for a productive dialog. it is likely that effective vaccines, and prophylactic or therapeutic drugs will become available, hopefully later this year. any such intervention inevitably carries risks of side effects, and the concept of riskrisk balancing is a key concept from risk analysis that should inform upcoming policy deliberations. while we all look forward to better days, we will get to them with less anguish if decisionmakers understand that public responses to policy recommendation and dictates depend on public trust in authorities. trust can be built (and earned) by methods written about in this journal for decades. first, trust requires belief in the science. this requires government officials to be clear about what they are doing, why, and when-for example, when they expect a vaccine, better test kits and other steps to be completed. second, trust in decisionmakers requires clear and frequent communications. people want to hear from a medical expert and an epidemiologist, not a communications expert. third, trust requires recognizing, although not necessarily accepting, people's values and beliefs. to date, in much of the world, there has been relatively little emphasis on what science is doing, and communications about policies and rationales have been numerous but inconsistent. this may be unavoidable when a crisis begins, but risk communication teaches ways to do better. people need to hear about positive steps that give reasons for hope and build trust in decisionmakers. explicit links should be forged between public, national, or other values and responses to the virus. these values could include trust-where warranted-in demonstrably sound science, government financial institutions, and public policy and risk management institutions to take well-considered actions to protect public health and the economy. risk analysts and risk analysis researchers should not be shy about contributing our skills to important policy developments during this crisis. we should be bold in learning from these events for future applications, and in documenting what we think we have learned so that others may benefit from and improve upon it. the entire team of editors at risk analysis welcomes papers on these and related topics that covid-19 engenders. risk comparisons and risk communication: issues and problems in comparing health and environmental risks the social amplification of risk: theoretical foundations and empirical applications perception of risk development of a dose-response model for sars coronavirus i thank michael greenberg, michael siegrist, and tony cox for useful comments and critiques of this editorial. key: cord-313183-4zmtijyo authors: li, jianping; feng, yuyao; li, guowen; sun, xiaolei title: tourism companies' risk exposures on text disclosure date: 2020-06-29 journal: ann tour res doi: 10.1016/j.annals.2020.102986 sha: doc_id: 313183 cord_uid: 4zmtijyo tourism is a risk-prone industry. but most studies focus on tourist risk perception while ignoring company risk exposure. as service providers, the companies play an important role in tourism activities, and systematically identifying the risks they face is vital to the development of the tourism industry. this paper attempts to identify tourism companies' risk exposures based on textual risk disclosure of financial statements. using 51,008 risk headings of 255 public companies, we adopt sentence-latent dirichlet allocation (sent-lda) method to discover 30 risk exposures of the tourism industry. further, we discuss the universality and industry representativeness of these risk exposures, as well as risk differences between different sub-industries and years. findings can help stakeholders develop reasonable and timely risk management strategies. tourism is a risk-sensitive industry. the intricate relationship between risk and tourism makes it necessary to have a thorough understanding of tourism risk factors. although these factors cannot be completely eliminated, we can implement risk early warning through risk identification to reduce the risk perception (sheng-hshiung et al., 1997) . in the existing related studies, the vast majority focus on the risk perception of tourists, especially after the 9/11 attacks (blake & sinclair, 2003; fuchs & reichel, 2011; kim et al., 2015; mansfeld & pizam, 2006; wolff et al., 2019) , and they have provided a reliable reference for tourism service optimization and tourist risk management. however, relatively few studies have focused on identifying the risks for tourism companies. among the few studies that take companies as research samples, the topics are more about risk management, assessing a specific risk related to an event, or the influence of company characteristics (such as corporate social responsibility and advertising spending) on their risk status (kim et al., 2013; lee & jang, 2011; paraskevas & quek, 2019; park et al., 2017) . while these studies provide specific recommendations for business management, they still lack a theoretical framework, resulting in a fragmented understanding of company risks in general. as an important participant in tourism activities, research on the risk exposure of tourism companies is even more urgent. the financial crisis of 2008 showed that markets usually underestimate risk, which always results in a severe economic recession or bankruptcy (hope et al., 2016) . therefore, identifying risk exposures that may cause business operations to suffer is effective in providing crisis warnings. for companies, risk exposure analysis not only enables them to fully understand the main threats within the industry and adapt their strategy accordingly, but also reduces information asymmetry with stakeholders and lowers the cost of equity (barry & brown, 1985; myers & majluf, 1984) . for investors and tourists, they can have a further understanding of the risks https://doi.org/10.1016/j.annals.2020.102986 received 17 february 2020; received in revised form 5 june 2020; accepted 15 june 2020 faced by companies, which are also what they may be subject to when buying products, services, or stocks. in this way, they can develop reasonable and timely risk-hedging strategies (penela & serrasqueiro, 2019) . however, due to the obstacle of data sources, this issue has not been addressed until recently. penela and serrasqueiro (2019) recognized the importance of risk identification for lodging companies and introduced textual risk disclosure data in form 10-k, which have been proved to be a feasible and effective data source to evaluate company risk exposure into the tourism sector (bao & datta, 2014; campbell et al., 2014; wei, li, li, & zhu (2019) ; wei et al., 2019c) . based on 40 sample documents from 20 lodging firms, penela and serrasqueiro (2019) successfully identified 7 main risk themes in 2008 and 2016 respectively using leximancer software, and compared the risk difference between these two distinct years. their work pioneered research on company risk identification in the tourism sector. however, in order to get more representative conclusions, the scope of sample companies, time span and experimental methods still have room for improvement. in this paper, we attempt to systematically identify the risk exposures of tourism companies from a holistic perspective. to this end, we introduce the sentence latent dirichlet allocation (sent-lda) model, which is an unsupervised clustering method that can effectively identify hidden knowledge from a large amount of text to analyze the textual risk disclosure data in forms 10-k by all listed tourism companies during 2006-2019. the main contributions of our work are summarized as follows. first, we systematically identify the risk exposures of the tourism industry and compensate for the shortcomings of fragmentation in existing research. second, through the division of sub-industries and comparison with other industries, we can understand the internal differences and industry representativeness of these risk exposures. third, we further depict the risk evolution and fluctuation trends in different years, which can convey richer information from the time perspective. finally, our work emphasizes the importance of risk identification of tourism companies and can provide a valuable reference for stakeholders to develop sound risk management strategies. with social progress and economic development, the disposable income and leisure time of tourists are increasing, making tourism activities increasingly popular (yang & nair, 2014) . according to the world bank, the number of international inbound and outbound tourists has exceeded one billion each year in the past decade and has maintained an average annual growth rate of approximately 5%. the increase in tourism activities has not only boosted employment and economic growth in the destinations but also exposed more potential risks attached to the tourism process (cui et al., 2016) . risk and tourism are intrinsically connected, and their relationship is intricate (yang et al., 2017) . first, tourism refers to traveling from a familiar place to relatively unfamiliar destinations, where people's tacit knowledge will be greatly reduced, which means that they are more likely to be targeted by risk (boksberger & craig-smith, 2006; williams & baláž, 2015) . second, as a service product, tourism is intangible and heterogeneous (roehl & fesenmaier, 1992; yang et al., 2017) , making it necessary for visitors to participate personally without a reliable expectation, which indicates that the decision to travel is a risk in itself (evans et al., 2012) . third, tourism is strictly time-bound. because there is no concept of storing, service providers (tourism companies) are required to sell as many tickets or rooms as possible within a limited time (williams & baláž, 2015) . besides, since many attractions are evidently seasonal (cuccia & rizzo, 2011; jang, 2004) , service providers have to make full use of resources within a few months, and once this time passes, the industry enters a relatively depressed phase. for service recipients (tourists), their reservations are also time-bound, so they can and must use them within a fixed period (dickinson & peeters, 2014; haldrup, 2004) . in case of unforeseen circumstances, making changes to their tickets (or allowing the tickets to expire) results in huge monetary loss for tourists (park & jang, 2014) . finally, tourism is highly dynamic, and its development is interlinked with other relevant fields such as tourism marketing, transportation, accommodation, attractions, and tourism regulations (leiper, 1979) . errors in any part will affect the normal operation of the entire chain, making tourism risk-sensitive. the company is one of the most important participants in economic activities. it is significant to comprehensively identify the risks it is facing. in the past, the main obstacle to company risk identification was data acquisition. taking tourism research as an example, in the study of tourist risk perception, most data comes from questionnaires administered to tourists, but this method often fails when the research objects are companies. the disclosure of company risks directly affects the perceived reliability of stakeholders, and hence, few companies are willing to accept surveys from researchers. in recent years, financial statements have garnered significant research attention. scholars have discovered that these financial statements contain important information for stakeholders to have a deep understanding of the development and potential risks of companies (zhu et al., 2016) . since financial statements are mandated by regulators and are issued by the company itself, the reliability can be guaranteed. in these reports, not only quantitative financial data but also textual data are included, the latter (named "item 1a. risk factors") of which is relatively new content that the u.s. securities and exchange commission (sec) has requested from all listed companies in their annual financial statements on forms 10-k since 2005. this part discusses "the most significant factors that make the offering speculative or risky" (u.s. securities and exchange commission, 2005) . it usually follows the description structure shown in fig. 1 -each risk disclosure is a description of a specific risk topic and consists of a risk heading and detailed explanation. in practical applications, because the heading describes the same risk as the subsequent explanation, it is used for analysis more widely. the effectiveness of it has been well verified in many other works. for example, campbell et al. (2014) used publicly listed companies in the u.s. to confirm that risk disclosure can effectively reflect the risks faced by companies. immediately afterward, bao and datta (2014) used similar samples and innovatively introduced a model to successfully quantify 30 types of risks from company risk disclosure and verify that effective risk disclosure will significantly affect investors' risk perception. as each industry has different characteristics and is affected by different business environments, their risk exposures are also different (borde, 1998; kim et al., 2012) . in recent years, more professional risk exposure identification for different industries has begun to appear. for example, wei, li, zhu, and li (2019b) ) and wei et al. (2019c) identified and quantified the risk exposures of the energy industry and its nine sub-sectors and constructed a comprehensive and systematic risk system in the energy field. similarly, wei et al. (2019b) analyzed the banking industry, and wang et al. (2019) analyzed the insurance industry. their research verifies that there are obvious differences between risk exposures in different industries, which implies the necessity of company risk identification in the tourism industry. tourism and hospitality are the most widely used terms in tourism and related fields. according to the definition of the oxford english dictionary, hospitality places more emphasis on serving guests with a sincere attitude, while tourism focuses on the elements of tourists, entertainment, and leisure (simpson & weiner, 1989) . in a sense, the tourism industry can be regarded as the "subset" of the hospitality industry, because not all customers of hotels and restaurants are tourists (keiser, 1998) . however, in practical applications, neither is a single industry, and it is difficult to strictly distinguish them. first, in academic research, these two words are often interpreted as a whole (kim et al., 2018; litvin et al., 2008; viglia & dolnicar, 2020) . singal (2015) even deemed that hospitality industry and tourism industry had the same structural characteristics and named them as ht industry. second, in the industry classification system, there is no separate tourism industry and hospitality industry. for example, the federal government's standard industry classification (sic) system divides each sub-sector involved in these two industries into different categories, where "retaileating places" falls in the office of trade & services, whereas "hotels & motels" is classified as real estate & construction (keiser, 1998) . in the work of leiper (1979) , the author defined the tourist industry as "all those firms, organizations and facilities which are intended to serve the specific needs and wants of tourists". draw lessons from his definition, we also use a broader perspective to define tourism companies in this paper-all ht companies with tourism as one of their main business, which can provide service to tourists. when conducting experiments, we adopt the industry categories provided by the global industry classification standard (gics) and select all companies with "gic industries" equal to 253010, which are named "hotels, restaurants & leisure" as a sample. the future is unknown, this unpredictability can be understood as risk (williams & baláž, 2015) . for tourists, tourism involves a destination that they are relatively unfamiliar with, so the absence of tacit knowledge of a relatively new environment will make j. li, et al. annals of tourism research 84 (2020) 102986 them feel more at risk than when they are shopping near their home. for tourism companies, the lack of tacit knowledge also plagues business development, especially for those trying to explore the international market (liesch et al., 2002) . another term with a similar definition is uncertainty, which is usually discussed in the same context as risk (knight, 1921; williams & baláž, 2015) . both are caused by limited tacit knowledge, but a material difference exists between them (polanyi, 2009) . knight (1921) defined risk as decision-making with available probabilities, and uncertainty as decision situations in which information is too blurred to be calculated by probabilities (kravet & muslu, 2013) . similar views exist in behavioral economics, where risks are probabilities for different outcomes (tversky & kahneman, 1974) , implying that risks are uncertainty with known outcome probabilities. in other words, the decision-maker knows both the possible outcome and the probability of the outcome when making a decision (zinn, 2004) . while uncertainty is completely unknown, and the decision-maker cannot predict the probabilities of the outcomes, or even grasp all the possible outcomes (knight, 1921) . with the development of the knowledge revolution and the advancement of information technology, people are forced to face a new dilemma of information overload (lee & lee, 2004) , and unable to extract valid information from a large amount of information, which cause risk to be gradually replaced by uncertainty (beck et al., 1992; taylor-gooby & zinn, 2006) . in most cases, risks and uncertainties are intertwined, and the same goes for tourism. while traveling, tourists really cannot know exactly whether the destination will have a riot, but they can estimate a reliable probability of "tomorrow will be a sunny day" based on the weather forecast. hence, following williams and baláž (2015) , cui et al. (2016) and sheng-hshiung et al. (1997) , this paper defines tourism risk as a general term for all the risks and uncertainties that arise from the uncertainty of the negative influence that the tourism subjects may have after making a decision, and the possibility of encountering various unexpected conditions while traveling. according to different participants, tourism risk can be further divided into the tourist risk, tourism company risk, and destination risk (williams & baláž, 2015) . accordingly, tourism company risk can be defined as the unpredictability of the negative impact on decision-making outcomes and the adverse market conditions that they may encounter in the daily production and operation process due to limited tacit knowledge. in terms of risk categories, haddock (1993) divided risk into real (absolute) risk and perceived (subjective) risk. real risk refers to risks that exist objectively in reality and does not change with the wishes of the subject. therefore, strictly speaking, regardless of the attributes of subjects, the risks they face are the same and cannot be eliminated (wong & yeh, 2009) . the objective existence of risk cannot be denied, but it must be clear that risks mean different things to different people (slovic et al., 1982) . in most cases, people will not pay attention to all real risks but only focus on risks that they define as real and where the results are beyond their tolerance (bauer, 1960; budescu & wallsten, 1985; thomas & thomas, 1928) . for example, health risks are the most common form of risk. yet, one does not constantly worry about falling ill. however, once a serious infectious disease occurs, one may become disturbed and perceive a strong health risk, that is, health becomes very important. table 1 shows the definition of risk perception in several high-impact studies. through these definitions, three elements of risk perception can be summarized: subjective feeling, objective assessment, and negative consequences (cui et al., 2016; glaesser, 2006) . therefore, in this paper, we define risk perception as the subjective feelings of tourists about the negative results beyond a tolerable range, caused by the various potential uncertainties in their traveling. the level of risk faced by tourism companies is determined not only by the volatility of objective risks but also by the exposure and vulnerability to these risks (cardona et al., 2012) . risk exposure is a quantitative concept in business management (harvey, 1995) . however, in our paper, we are concerned about facts rather than the extent, and we define risk exposure as the "risk perception" of a specific company, that is, the risk environment that the company believes may seriously affect future operations based on their subjective judgment of real risks. related definitions of risk perception. concept definition cox and rich (1964) perceived risk the nature and amount of risk perceived by a consumer in contemplating a particular purchase decision dowling and staelin (1994) perceived risk the consumer's perceptions of the uncertainty and adverse consequences of buying a product (or service) sheng-hshiung et al. (1997) perceived risk the consumer's perceptions both of the uncertainty and the magnitude of the possible adverse consequences reisinger and mavondo (2005) perceived risk the individual's perceptions of the uncertainty and negative consequences of buying a product (or service), performing a certain activity, or choosing a certain lifestyle huang et al. (2008) perceived risk the experience of anxiety or psychological discomfort resulting from tourist's spiritual and/or supernatural beliefs associated with the purchase and consumption of travel-related services for the destination adam (2015) perceived risk a subjectively determined expectation of a potential loss in which some measure of probability can be attached to each possible outcome williams and baláž (2015) risk perception how predetermined notions about particular places, objects or activities, influence tourist behaviour kapuściński and richards (2016) perceived risk the processing of physical signals and/or information about potentially harmful events or activities, and the formation of a judgment about seriousness, likelihood and acceptability of the respective event or activity wolff et al. (2019) perceived risk the subjective understanding of outcome severity weighted by outcome probability j. li, et al. annals of tourism research 84 (2020) 102986 in tourism risk research, the research on real risk is generally an after-the-fact study, and more inclined to analyze the impact of a specific risk event on the industry (including companies and tourists) and the countermeasures. the majority of risk perception researches focus on tourist risk perception, which is mainly conducted through questionnaires to assess the subjective judgments of tourists on the occurrence probability and severity of a certain risk. in contrast, the research on company risk exposure is relatively thin, which is exactly what this paper wants to make up for. companies disclose risk factors through unstructured text data, which makes it difficult to identify risk types using traditional econometrics methods. to address this issue, we turn to text mining technology which can automatically obtain valuable information and knowledge from text data. in specific, a kind of text mining technology named topic model is employed, which is a statistical model used for discovering a set of topics that describes text data (risk headings in this study). by using the topic model, risk factors telling different topics can be classified into different topic clustering, which can be the final risk exposures after labeled based on feature words of it (li, li, liu, zhu, & wei, 2020) . to identify the risk exposures disclosed in financial statements of tourism companies, this paper applies a topic model named sentence latent dirichlet allocation (sent-lda) proposed by bao and datta (2014) , which is an extension of the original latent dirichlet allocation model (lda). lda is a typical bag-of-words model developed by blei et al. (2003) , which specializes in processing a large amount of text data and is widely used in identifying potential topics in many research fields. the generation process of lda can be shown below: (1) for each topic k ∈ {1, ..., k}, draw a distribution over vocabulary words β k~d irichlet(η), where η is the hyperparameter of the dirichlet distribution. (2) for each document d ∈ {1, ..., d}, draw a vector of topic proportions θ d~d irichlet(α). (3) for each word w d, n in document d, draw a topic assignment z d, n~m ultinomial(θ d ), and a word w d, n~m ultinomial(β zd, n ). the concept of lda is to infer the topic distribution and the word distribution based on the observed documents. sent-lda inherits the basic concept of lda and further adjust its bag-of-words assumption as the rule that the boundary of sentence matters and each sentence discusses only one topic. in our research, the risk factor disclosure in form 10-k usually follows the structure as shown in fig. 1 -every risk heading describes one specific risk type (topic), which is significantly aligned with the "one topic per sentence" rule of sent-lda. therefore, we adopt sent-lda to identify the risk types of the tourism industry. another critical issue in using sent-lda is to choose the appropriate training algorithm to obtain the optimal parameters based on the observed documents. the widely used algorithms are collapsed gibbs sampling (cgs) (griffiths & steyvers, 2004) and variational expectation maximization (vem) algorithm (blei et al., 2003) . in this paper, we employ vem to train the sent-lda model, which has been proved to have a better performance than cgs in bao and datta (2014) . before applying sent-lda, we need to extract and store the risk headings from the same financial statement as a document d, and all documents form a document set d. then sent-lda will take the document set d as input and output a set of risk topics and further map each risk headings to a certain risk topic. besides, sent-lda can also quantify the topic by output variable θ d , showing the proportion of different topics in the document d. the greater the risk proportion, the more times the risk is disclosed, which can represent the universality of risk to a certain extent. as shown in eq. (1), we can express the importance of the risk factor i by calculating the ratio of the number of risk headings under a certain risk topic to the total number of risk headings (wei et al., 2019b; wei et al., 2019c) . to obtain as much data as possible, we first retrieve a list of sample companies with central index key (cik) from the compustat database based on the selection criteria "gic industries" equal to 253010. then, we further screen out the listed companies from the electronic data gathering and retrieval (edgar) database on the sec's website according to cik and locate the forms 10-k they released over the years. in the following process, based on the text characteristics shown in fig. 1 (the risk headings are represented by a special font and the different risk disclosures are segmented), a python program is written to complete the task of heading extraction. because there is no uniform template and prescribed format for risk disclosures, there will be considerable interference in the process of data crawling. to ensure the integrity and reliability of the data, we manually re-examine the documents that the program can recognize, and documents that cannot be processed are also manually classified. but there are still many "outliers". as shown in table 2 , we detail the process of sample selection and abnormal causes of these "outliers". finally, we obtain 51,008 risk headings from 1870 forms 10-k of 255 listed tourism companies during 2006-2019. while applying sent-lda, two necessary parameters-topic number k and hyperparameter α need to be set. following griffiths j. li, et al. annals of tourism research 84 (2020) 102986 and steyvers (2004), α in this paper is set to 50/k. the setting of topic number k is going to be discussed in detail later, since it has a great impact on clustering results. besides, the convergence criteria of vem also needs to be set. following bao and datta (2014) , this paper sets the convergence bound for variational inference as 10 −8 , the maximum number of iterations of em as 1500 and the convergence bound of em as 10 −5 . the results of 30 times training on the same topic number show that these parameter settings of vem can make the clustering results stable. to determine the topic number, an evaluation index named perplexity is introduced. perplexity can be easily understood as the uncertainty of the clustering results (azzopardi et al., 2003) . the smaller the perplexity, the higher is the accuracy of the model. in general, for a test set d test of m documents, the perplexity can be expressed as follows, where n d is the number of words in document d. perplexity is a monotone decreasing function with the number of topics, so it will continue to decrease as the number of topics increases. when k is set to the total number of sentences, we can get the minimum of the perplexity, but the classification at this time is meaningless. therefore, when using perplexity to determine the value of k, we are not focusing on the optimal solution but the stable point-the number of topics greater than or equal to the point where the perplexity begins to converge is preferred. fig. 2 shows the perplexity of our model by varying the number of topics from 2 to 200 with the step of 1, which is obtained based on 10fold cross validation as described in blei and lafferty (2007) . as seen in fig. 2 , when the number of topics reaches 120, perplexity tends to be steady. depending on the perplexity, it can roughly know the range of the optimal number of topics but still cannot determine an exact value. grimmer and stewart (2013) pointed out that to determine the number of topics, not only the statistical fit (perplexity in this study) but also the substantive fit need to be considered. therefore, this paper further intends to introduce a word intrusion task to further optimize the model. the purpose of the word intruder task is to find an intruder in a given set of words, that is, a word that does not belong to the same category as other words. when the experimenters think that removing a certain word will make the remaining words make sense together, then this word can be an intruder. although the intruder task can help us determine the number of topics, we do not need to conduct it on all models with k ≥ 120. because the intruder task is a labor-cost process, and when the number of topics increases little, the clustering result does not have a significant change. to depict the clustering similarity of two models with different topic numbers, we define the similarity index. the process of sample selection. denoting the model with k topics as m k , the set of risk topics generated by m k as t k , and the topic i of t k as t k, i i ∈ {1, …, k}, the model similarity of m k and m k−1 can be expressed as: among them, t k j 1 represents the topic set subtracting j − 1 topics that maximize similarity(t k−1, a , t k i a , 1 ), a ∈ {1, ..., j − 1} from t k . similarity(t k−1, j , t k i j , 1 ) is obtained by calculating the cosine value of the word distribution vector t k−1, j and t k i j , 1 through the vector space model (vsm), where the word distribution vector consists of the top 30 words with the highest frequency. fig. 2 shows the model similarity with k ranging from 3 to 200. as shown in the figure, after the perplexity tends to be stable (k ≥ 120), only when the values of k are 101, 130, 150, and 180, there are obvious differences between the clustering results of adjacent models. therefore, we only conduct intruder task on models within a certain interval after the perplexity starts to stabilize and several models with similarity changes obviously, that is k ∈ [120, 130] ∪ {101, 135, 150, 180}. to construct the experiment, we follow the process designed by chang et al. (2009) . first, we randomly select a topic and five words with the highest frequency within this topic. at the same time, a word with low probability in this topic but high frequency in other topics is randomly selected as an intruder. then, all six selected words are presented to the experimenters after shuffling the order. the accuracy of the model can be defined by eq. (4), which indicates the cognitive consistency between the experimenters and classification accuracy of the model. where the total number of people participating in the experiment is defined as s, i k s m , and w k m represent the intruder word selected by the experimenter s and the real intruder word, respectively. when the two words are the same, the indicator function i( ) is equal to 1, otherwise, it is equal to 0. the precision of the model m can be expressed as the average of mp k m over topics. in our work, the word intruder tasks are performed by four professionals. fig. 3 shows the boxplot of model precision. we can clearly see that the model has the highest precision when the number of the topic is set to 125. so, we finally choose 125 as the optimal value of the topic number k. by running sent-lda with topic number as 125, we can get 125 risk exposure topics. to clarify what each topic expresses, these 125 topics need to be labeled. although there are some automatic labeling methods (mei et al., 2007) , when the research focuses on a specific area that requires professional knowledge, these methods might be powerless. in general, in most works with the topic model, manual labeling methods are more popular for ensuring higher accuracy. to execute our task, we have designed a manual labeling process. first, we use the 32 risk factors defined by huang and li (2011) and bao and datta (2014) as our tag list. the experimenters need to use their expertise to match the 125 identified topics with the 32 categories. when the experimenters feel that a topic does not meet any of these 32 categories, they should label it as "other risk types", of which label will be determined later. to complete this experiment, we select four experts in the field of risk management as participants. before the experiment, they are provided with a thorough explanation of our study. then, they independently complete their work based on the high-frequency words under each topic and discuss and j. li, et al. annals of tourism research 84 (2020) 102986 optimize the experimental results together. finally, by comparing the results of the three participants, we find that their results are highly consistent, proving that risks identified by the sent-lda are interpretative. finally, 125 topic labels are determined. because it is difficult to describe 125 topics in detail, following dyer et al. (2017) and li et al. (2020) , we further divide them into 30 broader risk categories, which are shown in fig. 4 with labels. each graph contains 25 words with the highest frequency, and the larger font indicating a higher probability of occurrence within this category. for example, in r02, the three most common words are "new", "growth" and "market". two points need to be explained. first, to reduce the noise, we have added some common words that have high frequency but no practical meaning (such as preposition, noun related to tourism or risk, degree adverb, etc.), punctuation, and some special characters to stop word list before the experiment. second, due to the existence of some sentences that do not clearly describe a certain type of risk and describe multiple types of risks, it is difficult for us to accurately label some clustering results, which are classified as "others" categories (bao & datta, 2014) . so, we finally get 31 risk categories, and the description of them is shown in table 3 . focusing on the tourism industry allows us to discover some new risk exposures, which have been ignored in previous works using all listed companies as samples (bao & datta, 2014; huang & li, 2011) . these emerging risk exposures can reflect the characteristics of tourism to a certain extent. for example, seasonal risk can reflect the obvious seasonality of tourism activities, which further verifies "tourism is strictly time-bound" mentioned in the research background. epidemic risk can also present the fact that tourism as a consumer cyclical industry is particularly sensitive to a public health emergency, which has been verified by covid-19 (duan et al., 2020; yang et al., 2020) . the definitions and examples of these new risk exposures are shown in table 4 , and others can refer to the works of huang and li (2011) and bao and datta (2014) . to provide more specific information, we will discuss the identified risk exposures from the internal, external, and time perspective in this section. to verify whether our risk identification results are representative of the tourism industry, we compare the top 5 and industry representative risk exposures with other industries, including energy and banking. as shown in table 5 , regulation risk is in an absolute leading position in all these three industries, and stock market risk is also a relatively common one. the differences between industries are also very obvious. for the energy industry, risk factors related to energy price, exploration, and transmission are significant. for the banking industry, risk factors are more relevant to strategy, fund operations, and capital loan. for the tourism industry, the risk profile is completely different-business expansion risk has a higher proportion, cost risk, partnership risk, demand fluctuation risk, and epidemic risk can reflect the particularity of the tourism industry. taking partnership risk and demand fluctuation risk as examples, we can explain this phenomenon from the following two aspects: 1) tourism is an intangible product and there are many types of services involved. the sales of tourism products rely on third-party booking and payment platforms, and the perfect tourism services also depend on franchises (guo et al., 2013) ; 2) "tourism is best defined on the demand side" (keller, 2006: 18) . so, unlike the energy and banking industries, tourism is not necessary for daily life, and its demand is extremely sensitive to international political, economic, and climatic conditions. the consumer preference also has strong volatility, which results in significant demand fluctuation (gautam, 2012; ridderstaat et al., 2014) . all the facts prove the necessity and rationality of risk identification in the tourism industry. partnership risk a series of risks encountered in the course of business cooperation with partners, such as dependence on third-party platforms and uncontrollability of franchise operation. e.g., "investing through partnerships or joint ventures decreases our ability to manage risk." 2 insurance risk the amount of insurance cannot cover company losses, or losses are not covered by insurance, which could reduce anticipated profits. e.g., "our current insurance coverage may not be adequate, our insurance premiums may increase, and we may not be able to obtain insurance at acceptable rates or at all." 3 internal control risk defects in internal management and control. e.g., "if we fail to maintain an effective system of internal controls, we may not be able to accurately report our financial results." 4 asset impairment risk risks associated with a sudden decline in asset value, where assets include both fixed assets and intangible assets. e.g., "impairments of assets or goodwill may increase the risk of default under our debt obligations." 5 seasonal risk seasonal fluctuations in results. e.g., "our business is highly seasonal, and unfavorable weather conditions can adversely affect our business." 6 reputation risk the risk of negative evaluation of the company due to omissions in their daily operations, such as customer information leakage. e.g., "improper conduct of our employees could harm our reputation and adversely affect our business operations." 7 lease risk financial and contractual issues related to leases. e.g., "we may be locked into long-term and non-cancelable leases that we want to cancel, and may be unable to renew leases that we want to extend at the end of their terms." 8 food safety risk adverse effects related to food safety affairs. e.g., "food safety and food-borne illness concerns may have an adverse effect on our business." 9 epidemic risk obstacles to the normal operations caused by health concerns arising from outbreaks of diseases. e.g., "a regional or global health pandemic could severely affect our business." note: the results of the energy and banking industry are quoted separately from the work of wei et al. (2019c) , and wei et al. (2019b) . li, et al. annals of tourism research 84 (2020) 102986 we further divide the tourism industry into four sub-industries-casinos & gaming, hotels, resorts & cruise lines, leisure facilities, and restaurants-in accordance with gics. then, we calculate the top 10 risk exposures in each sub-industry and further compare them to distinguish the main threats of different sub-industries. as shown in table 6 , regulation changes, stock market risk, business expansion risk, and market risk have higher disclosure frequency in all sub-industries. there are also some visible differences between them. for casinos & gaming, debt risk, funding risk, and credit risk are relatively high compared to others due to its important economic attribute. the regulation on whether it operates legally will also be stricter. for leisure facilities, there is a certain similarity with the gaming industry, which are mainly reflected in the higher debt risk, human resource risk, and funding risk compared with the other two industries. furthermore, due to a large number of outdoor activities, the probability of catastrophes is relatively high. the larger floor space makes its real estate investment risk very significant, the same is true of hotels, resorts & cruise lines. for restaurants, the success of their growth strategy upon their ability to expand new restaurants and franchise operations, which led to a higher business expansion risk. as a sub-industry with the closest contact with consumers, its sale is easily affected by consumer preferences or discretionary spending, which brings strong fluctuations in demand. moreover, the restaurant industry is strongly dependent on the supply of raw materials, making supply risk, and cost risk relatively significant. litigation risk caused by food safety is also an important characteristic risk. for hotels, resorts & cruise lines, in addition to higher cost risk due to the similar reason with that of the restaurant industry, partner risk is also very prominent, because an increase in the use of third-party travel website and internet reservation channels may negatively impact their revenues (law, 2006) . these differences can reflect their distinct business characteristics, which have important implications for providing more targeted decision-making suggestions and risk hedging strategies between different sub-industries. to understand the performance of risk exposures in different years, we draw the annual changing trend of three types of risk exposure in fig as can be seen from fig. 5 (a), risk exposures with high disclosure proportion have been relatively stable over the years. among these risks, macro market risk and stock market risk have increased significantly after the financial crisis. the results in fig. 5(b) show that information technology risk not only has a higher exposure proportion but also shows a higher growth trend (4.98%), implying the significance of cyber security for business operations with the advent of the digital age and the popularity of online transactions. although the annual exposure proportion of epidemic risk and food safety risk is very low, it shows an obvious growth trend, with a growth rate of 5.86% and 4.36%, respectively. so, the emergencies related to visitor health also need to attract the attention of stakeholders. besides, the growth rate of tax risk and asset impairment risk is 5.98% and 5.25%, respectively. the exposure proportion of risks presented in fig. 5 (c) shows a downward trend over the years. among them, seasonal risk has the highest decay rate (4.47%). with the diversification of tourism products and the increasing universality of tourism activities, the season obstacles to the tourism industry will gradually decrease. the decay rate of other four risks-competition risk, stakeholder's interest risk, credit risk, and funding risk is 3.95%, 2.90%, 2.80%, and 2.57%, respectively. in this paper, we successfully use the text mining technology to identify the risk exposures of tourism companies from the textual risk disclosure in financial statements, which has compensated for the lack of research on company risk identification. by analyzing 51,008 risk headings from 255 public companies' financial statements, we discover 30 risk exposures for tourism companies. in which, the regulation changes, business expansion risk, and stock market risk are the most common risk exposures faced by tourism companies. business expansion risk, partnership risk, demand fluctuation risk, seasonal risk, food safety risk, and epidemic risk are the most representative risk of the tourism industry. from the internal perspective, each sub-industry has its unique business j. li, et al. annals of tourism research 84 (2020) 102986 characteristics, and the risk exposures it faces are also different. high debt risk, funding risk, and credit risk can reflect the economic attribute of casinos & gaming industry; partnership risk is the representative risk of hotels, resorts & cruise lines industry; high investment risk and catastrophe risk is the effect of many outdoor activities and larger floor space in the leisure facilities industry; supply risk, potential/ongoing lawsuits, and demand fluctuation risk can reflect the characteristics of restaurants industry. from the time perspective, most risk exposures maintain a relatively stable disclosure proportion. risk exposures with average fluctuation rate exceeding 5% include tax risk (5.98%), epidemic risk (5.86%), asset impairment risk (5.25%), information technology risk (4.98%), food safety risk (4.36%), and seasonal risk (−4.47%). the findings of our research have some practical implications. first, our findings can help investors better understand the risk status of the tourism industry, especially the newly identified risk exposures with industry representativeness in table 4 and table 5 , which usually has a more serious impact on the tourism industry. besides, when making more detailed investment choices, the risk differences between different sub-sectors can provide a reference for formulating a reasonable risk hedging strategy. for managers, they should pay more attention to the risk exposures with high disclosure frequency, and constantly optimize the business structure in the daily operation process to improve the replying ability. besides, although the epidemic risk and food safety risk have lower disclosure proportions, they are extremely volatile and uncertain. once it happens, the impact is devastating in most cases, which should cause great attention. to this end, managers need to strengthen food safety management, strictly control all aspects of procurement-production-sales, and carry out innovation to improve the intelligence level and diversity business types, which can play a key role in responding to public safety events. the current work is just a preliminary attempt. although we have solved the dilemma of tourism company risk identification in terms of data sources and analysis methods with the help of financial statements and topic model. there are also some limitations need to be solved in the future. first, form 10-k restricts sample selection to the scope of listed companies with a certain size, so, the information of smes is still unable to be effectively captured. in the future, risk identification for small and medium-sized tourism companies will be a new challenge worthy of attention. second, to obtain richer research conclusions, sentiment analysis can be considered to measure the severity and urgency of risk exposures. besides, as shown in the discussion section, although there are fewer disclosures of epidemic risk, its volatility is extremely strong, and once it happens, it is usually accompanied by a serious negative shock. the past outbreaks of sars and avian flu had a material and severe impact on the tourism industry (kuo et al., 2008) . the recent worldwide outbreak of covid-19 has brought the world to a standstill, and tourism has been one of the hardest-hit of all major economic sectors. it is estimated that in 2020 global international tourist arrivals could decline between 20% to 30%, and tourism could lose up to 18% of their usual output (world tourism organization, 2020). in the future, risk perception of covid-19 and its full impact on international tourism will become hotspots. backpackers' risk perceptions and risk reduction strategies in ghana investigating the relationship between language model perplexity and ir precision-recall measures simultaneously discovering and quantifying risk types from textual risk disclosures differential information and security market equilibrium consumer behavior as risk taking risk society: towards a new modernity tourism crisis management: us response to a correlated topic model of science latent dirichlet allocation customer value amongst tourists: a conceptual framework and a risk-adjusted model risk diversity across restaurants: an 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analysis of textual financial disclosures. computational intelligence (ssci) literature review: economics and risk. canterbury: university of kent (scarr working paper . we sincerely express our gratitude to the editors and reviewers. their constructive guidance and revision suggestions are very helpful for us to improve the quality of the paper. supplementary data to this article can be found online at https://doi.org/10.1016/j.annals.2020.102986. key: cord-317167-hzcl1hw3 authors: rodgers, rachel f.; lombardo, caterina; cerolini, silvia; franko, debra l.; omori, mika; fuller‐tyszkiewicz, matthew; linardon, jake; courtet, philippe; guillaume, sebastien title: the impact of the covid‐19 pandemic on eating disorder risk and symptoms date: 2020-06-01 journal: int j eat disord doi: 10.1002/eat.23318 sha: doc_id: 317167 cord_uid: hzcl1hw3 the current covid‐19 pandemic has created a global context likely to increase eating disorder (ed) risk and symptoms, decrease factors that protect against eds, and exacerbate barriers to care. three pathways exist by which this pandemic may exacerbate ed risk. one, the disruptions to daily routines and constraints to outdoor activities may increase weight and shape concerns, and negatively impact eating, exercise, and sleeping patterns, which may in turn increase ed risk and symptoms. relatedly, the pandemic and accompanying social restrictions may deprive individuals of social support and adaptive coping strategies, thereby potentially elevating ed risk and symptoms by removing protective factors. two, increased exposure to ed‐specific or anxiety‐provoking media, as well as increased reliance on video conferencing, may increase ed risk and symptoms. three, fears of contagion may increase ed symptoms specifically related to health concerns, or by the pursuit of restrictive diets focused on increasing immunity. in addition, elevated rates of stress and negative affect due to the pandemic and social isolation may also contribute to increasing risk. evaluating and assessing these factors are key to better understanding the impact of the pandemic on ed risk and recovery and to inform resource dissemination and targets. in many countries, the covid-19 pandemic has incurred restrictions in daily activities and movements with particularly constraining restrictions in areas of europe such as italy and france. for example, work and studying activities have been shifted to the home as much as possible, and all non-essential travel put on hold. these restrictions have substantial consequences for eating, physical activity, and sleep patterns, each of which may affect or increase the risk of ed behaviors. regarding eating patterns, the absence of clear routines and markers of time and space, such as mealtimes or separations between home and work areas, may increase risk of ed behaviors by removing structures that were supporting eating plans and, in turn, leading to increased snacking and grazing. furthermore, for those with families and at risk for eds, organizing mealtimes several times per day may sharply increase the time spent handling and being around food, which may negatively impact risk for disordered eating behaviors (heriseanu, hay, corbit, & touyz, 2017) . in addition, recommendations to limit activities such as grocery shopping, combined with perceptions of scarcity of certain food products, may heighten attentional focus on food and encourage individuals to stock up on foods more than usual, including snack foods, both of which could increase the likelihood of binge eating (waters, hill, & waller, 2001) . in some contexts, limitations have been placed on physical activity, with individuals allowed outside briefly for physical activity or asked to stay indoors at all times. such constraints may limit access to regular physical activity, which, in combination with disrupted eating patterns, may lead to heightened shape and weight concerns and disordered eating (haines, kleinman, rifas-shiman, field, & austin, 2010) . moreover, anxiety related to the pandemic and disrupted routines may negatively impact sleep quality, which is known to increase ed risk (lombardo, ballesio, gasparrini, & cerolini, 2020; lombardo, battagliese, venezia, & salvemini, 2015) . factors that serve to buffer or protect from ed risk have also been negatively impacted by the current covid-19 pandemic. social support has been identified as a global protective and resilience factor during stressful periods, and key to managing and reducing disordered eating (leonidas & dos santos, 2014; linville, brown, sturm, & mcdougal, 2012) . worldwide, one of the main strategies to contain and limit the pandemic has been the implementation of social distancing measures and stay-at-home orders. social isolation requirements may constitute a barrier to social support, making individuals more vulnerable to the effects of stressful circumstances. similarly, other activities that are helpful in terms of emotional regulation (e.g., visiting a therapist, engaging in pleasurable activities) may no longer be accessible to individuals (cook-cottone, 2016) , and instead, less adaptive emotional regulation strategies, including emotionally-induced eating, restrictive eating, or purging behaviors may be relied upon (lobera, estébanez, fernández, bautista, & garrido, 2009) . examining the ways in which the covid-19 pandemic may increase ed risk and symptoms by negatively affecting protective or buffering factors would be an important contribution. in addition, however, exploring ways in which resilience and protective factors (e.g., removal from stressful social circumstances or decreased daily hassles due to confinement or practice of mind-body activities) may also successfully buffer individuals from ed risk would be another interesting avenue of investigation. the restrictions placed on movement and disruption to routines may also negatively impact access to care. the covid-19 pandemic has the potential to increase need for healthcare services whilst simul the covid-19 pandemic may also be associated with increased risk for ed behaviors relative to media effects in three ways: (a) specific exposure to harmful eating and appearance-related media, particularly on social media; (b) effects of general media consumption; and (c) the increased use of video-conferencing while working from home. media use, including social media, is associated with increased risk for disordered eating in particular through exposure to thin idealand diet culture-related content as well as food advertising (boswell & kober, 2016; levine & murnen, 2009; rodgers & melioli, 2016) . the pandemic requirements of social distancing likely increase social media use as a means of communication, which may therefore heighten risk for disordered eating. furthermore, specific social media trends such as those jokingly referring to weight gain during the period of confinement ("covid-19" as a play on words alluding to the "freshman 15"; elizabeth, 2020), and greater social media attention to home cooking and "pandemic recipes" may create supplemental pressure via greater attention to weight and food that may serve to increase ed risk and symptoms. although frequency of social media use may vary across cultural contexts, preliminary data on use during the pandemic have shown association with mental health concerns in asia (gao et al., 2020; kantar, 2020; ni et al., 2020) . exploring how exposure to ed relevant social media, as well as pandemic-specific social media, is related to ed symptoms and risk would be a fruitful research direction, including cross-cultural examinations. f i g u r e 1 summary of the pathways through which the covid-19 pandemic may increase eating disorder risk and symptoms regarding media exposure more broadly, previous research has shown that exposure to media coverage of stressful and traumatic world events was related to increased disordered eating. for example, exposure to media coverage of the 2011 japanese earthquake was associated with increased dieting but not bulimic type behaviors (rodgers, franko, brunet, herbert, & bui, 2012) . during the pandemic, much news coverage is devoted to rising numbers of infections and fatalities, health and safety concerns worldwide, and the economic and social impact. as found previously (rodgers et al., 2012) , exposure to such news coverage may similarly increase risk of disordered eating. in addition to pathways related to media consumption, the increased use of videoconference technologies in the context of "stay at home" orders may also indirectly contribute to risk of ed behaviors by increasing preoccupation around appearance. body image avoidance is a common feature of body image and eating concerns, and posting self-images online has been shown to be harmful to body image and mood among young women (mills, musto, williams, & tiggemann, 2018) . it is likely that video conferencing may heighten focus on individuals' faces and appearance and therefore have similar effects. as this form of communication with family, friends, and in the work setting is likely to continue for some time, examining the effects of "looking in the mirror" repeatedly while talking to others may be an area of interest. the covid-19 pandemic has resulted in certain eating-and foodspecific anxieties (davis et al., 2020) . thus, fear of contagion from covid-19 may lead individuals to experience increased concerns regarding the quality of food or its capacity to be a vehicle of contagion. this may, in turn, increase restrictive eating patterns either through fear of leaving the house to purchase foods or the elimination of certain foods or food groups due to fear of contamination. disgust responses have been shown to be higher among individuals with ed behaviors and linked to anxiety sensitivity (anderson et al., 2018; davey & chapman, 2009; harvey, troop, treasure, & murphy, 2002) . although the directionality of these relationships is unclear, combined anxiety and disgust related to fears of contamination might increase ed risk or lead to worsening of existing concerns. patterns of disordered eating that are characterized by concerns related to health, rather than weight and shape, have been investigated in the context of orthorexia nervosa, defined by an excessively restrictive eating pattern driven by concerns regarding the quality of food and health concerns (dunn & bratman, 2016) . given the capacity for the covid-19 pandemic to increase health concerns, and the centrality in orthorexia nervosa of beliefs regarding the usefulness of manipulating diet to promote health, exploring the potential for the covid-19 pandemic to increase orthorexia symptomatology specifically would be important. relatedly, individuals may adopt restrictive diets believed to have immunity-related health benefits that may protect them from contracting the coronavirus or minimize its effects (navaro et al., 2017) . while these types of dieting are poorly characterized, they may result in restriction and the elimination of food groups, be accompanied by substantial negative impacts on overall functioning, and lead to increased risk of exposure to the virus due to rigid and specific dietary practices. in addition to these specific fears created by the covid-19 pandemic, the situation has substantially increased general levels of stress and emotional distress (brooks et al., 2020) , which are key risks for disordered eating (puccio, fuller-tyszkiewicz, ong, & krug, 2016) , including in the context of traumatic societal events (harada et al., 2015; rodgers et al., 2012) . thus, the pandemic may increase risk for key disordered eating patterns, including binge eating and purging, and restrictive, disinhibited, emotional, and external eating patterns. emotional eating during times of stress, particularly focused on high carbohydrate foods, can often serve as a trigger for binge eating in those with ed or at risk for one (klatzkin, gaffney, cyrus, bigus, & brownley, 2018) . importantly, some groups may be more vulnerable to the effects of natural disasters as well as to the present pandemic, in particular people with pre-existing mental disorders, including eds (pfefferbaum & north, 2020) . worldwide, one of the principal strategies to contain and limit the pandemic has been the implementation of social distancing measures. beyond the restrictions and limitations to daily activities and movement discussed above, these measures have major, negative psychological impacts (brooks et al., 2020) . reduced social and physical contact with others may be associated with boredom and frustration, which may in turn increase ed risk and symptoms by increasing emotion-related eating (braden, musher-eizenman, watford, & emley, 2018) . moreover, social isolation and loneliness, defined as a distressing feeling arising from perceived deficiencies in one's social relationships, that may also result from the social distancing measures may increase negative affect, and negatively impact circadian rhythms and self-regulation, thereby further increasing ed risk and symptoms (haines et al., 2010; lombardo et al., 2015 lombardo et al., , 2020 . importantly, the psychological impact of social distancing may persist for several months (brooks et al., 2020) , and therefore considering both the immediate and also delayed and longer-term effects is an additional important focus (reynolds et al., 2008) . in sum, the current covid-19 pandemic has created a situation across the globe likely to increase ed risk and symptoms through multiple pathways and to decrease protective factors and elevate barriers to care. here we propose pathways and mechanisms that may account for the effects of the pandemic on eds and we join the call for international researchers in the field to come together to collaboratively generate empirical data to test these potential relationships (touyz, lacey, & hay, 2020) . evaluating and assessing these factors, including across different cultural settings, are key to better understanding the impact of the pandemic on ed risk and recovery and to inform resource dissemination and targets. identifying high-risk groups, such as those with pre-existing disorders or histories of eds, or youth, due to their increased media consumption and the higher risk of ed onset during this period, will be critical. incorporating covid-related questions in existing longitudinal or cohort disordered eating studies (eik-nes, austin, blashill, murray, & calzo, 2018; micali et al., 2017; pearson et al., 2017; weissman & rosselli, 2017) and new studies with population-representative samples for comparison against existing norms may provide best evidence for disordered eating-related impacts of covid-19. the authors have no conflicts of interest to disclose. data sharing is not applicable to this article as no new data were created or analyzed in this 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bulimia nervosa access to evidencebased care for eating disorders during the covid-19 crisis reducing the burden of suffering from eating disorders: unmet treatment needs, cost of illness, and the quest for cost-effectiveness the impact of the covid-19 pandemic on eating disorder risk and symptoms key: cord-312183-zkoj5d8c authors: frydman, galit h.; boyer, edward w.; nazarian, rosalynn m.; van cott, elizabeth m.; piazza, gregory title: coagulation status and venous thromboembolism risk in african americans: a potential risk factor in covid-19 date: 2020-07-24 journal: clin appl thromb hemost doi: 10.1177/1076029620943671 sha: doc_id: 312183 cord_uid: zkoj5d8c severe acute respiratory syndrome coronavirus 2 infection (covid-19) is known to induce severe inflammation and activation of the coagulation system, resulting in a prothrombotic state. although inflammatory conditions and organ-specific diseases have been shown to be strong determinants of morbidity and mortality in patients with covid-19, it is unclear whether preexisting differences in coagulation impact the severity of covid-19. african americans have higher rates of covid-19 infection and disease-related morbidity and mortality. moreover, african americans are known to be at a higher risk for thrombotic events due to both biological and socioeconomic factors. in this review, we explore whether differences in baseline coagulation status and medical management of coagulation play an important role in covid-19 disease severity and contribute to racial disparity trends within covid-19. converting enzyme 2 receptor (ace2r), where it then undergoes proteolytic cleavage into spike protein 1 and 2 (sp1/sp2), resulting in successful host cell infection. 9 angiotensinconverting enzyme 2 receptors are expressed in a variety of tissues, including the lungs, various parts of the gastrointestinal (gi) tract, the heart, and brain/central nervous system. accordingly, the primary presentations of covid-19 in symptomatic patients include respiratory, cardiac, gi, and neurologic signs. [10] [11] [12] the range of clinical findings in covid-19 can span the gamut from asymptomatic to severe illness, requiring intensive care unit admission and mechanical ventilation. additionally, the severity of disease has been linked to the presence of various comorbidities. given the organ systems for which covid-19 has tropism (via localization of the host cell receptor expression, ace2r), patients with preexisting pulmonary and cardiovascular conditions are at increased risk. the risk is further heightened by the fact that many of these conditions, including congestive heart failure and chronic obstructive pulmonary disease (copd), are associated with increased levels of ace2r expression. [13] [14] [15] [16] although robust basic and clinical studies have yet to be published, various case series reports, clinical observations, and theories have been proposed regarding the pathogenesis of covid-19-related coagulopathies. upon exposure to a viral pathogen, such as sars-cov-2, there are multiple potential mechanisms that can trigger coagulation pathways, including leukocyte activation, complement activation, systemic inflammation, and pathological changes of infected host cells, such as endotheliitis, which may result in cellular damage and apoptosis, which may then further active inflammation and coagulation. [17] [18] [19] [20] in addition to the conditions that render specific organ systems at risk, such as copd and asthma, systemic diseases such as diabetes, obesity, autoimmune disorders, and cancer predispose patients to severe and rapid changes to their inflammatory system and, in many cases, also predispose a patient to being in a prothrombotic state. [21] [22] [23] [24] [25] individuals with these preexisting conditions, along with cardiopulmonary disease, appear to be at the highest risk for development of severe covid-19 as well as higher mortality rate. [13] [14] [15] [16] additionally, there is mounting evidence that a major pathological finding in severe covid-19 is the development of macrothrombi and microthrombi. multiple recent studies have demonstrated that there is pathological blood clot formation on a systemic level, including deep vein thrombosis (dvt), pulmonary embolisms (pe), pulmonary microthrombi, stroke, and even thrombus formation in the placenta. [26] [27] [28] [29] [30] [31] [32] [33] systemic thrombosis has been noted to result in acute bowel ischemia, leading to the need for emergency surgery. 34, 35 a growing body of literature describes the disproportionate effect of covid-19-related morbidity and mortality in minority populations, particularly african americans. according to a recent report from the chicago area, greater than 50% of covid-19 cases and 70% of covid-19-related deaths have been observed in african americans, although they make up only 30% of the study population. 7 similar trends have been noted in louisiana, michigan, and new york city. [17] [18] according to a johns hopkins university and america community survey, covid-19 rates were 3 times higher, and the death rate was at least 6 times higher, in 131 predominantly african american counties compared to infection and death rates from 2879 predominantly white counties, 6 predominantly asian counties, and 124 predominantly hispanic counties. 36, 37 health care disparities and socioeconomic status plays a major role in this increase in morbidity and mortality. however, to assume that these 2 factors explain the totality of the racial disparities in outcomes of covid-19 runs the risk of missing important therapeutic avenues for reducing burden of illness in these vulnerable populations. indeed, interrogating differences in comorbid conditions and baseline abnormalities of coagulation may provide critical inroads into mitigating the higher risk of adverse outcomes in minority racial groups such as african americans. recent studies have shown severe pulmonary and cardiac pathology, associated with increased thrombosis, is prevalent in african americans with severe covid-19. 26, 38 although more research into this area is needed to draw any conclusions, researchers and clinicians are beginning to take notice of the possibility of differences in baseline coagulation status, in conjunction with other variations, as potentially playing a potential role in the severity of covid-19. 38, 39 coagulation differences related to race or ancestry variations in coagulation activity can be dichotomized into congenital and acquired. congenital differences in coagulation status are due to genetic differences between individuals. limited studies describe genetic variation in coagulopathies, although faster and cheaper sequencing tools have changed our understanding of this topic. there are many genetic causes of both excess bleeding (eg, hemophilia) and excess clotting. although african americans have been shown to have an increased risk of thrombosis as compared to caucasians, most of the inherited mechanisms of thrombosis that have been studied are present primarily in caucasian populations, such as fv leiden, resulting in resistance to protein c, and prothrombin g20210a. 8, 40, 41 in general, strong evidence supports a tendency toward a prothrombotic phenotype in african americans. although the mechanism is not yet fully understood, this evidence includes a combination of differences in measured coagulation biomarkers as well as observations in increased thrombotic events. 42 african americans exhibit a well-documented trend toward having higher baseline levels of coagulation fviii, increased levels of vwf, increased thrombin generation, and elevated baseline levels of d-dimer ( figure 1 ). [43] [44] [45] [46] [47] [48] factor viii plays a role in the intrinsic coagulation pathway and is frequently elevated in patients with severe systemic inflammation, as it is a positive acute-phase protein. an increase in fviii can create an exaggerated coagulation response upon activation of the cascade and has been suggested to be related to resistance to heparin in critically ill patients. 49, 50 an increase in fviii has been observed in patients with severe covid-19. 4 another biomarker d-dimer is released upon the breakdown of a cross-linked fibrin clot, resultant from endogenous activation of the fibrinolytic pathway. increase in d-dimer is typically used as a marker of active thrombosis and fibrinolysis, such as for the exclusion of a pe, dvt, or stroke, in conjunction with other clinical tests, such as imaging. 51 african american women, in particular, have a higher incidence of thrombosis along with a higher level of d-dimer. 46 ,52 d-dimer has also been reported to be an important biomarker of serious covid-19 and has been shown to correlate with poor prognosis. [1] [2] [3] [4] african americans have at least a 30% higher prevalence of venous thromboembolism (vte), which is suspected to be at least in part due to variations in thrombomodulin, although there is conflicting evidence on the specific mechanism. 53, 54 thrombomodulin modulates thrombin and increases the activation of protein c. limited studies have also identified decreased levels of circulating protein c and protein s, endogenous anticoagulants, in african americans. [55] [56] [57] however, some genetic studies identify potential single-nucleotide polymorphisms (snps) that may affect the level of circulating protein c in multiple groups, including increased levels of protein c in african americans. 58 while fv leiden mutation, which results in activated protein c resistance, is a well-characterized mechanism of thrombosis in caucasian populations, direct changes in protein c, protein s, and thrombomodulin have been found in some african americans (as described above). african americans also have increased levels of lipoprotein (a), which is known to play a role in the development of atherosclerosis and the predisposition to thrombosis due to its similarity to plasminogen, as well as through platelet activation. 59, 60 these findings support the need for further research in this area to fully understand the variations in baseline coagulation status, as they relate to the development of coagulopathies. another potential cause of increased thrombotic events in african american patients is sickle cell disease (scd). sickle cell disease is an inherited blood disorder, caused by a mutation in the hbb gene, that results in production of abnormal hemoglobin and can be identified by the traditional c-shaped (sickleshaped) red blood cells in place of the traditional round cell shape. 61, 62 this morphologic change results in the cells having a higher likelihood of getting lodged in the microvasculature and more prone to aggregate than regular blood cells, causing blood flow obstruction and serving as a nidus for clot formation. 63 these morphological red blood cell changes along with activation of the coagulation system may result in a vasoocclusive crisis. 64 individuals with scd are at a significantly higher risk of developing dvt and pe. 61, 62 in addition to increasing the rate of thrombus formation, the presence of the sickle shape also appears to result in a denser thrombus and the clot itself appears to be more resistant to fibrinolysis. 65 although clinical scd is only present in an estimated 100 000 patients in the united states, the sickle cell trait is present in up to 8% of the african american population, with scd flagged as an important risk factor for vte. 42 a small number of studies have explored genetic variations in the context of coagulation and the response to anticoagulation therapy. some of these studies have suggested that african americans may require higher doses of warfarin to stay within the target prothrombin time/international normalized ratio therapeutic window. 66, 67 one study examined the vkorc1 and cyp2c9 genes in the context of the african american population and the variability in patient response to warfarin treatment. 68, 69 that study identified that a snp in the cyp2c cluster on chromosome 10 appeared to be associated with a clinically relevant effect on warfarin dose. other studies examining higher rates of d-dimer elevations in african americans have identified a potential genetic variation of the f3 loci, believed to be associated with this elevation. 24 studies evaluating metabolism of direct oral anticoagulants (doacs) have also identified potential differences in sulfation of active apixaban due to sult1a1*3, an allelic variant of sulta1 (a polymorphic variant of a sulfotransferase or sult), which may be associated with a moderate potential to affect the anticoagulation effects of apixaban. 70 genome studies also describe genetic variants in vwf specific to african american women, although the resulting phenotype of these changes is not clear. 71, 72 not all genotyping studies have demonstrated an increased risk factor in african americans; for example, a mutation in fii (prothrombin), called prothrombin g20210a, is found in 1 in 250 african americans, but is more common and represents a risk factor for caucasians. 73 genetic and phenotypic variations in accessories to the coagulation pathway, such as in platelets, among racial and ethnic minority groups have also been suggested. platelets play a major role in thrombosis and are a primary target, along with the coagulation pathway, in therapeutic regimens for the treatment of heart disease and other conditions associated with pathologic thrombosis. multiple studies have shown that african american women tend to have a higher platelet count than caucasians and latinos (no difference was seen between men of all races). [74] [75] [76] novel gene mutations linked to changes in platelet counts, primarily increased platelet counts (thrombocytosis), in african americans have been observed. additionally, potential differences in platelet sensitivity to some traditional platelet inhibitor drugs have been demonstrated with varying results. in particular, there are multiple studies showing differences in the protease-activated receptor-4 pathway, with african americans being less responsive to cyclooxygenase and p2y 12 receptor dual inhibition. 76, 77 these findings suggest that african americans may not respond to platelet inhibitors similar to other races, and this may alter therapeutic efficacy in this population. furthermore, several conditions indirectly affect coagulation status. one major example is systemic lupus erythematosus (sle), an autoimmune disease that involves the body raising antibodies against receptors on cell membrane components, such as phospholipids, which increase systemic inflammation and may heighten a patient's predisposition to thrombosis. 42 while typical symptoms of sle include systemic inflammation, swelling, and damage to the joints, kidneys, heart, and lungs, blood clotting is common as well. systemic lupus erythematosus is 3 times more common in african american women than in caucasian women, and up to 1 in every 250 african american women will develop sle. 78, 79 furthermore, its symptoms tend to be more severe in african americans than in other races. 79, 80 lupus anticoagulants, anticardiolipin antibodies, and b-2-glycoprotein i antibodies are antiphospholipid antibodies that are common in patients with sle (as well as certain other patients). it is common for women, especially african american women, to develop antiphospholipid antibodies during pregnancy, a major cause of miscarriage in african american women. 80, 81 interestingly, a few papers have demonstrated that there appears to be an increased frequency of lupus autoantibodies in patients with covid-19, although the frequency of lupus anticoagulant is currently debated. 82, 83 one of the more common conditions that is a strong predisposing factor for vte is chronic kidney disease (ckd). 42, 84 the development of mild-moderate ckd is associated with a 1.3-to 2-fold increased risk for vte, while severe ckd is associated with up to a 2.3-fold increased risk compared to the general population. the predisposition to vte formation in the face of ckd is due to many additive changes in coagulation that occur during renal impairment, including (1) elevated levels of d-dimer, c-reactive protein, fibrinogen, fvii, fviii, and vwf (likely due to increased synthesis); (2) lower levels of fix, fxi, and fxii (likely due to increased urinary loss); (3) decrease in endogenous anticoagulants, including at (likely due to increased urinary loss); (4) increase in platelet activation and aggregation; and (5) decreased fibrinolytic activity. 84 african americans have an increased rate of ckd and end-stage renal disease, with an odds ratio of 3.89, compared to 1 in caucasians, 2.74 in native americans, 1.56 in asians, and 1.45 in hispanics. 85, 86 in addition to the various factors listed above that may predispose african americans to thrombosis (although this list is by no means exhaustive), prevalence of other conditions, such as an increased rate of heart disease, hypertension, and diabetes, also increases the risk of thrombosis. some african americans may be genetically predisposed to a baseline prothrombotic state; adding on other conditions, such as atherosclerotic cardiovascular disease, heart failure, hypertension, diabetes, and other comorbidities, compounds the overall risk of coagulopathies. 87, 88 among the population of african americans who are infected with covid-19, some of these patients may already reside in a prothrombotic state prior to covid-19 because of higher baseline concentrations of fviii, vwf, and d-dimer, as well as increased platelet activation. this may potentially account for some of the increase in disease severity observed in this population. in addition to the physiologic mechanisms that may predispose african americans to a prothrombotic state, other key factors, such as socioeconomic status, may adversely affect coagulation management for this prothrombotic phenotype. although some common comorbid conditions may be inherited, access to medical care, medication, healthy food, and lifestyle habits play a key role in treatment and control of the disease. [89] [90] [91] patterns of increased covid-19 prevalence, morbidity, and mortality are concentrated in areas with lower socioeconomic status, coinciding with underserved racial and ethnic communities. 36, 37 these populations may have greater numbers of residents per household, be economically unable to miss work (even if sick) and are more likely to have multigenerational family members residing in one abode; these factors often make practicing social isolation difficult. this risk is further exacerbated by difficulties with travel or the ability to afford chronic care and long-term medications, creating a perfect storm for an infection such as covid-19. 36, 37, 92 disparities extend to treatment as well. studies have shown that african americans tend not to be managed with the same treatments as those commonly prescribed to other racial and ethnic groups. for example, some studies have noted that although african americans tend to exhibit higher rates of atrial fibrillation and thrombosis, they are less likely to be prescribed anticoagulants compared to their caucasian counterparts. 93, 94 even when prescribed, african american patients tend to spend less time within the therapeutic range for warfarin treatment. 66 similarly, prescription of doacs in the african american community has been limited compared to other racial and ethnic groups, despite the significant increase in doac use in the united states (now surpassing warfarin). interestingly, some studies have shown that these differences in anticoagulation trends are present even when controlling for socioeconomic variables. 66, [94] [95] [96] additionally, despite the evidence suggesting that genetic variations may alter the response to various anticoagulants and platelet inhibitors, as discussed in this article, african americans comprise fewer than 4% of the clinical trial population for many of these anticoagulants. 97 due to the low representation of african americans in these clinical trial populations, it is possible that any natural variation in clinical response would not be observed as the trial is likely not powered for this purpose. thus, the administration of standard anticoagulation therapy, as based on data sourced from caucasian patients, may be subtherapeutic in african american patients, potentially resulting in inadequate anticoagulation. in this report, we consider the contribution of both "nature" and "nurture" to the increased rate of covid-19-related morbidity and mortality among african americans. covid-19 produces severe inflammation and a prothrombotic state that culminates in thrombotic events. african americans are more likely than other racial and ethnic groups to be in a prothrombotic state or to be primed for a prothrombotic state. coupled with the higher rate of preexisting conditions that predispose patients to higher rates of covid-19 and disease, and the lower rate of therapeutic anticoagulation even when warranted, variation in coagulation status may be one of the factors that puts african americans at higher risk. given the potential differences in response to anticoagulant therapy, it remains unclear whether standard dosing effectively achieves the appropriate level of anticoagulation among hospitalized covid-19-positive african americans. although this work focuses on trends in african americans, further examination of covid-19 trends may demonstrate the urgent need for both personalized medicine and population-based care, particularly with respect to anticoagulation management. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: dr piazza has received research grant support from ekos, a btg international group company, bayer, the bristol myers squibb/pfizer alliance, daiichi-sankyo, portola, and janssen 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african americans high plasma levels of factor viii and the risk of recurrent venous thromboembolism risk factors for venous thrombosis in the black population factor viii may predict catheter-related thrombosis in critically ill children: a preliminary study elevated factor viii levels and the risk of thrombosis value of d-dimer testing on the exclusion of pulmonary embolism in patients with previous venous thromboembolism african american ethnicity is associated with higher plasma levels of d-dimer in adults with hypertension novel genetic predictors of venous thromboembolism risk in african americans failure to replicate genetic variant predictors of venous thromboembolism in african americans ethnic differences in markers of thrombophilia, implications for the investigation of ischemic stroke in multiethnic populations: the south london ethnicity and stroke study risk factors for thrombosis in an african population population-specific single-nucleotide polymorphism confers 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cord-303054-s1clwunc authors: velly, lionel; gayat, etienne; jong, audrey de; quintard, hervé; weiss, emmanuel; cuvillon, philippe; audibert, gerard; amour, julien; beaussier, marc; biais, matthieu; bloc, sébastien; bonnet, marie pierre; bouzat, pierre; brezac, gilles; dahyot-fizelier, claire; dahmani, souhayl; de queiroz, mathilde; maria, sophie di; ecoffey, claude; futier, emmanuel; geeraerts, thomas; jaber, haithem; heyer, laurent; hoteit, rim; joannes-boyau, olivier; kern, delphine; langeron, olivier; lasocki, sigismond; launey, yoan; saché, frederic le; lukaszewicz, anne claire; maurice-szamburski, axel; mayeur, nicolas; michel, fabrice; minville, vincent; mirek, sébastien; montravers, philippe; morau, estelle; muller, laurent; muret, jane; nouette-gaulain, karine; orban, jean christophe; orliaguet, gilles; perrigault, pierre françois; plantet, florence; pottecher, julien; quesnel, christophe; reubrecht, vanessa; rozec, bertrand; tavernier, benoit; veber, benoit; veyckmans, francis; charbonneau, hélène; constant, isabelle; frasca, denis; fischer, marc-olivier; huraux, catherine; blet, alice; garnier, marc title: guidelines: anaesthesia in the context of covid-19 pandemic date: 2020-06-05 journal: anaesth crit care pain med doi: 10.1016/j.accpm.2020.05.012 sha: doc_id: 303054 cord_uid: s1clwunc abstract objectives: the world is currently facing an unprecedented healthcare crisis caused by covid-19 pandemic. the objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the covid-19 pandemic. methods: the group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas: (1) protection of staff and patients; (2) benefit/risk and patient information; (3) pre-operative assessment and decision on intervention; (4) modalities of the pre-anaesthesia consultation; (5) specificity of anaesthesia and analgesia; (6) dedicated circuits and (7) containment exit type of interventions. results: the sfar guideline panel provides 51 statements on anaesthesia management in the context of covid-19 pandemic. after one round of discussion and various amendments, a strong agreement was reached for 100% of the recommendations and algorithms. conclusion: we present suggestions for how the risk of transmission by and to anaesthetists can be minimised and how personal protective equipment policies relate to covid-19 pandemic context the outbreak of covid-19 (sars-cov-2) has been spreading globally outside the first chinese outbreak since january 2020 and the world health organization (who) declared a pandemic situation on march 11, 2020 . the epidemic situation has led to a drastic reduction in hospital activities. the evolution of the pandemic allows us to resume some of these activities. beyond this resumption, the persistence of the virus defines a new situation that will have to be taken into account for the care of patients in the coming months. the size and type of activities that will resume depend on many factors outside the organisation of care within our establishments. these factors include the availability of personal protective equipment, anaesthesia/critical care drugs, and critical care beds. finally, it seems important to point out that the epidemic situation is fluctuating not only in time but also in space, so it will be necessary to modulate the recommendations according to the region of exercise and the incidence of covid-19 cases. we need to organise access to this care by meeting a dual imperative: 1) providing access to quality care for patients whose procedures cannot (or can no longer) be postponed, and 2) limiting the risk of contamination of these patients and healthcare professionals. the choice of specific measures to be implemented for the management of a patient in this context will be guided by the risk associated with the patient and the risk associated with the procedure. the persons at risk of serious forms of covid-19 are:  people aged 70 years and over (although people aged 50 to 70 years should be monitored more closely);  people with a history of cardiovascular disease: complicated high blood pressure, history of stroke or coronary artery disease, heart surgery, nyha stage iii or iv heart failure;  insulin-dependent diabetics who are unbalanced or have secondary complications;  people with chronic respiratory disease that may decompensate for a viral infection;  people with morbid obesity (body mass index > 30 kg/m 2 ).  concerning the risk related to surgery, two situations have been identified:  surgery with a high risk of contamination of caregivers by aerosolisation of sar-cov-2 (intervention with opening or exposure of the airways: lung resection surgery, ent surgery, neurosurgery of the base of the skull, rigid bronchoscopy);  major surgery, with a high risk of postoperative critical care stay, where the perioperative respiratory risk inherent to surgery and anaesthesia is likely to be increased by sar-cov-2 infection or even porting. the objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the covid-19 pandemic. the group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas. the basic rules of universal good medical practice in perioperative medicine were considered to be known and were therefore excluded from the recommendations. the recommendations made concern 7 fields: to the drafting of the recommendations to adopt a format of expert opinion. the recommendations were then drafted using the terminology "experts suggest doing" or "experts suggest not doing". proposed recommendations were presented and discussed one by one. the aim was not to necessarily arrive at a single, convergent expert opinion on all the proposals, but to identify points of agreement and points of divergence or indecision. each recommendation was then evaluated by each of the experts and subjected to an individual rating using a scale ranging from 1 (complete disagreement) to 9 (complete agreement). the collective rating was based on a grade grid methodology. in order to validate a recommendation, at least 70 per cent of the experts had to express a favourable opinion, while less than 20 per cent expressed an unfavourable opinion. in the absence of validation of one or more recommendations, the recommendation(s) was/were reformulated and submitted again for scoring with the aim of reaching consensus. the experts' synthesis work resulted in 51 recommendations. after one round of scoring, a strong agreement was reached for 100% of the recommendations and algorithms. in order to protect them during this pandemic, strict safety measures should be implemented. these measures should be carried out all throughout the patient's healthcare pathway: preanaesthetic assessment, operating theatres, recovery rooms, intermediate care units and critical care units. these safety measures will be implemented directly by providing healthcare professionals with adequate ppe, but also indirectly by supplying patients with the right equipment. administrative measures (patient information, preoperative laboratory testing, check-up modalities, anaesthesia modalities, dedicated healthcare pathways, patient and surgery selection), which also help protecting staff members, will be detailed in the following/other chapters. staff members should apply strict social and physical distancing measures when not caring for patients (team rounds, discussions about patients, hand-offs, breaks, meals...): they must keep at least 1 to 2 meters apart from one another, especially during times when wearing a mask is not possible. using alcohol-based hand sanitiser and put on a surgical mask type ii/iir when entering a hospital. this also applies to kids for whom fitted masks should be provided. page 11 of 57 j o u r n a l p r e -p r o o f 11 alcohol-based hand sanitiser before and after every contact with the patient or his surroundings, in addition to wearing a surgical mask type ii or iir and eye protection (goggles) during any clinical examination which requires the patient to take off his mask.  setting up a safety distance in addition to specific physical distancing devices (like temporary plexiglass barriers, interphones…) for those whose work position requires them to be in physical proximity to other people. these devices should be cleaned frequently, following the same cleaning procedures that are used on other surfaces;  removing magazines, documents and other commonly used objects from waiting rooms and common areas, including children's toys;  regularly cleaning surfaces (counters, computers, phones...) and equipment (blood pressure cuffs, pulse oximeter, stethoscopes…) after each patient. during this covid-19 pandemic, every patient could potentially be contaminated and should therefore protect other patients and hospital staff by applying alcohol-based hand gel and wearing a surgical mask type ii or iir. [1] [2] [3] by blocking large droplets, surgical masks protect staff members from droplet and contact transmission. 4 surgical masks can provide protection for healthcare professionals against droplet transmission within a one-meter radius of the patient. four rcts compared the efficiency of n95 or ffp2 masks and surgical masks in healthcare workers performing non aerosol-generating procedures. 5-8 a meta-analysis including these studies reported no significant difference in the occurrence of viral respiratory infections (rc 1,06; 95% ic 0, 25) between the 2 types of mask. 9 only one study specifically evaluated coronaviruses and reported no significant difference between the 2 types of masks in non-aerosol generating procedures. 6 1.3. operating theatre 12 r1.3.1 -experts suggest that healthcare professionals involved in airway management (intubation, extubation, supraglottic airway insertion and/or removal…), or those who could be brought to do so in some given situations, wear a fit tested respirator mask (respirator n95 or ffp2 standard, or equivalent) in addition to a disposable face shield or at least, in the absence of the latter, safety goggles, regardless of the patient's covid-19 status (table 1) there is a great risk of becoming infected during airway management. therefore, strict safety measures should be applied during aerosol-generating procedures such as bag mask ventilation, endotracheal intubation, open/endotracheal suctioning and extubation. the use of a respirator ffp (filtering face piece mask) type 2 is recommended by the french society of hospital hygiene (sf2h) and the french-speaking society of infectious disease for all healthcare professionals manipulating the airway. 10 respirators are tight fitting masks, designed to create a facial seal that protect the person wearing them from droplets and airborne particles inhalation. however, wearing this type of mask can bring more discomfort than wearing a surgical mask (overheating, page 13 of 57 j o u r n a l p r e -p r o o f 13 respiratory resistance...). they have the advantage of blocking at least 94% of aerosol particles (total inward leaking < 8%) and are more effective than surgical masks type ii/iir in blocking < 5 µm particles. 11 nonetheless, a poorly fitted n95 or ffp2 respirator does not protect more than a surgical mask. a leak test must be performed systematically. furthermore, a beard (even a stubble one) reduces the mask's adherence to the face and thus decreases its global efficiency. in case of n95 or ffp2 respirators shortage, some experts suggested using n99 or ffp3 respirators which block at least 99% of aerosol particles (total inward leaking < 2%). however, the problem with these respirators in that the air is most often exhaled through an expiratory valve without being filtered. they do not filter the wearer's exhalation, only the inhale. this one-way protection puts others around the wearer at risk, in a situation like covid-19. covid-19 can also be transmitted by aerosol contact with conjunctiva 12 and lead to a respiratory infection. 13 the fact that unprotected eyes increase the risk of transmission has been demonstrated with coronaviruses. 14 face shields provide a barrier against high velocity aerosol particles and are commonly used as alternatives to safety goggles as they provide greater face protection. 15 using a droplets simulator loaded with influenza viruses (mean droplet diameter: 3.4 µm) and a breathing simulator, it was demonstrated/shown that the use of a face shield reduces the risk of aerosol inhalation by 70%. 16 when spraying fluorescent dye (particle diameter = 5 µm) from a distance of 50 cm towards a mannequin head equipped with an n95 respirator and a face shield, no contamination was noted in either nostrils nor eyes nor mouth folds. the same researchers found that using safety goggles in combination with an n95 respirator did not prevent some eye contamination. 17 face shields also contribute to sparing n95 or ffp2 respirators by limiting their contamination with aerosol projections. n95 or ffp2 respirators can be used for up to 8 hours. during the pandemic period, and a minimal distance of 7-8 meters if an extubation is performed in the recovery room. whenever possible, in order to spare n95 or ffp2 respirators and to protect staff members and other patients, extubation should be performed in the operating theatre by the person who performed the intubation. if this is not possible, the same precautions should be taken in the recovery room for staff protection. in the latest world health organization (who) recommendations for covid-19, health care personnel and other staff are advised to maintain a one-meter distance away from a person showing symptoms of disease. 19 the centre for disease control and prevention recommends a two-meters separation. 20 however, these distances are based on estimates of range that have not considered the possible presence of a high-momentum cloud carrying the droplets long distances recent work has shown that exhalations, sneezes and coughs emit turbulent multiphase flows that can contain pathogen-bearing droplets of mucosalivary fluid. 21 when sneezing or coughing, these droplets/gas clouds can travel in the air for up to 7 to 8 meters. 22 this new understanding of respiratory emissions dynamics has implications on social distancing strategies during the covid-19 pandemic. similarly, swabs taken from air exhaust outlets in covid+ patients' rooms were found to contain rna fragments, suggesting that small virus-laden droplets may be displaced by airflows. 23 however, in this study, no viral culture was done to demonstrate virus viability. for these reasons, extubation should remain exceptional in the recovery room, and giving out surgical masks type ii/iir to patients after their extubation is essential.  administration of nebulised treatment by a device other than vibrating membrane nebulisers. r1.5.3 -when the patient's covid-19 status is unknown, experts suggest using a closed suction system for tracheal suctioning. if this system is unavailable, it is necessary to interrupt the patient's ventilation during suctioning, ideally with the help of a second operator. respiratory droplets are the main source of contamination in healthcare professionals. 2 during aerosol-generating procedures, there is a consensus on the efficiency of n95 or ffp2 respirators (see questions 1.3) and the wear of protective gear such as a fluid resistant long-sleeved gown or a combination of a conventional gown and a plastic apron. 10, 24 the number of asymptomatic patients carrying the virus is high 25 , which is why caregivers should systematically use protection during high-risk procedures. 10,24,25 1.6. paediatric particularities r1.6.1 -experts suggest allowing only one parent to be present during kids' preanaesthetic assessment. and gloves, when performing any procedure with a high transmission risk, particularly when examining the oral cavity. r1.6.3 -experts suggest wearing an n95 or ffp2 respirators, a head cap, a gown with an apron, gloves and a face shield or, failing that, protective goggles, when performing airway procedure in children who are awake in the recovery room, regardless of their covid status. during this covid-19 pandemic, applying enhanced safety measures for the paediatric population is justified due to the existence of a significant proportion of possibly asymptomatic covid+ children (up to 16% depending on the series) and the likely difficulty in complying with social distancing and safety measures (difficulty of continuous wearing of the surgical mask) by children. [26] [27] [28] these findings imply that anaesthesia staff should wear a surgical mask type ii/iir, protective goggles (or a face shield) and gloves when performing any procedure with a high risk of transmission, and particularly when examining the oral cavity during anaesthesia consultation. r2.1 -in asymptomatic patients, during a covid-19 pandemic, experts suggest evaluating the benefit/risk ratio of the intervention according to criteria related to the patient, the pathology and the procedure ( table 2) . the circulation of sars-cov-2 in the population and the existence of asymptomatic carriers affect the risk-benefit ratio of performing a planned surgical procedure during the covid-19 pandemic and require rigorous evaluation. this consideration must integrate three types of criteria related to the patient, the pathology and the procedure. the data in the literature, although heterogeneous and with a low level of evidence, identify several patientrelated risk factors for serious forms of covid-19 potentially associated with an increase in postoperative complications: asa class, obesity, age (> 65 years, < 1 year), underlying respiratory (asthma, copd, cystic fibrosis) or cardiovascular (hypertension, coronary artery disease and chronic heart failure) pathology, obstructive sleep apnoea syndrome, diabetes, and immunosuppression. 29, 30 this increase in perioperative risk is, however, offset by the potential deleterious effect of cancelling or postponing the procedure on the patient. 31 the loss of chance in the absence of intervention must be estimated and the effectiveness and availability of therapeutic alternatives (curative or waiting) explored. finally, two types of factors related to the surgical procedure must be considered: resource utilisation and the risk of transmission of cov-2-sars to the healthcare team. surgical time and expected length of stay provide an indication of the staff and hospital resources required. for each intervention, the foreseeable use of postoperative management in a critical care area must be anticipated in order to adapt surgical activity to the supply available at the time. transfusion needs must also be assessed due to the difficulties of public access to blood donation collection points. the number of personnel required must be taken into account as it increases the risk of contamination of the health care team due to the impossibility of complying with the recommendations for intraoperative distancing. finally, the risk related to the type of anaesthesia and the type of surgery must be evaluated. upper airway management has been identified as a high-risk event for potential transmission of the aerosolised airway secretion virus that persists several minutes after the procedure. 32, 33 the same risk is observed for upper aerodigestive tract and thoracic procedures. finally, the risk related to the surgical site must take into account the probability of postoperative mechanical ventilation, the consequences of which could be aggravated in the context of an infection, or even portage, with sars-cov-2. during the preanaesthetic consultation, detailed information must be provided to the patient and/or his/her legal representative about the perioperative strategy decided regarding his specific situation in the context of covid-19 pandemic. the message must be clear, objective and based on the currently available data, while trying to be reassuring for the patient and/or his legal representative. this message must be given orally during the consultation but also disseminated through a document (established and validated by each structure), which can be given to the patient and/or his legal representative during the preoperative consultation (surgical or preanaesthetic). this information must appear in the medical record. in the appendix, based on current data, we propose examples of model documents (appendix 1, 2 and 3). in the event of cancellation or postponement of the intervention, it is essential to keep in touch with the patient, mostly through the surgical teams, and to reassess the possible alternatives and the feasibility of the procedure according to the evolution of the circumstances. if the decision of postponement or cancellation of the surgery is taken by the patient, it must be recorded in the medical record. the use of a standardised questionnaire increases the completeness of the symptom collection and the reproducibility of the medical examination. it is an appropriate tool for collecting accurate information from a large number of subjects. the data collected are easily quantifiable and traceable. the essential qualities of such a questionnaire are acceptability, reliability and validity. the questions must be formulated to be understood by the largest number of patients, without ambiguity, and be based on validated items. because of the wide variety of symptoms attributable to the sars-cov-2, the questionnaire should be designed to look for the most frequent symptoms (fever, dry cough, etc.) and/or the most evocative ones (anosmia, ageusia, etc.), without however declining all the unusual symptoms that have been reported in the literature. an example of a standardised questionnaire distinguishing between major and minor symptoms is proposed for adults in the appendix #4 and for children in the appendix #5. cov-2 infection at the minimum during the preanaesthetic consultation/teleconsultation and during the preanaesthetic visit. whenever possible, searching symptoms during a phone call with the patient or his legal representative 48-72 hours before the intervention is also recommended to avoid a last-minute postponement of surgery. assessment of specific perioperative risk during the covid-19 pandemic requires, as in the usual situation, the joint consideration of the surgical, patient and anaesthetic risks. in addition, searching usual and/or evocative symptoms of sars-cov-2 infection is an important time of the preanaesthetic consultation in the current pandemic context and during the first months following the easing of the lockdown. the presence of major (i.e., very frequent or relatively characteristic) and/or minor (i.e. more inconsistent and/or less specific) symptoms allows to orient the preoperative covid-19 status assessment, and then to estimate the benefit/risk balance of maintaining or postponing the surgery, taking into account the risk of contamination of health personnel and others patients within the care structure. 34 the integration of these different risks must be collectively weighed against the potential consequences of postponing or cancelling a scheduled intervention. 31 this search for symptoms compatible with a sars-cov-2 infection must take place at the time of the preanaesthetic consultation in order to discuss the postponement of the intervention, if possible, and to anticipate the protective measures that should be applied for the health personnel, and the care circuit that should be used. the questionnaire can be completed by the patient himself, by a nurse just before the consultation or by the anaesthesiologist during the consultation. then, it must be explained that the patient must immediately contact the anaesthesia team, without waiting for admission to the hospital, in case one or more symptoms compatible with a sars-cov-2 infection appear between the preanaesthetic consultation and the day of the intervention. it will also be necessary to explain the importance of the strictest compliance with protective measures, particularly hand-washing and wearing systematically a face mask outside home, between the preanaesthetic consultation and the day of the intervention. if the local organisation allows it, a contact with the patient 48 to 72 hours prior to its admission to the hospital, to ensure that no symptoms have appeared, can also be planned. this timeframe can be adapted locally, the objective of this contact being to have a pcr performed and its results available before coming to the hospital for surgery if the patient has become symptomatic since the preanaesthetic consultation. however, taking into account that the delay between the preanaesthetic consultation and the intervention may correspond to the incubation period of the disease, and that spontaneous reporting by the patient of the onset of symptoms since the consultation will not be systematic nor exhaustive, the search for these same symptoms must be systematically renewed during the "physical" preanaesthetic visit the day before or on the day of surgery. fever, although non-specific, is a very common symptom of symptomatic sars-cov-2 infections, present in 75% to 95% of cases. [35] [36] [37] [38] the presence of fever is a major symptom and an important warning sign that should raise the suspicion of a possible sars-cov-2 infection during the current pandemic. however, since the sensation of fever is highly imperfectly correlated with the temperature objectively measured, 39 it is suggested that patient's temperature should be measured during the preanaesthetic consultation. in addition, antipyretic drug intake should also be systematically collected at the same time as the temperature measurement because acetaminophen (or even nsaids when taken as self-medication by the patient) can normalise the patient's temperature. as the delay between the pre-anaesthetic consultation and the intervention may correspond to the incubation period of the disease, an objective measurement of the patient's temperature must be renewed during the preanaesthetic visit the day before or on the day of the intervention. (figures 1 and 2) for the preoperative covid-19 status assessment and perioperative strategy before scheduled or emergency surgery. these 2 algorithms are the result of a work that tried to take into account a maximum number of clinical situations in a maximum number of structures, while trying to keep it simple. if local provisions, linked to access to diagnostic tests, to the typology of patients, to the prevalence of the virus in the geographical area concerned, or to an agreement between the different specialties at the local level, have led to propose a local algorithm different from those proposed, we suggest that the local algorithm may take precedence over those proposed here. if the patient presents with signs compatible with a sars-cov-2 infection but that the pcr is negative, the evocative paraclinical signs are absent, the ct-scan shows no signs of sars-cov-2 viral pneumonia, and the serology performed after at least 7-10 days of symptoms is negative, a differential diagnosis is then the most likely, and the intervention will be postponed until this other pathology has recovered. in a completely asymptomatic patient, a distinction should be made between: 1) surgeries with opening or exposure of the airways (ent surgery, thoracic surgery, oral surgery, surgery of the base of the skull, rigid bronchoscopy, etc.) for which there is a significant risk of aerosolisation for the operating theatre staff, motivating the realisation of a pcr even in an asymptomatic patient as long as the virus is circulating in the population; and 2) surgeries for which a sars-cov-2 infection could have serious postoperative consequences, thus motivating pcr testing. these surgeries can probably be summed up as "major" surgeries (open-heart surgery, major abdominal or pelvic surgery, organ transplantation, etc.), particularly due to their frequent respiratory impact, since the risk of synergy between sars-cov-2 and perioperative lung injury is not known. to date, this preoperative screening for covid-19 indicated by the type of surgery is based on pcr and there is no indication to perform a thoracic ct scan in this context. in these two situations, the pcr will ideally be performed in the 24 hours preceding the intervention, at most 48 hours, in order to have an idea of the viral carriage as close as possible to the high-risk procedure while taking into account the time required to obtain the results in each structure in order to have them available before the intervention. finally, non-major surgeries in an asymptomatic patient can be performed in a conventional non-covid-19 circuit. 46 if possible, it is suggested that the close contacts of these patients (such as the immediate neighbours in the postoperative recovery room) should be traced to facilitate contact tracing if the patient develops symptoms consistent with sars-cov-2 infection in the days following surgery. it should be noted that if the presence of antibodies in the plasma of a convalescent patient 7 to 10 days after the onset of symptoms has been reported, the positivity of the serology is sometimes later (up to several weeks). in addition, the antibody titre and their neutralising character against sars-cov-2 may vary depending on the patient. [47] [48] [49] [50] [51] [52] furthermore, diagnostic performances vary greatly depending on the type of kit used in the laboratory. finally, the neutralising character of the detected antibodies depends on the viral antigens against which the detected antibodies are directed. [47] [48] [49] [50] [51] [52] consequently, the only place of serology in the diagnostic strategy to date is in addition to a chest ct-scan and a new pcr sample if the first pcr in a symptomatic patient is negative and the symptoms have been evolving for at least 7 to 10 days. new data may change its place in the diagnostic algorithm in the future, especially if it allows the formal detection of patients who are genuinely cured and protected against re-infection, so that surgery can be performed without risk for the patient and staff. by definition non-deferrable, the surgery has to take place. however, pcr sampling should be performed in symptomatic or mildly symptomatic patients who have had close contact with a covid-19 patient within the last 15 days, or who themselves have risk factors for severe forms of covid-19 or are operated from surgery with postoperative respiratory risk. surgery is performed without waiting for the results. in the case of major surgery, a postoperative surveillance in the intensive care unit (potentially already justified by the complexity of the surgery and/or the patient's comorbidities) may be considered, especially in a symptomatic patient, as a risk of synergy between perioperative lung injury and infection/carry of sars-cov-2 cannot be excluded at this time. an outpatient procedure, the experts suggest that the covid-19 status should be sought, at a minimum by using the standardised questionnaire (paediatric version, appendix 5) at the call on d-1. if the interview proves positive, the procedure is rescheduled at least 15 days later. if the questioning does not appear to be interpretable, the child will, depending on the degree of urgency of the procedure, either be rescheduled or hospitalised with a pcr screening test. severe forms of covid-19 are uncommon in children compared to adults, with an estimated incidence of resuscitation of 0.6% of symptomatic forms. 53 clinical manifestations are generally limited to a mild form with fever, myalgia, dry (or productive) cough, runny nose and digestive disorders (nausea, vomiting, diarrhoea, abdominal pain) in 54% of cases. [53] [54] [55] finally, more specific to covid-19 is the presence of anosmia and/or ageusia without nasal obstruction, which are strongly suggestive of this pathology. 1, 2 the presence of skin signs such as pseudo frostbite or urticarial elements are also signs suggestive of covid-19 in children and adolescents. in all cases, the majority of reported paediatric cases are familial in origin and a history of covid-19 in the family environment should be considered a risk factor for this disease in children, even if the child is asymptomatic. 56, 57 radiological signs are identical to those in adults but are inconsistently found (43% of cases on average) and therefore do not contribute much to the diagnosis in this population. 56, 57 the same limitation applies to pulmonary ultrasonography given the lack of studies in the paediatric population. 58 biologically, the published series show lymphopenia or hyperlymphocytosis associated with increased crp. 56 it is important to note that recent studies conducted on cohorts of individuals on an epidemiological basis tend to show that for one person expressing the disease, 7 people are asymptomatic, which reflects the limitations of the clinic to screen all potentially contaminating patients (prepublication study 1) [9-10]. taking into account these elements and the asymptomatic or paucisymptomatic nature of the disease, the problem of the preoperative assessment in paediatrics is above all that of diagnosing this pathology in children, given the risks incurred by caregivers (representing between 3 and 15% of covid-19 infections) [6] , but also that of nosocomial contamination of other patients given the particularly high number of reproductions of this condition (between 2 and 3.5). 56, 57 in the same vein, ambulatory surgery should in theory be favoured in order to avoid cases of nosocomial contamination. it is therefore proposed to perform a pcr test for the virus for each paediatric patient before surgery. in the context of the emergency department, pcr is carried out on admission of the child, but surgery can be performed before the results are obtained. r4.1.1 -during covid-19 crisis, the experts suggest that telemedicine is an alternative to face-to-face consultation and must be used to reduce patient in-visit. the current outbreak of covid-19 has placed a heavy burden on global medical systems, particularly with regard to the preoperative assessment of patients for surgery. for all elective surgeries in france and in many countries for major surgery, preoperative physical assessment by physicians had become a standard of care. the current crisis has reduced this possibility because patients should not be exposed to potentially contagious structures. in for patients, prior agreement to carry out a telemedicine evaluation is a mandatory step. it is advisable to send beforehand a guide to prepare the teleconsultation (including: connection modalities, health questionnaire on current treatments, information documents...) to facilitate the smooth running of the consultation. if necessary, a person close to the patient or an interpreter may, if present during the tlc, assist the doctor in carrying data of the clinical examination within the limits of his or her competence. not all patients desire remote evaluation, and the exact reasons for this have not been elucidated. patient selection is an important step for virtual preoperative evaluation. for example, patients in whom arranging travel is complicated underwent successful telemedicine preoperative evaluation before oral and maxillofacial surgery with no complications, highlighting this patient population as one in whom remote evaluation may be beneficial. the use of telemedicine preoperative evaluation has been studied in a variety of patient populations. all types of surgery can be performed with telemedicine evaluation but major surgery (cardiac, vascular, thoracic, etc.) and patients with many comorbities or treatment are obstacles to the development of this technique. similarly, patients must be able to connect to a platform and know how to use the software. failure to undergo a preoperative anaesthesia evaluation may contribute to day of surgery cancellation, which has a negative financial impact on both patients and hospitals. up to 25% of day of surgery cancellations are due to inadequate preoperative workup, and it is well established that preoperative clinics reduce risk of such cancellations and delays. with telemedicine, we found a 1.3% last minute cancellation rate, consistent with the international average, in patients who underwent telehealth evaluation as opposed to an in-person visit, thus suggesting an equivalent performance between the 2 evaluation options. teleconsultation is carried out using tools that guarantee the security of patient data. it is carried out in conditions that must guarantee : authentication of the healthcare professionals involved in the procedure; identification of the patient; access by healthcare professionals to the patient's medical data required to perform the procedure; access by the patient to the patient's medical data required to perform the procedure. informed consent is an important factor in surgery and telemedicine itself is no different. the evaluation of the practices is advised to optimise these new modalities. as stated in the introduction, in the context of the covid-19 pandemic, the resumption of surgical activity is subject to several major limitations: the strain on the supply of certain anaesthesia drugs, the change in hospitalisation capacities, the risk of contamination of healthcare providers and patients and the application, throughout the patient's journey, of the "distancing" principle. in addition, some peculiarities of covid-19 patients (risk of drug interactions, worsening of the condition, etc.) are to be taken into account. these limitations lead us to propose an adaptation of anaesthesia procedures. favour strategies that reduce the exposure of health professionals to a risk of contamination while maintaining optimal safety conditions for the patient is one of the most important objectives. when safety conditions are met (especially for postoperative follow-up), outpatient management should probably be prioritised. r5.1.2 -experts suggest giving priority whenever possible to regional anaesthesia. regional analgesia and infiltration techniques should also be considered. tensions on drug stocks and even shortages of drugs such as propofol, midazolam, atracurium, cisatracurium or rocuronium require the choice of anaesthesia protocol that spares these drugs, which are otherwise subject to quotas. to do so, the experts propose several principles: -prefer regional anaesthesia (ra) for anaesthesia and analgesia, rather than general anaesthesia. in the context of -peripheral and topical local anaesthesia allow postoperative follow-up directly in the room or in a dedicated space, without going through the recovery room in accordance with regulations. this facilitates compliance with distancing measures specific to the current epidemic context. 65 in children, since ra techniques are regularly associated with general anaesthesia or sedation, they do not make it possible to bypass the recovery room. -when ga is required, inhaled anaesthesia should probably be preferred in this context to intravenous targetcontrolled anaesthesia. -monitoring of the depth of anaesthesia when possible, and of curarisation may be required in order to best adapt drug dosages. 66 these recommendations apply to both elective and emergency care. in conjunction with the institution's pharmacy, it is important to monitor local stock trends. epidemics" published by the srlf-sfar and to the "airway management principle" sheet, which are also applicable in the operating theatre. during the covid-19 pandemic period, the intubation of a covid+ patient in the operating theatre is based on the same rules as those issued in critical care units, due to the risk of spraying of the virus during this risky procedure. in order to minimise the risk of aerosolisation and contamination of personnel, it is necessary to: -limit the number of staff present in the operating theatre -avoid ventilating the patient with a face mask during the preoxygenation phase. -stop oxygen before removing the bag valve mask. -intubate the patient by the most experienced senior using a video laryngoscope -connect the ventilator after inflating the intubation tube balloon. highly suspected patients. patient. if general anaesthesia is required, the patient's clinical condition and covid-19 status should be considered in the airway management strategy. -if the patient is covid+ or highly suspected: the procedure described by sfar 46 should be followed with rapid sequence induction and intubation. special attention should be paid to tracheal extubation with the same barrier precautions as for intubation. this applies to patients under emergency management when the covid-19 status is unknown. special attention should also be paid to hand hygiene. -if the patient is non-covid or asymptomatic, there is no need to modify usual procedures because of the covid-19 pandemic. routine airway management is recommended. if intubation is chosen, conventional induction is recommended according to standard recommendations, with adaptation of the induction sequence according to haemodynamic conditions, drug contraindications, and compliance with fasting conditions and the patient's age. the frequency of anaphylaxis related to atracurium has been estimated to be 1/22451 administrations. the frequency of anaphylaxis due to fast-acting myorelaxant is about 10 times higher (succinylcholine: 1/2080 and j o u r n a l p r e -p r o o f 27 rocuronium: 1/2499). 67 the severe over-risk of allergy to the patient linked to a rapid sequence induction does not seem to be justified by the sole risk of sars-cov-2 contamination of the caregivers, this risk being low when protective measures are well respected (cf. item 1). readers are invited to refer to "guidelines on muscle relaxants and reversal in anaesthesia". 66 in a non-covid patient, spontaneous ventilation anaesthesia or the use of supraglottic devices such as laryngeal masks is possible. we insist on the importance during the preoperative checklist to share with the operating theatre staff, in addition to the usual information, the covid status of the patient which will determine his perioperative circuit and the strategy adopted by the anaesthesia team for airway management. cov-2 is available online from the university of liverpool. 68 a summary is provided below for drugs frequently used in the perioperative period ( table 3) . the hydroxychloroquine has multiple cardiac adverse events, including significant qt prolongation. combinations with other drugs that prolong the qt interval, frequently used in the perioperative period such as halogenated drugs, droperidol, ondansetron, or hypothermia related to surgery and anaesthesia may increase the risk of developing a serious arrhythmia, such as ventricular fibrillation. the combination of hydroxychloroquine and azithromycin, proposed by some, carries a risk of additive/synergistic qt interval prolongation. ecg monitoring is essential. in addition, the combination of lopinavir/ritonavir carries a risk of overdosage with amide type local anaesthetics (lidocaine, levobupivacaine, bupivacaine, prilocaine, mepivacaine, ropivacaine), ketamine, midazolam, sufentanil, oxycodone or tramadol due to ritonavir-related cytochrome p3a inhibition, but also to underdosage of propofol and morphine due to increased biotransformation of products metabolised by cytochrome p2c9 and p2c19 or by glucuronidation. remdesivir, tocilizumab, and interferon beta do not show significant interactions with drugs normally used perioperatively, nor do they have cardiac effects. nsaids may be associated with worsening of symptoms during respiratory viruses, with an increased risk of empyema. 70 despite recent alerts, there is no scientific evidence to date linking nsaid use to the aggravation of sars-cov-2 infection. a precautionary principle applies. 71 thus, in a patient with an established or strongly suspected sars-cov-2 infection, the prescription of nsaids will be avoided. however, in asymptomatic patients, there appears to be no contraindication to their use if their benefit is established. 72, 73 discontinuation of corticosteroids is not recommended in patients on long-term therapy. 70 steroid treatment of patients with covid-19 is controversial and is not currently recommended. 74 the single intraoperative injection of dexamethasone, at the usual recommended doses, does not appear to present an over-risk in the asymptomatic patient. anaesthesia is indicated, experts suggest that rapid sequence anaesthesia be performed regardless of the patient's covid-19 status. in the context of covid-19 pandemic, obstetric patients present two particularities. first, unlike scheduled surgical activities, obstetrical activity in essence cannot be postponed and therefore remained at its usual level at the peak of the pandemic. the organisation of care had to be adapted, with the establishment of specific care channels for women infected with sars-cov-2 or suspected of being infected, not only to optimise the care of these women, but also to avoid the contamination of other pregnant women and of caregivers working in maternity wards. these covid-positive or suspected covid-positive/non-covid channels are logically maintained as long as the pandemic persists. the resumption of surgical activity during the covid-19 outbreak exposes no-covid-19 patients and healthcare workers to contamination. the following expert proposals should be discussed within each institution in a collegial manner (extended executive board, operating theatre committee, healthcare infection control practices advisory committee) and lead to protocols that take into account the specific characteristics of each institution (architectural constraints, recruitment) and the local incidence of covid-19 infection. appropriate signage has to be applied throughout the specific covid-19 pathway. in the context of non-covid patients management in the operating theatre, the aim of this guideline was to avoid both the occurrence of nosocomial sars-cov-2 infection 87 and the contamination of caregivers by asymptomatic patients 88 . for any planned surgical procedure, the risk/benefit balance must be discussed in a multidisciplinary manner, given the probably high postoperative morbidity and mortality in this epidemic context. 88 management of "non-covid" patients must be considered in a specific pathway. 89 this pathway covers the entire patient's hospitalisation day: from the anaesthesia consultation to discharge from the hospital after surgery, following the guidelines for protection (chapter 1). suggest that for both adults and children, priority should be given to outpatient treatment and enhanced recovery after surgery as much as possible. in the context of covid-19 outbreak, outpatient management should be considered and preferred to conventional hospitalisation when feasible. outpatient management reduces the length of stay, thereby reduces the risk of patient exposure and the risk of contamination in case of asymptomatic infection. 90 outpatient management of surgical emergencies should be considered whenever possible. 91 outpatient pathways for resumption of activity during the pandemic period need to consider several points: 1/ the planning and convocation schedules should be staggered to avoid waiting times and gathering of patient; 2/ the use of single or isolated rooms should be preferred to wait or exit lounges; 3/ limit admissions in the postoperative recovery room must be applied as much as possible, in particular after performing locoregional anaesthesia. depending on the local outpatient surgery units, this recommendation may limit the number of patients treated. finally, waiting areas for companions should be arranged in order to respect the safe distances. 91, 92 the number of companions should be limited to one person per patient (adult or child). in case of conventional hospitalisation, enhanced recovery after surgery should be preferred as far as possible in order to reduce, once again, the length of stay. in the same way, hospitalisation on the day of surgery should be considered if the healthcare institution ensures that there is no risk of infected patient by the covid-19 (for example by a phone call the day before hospitalisation). the rapidly changing covid-19 pandemic situation requires a periodic review of the measures taken and an analysis of the clinical, social and economic context derived from each decision. the resumption of surgical activity will be gradual and spread over time. the objective is to summarise, as a priority and progressively, those activities that prove decisive in limiting the loss of chance for patients awaiting cancer or non-cancer surgery. 93 the gradual deployment of surgical activity in a controlled number of operating theatres will make it possible to achieve efficiency in open operating theatres and facilitate compliance with reinforced hygiene rules to ensure the safety and protection of patients and caregivers. experts suggest that public and private facilities agree to propose a common approach to the provision of care adapted to the population and regional conditions of the covid-19 pandemic. the pace of rescheduling elective surgery in children and adults will vary according to geographical location, epidemiological pressure, and the possibility of redeploying staff from critical care to operating theatres. elements to be evaluated for the resumption of surgical activity are the following:  timing of resumption: there should be a sustained reduction in the rate of new covid-19 cases in the geographical area concerned for at least 14 days before the resumption of elective surgery. 94  any resumption must be authorised by the relevant regional and national health authorities.  facilities are able to safely treat all patients requiring hospitalisation without the need for a crisis care organisation.  the facility has an appropriate number of critical and non-critical non-covid and covid+ beds, ppe, ventilators, drugs, blood products and all necessary medical and surgical equipment. the facility has a number of trained and educated staff appropriate to the planned surgical procedures, the patient population and the facility resources. health care staff fatigue and the impact of stress must be considered in order to perform planned procedures without compromising patient safety or staff safety and well-being. 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outbreak: is there still a place for scheduled surgery? "reflection from pathophysiological data the authors want to thank all the reviewers from others medical specialties who brought their expertise on several hand disinfection with a hydro-alcoholic based hand gel, a surgical mask type ii/iir.patients must wear a surgical mask type ii/iir when leaving their unit and heading for the or.coded covid-19 dedicated routes should be followed.surgical mask type ii/iir. discuss 1) a chest ct-scan, and/or 2) a control of the pcr on a new sample, and/or 3) a serology* key: cord-318683-1yxurnev authors: green, manfred s; leduc, james; cohen, daniel; franz, david r title: confronting the threat of bioterrorism: realities, challenges, and defensive strategies date: 2018-10-16 journal: lancet infect dis doi: 10.1016/s1473-3099(18)30298-6 sha: doc_id: 318683 cord_uid: 1yxurnev global terrorism is a rapidly growing threat to world security, and increases the risk of bioterrorism. in this review, we discuss the potential threat of bioterrorism, agents that could be exploited, and recent developments in technologies and policy for detecting and controlling epidemics that have been initiated intentionally. the local and international response to infectious disease epidemics, such as the severe acute respiratory syndrome and west african ebola virus epidemic, revealed serious shortcomings which bioterrorists might exploit when intentionally initiating an epidemic. development of new vaccines and antimicrobial therapies remains a priority, including the need to expedite clinical trials using new methodologies. better means to protect health-care workers operating in dangerous environments are also needed, particularly in areas with poor infrastructure. new and improved approaches should be developed for surveillance, early detection, response, effective isolation of patients, control of the movement of potentially infected people, and risk communication. access to dangerous pathogens should be appropriately regulated, without reducing progress in the development of countermeasures. we conclude that preparedness for intentional outbreaks has the important added value of strengthening preparedness for natural epidemics, and vice versa. the biological weapons convention prohibits the manufacture and use of biological weapons. it came into force in 1975, and has undergone periodic reviews, the last being in 2016. to date, 180 countries are signatories to the convention. unfortunately, terrorist groups or rogue governments are unlikely to feel bound by international agreements. the potential for bioterrorism is of particular concern, since it can cause disease, death, and panic-in great disproportion to the resources expended. 1 there have been a few well documented cases of bioterrorism. in 1984, a religious sect in the usa deliberately contaminated restaurant salad bars with salmonella typhimurium, intending to disrupt local elections. 2 the attack resulted in several hundred cases of salmonellosis and no deaths. the anthrax letters incident in 2001 in the usa resulted in 11 cases of inhalation anthrax, with five deaths, and another 11 cases of cutaneous disease. 3 extensive circumstantial evidence strongly suggests that the perpetrator was a civilian employee of the us military. however, no evidence of a clear motive was found. thousands of workers received prophylactic or post-exposure therapy, and affected buildings were decontaminated at huge expense. 4, 5 in 1993, a cult in japan carried out an attack using anthrax spores with no physical casualties, 6 but later, evidence of post-traumatic stress syndromes was found in victims of the attack. 7 the perpetrators were apparently planning to use other agents such as q fever bacteria, botulinum toxin, and ebola viruses, 8 but they were detained before they could implement further attacks. in this review, we discuss the threat of bioterrorism, potential perpetrators, and general preparedness principles. we examine the special characteristics of biological agents that could potentially be used for bioterrorism, advances in prevention and treatment of diseases caused by these agents, and the remaining deficiencies in the management and control of possible bioterrorist outbreaks. in all respects, the ways in which the resources developed for bioterrorism preparedness could be used for controlling naturally occurring epidemics remain a guiding principle. • preparedness for intentional outbreaks will strengthen the response to naturally occurring epidemics • high level leadership should be maintained with responsibility and authority • health-care providers should maintain awareness of biological agents with bioterrorism potential and consider the presence of unknown pathogens • emergency room and community physicians should be updated regularly about the clinical manifestations of diseases caused by potential bioterrorist agents and emerging infectious diseases. • personal protective equipment should be improved to become more user friendly • improved surge capacity (the ability to rapidly gear up the health system to cope with a sudden, large increase in patients with a serious, contagious disease) is required, particularly in peripheral areas • the capacity of general and reference laboratories should be increased, to keep developing faster, more reliable diagnostic tests • new and improved vaccines (pre-exposure and post-exposure) and treatment regimens should be developed • clinical and environmental surveillance needs to increase • syndromic surveillance systems can be maintained to register suspicious or confirmed cases reported by physicians, and the data can be used to improve risk communication programmes and to monitor the progress of an outbreak • an adequate stockpile of vaccines and medications should be maintained, both nationally and internationally • to improve preparedness for natural and bioterrorist outbreaks, international cooperation should include joint exercises involving multiple countries and constant improvement in the exchange of information on potential bioterrorism threats and management following the breakup of the former soviet union, there was concern that loss of control of their biological weapons programme could allow terrorist groups to gain access to both the weapons and scientific expertise. additionally, in the past few years, developments in the field of microbial genetics have heightened concern about the possible abuse of new technologies. since there are so many unknowns, it is extremely difficult to assess the risks and threats of bioterrorism. 9, 10 the most likely perpetrators could be disgruntled individuals, terrorist organisations, or rogue countries that are believed to support international terrorism. whereas individual attackers are unlikely to cause mass casualties, terrorist organisations could pose a substantial threat if they gain access to sophisticated biological weapons, materials, or scientific expertise. although regulations and safeguards for securing dangerous pathogens in research laboratories now exist in most countries, the scope of these regulations and the extent of the safeguards vary. 11 rogue countries have the necessary capabilities for a bioterrorist attack but might be restrained by the threat of the response of a unified global community. knowledge gained from legitimate research that could also be applied to bioterrorism 12 is considered dual-use. as a result, the regulation of legitimate research on infectious diseases has increased. there will always be a risk of the "insider threat", 12,13 which typically involves a single individual, so it is important to assure that new regulations truly increase security and have minimal negative effect on legitimate research. the cost of regulations applied to research on infectious diseases, in terms of missed opportunities for international collaboration, exchange of pathogens, and sharing of novel agents, is often intangible and overlooked. it is essential to promote healthy organisational cultures to enhance both safety and security in laboratories. 14 since a bioterrorist attack is a low-risk, high-impact event, effective and sustained preparedness is an essential component in both the deterrence and management of an attack. a bioterrorist attack has a lot in common with naturally occurring public health emergencies resulting from infectious diseases. however, there are some important differences. since it is a deliberate act to cause harm, there are the obvious security considerations. the resulting outbreak differs in some important ways from naturally occurring epidemics-for instance, it is more likely to be a point source outbreak initiated by simultaneous exposure to many people. the infectious agent used is likely to be uncommon and possibly not endemic to the region, might have been modified genetically to make it resistant to current medications and vaccines, and produced in a way that enhances its transmission or virulence. therefore, early clinical symptoms and signs after infection with a bioterrorist agent might be unusual, complicating both recognition and management of the disease. these factors could create greater public panic. despite the many similarities with naturally occurring outbreaks of infectious disease, preparedness for bioterrorist attacks is more complex. in many aspects, a bioterrorist attack has the characteristics of a mass casualty event, and thus preparedness involves strengthening of the specialised infrastructure that is required for treatment of seriously ill patients over a very short period of time. new prophylactic and treatment regimens for unusual diseases are required, to ensure their accessibility when needed, along with clear standards for the handling and study of dangerous pathogens. when the proportion of available resources poor international preparedness • delay before the who declared a public health emergency of international concern • delay in implementing coordinated international assistance • logistic challenges in delivering support to assist epidemic response • shortcomings in who's regional and country-level capacity exposed • lack of global plans to address an epidemic of a high-risk pathogen in the least developed urban centres • evaluation of promising vaccine and therapeutic interventions came too late 16 and ebola virus. 17 the local and international responses to the 2014 west african ebola virus epidemic revealed shortcomings that could allow highly contagious epidemics of infectious disease to spread widely before they are terminated (panel 1). 17 during the cold war, agents that could potentially be used as biological weapons were identified on the basis of the following characteristics: pathogenicity for humans, animals, or plants; ability to cause disability or death; stability and infectivity as small particle aerosols; and capability of being readily and rapidly produced and weaponised in munitions or delivery systems. more characteristics have been added, to include other features of biological agents such as the relative ease of medical prevention or treatment and the likelihood of harm to the perpetrator. the us centers for disease control and prevention (cdc) identified bacteria, viruses, and toxins that could potentially be weaponised (panel 2). in 2002, they categorised them into three groups-a, b, and cdepending on ease of dissemination, severity of illness caused, and ability to cause death. 18 biological agents can be infectious and contagious, infectious but not usually contagious, or toxins if they are neither. category a agents were considered the greatest risk to public and national security. the more recent classification of tier 1 select agents and toxins is similar to the category a classification (table 1) . other agents, such as naturally occurring pathogens, produce diseases that are considered of intermediate risk to the public (eg, brucellosis, glanders, q fever). they are moderately easy to disseminate, and include emerging and re-emerging infectious diseases. however, genetic modifications could make them more virulent, produce uncharacteristic clinical signs, increase their resistance to treatment and vaccines, and even change their transmissibility or host range. genetic modifications could be made using the tools of synthetic biology; such activities might be an example of dual-use research. 19, 20 for instance, in 2005, the 1918 spanish influenza pandemic virus was reconstructed, 21 and the poliovirus was synthesised nearly 20 years ago. 22 the addition of an immuno-modulatory gene to the mousepox virus genome in 2001, 23 rendered a mousepox vaccine ineffective, and this technology could potentially be applied to the smallpox virus. 24 the recent synthesis of the extinct horsepox virus 24 has been a reminder that the smallpox virus could be reconstructed, and that the regulations that have been put in place to prevent the misuse of powerful, cheap, and globally available tools must be reconsidered. 25 this possibility has also raised the issue of whether research results should sometimes be censored, or even refused publication, if the potential to cause harm is too high. 19 although bioterrorist agents could be disseminated through multiple routes, the aerosol route would likely maximise exposure. contagious agents could produce a large number of second and later generation cases, depending on the number of people initially exposed, the series average number of people who acquire the disease from one infected individual (r 0 ), and the disease generation time in humans. for instance, the r 0 of pneumonic plague has been estimated to be around 1·3, 26 whereas the r 0 for smallpox is likely to be around 5. 27 for diseases that are not contagious, such as inhalational anthrax, the number of cases of disease will depend almost entirely on the size of the population exposed and the timing of post-exposure antibiotic prophylaxis. 28 aerosolised agents remain the threat of most concern, but safety and security of food [29] [30] [31] and water supplies 32 are also important components of primary prevention (panel 3). new methods to detect toxins in food, such as antibody based assays, are being developed. 33 rapid diagnostics take on additional urgency in a bioterrorist event, because of both health and security concerns. 34 since the 2001 anthrax letters, there have been major advances in diagnostic capabilities. some of the greatest advances in the past decade have been in the speed and reduced cost of sequencing capabilities. 35, 36 highly sensitive and specific pcr-based systems, coupled with modern sample preparation technologies, have enabled sequencing technologies to become less costly, more portable, and multiplexed. with fieldable patient-side diagnostics and sequencing outputs directly connected via cloud-based networks, 37 health-care providers globally can make decisions more rapidly and respond more quickly for individual care or outbreak detection. a rapid, cartridge-based assay for francisella tularensis has been developed for use at point of care. 38 a system that uses a sensitive microsphere technology to detect both antibodies and antigens is now available to diagnose infections with ebola virus and lassa virus. 39 although diagnostic elisa tests are available for anthrax antibodies, 40,41 a compact system (genexpert) that includes both sample processing and pcr amplification can produce a result in about 90 minutes. 42 a rapid and sensitive method to detect smallpox virus has been developed for use at point of care, based on antibody immuno column for analytical processes (abicap) immunofiltration, that produces results in about 45 minutes. 43 however, diagnostic electron microscopy is also still considered a fast and efficient method 44 to identify smallpox and other viral agents. ebola virus was rapidly sequenced during the outbreak in sierra leone to link sporadic cases with the transmission chains. 35 advanced proteomics are also being developed as reference assays 45 and a new method for simultaneous immunodetection of anthrax, plague, and tularaemia from blood cultures has recently been reported, 46 using multiplexed suspension arrays. next generation safety and security of food [29] [30] [31] and water supplies 32 are important components of primary prevention: • intentional contamination of food should be considered, particularly during a large foodborne epidemic with a common source • salmonella and shigella species, enterohaemorrhagic escherichia coli (all serotypes), vibrio cholerae, cryptosporidium parvum, and noroviruses are all potential candidates for intentional contamination of food • contamination of water with biological agents should still be considered, even though it is unlikely to be the major target of bioterrorism, due to chlorination, dilution, and the need for large quantities of the agent to cause a substantial outbreak • c parvum and noroviruses are more resistant to chlorination than other agents, so can be a threat to the water supply • food-borne or water-borne dissemination of these biological agents might lead to higher rates of morbidity and case fatality than previously observed, if the population has been exposed to substantially higher infectious doses • algorithms could be developed to measure the likelihood that outbreaks of disease were a consequence of intentional contamination of food or water, using descriptive, analytical, and molecular epidemiologic tools (none are known to be available so far) 47 increased networking and collaboration of laboratories will also improve the response to intentional outbreaks. effective global surveillance of infectious diseases is essential to control both intentional and naturally occurring epidemics. 48 surveillance data can be used to monitor the progress of an outbreak, and for risk communication. to obtain information rapidly, the ongoing collection of health-related data (termed syndromic surveillance) has been introduced, to monitor patterns of symptoms and signs that are suggestive of an outbreak. [49] [50] [51] [52] although it was hoped that syndromic surveillance would be a more sensitive method for early detection of an epidemic, frequent reports of unusual increases in incidence of non-specific illnesses can desensitise and paralyse the system. 53 in fact, early detection will depend largely on alert, prepared clinicians. for example, when the 2001 anthrax attacks occurred, an astute clinician identified the index case. 34 emergency room and community physicians should be updated regularly on the clinical signs and symptoms associated with the most common bioterrorist agents. 54 the syndromic surveillance system would be more useful after suspicious or confirmed cases have been reported by physicians. a focused analysis of the surveillance data against non-specific, background disease rates could detect changes and provide information about the dynamics of the disease. special legislation might then be necessary, to gain access to medical records. 55 the internet facilitates other potential forms of surveillance and communication about infectious diseases. 56, 57 one such system is promed, which was established by the user community and has proven effective in connecting clinicians and scientists around the world; it has already served as an early warning system 58 standard contact and airborne precautions should be taken. 65 supportive therapy and antibiotics can be provided for secondary infections. there is some evidence of the potential efficacy of thiosemicarbazones. cidofovir has shown in vitro efficacy against variola, and has shown efficacy against other diseases caused by human orthopoxviruses, notably diseases caused by vaccinia viruses. it has also shown efficacy in animal models of orthopoxvirus infections. since 2012, the us food and drug administration (fda) has approved drugs and biologic agents developed under the animal rule. this rule allows for approval of a drug that cannot be tested for efficacy in humans, but is effective in animals and safe in humans. the first drug approved under this rule was the monoclonal antibody raxibacumab for treatment of inhalation anthrax. tecovirimat is a drug that inhibits all orthopoxviruses tested in vitro. it was found to be highly effective in treating monkeypox and rabbitpox in animals and is considered safe in humans. 66 tecovirimat is being considered by the fda for approval for use in humans to treat smallpox under the animal rule. standard and droplet precautions should be taken. 65 ciprofloxacin, levofloxacin, and doxycycline have been approved for the treatment of pneumonic plague. streptomycin and gentamicin have been found to be effective in treatment, although there is some evidence of the development of multiple resistance. 67, 68 tularaemia isolation of the patients is not necessary and standard precautions should be taken. ciprofloxacin, levofloxacin, and doxycycline are all approved for the treatment of tularaemia. streptomycin and gentamicin have been found to be effective. 68, 69 haemorrhagic fevers standard contact and airborne precautions should be taken until diagnosis is confirmed. subsequently, droplet precautions can be considered. supportive care and treatment of secondary infections can be provided. ribavirin is now approved for treatment of lassa fever and it also appears to be effective against new world arenaviruses and crimean-congo haemorrhagic fever. protective n95 respirators and clothing should be provided to health-care personnel. clothing of patients should undergo decontamination and thorough handwashing. supportive therapy is available, with antibiotics such as ciprofloxacin, doxycycline and ampicillin. if the bacteria are resistant to some of the antibiotics, the treatment regimen will depend on sensitivity testing. 60 the regulations require immediate reporting of serious health risks by all member countries. additionally, who has established the global outbreak alert and response network, and the european union has a programme called bichat to improve cooperation between member states in preparedness and response to biological and chemical attacks. they operate the early warning and response system for outbreaks of communicable diseases. the world organisation for animal health has developed plans to identify and deal with a bioterrorism attack on populations of food-producing animals. canada has established the global public health intelligence network for worldwide monitoring of threats to public health. 61 a major benefit of a less formal global collaboration is the development of networks of trust among knowledgeable scientists and clinicians, who are considered early warning posts for both natural and intentional outbreaks. 62 the one health initiative encourages collaboration between health professionals and is as important for bioterrorism preparedness as it is for management of emerging infectious disease and the global spread of antimicrobial resistance. 63 the management of patients that have been infected during incidents of bioterrorism can be challenging. 64 precautions and treatment regimens for several bioterrorist agents are summarised in panel 4. although supportive care serves as the basis of management for all agents, treatments for some of the relevant diseases have substantially progressed. the management of inhalation anthrax has advanced since the 2001 attack, 64, 70, 71 with improvements in critical care, and in treatment of acute lung injury and acute respiratory distress syndrome, severe sepsis, and septic shock. pleural effusions are routinely drained and there are more options for antimicrobial therapy. antibiotics are still recommended for 60 days after exposure or diagnosis, together with the anthrax vaccine. if the vaccine is given concurrently with antibiotic treatment, the period of treatment could be shortened. antibiotics for treatment of other bacterial infection are usually given for shorter periods, since the causative agents do not sequester spores. tularaemia is treated with ciprofloxacin or doxycycline. 72 for smallpox, antivirals such as cidofovir or a related acyclic nucleoside phosphonate analogue appear to be more effective than post-exposure vaccines in preventing mortality, according to experiments in non-human primates infected with monkeypox virus. 73 this suggests that antivirals might play an important role when preparing for a smallpox outbreak. for viral haemorrhagic fevers, ribavirin might have some efficacy in post-exposure prophylaxis. a small-molecule antiviral drug, gs-5734, has been developed that appears to be effective in treating ebola virus infection. 74 for intentional and other sudden outbreaks of contagious disease, isolation of patients and controlling risks to health-care workers remains extremely challenging, as was noted in the mers coronavirus, sars, ebola virus disease, and avian influenza epidemics. 75 hospital units adequately equipped for isolation are needed, similar to those equipped to care for filovirus-infected patients, with negative pressure air filtration. 76 if facilities are too small for the number of patients, a lower level of isolation with strict barrier nursing should be implemented, and in the event of a very large outbreak, there might be a need to set up isolation facilities in public buildings. in regions with poor infrastructure, it might be necessary to consider treating patients in their homes. people who have died should be regarded as infectious and handled with the same precautions used for patients. burial procedures might have to be modified, but every effort should be made to respect religious practices and traditions of the local culture. quarantining of people who might have been exposed to the infectious agent can be problematic, 77 as was the case in the sars and west african ebola virus epidemics. 78 since the quarantined population includes both people who were exposed and people who were not, the risk of disease transmission is higher. during the ebola virus outbreak in west africa, suspect cases were held until they could be cleared as negative, which took about 3 days pending the pcr results. on a national level, reducing the movement of populations is a sensitive issue, potentially interfering with commerce. 79 closure of schools is an important means of achieving social distancing to reduce spread. whether the public should use masks during an outbreak of a contagious disease is less clear, 80 and the efficacy of the masks is extremely variable. the most important reasons for variable efficacy are differences in facial shape, incorrect application, and duration of use. a substantial proportion of the cases and fatalities in the sars and ebola virus epidemics were among healthcare workers. clear guidelines specific to each agent are available to health-care personnel, public health workers, and emergency workers for the use of masks and personal protective equipment. the national ebola virus training and education center has been established in the usa to train health-care workers and assist hospitals in preparing for patients infected with high hazard virus in the usa and other countries. laboratory workers must be trained to work with dangerous pathogens and wear protective gear. designated threat pathogens must be stored, handled, and transported under a different set the role of vaccines in pre-exposure and post-exposure prophylaxis measures should be in place to protect the population from biological agents likely to be used in an attack before an incident occurs. however, since a bioterrorist incident is likely to be caused by biological agents not covered by routine immunisation, pre-exposure prophylaxis is generally confined to vaccines for military forces, health-care workers, and emergency response personnel. to the majority of the population, only postexposure prophylaxis is relevant. post-exposure prophylaxis for an intentional outbreak would include both those people known to be exposed during the incident and those people who were infected by others. the prophylaxis itself might consist of both vaccines and antimicrobials. when using live, attenuated vaccines, the relatively large proportion of the population who has some form of immunodeficiency has to be taken into account. 81, 82 monoclonal antibody preparations are now being considered for prophylaxis in select, high risk groups. 83 table 2 summarises pharmacological prophylaxis for tier 1 pathogens. currently, the vaccines that would most likely be used for pre-exposure or post-exposure prophylaxis are the smallpox and anthrax vaccines. since routine vaccination against smallpox was stopped in the 1980s, less than 50% of the world's population has been vaccinated, and antibody titres usually decline markedly after 5 to 10 years. 84 residual cellbased immunity can persist for many years. 85, 86 postexposure prophylaxis involves ring vaccination, which requires intensive tracing and vaccination of primary contacts, followed by vaccination of secondary contacts, 86 and finally, vaccination of all people in a defined affected region. for post-exposure prophylaxis of those directly exposed during the incident, vaccination can be effective if given within 3 to 4 days of exposure. 87 since it might take that amount of time to detect the first cases after exposure, the vaccine will generally only be effective for secondary and subsequent contacts. immune-boosting adjuvants 88 and toll-like receptor agonists have the potential to improve the immune response to post-exposure vaccination. 89 serious side-effects are relatively rare 90,91 but can affect com pliance. 92 in those cases, lower doses of vaccine might be administered, to provide adequate protection with fewer side-effects. 93 newer smallpox vaccines are in development, 94 including those that could immunise people who have atopic dermatitis. 95 because it is produced in small quantities by collecting antiserum from immunised humans, there might be a shortage of vaccinia immune globulin, used to treat people who would have serious side-effects with the vaccine. one possible solution to this shortage would be to use antibodies against other poxviruses, such as cowpox and monkeypox, 96 because of their cross-protective properties. since naturally occurring inhalation anthrax is extremely rare, there have been safety and immunogenicity profiles of the anthrax vaccine in humans, 97 but the efficacy has only been tested in animal models, and not in clinical trials. [98] [99] [100] the current anthrax vaccine is made from culture filtrates of a toxigenic, avirulent, nonencapsulated mutant of the bacillus anthracis vollum strain, and is administered in five intramuscular doses, followed by annual boosters. the protective, antigen specific memory b cells persist for many years after vaccination and are associated with humoral immunity. 99 serum igg response to the vaccine has been 100% after the fourth dose. 101 for post-exposure prophylaxis in unvaccinated people, the vaccine should be administered as a three-dose subcutaneous series (at 0, 2, and 4 weeks), in conjunction with a 60-day course of appropriate antimicrobial drugs. it has been given to thousands of us military personnel, and notable adverse events have been rare. 102 the anthrax vaccine is not recommended for pregnant women, although one study 103 with women in the us military, inadvertently vaccinated during pregnancy, did not show evidence of an increase in birth defects. in this study, 4418 women received the vaccine in the first trimester and 423 in the second and third trimeseter. more effective anthrax vaccines that require fewer doses are constantly being tested, 104, 105 such as the neat protein anthrax vaccine, 106 a dual purpose influenza vaccine that protects against anthrax, 107 and a combined anthrax-plague vaccine. 108 apart from the 17d yellow fever live attenuated vaccine and the junin virus vaccine, no vaccines for haemorrhagic fevers have been licensed. since the west african ebola virus epidemic, new ebola virus vaccines that have been long under development are being used successfully in the 2018 epidemic in the democratic republic of the congo. 109 essentially no other licensed vaccines are available for other tier 1 select agents. the previously licensed, formalin-inactivated, whole-bacilli plague vaccine has not proven effective against primary pneumonic plague in non-human primate models, 110 series us military. the vaccine has not been used widely for preexposure prophylaxis and has no place in post-exposure prophylaxis. new vaccines against tularaemia are under development 113, 114 including one that might provide crossprotection between plague and tularaemia. 115 the investigational pentavalent (abcde) botulinum toxoid vaccine was provided by the cdc for laboratory workers at high risk of exposure to botulinum toxin and it has also been given to military members that are at risk. the botulinum toxoid vaccine produces effective immunity after several months and has no value for postexposure prophylaxis because of the short latent period of the toxins. this vaccine was discontinued in 2012, 116 because of declines in immunogenicity and adverse events. new recombinant botulism vaccines are being developed, in addition to vaccines against glanders and rift valley fever. [117] [118] [119] efforts are ongoing to greatly shorten the time required to develop and produce new vaccines and other immune approaches. improved technologies are important for rapid scale-up and production of new treatment regimens, particularly following an attack with a contagious agent. the largely unpredictable nature of an epidemic initiated intentionally is likely to increase uncertainty and reduce public trust in the authorities. public education and effective risk communication are essential to increase public confidence and improve cooperation and compliance with recommended medical counter-measures. 120 the anthrax vaccine in military populations has caused considerable scepticism regarding the need for, safety, and efficacy of the vaccine. [121] [122] [123] clinicians and public health personnel should have access to up-to-date information, and the general public should be provided with nontechnical information and simple instructions on how to act during an emergency. sandman 120 has proposed that "one should not over-reassure, ack nowledge uncertainty, and share dilemmas". this behaviour would only cause overreaction or panic when new information about the risk is made public. risk communication will be necessary at all stages: before a bioterrorist incident occurs, when an incident is suspected, when it is confirmed, while it is taking place, and in the aftermath. credible and trusted spokespersons, including respected clinicians, scientists, and public servants for a country, should be adequately informed before an incident. during an outbreak, there could be unexpected events, such as atypical presentation of cases, varying responses to treatment (including unusual side-effects), and false positive and false negative diagnoses. the public might lose trust in the authorities if apparently unexposed people become ill. the advent and global distribution of social networking increases the risk of the dissemination of false or misleading information. lastly, a major infectious disease incident will also require flexibility and possible changes of established government policy. environmental detection of biological agents is another area of research that should be developed. to date, most systems of environmental detection have focused on anthrax, as a result of the anthrax attacks. 124, 125 however, a sensitive and specific set of recombinase polymerase amplification assays for fast screening, detection, and identification of b anthracis in a field setting has recently been developed. 126 the rare occurrence and likely small effect of an aerosol bioterrorist attack limits the practical use of environmental detection to special event venues, public transportation systems, and possibly some government buildings thought to be likely targets. many countries have national stockpiles of drugs and vaccines, for use in the event of a biological or chemical attack, or for serious outbreaks that might achieve epidemic proportions. the usa, for instance, maintains a strategic national stockpile of vaccines and other medical countermeasures. global stores of smallpox vaccines are held by who, in addition to stores held by individual countries. some countries have undertaken active vaccination programmes against smallpox and anthrax in the military and first responder populations. preparedness for bioterrorist incidents requires constant re-evaluation of policies. 127 although there is no evidence that the 2009 h1n1 influenza pandemic or the 2014-16 ebola virus epidemic in west africa were initiated intentionally, the local and international responses revealed strengths and weaknesses in the current state of preparedness for bioterrorist incidents. 128 the ebola virus epidemic spread to a number of countries, with more than 20 000 cases reported worldwide and a case fatality rate of more than 60%. imported cases of ebola virus disease were identified in the usa and spain. locally, in the affected countries in west africa, 10% of the people who died because of ebola virus disease were health-care workers. various shortcomings in the response to the epidemic have been identified since (panel 1). accurately predicting the intentional misuse of a biological agent to cause harm is difficult without intelligence data, but several attempts have been made to rationally predict the categories of risk: man-made, natural, accidental, contagious, and non-contagious. 129 series risks. 132 the risk of bioterrorism has called into question some of the dogmas related to eradication of diseases such as poliomyelitis and measles. 133 for example, if polio is successfully eradicated, universal vaccination might have to continue because of the risk of poliovirus being used as a bioterrorist agent. [134] [135] [136] emerging and reemerging infectious diseases will continue to be a threat, 137 but preparedness for bioterrorism is, in many ways, similar to preparedness for naturally emerging disease. all countries should collaborate to address the root causes of terrorism, and develop appropriate preventive strategies. effective preparedness is, in itself, a deterrent to bioterrorism, since it reduces the incentive to use biological weapons by making a country or region a hard target. it is also the cornerstone of consistent and effective responses to naturally occurring epidemics. the abuse of biological agents can be further reduced or discouraged with reliable intelligence and an effective response if it does occur. national and regional resources and capabilities will vary, but all will require infrastructures that are capable of recognising and dealing with a variety of biological agents. 138 the needs of specific populations, such as the paediatric population, pregnant women, 139 elderly people, and people with immunological disorders, must also be addressed. 140 funding for biodefence is crucial to adequate preparation and response to bioterrorist threats. 141 international preparedness for bioterrorism has the dual benefit of strengthening the infrastructure for responding to naturally occurring epidemics of highly pathogenic organisms. lessons from the 2014 west african ebola virus epidemic show that health-care providers must always be watchful for unusual presentations of disease, and new and improved approaches must be developed for early detection and response. health-care providers need more effective means of isolating infected patients, and better methods to control the movement of potentially infected people outside of the affected areas. personal protective equipment should be inexpensive and effective, and available to use with minimal training and under harsh environments. protection of health-care workers against infection remains particularly prob lematic, and should be a focus of research and development. the ebola virus epidemic has highlighted the importance of improving the logistics of moving human and material resources in areas with relatively poor infrastructure. risk communication and public education before and during an outbreak need to be improved. more clinical trials should be fast-tracked during development of new vaccines and antiviral drugs. preparedness for a low-risk, high-impact event that is bioterrorism should be monitored constantly, tested in tabletop exercises, 142, 143 and integrated into the routine functioning of the health system. here it would serve the dual purpose of ensuring that countries are prepared to meet the challenges of controlling epidemics of emerging and re-emerging infectious diseases. msg designed the review, did the literature search and was responsible for writing the manuscript. jld assisted in the literature search, revised the manuscript, and supplied technical expertise. dc assisted in the literature search and revised the manuscript. drf helped design the review, contributed source material, did the literature search, and helped write and revise the manuscript. we declare no competing interests. we searched pubmed and google scholar using the terms "bioterrorism", "sustainable bioterrorism preparedness", "all-hazards infectious disease preparedness", "biological threat agents", "bioterrorism preparedness", "emerging infectious diseases", "smallpox", "anthrax", "plague", "tularemia", "botulism", "hemorrhagic fevers", and "risk communication". we searched national and international reports from the who and us centers for disease control using the terms "bioterrorism", "bioterrorism preparedness", and "emerging infectious diseases". we also completed web searches for "disease surveillance", "infectious disease diagnostics", "medical countermeasures", "emergency healthcare delivery", and "risk management". we focused on academic literature in english and restricted most of our searches to documents published since 1990, with an emphasis on those published after 2001, and included mainly those published since 2008. federal funding for health security in fy2016 a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars investigation of bioterrorism-related anthrax, united states, 2001: epidemiologic findings remediation of bacillus anthracis contamination in the u.s. department of justice mail facility total decontamination cost of the anthrax letter attacks bacillus anthracis incident post-traumatic stress disorder symptoms in victims of tokyo subway attack: a 5-year follow-up study biological warfare and bioterrorism: a historical review the threat of bioterrorism: identifying the unknown. ffi focus biodefense in the 21st century department of health and human services (hhs). possession, use, and transfer of select agents and toxins-addition of bacillus cereus biovar anthracis to the hhs list of select agents and toxins. interim final rule and request for comments destruction of microbial collections in response to select agent and toxin list regulations implementing the select agent legislation: perfect record or wrong metric? gaps remain in china's ability to detect emerging infectious diseases despite advances since the onset of sars and avian flu health system resource gaps and associated mortality from pandemic influenza across six asian territories ebola: lessons learned and future challenges for europe public health assessment of potential biological terrorism agents responsible conduct by life scientists in an age of terrorism mitigating the risks of synthetic biology. council on foreign relations characterization of the reconstructed 1918 spanish influenza pandemic virus chemical synthesis of poliovirus cdna: generation of infectious virus in the absence of natural template expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox labmade smallpox is possible, study shows the de novo synthesis of horsepox virus: implications for biosecurity and recommendations for preventing the reemergence of smallpox epidemiologic determinants for modeling pneumonic plague outbreaks risk assessment and risk communication strategies in bioterrorism preparedness. nato security through science series a: chemistry and biology estimating time and size of bioterror attack threat of a biological terrorist attack on the us food supply: the cdc perspective a large food-borne outbreak of group a streptoccocal pharyngitis in an industrial plant: potential for deliberate contamination german outbreak of escherichia coli o104:h4 associated with sprouts water and bioterrorism: preparing for the potential threat to u.s. water supplies and public health a proteomics assay to detect eight cbrn-relevant toxins in food index case of fatal inhalational anthrax due to bioterrorism in the united states rapid outbreak sequencing of ebola virus in sierra leone identifies transmission chains linked to sporadic cases real-time pcr to identify variola virus or other human pathogenic orthopox viruses pocket dna sequencers make real-time diagnostics a reality sensitive detection of francisella tularensis directly from whole blood by use of the genexpert system comparison of magpix assays and enzyme-linked immunosorbent assay for detection of hemorrhagic fever viruses the early humoral immune response to bacillus anthracis toxins in patients infected with cutaneous anthrax specific, sensitive, and quantitative enzyme-linked immunosorbent assay for human immunoglobulin g antibodies to anthrax toxin protective antigen rapid detection of bacillus anthracis bloodstream infections by use of a novel assay in the genexpert system rapid and sensitive point-of-care detection of orthopoxviruses by abicap immunofiltration rapid viral diagnosis of orthopoxviruses by electron microscopy: optional or a must? striking against bioterrorism with advanced proteomics and reference methods simultaneous immunodetection of anthrax, plague, and tularemia from blood cultures by use of multiplexed suspension arrays the changing face of pathogen discovery and surveillance public health surveillance and infectious disease detection evaluation of a syndromic surveillance system using the wsare algorithm for early detection of an unusual, localized summer outbreak of influenza b: implications for bioterrorism surveillance syndromic surveillance during pandemic (h1n1) 2009 outbreak internet-based surveillance systems for monitoring emerging infectious diseases digital surveillance for enhanced detection and response to outbreaks if syndromic surveillance is the answer, what is the question? clinical recognition and management of patients exposed to biological warfare agents public health. ethics and the conduct of public health surveillance digital disease 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vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation-a systematic review of randomized trials, observational studies and case reports biosecurity: assessing the bioweapons threat a plague on your city: observations from topoff shining light on "dark winter key: cord-309350-7qen8z3y authors: peruzzi, mariangela; biondi-zoccai, giuseppe; carnevale, roberto; cavarretta, elena; frati, giacomo; versaci, francesco title: vaping cardiovascular health risks: an updated umbrella review date: 2020-06-16 journal: curr emerg hosp med rep doi: 10.1007/s40138-020-00219-0 sha: doc_id: 309350 cord_uid: 7qen8z3y purpose of review: modified risk products (mrp) such as electronic vaping cigarettes (evc) and heat-not-burn cigarettes (hnbc) are alternatives to traditional combustion cigarettes (tcc) with an expanding consumer base. yet, their cardiovascular health risks are still unclear. we aimed to summarize the evidence base on this topic by conducting an updated umbrella review. recent findings: we identified 7 systematic reviews, totaling 183 studies and reports, ranging from in vitro and in animal studies to clinical studies in apparently healthy volunteers and patients at risk of cardiovascular disease. overall, acute evc use was associated with several toxic effects at molecular, cellular, tissue, organ, and system level. in addition, evc impacted adversely on blood pressure (bp) management, caused tachycardia, and worsened arterial stiffness. finally, evc use was associated with an increased risk of adverse clinical events, including atrial fibrillation and myocardial infarction, even if the causal link is still debated. most reviews highlighted that the detrimental impact of evc was of lesser magnitude of that of tcc. in addition, the differential impact of liquids and nicotine was not clearly disentangled. finally, no review included studies on hnbc. summary: the present umbrella review suggests that evc, and likely hnbc, despite clearly causing an increase in overall cardiovascular risk, may represent a temporary lesser evil than tcc in a risk-reduction or risk-modification strategy, aiming for eventual abstinence from all tobacco or nicotine products. smoking represents one of the leading causes of preventable morbidity and mortality worldwide, causing a plethora of adverse medical conditions, including coronary artery disease, stroke, chronic obstructive pulmonary disease, and cancer, and its detrimental effects impact also on passive smokers [1•, 2-5] . even in the current coronavirus-associated disease 2019 (covid-19) pandemic, smokers, especially the elderly, appear to have an increased risk of getting infected, progressing toward severely symptomatic disease, and dying due to severe acute respiratory syndrome-coronavirus-2 (sars-cov-2) infection [6] [7] [8] [9] . abstinence is easy to preach but harder to achieve, and several strategies have been proposed to ensure smokers can discontinue and abstain from their habit, ranging from telemedicine, nicotine replacement therapy, varenicline, and bupropion [10••] . most recently, novel forms of smoking have been developed, which differ from traditional combustion cigarettes (tcc) as smoking is not due to combustion but vaporization of nicotine-containing liquids, i.e., electronic vaping cigarettes (evc), or heating of tobacco products without combustion, this article is part of the topical collection on cardiovascular care i.e. heat-not-burn cigarettes (hnbc) [11] [12] . collectively, these alternative ways to smoke are called modified risk products (mrp) or, more optimistically, reduced risk products (rrp) [13, 14••, 15-17] . substantial evidence continues to accrue on mrp, including results of randomized controlled trials (rct), and several systematic reviews have already been published on this topic [18••] . however, the interplay between mrp, cardiovascular physiology, and cardiovascular disease is still uncertain, with conflicting results provided by different scholarly sources [19] . we thus aimed at conducting an updated umbrella review of systematic reviews on the cardiovascular effects, in terms of both pathophysiology and symptomatic disease, of evc and hnbc [20•] . in keeping with prior similar projects led by our group, this work was designed as an umbrella review (i.e., overview of systematic reviews) following established recommendations for evidence synthesis [20•,21-22] . specifically, we searched pubmed in order to find pertinent systematic reviews on the cardiovascular safety of mpr using the following string: [29•] . from a total of 133 publications, no specific cardiac event was reported, but chest pain was relatively common in such compiled series of cases (22%). hua and talbot screened several databases looking for case reports of adverse events associated with evc use, retrieving two cases (a case of acute myocardial infarction in a young man and a case of atrial fibrillation in an elderly woman) [24] . in both cases reported in this hypothesis-generating systematic review, nicotinecontaining evc had been used. farsalinos and polosa conducted a systematic review on several different generations of evc focusing on their comparison versus tcc and nicotine gums, the impact of nicotine, and the risk of active as well as passive smoking [18••] . in particular, they synthesized evidence from 97 different reports, including several chemical studies, toxicological studies, and clinical trials. they concluded that, despite evident safety issues, including the presence of many toxic agents with established multidimensional risk (e.g., acetaldehyde, acrolein, aluminum, amino-tandalafil, copper, diethylene glycol, formaldehyde, iron, lead, nickel, particulate matter, rimonambant, and silica), evc represent an appealing alternative to tcc in a rrp strategy. in terms of hazards, they highlighted the risk of tachycardia and hypertension, as well as impaired left anterior descending flow reserve, even if it remained unclear whether these effects depended mainly on nicotine. interestingly, this old review was promising but limited by incomplete reporting and lack of quantitative synthesis. garcia and colleagues performed a systematic review and meta-analysis on the effects of evc on blood pressure (bp), heart rate (hr), and heart rate variability (hrv), pooling data from 19 studies, and using largely explicit and valid methods [23] . they concluded that evc are associated with acute increases in systolic blood pressure (sbp), diastolic blood pressure (dbp), and hr, and changes in hrv typical of sympathetic prevalence over vagal activity, even if mostly explained by nicotine exposure. notably, chronic use of evc still had adverse effects on hrv, but effects on bp and hr were much more diluted, potentially suggesting time-dependent adaptation. kennedy and colleagues reviewed several experimental and clinical studies on the cardiovascular safety of evc, highlighting that they may cause oxidative stress, cardiomyocyte dysfunction and mutagenesis, vascular inflammation, endothelial dysfunction, vasospasm, complement deposition, platelet aggregation, adhesion, and activation, with hypertension, tachycardia, arterial stiffening, atherosclerosis and thrombotic risk, albeit less intensely than tcc [25] . most importantly, they suggested that studies with conflicts of interest were less likely to report adverse events. skotsimara and colleagues reviewed 26 studies, ranging from preclinical to clinical ones, and then performed a formal meta-analysis of 14 trials [28] . overall, they identified the following as main signs of detrimental effects of evc: cytotoxicity, oxidative stress, endothelial dysfunction, bp, hr, arterial stiffness, and myocardial infarction. notably, most of these effects were heterogeneous and quantitatively less intense than those associated with tcc. finally, riley et al. conducted a systematic review originally focused on the interplay between hormonal contraception, evc, and cardiovascular risk [19] . no study explicitly focused on hormonal contraception was retrieved, and thus they expanded their analysis to the pathophysiologic link between evc and cardiovascular outcomes. after including a total of 13 studies they concluded that evc significantly impact of bp and hr, and may be associated with an increased risk of myocardial infarction. our umbrella review, poignantly synthesizing the evidence accrued so far from in vitro, in animal, in human volunteers, healthy subjects, and patients on the cardiovascular risk associated with evc use, either acute or chronic, shows that data are expanding progressively, but several conclusions can already be made on the 31] . first, acute evc use is associated with several toxic effects at molecular (e.g., dna), cellular, tissue, organ, and system level [25, 32] . for instance, oxidative stress, cytotoxicity, and cardiomyocyte dysfunction are established effects of evc [33] . second, evc impact adversely on bp management, cause tachycardia, and worsen arterial stiffness [19, 34] . third, evc use has been associated with an increased risk of adverse clinical events, including atrial fibrillation and myocardial infarction, even if the causal link is still debated [24, 35] . yet, most reviews highlighted that the detrimental impact of evc was of lesser magnitude of that of tcc. in addition, the differential impact of liquids and nicotine was not clearly disentangled. overall, these findings confirm prior reports and support further research on the topic of cardiovascular safety of evc. several avenues for research are worth exploring. for instance, translational studies on the precise cellular mechanisms involved in evc toxicity are needed, exploring for instance microrna, inflammatory cascade, autophagy, apoptosis, and regeneration [36] [37] [38] . observational studies on large samples are needed to accurately gauge the short and long-term risks of evc in apparently healthy subjects and in patients with cardiovascular disease [39] . in addition, randomized trials, from small-sample speculative ones to large pragmatic studies, are direly needed to ensure that the place of evc in current clinical practice is correctly defined [40] . indeed, our premise is that evc should be considered as an over-the-counter medical intervention suitable to support chronic smokers in their journey to eventual cessation. accordingly, only a comprehensive evidence platform, hopefully summarized in a formal network meta-analysis, will be able to precisely define the place and role, if any, of evc in a comprehensive approach aiming at smoking cessation and harm minimization [41] . pragmatically, and based on our personal and professional experience, we may suggest a stepwise use of evc and hnbc with the eventual aim of total and continued abstinence (fig. 2 ). yet, practitioners should be aware of the potential interactions between mrp and pharmacologic therapy in patients with or at risk of cardiovascular disease, ranging from atherothrombosis to heart failure and valvular heart disease [42] [43] [44] [45] [46] , as indeed it is plausible that many of the adverse cardiovascular effects of mrp depend on nicotine, thus raising the evident risk of cumulative toxicity if nrt and mrp are inadvertently combined. this umbrella review has several drawbacks, on top of those typical of this research design [20•] . first, studies and reviews discussed hereby are mostly of small size and limited followup, and often focus on apparently healthy subjects. second, data on long-term pulmonary and cancer risk are absent, but this cannot be considered proof of absence of oncologic risk, as only longitudinal studies will be able to inform on this safety dimension. another elephant in the room is the lack of comprehensive data on hnbc, which are a mainstay in the mrp arena, and can be considered for some aspects as safe or safer than evc, and for others worse (e.g., because of small but measurable combustion) [47•] . accordingly, we expect that additional research synthesis efforts will be needed in the future, including updated umbrella reviews. the information accrued in this umbrella review, coherently showing multidimensional adverse effects of hnbc and evc, highlights the evident risk of adverse cardiovascular events associated with mrp. accordingly, further restrictions to their usage could be considered, including equating them to over-the-counter or even prescription drugs. indeed, the best perspective is considering hnbc and evc as another management strategy to promote smoking cessation and maintain abstinence (fig. 2) . moreover, their usage should be monitored, minimized in intensity and duration, aiming for clear timelines to switch from hnbc to evc and then stop them altogether if a hnbc-first approach is chosen, or instead having a goal of evc usage followed by cessation if an evc-first approach is adopted. an apparently banal but potentially useful framework could indeed be considering mrp as a novel and more palatable nrt, maintaining many of the rituals of tcc without the abundance of combustion byproducts. nonetheless, dedicated large-scale and pragmatic randomized trials are needed to test the above strategy before recommending it to individuals and patients at large. the present umbrella review suggests that evc, despite clearly causing an increase in overall cardiovascular risk, may represent a temporary lesser evil than tcc in a risk-reduction or risk-modification strategy, aiming for eventual abstinence from all tobacco or nicotine products. conflict of interest the authors declare that they have no conflict of interest. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of the authors. tobacco smoking, harm reduction, and nicotine product regulation 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and improves phenotype of cardiosphere-derived cells morphological and chemical study of pathological deposits in human aortic and mitral valve stenosis: a biomineralogical contribution heat not burn tobacco product-a new global trend: impact of heat-not-burn tobacco products on public health, a systematic review publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-317739-2wojtboi authors: abo, stéphanie m.c.; smith, robert title: modelling the daily risk of ebola in the presence and absence of a potential vaccine date: 2020-10-15 journal: infect dis model doi: 10.1016/j.idm.2020.10.003 sha: doc_id: 317739 cord_uid: 2wojtboi ebola virus — one of the deadliest viral diseases, with a mortality rate around 90% — damages the immune system and organs, with symptoms including episodic fever, chills, malaise and myalgia. the recombinant vesicular stomatitis virus-based candidate vaccine (rvsv-zebov) has demonstrated clinical efficacy against ebola in ring-vaccination clinical trials. in order to evaluate the potential effect of this candidate vaccine, we developed risk equations for the daily risk of ebola infection both currently and after vaccination. the risk equations account for the basic transmission probability of ebola and the lowered risk due to various protection protocols: vaccination, hazmat suits, reduced contact with the infected living and dead bodies. parameter space was sampled using latin hypercube sampling, a statistical method for generating a near-random sample of parameter values. we found that at a high transmission rate of ebola (i.e., if the transmission rate is greater than 90%), a large fraction of the population must be vaccinated ( 80%) to achieve a 50% decrease in the daily risk of infection. if a vaccine is introduced, it must have at least 50% efficacy, and almost everyone in the affected areas must receive it to effectively control outbreaks of ebola. these results indicate that a low-efficacy ebola vaccine runs the risk of having vaccinated people be overconfident in a weak vaccine and hence the possibility that the vaccine could make the situation worse, unless the population can be sufficiently educated about the necessity for high vaccine uptake. trary to vsv-based vaccine vectors, meaning that the antigen is not present on the surface of the vector but is expressed at high levels once the vector enters the target cells of the vaccinated individual [25] . the candidate cad3-zebov is a non-replicative vector-based ebola vaccine (i.e., genes essential for the life cycle of the vector virus are deleted to restrict the transcription and replication) that encodes the glycoprotein from the zaire ebolavirus [8] . the chimpanzee adenovirus type 3 (chad3) is used as a carrier to deliver benign genetic material of the zaire strain [16] . among the many studies on ebola virus, we note two recurring goals of most computational models: quantifying the effects of possible interventions on the incidence rate [37] and developing predictive models to estimate the total number of infected cases, the reproduction number, the number of deaths and the duration of outbreaks [1, 13] . some other studies focus on examining assumptions about how the disease spreads, such as uniform transmissibility vs. homogeneous mixing within a population [8] . there are also several studies with the common goal of understanding the impact of public-health initiatives on the dynamics of an outbreak and control of the virus [11, 22] . those studies often analyze the role of behavior change induced by health education or use consumer-centric models of public-health intelligence [9, 22] . other models of ebola have focused on interventions such as quarantine, distribution of household kits, emergency treatment care (etc) expansion and accelerating case tracking. lewnard et al. suggested that the existing etc capacity necessary to decrease the severity of the current outbreak was impractical [21] . legrand et al. provided a stochastic compartmental model incorporating transmission in the community, in the hospital and during burial ceremonies in order to suggest where interventions are best suited [19] . rivers et al. [31] investigated the efficiency of increased contact tracing, improved infection-control practices and a hypothetical pharmaceutical intervention to improve survival of hospitalised patients aimed at reducing the reproduction number of the ebola virus. chowell et al. [10] used an seir model to determine r 0 , the final size of the epidemic and performed a sensitivity analysis, showing that education and contact tracing with quarantine would reduce the epidemic by a factor of 2. fisman et al. [15] used a two-parameter model to determine the degree to which the epidemic was being controlled, finding only weak control in west africa as of the end of august 2014 and essentially no control in liberia. webb and browne [41] developed an age-structured model, tracking disease age through initial incubation, followed by an infectious phase with variable transmission infectiousness. browne et al. [7] showed that, if contact tracing was perfect, then the critical proportion of contacts that need to be traced could be derived. bartlett et al. [2] utilized a discrete-time model to represent the clinical progression of the ebola virus and estimate the number of infections and deaths in sierra leone. waife et al. [39] used sensitivity analysis to show that an ebola vaccine could be effective if contact rates with unvaccinated individuals could be sufficiently lowered. risk equations have been used to determine contributing morbidity and mortality factors for a variety of infections, such as heart disease [26] , kidney failure [38] , diabetes [35] and hiv [28] . per-day risk equations to assess the potential effect of treatment have been used for vaginal microbicides as a potential hiv prophylaxis [36] . although the use of such equations in infectious disease modelling is relatively new, this kind of risk assessment has become an accepted component of clinical guidelines and recommendations in cardiovascular medicine, for example [18] our aim in this paper is to determine the daily risk of ebola infection during an epidemic, both before and after a potential vaccination using daily risk equations. we address the following research questions: 1. could vaccination result in a net increase in risk? 2. can we determine conditions that optimize vaccine efficacy? 3. which is more important to maximise, vaccination efficacy or use? in order to evaluate the potential effect of vaccination, we develop risk equations for the daily risk of ebola infection both currently and after vaccination. when hazmat suits, reduced contact with the living or dead or vaccination is employed, the probability that ebola is transmitted is reduced from the probability β to β (where β < β). we have modelled single exposure events, and thus the transmission probability of each event is significantly less than the transmission probability over the duration of the outbreak. if β is the probability of transmission during a single exposure event with a given protection type (hazmat suit, reduced contact, vaccination, any combination thereof, or no protection), then the probability of remaining uninfected during a single exposure event is (1 − β ). the probability of remaining uninfected after n exposure events is thus (1 − β ) n . thus the probability of ebola infection for an individual is where p i is the proportion of times a given protection protocol is employed (including no protection). the risk equations account for the basic transmission probability of ebola (β), the lowered risk due to various protection protocols: hazmat suits (e h ), reduced contact with the infected living (e c i ), vaccination (e v ) and reduced contact with dead bodies (e c d ). we denote the use of no protection by 1 − β. our risk equations also include the proportions of use (individually or in combination) of these protection protocols. we denote these proportions by p i if applied before vaccination and q i if applied after. the proportion of use of all protection types sums to 1 in each case. since ebola is a pervasive disease with extreme transmission rates, we focus our analysis on the higher range of transmissibility; i.e., when the basic risk of transmission (β) is between 0.5 and 1. as the exact transmission rate of the virus is still unknown, we have modelled low (50-55%), moderate (70-75%) and high (90-95%) levels of transmissibility to analyze how the performance of different protection protocols can change across these levels of transmission. currently (when the only protection protocols are to reduce contact with the infected living and dead (e c i , e c d ), hazmat suits (e h ) and no protection (1 − β)), the daily risk of contamination for a susceptible individual is where p 0 , p 1 , p 2 , p 3 , p 4 , p 5 and p 6 are the proportions of use of protection protocols outlined in table 1 . post-vaccine (when the available protection protocols are vaccine (e v ), reduced contact with the infected living and dead (e c i , e c d ), hazmat suits (e h ) and no protection (1 − β)), the daily risk of contamination is where q 0 , q 1 , ..., q 13 are the proportions of use of protection protocols available after the vaccine is introduced. parameter values are given in table 1 . initially, we assumed a uniform use of all protection protocols available (including using no protection). there are eight possible combinations of protection protocols: p 0 through p 6 and the fraction of people using no protection ). as such, the upper bound of the range of values for each proportion is set to 0.125 (see table 1 ). by equating the current daily risk of contracting the disease, r 1 , and the daily risk after the introduction of the vaccine, r 2 , we obtain an analytical expression for the threshold level of vaccine efficacy and use that would be necessary to 5 j o u r n a l p r e -p r o o f induce a net decrease in the daily risk of infection: the risk ratio r * serves as a threshold indicating when the introduction of a vaccine can improve the situation. in particular, r * provides information on the levels of vaccine efficacy and use needed to reduce the daily risk of contamination. the benchmark value for r * is 1. at this value, the risk before the vaccine is identical to the risk after vaccination of catching ebola, which means that the introduction of a vaccine has no effect on the daily risk of infection. the vaccine will be favorable if r * > 1 and detrimental (i.e., increase the daily risk) if r * < 1. we evaluated the impact of potential vaccination using latin hypercube sampling (lhs) and partial rank correlation coefficients (prccs) to explore the sensitivity of the daily risk of infection to parameter variations. lhs is a statistical sampling method that generates a quasi-random sampling distribution. it allows for an efficient analysis of parameter variations across simultaneous uncertainty ranges in each parameter [4, 5] . prccs rank each parameter by the amount of effect on the outcome, regardless of whether that effect is positive or negative [4] . we performed an uncertainty analysis using monte carlo simulations and multivariate sensitivity analysis to analyze our risk equations. we computed the risk over a wide parameter space to assess the variability of our dependent variable (risk per day of catching ebola r 1 or r 2 ), using lhs to sample parameter space. finally, we evaluated the potential risk-reduction effect of vaccination depending on the fraction of vaccinated people. a candidate vaccine will be beneficial (i.e., decrease the daily risk of infection) if the risk of transmission after the introduction of the vaccine is lower than the current risk. to show which parameters the daily risk is most sensitive to, we used plots of prccs for each of the independent parameters. parameters with prcc > 0 increase a susceptible's daily risk as the parameter value increases, whereas parameters with prcc < 0 decrease a susceptible's daily risk as the parameter value increases. 6 j o u r n a l p r e -p r o o f figure 1 illustrates the degree of sensitivity of the daily risk of infection before the vaccine is introduced. at relatively low transmissibility levels, reducing contact with infected individuals (e c i ) is the most effective alternative to decrease the daily risk of infection. when the rate of transmission is moderate and there is no vaccine, wearing hazmat suits and reducing contact with the dead has a better protective impact. as the transmission rate rises, a higher proportion of use of those protection protocols becomes necessary. when the transmission probability is high and there is no vaccine available, all protection protocols are similar in terms of their efficacy, but none has a substantial effect on protecting against the virus. it is here that the introduction of a vaccine will benefit populations at risk the most. the remainder of our focus is on the case of high transmissibility when β ranges from 90% to 95%. we analysed the impact of a potential vaccine with efficacy that ranged from moderate to high (e v ranges from 0.35 to 1). figure 2 illustrates the effect of the transmission rate (β) on the post-vaccination daily risk of infection (r 2 ) when susceptibles use the vaccine as their sole protection protocol. the proportion of vaccine use q 7 ranges from 0 to 1 (see table 1 ). the red dots represent the current risk of infection, and the blue dots represent the risk after vaccination. as shown in figure 2 , introducing the vaccine could result in one of two outcomes: in some cases, the vaccine may reduce the risk of contamination, but in others, we run the risk of having more cases following the introduction of an ebola vaccine. as the outcome is uncertain, it is important to understand which variables play a role in effectively decreasing the risk of infection and what levels are needed for these parameters. figure 3 shows that a large fraction of the population must be vaccinated (> 80%) to achieve a 50% decrease in the daily risk of infection. figure 4 illustrates the ideal situation where everyone in an area at risk gets vaccinated. in this case, q 7 = 1. at any level of transmissibility, the daily risk of catching ebola is significantly less than without the vaccine. a strong vaccine (>50% efficacy) leads to a 50% decrease in the daily risk of ebola if everyone receives it. we can reasonably infer that, with an effective vaccination campaign and more awareness about how ebola is transmitted, we can reach a stage of disease control if the vaccine is not too weak. figure 5 illustrates three scenarios: currently (no vaccine), the vaccine being the sole protection protocol available (no protection is also an option) and with the vaccine being the only protection protocol used by everyone. without a vaccine, the daily risk of infection r 1 remains above 80%. in the second scenario, the candidate vaccine is introduced, and people who initially used a protection protocol now replace it with the vaccine, while those who have not used protection continue to do so. the median post-vaccine risk of infection r 2 is less than 80% in this case. however, the range of r 2 is wide (0% ≤ r 2 ≤ 97%), which implies a high volatility in the daily risk. in the third scenario, the ideal case of absolute vaccine uptake, the median per day-risk r 2 drops to 30%, ranging from 0 to 60%, a net decrease from the initial risk r 1 of 80% and a decrease in volatility. this indicates that a high rate of vaccine uptake would be required to continuously maintain the risk of infection below its current value. figure 6 shows prccs of the parameters that affect r * . for general vaccine uptake, the fraction of people who get vaccinated q 7 is the only variable that has a significant impact on r * (figure 6(a) ). when the vaccine uptake is high (0.7 ≤ q 7 ≤ 1), figure 6 (b) shows that the transmission probability β and vaccine efficacy e v affect r * significantly. figure 7 shows that there is a threshold whereby the fraction of people who use the vaccine (q 7 ) is guaranteed to increase the risk is if it sufficiently low (< 25%) but guaranteed to decrease the risk if it is sufficiently high (> 70%), regardless of the protective behavior or lack thereof. if a vaccine is introduced, it must have at least 50% efficacy, and at least 70% of people in the affected areas must receive it to start seeing an effective reduction in the risk of disease. to halve and control the risk of an ebola outbreak, at least 80% of people need to be vaccinated with a vaccine that is at least 50% effective. vaccine uptake has a stronger impact on disease control than vaccine efficacy. finally, we examined some possibilities for parameter ranges beyond the ranges given in table 1 . in particular, we constrained the eight pre-vaccination proportions as 0 ≤ p j ≤ 0.125 in order to consider all protection protocols equally. however, in order to stress test this, we examined three potential scenarios: (a) in the absence of hazmat suits, (b) if contact with the living was unchanged and (c) if contact with the dead was unchanged. these possibilities may arise if hazmat suits are not available, if people fail to follow social distancing or if funeral practices are unchanged. note that the absence of a protection protocol also implies its absence in any combination protocol. thus, for (a), we not only have p 2 = 0 but also p 4 = p 5 = p 6 = 0, but we increased the range of the remaining protection protocols to 0 ≤ p 0 , p 1 , p 3 ≤ 0.333. the results are illustrated in figure 8 . in the absence of hazmat suits, the most significant protocol is p 3 , the fraction of people reducing contact with the infected living and dead bodies. the next most significant parameters are e c i and e c d , the effectiveness of contact reductions with the living and the dead, respectively. that is, in the absence of hazmat suits, the combination of remaining protection protocols becomes crucial. likewise, if contact with the living is unchanged, then the most significant parameter is p 4 , the fraction of people who use hazmat suits and reduce contact with the dead, followed by the efficacies of these two protection protocols. finally, if contact with the dead is unchanged, then p 5 , the fraction of people who use hazmat suits and reduce contact with the living, becomes the most significant parameter, followed by the efficacies of these two protection protocols. according to our results, the parameters with the greatest effect on the ebola epidemic are the transmission probability (β), the fraction of people using the vaccine (q 7 ), vaccine efficacy (e v ), reducing contact with dead bodies (e c d ) and wearing hazmat suits (e h ). the increased risk due to dead bodies is likely due to the fact that infectious dead bodies remain infectious for up to a week after death 8 j o u r n a l p r e -p r o o f [30] . safe burial methods enforced by the us centers for disease control (cdc) have proven useful in reducing case incidence rates and hence transmissibility [27] . the transmission probability is the most influential parameter in our risk equations. our results indicate that any efforts to reduce this transmission, such as a vaccine, would have a significant effect on reducing the overall epidemic if populations can be sufficiently educated about the necessity for high vaccine uptake. in the absence of a vaccine, we also showed that if one of the protection protocols is not followed, then the combination of the remaining protection protocols becomes crucial. several interventions have already been used to reduce the spread of ebola including extensive awareness campaigns meant to educate susceptible individuals on transmission, symptoms and health risks of the disease. quarantine of individuals found through aggressive contact tracing and isolation of infected individuals while they are treated have also been effective methods to reduce the daily risk of infection [3] . the cdc has employed safe burial teams, which are tasked with safely burying corpses [27] . this results in less contact between susceptible individuals and infected dead bodies. there have been recent trials for an ebola vaccine, some of which have been promising [11] . an excellent vaccine would reduce the case incidence rate; however, a reasonably good vaccine that can be administered to most people would likely lower the transmissibility and help to control disease spread. our model has several limitations, which should be acknowledged. initially, before a vaccine is introduced, we assumed a uniform use of all protection protocols available, including using no protection, which may not hold as populations become more aware of the disease and adjust their protective behaviours. we assumed the same transmission probability for the living and dead, which may not be true. after the recent outbreak in west africa, efforts to develop an effective vaccine against the ebola virus disease have increased. we have shown that a vaccine can control the epidemic, even when transmission rates are high (above 90%). we found that at a high transmission rate of ebola, a large fraction of the population must be vaccinated (> 80%) to achieve a 50% decrease in the daily risk of infection. if a vaccine is introduced, it must have at least 50% efficacy, and almost everyone in the affected areas must receive it to effectively control outbreaks of ebola. these results indicate that a low-efficacy ebola vaccine runs the risk of having vaccinated people be overconfident in a weak vaccine and hence the possibility of the vaccine making the situation worse, unless the population can be sufficiently educated about the necessity for high vaccination rates. the question of how effective and widely distributed a vaccine needs to be to have a beneficial impact on public health extends far beyond the application to ebola. given the economic costs and personal inconvenience of the mitigation strategies in use for covid-19, for example, many of the existing strategies may end once a vaccine becomes available. hence, more modelling along these lines will provide further insights to other infectious diseases. j o u r n a l p r e -p r o o f table 1 : parameter values before and after vaccine introduction. we assumed a uniform use of all available protection protocols (including no protection) before the vaccine. thus, there are eight possible combinations of protection protocols: p 0 through p 6 and no protection (1 − p 1 − p 2 − p 3 − p 4 − p 5 − p 6 ). the upper bound of the range of values for each proportion is equal to 0.125. after the introduction of a vaccine, we considered the extreme case where vaccination was the only available protection protocol (0 < q 7 < 1) and that the vaccine was at least 35% effective. fraction of people using hazmat suits 0-0.125 p 3 fraction of people reducing contact with the infected living and dead bodies 0-0.125 p 4 fraction of people using hazmat suits and reducing contact with dead bodies 0-0.125 p 5 fraction of people using hazmat suits and reducing contact with the infected living 0-0.125 p 6 fraction of people using hazmat suits and reducing contact with the infected living and dead bodies 0-0.125 q 0 fraction of people reducing contact with dead bodies 0 q 1 fraction of people reducing contact with the infected living 0 q 2 fraction of people using hazmat suits 0 q 3 fraction of people reducing contact with the infected living and dead bodies 0 q 4 fraction of people using hazmat suits and reducing contact with dead bodies 0 q 5 fraction of people using hazmat suits and reducing contact with the infected living 0 q 6 fraction of people using hazmat suits and reducing contact with the infected living and dead bodies 0 q 7 fraction of people using the vaccine 0-1 q 8 fraction of people using the vaccine and reducing contact with the infected living 0 q 9 fraction of people using the vaccine and wearing hazmat suits q 10 fraction of people using the vaccine and reducing contact with dead bodies 0 q 11 fraction of people using the vaccine, wearing hazmat suits and reducing contact with dead bodies 0 q 12 fraction of people using the vaccine, wearing hazmat suits and reducing contact with the infected living 0 q 13 fraction of people using the vaccine and reducing contact with dead bodies and the infected living 0 figure 1 : prccs before vaccine introduction for low (50-55%), moderate (70-75%) and high (90-95%) levels of transmissibility. the outcome variable is the daily risk of infection before vaccination, r 1 . figure 2 : sensitivity of the daily risk of ebola to transmission rates when the only protection protocol available is the vaccine. the red dots represent the current daily risk of infection while the blue dots represent the post-vaccine daily risk of contamination. the proportional vaccine uptake q 7 ranges from 0 to 1 and the transmission rate β is between 0.9 and 0.95. figure 3 : sensitivity of the daily risk of ebola to the effectiveness of the vaccine e v , its proportion of use q 7 and the fraction of people not using any protection. the proportional vaccine uptake q 7 varies from 0 to 1, and vaccination is the only available protection protocol. the transmission rate β is between 0.9 and 0.95. figure 4 : sensitivity of the daily risk of ebola to transmission rates and vaccine efficacy when all susceptible individuals get vaccinated. the red dots represent the current risk of infection while the blue dots represent the post-vaccine risk of ebola. this is an ideal case, and the proportion of use of the vaccine q 7 is set to 1. the transmission rate β is between 0.9 and 0.95. figure 5 : boxplots of 1000 sampled values using the lhs ranges from table 1 . the horizontal red line indicates the median value. we present the daily risk of ebola under three scenarios: before the vaccine, imperfect vaccine uptake (0 < q 7 < 1) and perfect vaccine use (q 7 = 1). figure 6 : prccs for parameters that affect r * . (a) the case for general vaccine uptake (0 < q 7 < 1). (b) the case for high vaccine uptake (0.7 < q 7 < 1).the transmission rate β is between 0.5 and 1 figure 7 : sensitivity of the threshold level r * to (a) the fraction of people using the vaccine q 7 and (b) the fraction of people not using any protection. the transmission rate β is between 0.5 and 1. inset: the range q 7 > 70% that guarantees risk reduction. figure 8 : prccs for some possibilities outside the ranges in table 1 : (a) the absence of hazmat suits, (b) when contact with the living infected is unchanged and (c) when contact with dead bodies is unchanged. in each case, the most significant influence on the outcome is the combination of the remaining protection protocols, followed by the efficacies of those remaining protection protocols. estimating the reproduction number of ebola virus (ebov) during the 2014 outbreak in west africa mathematical modeling of the assessment of the risk of ebola virus transmission from bodily fluids and fomites sensitivity and uncertainty analysis of complex models of disease transmission: an hiv model, as an example predicting the unpredictable: transmission of drug-resistant hiv a tale of two futures: hiv and antiretroviral therapy in san francisco modeling contact tracing in outbreaks with application to ebola testing modeling assumptions in the west africa ebola outbreak public health intelligence: learning from the ebola crisis the basic reproductive number of ebola and the effects of public health measures: the cases of congo and uganda transmission dynamics and control of ebola virus disease (evd): a review the ebola outbreak, 2013-2016: old lessons for new epidemics modeling the spread of ebola. osong public health and research perspectives ebola haemorrhagic fever. the lancet early epidemic dynamics of the west african 2014 ebola outbreak: estimates derived with a simple two-parameter model efficacy and effectiveness of an rvsv-vectored vaccine in preventing ebola virus disease: final results from the guinea ring vaccination, open-label, cluster-randomised trial an overview of ebola virus disease global cardiovascular risk in patients with hiv infection: concordance and differences in estimates according to three risk equations (framingham, score, and procam) understanding the dynamics of ebola epidemics ebola and marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for africa dynamics and control of ebola virus transmission in montserrado, liberia: a mathematical modelling analysis modeling the role of public health education in ebola virus disease outbreaks in sudan vesicular stomatitis virus-based ebola vaccines with improved cross-protective efficacy vesicular stomatitis virus-based vaccines for prophylaxis and treatment of filovirus infections immunomonitoring of human responses to the rvsv-zebov ebola vaccine. current opinion in virology validation of the atherosclerotic cardiovascular disease pooled cohort risk equations improving burial practices and cemetery management during an ebola virus disease epidemic -sierra leone increased risk of cardiovascular disease (cvd) with age in hiv?positive men: a comparison of the d: a: d cvd risk equation and general population cvd risk equations the survival of filoviruses in liquids, on solid substrates and in a dynamic aerosol postmortem stability of ebola virus modeling the impact of interventions on an epidemic of ebola in sierra leone and liberia wild animal mortality monitoring and human ebola outbreaks, gabon and republic of congo ebola virus: promising vaccine candidates ebola vaccine: how far are we? performance of the uk prospective diabetes study risk engine and the framingham risk equations in estimating cardiovascular disease in the epic-norfolk cohort evaluating the potential impact of vaginal microbicides in reducing the risk of hiv acquisition in female sex workers computational modelling and optimal control of ebola virus disease with non-linear incidence rate multinational assessment of accuracy of equations for predicting risk of kidney failure: a meta-analysis using sensitivity analysis to examine the effects of an ebola vaccine ebola vaccines in clinical trial: the promising candidates a model of the ebola epidemics in west africa incorporating age of infection single-vector, single-injection recombinant vesicular stomatitis virus vaccines against high-containment viruses report of an international commission ebola virus disease in nonendemic countries acknowledgements rs? is supported by an nserc discovery grant. for citation purposes, please note that the question mark in "smith?" is part of his name. key: cord-314500-89ovdnxl authors: dunachie, susanna; chamnan, parinya title: the double burden of diabetes and global infection in low and middle-income countries date: 2018-12-04 journal: trans r soc trop med hyg doi: 10.1093/trstmh/try124 sha: doc_id: 314500 cord_uid: 89ovdnxl four out of five people in the world with diabetes now live in lowand middle-income countries (lmic), and the incidence of diabetes is accelerating in poorer communities. diabetes increases susceptibility to infection and worsens outcomes for some of the world’s major infectious diseases such as tuberculosis, melioidosis and dengue, but the relationship between diabetes and many neglected tropical diseases is yet to be accurately characterised. there is some evidence that chronic viral infections such as hepatitis b and hiv may predispose to the development of type 2 diabetes by chronic inflammatory and immunometabolic mechanisms. helminth infections such as schistosomiasis may be protective against the development of diabetes, and this finding opens up new territory for discovery of novel therapeutics for the prevention and treatment of diabetes. a greater understanding of the impact of diabetes on risks and outcomes for infections causing significant diseases in lmic is essential in order to develop vaccines and therapies for the growing number of people with diabetes at risk of infection, and to prioritise research agendas, public health interventions and policy. this review seeks to give an overview of the current international diabetes burden, the evidence for interactions between diabetes and infection, immune mechanisms for the interaction, and potential interventions to tackle the dual burden of diabetes and infection. there are now 336 million people with diabetes living in low-and middle-income countries (lmic). 1, 2 diabetes increases susceptibility to infection and worsens outcomes for diseases such as tuberculosis (tb), 3 and the under-recognised tropical disease melioidosis. 4, 5 current international treatment guidelines for diabetes are based on research conducted in high-income countries focussed on preventing adverse cardiovascular outcomes and early death. there is a lack of evidence upon which to base guidelines for people living in lmic, where there is an increased burden of infectious diseases compared with high income countries. diabetes has traditionally been viewed as a 'disease of the wealthy', mostly found among elderly people in developed countries. now, however, diabetes affects every strata of society, and has become a fast-growing problem in poorer communities. the global burden of disease (gbd) study estimated there were 1.4 million deaths worldwide from diabetes in 2016, 6 representing a 31% increase from 2006. of the estimated 425 million people with diabetes worldwide, four-fifths currently live in lmic and increasing numbers of children and young adults have been diagnosed with the disease. 1 this number is projected to increase to 629 million by 2045, and most of the rising burden will occur in lmic ( figure 1 ). in addition, diabetes is more likely to be undiagnosed or poorly treated in lmic. 1 data from the ncd risk factor collaboration 2 show that agestandardised diabetes prevalence in adults has increased or remained unchanged since 1980 in every country. 2 importantly, the burden of diabetes has increased faster in lmic than in high-income countries. 2 this rising prevalence of diabetes in lmic is believed to be associated with many factors, including ageing populations, urbanisation, cultural and social changes, dietary changes, physical inactivity, changes in diagnostic criteria and screening practices, better treatment and survival, and increasing trends in overweight and obesity. classification of diabetes table 1 shows the current classification of diabetes by who and the american diabetes association (ada), 7, 8 which includes four clinical and aetiological classes: type 1 diabetes (t1dm), type 2 diabetes (t2dm), gestational diabetes mellitus, and other specific types of diabetes due to other causes. t1dm is caused by an autoimmune reaction which destroys the insulin-producing beta cells in the islets of the pancreas, leading to no or low production of insulin. t2dm is the most common type of diabetes, accounting for approximately 90% of all cases of diabetes worldwide. 1 it is characterised by an inadequate production of insulin and an inability of the body to respond fully to insulin, defined as insulin resistance. it is important to note that assigning a type of diabetes to an individual is often reliant on the circumstances present and additional testing at the time of diagnosis, and that many patients with diabetes do not easily fit into a single class. in lmic, it is often unknown which type of diabetes a person has, and therefore this review will use the general term 'diabetes', but >90% of patients with diabetes in lmic are believed to have t2dm. 1 table 2 summarises the modifiable and non-modifiable risk factors for t2dm, which is a disease caused by a complex interplay between genetic and environmental factors. 9 the rapid increase in the prevalence of diabetes over recent decades suggests that environmental and lifestyle factors might play an increasingly important role in the development of the disease. it is generally recognised that people with diabetes are at increased risk of infection and worse outcomes, 10, 11 including diabetic foot infection, urinary tract infections (especially from tuberculosis (tb) is a leading cause of disease and death worldwide, with an estimated 9 million cases of tb and 1.2 million deaths in 2017. 6 diabetes is associated with a threefold increased risk of developing tb, 3 and increased risk of death or treatment failure in tb. 12 the gbd group reported diabetes accounting for 10.6% of the tb mortality in hiv-negative people. 13 in 2017, 790 000 cases of tb were attributable to diabetes, 14 and the absolute numbers of people with tb-diabetes co-morbidity is now similar to people with tb-hiv co-infection. more than half of the world's tb cases occur in five countries, 15 which have significant prevalence rates and total numbers of diabetes cases in adults aged 20-79 years as follows: china (10.9%, 114 million), india (8.8%, 73 million), indonesia (6.2%, 10 million), philippines (6.2%, 3.7 million) and pakistan (6.9%, 7.5 million). 1 there is evidence that the presence of clinical tb disease drives stress hyperglycaemia, impacting on clinical outcomes and response to treatment. 16 as rates of diabetes continue to rise, and the tb epidemic continues, there is a pressing need for bidirectional screening in countries facing the double burden of tb and diabetes. work in india has shown success at screening newly diagnosed tb cases for diabetes, 17 due to the availability of a simple screening blood test (hba1c) and the use of existing systems established to screen tb cases for hiv. screening people with diabetes for tb is more difficult due to the reliance on symptom questionnaires followed by chest xray. a blood test to diagnose tb in this setting is highly desirable, but current interferon gamma release assays (igras) do not have sufficient sensitivity and specificity for this purpose. diabetes is also associated with higher rates of mycobacterium leprae. 18, 19 the greatest increased risk for infection in people with diabetes is seen for the grossly under-recognised tropical disease melioidosis, which is caused by the gram-negative bacterium burkholderia pseudomallei. people with diabetes have a twelvefold increased risk of melioidosis, and over half of all cases of melioidosis have diabetes. 20 b. pseudomallei is an environmental saprophyte with a predilection for rice paddy fields, and melioidosis is typically seen in adults in middle age and above, often in rice-farming communities. a broad range of clinical presentations are seen, including pneumonia, acute sepsis with bacteraemia, abscess formation in any organ site, chronic subacute disease and latency. 21, 22 transmission of the bacterium to humans occurs via three routes: inhalational, cutaneous via skin abrasions and ingestion of contaminated drinking water. 23 the disease is commonly diagnosed in southeast asia and northern australia, but is now known to be present in 45 countries across tropical regions, with an estimated annual 165 000 cases and 89 000 deaths. 24 if rates of diabetes continue to rise as predicted, coupled with an increased reliance on older people for rice farming due to exodus of the younger generation to urban areas, then the burden of melioidosis will also rise. studies in high-income countries have shown that people with diabetes have high rates of infection from many common bacteria, 25 but some bacterial species are more frequently reported in association with diabetes. diabetes is an established risk factor for invasive infection with staphylococcus aureus. 26 s. aureus is the commonest cause of tropical pyomyositis, an infection of skeletal muscle featuring intramuscular abscesses that is commonly seen in tropical regions and can account for 1-4% of acute admissions. 27 pyomyositis occurs less frequently in temperate zones, where diabetes is a known risk factor. 28, 29 while diabetes has been reported in some case reports of tropical pyomyositis, 30 further research is needed to establish the box 1. relationship between diabetes and susceptibility/increased disease severity for significant pathogens in low-and middle-income countries. see text for discussion of evidence. 31 diabetes was associated with around a threefold increased risk of infection with s. enteritidis following exposure in a us hospital outbreak. 32 people with diabetes have an increased risk of klebsiella infections, 33 especially klebsiella liver abscess in asia. 34, 35 scrub typhus is a febrile illness caused by the rickettsial group intracellular pathogen orientia tsutsugamushi. around a million cases a year occur in asia, 36 and it is believed to exist in other tropical regions outside asia. 37 diabetes was an independent risk factor for more severe disease in a prospective study of eschar-positive scrub typhus. 38 it remains to be established why diabetes confers much greater susceptibility to, and worse outcomes for some bacteria than to others. several of the bacteria most closely associated with diabetes, such as m. tuberculosis and b. pseudomallei, are predominantly intracellular bacteria. impairments in phagocyte function and adaptive t cell immunity in diabetes may contribute to increased susceptibility to intracellular pathogens. diabetes is associated with antimicrobial resistance (amr). diabetes status is associated with increased rates of drug resistance in tb, including multidrug-resistant tb. 39, 40 besides tb, people with diabetes are over-represented in cohorts with multi-drugresistant infections, 41 but there is a lack of evidence at present of higher rates of amr in bacterial isolates from people with diabetes compared with isolates from non-diabetics. what is clear is that increasing rates of amr will have a larger impact on people with diabetes, due to their higher risk of infection and increased need for healthcare exposure and interventions. dengue causes an estimated 101 million clinical cases per year and 37 800 deaths. 6 an association between diabetes and severe presentations of dengue is now broadly accepted. 42 however, studies are typically retrospective, often small in nature, and use varying definitions of severe dengue. in a metaanalysis of five case-control studies of acute dengue, diabetes was associated with an increased risk of a severe clinical presentation of dengue compared with either asymptomatic infection or non-severe acute dengue, 43 although given the limited data, the authors emphasised this was only suggestive of a link. this finding has been supported by further studies in malaysia 44 and china. 45 a systematic review 46 to evaluate the contribution of non-communicable diseases (ncds) to the development of severe dengue identified 16 relevant publications and gives a clear overview of this literature, but given the heterogeneity of the studies the authors concluded that the existing literature was inadequate for meaningful estimation of the impact of diabetes and other ncds on dengue severity. the following year a canadian group 47 reported a nearly three-fold higher prevalence of diabetes in 3236 patients in 22 studies with severe dengue than the prevalence of diabetes in 9067 subjects in 13 studies with non-severe dengue. the same analysis found hypertension, heart disease and obesity (conditions interrelated with diabetes) to be significantly more prevalent in severe dengue, and also reported a four-fold increased prevalence of diabetes in severe west nile fever cases by the same methodology, supporting an earlier study 48 . the authors acknowledge the multiple limitations of this approach, including the heterogeneity of the studies and publication bias for studies included. there is clearly a need for further high-quality epidemiological studies to further define the association. there is some evidence that diabetes is associated with more severe disease in chikungunya disease, 49 but there is a current lack of data for analysing the relationship with zika virus. other viral infections may be associated with diabetes. people with diabetes are an at-risk group for clinical illness, disease severity and death from influenza, 50 with a meta-analysis of 234 articles 51 showing diabetes to be a risk factor for death from pandemic influenza (predominantly h1n1), although there was a lack of high-quality cohort studies to demonstrate this in seasonal influenza. it is estimated that 260 million people are chronic carriers of the hepatitis b virus (hbv), 52 and hbv has recently been described as a neglected tropical disease. 53 a number of studies have shown a higher prevalence of hbv in people with diabetes, [54] [55] [56] and people with chronic hbv are reported to have an increased risk of developing diabetes, 57 although this has not been demonstrated to date in sub-saharan africa. 58, 59 in addition, diabetes is associated with disease progression of hbv, 60-62 which has also been reported for hepatitis c. 63 varicella zoster virus (vzv) causes chickenpox as a primary infection which can reactivate as herpes-zoster (shingles), especially in older people. diabetes is an established risk factor for shingles. 64, 65 diabetes is considered a risk factor for middle east respiratory syndrome (mers). a recent systematic review 66 identified 58 published works for analysis, with several reporting diabetes as a risk factor for infection and death, but meta-analysis to quantitate the increased risk of diabetes across the studies was not possible due to the small number of studies addressing this risk factor. people living with hiv (plhiv) who receive combined antiretroviral therapy (art) now have excellent long-term survival, but increased rates of metabolic disorders such as impaired glucose tolerance, hyperlipidaemia and body morphological changes (lipodystrophy syndrome) have been reported. 67 increased rates of insulin resistance in plhiv could occur due to the proinflammatory effects of chronic viral infection, direct effects of art, and also indirect effects of art such as dyslipidaemia and body fat distribution changes. although studies in high-income western countries have shown inconsistent results as to whether hiv infection increases the risk of t2dm or merely represents earlier diagnosis in a closely monitored population, 68 there is evidence that hiv increases the risk of diabetes in asian and african populations. a study in taiwan suggested plhiv to be as much as sixfold more likely to develop diabetes than the rest of the population, 69 and a recent thai study of plhiv showed diabetes developed at a younger age compared with the general population. 70 increased rates of diabetes have also been reported in plhiv in south africa, 71 tanzania 72 and ethiopia. 71 older art drugs such as stavudine and zidovudine are known to increase the risk of metabolic syndrome and diabetes, and are used less now, so future studies may not confirm this relationship. parasitic malaria remains one of the world's largest causes of mortality from infectious diseases, with an estimated 213 million cases and 720 000 deaths per annum. 6 in 2010, researchers reported a 46% increased risk of malaria in people with diabetes 73 in a case-control study in an urban setting in ghana. the malaria was predominantly p. falciparum, asymptomatic and diagnosed by pcr. the comparison of probability of malaria infection was made between patients with diabetes (n=675) and a control group (n=791) comprising patients attending hypertension clinics, patients attending other hospital clinics, and hospital staff. the groups were not matched in that the diabetes group were older by a mean of 7.6 years and had a socio-economic profile associated with greater poverty, and the adjusted odds ratio for diabetes as a risk factor for p. falciparum infection was just outside significance in a multivariate analysis adjusting for these parameters (adjusted or 1.36, 95% ci 0. 98-1.90 ). this report is very interesting, but there have been no further published clinical studies addressing the relationship between diabetes and malaria. if diabetes increases the risk of malaria this would be of huge significance on a global scale. as india is a country with a high burden of both diabetes and p. vivax malaria, 74 one might expect evidence of a relationship between diabetes and vivax malaria to emerge from research in this region. further prospective studies with well-matched cohorts, and research into the effect on outcomes for people with malaria is needed. diabetes has been linked to increased risk of cutaneous 75,76 and visceral leishmaniasis, 77 and diabetes and hyperglycaemia were more frequently reported in cardiomyopathy caused by trypanosoma cruzi (chagas disease) than in controls. 78 there are a lack of data on the relationship between diabetes and most neglected tropical diseases (reviewed 79 ) and prospective studies of people with diabetes in tropical regions are needed to evaluate this. some interesting findings have been reported for a lower risk of diabetes following helminth infections including schistosomiasis, strongyloides and filariasis, as reviewed by berbudi and colleagues. 80 the mechanism for such a protective effect could be by helminth infection inducing a shift towards type 2 (anti-inflammatory) immune responses, and reducing chronic low-grade inflammation. a mouse model 81 demonstrated greater insulin sensitivity following s. mansoni infection in mice fed a high-fat diet, with an increase in type 2 cytokines and the ratio of m2 to m1 macrophages in white adipose tissue. further research is evaluating whether helminth-derived molecules could be developed as novel therapeutic approaches to diabetes and metabolic syndrome. 82 in addition, a prospective randomised-control trial of helminth eradiation by albendazole therapy in indonesia 83 is underway evaluating the impact of helminth infections on insulin resistance. the mechanisms by which diabetes confers altered susceptibility to infections are likely to be via multiple effects on the human immune system. people with diabetes have altered skin flora, including increased colonisation with s. aureus. 84 breaches in the skin's integrity as a physical barrier to infection occur more commonly in diabetes due to the impact of chronic hyperglycaemia on peripheral nerves and vascular supply. diabetes and its treatment has an impact on the composition of the gut microbiome, 85 and the pivotal role of the gut microbiome in modulating human innate and adaptive responses via pathogen recognition receptor pathways and secretion of immunomodulatory molecules by gut bacteria is now emerging. 86 in vitro, mild hyperglycaemia may favour pathogen growth, and while the contribution of this to human susceptibility to infection is unknown, glycosuria favours urinary tract infections. in addition, hyperglycaemia has a number of immunosuppressive effects, including impairment of neutrophil degranulation, complement activation and phagocytosis. 50 hyperglycaemia does not, however, appear to be a key mechanism for the increased susceptibility to tb. 87 diabetes is associated with endothelial dysfunction, oxidative stress and chronic inflammation. 88 in infections like dengue, this may support a shift towards an excessive pro-inflammatory response, leading to the cytokine storm, shock, vasculopathy and coagulopathy that feature in severe dengue. 47 finally, people with diabetes have higher rates of hospital admissions, 1 which exposes them to hospital-acquired infections and the risk of amr. there is overlap between the spectrum of pathogens that people with diabetes have, notably increased susceptibility to such as s. aureus and invasive fungi, and the infections seen in chronic granulomatous disease (cgd), 89 which is congenital deficiency in phagocytic function. this suggests impairment of neutrophil and macrophage function in people with diabetes as a key mechanism of susceptibility. this is supported by studies showing impaired neutrophil migration, phagocytosis and intracellular killing in the host response to b. pseudomallei in people with diabetes. 90 however, people with cgd are not known to have increased susceptibility to viral infections, and therefore this impairment of phagocyte function is unlikely to be the only cause of increased susceptibility to infection in diabetes. the literature on humeral responses to infection in people with diabetes does not suggest that poor antibody response is a dominant mechanism for the increased susceptibility to infection seen in diabetes. most studies support adequate induction of antibodies in response to licenced antibody-inducing vaccines in people with diabetes [91] [92] [93] . higher antibody responses to influenza vaccine were seen in a us study of elderly people with diabetes compared with elderly non-diabetic people, 94 and antibodies induced by natural exposure to melioidosis were higher in those with diabetes. 95 such higher responses in diabetes could be due to chronic hyperactivation of the innate immune response in t2dm resulting in polyclonal b-cell stimulation and enhanced antibody production to stimuli. 96 beyond neutrophil changes, people with diabetes have alterations in the function of several cell types including macrophages, s. dunachie and p. chamnan natural killer cells, cd4 t cells and cd8 t cells function. 97 t cell responses are known to be important in host defence against intracellular pathogens, with intracellular antigens presented to cd8 t cells via the mhc class 1 antigen presentation pathway, and digested antigens from both extracellular and intracellular sources presented to cd4 t cells via the mhc class 2 system. hiv results in reduction of cd4 t cells, and the huge increased risk of tb seen in advanced hiv demonstrates the importance of cd4 cells in defence against tb. there is evidence of impaired antigenspecific t cell responses in people with diabetes in response to early tb 97 , b. pseudomallei 20 and vzv 98 , although in established tb the cellular response appears to be higher in diabetes. 97 in addition, differences in the regulation and orchestration of the immune response are seen in dengue. 99 for further detailed discussion of immune mechanisms, the reader is referred to a number of excellent reviews of immune impairment in diabetes. 97, 100 overall, diabetes can impair the immune system at a systemic, cellular and molecular level, but it is the alteration of t cell function that is most amenable to boosting with targeted vaccination strategies. acute infection is known to lead to hyperglycaemia as a consequence of the stress-response activation of the hypothalamicpituitary-adrenal axis to increase secretion of cortisol and other hormones which promote peripheral insulin resistance, alongside alteration of insulin-receptor signalling by pro-inflammatory cytokines (reviewed 101 ). sepsis-related hyperglycaemia may be a risk factor for future development of t2dm, 101 and stress hyperglycaemia induced by chronic infections such as tb may contribute to the global burden of diabetes. 16 concerted international efforts to stem the tide of advancing diabetes in lmic are urgently required. implementation of evidencebased approaches that are effective at both prevention and early intervention for diabetes are needed. such approaches require behavioural changes in diet and physical inactivity, raising public awareness of diabetes, and convincing policy-makers and the public alike of the benefits of early diagnosis for disease reversal and management. one of the targets for the un's sustainable development goal 3 (good health and well-being) is to reduce by one-third premature mortality from ncds through prevention and treatment by 2030, with action on diabetes essential. actions include implementation of national diabetes programmes and extension of health promotion activities. 1 tackling the interaction between diabetes and infection requires a greater understanding of the immune mechanisms underlying the altered susceptibility to infection seen in diabetes, and knowledge of how therapeutic management of diabetes impacts on risk of infection. it is likely that tight control of hyperglycaemia lowers the risk of infection, although this has yet to be comprehensively demonstrated in prospective studies. current international treatment guidelines for t2dm are based on research conducted in high-income countries focussed on preventing adverse cardiovascular outcomes and early death. there is a lack of evidence on which to base guidelines for people living in lmic, and choice of glucose-lowering therapy may impact on infection risk and outcomes. for example, there is emerging evidence for beneficial infection outcomes in people with diabetes taking metformin compared with other therapies, [102] [103] [104] and glyburide/glibenclamide has been associated with anti-inflammatory properties and lower mortality in melioidosis. 105 vaccination remains the cornerstone in controlling infectious diseases, and people with diabetes are prioritised as a high-risk group for vaccination against a range of pathogens including pneumococcus, influenza and vzv. development of highly efficacious vaccines against intracellular infections such as tb, melioidosis and leishmaniasis, to which people with diabetes are at greater risk, is an important priority, and progress requires consideration of how to overcome the specific immune impairments seen in diabetes. characterising the impact of diabetes on protective immunity is particularly important for melioidosis, where more than half of all cases occur in people with diabetes, and cost-effective implementation of a successful vaccine is likely to involve targeting this group. 106 b. pseudomallei therefore represents an exemplar pathogen for defining the immune deficits in diabetes, and how to overcome them. the collision of diabetes and the world's global infections is a highly neglected area. more research to clearly define the epidemiology and illuminate successful interventions needs prioritising. the majority of the evidence for associations between diabetes and specific infections relies on the use of relatively small retrospective case-control studies, and meta-analysis approaches are limited by the heterogeneity of patient-level factors across studies. diabetes is interrelated with obesity, hypertension and cardiovascular diseases that share similar risk factors and are each linked to adverse disease outcomes, rendering elucidation of the precise contribution of diabetes to excess morbidity and mortality difficult. the causal interaction between diabetes and infection rates and outcomes is also challenging. for some chronic viruses such as hbv and hiv, the association with diabetes may represent increased risk of diabetes by pathogenesis mechanisms resulting in insulin resistance related to chronic inflammation, rather than the other way around. high-quality, large prospective epidemiology studies are needed to quantitate the problem, alongside randomised controlled trials of interventions to define optimal treatment strategies in diabetes. raising awareness of the interaction of diabetes and infection with policy-makers, and ensuring the engagement of social scientists, health economists and the pharmaceutical industry in developing new strategies to fight this double burden in lmic is vital. authors' contributions: sd and pc wrote and reviewed the manuscript together. international diabetes federation worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies the epidemiology of melioidosis in ubon ratchatani, northeast thailand melioidosis epidemiology and risk factors from a prospective whole-population study in northern australia gbd causes of death collaborators. global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the global burden of disease study world health organization. definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. geneva: world health organization american diabetes a. 2. classification and diagnosis of diabetes international diabetes federation: a consensus on type 2 diabetes prevention influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome increased risk of common infections in patients with type 1 and type 2 diabetes mellitus impact of diabetes mellitus on treatment outcomes of patients with active tuberculosis the global burden of tuberculosis: results from the global burden of disease study geneva: world health organization 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for development of type ii diabetes metformin and other glucoselowering drug initiation and rates of community-based antibiotic use and hospital-treated infections in patients with type 2 diabetes: a danish nationwide population-based cohort study metformin as adjunct antituberculosis therapy metformin use and severe dengue in diabetic adults glyburide is antiinflammatory and associated with reduced mortality in melioidosis melioidosis vaccines: a systematic review and appraisal of the potential to exploit biodefense vaccines for public health purposes acknowledgements: none. ethical approval: not required. key: cord-327748-8ob6okeh authors: feng, tianjun; keller, l. robin; wang, liangyan; wang, yitong title: product quality risk perceptions and decisions: contaminated pet food and lead‐painted toys date: 2010-07-09 journal: risk anal doi: 10.1111/j.1539-6924.2010.01459.x sha: doc_id: 327748 cord_uid: 8ob6okeh in the context of the recent recalls of contaminated pet food and lead‐painted toys in the united states, we examine patterns of risk perceptions and decisions when facing consumer product‐caused quality risks. two approaches were used to explore risk perceptions of the product recalls. in the first approach, we elicited judged probabilities and found that people appear to have greatly overestimated the actual risks for both product scenarios. in the second approach, we applied the psychometric paradigm to examine risk perception dimensions concerning these two specific products through factor analysis. there was a similar risk perception pattern for both products: they are seen as unknown risks and are relatively not dread risks. this pattern was also similar to what prior research found for lead paint. further, we studied people's potential actions to deal with the recalls of these two products. several factors were found to be significant predictors of respondents’ cautious actions for both product scenarios. policy considerations regarding product quality risks are discussed. for example, risk communicators could reframe information messages to prompt people to consider total risks packed together from different causes, even when the risk message has been initiated due to a specific recall event. the year 2007 was called "the year of the recall" due to the recalls of pet food and children's toys in the united states. (1) in particular, the 2007 pet food contamination crisis led to the widespread recall of more than 5,300 pet food products, mainly from menu foods, beginning in march 2007. (2) according to the u.s. food and drug administration (fda) newsletter, (3) as of april 26, 2007 , the fda had received consumer reports of approximately 2,200 deaths of dogs and 1,950 deaths of cats with 14 cases confirmed. further investigation revealed that, though not yet proven, the presence of melamine and melamine-related compounds, such as cyanuric acid, in the ingredients of the affected food appears to be the cause of kidney failure that killed thousands and sickened tens of thousands of pets. meanwhile, on august 2, 2007, the toy-making giant mattel recalled 967,000 toys, including dora the explorer and sesame street toys, due to violations of lead paint standards, 4 which was followed by a rash of toy recalls in august and september 2007. (4) children who suck on or ingest toys with high lead content may have elevated blood lead levels and may get lead poisoning. this can lead to learning and behavior problems, and at very high levels, seizures, coma, and even death (u.s. centers for disease control and prevention (cdc)). 5 we are interested in how consumers perceive the quality risk of a product under threat of recall and how they make a decision about actions to take upon hearing news of an actual or threatened product recall. here, product quality risk refers to the risk of a product (e.g., health, financial, safety risk, etc.) caused to customers and generated by its inherent quality problems (e.g., in raw materials, ingredients, production, logistics, or packaging). we examine risk perceptions and decisions using the contaminated pet food and lead-painted toys as examples in the same study for a number of reasons. first, pets and children are vulnerable members of a household that adults have a responsibility to protect. 6 second, both involved potentially serious health threats. third, the recalls occurred in the same time span. finally, both products originated in china and were destined for the u.s. market. for these two recalls, there was a great deal of media attention, including anecdotal stories of relatively extreme actions by consumers. for instance, in response to the recall of lead-painted toys, some parents were so concerned and scared that they tested all of their children's toys for lead and threw away the toys on the recall list. (7) for regulators, consumers, and the companies in the supply chain for these products, it will be valuable to understand the components of people's reactions to such events. this line of work should be helpful in future recalls of other products to gain a quick understanding of likely patterns of consumer reactions. to explore risk perceptions of these two product recalls, we used two approaches that have been widely adopted in the risk perception literature. the first approach was to elicit judged probabilities of the adverse quality risk with respect to these two product recalls. (8, 9) specifically, we elicited judged 5 more information about children's risks and opportunities to manage them can be found at http://www.kidsrisk.harvard.edu/, a project created and directed by professor kimberly thompson at the harvard school of public health. 6 the public tends to have different perceptions and attitudes toward risks faced by children and adults, respectively, (5) and probably the same is true for humans and pets. in addition, while our study focused on making decisions on behalf of a child or a pet, similar decisions might also apply when made for adults (e.g., johnson et al.) . (6) probabilities that (1) a dog will die from eating contaminated dog food within the next month (in the case of the dog food recall) and (2) an under-sixyear-old child will have elevated blood lead levels from playing with lead-painted toys within the next couple of months (in the case of the children's toys recall). we then examined biases in judged probabilities of quality risks of these two products due to using a packed frame (lumping together multiple items) or unpacked frame (listing items separately). we chose to investigate this since companies or regulators in future recall crises would have the ability to frame probability information and other messages using packed or unpacked probability frames. people tend to have an overall higher judged probability for a focal event's occurrence when the description of an event is unpacked into its individual components. (10−16) also tversky and kahneman (17) showed that when a described specific case seems very representative of a general category, this "representativeness" may lead to higher judged probabilities. in this study, an adverse health effect from the recalled product may be incorrectly seen as more likely to occur than that same health effect from any cause. in the second approach, we applied the wellknown psychometric paradigm (18−20) developed by slovic and his colleagues to further examine risk perceptions of the two product recalls. this approach has been widely adopted to understand and predict people's responses to various risks by identifying similarities and differences among those risks. analyzing newly arising risks and comparing them with existing ones along a number of dimensions will help policymakers understand each new risk and potentially help the general public accurately perceive the risks. accordingly, we considered eight hazardous products and risky situations, including the two recalled products and six additional risks spanning sickness risks from food 7 and nonfood consumer products, 8 on seven qualitative rating scales. the six comparison risks include avian flu (because it poses severe health risks to both birds and humans), (42−44) mad cow disease (bovine spongiform 7 studies of perceived health risks of various human food products have been done on modified food, (21−23) organic food and conventional food, (24−26) salmonella food poisoning, (27) and general food safety issues. (28−33) little or no attention in this stream of work has been on pet food. 8 perceived health and safety risks of technologies have been done on gene technology, (34) biotechnology, (35) nuclear power, (36) environmental risk and technology, (37−40) and other technologies. (41) , which has raised consumer anxiety about beef consumption, (45−47) severe acute respiratory syndrome (sars), contaminated spinach, smoking cigarettes, (48−54) and cell phone radiation. this allows us to establish the risk perception map, which helps investigate how these newly recalled products score on factors shown in the past to influence risk perception and how they compare with the six comparison risks. as discussed before, both recalled products originated in china. the well-documented country-oforigin literature emphasizes that a product's origin plays an important role in consumers' perceptions of the product. (55) thus, we conjecture that the country of origin may influence risk perceptions of the two contaminated products. in this study, we examined this issue for four original sources of products (the united states, china, japan, and mexico). finally, it has been shown that risk perceptions influence people's decisions in risky situations. (9, 46) accordingly, we examined people's actions in response to the product recalls. for example, a pet owner may choose to gain more information about the recalls before taking further actions, or a child's parents may decide to throw away all toys at home when they hear about the recall announcements. further, we identified the factors most predictive of their cautious actions. our survey had three versions depending on the information format of the focal events. table i shows the main difference between these three versions of the survey. first, we asked all participants to think about dogs that had eaten the contaminated dog food. in version a, one group of participants reported their estimate of the probability of one of those dogs dying due to eating the contaminated dog food. the version b group was asked what the probability is of one of those dogs dying (with no cause mentioned). in contrast, the version c group received an unpacked framing of the question in version b, in which they judged the probability of one of those dogs dying from eating contaminated food and then judged the probability of one of them dying from other causes. the question design of these three versions was similar for the scenario of lead-painted children's toys, except that we asked respondents to estimate the probability of one of those under-sixyear-old children having elevated blood lead levels (from playing with lead-painted toys, from unspecified causes, or from other causes). 9 each participant received the same version of the questions for both the food and toy scenarios. all the other questions in the survey were the same across all participants, including questions on the characterization of perceived quality risks on various dimensions and on trust in the original sources of products. several other short questions were designed to measure participants' knowledge and actions toward the recalls of contaminated pet food and lead-painted children's toys. to identify 9 there are several other causes that could lead to elevated blood lead levels for young children. according to the case studies from the u.s. center for disease control (cdc), the primary source of lead exposure to children in the united states is leadcontaminated household dust. landrigan (56) claimed that childhood lead poisoning is the major factor that contributes to the costs of all pediatric environmental disease in the united states, which amount to approximately $43.4 billion every year. determinants that are significant predictors of respondents' potential actions, we also asked for information about demographic characteristics, such as gender and personal experience with dogs or cats. two hundred and five survey participants, ranging in age from 18 to 45, were recruited from the human subject pool at the university of california, irvine. (in total, 210 respondents, all enrolled in undergraduate classes, participated in our study. among them, five participants did not complete their survey and thus were removed from the data analysis.) they were randomly assigned to three groups of 67, 69, and 69 participants for versions a, b, and c. note that college student samples have been used in several prior risk perception papers. (57−62) participants received one hour of course extra credit. table ii provides the demographic data. eighty-eight percent of the participants were female. 10 approximately 41% of the respondents and their families have had 1-2 dogs and 18% of them have had more than two dogs. nearly 86% of the respondents do not have siblings under six years old, but 68% of them had been a babysitter. survey data were collected through surveymonkey.com, recorded in a microsoft excel spreadsheet and analyzed using the spss statistical software. participants took about 40 to 50 minutes to complete this online survey. statistical analyses included tests of differences in means, factor analysis, anova, multiple regression, and logistic regression. for comparability, a common set of independent variables was used to estimate all regression models. after reading a short description of both the food and toys recalls, respondents gave an estimate of how many dogs died in the united states from contaminated dog food in 2007 and how many undersix-year-old children got elevated levels of lead in their blood in the united states from playing with lead-painted toys in 2007. the median responses on these two questions were 5,000 dogs (mean: 61,600, sd: 303,622) and 6,000 children (mean: 202,871, sd: 1,146,795), respectively. note that for pet food, approximately 2,200 dog deaths were attributed to the contaminated food, according to the fda. the large standard deviations indicated that respondents held varied opinions about impact of the recalled products. trust in institutions is closely related to subjective risk judgments regarding human food quality risks. (26, 27, 33) an individual who trusts less in institutions for food quality information tends to perceive a higher probability of risk. using three 7-point rating scales, we also asked questions related to participants' trust in institutions, information 10 while this uneven gender distribution was partly due to the fact that female students account for a majority of the university's human subject pool, we believe that such a distribution would also hold for pet food and children's toy shoppers. participants selfselected the experiments they would participate in. those selecting our study were told: "we are conducting a study on how people react to product quality related crises, with a focus on the recent recalls of contaminated pet food and lead-painted children's toys." we further analyzed the relationship between participants' gender and their subjective probability judgment for all three versions, and we did not find significant differences. therefore, we conducted the analyses based on the pooled data from both male and female respondents. sufficiency, and overall concerns about these product quality risks, as shown in table iii . respondents had a fairly good level of trust in the information that the authorities provided on both food (mean = 4.85 out of 7, where 7 is full trust) and toys (mean = 4.75), but did not think that they had fully received enough information for either recall (mean = 3.57 for food, and mean = 3.75 for toys). participants were highly concerned about the safety of dog food (mean = 4.86) and had significantly more concern about toys (mean = 5.82, p < 0.0001). since respondents had a relatively high level of trust in the authorities and concern about these products' safety, but felt they did not have enough information, government agencies and companies could provide people with more information to aid them in making more informed decisions. we first elicited judged probabilities in response to the two product recalls, which are shown in table iv . in survey version a, participants gave an estimate of the number of dogs dying from eating the food within the next month. for instance, if an estimate was 2,000, this participant's judged probability of dogs dying from eating the contaminated food was 20% = 2,000/10,000 (i.e., participants were told in the survey to suppose that 10,000 dogs ate the same contaminated dog food). a similar structure was used for toys. thus, using version a, we elicited participants' subjective probabilities for the two scenarios and found that the mean judged probability of dogs dying from eating the contaminated food was 46.9% and the mean judged probability of children having higher blood lead levels from lead-painted toys a version c (unpacked condition) had a significantly higher mean judged probability than version b (packed condition) at the 1% level using a t-test (p = 0.0002 for contaminated dog food and p = 0.0018 for lead-painted toys). was 51.7%. we believe that our participants tended to overestimate their probability judgments for the potential adverse reactions with these two recalls. 11 this is very likely due to the availability heuristic, (17) which states that people predict the frequency and probability of an event by the extent to which occurrences of that event are easily "available" in memory. 12 clearly, there was extensive media coverage on the two product recalls during the recall crisis and thus adverse examples could be readily brought to mind for respondents. note that a similar pattern has also been observed in the prior literature on risk perception. for example, by using a large-scale national survey, viscusi (48) found that both smokers and nonsmokers significantly overestimated the lung cancer risk of cigarette smoking. interestingly, when participants focused on the adverse effects due to the recall event (version a), their answers were higher than when they considered all adverse effects from any cause (version b). this may be seen as falling prey to the representativeness 11 according to the u.s. pet ownership & demographics sourcebook, (63) there are approximately 72,114,000 pet dogs in the united states, so roughly every fourth person owns a pet dog (the total population of the united states by july 1, 2007 was around 301,621,157 based on the 2007 population estimates from the u.s. census bureau). the fda received reports that about 2,200 dogs died from eating contaminated food with 14 cases confirmed, including the confirmed deaths of cats. assume that only 0.1% of the dogs in the united states had eaten the contaminated dog food during the recall crisis in 2007, which is a relatively low estimate since several major pet food manufacturers recalled more than 5,300 products, with most of the recalls coming from menu foods, the largest maker of wet dog and cat food in north america. then the "actual" probability of a dog dying from eating the contaminated food would be as low as 3.1% (i.e., 2,200/72,114 = 3.1%). as a result, respondents apparently generally overestimated the probability of a dog dying from eating the contaminated food. in the case of children's toys, although the real data about the number of under-six-year-old children who had elevated blood lead levels from playing with lead-painted toys during the recall were not available, we suspect that respondents' judged probabilities were higher than the actual probabilities. in 2007, mattel inc., the world's largest toy company, recalled over 19 million chinese-made toys, including dolls, cars, and action figures. from this, one might expect that at least several millions of children could have played with the lead-painted toys. on the other hand, there was very little news coverage on the reports of children's lead poisoning cases due to playing with the lead-painted toys in 2007. consequently, we are led to believe that the actual probability of an under-six-year-old child having elevated blood lead levels from playing with lead-painted toys would be much lower than 51.7%. 12 we are grateful to an anonymous referee for this suggestion. it is possible that participants tend to err on the high side since pets and children are vulnerable in general and there is no cost to overestimating. heuristic of tversky and kahneman. (17) more specifically, since the vivid and recent stories about product recalls seem to represent well the category of dog deaths or sources of lead paint for children, when people were asked just about adverse effects of the recall event in version a, the high representativeness of the recall to the category may have led to higher probability estimates. in contrast, in version b, the general set of causes of the adverse event may not have been very available in people's imagination, and thus their estimates for the probability of the larger category of adverse events from all causes may have been lower, since it might have been harder to bring to mind other instances of the adverse event not from the recalls. next, we examined biases in judged probabilities of quality risks of these two products due to using a packed frame or unpacked frame. in version b, participants estimated the number of those dogs dying within the next month. since those dogs might die from other possible causes in addition to the contaminated food in the next month (e.g., natural death from aging, dying from a car accident, etc.), version b is a packed frame of the focal event of death. in contrast, version c is an unpacked frame, in which participants explicitly provided an estimate of the number of those dogs dying from eating contaminated food and the number of those dogs dying from other causes. by comparing responses between versions b and c, we examine biases in probabilities due to packing or unpacking of the focal event. for children's toys, we asked respondents to think about those under-six-year-old children who played with the lead-painted toys. hence the focal event in the scenario of lead-painted toys is that an under-sixyear-old child has a higher blood lead level from any cause within the next couple of months. shown in table iv , in the packed condition (b) of the contaminated dog food scenario, the mean probability of dogs dying (from any cause) was 38.5%, while the mean probability of dogs dying from any cause calculated by summing the responses for food-caused and other deaths in the unpacked condition (c) was significantly higher (56.8%, t = 3.648, d.f. = 136, p = 0.0002). the pattern also held in the lead-painted toys scenario (t = 2.959, d.f. = 136, p = 0.0018). specifically, the mean probability in the packed condition and unpacked condition was 40.6% and 56.8%, respectively. so our result is consistent with support theory (15) in that people tend to judge an overall higher probability when the description of the focal event is unpacked. this suggests that extensive recall publicity that may focus people's attention on the focal recall event, and thus lead them to mentally unpack adverse health effects into different causes, could lead to overestimating the actual probability. using the psychometric paradigm, we now examine the ratings on seven risk perception dimensions of eight hazardous products or risky situations, including contaminated dog food, lead-painted toys, contaminated spinach, avian flu, mad cow disease, sars, cell phone radiation, and cigarette smoking. we chose to examine contaminated spinach, since it is a contaminated food, like the dog food. we chose to examine sars, avian flu, and mad cow disease since they are health risks beginning in outbreaks outside of the united states with the potential to spread to the united states, like both the dog food and toys. (contaminated beef from mad cow disease could be seen as contaminated food or as a disease without the focus on food.) we chose to examine cell phones and smoking since they involve nonfood consumer products with ear/mouth/nose contact leading to possible adverse health effects, like the toys. for some items, we provided participants with a onesentence description. 13 the seven 7-point psychometric scales reflecting risk characteristics have been used to characterize perception of risk in previous research. (18, 68) the potential influence of these dimensions was suggested in early risk research, (69, 70) verified by fischhoff et al. (68) and applied widely in further work, such as slovic et al. (18) and mcdaniels et al. (71) table v describes the seven rating scales of controllability, dread, severity of consequences, voluntariness, known to the exposed, immediacy of effect, and risk newness. 13 four items were described. the contaminated spinach outbreak occurred in september 2006 and people faced a risk of getting sick or even dying due to infection from eating uncooked spinach with e. coli bacteria. (64) avian flu refers to an illness mainly caused by the influenza subtype h5n1 virus adapted to birds and it could lead to clinically severe and fatal human infections through bird-to-human transmissions. (65) mad cow disease, also known as bse, is a degenerative neurologic disease of cattle that affects the central nervous system and humans could have degeneration of physical and mental abilities, and ultimately die from eating contaminated beef. (66) severe acute respiratory syndrome (sars) is a viral respiratory disease in humans caused by the sars coronavirus and this highly contagious virus could cause substantial illness and death among the general population. (67) the mean ratings on the risk dimensions for the eight risks are shown in table vi . among the eight risks, contaminated dog food had the highest mean ratings on the 1-7 scale on the dimensions of unknown to the exposed (mean = 4.90, where 1 = precisely known to the dog owners) and newness (mean = 4.93 where 1 = old), but the lowest mean ratings in terms of dread (mean = 3.22, where 1 = not dreaded). compared to other contaminated food for human consumption (i.e., spinach and beef), respondents viewed the risk of contaminated dog food to be the least dread. the lead-painted toys were the third most unknown (mean = 4.74), third most new (mean = 4.32), and second least dread (mean = 3.66). meanwhile, sars was rated to be the most uncontrollable risk (mean = 4.67), the most dread risk (mean = 4.48), the risk with the most fatal consequence (mean = 5.64), the most involuntary risk (mean = 5.66), and the risk of the most immediate effect (mean = 3.44). this was likely because of the extensive media coverage on the rapidly increasing number of infected cases and death during the outbreak of sars between november 2002 and july 2003. in contrast, perhaps due to its prevalence in the general population, cigarette smoking received the lowest ratings on four scales, including controllability (mean = 3.14), voluntariness (mean = 2.96), known to the exposed (mean = 2.47), and newness (mean = 1.94). cell phone radiation was seen to be the least fatal (mean = 3.81) and to have its negative effect delayed the most (mean = 5.48). table vii provides the intercorrelations among the mean ratings of the seven risk characteristics. there were high associations between many scales and no association between a few others (e.g., dread and known to the exposed, r = 0.02). given that there were sufficiently high intercorrelations for several pairs of the seven risk characteristics, we conducted a principal component factor analysis with a varimax rotation to seek any key factors underlying the seven risk characteristics. the seven characteristics loaded onto the two factors displayed in table viii . the two orthogonal factors explained almost 94% of the variance, which was sufficiently high to account for the observed intercorrelations. factor 1 was highly correlated with all risk characteristics except risk dread and severity of consequence. factor 2 was highly correlated with both the risk's severity of consequence and risk dread, and moderately highly associated with risk controllability, though a little bit lower than the two risk characteristics mentioned above. thus, as used in the previous literature, we refer to factor 1 as the "unknown risk factor" and factor 2 as the factor of "dread risk." (18, 72) following the procedures of slovic et al., (18) we computed two factor scores for each risk item by weighting the ratings on each risk scale proportionally to the scale's importance in determining each factor and then summing across all scales. note that respondents' ratings on each risk dimension were recoded from the 1-7 scale into a scale with endpoints −3 and 3, with a midpoint 0, to highlight the relationship between responses and the scale midpoints. fig. 1 depicts the relative position of each of the eight risks within the two-factor space, with factor 1 on the vertical axis (i.e., "unknown risk") and factor 2 on the horizontal axis (i.e., "dread risk"). this figure is also known as a risk perception map in the literature. (19, 71) the upper extreme of factor 1 is associated with risk being unknown, new, involuntary, uncontrollable, and having delayed consequences. items at the far right of factor 2 are construed as dread, having fatal consequences, new, and uncontrollable. from fig. 1 , we observe that contaminated dog food and lead-painted toys almost overlapped in the upper left quadrant, with both being perceived as moderately unknown and relatively neutral on the scale of dread to not dread risks. their location is similar to that found in prior work for lead paint. (19, 72) cell phone radiation was also in this quadrant. the most extreme item in the upper right quadrant was sars, which was perceived as highly unknown and dread. in that quadrant, avian flu had a pattern similar to sars, except that it was seen as slightly less dread. one possible explanation is that both of them were contagious diseases and had recently broken out primarily in asia. the two contaminated human food items, mad cow disease (i.e., contaminated beef) and contaminated spinach, were also located in this upper right quadrant. respondents perceived nearly the same level of un-known risks for both contaminated human food and pet food and they considered contaminated human food to be more dread than contaminated dog food. cigarette smoking was located at the lower left quadrant, seen as rather known and slightly not dread. this is consistent with the pattern of smoking found previously. (19, 72) finally, note that none of the eight items considered in this study was included in the lower right quadrant, in which risks were perceived to be known but dread (e.g., handguns were found to be located in this quadrant in prior research). (19, 72) in this section, we examine country-of-origin effects on risk perceptions of the two contaminated products. specifically, using a 7-point scale, we asked participants to rate how much they trust products made in the united states, china, japan, and mexico in terms of health and safety risks, how much they are satisfied with those products in terms of a good affordable price with decent product quality, and how much they are satisfied with those products in terms of product quality. as shown in table ix , there were significant differences in the respondents' evaluations between the four countries for each of the three ratings scales above based on an anova. this is consistent with the literature that country of origin has a strong influence on perceived quality or product evaluation. (73, 74) moreover, through tukey's tests, we found that for each of the three scales, the united states and japan on average received significantly higher ratings than both china and mexico. however, for each of the three scales, there was no significant difference between the two developed countries, the united states and japan. similarly, between the two developing countries, china and mexico, we might have found insignificant differences since china and mexico were the second a the hypothesis that the means of these three scales between the four countries are equal was rejected at the 1% level using anova. and third largest countries that the united states imported products from in 2007, with each country accounting for 16.5% and 10.8% of the u.s. annual total imports, respectively (according to the u.s. census bureau, the year report of 2007). but, interestingly, we found that respondents had significantly higher (more favorable) ratings of products made in china than those of products made in mexico for all three rating scales despite the fact that the focus of our study was on recalled pet food and children's toys that were made in china. we provide an alternative explanation as follows. prior literature suggested that differences in economic development or industrialization levels are an important factor in accounting for the country-of-origin effect, that is, the higher the level of economic development or industrialization, the more favorable is the perception of the quality of its workers, as well as the perceived quality of its products. (73−77) despite the privileged tariff status set by the north american free trade agreement, mexico appears to be losing its u.s. export marketing shares; whereas with its accession to the world trade organization, china has played a very important role in today's world economy, that is, china has become the world's third largest economy since 2007, behind only japan and the united states (cnn news, january 15, 2009 ). this might lead to a difference in people's perceived quality between products made in china and products made in mexico. more interestingly, we found that there was a significant difference in perception of products from asian countries between the asian-american and non-asian-american subjects. 14 the general quality index of products from each country was considered by averaging respondents' ratings of products made in that country on the three scales above, where 1 represents "do not trust/not satisfied," and 7 represents "fully trust/satisfied." specifically, asian14 nearly half of the respondents were asian americans in our study (note that according to the undergraduate profile of university of california, irvine, in fall 2007, our sample was quite representative in terms of distribution by race). although we did not ask our subjects how long their family had been in the united states, one may expect a difference in risk perception based on how many years their family has been in the united states, or even a difference in risk perception among different generations of family members. wong-kim et al. (78) suggested that length of stay in the united states and fluency with the english language affected people's beliefs. bonin et al. (79) found that there was a difference in risk preference between first-generation immigrants (born abroad) and the second generation (born in the immigrated country). future studies could investigate this. american respondents had significantly lower general quality ratings of products made in china (mean = 3.99) than non-asian-american respondents (mean = 4.53) (p < 0.01). on the contrary, products made in japan received significantly higher ratings from asian-american respondents (mean = 5.57) relative to non-asian-american respondents (mean = 5.00) (p < 0.01). we did not find a significant difference in perceived quality of products made in the united states or mexico between these two groups. this finding makes a contribution to the country-of-origin literature and complements results from public opinion surveys. 15 respondents' possible actions to deal with the product recalls are in table x . participants said they would take a variety of actions when they were asked what they would do with the pet food or the toys at home when they heard about recalls of contaminated pet food and lead-painted children's toys. the pattern was similar for food and toys in that the top three options for both scenarios included "check websites for more information," "read/listen to news coverage," and "throw away all dog food/toys," each of which had more than 60% of the respondents selecting it. (some participants provided other alternatives, such as "take dogs to the vet for checkup," "purchase dog food without contaminated ingredients," "test child for lead poisoning," "return item and ask for refund," "put them away for a period of time until i have more information about the topic," "sue toy makers if my child has been poisoned," etc.) this suggested that when faced with a product recall event, people may collect more information about the product itself before taking any further actions or simply proceed to take cautious actions (i.e., 15 our results on perceptions of country sources are fairly consistent with other surveys of adult consumers in the united states. in the context of imported food, dewaal (80) found 616 of the survey respondents who answered a question to place countries/regions in order of concern from greatest to least concern, on average gave the order of china (greatest concern), mexico, european union, australia, canada (least concern). similarly, weise (81) reported on a usa today/gallup poll of 921 adults (who shop for groceries) showing that products "from china rank highest on those shoppers' suspicion scale: 83% are concerned about food from china, compared with 61% concerned about foods from mexico and 39% concerned about foods from the usa." what would you do with the dog food at your home when you heard that some dog food has recently been contaminated? check all that apply. • check websites for more information * 85% contaminated • throw away all dog food * 75% • read/listen to news coverage * 73% pet • talk with friends about what their experience is with this issue 47% • cook dog food from fresh ingredients 28% food • trust store to remove recalled items 20% • modify use (e.g., give food to bigger dogs, not puppies) 2% • other 5% what would you do with the toys at your home when you heard that some toys have recently been recalled due to lead-paint? check all that apply. • check websites for more information * 83% lead • read/listen to news coverage * 78% • throw away all toys * 62% painted • talk with friends about what their experience is with this issue 49% • test toys for lead 38% toys • trust store to remove recalled items 24% • wash toys 24% • modify use (e.g., give toys to bigger kids, not infants/toddlers) 16% • other 6% * actions in bold italic font were selected by more than 60% of respondents. dispose of the products before complete information has been obtained). we were interested in identifying the determinants of respondents' cautious actions to "throw away all dog food/toys." thus we developed two logistic regression models using maximum likelihood estimation to determine the factors most predictive of their cautious actions for both the contaminated dog food scenario and the lead-painted toys scenario based on the data in version a. table xi shows the results from the two logistic regression models. from this table, we can see that both models had moderate explanatory power in predicting respondents' actions to "throw away all dog food/toys." specifically, respondents' subjective probabilities were found to be a consistent predictor of their cautious actions to "throw away all dog food/toys" at the 0.05 level for both product scenarios (wald statistic = 4.45, p = 0.035 for dog food, and wald statistic = 4.26, p = 0.039 for toys). for example, respondents who had higher subjective probabilities were more likely to choose cautious actions, that is, throwing away all dog food/toys. several other factors were found to be significant predictors in specific product scenarios. in the logistic regression model for the dog food scenario, race was a significant predictor of throwing away all dog food at the 0.05 level (wald statistic = 4.48, p = 0.034), that is, asian-american respondents were more likely to choose to throw away all dog food than non-asian-american participants. this is consistent with the previous country-of-origin finding that asian-american respondents perceived significantly lower quality for products made in china (where the recalled dog food was from) than their non-asian-american counterparts. two of the seven risk dimensions were found to be significant predictors of throwing away all dog food at the 0.10 level. dread was positively associated with throwing away all dog food (wald statistic = 2.88, p = 0.09), which implies that respondents who perceived the risk of contaminated dog food to be more dread were more likely to take cautious actions. conversely, newness was negatively associated with this cautious action (wald statistic = 3.15, p = 0.076), since, for a new risk, respondents might need to know more about it before they decide to throw away all dog food. respondents who more frequently wear a seatbelt when riding in a car were generally more cautious and more likely to choose to throw away all dog food (wald statistic = 3, p = 0.083). in the logistic regression model for the children's toys scenario, trust in authorities was positively associated with the cautious action of throwing away the toys (wald statistic = 3.29, p = 0.07). this implies in the contaminated dog food scenario, the dependent variable is the action of "throw away all dog food." in the lead-painted toys scenario, the dependent variable is the action of "throw away all toys." b 1 = do not trust/not satisfied; 7 = fully trust/satisfied. we averaged respondents' ratings of products made in china on the three scales to be the general quality index of china in both logistic regression models. * significant at 0.10 level; * * significant at 0.05 level; * * * significant at 0.01 level. that respondents who had more trust in the product recall information provided by the government were more likely to adopt cautious actions against potentially contaminated products. the risk being known to those exposed was also found to be a significant predictor of the cautious action of throwing away all toys at the 0.10 level (wald statistic = 2.82, p = 0.093). so, respondents who perceived the risk of lead-painted toys to be known precisely were more likely to throw away the toys. we examined both the pet food and children's toys product recalls in a single study since we felt that both would have similar response patterns, being products for protected household members where their adverse effects come from ingestion via the mouth. when participants focused on the adverse ef-fects due to just the recall event, their probability answers were higher than when they considered all adverse effects from any cause. so, when faced with a product recall event, extensive news coverage could make the public overestimate the actual probability for potential adverse outcomes. thus, companies or regulators could provide information about future recall risks by putting the current risk in perspective by lumping it with other similar risks. a focus on all risks might lead consumers to display less bias in their probability judgments. however, we also found that when risks are unpacked, the probability judgment is higher than when they are packed together. the challenge for risk communication is to reframe information messages to get people to consider total risks from different causes in a lumped together way, even when the risk message has been prompted by a specific recall event. our results also suggest that there might be a paradox in the value of information when people are faced with a product recall event. on one hand, we find that when a recall is publicized, it can lead to greater overestimation of the actual probability for potential adverse outcomes associated with the focal recall event. this implies that more information leads to an upward bias in people's subjective risk judgments. on the other hand, we found that "check websites for more information" is the option that people choose the most during the outbreak of a product recall. that is, more information is desirable for the general public before they make their product use/disposal/repurchase decisions. more empirical research is needed to examine this possible paradox in the effect of added information when product quality risks are involved. our results could also help policymakers frame additional information gathering efforts. questions that could be investigated regarding pet food and toy safety include: at what level of perceived risk would individuals call the emergency (911) number or the poison control center? when would they use government resources to help mitigate risk? if the government or an agency recommended that they throw out the items, would they comply? are the respondents concerned about the businesses that might suffer from the recall? 16 risk communication has also been examined from a sociological perspective. (82, 83) for instance, mileti and fitzpatrick (84) constructed a model to describe public perception and response to communication about natural hazards risks. they found that additional communications encouraged personal search for more information. more specifically, from the information processing perspective, people's response to hazard information can be divided into eight stages: (85−88) (1) receiving the warning; (2) understanding the warning; (3) believing the warning; (4) confirming the threat; (5) personalizing the threat; (6) determining whether or not protective action is needed; (7) determining whether protective action is feasible; and (8) taking protective action. note that although our work originated from a psychological perspective, our study does contribute to several stages in the above framework, such as stage 2 (how probabilistic information is understood in different formats), stage 3 (participants' trust in institutions), and stages 6, 7, and 8 (analysis of participants' actions). our results on perceptions of toys with lead paint risks are timely since the united states has recently enacted higher safety standards for toys with lead paint risks via the consumer product safety improvement act (cpsia), which added certification and testing requirements for all products subject to cpsc standards or bans, including lead in paint on toys. this is consistent with consumers' opinions regarding lead paint in toys. 17 however, the cpsc recently issued a one-year stay of enforcement until february 10, 2010 for certain testing and certification requirements of the cpsia for manufacturers and importers of regulated products, including products intended for children 12 years old and younger. the stay of enforcement permitted toy providers to not have to prove they had tested their products, but they were still required to meet the lead standards. food safety also is a continuing public concern. at the national center for food protection and defense, founded in 2004 at the university of minnesota, researchers are working on developing best practices for effective risk communications related to potentially catastrophic food bioterrorism incidents from a practice-oriented viewpoint. they have developed a risk communication tool kit and several case studies, including one on the schwan's salmonella crisis (89) and one on tainted strawberries. (90) similarly, our findings on country of origin of products are timely, since the u.s. department of agriculture's mandatory country-of-origin labeling program's final regulation became effective on march 16, 2009 , requiring labels for meat, fish, fruits, vegetables, and some nuts. this recent labeling policy is also consistent with consumers' opinions. 18 in addition, the american veterinary medical 17 more specifically, lead paint in toys is of broad concern as demonstrated in the nationwide pew food safety survey (2008), where 1,002 u.s. adult interviewees were asked whether they considered "toys for children being made with unsafe materials, such as lead-based paint" to be a serious problem. fifty-seven percent said it was a "serious problem that is fairly common," and 27% said it was a "serious problem that rarely occurs." a larger percentage felt that toys were a fairly common serious problem than were prescription medications marketed prior to adequate testing (44%), fresh fruits and vegetables contaminated with bacteria that make them unsafe to eat (42%), or automobiles having flaws or faulty parts making them unsafe to drive (35%). 18 for example, among u.s. respondents (who described themselves as interested in food safety) in an august 2008 u.s. food safety survey by the center for science in the public interest, 51.6% were very concerned with the safety of domestically produced foods and 78.9% were very concerned with the safety of imported foods. regarding u.s. food safety, 93% of the consumers in the dewaal (80) survey were very supportive of association also approved policy changes on june 10, 2008 to use "pet food health claims" to replace the existing policy on "pet food therapeutic claims," which indicated the increasing attention on health aspects of pet food. during the summer of 2008, there was a new food contamination outbreak of the salmonella saint paul strain in the united states, apparently from fresh vegetables. (91) at first thought to be in tomatoes, later investigations pointed toward jalapeño or serrano peppers grown with contaminated water on a farm in the state of nuevo leon in northeastern mexico as the potential source. (92) our work can help shed light on such an evolving issue in the multinational food supply chain, both by providing a template for future surveys on evolving risks and by examining our results on the pattern of responses for products from different countries (in this case from mexico) and where other contaminated food items fell in the factor analysis in fig. 1 . contaminated spinach was near dog food on the vertical axis at moderately unknown risk and spinach was a bit more dread than dog food on the horizontal axis. mad cow disease was even more dread. for future recall events, an examination of where the new risk falls on these dimensions could aid in understanding how the public might react. following the recent media focus on product quality risks in the contaminated pet food and leadpainted toy recalls, we examined risk perceptions and decisions related to these two recalls. two approaches were used to explore risk perceptions of the product recalls. in the first approach, we elicited judged probabilities and found that people appear to have greatly overestimated the actual risks for both product scenarios. in the second approach, we applied the psychometric paradigm to examine risk perception dimensions among eight health risks. it was found that the contaminated dog food was most unknown, most new, but least dread. the lead-painted toys were the third most unknown, third most new, and second least dread. examining these results via factor analysis, we found that both contaminated dog food and lead-painted toys were near each other and near contaminated spinach and cell phone radiation in the two-factor space of the risk perception map, country-of-origin labeling. eighty percent would support more detailed labeling, down to region, country, state, and farm. and had similar patterns to what prior research found for lead paint. further, we found that the top three actions would be the same under the scenario of people hearing of pet and child risks: "check 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studies in crisis communication crisis plans and interagency coordination: lessons learned from tainted strawberries in the school lunch program salmonella "smoking gun" located grown jalapeño and serrano peppers not connected to salmonella saintpaul outbreak the authors gratefully thank the editor michael greenberg, the area editor ann bostrom, and three anonymous reviewers for their extremely thoughtful and constructive reviews, which have significantly helped improve the article. portions of this work were supported by grants to professor tianjun feng from the national natural science key: cord-332142-lk95akg5 authors: skovdal, morten; pickles, michael r.; hallett, timothy b.; nyamukapa, constance; gregson, simon title: complexities to consider when communicating risk of covid-19 date: 2020-07-23 journal: public health doi: 10.1016/j.puhe.2020.07.015 sha: doc_id: 332142 cord_uid: lk95akg5 nan the response to the spread of sars-cov-2 around the world has so far been characterised 28 by governments issuing instructions about the action to take. however, as governments 29 begin to ease restrictions, the potential for covid-19 to spread is increased. we argue that 30 correct understanding of individuals' risks of becoming infected and dying is a prerequisite 31 for people and communities to take responsibility and engage in prevention practices, both 32 for self and others; and also to reduce unnecessary anxieties and other unintended negative 33 outcomes. at the same time, effective communication of these risks is fraught with difficulty 34 and there are important complexities that must be recognised and addressed. in our view, 35 there has been little scientific discussion on the complexities, determinants and impacts of 36 covid-19 risk communication. here, we highlight seven major complexities in 37 communicating risk and suggest directions for addressing these (see panel). they serve as a 38 framework for governments, researchers, policy and public health workers to critically 39 appraise covid-19 risk messaging efforts. as we are trying to highlight complexities that 40 are widely applicable (rather than specific to certain countries or regions), their relevance will 41 differ from context to context. one: the risks of acquiring sars-cov-2 infection and of dying from covid-19 disease 45 once infected vary considerably by epidemic context and between individuals 1 . nevertheless, 46 it is apparent that the risk of infection varies with the stage of the epidemic, which varies by micro-region, and an individual's exposure, which is often much higher for healthcare 48 workers and carers, and elevated for those with jobs that cannot be done from home, amongst 49 whom ethnic minority groups and people living in greater depravation may be over-50 represented 2 . the risk of death from covid-19, given infection, varies substantially 51 according to age, male-sex, obesity and other factors 3 . thus, there is no "one number" to 52 quote to people for their risk; but, at the same time, everyone should know the range in which 53 their risk is likely to fall. finding ways to provide clear and targeted information about who is 54 at increased risk whilst also recognising the intersectionality of these factors is essential. two: unintended outcomes -such as anxiety, avoiding going to work, and limited healthcare 56 seeking -can result for some people. thus, over-estimating one's own risk could be as 57 unhelpful to economic wellbeing and health overall as under-stating one's own risk. 58 moreover, some people aware of their individual risk may (un)willingly take risks, for 59 instance by doing a trade-off between risk and maintaining a livelihood. communicating risk 60 of sars-cov-2 infection must be considered in the broader context of a group of risks as 61 great or greater than that from covid-19. therefore, developing strategies to mitigate these 62 risks is important too. • avoid over-simplified 'one-size-fits-all' risk messages • distinguish between risk of sars-cov-2 infection and risk of severe covid-19 disease • target risk messages to people according to their levels of risk and capacity to adopt alternative prevention methods • communicate the uncertainty of risk estimates and that new data may lead to changes • develop risk messaging that reflects the broader socio-economic and health context and is actionable by local people. • include messaging to mitigate other forms of risk (e.g. young women should still adhere to government advice but not put off trips to hospital for breast cancer screening) • avoid using unhelpful metaphors (e.g. war, enemy) in risk messaging. • avoid using language that can cast shame or blame to people • monitor the emergence and spread of myths and misinformation on social media and within the community • utilize locally trusted institutions and individuals to address misinformation and channels that are widely used by the relevant population • promote trust in official sources by ensuring that messaging from all such sources is consistent reflect changes in the nature of risk and risk perception as the epidemic evolves • review, revise and explain changes in risk messages as the epidemic evolves • develop risk messages that counteract innate tendencies for message 'fatigue' • use data on risk to stimulate and strengthen motivation to follow government guidance • encourage people to think creatively and tailor prevention methods to their own circumstances (e.g. to find effective ways to shield vulnerable family members) • foster a sense of collective responsibility (e.g., risk messaging that emphasises that your actions benefit others) • recognise and address social and health inequities, discrimination, and political agendas, which put some people at greater risk, or prevent them from engaging with risk-reducing practices. • freely avail health services and equipment to assist risk-reducing practices panel: considerations and recommendations to communicate risk in the covid-19 response • avoid over-simplified 'one-size-fits-all' risk messages • distinguish between risk of sars-cov-2 infection and risk of severe covid-19 disease • target risk messages to people according to their levels of risk and capacity to adopt alternative prevention methods • communicate the uncertainty of risk estimates and that new data may lead to changes • develop risk messaging that reflects the broader socio-economic and health context and is actionable by local people. • include messaging to mitigate other forms of risk (e.g. young women should still adhere to government advice but not put off trips to hospital for breast cancer screening) avoid negative social consequences of risk messaging • avoid using unhelpful metaphors (e.g. war, enemy) in risk messaging. • avoid using language that can cast shame or blame to people • monitor the emergence and spread of myths and misinformation on social media and within the community • utilize locally trusted institutions and individuals to address misinformation and channels that are widely used by the relevant population • promote trust in official sources by ensuring that messaging from all such sources is consistent reflect changes in the nature of risk and risk perception as the epidemic evolves • review, revise and explain changes in risk messages as the epidemic evolves • develop risk messages that counteract innate tendencies for message 'fatigue' • use data on risk to stimulate and strengthen motivation to follow government guidance • encourage people to think creatively and tailor prevention methods to their own circumstances (e.g. to find effective ways to shield vulnerable family members) • foster a sense of collective responsibility (e.g., risk messaging that emphasises that your actions benefit others) • recognise and address social and health inequities, discrimination, and political agendas, which put some people at greater risk, or prevent them from engaging with risk-reducing practices. • freely avail health services and equipment to assist risk-reducing practices estimates of the severity of covid-19 disease opensafely: factors associated with covid-19-123 related hospital death in the linked electronic health records of 17 million adult nhs 124 patients estimating excess 1-year mortality associated with the covid-126 19 pandemic according to underlying conditions and age: a population-based cohort study online first how do we balance tensions between covid-19 public health responses 129 and stigma mitigation? learning from hiv research coronavirus: the spread of misinformation risk perceptions of covid-19 around the world relationships between changes in hiv risk perception and 136 condom use in east zimbabwe 2003-2013: population-based longitudinal analyses key: cord-319910-s2e56ety authors: jani, b. d.; ho, f. k.; lowe, d. j.; macbride-stewart, s.; mair, f. s.; pell, j. p. title: comparison of covid-19 outcomes among shielded and non-shielded populations: a general population cohort study of 1.3 million date: 2020-09-21 journal: nan doi: 10.1101/2020.09.17.20196436 sha: doc_id: 319910 cord_uid: s2e56ety background shielding (extended self-isolation) of people judged, a priori, to be at high-risk from covid-19 has been used by some countries to protect the individuals and reduce demand on health services. it is unclear how well this strategy works in either regard. methods a general population study was conducted using linked primary care, prescribing, laboratory, hospital and death records up to end of may 2020. poisson regression models and population attributable fractions were used to compare covid-19 outcomes by overall risk category, and individual risk criteria: confirmed infection, hospitalisation, intensive care unit (icu) admission, population mortality and case-fatality. results of the 1.3 million population, 32,533 (2.47%) had been advised to shield, a further 347,374 (26.41%) were classified as moderate risk. testing for covid-19 was more common in the shielded (6.75%) and moderate (1.99%) than low (0.72%) risk categories. referent to low-risk, the shielded group had higher risk of confirmed infection (rr 7.91, 95% 7.01-8.92), case-fatality (rr 5.19, 95% ci 4.12-6.53) and population mortality (rr 48.64, 95% 37.23-63.56). the moderate risk had intermediate risk of confirmed infection (rr 4.11, 95% ci 3.82-4.42) and population mortality (rr 26.10, 95% ci 20.89-32.60), but had comparable case-fatality (rr 5.13, 95% ci 4.24-6.21) to the shielded, and accounted for a higher proportion of deaths (paf 75.27% vs 13.38%). age [≥]70 years made the largest contribution to deaths (49.53%) and was associated with an 8-fold risk of infection, 7-fold case-fatality and 74-fold mortality. conclusions shielding has not been effective at preventing deaths in those with highest risk. to be effective as a population strategy, shielding criteria would need to be widely expanded to include other criteria, such as the elderly. background 1 2 early in the covid-19 pandemic, one of the greatest concerns was that the demand on 3 health services would exceed capacity in terms of hospitalisations, admissions to intensive 4 care units (icu) and requirement for ventilation 1 . based on past experience, it was assumed 5 that sub-groups of the population would have worse prognosis and, therefore, contribute 6 disproportionately to adverse outcomes and healthcare demands. 7 8 asian countries have generally relied solely on population-wide strategies 2 . early, 9 widespread 'test, trace, isolate' strategies were made possible by higher testing capacity and a 10 greater willingness to monitor and enforce compliance. in contrast, european countries have 11 generally adopted a two-pronged approach 2 , whereby general population interventions, such 12 as physical distancing and hand hygiene, designed to reduce transmission in the population as 13 a whole, have been supplemented by shielding of those assumed to be at higher risk. notably, 14 sweden, an outlier in having not applied lock-down, nonetheless mandated shielding 3 . 15 studies suggest that shielding can have negative physical and psychological impact on those 16 required to undertake strict isolation over a protracted period. 4,5 17 18 in the united kingdom, a shielded patient list (initially referred to as the vulnerable patient 19 list) was produced comprising two categories(supplementary table 1) 6 . the two groups 20 have been labelled high risk, highest risk or clinically extremely vulnerable and moderate 21 risk, at risk or clinically vulnerable by various uk organisations. for the purposes of this 22 study they are referred to as shielded and moderate risk, with the remaining population 23 labelled low risk. in the united kingdom, the shielded group received individual letters 24 strongly recommending that they self-isolate over a protracted period, by not leaving their 25 homes and avoiding non-essential contact with their household members, and were provided 1 with support at home such as the delivery of food packages. the advice to the moderate risk 2 category was simply to be vigilant in adhering to the general population measures. 3 4 the definitions of high and moderate risk were based largely on expert opinion informed by 5 our understanding of previous viruses and the critical need for better definition of high risk 6 has been highlighted 7 . studies are emerging of the individual risk factors associated with 7 covid-19 outcomes. for example, among two million uk community-based app users self-8 reported heart disease, kidney disease, lung disease, diabetes and obesity were associated 9 with self-reported hospital admission and respiratory support for covid-19 8 . similarly, 10 linkage of primary care records of 17 million people in england demonstrated that a wide 11 range of long-term conditions were associated with in-hospital death from covid-19 12 including: respiratory, heart, liver and kidney disease, diabetes, cancers, stroke and organ 13 transplantation 9 . unfortunately, the investigators did not have access to deaths in the 14 community. covid-19 risk scores are being developed in an attempt to improve 15 identification of high risk individuals who would be advised to shield 10 but attempts to 16 investigate the potential contribution of a shielding strategy to population-level outcomes and 17 healthcare demands have so far been limited to abstract mathematical modelling 11-19 . 18 19 the aims of this study were to compare those classified, a priori, as high risk (and therefore 20 advised to shield) and those classified as moderate and low risk, in terms of their individual 21 risk of covid-19 infection and outcomes and the extent to which they accounted for 22 covid-19 related outcomes at a population level. the chi register provided sociodemographic information (age, sex, socioeconomic 11 deprivation). socioeconomic deprivation was derived from the scottish index of multiple 12 deprivation (simd), an area-based measure derived from seven domains -income, 13 education, health, employment, crime, housing, and access to services -which 14 was categorised into general population quintiles. the electronic communication of 15 surveillance in scotland (ecoss) database collects laboratory data on infectious diseases, 16 including test date and result. emis and vision are the primary care electronic health record 17 systems used in nhs ggc. data are extracted using albasoft software. the pis collects data 18 on all medications prescribed by community-based healthcare workers, including general 19 practitioners. the rapid database collects real-time data on every patient admitted to a 20 general (i.e. non-psychiatric) hospital in scotland including dates of admission and discharge, 21 and type of ward (e.g. icu) but does not record disease codes. subsequently, the scottish 22 morbidity record 01 (smr01) records the same information, in addition to disease codes. 23 death certificates provide the date and cause of death for all deaths, whether they occur in-24 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . hospital or in the community. follow-up data were available until the end of may 2020, 1 before the recommendation to shield was lifted. 2 3 supplementary table 1 lists the criteria for the shielded and medium risk categories being 4 applied in the united kingdom at the time of data extraction. all remaining patients are 5 categorised as low risk. the scottish list of high-risk individuals is compiled, and regularly 6 updated, centrally using data obtained from a number of sources including albasoft 7 extraction of general practice data, smr01 (hospital admissions), smr06 (cancer registry), 8 national disease registries, and the pis. the list is sent to individual general practitioners to 9 check for completeness and accuracy, before letters are sent to patients with advice to shield. 10 the nhs ggc shielding list contains the validated data including the criterion satisfied. we 11 ascertained people who met the criteria for moderate risk via albasoft extraction of emis 12 laboratory-confirmed cases were defined as patients who had a positive pcr test for 23 covid-19. clinically-confirmed cases were defined as patients who either had a positive 24 pcr test or who died from covid-19 without testing. covid-related deaths were defined 25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . as deaths with international classification of diseases 10 th revision (icd-10) code u07.1 or 1 u07.2 recorded on the death certificate. covid-related hospitalisation was defined as an 2 smr01 record of hospitalisation with an icd code u07.1 or u07.2 or, for more recent 3 admissions, a rapid record of hospitalisation with a positive covid-19 test taken between 4 two weeks before and two days after admission to hospital. icu admission during such 5 hospitalisations was assumed to be covid-related. 6 7 the sociodemographic characteristics of people were compared by risk category using chi-8 square tests. poisson regression models with robust standard errors were used to compare the 9 risk ratios (rr) for the high and moderate risk categories referent to the low risk category for 10 each outcome in turn. the models were run univariately and then adjusted for sex and simd 11 quintiles as potential confounders. age was not included as a covariate because it was a 12 moderate risk criterion. the models were re-run using the individual criteria for the high and 13 moderate risk categories as the exposure variables, referent to the low risk category. 14 15 population attributable fractions (pafs) were calculated, from prevalence and adjusted rr, 16 to determine the proportion of each outcome that could be attributed to being high and 17 moderate risk, as well as the proportion due to each of the individual criteria. the pafs of 18 individual criteria were proportionally calibrated so that the sum of pafs of individual 19 criteria equated to the overall paf of the relevant risk category. paf confidence intervals 20 were estimated using bootstrapping (x 1000). 21 ethical approvals 23 24 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . followed similar patterns as testing. it increased with age, was higher in women, and was 25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . highest in the shielded group and lowest in the low-risk category (table 2) . after adjustment 1 for sex and deprivation quintile, the risk of laboratory-confirmed infection remained higher in 2 the moderate-risk category and highest in the shielded group (table 3). 3 4 overall, 1,661 people were admitted to hospital for covid-19. within the general 5 population, hospitalisations increased with age but were comparable between men and 6 women ( table 2 ). hospitalisations were more common in the moderate-risk category and 7 most common in the shielded group (table 2 ) and remained so after adjustment for sex and 8 deprivation quintile (table 3) . overall, 122 people were admitted to icu wards for covid-9 19. icu admissions were significantly more common among people aged 45-64 years of age 10 than among older people (table 2) . compared with the low risk category, the shielded group 11 were 18 times more likely to be hospitalised but only 4 times more likely to be admitted to 12 icu (table 3) . overall, 1,027 (0.08%) people died from covid-19. within the general 13 population, mortality increased with age but was similar in men and women (table 2) . 14 population mortality was higher in the moderate-risk category and highest in the shielded 15 group (table 2 ) and remained so after adjustment for sex and deprivation quintile (table 3) . 16 17 among the sub-group with laboratory-confirmed (test-positive) covid-19 infection, 1,661 18 (49.6%) were hospitalised. hospitalisations increased with age but were comparable between 19 men and women (table 4 ). the moderate-risk category was more likely to be hospitalised 20 and the shielded group most likely (table 4 ) and remained so after adjustment for age and 21 deprivation quintile (table 5) . among the sub-group with laboratory-confirmed covid-19 22 infection, icu admissions were more common in men and more common in people aged 45-23 64 years than those older (table 4 ). low risk cases were more likely to be admitted to icu 24 than those in the moderate-risk category and shielded groups (tables 4 & 5) . among the sub-25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . group with clinically-confirmed (test-positive or covid-19 related death) covid-19 1 infection, 1,027 (26.70%) died (table 4) . case-fatality increased by age and was higher in 2 men than women. it was lowest in the low-risk category but not significantly different in the 3 moderate-risk category and shielded group (p=0.64) ( 28.8% of the population would have had to receive the current level of shielding including 10 those with five criteria currently classified as moderate risk (supplementary figure 1) . 11 12 individual risk criteria 13 14 due to insufficient numbers, the models for individual risk criteria could not be run for 15 pregnant women with severe heart disease or for covid-19 related icu admission in the 16 high-risk category. all of the remaining individual risk criteria were associated with higher 17 likelihood of being tested for covid-19 (table 1 ) and higher likelihood of having 18 laboratory-confirmed infection (table 2) . they were all associated with higher risk of 19 hospitalisation, population mortality (table 3) and case-fatality (table 5 ) independent of sex 20 and deprivation quintile. among the moderate-risk category criteria, age ≥70 years and 21 weakened immune system had risks of population mortality (table 3) and case-fatality (table 22 5) that were at least as high as the overall shielded group. apart from the 0.13% of people 23 with relevant rare diseases and inborn errors of metabolism, the strongest associations were 24 observed for those aged ≥70 years who were eight times more likely to have confirmed 25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . infection (table 3) ; seven times more likely to die following confirmation of infection (table 1 5); and seventy four times as likely to die overall (table 3) table 2 ). among those admitted to hospital for covid-19, the 5 likelihood of being admitted to icu was significantly lower for all of the individual risk 6 criteria included in the moderate risk category, other than diabetes (table 5 ). in particular, 7 hospitalised patients over 70 years of age were 14 times less likely to be admitted to icu than 8 low risk hospitalised patients (table 5) . 9 10 discussion 11 12 the 2.47% of people who had been advised to shield were, nonetheless, eight times more 13 likely to have confirmed infections than the low risk category, five times more likely to die 14 following confirmed infection and 49 times more likely to die from covid-19 overall. whilst 15 selective testing of potential cases might explain the first outcome, it does not explain higher 16 overall mortality which suggests that the shielding strategy has not been as effective as was 17 hoped. 18 one quarter of the population were classified as moderate risk and not advised to shield. 20 nonetheless, they were four times more likely to have confirmed infections than the low risk 21 category, five times more likely to die following confirmed infection and 26 times more 22 likely to die overall, suggesting that consideration should be given to expanding the shielding 23 criteria to include many currently classified as moderate risk. in particular, older age needs to 24 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . be considered since the elderly are both at high individual risk and contribute significantly to 1 population burden due to their relatively high numbers. 2 3 paradoxically, people in the shielded and moderate risk categories were less likely to be 4 admitted to icu following hospitalised for covid-19 in spite of their poor prognosis. 5 patients over 70 years were particularly unlikely to be admitted to icu. this is likely to be 6 due to selective admission policies applied in order to avoid demand exceeding supply, as 7 experienced by some other countries. this finding reinforces the importance of prevention in 8 those with the worst prognosis. 9 10 comparison with existing literature 11 12 our finding of 26.41% percent of people satisfying the moderate risk criteria is consistent 13 with the limited existing evidence. a previous study linking english primary and secondary 14 care records on 3.9 million people reported that 20% of the population satisfied similar 15 criteria 20 . similarly, a study using data from the global burden of diseases study estimated 16 that 22% of the global population are at increased risk of severe covid-19 disease 21 . a usa 17 study using data from the behavioral risk factor surveillance system reported that 45.4% of 18 444,649 adults had one or more of a longer list of morbidities that may be associated with 19 higher risk from covid-19 22 . another usa study estimated that 14.2% of participants in the 20 national health interview survey had more than two-fold risk and 1.6% had more than 10-21 fold risk 23 . 22 the evidence on covid-19 related complications among those people classified as high risk, 24 and therefore advised to shield, has mainly come from case series, expert opinions, 25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . unpublished reports. evidence from case reports found higher covid-19 related 1 complications among organ transplant recipients 24,25 , patients receiving active cancer 2 treatment (chemotherapy, radiotherapy or immunotherapy) 26,27 , and patients with 3 haematological cancers 28 . systematic review of case reports found higher covid-19 4 complication risk among copd patients, but the effect of copd severity was not 5 investigated 29 . patients with cystic fibrosis and sickle cell disease were regarded as high risk 6 for covid-19 complications based on expert opinions 30,31 . while pregnant women with 7 covid-19 were found to have higher risk of poor maternal and perinatal outcomes 32,33 , 8 outcomes were not investigated specifically for pregnant women with heart disease. there 9 was no evidence found for higher covid-19 related complications for patients on various 10 immunosuppressants 34 . a large community study in england found strong association 11 between severe asthma (hazard ratio 1.25) and covid-19 related mortality but they did not 12 investigate the risk of covid-19 infection or hospitalisation 9 . 13 in common with previous studies, we demonstrated that age was associated with one of the 15 highest relative risks of death. additionally, we showed the large extent to which age 16 contributed to adverse outcomes at a population level with 79.14% of deaths attributable to 17 age ≥70 years. the higher mortality in the elderly was mediated in part by their higher case-18 fatality but they also had a higher incidence of infection, possibly due to transmission within 19 care homes. their lower likelihood of being admitted to icu once hospitalised for covid-20 19 may have contributed to their higher case-fatality. previous studies have reported that men 21 are at highest risk of from our study demonstrated that men are less likely than 22 women to be tested for covid-19, less likely have confirmed infection and slightly less 23 likely to be hospitalised. they have comparable overall mortality from covid-19, due to 24 their lower incidence, but their case-fatality is significantly higher. 25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. this study adds to the existing evidence of the possible effectiveness of a shielding strategy 4 which is currently limited to mathematical modelling of population effects based on 5 assumptions [11] [12] [13] [14] [15] [16] [17] [18] [19] . ours was a large-scale, unselected general population study. the data 6 cover a period when shielding was in place. linkage of primary care, laboratory, hospital and 7 death data enabled us to examine a range of covid-19 outcomes and study a range of 8 exposure variables including the overall risk categories and their individual criteria. the 9 datasets were linked using exact, rather than probabilistic, matching. we were able to adjust 10 for potential sociodemographic confounders. the exposure data were collected prior to the 11 outcomes occurring avoiding potential reverse causation and recall or recording bias. we did 12 not have data on potential lifestyle confounding factors such as smoking and obesity, or 13 ethnicity. we did not analyse multimorbidity or other potential risk factors not currently 14 included in the high or moderate risk categories as the aim was to evaluate the current 15 strategy. the shielding and moderate-risk criteria were correct at the time of extracting data 16 but may be revised over time. 17 18 implications of findings 19 20 our findings suggest that our attempts to shield those at highest risk have not been as 21 successful as hoped, with those advised to shield experiencing higher rates of infection and 22 death. icu provision has been successfully protected but via systematic exclusion of those 23 with worse prognosis, rather than prevention of infection in those highest at risk. for 24 shielding to be effective as a population level strategy, the current criteria would need to be 25 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september 21, 2020. . expanded since three-quarters of deaths were associated with moderate risk criteria for which 1 shielding has not hitherto been recommended. in our study, more than one-quarter of the 2 general population would have needed to be effectively shielded to prevent over 80% of 3 deaths. since this is unlikely to be acceptable at a time when governments are under pressure 4 to ease lock-down restrictions, shielding is probably best viewed as an individual-level 5 intervention to be used alongside other population-wide interventions such as physical 6 distancing, face coverings and hand hygiene. 7 8 9 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september 21, 2020. . the dataset supporting the conclusions of this article is available in the glasgow safe haven 2 (https://www.nhsggc.org.uk/about-us/professional-support-sites/safe-haven/services/). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september 21, 2020. . bj, fh, and jp serves as the guarantor of the manuscript and accepts full responsibility for 1 the work and/or the conduct of the study, had access to the data, and controlled the decision 2 to publish. the corresponding author attests that all listed authors meet authorship criteria 3 and that no others meeting the criteria have been omitted. 4 cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . 34. minotti c, tirelli f, barbieri e, giaquinto c, d d. how is immunosuppressive status 8 affecting children and adults in sars-cov-2 infection? a systematic review. j 9 infect. 2020;s0163-4453. doi:10.1016/j.jinf.2020.04.026 10 11 12 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september 21, 2020. . 28) 6,767 (0.72) moderate moderate risk criteria chronic respiratory disease 149,325 (98.33) 2,540 (1.67) <0.0001 heart disease ) 1,174 (55.83) 929 (44.17) sex key: cord-324387-mnucvmr1 authors: dunn, michael; sheehan, mark; hordern, joshua; turnham, helen lynne; wilkinson, dominic title: ‘your country needs you’: the ethics of allocating staff to high-risk clinical roles in the management of patients with covid-19 date: 2020-05-14 journal: j med ethics doi: 10.1136/medethics-2020-106284 sha: doc_id: 324387 cord_uid: mnucvmr1 as the covid-19 pandemic impacts on health service delivery, health providers are modifying care pathways and staffing models in ways that require health professionals to be reallocated to work in critical care settings. many of the roles that staff are being allocated to in the intensive care unit and emergency department pose additional risks to themselves, and new policies for staff reallocation are causing distress and uncertainty to the professionals concerned. in this paper, we analyse a range of ethical issues associated with changes to staff allocation processes in the face of covid-19. in line with a dominant view in the medical ethics literature, we claim, first, that no individual health professional has a specific, positive obligation to treat a patient when doing so places that professional at risk of harm, and so there is a clear ethical tension in any reallocation process in this context. next, we argue that the changing asymmetries of health needs in hospitals means that careful consideration needs to be given to a stepwise process for deallocating staff from their usual duties. we conclude by considering how a justifiable process of reallocating professionals to high-risk clinical roles should be configured once those who are ‘fit for reallocation’ have been identified. we claim that this process needs to attend to three questions that we consider in detail: (1) how the choice to make reallocation decisions is made, (2) what justifiable models for reallocation might look like and (3) what is owed to those who are reallocated. as the covid-19 pandemic impacts on health service delivery, health providers are modifying care pathways and staffing models in ways that require health professionals to be reallocated to work in critical care settings. many of the roles that staff are being allocated to in the intensive care unit and emergency department pose additional risks to themselves, and new policies for staff reallocation are causing distress and uncertainty to the professionals concerned. in this paper, we analyse a range of ethical issues associated with changes to staff allocation processes in the face of covid-19. in line with a dominant view in the medical ethics literature, we claim, first, that no individual health professional has a specific, positive obligation to treat a patient when doing so places that professional at risk of harm, and so there is a clear ethical tension in any reallocation process in this context. next, we argue that the changing asymmetries of health needs in hospitals means that careful consideration needs to be given to a stepwise process for deallocating staff from their usual duties. we conclude by considering how a justifiable process of reallocating professionals to highrisk clinical roles should be configured once those who are 'fit for reallocation' have been identified. we claim that this process needs to attend to three questions that we consider in detail: (1) how the choice to make reallocation decisions is made, (2) what justifiable models for reallocation might look like and (3) what is owed to those who are reallocated. the covid-19 pandemic is placing increasing demand on health services, particularly in critical care. this has required healthcare providers to change well-established care pathways and staffing models. specialised roles are being created, including the development of 'intubating teams'. 1 these are teams made up of anaesthetists, anaesthetic nurses and operating department practitioners whose primary role is to provide safe intubation to critically ill patients able to benefit from intensive care therapy. more broadly, staff members are being reallocated from clinical specialities in other parts of the health service to acute care settings such as the intensive care unit or the emergency department. similar reallocation strategies are also being invoked in community health and care settings. these health and care professionals are being asked to provide care, or to deliver specific interventions, in environments that pose new and significant risks to themselves. there is particular concern that these professionals are at increased risk of acquiring covid-19 themselves. this is because the airway secretions of patients who become seriously ill with covid-19 contain the highest concentration of virus particles, and therefore, clinical interventions that expose healthcare workers to these secretions are particularly dangerous. these include interventions, such as intubation, that create aerosols of virus-laden secretions. 2 there is anecdotal evidence that covid-19 has qualities of dose-dependency and therefore those undertaking these high-risk interventions might develop more severe illness. 3 as members of clinical ethics advisory groups supporting hospitals at this time, we have encountered considerable uncertainty and worry among health professionals about whether and how they and their peers should be allocated to high-risk clinical roles. in this paper, we seek to make progress in analysing this issue. practical questions of staff allocation might be seen as ethically straightforward if a simplistic account of health professionals' obligations towards patients is endorsed. this account might go something like this: doctors have well-established professional duties towards patients by virtue of their social roles, and these duties extend to what is sometimes described as a 'special positive duty' to treat patients when they possess the relevant skills. such an account looks consistent with recent guidance produced in the uk, which states that 'doctors are bound by their duty of care for patients in the pandemic… to uphold this duty of care, doctors will need to be flexible, and may need to work in locations or clinical areas outside their usual practice'. 4 if doctors have a strong duty to treat, then any proposed means of allocating staff that maximises benefit for patients might be justified. the key question here is whether health professionals' 'obligation to treat' is sufficient to ground a requirement to discharge this duty in a pandemic scenario where doing so poses a high risk of harm to the professionals concerned. in line with other commentators, our view is that there are good reasons to conclude that health professionals' duties do not necessarily extend to an overarching and compulsory requirement to treat patients in such circumstances. writing in response to the previous sars epidemic, malm et al 5 identify compelling counterarguments against a number of claims that attempt to ground the 'obligation to treat'. such claims include the provision of explicit or implied consent, the social contract that health professionals have entered into and the existence of professional oaths or codes. their arguments are that, in the face of personal risk, the 'obligation to treat' position does not outweigh the duties professionals have to themselves and their families. if it is correct that professionals do not have an all-thingsconsidered duty to provide treatment to patients with sars, then whether this claim applies to covid-19 will depend in part on how the risk compares. since the risk for health professionals from covid-19 appears to vary with different roles, this might mean that professionals could opt out of some duties in this pandemic (performing interventions associated with increased risks) but not others (providing ancillary care, comfort care, palliative care and non-risky interventions to patients). one obvious objection to the view that health professionals do not have a 'duty to treat' in this context is that it must also apply also to those professionals who are not being redeployed but who are facing increased risks in the performance of their usual clinical duties. could those working in the intensive care unit (icu), for example, opt out of working in this setting during the pandemic on this basis? the 'implied consent-based' reasons might be stronger here since those who regularly work in the icu could reasonably expect their usual clinical activities to give rise to some additional risks. however, it is unlikely that icu staff, for example, have given explicit or implicit informed permission to take on greater than normal risks. furthermore, such consent, even if given, would not usually be taken to be binding. professionals might revoke their prior consent and now decline to fulfil these tasks. our conclusion here is that the duty to treat arguments, whatever force they have, apply both to those now working in higher risk areas and to those being redeployed. accepting the position advanced by malm and colleagues, and developed in this way, produces an interesting tension between the existence of an overarching obligation on the health service to meet patients' needs and the persuasive view that an individual health professional's duties do not extend to treating patients when doing so would place them at heightened risk of harm. this essentially is the ethical bind that lies at the heart of the issue: pandemic treatment needs to be provided, but no individual in a healthcare role is specifically obliged to provide it. the underpinning rationale for staff reallocation is that healthcare depends on having professionals with the appropriate skills in the right place at the right time. the aim is to ensure the best outcomes for all patients. the covid-19 pandemic is leading to increasing asymmetries of need across the whole health service, and reallocating clinical staff becomes an important responsive strategy, when staffing levels are finite, to address this issue. it makes sense to distinguish three distinct steps in any process of redeploying staff from one part of the healthcare system to another: 1. an overall assessment of the nature of the need and the asymmetry. 2. a deallocation or deprioritisation process in which staff are freed from their established roles and responsibilities. in what follows further, we are mostly concerned with the third step, but it is important to articulate how the first two steps ought to be managed. the contexts we are considering here are those where there is an asymmetry of provision and so, presumptively, a newly emerging and ethically problematic inequality in care for patients overall. it is important that the need for redeployment and the benefit achieved/harm avoided by redeployment is articulated clearly and that those involved understand the purposes of these changes. this means explicitly considering the losses to non-covid-19 patients. some staff will need to be removed from their current positions. this requires a prioritisation exercise in the 'home' area. this is ethically significant because it is very likely to affect the care of patients in ways that are problematic: if there are fewer staff in oncology, then oncology patients are likely to suffer. we propose the following three bands to approach the deallocation process. ► band 1: urgent. the group of patients for which there are significant and avoidable harms associated with delaying treatment. ► band 2: low priority. the group of patients for which (1) there are no, or limited, harms associated with delaying treatment and (2) the group of patients for which there is very low chance of treatment being effective. ► band 3: mitigation. the group of patients for whom there are measures that can be put in place to mitigate the harms associated with delaying treatment. these bands are intended to help with general allocation of staff as well as specific cases and case load management in the context of a pandemic. for general staffing, the number and specialisation of staff should be such that: (1) urgent cases can continue to be managed, (2) mitigation measures are established and (3) basic level care, including comfort and palliative care, can be provided, in line with the ethical principle of non-abandonment. 6 each of these bands should be considered temporally. for example, it might be required to assess whether there would be 'significant and avoidable harm involved in delaying treatment for 2 weeks'. the precise timeframe should be determined on the basis of the general resource pressure and also according to what is practical in the context. equally, as resources are stretched, the level of harm able to be accommodated in the urgent band will go up (and vice versa). in extreme resource scarcity, difficult decisions made about the provision of even basic level care might be required. patients should be reassured that the judgements about these bands will be revisited and that there is likely to be movement between bands, depending on context. transparency here is important. once an overall strategy of deallocation has been formulated, the question of reallocation should be attended to. here, an additional set of issues arises: what approach should be adopted to determine which health professionals who are identified as being 'fit for reallocation' are chosen for redeployment? there are three subsidiary questions here: (1) what constitutes a justifiable process for deciding which staff are chosen to be reallocated, (2) what reallocation models for making these choices are justifiable and (3) what is owed to those reallocated to high-risk clinical roles? what would constitute an appropriate process to make decisions about staff reallocation? addressing the first question requires an appropriate procedure for making a choice about reallocation to be determined. there are three broad options for determining how such choices could be made: option 1: no choice. the first option is for those who are organising or coordinating healthcare delivery (perhaps administrators or clinical leaders in a hospital) to redeploy staff in a way that best addresses the new asymmetry of need. adopting this option requires staff to be conscripted into roles, irrespective of their preference. health professionals could, in principle at least, be unable to opt out of being reallocated. this approach is likely to be efficient, particularly given the need to make decisions rapidly. it may also be the most informed approach, since those at higher levels will potentially have most knowledge of the relevant logistics and clinical demand. however, such an approach will be manifestly unfair and, arguably, unethical: it would allow no staff member to retain control over how their job is configured and enacted, nor potentially to uphold other duties that they possess beyond those connected to their working lives. option 2: individual choice. the second option accords the choice about reallocation to each individual professional. on this option, professionals are able to volunteer, or not, on the basis of their individual preferences. the pros and cons of this approach to making a choice are considered below, in the 'volunteering model' of redeployment. option 3: collective choice. the third option comprises a series of potential strategies of choosing that are connected by the fact that they accord some decision-making authority to those in the relevant group of professionals who are 'fit for reallocation'. this option encapsulates a range of decision-making frameworks for collective choice. such frameworks would include deliberative, consensus-building decisions or a consultation approach in which the final decision is shaped outside of the collective by an administrator or clinical leader. there are two main arguments in favour of collective choice. first, giving control over the reallocation process to those who are in the frame to be reallocated is likely to ensure that wellestablished and productive team dynamics are not disrupted (although it is possible that, if no consensus can be reached, this reality might produce new and problematic dynamics of its own). second, this approach also preserves individuals' moral agency. the relevant professionals get to decide the basis on which they ought to discharge their responsibilities as a team that recognises their shared responsibilities to act in the interests of patients when there is no one else who can fulfil this task. concerns might, however, arise. a participatory model of decision making might be easiest and most practical with small groups of professionals, and it may be challenging or impossible with large or disparate groups to reach a meaningful consensus in a short period of time. moreover, an emerging consensus might be forged in a way that largely replicates existing and potentially toxic power dynamics within a group, for example, between doctors, nurses and allied health professionals or between grades within any one such cohort. whether it is feasible or appropriate to involve professionals themselves in determining decisions about reallocation, it is also important to consider different reallocation models. we think that there are three main models worthy of consideration. of course, if the choice rests in the hands of the community of professionals, these professionals might diverge from these models in the process of consultation or building consensus. they might also decide that aspects of these different models should be combined or that additional components (such as opt-out procedure) should be invoked. notwithstanding this, considering viable models provides a useful starting point for the strategies that a collective decision-making process might consider. the volunteering model adopts an 'opt-in' process to select staff for redeployment. potential volunteers would need to be provided with full information about the roles that they would be adopting, including information about the likelihood of the raised risks involved. it would also be important to explain the background rationale for redeployment to potential volunteers, outlining that redeployment is necessary to meet the health service's basic duty to meet all patients' health needs. in so doing, volunteers will be in a position to make a decision in line with their personal assessment of the ethical trade-off to be made. candidate volunteers are likely to have different motivations (altruistic or non-altruistic) for volunteering; these motivations should not necessarily have implications for whether an individual is permitted to volunteer. enabling volunteers to come forward recognises individuals' understanding of their own professional identity or sense of vocation and the sense of obligation that many individuals will freely accept pursuant to that identity or sense of vocation. not only then will people remain in full control of their actions within their professional roles, but they will also have an opportunity to freely realise an important part of their vocation at this pivotal moment in their own professional and personal lives. the viability of the volunteering model will hinge on local characteristics. it might not be possible to recruit sufficient volunteers, particularly if people are being asked to step into specialised roles drawn from a small cohort of qualified personnel. there might also be justifiable limits placed on those eligible to volunteer. some potential volunteers might be at higher than average risk of harm through exposure to covid-19 once reallocated. this might include, for example, pregnant women (where there is current uncertainty about the risks to the fetus), staff from black and minority ethnic backgrounds (where there is current uncertainty about the heightened risk that these groups face), staff with pre-existing health problems, older age or compromised immune systems and, potentially, staff identified as being of particular risk of stress or burnout. an overall judgement needs to be made about whether the healthcare system's obligation to ensure that professionals are protected in the performance of their job outweighs the benefit to patients in them taking on this role. if so, it would be justifiable to prevent these people from volunteering. preventing people from volunteering might look unreasonably paternalistic, since we usually allow people to make decisions in their everyday life that are associated with significant risk. indeed, even in their professional lives, doctors are permitted to volunteer for risky roles in overseas humanitarian organisations, for example. however, if a volunteer were to be at elevated risk of critical illness, and then to become critically ill, this would consume limited resources and reduce staffing levels further. this is also likely to justify a rule that excludes some individuals from volunteering. even if it is possible to achieve a sufficient pool of (lower risk) volunteers to meet clinical demand, there is a further question about fairness and the distribution of risk. for example, imagine that out of a pool of 100 eligible anaesthetic staff, 50 volunteers are to be deployed in intubation teams. in that situation, assuming that risk correlates with exposure, those 50 volunteers will be exposed to an additional risk of infection that is two times the risk that they would have faced if the task had been divided evenly among the whole team. furthermore, those not opting-in will face no additional risk and might be thought to be freeriding on the good will of their colleagues. so, while the volunteering model does allow individuals greater control over the risks that they are exposed to, it will permit potential unfairness in how exposures to those risks are configured. an alternative (or indeed necessary addition) to the volunteering model, and one which directly attends to that model's intrinsic unfairness, is to randomly allocate staff for redeployment. random allocation is arguably the fairest way to fulfil this requirement as it gives everyone an equal chance of being exposed to additional risk. of course, this approach leaves the decision entirely to chance and thereby does not enable staff members to retain control over the configuration of their working lives or to realise their sense of professional identity in practice. the lottery might be configured such that people can be allocated to different kinds of roles, depending on how clinical needs arose locally. there could, for example, be a lottery for redeployment to high-risk frontline acute care roles, and one for redeployment to roles that pose lower risks. eligibility for entry into these different lotteries could be configured on the basis of background skills, as well as pre-existing conditions that render the person more likely to come to harm. equally, as in provisions that often characterise a draft into military service, a permission for conscientious refusal to be entered into the lottery could be built into the system. this would allow for individuals to provide reasons why they should not be included, whether clinical or personal, which should be attended to compassionately. a final model of distribution endeavours to share the risks equally between all, rather than randomly allocating staff. on this model, everyone participates, and a rota might be set up that ensures that each eligible member of staff is broadly exposed to the same amount of risk. this model, like the random allocation model, removes individual control and specific choice in favour of fairly sharing the risks. the key difference between equal sharing and random allocation is how we handle our knowledge of the risks and where they are likely to be incurred. in a setting where we have good reason to think that the risks to staff are higher when intubating patients with covid-19, say, it makes sense to use this knowledge to improve risk sharing in the distribution process. adopting this model ensures that those redeployed into high-risk roles do not face inequitable exposure to risk. roles should be devised and scheduled in such a way that those who are allocated share the responsibility (and risk) equally between themselves. such roles would also need to be flexible in order to ensure that all professionals are maximally enabled to discharge their additional responsibilities, including those relating to childcare or other caregiving activities. it would also be unjustifiable for one person to be allocated such that they undertake more intubations than others or for that person to be positioned such that they consistently undertake more high-risk interventions. what is owed to those allocated to high-risk roles? once an ethically appropriate model has been adopted, it is necessary to consider whether anything special is owed to those professionals redeployed to high-risk roles. these roles are being configured in ways that do not adhere to standard and agreed responsibilities and entitlements: people are being tasked with providing care that is risky to themselves. regardless of which model is adhered to, the high risks associated with redeployment give rise to a duty on the health service to provide appropriate acknowledgement of those facing these risks. depending on what is practically feasible, this could comprise an additional financial payment or professional recognition of some kind. those staff members from outside the uk who work in the health service on temporary employment visas, and who are redeployed in these ways, could have their immigration status, and that of their families, changed such that they are given 'indefinite leave to remain' in the uk. importantly, these kinds of acknowledgement would function to recognise the special demands of these roles. therefore, such acknowledgements are not being instigated as incentives to encourage participation in the volunteering model, nor can they be opted out of in any decision-making process for determining how reallocations occur, including a collective one (though, of course, any particular individual might decline acceptance of this acknowledgement). thus, even if an appropriate acknowledgement has the de facto effect of incentivising people who might otherwise not volunteer to be redeployed, this would not undermine their justification within that model of reallocation. those redeployed to high-risk roles need to be appropriately prepared to undertake their responsibilities in these roles. they ought to be given the necessary training and support to be able to work to the requisite level and inducted into established clinical teams. additionally, limited stocks of personal protective equipment need also to be allocated to those redeployed into high-risk roles. there has been discussion about whether healthcare professionals should be prioritised for access to the icu or ventilation if they acquire covid-19 and require critical care, when they are judged to be at equal clinical need as a non-health professional when there are insufficient resources for all patients. 7 if the arguments that underpin this claim are taken to be convincing, then the health system might also elect to guarantee additional or equal high priority to those who are being redeployed. it is also arguable that, at a national level, priority provision for compensation should be made for all those being reallocated to high-risk roles, whether on a voluntary basis or not, in the event of their death or of long-term negative health consequences associated with becoming seriously ill with covid-19. the allocation of health professionals to high-risk clinical roles raises distinctive ethical uncertainties. while there is an overarching requirement for health services to meet the needs of patients with severe illness, there is no specific obligation that falls on any individual health professional to provide treatment. equally, there are tensions between ensuring that staff are allocated to meet needs and ensuring a decision-making process that most fairly and ethically distributes the exposure to risks arising through reallocation. in this paper, we have sought to clarify the steps that need to be considered in any defensible process of allocating staff to high-risk clinical roles in the face of the covid-19 pandemic. precisely how these steps are attended to in practice will be dependent on context: the size of the workforce, the specific manifestation of patients' needs across a health service and the ways in which roles, responsibilities and working relationships are configured. having said that, a justifiable process of allocating staff in context will need to attend carefully to distinctive stages of decision making: first, to decisions about both deallocation and reallocation, and second, to decisions about how the process of reallocation is determined and what specific models of reallocation are adopted in this process. twitter mark sheehan @mark_sheehan_ox, joshua hordern @oxfordhvp, helen lynne turnham @helenturnham and dominic wilkinson @neonatalethics contributors all authors contributed to the preparation of the draft manuscript. md led the initial drafting and formulation of the arguments. he also completed the final draft. ms, jh, hlt and dw contributed to revising the draft, adding academic content in the revision process. all authors have agreed the final draft. disclaimer the views expressed are those of the author and not necessarily those of the nhs, the nihr or the department of health and social care. clinical guide for the management of critical care patients during the coronavirus pandemic consensus guidelines for managing the airway in patients with covid-19 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention ethical dimensions of covid-19 for frontline staff. london: royal college of physicians 2020 ethics, pandemics, and the duty to treat nonabandonment: an old obligation revisited fair allocation of scarce medical resources in the time of covid-19 groups providing support to nhs trusts within the south-east of england. this includes, at the present time, providing advice on the issues discussed in this article. key: cord-348138-wca7jaje authors: safarpour, hamid; farahi-ashtiani, iman; pirani, davoud; nejati, bayram; safi-keykaleh, meysam title: risk communication in the covid-19 outbreak: two sides of the same coin date: 2020-09-09 journal: disaster medicine and public health preparedness doi: 10.1017/dmp.2020.327 sha: doc_id: 348138 cord_uid: wca7jaje nan one of the most significant and effective interventions in the response of public health to any event is establishing an active engagement with what is known, as well as what it takes to get more information, in order to minimize the negative consequences. the outbreak of sars-cov-2 has challenged public health systems and their capacity for establishing effective engagement with the communities. 2 production, transmission, and spread of the information related to covid-19 are accompanied by remarkable rumors and misinformation. 3 misinformation disrupts people's perception of risk and diverts community from understanding the original risk. 4 meanwhile, ineffective communication in risk and unreliability situations could lead to consequences, such as the loss of trust and reputation, socioeconomic effects, psychological effects, and, in worst case scenarios, loss of lives. 2 the production and release process of scientific and public health information and the adoption of this information by the media as the main source of correct information for the citizens include various stages, each of which could cause exaggeration or misinformation. 1, 5 the rapid increase of internet-based health news and information might encourage the selection of media and academic research articles that exaggerate the power of causal inference. 1 reporting the state of affairs to the media in due time and in an honest way by the authorities can lead to dissemination of correct and timely information. trustworthiness of official information channels about covid-19 may be influenced by the communities' trust on those official channels. it is recommended that communication behaviors be improved to solve miscommunication at times of pandemics like sars-cov-2. because of the constant changes in the effects of covid-19 and the exaggerated public perception of its mortality risk because of the difficulty of estimating the mortality rate, 6 the response of global media to covid-19 remains unbalanced. 1 to protect global health security, it is essential that developed dialogue and altruistic intentions with appropriate authorities are focused by media. 1 effective communication not only brings about a decrease in the risk of misbehavior, such as unnecessary hospital visits, but it also assists in removing fake information and discrimination against the patients and their visitors. 5 globally, the total number of social media users is estimated to grow to 3.29 billion users in 2022, which will be 42.3% of the world's population. 7 moreover, data gathered on the global television market showed that there were 1.67 billion pay tv households worldwide in 2018. therefore, 1 way to ensure proper communication is to use social media, radio, and tv channels and ensure the constant presence of the media using the world health organization (who) principles for effective communication: accessible, actionable, credible and trusted, relevant, timely, and understandable. 8 risk communication and community engagement contribute to the prevention of infodemics (too much information about a problem, which makes it difficult to identify the solution) 2 and increase the chance of health advice following for self-protection by creating trust in response. 2, 9, 10 academic circles strongly advise to avoid panic 6 since fake news lead to undue fear or lack of enough sensitivity in taking preventive measures, thus increasing spread of the disease. 5 establishing honest engagement with the people through licensed official media with cooperation of the ministry of health and other governmental agencies could prevent miscommunication and misunderstanding. 11 people have every right to receive sufficient information about the risks that threaten their health to be able to conceive of the situation. risk perception among the affected population is usually different from that of the experts and officials. risk communication and community engagement for monitoring, reporting the cases, tracing the contacts, taking care of patients, offering clinical service, and compiling local support for any kind of logistical and operational demand are necessary for responding. based on the interim guidance of the who, all governments can engage their communities in many ways, including stabilizing communication proactively, identifying community influencers (community and religious leaders, health workers, and traditional healers), and anticipating peoples' needs, concerns, beliefs, and attitudes. 2 risk communication and effective community engagement can minimize social disorder, as well as protect health, the economy, and tourism. 2 disaster risk communication, in general, and the case of covid-19, in particular, resemble 2 sides of a coin. on 1 side, there is timely, correct, and trusty risk communication, which contributes to a timely and proper response by public participation. on the other side, there is flawed risk communication and faulty communications, which result in an ineffective response, making the situation worse. therefore, it is recommended that the health systems of countries provide correct, timely, and trusted information and training packages for their people through media with the participation of the who and taking into account the cultural contexts, disease and epidemic status, and population features, including various age groups as well as education and awareness levels. furthermore, it is recommended that the government officials encourage the people to participate in the prevention and care processes via social media and other media channels. toning down the 2019-ncov media hype -and restoring hope world health organization. risk communication and community engagement readiness and initial response for novel coronaviruses (ncov): interim guidance v1 statement in support of the scientists, public health professionals, and medical professionals of china combatting covid-19 fact-checking as risk communication: the multi-layered risk of misinformation in times of covid-19 2019-ncov, fake news, and racism covid-19: fighting panic with information the future of social media in marketing world health organization. who strategic communications framework for effective communications risk communication and public confidence in health departments risk communication, trust and patient commitment risk, communication and trust: towards an emotional understanding of trust the authors have no conflicts of interest to declare. key: cord-322815-r82iphem authors: zhang, weiping; zhuang, xintian; wang, jian; lu, yang title: connectedness and systemic risk spillovers analysis of chinese sectors based on tail risk network date: 2020-07-04 journal: nan doi: 10.1016/j.najef.2020.101248 sha: doc_id: 322815 cord_uid: r82iphem abstract this paper investigates the systemic risk spillovers and connectedness in the sectoral tail risk network of chinese stock market, and explores the transmission mechanism of systemic risk spillovers by block models. based on conditional value at risk (covar) and single index model (sim) quantile regression technique, we analyse the tail risk connectedness and find that during market crashes, stock market exposes to more systemic risk and more connectedness. further, the orthogonal pulse function shows that herfindahl-hirschman index (hhi) of edges has a significant positive effect on systemic risk, but the impact shows a certain lagging feature. besides, the directional connectedness of sectors shows that systemic risk receivers and transmitters vary across time, and we adopt pagerank index to identify systemically important sector released by utilities and financial sectors. finally, by block model we find that the tail risk network of chinese sectors can be divided into four different spillover function blocks. the role of blocks and the spatial spillover transmission path between risk blocks are time-varying. our results provide useful and positive implications for market participants and policy makers dealing with investment diversification and tracing the paths of risk shock transmission. in recent years, financial markets have become extremely volatile, especially the global financial crisis in 2008 and the continued global plunge in global stock markets caused by the covid-19 1 in 2020. this has drawn lots of attention from academia trying to measure systemic risks and grasp the system risk spread across sectors or markets. there is some evidence that financial systemic risk threatens "the function of a financial system" (european central bank (ecb), 2010) and impairs "the public confidence or the financial system stability" (billio et al., 2012) . it is widely observed that systemic risk spillovers have a significant "production-contagion-re-contagion" patterns. for the interconnectedness within a market, once one sector encounters a risk shock, the risk will affect other sectors through strong linkages and contagion mechanisms, and even spread to the entire financial markets. in this context, investigation into the connectedness among financial markets and the systemic risk spillovers contagion mechanism across sectors or markets become important and necessary, which is helpful for regulars to identify sources of risks and formulate intervention strategies, and for investors to make smarter portfolio strategies. the complex relationship between financial markets and their internal elements is the carrier of systemic risk transmission, and their connectedness patterns or structures play an important role in the formation and infection process of systemic risks. moreover, the concept of systemically important financial institutions (sifis) can be extended to broader markets or sectors. some scholars find that sectors have different response to shocks due to their own market and sectoral heterogeneity and risk features (ewing, 2002; ranjeeni, 2014; yang et al., 2016; wu et al., 2019) . for stock market participants, sectoral indexes can be used as a significant indicator to access portfolio performance. identifying which sector is the most influential and how systemic risks spillover among sectors is essential for effective risk management and optimal portfolios. therefore, in addition to cross-institution risk spillovers, cross-sector and cross-market risk transfer has become increasingly prominent. it not only greatly increases the probability of cross-contagion of financial risks, but may also trigger broader systemic risks. referring the knowledge of sifis, this paper measures the systemic risk of each sector in chinese stock market, analyzes the spatial connectedness of various sectors to determine which sectors play a leading role in risk spillover or market co-movements, and explores the risk spillover transmission paths. the results of this study could manage the systemic risk and preserve financial stability, which in turn, contribute to the smooth functioning of the real economy. although its (cross-sectors) great important, the existing literature on this topic is relatively scarce. this study we first develop and apply the tail risk network with the single-index generalized quantile regression model of h rdle et al. (2016) , which takes into consideration non-linearity a relationships and variable selection. further, we investigate the tail risk network topology and its dynamic changes to analyze the spatial connectedness of 24 chinese sectors during 2007-2018. in order to understand the impact of network connectivity on systemic risk, we draw on the orthogonal pulse function to find that hhi of edges has a significant positive effect on systemic risk. second, we adopt pagerank index to identify systemically important sector. it is observed that although the systemically important industries are time-varying, and the utilities and financial sectors (including banks, insurance and diversified finance) still should be received more attention. finally, we innovatively use block models to assess the roles of different spillover blocks, and excavate the transmission paths of risk spillover in different blocks. the remainder of the paper is organized as follows. in section 2 related literature about our study is outlined. section 3 shows the data and methodology. section 4 is the empirical results. section 5 presents our conclusion. systemic risk threatens the stability and functioning of financial markets when the stock market is confronted with sharp downtrend, reduced with market confidence and willingness of risk taking. and it is considered to be the risk of causing a large number of participants in the market to suffer serious losses at the same time and quickly spread into the system (benoit et al., 2017) . a number of researchers have discussed the measurement of financial system's systemic risk and the macroprudential risk management approaches (laeven et al., 2016; acharya et al., 2012) . the relevant literature in this filed can be roughly divided into four categories: the first is conditional value-atrisk (covar). adrian and brunnermerier (2007) put forward the covar, defined as the var of the financial system when a single market or sector encounters some specific events. and then they proposed a measure of systemic risk, δcovar (adrian and brunnermerier, 2016), which is defined as the difference between covars when a sector is and is not under turmoil. girardi and ergun (2013) used covar approach to measure the systemic risk contribution of four financial sectors composed by lots of institutions, and investigated the relationship between institutional characteristics and systemic risk contributions. the second method emphasizes the default probability of financial institutions through the interrelationships between financial assets. for example, principal component-based analysis, e.g. kritzman et al. (2011 ), bisias et al. (2012 , rodriguez-moreno et al. (2013) and others; cross-correlation coefficient-based analysis, e.g. huang et al (2009 ), patro et al. (2013 . the third category uses the copula function to calculate the systemic risk with biased tail of stock market. krause et al. (2012) adopted copula function to calculate the nonlinear correlation of time series and established an interbank lending network. the results show that externally failed banks can trigger potential banking crisis and analyze the spread of risks within the banking system. the last category looks at an institution's expected equity loss when the financial system is suffering losses. acharya et al. (2017) proposed marginal expected shortfall (mes) and systemic expected shortfall (ses), which are two systemic risk measures. further approaches take into the information of market capitalization and liability, such as, the srisk (brownlees et al., 2017) and the component expected shortfall (ces) (banulescu et al., 2015) . both the srisk and ces methods especially focus on the interdependence between a financial institution and the financial system, and ignore the interconnectedness among financial agents from a whole system perspective. however, as pointed out by bluhm et al. (2014) macro-prudential monitoring is still at a very early stage, quantifying the magnitude of systemic risk and identifying the transmission paths need more scientific analysis. to do so we apply network methodology to quantify the interconnectedness among sectors in financial system. network theory has always been a leading tool for analyzing the intricate connectedness relationship because it can conquer the "dimension barrier" of multivariate econometric models and simplify complex financial systems (acemoglu et al., 2015; battiston et al., 2016; huang et al, 2018) . and in financial network, financial entities (e.g. institutions, sectors and markets) are abstracted to nodes, and correlations among agents are abstracted to edges. the early literature on classic network construction methods is correlation-based networks, such as the minimal spanning tree (mst) (mantegna, 1999) , the planar maximally filtered graph (pmfg) (tumminello et al., 2005) and the partial correlation-based network . the main disadvantage of the correlation-based network is that the economic or statistical meanings of their topological constraints are unclear (onnela et al., 2003; kenett et al., 2015; zhang et al., 2019) . more recently, several econometric-based networks have been constructed to uncover information spillover paths and contagion sources (výrost et al., 2015; ly csa et al. 2017; belke et al. 2018) . o the extensively econometric-based networks are classified into three groups: (i) mean-spillover network (also called granger-causality network), which is proposed by billio et al. (2012) ; (ii) volatility spillover network, e.g., the variance decomposition frame-based network of diebold and yilmaz (2014) , and the garch model-based network of liu et al. (2017) ; (iii) risk spillover network, which major includes tail-risk driven network of hautsch et al. (2015) and h rdle et al. a (2016), and extreme risk network of wang et al. (2017) . of course, many studies have discussed the application of spillover networks. this study is distinguished from existing information spillover literature by focusing on systemic risk spillover, especially tail risk spillover. the last strand is associated with the tail risk spillover network and its applications. hautsch et al. (2015) used the least-absolute shrinkage and selection operator (lasso) method to build a tail risk network for the financial system, and evaluated the systemic importance of financial firms. the 2016) and is constructed by semiparametic quantile regression framework that considers non-linearity and variable selection. they have discovered the asymmetry and non-linear dependency structure between financial institutions and identified systemically important institutions. wang et al. (2017) applied caviar tool and granger causality test to measure systemic risk spillovers, and then proposed an extreme risk spillover network for studying the interconnection among financial institutions. our work contributes to the literature in three major aspects. first, we analyze the characteristics of spatial connectedness and systemic risk spillovers of tail risk network using sectoral data in chinese stock market. we extend the literature on interconnectedness and systemic risk of sectors level data while extant literature generally focuses on the financial institutions data. second, we innovatively adopt orthogonal pulse function to explore the impact of network connectivity on systemic risk of financial system. besides, we employ pagerank index to identify systemically important sectors that spread systemic risk spillovers to entire system. third, we apply block model in our study to assess the roles of different spillover blocks of 24 sectors in risk contagion process, and excavate the tail risk transmission paths and contagion mechanisms. the existing literature focuses more on the network topology and the identification of important financial institution nodes in the financial institution network, but lacks the risk propagation mechanism analysis. importantly, it is necessary to clarify how system risk transfers across sectors. in order to analyze the systemic risk spillovers and its interconnectedness across chinese sectors, we select the weekly closing prices of 24 sectors in china's stock market (name abbreviations , of 24 industries are seen in appendix table a1 ). the sample data ranges from january 4, 2007 to december 31, 2018 (total of 613 trading weeks), and the industry classification data is available from wind database. our analysis centralizes the weekly returns of each sector, which is defined as . table 1 presents the descriptive statistics for weekly returns of 24 sectors , = ln ( , / , -1 ) during the sample period. note that maximum of return series except for pbls and df, is less than the absolute minimum, implying that there is extreme risk in the left-tail of the yield distribution. besides, the jb statistics for each sector is significant at 1% level that rejects the null-hypothesis of gaussian distribution for the series. thereby, we can use single-index model (sim) quantile regressions to estimate the covar. apart from the closing price data, motivated by , we also collect five macro state variables and four internal variables. the macro state variables contain the weekly market returns, the market volatility, the real estate sector returns, the credit spread and liquidity spread, which depict the economic situation. the internal variables contain the size, the turnover rate, the p/e ratio and p/bv, which reflect the influence of industry from the fundamental characteristics. the detailed definition of these variables can be seen from table 2 . notes: *** denote significance at 1%. table 2 variable definitions. weekly market returns calculated by shanghai securities composite index. defined as the conditional variances of the shanghai composite index returns estimated by garch(1,1) real estate sector returns the weekly logarithmic yield of real estate index. credit spread difference between 10-year treasury bond and aaa-rated corporate bond yield liquidity spread difference between three-month shanghai interbank offered rate and three-month treasury bond yield. size defined as the turnover, which is equal to the volume multiplied by the average price. the weekly turnover rate can be available from wind info. p/e ratio the weekly price earnings ratio. p/bv calculated by price/book value. in this paper, we adopt the novel tenet framework proposed by h rdle et al. (2016) to a measure the tail risk interconnectedness among various industries and build dynamic evolution tail risk network in china's stock market. as we all known, adrian and brunnermeier (2016) only perform linear interaction between two financial institutions, however, chao et al. (2015) find that any two interacting financial assets show non-linear dependency, especially in uncertain economic periods. therefore, accounting for non-linearity dependency, h rdle et al. (2016) develop the a bivariate model to a high-dimensional state and solve the variable selection problem by single-index quantile regressions. accordingly, we also exert three estimation steps to complete tail risk network's construction. first step, the var for each industry i at quantile level should be first estimated by ∈ (0,1) using linear quantile regression. given the return of industry i at time t: represents the macro state variables, is the estimated parameters. -1 second step, the covar is the basic element of the network, and it can reflect the systemic (tail) risk interconnections of sectors. the tail risk interconnectedness from one industry to another in the tail risk network stands for the systemic risk contagion and network spillovers. thus the covar should be second estimated. we perform a risk connectedness analysis by accounting for nonlinear dependency in high dimensional variables, and adopt sim quantile regression technique to gain the systemic risk contribution due to a change in the relevant industry. it is obtained via 2 : , -1 , , -1 } -, = { 1, , 2, ,…, , } independent variables including the returns of all industries apart from industry j; n denotes the number of sectors; is the internal features of every industry, i.e., size, turnover rate, p/e , -1 ratio, p/bv; is the parameters, and . the represents network risk triggered by tail-event, which includes of all other relevant industries on industry j and the non-linearity that is reflected by the function quantifying the marginal effect of covariates, and is the componentwise where could reflect the risk spillover effects among sample industries. note that we only centralize the partial derivatives of industry j on the other industries ( ) in given network. additionally, we can also use rolling window estimation to estimate all |parameters. last step, the directed tail risk network should be constructed. it is denoted as graph g (v, e) with a set of nodes and a set of edges e. the adjacency matrix with all = { 1 , 2 ,…, } linkages at window s is to be: (7) where denotes the name of industry i. the absolute value of is the element of weighted matrix, and it | is the risk connectedness from industry i to j. (1) network concentration concentration is also an important indicator of network structure and represents the density of the linkages. following fang et al. (2019) , we apply the herfindahl-hirschman index (hhi) that is generally used to measure the extent of concentration in an industry. hhi index equals the sum of the square of market share of each financial institution, and can be used to measure the degree of monopoly. thereby, the hhi index can reflect the degree of risk network concentration, which is consistent with our definition. it is calculated by: where is the number of edges connected for the node i at window s, is the total number of network edges, and denotes the proportion of connected edges of node i to in window , which stand for the degree of node i's relative linkages. (2) node strength the node strength considers not only the number of directly connected edges but also the weights of edges. it can be seen from the adjacency matrix of formula (7) that risk spillover is directional. therefore, this article pays more attention to the sectors that spread or absorb risks, that is, the out-strength (in-strength) is used to measure the risk contagion (absorption) ability of each sector. now, we introduce two directional measures of the sector strength, i.e., the out strength and the in strength, and these are used to measure each sector's outgoing and incoming connectedness, respectively. the out-strength (os) of sector i is the sum of weights of outgoing edges from | | | sector i to other sectors, as follows: in-strength (is) of a sector i is the sum of weights of incoming edges from other sectors to | | | sector i, as follows: (3) pagerank assume that node i has a direct link to node j, the more important of node i is, the higher the contribution value of node j is. thereby, the pagerank reflects the connectedness between one industry and another while considering the influence ability of its neighbors. pagerank algorithm is a variant index of the eigenvector centrality in "adjacency matrix". as in wang et al. (2019) , we compute the pagerank (pr) indicator through the iterative method which introduces a dynamic process of information spread. first, we compute the centrality value of sector i based on the risk network matrix (eq. (7)). and the effect weight is normalizing as follows: where denotes the effect weight by sector i on sector j at window s. second, we adopt the , pagerank algorithm proposed by page et al. (1999) to get pagerank: , where d is a damping factor (generally set to 0.85), is the pagerank of sector i and its value always positive. a higher value means that sector i has a greater contribution to systemic risks of network. the block model is the main method for spatial cluster analysis of the complex financial networks. it is first proposed by white et al. (1976) , which is a method of studying network location modules and is to view social life as an interconnected system of roles. later, scholars conducted in-depth research and promotion of this concept from many aspects. in addition, many scholars also use the "block model" to study some specific issues, such as the study of the scientific community (breiger, 1976) , the world economy (snyder et al., 1979) , the organizational issues and the regional contagion effects (shen et al., 2019) . in short, the concept and the method of the block model have been widely used. therefore, the block model could identify the aggregation characteristics among individuals to divide the network into location blocks. actually, this method not only determines the members included in each block, but also analyzes the role played by each block in the risk propagation process, and explores the risk spatial propagation path (li et al., 2014; zhang et al., 2020) . there are four role blocks: (i) main benefit, members of this block receive links not only from external members but also from their own members, and the proportion of internal relations is large, while the proportion of external relations is small. in extreme cases, it is called isolated block, that is, the block has no connection with outside. (ii) main spillover, members of this block send more links to other blocks, but send less links to inside members, and receive less links from external. (iii) bilateral spillover, its members send more links to their own members and other blocks' members, but receive very few external links from other blocks. (iv) brokers, its members both send and receive external relationships, while there are fewer connections between their internal members. motivated by wasserman et al. (1994) , we analyze the relationship of each member from block by the evaluation indicators shown in table 3 . there are nodes in block , then the number of possible relationships inside is . the entire network contains n nodes, so ( -1) all possible relationships among members in are . in this way, we expect the total ( -1) relationships expectation ratio of the block to be . ( -1)/ ( -1) = ( -1)/( -1) table 3 four types of blocks. received linkages ratio internal linkages ratio ≈ 0 > 0 ≥ ( -1)/( -1) bilateral spillover main benefit < ( -1)/( -1) main spillover brokers in this part, we apply sliding windows to estimate time-varying var, covar and construct dynamic evolution tail risk network. we use linear or non-linear quantile regression model to estimate var and covar at the quantile level 3 , and the sliding window size is set to be = 0.05 trading weeks (corresponds to one year's weekly data). though the way, we get whole = 50 . to obtain the preliminary analysis about the whole sample dataset, we present = 563 the log returns and covar of 24 sectors, and the dynamic evolution about the total connectedness and average lambda of tail risk network from 2008-01-04 to 2018-12-31 (window size w=50, w=563). from fig. 1 , we can find that chinese stock market ( fig.1 (bottom) shows the dynamic evolution of the total connectedness of the tail risk network. we observe that the value appeared twice λ obvious peaks, corresponding to the us subprime mortgage crisis in 2008 and the domestic stock market turmoil in 2015. however, the total connectedness of tail risk network had at least five peaks, corresponding to the us subprime mortgage crisis in 2008, the european debt crisis in 2011, the money shortage in 2013, the stock market turmoil in 2015 and the trade friction between us and china in 2018. this phenomenon reflects that the total connectedness of tail risk network is more sensitive to the shock of chinese stock market, and may be an alarm before the market turmoil. in this section we first measure the network edge concentration to reflect the overall connectivity of chinese sectoral tail risk network, and investigate the impact of network edge concentration on systemic risk at the global level. fig.2 shows the dynamic evolution trend of the sectoral tail risk spillover network edge concentration. from fig.2 we can see that the sectoral tail risk network edge concentration (hhi) has apparent periodic variation characteristics. this finding is basically consistent with the periodic evolution of systemic risk in the time dimension. further, the first and last peaks are most notable, which correspond to the 2008 financial crisis and the 2015 domestic stock market turbulence. now, we take the period (2015/1/30-2016/12/30) of the last peak as an example. in this period, the most significant change of the hhi value is a rapid climb from 0.187 (may 2015) to 0.228 (july 2015). as the potential risks continue to accumulate, the concentration of edges reaches a maximum of 0.232 (january 2016). in the early stage, the chinese government issued a series of economic reform measures, which stimulated investors' blind optimistic expectations. besides, large-scale funds of financial institutions entered the stock market through the way of "highly leveraged" off-market allocation, and the excessive risk-taking behavior of different types of firms in the stock market has led to an increase in indirect correlation. gradually, due to the downward pressure of china's macro economy and the strict investigation of off-market allocation by the china securities regulatory commission, a large-scale withdrawal of credit funds and an avalanche-like chain reaction led to the 2015-2016 stock market crash. this shows that as the market turbulence intensifies, the concentration of the risk network will increase, and the edges of the entire network are mostly concentrated in a few highly centralized sectors. at this time, the stability of the network structure is very poor. if these nodes encounter a risk shock or infection, the systemic risk will quickly spread throughout the network, and the risk spillover effect between sectors will be significantly strengthened. conversely, as the risk is released, the market gradually stabilizes or rises, and the hhi indicator value will become smaller. this phenomenon indicates that the tail risk network exhibits the characteristics of multi-centers rather than a central node. the multi-center network structure facilitates the dispersal of risk information through multiple channels and is conducive to maintaining the stability of the stock market network. ) is the source of shock. here, we adopt orthogonal pulse function to test the hhi short-term dynamic relationship between network edges concentration and systemic risk. this method is widely used to analyze the relationships between variables (pradhan, 2015; berument et al., 2009 ). the pulse function not only presents the direction of the influence, but reflects significance level and time lags. fig.3 depicts the response of systemic risk to network edges concentration. in fig.3 , the vertical axis denotes the systemic risk for the same sector, while the horizontal axis denotes the time lag after the shock in the sample sectors for that month. it is observed that the hhi of edges initially has no significant positive effect on systemic risk. with the accumulation of risks, hhi begins to shows a positive effect on systemic risk from the second month, and reaches the maximum in the fourth month. gradually, variable hhi disappears to meaningless after nine months. the result shows that hhi has a significant positive impact on systemic risk, but the impact shows a certain lagging feature. the reasonable explanation for this phenomenon is that as the hhi value increases, the connected edges in the network are more controlled on a few central nodes. so, the systemic risks of the network are cumulatively amplified. however, the characteristics of systemic risk "slow accumulation and rapid release" and the shortcomings of chinese financial market under severe macro-regulation are important reasons for the lagging effect. of course, it provides strong evidence supporting the results in fig.1 , which proposes that the concentration of the risk network is more sensitive to the cumulative systemic risks. in addition to analyzing the overall connectedness of the tail risk network, we also analyze the weighted and directed edges of individual industry nodes. fig.4 and fig.5 reflect the dynamic evolution of the risk propagation and risk absorption of each sector during the entire period, respectively. first of all, we can see that both the ability of risk propagation or risk absorption of each sector change over time. many in-strength values are less than one, and only a few sectors have larger values (see fig.4 ), suggesting that these few sectors are seriously infected by external shocks and receive the highest tail risk. in the first shock event period (2008/1/25-2009/12/31), four sectors, i.e., business and professional services (bps), media (med), home and personal items (hpi), healthcare equipment and services (hes) have the largest in-strength values and are the top receivers of tail risk. the results show that the systemic risk from us subprime mortgage crisis has seriously shocked china's real economy sectors, and these industries have accumulated more tail risks. in the second extreme event period (2010/1/29-2012/12/28) that covers the european sovereign debt crisis, the healthcare equipment and services (hes), software and service index (ss) and semiconductor and semiconductor production equipment (sspe) receive the largest incoming links. during the "chinese stock market turbulence" period (2015/1/30-2016/12/30), the strong incoming links come from business and professional services (bps), media (med), software and service index (ss) and semiconductor and semiconductor production equipment (sspe). in the "trade friction between us and china" period (2017/1/26-2018/12/28), five sectors, i.e., software and service index (ss), semiconductor and semiconductor production equipment (sspe), insurance (ins), utilities (ut) and business and professional services (bps) have the strong incoming links, showing that these sectors are the most affected by tail risk. this finding supports the evidence that in 2018, the us imposes trade sanctions on various industries' commodities in china, including: communications, electronics, machinery and equipment, automobiles, furniture and so on, which corresponds to the above-mentioned industry classification. hence, the greater the in-strength value, the deeper the bad impact of a sector by other sectors, and more serious of the damage. out-strength fig. 5 out-strength of each sector for dynamic tail risk network notes: the horizontal axis (x) denotes time windows, and the vertical axis (y) denotes the abbreviation code of sectors (the corresponding full name of each code is presented in appendix table a1 ). as can be seen from fig.5 , the distribution of the out-strength differs from that of the in-strength and is relatively even. for example, many sectors have the lower out-strength value, and only a few out-strength values are larger 4, indicating that the few sectors emit the highest systemic risk. in the first event period (2008/1/25-2009/12/31), the strong connected sectors with outgoing links are energy (ene), diversified finance (df), insurance (ins), and utilities (ut). it indicates that affected by the us subprime mortgage crisis, these industries are the main senders of tail risk. in the third event period (2013/1/25-2014/12/31), which covers the money shortage in 2013, the home and personal items (hpi), media (med), and diversified finance (df) send the largest outgoing links to others. one of the reasons for the sector of home and personal items with a high level of outgoing links is that the reduction of currency circulation in the market directly reduces the daily consumption level of consumers. in the fourth event period (2015/1/30-2016/12/30) which covers the "2015-2016 china stock market turbulence", two financial sectors including bank (bank) and diversified finance (df), and media (med) have strong outgoing links and are involved in most risk spillovers. this phenomenon proves that financial institutions (especially security sector) trigger the recent bear market. overall, the greater the value of the out-strength, the stronger the ability of one sector to spread the tail risk to other sectors, and the greater the impact on others. connectedness alone cannot stand for the systemic importance of an individual sector. we thus calculate the pagerank index since it considers both the interconnectedness and the influence ability of neighbor nodes. to achieve a comprehensive knowledge of the systemic importance for each sector, we draw the heatmap of pagerank value which is shown in fig.6 . obviously, the influence of different industries in different periods varies greatly. from fig.6 , we observe that the pagerank value of most industries is less than 0.05, while only a few sectors have high hhi, showing that these sectors could act as influential sector in chinese stock market. for example, in first risk event period, the top three sectors are utilities (ut), diversified finance (df) and media (med), which are thus systemically important. and utilities (ut) and insurance (ins) are the systemically important sectors in second risk event period. the most important reason why ut becomes a systemically important industry is that the utility industry provides infrastructure protection for the development of other industries. furthermore, in third risk event period the home and personal items (hpi) and diversified finance (df) have larger pagerank value and are thus the largest tail risk contributors during that period. in fourth risk event period only diversified finance (df) consistently presents higher pagerank value. one of the major reason for diversified finance being the influential sector is that large-scale abnormal securities margin transactions have caused a surge in systemic risk under unregulated conditions, which in turn affects many associated industries due to asset-liability relationships or high leverage. at the end of 2017, utilities (ut) and energy (ene) are systemically important sectors. as mentioned above, the utilities and financial sectors should be received more attention in the overall time period from both regulators and investors as they become systemically important sectors in many risk event periods. therefore, in the near future, the dependence of utilities industry not reduce significantly, which may reinforce the utilities stocks. besides, for financial sectors, the development of the whole industry depends much on balancing financial structure, strengthening financial regulation and improving financial innovation. the most fundamental reason is that the financial sector is an important sector in the national economy. it has the characteristics of high industry linkage and strong driving ability. it provides financial support for the development of enterprises in many sectors. once the financial industry is in a downturn, it will affect the development of the entire industry chain. fig. 6 heat map of the pagerank value of each sector for dynamic tail risk network. notes: the horizontal axis (x) denotes time windows, and the vertical axis (y) denotes the abbreviation code of sectors (the corresponding full name of each code is presented in appendix table a1 ). this section divided 24 sectors into different blocks through block model, and find out which sectors are likely to cluster in the same community, and then further to examine the relative roles of each block in the sectoral tail risk network. this method can more simply and clearly reflect the function of various industries and risk propagation paths in the risk spillover process. and it is more conducive for the regulatory authorities and investors to grasp risks transmission mechanism, formulate risk prevention measures and optimize asset allocation strategies. here, we conduct a segmented sample study which covers five sub-samples: period 1 is us subprime crisis from 2008 to 2009; period 2 is european debt crisis from 2010-2012; period 3 is money shortage period from 2013-2014; period 4 is 2015-2016 chinese stock market turbulence; period 5 is trade friction between us and china from 2017 to 2018. according to existing research practices (chen et al., 2019; zhang et al., 2020) , we used the ucinet software to divide the block position of the tail risk network adjacency matrix. and, in this process we choose maximum separation depth is 2 and the convergence criterion is 0.2. therefore, we get four risk spillover blocks in five sub-samples. table 4 presents the spatial connectedness and role analysis between risk blocks of sectors in five sub-samples. from table 4 , it is observed that there are significant differences in the roles played by the four major blocks and the features of different blocks vary across time. now we take the period 1 and period 5 as examples to analyze risk spatial linkages of 24 sectors. specifically, in the period 1 and 5, the internal linkages between the four blocks are 69 and 28, respectively, while the cross-linkages between four blocks are 67 and 88, respectively. it indicates that the spatial spillovers between four blocks are very obvious. in period 1, the number of sending relations in first block is 13, of which there are 5 relations within the block, and the receiving relations from other blocks are 19; the expected internal relation ratio is 13.04%, and the actual relation ratio is 38.46%, so it is called "main benefit block". members of first block are ene, ut, bank and re, indicating that the tail risk spillovers between these sectors are closely linked and they are easily affected by the external risk shocks. furthermore, the number of sending relations in second block is 22, of which there are 9 relations within the block, and the receiving relations from other blocks are 12; the expected internal relation ratio is 13.04%, and the actual relation ratio is 40.91%, so it is called "bilateral spillover block". similarly, the third and fourth block are all "bilateral spillover block". members of the second block are tsp, cs, df and ins, showing that if fluctuations generated by these sectors, there will be great subsequent fluctuations to other sectors. e.g., the transportation industry (tsp) is an upstream industry for many industries, and when risks occur, the risks are transferred to other industries through sector linkages. overall, the internal links ratio of the first and second blocks is low, while the ratio of the third and fourth blocks is high and the third-fourth block emit more links with each other. in period 5, the number of sending relations in first block is 46, of which there are 16 relations within the block, and the receiving relations from other blocks are 17, including 10 links from fourth blocks; the expected internal relation ratio is 26.09%, and the actual relation ratio is 34.78%, thereby it is called "bilateral spillover block". the sending links in second block is 4, and the internal links of this block is 0, while only 1 link send to fourth block; so the actual relation ratio of second block is 0% and it is called "net benefit block". members of second block are re, bank, tsp, mat and the, indicating that these industries are more sensitive to external risk shocks and are the largest systemic risk contributors during the us-china trade friction period. such as, the most possibility reason for the real estate industry (re) to act as the risk transmitter in the risk network is that, it has a high degree of industry connectivity, which drives the development of materials, manufacturing, bank, home and personal items and other industries. once the real estate industry is sluggish, it will cause turmoil in the entire industry chain. the sending links of third block is 20, of which 3 links are in this block, and it mainly accepts the relationship from the fourth block; the expected internal relation ratio is 26.09%, and the actual relation ratio is 15%, thereby it is called "broker block", which plays a role as a "bridge" in systemic risk transmission. importantly, strong spillover transmission between blocks may depend on the functions of "broker block". the reason may be that mutual linkage and bidirectional economic or financial effects between their members and other blocks' members. the sending links of the fourth block is 45, of which 9 internal links of this block, and it mainly sends the relationship to third block; the expected internal relation ratio is 21.74%, and the actual relation ratio is 20%, thereby it is called "main spillover block". members of fourth block are bps, dcgc, df, ins, ss and sspe, which are levied high tariffs by the us, therefore they become the spillover engine. overall, the internal links ratio of the first block is high, while the ratio of the second and third blocks is low. the detailed analysis of period 2-4 are not listed due to space limitations, and the detailed results are shown in table 4 . in order to more clearly reveal the spillover distribution and relative roles of the tail risk relationship between the 24 sectors, we calculate the density matrix and image matrix of each block (shown in table 5 ). the overall density values of the tail risk network in five periods are 0.246, 0.257, 0.219, 0.230 and 0.210, respectively. here, the overall network density is selected as the critical value. if a block's density is greater than the overall network density, the corresponding position in the image matrix is assigned 1, otherwise, the value is 0. for example, in period 1, the density of first block is 0.417 that is greater than the overall network density (0.246). it shows that the block's density is greater than the average value of whole network, and the risk spillover linkages within a block have a significant tendency to concentrate. from the image matrix in table 5 , take period 1 as an example, we find out that: (i) the diagonal elements of the image matrix in four blocks are 1, showing that internal risk spillovers in the block are closely related and indicating that it has obvious "rich-club" effect; (ii) the first block receives risk spillover connections from the second and fourth blocks; (iii) the second block receives risk spatial connections main from the third block, and it plays the role of a "bridge" and realizes the interconnection of risk spatial spillover in the first and third blocks; (iv) the fourth block realizes the correlation and interaction with other blocks due to the risk spillover association to the first block. the results prove that the interconnections between the different blocks do not occur directly, mainly through the transfer of the first and second blocks. in the following, we continue to analyze our tail risk spillover across blocks. in this context, fig.7 displays the dynamic evolution of the risk spillover transmission mechanism between four blocks. it is observed that the spatial connectedness between the risk spillover blocks is time-varying since the members of the blocks are also time-varying, thereby the blocks' features in the risk transmission process are different at different periods. from fig.7 , it is easy to find that the risk transmission path across the blocks is more complicated during the first, second and fifth periods, and the risk transmission path across the blocks is simpler in the third and fourth periods. the most likely reason is that the sources of risk are different, i.e., the first, third and fifth periods are caused by the turmoil in the foreign market, which causes the changes in the relevant industries in the china; the second and fourth periods are caused by domestic macroeconomic regulation or certain sectors with higher levels of accumulation systemic risk. thus, risk shocks originated in a particular sector spread globally to the sectors of other blocks in a more or less homogeneous way, although some blocks are not directly related to each other. for example, in period 3, the source of infection between the risk spillover blocks is the second block, which spreads systemic risk shock to the first, third and fourth blocks simultaneously. however, there is no significant transmission channel of risk between the first and third blocks. members of second block are cs, fbt, hes, pbls and bank, which should be received more attention and supervision from the regulatory authorities, and investors should avoid investment in these industries. in addition, in period 5, the forth block acts as the risk spillover engine and directly transmits the risk shocks to first, second and third blocks. the members of forth block include bps, dcgc, df, ins, ss and sspe, of which dcgc, ss and sspe are subject to high tariffs of the trade policy in the us to china, and in this vein, the export of related products in these sectors are seriously affected, which in turn can easy to break out systemic risk. simultaneously, both the first and third blocks transmit the tail risk from the fourth block to the second block which acts as a distinct bridge and hub. therefore, the second block is the most sensitive block since it accepts the risk spillover from all blocks. due to the space limitations, 20 the analysis of risk transmission paths in other periods will not be repeated. this paper applies single-index model in a generalized quantile regression framework to assess non-linearity relationship and variable selection, and in this vein, we construct dynamic tail risk network for 24 chinese sectors from 2007-2018. at the global level, we first analyze the connectedness of systemic risk spillovers in tail risk network, and investigate the impact of network concentration on systemic risk. at the individual sector level, we calculate the risk contagion or absorption intensity of each sector, and adopt pagerank method to identify systemically important sector. finally, using block model to study the spillover distribution and relative roles of the tail risk relationship between the 24 sectors, and understand the financial risks transmission process across various sectors. in this research, we report the following findings. first, there is a tail risk network that connects all sectors in chinese stock market, and it exposes to more systemic risk and total connectedness during market distress. further, the edge concentration of risk network (hhi) is used to measure risk network interconnectedness and concentration, and it exhibits obvious cyclical features. during the tail event (market downside) periods, the hhi index increases significantly, and then the risk network is relatively single central node structure, thereby, the network stability is poor. the results show that multi-centered financial network, rather than a single pivotal center, can maintain financial market stability. second, the directional connectedness of sectors shows that systemic risk receivers and transmitters vary across time, and provide an evidence about "too linked to fail". besides, we identify two influential sectors released by utilities and financial sectors, which should be received more attention in the overall time period from both regulators and investors. finally, we find that the sectoral tail risk network can be divided into four different spillover function blocks by block model, which can more clearly reflect risk spillover distribution and roles of relevant industries in the process of systemic risk transmission. the role of blocks and the spatial spillover transmission path between risk blocks are time-varying. this study has important policy implications for cross-sector linkages and systemic risk spillovers in chinese stock market. first, it is necessary for the government to issue favorable policies such as the sectoral development policies or macro-control policies in a timely manner, which will promote the influence of relevant industries in the stock market, and thus create a multicentered node to maintain the financial market network stability. second, for investors, they should pay more attention to the systemically important sectors and make reversal strategies around these sectors to configure their assets and portfolios for risk minimization. for supervision department, they may consider the features of four blocks and its spillover paths to formulate different financial regulatory policies that improve the macro-prudential framework during stock market recession and instability periods. a thorough analysis about sectoral tail risk spillover and its spatial connectedness could successfully monitor systematic risks and keep financial system stability, which in turn, contributes to the smooth functioning of the real economy. systemic risk and stability in financial networks capital shortfall: a new approach to ranking and regulating systemic risk measuring systemic risk covar. federal reserve bank of new york staff report which are the sifis? a component expected shortfall 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correlations: taxonomy and portfolio analysis the pagerank citation ranking: bringing order to the web a simple indicator of systemic risk orthogonal pulse based wideband communication for high speed data transfer in sensor applications sectoral and industrial performance during a stock market crisis systemic risk measures: the simpler the better? china's regional financial risk spatial correlation network and regional contagion effect structural position in the world system and economic growth, 1955~1970: a multiple network analysis of transitional interactions a tool for filtering information in complex systems analysing the systemic risk of indian banks granger causality stock market networks: temporal proximity and preferential attachment extreme risk spillover network: application to financial institutions correlation structure and evolution of world stock markets: evidence from pearson and partial correlation-based networks interconnectedness and systemic risk of china's financial identifying influential energy stocks based on spillover network social network analysis: methods and application social structure from multiple networks i: block models of roles and positions connectedness and risk spillover in china's stock market: a sectoral analysis study on the contagion among american industries spatial spillover effects and risk contagion around g20 stock market based on volatility network spatial connectedness of volatility spillovers in g20 stock markets: based on block models analysis ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐the authors declare the following financial interests/personal relationships which may be considered as potential competing interests:no! key: cord-339036-nmmworwk authors: fabregues, f.; peñarrubia, j. title: assisted reproduction and thromboembolic risk in covid-19 pandemic date: 2020-06-25 journal: reprod biomed online doi: 10.1016/j.rbmo.2020.06.013 sha: doc_id: 339036 cord_uid: nmmworwk covid-19 pandemic has increased significantly to mortality in many countries with the number of infected cases increasing exponentially worldwide. one of the main determining factors of the poor prognosis in these patients is the development of coagulopathy. moreover, it is well known that art procedures confer a risk of thromboembolic complications. in this commentary we analize specific coexisting aspects between the thrombotic risk described during virus infection and that one reported in the context of assisted reproduction treatments. based on known pathophysiological aspects of both virus infection and those identified during ovarian stimulation (os), we found common elements that deserve to be taken into account. in the present context, any risk of hyperstimulation should be avoided. gnrh agonist triggering should be mandatory in high responders patients and/or with covid infection. in both cases, the cycle should be segmented. we propose prophylactic with low molecular weigth heparin (lmwh) not only in those cases in which the oocyte recovery has been performed, but also in those in which the cancellation has been decided. in addition, the endometrial preparation to the frozen-thawed embryo transfers (fets) should be using the transdermal route in order to minimize the higher thrombotic risk of the oral route. from the first case identified in wuham (china) in late december 2019 until today, severe acute respiratory syndrome coronavirus 2 (sars.co-2) has caused more than 5 million affected, reported in 187 countries, resulting in more tan 300.000 deaths. the outbreak has been brought to global attention and declared a pandemic by the world health organization (who) on march 11, 2020 (who., 2020 . mortality occurs mainly due to severe lung involvement causing an acute respiratory distress syndrome (ards), although sometimes a multi-organ failure occurs with significant coagulation disorders (zhou et al., 2020) due to the large increase in reported cases and the impact of the covid-19 coronavirus on public health, eshre on march 19, 2020 and asrm on march 30, 2020 recommended the cessation of any activity related to assisted reproduction. recently, both societies, eshre on april 23 and asrm on april 24, have authorized the resumption of healthcare activity with the general safety recommendations established by government authorities in each country. these measures persue minimizing of contagion and are also based on the fact that infertility is a disease whose prognosis can worsen over time. protocols have been established in order to minimize the risk of contagion for both patients and staff. however, have been established few measures regarding ovarian stimulation protocols, triggering and other considerations related to the clinical management of patients. the aim of this review is to analyze a specific coexisting issue between the thrombotic risk described during virus infection and that one reported in the context of assisted reproduction treatments. thromboembolic risk in covid-19 patients. current understanding of the pathogenesis as mentioned above, covid-19 has a special affinity for the lung, however, a key factor in the poor prognosis of the infection is the presence of coagulopathy and thromboembolic complications. (connors and levy., 2020; tang et al,.2020 ). the three essential elements of the so-called virchow's triad for thromboembolic risk occur during virus infection. first, endotelial injury has been related to the virus's affinity for ace-2 receptors wich are present in many organs, including the vascular endothelium (south et al., 2020) . secondly, the situation of stasis of blood flow is due to the immobilization during hospitalization of critically ill patients and thirdly, a hypercoagulability state occurs as a consequence of the large number of prothrombotic circulating factors that have been reported in patientes with severe covid-19 (thachil et al.,2020) . based on the currently available literature it has been suggested that some coagulation markers as d-dimers, prothrombine time and platelet count (in decreasing order of importance) are associated with high mortality in covid-19 patients. in this line, it has been demostrated that the use of anticoagulant therapy with heparin has shown a decrease mortality suggesting positive effects to endotelial disfunction and inflamation state (thachil ., 2020) interestingly high levels of d-dimer could predict the degree of coagulopathy even in asymptomatic covid-19 patients. in this context , the international society of thrombosis and haemostasis (isth) recommends the use of prophylactic low molecular weigh heparin (lmwh) in all patients (including non-critically ill) who require hospital admission and on those who have co-morbidities (thachil., 2020) thromboembolic risk in art. current understanding of the pathogenesis it is well known that art procedures confer a risk of thromboembolic complications. most thrombotic complications have been reported in the context of ohss and prophylactic guidelines have been established in this regard, which were not considered necessary during ovarian stimulation in abscence of risk factors. even though the incidence is low in absolute terms, it is similar to the risk of venous thrombosis during pregnancy, and suppos an increase in risk 10 times higher than the women´s risk of reproductive age. thromboembolic complications can be arterial and venous, with differences in timing and location. unlike arterial events that occur preferentially at the start of ohss, venous events can occur weeks later even after resolution of the complication.on the other hand while arterial thromboses are predominantly cerebrovascular accidents, venous events are mostly reported in unusual sites such as the upper extremities. (chan., 2009) besides, it is worth noting that the risk of venous thromboembolism (vte) is higher in pregnant women after ivf compared to women who had normal pregnancies. studies demostrated that the risk is significantly higher in the first trimester of pregnancy after ivf . in addition, pregnancies complicated by ohss showed a 100-fold increased risk of vte, as opposed the fivefold increased risk seen in the abscence of ohss. therefore, ovarian stimulation, ohss and pregnancy exponentially increase the risk of vte. ( grandoni and villani., 2015) despite the fact the causes of the increased thrombotic risk in the context of art are not well known, according to the scheme established in the previous section, we can analyze the different aspects outlined in the virchow's triad. concerning endothelial injury there is a relevant aspect regarding the os and ohss. according to the knowledge about haemodynamic and neurohormonal during severe ohss , arteriolar vasodilation is a constant finding in patients with severe forms of the syndrome . this produces underfilling of the arterial vascular compartiment (i.e. decreased "effective arterial blood volume") and, resulting arterial hypotension which leads to high-pressure baroreceptor-mediated stimulation of endogenous vasoactive systems (renin-angiotensin-aldosterone ,sympathetic nervous systems and adh). the simultaneous occurrence of these compensatory mechanisms compose the so-called 'hyperdynamic circulation' that characterizes conditions associated with oedema formation (schrier et al., 1990) . in this line, it has been shown that this hemodynamic alteration occurs universally during coh in ivf cycles, with significant activation of endogenous vasoactive systems in the luteal phase . the degree of activation of those endogenous vasoactive systems, it was less intense than that observed in patients with severe ohss. ( manau et al., 1998) . this suggests that the extreme circulatory dysfunction observed during severe ohss, appears mor attenuated in all women undergoing ivf. in this context we can speculate that the role of the renin-angiotensin system could be affected by the special affinity of the covid_19 by ace-2 receptor and thereby give place to new unknown clinical scenarios (south et al., 2020) . according to what has been previously mentioned, hyperdynamic circulation demonstrated in os and in more intense cases with ohss, it has been linked to the tissue factor wich is essential and is now considered to be the primary and most potent activator of the blood system coagulation. it is accepted that, circulating monocytes are the cells of the vascular system that can trigger blood coagulation through the tissue factor-dependent pathway (witkowski et al.,2016) .the wall shear stress increased in conditions of hyperdynamic circulation and the arteriolar vasodilatation can induce the formation of interstitial oedema by increasing capillary permeability. due to the surface area for filtration and hydrostatic pressure it is possible that changes in the vessel wall during the os take place and make the blood monocytes more sensitive to tissue factor activity. on the other hand,tissue factor pathway inhibitor (tfpi) that play a relevant role regulating haemostatic equilibrium decreases progressively throughout the os, this would explain the hypercoagulable status, occurring during assisted reproduction (romagnuolo et al., 2014) accordingly, a pro-thrombotic state has been demonstrated in cases with ohss with the increase of markers like thrombin (thrombin-antithrombin complex and prothrombin fragment 1 + 2) and fibrin (d-dimer) (balasch et al., 1996) . regarding stasis, it is evident that hospital admission and immobilization represent an added risk of prothrombotic risk, as occurs in cases of severe ohss. furthermore, hemoconcentration present in most cases has shown to be a more serious factor in patients with ohss and should therefore be avoided . this situation should not occur in the absence of ohss, however it would be prudent to take it into account. the third aspect related to the pathogenesis of hypercoagulability is the hypercoagulable state, that is the changes in the prothrombotic circulating factors that have been reported during the os and with the ohss. it has been shown that plasma fibrinogen increases and antithrombin decreases, together with decreasing markers of fibrinolytic activity following controlled ovarian hyperstimulation in ivf (westerlund et al., 2012) . the increase in coagulation factors indicates a trend towards a procoagulable state. as noted above, an increase of tissue factor and consequently of d-dimer has been demonstrated in ohss (balasch et al., 1996) . furthermore, it has recently been reported that with os in ivf cycles with its boost of endogenous oestrogens has increased the levels of procoagulant microparticles (mps). in this line phenotyping of mps showed that the increase in the level of estrogens was correlated with platelet-derived mps, monocyte-derived mps as well as endothelial-derived mps (olausson et al., 2016) . finally and summarizing we can point out that many aspects related to the hypercoagulability state are present during os and very prominently in the extreme situation of ohss added risk in current clinical practice in art government recommendations in the different countries, as well as those of eshre and asrm clearly minimize the risks of covid-19 transmission. however, there are aspects related to os and the risk of ohss that should be highlighted. having ruled out patients with co-morbidities who should obviously postpone assisted reproduction treatments, there are aspects related to clinical management in the field of assisted reproduction that must be observed. in the present context, any risk of hyperstimulation should be avoided . gnrh agonist triggering should be mandatory in high responders patients and/or covid infection. in both cases, the cycle should be segmented, which although it does not totally rule out the possibility of ohss, it does minimize it. based on what is mentioned in this article, we would propose prophylactic with lmwh not only in those cases in which the oocyte recovery has been performed, but also in those in which the cancellation has been decided.. covid-19 infection before oocyte recovery or during the luteal phase would significantly increase the risk in these patients. the association of os, ohss , pregnancy and covid infection would be dramatic, since all our efforts should be directed to avoid this sequence.even when applying this therapeutic measure, attention should be paid to the luteal phase of these patients, given that the studies have shown that hemodynamic and other aspects related to the hypercoagulability status of these patients, would dramatically increase their risk in the case of infection by covid-19. finally, another interesting aspect to address in the current situation is the one referring to endometrial preparation to the frozen-thawed embryo transfers (fets). over the last decade, the proportion of fets has substantially increased and therefore, there is a large number of infertile patients who perform endometrial preparation with hormonal therapy replacement (htr). in this sense, and based on studies conducted in menopausal patients undergoing htr, there is evidence that the risk of vte is closely related to the route of administration, with a threat 4 times higher with the oral vs. transdermal route ( olie et al., 2010) . thus, we would suggest the latter, since in the current scenario in which the number of visits to reproduction centers should be minimized, endometrial preparation in the natural cycle should be avoided. in cases of suspected or confirmed covid infection after fets thromboprophylaxis with lmwh should also be performed. furthermore, due to the increased thrombotic risk in case of twin pregnancies, we would suggest set during the pandemic period. in conclusion, in the current situation of uncertainty and risk, the specialists in the reproductive field should maximize prophylactic measures of thrombotic risk. based on previous knowledge about thrombogenic risk in the context of assisted reproduction and recent knowledge regarding covid-19 infection, we could find unexpected clinical scenarios increased induced monocyte tissue factor expression by plasma from patients with severe ohss peripheral arterial vasodilation hypotesis: a new insigth into the pathogenesis of ohss covid-19 and its implications for thrombosis and anticoagulation bood art" thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology leucocyte and platelet counts and the severity of the ovarian hyperstimulation síndrome assisted reproductive technologies and thrombosis circulatory disfunction in asimptomatic in vitro fertilization patients. relationship with hyperestrogenemia and activity endogenous vasodilators microparticles reveal cel activation during ivf: a posible early marker of prothrombotic state during the first trimester risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women is tissue factor pathway inhibitor a marker of procoagulable status in healthy infertile women undergoing ovarian stimulation for assisted reproduction? body fluid volumen regulation in health and disease: a unifying hypothesis covid-19, ace2, and the cardiovascular consequences anticoagulant treatment is associated with decreased mortality in severe coronavirus disesase 2019 patients with coagulopathy isth interim guidance on recognition and management of coagulopathy in covid-19 the versatile heparin in covid-19 who director-general's opening remarks at the media briefing on covid-19-11 tissue factor as a link between inflammation and coagulation clinical course and risk factors for mortality of adult in patients with covid-19 in wuhan, china: a retrospective cohort study key: cord-313615-cts45n3j authors: tam, john s; barbeschi, maurizio; shapovalova, natasha; briand, sylvie; memish, ziad a; kieny, marie-paule title: research agenda for mass gatherings: a call to action date: 2012-01-15 journal: lancet infect dis doi: 10.1016/s1473-3099(11)70353-x sha: doc_id: 313615 cord_uid: cts45n3j public health research is essential for the development of effective policies and planning to address health security and risks associated with mass gatherings (mgs). crucial research topics related to mgs and their effects on global health security are discussed in this review. the research agenda for mgs consists of a framework of five major public health research directions that address issues related to reducing the risk of public health emergencies during mgs; restricting the occurrence of non-communicable and communicable diseases; minimisation of the effect of public health events associated with mgs; optimisation of the medical services and treatment of diseases during mgs; and development and application of modern public health measures. implementation of the proposed research topics would be expected to provide benefits over the medium to long term in planning for mgs. a mass gathering (mg), as defi ned by who, is "any occasion, either organized or spontaneous, that attracts suffi cient numbers of people to strain the planning and response resources of the community, city or nation hosting the event". 1 mgs can be spontaneous or organised and include sports events, social or cultural functions, gatherings of displaced populations due to natural disasters or war, and political or religious congregations. [2] [3] [4] [5] major mgs are likely to involve communities from diff erent parts of the world. participants and host and home communities face health risks that are of international concern. therefore, the control of infectious diseases and provision of medical services for non-communicable dis eases and other risks to health are increasingly important in the planning for mgs. risks commonly associated with mgs include health systems having to accom modate a surge in capacity; challenges to existing health interventions; introduction and transmission of non-endemic diseases during and after mgs; diffi culties associated with risk communication to participants from diff erent cultures; and those arising because of the high profi le of some events, such as security risks. international mgs can amplify the transmission of infectious diseases, and infections can spread from the home to the host community during travel to and from the event and from the host to the home community on return. 6 such events can pose substantial risks to global health security and present challenges for surveillance of the spread of such diseases to new ecological settings and vulnerable populations. 7 in addition to risks of infectious diseases during mgs, non-communicable risks include cardiovascular diseases, environment-related heat injury, fi re-related injury, illnesses related to use of drugs and alcohol, occupational injuries, trauma or crush injuries associated with stampedes, exacerbation of respiratory diseases, and crowd safety. 8 large mgs can also provide opportunities for terrorist activities. in planning for mgs, international and local health authorities need to ensure that the strengthened public health systems and rapid responses to health risks are integrated with other important components of the overall event management. eff ective public health policy should be based on evidence. the organisation of international mgs generally requires provision of huge amounts of resources by the host country and the dividend of such high visibility is called legacy. this legacy should be measured not just in terms of absolute improvements (eg, new roads and ambulances) but also in terms of improvements to the public health system and society as a whole. for example, the legacies of strengthened integration of clinical or laboratory services, early warning or syndromic surveillance, and fi eld epidemiology or response adopted for the past summer olympics (sydney, australia, athens, greece, and beijing, china) [9] [10] [11] are used routinely in the health systems. the development of eff ective methods for, and improvement of, planning and handling of the health risks associated with mgs will strengthen global health security, prevent excessive emergency health problems and associated economic loss, and mitigate potential societal disruption in host and home communities. such development requires credible evidence to support activities that can reduce the global eff ect of infectious diseases and address local public health issues related to morbidity and mortality resulting from noncommunicable diseases during mgs. however, there are gaps in knowledge about many public health issues that contribute to eff ective planning. 6, 12, 13 therefore, a robust knowledge about illnesses, from basic scientifi c understanding to societal eff ects of infections and noncommunicable diseases, is essential for modern public health practices and policy development related to the planning for mgs. several reports [11] [12] [13] [14] [15] and who planning and guidance documents 1,16-18 have drawn attention to the importance series of research into public health issues associated with mgs and identifi ed those that need immediate attention. despite these eff orts, an overarching research agenda based on public health to address the gaps in knowledge in mg health has not yet been developed. moreover, international coordination to prioritise and enable the funding and implementation of such an agenda has been lacking. the recent recognition and rapid development of mg health can provide focus on such issues. previously identifi ed research priorities for mgs tended to focus on logistical issues relating to site security and emergency management, crowd control, and surge in the need for medical services. 12, 13 other specialties tend to focus on each of the specifi c public health topics that are associated with mgs. much research into existing and emerging infectious diseases is devoted to the development of rapid diagnostic methods, surveillance and response, and treatment and vaccines. although a research agenda based on public health must be underpinned by basic science, applied science and operational research are areas of particular interest to the organisers of mgs and the decision makers for public health, especially those in poorly resourced countries. the modern day idea of mg health has developed from the notion that "mass gatherings medicine is concerned with the provision of emergency medical care at organized events with >1000 people in attendance" 18 to include several specialties (fi gure). the intricate interactions between the diff erent specialties is essential for the planning and success of mgs. new advances or interventions undertaken in other specialties should be integrated with research into mgs. the proposed research agenda is a broad strategy for research into public health, with a focus on issues related to mgs. it is not intended to be an exhaustive compilation of all possible research questions about the strategic planning for and operation of mgs. instead the agenda is an outline of key research into methods to control public health and policy. the results of this research can provide an evidence-based platform for policy decisions and practices to reduce the risks and eff ects of mg-associated health issues and global security risks to public health. the principal objectives of this research agenda are to identify topics for research and underpin and prioritise their importance in achieving interventions for the control of public health; provide a research framework to gather evidence to address health issues associated with mgs and global security risks to public health; ensure focus on less well addressed issues such as operational and implementation research, particularly for under-resourced regions; provide a platform to enable co ordination, discussion, and interaction among organisers of mgs, public health professionals, and researchers; and encourage a multidisciplinary approach to address gaps in knowledge about health risks associated with mgs and their control. the proposed research agenda is organised as a framework of fi ve major public health research directions. although many public health emergencies associated with mgs are not predictable, much can be done to prevent and minimise their eff ects. continuous monitoring of participants' vulnerability to health risks at mgs and understanding trends in risks that are associated with specifi c events (religious, sports, or concerts) can be used to predict what might happen in the future. they are also essential for successful preparedness and management of risk reduction and strengthening the response capacity of host and home communities. recognition and analysis of the changing risks and vulnerabilities during mgs are starting points for raising awareness and communication of pending risks. building global capacity for health intelligence for noncommunicable and infectious diseases is important for the elucidation of the risks associated with mgs. most of this information is available through networks such as the emerging infectious disease networks 19, 20 and the who global non communicable disease network. 21 importantly, the information can be used to implement strategies for risk assessment and mitigation in planning for specifi c mgs (panels 1, 2). morbidity and mortality at mgs can be mitigated through the assessment and management of risks associated with pre-existing non-communicable diseases. mitigation methods such as the provision of essential drugs and information about their availability at the mg can be initiated during pretravel medical care and advice. 5, 26 incidence of trauma and heat-related illness at a site can be reduced with the provision of advice and installations to combat the eff ects of weather, and eff ective crowd control. 5 models for the prediction of the spread of infections and occurrence of other emergency health issues during mgs have yet to be validated. 7 many of the diffi culties in restricting the spread of emerging communicable diseases [6] [7] [8] 23 are not new and have proven diffi cult to resolve. there is also uncertainty global clinical and laboratory surveillance systems for communicable diseases, such as those for seasonal and pandemic infl uenza, 22 are well established. the establishment of country-level surveillance systems for infectious diseases that can be adapted to diff erent epidemiological settings for mass gatherings (mgs) could also provide alerts for the occurrence of non-communicable diseases, such as radiation-related or chemical-related illnesses or those caused by extreme environmental temperatures (eg, program for monitoring emerging diseases). 23 an important component of the alert and response strategy is an integrated event management system that provides a platform for rapid dissemination of devices and procedures required for the management of health risks. research into their development and implementation is needed. syndromic surveillance can potentially provide rapid initial information about the occurrence of both non-communicable and infectious diseases. however, its establishment and assessment of eff ectiveness during mgs might require further assessment. further work is also needed to identify appropriate parameters for assessment of the eff ectiveness of such surveillance systems during mgs. surveillance of non-communicable diseases is a formidable but necessary step for the improvement of the health of the global community. an estimated 63% of global mortality in 2008 was attributable to non-communicable diseases and 80% of such deaths occurred in low-income and middle-income countries. 24 age-specifi c and sex-specifi c profi les of non-communicable diseases by country 25 allow host countries of mgs to estimate possible risks of non-communicable diseases in participants from specifi c countries and plan for mitigation strategies. although the challenges for the organisers of mgs and the eff ects of infectious diseases at such events have been summarised, 6, 14 there are many gaps in our understanding of emerging communicable diseases. integration of information from local and international surveillance of infectious diseases is important for strengthening the intelligence about the global threats before, during, and after mgs. 23 the risks of non-communicable and infectious diseases during mgs are proportional to the probability of occurrence of risk factors during the event. the identifi cation of these risks factors for the diff erent types of mgs will provide a scientifi c basis for planning eff ective prevention. although major risk factors associated with non-communicable and communicable diseases are likely to be similar worldwide, factors specifi c to the type of mg might lead to health problems. systematic risk assessment helps identify potential risks of outbreaks and guides the establishment of eff ective risk management solutions. systematic assessment will also identify potential or deliberate health security risks that require assistance from other authorities and government agencies. the leading causes of morbidity and mortality during the hajj are heat-related illnesses and trauma-related injuries. identifi cation of such risks allowed event planners to instigate preventive measures and rapid response strategies. provision of shaded areas can reduce the incidence of heat-related illnesses and eff ective crowd control reduces the risk of a stampede. drug and alcohol use were identifi ed as health risks for other types of mgs; 26 therefore, restriction of their use can mitigate the associated illnesses. the types and magnitude of health risks associated with spontaneous mgs due to natural disasters and confl icts are diff erent from those of organised mgs. objectives for risk management at such events are focused on facility-based health-care provision in addition to prevention. the potential for importation and subsequent global spread of infectious diseases during mgs are well understood. many emerging human infections are recognised as zoonotic diseases (eg, severe acute respiratory syndrome [sars], infl uenza a h5n1, nipah virus infection). the emergence of novel or rare pathogens in home communities and their subsequent spread to the host community and beyond can be amplifi ed during mgs. planning for the potential risks and hazards that are associated with mgs is essential to ensure success. many reports and manuals are available for planning mgs; 1,27-32 however, their use should be tempered by the results of the risk assessment. importantly, planning should maximise the legacy of the mg. the conceptual model of a lasting public health legacy as a framework for the relation between planning inputs, implementation, and public health outcomes was put forward by who and the international olympic committee to ensure sustainable, positive health eff ects for the host communities after the olympic games. 11 legacy planning should also include passing the knowledge gained to future hosts of similar mgs. series about how observations pertaining to particular pathogens, population groups, or settings can be used to develop public health policies for planning diff erent types of mgs. the development of evidence-based strategies for non-pharmaceutical inter ventions is urgently needed to address infection control and mitigate spread in the absence of available drugs and vaccines. additionally, such strategies are of particular concern for countries that do not have adequate access to pharmaceutical interventions such as vaccines and antimicrobial drugs. in some instances, available data for planning mgs might not have been assimilated in the best way for policy. a balance between basic scientifi c research and operational research is essential to inform the implementation of prevention strategies, best practices, and public health decision making (panel 3). research into how to contain the spread of infectious diseases should have the broadest possible applicability in diff erent settings and at diff erent resource levels. however, some results might not be generalisable to the planning for mgs, such as those from studies of pathogen transmission in health-care settings. eff ective management of health risks for noncommunicable and infectious diseases during mgs requires planning in advance. it is an integral part of planning that consists of risk identifi cation, communication, analysis, assessment, prevention, and monitoring. 23, 28, 29 many of the processes for risk management of non-communicable and infectious diseases during mgs are common. however, each can be specifi c to the type of mg and needs to be addressed accordingly. 8, 26 high visibility of mgs complicates risk management and can lead to political and media pressure and thereby aff ect the decision-making process. prevention of the occurrence of non-communicable and infectious disease at mgs requires coordinated risk assessment and management before, during, and after the event as shown in the planning for the hajj. [2] [3] [4] [5] [6] 26 ideally, the primary prevention of human infections with emerging communicable diseases is the eff ective control of pathogens at their source. since at-source elimination of all emerging pathogens is not possible, secondary interventions (eg, pharmaceutical or nonpharmaceutical) are needed to mitigate the spread of infection during mgs. however, the eff ectiveness of such interventions has not been established. 33, 34 in addition to reduction of the rates of morbidity and mortality associated with human infections during mgs, reduction of both the circulation of pathogens and human exposure might lessen the global health security risks. the eff ect of emergencies and crises on health can be substantially reduced if home and host communities are well prepared and are able to reduce their risks. the main challenge during mgs is the existence of systematic operative capacities such as risk assessment plans, coordinating mechanisms and standard procedures, institutional capacities, legislation and budgets, skilled vaccination is highly eff ective in the prevention of infectious diseases. however, many countries, particularly those with insuffi cient resources, have not developed strategies for vaccinating their populations at risk and people travelling to mgs. the reason is partly related to the lack of information about the transmission of infectious diseases (eg, infl uenza) and the social, economic, and health eff ects to the host and home communities. public health authorities need to decide how to eff ectively prioritise vaccine use on the basis of available information about disease burden and severity, epidemiology, and vaccine eff ectiveness and safety for vaccine-preventable infections associated with mgs. 6 a failure to promote and implement the polio vaccination programme caused the re-emergence of poliovirus in nigeria and subsequent international spread, 35,36 emphasising the risks associated with insuffi cient vaccine coverage for participants at mgs. an outbreak of neisseria meningitides serogroup a (originating from africa) during the hajj in 1987 37 was later successfully controlled with the introduction of mandatory pretravel vaccination and use of fl uoroquinolones among african pilgrims. 38 however, there are infectious diseases, including some of the most important and most dangerous, for which there are no vaccines. risk assessment and management during the planning for mgs can enable the development of eff ective health policies. strategic risk assessments are used to gather, coordinate, and analyse data that are necessary to identify existing risks, anticipate potential diffi culties, establish â�¢ enhance applications of existing vaccines against possible infectious diseases that are associated with mgs â�¢ assess the global vaccine supply and production to improve the processes of rapid response, surge in capacity, and rapid deployment and tracking of vaccine use for planning mgs â�¢ develop innovative clinical trial methods to study the eff ectiveness and safety of novel vaccines before and after licensing â�¢ develop new vaccines, platforms, and formulations that are safe with enhanced immunogenicity, especially in children and elderly people series priorities, and provide the basis for enacting targeted policies and implementation of corrective interventions. a system is needed for the measurement of the eff ect of public health policy and estimation of the probability of success. these interlinking processes are well described for regularly organised events such as the hajj and olympic games. 5, 11, 14 an example of the eff ective development of health policy is the organisation of the hajj-such as a smoke-free environment for the prevention of fi re, structural changes to prevent crowding, and recommendations for vaccination of pilgrims to prevent transmission of infectious diseases (eg, infl uenza, meningitis, poliomyelitis). 5 however, such eff ective policies are not possible for spontaneous mgs such as population displacement as a result of natural disasters or confl icts. development of vaccines for emerging infectious diseases presents substantial challenges and can take many years for diseases that are caused by novel pathogens such as severe acute respiratory syndrome (sars; panel 4). even if a vaccine exists, it might need to be regularly updated, clinically assessed for safety and effi cacy, and promptly produced for immediate use (eg, infl uenza vaccines). the effi cacy and eff ectiveness of a vaccine are dependent on the immune responses that are determined by the age of the recipient and composition of the vaccine (eg, conjugated or adjuvanted). improvements to vaccines and formulations that can provide longer-lasting and broader activity aff ord better protection, increase the applicability of vaccines, and reduce the frequency of vaccination. during an outbreak, the important factors are the rapid production and equitable distribution of vaccines to countries in need. ensuring rapid and eff ective management of patients and prevention of diseases requires robust health services at mgs. providers of emergency services play an important part in ensuring public safety during such events. knowledge and monitoring of medical service provision during mgs has been rapidly increasing in the past decade. 12, 13, 39 however, a lack of consolidated data for diff erent types of mgs means that organisers are not able to plan accordingly for the emergency medical services that might be needed. improved and targeted clinical management and infection control can substantially reduce the incidence and transmission of infectious diseases during mgs. optimum clinical management must be based on an improved under standing of the pathogenesis of these infections, advances in laboratory diagnosis, development and application of eff ective antimicrobial drugs, and other treatment modalities (panel 5). there are many gaps in our basic understanding of how many of the pathogens that are associated with mgs cause disease in people and what factors aff ect severity of illness. host immune responses, underlying comorbidity, age, and the properties of the infecting pathogen can all contribute to severity. the clinical presentation of many infections, such as infl uenza, is not specifi c, which makes diff erential diagnosis and early treatment to reduce further transmission and severe outcomes diffi cult. for example, antibiotics can help control severity and further spread of travellers' diarrhoea caused by bacteria. rapid and reliable diagnostic testing can expedite the initiation of timely and appropriate treatment and infection control. increase in and optimisation of the repertoire of antimicrobial drugs immunomodulator drugs, immunoglobulins, and natural products) that are applicable in low-resource areas and in fi eld conditions (such as availability, whether licensed or not, acceptance, and effi cacy in diff erent ethnic, sex, and age groups) and are easy to administer in paediatric-care and emergency-care settings â�¢ optimise management of people who are at risk of severe disease and complications, including emergency-care practices that are applicable across a range of resource settings health-care capacity and response â�¢ assess the eff ectiveness of global, national, and local responses to outbreaks of communicable diseases and develop new methods for assessment â�¢ undertake operational studies to investigate the surge capacity needs, particularly in host countries for mgs, including development of triage schemes in diff erent health-care and resource settings, and surge planning to maintain adequate resources â�¢ undertake studies to identify evidence-driven clinical-care pathways and principles that optimise health-care delivery in a range of resource settings â�¢ undertake studies to develop principles and practices for rapid assessment and introduction of new interventions during health emergencies, including systems for collation, sharing, and assessment in real time of clinical data series and development of clinical research to assess effi cacy of putative adjuvant treatments such as immunomodulator drugs, passive immuno therapy, and traditional medicine that are suitable for use in under-resourced areas would be most benefi cial in the preparation for mgs (panel 5). the availability and quality of health services contributes to the eff ect of infectious diseases in the source and home countries (panel 5). the same pathogen that might have a small eff ect on the rates of morbidity and mortality in countries with well organised health-care systems can be devastating in countries where health-care systems are suboptimum. new public health methods need to be harnessed to help reduce the eff ect of health problems during mgs. use of innovative communication channels, such as the internet and mobile phone networks, have the potential to aid surveillance, rapid risk assessment, and dissemination of accurate information. 23, 40, 41 mathematical modelling and risk communication have potential applicability in all aspects of research into health risks associated with mgs. some countries and mg organisers use state-of-the-art approaches for early detection and monitoring of diseases such as syndromic surveillance. 3, 29 in some countries computerised health-care and laboratory-based infor mation systems are used for planning mgs and these systems can be adapted for monitoring large-scale outbreaks. other innovative technologies such as mobile phones can be used in remote areas or countries that lack the resources to gather and transmit health-related data in real time, provide rapid feedback, and train health-care workers. 7, 23 applicability and use of these modern methods of monitoring in diff erent settings and contexts require further investigation, with special attention to issues related to integration and interoperability of initiatives for infection control during mgs (panel 6). evidence-based public health decision making in planning and mitigating health risks requires rapid access to information. however, such information is often incomplete, evolving, and derived from an increasingly complex array of sources such as basic science researchers, epidemiologists, social and political scientists, and economists. modelling is useful in that it can incorporate diverse data to inform public health policy and decision making. 42, 43 advances in mathematical modelling for public health are expected to include computational structural biology; integration of epidem iological and geographical data into phylogenetic models; within-host and population-level susceptibility models; behavioural modelling; and assessment of the eff ects of climate change on disease transmission and the use of novel datasets on contact patterns and population mobility. [44] [45] [46] [47] [48] communication is a key strategy in risk management in planning for mgs. the sars outbreak in 2003 reinforced the idea that a timely and transparent public information policy could help reduce excessive and inappropriate public health responses and minimise the social disruption and economic consequences of a fast-moving global epidemic. 49, 50 increased investment in identifying eff ective approaches and developing and assessing new communication methods will benefi t risk prevention and control eff orts. the specifi c challenge is to provide clear, credible, and appropriate communication to meet the needs of diverse communities and retain public trust in a dynamic yet unknown process. 51, 52 some of the main research topics in this specialty include the link between communication and behaviour change models; development and assessment of methods that can be quickly accessed and used in mgs; and assessment of best practices, challenges, and barriers in risk research in early detection and monitoring of disease â�¢ identify, develop, and adapt modern technologies for early detection of outbreaks of communicable diseases and their application in disease surveillance during mgs â�¢ integrate and continuously assess innovative approaches and channels for disease surveillance and monitoring â�¢ develop effi cient mechanisms to address the global challenges to sharing information, data, and details about pathogens identifi ed during outbreaks at mgs in terms of local, ethical, legal, and research perspectives â�¢ defi ne the timeliness and quality of data required for early detection of disease from local to district, regional, national, and global levels â�¢ assess the application of modelling to understand and estimate key parameters for risk management â�¢ investigate the role of modelling to assess eff ect of public health policies for diff erent mgs â�¢ assess modelling in public health policy planning and strategic decision making in mg planning research into health issues related to mgs is at an early stage. research directions outlined here should contribute to the evidence that can be used to formulate risk management guidelines and assist event planning and health-care policy makers. the research agenda presented here is not intended to be restricted to specifi c aspects of health research but rather to encourage a multidisciplinary approach focused on mg health and to help gain more knowledge. in the future, the focus should be on strategies directed towards developing common research frameworks and defi nitions. additionally, the knowledge generated by use of the multidisciplinary approach to research ought to be assessed for direct relevance to mgs in terms of their capacity for integration in legacy building and systemic sharing of information. jst wrote the text. mb planned the outline for the review, and provided and consolidated who policies and guidelines about mgs. zam provided the concept for the review and planned the content with the team. ns provided the outline and wrote the section about risk communication. sb provided information about outbreak control and research agenda for infl uenza. m-pk contributed information about health research directions and vaccine development. all authors reviewed and provided advice on drafting the review. we declare that we have no confl icts of interests. we identifi ed references for this review by searching pubmed, medline, and the internet for articles published in english from january, 1960, to june, 2011, by using the search terms "mass gatherings", "research", "infectious diseases", "communicable diseases", "non-communicable diseases", "public health", "alert and response", "mass gatherings planning", "legacy", "outbreak", "surveillance", "prevention", "treatment", "olympic games", and "hajj". we reviewed the articles and information found during these searches. additional references cited in the articles were also reviewed. communicable disease alert and response for mass gatherings the hajj: communicable and non-communicable health hazards and current guidance for pilgrims public health surveillance for mass gatherings a literature review of the health and safety risks associated with major sporting events: learning lessons for the london 2012 olympic and paralympic games health risks at the hajj global perspectives for prevention of infectious diseases associated with mass gatherings crowd and environmental management during mass gatherings non-communicable health risks during mass gatherings public health legacy: experiences from vancouver 2010 and sydney 2000 olympic and paralympic games mass gatherings and public health: the experience of the athens 2004 olympic games who western pacifi c region. the health legacy of the beijing olympic games: successes and recommendations mass gathering medicine: a review of the evidence and future directions for research the development of conceptual models for mass gathering health preparing for infectious disease threats at mass gatherings: the case of the vancouver 2010 olympic winter games the quest for public health security at hajj: the who guidelines on communicable disease alert and response during mass gatherings asia pacifi c strategy for emerging diseases: technical papers mass-gathering medical care: a review of the literature global capacity for emerging infectious disease detection networks and the epidemiology of infectious disease global noncommunicable disease network (ncdnet): report of the first global forum convened by the world health organization who global technical consultation: global standards and tools for infl uenza surveillance infectious disease surveillance and modelling across geographic frontiers and scientifi c specialties who. global status report on noncommunicable diseases 2010 who. noncommunicable diseases country profi les emergence of medicine for mass gatherings: lessons from the hajj safe and healthy mass gatherings: a health, medical and safety planning manual for public events who. global forum on mass gatherings communicable disease alert and response for mass gatherings: key considerations who. interim planning considerations for mass gatherings in the context of pandemic (h1n1) 2009 infl uenza federal emergency management agency, usa. special events contingency planning manual federal emergency management agency, usa. special events contingency planning: job aids manual world health organization writing group. non-pharmaceutical interventions for pandemic infl uenza, international measures non-pharmaceutical public health interventions for pandemic infl uenza: an evaluation of the evidence base nigerian states again boycott polio-vaccination drive global poliomyelitis eradication: status and implications epidemic group a meningococcal disease in haj pilgrims meningococcal disease and travel measuring emergency services workloads at mass gathering events automated vocabulary discovery for geo-parsing online epidemic intelligence use of unstructured event-based reports for global infectious disease surveillance mass gathering medicine: a predictive model for patient presentation and transport rates the impact of mass gatherings and holiday traveling on the course of an infl uenza pandemic: a computational model modeling the impact of global warming on vector-borne infections computational procedures for optimal experimental design in biological systems deterministic epidemic models on contact networks: correlations and unbiological terms how to make predictions about future infectious disease risks modeling and public health emergency responses: lessons from sars sars revisited: managing "outbreaks" with "communications responding to global infectious disease outbreaks: lessons from sars on the role of risk perception, communication and management perceived risk and effi cacy beliefs as motivators of change: use of the risk perception attitude (rpa) framework to understand health behaviors eff ective media communication during public health emergencies. a who handbook communicating uncertainty-how australian television reported h1n1 risk in 2009: a content analysis key: cord-337315-qv8ycdhe authors: miller, maureen; hagan, emily title: integrated biological–behavioural surveillance in pandemic-threat warning systems date: 2017-01-01 journal: bull world health organ doi: 10.2471/blt.16.175984 sha: doc_id: 337315 cord_uid: qv8ycdhe economically and politically disruptive disease outbreaks are a hallmark of the 21st century. although pandemics are driven by human behaviours, current surveillance systems for identifying pandemic threats are largely reliant on the monitoring of disease outcomes in clinical settings. standardized integrated biological–behavioural surveillance could, and should, be used in community settings to complement such clinical monitoring. the usefulness of such an approach has already been demonstrated in studies on human immunodeficiency virus, where integrated surveillance contributed to a biologically based and quantifiable understanding of the behavioural risk factors associated with the transmission dynamics of the virus. when designed according to strengthening the reporting of observational studies in epidemiology criteria, integrated surveillance requires that both behavioural risk factors – i.e. exposure variables – and disease-indicator outcome variables be measured in behavioural surveys. in the field of pandemic threats, biological outcome data could address the weaknesses of self-reported data collected in behavioural surveys. data from serosurveys of viruses with pandemic potential, collected under non-outbreak conditions, indicate that serosurveillance could be used to predict future outbreaks. when conducted together, behavioural surveys and serosurveys could warn of future pandemics, potentially before the disease appears in clinical settings. traditional disease-outcome surveillance must be frequent and ongoing to remain useful but behavioural surveillance remains informative even if conducted much less often, since behaviour change occurs slowly over time. only through knowledge of specific behavioural risk factors can interventions and policies that can prevent the next pandemic be developed. no other modern epidemic or pandemic mobilized the global health community to action like the 2013-2016 ebola virus disease outbreak in western africa. following the outbreak, calls for pandemic-threat warning systems came from both traditional public health policy-makers 1,2 and national governments. 3 as currently conceptualized, the first step in the identification of a pandemic threat requires an outbreak of sufficient size to come to the attention of medical personnel who are sufficiently influential and persistent to ensure action. 4 once an outbreak is verified, well-established protocols for disease investigation and control can be swiftly put in place -although it may be many months before the main risk factors and most effective control measures are identified. the ebola outbreak in western africa probably began in december 2013 5 but it took another year before traditional burial practices were found to be a leading cause of the rapid spread of the causative virus. 6 although human behaviours often increase the risk of acquiring an infectious disease, the systematic investigation of human risk behaviours is seldom included in disease surveillance strategies. 7 however, behavioural surveillance to improve the understanding of human immunodeficiency virus (hiv) and acquired immunodeficiency syndrome has been ongoing for decades. behavioural assessment was key to the identification of injecting drug users as a high-risk group for hiv infection in the early 1980s. 8 it was also crucial in documenting the risks posed by hiv to women. 9 subsequently, an innovative, practical method, which combines biological outcome data with behavioural risk factor data -i.e. exposure variables -was developed to document hiv transmission dynamics. such integrated biological-behavioural surveillance has since become well established and standardized and been frequently implemented globally. 10, 11 it has contributed extensively to a biologically-based and quantifiable understanding of the behavioural risk factors associated with the acquisition and transmission of hiv 12 and the early identification of subgroups of the population that may be more vulnerable to hiv infection. 9 more recently, data from integrated surveillance have been used to evaluate the impact of evidence-based interventions to prevent hiv infection and to monitor treatment uptake. 13 similar surveillance could help identify behavioural risk factors and high-risk subgroups for zoonotic infections such as ebola -potentially before diseases of pandemic potential are identified in clinical settings or major outbreaks occur in communities. approximately half of the emerging pandemic threats are zoonotic in origin. 14, 15 at the time of writing, the most lethal and costly pandemics of the 21st century, i.e. avian influenza, ebola, middle east respiratory syndrome (mers) and severe acute respiratory syndrome (sars), have all been caused by zoonotic viruses. [16] [17] [18] [19] little is known about either the risk factors that lead to the initial spillover of a zoonotic disease into human populations or the dynamics of any subsequent humanto-human transmission. 20 much more is known about (i) the locations of so-called hotspots where, many scientists believe, new pandemics of zoonotic disease are likely to emerge; 14 (ii) the kinds of ecological and environmental activities that have been associated with spillover and outbreaks of zoonotic disease in the past; 21 and (iii) the distinct spatial groupings of specific infectious diseases on a global scale, and the associ-abstract economically and politically disruptive disease outbreaks are a hallmark of the 21st century. although pandemics are driven by human behaviours, current surveillance systems for identifying pandemic threats are largely reliant on the monitoring of disease outcomes in clinical settings. standardized integrated biological-behavioural surveillance could, and should, be used in community settings to complement such clinical monitoring. the usefulness of such an approach has already been demonstrated in studies on human immunodeficiency virus, where integrated surveillance contributed to a biologically based and quantifiable understanding of the behavioural risk factors associated with the transmission dynamics of the virus. when designed according to strengthening the reporting of observational studies in epidemiology criteria, integrated surveillance requires that both behavioural risk factors -i.e. exposure variables -and disease-indicator outcome variables be measured in behavioural surveys. in the field of pandemic threats, biological outcome data could address the weaknesses of self-reported data collected in behavioural surveys. data from serosurveys of viruses with pandemic potential, collected under non-outbreak conditions, indicate that serosurveillance could be used to predict future outbreaks. when conducted together, behavioural surveys and serosurveys could warn of future pandemics, potentially before the disease appears in clinical settings. traditional disease-outcome surveillance must be frequent and ongoing to remain useful but behavioural surveillance remains informative even if conducted much less often, since behaviour change occurs slowly over time. only through knowledge of specific behavioural risk factors can interventions and policies that can prevent the next pandemic be developed. integrated surveillance for pandemic threats maureen miller & emily hagan ated ecological and virological barriers to the dispersal and establishment of those diseases. 22 in the development of pandemic-threat warning systems, integrated biological-behavioural surveillance can be tightly focused on specific viral families in the high-risk population subgroups that live in identified hotspots and are environmentally or occupationally exposed to animals. the remainder of this article presents an overview of issues relevant to the design of rigorous behavioural surveys to assess the spillover of emerging zoonotic disease and the associated transmission risk factors, which is the first step in designing effective integrated surveillance. we identified community-based serological surveys of viruses with pandemic potential as a possible source of useful biological outcome data. we summarize the results of such serosurveys, conducted in nonoutbreak settings in africa, and evaluate their usefulness -especially when used in combination with behavioural surveillance -in the prediction of future outbreaks. when designed according to strengthening the reporting of observational studies in epidemiology criteria, 23 integrated surveillance requires that both disease-indicator outcome variables and behavioural risk factors be measured in behavioural surveys. behavioural risk factors, i.e. exposure variables, simply represent the population prevalence of behaviours that may or may not increase the risk of disease. without the outcome variables, the exposure variables are of little use in elucidating the mechanisms of the spillover of zoonotic disease to humans or of subsequent human-to-human transmission. effective surveillance requires questions that assess a range of animal exposures, document experiences of unusual illness and measure contextual factors that can lead to an increase or decrease in the probabilities of behavioural risk factors and disease. in studies on zoonoses, the assessment of behavioural risk factors is complicated because different zoonotic diseases may be associated with different kinds of animal exposure. the spillover of zoonotic viruses from wildlife, the source of most emerging zoonoses, 15 has been difficult to document. behavioural risk may be either direct or indirect. direct contact with primate blood or bodily fluids has been associated with several zoonotic viruses found in humans, such as human t-lymphocyte virus, 24 simian foamy virus 25, 26 and, possibly, ebola. 5 indirect contact was responsible for the transmission of nipah virus to humans, which was mediated through date-palm sap contaminated with the urine of infected bats, 27 and hantavirus transmission is most frequently associated with inhalation of aerosolized virus from the excreta of infected rodents. 28 both general exposure to animals, e.g. when buying live animals at market, and more intimate exposure, e.g. during the slaughter of animals or as the result of animal bites, must therefore be assessed. syndromic surveillance is widely used to monitor illnesses of unknown etiology in clinical settings and can provide a useful referent in the identification of the outcome variables to be measured in behavioural surveys. several zoonotic diseases, such as avian influenza, 17 mers 16 and sars, 29 were identified via syndromic surveillance networks, from localized increases in the incidence of influenza-like illness or severe acute respiratory infection. by using standardized definitions, it should be easy to develop questions or symptom checklists for syndromic surveillance based on self-reported data. such definitions already exist for influenza-like illness, 30 severe acute respiratory infection 30 and other syndromes consistent with zoonotic infection, such as encephalitis of unknown origin, 31 fever of unknown origin 32 and haemorrhagic fever of unknown origin. 33 the risks posed to humans by exposure to animals may be modified by various biological, ecological, economic, political and sociocultural factors. 34 for example, poverty can place individuals and communities at the forefront of zoonotic disease risk through several mechanisms. exposure to dense or diverse rodent populations in urban or rural environments 35, 36 and the displacement of wildlife populations as land is cleared for crops are some mechanisms. 36 understanding the context within which spillover to humans can occur is an important component in the prevention of zoonotic outbreaks. the same behavioural risk factors may be risky in one context but not in another. for instance, the sharing of a water source with animals displaced by a change in land use may only have an adverse effect on human health if there is faecal-oral transmission of the zoonotic pathogen to humans. if such transmission requires contact with the animal blood, then the sharing of the water source should not increase the risks of either spillover or transmission. once human-to-human transmission of a zoonotic pathogen occurs, additional risks come into play, often as a consequence of the human infection, and these should also be measured pre-emptively. burial practices and health-care-seeking practices were associated with explosive increases in, respectively, the incidence of human infection with ebola virus in western africa 6 and mers in the republic of korea. 37 even in the absence of detailed biological outcome data, behavioural surveillance may be used to assess relationships between behavioural risk factors and self-reported experiences of unusual illness that are consistent with the symptoms of zoonotic disease. this could be done both rapidly and at a scale that facilitates epidemiologically relevant analyses. although not as conclusive as biological data, self-reported data could provide substantially more information than is currently available. in the field of pandemic threats, biological outcome data could address the weaknesses of any self-reported data collected in behavioural surveys. the ideal source of biological outcome data, i.e. data that provide the strongest evidence of zoonotic disease spillover, would be community-based screening for acute infection with zoonotic viruses. however, as such infection is rare under nonoutbreak conditions, many thousands of individuals would usually have to be screened for a meaningful analysis of the behavioural risk factors. serological assays, in which previous exposure to a virus is demonstrated by a positive result, can provide alternative biological outcome data. since many more individuals may have been exposed to a virus than are currently ill with the virus, serology can provide the larger number of individuals, with known viral exposure, required for powerful analyses of behavioural risk factors. we therefore investigated the results of serosurveys for their potential usefulness in the prediction of future outbreaks. we focused on studies conducted in communities under non-outbreak settings in africa. we collated results presented in peer-reviewed publications -in english, french or spanish -that we identified via google scholar and web of science searches that ended on 31 december 2015 (available from the corresponding author). we used "africa", "antibody", "serology", "serosurvey", "zoonoses" and "zoonotic disease" as search terms. we identified additional relevant results through the citations in the articles identified in the searches. serosurveys of zoonotic viruses have been conducted since the discovery of the ebola virus in the 1970s, mostly during or shortly after an outbreak of zoonotic disease. our searches revealed 38 serosurveys of zoonotic viruses in africa that had been conducted during non-outbreak conditions. 25, 26, [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] to identify any associations between population subgroup risk and seroprevalence, we divided the subjects of the serosurveys into three risk categories, based on the limited data from previous research on zoonotic disease spillover. for example, hunters have been consistently found to be a high-risk population subgroup, 25, 26, 42, 45, 48 followed by rural populations, who have been categorized as medium-risk because of their close and regular proximity to wildlife. 38, 39, 41, 43, 44, 46, 49 randomized or representative samples of general populations 40, 47 have been considered to be low-risk. serological assays for several different zoonotic pathogens were conducted as part of serosurveillance in each of the 14 studies included in our analysis. use of these assays led to the recording of a total of 38 unique zoonotic pathogen seroprevalences that ranged from 0% to 24%. of these 38 seroprevalences, nine were recorded for high-risk population subgroups, 19 for medium-risk and 10 for low-risk. evidence of previous exposure to a zoonotic pathogen, i.e. a seroprevalence of more than zero, was detected in eight (89%) of the high-risk population subgroups, 16 (84%) of the medium-risk and seven (70%) of the low-risk (available from the corresponding author). high seroprevalences, i.e. seroprevalences of at least 1%, represented the results for all eight of the high-risk subgroups with evidence of previous exposure to a zoonotic pathogen, 12 (75%) of the medium-risk subgroups with such evidence and three (48%) of the low-risk subgroups with such evidence (available from the corresponding author). exposure to wildlife therefore appeared to be associated both with any evidence of viral exposure and with high seroprevalence. since the first known outbreak in 1976, the united states centers for disease control and prevention have recorded 35 documented ebola outbreaks in africa. 50 more than 5% of the subjects included in serosurveys in gabon in 1981 43 and liberia in 1982 46 showed evidence of exposure to ebola virus, that is decades before an ebola outbreak was first reported in either of these countries. between 1.9% and 12.4% of the subjects included in ebola serosurveys in three countries that have never reported an ebola outbreak, the central african republic, 40, 44, 48 madagascar 47 and zimbabwe, 39 were also found to be seropositive. although serological assays exist for the coronaviruses that cause mers and sars, hantaan viruses and paramyxoviruses, most serosurveys of zoonotic viruses in africa have focused on haemorrhagic fevers. most of the serosurveys we reviewed had also been done before the widespread availability and use of viral detection tests. recently, population-based serosurveys have been increasingly adopted, in recognition of their utility in preparing health authorities for potential outbreaks or epidemics. 26, 38, 49 current serological assay methods tend to be labour-intensive and to suffer from cross-reactivity that prevents distinction between several antigenically related viruses. however, the last few years have witnessed major advances in the development of economically feasible methods for comprehensive serological profiling 51, 52 and these should facilitate the investigation of zoonotic spillover into human populations. we review the potential contributions that integrated biological-behavioural surveillance could make to pandemicthreat prediction, prevention and risk mitigation. if we are to mitigate the risk of a zoonotic disease outbreak, we need a better understanding of the mechanisms behind the spillover of zoonotic disease into human populations. by making such mechanisms the focus of integrated surveillance, we should be able to: (i) monitor the presence and prevalence of behavioural risk factors and the seroprevalence of specific zoonotic pathogens within particular population subgroups; (ii) deploy targeted control and mitigation strategies rapidly; and (iii) evaluate the efficacy of prevention policies and interventions. although traditional disease surveillance must be frequent and ongoing to remain useful, behavioural surveillance remains informative even if conducted much less often, since behaviour change occurs slowly over time. to be effective as a prevention tool, integrated biological-behavioural surveillance should be implemented as a baseline measure -to identify behavioural risk factors, determine the prevalence of those risk factors, especially in any population subgroups that are considered at higher risk of zoonotic spillover, and establish seroprevalence. should an outbreak occur, a database that documents local behaviours and practices, as well as the context within which such behaviours occur, can contribute to the development of appropriate and feasible strategies for disease control and mitigation. finally, data from integrated surveillance will be invaluable in both informing realistic and effective interventions and policies for the prevention of zoonotic spillover and transmission, and evaluating the impact of such interventions and policies efficiently. relative to the economic, social and political costs of epidemics, prevention will always be less expensive 3, 19 if the targets of prevention activities are well understood and acted upon. the fact that success can feel more like the status quo is a challenge unique to prevention. the political commitment for prevention activities will often be less than that for a reactive response elicited by the emergence of a terrifying new infectious disease. however, political support may be improved if surveillance is made to be, and appear, more cost-effective, by focusing on specific diseases 22 in population subgroups who live in ecologically fragile hotspots. 14, 21 there is substantial overlap between areas considered to be hotspots for zoonotic disease spillover and those considered hotspots for hiv, perhaps the best known zoonotic virus. 14, 53 this overlap opens a real possibility of merging attempts to detect zoonotic disease spillover with pre-existing population-based systems that have been used to investigate the hiv epidemic for several decades. for example, the demographic and health surveys program is implemented globally in settings without high-quality civil registration and has extensive experience in collecting integrated biological-behavioural surveillance data in community settings. 54 integrated surveillance will never be a viable alternative to traditional clinical disease surveillance for assessing active viral infections. rather, it can serve to complement virus detection efforts, by potentially identifying pandemic threats before the need for large-scale clinical intervention. as current behaviours may not reflect the behaviours that originally exposed the individuals who are found seropositive to the virus of interest, both current and lifetime behaviours need to be investigated. this is the strategy that has proved successful in identifying subtle exposure risks in the field of hiv, such as backloading of syringes with drug solution by injecting drug users. 55 in identifying specific behavioural risk factors, integrated biological-behavioural surveillance will be most effective when the reported syndromic symptoms are recent, e.g. occurring in the previous 12 months, and their probable association with a zoonotic virus can be confirmed by a positive serological test result. current pandemic-threat warning systems rely almost exclusively on disease surveillance in clinical settings. standardized biological-behavioural surveillance, in which both disease outcome data -self-reported and biological -and behavioural risk factors are measured, would complement traditional surveillance and greatly advance the understanding of behaviours and practices that could be targeted for risk mitigation and, ultimately, for prevention. the implementation of integrated biological-behavioural surveillance need not be frequent to be informative and useful in preventing the spillover of zoonotic agents with pandemic potential. ■ отличительной чертой 21-го века являются вспышки заболеваний, оказывающие разрушительный эффект на экономику и политику. хотя причины пандемий кроются в поведении людей, современные системы наблюдения, предназначенные для выявления угроз пандемии, в значительной мере полагаются на мониторинг исходов заболевания в клинических условиях. стандартизованное, комплексное, биологически поведенческое наблюдение можно и следует применять в условиях общин как дополнение к подобному клиническому мониторингу. целесообразность такого подхода уже была продемонстрирована в исследованиях вируса иммунодефицита человека, в рамках которых комплексное наблюдение способствовало биологически обоснованному и поддающемуся количественной оценке пониманию факторов поведенческого риска, связанных с динамикой передачи вируса. для комплексного наблюдения, разработанного в соответствии с критериями устранения недостатков предоставления информации в наблюдательных исследованиях по эпидемиологии, необходимо измерение фак торов поведенческого риска, т. е. переменных подверженности воздействию, и выходных переменных индикаторов заболеваемости в рамках исследований поведения. в сфере угроз пандемии с помощью информации о биологических исходах можно было бы устранить недостатки предоставленных респондентами данных, полученных в рамках поведенческих исследований. судя по данным серологических исследований вирусов, имеющих пандемический потенциал, которые были получены в условиях отсутствия вспышки, эпидемиологический надзор может быть использован для прогнозирования будущих вспышек. проведение поведенческих и серологических исследований вместе позволило бы спрогнозировать будущие пандемии теоретически до того, как заболевание возникнет в клинических условиях. польза традиционного наблюдения исходов заболеваний зависит от частоты и непрерывности его проведения, в то время как поведенческое наблюдение позволяет получить ценную информацию, даже если осуществляется гораздо реже, поскольку поведение со временем изменяется медленно. только зная конкретные факторы поведенческого риска, можно разработать мероприятия и политики, способные предотвращать будущие пандемии. los brotes de enfermedades perjudiciales para la economía y la política son una característica del siglo xxi. a pesar de que las pandemias se ven impulsadas por el comportamiento humano, los sistemas de vigilancia actuales para identificar amenazas de pandemia dependen enormemente del seguimiento de los resultados de las enfermedades en entornos clínicos. la vigilancia integrada y normalizada de datos biológicos y del comportamiento podría y debería utilizarse en comunidades como complemento de dicho seguimiento clínico. su utilidad ya se ha demostrado en varios estudios sobre el virus de la inmunodeficiencia humana, en los que la vigilancia integrada contribuyó a la comprensión cuantificable y biológica de los factores de riesgo del comportamiento asociados con la dinámica de la transmisión del virus. al estar diseñada según los criterios del fortalecimiento de la notificación de los estudios observacionales en epidemiología, la vigilancia integrada requiere tanto los factores de riesgo del comportamiento (es decir, las variables de exposición) como las variables de resultados del indicador de enfermedades se midan en encuestas sobre el comportamiento. en el campo de las amenazas de pandemia, los datos de los resultados biológicos podrían abordar la debilidad de los datos autodeclarados recopilados en las encuestas sobre el comportamiento. la información de las encuestas serológicas sobre virus con potencial pandémico, recopilada en condiciones en las que no se había reportado un brote, indica que podría utilizarse la vigilancia serológica para predecir futuros brotes. al realizarse juntas, integrated surveillance for pandemic threats maureen miller & emily hagan las encuestas serológicas y sobre el comportamiento podrían advertir sobre futuras pandemias, probablemente antes de que la enfermedad aparezca en entornos clínicos. la vigilancia tradicional de los resultados de las enfermedades debe ser constante y frecuente para que sea útil, aunque la vigilancia sobre el comportamiento sigue siendo meramente informativa, incluso si se realiza con menos asiduidad, dado que los cambios de comportamiento se producen lentamente con el paso del tiempo. únicamente a través del conocimiento de los factores de riesgo del comportamiento específicos se pueden desarrollar las intervenciones y las políticas capaces de evitar el desarrollo de la próxima pandemia. 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evidence for henipavirus spillover into human populations in africa outbreaks chronology: ebola virus disease comprehensive serological profiling of human populations using a synthetic human virome determination of binding specificities in highly multiplexed bead-based assays for antibody proteomics geneva: joint united nations programme on hiv/aids innovations in health and demographic surveillance systems to establish the causal impacts of hiv policies syringe-mediated drug-sharing (backloading): a new risk factor for hiv among injecting drug users key: cord-325155-lqzgz6p3 authors: gallo, juan e.; ochoa, juan e.; warren, helen r.; misas, elizabeth; correa, monica m.; gallo-villegas, jaime a.; bedoya, gabriel; aristizábal, dagnóvar; mcewen, juan g.; caulfield, mark j.; parati, gianfranco; clay, oliver k. title: hypertension and the roles of the 9p21.3 risk locus: classic findings and new association data date: 2020-09-15 journal: nan doi: 10.1016/j.ijchy.2020.100050 sha: doc_id: 325155 cord_uid: lqzgz6p3 background the band 9p21.3 contains an established genomic risk zone for cardiovascular disease (cvd). since the initial 2007 wellcome trust case control consortium study (wtccc), the increased cvd risk associated with 9p21.3 has been confirmed by multiple studies in different continents. however, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major cv risk factor, nor with blood pressure (bp). theory in this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead cvd risk snps, while the other block contains the first exon and regulatory dna of the gene for the cell cycle inhibitor p15. we consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus. results we present original results from a colombian study revealing moderate but persistent association signals for bp and hypertension within the classic 9p21.3 cvd risk locus. these snps are mostly confined to a ‘hypertension island’ that spans less than 60 kb and coincides with the p15 haplotype block. we find confirmation in data originating from much larger, recent european bp studies, albeit with opposite effect directions. conclusion although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk. legend to graphical abstract: schematic depiction of the main observation presented and discussed in this article. two adjacent haplotype blocks characterize the 9p21.3 cardiovascular risk locus: left, the block or island containing the first part of the p15 gene and its wellcharacterized promoter, in which we observed clearly elevated associations (red) with blood pressure (dbp, sbp) and/or hypertension in a colombian and a european study sample, and right, the block hypertension and bp association 'hypertension island' * (haplotype block < 60 kb) lead cvd risk snps (haplotype block < 60 kb) significance of association strongest cvd association current threshold for genome-wide reporting ( p = 5 x 10 -8 ) fair cvd association contains start and promoter of p15 gene contains no protein-coding genes it had long been a widely held belief that common genetic variation in the established cardiovascular risk locus of cytogenetic band 9p21.3, as discovered and delimited via corresponding genetic associations in 2007 [1, 2, 3] , is not reproducibly associated with high blood pressure or hypertension, a prime risk factor for cardiovascular disease [4, 5] . the pleiotropic nature of the ≈ 120-kb classic risk locus of 9p21.3, the strongest known single contributor in the human genome to genetic risk of cardiovascular disease [6, 7, 8] , viewed together with the complexity of the genetic and molecular regulation of hypertension, prompted us to reopen the question if this region might, after all, be associated with a contribution of hypertension to the increased cardiovascular risk that characterizes the locus. in the theory section, we briefly depict the classic two-block structure of the region in the light of current knowledge, and review some findings and hypotheses that could admit a step of a hypertension etiology being modulated at this locus. in the results we first present results from an original, small colombian association study focusing on 9p21.3 variation. we then present largely corroborating results from much larger, recently published european studies, which we identified in a second step. taken together, the evidence accumulating so far suggests that common genetic variation in a well-described block (< 60 kb) of the 9p21.3 risk region -and, more specifically, in the regulatory dna of the p15 gene it harbors -may play a role in promoting hypertension, for example via vascular modifications in resistance arteries (arterioles). demographic and clinical information, including selected cardiovascular risk factors, was collected for all participants in a study conducted in medellín, colombia (see supplementary data). systolic (s) and diastolic (d) blood pressure (bp) levels were defined by the average of two conventional auscultatory bp measurements through a mercury manometer according to an approach in line with current european guidelines [9] . presence of hypertension was identified based on physician's diagnosis, prescription of antihypertensive drugs, average office sbp ≥ 140 and/or dbp ≥ 90 mmhg, or any combination of these possibilities. a total of 357 participants were genotyped. in view of this small sample size and in line with traditional case-control methodology [10] , [11, chapter 9] , the highest and lowest dbp tertiles of the population were slightly overrepresented in the genotyped individuals. dna was extracted from white blood cells following standard salting-out procedures and genotyped by lgc group, uk with kasp tm technology (https://www. biosearchtech.com). all snps genotyped were biallelic in our study sample. snp rs10738605 is triallelic in some other 1kg populations (not clm), its rare third allele frequency being 0.0014 in amr, 0.006 in eur and 0.0008 in afr. statistical analyses were performed considering bp either as a continuous or a categorical variable (above or below the current [9] threshold for hypertension diagnosis). effect sizes were defined as differences of mean values for continuous variables (e.g., sbp, dbp), and as odds ratios for dichotomous variables (e.g., presence or absence of hypertension). variables considered as possible covariates in the statistical analyses included gender, age, smoking and body mass index (bmi). to calculate association p-values and effect sizes between snp states and phenotypic variables we used the r package snpassoc [12, 13] . models fitted included codominant, dominant, recessive, overdominant and log-additive models. participants signed an informed consent formulated for this genotype-phenotype association study. the study was approved by the ethical committee of the corporación para investigaciones biológicas, medellín, colombia. all procedures were performed in agreement with the declaration of helsinki. additional material and methods are given in supplementary material s1. methods of european studies were as described in the publications presenting those studies [14, 15, 16] . the originally described risk locus of 9p21.3 has a bipartite or two-segment structure, in which each of the two mutually adjacent segments is dominated by a distinct haplotype block. although the haplotypes (i.e., states) of the two blocks are correlated, via a linkage disequilibrium originally estimated as around 0.6 (for average |d |) [2] , their frequencies are different. the minor allele frequency (maf) plots shown in figure 1 depict individual snp-and haplotype-level variation in the locus. two of the superpopulations that were sequenced and genotyped by the 1000 genomes project (1kg; [17]) are represented: amr (populations from the americas having a native american ancestry component) and eur (populations of european ancestry). the 'left-hand' block of the risk region, colored green in figure 1 , is composed of essentially three haplotype classes, giving one low and two higher, similar minor allele frequencies (separated by a green horizontal bar). the 'right-hand' block is dominated by two haplotype classes and has fairly constant allele frequencies close to 50%; the lead cvd risk snps of the region are at its rightmost fringe, denoted by ochre triangles. the left-hand block includes the upstream regulatory dna and start of the protein-coding gene encoding p15 (transcribed leftward). the figure shows a big difference between amr and eur in this block. the figure also shows a matrix, in 0/1 haplotype (schema) coding, for 16 snps that are representative of variation within this block, as obtained by 1000 genomes' sampling of 94 individuals (i.e., 188 chromosomes) from clm (medellín, colombia, an amr population). where three or more major haplotype classes dominate a region, individual bialellic snps can provide only aggregated resolution of what is happening at the haplotype level [18] . here, snp classes s1 (blue identifiers), s2 (red) or s3 provide information on, respectively, the contrast of haplotype class c2, c1 or c3 versus the remaining two haplotype classes of the haplotype block. the cvd risk locus in 9p21.3 is a confirmed risk locus not only for cardiovascular disease but also for other diseases, including cancers. the pleiotropies appear to be partly antagonistic, in that the risk allele for one disease can be the protective allele for another disease. for example, the nhgri-ebi gwas catalog (www.ebi.ac.uk/gwas) reports snps of the left block where the protective allele for an age-related condition (e.g., cvd, glaucoma) would be the risk allele for a cancer-related condition (e.g., breast cancer, glioma, pediatric brain tumor, endometriosis; see supplementary material s2.1). antagonistic pleiotropies have been noted or proposed before for this locus ( [19] ; see also [20] ), with data suggesting a corresponding positive selection in some populations having native american ancestry [21] . recent literature on the risk locus of 9p21.3 and its associations has emphasized the enigmatic long noncoding rna (lncrna) gene anril, which has regulatory roles that are still only partly understood, but that can affect expression of proteincoding genes in the risk locus [22] . earlier molecular biology studies had focused on two protein-coding genes for cyclin-dependent kinase inhibitors, which when activated can arrest or inhibit the cell cycle at the g1 stage: the gene cdkn2a encodes both p14 arf (p14) and p16 ink4a (p16), and cdkn2b encodes p15 ink4b (p15). a third protein-coding gene, mtap, which is located outside the risk locus, is also relevant for understanding the region. mtap encodes a key enzyme in the biosynthetic pathway of polyamines (which plays an important role in the stabilization of atherosclerotic plaques); there is also evidence that mtap may be partly regulated from within the 9p21.3 cvd risk locus despite the intervening distance [23, 24, 16] . 3.4. the p15 gene some common genetic variation in the p15 haplotype block is in regulatory dna, where it could in principle modulate transcription of the p15 gene. thus, the common snp rs2069418, in an established promoter of the p15 gene, borders a tetranucleotide that was critical for c/ebpβ binding and transcription of the p15 gene in experiments in vitro ( figure 2 ) [25, 26, 27] ; its common variation might also modulate a predicted stemloop (see supplementary material s2.2). the functionally strategic position of snp rs2069418 was also noted before, but in the apparently antagonistic context of glioma risk [28] . the well-studied promoter of the p15 gene [29] is a 'battlefield' in which the proto-oncogene c-myc and tgfβ/smad struggle to control the p15 gene. indeed, control of this gene can be important: where expression of the cell cycle inhibitor and tumor suppressor p15 is suppressed, cancer risk can rise [27] . tgfβ is a main 7 j o u r n a l p r e -p r o o f regulator of blood vessel development and maintenance, but it acts through several alternative 'arms', or pathways, e.g., via crosstalk. we ask when and where the arm of tgfβ's activities that utilizes p15, as part of the tgfβ/smad pathway, might be employed under physiological conditions in a context that would be relevant for the genesis of hypertension. figure 3 shows a rough sketch of elements of three pathways in which tgfβ can play a role and/or modulate hypertension etiologies: the tgfβ/smad pathway with target gene p15, in the central lane, and two other pathways that are trans-activatable by 'crosstalk'' with tgfβ, respectively mediated by the type 1 angiotensin-ii receptor (at1r / classic ras pathway, left) and the epidermal growth factor receptor (egfr, right). the central and rightmost of these three pathways and their crosstalk, for which roles in hypertension etiologies remain to be elucidated in more detail, are examined in this context in supplementary material s2.3; refs. [27, 30, 31, 32] describe experimental results that may be relevant. in addition to such cues from experiments, an independent line of evidence supporting a likely role for the central pathway comes from large-scale wholegenome association studies and metastudies that can now identify whole networks showing evidence of collective association with blood pressure [15, 16] . the results indicate that the tgfβ/smad pathway plays an important role in bp regulation, as it is enriched for bp-associated genes [16] . it then seems a plausible hypothesis that p15, as an important tgfβ/smad-responsive target, could be involved in the modulating of blood pressure. although the complexity and possible sensitivity of such a network can render difficult the prediction of how a genetic change at a given locus will affect bp or the risk of developing hypertension, already figure 3 hints that the p15 context puts us in a locus and a scenario where key players, such as cell cycle inhibitors, are only a step away from etiologically familiar routes to pathogenesis of hypertension or its prevention. we conducted a local, small study in the city of medellín, colombia (n=357 individuals without overt cvd) to explore possible associations between hypertension and 9p21.3 (67 common snps spanning > 300 kb). one of the motivations for the study was that we knew of no 9p21.3 studies of a population living in latin america. it was immediately clear from the sample size that even for minor allele frequencies (maf) above 20% we would find at best nominally significant evidence for associations from this study alone (0.05 > p ≥ 5 × 10 −8 ; [33] ). still, we wished to see what could be achieved by collecting and analyzing local data of modest size and integrating them into the global knowledge base [34, p. 6] , [35] . the screening of 9p21.3 for associations in the colombian study sample revealed an 'island' spanning 16 consecutive snps (58.2 kb), in which sbp and dbp levels as well as the presence of hypertension gave consistent association signals, and the island coincided almost exactly with the 'left' haplotype block of the 9p21.3 risk locus (figures 1 and 2 ; see theory). effect sizes for the 16 snps in the island were approximately allele-additive. snps in the immediately flanking regions gave only sporadic or no association signals (supplementary material s3.1). for instance, despite the small sample size, snp rs564398 in the island achieved p values of 2 × 10 −6 for hypertension, and 2 × 10 −3 / 5 × 10 −4 for sbp/dbp increase, with a per-allele odds ratio of 2.44 for hypertension and a mean difference (effect size) of 2.94 / 3.14 mmhg for sbp/dbp levels, after correcting for sex and age. comparable results were obtained when including smoking and/or bmi as covariates (supplementary material s1.4 and supplementary data). we compared the inferred risk and protector alleles for hypertension or blood pressure at our genotyped snps with the risk and protector alleles of disease phenotypes that had been previously reported at those same snps. risk alleles were defined as those for which mean difference or beta was positive (continuous variables), for which effect size was greater than one (dichotomous variables), or that were explicitly labeled as 'risk allele'. previously published associations listed in the nhgri-ebi gwas database suggested two mutually 'antagonistic' groups (see section 3.2, supplementary material s2.1, or [19, supplementary information]), the risk alleles for the cvd-or aging-related conditions (e.g., coronary heart disease, or intracranial aneurism) being the protector alleles for cancerrelated conditions (e.g., glioma). in our colombian study and in the 9p21.3 island where we observed the best association signals, the inferred risk alleles for hypertension or bp (e.g., a, the major allele, for rs7865618) were also the previ-9 j o u r n a l p r e -p r o o f ously reported risk alleles for cvd-or aging-related conditions at all snps that we genotyped. although our study focused on blood pressure variables and hypertension, we did consider, and subjected to the same basic phenotype-genotype analysis, several dozen (not all independent) alternative candidates for the phenotypic/outcome variable of primary interest, selected on the basis of their hemodynamic or other relevance to the development of hypertension (listed in supplementary data). however, the bp and hypertension variables consistently gave by far the best support for an association at the snps we genotyped (see supplementary data for the results obtained for rs7044859 and rs2069418, representing the two equivalence classes of snps s1 and s2, which are characterized by high linkage disequilibrium). a review of the data from recently published large european studies [14, 15, 16] with detailed look-ups of results in this region of interest, again showed higher dbp association signals in the same island that we had delimited in the colombian study than in its flanking dna, with p-values that almost reached genome-wide significance. thus, in the studies by warren et al. [15] and by evangelou et al. [16] (n > 750,000), the two lowest p-values for dbp, 1.23 × 10 −7 and 9.22 × 10 −7 , were found, respectively, at the 'left' fringe of the island's haplotype block (rs3217992) and at a snp in the interior of the island that we had not genotyped in the colombian study (rs7874604). furthermore, in the european blood pressure studies [15, 16] genome-wide significance of dbp associations was attained, outside of the classic 9p21.3 cvd risk locus and its flanking regions, in the next gene mtap (see figure 2 and theory), with a lowest p-value of 1.3 × 10 −10 for the sentinel snp rs4364717 (red asterisk and red horizontal bar at left in figure 2 ; see also the locuszoom plot in supplementary material s3.2) . the bp association with the mtap gene had not been noted in previous studies, and indeed the region had not been sufficiently covered in earlier imputation panels. in the earlier study by ehret et al ( [14] , n > 180,000), the best p-values observed were within the island, and again for dbp, although they did not reach values below 0.002 (see supplementary material, subsection s3.2). we were even able to detect concordant results as far back as 2011, in a study screening close to 2.5 million snps for bp associations [36] . the snps in the island again had much lower p-values than those in the lead cvd risk zone and regions flanking the island. thus, the snp that had the lowest p-value for hypertension in our colombian study sample, rs564398, had similarly the lowest p-value for dbp in the island in ref. [36] , namely 0.0161 as its genome-wide meta-analysis p-value corrected for genomic control. a notable difference with respect to the colombian results was the effect direction. indeed, directions of the bp effects in the european studies [15, 16] were consistently opposite to those observed in the colombian study at the same snps. in other words, the bp effects were also opposite to the established cvd effects for those snps in the literature. the now established cvd effect directions within the island are the same in european populations, deduced via direct genotyping of island snps, as they are in populations with a latin american or native american ancestry component (e.g., [37, 38] ), where they can be inferred from genotyped snps in linkage disequilibrium located close to the island. thus, in the european study samples, but not in the colombian study sample, the inferred protector alleles for hypertension (i.e., earlier in disease etiology) are the known, constant risk alleles for cardiovascular disease or events (i.e., later in the etiology). three other european reports we found, in ref. [39] and in the phenoscanner and roslin geneatlas association databases, had varying significance and independence, but the reported effect directions appear compatible with our findings (supplementary material s3.3). j o u r n a l p r e -p r o o f the results from the trans-ethnic investigations we describe here are compatible with the persisting presence, in a south american and in a european population, of associations between bp levels/hypertension and genetic variation specifically in a previously identified haplotype block or 'island' nested within the cardiovascular risk locus of band 9p21.3. in the european population, dense coverage of the association screening also allowed the recognition of an association peak for bp in a neighboring gene, mtap, which is located at about 140 kb from the risk locus. according to the data collected so far, the hypertension or bp effect within the cvd risk locus 9p21.3 would have the opposite direction in the south american compared to the european population, whereas the cvd effect appears to be the same in both populations, according to published reports [37, 38] . to our knowledge, however, our study is the first screen of the 9p21.3 'island' for hypertension or bp associations in a south american population, and we also know of no dedicated cvd association study with dense coverage in this part of the 9p21.3 risk zone. it is therefore too early to generalize or extrapolate from this one small study, and we must await confirmation from independent genotypephenotype screening in future, if possible also in south american populations having other ancestry proportions, such as those of peru or bolivia (see, for example, [40] ). the larger networks in which the p15 gene is embedded (e.g., the pathways of figure 3 ) are likely to be complex and resilient, and not just genetic background but also environment (e.g., diet) and local epidemiology (e.g., disease prevalences) could influence routing or rebalancing of the networks and thus affect associations. according to theoretical arguments, genotype-phenotype associations that change direction of effect between geographic, population or other environments (e.g., in the form of crossing reaction norms [41, 42] ) could actually be favored, because a variant that is inferior in all environments would be rendered unstable and would eventually be eliminated from the gene pool [43, 41] , [44, section 5] . in line with this view, trans-ethnically significant bp associations can exhibit sizable directional inconsistency rates. for example, among 562 snps genome-wide that were associated with bp traits (sbp, dbp, or pulse pressure) at a high significance of p < 10 −10 in a european sample (n = 757,601) in ref. [16, supplementary table 18] , 20 of the 32 snps having p < 0.01 also in a south asian population, and 6 of the 22 snps having p < 0.01 in an african population, had effect directions that were opposite to those in the european population. as a final note, a wider view of physical or regulatory gene interactions may 12 help understand potential roles of the cvd risk locus in modulating blood pressure or hypertension. one line of investigation that could be relevant is represented by hi-c data that capture interactions between different chromosomal regions. thus, hi-c data reported in ref. [16, supplementary table 8] show, at least in mesenchymal stem cells, an interaction cluster that includes the classic risk region and other regions from almost all of cytogenetic band 9p21.3 (4.7/5.7 mb; for details see supplementary material s3.4). the clustering regions include (or immediately flank) the 9p21.3 interferon gene group, relevant in inflammation, and two genes (gadd45g and focad) that have been considered of interest in cardiovascular as well as cancer contexts. of particular note, the cluster also includes the mtap and dmrta1 genes, which have been recently reported to be associated with dbp [15] and sbp [16] , respectively, and are located at a distance on either side of the classic risk region. such findings suggest that a full understanding of the potential role of p15 and the classic cvd risk locus in modulating hypertension and cvd might require a wider view that takes into account the regulatory interactions among genes distributed across, and possibly beyond, the 5.7-mb cytogenetic band 9p21.3. additional (extended) materials & methods, theory, and results are included in supplementary material sections s1, s2, and s3, respectively. de-identified genotype data and detailed association results of the medellín study are given in a supplementary data file (excel workbook) and described in supplementary material section s4. j o u r n a l p r e -p r o o f pomethylation that is disrupted in some cancers [45] ) illustrate the functional importance of the region around snp rs2069418. bottom: functional p15 promoter binding sites (boxes), critical subsequences (beige) and attempted experimental replacements [25, 26] that compromised normal transcription of p15 (bottom subsequences). legend to figure 3 : schematic diagram sketching three well-characterized pathways (3 vertical lanes) in which tgfβ plays a role via signaling and/or transactivation/crosstalk and which may act to promote or prevent hypertension. at the top of each lane, preparation steps needed for a master product that is essential for the pathway's activation are summarized. asterisks and daggers indicate gene products in which common snps in or in the gene's vicinity have been reported to be associated with blood pressure or hypertension in ref. [15, 16] (*; (*) for pathway) or have been reviewed as being associated with bp or hypertension in ref. [46] ( †). dashed horizontal arrows indicate experimentally observed or hypothesized crosstalk/transactivation between pathways (not just receptors). not shown, for simplicity, is another potentially relevant system, descending alongside the classic ras pathway at left, namely the 'nonclassical' ras, composed primarily of the angii/ang iii-at2r pathway and the ace2-ang-(1-7)-at7r axis [47] , which generally counteracts the effects of a stimulated classic ang ii-at1r axis as shown in the figure rs1063192 rs3217986 rs2069418 rs495490 rs7044859 rs496892 rs615552 rs10965215 rs564398 rs662463 rs7865618 rs1360590 rs17694493 rs10738605 rs11790231 rs2184061 1kg-clm,% 1kg-gbr,% class s2 s2 s1 s1 s2 s1 s2 s3 s2 s1 s3 s1 s2 188 j o u r n a l p r e -p r o o f rs7044859 genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls genomewide association analysis of coronary artery disease a common allele on chromosome 9 associated with coronary heart disease chromosome 9p21.3 locus for coronary artery disease: how little we know alu elements in anril non-coding rna at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. arterioscler from genotype to phenotype in human atherosclerosis -recent findings genomic risk prediction of coronary artery disease in 480,000 adults: implications for primary prevention esc/esh guidelines for the management of arterial hypertension haplotypes of the beta-2 adrenergic receptor associate with high diastolic blood pressure in the caerphilly prospective study principles of statistical inference snpassoc: an r package to perform whole genome association studies basic statistical analysis in genetic case-control studies the genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals genomewide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits genomes project consortium. a global reference for human genetic variation toward multiple snp motif analyses of loci associated with phenotypic traits antagonistic pleiotropy and mutation accumulation influence human senescence and disease chromosome 9p21 snps associated with multiple disease phenotypes correlate with anril expression genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy long noncoding rna anril: lnc-ing genetic variation at the chromosome 9p21 locus to molecular mechanisms of atherosclerosis expression of chr9p21 genes cdkn2b (p15 ink4b ), cdkn2a (p16 ink4a , p14 arf ) and mt ap in human atherosclerotic plaque cytoplasmic mtap expression loss detected by immunohistochemistry correlates with 9p21 homozygous deletion detected by fish in pleural effusion cytology of mesothelioma tgfβ influences myc, miz-1 and smad to control the cdk inhibitor p15 ink4b c/ebpβ at the core of the tgfβ cytostatic response and its evasion in metastatic breast cancer cells tgf-β family signaling in tumor suppression and cancer progression variants in the cdkn2b and rtel1 regions are associated with high-grade glioma susceptibility battle at the p15 promoter tgf-beta regulation by emilin1: new links in the etiology of hypertension loss of emilin-1 enhances arteriolar myogenic tone through tgf-β (transforming growth factor-β)-dependent transactivation of egfr (epidermal growth factor receptor) and is relevant for hypertension in mice and humans dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis p <5 × 10 −8 has emerged as a standard of statistical significance for genome-wide association studies promoting cardiovascular health in the developing world: a critical challenge to achieve global health the missing diversity in human genetic studies genetic variants in novel pathways influence blood pressure and cardiovascular disease risk susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic advance study the effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study association of a chromosome locus 9p21.3 cdkn2b-as1 variant rs4977574 with hypertension: the tam-risk study natural selection on genes related to cardiovascular health in high-altitude adapted andeans the evolution of life histories introduction to genetic analysis trade-offs in life-history evolution the causes of evolution selective variegated methylation of the p15 cpg island in acute myeloid leukemia elastin microfibril interface-located protein 1, transforming growth factor beta, and implications on cardiovascular complications nonclassical renin-angiotensin system and renal function abstract: schematic depiction of the main observation from association data presented or discussed in this article. two adjacent haplotype blocks characterize the 9p21.3 cardiovascular risk locus: left, the block or island containing the first part of the p15 gene and its well-studied promoter, characterized by elevated associations (red) with blood pressure (dbp, sbp) and/or hypertension in colombian and european studies, and right, the block containing lead cardiovascular risk 1kg-eur and 1kg-amr, representing mainly european origin and mainly or partly native american origin, respectively. color-shaded matrix shows 16-snp haplotype motifs (rows of red 0's/major allele and 1's/minor allele: master motifs, yellow shading: one-snp mutants) of the 94 1kg-amr individuals (188 haplotypes) from medellín, 1kg-clm, which correspond in ancestry and admixture to the 357 individuals m357-clm studied here from the same city (snp allele frequencies are shown below matrix). the 3 major haplotype classes are shaded light green (c1), light blue (c2) and sand (c3); by inclusion/exclusion they define the 3 snp classes s1(blue rs identifiers), s2 (red rs identifiers) and s3. relative haplotype frequencies are shown at right for 1kg-clm, corresponding to our association results from medellín, and for the british population this figure illustrates a nested-plot overview of genotyped 9p21.3 snps, the association signals for hypertension in the medellín study, and elements of a causal hypothesis involving a snp in the p15 promoter. colored bars and asterisks (top track) show extent and sentinel/lead snp of regions of strongest bp (red) or cardiovascular risk (blue) association in the studies by warren we thank professors i. king jordan and greg gibson (georgia institute of technology) for suggestions and references early in this study, drs. edwin garcía and juan ramón gonzález for advice on association analysis, and richard jacobs and jane mcdougall (lgc genomics uk) for genotyping assistance. we also thank two anonymous referees of a earlier version of this paper for suggestions. this rs2069418 rs2069418 rs7023954 rs15735 rs1134871 rs3731257 rs3088440 rs11515 rs3731249 rs3731239 rs3814960 rs36228834 rs7036656* rs2811711 rs2518723 rs3218022 rs3218020 rs2811712 rs3218018 rs3218012 rs3218005 rs3217992 rs1011970 rs2383207 rs10811650 rs1537375 rs16905599 rs1333045 rs10116277 rs10738610 rs10965227 rs10757278 rs1547705 rs1333049 rs10965228 rs1333050 rs1333040 rs10965243 rs1537370 rs2891169 rs7857345 rs2383208 rs10757274 rs7045889 rs4977574 rs10811659 rs2891168 rs10757282 rs10125231 rs10811661 rs2383206 key: cord-302937-3yivxfi8 authors: robertson, christopher t; schaefer, k aleks; scheitrum, daniel; puig, sergio; joiner, keith title: indemnifying precaution: economic insights for regulation of a highly infectious disease date: 2020-05-30 journal: j law biosci doi: 10.1093/jlb/lsaa032 sha: doc_id: 302937 cord_uid: 3yivxfi8 economic insights are powerful for understanding the challenge of managing a highly infectious disease, such as covid-19, through behavioral precautions including social distancing. one problem is a form of moral hazard, which arises when some individuals face less personal risk of harm or bear greater personal costs of taking precautions. without legal intervention, some individuals will see socially risky behaviors as personally less costly than socially beneficial behaviors, a balance that makes those beneficial behaviors unsustainable. for insights, we review health insurance moral hazard, agricultural infectious disease policy, and deterrence theory, but find that classic enforcement strategies of punishing noncompliant people are stymied. one mechanism is for policymakers to indemnify individuals for losses associated with taking those socially desirable behaviors to reduce the spread. we develop a coherent approach for doing so, based on conditional cash payments and precommitments by citizens, which may also be reinforced by social norms. in the medium-term time horizon until a vaccine is developed, and perhaps thereafter, management of the covid-19 pandemic will largely depend on broad behavioral changes at the population level. under a strategy of social distancing, lockdown, or quarantine, individuals are directed or suggested to exercise precautions including staying home, closing businesses, wearing masks, and avoiding physical proximity to other persons. 1 presymptomatic patients are a reservoir for spread, but such precautions depend on them believing that spread is both important and preventable. 2 individuals have inherent incentives to undertake such measures, because they are self-protective, reducing the chance of the actor herself becoming infected and suffering. accordingly, policymakers can expect a substantial degree of voluntary compliance, as long as the public receives, and believes, accurate information about the risk. that is, regrettably, a nontrivial assumption, but that problem is not our focus here. 3 notwithstanding the self-protective effects of these measures, microeconomic analysis suggests a likely market failure, due to heterogeneity in the population. part of the heterogeneity is biological-some individuals (eg younger persons and women) appear less likely to suffer harm from infection, whereas other individuals (eg older persons, men, and those with other medical conditions) face greater risk of harm if infected. 4 the costs of precaution are also heterogeneous. for individuals who would otherwise be actively building careers or businesses, searching for romantic partners, or providing for dependents including children, the costs of staying at home are much more substantial, compared with others who are already retired from work, settled with spouses and partners, and no longer have dependents. 5 certainly, the consequences of loss of life are more dire for the younger as they have more years of life to lose. however, younger people tend to discount the future more heavily than older individuals and may not place much value on the additional years of life at risk. 6 perhaps most important, the greatest risk to individuals in this younger group, particularly teenagers, is the loss of the social interactions through school, sports, and other activities that are essential to combat depression, among other risk factors for health. 7 suicide and suicide attempts in younger individuals dwarf the magnitude of risk from covid-19, which makes the pandemic precautions particularly burdensome for this population, even if yielding spillover benefits for everybody else. 8 perilously, young people are starting to venture into 'covid-19 parties' organized, so that people can mingle with infected people to get the illness 'out of the way' and carry on with life. 9 in rough terms, for the age gradient in particular, these observations suggest a stark misalignment of incentives-younger persons personally receive the fewest benefits from precautions, but suffer the greatest costs of taking them. on the margin, some individuals will see the personal costs of taking a precaution to be greater than the personal benefits. the heterogeneity in the population suggests a classic market failure, known in the law and economics literature as an 'externality' . 10 those who do not comply with precautions disproportionally impose the costs of noncompliance on others, who are more likely to suffer from infection. similarly, for seasonal flu where vaccination is a primary precaution, the rate of vaccination in the 18-49 age bracket has not in recent years exceeded 35%, which is just over half the rate of older adults. 11 in a recent survey, young millennials were the least well informed about influenza, and the most likely to believe anti-vaccine rhetoric. 12 accordingly for covid-19, we can expect that for those who can get infected without bearing healthcare costs, suffering, or unemployment, precautions may seem unnecessary. this is especially true given that persons have private information about their preventive measures, but may not possess information about whether they are infected. how can governments effectively regulate this situation in the complex environment of an infectious disease, like covid-19? we make the nontrivial assumption that governments can promulgate policies about what activities may be optimal at a given point in time (ie whether to return to work), but we focus on mechanisms of compliance, recognizing that many micro-level decisions are difficult for the government to monitor, much less to enforce. from a normative perspective, the goals are clear: to minimize the net harm to aggregate social welfare caused by the pandemic, accounting for both the public health losses (mortality and morbidity, and the costs of treating or suffering with the same) and the economic losses associated with taking precautions (lost wages and forgone consumption of welfare-enhancing goods and services). we generally assume, for the sake of argument, that certain levels of specific precautions are worthwhile from this social utility perspective. yet, for the reasons just stated, the costs and benefits of taking those precautions are poorly distributed. we do not offer a normative theory of optimal distribution, but rather a behavioral one: how to align the costs and benefits of precautions so that the precautions will be sustainably undertaken. one mechanism to address that problem is for policymakers to indemnify individuals for losses associated with taking those socially desirable behaviors to reduce the spread. we discuss a coherent mechanism for encouraging the taking of costly precautions, which may also be reinforced by social norms. the concept of 'moral hazard' is that individuals are more likely to take risky or costly behaviors when those costs are borne by others. 13 in health policy, most of the focus on moral hazard has been in the design of health insurance policy, using deductibles and copays, to insure that once ill or injured, a patient does not wastefully consume healthcare. 14 that form of moral hazard is sometimes distinguished as 'secondary', or 'ex post', after the illness arises. notwithstanding an overwhelming emphasis in health policy, the literature suggests that 'ex post' moral hazard is a relatively small driver of healthcare consumption for several reasons, including patients' lack of agency in making many of their own healthcare choices in practice. 15 accordingly in the covid-19 infectious disease context, where underconsumption is a greater risk than overconsumption, congress provided that tests be covered without cost exposures and insurance companies have largely covered associated treatments. 16 in contrast, 'primary', or 'ex ante', moral hazard applies where individuals who have healthcare costs largely externalized to the insurance pool may undertake risky behaviors (eg smoking or skydiving) increasing chances of having an injury or illness in the first place. 17 for health insurance design, primary moral hazard may have a relatively small effect on risk-taking behavior, because individuals personally suffer many of the other risks associated with illness or injury (including pain, suffering, lost work, chance of death). 18 these other costs are likely more salient to a person selecting a risky behavior than is the fact that some of the healthcare costs will be insured. for the policy of managing infectious disease, primary moral hazard is likely to be a more important driver of behavior where the chance of suffering any disutility whatsoever is heterogeneous. in this case, although the risk does not approach zero, it is as if relative youth provides partial indemnity insurance against not only the healthcare costs, but also the pain, suffering, lost work, and chance of death that are associated with covid-19 infection. traditional health insurance policy has conceived healthcare as a cost when a risk materializes, but healthcare is often itself a precaution against a greater future risk. baicker and colleagues have coined the term 'behavioral hazard' to refer to the phenomenon of people declining to consume worthwhile healthcare. 19 this body of research in the health insurance domain demonstrates the more general phenomenon of how policy may strike the wrong balance, for example, if actors are biased away from optimal precaution-taking decisions, because the immediate costs of care (eg copayments for insulin) seem more salient than the longer-term costs (eg treating neuropathy for uncontrolled diabetes). 20 of course, that problem is exacerbated if the costs of precaution are so high that individuals simply cannot afford to take them, even if they would prefer to do so. 21 accordingly, the affordable care act now requires coverage of certain preventive services without cost exposure at all-indemnifying the cost of precaution-an approach that may improve welfare and reduce spending overall. 22 in the recent past, few global diseases in human health have been comparable to covid-19 with respect to the simultaneous level of transmissibility and pathogenicity. yet policymakers are not 'flying blind' . in other infectious disease contexts, moral hazard and risk-seeking behavior have been confirmed empirically. for example, in the uk, policymakers have struggled to manage an outbreak of bovine tuberculosis. 23 the primary policy mechanism is a surveillance program, where agricultural agents visit farms and test animals for the disease. if it is discovered, the animal is killed, and the farm is put on a disease-restricted status (like a quarantine or lockdown) for 60 days. 24 the farmers are able to take various costly precautions (eg maintaining fences, disinfecting trailers) to reduce the risk of infection. one might suppose that the risks of having beef purchasers reject infected meat, of having an infected animal discovered and slaughtered, and having the farm put on lockdown would be sufficient to induce optimal rates of precaution-taking. however, the policy also includes a provision to indemnify the farmer for the loss of the infected animal that must be destroyed by law. forthcoming empirical work shows that higher levels of indemnity may lead to higher rates of infection likely because farmers take fewer precautions when facing larger indemnities. 25 in this case, the government has in part exacerbated the moral hazard problem, by paying an indemnity that lowers the farmer's risk exposure, reducing the inherent incentive he would otherwise have to keep his cattle healthy. this indemnity is similar to the young, female, otherwise healthy human in the age of covid-19, who may be less likely to suffer adverse effects of infection, and thus has reduced inherent incentives to take precautions. as in human health, a farm experiencing a disease breakdown generates a negative externality for its neighbors through spatial disease transmission. by taking steps to minimize the likelihood of a breakdown on her own farm, the farmer also reduces the likelihood of infection for her neighbors. the indemnity payment relieves the farm of a portion of the costs of contracting the disease and, by doing so, reduces the incentive to invest in on-farm biosecurity. consequently, not only do high indemnity rates lead to higher rates of disease, directly, by disincentivizing precautionary steps, but also the spatial feedback effect runs the risk of generating further infections in the surrounding area. 26 again, the example of animal disease management echoes the human experience. in the agricultural settings, the unfortunate policy of indemnifying farmers against the costs of their failing to take precautions may reflect a constitutional, legal, or political limit to governmental enforcement. the payment of an indemnity may reflect a political bargain, allowing a relatively intrusive regulatory mechanism, such as mandatory testing, to be agreeable to the agricultural lobby, if accompanied by a payment from the treasury to offset some of the costs thereof. 27 similarly, under the us constitution's due process clause, the government must generally compensate individuals for 'takings' of their property. 28 moreover, under international commercial agreements, businesses may enjoy a remedy against excessive regulatory interventions that cause economic injury. 29 more generally, the us constitution limits the powers of the state and federal governments to restrict certain liberties, but the supreme court has generally upheld reasonable public health interventions, especially in times of emergency. 30 in the 1905 case of jacobson v. massachusetts, for example, the supreme court upheld a local massachusetts law requiring smallpox vaccination. 31 the courts have, however, struck down public health enforcement actions that were motivated by racial animus, or which were not appropriately tailored to the risks at hand. 32 nonetheless, the government has broad powers in this domain. 33 accordingly, to enforce orders for social distancing, or staying at home in particular, some governmental actors made strict orders backed by the coercive power of the state. 26 on april 5, for example, police officers throughout the state of california began issuing citations for those who refused to close businesses or maintain social distance on beaches. 34 if these sorts of citations, or more severe sanctions such as imprisonment, have a deterrent effect, they may solve the collective action problem. however, deterrence theory suggests that to be effective, enforcement has to find the optimal mix between detecting noncompliance and then sanctioning it once found. 35 for a rational actor, the risk of suffering the sanction is the product of these two variables. although it may be relatively easy for the police to detect and enforce against business operators and beach goers, it will be much more difficult to detect individuals who meet to have sex, for example. similarly the war on illicit drugs has been stymied by such difficulties of detection. 36 whether such black markets can be kept small enough to keep infection rates at manageable levels, is a key question. in this case, deterrence is also stymied by the realities of an infectious disease, such as covid-19. law enforcement typically employs escalating consequences for violations, starting with the threat of fines and culminating with imprisonment as the ultimate consequence short of death. yet, fines may affect communities that have already been hit hard by the pandemic and are generally hard to enforce, when individuals have little or no funds to pay (a problem known as 'judgment proofing'). 37 indeed, the power to fine is ultimately backed by the power to imprison those who refuse to pay. 38 moreover, prisoners are particularly vulnerable to covid-19 due to overcrowding, poor ventilation, unsanitary facilities, and poor access to healthcare services. 39 prisons easily become epicenters of disease, threatening the health and safety of the inmates as well as the surrounding community. 40 inmates from prisons to home confinement. 41 some prisoners have reportedly even tried to get themselves infected, as a basis for then getting early release. 42 thus, governments are hamstrung in how they are able to enforce compliance with social distancing and quarantine requirements. fines are regressive and imprisoning an individual violating quarantine guidelines would be counterproductive as they could introduce the disease into a particularly vulnerable population where the chance of spread is high. governors and law enforcement agencies have dramatically reduced arrests. 43 by may 2020, some local governments were already refusing to enforce 'stayat-home' orders for political, ideological, or other reasons. 44 hence, governments will have to look beyond the threat of fines and imprisonment to compel compliance with precautionary measures. these difficulties may explain why, in march and april 2020, the usa saw private actors merely encouraging people to take precautions, and even some governmental actors, such as state governors, who had the power to exercise the coercive role of the state, declined to do so, in favor of mere exhortation and encouragement. 45 the literature on 'private ordering' and the broader literature on social norms, together suggest that individuals may provide socially desirable behaviors, even when it is not compelled to do so under strict rationality. 46 economics literature suggests the possibility of repeated interactions with individuals and the threat of social retaliation may be sufficient to establish and uphold social norms (ie 'don't burn bridges'). 47 for instance, adherence to government recommendations to social distance may be achieved simply through the universal fear of loss of status or reputations if one is discovered to disregard recommended behavior. in hong kong and elsewhere, internet users shamed people they believed had flouted lockdown orders, traveled, or socialized recklessly during the pandemic. 48 vendors may also voluntarily embrace precautions to burnish their own reputations for safety. for covid-19, government directives were initially crude-just a binary decision to allow businesses to remain open (if essential) versus mandate closure (if not). yet, the market responded innovatively: in some 'essential' stores, there were no limits on the number of shoppers in the store, no systematic disinfection of carts or baskets or checkout counters, no masks or other protective equipment of store personnel, and the like. conversely, some stores voluntarily created waiting lines outside the store, with tape demarcating 6 foot intervals, allowing entry into the store only with exit of another shopper, thoughtful distancing of carts from other shoppers on checkout, a designated position for the customer while items are scanned, and more. stores may have enacted voluntary precautions in hopes of boosting business by being seen as a safe place to shop, reducing liability exposure in the event of infected employees, or simply to minimize the chance of disease spread for safety reasons. eventually, governments may catch up to prescribing the sort of granular policies for managing covid-19 as they have, for example, for handling food-borne illness in foods. 49 yet, reputational sanctions tend to work best when used against members within identifiable groups, such as a close-knit religious or ethnic community, but can cut against compliance of formal rules. 50 in communities in which government authority conflicts with strong social norms or fear of loss of status or reputations, governmental orders can also be harder to enforce. it has been reported that an important factor contributing to the outbreak in south korea included mistrust by a close-knit community. 51 economic and behavioral insights are powerful for understanding the problems inherent in managing a highly infectious disease, but what do they recommend as solutions? the overarching principle is to make it easier (ie less costly) for individuals to take reasonable precautions than to not take reasonable precautions. in this essay, we are primarily focused on regulatory mechanisms prior to a vaccine becoming available. however, the american experience with vaccine mandates is illustrative of our economic and behavioral analysis so far. consider a parent's choice about whether to vaccinate her child prior to covid-19. her state may nominally require vaccination unless an exemption applies, but an indifferent or harried parent may find it easier to scribble her name on an exemption form rather than go to the hassle of finding a pediatrician, making an appointment, and securing the vaccination. indeed, scholars have found that vaccination rates vary substantially depending on the procedure required to invoke such an exemption. 52 for example, in 2011 washington state implemented a requirement that parents have a counseling session with a physician prior to securing such an exemption, and exemption rates went down by 40%. 53 in addition to any information delivered, these requirements function as behavioral speed bumps for the parent, with the inconvenience (ie non-monetary cost) serving to ration the scarce resource of non-vaccinated parents. 54 in this way, the precaution is made less costly than not taking the precaution. for covid-19, when a vaccine is available, it may begin as a scarce resource to be rationed across many people desiring it, but once it achieves a certain saturation, there will likely remain a minority of persons who resist vaccination, unless properly incentivized. the usa has generally focused only on childhood vaccinations, but strategies for incentivizing adults will then be required as well. for example, participating in some valuable but risky activities, such as airline travel, could be conditioned on vaccine compliance. 55 returning to our focus on the prevaccine era, in order to diminish the negative impact on the economy and citizens' finances, some governments are considering issuing 'immunity certificates' to individuals who have recovered from the disease and are presumed to be immune from reinfection as well as unable to spread disease. 56 these individuals with immunity certificates would then be able to re-enter society and resume their employment as well as patronize businesses and continue participating in the economy. assuming that fundamental questions regarding immunity can be answered affirmatively by medical science, and that a technological solution can be employed to ensure validity over counterfeiting concerns, such a policy could then receive support in judicial review, as discriminating against those with and without immunity, not unlike the way extant and potential policies discriminate against those who are unvaccinated. 57 still, this sort of certificate policy could backfire, especially as it creates an incentive to contract the disease-a 'get-out-of-jail-free' card, creating a risk of community spread, prior to the hypothesized benefit of immunity being secured. intentionally seeking out disease like in the form of 'covid-19 parties' has precedents in the form of 'chicken pox parties' in order to obtain immunity as a young child as well as the concept of 'gift giving', the intentional transmission of hiv. 58 unless the infection is secured in controlled conditions (eg exposure followed by 2 weeks of quarantine), the net effects may be negative overall. this analysis suggests that the immunity certificates policy could exacerbate the same moral hazard problem, which already discourages some people from taking reasonable precautions. this problem may be overstated, to the extent that individuals are already actively flouting stay-at-home orders, immunity certificates may do little to alter their private risk calculus toward less precaution. thus, the primary concern is the population on the margin, who otherwise would have abided by shelter-in-place and social distancing, but due to immunity certificates, will be tipped toward reckless behavior. those who are extremely financially insecure, those who perceive themselves to not be at risk of serious adverse consequences of the disease, or those who believe contracting covid-19 is inevitable have an incentive to eschew precautionary measures and seek out the disease in order to shorten the length of time they are out of work. this problem reinforces the more fundamental need, discussed below, to further indemnify individuals who are taking precautions, including through substantial increase in unemployment compensation, as already beginning in the cares act (discussed below). speaking more broadly, while the immunity card solution allows identification of individuals who are no longer disease susceptible, it fails to solve the primary imperfect information problem-identifying who is contagious. expanded testing capacity and faster tests would allow for more direct targeting of the moral hazard problem. improved testing would dramatically reduce the need for population-wide 'shelter in place' strategies. under this scenario, quarantine restrictions could be limited only to individuals that test positive and their contacts. this strategy imposes the economic costs of contagion on precisely the right individuals-those that are contagious. and unlike the immunity card strategy, it does not create a perverse incentive to become infected, but rather imposes the costs of quarantine on those who become infected. note that such an analysis need not suggest that all individuals who become infected are in some way at 'fault' for having become infected (though some may have been, if they failed to take reasonable precautions to avoid infection). once infected due to any cause, in economics jargon, the infected individuals generate a negative externality, and, thus, they are the appropriate population to be isolated. 59 regardless of the source of infection, it may then be unreasonable for such a person to engage in activities that risk harm to others. we also emphasize below that the individuals under targeted quarantine could be compensated for the private costs of quarantine through private or public insurance programs. a test-and-quarantine strategy would allow the economy-susceptible and immune individuals alike-to resume normal life while actively and effectively mitigating the spread of the disease. of course, this targeted quarantine strategy still requires compliance with guidelines to stay at home on the part of the covid-19-positive individuals. compliance may be achieved more easily in this scenario as subjects of quarantine will know the restrictions are temporary. additionally, because those quarantined have tested positive or come in contact with a positive case, they will face more severe social pressure to avoid contact with others. however, unless widespread testing could be implemented and made mandatory (at least conditional on certain risky behaviors), other imperfections in the healthcare system confound this strategy. if tests were not mandatory, symptomatic individuals could simply avoid testing so as not to be detected as a positive case and removed from employment. for instance, those who are financially insecure and without any sickleave program that would provide compensation during the quarantine period would have incentive to avoid the test to prevent loss of income. for covid-19 across all these particular policy tactics, the fundamental mechanism must be to reduce the costs associated with individuals taking precautions, so that the net individual cost of precaution is lower than not taking the precaution. the most costly form of precaution is to stay home from work. one obvious solution is to effectively indemnify persons who lose income due to lost work. prior to the covid-19 crisis, this was a weakness of us policy, compared with other industrialized countries, which tend to have robust provisions for paid sick leave and unemployment insurance. for people who actually lose their jobs, unemployment insurance in the usa pays for up to 26 weeks and is even then capped to cover only a portion of prior income. 60 in one study, those receiving unemployment insurance only recouped half of their lost wages on average. 61 the $2 trillion package passed by congress in mid-march provides a one-time payment at about $2400 plus $500 per child for most families (and less or none for others). 62 it is worthwhile that these payments went to both workers and nonworkers, because even nonworkers face substantial disutilities in complying with social distancing protocols. however, for workers at least, the payments are far from sufficient to indemnify the costs of precaution: the median american family would need about $5000, to compensate for a single lost month of work. 63 additionally, the usa has increased weekly unemployment benefits by $600. 64 even with the increased weekly payment for the unemployed, the benefit may end in the near future and it does not scale with income to the detriment of those living in high cost-of-living areas. 65 this suggests that noncompliance will remain a very substantial problem (not to mention the substantial disutility suffered by those under the current income shock and the larger economic effects due to contraction). of course, with broader public spending on income replacement and broader compensation for taking precautions, someone must pay those costs. as younger persons today may be disproportionately taking precautions for the sake of protecting older persons (as we suggest in the introduction), it may not be sensible to use deficit financing, where younger persons would ultimately bear those costs. however, we set aside the point of intergenerational justice. behaviorally, it may be more sensible to distribute the burdens across current taxpayers more rationally. current us tax policy is relatively flat, unlike the wartime era of the 1940s, when marginal tax rates went as high as 94% for the highest-income earners. 66 we cannot here make a comprehensive case for the optimal tax policy, recognizing complications like tax avoidance. 67 however, it remains true that wealthier individuals suffer less disutility for each dollar expropriated through taxation, compared with poorer individuals who suffer greater deprivations on the margin. 68 this 'diminishing marginal utility' of money (as it is known in the economics literature) suggests a substantial opportunity to reallocate the costs of precaution to minimize the disutility. most importantly, this special pandemic situation inverts some of the classic arguments against progressive taxation as undermining incentives to work. 69 here, the rush to get back to work may impose more social costs (in terms of infections) than social benefits (in terms of economic productivity). in this way, government payments to those who are complying with social distance or quarantine protocols are designed to indemnify them against the costs of taking those prosocial precautions. of course there is a risk of mismatch-people receiving the payments who are nonetheless not complying with distancing/quarantine guidelines. to make the bargain more explicit, the payments could be made conditional on agreeing to comply with stay-at-home or social distancing orders. given the extensive literature on the deep evolutionary basis of reciprocity for human behavior, we hypothesize (subject to testing) that such an explicit promise to comply as a reciprocal condition of accepting funds (a 'carrot' strategy) may have behavioral advantages over other ('stick') forms of enforcement, such as fines or imprisonment. 70 our point is not about the cost of noncompliance (assume equal probability of detection and an equal-size penalty), and we are not suggesting a differential framing according to prospect theory (in both cases it may be framed as a loss conditional on noncompliance, rather than a gain). 71 rather, asking individuals to explicitly commit to compliance as a condition of accepting payment reinforces a social norm of compliance. 72 moreover, the breaking of the promise creates a cognitive dissonance, which itself may be experienced as a disutility. 73 the explicit promise and size of these payments are likely to make them more effective than the sorts of small fines that may have perverse effects. 74 in addition to self-policing by people feeling motivated to keep their own promises, compliance may be buttressed by other members of the public shaming those who do not comply or even reporting them to authorities, because they represent not only a hypothetical risk for infection but also expropriation of public funds. in this way, the noncompliance can also be connected to standard law enforcement mechanisms, where an individual convicted of violating a legitimate order suffers revocation of the payment as a penalty, with full due process protections of course. even with such a standard (rational) deterrence theory, the explicit promise to forfeit the funds upon noncompliance may make that risk seem more salient to the citizen and thus increase compliance. overall, these economic and behavioral principles suggest that to manage a pandemic prior to dissemination of a vaccine, policymakers should use conditional payments to encourage compliance with social distancing, stay-at-home, and quarantine directives. the key is to make compliance easier and cheaper than noncompliance, especially for those that would otherwise feel the greatest compulsion to not comply. adolescents are paying a high price for covid-19 prevention (suicide is the second leading cause of death for individuals 10-34 years of age new source of coronavirus spread: 'covid-19 parties', nytimes fatal tradeoffs: public and private responsibilities for risk flu vaccination coverage insurance coverage of emergency care for young adults under health reform families first coronavirus response act health insurance providers respond to coronavirus (covid-19) anticipatory ex ante moral hazard and the effect of medicare on prevention, 20 health econ health insurance increases preventive care, not risky behaviors diabetes outpatient care and acute complications before and after high-deductible insurance enrollment: a natural experiment for translation in diabetes (next-d) study. 177 the theory of demand for health insurance effects of a cost-sharing exemption on use of preventive services at one large employer, 25 health aff bovine tb strategy review: summary and conclusions, department for environment food & rural affairs actions once tb is suspected or confirmed, tb hub cruel to be kind: moral hazard in british animal disease management memorandum on prioritization of home confinement as appropriate in response to covid-19 pandemic inmates tried to infect themselves with the coronavirus to get early release, los angeles county sheriff says portland police will not take misdemeanor arrests to jail during the covid-10 outbreak, to avoid overcrowding, willamette week northam encourages police to avoid arrests, imprisonment in wake of covid-19 virus coronavirus: officers make fewer arrests during covid-19 emergency two arizona sheriffs say they will not enforce governor's stay-at-home order, the hill to-know-about-face-masks-and-staying-home-as-virus-spreads#transcri pt (national institute for allergies and infectious diseases director anthony fauci interviewed: 'q. but when lives are at stake, why aren't command measures requiring people to do this appropriate now? a. that generally is not the way things operate in the relationship between the federal government and the states order without law: how neighbors settle disputes credible commitments: using hostages to support exchange social norms and community enforcement medical-exemptions-questions-and-answers/ (a 2019 california law allows the health department to report physicians to the medical board if they issue too many such exemptions can rationing through inconvenience be ethical? vaccines and airline travel: a federal role to protect the public health. 42 covid-19 see robertson supra note 55 chickenpox transmission, ctrs. for disease control & prevention the intentional transmission of hiv by hiv-positive men to their hiv-negative sex partners, 2 automobile accidents, tort law, externalities, and insurance: an economist's critique introduction to unemployment insurance senate passes $2 trillion coronavirus relief package, npr budget office, average household income, by income source and income group extra $600 unemployment benefits will start flowing as early as this week for a lucky few unemployment benefits will be reduced after federal individual tax rates history, nominal dollars joel slemrod & shlomo yitzhaki, tax avoidance, evasion, and administration, in 3 handbook of public economics social welfare and the rate structure: a new look at progressive taxation, 75 cal. l. rev. 1905 (1987) (arguing that the diminishing marginal utility of money makes it efficient to take more from higher-paid individuals); see also leo p. martinez see generally, philippe chonã© & guy laroque, optimal incentives for labor force participation the case for a progressive tax: from basic research to policy recommendations, 25 perhaps the most remarkable aspect of evolution is its ability to generate cooperation in a competitive world thus, we might add 'natural cooperation' as a third fundamental principle of evolution beside mutation and natural selection erc: a theory of equity, reciprocity, and competition prospect theory: an analysis of decision under risk applying behavioral economics to public health policy: illustrative examples and promising directions, 50 legal promise and psychological contract the neural circuitry of a broken promise numerous psychological and economic experiments have shown that the exchange of promises greatly enhances cooperative behavior in experimental games fine enough or do not fine at all, 59 a fine is a price. 29 the authors thank andrea sharp and jacqueline salwa for research assistance, and bert skye for administrative support. the manuscript benefited from two anonymous peer reviewers. key: cord-340713-v5sdowb7 authors: bird, jordan j.; barnes, chloe m.; premebida, cristiano; ekárt, anikó; faria, diego r. title: country-level pandemic risk and preparedness classification based on covid-19 data: a machine learning approach date: 2020-10-28 journal: plos one doi: 10.1371/journal.pone.0241332 sha: doc_id: 340713 cord_uid: v5sdowb7 in this work we present a three-stage machine learning strategy to country-level risk classification based on countries that are reporting covid-19 information. a k% binning discretisation (k = 25) is used to create four risk groups of countries based on the risk of transmission (coronavirus cases per million population), risk of mortality (coronavirus deaths per million population), and risk of inability to test (coronavirus tests per million population). the four risk groups produced by k% binning are labelled as ‘low’, ‘medium-low’, ‘medium-high’, and ‘high’. coronavirus-related data are then removed and the attributes for prediction of the three types of risk are given as the geopolitical and demographic data describing each country. thus, the calculation of class label is based on coronavirus data but the input attributes are country-level information regardless of coronavirus data. the three four-class classification problems are then explored and benchmarked through leave-one-country-out cross validation to find the strongest model, producing a stack of gradient boosting and decision tree algorithms for risk of transmission, a stack of support vector machine and extra trees for risk of mortality, and a gradient boosting algorithm for the risk of inability to test. it is noted that high risk for inability to test is often coupled with low risks for transmission and mortality, therefore the risk of inability to test should be interpreted first, before consideration is given to the predicted transmission and mortality risks. finally, the approach is applied to more recent risk levels to data from september 2020 and weaker results are noted due to the growth of international collaboration detracting useful knowledge from country-level attributes which suggests that similar machine learning approaches are more useful prior to situations later unfolding. according to the future of humanity institute there is a 2.05% chance that mankind will go extinct by the year 2100, through either a natural or engineered pandemic [1] . if there is one lesson to learn from the ongoing covid-19 coronavirus (sars-cov-2) pandemic, it is that a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 we were not prepared. the virus initially spread rapidly across the globe, mortality began to rise, and countries desperately struggled to test their citizens for the virus once it became known that many infectious carriers of it show no noticeable symptoms [2] [3] [4] . this suggests three main risk factors to be observant of: the initial risk of transmission due to varying factors such as, for example, population density [5] and international travel [6] ; the risk of mortality due to ageing populations [7] and underlying health issues [8, 9] ; and finally the risk of a country not being able to test citizens aptly and thus producing possibly under-reported measures of the previous two [10] . machine learning has shown success in contributing to research during the covid-19 pandemic. health service data trend models have shown to aid in classification of the virus [11, 12] , vaccine design [13] , estimation of cases, deaths, and recoveries [14, 15] , simulating what could have happened if 'lockdown' was not instituted [16] , and also simulating behaviour of the spread of the disease by prior knowledge from other locations [17] . in this work, we devise a machine learning based strategy to predict three-fold risk at the country-level: (i) risk of transmission, (ii) risk of mortality, and (iii) risk of inability to test. through these three quantifiable measures, preparedness and risk can be assessed, providing some quantitative reasoning behind global decisions, should another deadly disease grip our species again. our main contribution is the exploration of the idea that country-level demographic and geopolitical attributes can aid in the classification of pandemic risk and preparedness in terms of transmission, mortality, and an inability to test (which the previous two depend on, since testing allows for accurate measurements of transmission and mortality). in order to do this, various supervised learning classifiers are explored in order to discern how much useful information these country-level attributes carry for the classification of these three risks. we note that the classification problems are difficult, where many powerful techniques achieve unsatisfactory scores on the dataset, scoring around 10-20% higher than an approximate 25% random guess on the dataset, showing that learning useful rules from the data is not an easy task. this is not unexpected, since the classes have not been directly derived from the data used to predict them, rather, they have been derived from covid-19 statistics and then given as classes for country-level demographic and geopolitical information. due to this, strategies of linear searching and genetic optimisation are also followed in order to achieve more accurate results. although results are varied, the fact that all final models achieve much higher than 25% accuracy we formulate the problem as a 4-class problem. (which would be achieved via a random guess), shows that the geopolitical and demographic attributes at the country-level do carry predictive ability when it comes to pandemic risk and preparedness. the final models chosen are characterised by high classification accuracy for the risks of transmission, mortality, and inability to test, and are trained with no prior knowledge of the new coronavirus pandemic (other than the class). this may allow for generalisation to classify a nation's risk in the early days of a future pandemic. the remainder of this work is organised as follows: section 2 details the method followed with subsection 2.1 describing machine learning approaches in particular. section 3 presents the results for the risk of transmission (3.1), the risk of mortality (3.2) and the risk of inability to test (3.3) . finally, the limitations of the study are described, future work is suggested, and the study is concluded in section 4. collected from [18] formalised on the 12th may 2020, updated experiments for newer data can be found in section 3.7, with the relative ordering based on the three metrics with regards to population (cases, deaths, and tests per million). the risk classes are low, medium-low, medium-high and high for each type of risk. as defined in other works [19] [20] [21] , discretisation of the continuous features into bins is performed by the k% method in which k = 25 (equal frequency binning), resulting in four close-to-equal classes, with the difference being that the highest risk class is a minor 1.2% larger than the other three classes. future work aims to explore other methods of discretisation, whereas this work initially focuses on the machine learning pipeline on the basis of equal class error weighting. covid-19 data are then removed, and the attributes to complement the country-level classes are the following: un region [22] , 2020 population estimate [18] , median age [18] , population density per km 2 [18] , urban population % [18] , urban population total [18] , nursing and midwifery personnel per 10,000 (most recently recorded) [23] , medical doctors per 10,000 (most recently recorded) [23] , tobacco prevalence 2016 [24] , obesity prevalence 2016 [25] , gross domestic product 2019 [22] , land area km 2 [22] , net migration [22] , infant mortality per 1,000 births [22] , literacy rate % [22] , arable land % [22] , crop land % [22] , other land % [22] , climate classification type [22] , birth rate per 1,000 [22] , death rate per 1,000 [22] , gdp expenditure on agriculture [22] , gdp expenditure on industry [22] and gdp expenditure on services [22] . since some countries are not recorded by the world health organisation, figures for nursing, midwifery and medical doctors personnel per 10,000 people from hong kong are collected from an alternative source [26] . missing data which occurred mostly for tobacco prevalence, was given as '-1', which flags as an attribute that the data have not been collected (which could in itself provide useful information). the classification problem of risk is therefore formulated based on prior knowledge of the pandemic in terms of class only, but the attributes to attempt to classify them are purely country-level information regardless of number of cases, deaths and other coronavirus specific data. thus the problem becomes a pandemic risk and preparedness classification problem based on demographic and geopolitical attributes only. we aim for a generalisable model, which can be applied to the future state of countries, should another potential pandemic begin prior to any meaningful measurements being available. the method is illustrated in fig 1. following this, a set of machine learning models are tasked with predicting a country's risk class by learning from all other countries in a process of leave one out cross-validation [27], which is performed for all three types: finally, the best models for each risk factor are organised into a predictive framework, which produces an output for the three risks. since testing is taken into account, countries that have not reported testing data cannot be considered, but are later classified by the model generalised on those countries that do. a three-fold machine learning approach is proposed following observing the maps for the three separate risk quarters in figs 2, 3 and 4 which show the discretised inability to test risk, transmission risk, and mortality risk respectively. we note that the countries with seemingly fewer cases have performed far fewer tests as can be observed in that the growth of cases and testing tend to increase alongside one another. that is, a country with more cases will test more, and as such will have more confirmed cases, since the larger number of tests have identified more cases. the data for the two experiments were accessed on 12 th may 2020 and 16 th september 2020. trained with the strategy of leave one out cross-validation (loo cv) where every country's risk is predicted based on learning from all other countries, a set of supervised classification models are benchmarked. this section details the models focused upon, and the methods used to search for others. the metrics reported following the models described in this section are mean classification accuracy due to close-to-equal class balance [28] (low, med-low, med-high are equal and high is minimally larger by a factor of 1.2%) and high variance often observed due to the nature of loo cv [29, 30] . decision trees are tree structures, where each internal node represents a condition based on attributes that allows splitting the data and leaf nodes represent class labels [31] . a random decision forest (rdf) [32], used in this study, creates multiple random decision trees, where note that many countries at "low risk" by number of cases are at "high risk" for inability to test. https://doi.org/10.1371/journal.pone.0241332.g003 note that many countries at "low risk" by number of deaths are at "high risk" for inability to test. https://doi.org/10.1371/journal.pone.0241332.g004 each decision tree votes on the class of the input data object, and the predicted class is that, which receives the majority vote. splitting of the trees is based on information gain: where ig is the observed difference in information entropy, which is expressed in eq (2), that is, the nodes split data based on reducing the randomness of object class distribution. k-nearest neighbours (knn) is similar to an rdf in that the prediction is derived by a majority vote. the voters, rather than decision trees, are the data objects within the observations that are closest in terms of n-dimensional euclidean space where n is the number of attributes. gradient boosting [33] forms an ensemble of weak learners (decision trees) and aims to minimise a loss function via a forward stage-wise additive method. in these classification problems, deviance is minimised. at each stage, four trees (n = classes) are fit on the negative gradient of the multinomial deviance loss function, or cross-entropy loss [34, 35]: where, for k classes, i is a binary indicator of whether the prediction that class y is the class of observed data x is correct, and finally p is the probability that aforementioned data x belongs to the class label y. xgboost [36] differs slightly in that it penalises trees, leaves are shrunk proportionally, and extra randomisation is implemented. naïve bayes is a probabilistic classifier that aims to find the posterior probability for a number of different hypotheses and selecting the most likely case. bayes' theorem is given as: where p(h|d) is the posterior probability of hypothesis h given the data d, p(d|h) is the conditional probability of data d given that the hypothesis h is true. p(h) i.e., the prior, is the probability of hypothesis h being true and p(d) = p(d|h)p(h) is the probability of the data. naïvety in the algorithm is due to the assumption that each probability value is conditionally independent for a given target, calculated as pðdjhþ ¼ q n i¼1 pðd i jhþ where n is the number of attributes/ features. linear discriminant anaylsis (lda), based on fisher's linear discriminant [37] , is a statistical method that aims to find a linear combination of input features that separate classes of data objects, and then use those separations as feature selection (opting for the linear combination) or classification (placing prediction objects within a separation). classes k 2 {1, . . ., k} are assigned priorsp k ( (3) in mind, maximum-a-posteriori probability is thus calculated as: where f k (x) is the density of x conditioned on k: s k is the covariance matrix for samples of class k and class covariance matrices are assumed to be equal. the class discriminant function δ k (x) is given as: wherem k is the class mean, and finally classification is performed via quadratic discriminant analysis (qda) is an algorithm that uses a quadratic plane to separate classes of data objects. following the example of lda, qda estimates the covariance matrices of each class rather than operating on the assumption that they are the same. qda follows lda with the exception that: support vector machines (svm) optimise a high dimensional hyperplane to best separate a set of data point by class by maximising the margin and minimising the empirical risk, and then predict new data points based on the distance vector measured from the hyperplane [38]. the optimisation of the hyperplane is to achieve the goal of maximising the average margins between the points and separator. generation of a multi-class svm is performed through sequential minimal optimisation (smo) [39] by breaking down the optimisation into smaller linearly-solvable sub-problems. for multipliers a, reduced constraints are given as: where there are data classes y and k are the negative of the sum over the remaining terms of the equality constraint. stacked generalisation (stacking) [40] is the process of training a machine learning algorithm to interpret the predictions of an ensemble of algorithms trained upon the dataset in a process of meta-learning. generally, a stack can represent any kind of ensemble, but the interpretation algorithm is often logistic regression. it has been noted in multiple domains that stacking often outperforms the individual models in the ensemble [41-43]. it was observed during experimentation that the classification problems were difficult, leading to many models achieving relatively bad results, i.e., the results outperformed an approximate 25% chance random guess by around 10-20% classification accuracy, with many stateof-the-art models predicting the wrong value more than half of the time (< 50%). the solutions explored to solve this are the following: a linear search is performed for random decision forests (rdf) and k-nearest neighbours (knn) from 10, 20, . . ., 1000 decision trees and 1, 2, . . ., 50 neighbours, respectively. random forests are often found to be powerful ml algorithms, and so an in-depth search is performed in order to maximise their ability. this is also followed for knn since it is of low complexity and can thus be quickly benchmarked. a genetic search is also performed via the tree-based pipeline optimization tool (tpot) algorithm detailed in [44] with consideration to the whole scikit-learn toolkit [45] where not detailed in the previous section, more information is available on the models in [46] . tpot is an algorithm that treats each machine learning operator as a genetic programming (gp) primitive which include, modified features, feature combinations, feature selections and dimensionality reductions, learning algorithms as well as their predictions (for exploration of ensembles). gp trees were chosen since they best represented a machine learning pipeline and are implemented with the deap framework [47] , and best solutions are selected by the multi-objective nsga-ii algorithm [48] by aiming to increase classification accuracy while reducing minimising the number of machine learning operators as previously described. 5% of offspring produced by the best models cross-over with another through a process of onepoint crossover, and the remaining offspring randomly mutate at a 33% chance of point, insertion, or shrinkage. thus, the algorithm introduces and tunes ml operators with promising effect and removes operators that cause the results to degrade. finally, the best machine learning pipeline is presented from the search. to conclude, the method described in this section follows the process of manual exploration, linear search, and genetic programming in order to explore the best classification models for these problems in terms of classification accuracy. as previously described, accuracy is chosen as the metric of comparison since the datasets are closely balanced, and the drawback of loo is high variance (large standard deviation due to binary per-fold results) while enabling classification model validation of a small dataset. all of the experiments in this paper were performed using the scikit-learn toolkit [45] implemented in python. the algorithms were executed on an intel core i7 processor (3.7ghz). due to the large computational complexity when searching a problem space with loo, the algorithm was executed three times with a population size of 10 for 10 generations, if a model scored lower than the manually or linearly explored models then it was discarded, and otherwise presented if it achieved a higher score. this decision was based on the fact that results for the three problems attained were only 49.67%, 43.79%, and 56.21%, and more robust models were required in order to provide accurate predictions. in this section, the three sets of results are presented. for readability purposes, linear searches of rdf and knn are presented as the same figs (6) and (7). the linear searches for rdf and knn are shown in figs 6 and 7, respectively. the best rdf was a forest of 230 trees which scored 43.8%, and the best knn had a value of k = 30 which scored 36.6%. fig 9 shows the model comparison for risk of mortality. the difficulty of the problem can be seen with the low results achieved, with the exception of two models discovered by the genetic model search algorithm. the second best model, which utilised extra trees via recursive feature elimination scored 61.97% and the best model found was a process of stacking svm and extra trees which had a classification ability of 71.24%. country-level pandemic risk and preparedness classification based on covid-19 data fig 10 shows a comparison of other models that were explored. many solutions were quite weak, but achieving higher results in comparison to the other two problems, suggesting that the problem is a slightly less difficult one. the best algorithms, as was the case for the other problems, were also discovered by the genetic search algorithm. unlike the previous two problems, the best models found were singular rather than either an ensemble or feature elimination pipeline, where extra trees scored 71.21% and gradient boosting scored 77.12%. following the original outline of the experiment in figs 1 and 11 builds upon this by including the best findings from the three benchmarking experiments. the best model for risk of transmission was a stacking algorithm combining gradient boosting and a decision tree for 74.51% accuracy, the best model for risk of mortality was a stacking algorithm combining support vector machine and extra trees for 71.24% accuracy, and the best model for risk of inability to test was a gradient boosting algorithm for 77.12% accuracy. all of the best models were found by the genetic model search algorithm. as previously discussed, the classification of risks must be interpreted relative to one another. for example, if the maps in figs 2, 3 and 4 are observed, note that countries that do not test much also seemingly, on the surface, report fewer cases and deaths per million. on one hand, this could simply be due to the fact that there are fewer cases and thus fewer tests are country-level pandemic risk and preparedness classification based on covid-19 data required, but on the other hand, could imply that fewer tests performed have themselves led to unreported figures of the other two [49] [50] [51] [52] . with this in mind, it is important to consider the output for risk of inability to test in order to interpret the other two risks. in the case where the risk of inability to test is towards the lower end of the spectrum, then risks for transmission and mortality are more likely to be an accurate representation of the situation. vice versa, though, where there is a high risk of inability to test, this in itself should be considered the most descriptive risk factor for the country since there is less prior knowledge to base risks of transmission and mortality upon. country-level pandemic risk and preparedness classification based on covid-19 data table 1 shows the predicted class values for the best models applied to each of the respective risk classification problems. please note the discussion of interpretation in section 3.4, where high inability to test is often coupled with lower risks of the prior two, as can be seen in fig 5, for as of yet unknown reasons i.e. they could either be actually true to the pattern observed, or on the other hand, very low testing leads to naturally fewer reported cases and deaths than the actual values. many countries bare similarity to others and so have been generalised, further outliers still such as china may not have accurately predicted labels since the population is much larger than those observed in the training data, likewise this may be the case with other geopolitical information within the outlier set. in this section, we perform a preliminary exploration of how useful country-level attributes are in addition to lag-window features (seven days prior, with mean and standard deviation for days 1 − n via a growing lag-window). the process is implemented via a 10-fold temporal validation process (predicting future fold k from growing training data 1 to k − 1). this approach is explored for the forecasting of cases and deaths. appendix a in s1 appendix shows the pearson correlation coefficient of each attribute in relation to the total cases for each day. as can be expected, the most correlative feature are the cases recorded for the previous day. interestingly, mean values of the previous two and three days have more correlation to the total cases on the current day compared to the previous day lag value alone. gross domestic product and urban population have a weak but useful correlation for regression of the total cases. as can be expected, the singular pearson's correlation coefficient of each of the isolated attributes tend to be low with exception to the lag windows due to the nature of increasing growth in infections. the tables within appendices b, c, and d in s1 appendix detail the scores given to the attributes by linear regression, m5p and svr respectively. it is observed that the rankings achieved by the lag window attributes are the same for each algorithm, and the order otherwise is relatively similar. all algorithms then rank the country at the same place above other features, which actually had a negligible correlation of 0.03. another interesting observation is that the m5p algorithm ranks medical doctors per 1,000 population as relatively high in the ranking, second only to country when lag windows are not considered. urban population totals are considered important by all of the algorithms, likely since this is an indication of both spread as well as a rule of thumb for total number of infected. table 2 shows the results for total case prediction by all of the chosen algorithms. the best algorithm achieved a rmse of 325.66 when considering 41 features chosen by linear regression ranking, which were the 19 time-window attributes and 22 geopolitical or demographic attributes. this provides a decrease in rmse of 17.08 when this algorithm only considers lags of the series, and many instances can be observed in which this metric was reduced by considering additional attributes explored within this study. the best results achieved by all of the seven algorithms considered at least two of the additional attributes, it is worth noting that the best of the best models is also the model which chose the most of the additional attributes (as well as the best svr, which also chose 41 attributes in total). appendix e in s1 appendix shows the correlation of each singular attribute towards the prediction of deaths. as can be observed, the rankings of the lag windows are the same as those for total confirmed infections described in the previous section. otherwise, rankings are similar and differ only slightly, as well as their observed correlation. appendices f, g, and h in s1 appendix detail the scores given to each attribute by the linear regression, m5p and support vector regression algorithms respectively. as can be expected, the rankings match those of the highest correlation coefficient. interestingly, a small change is noted within the attributes for svr whereas quite a disparity can be seen when observing the scores given by the other two algorithms. table 3 shows the 189 models trained for forecasting total deaths. similarly to the total case predictions, the best model found was within a voting ensemble of linear regression and svr. unlike total case predictions, introducing geopolitical and demographic attributes had negative effect on the result, with the best model taking only the temporal lag window features as input. once 40 attributes were introduced, the linear regression model had an absurdly high rmse of 2.93e+05, which since average values were taking during voting regression, also affected the ensembles that included it. given the nature of research and peer review, the approach in this work was formalised on the 12th of may 2020 and as such the data is over three months out of date at the time of writing (16th of september, 2020). given this, the experiments devised in this work are re-applied to the new data. it was noted that all manual models failed to generalise with the new data. that is, a range of scores between 24.95% to 28.63% for all models, for all three risk classification problems. this is most likely due to international collaboration towards the three risk factors, and as such, country-level attributes lose classification prediction ability towards the risk factors. with the previous successful experiments in mind, this argues that risk classification would be more useful when performed prior to the situation unfolding, given that country-level information is seemingly more important at this stage when compared to the current postpeak climate. though much weaker results are now observed, this could in fact be viewed as a positive situation, given that country-level data i.e. who you are and where you are from no longer impacts risk as it was observed to in the initial experiments performed in may 2020. it has been noted during mid-2020 that organisations such as the united nations and world health organisation have implemented and released humanitarian packages to lower economically developed countries (ledcs) [53] [54] [55] . it has also been noted that many healthcare professionals returned to their native countries (often also ledcs) in order to aid in tackling the virus [56] . the positive effects of these factors likely contribute towards the reason why country-level information was useful for risk classification earlier in the pandemic, but are less-so later on post-peak. with the nature of the data streaming from the ongoing pandemic with regards to the time taken to run model benchmarks, the largest and most obvious limitation to this study is that the models are constantly going out of date by the day, since more up to date data is constantly becoming available. it is for this reason that the models should be updated at a later date, and the statistical differences that occur, if any, noted. secondly, though relatively good results were found through a complex process of genetic optimisation, further models could be explored in order to possibly reach better results than the final models in this study. finally, the interpretation that is required as aforementioned, i.e. that the risk of inability to test is the most important metric and possibly enables the other two for interpretation, suggests that the ternary approach followed could be better optimised through a unified approach. that is, one singular "metric of risk" that is calculated via the three metrics explored in this work as separate problems. prior to this study, a metric of (c + d)/t was explored (where c, d, and t denote cases, deaths, and tests respectively, all with regards to per million population), but this metric is, at this point, impossible to classify. the k% method was used to divide the continuous features into four bins where k = 25. other methods of binning such as mdl [57] , caim, cacc, and ameva [58] could also be explored and benchmarked in future experiments. to conclude, the main hypothesis that this work has argued in favour of is that geopolitical and demographic attributes at the country-level hold value in terms of classifying risk produced by the covid-19 dataset. this was shown when the four class distribution which was close to equal ('high' was 1.2% larger than the other classes) could be classified far above the approximate 25% class distribution through loo cv. though this is observably possible from the results presented in this study, it is worth noting that the classification problem proved extremely difficult for many powerful machine learning techniques, which often scored around only 40%, and a genetic search had to be followed in order to devise complex strategies of ensemble and hyperparameter optimisation in order to achieve better results at 74.51%, 71.24%, and 77.12% for the three problems. future work aims to keep the data up to date to the point at which the pandemic is over, and also to explore other methods of solving the issue of risk and preparedness classification through a more unified approach as well as through stronger machine learning models, if possible. global catastrophic risks survey presumed asymptomatic carrier transmission of covid-19 estimation of the asymptomatic ratio of novel coronavirus infections (covid-19) covid-19: identifying and isolating asymptomatic people helped eliminate virus in italian village sjö din h. high population densities catalyse the spread of covid-19 the effect of travel restrictions on the spread of the 2019 novel coronavirus (covid-19) outbreak case-fatality rate and characteristics of patients dying in relation to covid-19 in italy obesity in patients younger than 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covid-19 in various countries: preliminary retrospective results based on wavelets and deterministic modeling estimating the fraction of unreported infections in epidemics with a known epicenter: an application to covid-19 will covid-19 be a litmus test for post-ebola sub-saharan africa? the coronavirus knows no borders. tidsskrift for den norske legeforening health prevention and response policies against infectious diseases: is the world ready for a novel coronavirus pandemic? proceedings book the world health organisation. how is who responding to covid-19? azerbaijani doctors return home to help their country face covid-19 multi-interval discretization of continuous-valued attributes for classification learning supervised and unsupervised discretization of continuous features the authors would like to show their gratitude to all of the medical professionals working to treat and cure covid-19 across the world, as well as the researchers working vigorously on vaccines and antibody tests for the disease. we would also like to thank all of the key workers for their effort to make life as normal as possible during these difficult times. key: cord-322612-vlxewj5k authors: hooker, claire; leask, julie title: risk communication should be explicit about values. a perspective on early communication during covid-19 date: 2020-11-09 journal: j bioeth inq doi: 10.1007/s11673-020-10057-0 sha: doc_id: 322612 cord_uid: vlxewj5k this article explores the consequences of failure to communicate early, as recommended in risk communication scholarship, during the first stage of the covid-19 pandemic in australia and the united kingdom. we begin by observing that the principles of risk communication are regarded as basic best practices rather than as moral rules. we argue firstly, that they nonetheless encapsulate value commitments, and secondly, that these values should more explicitly underpin communication practices in a pandemic. our focus is to explore the values associated with the principle of communicating early and often and how use of this principle can signal respect for people’s self-determination whilst also conveying other values relevant to the circumstances. we suggest that doing this requires communication that explicitly acknowledges and addresses with empathy those who will be most directly impacted by any disease-control measures. we suggest further that communication in a pandemic should be more explicit about how values are expressed in response strategies and that doing so may improve the appraisal of new information as it becomes available. behavioural responses-both practicing recommended behaviours (such as putting on a mask) and the refusal to do so are reactions to perceive loss of control (jetten et al. 2020; wong 2020) . "self-determination" is used in relation to communities as much as to individuals, which may provide new understandings or representations for relations between individual and communal self-shaping in the context of pandemics (eichler 2019) . given the extensive and growing data that reveals values and ideologies as often the strongest determinants of people's attitudes to health protection behaviours (e.g., dryhurst et al. 2020; seale et al. 2020) , we suggest that rich accounts of self-determination, autonomy, and/or freedom beyond "thin" versions of liberty (e.g., to travel or not wear masks) will have much to offer pandemic ethics in future research. in this paper we make a modest beginning on exploring what adding a "values perspective" to risk communication might look like by examining one risk communication principle, "communicate early and often," in the very first stages of the pandemic. our argument is that use of this principle could have minimized some of the negative impacts seen in australia and the united kingdom in february and march 2020. we contend that a hitherto undiscussed reason for why this principle is effective is because it conveys value for people's self-determination, even as this is threatened by both disease and the measures needed to control the disease. we discuss how proactive communication might have improved community preparedness but also suggest that being more explicit about this value should have involved better acknowledgement of, and empathetic engagement with, those who were most directly impacted by control measures at that time. as a result, the australian government could have better addressed stigma, racism, and xenophobia during late january and february and mitigated or avoided food and hygiene product stock-outs in early march. we conclude with a brief discussion of how communication of values might have avoided the loss of trust and misunderstandings associated with the misnamed strategy of achieving "herd immunity" when discussion of this emerged in the united kingdom. we conclude by suggesting that the communication of values can improve the quality of pandemic response and can increase the degree of trust placed in responding authorities. when people face the heightened fear of a novel, uncontrolled, and uncertain risk such as the pandemic of sars-cov_2, self-determination in multiple dimensions is compromised and well-being is reliant on the knowledge and decisions of experts and governments (siegrist and zingg 2014) . risk communication must connect as much as possible with people's sense of selfdetermination, even (perhaps especially) in contexts where individual liberties may become limited. how c a n t h i s b e d o n e ? t h e p r i n c i p l e s o f r i s k communication-for example communicating early and often, being open and transparent, and not dismissing concerns as "panic"-are all means of affording some sense of control in people facing a situation of high concern and uncertainty. transparency is a core recommendation for pandemic risk communication (van der weerd et al. 2011) , because it enables citizens' knowledge and confidence (earle, siegrist, and gutscher 2007; siegrist and zingg 2014 ) that the response strategy will occur as expected. because values and moral commitments are intrinsic to all pandemic responses, we argue that true transparency requires that pandemic risk communication is explicit about the values that guide it. further, we suggest that part of the task of managing a pandemic is to cultivate public convergence (kahan 2012) on the guiding values. this is important because a pandemic response, and communicating about it, are not actually separable: action is, in itself, a very powerful form of communication (amabile and kabat 1982) , as we discuss below. we suggest that conveying respect for selfdetermination involves early, proactive communication with those who are directly affected by any response strategy. this will involve addressing issues of fairness or justice, since these are present in virtually all ethical frameworks for pandemic response (australian government department of health 2019; kinlaw, barrett, and levine 2009 ; n e w z e a l a n d n a t i o n a l e t h i c s a d v i s o r y committee-kāhui matatika o te motu 2007; thomas, dasgupta, and martinot 2007) and have also been shown to strongly influence peoples' perceptions of, and responses to, risk (siegrist, connor, and keller 2012) . the earliest representations of the new coronavirus in media coverage of the disease in australia and the united kingdom conformed to what priscilla wald has identified as "the outbreak narrative," in which a disease emanating from a non-white, non-western nation is eventually contained as a result of the scientific and technologic prowess of democratic western societies (wald 2008) . through january and february 2020, health risk communicators from who and government health authorities balanced communication of the potential seriousness of the new disease (clun 2020; the sydney morning herald 2020), with caution about acting too strongly or too soon. nonetheless several elements in news media coverage of the novel coronavirus disease in this period together tended to frame the disease as unlikely to significantly threaten australia or the united kingdom (the guardian 2020). these included comparisons with sars, mers, and ebola, and associations of the new disease with chinese political authoritarianism, which somewhat signalled that these diseases were unlikely to cause widespread disease in western nations (boseley 2020) . the discourse of "technology as saviour" (hooker, king, and leask 2012; wald 2008) , in the form of early and frequent expectation that a vaccine and effective treatment would be rapidly developed by scientists, was prominent (garcia 2020; mannix 2020) . media coverage identified that mortality was strongly associated with the elderly and those with comorbidities. media commentators have noted that this reporting often portrayed the elderly, and those with significant health issues, as a passive, vulnerable minority, even one that was expendable or burdensome (ashimoni 2020). these representations have continued to raise considerable concern (see, for example, people with disability australia (pwda) et al. 2020) and provides an important context for later discussions of "herd immunity." ii. "communicate early and often" in this discursive media environment, we argue that earlier, proactive communication signalling that nations outside china might become affected and about the possibility of a pandemic was needed. early communication could have supported earlier sense-making, encouraged citizen engagement, and provided potential convergence towards a response strategy. by 20-25 february, the who and other health authorities were considering the possibility of a pandemic increasingly likely (callaway 2020 ). yet in australia there was little proactive public communication at this time-indeed, australian government websites only contained advice pertinent to travellers. the australian health sector emergency response plan for novel coronavirus (covid-19) was released on february 27 (grattan 2020) but was accompanied by little transparent communication about what was being done or which elements of the plan were receiving attention. this created a "risk communication vacuum" (leiss 2001) . in this vacuum, messages came from sources not privy to government planning. one was virologist dr ian mackay, who recognized and attempted to fill the space by publishing an opinion piece in the sydney morning herald (mackay 2020) . this advised australians to prepare for a pandemic and suggested that australians moderately stock up on basic consumer items and medicine, urging people to "prepare, but do not panic." a steeply-increasing, sometimes harmful, and prolonged period of stockpiling of basic supplies like hand sanitizer, toilet paper, and flour swiftly followed in australia, fed by escalating public anxiety. we contend that earlier and values-oriented communication could have reduced the anxiety that was later expressed in stockpiling behaviours by enabling longer and more moderated preparation for what could be ahead. respect for citizens' complex selfdetermination within the context of potential outbreaks could be conveyed in the cautious communication of concrete scenarios concerning what people might consider in their own family preparation (for example, of how to manage if somebody became sick). this period of sense-making and preparation can allow proactive communication of values around which people might shape their responses, such as providing support for neighbours (e.g., new zealand national ethics advisory committee-kāhui matatika o te motu 2007). proactive early communication with supermarket managers could have limited or avoided stockpiling (poloyo 2020) . in attempting to avoid early overreactions, which unintentionally communicates a lack of trust in the public, government effectively intensified a problem, rather than reducing it. early communication centred on ideas of selfdetermination (acknowledging individual and communal aspects of this) could have helped address the challenge that most pandemic response measures affect people unequally (howse et al. 2020; vaughan and tinker 2009) . racism and stigmatization have been a feature of almost every epidemic in history (wailoo 2006) , with anti-asian prejudice and sinophobia widespread during the outbreaks of sars in 2003 (leung 2008) . explicitly confronting this through communication is crucial, not only to reduce violence and injustice but because these issues are entangled in epistemic judgements, as occurred in debates in australia during february, concerning racism in relation to containment measures. as reports of racism and a range of sinophobic behaviours (including avoidance of chinese businesses, suburbs, and people) began to appear in the media from the end of january (vrajlal 2020; young 2020), a range of containment measures that primarily, but not exclusively, affected chinese people were enacted. a number of wealthy, independent secondary schools in australia had unilaterally acted to temporarily exclude students who had recently travelled in china (most of whom were chinese), including imposing segregated quarantine, in contravention of commonwealth government health advice (hooker, silva, and anderson 2020). on february 1, the australian government announced that foreign national travellers from mainland china would not be allowed entry into australia; australian citizens (most of whom were chinese) returning from china were quarantined in offshore detention facilities notorious for their use with refugees. while it is now generally agreed that early border measures to limit transmission of disease into australia were effective, at the time, school exclusions, selective border controls, and travel-related quarantines in immigration detention camps were questioned as unnecessary and were sometimes perceived as forms of racism (bedo and mcphee 2020; hooker, silva, and anderson 2020) . to convey respect for people's self-determination, leaders should reflexively examine how their actions might also be interpreted as disrespectful and discriminatory. actions such as containment (border control) measures are strong forms of communication (sandman and lanard 2009 ). while we do not suggest that this was not an important measure at the time, communication needed to address (particular through pre-established two-way channels) those likely to be directly affected by containment measures-in this case, chinese and other asian australians. the predictable harms of stigmatization needed to have been explicitly acknowledged alongside the scientific rationale (major et al. 2018 ). risk communication handbooks should urge authorities to be open and honest about the potential for discrimination, in the same way they are encouraged to be explicit about uncertainty. early communication proactively addressing the potential for stigmatization and racism might have not only limited some of the direct racism experienced by asian australians and u.k. nationals but helped to clarify judgements around containment measures by ensuring they were not confused with forms of racism. we note that sometimes violent racism is continuing in australia at the time of writing (fang, yang, and zhou 2020) . perhaps the most intractable feature of covid-19 in its early stages was the persistent framing of pandemic response strategies as a choice between "the economy" and "saving lives." this frequently contested (hamilton et al. 2020 ; zeballos-riog 2020) framing exemplified the tendency toward values-based polarization in views about the best response to covid-19 (kahan 2012) . early communication with the groups most likely to be affected by any given containment strategy could help with this seemingly incommensurable choice. we discuss how improved communication might have contributed to the pandemic response in the united kingdom when this was first announced on march 12, the day after the who formally declared a pandemic. a crucial period for communication about covid-19 in australia and the united kingdom were the first two weeks of march 2020: the period in which the reality and likelihood of a pandemic was dawning, exponential growth feared in both countries (churley 2020) , and news of crisis from iran and italy were fresh. this period of adjustment was critical for sense-making amid uncertainty, through which convergence on a response strategy could occur. in the united kingdom there was reportedly heated disagreement between members of the scientific advisory group for emergencies over what response strategy to pursue. such disagreement is a predictable but highly confounding feature of emergency response (christensen and painter 2004) . these differences were epistemic-they involved different appraisals of the evidence available and different assumptions about "herd immunity"-but they were fundamentally driven by different values. how the term "herd immunity" was constructed and interpreted in relation to covid-19 is worthy of a study in itself. the indirect protection of susceptible individuals resulting from high levels of immunity across a population (d'souza and dowdy 2020), "herd immunity" is a concept associated most with vaccination (hanage 2020; macintyre 2020) . for the first two weeks of march, the u.k. government pursued a "mitigation" (wickham 2020) strategy with little social restriction under the belief that there was ultimately little the government can do to stop the virus (shipman and wheeler 2020); social distancing restrictions would incur a high economic cost, be unsustainable for a long period, and would produce a more severe second wave of infection in winter (wickham 2020) . this approach assumed that reaching "herd immunity" through widespread infection would resolve the pandemic (the times 2020). this strategy fitted with prime minister boris johnson's values of limiting state intervention and government spending (wickham 2020) ; we note that it also fitted with the cluster of values termed "hierarchical individualism" in cultural cognition theory (kahan 2012) . within twenty-four hours of johnson's announcement of this policy on march 12, outrage was rising as the strategy's scientific credibility was disputed by epidemiologists and others (sandle and boyd 2020) , who pointed out that the "mitigation" strategy would result in an overwhelmed national health service and that achieving high exposure across the population should not be anticipated to achieve long lasting population immunity and thus conclude the pandemic. the mitigation strategy was perceived as a callous sacrifice of lives, with the media widely reporting that top government aide dominic cummings had told a private meeting that the government's strategy was "herd immunity, protect the economy and if that means some pensioners die, too bad" (buchan 2020) . a "crisis of trust" (smyth 2020) followed. even though modelling from imperial college, london (ferguson et al. 2020) , indicated how swiftly the nhs would be overwhelmed, and convinced the u.k. government to introduce a "suppression" strategy (wickham 2020) from monday march 16, doubts remained. the government was urged to "come clean" about the sources of the information on which the mitigation strategy was based (smyth 2020) , and media investigations followed. earlier communication in this case, where valuesdriven disputes existed between experts (kahan 2012), likely would not have prevented political crisis, but it would have allowed more time for sense-making processes in scientific, medical, and public communities. we recommend a commitment in pandemic planning documents to sharing sources, models, and evidence at the time of deliberation, and with it, the questions advisors are asking (such as, will the same number of deaths occur regardless of strategy over the long term?) earlier public discussion of these questions might at least have somewhat disrupted simplistic framing and use of "herd immunity," by enabling early and public scientific challenge from epidemiologists, as occurred from mid-march (armitage and hawke 2020; barr 2020; macintyre 2020). we note that the simplistic expectation that "herd immunity" would end the pandemic remains widespread (e.g., hasan 2020). earlier communication that explicitly discussed values might have enabled better public sense-making about the "mitigation" and "suppression" strategies. because each strategy invoked values differently and prioritized different values, we suggest that better communication is needed to explain how values such as being "proportionate" (australian government department of health 2019) are expressed in these strategies. because the costs of different strategies tend to fall on different members of the community, valuesexplicit communication could more effectively engage with the concerns and needs of those most affected when a strategy is selected. this paper offers some early thoughts for why the principles of risk communication should include the recommendation to be explicit about values. we are not suggesting that better communication alone can prevent or resolve either epistemic or political disagreements in pandemic management nor alleviate every anxiety nor uncertainty. but we do suggest that, given that disagreements about pandemic responses are very often driven by different value commitments, a "values turn" in risk communication (feinberg and willer 2019) is likely to produce significant benefits, including clearer communication, with greater impact. with regard to the principle of communicating early, we have shown that this is a means of conveying respect for peoples' threatened sense of self-determination, understood broadly. we suggest that this communication of value offers a richer explanation for why early communication, especially where directed with empathy at those most affected by response measures, is important. values-based risk communication will enable a more effective pandemic response. when self-descriptions contradict behavior: actions do speak louder than words what is herd immunity and could it slow the spread of coronavirus covid-19 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advisory committee of the director the chamber of risks: understanding risk controversies the yellow peril revisited: the impact of sars on chinese and southeast asian communities risk communication in public health risk communication: a handbook for communicating environmental, safety, and health risks busting the myths about covid-19 herd immunity, children and lives vs jobs. nhmrc centre for research excellence integrated systems for epidemic response. blog you and i may get coronavirus-and live with it: here's how to prepare for a pandemic. the sydney morning herald public health with a punch: fear, stigma, and hardhitting media campaigns csiro to begin testing coronavirus vaccines within weeks. the sydney morning herald national ethnic disability alliance (neda), et al. 2020. statement of concern -covid-19: human rights, disability and ethical decisionmaking a toilet paper run is like a bank run. the economic fixes are about the same. the conversation four questions for risk communication: a response to roger kasperson coronavirus: boris johnson warns "many families will lose loved ones" because of virus. the mirror containment as signal: swine flu risk miscommunication. peter sandman risk communication website covid-19 is rapidly changing: examining public perceptions and behaviors in response to this evolving pandemic crisis communication and the public health coronavirus: ten days that shook britain-and changed the nation for ever trust, confidence, procedural fairness, outcome fairness, moral conviction, and the acceptance of gm field experiments the role of public trust during pandemics: implications for crisis communication perception of risk ministers urged to come clean on model for british response. the times keep coronavirus risk in perspective the theory of self-determination ethics in a pandemic: a survey of the state pandemic influenza plans ethics and risk communication the times. 2020. the times view on boris johnson's handling of the coronavirus crisis: no immunity effective health risk communication about pandemic influenza for vulnerable populations chinese-australians facing racism after coronavirus outbreak stigma, race, and disease in 20th century america monitoring the level of government trust, risk perception and intention of the general public to adopt protective measures during the influenza a (h1n1) pandemic in the netherlands heated" debate between scientists forced the psychology behind why some people refuse to wear face masks communicating risk in public health emergencies: a who guideline for emergency risk communication (erc) policy and practice this is racism": chinese-australians say they've faced increased hostility since the coronavirus outbreak began top economists are deriding the "false choice" between saving lives from coronavirus and maximizing economic growth publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments no funding or conflicts of interest are associated with this manuscript. the authors wish to gratefully acknowledge the very useful feedback provided by two reviewers of this article.author statement all authors contributed to the study conception and design. media analysis and the first draft of the manuscript was written by claire hooker. both authors edited and discussed subsequent versions of the manuscript. claire hooker completed the revisions in response to reviewers. all authors read and approved the final manuscript. key: cord-328620-d2jrn1ip authors: van gageldonk-lafeber, arianne b; van der sande, marianne ab; heijnen, marie-louise a; peeters, marcel f; bartelds, aad im; wilbrink, berry title: risk factors for acute respiratory tract infections in general practitioner patients in the netherlands: a case-control study date: 2007-04-27 journal: bmc infect dis doi: 10.1186/1471-2334-7-35 sha: doc_id: 328620 cord_uid: d2jrn1ip background: acute respiratory tract infections (arti) are an important public health problem. improved identification of risk factors might enable targeted intervention. therefore we carried out a case-control study with the aim of identifying environmental risk factors for arti consultations in the dutch general population. methods: a subset of patients visiting their gp in the period of 2000–2003 with an arti (cases) and age-matched controls (visiting for other complaints) were included in a case-control study. they were asked to complete a questionnaire about potential risk factors. conditional logistic regression was used to calculate odds ratio's (or) and 95% confidence intervals (ci) to estimate the independent effect of potential risk factors. results: a total of 493 matched pairs of case and control subjects were enrolled. exposure to persons with respiratory complaints, both inside and outside the household, was found to be an independent risk factor for visiting a gp with an arti (respectively or(adj )= 1.9 and or(adj )= 3.7). participants exposed to dampness or mould at home (or(adj)=0.5) were significantly less likely to visit their gp. in accordance with the general risk of consultations for arti, participants with a laboratory-confirmed arti who were exposed to persons with respiratory complaints outside the household were also significantly more likely to visit their gp (or(adj)=2.5). conclusion: this study confirmed that heterogeneity in the general population as well as in pathogens causing arti makes it complicated to detect associations between potential risk factors and respiratory infections. whereas it may be difficult to intervene on the risk posed by exposure to persons with respiratory complaints, transmission of arti in the general population might be reduced by improved hygienic conditions. acute respiratory tract infections (arti) are an important public health problem. worldwide they are responsible for considerable morbidity and mortality, and lead to an increase in absence from work and school and an increased number of consultations with clinicians [1] [2] [3] [4] [5] [6] . based on a population of 16 million individuals, it is estimated that, in the netherlands, almost 900,000 persons annually visit their gp for an arti [4] . although antibiotics are effective against bacteria, many arti are caused by a multitude of other micro-organisms, mainly viruses [4, 5, [7] [8] [9] [10] . the development of an effective universal treatment for arti is hampered by this great number of different pathogens causing arti as well as a diagnostic deficit of around 30% [7] . symptomatic management therefore remains the only therapeutic option. the development of preventive initiatives to reduce morbidity and mortality, like vaccines or antiviral agents, is also hindered by the mixed pathogenesis [1, 11] . another approach towards prevention is to intervene in risk factors contributing to respiratory infections. identification of these risk factors may be useful for efforts to interrupt transmission. a multitude of studies have identified various risk factors for arti. studies in developing countries have identified risk factors to be among others crowding, nutritional factors, and parental smoking [12] [13] [14] [15] . because of major differences in living conditions and environmental circumstances these study outcomes can not directly be extrapolated to industrialised countries. studies in industrialised countries can roughly be divided into studies addressing children, and studies addressing specific respiratory diseases. known risk factors for children are for instance young age [16] , environmental tobacco smoke [17, 18] , home-dampness [19, 20] , and attending day-care centres [19, 21, 22] . risk factors noted in relation with specific respiratory diseases, like asthma, copd and tuberculosis, are active smoking, low socioeconomic status, occupational exposure and exposure to air pollution [23] [24] [25] [26] [27] [28] . however, little is known about the role of risk factors for arti in the general population in industrialised countries. to contribute to the present knowledge of artis we have carried out a case-control study with the aim of identifying environmental risk factors in the dutch general population. this study was performed in collaboration with the network of general practices in the continuous morbidity registration of the netherlands institute of primary health care (nivel). this network constitutes a representative group of about 67 general practitioners (gps) in 45 practices. their patient population accounts for approximately 1% of the dutch population and is representative with regard to age, sex, regional distribution, and degree of urbanization. from october 2000 through october 2003 all patients who presented with arti were classified by week of consultation and age to obtain stratified incidence rates. in addition in this period, almost half of the practices (22 in 2000-2001; 19 in 2001-2002; and 18 in 2002-2003) , consented to participate in a case-control study [4] . patients were classified by the gp's. inclusion criteria for cases were: consulting gp for acute respiratory complaints, and being diagnosed as influenza-like illnesses (ili) or another arti, and consulting gp for the first time in that episode. patients were not eligible for inclusion when they reported use of antibiotics or anti-viral medication in the last two weeks. for each case patient a control patient, matched by age group (0-4, 5-14, 15-24, 25-44, 45-64 and ≥ 65 year), was recruited within 1 week of consultation. inclusion criterion for controls was a consultation of the gp for complaints other than respiratory. exclusion criteria were: complaints of an arti in the last two weeks, belonging to the same household as the case, and the use of antibiotics or anti-viral medication in the last two weeks. from all participants, 1 nose and 2 throat swabs were obtained during the visit. furthermore, both cases and controls were asked to complete a detailed questionnaire about potential risk factors. these questionnaires extracted information about exposure to persons with respiratory complaints within or outside their household in the week before consulting the gp, family composition (number of children and adults, presence of children attending day-care, primary school or secondary education), working outside the home and kind of job, use of public transport, type of heating system, exposure to mechanical ventilation system, exposure to dampness or mould at home, keeping pets or cattle, smoking behaviour, and exposure to passive smoking (see additional file 1). parents or guardians were asked to complete questionnaires for young children. to assess the burden of the arti, the questionnaires of case patients also extracted information about restriction of daily activities, bed rest, and absence from school or work. moreover, after the first and second year of study all gps participating in the casecontrol study were asked to complete a questionnaire for each reported case patient. these follow-up questionnaires obtained information about additional consultations, referral to specialists and hospitalisation for the reported episode of arti. viral culture and polymerase chain reaction (pcr) were performed at the national institute of public health and the environment. both nose and throat swabs were tested for adeno-, corona-, entero-, human metapneumo-(hmpv), influenza-, para-influenza-, rhino-, and respiratory syncytial (rs) virus, and also for m. pneumoniae, c. pneumoniae and c. psittaci [29] [30] [31] [32] . bacteriological cultures were performed at the regional public health laboratory in tilburg using the throat swabs to detect bacterial pathogens known to cause 'community acquired' respiratory infections [4] . apart from the original matching at the selection of cases and controls, a secondary matching was done to match single cases and controls. first of all for every single case a control was sought in the same age group, the same practice and within a period of three months. if no control could be selected within the same practice, a control from a different practice was selected. associations with potential environmental risk factors were assessed by comparing all case patients with control patients matched by age. a sub analysis addressed only these case patients in whom at least pathogen was detected and their matched control patients. conditional logistic regression was used to calculate odds ratio's (or) and 95% confidence intervals (ci) to estimate the independent effect of potential risk factors. sex was included in the multivariate regression model in order to adjust for confounding. variables were excluded from the regression model if the crude or was not significant (p > 0.2). an exception was made for variables with respect to smoking because of the existing data on of adverse health effects of (passive) smoking [33] [34] [35] . in total, nose and throat swabs were obtained from 645 case patients and 558 control patients. three hundred and thirty two (332) originally matched pairs of case patients and control subjects could be included. after the secondary matching, an additional 162 pairs could be formed, thus 493 pairs were included in the matched analyses. characteristics of case patients and control subjects are summarized in table 1. viruses were detected in 248 of the 493 case patients (50%), β-haemolytic streptococci in 41 (8%), and mixed infections in 13 case patients (3%). influenza and rhino viruses were the most common pathogens. no pathogens were detected in 191 of the 493 case patients (39%). moreover, pathogens were detected in 97 of the 493 control subjects (20%). the percentage of nose and throat swabs obtained from case patients with arti and from control patients that tested positive for one or more pathogens, according to age group, is shown in figure 1 . in general, the proportion of positive nose/throat swabs decreased with increasing age group for both case patients and control subjects. these data have been described in more detail previously [4] . perceived restrictions in daily activities were reported by 79% of the case patients with a median duration of 5 days. both bed rest and absence from school or work were reported by approximately 65% of the cases patients (median duration respectively 2 and 5 days). these findings apply for all case patients as well as for those with a laboratory-confirmed arti. a total of respectively 259 and 165 follow-up questionnaires were received after the first and second year of study. all questionnaires were included in the analyses, whether or not cases fulfilled the in-/exclusion criteria. in the first year of study 66 of the 259 case patients (25%) consulted their gp more than once for the same episode. for 47 of these 66 (71%) medication, like antibiotics, codeine, and prednisone, was prescribed at a later stage. three patients were referred to an ent specialist, two to a lung specialist and two to a paediatrician. three patients were hospitalized for an arti, of which two with tonsillitis and one with pneumonia. in the second year of study 43 of the 166 case patients (26%) consulted their gp more than once, of which 30 (70%) were prescribed medication. two patients were referred to an ent specialist and three to a lung specialist. five patients were hospitalized for an arti (2 tonsillitis and 3 pneumonia). table 2 presents the results of the univariate and multivariate risk factor analyses for all case patients consulting their gp for an arti compared with their matched control subjects. in the univariate risk factor analyses no significant association was observed for number of adults in the household, belonging to families with children attending day-care centres, working outside the home, use of public transport, type of heating system, keeping pets or cattle, and educational level. therefore these potential risk factors were not included in table 2. exposure to persons with respiratory complaints, both inside and outside the household, was found to be an independent risk factor (respectively or = 1.9 and or = 3.7 after adjustment for other relevant factors). persons who reported to be uncertain about their exposure were significantly more prone to visit their gp with complaints due to arti then persons without such exposure (or adj = 3.9). participants belonging to families with children in secondary education had a significantly lower risk of consulting a gp with arti (or adj = 0.3). in addition, participants exposed to dampness or mould at home were significantly less likely to visit their gp with an arti (or adj = 0.5). apart from the overall smoking behaviour we also looked at the extent of reported smoking. the participants were divided into five classes based on the daily number of smoked items (including cigarettes, cigars and/of pipes). we compared non-smokers with participants smoking <5, 5-9, 10-19, and ≥20 items daily. participants reporting smoking less than 5 items a day had a significantly higher risk of consulting a gp (or adj = 4.6 [1.2-17.9 ]) compared with non-smokers. in contrast, among participants smoking of 5 or more items a day, the risk of a consultation for arti was not significantly different from that of nonsmokers (or = 0.9 [0.3-2.6], 0.7 [0.3-1.8] and 0.7 [0.2-2.1] when the daily number of smoked items is respectively 5-9, 10-19 and ≥20). table 3 presents the results of the univariate and multivariate risk factor analyses for a sub analysis of case patients with a laboratory-confirmed arti (i.e. ≥1 pathogen detected) and their matched control patients. in the univariate risk factor analyses no significant association was observed for number of adults in the household, belong-ing to families with children attending day-care centres, primary or secondary school, working outside the home, use of public transport, type of heating system, keeping pets or cattle, and educational level. therefore these potential risk factors were not included in table 3. in line with the general risks of consultations for arti, participants with a laboratory-confirmed arti who were exposed to persons with respiratory complaints outside the household were also significantly more likely to visit their gp (or adj = 2.5). also persons with a laboratory-confirmed who reported to be uncertain about their exposure were significantly more prone to visit their gp then persons without such exposure (or adj = 3.5). in contrast, exposure to persons with respiratory complaints inside the household and exposure to passive smoking as well as to dampness or mould at home were not significantly associated with laboratory-confirmed arti, while being associated with consultations for complaints due to any arti. with respect to the extent of smoking we again found that participants smoking less than 5 items a day were at higher risk for arti with a microbiological pathogen identified (or adj = 6.9 [1.1-41.8]) compared with non-smokers. for participants smoking 5 or more items a day this was not significantly different from that of nonsmokers (or = 0. to our knowledge, this is the first case-control study investigating the role of risk factors for arti in the general population in an industrialised country. our study showed that exposure to persons with respiratory complaints, both inside and outside the household, is a risk factor for consulting a gp with an arti. only exposure outside the household appears to be a risk factor for a laboratory-confirmed arti. while it may be difficult to intervene on this risk factor, transmission of respiratory infections might be reduced by improved hygienic conditions. considering the substantial morbidity it is worthwhile to investigate number of nose and throat swabs in case patients and con-trol subjects that tested positive for one or more pathogens, by age group figure 1 number of nose and throat swabs in case patients and control subjects that tested positive for one or more pathogens, by age group. * number of matched case-control pairs. the feasibility and effect of intensified hygiene on illness transmission in the general population. this study adds that risk factors found in specific study populations can not be extrapolated to the general population. we demonstrated that in the general population (passive) smoking, dampness or mould at home and having family members attending day-care were not associated with a higher risk for arti, which is in contrast with studies carried out in children or patients with specific respiratory diseases. the pathogenesis of arti involves a complex interplay between pathogens and the host's inflammatory response [1, 11] . this complicated mechanism in combination with a diagnostic deficit of over 30% [7] might account for differences between risk factors found in specific study populations and in the general population. in contrast with our findings in the general population, many studies in children concluded home dampness to be associated with increased respiratory symptoms [19, 20, 36, 37] . knowledge about the mechanisms behind the association between dampness and health effects and the effect of moulds on the immune system is still limited [19, 38] . it cannot be excluded that the presence of dampness or mould at home in our study, based on selfreported questionnaire-data, is not observed in enough detail to assess the relation with arti in the general population. several studies describe an association of cigarette smoking or exposure to environmental tobacco smoke with the occurrence and severity of arti [17, 18, [39] [40] [41] . smoking is believed to exacerbate respiratory diseases by harming respiratory defence mechanisms [33] . nevertheless, in this study smoking or exposure to passive smoking was not a risk factor for consulting a gp with an arti nor for consulting with a laboratory-confirmed arti. it is possible that, selection bias is part of the explanation for this finding. smokers might be less inclined to visit a gp with respiratory complaints as compared with non-smokers. moreover, our findings are based on questionnaire-data about exposure, which are often prone to recall bias. questionnaires are relatively cheap and easily used, but are likely to be less valid and reliable then the measurement of biomarkers in body fluids for true exposure [34] . furthermore, awareness of the adverse health effects of passive smoking has increased substantially in the past years because of extensive information. this might have resulted in lower exposure levels, explaining the lack of association with arti in the general population. a recent study in school children also concluded that smoking by a care-provider was not significantly associated with respiratory infections [20] . looking at the intensity of reported smoking, only moderate smoking (less than 5 items a day) was a risk factor for consulting a gp with a (laboratory-confirmed) arti in our study. the intensity of smoking is only a rough indication based on questionnaire-data, without taking into account the number of years smoking. recall bias with regard to the extent of exposure may certainly play a part as well. besides, it cannot be ruled out that the extent of smoking is related to care-seeking behaviour. therefore, this finding must be interpreted with caution. several studies noted attendance to day-care centres to increase the risk of upper respiratory symptoms in young children [17, 22] . it is plausible that day-care centre children would transmit respiratory infections to their family members [41, 42] . nevertheless, we find that having family members attending day-care, was not associated with a higher risk in the general population for consulting a gp with an arti. this might be an underestimation of the real number of patients with an arti, because an unknown proportion of subjects with an arti will not visit a gp. selection bias could also play a role, persons with family members attending day-care might be less inclined to visit a gp with respiratory complaints. some limitations of our study should be mentioned. first the study was carried out in a period of moderate influenza-activity, affecting the number of consultations for ili as well as other arti [43] . as a consequence of a limited sample size, risk factors could not be analyzed in relation to the separate pathogens, but only to the entity of arti. secondly, questionnaire data were used to measure exposure to potential risk factors. this could be less reliable compared with observational data. moreover, heightened attention to the cause of their complaints by patients with an arti may have caused recall bias. thirdly, we cannot rule out the possibility that controls were in the incubation period for an arti, even though they had no respiratory complaints. we expect the number of controls developing those infections to be low, because the gp's actively asked for the presence of respiratory symptoms at the moment the nose and throat swabs were taken. nevertheless, this might have diluted the investigated relations between potential risk factors and arti. this study showed that heterogeneity in the general population as well as in the pathogens causing arti in combination with the diagnostic deficit makes it complicated to observe associations between potential risk factors and respiratory infections. the risk factor found in this study, exposure to persons with respiratory complaints, can hardly be avoided. yet better understanding of disease transmission might result in improved hygienic conditions, like hand washing more frequently, and so affect the transmission of arti in the general population. increasing awareness of the importance of hygienic measures with regard to prevention and control of arti will also be useful facing a potential pandemic threat, 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practitioners with influenzalike illness, 1987-96: a study of the demography of influenzalike illness in sentinel practice networks in england and wales, and in the netherlands the author(s) declare that they have no competing interests. ag participated in the coordination of the study, performed the statistical analyses and drafted the manuscript. ms participated performing the statistical analyses and drafting the manuscript. m-lh participated in the design and coordination of the study. mp participated in the design and coordination of the study, and was responsible for the bacteriological assays. ab participated in the design and coordination of the study, and headed the network of general practices. bw participated in the design and coordination of the study, and was responsible for the virological assays. all authors read and approved the final manuscript. the pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/7/35/prepub key: cord-327574-24t10fs4 authors: fakih, mohamad g.; sturm, lisa k.; fakih, rand r. title: overcoming covid-19: addressing the perception of risk and transitioning protective behaviors to habits date: 2020-06-09 journal: infection control and hospital epidemiology doi: 10.1017/ice.2020.284 sha: doc_id: 327574 cord_uid: 24t10fs4 nan to the editor-we started this year facing an incredible challenge that defied many assumptions regarding pathogens. the coronavirus disease 2019 (covid-19) has spread from china across borders and oceans to become a pandemic. our unfamiliarity with the nature of the disease, from asymptomatic infection to presymptomatic contagiousness, to its efficiency of transmission and the varied nonspecific clinical presentations, made containment of its early spread difficult. the risk of contracting covid-19 infection depends on the prevalence within a community, the efficiency of viral transmission, and the behavior of the susceptible host. some regions within the united states have been disproportionately affected, 1 but the uncertainty related to the risk for exposure and severity of outcome, combined with the desire to return to our normal lives for economic and mental health reasons, has led to varied practices across the nation. social distancing (shelter in place or stay at home) imposed by states, curtailed the outbreak in many of our communities. in the absence of a treatment or a vaccine that delivers protection, along with greater herd immunity, effective management of this disease is contingent to a large extent on the protective behaviors adopted by the population at large. for decades, we have struggled with hardwiring the compliance with hand hygiene before and after caring for patients, although many providers acknowledge that poor compliance leads to transmission of multidrug-resistant organisms and patient harm. 2 we also accept contracting a cold or influenza as an unavoidable, expected event. we marginally altered our behavior even when a seasonal influenza vaccine was not a good match. the contrast between our approach to covid-19 and previous epidemics and pandemics is our perception of risk. the mortality of covid-19 patients is thought to be up to 10 times that of influenza, creating the urgency to intervene. 3, 4 on the other hand, other threats to society, such as climate change are uncommonly perceived as an emergency, hence the action may not be pressing. our reaction to covid-19 threat has been based on our variable interpretation of such risk. the approach to curbing further transmission of covid-19 within communities focuses on the institution of measures (1) to detect and isolate those infected, (2) to practice point source control, (3) to reduce environmental contamination, and (4) to optimize engineering controls. symptoms and epidemiologic risk (eg, travel, known exposure) screening has been widely used to identify suspected cases as a prequel to molecular testing and identifying active infection. testing, however, is not failure proof and may risk providing a false sense of security. recent data on rapid polymerase chain reaction testing reported potentially inaccurate results. 5 on the other hand, instituting behaviors such as selfisolation for 10-14 days prior to a surgery, eliminates the risk of a patient being actively infected at the time of the procedure. environmental cleaning reduces the chance for persons to contact contaminated surfaces, and engineering control through deploying spatial separation and reducing crowding will lessen the chances of exposure to the pathogen. to achieve long-lasting benefits that help reduce covid-19 and other future infectious outbreaks, we will need to learn and adopt precautionary actions. one of the main predictors of people's engagement in protective behavior is risk perception. [6] [7] [8] people are more likely to comply with the recommended precautionary behaviors if they think that they are susceptible to contracting the disease (ie, perceived vulnerability) and if that illness is deemed to lead to severe health consequences (ie, perceived severity). 7, 9 however, according to the protection motivation theory, 7 risk perception is an imperative but insufficient precursor for the adoption of protective behaviors. 6 in times of stress, people also assess their ability to cope with the threat (ie, coping appraisal). thus, the motivation to engage in protective behavior is heightened with the belief that the recommended protective measures would lead to successful outcomes (ie, response efficacy) and when there is confidence in one's ability to perform healthy behaviors (ie, self-efficacy; for example, "i am able to constantly perform hand hygiene and mask."). 7 in addition, risk perception and self-efficacy beliefs are greatly influenced by the sources of information to which individuals are exposed (eg, media, friends, governmental health agencies). information deemed questionable or coming from a noncredible source may negatively influence one's motivation to adopt protective behavior. 6 behavioral change requires understanding the risk we are facing, learning through effective means how to mitigate the risk, and sustaining protective behaviors to become effortless habits. 10 we suggest moving our population to adopt healthy behavior as the primary venue to minimize exposure to pathogens transmitted through droplets or contact. this includes regular hand hygiene, no hand shaking or sharing objects, following respiratory etiquette, and avoiding exposure to those that are sick. in addition, we need to continue public education on how to perform hand hygiene, how to mitigate the risk of fomite transmission, and how to use cloth face coverings correctly. the messages are then culturally accepted and espoused by the community so the actions become part of our regular activities. in addition, structural changes within the community and public settings may be required to establish an environment that is favorable to the concepts of minimizing ongoing risk. finally, similar to enjoying our coffee every morning as part of our daily routine, we will need to experience the satisfaction and reward of performing these safe behaviors as an anchored habit. covid 19): cases, data, and surveillance interventions to improve hand hygiene compliance in patient care estimating the infection fatality rate among symptomatic covid-19 cases in the united states cardiovascular disease, drug therapy, and mortality in covid-19 covid-19) update: fda informs public about possible accuracy concerns with abbott id now point-of-care test. us federal drug administration website risk perceptions and behaviour: towards pandemic control of emerging infectious diseases: international research on risk perception in the control of emerging infectious diseases protection motivation and self-efficacy: a revised theory of fear appeals and attitude change perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey meta-analysis of the relationship between risk perception and health behavior: the example of vaccination social psychology in action: evidence-based interventions from theory to practice acknowledgments. none.financial support. no financial support was provided relevant to this article.conflicts of interest. all authors report no conflicts of interest relevant to this article. key: cord-282783-ps5jyjkl authors: nan title: full issue pdf date: 2020-09-30 journal: jacc: cardiooncology doi: 10.1016/s2666-0873(20)30180-0 sha: doc_id: 282783 cord_uid: ps5jyjkl nan disease, coronary artery disease, arrhythmias, and pericardial disease, depending on the exact cardiotoxic agent (3) . in this state-of-the-art review, we focus on long-term cardiac diseases after treatment for childhood cancer. we discuss the prevalence, risk factors, prevention, prediction, and surveillance of cardiac disease in this population (central illustration). we systematically searched pubmed for studies that described cardiac adverse events in children treated with cardiotoxic cancer treatments. we limited the search to full-text articles written in english and articles published within the last 10 years. we selected articles with a study cohort of which >50% were treated for childhood cancer before the age of 21 years. for studies describing the prevalence or cumulative incidence of heart failure, we reviewed articles with a minimum of 500 ccs; a minimum of 100 ccs was required for the other outcomes. studies on primary prevention strategies were identified from previous cochrane searches (4) (5) (6) . based on these criteria, 74 studies were considered to be described in this review ( figure 1 ). the full search strategy is provided in supplemental table 1 . (7) (8) (9) (10) (11) (12) (13) (14) (15) . anthracyclines are clearly associated with cardiomyocyte damage. although the exact mechanism of anthracyclineinduced cardiotoxicity has not been fully elucidated, early studies indicate that cardiotoxicity through reduction-oxidation reaction cycling and the generation of reactive oxygen species may be the cause. more recently, topoisomerase 2b has been proposed to be a mediator of doxorubicin-induced cardiac injury (16) . systolic dysfunction can eventually progress to heart failure. heart failure is one of the most frequent cardiac late effects in ccs (17, 18) , and contributes to significant morbidity and non-cancer-related mortality later in life (19, 20) . a large cohort from the childhood cancer survivor study investigated the occurrence of heart failure, defined by the common terminology for criteria adverse events as grade 3 to 5. based on questionnaires concerning long-term ccs, the reported cumulative incidence is 4.8% by 45 years of age (17) . these results confirmed earlier reports that anthracyclines and chest rt are strongly associated with heart failure (21) . recently, it has been shown that even low-to-moderate chest rt doses increase the risk of heart failure substantially (22, 23) . in the dutch later (late effects after childhood cancer) cohort, feijen et al. (10) reported a cumulative heart failure incidence of 10.6% 40 years after childhood cancer diagnosis in ccs who received cardiotoxic cancer treatment. higher exposure to mitoxantrone and cyclophosphamide were suggested as novel treatment-related risk factors (10) . although mitoxantrone has traditionally been classified as an anthracycline, it has been suggested that mitoxantrone results in cardiotoxicity through mechanisms different from anthracyclines (24, 25) . mitoxantrone has a nonlinear dose-response relationship with heart failure risk (10, (26) (27) (28) , and compared to doxorubicin, mitoxantrone is 10 times more cardiotoxic. in addition, a younger age at diagnosis and presence of traditional cardiovascular risk factors may play a role in the development of heart failure (29) . the influence of sex on the development of myocardial dysfunction is still incompletely conclusive (8, 9, 11, 12, 30) . coronary artery disease. the risk of coronary artery disease (cad) is substantially increased in ccs. in the childhood cancer survivor study, the cumulative incidence of cad by age 45 years was 5.3% in survivors with and without exposure to cardiotoxic cancer treatments (17) . this risk is dependent on chest rt dose with no established safe dose; this risk is also higher in males. the cumulative incidence of symptomatic cad at age 50 years the main risk factors for cardiac disease in childhood cancer survivors are anthracyclines, mitoxantrone, and chestdirected radiotherapy dose. primary prevention strategies may reduce the risk of anthracycline-induced cardiomyopathy. there is an increased prevalence of traditional cardiovascular risk factors in childhood cancer survivors; screening and early management are important to modify risk. multivariable risk prediction models may help to individualize prevention and surveillance strategies. increases to 20% in males exposed to >35 gy of radiation (18, 31) . the st. jude lifetime cohort study detected cad based on either history, electrocardiogram (ecg), or echocardiography in 3.8% of asymptomatic ccs 22.6 years after cardiotoxic therapy (30) . however, evidence from (non)invasive coronary angiography is scarce. a study evaluating computed tomography in asymptomatic hodgkin lymphoma ccs 55 years old or younger (n ¼ 31) exposed to chest rt showed coronary artery lesions to be very proximal, placing large portions of the myocardium at risk (32) . valvular (30, 33, 35) . chest rt has been identified as an important risk factor that increases at higher doses (35) . other risk factors are treatment with anthracyclines, hypertension, congenital heart disease, and younger age at diagnosis, although these have not been uniformly shown in all studies (11, 30, 33) . mild tricuspid regurgitation was most prevalent in 2 studies describing valvular disease, but this is also very common in the general population (30, 33, 36) . in lymphoma ccs who were exposed to chest rt, valvular heart disease, defined as mild or higher for left sided valves and moderate or higher for right sided valves, was most frequently detected in the aortic and mitral valves (35) . valvular abnormalities after chest rt are most likely caused by direct irradiation injury to the valve cusps or leaflets, causing thickening, fibrosis, and calcification (30, 37) . these processes progress with age and increase in prevalence over time (30, 35) . hence, ccs without echocardiographic abnormalities after a short followup period are still at risk of severe valvular heart disease. pericardial disease. besides paraneoplastic and infectious causes, pericardial disease can arise from chest rt. late constrictive pericarditis, in particular, can lead to disabling symptoms and a poor prognosis (38) . however, data on pericardial disease in ccs are limited. the childhood cancer survivor study showed a 10-fold higher risk of pericardial disease in all ccs versus siblings (30year cumulative incidence, 3 .0%) and a dose-response relation with chest rt (11) . a single-center study in ccs older than 5 years after diagnosis (n ¼ 1,362; 47% no cardiotoxic therapy), reported symptomatic pericarditis in only 2 ccs (18) . although the diagnosis of constrictive pericarditis is difficult by echocardiography, thickening of the pericardium as well as hemodynamic consequences (e.g., "septal bounce," abnormal respiratory variations in doppler findings) can be suggestive. upon high clinical suspicion, cardiac computed tomography, magnetic resonance imaging (mri), and/or invasive hemodynamic evaluation may be needed to confirm the diagnosis (39) . arrhythmias. the prevalence of symptomatic cardiac arrhythmias in long-term ccs is reportedly low (11, 17, 18, 40) . in 10,724 ccs, the cumulative incidence of grade 3 to 5 arrhythmia by 45 years of age was 1.3% (17) . a subsequent study (n ¼ 23,462) showed that chest rt >35 gy, anthracycline dose $250 mg/m 2 , dyslipidemia, and hypertension are risk factors for symptomatic arrhythmia (11) . myocardial fibrosis caused by chest rt may contribute to the occurrence of arrhythmias. other frequently used cancer agents for pediatric cancers such as cisplatin, cyclophosphamide, and tyrosine kinase inhibitors may also be associated with supraventricular and ventricular arrhythmias (41, 42) . prolonged qtc interval, which has arrhythmogenic potential, has been shown in ccs who received anthracyclines with and without chest rt (43, 44) . also, rhythm disturbances such as premature ectopic beats and atrioventricular blocks have been reported in ccs (45) (46) (47) . the literature on ecg abnormalities in large cohorts of long-term ccs is sparse (46, 47) , data on the use of ambulatory ecg monitoring to define the prevalence of brady-and tachyarrhythmias induced by cardiotoxic cancer treatments are needed, but must be carefully weighed against the potential patient burden and clinical significance. childhood cancer survivors preventive measures for cancer treatment-induced cardiotoxicity. as the risk of cardiac disease is high in chest rt and anthracycline-treated survivors, and as omitting or diminishing the use of cardiotoxic treatments is not always possible, prevention is critical (48) . advanced radiotherapy techniques to minimize exposure to the heart have been developed; the impact of those improvements is reflected by the decrease in cad in more recent treatment eras (11) . extensive research has been devoted to the identification of possible cardioprotective interventions during anthracycline treatment that do not have negative effects on antitumor efficacy or other noncardiac adverse effects. below we discuss 3 preventive measures that have been studied during anthracycline treatment. we focus primarily on randomized controlled trials (rcts) as they provide the highest level of evidence to answer this type of question. because of developmental changes and the differences in the body composition of children, data from adults cannot be reliably extrapolated to children (49) . d e x r a z o x a n e . dexrazoxane is one of the most widely investigated cardioprotective pharmacologic interventions. it has been shown in adult cancer patients to prevent clinical and subclinical cardiac damage (4) . the few published pediatric rcts have included participants diagnosed with leukemia, lymphoma, and sarcoma (50) (51) (52) . these studies suggest that there are no significant differences in clinical heart failure between dexrazoxane and control patients (4, 53) , although dexrazoxane might have a protective effect on asymptomatic cardiotoxicity (53, 54) . all studies included relatively short-term follow-up, and the impact on outcomes after longer follow-up is yet unknown. currently, dexrazoxane is not routinely used in clinical practice for all children treated with anthracyclines. this might be explained by a concern over interference with antitumor efficacy and the occurrence of secondary malignancies (55). however, high-quality evidence to support an increased risk of secondary malignancy is lacking. a cochrane systematic review identified no significant differences between treatment groups (4) , which is in line with more recently published randomized trials (50, 53) . a recently published nonrandomized study in pediatric patients with acute myeloid leukemia mortality. an overview of validated prediction models in ccs is provided in supplemental table 2 . heart failure prediction models. practical models to predict heart failure onset before the age of the discriminatory abilities of the model were further shown by a cumulative incidence of heart failure at age 40 years of 0.5% in the low-risk group, whereas this was 11.7% in the high-risk group. importantly, 45 .2% of the ccs were at low risk according to the model and thus unlikely to develop heart failure. (17) . thus, early, at 5 years after diagnosis, cardiovascular risk factors have been shown to provide little incremental information to prediction models for heart failure and ischemic heart disease (29, 31) . in a more recent study, diabetes, hypertension, and dyslipidemia were used in the prediction of heart failure and ischemic heart disease in ccs who were 20, 25, 30, or 35 years of age at time of prediction, with relative risks comparable to moderate doses of anthracyclines (74). cardiovascular risk factors were present in approximately 10% of the ccs at the age of 35 years and were strong predictors of heart failure and ischemic heart disease. although the discrimination of the prediction models improved with the addition of cardiovascular risk factors, the c statistics were modest for both events ranging from 0.69 to 0.79 in the derivation cohort with successful replication in the other one-half of the cohort. both the heart failure and the ischemic heart disease predictions models showed good calibration. a small, very-highrisk group was identified with cumulative incidences of heart failure or ischemic heart disease of w10% at age 50 years; survivors in this very-high-risk group may benefit from more frequent surveillance and/or early interventions to modify their risk. however, low-risk survivors who may be excluded from further surveillance could not be identified with these models as cumulative incidences of heart failure (w1.5% to 2.5%) and ischemic heart disease (w1% to 1.5%) were still significantly higher compared to siblings at the age of 50 years. in the context of prediction model-guided surveillance, this can be seen as the benefit of early detection of asymptomatic cardiac dysfunction among those who will develop heart failure (true positives) weighted against the potential harm of an unnecessary diagnostic workup and/or treatment in those who will not develop heart failure (false positives). through decision modeling using simulations it has been shown that routine echocardiographic surveillance for asymptomatic cardiomyopathy every 10 years may be more cost-effective, especially in those treated with an anthracycline dose <250 mg/m 2 (85). decision modeling provides weaker evidence on the clinical impact compared to an rct, but it requires no follow-up and is less expensive to perform. such analyses could be performed to assess clinical impact and cost-effectiveness before conducting an rct. there are different methods and techniques available to detect anthracycline treatment induced cardiomyopathy. much of the research in detection of cardiac diseases is focused on improving early detection of myocardial dysfunction. we will describe diagnostic methods that have been studied over the past decade in ccs. an abnormal gls in 28% of the cohort who were exposed to anthracyclines and/or chest rt and had normal lvefs. both cumulative anthracycline dose >300 mg/m 2 and any cardiac rt dose were associated with an increased risk for abnormal gls (7) . it is currently unknown whether an abnormal gls is associated with development of an lvef <50% or clinical heart failure in ccs. diastolic dysfunction after cardiotoxic cancer treatment has also been described in ccs (8, 94) . in the st. jude lifetime cohort, diastolic dysfunction grades 1 to 3 (based on peak mitral flow velocity, mitral septal and lateral early diastolic velocity, and left atrial volume) was detected in 11% of all ccs who were exposed to cardiotoxic treatment and in 8.7% with normal lvef (7) . one must be aware of the diftable 1 ). the current lack of mechanistic insights for (9,10) tyrosine kinase inhibitor(11) , and trastuzumab-related cardiotoxicity (12) . inflammation studied primarily to reduce major adverse cardiovascular events was associated with a significant reduction of lung malignancy (4). meta-analyses of therapies lowering low-density lipoprotein cholesterol (ldl-c) demonstrated that prevention of cardiovascular events was proportional to the absolute reduction in ldl-c levels with no major safety concerns, specifically no increase in malignancies (5, 6) . however, available data from previous ldl-c-lowering clinical trials have not systematically adjudicated data for malignancy, because these were not considered disease-related events (7) . an increased rate of malignancy associated with the use of the combination of ezetimibe and simvastatin was unexpectedly reported in the seas (simvastatin and ezetimibe in aortic stenosis) trial (8) , which compared simvastatin-ezetimibe to placebo in 1,873 adults with mild-to-moderate aortic stenosis over a median follow-up of 4.4 years (8). ezetimibe is a nonstatin drug that inhibits the intestinal absorption of cholesterol by targeting the transmembrane protein, nieman-pick c1-like 1 (9) . it is recommended for further ldl-c reduction in combination with a statin (10 values are median (25th, 75th percentiles) or n (%). wilcoxon rank-sum test of differences between with and without primary malignancies for continuous variables. chi-square test of frequencies between with and without malignancies for categorical variables. *the no-malignancy group summary statistics are based on patients without malignancy diagnosis prior to death, loss to follow-up or end of the study. acei ¼ angiotensin-converting enzyme inhibitor; acs ¼ acute coronary syndromes; arb ¼ angiotensin receptor blocker; hdl-c ¼ high-density lipoprotein cholesterol; hs-crp ¼ high-sensitive c-reactive protein; iqr ¼ interquartile range; ldl-c ¼ low-density lipoprotein cholesterol; mi ¼ myocardial infarction; trs2p ¼ timi risk score for secondary prevention (13) . of the skin, as well as limiting malignancy events to only those with available pathology reports. we also performed a competing risk analysis integrating allcause death as a competing outcome in the model using fine and gray's method. finally, we also evaluated the hrs in both arms with increasing duration of follow-up as done in previous publications (14, 15) . all analyses were performed using sas software, simvastatin/ezetimibe (red) and placebo/ezetimibe (blue). the primary malignancy endpoint was defined as new, relapsing, or progressive malignancy (excluding nonmelanotic skin malignancy). the cumulative incidence plots were presented graphically using kaplan-meier product-limit method. ci ¼ confidence interval; hr ¼ hazard ratio. simvastatin/ezetimibe (red) and placebo/ezetimibe (blue). the cumulative incidence plots were presented graphically using kaplan-meier product-limit method. ci ¼ confidence interval; hr ¼ hazard ratio. table 3) . results were similar between treatment groups for deaths due to malignancy by location table 2 . values are n (%). (p > 0.05 for each comparison) (supplemental table 4 ). further analyses by gender showed no significant differences between treatment groups for both the primary malignancy endpoint (p > 0.05 for each comparison) (supplemental tables 5 and 6 ) and deaths due to malignancy (p > 0.05 for each comparison) (supplemental tables 7 and 8 ). finally, we did not observe any differences in the extent of malignancy by treatment arm ( table 4) . in subgroup analyses, the rates of the primary malignancy endpoint were similar between treatment groups for each of the 8 pre-specified high-risk subgroups (each p for interaction >0.05) ( figure 2 (figure 3 ). during the 7 years of follow-up, there was no divergence in the km curves over time ( figure 1) ; the year-by-year hrs for the primary malignancy endpoint comparing the two treatment arms did not demonstrate a progressive trend over time ( table 5) . the number of events and the 7-year kaplan-meier rates are shown. total cholesterol: 25th percentile ¼144.0 mg/dl, 50th percentile ¼ 162.4 mg/dl and 75th percentile ¼ 181.0 mg/dl. abbreviations as in figure 2 . some concern has been expressed that statin and other ldl-c-lowering drugs might be carcinogenic and consequently part of the malignancy data was collected retrospectively. fifth, although the analyses of outcomes stratified by subgroups were pre-specified, the power was low in these subgroups. finally, we did not measure phytosterols or other potential protective or tumor-promoting factors in blood to evaluate the effect of ezetimibe on the potential mechanistic pathways related to malignancy. we found that ezetimibe did not increase the rates of malignancy nor deaths due to malignancy in 17,708 patients with recent acs treated with simvastatin and followed up for a median of 6 years totaling 96,377 patient-years of follow-up. acknowledgment therapies to reduce ldl-c such as statins or ezetimibe have significantly improved cardiovascular outcomes; this benefit has been ascribed to pleiotropic effects beyond lowering ldl-c. however, such pleiotropic mechanisms have raised safety concerns about long-term use. a potential carcinogenic effect has been of particular concern as earlier studies sug10-year risks in cantos were 26% (range 1% to 52%) and 13% (range 1% to 31%) for total cancer; 4% (range 0% to 13%) and 2% (range 0% to 6%) for colorectal cancer; and 5% (range 0% to 37%) and 2% (range 0% to 24%) for lung cancer. conclusions lifetime and 10-year risk of total, colorectal, and lung cancer can be estimated reasonably well in patients with established cvd with readily available clinical predictors. with additional study, these tools could be used in clinical practice to further aid in the emphasis of healthy lifestyle changes and to guide thresholds for targeted diag(12) . for the current study 9,322 patients were included, after exclusion of patients younger than 45 years or older than 80 years. detailed descriptions of the ucc-smart cohort and the cantos trial have been published elsewhere (12) (13) (14) . the studies were approved by institutional review boards and all participants provided written informed consent. an overview of eligibility criteria is provided in supplemental table 1 . missing data (per variable #1.1% for ucc-smart and #0.2% for cantos) were singly imputed by weighted probability matching using multivariable regression for the baseline and outcome data. complete case analysis yielded similar model coefficients. continuous variables were truncated at the 1st and 99th percentile to limit the effect of outliers on the model coefficients (i.e., leverage) (17) . to prevent overfitting, predictors were preselected based on presence in previously published risk prediction models of multiple cancer types. antiplatelet use (aspirin, p2y12-adp receptor antagonist, or other, such as dipyridamole) was added as a predictor, due to its inclusion in multiple previously published prediction models for colorectal cancer and due to the common use of antiplatelet therapy in patients with cvd. furthermore, it was required that the variables were readily clinically available, as well as present in the derivation dataset. this led to the following predictors: age, sex, smoking status, weight, height, alcohol use, use of antiplatelet medication, and diabetes mellitus (supplemental table 4 details an overview of predictor selection). in addition, crp was added as a predictor after a literature search for predictors of cancer was performed (3, 15, 18, 19) . definitions of the predictors in the ucc-smart cohort and cantos trial are provided in supplemental table 5 . was calculated for each following life-year. next, for each subsequent age year the probability of being healthy and alive at the start of that time interval (age year) (e t þ1) was calculated by multiplying the survival probability (e t ) by the event-free survival probability during that year (1 à a t à b t ). these steps were repeated from the age at baseline of an individual patient to the maximum age of 90 years, and together these predictions form an individual lifetable (10, 23) . the cancer-free life expectancy was determined as the age at which the median estimated cancer-free survival curve is 50%. for 10-year and lifetime risk of cancer, the cumulative cause-specific risks were truncated at 10 years after the age at baseline, and at the age of 90 years, respectively. cantos study populations are shown in table 1 (1), leading to restricted variation in cancer types. our cancer prediction models performed reasonably well, and calibration plots before and after (7). second, complex models based on machine learning would not be expected to provide improved performance or better prognostication in the current study, consistent with other large-scale external validation studies (8, 9) . from a clinical perspective, a key concern should be whether the predictions from the risk calculator are well calibrated (5) . for example, the 70-year-old male in the example calculation sheet has a predicted 1.1% risk of lung cancer, while the risk may in fact be 0.5%, or 2%. this type of miscalibration has been common in earlier evaluations of lung cancer prediction models (10) . indeed, the investigators state that "calibration is a more clinically relevant for risk (11) . it was recently rediscovered and presented through a "decision curve" (12, 13) , which is unfortunately missing from the current report. future work should consider the clinical decisionmaking perspective more fully, with net benefit in a decision curve as a step towards a more comprehensive cost-effectiveness analysis. in sum, the presented risk calculator is very promising given its high-quality data sources, large values are mean ae sd or %. *p < 0.05 across diuretic categories. †defined as nt-probnp >3,000 pg/ml or bnp >600 pg/ml. ‡defined as troponin-t >0.05 ng/ml or troponin-i >0.1 ng/ml. ace ¼ angiotensin converting enzyme; arb ¼ angiotensin receptor blocker; attr ¼ transthyretin amyloidosis; bmi ¼ body mass index; bnp ¼ b-type natriuretic peptide; dbp ¼ diastolic blood pressure; egfr ¼ glomerular filtration rate; gdmt ¼ guideline directed medical therapy; hf ¼ heart failure; lvef ¼ left ventricular ejection fraction; mra ¼ mineralocorticoid receptor antagonist; nt-probnp ¼ n-terminal pro-b-type natriuretic peptide; nyha ¼ new york heart association; sbp ¼ systolic blood pressure; shfm ¼ seattle heart failure model. table 3 ). figure 3a) . similarly, for the uk þ diuretic dose þ nyha functional class model, survival was 6.5 years, 3.8 years, and 1.9 years for the low-, intermediate-, and high-risk groups, respectively (log-rank p < 0.001) ( figure 3b ). we also tested the ability of the risk scores to predict a combined outcome of mortality or cardiac transplantation ( table 3 ). optimism-adjusted aucs at 2 years ( adding diuretic dose to the uk score increased the auc from 0.711 to 0.787 and additionally adding nyha functional class, increased it to 0.816. for diuretic dosing, 0 points were assigned for 0 mg/kg, 1 point for >0 to 0.5 mg/kg daily dose, 2 points for >0.5 to 1 mg/kg daily dose, and 3 points for >1 mg/kg daily dose. *difference in discrimination slopes between 2 models, where the discrimination slope is the difference between the mean predicted probabilities for events and nonevents. †sum of net proportions of persons with and without the event correctly assigned to a different risk category; ranges from à2 to 2. ‡similar to the idi except compares difference between median predicted probabilities. idi ¼ integrated discrimination improvement; nri ¼ net reclassification index; other abbreviations as in tables 1 and 2 . for diuretic dosing, 0 points were assigned for 0 mg/kg, 1 point for >0 to 0.5 mg/kg daily dose, 2 points for >0.5 to 1 mg/kg daily dose, and 3 points for >1 mg/kg daily dose. abbreviations as in tables 1 to 3 . cheng et al. study limitations. our cohort included both wtattr and hattr. it is possible that risk markers may be differentially predictive in these distinct cohorts because natural disease progression is more aggressive with hattr, and there may also be differences between mutation types. of note, the mayo risk score (2) only the latter remained significant in multivariable analysis. cardiovascular diagnosis usually includes imaging; thus cardiologists and patients have a tendency to focus on those results. although cardiovascular imaging has revolutionized the diagnosis of cardiac amyloidosis, the role in prognosis is less clear. when the addition of imaging variables to the staging systems is considered, the availability, reproducibility, and incremental value must also be considered. in contrast to the current study, nyha functional rodney falk appropriately coined the term "toxicinfiltrative cardiomyopathy" in reference to the toxicity of circulating light chains (al) to cardiomyocytes in al (7). similar mechanisms of cardiomyocyte toxicity due to ttr oligomeric intermediates have been reported in attr (8, 9) . cardiac amyloidosis is not a simple infiltrative condoacs in cancer such as those related to trial designs or the risk for contamination or crossover between the groups. data synthesis and analysis. we extracted data from the original primary publications (9) (10) (11) (12) the flowchart describes study search, screening, and selection processes. sabatino et al. were included in the systematic review and metaanalysis (9) (10) (11) (12) . the study flowchart is described in figure 1 . table 4 . supplemental figure 1 . overall, the risk for selection table 1 . figure 3d) . overt bleeding that was associated with a decrease in the hemoglobin level of $2 g/dl, led to a transfusion of $2 u of blood, occurred in a critical site, or contributed to death overt bleeding that did not meet the criteria for major bleeding but was associated with the use of medical intervention, contact with a physician, interruption of the assigned treatment, discomfort, or impairment of activities of daily living. mcbane et al. (11) ; 2020 overt bleeding plus a hemoglobin decrease of $2 g/dl or transfusion of $2 u of packed red blood cells, or intracranial, intraspinal/epidural, intraocular, retroperitoneal, pericardial, intra-articular, or intramuscular with compartment syndrome, or fatal bleeding overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, an unscheduled contact with the health care team, or temporary anticoagulant cessation gi ¼ gastrointestinal; other abbreviations as in table 1 . sabatino et al. over the past few years, the use of doacs has revovalues are n (%). *basal cell or squamous cell carcinoma of the skin, primary brain tumor or known intracerebral metastases, and acute leukemia were not included in the caravaggio trial. †basal cell or squamous cell carcinoma of the skin were not included in the select-d trial. ‡basal cell or squamous cell carcinoma of the skin were not included in the hokusai vte cancer trial. §other than brain tumors. ǁ data not available, because brain tumors were included under "other tumors". abbreviations as in tables 1 and 3 . the data from the caravaggio trial concerning the risk of major bleeding were particularly noteworthy. it appears that this finding was not related to any differences in the definition of major bleeding, because this was relatively consistent across trials ( table 3 ). in contrast, the differences in reported major bleeding risk might have resulted from the heterogeneity in enrolled populations. patients with primary brain tumors, brain metastases, and acute leukemia were excluded from the caravaggio trial. patients with a recent diagnosis of testicular/retroperitoneal germ cell cancer and orchidectomy #8 weeks prior scheduled for cisplatin-based chemotherapy or active surveillance were recruited. participants were stratified into 3 groups by management: 1) active surveillance for stage 1 low-risk disease; 2) 1 to 2 cycles of adjuvant bleomycin, etoposide, and cisplatin (bep) chemotherapy for stage 1 high-risk disease; or 3) 3 to 4 cycles bep chemotherapy for metastatic disease. red circles illustrate study assessments. blood samples were simultaneously drawn from each table 2) . this remained numerically greater than baseline thereafter, but was not statistically significant. there were trends toward abbreviations as in table 2 . table 2) . there was no differences between groups (p ¼ 0.285). endothelial dysfunction is a key feature in de novo thrombosis and rupture of pre-existing atherosclerotic plaque (25) . as such, it is an important component to the risk of thrombotic cardiovascular events in the early period following cisplatin-based chemotherapy. in our cell-based study, exposure of haecs to cisplatin was associated with decreased t-pa mrna expression and activation of akt and erk 1/2. in previous work, cisplatin has been shown to reduce endothelial cell survival and induce apoptosis in human dermal microvascular endothelial cells (hmec-1) (26) and in the vasa nervorum in rats (27) . these data support the hypothesis that cisplatin induces direct endothelial toxic effects resulting in increased stress kinase signaling and a propensity for thrombosis via reduction in the capacity for endogenous fibrinolysis. although adverse thrombotic effects are most frequently observed in the early period following chemotherapy, cisplatin is detectable in serum for several years after treatment (28) . this chronic exposure may provoke low-grade endothelial stimulation and a consequent pro-atherogenic environment (28, 29) . our subsequent assessment was with forearm venous occlusion plethysmography, the gold standard for assessing endothelial function (12) . in appears to be the time period of increased cardiovascular risk. while these effects predominantly occur in the early period after treatment, cisplatin is detectable in serum several years after treatment (28) . it remains possible that chronic exposure to low levels of cisplatin may cause low-grade endothelial stimulation that contributes to the pathophysiology underlying cardiovascular events occurring more than a decade after initial exposure (8, 28) . nephrotoxicity is a major, dose-limiting side effect of cisplatin that affects 20% to 40% of patients (4, 36) . we found evidence of early nephrotoxicity following cancer an acute decrease in fmd was seen as early as with the first cycle of carboplatin and paclitaxel chemotherapy (11) . in conjunction with the current findings, one would conclude that the common denominator is platinum drugs and that there is no gender-related difference. furthermore, one would conclude that platinum drugs seemingly induce relatively acute changes in endothelial cells that translate into a reduction in flow-mediated vasodilation and alterations in nitric oxide bioavailability. interestingly, a prior study in testicular cancer survivors showed that those patients who were exposed to cisplatin-based chemotherapy nearly 3 to more than 20 years ago had a more severe reduction in fmd and higher levels of circulating endothelial cells than those not exposed (13) . the fact that cisplatin levels are detectable even nearly 30 years from therapy supports the theory of long-term exposure and endothelial injury (14) . a difference in vascular reactivity between cisplatin-exposed and cisplatin-nonexposed was not seen in the current study by cameron et al. (10) . it is important, however, to realize that the vascular response was blunted in both groups, even in comparison with patients with metabolic syndrome (considered to account for the vascular outcomes in testicular cancer survivors as mentioned) (15) . such results can also not be unequivocally attributed to hypogonadism (16, 17) . (3) (4) (5) (6) . in patients that survive beyond 5 years, mortality rates are 4 to 9 times higher than the general population, corresponding with a 30% shorter life expectancy regardless of age at transplantation (7) . the incidence of heart failure (hf) has been reported to be between 5.6% to 10.8% in those who have survived at least 10 years after hsct (4, 5, 8, 9) , and the risk of cardiovascular (cv) related mortality is 2 to 4 times higher in hsct survivors than in the general population (4 were measured on separate occasions to reduce bias. studies followed current guidelines for evaluation of lv function and cardiotoxicity (14, 15) . measurements were averaged from 3 consecutive heart cycles. 2d-lvef was manually traced using the modified simpson's biplane method (14) . 3d-lvef was calculated with semiautomated software for endocardial detection, and was subsequently manually adjusted. a 3d pyramid volume acquisition was obtained from 4 to 6 cardiac cycles, adjusting for depth and sector width (60 to 70 ), resulting in an average volume rate of 39 frames/s (range 29 to 51 frames/s). sex-specific cutoffs for 2d-lvef were used as recommended (14) . gls (4, 8, 17, 18) . however, this study cannot discern the precise timing of lvsd onset, and one could potentially speculate that cardiac injury occurred at time of therapy, with a further worsening in lvsd over time. another possible explanation is that young patients are at higher risk of heart disease due to organ immaturity and growth disturbances caused by cardiotoxic therapies (19) . this may explain the smaller lv size in survivors compared with control subjects, even after consideration for cv disease and confounders. sex has previously been implicated as a risk factor for cardiotoxicity (8, (19) (20) (21) , but this association was not found in our study. cyclophosphamide has historically been noted to have cardiotoxic effects (22) . however, published data linking alkylating agents to long-term heart disease is scarce. in contrast, anthracycline exposure is known to cause myocyte depletion, and is shown to increase the risk of hf by 5-fold in long-term (8, 9, 19, 21, 23) . in addition to cardiotoxic therapies, we found that traditional cv risk factors have a potential role in modifying the risk for lvsd in long-term survivors of allo-hsct. cv risk factors are commonly reported in hsct survivors, occurring more frequently in allo-hsct compared with autologous-hsct survivors, resulting in a higher prevalence of heart conditions in allo-hsct survivors (6, 18, (24) (25) (26) . survivors in this study had a high prevalence of cv risk factors, but at a level comparable to other studies (6, 18, 20, 21, (24) (25) (26) . abbreviations as in table 4 . treated with hsct at various ages (5, 9, 20, 21, 24, 25) . the significance of hypertension in contributing to prevailing cardiac disease in hsct survivors has previously been shown (5, 21) . however, in our study, given that the onset and duration of hypertension is unknown, it is unclear if the cumulative consequences of hypertension were fully manifested. indeed, the echocardiograms showed little evidence of concentric remodeling beyond a small but significant difference in indexed lv end-diastolic volume. however, hypertension is known to cause myocardial fibrosis that leads to reduced longitudinal shortening of the heart (27) . this may explain why hypertension was found to be an independent predictor of gls. hypothyroidism has been reported in 30% of longterm survivors of hsct with busulfan conditioning (28) . hypothyroidism was found in 9.6% in our cohort, although no association with lvsd was found in our data. dyslipidemia has been reported in 13% to 52% of survivors of hsct (5, 6, 18, 20, 24, 25) . in our study, gvhd was found to be a highly prevalent complication of allo-hsct survivors. there is limited evidence that gvhd directly mediates myocardial damage. however, active chronic gvhd values are median (25th, 75th percentiles), n (%), or mean ae sd. *significant difference between anthracycline $300 mg/m 2 and <300 mg/m 2 in bonferroni post hoc analysis (<0.05). †significant difference with both treatment groups (anthracycline $300 mg/m 2 and <300 mg/m 2 ) with no anthracycline group in bonferroni post hoc analysis (<0.05). ‡no significant difference between treatment groups in bonferroni post hoc analysis. §echocardiographical parameters are adjusted for covariates of age, heart rate, body mass index, and diastolic blood pressure. ksignificant difference between anthracyclines $300 mg/m 2 and no anthracycline in bonferroni post hoc analysis (<0.05). ¶ase cube formula (14) . table 3 . has been shown to be associated with a higher risk of cv death (5) . it is thought that the chronic inflammation processes instigated by gvhd results in endothelial damage leading to accelerated atherosclerosis (29) . we did not find gvhd (acute or chronic) to be consistently associated with lv systolic function, and found a very modest association with remodeling (15, 33) . a remaining challenge with gls is the lack of consensus in defining absolute cutoffs for dysfunction, variability, and intervendor differences (27) . the gls cutoff used in our analysis was based on our normal data, using the same equipment and operator. this value (à17%) is conservative when compared with a meta-analysis performed by yingchoncharoen et al. (27) , which found the 95% ci for normal gls to be à18.9% to à20.4% (27) . 1â phosphate-buffered saline) and sacrificed 4 weeks later. as observed in previous studies (16, 23) , body mass at the time of sacrifice was lower (à12%) in the group administered with doxo ( table 1) . lower body mass with doxo was associated with lower heart, quadriceps, gastrocnemius, and epididymal white adipose tissue mass, food consumption (à17%), and water intake (à26%) ( table 1 ). there were no significant differences in the mass of other tissues and organs (supplemental table 1 ). we first sought to establish that total ros bioactivity was increased in huvecs exposed to plasma from doxo-treated mice compared with sham control mice. to do so, we assessed total cellular ros using the cellrox fluorescent probe (thermo fisher [waltham, massachusetts]; catalog# c10422) and found that ros bioactivity was greater in huvecs incubated with plasma from doxo-treated mice compared with sham control mice (p < 0.001) ( figures 4a and 4e ). next, we aimed to determine if enhanced mitochondrial ros contributed to the greater total huvec ros induced by doxo administration by assessing mitochondrial ros bioactivity using the mitosox fluorescent probe (thermo fisher, catalog# m36008). we observed greater mitochondrial ros in huvecs exposed to plasma obtained from doxo compared with sham-treated animals (p < 0.001) (figures 4b and 4e ). to determine if this greater ros bioactivity was linked to changes in mitochondrial volume, we figure 2) . to determine associations of these plasma metabolites with mitochondrialspecific aortic ros, we performed linear regression analyses. we found that plasma diphosphate (p ¼ 0.053) and lactate (p ¼ 0.067) tended to be positively associated with aortic mitochondrial ros (supplemental figure 3) . a full report of metabolite abundance is provided in supplemental table 2 . dot blot array. to expand on this initial analysis of potential circulating signals influenced by doxo treatment, we next targeted inflammatory pathways, given that doxo administration is associated with higher levels of pro-inflammatory proteins in the circulation (32) . to address this aim, we assessed plasma concentrations of 20 different cytokines and chemokines via a dot-blot array. we found that all but 2 of these markers did not differ significantly in plasma from doxo-treated mice compared with sham control mice ( table 2 ). the exceptions were the antiinflammatory cytokine interleukin-4, which was only slightly (<5%), but significantly (p ¼ 0.043) lower in the doxo mice, and vascular endothelial growth factor-a (vegf-a), which stood out as being 40% lower in the doxo treated group (p < 0.001). moreover, plasma vegf-a was inversely associated to accomplish this, we supplemented plasma from table 3 ). doxo chemotherapy has been shown to impair endothelial function (i.e., reduce edd) in conduit arteries of cancer survivors (18) . however, the underlying mechanisms and associated therapeutic targets have not been established, because mechanism-focused investigations to date have been largely limited to endothelial cell culture models (35, 36) . in the present study, we first determined that these findings also are in agreement with previous work reporting excess production of mitochondrial ros and impaired vascular endothelial function in mice with genetic sod2 insufficiency (41) . it should be noted that other ros generating pathways may also contribute, including oxido-reductases such as endothelial no synthase or nadph cytochrome p450 reductase (42) . another key finding from our experiments was that changes in the composition of the circulating milieu may contribute to doxo treatment-associated anthracycline treatment in these same children (6) . the decrease in nrg after anthracyclines has also been observed in adults undergoing anthracyclinebased chemotherapy, which is interpretable as a sign of vascular endothelial cell injury (7). endothelial cell-derived nrg acts through the erbb receptor tyrosine kinase family to regulate the growth and survival of cardiac myocytes, and protects from anthracycline cardiac cytotoxicity (8, 9) . mitoq and other coenzyme q10 preparations are available over the counter, and coenzyme q10 supplementation has been studied not only as a way to limit injury to the cardiovascular system, but also kidney and reproductive organs (11, 12) . these promtable 1 ). fulfilled criteria for myocarditis was based on european were receiving dexamethasone as palliative treatment for metastatic disease (supplemental table 3 ). and with other noncardiac iraes. crp in patients with no iraes was <20 mg/l at baseline and between c6 and c8 also was not significantly different (p ¼ 0.168). in this retrospective study of lung cancer patients receiving ici, there was an 11% incidence of mace to the rural population of eastern nc (12, 13) . indeed, higher inflammatory signals and incidence of pneumonitis were also observed in this lung cancer population in comparison to those reported previously (13, 19) . furthermore, in the lung cancer patients who received radiation, it has been suggested that the synergistic effect of radiotherapy and immunotherapy for priming of an endogenous antigenspecific immune response may contribute to a higher incidence of mace by t-cell recognition of shared antigens (20) . values are mean ae sd or n (%). *analysis was not performed secondary to limited sample size. bb ¼ beta-blocker; bnp ¼ brain natriuretic peptide; cad ¼ coronary artery disease; ccb ¼ calcium channel blocker; ckd ¼ chronic kidney disease; copd ¼ chronic obstructive pulmonary disease; crp ¼ c-reactive protein; cva ¼ cerebrovascular disease; dm ¼ diabetes mellitus; egfr ¼ estimated glomerular filtration rate; hld ¼ hyperlipidemia; htn ¼ hypertension; nlr ¼ neutrophil-lymphocyte ratio; raas ¼ renin-angiotensinaldosterone system; wbc ¼ white blood cell count; other abbreviations as in table 1 . timing of the development of mace with a median delay of 46 days and a median of 3 doses from the first ici administration in this study was similar to that previously reported (5, 21, 22) . in view of this timing of onset from earlier studies, there is a general recommendation that baseline and surveillance cardiac testing (echocardiogram, ecg, tni and bnp) be considered during this potential mace window period, noted as after the second and after the fourth ici cycle administration (21) . most of the present mace cases were not associated with a decrease in ef from baseline, which is consistent with previous studies (18, 21) , suggesting that relying solely on ef in ici-treated patients with mace may be limited for the detection of ircs. tni was observed to be mildly elevated at the time of mace. however, elevations in tni have also been observed in cancer patients receiving cancer therapy, including icis without any cardiotoxicities (23, 24) , thus suggesting that its utility may also be limited for the detection of irc. as demonstrated by this study, symptoms of irc may be variable, including nonspecific symptoms of our institution that observed a significant increase in crp with nivolumab-related pneumonitis that was mitigated with use of tocilizumab (19) . similar inflammatory-mediated mechanisms such as interleukin (il)-6 may be observed in car t cell-related cardiotoxicities (26) further highlighting and extending the utility of crp in the detection of ircs. another inflammatory marker that has been previously studied in noncardiac iraes and observed to be elevated at the time of irae is nlr (8, 11) . nlr is easily obtained, inexpensive, and a routine test, and is calculated from the total white blood cell count that reflects the ratio of the innate (neutrophils) and the adaptive (lymphocyte) immune pathways, whereby an elevation results in an imbalanced toxic inflammatory response with release of cytokines (27) . we observed an increase in nlr in patients who experihowever, ici treatment can result in immune-related adverse events (iraes) targeting any organ. cardiovascular iraes, particularly myocarditis, have received considerable attention due to their potentially fatal outcome (3, 4) . ici were initially tested and approved as single therapy in patients with metastatic melanoma, a cancer type that historically had few treatment options and poor survival (5) . later, these therapies were tested in patients with lung cancer and renal cell carcinoma (6, 7) . in the latter studies, ici were tested either in combination with or following exposure to classic chemotherapies or targeted therapies. as a result, there was a growing need to define the cardiovascular sequelae in lung cancer patients treated with ici, where the cardiovascular risk was complicated by exposure to cardiotoxic nonimmune-based cancer therapies and a high prevalence of conventional cardiovascular risk factors (8) . there was also a need to identify biomarkers or imaging approaches that screened for early cardiotoxic effects from immunotherapy and to identify patients at risk who would benefit from closer monitoring (9) . histopathological analysis of the emb specimen showed intense myocardial inflammation comprised of numerous giant cells associated with many mononuclear cells, and prominent myocyte necrosis ( figure 1 ). immunohistochemistry showed that the inflammatory cells were mainly cd68positive giant cells and macrophages and cd8-positive t-lymphocytes, many of them exhibiting granzyme b, perforin, and tia1 cytotoxicity markers. pd-l1 was expressed only by inflammatory cells and not by cardiomyocytes. cd4 and cd20 lymphocytes as well as nkp46-positive nk cells were poorly represented (not shown). immunohistochemistry for viral protein 1 detection was performed on heart biopsies and showed foci of positive cardiomyocytes surrounded by inflammatory infiltrates, indicating endomyocardial viral protein synthesis activities. steroids were gradually tapered and discontinued at 3 months in light of the viral analysis. cardiac magnetic resonance imaging showed at 6 weeks: 1) resolution of myocardial edema (average myocardial t 2 ¼ 50 ms (figure 1) , t 1 values of 917 ms, and extravascular volume decreased to 29%); 2) recovery of lvef to 68%; and 3) improvement of right ventricular function with an ejection fraction of 44% at 6 weeks to 51% at 6 months follow-up. the cancer had not progressed at 6 months follow-up, and the patient reported normal functional status. ici therapy was not restarted at the time of last follow-up. this case highlights the heterogeneity of pathogenesis of acute myocarditis on ici therapy. we describe here acute myocarditis with long-term ici therapy, secondary to giant cell myocarditis due to enterovirus. giant cell myocarditis is uncommon; its pathogenesis is poorly understood, and prognosis is poor. recent data from an international registry including 220 patients with histologically proven severe myocarditis demonstrated that giant cell myocarditis bears the worst prognosis (6). the favorable outcomes in our patient, although the number of patients eligible to ici treatment is increasing dramatically, the pathogenesis of myocarditis needs to be further investigated. based on only 2 extensively studied cases (5) emerging clinical syndromes (9) . the american heart association (aha) has recently proposed diagnostic criteria for ici myocarditis diagnosis based mainly on clinical characteristics, abnormal biomarkers, and/or cardiac imaging abnormalities (9) . the recent publication of ici myocarditis definitions by the aha has the value of standardizing criteria to improve reporting. steroids are the first-line front treatment of ici myocarditis, despite poor evidence to support this, followed by other immune modulators, plasma exchange, or even ctla-4 agonist (abatacept) infusions. in the present study case, steroids were introduced and then discontinued after the confirmation of active viral markers on emb. indeed, the prognosis of t-cell ici myocarditis is partly driven by early initiation of steroid treatment (10), which should not be held when awaiting histological or viral results. endomyocardial biopsy is recommended whenever possible in fulminant myocarditis (9) . it is, however, likely to be overlooked in cancer patients. this case report emphasizes the risk for opportunistic viral infection during long-term ici therapy and utility of biopsy. the first mechanism to be considered in the setting of ici myocarditis is t-cell mediated, prompting steroids as a first-line therapy early after hospital admission. endomyocardial biopsy should be performed whenever possible to rule out infectious causes of myocarditis to guide therapy and further our understanding of the potential varying presentations of ici myocarditis. were paramount in preventing discordant care, especially when her clinical status had many rapid changes while she was in the intensive care unit. she completed car t cell therapy and was discharged to acute rehabilitation after a one-month hospitalization. she was unable to be restarted on gdmt due to hypotension. her pa d was 6 mm hg at discharge. the plan was to obtain a positron emission tomography scan after acute rehabilitation to reevaluate her cancer. her initial course at the facility was uncomplicated, and she was able to participate in physical therapy. she had weekly appointments in the oncology clinic and an appointment with the advanced hf team. the propatients (2) . hypotension is typically treated with intravenous fluids to maintain systolic blood pressure >90 mm hg. third-spacing of fluids with capillary leak is common, and this can lead to noncardiogenic pulmonary edema. a single-center retrospective study demonstrated that 12% of patients developed the composite outcome of arrhythmias, decompensated hf, or cardiovascular mortality (3). the cardiac toxicities associated with car t cell therapy have led many centers to view significant cardiovascular disease as a relative contraindication (4). in 2 of the main clinical trials for car t cell therapy in patients with refractory dlbcl, patients were excluded if their lvef was #45% to 50% (4). our team decided to proceed with car t cell therapy in the patient described in this report because of her lack of other comorbidities, preserved performance status, and normal invasive hemodynamics. it was also her only treatment option for refractory dlbcl. the cardiomems device-which is typically used to manage outpatients with hf-was an essential component of our patient's medical treatment (5) . for example, at 2 periods in the patient's hospitalization she was found to have diffuse pulmonary infiltrates, hypoxemia, and hypotension. her pa d was 10 and 23 mm hg the incidence of secondary metastatic tumors to the heart is 22 to 132 times more common than primary malignant tumors, and estimated to be in the range of 0.7% to 3.5% at autopsy series in the general population, and up to 14.0% in patients with known malignancies (5, 6) . the incidence of cardiac metastases has increased over the past decades, likely due to improved life expectancy of oncological patients and advances in diagnosis (5, 6) . the most common primary malignancies metastasizing to the heart include lung cancer, breast cancer, malignant melanoma, germ cell tumors, and hematological malignancies (5-7). the most frequent mode of metastatic spread of scc of the cervix is via the lymphatics to the para-iliac and para-aortic lymph nodes (1). hematogenous spread is unusual and most commonly involves the lungs, bone, liver, and brain (1). cardiac metastases from cervical cancer are exceedingly rare (2) (3) (4) . the vast majority of cases have involved the right heart, presumably due to hematogenous spread of cervical cancer to the inferior vena cava via the uterine veins, coupled with filtration of tumor cells by the lungs. patients with cardiac metastases from cervical cancer present with a myriad of symptoms that depend on tumor location and size, leading to heart failure, arrhythmias, or tamponade (2-4). many cases were diagnosed postmortem. antemortem diagnosis was usually achieved by multimodality imaging including transthoracic and transesophageal echocardiography, ct angiography of the heart, cmr, and 18 f-fdg pet/ct (2-7). tissue diagnosis should be pursued for prognostic implications and optimizing treatment, but may not be feasible. our patient had no symptoms related to the cardiac metastasis. the tumor was discovered by 18 f-fdg pet/ct during the process of initial clinical staging of the disease. 18 f-fdg pet/ct is a particularly useful imaging modality in this setting. together with cmr for detailed tumor characterization, these imaging modalities provide a comprehensive assessment of disease status that is essential for optimal shared decision making (6, 7) . the median survival of patients diagnosed with cardiac metastasis from cervical cancer is 4 months (0 to 13 months) (2) (3) (4) . the management of these patients should be individualized and discussed within a dedicated multidisciplinary tumor heart team (5-7). a multimodality treatment strategy including chemoradiation, biological therapy, and surgery is necessary to prolong survival and maintain quality of life. in this regard, in a prospective randomized trial, bevacizumab has been shown to improve survival when added to the commonly used platinum-paclitaxel and topotecan-paclitaxel chemotherapy regimens (8) . of note, treatment with bevacizumab has been shown to be associated with increased incidence of adverse cardiovascular side-effects such as uncontrolled hypertension, thromboembolism, cardiac ischemia, and heart failure (8) . the decrease in lvef in our patient occurred immediately after resection and remained stable, and our patient did not have severe cardiac limitations during follow-up. her low lvef was readily managed with cardiac medications. near-complete resection of the interventricular septum via a right ventriculotomy parallel to the interventricular septum. reconstruction of the septum using a bovine pericardial patch (asterisk) sewn into the left ventricular side of the septum. lad ¼ left anterior descending coronary artery; other abbreviations as in figure 1 . surgical resection should be considered for isolated cardiac metastasis in patients with favorable response to initial therapy and in whom complete resection is deemed feasible (2-7). our patient had excellent response of the disease in the cervix and of the single pelvic bone metastasis with no evidence of new disease, with the exception of the cardiac metastasis, which remained metabolically active. this is not an infrequent clinical phenomenon in patients with primary or secondary malignant tumors of the heart (7), presumably due to differential response of the tumor to cancer therapy in different tissue environments (9) . given the patient's young age, good functional status, imaging suggesting feasibility of complete resection, as well as lack of an alternative effective treatment, we proceeded with surgery followed by intensive chemoradiation and bevacizumab with curative intent. although the pathological examination in our case did not reveal residual tumor in the tissue specimen, surgical resection had an important impact on the design of her concurrent therapy and prognosis. the local recurrence supports the presence of tumor and findings of the pre-operative 18 f-fdg pet/ct, highlighting the potential for false-negative tumor histological examinations following neoadjuvant chemotherapy (10) . the radiological evidence of local recurrence in the area of slim resection margins-the basal-posterior septum-underscores the technical challenge of achieving complete r0 resection with clean margins when treating primary or secondary malignant tumors of the heart (6,7). in summary, cardiac metastases from cervical cancer should be included in the differential diagnosis of secondary malignant tumors of the heart. we believe that the patient-specific, multimodality management with curative intent strategized and delivered by an experienced and dedicated multidisciplinary team was key to achieving exceptional survival in our patient. twitter: @ayeletdaniels. distribution in the basal inferolateral and anterolateral free wall of the left ventricle. the etiology of this scar was unclear because the patient had no prior cardiac history, and to our knowledge, ibrutinib had not been known to be associated with myocardial scar. no abnormality was noted in the right ventricular apical region, which was the likely origin of his va. initially, the patient was managed with intravenous amiodarone for recurrent vt. after extensive multidisciplinary discussions among cardiology, electrophysiology and oncology teams, ibrutinib was discontinued due to its potential association with vt. the patient was started on metoprolol, and an implantable cardioverter-defibrillator (icd) was placed for secondary prevention. in terms of af, his cha 2 ds 2 -vasc score was 1, and anticoagulation was deferred, particularly given the potential bleeding risks with ibrutinib (1). although it remained uncertain if ibrutinib played an integral role in the pathophysiology of vt, the medication was discontinued with close outpatient cardiology and oncology follow-up. because he had been in remission for several years, he was not started on alternative therapy for wm. on follow-up visits with close surveillance every 3 months with cbc, comprehensive metabolic panel, and igm levels, he continued to be without evidence of symptomatic cytopenias, hyperviscosity, hepatosplenomegaly, lymphadenopathy, neuropathy, amyloidosis, cryoglobulinemia, or cold agglutinemia and did not meet criteria for reinitiation of therapy. on icd interrogation at 3 months after cessation of ibrutinib, there were no further arrhythmias. ibrutinib is an oral, irreversible bruton's tyrosine kinase inhibitor used to treat a broad spectrum of b-cell proliferative disorders, including chronic lymphocytic leukemia (cll) as first-line therapy, mantle cell lymphoma, marginal zone lymphoma, and wm (2) . cardiovascular toxicities associated with ibrutinib are the association of ibrutinib with vas is becoming increasingly recognized (3, 5, 6) . in randomized controlled trials, the incidence of all-grade vas in patients treated with ibrutinib (n ¼ 1,157) compared with patients in the control arm (n ¼ 958) was 1.0% versus 0.4%, and for grade 3 or greater vas was 0.3% versus 0% (7). in analyses from a u.s.-based comprehensive cancer registry cohort, male sex, previous af, hf, coronary artery disease, diabetes, widened qrs, and valvular disease were associated with the development of any arrhythmias (va and supraventricular tachyarrhythmias) (6). among those without baseline hf or coronary artery disease, the estimated 100,000 person-year incidence rate for vas was 596 compared with 48.1 among similar nonibrutinibtreated subjects, which suggested an observed versus expected relative risk of 12.4 (p < 0.001). regarding drug dosage, in 1 study in which approximately 80% of the patients experienced vas, 91% were taking at least 420 mg of ibrutinib per day, and only 9% were taking 280 mg or lower per day (3). among those with ibrutinibassociated vas, the median time-to-event was 16 months (range 0.7 to 57.6 months) (6). ibrutinib has been reported to cause polymorphic vt without qtc prolongation as well as in the absence of structural heart disease (8, 9) . tomcsányi et al. (9) reported the case of a 74-year-old woman on ibrutinib for cll with underlying left bundle branch block and af who experienced ibrutinib-induced polymorphic vt in the absence of other causes (9) . the initiation of vt was not characterized by short-long-short cycles as is seen in torsade de pointes. in polymorphic vt not related to prolonged qt, an alteration in the cardiac calcium homeostasis associated with ryanodine receptor-calmodulin-dependent protein kinase pathways is suspected. as such, it has been hypothesized that an interaction between these and pi3k-akt pathways could potentially lead to polymorphic vt with ibrutinib (3). although the awareness of ibrutinib-associated va is increasing, there are no published management guidelines. our patient was initially treated with amiodarone, then started on a beta-blocker. in the case described by tomcsányi et al. (9) , the patient was treated with amiodarone and remained arrhythmia-free for 4 months. amiodarone was thereafter discontinued due to pulmonary toxicity, and discontinuation led to the recurrence of vt. sotalol was found to be ineffective, as were class i antiarrhythmic agents (9) . as ibrutinib is primarily metabolized by hepatic cytochrome p450 3a4 (cyp3a4), caution must be exercised when used in combination with amiodarone and the calcium-channel blockers diltiazem and verapamil, given that they inhibit cyp3a4 and potentially result in increased serum levels of ibrutinib (7) . amiodarone may increase the plasma concentration of ibrutinib by 6-to 9-fold (1). ibrutinib interruption or dose adjustment may be appropriate prior to the initiation of amiodarone. furthermore, the class ia antiarrhythmic quinidine and the beta-blockers carvedilol and nadolol also interact with ibrutinib, increasing the serum concentrations of the antiarrhythmic drugs (7) . according to the ibrutinib package insert, ibrutinib interruption is recommended for any nonhematological toxicity that is grade 3 or greater. once the toxicity has resolved to grade 1 or baseline, ibrutinib may be reintroduced at a low dose (7) . for severe or refractory arrhythmias, such as seen in our patient, drug discontinuation may be necessary. in general, icd implantation is recommended for the secondary prevention of sudden cardiac death due to life-threatening vt/ventricular fibrillation in patients in whom a completely reversible cause cannot be identified (10) . our patient had hemodynamically unstable vt episodes requiring resuscitation, and although ibrutinib was felt to be the culprit, the presence of delayed enhancement on cardiac magnetic resonance imaging made it difficult to rule out underlying structural heart disease, such as an infiltrative cardiomyopathy. additionally, an icd is indicated if it is expected to improve overall mortality. because our patient's long-term prognosis from wm was favorable, it was felt that he would benefit from an icd, particularly because ibrutinib or another therapy could be indicated in the future. in patients with cancer whose overall prognosis is poor (i.e., low expectation of survival with an acceptable functional status beyond 1 year), icd therapy is not recommended. as ibrutinib is often used in patients with cll whose prognosis is generally favorable, icds for secondary prevention have a potential for long-term benefit. an additional advantage of an icd is providing prognostic parameters, such as the burden of atrial arrhythmia, nonsustained vt, and treated episodes of vt/ ventricular fibrillation, which could help to risk-stratify patients in the future prior to reintroduction of potentially cardiotoxic drugs. ibrutinib is a bruton's tyrosine kinase inhibitor associated with a well-known side effect of af. reported cases of vas associated with ibrutinib are rare. we present a case of vt storm in a patient receiving ibrutinib for wm. as the recognition of ibrutinib-associated vas is increasing, more data are needed to guide best management strategies for vas triggered by ibrutinib. the following clinical scenarios focused on cancer prevention highlight the value of systematic cardiovascular risk assessment in individuals at high risk of cancer who are treated with cancer risk-reducing therapies. recommendations regarding the evaluation of lipid abnormalities and the role of coronary artery calcium (cac) scan are provided, balancing existing evidence with the need for rigorous data that specifically applies to cancer populations. in terms of additional potential cardiovascular risk factors, brca1 has been implicated in the repair of dna double-stranded breaks, and its loss-of-function is associated with reduced cardiac performance and accelerated cardiomyocyte death in murine models. human studies investigating the association between brca1/2 mutations and incident cardiovascular disease (cvd) have shown conflicting results, potentially due to variable sample sizes and ethnic-specific differences in the pathogenesis of cvd (1). bilateral prophylactic oophorectomy is associated with a 96% reduction in the risk of epithelial ovarian cancer in brca1/2 mutation carriers. in women younger than 45 years of age, the risk of cardiovascular death after surgical oophorectomy is 44% higher than that of healthy control subjects (2) . premature menopause was shown to predict future coronary heart disease and stroke in the mesa (multi-ethnic study of atherosclerosis) cohort and represents an important risk-enhancing factor (3). the patient has a borderline-range (5% to 7.4%) estimated ascvd risk in the presence of a risk-enhancing factor, namely premature menopause. given this, we would advocate for a discussion regarding initiation of moderate-intensity statin therapy. however, the patient has expressed a preference to avoid taking additional medications. in this case, a cac scan could help refine ascvd risk assessment (4) . an agatston score of $100 and/or a cac score $75th percentile for the patient's age, sex, and race would suggest a benefit to statin initiation, although there are no randomized clinical trial data supporting the use of cac in treatment decisions. a cac score of 300 would increase this patient's 10-year coronary heart disease risk to 10% using the mesa risk score calculator, and would further support the use of lipid-lowering therapy. nicotine cessation should be a primary strategy to reduce cvd risk in this patient, while the importance of healthy lifestyle habits, normal-range blood pressure and lipid profile, weight loss, and glycemic control should also be emphasized. aspirin and sulindac are commonly used, contemporary pharmacoprophylactic therapies in patients who are at high risk of colorectal cancer, with the former being the preferred drug for individuals with sporadic adenomas and the latter for those with fap. in the late 1990s, celecoxib was approved for use in patients with fap. the risk-reduction benefit appeared to be significant with a 31% lower colorectal polyp burden rate in fap patients treated with celecoxib and a 15% lower incidence of duodenal polyps. however, in a large study of colorectal adenoma prevention, long-term use of celecoxib (200 or 400 mg twice daily) was associated with a 3.4-fold increased risk of death from cvd, myocardial infarction, stroke, or heart failure (5). in addition, a meta-analysis of randomized controlled trials showed that celecoxib use was associated with a 3-fold increased risk of myocardial infarction. a subsequent prospective investigation, assessing the safety of a lower dose of celecoxib (200 mg daily), did not demonstrate a statistically significant hazard; as such, the cardiovascular risk mediated by celecoxib remains incompletely understood (6) . in 2004, due to high cardiovascular event rates, rofecoxib was removed from the market, and a black-box warning was issued for celecoxib the following year. this patient is in an intermediate-risk ascvd category, but has 2 additional factors that increase his likelihood of future cardiovascular events: chronic nonsteroidal anti-inflammatory drug (nsaid) use and a strong family history of premature ascvd. importantly, the presence of diabetes mellitus in an individual 40 to 75 years of age is an indication for the use of moderate-intensity statins regardless of ascvd score, and in an individual it is important to understand that patients with fap who are treated with preventive total colectomy have favorable long-term survival outcomes. the notion that cvd represents an important competing risk to cancer mortality should be conveyed and serve as a motivating factor to introduce lifestyle changes and consideration of pharmacological therapies. consideration of chronic nsaid initiation in this patient, especially in the context of conventional cardiovascular risk factors, should prompt referral to an internist or cardiologist. numerous risk-reducing interventions are utilized by cardiologists and oncologists in patients at risk of developing cardiovascular disease or cancer. some therapies used to lower the incidence of cancer in individuals at increased risk for malignancy (e.g., prophylactic bilateral oophorectomy in carriers of brca1/2 mutations, sulindac in patients with familial adenomatous polyposis) may potentially increase the risk of cardiovascular disease. consideration of such interventions, particularly in individuals with coexisting cardiovascular risk factors or comorbidities, should prompt referral to cardiology for careful risk assessment and modification that integrates traditional risk factors and the effects of cancer risk-reducing therapies. ascvd ¼ atherosclerotic cardiovascular disease; cv ¼ cardiovascular; nsaid ¼ nonsteroidal antiinflammatory drug. importantly, decisions regarding long-term nsaid therapy should balance the reduced polyp and potential colorectal cancer rate with the increased cvd risk. attainment of optimal blood pressure and glycemic control should be targeted. in addition, a cac scan could be considered. if highly abnormal, it could be used to counsel and motivate this patient to further modify his lifestyle (4) . it would also be reasonable to check a lipoprotein(a) level given the strong family history of premature atherosclerosis. due to the expected long-term use of sulindac, statin therapy and improved lifestyle habits would be appropriate risk-reduction interventions in this case. cardiovascular risk assessment in individuals who are deemed to be at high risk for cancer is distinct from that in patients with an established cancer. specific therapies aimed at reducing the risk of cancer may augment cardiovascular risk and deserve careful consideration. two important tenets of cardiovascular risk assessment include evaluation of lipid abnormalities and understanding the role of cac imaging in refining ascvd risk stratification in this unique population. although more research is needed regarding the value of cac burden in patients with cancer, available evidence suggests that elevated cac scores are predictive of both future cardiovascular events and cancer. in a recent study, cac >300, when compared with a score of 0, was associated with a 3.7-fold increase in the risk of cv death and a 30% increase in the risk of cancer death (7). the most common cause of death among individuals with 0 cac was cancer (50%), whereas patients with cac >300 experienced most of the mortality due to cvd. in a study of 464 patients with locally-advanced nonsmall-cell lung cancer treated with thoracic radiation therapy, an increased cac score, measured from planning radiation therapy computed tomography, was associated with an elevated risk of all-cause mortality (hazard ratio: 1.29; confidence interval: 1.0 to 1.6; p ¼ 0.027) (8) . in a separate analysis of breast cancer patients who had received radiation therapy, higher pre-rt cac scores were associated with a higher likelihood of acute coronary syndrome at 9 years of follow-up (hazard ratio: 1.42; confidence interval: 0.49 to 4.17; p ¼ 0.519) (9) . coronary calcification is therefore a predictor of cvd in the cancer population and further research is needed to better characterize the contribution of cause-specific mortality and cardiovascular events in cancer patients according to cac levels (10) . last, breast arterial calcifications detected on screening mammogram are an independent marker for the presence of coronary artery disease and may help identify women at higher risk of ascvd. lipid-lowering therapies should be considered in patients with cardiovascular risk factors or disease, as per the standard ascvd risk score. particular medical interventions to decrease the risk of cancer, such as prophylactic oophorectomy or long-term nonsteroidal anti-inflammatory drugs, may increase the risk of ascvd and should be regarded as deleterious factors. in the coming decade, cardio-oncologists may be asked to assess and manage cardiovascular toxicities in individuals who receive cancer risk-reducing interventions but who are free of cancer. given the increasing data supporting an overlap between the molecular and clinical underpinnings of cancer and heart disease, oncologists should consider involving their cardiovascular medicine colleagues for risk assessment and preemptive management. in addition, longitudinal cardiovascular safety evaluations of specific patient subgroups in whom prophylactic anticancer therapies are considered should be performed to provide an evidence-based understanding of the risks and benefits of such therapies. cardiotoxic risk (13) (14) (15) (16) ; and the intersection between cardiovascular disease and cancer in our patients (17) (18) (19) . in the second quarter of 2020 alone, we had nearly 130,000 article usage sessions, and each quarter, this number has grown. the work of our authors is being read for utilization in clinical practice and research, which is always the most important metric for a jacc journal. as a physician scientist, i recognize that the choice of "which journal" is not an easy one and requires careful consideration. we remain committed to serving our authors and working tirelessly to ensure that the peer review process is respectful, fair, constructive, and as seamless as possible. our average time to first decision in second quarter 2020 was 15 days, and we will strive to maintain this standard. we seek to partner and work collaboratively with our authors to ensure the highest quality contribution to our community. i am grateful to the reviewers, who provide timely, incisive insight and lend their valued expertise to help ensure the quality of our journal. we have had nearly 300 peer reviewers contribute their evaluaover the next year, we will improve access to jacc: cardiooncology through additional platform changes to improve searchability and integration across the jacc journals. clinical, translational, and basic science original research manuscripts will continue to serve as our foundation. as we evaluate each manuscript, we will continue to ask ourselves the following key questions: are the findings valid? is the methodology rigorous? is the topic of clinical importance? are the findings incremental to our current understanding of the topic and do they fulfill an evidence gap? what is the potential clinical impact and the potential for advancing the field? we will continue to publish state-of-the-art reviews and primers, and similarly ask ourselves: is this an authoritative, critical appraisal of the literature? is it comprehensive, yet focused? is this data-driven and accurately reflective of the current evidence? we will look to clinical case challenges to provide evidence-based descriptions of unique cases that thoughtfully illustrate the diagnostic and therapeutic dilemmas that we as clinicians face as we care for our patients (20) . our viewpoints will continue to express opinion pieces on important and timely topics, and present thought-provoking, community-building, evidence-based perspectives. we will continue to grow our international engagement events, podcasts, live journal clubs, and dynamic case presentations, each occurring at least once per quarter. we also will launch a new "how to" series that will offer practical, evidence oncologists primarily consulted general cardiology (58%), as compared with cardio-oncology (38%) for evaluation of treatment-related cardiotoxicity. overall, a lack of awareness (63%) and lack of and education in the growing field of cardiooncology. considering these respondents likely represented a more engaged group of practitioners, there was a lack of general cardio-oncology knowledge, uncertainty of local available resources, and low reported rate of cooperation between cardiologists and oncologists. although we were not able to assess the reasoning for these observed practice patterns, as it was beyond the scope of this study, enhanced collaboration between disciplines will be important and necessary to deliver optimal cardiovascular and oncologic care to this patient group. previous studies indicate that approaches vary between cardiologists and oncologists when using cardio-oncology services for the treatment of patients with cancer. peng et al. (7) reported that most cardiologists (55%) felt that they should monitor for cardiotoxicity even in the absence of symptoms. however, the same study indicated that only 12.5% of oncologists shared this view. furthermore, 50% of oncologists felt that cardiologists should be involved only when patients developed cardiotoxicities, but only 6.5% of cardiologists agreed with that opinion. most cardiologists believed that access to cardiooncology services would improve prognosis (88.3%), whereas only 45.8% of oncologists shared this view. our study did not directly address this same question, but found that only 38% of oncologists and 34% of cardiologists indicated that they felt "very comfortable" interacting with their colleagues for comanagement of cancer and heart disease. sadlerd@ccf.org. twitter: @dsadlermd, @floridaacc, @flasco_org, @accintouch, @dr_mike_fradley, @dr_roohikhan. transthyretin amyloid cardiomyopathy: jacc state-of-the-art review natural his a new staging system for cardiac transthyretin amyloidosis cardiovascular disease mortality after chemotherapy or surgery for testicular nonseminoma: a populationbased study testicular cancer: a mechanisms of cisplatin nephrotoxicity white-paper-1.pdf a new equation to estimate glomerular filtration rate crosstalk between vascular redox and calcium signaling in hypertension involves trpm2 (transient receptor potential melastatin 2) cation channel marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers: smoking, thrombin, and vascular responses in vivo intra-arterial substance p mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans vascular effects of apelin in vivo in man the vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension fire simulation and cardiovascular health in firefighters vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro antiangiointravascular ultrasound imaging for coronary thrombosis after cisplatin-based chemotherapy caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis arterial events in cancer patients-the case of acute coronary thrombosis vascular toxic effects of cancer therapies treatmentrelated cardiovascular toxicity in long-term survivors of testicular cancer comprehensive characterisation of the vascular effects of cisplatin-based chemotherapy in patients with testicular cancer impact of platinum-based chemotherapy on the progression of atherosclerosis vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy cardiovascular risk in long-term survivors of testicular cancer long-term platinum retention after platinumbased chemotherapy in testicular cancer survivors: a 20-year follow-up study hematopoietic stem cell transplantation in europe 2014: more than 40 000 transplants annually reduced mortality after allogeneic hematopoietic-cell transplantation late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the bone marrow transplant survivor study vascular endothelium as 'novel' target of graft-versus-host disease pericarditis in patients with chronic graft-vs-host disease national institutes of health hematopoietic cell transplantation late effects initiative: the cardiovascular disease and associated risk factors working group report prevalence of outpatient cancer treatment in the united states: estimates from the medical panel expenditures survey (mpes) chemotherapy-induced cardiotoxicity: detection, prevention, and management long-term chemotherapy-related cardiovascular morbidity cardiovascular disease in adult survivors of childhood cancer epirubicin versus doxorubicin: which is the anthracycline of choice for the treatment of breast cancer? gp91phox-containing nad(p)h oxidase increases superoxide formation by doxorubicin and nadph enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin redox cycling of anthracyclines by cardiac mitochondria. i. anthracycline radical formation by nadh dehydrogenase adriamycin-induced interference with cardiac mitochondrial calcium homeostasis cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin role of endothelium in doxorubicin-induced cardiomyopathy a critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib glabridin prevents doxorubicin-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice vegf-b gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection endothelial function in young adult survivors of childhood acute lymphoblastic leukemia cellular senescence promotes adverse effects of chemotherapy and cancer relapse mitochondria-targeted antioxidant (mitoq) ameliorates age-related arterial endothelial dysfunction in mice sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens shortterm interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle oxidant stress and endothelial cell dysfunction redox regulation of mitochondrial function increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a p-glycoprotein redox homeostasis and antioxidant signaling: a metabolic interface between stress perception and physiological responses innovative medicine: basic research and development antioxidants and cancer prevention antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy endothelial nitric oxide synthase-dependent superoxide generation from adriamycin doxorubicin accumulation in individually electrophoresed organelles doxorubicin induces endotheliotoxicity and mitochondrial dysfunction manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase mechanism of guanine-specific dna damage by oxidative stress and its role in carcinogenesis and aging nuclear factor-{kappa}b activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans chronic supplementation with a mitochondrial antioxidant (mitoq) improves vascular function in healthy older adults the mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase ii study of hepatitis c patients a double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant mitoq as a disease-modifying therapy in parkinson's disease vitamin c mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy protective effects of mito-tempo against doxorubicin cardiotoxicity in mice doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by mito-q. biophys the role of endothelins and their receptors in heart failure plasma endothelin-1 and doxorubicin cardiotoxicity plasma endothelin-1 as a marker for doxorubicin cardiotoxicity doxorubicin-induced oxidative stress and endothelial dysfunction in conduit arteries is prevented by mitochondrial-specific antioxidant treatment coenzyme q10 for prevention of anthracycline-induced cardiotoxicity anthracycline causes impaired ventricular-arterial coupling in breast cancer patients after treatment with anthracycline-containing adjuvant chemotherapy serum cardiovascular growth factors during doxorubicin chemotherapy in children with leukemia circulating neuregulin during the transition from stage a to stage b/c heart failure in a breast cancer cohort cardiac endothelial cells regulate ros-induced cardiomyocyte apoptosis through neuregulin-1beta/ erbb4 signaling neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbb4-dependent activation of pi3-kinase/akt endothelial cells regulate physiological cardiomyocyte growth via vegfr2-mediated paracrine signaling protective mechanisms of coenzyme-q10 may involve up-regulation of testicular p-glycoprotein in doxorubicin-induced toxicity reno-protective efficiency of coenzyme q10 on adriamycin-induced nephrotoxicity fundamental mechanisms of immune checkpoint blockade therapy immune checkpoint blockade therapy for cancer: an overview of fda-approved immune checkpoint inhibitors immunerelated adverse events associated with immune checkpoint blockade fulminant myocarditis with combination immune checkpoint blockade cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study immune checkpoint inhibitors-related cardiotoxicity cardiotoxicity associated with ctla4 and pd1 blocking immunotherapy cardiotoxicity of immune checkpoint inhibitors association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study risk factors for immune-related adverse events associated with anti-pd-1 pembrolizumab healthy north carolina 2020: social determinants of health indicators 10 inflammatory signature difference in rural urban and regional occupational exposure in lung cancer current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european society of cardiology working group on myocardial and pericardial diseases myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology what is the normal value of the neutrophil-to-lymphocyte ratio? immune checkpoint inhibitor-related adverse cardiovascular events in patients with lung cancer tocilizumab for the management of immune mediated adverse events secondary to pd-1 blockade myocarditis in patients treated with immune checkpoint inhibitors influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients prognostic value of troponin t in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy cardiovascular events among adults treated with chimeric antigen receptor t-cells (car-t) car t cell-induced cytokine release syndrome is mediated by macrophages and abated by il-1 blockade vinten-johansen j. involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury impairment of the pd-1 pathway increases atherosclerotic lesion development and inflammation proatherogenic immune responses are regulated by the pd-1/pd-l pathway in mice ctla4-igg ameliorates homocysteine-accelerated atherosclerosis by inhibiting t-cell overactivation in apoe-/-mice impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer trends in stage distribution for patients with nonsmall cell lung cancer: a national cancer database survey pembrolizumab versus chemotherapy for pd-l1-positive non-small-cell lung cancer cardiovascular toxicities associated with immune checkpoint inhibitors fulminant myocarditis with combination immune checkpoint blockade improved survival with ipilimumab in patients with metastatic melanoma nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma cardiovascular toxic effects of targeted cancer therapies management of cardiac disease in cancer patients throughout oncological treatment: esmo consensus recommendations characterization of immune checkpoint inhibitor-related cardiotoxicity in lung cancer patients from a rural setting grounding cardio-oncology in basic and clinical science acc/aha key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the american college of cardiology/american heart association task force on clinical data standards (writing committee to develop cardiovascular endpoints data standards) myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology pd-1 modulates radiation-induced cardiac toxicity through cytotoxic t lymphocytes cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study key words immune checkpoint inhibitors, inflammatory markers, myocarditis, neutrophil-tolymphocyte ratio management and outcomes of severe aortic stenosis in cancer patients healthcare cost and utilization project (hcup) aha/acc focused update of the 2014 aha/acc guideline for the management of patients with valvular heart disease: a report of the american college of cardiology/american heart association task force on clinical practice guidelines transcatheter aortic valve replacement in oncology patients with severe aortic stenosis cardiac complications of thoracic irradiation roadmap for biomarkers of cancer therapy cardiotoxicity early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy for breast cancer, lung cancer, and lymphoma normalization of ejection fraction in subjects with systolic heart failure. is it really normal? a myocardial deformation study assessment of early radiation-induced changes in left ventricular function by myocardial strain imaging after breast radiation therapy late-onset giant cell myocarditis due to enterovirus during treatment with immune checkpoint inhibitors i mmune checkpoint inhibitor (ici) therapy has significantly improved the prognosis of many advanced cancers cardiovascular adverse effects such as myocarditis are uncommon, but bear high mortality rates of nearly 50% (2). ici myocarditis typically occurs early, and potential factors associated with ici myocarditis are combination therapy however, the clinical presentation of ici myocarditis is heterogeneous, with preserved left ventricular ejection fraction in one-half of the cases, and high rates of conduction abnormalities and ventricular arrhythmias (3). ici myocarditis can also occur late, although notably, there is limited information on late-onset myocarditis with long-term ici therapy a 57-year-old male patient presented with myalgias and dyspnea after the 27th course of 2nd-line ici monotherapy (nivolumab [anti-pd-1] 3 mg/kg every 3 weeks) for metastatic renal cell carcinoma. the electrocardiogram showed sinus tachycardia, low qrs voltage, and t-wave inversion in the anterior leads with no st-segment changes. cardiac biomarkers were elevated (troponin i 4,700 ng/l, b-type natriuretic peptide 466 ng/l). left heart catheterization revealed normal coronary arteries. cardiac magnetic resonance issn cardiovascular imaging the authors attest they are in compliance with human studies committees and animal welfare regulations of the authors fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study clinical features, management, and outcomes of immune checkpoint inhibitorrelated cardiotoxicity myocarditis in patients treated with immune checkpoint inhibitors fulminant myocarditis with combination immune checkpoint blockade fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab aberrant pd-1 ligand expression contributes to the myocardial inflammatory injury caused by coxsackievirus b infection myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy report a 66-year-old woman with advanced diffuse large b-cell lymphoma (dlbcl) was referred for chimeric antigen receptor (car) t cell therapy. she was diagnosed with dlbcl 6 years prior to presentation and had no significant past medical history. she received a total of 10 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (r-chop), with a lifetime exposure of doxorubicin >500 mg/m 2 . she underwent an autologous hematopoietic stem cell four years later, her dlbcl recurred, requiring 6 more cycles of r-chop. one month after she completed the last cycle, her transthoracic echocardiogram (tte) demonstrated a left ventricular ejection fraction (lvef) of 55% to 60% and global longitudinal strain of à12% (normal: à19% to à22%). two months following therapy, she was admitted to the hospital with acute decompensated heart failure (hf) coronary computed tomography demonstrated mild coronary artery disease, and cardiac magnetic resonance imaging showed no evidence of infiltrative or inflammatory disease. she was presumed to have anthracycline-induced cardiomyopathy and was initiated on furosemide and guideline-directed medical therapy (gdmt), including lisinopril 2.5 mg and metoprolol succinate 12.5 mg daily. up-titration of gdmt was limited, and spironolactone or eplerenone could not be added, secondary to hypotension. she was referred to a cardio-oncologist for risk stratification prior to car t cell therapy. she had good exercise tolerance, riding a stationary bike for 10 to 15 min at a time. a right heart catheterization (rhc) demonstrated mildly elevated biventricular filling pressures with normal cardiac output (right atrium 10 mm hg, pulmonary artery 36/20/27 mm hg it was felt that car t cell therapy was her only therapeutic option. multidisciplinary discussions between her hematologist/oncologist, cardio-oncologist, and advanced hf team were held to determine feasibility. derangements in blood pressure and oxygenation, ranging from mild hypotension and hypoxemia to issn dr. bishop has received nonfinancial support from articulatescience llc; and has received personal fees from united healthcare, seattle genetics, celgene, juno therapeutics, novartis, crispr therapeutics, kite pharma, and pharmacyclics. dr. uriel has received grant support from abbott the authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and food and drug administration guidelines, including patient consent where appropriate. for more information chimeric antigen receptor t-cell therapies for lymphoma chimeric antigen receptor t-cell therapy for cancer and heart: jacc council perspectives cardiovascular events among adults treated with chimeric antigen receptor t-cells (car-t) yakoub-agha i. an international survey on the management of patients receiving car t cell therapy for haematological malignancies on behalf of the chronic malignancies working party of ebmt design and rationale of haemodynamic guidance with cardiomems in patients with a left ventricular assist device: the hemo-vad pilot study advances in diagnosis and treatment of metastatic cervical cancer cardiac metastasis in cervical cancer a rare case of cardiac metastatic mass case report of cardiac metastasis from cervical squamous carcinoma and its literature review tumors metastatic to the heart cardiac tumors: jacc cardiooncology state-ofthe-art review surgery for tumors of the heart improved survival with bevacizumab in advanced cervical cancer differential growth and responsiveness to cancer therapy of tumor cells in different environments akim@uchc.edu. twitter: @agnesskim2, @hmadgula ibrutinibassociated atrial fibrillation ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia cardiovascular toxicities associated with ibrutinib the risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis ventricular arrhythmias and sudden death in patients taking ibrutinib ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies highlights of prescribing information ibrutinib, an approved tyrosine kinase inhibitor as a potential cause of recurrent polymorphic ventricular tachycardia ventricular tachycardia caused by ibrutinib dr. kopecky has served as a consultant for prime therapeutics; has received research support from true health; has served as data safety and monitoring board chair for applied clinical intelligence; has served as a board member for mayo clinic support services; and has served as a task force member for mayo clinic cv p&t. dr. gersh has served as cro for trials involving edwards percutaneous valve devices through baim institute; has served on the dsmb for the reprise study ); has served as a general consultant for myokardia; and has served on the steering committee of the garfield study (thrombosis research institute) risk of cardiovascular disease in women with brca1 and brca2 mutations increased cardiovascular mortality after early bilateral oophorectomy early menopause predicts future coronary heart disease and stroke: the multi ethnic study of atherosclerosis association of coronary artery calcium in adults aged 32 to 46 years with incident coronary heart disease and death cardiovascular risk associated with cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis coronary artery calcium and the competing long-term risk of cardiovascular vs. cancer mortality: the cac consortium elevated coronary artery calcium quantified by a deep learning model from radiotherapy planning scans predicts mortality in lung cancer is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy? breast arterial calcium: a game changer in women's cardiovascular health? jacc: cardiooncology: poised to serve a maturing, collaborative field proceedings from the global cardio-oncology summit jacc: cardiooncology videos resiliency and our cardio-oncology community the novel coronavirus disease (covid-19) threat for patients with cardiovascular disease and cancer covid-19 clinical trials: a primer for the cardiovascular and cardiooncology communities al amyloidosis for the cardiologist and oncologist efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy safety of continuing trastuzumab despite mild cardiotoxicity: a phase i trial efficacy of dexrazoxane in preventing anthracycline cardiotoxicity in breast cancer repeated remote ischemic conditioning reduces doxorubicin-induced cardiotoxicity osimertinib-induced cardiotoxicity: a retrospective review of the fda adverse events reporting system (faers) increase in blood pressure associated with tyrosine kinase inhibitors targeting vascular endothelial growth factor car t-cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity? cardiovascular safety of degarelix versus leuprolide for advanced prostate cancer: the pronounce trial study design hypertension in cancer patients and survivors: epidemiology, diagnosis, and management increased cancer prevalence in peripartum cardiomyopathy ischemia and bleeding in cancer patients undergoing percutaneous coronary intervention infiltrative lymphoma-associated bradycardia and cardiac conduction abnormalities deaths: leading causes for 2017 the economic burden of chronic cardiovascular disease for major insurers health of patients with cancer and cancer survivors an international survey of healthcare providers' knowledge of cardiac complications of cancer treatments practices in management of cancer treatmentrelated cardiovascular toxicity: a cardio-oncology survey acc multistate chapter cardio oncology network to improve physician participation, awareness, and education in cardio oncology myocardial ischemia: leading the differential diagnosis of polymorphic vt in a 68-year-old man was acute coronary syndrome.heart failure (hf): he did not have symptoms or signs of hyperviscosity syndrome or hf. systemic amyloidosis associated with wm leading to amyloid cardiomyopathy was also considered.drug toxicity: a high index of suspicion was maintained about the potential association between ibrutinib and ventricular arrhythmia (va). electrocardiogram at the time of evaluation by emergency medical services showed af with a ventricular rate of 120 beats/min and nonspecific st/t-wave abnormalities. complete blood count, serum electrolytes, and renal function were within normal limits at the time of admission, and serial serum troponin levels were undetectable. a transthoracic echocardiogram showed normal biventricular size and function with no regional wall motion abnormalities. furthermore, coronary angiography demonstrated very mild luminal irregularities without obstructive disease. in the cardiac intensive care unit, he was noted to have multiple premature ventricular complexes and nonsustained vt with a left bundle branch block morphology and right superior axis, indicating an origin at the right ventricular apex (figure 2 ). he underwent cardiac magnetic resonance imaging, which demonstrated a small area of mid-myocardial delayed enhancement in a nonvascular key: cord-331068-rjc3b4br authors: ritterson, ryan; casagrande, rocco title: basic scholarship in biosafety is critically needed to reduce risk of laboratory accidents date: 2017-03-29 journal: msphere doi: 10.1128/msphere.00010-17 sha: doc_id: 331068 cord_uid: rjc3b4br our firm conducted a risk/benefit assessment of “gain-of-function” research, as part of the deliberative process following a u.s. moratorium on the research (u.s. department of health and human services, u.s. government gain-of-function deliberative process and research funding pause on selected gain-of-function research involving influenza, mers, and sars viruses, 2014). due to significant missing but theoretically acquirable data, our biosafety assessment faced limitations, and we were forced to provide a relative, instead of absolute, measure of risk (gryphon scientific, llc, risk and benefit analysis of gain of function research, 2016). here, we argue that many of these types of missing data represent large and stunning gaps in our knowledge of biosafety and argue that these missing data, once acquired via primary research efforts, would improve biosafety risk assessments and could be incorporated into biosafety practices to reduce risk of accidents. governments invest billions in biological research; at least a small fraction of this support is warranted to prevent biological accidents. i n 2014, the white house issued a moratorium on so-called gain-of-function research involving influenza virus and severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) coronaviruses and initiated a deliberative process to be managed by the national science advisory board for biosecurity (nsabb), a process which recently concluded with the release of the white house office of science and technology policy's (ostp) recommended policy guidance document (1, 2) . in an earlier stage of the process, our firm was contracted by the national institutes of health to perform and deliver a risk/benefit assessment of this research to independently investigate its biosafety and biosecurity risks, as well as the scientific and public health benefits it may bring. as part of our biosafety risk assessment, we were asked to provide a measurement of the absolute risk of a biosafety incident. however, due to significant missing, but theoretically acquirable data, our work faced limitations, and we were forced to provide a relative, instead of absolute, measure of risk (3) . many of these types of missing data represent large and stunning gaps in our knowledge of biosafety. these missing data, once acquired via relatively simple primary research efforts, would not only improve biosafety risk assessments but also could be immediately incorporated into biosafety practices to reduce the risk of accidents. governments invest billions of dollars to support biological research with the purpose of improving the human condition; clearly, at least a small fraction of this support should be used to prevent the biological accidents that imperil that basic goal. to the best of our knowledge, gryphon scientific's biosafety risk assessment was the first to comprehensively consider the probability and types of human error that play a role in laboratory accidents, and we identified it as the dominant component of laboratory biosafety risk. this dominance of human errors is based on multiple factors. first, most plausible pathways to laboratory-acquired infection or accidental release require a human error to precipitate. for example, spills and needlesticks begin with a person making a motor control mistake. second, humans fail more frequently than equipment. for example, in our aerosol release scenarios, the median chance of an exhaust fan failing was estimated to be 1.5 orders of magnitude less likely than the chance of someone improperly responding to an airflow alarm should the fan fail (4). these relative probabilities align with our common sense-most laboratory scientists have likely experienced a simple human error, such as a dropped plate or tube, many times more often than we have experienced random mechanical failures. the last, but perhaps most important contribution of human error to laboratory incidents comes after an incident has already begun: human errors after an exposure, whether due to ignorance, panic, or expediency, can drastically exacerbate the consequences of that event. a laboratory worker who immediately notifies appropriate personnel and follows proper health surveillance and isolation protocols after an exposure is significantly less likely to cause secondary infections, limiting the consequences of the incident. despite the dominance of human error in determining risk, we could find limited data to support a quantitative estimate of human failure rates. publicly available quantitative biosafety risk assessments done by others focused primarily on detailed measurements of equipment and mechanical failure rates, and either omitted a quantitative treatment of human error entirely (5, 6) or used a flat failure rate for all types of errors in all incidents (7) . the available primary data were similarly limited, and we identified only a single source of human error measurements taken directly from biological laboratories (8) . due to these data limitations, we instead analogized the rate of human failures in laboratories to that of similar errors in other industries, primarily aerospace and nuclear power (9) . indeed, in contrast to the life sciences, these other industries invest heavily in the study of human error. for decades, many technical industries have turned to formalized assessments of human performance and mistake rates, termed human reliability assessments (hras) (10, 11) . these hras provide analytical frameworks to rigorously identify the type and frequency of the mistakes humans make, as well as the circumstances in which they are most likely to make them. armed with the knowledge of how and when things may go wrong, risk and safety managers can work to redesign systems and update practices to best prevent common and/or serious mistakes before they occur. these investments are made even though the scale of potential consequences of an accident in the power and transportation industries is dwarfed by the consequences of a global infectious disease outbreak. not only is scholarship lacking on how mistakes may be made, data are not collected on how mistakes have been made either. despite a clear need for keeping these records, the united states has no standardized or comprehensive system for tracking laboratory incidents or near misses in high-containment laboratories. astoundingly, we appear to lack even the most basic knowledge of how many high-containment laboratories are currently in operation (12) . although some partial reporting systems exist (13, 14) , none of these systems are sufficiently standardized, complete, or of high-enough quality and detail to provide usable statistics about the type, magnitude, and kind of incidents that occur in biological laboratories. this lack of centralization and standardization hinders the spread of lessons learned and best practices between laboratories, which likely results in us suffering the same mistakes in multiple laboratories. other industries have discovered that centralized tracking of incidents can significantly reduce risk. in 1974, twa flight 514 crashed outside washington's dulles airport, killing 92 people (15) . during the investigation, it was discovered that a united airlines flight had a near miss due to the same cause just weeks earlier, and although united had alerted its pilots of the danger, the warning did not spread industry-wide. in the wake of the accident, the federal aviation administration (faa) created-and has maintained ever since-a no-fault system of reporting aviation incidents and mistakes, no matter how minor. this reporting correlates with a decrease in risk: airline industry sources show a substantial and continuing decrease in accident rates from 1976 to today (today's rate is about a third of the rate in the early 1970s) (16, 17) . similar measures have been undertaken in the nuclear power and chemical manufacturing sectors, which greatly improve the ability to predict potential accidents and prevent them (18, 19) . although we note that these industries have had decades of additional time and experience beyond that of the relatively new life science industry to advance their state of risk assessment and prevention, we believe that the life sciences industry should strive, over time, to meet the same standards those industries have pioneered. also, although these industries are dominated by a few giant concerns, the fact that the government and a handful of companies are responsible for the large majority of research on dangerous pathogens enables a similarly few number of influential players to effect significant change. the combination of prospective human reliability primary data gathering to assess what might go wrong and historical incident record keeping to assess what did go wrong provides a powerful path to reducing biosafety risk. using these data, laboratory safety practices can be improved, lowering the risk to the researchers and to their surrounding communities. in addition, training, equipment, and safety systems can be redesigned to prevent common mistakes before they happen. beyond these benefits in risk reduction, gathering data on human reliability and biosafety incidents will also support the development of absolute biosafety risk assessments, which is desirable for several reasons. first, biosafety levels can begin to be defined by the maximum risk of an experiment allowable under that safety level, instead of being defined by organism phenotype, ensuring that the riskiest experiments remain tightly protected without unnecessarily burdening others. second, absolute numbers enable comparisons across industries and activities, which contextualizes the level of biosafety risk we are assuming. by making risk less subjective, policy debates can be more focused and targeted. in our experience with the gain-of-function debate, our inability to provide absolute numbers left unresolved questions about the baseline acceptable level of risk, distracting from the policy questions at hand. in sum, gathering these data is achievable and would provide immense benefits. as such, we believe significantly more funding is urgently and immediately needed to support three basic thrusts: (i) development of a national incident reporting system, (ii) primary research programs focused on hras, equipment failures, and decontamination efficiencies, and (iii) sharing of best practices. we believe the reporting system should be structured like the faa's database and should include not only consequential incidents but also reports of near misses, defined as situations that required a response but where no infections or consequences resulted. consequential incidents are often rare outcomes of a series of common mistakes or failures. by reporting near misses that may contain these same common mistakes, the mistakes can be identified and remedies can be put into place prior to the mistakes precipitating high-consequence events. the nsabb's recommendations for overseeing gain-of-function research includeddue to prompting by us and others-a recommendation to create such a database of incidents and near misses, and we strongly agree with their recommendation (20) . ostp's guidance document in response to nsabb's recommendations (2) does not address this data gap, and we fear momentum for the creation of the database is at risk of being lost. creation of such a database is not without challenges. currently, many institutions have expressed reluctance to share information about biosafety incidents, due to fears of how that information may be shared by organizations beyond their control, for example, in the series of articles usa today has published (21, 22) . in addition, some institutions have hesitated to share data on incidents due to a lack of standard definitions of what qualifies as reportable, and no institution wants to be penalized as unsafe for the good deed of overreporting. although daunting, these challenges can-and should-be overcome. one first step would be to identify the largest current disincentives to reporting and potential approaches to removing them. a second step would be building consensus for a complete definition of what should be reportable. we believe efforts to accomplish these steps should be led by the biosafety and research communities, similar to how these same communities led the efforts at asilomar in 1975 to establish biosafety guidelines for work with recombinant dna (23) . to address biosafety knowledge gaps, federal grant funds should be made available for primary research studies. although the federal government does fund biosafety education and training programs, there appears to be little spending on quantitative studies of laboratory biosafety practices and accidents, despite a national institute of allergy and infectious disease (niaid) operating budget of $4.7 billion in fiscal year 2016 (24) . we note that a new annual allocation of a mere 1/10th of 1% of that number-$5 million per year-set aside for biosafety research and tracking could make significant strides to cover these gaps and greatly increase our ability to predict and prevent accidents. the funding for investigations of accidents and research into their causes by agencies whose primary mission is safety in the transportation (nearly $1 billion, via the national transportation safety board [ntsb] and national highway traffic safety administration [nhtsa]) and nuclear and chemical industries (more than $1 billion via the nuclear regulatory commission [nrc] and chemical safety board [csb]) demonstrates that the united states has already recognized the importance of these types of studies. in addition to studies investigating human reliability, applied, laboratory-based studies should also be conducted to gather additional data about failures due to mechanical systems or decontamination protocols. given the recent widespread attention on failures of inactivation protocols (25, 26) , learning how these protocols fail will also enhance safety and our ability to ascertain risk. finally, although failure rates for many types of personal protective equipment (ppe) are known, many kinds of data are still lacking. primary research in this area would be straightforward and would additionally improve biosafety risk assessments. although incident recordkeeping and human reliability are the two largest and most urgent areas, other areas of biosafety research have also suffered due to a lack of funding. in our experience visiting laboratories undertaking gain-of-function research, we noted some institutions maintained a strong safety culture that likely played a significant role in reducing the risk of accident in these labs. yet, how to create this culture and the effect it has on overall safety remain understudied. in addition, we noted that some labs put into place some unique best practices, such as maintaining a separate entrance at the designated local clinic for potentially exposed laboratory personnel, limiting public exposure, yet these practices were not widely known or shared within the biosafety community. funding for collection and dissemination of these best practices is sorely needed, would be relatively modest, and would have a nearly immediate return on investment. federal, state, and local governments, educational institutions, and industry participants do commit significant resources to biosafety and biorisk management, through biosafety officers, institutional biosafety committees, the biosafety in microbiological and biomedical laboratories manual (27) , and a host of risk assessment practices, polices, and reporting requirements. these efforts play a critical role in ensuring that biological research is conducted safely. however, despite these efforts, large gaps in our knowledge on how accidents did and could occur in laboratories still exist, and this fact is surprising and inexcusable, given that an accident in a biological laboratory, while already extremely unlikely under today's safety precautions, could lead to a global infectious disease outbreak that kills more people than all aviation and industrial accidents combined. given the vast gaps in knowledge that exist, a significant return on investment could be expected in terms of reduced biosafety risk in the near term, making this one of the safest research investments the federal government could make. transforming biosafety into a quantitative practice would ensure that our research enterprise can produce the cures and treatments to improve our quality of life without a single accident vitiating millions of hours of toil at the bench. it is time to make that transition a reality. government gain-of-function deliberative process and research funding pause on selected gain-of-function research involving influenza, mers, and sars viruses. us department of health and human services recommended policy guidance for potential pandemic pathogen care and oversight (p 3 co) supporting an estimate of absolute risk risk and benefit analysis of gain of function research, supplemental information for chapter biosquare phase ii supplemental final environmental impact report final revised environmental assessment for the proposed construction and operation of a biosafety level 3 facility at lawrence livermore national laboratory national bio and agro-defense facility, science and technology directorate, us department of homeland security evaluation of risk and protective factors for work-related bite injuries to veterinary technicians certified in minnesota human reliability assessment in biological laboratories a guide to practical human reliability assessment human reliability assessment: theory and practice high-containment laboratories: national strategy for oversight is needed. us government accountability office publication no. gao-09-574 nih guidelines for research involving recombinant or synthetic nucleic acid molecules animal and plant health inspection service, department of agriculture. part 331. possession, use, and transfer of select agents and toxins the development of the nasa aviation safety reporting system. nasa reference publication 1114. scientific and technical information branch commercial aviation accidents 1958 -2014. a statistical analysis boeing commercial airplanes. 2016. statistical summary of commercial jet airplane accidents: worldwide operations 1959 -2015. aviation safety, boeing commercial airplanes reporting and preventing medical mishaps: lessons from non-medical near miss reporting systems near-miss incident management in the chemical process industry recommendations for the evaluation and oversight of proposed gain-of-function research. national science advisory board for biosecurity hundreds of safety incidents with bioterror germs reported by secretive labs cdc failed to disclose lab incidents with bioterror pathogens to congress summary statement of the asilomar conference on recombinant dna molecules niaid budget data comparisons. national institute of allergy and infectious disease biosafety lapses prompt us cdc to shut labs and launch review review committee report: inadvertent shipment of live bacillus anthracis spores by dod. committee for comprehensive review of dod laboratory procedures, processes, and protocols associated with inactivating bacillus anthracis spores, us department of defense, the pentagon public health service, centers for disease control and prevention, and national institutes of health, us department of health and human services key: cord-300965-ivczo1a7 authors: brown, m. m. title: don’t be the “fifth guy”: risk, responsibility, and the rhetoric of handwashing campaigns date: 2017-08-29 journal: j med humanit doi: 10.1007/s10912-017-9470-4 sha: doc_id: 300965 cord_uid: ivczo1a7 in recent years, outbreaks such as h1n1 have prompted heightened efforts to manage the risk of infection. these efforts often involve the endorsement of personal responsibility for infection risk, thus reinforcing an individualistic model of public health. some scholars—for example, peterson and lupton (1996)—term this model the “new public health.” in this essay, i describe how the focus on personal responsibility for infection risk shapes the promotion of hand hygiene and other forms of illness etiquette. my analysis underscores the use of constitutive and stigmatizing rhetoric to depict individual bodies, rather than environments, as prime sources of infection. common among workplaces, this rhetoric provides the impetus for encouraging individual behavior change as a hedge against infection risk. i argue, though, that the mandating of personal responsibility for infection risk galvanizes a culture of stigma and blame that may work against the aims of public health. signal that a pandemic [was] imminent.^so, the 100th day's headlining issues of economic recovery, job creation, and the wars in afghanistan and iraq came second to obama's discussion of h1n1, the pandemic strain of the influenza virus. obama opened his remarks, for example, by outlining the steps that his government had taken to protect the american people from the devastations of outbreak. 1 measures adopted to fend off h1n1 included carefully monitoring the spread of the novel strain and stockpiling medical supplies and drug treatments. on the advice of public health experts, the u.s. government had also considered closing public schools in response to suspected or confirmed cases. obama also urged parents and employers to develop contingency plans if the spread of h1n1 led to massive workplace and school closures. band finally,^obama continued, bi've asked every american to take the same steps you would to prevent any other flu: keep your hands washed, cover your mouth when you cough, stay home from work if you're sick, and keep your children home from school if they're sick.^adopting these various forms of illness etiquette, obama implied, demonstrated one's assumption of personal responsibility in response to the heightened risk of infection. this essay contributes to the ongoing examination among rhetoricians of health and medicine of constructions of responsibility and risk. 2 specifically, i explore the centrality of a rhetoric of personal responsibility to discursive efforts to manage infection risk. health humanities scholars and rhetoricians of health and medicine share a common concern for the ethical issues that arise from risk-management exercises undertaken in the name of public health. 3 practitioners, too, have a stake in more detailed understandings of the impact of risk discourse on the formation of health subjectivity. however, as keränen (2014b) explains in the health humanities reader, ba rhetorical perspective focuses on how specific symbolic patterns structure meaning and action^in health and public-health contexts (37). writing for this journal, for example, ding (2014b) stresses the economic and sociocultural effects of media portrayals of bat risk^populations during severe acute respiratory syndrome (sars). 4 my essay contributes to this scholarship with an account of how messaging that seeks to engage publics in outbreak management shapes their perceptions of responsibility and risk, not to mention of public health. as i argue, handwashing campaigns reinforce an individualistic model of public health, one premised to a significant extent on the necessity of behavior change rather than structural intervention. some scholars-for example, peterson and lupton (1996) -term this model the bnew public health.p ersonal responsibility serves essential functions in response to the threat of infection. however, the mandating of personal responsibility for infection risk has the potential to galvanize a culture of stigma and blame. too narrow a focus on personal responsibility may also diminish perceptions of the effectiveness of improved structural supports for those infected. during h1n1, for example, universal paid sick leave became a topic of debate, serving as a reminder of the need for an environment supportive of individual efforts to manage infection risk. in this essay, i characterize hand hygiene promotion as both a bconstitutive rhetoric^and a bstigmatizing rhetoric.^whereas a constitutive rhetoric encourages action through the cultivation of subjectivity, a stigmatizing rhetoric uses stigma to shape perceptions-also typically for the sake of influencing behavior change. i also describe how scholars of rhetoric of health and medicine have employed these two theories and explain their value to health humanities practitioners and scholars. i then examine the uses of constitutive and stigmatizing rhetoric in a u.s. state-level campaign to enforce bhygienic norms^(including, importantly, hand hygiene) within the workplace. my analysis reveals the centrality of stigma and blame to these efforts to encourage the assumption of personal responsibility. research on hand hygiene promotion finds that handwashing campaigns have a proven impact on health behaviors and thus, by extension, on health outcomes. so, why might those of us who have been exposed to these campaigns concern ourselves, perhaps unnecessarily, with their implications for our views of risk, responsibility, and public health? the reason i turn to in my conclusion is that the rhetorical means used to encourage personal responsibility may obscure perceptions of more effective approaches to the management of infection risk. handwashing campaigns also create opportunities to profit from and even exploit the stigma and blame that these texts associate with failures of personal responsibility. my goal, then, is mainly to explore the limits of personal responsibility-not just as an approach to infection risk, but more generally as a cornerstone of twenty-first-century public health. personal responsibility may be a cornerstone of public health, but hand hygiene promotion is an especially persuasive vehicle for popularizing an individualistic conception of infection risk. by bhand hygiene promotion,^i mean efforts to instruct a broad, lay public in hygiene practices typically used to reduce the transmission of disease-causing pathogens in hospitals and clinics. in this essay, i use bhandwashing campaigns^and bhand hygiene promotionî nterchangeably to describe the discursive encouragement of this habit. i also focus mainly on hand hygiene promotion within north america, where amid h1n1 handwashing campaigns and hand hygiene products alike became endemic. commenting on this trend in a new yorker essay, owen (2013) links the phenomenal success of gojo industry's blockbuster hand sanitizer, purell, to anxieties about infection risk. 5 today, hand sanitizer is a product category in its own right, and its popularity is sometimes regarded critically as both indicative of and responsible for a distinct shift in cultural perceptions of infection risk. 6 in my view, however, purell's unprecedented sales figures 7 are inextricably tied both to the increased promotion of hand hygiene in recent decades and to the ongoing individualization of public health. a drawback of undertaking a critique of hand hygiene is appearing to be against hand washing and other expressions of illness etiquette. hand hygiene is a vital form of infection control, and as such, it is also an ethical practice, particularly during an outbreak. rather than argue against hand hygiene, i explore the limits of hand hygiene promotion, as well as its implication in the deepening entrenchment of the new public health. in this respect, my essay draws its inspiration from the work of metzl, who in the introduction to his co-edited multidisciplinary anthology against health, writes that health is a bdesired state, but it is also a prescribed state and an ideological position^(2010, 2). the same argument applies to public health, which broadly speaking entails the strategic, organized effort to bpersuade a defined public to engage in behaviors that that will improve health or refrain from behaviors that are unhealthy^ (springston 2013, 713) . hand hygiene promotion especially invites further scrutiny because its prescriptive, ideological qualities far too often go unnoticed. hence, i focus my attention here on describing how handwashing campaigns benefit the overarching emphasis on personal responsibility for infection risk. an important precedent for my critique is plyushteva's analysis (2009) . 8 plyushteva examines the promotion of hand hygiene in developing countries, which she sees as having applications beyond the potential reduction high mortality rates due to infection. in fact, just as in north america, hand hygiene promotion directed at publics in developing countries aims to empower these publics to protect themselves from the risk of infection. since 2008, for example, global handwashing day has been celebrated annually on october 5. an initiative of the global public-private partnership for handwashing with soap (global ppphw), global handwashing day is bdedicated to increasing awareness and understanding about the importance of handwashing with soap as an effective and affordable way to prevent diseases and save lives.^the celebration also presents ban opportunity to . . . encourage people to wash their hands^-or, as explained in a global handwashing day press release, to inspire personal responsibility. 9 in developing countries, hand hygiene promotion's emphasis on personal responsibility may affect perceptions of entitlement to care. indeed, global handwashing day presents infection risk as managed not through the provision of clean water or proper sanitation but rather through the adoption of appropriate personal measures. underwritten by an array of corporate sponsors, global handwashing day also teaches people living in developing countries to become faithful consumers of hand sanitizer and soap, just like their counterparts in developed countries. current sponsors include colgate-palmolive, procter and gamble, and unilever, all companies with a massive stake in the global marketplace for personal hygiene products. (corporate sponsors may also have influenced the naming of the global public-private partnership for handwashing with soap. even the scholarship produced by the researchers working for this partnership typically includes this addendum.) global handwashing day's instruction in the consumption of personal hygiene products, too, has ties to the overarching emphasis on personal responsibility that defines the new public health. hand hygiene is promoted as a bdo-it-yourself vaccine,^a hedge against infection risk (apparently) even in settings in which infection risk often stems from poor sanitation and lack of access to clean water. 10 of course, regardless of context, hygiene habits have a proven impact on the transmission of disease-causing pathogens. hand hygiene limits the spread of diarrheal and respiratory diseases, which are among the leading causes of child mortality in developing countries. 11 children thus comprise a key audience for global handwashing day, which seeks to transform them into bchange agents^who have the capacity to bpositively influence other people's health behaviours^ (global ppphw 2015) . however, as plyushteva observes, global handwashing day's celebration of the life-saving power of individual behavior change potentially obscures understandings of the structural factors that shape infection risk. in developing countries, for example, the spread of disease stems from lack of access to clean water and adequate waste disposal and not mainly from a lack of agency per se. in tying infection risk to the bsuboptimal behaviour of the poor^(2009, 428), handwashing campaigns in developing countries exacerbate longstanding power imbalances, potentially reinforcing rather than removing obstacles to meaningful change. at the same time, hand hygiene promotion in this context expands the global marketplace for personal hygiene products, forging new opportunities to profit from the intractable problem of infectious disease. plyushteva's analysis is helpful to my own because she draws attention to hand hygiene promotion's insidiousness and stresses its consequent potential to serve a range of motivations. some of these motivations in fact conflict with the aims of public health, particularly in developing countries. bat first glance,^she argues, bthe cause of handwashing appears as apolitical and uncontroversial as can be^(428). so unproblematic is hand hygiene, and so important are efforts to promote it, that the very few criticisms of global handwashing day have largely been ignored. 12 for her part, plyushteva takes issue with the celebration's stigmatizing of people in developing countries bas traditional or backward, or, in a teleological view of development, pre-modern^(424). hand hygiene's buncontroversial façade^(420) also obscures the reality that individual behavior change is only ever a bpartial solution^(429) to the spread of disease. efforts to quell the spread of disease through behavior change also depend on the implementation of structural interventions-changes that create an environment supportive of personal responsibility. (i return to these limitations of personal responsibility in my conclusion.) i quote plyushteva at length because hers is the most recent scholarly critique of contemporary, globalized efforts to promote hand hygiene promotion. 13 her writing establishes a precedent for my critique of north american handwashing campaigns, which may also do more, politically and economically, than simply diminish the risk of infection. circulated within workplaces, schools, transit hubs, airports, community centers, groceries stores, and shopping malls, handwashing campaigns portray individual bodies, and body parts, as dangerous vectors of infectious disease. what makes these bodies, and parts, dangerous is both that they spread infection and because the disease-causing pathogens they transmit remain invisible to the individuals who transmit them. as a caption for a handwashing poster created by yale university's emergency management department in 2009, in response to h1n1, puts it, byou've got a mystery on your hands.t aking the form of pamphlets, posters, transit ads, web infographics, social media campaigns, and public service announcements, these texts caution that the power to prevent (and spread) infection is in our hands. sales figures for hand sanitizer alone illustrate the impressive new revenue streams generated by this individualization of infection risk. even in developed countries, where the assumption of personal responsibility is less likely to be impeded by structural issues, hand hygiene promotion may nevertheless skew perceptions of contextual or social determinants of infection risk. most notable among these factors may be the availability of sick leave or the effects on susceptibility of feelings of anxiety or stress. hand hygiene promotion invariably serves two distinct purposes. at one level, as exercises in risk communication, handwashing campaigns satisfy the obligation to inform publics about how to diminish the risk of infection. the most effective display of hand hygiene promotion's function as a form of risk communication may be the infographics, often posted in public restrooms, that illustrate the handwashing procedures practiced by healthcare professionals. these infographics teach handwashing methods, but they also serve to emphasize the need for personal responsibility in public settings. indeed, at another level, many handwashing campaigns often serve more expressly rhetorical goals. the most effective-and the most problematic-is the use of hand hygiene promotion to exacerbate a whole host of negative emotions, from anxiety, distrust, fear, and doubt to nausea and disgust. some of the most prominent voices behind the turn to hand hygiene promotion, particularly in developed countries, have emphatically defended the rhetorical utility of public health campaigns that inspire feelings of disgust. 14 in my close reading, i focus more on this latter function of handwashing campaign-that is, its use to foster emotional states that predispose audiences to the adoption of personal responsibility. hand hygiene promotion's alignment with an axiom of neoliberalism-the emphasis on personal responsibility-is also worthy of further examination. harvey describes the typical characteristics of the neoliberal state and explains, the bsocial safety net is reduced to a bare minimum in favour of a system that emphasizes personal responsibility. personal failure is generally attributed to personal failings, and the victim is all too often blamed^ (2005, 76) . harvey's account stresses the economic advantages of the neoliberal emphasis on personal responsibility. indeed, a neoliberal approach to infection risk has both shifted attention away from costlier programs of outbreak management and accorded private stakeholders unparalleled economic advantages. arguably, the main benefactors of personal responsibility for infection risk are the corporations that develop and distribute products in support of illness etiquette. yet the recent popularity of hand sanitizer does more than reflect the successful marketing of hand hygiene as an antidote to both uncertainty and infection. rather, this shift in consumptive patterns also illustrates the tremendous impact of handwashing campaigns on a risk-oriented subjectivity. alongside promoting a habit that may reduce the transmission of disease, handwashing texts heighten awareness of those who fail in their duty to limit the spread of infection. noncompliance with the dictates of hand hygiene promotion becomes grounds not merely for blame but also for suspicion about a person's moral worth. contemporary handwashing campaigns thus form a constitutive rhetoric, a mode of rhetorical appeal that calls into existence a shared collective identity. within hand hygiene promotion, the collectivity identity called into existence is that of the health citizen for whom participation in containing an outbreak is a personal responsibility. 15 white describes bconstitutive rhetoric^(a term that he coined) as bthe central art by which culture and community are established, maintained, and transformed^ (1985, 28) . scholars use constitutive rhetoric to explain the discursive formation of new social and political subjectivities. in demonstrating how some rhetorics discursively constitute the very subjects they address, many critics follow charland's model of constitutive rhetoric (1987) . 16 into white's theory, charland incorporates burke's notion of identification (1969) and althusser's idea of interpellation, or bhailing^(1971). as charland observes, constitutive appeals produce and reinforce new subject positions (1987) . by responding to these appeals, individuals affirm their membership in the community. constitutive rhetoric has been a useful analysis for health humanities scholars and practitioners. 17 anthropologist joseph dumit, for example, argues that strategies employed in pharmaceutical discourse create new opportunities for marketing drugs by constituting the individual as a body at risk of disease (2012). the strategic constitution of bodily risk, dumit argues, is essential to keeping americans on bdrugs for life.^scholars of rhetoric of health and medicine have employed constitutive rhetoric to critique the interpellation of headache patients as well as of patients as narrative subjects (segal 2005 ). derkatch has used constitutive rhetoric to account for the maintenance of professional boundaries in medicine (2012), whereas kopelson has shown in response to breast cancer, public health organizations mobilize citizens as consumer-activists (2013). majdik and platt describe the health subject constituted by the marketing campaign for a genetic testing product (2012). interpellation has also been a productive means for scholars to describe how public health officials shape perceptions of risk and responsibility in response to outbreak (briggs 2004; davis, stephenson, and flowers 2011) . hand hygiene promotion presents an opportunity to examine the constitutive functions of efforts to foster personal responsibility for infection risk. handwashing campaigns transform perceptions of responsibility for disease outbreaks. they do so by situating the risk of infection in individual bodies. the adoption of illness etiquette in response to hand hygiene promotion thus signals at least a partial acceptance of the new public health. 18 because it singles out the individual bodies-and individual body partsthat spread infection, hand hygiene promotion might be understood as both a constitutive rhetoric and a bstigmatizing rhetoric.^proposed by metzl in against health (2010) and premised on the writings of goffman ([1963] 1986), a stigmatizing rhetoric derives its conception of the bhealthy^from portrayals of the bunhealthy.^in other words, notions of poor health shore up understandings of good health. as metzl asserts, within a stigmatizing rhetoric, the baffirmation of one's own health depends on the constant recognition, and indeed the creation, of the spoiled health of others^ (2010, 5) . taking up metzl's refrain, some of the contributors to the multidisciplinary anthology, against health, critique the centrality of stigmatizing rhetoric to a neoliberal model of public health. lebesco, for example, argues that u.s. anti-obesity campaigns reinforce the valuing of bgood citizens [who] take care of their own health^ (2010, 78) at the expense of those classified as overweight or obese. handwashing campaigns potentially display such a stigmatizing rhetoric whenever their promotion of hand hygiene casts it as a prosocial behavior rather than as merely a method of infection control. according to these stigmatizing texts, the failure to observe hand hygiene has profound consequences in addition to the potential for infection. created by the florida department of health in response to h1n1, the bfifth guy^campaign illustrates the use of a constitutive, stigmatizing rhetoric to endorse the assumption of personal responsibility for infection risk. i chose this campaign both because of its focus on the workplace and because its messages about risk and responsibility later saw replication in other states (for example, by the michigan department of health). 19 the fifth guy campaign includes an interactive website that hosts a series of public service announcements (psas). together, these psas underscore the need for personal responsibility by dramatizing the tensions that arise when someone in the workplace ignores his duty to limit the spread of infection. underlying the fifth guy, as i argue, is the message that infection risk is exacerbated mainly by the failure to assume personal responsibility. my close reading of the fifth guy also reveals an emphasis on feelings of anxiety, fear, and even self-doubt. as a stigmatizing rhetoric, the fifth guy foregrounds these negative emotions to shore up the value of personal responsibility-in particular, its role in the maintenance of good health. the florida department of health's campaign employs the notion of the bfifth guy^to single out the person who ignores rather than assumes personal responsibility. (my references to the bfifth guy^describe the campaign, whereas discussions of the bfifth guy^refer to its main character.) the campaign has a basis in a study conducted by the american society for microbiology (asm), which found that four out of five people do wash their hands after using the restroom. in this campaign, the fifth guy is not only male but also young, able-bodied, and white. the fifth guy seeks to billustrate a simple point-most people respect certain hygienic norms.^those who do not observe these norms become bthat one person everyone whispers about.^within the campaign's configuration of personal responsibility, displays of illness etiquette are represented as much measures of moral worth as they are forms of infection control. the bfifth guy,^further, is portrayed as at risk of both sickness and social quarantine-exclusion from the group because he poses a threat to public health. to stress the value of personal responsibility, video public service announcements (psas) both televised and posted online exaggerate as deviant the fifth guy's violation ignorance of a workplace's bhygienic norms.^played by comedic actor ben spring, the fifth guy is, not surprisingly, central to the campaign's narrative of personal responsibility. two of the three psas showcase ben's tendency to come to work sick, for him, a point of pride, and for his coworkers, a source of disdain. ben also coughs and sneezes without covering his mouth and nose with his elbow. the videos bcougher^and bsick at home^dedicate considerable footage to shots of ben coughing into his hands, onto food in the lunchroom, during meetings, and in the faces of his fellow coworkers. ben is quite clearly ignorant of his body as potentially-and, in most instances, quite literally-a source of infection risk to the people around him. however, the fifth guy is used to emphasize the necessity of his coworker's efforts to compensate for his ignorance. bhow would i describe ben to you? the next black plague,b en's manager tells the camera in one psa: bthey're gonna say, 'how did it happen, was it rats?' no, it was ben over at amalgamated, responsible for the death of europe.^ben's violations of the dictates of illness etiquette make him an object of disgust within his workplace. more importantly, when illness arises within a workplace, his coworkers come to regard ben's body as its likeliest source. in the fifth guy, attention is paid to ben's body not as a site of sickness-or, put differently, a site of suffering-but as a site of infection risk. this situating of infection risk in individual bodies teaches the importance of avoidance of certain others as potentially (or, in ben's case, it seems, inherently) vectors of infectious disease. ben's coworkers leave the lunchroom when he enters, refuse to shake his hand or give him high fives, and send emails and issue prank calls urging him to go home. in other words, ben is to be avoided because he embodies the risk of infection in public. so, in avoiding ben, his coworkers assume personal responsibility for infection risk. ben's failures in this respect in turn imply that those who succumb to infection have only themselves to blame, perhaps because they, too, ignored the dictates of illness etiquette. avoidance and exclusion, however, are not the only strategies endorsed as both infectioncontrol measures and displays of personal responsibility. in the fifth guy, hand hygiene represents a hedge against infection risk and its absence a violation of the dictum of personal responsibility. bjust another day in the office^illustrates this dual function. in this psa ben's poor hand hygiene habits graphically come to life in the form of a urinal he carries around the office after leaving the restroom. in one scene, ben proudly places his urinal on a coworker's desk while asking for some paperwork. in other scenes, he dances along the office's corridors, embracing his urinal in a mock tango. depicting poor hand hygiene as a urinal makes some sense from the perspective of theories of fomite transmission of infection. these theories explain that, unless properly sanitized, inanimate materials or objects can become contaminated with infectious agents such as influenza virus. similarly, poor hand hygiene-or a lack of hand hygiene-increases the likelihood of the transmission pathogens, both from contaminated surfaces to individuals and between individuals as well. 20 yet, the goal of ben's urinal appears not to be to instruct the workers of florida in the problem of fomite transmission. instead, by emphasizing ignorance of illness etiquette as akin to intentionality, ben's out-ofplace urinal serves as an object lesson in hand hygiene as an expression of personal responsibility. ben is stigmatized-literally marked-to distinguish him from those who observe their obligation to illness etiquette. certainly, the fifth guy teaches hand hygiene as a display of personal responsibility. yet the campaign also reveals another expectation of the new public health, and that is the enforcement of individual behavior change among the non-compliant. frequently lacking the ability to confront him directly, ben's coworkers take advantage of the opportunity to make their concerns known to the camera. byes, i'd say he's a walking pandemic,^the receptionist comments just seconds after ben has left the restroom with his urinal-germs in tow. bquite frankly,^says the coworker whose desk has been sullied by ben's metaphorical urinal hands, bhe scares me.^acknowledging that it can be difficult to reproach our colleagues, bjust another day^ends with the words of a voiceover narrator: bfour out of five people wash their hands in the restroom. could someone talk to the fifth guy?^strategies for doing so appear on the page of the bfifth guy^website on which bjust another day^is posted. tips include emailing your coworker one of the campaign videos with the comment, bhey, sure glad you're nothing like this^or giving him or her ba new nickname like 'big loogie' or 'thunder cough'.^as these rather passive-aggressive strategies suggest, the assumption of personal responsibility for infection risk also involves participation in its enforcement. nevertheless, in using stigma to underscore personal responsibility, the fifth guy potentially both validates anxieties about infection risk and reassures that risk can always be managed. those who regularly encounter infection in the workplace or witness handhygiene violations in public restrooms may feel vindicated by the campaign's mockery of ben, the boffice superspreader.^after all, as the campaign implies, only careless people spread disease. with care, infection can invariably be avoided. the fifth guy's attributions of intentionality may be the campaign's most problematic feature and not simply because such attributions may be likely to exacerbate interpersonal conflicts within public settings. the use of a constitutive, stigmatizing rhetoric has consequences for shared perceptions of infection risk. it is to these perceptions that i now turn my attention. three configurations of infection risk emerge from the fifth guy's encouragement of personal responsibility. first, the most serious risk depicted throughout the campaign is exposure to ben, who is a bwalking pandemic,^possibly even the source of plague. in implying that infection risk is determined mainly by exposure to others, this configuration places undue emphasis on the need for hypervigilance in interpersonal interactions. in ben's story, the assumption of personal responsibility for infection risk takes the form of a kind of citizenepidemiology, with everyone working to root out sources of infection. yet shy of engaging in self-quarantine, most people exercise only limited control over their exposure to others. perhaps in recognition of this fact, the bfifth guy^instructs in subtle pressures that might be applied to those individuals determined to be the potential source of infection-for example, through stigma. second, infection risk is determined largely by one's ability to control and manage certain behaviors. conversely, failure to change habits increases our risk. different scenes from the fifth guy illustrate this formulation of infection risk. motivated by the threat of ben's behavior, his coworkers more than once demonstrate for the camera different practices for limiting infection risk. in displaying their compliance with illness etiquette to the camera rather than to ben, his colleagues indicate the necessity of habitual and bodily responses to the management of infection risk. a third assumption is underscored within the numerous texts that together form the campaign's overarching message about risk and responsibility. in the fifth guy, a lack of knowledge increases one's risk of infection. ben, who displays ignorance of his duty to manage risk, teaches that being knowledgeable reduces the risk of infection (not to mention the threat of expulsion from the group). other elements of the campaign reinforce this equation of knowledge with the assumption of responsibility for infection risk. visitors to the bfifth guy^website can, for example, take a quiz that tests their bhygiene iq.^their scores determine bwhich person^they are in the workplace drama of illness and infection. yet, as anyone who takes the quiz may quickly realize, it is only possible to either be the bfifth guy( ignorant) or not the fifth guy (not ignorant). users who select the incorrect answer to a series of five questions are also goaded to correct their mistakes by the message, bwrong. who are you, the fifth guy?^most of these wrong answers correspond with ben's behaviors in different scenes from the campaign psas. the didacticism of the campaign's testing of hygiene iq raises the question: what knowledge, exactly, do audiences gain through exposure to the bfifth guy^and campaigns like it? perhaps most importantly, the formulation of knowledge as a defense against infection risk teaches an individualistic approach to risk management. within this conception, the complex problem of emerging infectious diseases is most effectively resolved through personal transformations of our daily habits, not to mention of our relationships to one another. in the coming decades, it seems likely that the containment of outbreaks will depend more and more on a program of risk communication that teaches individuals how to protect themselves against infection. within the new public health, this focus on behavioral change is frequently regarded mainly as an alternative to the implementation of costlier, more comprehensive forms of protection, treatment, and care. problematically, however, this encouragement of the personal responsibility for infection risk ignores the influence of contextual and environmental factors. complex economic and social factors, from social support networks to gender, ethnicity, race, and culture, shape and determine the health of populations. instead, even those campaigns that single out the person who (like ben) does not adhere to the dictates of illness etiquette imply equality in our susceptibility to (or risk of) infection. despite its shortcomings, critics have only occasionally spoken out against the emphasis on personal responsibility for infection risk and the neoliberal model of public health it entails. shortly after president obama advised americans to help fend off a global pandemic by washing their hands, for example, cohen wrote a new york times column about the ethical dimensions of the 100th-day address (2009). was obama's counsel to americans to do their part by washing their hands and staying home from work bmerely good manners,^cohen wondered. or, should his comments instead be understood as a moral injunction, with serious implications for how the nation would cope with the outbreak? put simply, is hand hygiene a matter of etiquette-or is it a matter of ethics? while etiquette may bhave a trivial impact on others,^cohen deemed obama's h1n1 advisory a matter of ethics bbecause it concerns the effect of our actions on other people.ŵ ashing one's hands removes harmful, disease-causing pathogens, making the endorsement of the act an bethical imperative, meant to mitigate the harm we might do to others.^that hand hygiene has a personal benefit does not make the habit any more ethical-just more desirable, perhaps, because self-care for the most part overlaps with care of others. yet in defending hand hygiene as an ethical imperative, cohen claimed that even this commonsense health habit has its limits. a program of risk management that depends for its success on the assumption of personal responsibility may similarly be too limited an approach to the problem of infection. as cohen put it, the dictates of illness etiquette, although bfundamentally ethical, are not universally applicable.^efforts to mobilize citizens against infection risk require an environment supportive of their participation. adequate supports must exist to ensure that citizens can bdo the right thing.^to illustrate the limits of personal responsibility, cohen discussed the example of labour law: some employees, particularly low-wage workers, risk losing pay or even getting fired if they stay home from work to avoid infecting their coworkers. if we expect individuals to act ethically, we have a societal obligation to protect them when they do-for instance, by guaranteeing paid sick days to all. (2009) during h1n1, concern about the ability of individuals to behave according to the dictates of public health led to the introduction in the u.s. congress of a bill that would require most employers to provide workers sent home with infections such as influenza a minimum of five paid sick days. paid sick leave, supporters argued, could even be a benefit to the economy, since the policy could both increase productivity and reduce the spread of illness and infection around the workplace. i quote cohen's comments at length because he is one of few critics to publicly speak out about the ethical issues that arise from the increasing encouragement of personal responsibility for infection risk. (even owen [2013] , in describing in detail the brise of purell,^shies away from too staunch a critique of the implications of the turn to hand hygiene promotion.) despite the appeal of the argument that infection risk can be managed mainly through individual behavior change, most exercises in risk management depend for their success on an environment supportive of these changes. in implying that infection risk may be equally distributed across populations, handwashing campaigns exclude the insights of decades of research on the social determinants of health and diseases. in this context, rhetoricians of health and medicine and health humanities scholars contribute meaningful investigations of the rhetoric of personal responsibility and specifically of its emphasis on fear, anxiety, distrust, stigma, and blame. such analyses are sure to deepen conversations among scholars and practitioners about the long-term implications of a seemingly uncontroversial enterprise-the promotion of hand hygiene. as mentioned at this essay's outset, i do not wish to question hand hygiene's efficacy as a form of infection control. myriad studies report on the impact of hand washing on the risk of infection with the majority suggesting that the habit significantly limits the transmission of communicable diseases. 21 to abandon hand hygiene because of concerns about the rhetoric used to promote makes no sense. far from opposing handwashing campaigns, i have illuminated their broader implication in the ongoing individualization and responsibilization of public health, which is also in essence a neoliberalization of public health. hand hygiene promotion, as my analysis suggests, moralizes the spread of infection, making its publics more sensitive to their capacity to sicken, and be sickened, by others. in the context of outbreak, such a perception both potentially lessens expectations of various kinds of support, for example in the form of employment or health benefits. this perception also creates new opportunities for those who stand to profit from the negative emotions often highlighted in messaging about personal responsibility for infection risk. as the target of handwashing discourse, one might thus be wary of the implications of the turn to hand hygiene as a universal antidote to the crisis of emerging infectious diseases. despite its seemingly neutral objective as a form of risk communication, hand hygiene promotion galvanizes a culture of stigma, blame, and distrust in response to the threat of infection. to what extent might these effects in fact inhibit the need for cooperation in the face of a catastrophic outbreak? handwashing campaigns transform perceptions of infection risk, casting illness as a personal failing. this is not to say that infection is not partly a consequence of poor hand hygiene, but the reality is just that. poor hand hygiene is only a contributing factor and not the root cause of the heightened risk of outbreak. it may thus be time to consider alternatives, or complements, to a neoliberal model of public health. personal responsibility has its advantages-that much is clear-but a more expansive approach might better facilitate the cooperation, and compassion, that infectious-disease outbreaks demand. endnotes 1 for the full text of president obama's remarks, see btranscript: president obama's 100th-day press briefing^(2009). 2 see, for example, keränen (2011) ; angeli (2012); ding (2014a; 2014b) . 3 keränen also stresses a common interest in the formation of publics, not just through the bofficial texts of biomedicine,^but also through the practices they adopt in response to these texts (2014, 104). 4 wald (2008) in turn proposes the theory of the boutbreak narrative^to describe the influences of both media and popular culture on responses to infectious disease-in particular, those responses that generate stigma or discrimination. 5 in fact, for a decade prior to sars, purell languished in obscurity (owen 2013, 30) . 6 see sadler (2009) , which incorporates critiques of hand-sanitizer use from health historians jacalyn duffin and nancy tomes, both of whom regard the product's popularity as tied to anxieties about infection risk. 7 while worldwide sales figures vary from one source to another, a cnn story reports that shipments of hand sanitizer tripled during h1n1, from 1 million kilograms to 3 million kilograms (rooney 2009) . a more recent report (fottrell 2013) states that u.s. sales of hand sanitizer reached $300 million in 2009, and have since averaged nearly $200 million per year. 8 plyushteva's (2009) critique of hand hygiene promotion in developing countries documents only the latest stage in a longer arc of handwashing campaigns developed to generate sales for hand soap. vinikas (1989) , for example, chronicles the creation by soapmakers of the 1920s and 1930s of the cleaning institute, which worked to increase soap sales by inculcating schoolchildren into personal hygiene habits. see, also, vinikas (1995) , which illuminates the significance to modern advertising of early-twentieth-century efforts to promote personal hygiene. 9 for the full text of this press release, see royal society for the protection of nature, bglobal handwashing day observed in yoeseltse mss in samtse.1 0 the quotations in this paragraph derive from globalhandwashing.org, the website for the global ppphw. for a recent systematic review of the impact of hand hygiene promotion in developing countries, see whom plyushteva quotes, openly criticizes hand hygiene promotion in kerala as a poor substitute for structural interventions, such as the improvement of sanitation systems or provision of clean water another important historical precursor to plyushteva's critique is tomes, which documents the work of latenineteenth and early-twentieth century public health advocates to transform lay understandings of the spread of infection. tomes points out that bentrepreneurs and manufacturers curtis's (2011) review of the emerging body of scholarship on the use of public health discourse to trigger a disgust response in order to motivate individual behavior change my view of health citizenship derives mainly from petersen and lupton (1996), but it also has loose ties to rose and novas' (2005) notion of biological citizenship argues that before the 1980 provincial referendum the government of quebec sought support for quebec's separation from canada by constituting the province's inhabitants as ba distinct peuple.^by voting in support of separation a constitutive perspective is also consistent with foucault's theory of subjectivity formation. for a discussion of foucault's significance to health humanities, see petersen which instructs americans to bkeep calm and wash [their] hands,^implying that in washing their hands, citizens consent to their duty to cooperate in the event of an outbreak the fifth guy campaign has also been the subject of social-marketing case studies which is transmitted by fomites. among others, wald (2008) stresses the role of popular culture in circulating certain conceptions of outbreak-views of causality that overstate the role of the individual in triggering an outbreak. similarly, many of the essays in a 2002 special issue of american literary history discuss the longstanding influence of popular culture on understandings some of the most frequently-cited references to studies in support of hand hygiene appear on bshow me the science bideology and ideological state apparatuses.^in lenin and philosophy and other essays translated by ben brewster bmetaphors in the rhetoric of pandemic flu: electronic media coverage of h1n1 and swine flu btheorizing modernity conspiratorially: science, scale, and the political economy of public discourse in explanations of a cholera epidemic a rhetoric of motives health promotion materials. the u.s. centers for disease control and prevention bconstitutive rhetoric: the case of the 'peuple québécois bflu fighters.^the new york times bcompliant, complacent, or panicked? investigating the problematisation of the australian general public in pandemic influenza control global handwashing day. deb group ltd bdemarcating medicine's boundaries: constituting and categorizing in the rhetoric of a global epidemic: transcultural communication about sars. carbondale: southern illinois university press drugs for life: how pharmaceutical companies define our health btalk to the fifth guy bhand sanitizer spread faster than the flu.^marketwatch bhygiene and health: systematic review of handwashing practices worldwide and update of health effects bchildren as handwashing agents of change.^the global public-private partnership for handwashing with soap. accessed stigma: notes on the management of a spoiled identity bconcocting viral apocalypse: catastrophic risk and the production of bio(in)security 2014b. b'this weird, incurable disease': competing diagnoses in the rhetoric of morgellons.^in health humanities brisky appeals: recruiting to the environmental breast cancer movement in the age of 'pink fatigue bfat panic and the new morality.^in against health: how health became the new morality bselling certainty: genetic complexity and moral urgency in myriad genetics bintroduction: why against health?^in against health: how health became the new morality bhands across america: the rise of purell the new public health: health and self in the age of risk btalk to the fifth guy: a lesson in social marketing.ĉ ases in public bthis benevolent hand gives you soap: reflections on global handwashing day from an international development perspective.^journal of health management bpresident obama's 100th-day press briefing.^2009. the new york times. accessed bhand sanitizer in short supply as swine flu hits.^cnn money. accessed bbiological citizenship.^in global assemblages: technology, politics, and ethics as anthropological problems bglobal handwashing day observed in yoeseltse mss in samtse bdo you really need hand sanitizer?^cbc news health and the rhetoric of medicine bpublic health campaign.^in sage encyclopedia of public relations bhandwash or eyewash? selling soap in the name of public private partnerships.^india resource center blife in a time of germaphobia.^the globe and mail the gospel of germs: men, women, and the microbe in american life soft soap, hard sell: american hygiene in an age of advertisement contagious: cultures, carriers, and the outbreak narrative bcurrent who phase of pandemic alert for pandemic (h1n1).^the world health organization g l o b a l a l e r t a n d r e s p o n s e ( g a r ) . a c c e s s e d 2 9 a p r i l 2 0 0 9 key: cord-311694-2b2swi0l authors: grima, simon; kizilkaya, murat; rupeika-apoga, ramona; romānova, inna; dalli gonzi, rebecca; jakovljevic, mihajlo title: a country pandemic risk exposure measurement model date: 2020-10-09 journal: risk manag healthc policy doi: 10.2147/rmhp.s270553 sha: doc_id: 311694 cord_uid: 2b2swi0l purpose: the purpose of this study is to develop a pandemic risk exposure measurement (prem) model to determine the factors that affect a country’s prospective vulnerability to a pandemic risk exposure also considering the current covid-19 pandemic. methods: to develop the model, drew up an inventory of possible factor variables that might expose a country’s vulnerability to a pandemic such as covid-19. this model was based on the analysis of existing literature and consultations with some experts and associations. to support the inventory of selected possible factor variables, we have conducted a survey with participants sampled from people working in a risk management environment carrying out a risk management function. the data were subjected to statistical analysis, specifically exploratory factor analysis and cronbach alpha to determine and group these factor variables and determine their reliability, respectively. this enabled the development of the prem model. to eliminate possible bias, hierarchical regression analysis was carried out to examine the effect of the “level of experienced hazard of the participant (leh)” considering also the “level of expertise and knowledge about risk and risk management (lek)”. results: exploratory factor analysis loaded best on four factors from 19 variables: demographic features, country’s activity features, economic exposure and societal vulnerability (i.e. the prem model). this model explains 65.5% of the variance in the level of experienced hazard (leh). additionally, we determined that lek explains only about 2% of the variance in leh. conclusion: the developed prem model shows that monitoring of demographic features, country’s activity features, economic exposure and societal vulnerability can help a country to identify the possible impact of pandemic risk exposure and develop policies, strategies, regulations, etc., to help a country strengthen its capacity to meet the economic, social and in turn healthcare demands due to pandemic hazards such as covid-19. the coronavirus or, as it is better known, covid-19 has disrupted life as we knew it. this virus is causing a national disaster of epidemic nature with considerable economic and social impact. the united nations (un) defines disaster as a serious disruption of the functioning of a community or a society at any scale due to hazardous events interacting with conditions of exposure, vulnerability and capacity, leading to one or more of the following: human, material, economic and environmental losses and impacts. 1 the centre for research on the epidemiology of disasters (cred) identifies a disaster if at least one of the following criteria is met: 10 or more people are reported killed; 100 people are reported affected; a state of emergency is declared; a call for international assistance is issued. 2 the pandemic covid-19 meets all these criteria. a pandemic is defined as "an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people". 3 on the other hand, a pandemic can be defined as a natural event that causes a disruption in the functioning of the economic system that has a significant negative impact on assets, production factors, output, employment or consumption, etc. 4 when a hazard arises, such as that of a pandemic, it leads to the loss of life and damage to infrastructure, emphasizing the reality that society and its assets are vulnerable to such events. according to the sendai framework for disaster risk reduction 2015-2030, a hazard is a process, phenomenon or human activity that may cause loss of life, injury or other health impacts, property damage, social and economic disruption or environmental degradation. 1 can be characterised as a biological hazard, since biological hazards are of organic origin or conveyed by biological vectors, including pathogenic microorganisms, toxins and bioactive substances. examples are bacteria, viruses or parasites, as well as venomous wildlife and insects, poisonous plants and mosquitoes carrying disease-causing agents. the covid-19 pandemic outbreak so far, during march to june 2020 has substantially influenced the majority of the countries in the world, besides, according to the research note of german deutsche bank, experts already speak about the second wave of the virus, and highlight that during the next ten years the world can face a much more serious pandemic than covid-19. 5 therefore, there is a need to understand the objective factors that indicate the experienced level of hazard that a country may be faced with, if or when pandemics such as covid-19 or similar outbreaks strike. the purpose of this study is to develop a pandemic risk exposure measurement (prem) model to determine the factors that affect a country's prospective vulnerability to a pandemic risk exposure such as covid-19. these factors can be indirectly and directly affected by different factors on each other and similarly have a direct and indirect effect on vulnerability. the idea is to answer the following a priori research questions: rq1 -what are the factors that enable the measurement of a country's vulnerability to a pandemic risk exposure such as covid-19? rq2 -do the factors vary according to the level of experienced hazard of a country (leh)? rq3 -do the factors vary according to level of expertise and knowledge of the respondents (lek)? the questions above and the forecasts noted above increase the importance of developing such a model, which can be used as a checklist for determining the status of a country in terms of possible vulnerabilities, which can later develop into hazards. it is useful for risk managers and policymakers to proactively identify the factors that make the country more vulnerable to the pandemic risk and if necessary, manage them and/or set tolerance limits, policies, regulations, rules, standards, etc. prem could also serve as a guide for businesses in developing their business continuity plans and insurance policy documents. insurance underwriters can also utilise this model to set the correct policy wording and premiums when underwriting risks. although there are various studies that have indicated factor variables that are important for addressing and measuring the vulnerability of countries, the covid-19 pandemic has indicated a serious need to go back to the drawing board. it is important to understand the areas or functions that have been missed and to develop a tool that is flexible enough to help national risk managers and policymakers proactively identify and determine the risk vulnerabilities of their country; and devise a continuity plan that improves the measure of vulnerability of a country. this is important so as to determine when to take action or flag the problem, based on a present tolerance level. to develop this inventory of factor variables we consulted literature on pandemics such as the covid-19 and identified variables that might not have yet been considered. therefore, the case of the covid-19 pandemic was used to help add value to current measures, by updating the model with new important factor variables that might not have been seen as important until now. for the purpose of this study, a purposely built semistructured survey was designed by creating an inventory of factor variables that can be used to measure a country's exposure to a pandemic risk such as covid-19. to develop such an inventory we participated in various online forums, grima et talks, webinars and sub-groups related to risk management during disruptions of infectious diseases such as that of covid-19 and asked other participants and colleagues (who worked in a risk management function) to provide us with those aspects that in their opinion safeguarded or hindered a country's preparedness against infectious diseases. this information together with that gathered from the research literature and using a thematic approach 6 resulted in the construction of an initial set of 25 variables and 2 additional data measurements that reflect vulnerability of a country for a pandemic (see table 1 ). there exists a variety of studies on different aspects of country's development. some studies 8 suggest such factor variables as "population density" measured by the number of persons per square kilometre, "night-time light intensity" measured by the night light development index. 9, 11, 12 as well as 'the ecological footprint index, 13 "transport network density" 14, 15, 52 and "net migration rate". 16, 53, 54 various studies suggest using "human development index (hdi)" as a composite index of life expectancy, education, and per capita income indicators 55 and "tourism". 24 recent studies suggest population age structure related indicators as 'population over/below 65ʹ 25, 26, 48 in conjunction with gender. 56 studies on population health measures commonly use "the infant mortality rate (imr)". 27, 28 healthcare system capacity studies emphasize the "hospital beds available per capita", 29, 30, 35, 57 "out-of-pocket expenditure (oops)" 31, 32, 58 and "health care expenditure % to gdp". 30, [34] [35] [36] 57, 59, 60 there is a variety of widely used economic factor variables that influence country's vulnerability as 'gross domestic product' 18 and "gdp per capita"; 19,61 "public and private debt to gdp" 38, 39 and "government expenditure to gdp", 40,41 "inflation rate" 7 and "unemployment rate" 45, 46 as well as "current account balance to gdp". 47 taking into account the specifics of the recent covid-19 outbreak such indicators as 'socio-cultural disparity' 42 and use of "telecommunication" tools 37 became important. although at the time of writing, studies on the covid-19 pandemic and its effect on a country's economic, social and health vulnerability measures were still limited, we were still able to uncover studies on covid-19 and others based on similar infectious diseases and pandemics such as severe acute respiratory syndrome (sars), the human immunodeficiency viruses (hiv), etc., which helped us build the inventory laid out in table 1 . the survey was administered as an online survey via weblink on qualtrics to contacts of the authors on social media, namely linkedin, facebook and twitter, who worked in a risk management function (non-probability purposive sampling). moreover, respondents were also invited using direct emails and were also asked to send this link to others working in the risk management function (non-probability snowballing sampling). responses were collected through qualtrics. the url was set to limit only one response per computer, but respondents had the option of going back to edit or update their answers until they finished. confidentiality of responses was guaranteed. a total of 2831 completed surveys were received between may and june of 2020. the survey consisted of three sections. the first section consisted of 2 questions, wherein question1 we asked the participants to state whether they are working in a risk management function, which was the main filter to allow participants to continue with the survey only in the event of a positive response, and then in question 2 (q1), we asked them to indicate on a likert scale of '1ʹ-being the lowest lek and '5ʹ-being the highest lek of the participant, their lek. this was done to understand whether the level of expertise and knowledge (lek) affected the scores provided by participants (who worked in a risk management function) in the development of the model. in the next section, which consisted of 1 main question (question 2), the participants were required to indicate on a 5-point scale their level of agreement with each of the 25 inventory items (q2 to q26) developed as described above. these items were individually operationalized via a five-point likert scale ranging from "1" for strongly disagree to "5" for strongly agree. the final section, question 4 and q27 in our proposed inventory we asked participants to provide us with an indication of their country of residence to enable us to determine their country's exposure to the hazard/disruption and asked them to add any comments they would like to express about the subject. we then determined "the level of experienced hazard of the participant (leh)", q27, through the number of coronavirus (covid-19) cases per 1 million population as of the 9th june 2020 of their country of residence provided by the participant. the data were determined from the worldometer website. 62 we used the following scale: a score of "1"-for the lowest risk with under 499 cases; "2" -between 500 and 999 cases; "3" -between 1000 and 1999 cases; "4" -between 2000 and 2999 cases; and "5" -for the highest risk with over 3000 cases per 1 million population. participants with the lowest risk experience, i.e. level 1-9.9%, level 2-0%, level 3-14.5%, level 4-12.8% and level 5 -the highest level of risk exposure 62.8%. we then loaded all the data in a quantitative format onto ibm spss v26 software package through which we carried out all our statistical analysis. as a next step, to answer research question 1 (rq1) we selected the variables and developed the prem model using exploratory factor analysis. exploratory factor analysis, via principal components extraction with orthogonal rotation (varimax with kaise normalization), was used to assess the construct validity of the country risk exposure index while internal-consistency reliability was assessed by computing cronbach's alpha coefficients. this further supported continuance of factor analysis and so the analysis proceeded. cronbach's alpha reliability coefficient was 0.789, kmo value was 0.712, and bartlett test was found to be 24352.006, df 171 p <0.001. we used varimax rotation because the factor variables are interrelated and we reduced them to 4 grouped factors consisting of 19-factor variables. hierarchical regression analysis was carried out to see the effect of 4 factors on "level of expertise and knowledge (lek)" and on "the level of experienced hazard of the participant (leh)" to enable us to provide an answer to research question 2 and 3 -(rq2) and (rq3). the hierarchical regression analysis was carried out with the obtained data in two steps. in the hierarchical regression analysis, "leh" was used as the dependent variable. in the first stage of analysis (model 1), the 4 obtained factors as a result of factor analysis were used as independent variables. in the second stage (model 2), the analysis was repeated by adding the "lek" variable to the four factors in the first stage. thus, the effects of both 4 factors and lek on "leh" were measured. analysing the completed surveys, we conclude, that 9.3% of the participants stated that their lek was 1; 20.4% stated that their level was 2, 41.6% stated that their level was 3; 22.9% stated that their level was 4 and 5.8% stated that their level was 5. using exploratory factor analysis, we determined that 6-factor variables were eliminated from the model, q6 -"net immigration", q7 -"gross domestic product", q16-"health care expenditure % to gdp", q26 -"gender", q24 -"population of males below 65 years" and q25 -"population of females below 65 years". this was because these variables explained too little of the variance and this made them unstable and often unreliable because they were defined by other variables. 63 this left us with the 19-factor variables included in the prem model and exhibited in table 2 . all factors have been carefully interpreted and omitted scientifically. the factor variable q18 -"public and private debt to gdp," which is highly related to one of two factors (factor 3 and 4), but lower to factor 4, was attached to factor 3. based on the analysis made, we have identified four factors indicating vulnerability of the country: factor 1 'country's activity features', factor 2 "demographic features', factor 3 'societal vulnerability', and factor 4 'economic exposure'. these factors affect a country's prospective vulnerability to pandemic risk exposure. table 3 shows the factors and reliability values of the four identified factors. cronbach's alpha coefficient of these factors varies between 0.688 and 0.861. of the four factors, the total variance in the survey explained 59.03%, while the factor common variances were observed to vary between 0.235 and 0.851. the results of the hierarchical regression analysis are shown in table 4 . results show that the 4 factors composing the prem model [factor 1 (country's activity features), factor 2 (demographic features), factor 3 (societal vulnerability), and factor 4 (economic exposure)] explained 64% of the change in leh with a high level of statistical significance (p< 0.001). when the lek variable was included in the analysis in the second stage, the rate of the total variance increased from 64% to approximately 66%. therefore, we can conclude that the lek variable helped to explain only another 2% with a high level of statistical significance (p < 0.05). as noted in table 2 , the exploratory factor analysis loaded best under four factors. factor 1 includes population density (q2), night-time light intensity (q3), ecological footprint (q4) and transport network density (q5). there is a variety of factor variables that can promote the spread of diseases, such as high population density and economic activity, ubiquitous air travel and with fast transportation comes a quick and extensive diffusion of a communicable disease. 14 many studies have shown that light at night and population density can be used as indicators of economic activity. 11,12 population density is one of the key parameters for assessing the magnitude of the population exposed to risk. 8 the increase in human population density and the growth in transportation networks of roads, container ships, and airways that has now linked the global population presents more rapid and robust pathways for infectious pathogens. 15 whereas ecological footprint as a measure of human impact on the land by urbanization shows country exposure to the pandemic risk. 9 summing up, we label factor 1, as country's activity features, as it represents the people's activity features and infrastructure located in hazard-prone areas. factor 2 includes gdp per capita (q8), hdi (q9), tourism (q10), old population male over 65 (q11), old population female over 65 (q12), imr (q13), hospital beds available per capita (q14) and oops (q15). gdp per capita is a commonly used indicator for economic and human development 21 and as poverty measure 20, 64 .hdi is a statistic composite index of life expectancy, education, and per capita income indicators, ranking countries in human development. 22 cities with robust governance and health infrastructure are in a better position to manage pandemics and have lower case fatality rates and excess mortality than those that do not. 23 meanwhile, the infant mortality rate (imr) is a commonly used measure of population health. imr is associated with other factor variables affecting the health status of an entire population, such as its economic development, general living conditions, social well-being, incidence rate and environmental quality. 27, 28 also, covid-19 statistics show that the older population is, the more vulnerable to the virus it is. in many countries, an ageing population is challenging the healthcare system, social security, fiscal system. 25, 26, 48 one of the proxies for healthcare system capacity is the number of hospital beds available per capita. 29 this variable has become critical because of covid-19, as availability of excess beds means more lives are saved. 35 out-of-pocket payments (oops) signify spending on health directly out of pocket by households in each country. dependence on oops varies widely around the world, but there is a very strong correlation between the level of oops and the incidence of catastrophic and impoverished health expenditures. these two indicators are determined by the extent to which oops absorb a household's financial resources. [31] [32] [33] besides, the current situation with covid-19 has shown that countries with a high level of tourism, such as italy, are more vulnerable to pandemics due to population flows. in this paper, we label factor 2 as demographic features, because it represents variables that increase a person's and in turn the country's vulnerability to the effects of hazards. factor 3 includes telecommunication (q17), public and private debt to gdp (q18), government expenditure to gdp (q19), and socio-cultural disparity (q20). the modern economy is characterized by the increased use of telecommunication tools. during the recent covid-19 outbreak, mobile phone data were actively used to tackle the pandemic and internet provided timely informing and warning of population. 37 meanwhile, debt has an important role in ensuring the resilience of the country to macroeconomic and other shocks. 38, 39 we believe that lower level of public and private debt in case of pandemic enables the country to provide timely financial support of the economy, providing external and internal access to finance. 30 government expenditure to gdp indicates total government consumption, investment and transfer payments as a share of the country's gdp. this indicator is seen as a factor of a country's fiscal behaviour 40 and the determinant of output volatility, 41 whereas increasing government expenditure allows for reducing the negative effects of output volatility. besides, higher government expenditure is increasing disaster mitigation capability of the country. according to alesina et al, 42 the sociocultural disparity has an impact on the behaviour of individuals and the community as a whole especially in the case of a hazard. the contribution of the socio-cultural disparity to the pandemic risk exposure is not unambiguous. factor 3 we label as societal vulnerability due to the variables indicating vulnerability of society to pandemics. factor 4 includes inflation rate (q21), unemployment rate (q22), current account balance to gdp (q23). the inflation rate is one of the fundamental indicators of a country's macroeconomic conditions. however, the contribution of the inflation rate to the country's exposure to pandemic risk is not uniform. moderate inflation stimulates economic growth making the country less vulnerable to the risk, whereas high inflation rate implies rising prices good and services, including healthcare expenditures, increasing out-of -pocket payments and making the country more vulnerable to pandemic risk. the unemployment rate is one of the fundamental macroeconomic indicators showing the number of unemployed people as a share of the labour force. 45 given a higher unemployment rate, the total output is more sensitive to demand shocks, 46 making countries more vulnerable to pandemic risk. the current account balance to gdp is one of the measures of a country's external imbalances. it indicates the level of the international competitiveness of the country. high current account deficit increases the probability of capital flow contraction 47 increasing the country's vulnerability to external shocks and more vulnerable to pandemic risk. factor 4 we label as economic exposure following the economic nature of the included variables. to the knowledge of the authors, it is the first paper, which provides a pandemic exposure measurement risk model to determine the factors that affect a country's prospective vulnerability to a pandemic risk exposure such as covid-19. before the covid-19 pandemic, the global health security index (ghsi) was used as a measure of the country's pandemic preparedness. 65 the more developed and prosperous countries are better equipped to deal with pandemics, according to ghsi. in practice, it is better to benchmark countries during a pandemic in ways that allow information on outcomes and performance to be obtained, analysed, reported, and used in real-time. 66 the recent study of measuring the economic risk of covid-19 has computed measures for exposure (population, night-time light and transport density), vulnerability (data on economic outcomes, human development, tourism, and health quality) and resilience (internet access, public and private debt, government expenditure, sociocultural disparity) of the local economy to the shock of the epidemic. the study concludes that the highest economic risks are in countries and regions that do not get much global attention in normal times (such as sub-saharan africa) and get even less during pandemic's spread. 9 another study used 16 independent variables, such as hospital, mosque, atm, bank, fuel, attraction, city, footprint, road, and village, to model and map the risk of covid-19. 67 based on the analysis of existing literature, including literature on covid-19, consultations with experts and associations and survey conducted with risk managers we have identified the unaddressed factor variables for determining the vulnerability of countries to the pandemic. with this study we aimed to develop a pandemic risk exposure measurement (prem) model to determine the 68 this event has revealed the limits of extension of the national hospital and intensive care unit capacities in scenarios of sudden exceptional demand for medical care. the comprehensive burden was exposed to the mature post-industrial societies and emerging markets 69 and other lmics countries alike. due to a variety of distinctively different historical legacies of national health system establishments, they all responded with an array of adaptive strategies. despite the burden, efficient responses came from india, china, russia 70 and few other non-oecd economies. 71 another side of the equation was the unstable response burdened with several core inefficiencies in the traditional western european high-income societies such as italy, spain 72 and few others. thus, covid-19 has revealed huge mutual interconnectivity among the distant economic hubs of the modern-day world. proper risk assessments and the development of effective coping strategies might be highly valuable for the public health challenges of the future. besides, supranational actions might be needed to build up both public and private capacity to deal with pandemics. 73 the developed prem model consists of factor 1 (country's activity features), factor 2 (demographic features), factor 3 (societal vulnerability), and factor 4 (economic exposure), and explains 65.5% of the variance in "the level of experienced hazard of the participant (leh)". we also found that "the level of experience and knowledge of the participant" (leh) explains only approximately 2% of leh. our developed prem model is useful for risk managers and policymakers to proactively identify the factors that make the country more vulnerable to the pandemic risk and if necessary, manage them and/or set tolerance limits, policies, regulations, rules, standards, etc. it is not the intention with this study to design a one size fits all model but to provide policymakers and risk managers with a list of factors to enable the identification of country exposure and thereby enable proactive management and the development of a business continuity plan. moreover, as noted in the methodology section the study analysis is based mainly on self-reported responses to an online survey. this was built after consultation of the literature and case studies and deliberation with experts in the area of risk management. despite known weaknesses of this methodology, such as participant bias due to personal experiences; may result in classification error and underestimation or overestimation of measures. 74 the case studies used, deliberation with peers and the literature review was carried out before choosing the measures, to limit this and provide a robust list of measures. 36 moreover, hierarchical regression analysis showed that the difference in the explanation of variances when q1 -"the level of experience and knowledge of the participant" was added was of only approximately 2%. therefore, we can conclude that monitoring of these factors can help a country manage the change in their leh and devise policies to ensure that the country strengthens its capacity to meet demands for healthcare brought about by pandemic hazards such as covid-19. that is, to flatten the curve of healthcare, social and economic demands below the capacity and thus provide to this demand over some time. this is a flexible model which can be adjusted to the specificities of the relevant countries since the aim is to provide a way to measure vulnerability without considering the tolerance level and the controls put in place, which is dependent on the country itself. therefore, only when the latter two variables are considered can a country give value to the prem measure and prepare an accurate plan to ensure continuity of the norm (the variables to be considered by each country in addition to the prem model are tolerance and the controls in place). we declare that we have abided by the research ethics review procedures of the university of malta, faculty of economics, management and accountancy, malta ethics committee and gdpr directive -research and data protection unique form id: 5581_31052020, submitted by professor simon grima to the faculty of economics, management and accountancy ethics committee (frec). since there were no ethical issues or personal data collected we were provided with an automated ethical clearance and the clearance was submitted for filing with frec. the survey was administered as an online survey via weblink on qualtrics to contacts of the authors on social media, namely linkedin, facebook and twitter, who worked in a risk management function (non-probability purposive sampling). moreover, respondents were also invited using direct emails and were also asked to send this link to others working in the risk management function (non-probability snowballing sampling). responses were collected through qualtrics, no personal data were collected and/or maintained (anonymous response) and participants participated on a voluntary basis. the only filters, were that participants had to tick a box noting that they worked within a risk management function and that they consent (an informed consent) that we use the information collected for the analysis purposes of our study, before they could continue to answer the survey. an introductory paragraph describing the study was also provided at the beginning of the survey. risk management and healthcare policy is an international, peerreviewed, open access journal focusing on all aspects of public health, policy, and preventative measures to promote good health and improve morbidity and mortality in the population. the journal welcomes submitted papers covering original research, basic science, clinical & epidemiological studies, reviews and evaluations, guidelines, expert opinion and commentary, case reports and extended reports. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. submit your manuscript here: https://www.dovepress.com/risk-management-and-healthcare-policy-journal report of the open-ended intergovernmental expert working group on indicators and terminology relating to disaster risk reduction a dictionary of epidemiology underlying differences in health spending within the world health organisation europe region-comparing eu15, eu post-2004, cis, eu candidate, and carinfonet countries after covid: the next massive tail risk thematic analysis exploring factors affecting the proper use of derivatives: an empirical study with active users and controllers of derivatives. managerial finance fine-scale population density data and its application in risk assessment measuring the economic risk of covid-19 global metropolis: 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firms statistical downscaling and bias correction of climate model outputs for climate change impact assessment in the u.s. northeast immigration as a social determinant of health migration and health in the world: a global public health perspective using human development indices to identify indicators to monitor the corona virus pandemic the impact of gender on productivity and satisfaction among medical school psychologists factors associated with increases in us health care spending high out-of-pocket health spending in countries with a mediterranean connection adjusting health spending for the presence of comorbidities: an application to united states national inpatient data comparison of historical medical spending patterns among the brics and g7 mis-measuring our lives: why gdp doesn't add up? using multivariate statistics real gdp growth rates and health care spending -comparison between the g7 and the em7 countries assessing national performance in response to covid-19 spatial modelling, risk mapping, change detection, and outbreak trend analysis of coronavirus (covid-19) in iran (days between health financing constrained by population aging-an opportunity to learn from japanese experience comparison of historical medical spending patterns among the brics and g7 the impact of health expenditures on public health in brics nations the people's bank of china's response to the coronavirus pandemic-a quantitative assessment. economic modelling emerging evidence of a silver lining: a ridge walk to avoid an economic catastrophe in italy and spain. safe white paper prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the global burden of disease study we would like to thank primo -public risk management organisation https://www.primo-europe.eu/ for their help and guidance when preparing the inventory. the authors report no conflicts of interest in this work. key: cord-347449-mey7e8gd authors: albers, heidi j.; lee, katherine d.; rushlow, jennifer r.; zambrana-torrselio, carlos title: disease risk from human–environment interactions: environment and development economics for joint conservation-health policy date: 2020-07-09 journal: environ resour econ (dordr) doi: 10.1007/s10640-020-00449-6 sha: doc_id: 347449 cord_uid: mey7e8gd emergence of covid-19 joins a collection of evidence that local and global health are influenced by human interactions with the natural environment. frameworks that simultaneously model decisions to interact with natural systems and environmental mechanisms of zoonotic disease spread allow for identification of policy levers to mitigate disease risk and promote conservation. here, we highlight opportunities to broaden existing conservation economics frameworks that represent human behavior to include disease transmission in order to inform conservation-disease risk policy. using examples from wildlife markets and forest extraction, we call for environment, resource, and development economists to develop and analyze empirically-grounded models of people’s decisions about interacting with the environment, with particular attention to lmic settings and ecological-epidemiological risk factors. integrating the decisions that drive human–environment interactions with ecological and epidemiological research in an interdisciplinary approach to understanding pathogen transmission will inform policy needed to improve both conservation and disease spread outcomes. soon after the discovery of sars-2-cov, covid-19 became a pandemic event that spread worldwide, infected millions of people, and created unprecedented economic impact (who 2020a; guan et al. 2020) . current evidence suggests that covid-19 resulted from a zoonotic pathogen "spillover" event-transmission of a pathogen from wildlife to humans (andersen et al. 2020) . the majority (~ 60%) of the emerging infectious diseases (eids) since 1940 had an animal origin with most of these (> 70%) caused by pathogens associated with wildlife (jones et al. 2008) . although pandemics are rare, zoonotic disease incidence and novel spillover events cause frequent and serious health, social, and economic losses in tropical low and middle income countries (lmics) (morse et al. 2012) . as covid-19 spread around the globe, several countries in latin america experienced an extreme outbreak of dengue and other vectorborne diseases (lorenz et al. 2020 ) and the democratic republic of the congo endured their eleventh ebola outbreak since 1976 (who 2020b). because zoonotic spillover events occur in human-animal interfaces, policy to address such disease risks requires interdisciplinary analysis of the epidemiological, environmental, and human processes occurring on the landscape. data analyses find that disease emergence and biodiversity loss share common anthropogenic drivers: land use change, habitat fragmentation, expansion of the agriculture frontier, and wildlife harvest and trade (patz et al. 2004; wolfe et al. 2005; loh et al. 2015; huong et al. 2020) . given that people's decisions are the root of these drivers, the choices people make about interactions with the environment influence both conservation outcomes and infectious disease risk (murray and daszak 2013) . in many lmics, human-environment interactions occur during activities that are integral to daily life and are a function of specific socio-economic and institutional settings (albers and robinson 2013; nielsen et al. 2017) . establishing policy to increase conservation and reduce disease risk requires understanding both people's decisionsincluding land use, resource extraction, and market activities-within their context, and how environment-human interactions lead to disease risk. environment, resource, and development economists explore models and data to determine why and how humans interact with the environment in lmics, which informs conservation policy. here, we review how these economic frameworks capture-or do not capture-drivers and characteristics of the human-environment interaction, while reflecting the natural and socio-institutional settings of lmics. we then propose how modeling frameworks can be expanded to incorporate the disease risk posed by that interaction to inform needed socio-enviro-epidemiological research and policy analysis, using an iterative process of data collection and modelling in an interdisciplinary setting. finally, we discuss how expanded models can provide insight into behavioral drivers of risk and inform design of policy for two general types of pathogen transmission pathway from wildlife to humans: direct-contacting a pathogen through hunting, marketing, or consumption of wildlife, with an example from indonesian wildlife markets; and indirect-exposure to pathogens while undertaking livelihood activities, with an example of malaria transmission. filling this research gap will address calls from many conservation and health actors to incorporate human dimensions of disease risk into joint conservation-health policy (romanelli et al. 2014; díaz et al. 2015; whitmee et al. 2015; who 2015) . the effectiveness of conservation policy is dependent on its ability to influence human-environment interactions. conservation economics in lmics provides both empirical and theoretical models of human behavior that inform conservation policy to address anthropogenic causes of biodiversity loss, as called for by conservation scientists (reddy et al. 2017; dobson et al. 2019) . these frameworks recognize that patterns of land use are informed by, and inform, decisions of people in lmics that cause biodiversity loss (e.g. pfaff 1999; andam et al. 2008; pfaff et al. 2009; albers et al. 2019) . both environmental and socio-economic characteristics of lmics inform people's decisions and interactions with their environment and are often critical considerations in conservation policy. governments, large scale land actors, and individual people make decisions that combine to determine the pattern of landscapes and land uses. in turn, tropical lmic people's land use and environmental interaction decisions consider patterns of government investments in roads and protected areas, larger scale land users, and agricultural policies (albers et al. 2017) . here, we discuss the empirical analyses that identifies drivers of conservation outcomes, critique their ability to identify policy tools to influence individual decisions, and describe existing lmic models of human-environmental interaction with conservation policy levers to form the basis for the next section's discussion of incorporating disease risk in these frameworks. investigating deforestation, land use change, fragmentation, and park effectiveness, econometric analysis of spatial imagery and gis datasets identifies correlations between physical and socioeconomic characteristics and conservation outcomes (e.g. pfaff 1999; andam et al. 2008; pfaff et al. 2009; busch et al. 2015; leblois et al. 2017) . roads both create fragmentation and encourage follow-on land conversion and fragmentation (saunders et al. 2002; freitas et al. 2010) , and protected areas and community management alter fragmentation (sánchez-azofeifa et al. 1999; southworth et al. 2004; nagendra et al. 2008; sims 2014) . although such empirical analysis is important for identifying big-picture issues and correlations, this style of empirical analysis presents three challenges for policy to influence people's behavior. first, such analysis obscures the incentives driving behavior and considers the actions of people only implicitly, which complicates identification of behavioral policy levers. second, remotely sensed datasets often do not contain information about socio-economic and institutional settings that influence behavior, such as which forests are effectively managed by community organizations or which villages face costly market access ghate et al. 2009 ). third, heterogeneity of cultures, landscapes, and other characteristics of individual lmics make extrapolating empirical results from one location to another difficult (leblois et al. 2017) , such as across settings with different acceptability of eating primate meat between muslims and christians (nyanganji et al. 2011) . conservation economics modeling work in lmics emphasizes the role of the socioinstitutional and ecological settings in which people make decisions on human-environment interactions (e.g. gunatileke and chakravorty 2003; albers and robinson 2013) . in lmics, many production and labor allocation decisions are influenced by natural environments, such as agricultural activities and non-timber forest product (ntfp) extraction, including hunting (robinson 2016; nielsen et al. 2017) . costly or limited market access influences decisions about how much to interact directly with natural environments for extraction and farming when facing a subsistence need or cash requirement (robinson et al. 2002; sills and abt 2003; muller and albers 2004; ghate et al. 2009 ). decisions to consume or trade wildlife depend on market access, prices, and opportunity costs (damania et al. 2005; wilkie et al. 2005) , in addition to other aspects of the household's production function including protecting crops from wildlife (johannesen and skonhoft 2004; bulte and rondeau 2007) . lack of clearly defined or enforced property rights create incentives that result in de facto open access use and habitat degradation (bulte and engel 2006; lópez-feldman and wilen 2008) . models that incorporate spatial decisions-about extraction and land use-provide a more explicit representation of the human-environment interactions that drive conservation outcomes and reflect the impact of property rights, community management, resource density, and market access on those interactions (robinson et al. 2002 albers et al. 2019 ). these economic decision models provide a lens through which to interpret data correlations and highlight policy levers for steering human interactions with the environment. developing general models of people's decisions within their social and ecological context, augmented with appropriate observation and data, can help form context-specific policy that focuses on changing people's behavior in pro-conservation ways that data analysis identifies as policy priorities. economists, health scientists, and conservation actors alike call for more research and policy that simultaneously addresses conservation and disease risk (salkeld et al. 2013; civitello et al. 2015; pattanayak et al. 2017) . often, conservation policy mitigates disease risk simply because conservation policy reduces contact between people and natural environments and wildlife. 1 deforestation, land use change, and fragmentation all correlate with both biodiversity loss and zoonotic disease risk (patz et al. 2004; suzán et al. 2008; morand et al. 2019) . ecological models predict the geographic locations where new diseases may emerge or from which wildlife species they may emerge, but, despite including demographic variables, these models do not explicitly consider the interactions of people with their environment, which is a factor in the risk of zoonotic disease transmission (allen et al. 2017; olival et al. 2017 ). that transmission occurs through a combination of environmental, epidemiological, and human behavioral factors: first, human decisions determine the characteristics of the ecological landscape; second, the resulting environmental conditions determine the distribution of, and intensity of infection in, reservoir hosts; and third, the choice of activity and amount of time allocated to specific activities (hunting, farming, harvesting ntfps) drive the risk of exposure to pathogens (plowright et al. 2017) . as an example, the likelihood of mosquito-borne pathogen transmission depends on the abundance of mosquito vectors on a landscape, the pathogen load within the mosquito population, the chance that a pathogen-carrying mosquito bites a person, and the probability that the pathogen successfully infects the human (baeza et al. 2017 ). to depict risks on the landscape, disease ecologists create global emerging infectious disease "hotspot" maps that correlate past emerging infectious disease events, demographic data, and environmental variables to estimate the spatial relative risk of zoonotic spillovers worldwide. these models were developed at a coarse spatial resolution due to the sparsity of the data and multi-scale variables (allen et al. 2017) . human decisions around resource use and environmental interactions occur at a finer scale, making those interactions difficult to represent in this framework despite their critical role in determining the risk of disease. to address how humans influence zoonotic disease risk borne from environmental interactions, these hotspot maps can be combined with economic decision models at fine resolution that specify markets and institutions, landscape patterns, and resource use in lmics, and thereby illustrate the decisions behind where and how people overlap with pathogen hosts, which influences their pathogen exposure. using conservation economics models as a basis for developing policy that addresses both conservation and disease risk requires modeling extensions and new information. first, because both the amount of time and the locations of human-environment interactions contribute to disease risk within the ecological setting, expanding models of decisions about agricultural expansion, wildlife hunting and marketing, and resource extraction to incorporate space and time as decision variables provides a mechanism for characterizing the disease risk of such actions and for policies to internalize the disease risk into decisions. second, because both the ecological landscape of pathogens and human activities vary seasonally, economic models at the sub-annual level could identify seasonally targeted policies to mitigate disease risk. third, although empirical analysis signals the role of fragmentation in both biodiversity loss and zoonotic disease incidence, little ecological, economic, or interdisciplinary research depicts the process of fragmentation in a manner that helps define policy tools that influence people's actions in ways that could limit conservation losses and disease risk from fragmentation. in addition to such extension of modeling frameworks to address disease risk in the lmic context, we propose an interdisciplinary and iterative process of on-the-ground observation; economic, behavioral, and epi-ecological modeling to guide further field work; and data collection in a standardized manner to inform further research and policy efforts. that iterative process might begin with observation, both finding correlations in data and through stakeholder input; followed by economic analysis of models of human decisions parameterized with empirically-relevant values to identify the critical mechanisms and drivers of the human-environment interaction and potential for policy; followed by prioritization of ecological or economic data collection to form policy in specific settings; and an iteration back to broader data analysis to discern policy impact. such interdisciplinary analysis incorporating economic modeling will improve our ability to define factors that influence people's decisions involving interaction with the environment and the related disease risk. in the next two sub-sections, we discuss how to extend economic models of environmental interactions in lmics to incorporate disease risk in settings in which the risk is directly related to the actions taken by people, such as wildlife marketing, and in settings in which the disease risk derives indirectly or incidentally from the environment, such as siting livestock operations at the forest margins. the trade in legal and illegal wildlife is worth billions of dollars, with hundreds of millions of animals and plants traded globally (fukushima et al. 2020) . wildlife trade creates a direct human-wildlife interaction through intentional contact with the live or dead wildlife species at any point along the supply chain-from hunting to trading and selling to consumption (daszak et al. 2000; kruse et al. 2004; breed et al. 2006) . for example, sars-cov and sars-2-cov are linked to wildlife trade in china, hiv to primate bushmeat hunting, monkeypox virus to the exotic pet trade, and h5n1 and h7n9 to domestic poultry (karesh et al. 2005; gilbert et al. 2014; andersen et al. 2020) . capturing, raising, and transporting live animals brings many individuals into close proximity, creating opportunities for inter-and intra-species pathogen transmission and potentially spillover to humans. for example, sars originated in wet markets where the pathogen spilled over from bats to civets (li et al. 2005) , and sars-2-cov may have originated with pangolins as an intermediary host (andersen et al. 2020) . in these cases, the lack of regulations and poor biosafety at nodes on the supply chain increased the risk for vendors and purchasers further downstream. as the starting point of the wildlife supply chain, hunting activity that supplies markets poses a risk of disease spread as hunters interact with live animals (wolfe et al. 2005) . given that interaction, the drivers of hunting decisions can be targeted by policy to reduce disease risk and promote conservation. households face tradeoffs in their decisions to allocate time or land between agriculture and wildlife harvesting (bulte and horan 2003) . when these households also consume harvested wildlife, the income elasticity of demand for bushmeat drives the response to an alternative livelihood policy, identifying this elasticity as priority data (damania et al. 2005 ). response to policy may also differ when the hunted species are considered a nuisance to agriculture and are taken to defend crops as well as for consumption or sale. this dual purpose of hunting affects the tradeoffs hunters face when reacting to policy (johannesen and skonhoft 2004; bulte and rondeau 2007) . empirical analyses find variation in the response of hunters to the relative costs of hunting in an environment, such as park proximity; labor tradeoffs with other activities, particularly livestock; and household characteristics (e.g. brashares et al. 2011; foerster et al. 2012; van velden et al. 2018) . hunters may respond to the increased opportunity cost of hunting by switching to more efficient hunting techniques and more valuable species, which does not address disease risk and presents a conservation risk when those valuable species are protected species (damania et al. 2005) . when hunters cannot discriminate in the species they hunt, enforcement policies may have unintended consequences around consumption of protected species (robinson 2008) . hunters' decisions rarely include disease risk mitigating activities, perhaps due to a lack of knowledge of the risk the animal presents (harrison et al. 2011) . policies to alter incentives for bushmeat hunting and consumption include enforcement of illegal hunting, community-based conservation, and alternative or additional livelihoods and protein sources (foerster et al. 2012; van velden et al. 2018) . models predict the outcomes of these policies, showing in what circumstances alternative livelihoods, enforcement, and expanding protected areas lead to negative conservation outcomes (damania et al. 2005; johannesen 2007; robinson 2008) . policies that reduce hunting itself create conservation and disease risk mitigation but can impose economic burdens on hunters and demand for wildlife/bushmeat continues to create incentives for hunting. policies that promote safer hunting practices, information about disease risk, and incentives to hunt lower risk species directly alter the disease risk within the context of ongoing hunting. between the hunters and the final markets, traders, middlemen, and sellers in the wildlife/bushmeat supply chain serve a crucial role in lmics by providing access to markets, and also face disease risk. yet, few economic models and empirical analyses include the role of these other actors, which misses additional points of human-disease interaction that could respond to policy (bowenjones et al. 2003; cowlishaw et al. 2005; kamins et al. 2011; nielsen et al. 2014; bachmann et al. 2019; van vliet et al. 2019; latinne et al. 2020) . middlemen with sufficient market power can pay lower prices to hunters than middlemen operating competitively and prevent the system from reaching the open access outcome (tháy et al. 2019 ). this role of middlemen is relevant in modeling wildlife supply chains and the resulting disease externality because they drive two elements of the disease risk: the amount of wildlife being harvested and the number of people directly contacting the wildlife. all points of human-wildlife contact along the supply chain represent areas of zoonoses spillover risk and possible opportunities for changing human behavior with policy levers. both local and global consumers contribute to the demand for wildlife and bushmeat (mcnamara et al. 2019; fukushima et al. 2020) . local demand in lmics is largely driven by wealth, nutritional needs, and prices (wilkie et al. 2005; fa et al. 2009; godoy et al. 2010) . analysis of demand across countries finds a range of income elasticities and price elasticities for bushmeat (wilkie and godoy 2001; east et al. 2005; wilkie et al. 2005; mcnamara et al. 2019) . policy can be aimed at manipulating the prices of bushmeat to reduce demand, and thereby reduce disease risk to consumers and the supply chain by reducing supply, but variation across settings in demand response imply a need for contextspecific information. here we demonstrate the role of balancing observation and data collection with modeling of people's decisions around their interaction with wildlife to inform conservation and disease policy. the wildlife markets in north sulawesi, indonesia sell a variety of wildlife and domestic animals, including bats like large flying foxes, which could potentially lead to disease spillover events. bat sales in these markets have been increasing for decades (clayton and milner-gulland 2000; lee et al. 2005; latinne et al. 2020 ) and concerns about declining bat populations and potential pathogen spillovers led to calls for policy to reduce bat harvesting (sheherazade and tsang 2015; latinne et al. 2020) . latinne et al. (2020) conducted stakeholder interviews with hunters, local collectors, middlemen, and vendors, and collected market data during 2016-2019 to describe the supply chain and estimate quantities of marketed bats. an important feature of these markets is that regional resource use and cultural differences between geographic regions create the current structure of the supply chain. demand for bat protein stems from christians in northern sulawesi, where hunting has historically occurred and reduced bat populations. current supply is transported from provinces in southern sulawesi, which are predominantly muslim and do not consume bats, and therefore have larger populations to hunt (clayton and milner-gulland 2000; lee et al. 2005; sheherazade and tsang 2015) . hunters sell the bats to either to local collectors or directly to middlemen, who transport the bats to the markets in the north (latinne et al. 2020) . by identifying the actors and collecting data on revenues and costs, latinne et al. (2020) identifies two salient characteristics of this market for policy development-hunters operate under open access conditions and middlemen transport animals to markets, factoring transportation costs into prices. combining observations, stakeholder interviews, and data collection, followed by modeling the entire supply chain, highlights specific incentives to target in order to conserve bats and mitigate pathogen spillovers from wildlife. the construction of the trans sulawesi highway in 1980 allowed vendors to travel further to collect wildlife and expanded the region over which bat harvest creates conservation losses and disease risk (clayton and milner-gulland 2000) . policies such as highway tolls that increase transportation costs to middlemen could reduce the volume of bats traded because hunters cannot readily access markets. in this case, data collection on the elasticities of demand for bat meat would be a critical piece of information to collect to determine whether the middlemen may pass on the price increase to consumers. second, policies aimed at providing alternative income sources to hunters could increase middlemen costs and reduce both harvest and disease risk. the policy could also increase the practice of middlemen transporting hired hunters to harvest the area, and disease risk and conservation concerns would continue (latinne et al. 2020) . to counter coordination between middlemen and hunters, policies that provide incentives for people in southern sulawesi to both forego hunting and protect bats from hunting could prevent these migrant hunters from accessing bat habitat. despite the valuable ecosystem services provided by bats, including fruit pollination, bats are generally considered a nuisance species by fruit farmers on sulawesi, which limits the farmers' interest in providing such incentives to bat hunters (banack 1998; latinne et al. 2020) . closer collaboration between conservation and health organizations could support payments for ecosystem services to potential bat hunters to discourage bat harvest and disease risk while promoting bat conservation for bat pollination and seed dispersal services. the iterative process of field work and modeling the supply chain, informed by stakeholder interviews, establishes a fuller picture of the disease externality risk at each contact point and the decisions of all actors and forms the basis for policy analysis aimed at reducing human-wildlife contact's disease risk and promotes conservation. some risk of disease arises through frequent human interactions with the environment in which contact with wildlife hosting a pathogen is incidental or an unintended consequence. these types of environmental interactions tend to drive persistence of endemic infectious diseases. for example, while harvesting fuelwood or other ntfps, individuals increase their exposure to arthropods or non-target wildlife species that are carriers of infectious pathogens like malaria and yellow fever (barros and honório 2015) . in southeast asia, pathogen transmitting mosquito species are found in greater abundance near deforested land and oil palm plantations (young et al. 2020) . the expansion of agricultural land, in particular oil palm and rubber in liberia and sugar-cane in bolivia, has increased the frequency of contact between plantation workers and rodents that are attracted to these environments, increasing thus the risk of hemorrhagic fevers (e.g. lassa fever in africa or ordog fever in south america) (olugasa et al. 2014; patterson et al. 2014; gibb et al. 2017) . the decision to site livestock operations near forest habitat increases the likelihood of interactions and conflicts between livestock and potential wildlife reservoirs for pathogens. for example, the emergence of nipah virus in malaysia was directly linked to agricultural intensification. pig farms were established in close proximity to forest; farmers planted fruit trees for additional income with the unintended result of attracting bats, which are natural reservoirs of nipah virus . in each of these examples, the risk of disease is endogenous in the decision to interact with the environment, but the risk is incidentally related to that decision. in these settings, the context of when, where, and how individuals interact with the environment plays an important role in the risk of disease. indirect interactions with disease risk are driven by choices individuals make about how and where they spend their time with respect to activities such as subsistence farming, collecting ntfps, mining, or working in the agricultural sector. these choices affect the land covers, habitat degradation, and wildlife with which individuals interact. as an example of a modeling opportunity, the ecological literature indicates that disease risk is greatest in altered or degraded natural habitats (murray and daszak 2013) , which could link to people's decisions as a function of resource quality. modeling the choice of labor allocation within a particular socio-institutional setting explicitly allows for representing trade-offs of allocating time to specific activities across land covers. labor allocation results can be combined with ecological models or data on vector or pathogen abundance across landscapes to determine individual pathogen exposure risk. the setting's institutions can also influence disease risk. for example, introducing markets for fuelwood substitutes alters the labor allocation to that environmental interaction and exposure to pathogens. similarly, establishing community property rights in forests that have been degraded by overextraction in de facto open access mitigates disease risk by reducing pathogen prevalence and reducing extraction within the forest. with more contextual information about activity choices from socio-economic field work, the daily and seasonal timing of activities can further inform infection risk. for example, if a wildlife species has crepuscular activity and agricultural work is conducted in the cool early morning, high vector activity and human presence on the same landscape may create a high-risk setting for pathogen transmission (vittor et al. 2006) . policy to reduce the risk of disease transmission through indirect interactions can take one of two approaches, either limiting resource extraction or limiting exposure to pathogens in risky environments. limiting the extent of extractive industries can simultaneously address conservation and health policy goals, but limiting opportunities for economic activities can result in illegal resource extraction, and disease incidence is often greater around illegal resource extraction operations (castellanos et al. 2016) . to limit extractive industries would therefore require creating alternative (legal) economic opportunities or payment for ecosystem service programs (cárdenas 2017 ) and monitoring and enforcing regulations. alternatively, policies can be developed using information about which specific actions increase human contact with the pathogen, and therefore create the greatest risk of pathogen transmission. for example, if oil palm plantation workers live near fields, increasing their risk of exposure to rats and lassa fever, housing can be sited in locations farther away from the source of risk. finally, disseminating information about how specific activities increase disease risks may be a viable policy to mitigate pathogen transmission. here, we explore an example of how leveraging empirical findings and expanding existing models, in combination with socio-economic and environmental observations, can inform policy to reduce malaria risk. a majority of the empirical disease research examines disease incidence from incidental interaction between humans and disease vectors stemming from economic activities such as land use change. ecological research suggests that deforestation opens the forest canopy, which modifies moisture and sunlight that reaches the ground and creates ideal breeding conditions for mosquitoes, which can transmit malaria (de castro et al. 2006; vittor et al. 2006 vittor et al. , 2009 . simultaneously, deforestation reduces the abundance of species that feed on mosquitoes, amplifying both the density of the vector and pathogen (baeza et al. 2017 ). in the amazon region of south america, the malaria vector species anopheles sp. occurs in greater abundance at forest edges and agricultural landscapes and in lower densities in forests and protected areas; anopheles abundance and diversity varies across land cover types (space); and anopheles feeding activity varies by time of day and season (stefani et al. 2013; bauch et al. 2015) . these findings imply that where and when people choose to perform activities is important in exposure to pathogens and disease risk. combining evidence from the natural sciences with economic models that explicitly represent when and where individuals spend time between, for example, collecting ntfps in a protected area and working in agricultural fields can provide insight into how incentives shape risk of infectious disease. existing econometric studies relating deforestation to malaria incidence have been conducted for south america, africa, and asia, and rely on geospatial datasets in combination with either regional epidemiological data (valle and clark 2013; hahn et al. 2014; terrazas et al. 2015; garg 2019) or individual health survey data (berazneva and byker 2017; bauhoff and busch 2020) . while the majority of studies find either positive correlation or causation between deforestation and disease incidence, these results are not consistent across all published works (e.g. valle and clark 2013; bauhoff and busch 2020) . although the increasing availability of geospatial and large datasets provides insight into global trends and hotspots for diseases, how people's decisions contribute to the risk of disease spread cannot be discerned from data at the parcel or pixel unit of analysis. as a result, the policy implications and ability to generalize results from these empirical studies are limited to identifying specific demographics that can be targeted for malaria prevention and control programs and broad statements about curbing rates of deforestation. as one possible starting point, albers et al. (2019) 's model of labor time allocation between wage labor and ntfp extraction incorporates both an individual spatial extraction path decision and an aggregate spatial equilibrium of ntfp extraction in a forest. that framework could be expanded to replace wage labor with agriculture, to further refine the timing and seasonality of decisions, and to reflect a range of socio-institutional and ecological settings. this modeling framework can be validated and parameterized using stakeholder interviews and observational data. then, overlaying this economic spatial land use model with ecological models that determine mosquito bite rate probabilities in agricultural land, fringe forest, deeper forests, and protected areas allows the model's solution to define the malaria transmission risk facing each individual based on their where and when they decide to perform specific activities. analyzing the spatial pattern of resource extraction decisions as a function of ecological, socio-institutional, and market settings can reveal the characteristics of settings and individuals that drive malaria risk and provide insight for policy development. simultaneously considering the daily and seasonal timing of human and vector activity (mosquitoes are most active at dawn and early evening, and most abundant around rainy seasons (de castro et al. 2006) ) can avoid creating policies that unintentionally increase pathogen transmission risk. for example, creating alternative fuel sources may decrease the total time spent in forests extracting fuelwood but focus that reduced time in ntfp extraction in fringe forests that have higher mosquito abundance, thereby increasing disease risk. joint consideration of the impact of policies on conservation and health outcomes can avoid perverse incentives and unintended outcomes. supplementing sensitivity analysis with stakeholder observations and data to describe particular settings produces stronger understanding of the drivers of decisions that create the disease risk and identifies the information and data necessary to provide the right policies for the ecological and institutional setting, across seasons. environment, resource, and development economists are particularly well-suited to developing frameworks of people's decisions to interact with their environments; and such models can identify policy levers that alter people's actions in ways that promote both conservation and disease risk mitigation. we suggest three guides for policy-relevant research: data analysis to identify correlations between land/resource characteristics and disease risk is necessary and important but not sufficient to guide joint conservation and disease-risk mitigating policy. empirical analysis that defines correlations but is not specific to people's decisions does not provide information about how human-environment interactions affect conservation or disease spread, which implies that policy levers are difficult to identify below generalities, such as "slow deforestation," "limit fragmentation," and "close wildlife markets." modeling people's decisions to interact with natural resources in a lmic setting, while using an iterative process that incorporates context and data, enables policy design based on people's decisions and disease spread mechanisms that can be modified for specific settings. because empirically-informed models characterize decisions about interactions with the environment, they can be used to identify how people react to policies that drive both conservation and disease risk outcomes. in the absence of detailed data at every site of conservation and disease policy interest, general models can prioritize particularly important data collection to enable the model's application in other eco-institutional settings. although economic models of people's decisions to interact with the environment are important for defining conservation-disease policy, interdisciplinary research with ecologists and epidemiologists is necessary to accurately reflect the mechanisms of disease spread that matter for policy. the risk of disease spread is a function of people's choices and of how those choices lead to pathogen exposure, which implies that economic models must be paired with data and models of those disease risks. economic models of humanresource interaction that differentiate across choices of locations and time spent, and across seasons, may be necessary to characterize human infection risk. in turn, economic policy analysis can prioritize further research into ecological mechanisms that drive risk in specific environments. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes 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345717 cord_uid: ktajrf7d we report on a study conducted in guangdong province, china, to characterize behaviors and perceptions associated with transmission of pathogens with pandemic potential in highly exposed human populations at the animal-human interface. a risk factor/exposure survey was administered to individuals with high levels of exposure to wildlife. serological testing was performed to evaluate prior infection with several wildlife viral pathogens. follow up serology was performed on a subset of the cohort as well as close contacts of individuals. 1,312 individuals were enrolled in the study. contact with a wide range of wildlife species was reported in both occupational and occasional contexts. the overall proportion of individuals seropositive to any of the tested wildlife pathogens was approximately 4.0%. however, persons employed as butchers demonstrated a seropositivity of 9.0% to at least one pathogen of interest. by contrast, individuals working as hunters had lower rates of seropositivity. among the study population, a number of other behaviors showed correlation with seropositivity, including contact with particular wildlife species such as field rats. these results demonstrate the need to further explore zoonotic risks of particular activities regarding wildlife contact, and to better understand risks of persons working as butchers with wildlife species. the majority of human infectious diseases have an animal origin, therefore understanding the human-animal interface as it relates to disease emergence and risk is of upmost importance [1] . the increasing frequency and variety of human-wildlife interactions in china provide opportunities for the transmission of zoonotic pathogens from animals to humans [2] . a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 handling, transporting, and butchering of hunted or farmed wildlife poses a risk of pathogen spillover into humans [3] . in southern china provinces, including guangdong, a significant percentage of the population obtains fresh meat for consumption from wet markets, community markets that specialize in selling and butchering live animals, including animals that are rare and endangered. research has demonstrated that human-animal interfaces, such as within these wet markets, provide an ideal environment for infectious disease emergence, transmission, and amplification [4] [5] [6] [7] . wet markets and restaurants that butcher and sell wild animals are common in china and south east asia, creating a high-risk interface where humans come into regular contact with the blood and bodily fluids of wild and domesticated animals. intermingling of wildlife in wet markets can lead to inter-species transmission of pathogens, amplifying and maintaining these pathogens, and may result in spillover into a species that can more efficiently transmit the pathogen to humans [8] . furthermore, increasing numbers of individuals are traveling to urban-rural interface areas to eat at "wildlife" restaurants. hunted or farmed wildlife are transported and kept alive at these restaurants until consumption, increasing the risk of pathogen spillover. the wildlife trade has played a role in the emergence of severe acute respiratory syndrome (sars), avian influenza, ebola, and other diseases of wildlife origin [2, 9] . guangdong province in china was the site of the first cases of sars in 2002. now known to have originated in bats [10] , sars emerged in humans and other mammals in wet markets, such as himalayan palm civets (paguma larvata) and raccoon dogs (nyctereutes procyonoides) [11] . the disease spread to 26 countries and infected over 8,000 people; killing nearly 800 [12] . sars shut down trade of domestic animals and resulted in nearly $40 billion in losses to the global economy [13] . h5n1 outbreaks during 1999-2008 and h7n9 in 2013 have demonstrated the realities of the risk of disease transmission and spread in china and the detriments to animal and human health, as well as human livelihoods [9, 14] . these epidemics shed new light on how quickly and how far newly emerged zoonotic diseases can spread in today's world. these outbreaks continue to challenge scientists, policymakers, and public health systems, exemplifying the need for a better understanding of the factors leading to emergence, and clarity regarding emerging infectious disease policy, particularly as it concerns high-risk human-animal interfaces. although mounting evidence implicates illegal trade and behavioral and cultural factors as influencing disease emergence, it is clear that more research is needed to identify these drivers [2, 4, 6, 7, 15] . a key aspect of understanding human-wildlife interfaces is the characterization of risk behaviors and perceptions of individuals who have wildlife contact. specifically, there is a need to evaluate whether particular behaviors are associated with increased risk of transmission. as well, serological studies may be helpful to evaluate exposure, either current or prior, to zoonotic agents. for example, when guan et al. (2003) surveyed animals in markets for evidence of sars-like coronavirus [11] , they also performed serological analysis on market employees. seroprevalence in their study ranged widely between traders (wild-animal to vegetable), butchers and community controls. the present study focuses on the potential for zoonotic viral transfer through contact with wildlife in guangdong prefectures in china, and seeks to augment our understanding and identification of risky populations, occupations, and behaviors, as well as the perceptions of risk at these interfaces. we performed a serological survey and concurrent behavioral questionnaire of individuals with wildlife contact in guangdong province, china, in order to better characterize occupations and community-level behavioral risks that contribute to zoonotic transmission of various wildlife pathogens with pandemic potential. this study took place in guangdong province (23˚24'n, 113˚30'e), china from 2009-2013. guangdong is located on the south china sea coast, bordering guangxi province, hunan province, jiangxi province and fujian province. it neighbors hong kong and macau, and has over 50 million residents living in 9 cities: guangzhou, shenzhen, dongguan, foshan, zhongshan, zhuhai, jiangmen, huizhou and zhaoqing. enormous consumption of animal and animal products in this region is believed to serve an economical incentive for butchers, cooks and hunters in less developed guangdong prefectures, e.g. qingyuan, yunfu and meizhou. guangdong province has consistently reported the largest population in china since 2005, with the highest gdp rankings for the last 25 years. its economy is highly dependent on the pearl river delta region, which contributes around 80.0% total provincial gdp while supporting 29.0% of the provincial population. the study was conducted in 12 prefectures within the guangdong province: dabu, jiaoling, pingyuan, lianping, heping, lianshan, lianzhou, yunfu, yunan, xinyi, deqing and fengkai (fig 1) . we chose field sites within the identified prefecture areas that have wet-markets, wildanimal restaurants, and other environments with a higher risk of animal-to-human pathogen transmission. these environments, particularly the markets, were deliberately chosen due to their size and character. similar species of wildlife, both live and butchered, were present, with similar butchering methods being utilized. populations in these environments with high-risk animal-to-human pathogen transmission activities, such as hunting, and butchering in wetmarkets and wild-animal restaurants were selected. we targeted high-risk individuals, defined as individuals with high levels of exposure to wildlife (wild animal blood or bodily fluids)-primarily hunters, persons working in wet markets and restaurants that butcher wild game, who could be followed over a period of time. inclusion criteria included participant age between 18-65, and individuals that reported previously hunting, selling, butchering, or eating wild animals. individuals who did not provide informed consent and/or did not agree to biological sample collection were excluded. individuals were residents of the site area so that they were available for follow up visits. more than 20 potential field sites were visited to gauge level of risk at the site (number of high-risk animal-human interfaces). local prefecture-level chinese center for disease control (cdc) teams were asked to pre-enroll individuals who fit the inclusion criteria and would be available for follow up visits for up to three years. based on pre-enrollment numbers and human-animal interfaces identified at each site, 12 field sites that were identified in the previously named prefectures: dabu, jiaoling, pingyuan, lianping, heping, lianshan, lianzhou, yunfu, yunan, xinyi, deqing and fengkai were chosen to participate in the study (fig 2) . study participation was voluntary and respondents were given the equivalent of 5 usd (approximately 30 cny) as compensation for their time. informed consent was obtained from all enrolled participants prior to enrollment and specimen collection. in total, 1,267 participants were enrolled in the first round of the study. the prefecture-level cdc research teams were trained in all enrollment procedures (biological and behavioral questionnaire). ten (10) ml of peripheral venous blood was collected using pre-labeled vacuum edta blood collection tubes. all blood samples were chilled immediately at 4˚c, and transferred to participating cdc laboratories at surveillance sites within 2 hours after sampling. upon arrival of blood samples into the laboratories, sera were isolated by 1,500 g centrifugation for 15 min. serum was aliquoted, flash frozen in liquid nitrogen, and then stored at -80˚c. all study participants responded to a detailed questionnaire including questions about demographics, occupation, rural vs. urban habitation, zoonotic disease risk perceptions, and contact with particular types of wildlife through hunting, butchering, or eating. the questionnaire was based on a previous study in cameroon and is available in the s1 file [16, 17] . it was adapted in english for the study environment in china and then translated into simplified chinese. during the training of the local cdc research teams, pretesting of the questionnaire was done to ensure the intelligibility of the questions and proper translation. pretesting was also done with the study population during the pre-enrollment phase for the study sites. during enrollment, a trained member of the local cdc team who was fluent in the local language of the study site administered the questionnaire. in guangdong province, both mandarin and cantonese are spoken in the study sites. the questionnaire was administered in either mandarin or cantonese depending on the respondent. all follow up study respondents were contacted by a member of the trained research team regarding their test results. seropositive individuals or those with indeterminate results were referred to a local clinic/hospital where they could follow up on their results. this study did not provide additional financial or medical support for respondents who tested positive. all results were kept confidential and only reported to the respondent themselves. 95 individuals who tested seropositive from the first enrollment were asked to participate in an additional follow up sampling visit. they were also asked to invite up to three of their close contacts to enroll in the follow up study. we aimed to continue behavioral information and biological sample collection towards gauging virus transmissibility. prior to sampling, we re-consented seropositive individuals and consented their close contacts. due to geographic reallocation of some respondents, we were unable to locate 52 individuals with indeterminate or seropositive results for inclusion in our follow up study. we successfully re-enrolled 43 seropositive respondents and 45 of their close contacts in our follow-up study (fig 2) . the serological investigation focused on detection of hantavirus, sars cov, and severe fever with thrombocytopenia syndrome (sfts) bunyavirus. this study aimed to demonstrate viral transfer associated with exposure to wildlife and the virus targets for this study were selected based on prevalence and infection associated with animal/wildlife contact as well as an interest by the gdcdc [18] [19] [20] . to determine hantavirus specific antibodies in study respondents, stored human sera were tested using hantavirus hantaan igg/igm elisa in a single well for each sample (ibl, hamburg, germany) [21] . microtiter plates were pre-coated with recombinant nucleo-capsidprotein of hantaan virus. according to the manufacturer's instructions, control groups and experiment group sera were diluted at 1: 100 using 1×pbs, ph 7.4, and incubated at 37˚c. coated wells were washed, and then incubated with 100 μl diluted peroxidase conjugated anti-igg enzyme at 37˚c. color development reaction was initiated by adding a chromogenic substrate, tetramethylbenzidine, followed by a 10 minute incubation at room temperature. reaction was quenched by adding 100 μl 0.5 m h 2 so 4 , and then measured at 450 nm to obtain its optical density. human sera were also tested for sars cov using the sars coronavirus igg diagnostic kit (bgi, shenzhen, china) [22] [23] [24] . microtiter plates were pre-coated with vero e6 cell lysate. cells were previously infected by sars coronavirus that was isolated during the sars outbreak in 2002 in china. sera preparation and indirect elisa were conducted as described above. the average optical density (od) of negative control sera plus 0.13 was used as the cut off value as suggested by the manufacturer. we adopted recombinant coating antigen in the diagnosis of sfts bunyavirus using indirect elisa. gene encoding 6×his tagged sfts bunyavirus hb29 nucleocapsid (n) protein was expressed in e. coli, and purified using nickel affinity chromatography. recombinant anti-sftsv igg was immobilized in 96-well plate as coating antigen. sera were diluted at 1: 100 using 1×pbs, ph 7.4, and incubated at 37˚c. we used horseradish peroxidase (hrp)-conjugated anti-human igg antibody (sigma, saint louis, mo) as the secondary antibody for color development. od was measured at 450 nm, with a reference wavelength of 620 nm. cut-off value was determined by adding 3× sd to the mean of od values resulting from analyses of negative control sera. moreover, a microneutralization assay was performed to detect neutralizing antibodies against sfts bunyavirus [25] . this was done to ensure the highest level of certainty given the newness of the sfts virus assays. fifty (50) μl serially diluted human sera were mixed with an equal volume of 100 tcid50 /0.1ml of sfts bunyavirus hb29, and then incubated at 37˚c for 1.5 h. incubated mixture was added to cultured vero cells in a 96-well plate in quadruplicate. subsequently, the plates were incubated at 37˚c with 5.0% co 2 for 7 d. viral infection was assessed via an immunofluorescence assay using mouse polyclonal anti-sfts bunyavirus antibody. end-point titer was then expressed as the reciprocal of the highest dilution of serum with viral infection prevention capability. laboratory results and behavioral data from the questionnaire were manually entered twice (double entry system) and compared for entry error. hand checks were also done on 10.0% of the database to further reduce chances of human entry error. questionnaire responses and serological test results were then analyzed and compared using sas (version 9.4; sas institute inc., cary, nc, usa). we assigned primary occupation to the categories of hunter, agriculture worker, butcher, market worker, and restaurant worker based on questionnaire responses. we also aggregated reported behaviors to assign an "ever" status to each individual in terms of eating, butchering, or hunting wildlife. basic descriptive univariate statistics were carried out on the data set. we then examined bivariate associations between serological status for the three viruses of interest and independent demographic and risk behavior variables. variables showing bivariate association with seropositivity at a p value of 0.1 or less were included in multivariate logistic models for seropositivity to individual viruses or any of the three viruses using firth's penalized likelihood adjustment to address small sample size and possible collinearity [26] . since butchers were the only occupational group showing increased risk of seropositivity, we also performed a subanalysis of specific behaviors performed by butchers, again including behaviors with bivariate association of p = 0.1 or less in a multivariate logistic model. a total of 1,267 individuals provided a baseline blood sample for serological testing and completed a behavioral risk factor survey. the demographics of these individuals are shown in table 1 . the study population was predominantly younger than age 60, with a mean age of 36.97 ±11.03 years. junior high school was most frequently reported as the highest level of education attained. most of the respondents were married or living with their partner and had between 1-2 children, with a total of 3-6 people living in the house. traveling to a forest at least once a month, which may provide additional exposure to wild animals, was reported by 67.0% of respondents (data not shown). some of the most common reasons for traveling to the forest were fieldwork (56.0%), gathering of fruit and vegetables (21.0%), collecting firewood (11.0%), and hunting (10.0%). more respondents reported ever living in a city than not, with the most common urban occupations being restaurant work followed by "other" and factory jobs. table 2 describes type and location of occupational activities. restaurant-related occupations such as cook or kitchen worker were the most commonly reported primary occupation, followed by agriculture, butcher, and jobs working in a market. table 3 summarizes reported exposures to wild animals. almost all respondents indicated that they had ever touched any live or dead wild animal. having butchered and eaten wild animals were the most common types of animal interactions, and injury was experienced by less than a quarter of the respondents. table 4 shows the beliefs and reported protective behavior regarding contact with animals and zoonotic disease transmission. less than one third of respondents reported believing that they could get infected from contact with blood or other types of contact with wild animals. a smaller proportion reported taking at least one type of protective measure to prevent infection in such circumstances. among those who reported taking protective measures, use of gloves, and avoiding touching the animal were the most commonly reported protective practices. risk factors for seropositivity. table 5 summarizes the results of baseline testing of blood for evidence of antibodies against zoonotic wildlife viruses. the overall rate of seropositivity to any of the other three tested pathogens (hantavirus, sars cov, or sfts bunyavirus) was low among the study population (approximately 4%). seropositivity in respondents was only found in the first phase of enrollment. among contacts of these seropositive respondents (n = 45), all individuals were seronegative for the pathogens of interest. the most common seropositivity was for hantavirus (2.3% of the study population). however, among the 112 persons reporting that their occupation was a butcher, the rate of seropositivity to at least one pathogen was higher (9.0%), and this elevated risk was statistically significant (fisher's exact test, p = 0.005). butchers had elevated seropositivity rates to all three of the viruses compared to the overall study population. no other occupational group showed an increased risk of seropositivity. in a multivariate model of the butchers, those who reported butchering porcupines showed an elevated risk of seropositivity (data not shown). there was no increased risk among the butchers associated with not wearing gloves or taking fewer protective measures. by contrast, the 38 persons reporting hunting as a profession showed a decreased risk for seropositivity as did those reporting their profession as housework. no other occupational groups showed significantly increased or decreased risk. persons who reported ever hunting also had a lower risk of seropositivity compared to those who never hunted. age and gender did not show a significant association with seropositivity, nor did reporting living in a city or going frequently into the forest. while 111 persons reported butchering as a profession, a larger number (966) reported ever butchering a wild animal; this was associated with an elevated risk of seropositivity, however when the professional butchers were removed from this group, the risk was no longer significant. as shown in the table s1 table, reported contact with certain wildlife species such as civets (for hanta and bunyavirus) and field rats (for sars) showed elevated risk for certain viruses in bivariate analyses. in multivariate models of specific wildlife contact, (table 6) , the principal association remaining significant was eating civets (associated with hantavirus seropositivity). the risk estimate for bunyavirus was elevated but did not reach statistical significance. this study, examining the association between reported wildlife contact and seropositivity for wildlife zoonotic viruses, found detectable levels of antibodies for several pathogens in the population surveyed. overall, the population had contact with multiple species of animals. among reported primary occupations, working as a butcher was associated with an increased risk of infection with wildlife pathogens, while professional hunters were at decreased risk, and no increased risk was seen for market or restaurant workers. contact with certain animals, such as civets and field rats, showed evidence of increased risk of seropositivity. few people in the study reported using protective measures such as gloves when working with wild animals, and less than a third of individuals reported believing that they could become infected through wildlife contact. when seropositive individuals were followed over time, no evidence of infection of close contacts was seen, although the number of contacts enrolled was small and there are limited conclusions that can be draw about alternative transmissions risks. further investigation is warranted to gauge transmissibility of the viruses studied. these findings have a number of implications for prevention of zoonotic disease transmission and outbreaks. those individuals at the animal-human interface (such as persons butchering wild animals) that are highly exposed to wild animals are influential in disease amplification and dissemination and reduction of risk factors can play a large role in mediating potential outbreaks. while we identified butchers as an occupational group at increased risk, better understanding of the specific exposures driving this increased risk would require more in-depth study. among butchers, we did find an elevated risk of virus seropositivity associated with butchering porcupines, but due to small numbers, such a finding must be considered preliminary. this study also identified an increased risk of seropositivity with contact with civets and field rats which could be due to multiple factors. civets and field rats are among the most popular types of wild animals found in markets and restaurants and prolific contact may result in higher risk. there is also a bias related to the viruses that the study targeted with two of the three (sars cov and hantavirus) associated with both civets and rats. this study had a number of limitations, including selection bias. we deliberately targeted high risk individuals, making our sample less representative of the general population. conversely, it is possible that there could be differential participation rates between high risk and lower risk individuals, further limiting any extrapolation to community levels. we focused on wildlife contact, and therefore were unable to assess the risk impact of contact with other animal species including livestock and companion animals. further research should aim to include larger sample sizes from more geographically diverse regions, and assess seroprevalence rates in random population samples. underreporting of risk activities on the behavioral survey may have occurred, since many activities related to wild animals are illegal in china. in addition, since this was a hypothesis generating study, the analysis involved multiple comparisons. therefore, any reported association should be viewed with caution. while this study involved serological testing for more than one potential wildlife pathogen, there are numerous other wildlife pathogens, including bacterial and viral agents, which the study did not investigate. it is therefore possible that this study failed to detect other significant transmission events of human health relevance. future studies should consider such possibilities. the finding that less than one third of the surveyed population, most of whom reported wild animal contact, believed that they could become infected through such contact, indicates the need for targeted educational programs for prevention, especially among those involved in butchering wildlife for consumption. targeted education programs should aim to increase knowledge of disease risk, perception of risk, and risky behaviors in the identified high-risk sub groups. previous studies indicate the need to target the high-risk sub group of hunters [16, 17] . in this study, however, hunters and persons reporting ever hunting or hunting as a profession exhibited a lower rate of seropositivity compared with the overall population. it is possible that hunting activities may be underreported, but the results of this study indicate some of the difficulties of relying on self report to identify individuals at increased risk. due to the huge demand by the local residents and immigrants in the larger pearl river delta area, which includes guangdong, hong kong and macau, increasing number of individuals engaged in animal production and value chain systems are believed to continue to come into contact with wild animals and engage in risky behaviors increasing the risk of a possible infectious disease outbreak that could have a potentially severe impact. wild animals are an important part of southern chinese economy and culture, and pragmatic policy changes should be implemented to control the risks of possible disease outbreaks. these policy changes should aim to increase risk perception and uptake of precautionary behaviors without risking the cultural and financial security of the community. results of the analyses of these research findings can be used to inform public health strategies such as communication and educational campaigns, targeting those behaviors that place individuals at higher risk of disease. our study provides evidence towards recommendations that include: an increase in the level of collaboration between animal and human health programs targeting human-animal interfaces to increase efforts to control and prevent outbreaks; development of new educational campaigns to increase knowledge and awareness of infectious diseases that target specific sub-groups, such as butchers, that are at increased risk; and increase monitoring of highrisk groups to detect continued transmission of zoonotic diseases in a timely manner. supporting information s1 file. study questionnaire for persons hunting, butchering, eating and/or keeping wild animals as pets. (pdf) s1 table. prevalence of seropositivity for tested viruses, by reported wildlife exposure. (pdf) global trends in emerging infectious diseases wildlife trade and global disease emergence. emerging infectious disease bushmeat hunting, deforestation, and prediction of zoonotic disease wet markets-a continuing source of severe acute respiratory syndrome and influenza? the lancet animal movements and the spread of infectious diseases disease and destiny-mystery and mastery infectious diseases emerging from chinese wet-markets: zoonotic origins of severe respiratory viral infections the role of wildlife in emerging and re-emerging zoonoses emergence and predominance of an h5n1 influenza variant in china bats are natural reservoirs of sars-like coronaviruses isolation and characterization of viruses related to the sars coronavirus from animals in southern china sars-beginning to understand a new virus learning from sars: preparing for the next disease outbreak: workshop summary. the national academies collection: reports funded by national institutes of health human infection with a novel avian-origin influenza a (h7n9) virus emerging angiostrongyliasis in mainland china emergence of a novel and highly divergent htlv-3 in a primate hunter in cameroon new directions in conservation medicine: applied cases of ecological health hantavirus infections in humans and animals distribution of tick-borne diseases in china a national assessment of the epidemiology of severe fever with thrombocytopenia syndrome a global perspective on hantavirus ecology, epidemiology, and disease the life cycle of sars coronavirus in vero e6 cells establishment of vero e6 cell clones persistently infected with severe acute respiratory syndrome coronavirus diagnosis of severe acute respiratory syndrome (sars) by detection of sars coronavirus nucleocapsid antibodies in an antigen-capturing enzyme-linked immunosorbent assay fever with thrombocytopenia associated with a novel bunyavirus in china. the new england journal of medicine the application of firth's procedure to cox and logistic regression university of vienna, section of clinical biometrics domcs we thank prefecture cdcs at dabu, jiaoling, pingyuan, lianping, heping, lianshan, lianzhou, yunfu, yunan, xinyi, deqing and fengkai for their efforts in participant enrollment and specimen collection. there are no competing interests in this scientific work. key: cord-292094-vmsdhccp authors: mandell, lionel a.; wunderink, richard g.; anzueto, antonio; bartlett, john g.; campbell, g. douglas; dean, nathan c.; dowell, scott f.; file, thomas m.; musher, daniel m.; niederman, michael s.; torres, antonio; whitney, cynthia g. title: infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults date: 2007-03-01 journal: clin infect dis doi: 10.1086/511159 sha: doc_id: 292094 cord_uid: vmsdhccp nan improving the care of adult patients with communityacquired pneumonia (cap) has been the focus of many different organizations, and several have developed guidelines for management of cap. two of the most widely referenced are those of the infectious diseases society of america (idsa) and the american thoracic society (ats). in response to confusion regarding differences between their respective guidelines, the idsa and the ats convened a joint committee to develop a unified cap guideline document. the guidelines are intended primarily for use by emergency medicine physicians, hospitalists, and primary care practitioners; however, the extensive literature evaluation suggests that they are also an appro-reprints or correspondence: dr. lionel a. mandell priate starting point for consultation by specialists. substantial overlap exists among the patients whom these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (hcap). pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the hcap guidelines. however, certain other patients whose conditions are included in the designation of hcap are better served by management in accordance with cap guidelines with concern for specific pathogens. 1. locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (strong recommendation; level i evidence.) it is important to realize that guidelines cannot always account for individual variation among patients. they are not intended to supplant physician judgment with respect to particular patients or special clinical situations. the idsa considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. enthusiasm for developing these guidelines derives, in large part, from evidence that previous cap guidelines have led to improvement in clinically relevant outcomes. consistently beneficial effects in clinically relevant parameters (listed in table 3) followed the introduction of a comprehensive protocol (including a combination of components from table 2) that increased compliance with published guidelines. the first recommendation, therefore, is that cap management guidelines be locally adapted and implemented. documented benefits. 2 . cap guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (strong recommendation; level iii evidence.) 3. development of local cap guidelines should be directed toward improvement in specific and clinically relevant outcomes. (moderate recommendation; level iii evidence.) almost all of the major decisions regarding management of cap, including diagnostic and treatment issues, revolve around the initial assessment of severity. site-of-care decisions (e.g., hospital vs. outpatient, intensive care unit [icu] vs. general ward) are important areas for improvement in cap management. hospital admission decision. 4 . severity-of-illness scores, such as the curb-65 criteria (confusion, uremia, respiratory rate, low blood pressure, age 65 years or greater), or prognostic models, such as the pneumonia severity index (psi), can be used to identify patients with cap who may be candidates for outpatient treatment. (strong recommendation; level i evidence.) 5. objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (strong recommendation; level ii evidence.) 6. for patients with curb-65 scores у2, more-intensive treatment-that is, hospitalization or, where appropriate and available, intensive in-home health care services-is usually warranted. (moderate recommendation; level iii evidence.) physicians often admit patients to the hospital who could be well managed as outpatients and who would generally prefer to be treated as outpatients. objective scores, such as the curb-65 score or the psi, can assist in identifying patients who may be appropriate for outpatient care, but the use of such scores must be tempered by the physician's determination of additional critical factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. icu admission decision. 7 . direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (strong recommendation; level ii evidence.) 8. direct admission to an icu or high-level monitoring unit is recommended for patients with 3 of the minor criteria for severe cap listed in table 4. (moderate recommendation; level ii evidence.) in some studies, a significant percentage of patients with cap are transferred to the icu in the first 24-48 h after hospitalization. mortality and morbidity among these patients appears to be greater than those among patients admitted directly to the icu. conversely, icu resources are often overstretched in many institutions, and the admission of patients with cap who would not directly benefit from icu care is also problematic. unfortunately, none of the published criteria for severe cap adequately distinguishes these patients from those for whom icu admission is necessary. in the present set of guidelines, a new set of criteria has been developed on the basis of data on individual risks, although the previous ats criteria format is retained. in addition to the 2 major criteria (need for mechanical ventilation and septic shock), an expanded set of minor criteria (respiratory rate, 130 breaths/min; arterial oxygen pressure/fraction of inspired oxygen (pao 2 /fio 2 ) ratio, !250; multilobar infiltrates; confusion; blood urea nitrogen level, 120 mg/dl; leukopenia resulting from infection; thrombocytopenia; hypothermia; or hypotension requiring aggressive fluid resuscitation) is proposed (table 4). the presence of at least 3 of these criteria suggests the need for icu care but will require prospective validation. 9. in addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (moderate recommendation; level iii evidence.) recommended diagnostic tests for etiology. 10 . patients with cap should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (strong recommendation; level ii evidence.) recommendations for diagnostic testing remain controversial. the overall low yield and infrequent positive impact on clinical care argue against the routine use of common tests, such as blood and sputum cultures. conversely, these cultures may have a major impact on the care of an individual patient and are important for epidemiologic reasons, including the antibiotic susceptibility patterns used to develop treatment guidelines. a list of clinical indications for more extensive diagnostic testing (table 5) was, therefore, developed, primarily on the basis of 2 criteria: (1) when the result is likely to change individual antibiotic management and (2) when the test is likely to have the highest yield. 11 . routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients with cap. (moderate recommendation; level iii evidence.) 12. pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in table 5 but are optional for patients without these conditions. (moderate recommendation; level i evidence.) 13. pretreatment gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained and quality performance measures for collection, transport, and processing of samples can be met. (moderate recommendation; level ii evidence.) 14. patients with severe cap, as defined above, should at least have blood samples drawn for culture, urinary antigen tests for legionella pneumophila and streptococcus pneumoniae performed, and expectorated sputum samples collected for culture. for intubated patients, an endotracheal aspirate sample should be obtained. (moderate recommendation; level ii evidence.) the most clear-cut indication for extensive diagnostic testing is in the critically ill cap patient. such patients should at least have blood drawn for culture and an endotracheal aspirate obtained if they are intubated; consideration should be given to more extensive testing, including urinary antigen tests for l. pneumophila and s. pneumoniae and gram stain and culture of expectorated sputum in nonintubated patients. for inpatients without the clinical indications listed in table 5, diagnostic testing is optional (but should not be considered wrong). empirical antimicrobial therapy. empirical antibiotic recommendations (table 7) have not changed significantly from those in previous guidelines. increasing evidence has strengthened the recommendation for combination empirical therapy for severe cap. only 1 recently released antibiotic has been added to the recommendations: ertapenem, as an acceptable b-lactam alternative for hospitalized patients with risk factors for infection with gram-negative pathogens other than pseudomonas aeruginosa. at present, the committee is awaiting further evaluation of the safety of telithromycin by the us food and drug administration before making its final recommendation regarding this drug. recommendations are generally for a class of antibiotics rather than for a specific drug, unless outcome data clearly favor one drug. because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. 19 . a b-lactam plus a macrolide (strong recommendation; level i evidence) (preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level iii evidence] as an alternative to the macrolide. a respiratory fluoroquinolone should be used for penicillin-allergic patients.) increasing resistance rates have suggested that empirical therapy with a macrolide alone can be used only for the treat-ment of carefully selected hospitalized patients with nonsevere disease and without risk factors for infection with drug-resistant pathogens. however, such monotherapy cannot be routinely recommended. inpatient, icu treatment 20. a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level ii evidence) or a fluoroquinolone (level i evidence) (strong recommendation) (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) 21 . for pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) or the above b-lactam plus an aminoglycoside and azithromycin or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above b-lactam). (moderate recommendation; level iii evidence.) 22 . for community-acquired methicillin-resistant staphylococcus aureus infection, add vancomycin or linezolid. (moderate recommendation; level iii evidence.) infections with the overwhelming majority of cap pathogens will be adequately treated by use of the recommended empirical regimens. the emergence of methicillin-resistant s. aureus as a cap pathogen and the small but significant incidence of cap due to p. aeruginosa are the exceptions. these pathogens occur in specific epidemiologic patterns and/or with certain clinical presentations, for which empirical antibiotic coverage may be warranted. however, diagnostic tests are likely to be of high yield for these pathogens, allowing early discontinuation of empirical treatment if results are negative. the risk factors are included in the table 5 recommendations for indications for increased diagnostic testing. risk factors for other uncommon etiologies of cap are listed in table 8, and recommendations for treatment are included in table 9 . pathogen-directed therapy. 23 definitions and classification. 38 . the use of a systematic classification of possible causes of failure to respond, based on time of onset and type of failure (table 11) , is recommended. (moderate recommendation; level ii evidence.) as many as 15% of patients with cap may not respond appropriately to initial antibiotic therapy. a systematic approach to these patients (table 11) will help to determine the cause. because determination of the cause of failure is more accurate if the original microbiological etiology is known, risk factors for nonresponse or deterioration (table 12) figure prominently in the list of situations in which more aggressive and/ or extensive initial diagnostic testing is warranted ( [2] . despite advances in antimicrobial therapy, rates of mortality due to pneumonia have not decreased significantly since penicillin became routinely available [3] . groups interested in approaches to the management of cap include professional societies, such as the american thoracic society (ats) and the infectious diseases society of america (idsa); government agencies or their contract agents, such as the center for medicare and medicaid services and the department of veterans affairs; and voluntary accrediting agencies, such as the joint commission on accreditation of healthcare organizations. in addition, external review groups and consumer groups have chosen cap outcomes as major quality indicators. such interest has resulted in numerous guidelines for the management of cap [4] . some of these guidelines represent truly different perspectives, including differences in health care systems, in the availability of diagnostic tools or therapeutic agents, or in either the etiology or the antibiotic susceptibility of common causative microorganisms. the most widely referenced guidelines in the united states have been those published by the ats [5, 6] and the idsa [7] [8] [9] . differences, both real and imagined, between the ats and idsa guidelines have led to confusion for individual physicians, as well as for other groups who use these published guidelines rather than promulgating their own. in response to this concern, the idsa and the ats convened a joint committee to develop a unified cap guideline document. this document represents a consensus of members of both societies, and both governing councils have approved the statement. purpose and scope. the purpose of this document is to update clinicians with regard to important advances and controversies in the management of patients with cap. the committee chose not to address cap occurring in immunocompromised patients, including solid organ, bone marrow, or stem cell transplant recipients; patients receiving cancer chemotherapy or long-term (130 days) high-dose corticosteroid treatment; and patients with congenital or acquired immunodeficiency or those infected with hiv who have cd4 cell counts !350 cells/mm 3 , although many of these patients may be infected with the same microorganisms. pneumonia in children (р18 years of age) is also not addressed. substantial overlap exists among the patients these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (hcap) [10] . two issues are pertinent: (1) an increased risk of infection with drugresistant isolates of usual cap pathogens, such as streptococcus pneumoniae, and (2) an increased risk of infection with less common, usually hospital-associated pathogens, such as pseudomonas and acinetobacter species and methicillin-resistant staphylococcus aureus (mrsa). pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the hcap guidelines. however, certain other patients whose conditions are included under the designation of hcap are better served by management in ac-cordance with cap guidelines with concern for specific pathogens. for example, long-term dialysis alone is a risk for mrsa infection but does not necessarily predispose patients to infection with other hcap pathogens, such as pseudomonas aeruginosa or acinetobacter species. on the other hand, certain patients with chronic obstructive pulmonary disease (copd) are at greater risk for infection with pseudomonas species but not mrsa. these issues will be discussed in specific sections below. the committee started with the premise that mortality due to cap can be decreased. we, therefore, have placed the greatest emphasis on aspects of the guidelines that have been associated with decreases in mortality. for this reason, the document focuses mainly on management and minimizes discussions of such factors as pathophysiology, pathogenesis, mechanisms of antibiotic resistance, and virulence factors. the committee recognizes that the majority of patients with cap are cared for by primary care, hospitalist, and emergency medicine physicians [11] , and these guidelines are, therefore, directed primarily at them. the committee consisted of infectious diseases, pulmonary, and critical care physicians with interest and expertise in pulmonary infections. the expertise of the committee and the extensive literature evaluation suggest that these guidelines are also an appropriate starting point for consultation by these types of physicians. although much of the literature cited originates in europe, these guidelines are oriented toward the united states and canada. although the guidelines are generally applicable to other parts of the world, local antibiotic resistance patterns, drug availability, and variations in health care systems suggest that modification of these guidelines is prudent for local use. methodology. the process of guideline development started with the selection of committee cochairs by the presidents of the idsa [12] and ats [13] , in consultation with other leaders in the respective societies. the committee cochairs were charged with selection of the rest of the committee. the idsa members were those involved in the development of previous idsa cap guidelines [9] , whereas ats members were chosen in consultation with the leadership of the mycobacteria tuberculosis and pulmonary infection assembly, with input from the chairs of the clinical pulmonary and critical care assemblies. committee members were chosen to represent differing expertise and viewpoints on the various topics. one acknowledged weakness of this document is the lack of representation by primary care, hospitalist, and emergency medicine physicians. the cochairs generated a general outline of the topics to be covered that was then circulated to committee members for input. a conference phone call was used to review topics and to discuss evidence grading and the general aims and expectations of the document. the topics were divided, and committee members were assigned by the cochairs and charged with presentation of their topic at an initial face-to-face meeting, as well as with development of a preliminary document dealing with their topic. controversial topics were assigned to 2 committee members, 1 from each society. an initial face-to-face meeting of a majority of committee members involved presentations of the most controversial topics, including admission decisions, diagnostic strategies, and antibiotic therapy. prolonged discussions followed each presentation, with consensus regarding the major issues achieved before moving to the next topic. with input from the rest of the committee, each presenter and committee member assigned to the less controversial topics prepared an initial draft of their section, including grading of the evidence. iterative drafts of the statement were developed and distributed by e-mail for critique, followed by multiple revisions by the primary authors. a second face-to-face meeting was also held for discussion of the less controversial areas and further critique of the initial drafts. once general agreement on the separate topics was obtained, the cochairs incorporated the separate documents into a single statement, with substantial editing for style and consistency. the document was then redistributed to committee members to review and update with new information from the literature up to june 2006. recommended changes were reviewed by all committee members by e-mail and/or conference phone call and were incorporated into the final document by the cochairs. this document was then submitted to the societies for approval. each society independently selected reviewers, and changes recommended by the reviewers were discussed by the committee and incorporated into the final document. the guideline was then submitted to the idsa governing council and the ats board of directors for final approval. grading of guideline recommendations. initially, the committee decided to grade only the strength of the evidence, using a 3-tier scale (table 1) used in a recent guideline from both societies [10] . in response to reviewers' comments and the maturation of the field of guideline development [14] , a separate grading of the strength of the recommendations was added to the final draft. more extensive and validated criteria, such as grade [14] , were impractical for use at this stage. the 3-tier scale similar to that used in other idsa guideline documents [12] and familiar to many of the committee members was therefore chosen. the strength of each recommendation was graded as "strong," "moderate," or "weak." each committee member independently graded each recommendation on the basis of not only the evidence but also expert interpretation and clinical applicability. the final grading of each recommendation was a composite of the individual committee members' grades. for the final document, a strong recommendation required у6 (of 12) of the members to consider it to be strong and the majority of the others to grade it as moderate. the implication of a strong recommendation is that most patients should receive that intervention. significant variability in the management of patients with cap is well documented. some who use guidelines suggest that this variability itself is undesirable. industrial models suggesting that variability per se is undesirable may not always be relevant to medicine [15] . such models do not account for substantial variability among patients, nor do they account for variable end points, such as limitation of care in patients with end-stage underlying diseases who present with cap. for this reason, the committee members feel strongly that 100% compliance with guidelines is not the desired goal. however, the rationale for variation from a strongly recommended guideline should be apparent from the medical record. conversely, moderate or weak recommendations suggest that, even if a majority would follow the recommended management, many practitioners may not. deviation from guidelines may occur for a variety of reasons [16, 17] . one document cannot cover all of the variable settings, unique hosts, or epidemiologic patterns that may dictate alternative management strategies, and physician judgment should always supersede guidelines. this is borne out by the finding that deviation from guidelines is greatest in the treatment of patients with cap admitted to the icu [18] . in addition, few of the recommendations have level i evidence to support them, and most are, therefore, legitimate topics for future research. subsequent publication of studies documenting that care that deviates from guidelines results in better outcomes will stimulate revision of the guidelines. the committee anticipates that this will occur, and, for this reason, both the ats and idsa leaderships have committed to the revision of these guidelines on a regular basis. we recognize that these guidelines may be used as a measure of quality of care for hospitals and individual practitioners. although these guidelines are evidence based, the committee strongly urges that deviations from them not necessarily be considered substandard care, unless they are accompanied by evidence for worse outcomes in a studied population. 1. locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (strong recommendation; level i evidence.) enthusiasm for developing this set of cap guidelines derives, in large part, from evidence that previous cap guidelines have led to improvement in clinically relevant outcomes [17, [19] [20] [21] . protocol design varies among studies, and the preferable randomized, parallel group design has been used in only a small minority. confirmatory studies that use randomized, parallel groups with precisely defined treatments are still needed, but a consistent pattern of benefit is found in the other types of level i studies. documented benefits. published protocols have varied in primary focus and comprehensiveness, and the corresponding benefits vary from one study to another. however, the most impressive aspect of this literature is the consistently beneficial effect seen in some clinically relevant parameter after the introduction of a protocol that increases compliance with published guidelines. a decrease in mortality with the introduction of guidelinebased protocols was found in several studies [19, 21] . a 5-year study of 28,700 patients with pneumonia who were admitted during implementation of a pneumonia guideline demonstrated that the crude 30-day mortality rate was 3.2% lower with the guideline (adjusted or, 0.69; 95% ci, 0.49-0.97) [19] , compared with that among patients treated concurrently by nonaffiliated physicians. after implemention of a practice guideline at one spanish hospital [21] , the survival rate at 30 days was higher (or, 2.14; 95% ci, 1.23-3.72) than at baseline and in comparison with 4 other hospitals without overt protocols. lower mortality was seen in other studies, although the differences were not statistically significant [22, 23] . studies that documented lower mortality emphasized increasing the number of patients receiving guideline-recommended antibiotics, confirming results of the multivariate analysis of a retrospective review [24] . when the focus of a guideline was hospitalization, the number of less ill patients admitted to the hospital was consistently found to be lower. using admission decision support, a prospective study of 11700 emergency department (ed) visits in 19 hospitals randomized between pathway and "conventional" management found that admission rates among low-risk patients at pathway hospitals decreased (from 49% to 31% of patients in pneumonia severity index [psi] classes i-iii; p ! ) without differences in patient satisfaction scores or rate of .01 readmission [20] . calculating the psi score and assigning the risk class, providing oral clarithromycin, and home nursing follow-up significantly ( ) decreased the number of low-p p .01 mortality-risk admissions [25] . however, patient satisfaction among outpatients was lower after implementation of this guideline, despite survey data that suggested most patients would prefer outpatient treatment [26] . of patients discharged from the ed, 9% required hospitalization within 30 days, although another study showed lower readmission rates with the use of a protocol [23] . admission decision support derived from the 1993 ats guideline [5] recommendations, combined with outpatient antibiotic recommendations, reduced the cap hospitalization rate from 13.6% to 6.4% [23] , and admission rates for other diagnoses were unchanged. not surprisingly, the resultant overall cost of care decreased by half ( ). p p .01 protocols using guidelines to decrease the duration of hospitalization have also been successful. guideline implementation in 31 connecticut hospitals decreased the mean length of hospital stay (los) from 7 to 5 days ( ) [27] . an ed-p ! .001 based protocol decreased the mean los from 9.7 to 6.4 days ( ), with the benefits of guideline implementation p ! .0001 maintained 3 years after the initial study [22] . a 7-site trial, randomized by physician group, of guideline alone versus the same guideline with a multifaceted implementation strategy found that addition of an implementation strategy was associated with decreased duration of intravenous antibiotic therapy and los, although neither decrease was statistically significant [28] . several other studies used guidelines to significantly shorten the los, by an average of 11.5 days [20, 21] . markers of process of care can also change with the use of a protocol. the time to first antibiotic dose has been effectively decreased with cap protocols [22, 27, 29] . a randomized, parallel group study introduced a pneumonia guideline in 20 of 36 small oklahoma hospitals [29] , with the identical protocol implemented in the remaining hospitals in a second phase. serial measurement of key process measures showed significant improvement in time to first antibiotic dose and other variables, first in the initial 20 hospitals and later in the remaining 16 hospitals. implementing a guideline in the ed halved the time to initial antibiotic dose [22] . 2. cap guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (strong recommendation; level iii evidence.) common to all of the studies documented above, a comprehensive protocol was developed and implemented, rather than one addressing a single aspect of cap care. no study has documented that simply changing 1 metric, such as time to first antibiotic dose, is associated with a decrease in mortality. elements important in cap guidelines are listed in table 2. of these, rapid and appropriate empirical antibiotic therapy is consistently associated with improved outcome. we have also included elements of good care for general medical inpatients, such as early mobilization [30] and prophylaxis against thromboembolic disease [31] . although local guidelines need not include all elements, a logical constellation of elements should be addressed. in instituting cap protocol guidelines, the outcomes most relevant to the individual center or medical system should be addressed first. unless a desire to change clinically relevant outcomes exists, adherence to guidelines will be low, and institutional resources committed to implement the guideline are likely to be insufficient. guidelines for the treatment of pneumonia must use approaches that differ from current practice and must be successfully implemented before process of care and outcomes can change. for example, rhew et al. [32] designed a guideline to decrease los that was unlikely to change care, because the recommended median los was longer than the existing los for cap at the study hospitals. the difficulty in implementing guidelines and changing physician behavior has also been documented [28, 33] . clinically relevant outcome parameters should be evaluated to measure the effect of the local guideline. outcome parameters that can be used to measure the effect of implementation of a cap guideline within an organization are listed in table 3. just as it is important not to focus on one aspect of care, studying more than one outcome is also important. improvements in one area may be offset by worsening in a related area; for example, decreasing admission of low-acuity patients might increase the number of return visits to the ed or hospital readmissions [25] . almost all of the major decisions regarding management of cap, including diagnostic and treatment issues, revolve around the initial assessment of severity. we have, therefore, organized the guidelines to address this issue first. hospital admission decision. the initial management decision after diagnosis is to determine the site of care-outpatient, hospitalization in a medical ward, or admission to an icu. the decision to admit the patient is the most costly issue in the management of cap, because the cost of inpatient care for pneumonia is up to 25 times greater than that of outpatient care [34] and consumes the majority of the estimated $8.4-$10 billion spent yearly on treatment. other reasons for avoiding unnecessary admissions are that patients at low risk for death who are treated in the outpatient setting are able to resume normal activity sooner than those who are hospitalized, and 80% are reported to prefer outpatient therapy [26, 35] . hospitalization also increases the risk of thromboembolic events and superinfection by more-virulent or resistant hospital bacteria [36] . 4. severity-of-illness scores, such as the curb-65 criteria (confusion, uremia, respiratory rate, low blood pressure, age 65 years or greater), or prognostic models, such as the psi, can be used to identify patients with cap who may be candidates for outpatient treatment. (strong recommendation; level i evidence.) significant variation in admission rates among hospitals and among individual physicians is well documented. physicians often overestimate severity and hospitalize a significant number of patients at low risk for death [20, 37, 38] . because of these issues, interest in objective site-of-care criteria has led to attempts by a number of groups to develop such criteria [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] . the relative merits and limitations of various proposed criteria have been carefully evaluated [49] . the 2 most interesting are the psi [42] and the british thoracic society (bts) criteria [39, 45] . the psi is based on derivation and validation cohorts of 14,199 and 38,039 hospitalized patients with cap, respectively, plus an additional 2287 combined inpatients and outpatients [42] . the psi stratifies patients into 5 mortality risk classes, and its ability to predict mortality has been confirmed in multiple subsequent studies. on the basis of associated mortality rates, it has been suggested that risk class i and ii patients should be treated as outpatients, risk class iii patients should be treated in an observation unit or with a short hospitalization, and risk class iv and v patients should be treated as inpatients [42] . yealy et al. [50] conducted a cluster-randomized trial of low-, moderate-, and high-intensity processes of guideline implementation in 32 eds in the united states. their guideline used the psi for admission decision support and included recommendations for antibiotic therapy, timing of first antibiotic dose, measurement of oxygen saturation, and blood cultures for admitted patients. eds with moderate-to high-intensity guideline implementation demonstrated more outpatient treatment of low-risk patients and higher compliance with antibiotic recommendations. no differences were found in mortality rate, rate of hospitalization, median time to return to work or usual activities, or patient satisfaction. this study differs from those reporting a mortality rate difference [19, 21] in that many hospitalized patients with pneumonia were not included. in addition, eds with low-intensity guideline implementation formed the comparison group, rather than eds practicing nonguideline, usual pneumonia care. the bts original criteria of 1987 have subsequently been modified [39, 51] . in the initial study, risk of death was increased 21-fold if a patient, at the time of admission, had at least 2 of the following 3 conditions: tachypnea, diastolic hypotension, and an elevated blood urea nitrogen (bun) level. these criteria appear to function well except among patients with underlying renal insufficiency and among elderly patients [52, 53] . the most recent modification of the bts criteria includes 5 easily measurable factors [45] . multivariate analysis of 1068 patients identified the following factors as indicators of increased mortality: confusion (based on a specific mental test or disorientation to person, place, or time), bun level 17 mmol/l (20 mg/dl), respiratory rate у30 breaths/min, low blood pressure (systolic, !90 mm hg; or diastolic, р60 mm hg), and age у65 years; this gave rise to the acronym curb-65. in the derivation and validation cohorts, the 30-day mortality among patients with 0, 1, or 2 factors was 0.7%, 2.1%, and 9.2%, respectively. mortality was higher when 3, 4, or 5 factors were present and was reported as 14.5%, 40%, and 57%, respectively. the authors suggested that patients with a curb-65 score of 0-1 be treated as outpatients, that those with a score of 2 be admitted to the wards, and that patients with a score of у3 often required icu care. a simplified version (crb-65), which does not require testing for bun level, may be appropriate for decision making in a primary care practitioner's office [54] . the use of objective admission criteria clearly can decrease the number of patients hospitalized with cap [20, 23, 25, 55] . whether the psi or the curb-65 score is superior is unclear, because no randomized trials of alternative admission criteria exist. when compared in the same population, the psi classified a slightly larger percentage of patients with cap in the lowrisk categories, compared with the curb or curb-65 criteria, while remaining associated with a similar low mortality rate among patients categorized as low risk [56] . several factors are important in this comparison. the psi includes 20 different variables and, therefore, relies on the availability of scoring sheets, limiting its practicality in a busy ed [55] . in contrast, the curb-65 criteria are easily remembered. however, curb-65 has not been as extensively studied as the psi, especially with prospective validation in other patient populations (e.g., the indigent inner-city population), and has not been specifically studied as a means of reducing hospital admission rates. in eds with sufficient decision support resources (either human or computerized), the benefit of greater experience with the psi score may favor its use for screening patients who may be candidates for outpatient management [50, [57] [58] [59] . 5 . objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (strong recommendation; level ii evidence.) studies show that certain patients with low psi or curb-65 scores [20, 60, 61] require hospital admission, even to the icu [49, 62, 63] . both scores depend on certain assumptions. one is that the main rationale for admission of a patient with cap is risk of death. this assumption is clearly not valid in all cases. another is that the laboratory and vital signs used for scoring are stable over time rather than indicative of transient abnormalities. this is also not true in all cases. therefore, dynamic assessment over several hours of observation may be more accurate than a score derived at a single point in time. although advantageous to making decisions regarding hospital admission, sole reliance on a score for the hospital admission decision is unsafe. reasons for the admission of low-mortality-risk patients fall into 4 categories: (1) complications of the pneumonia itself, (2) exacerbation of underlying diseases(s), (3) inability to reliably take oral medications or receive outpatient care, and/or (4) multiple risk factors falling just above or below thresholds for the score [62] . use of the psi score in clinical trials has demonstrated some of its limitations, which may be equally applicable to other scoring techniques. a modification of the original psi score was needed when it was applied to the admission decision. an arterial saturation of !90% or an arterial oxygen pressure (pao 2 ) of !60 mm hg as a complication of the pneumonia, was added as a sole indicator for admission for patients in risk classes i-iii as an added "margin of safety" in one trial [42] . in addition to patients who required hospital admission because of hypoxemia, a subsequent study identified patients in low psi risk classes (i-iii) who needed hospital admission because of shock, decompensated coexisting illnesses, pleural effusion, inability to maintain oral intake, social problems (the patient was dependent or no caregiver was available), and lack of response to previous adequate empirical antibiotic therapy [64] . of 178 patients in low psi risk classes who were treated as inpatients, 106 (60%) presented with at least 1 of these factors. other medical or psychosocial needs requiring hospital care include intractable vomiting, injection drug abuse, severe psychiatric illness, homelessness, poor overall functional status [65] , and cognitive dysfunction [61, 66] . the psi score is based on a history of diseases that increase risk of death, whereas the curb-65 score does not directly address underlying disease. however, pneumonia may exacerbate an underlying disease, such as obstructive lung disease, congestive heart failure, or diabetes mellitus, which, by themselves, may require hospital admission [60, 67] . atlas et al. [25] were able to reduce hospital admissions among patients in psi risk classes i-iii from 58% in a retrospective control group to 43% in a psi-based intervention group. ten of 94 patients in the latter group (compared with 0 patients in the control population) were subsequently admitted, several for reasons unrelated to their pneumonia. also, the presence of rare illnesses, such as neuromuscular or sickle cell disease, may require hospitalization but not affect the psi score. the necessary reliance on dichotomous predictor variables (abnormal vs. normal) in most criteria and the heavy reliance on age as a surrogate in the psi score may oversimplify their use for admission decisions. for example, a previously healthy 25-year-old patient with severe hypotension and tachycardia and no additional pertinent prognostic factors would be placed in risk class ii, whereas a 70-year-old man with a history of localized prostate cancer diagnosed 10 months earlier and no other problems would be placed in risk class iv [42] . finally, patient satisfaction was lower among patients treated outside the hospital in one study with a psi-based intervention group [25] , suggesting that the savings resulting from use of the psi may be overestimated and that physicians should consider additional factors not measured by the psi. 6. for patients with curb-65 scores у2, more-intensive treatment-that is, hospitalization or, where appropriate and available, intensive in-home health care services-is usually warranted. (moderate recommendation; level iii evidence.) although the psi and curb-65 criteria are valuable aids in avoiding inappropriate admissions of low-mortality-risk patients, another important role of these criteria may be to help identify patients at high risk who would benefit from hospitalization. the committee preferred the curb-65 criteria because of ease of use and because they were designed to measure illness severity more than the likelihood of mortality. patients with a curb-65 score у2 are not only at increased risk of death but also are likely to have clinically important physiologic derangements requiring active intervention. these patients should usually be considered for hospitalization or for aggressive in-home care, where available. in a cohort of ∼3000 patients, the mortality with a curb-65 score of 0 was only 1.2%, whereas 3-4 points were associated with 31% mortality [45] . because the psi score is not based as directly on severity of illness as are the curb-65 criteria, a threshold for patients who would require hospital admission or intensive outpatient treatment is harder to define. the higher the score, the greater the need for hospitalization. however, even a patient who meets criteria for risk class v on the basis of very old age and multiple stable chronic illnesses may be successfully managed as an outpatient [23] . 7. direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (strong recommendation; level ii evidence.) the second-level admission decision is whether to place the patient in the icu or a high-level monitoring unit rather than on a general medical floor. approximately 10% of hospitalized patients with cap require icu admission [68] [69] [70] , but the indications vary strikingly among patients, physicians, hospitals, and different health care systems. some of the variability among institutions results from the availability of high-level monitoring or intermediate care units appropriate for patients at increased risk of complications. because respiratory failure is the major reason for delayed transfer to the icu, simple cardiac monitoring units would not meet the criteria for a highlevel monitoring unit for patients with severe cap. one of the most important determinants of the need for icu care is the presence of chronic comorbid conditions [68] [69] [70] [71] [72] . however, approximately one-third of patients with severe cap were previously healthy [73] . the rationale for specifically defining severe cap is 4-fold: • appropriate placement of patients optimizes use of limited icu resources. • transfer to the icu for delayed respiratory failure or delayed onset of septic shock is associated with increased mortality [74] . although low-acuity icu admissions do occur, the major concern is initial admission to the general medical unit, with subsequent transfer to the icu. as many as 45% of patients with cap who ultimately require icu admission were initially admitted to a non-icu setting [75] . many delayed transfers to the icu represent rapidly progressive pneumonia that is not obvious on admission. however, some have subtle findings, including those included in the minor criteria in table 4, which might warrant direct admission to the icu. • the distribution of microbial etiologies differs from that of cap in general [76] [77] [78] [79] , with significant implications for diagnostic testing and empirical antibiotic choices. avoidance of inappropriate antibiotic therapy has also been associated with lower mortality [80, 81] . • patients with cap appropriate for immunomodulatory treatment must be identified. the systemic inflammatory response/severe sepsis criteria typically used for generic sepsis trials may not be adequate when applied specifically to severe cap [82] . for example, patients with unilateral lobar pneumonia may have hypoxemia severe enough to meet criteria for acute lung injury but not have a systemic response. several criteria have been proposed to define severe cap. most case series have defined it simply as cap that necessitates icu admission. objective criteria to identify patients for icu admission include the initial ats definition of severe cap [5] and its subsequent modification [6, 82] , the curb criteria [39, 45] , and psi severity class v (or iv and v) [42] . however, none of these criteria has been prospectively validated for the icu admission decision. recently, these criteria were retrospectively evaluated in a cohort of patients with cap admitted to the icu [63] . all were found to be both overly sensitive and nonspecific in comparison with the original clinical decision to admit to the icu. revisions of the criteria or alternative criteria were, therefore, recommended. for the revised criteria, the structure of the modified ats criteria for severe cap was retained [6] . the 2 major criteriamechanical ventilation with endotracheal intubation and septic shock requiring vasopressors-are absolute indications for admission to an icu. in contrast, the need for icu admission is less straightforward for patients who do not meet the major criteria. on the basis of the published operating characteristics of the criteria, no single set of minor criteria is adequate to define severe cap. both the ats minor criteria [75] and the curb criteria [45] have validity when predicting which patients will be at increased risk of death. therefore, the ats minor criteria and the curb variables were included in the new proposed minor criteria (table 4) . age, by itself, was not felt to be an appropriate factor for the icu admission decision, but the remainder of the curb-65 criteria [45] were retained as minor criteria (with the exception of hypotension requiring vasopressors as a major criterion). rather than the complex criteria for confusion in the original curb studies, the definition of confusion should be new-onset disorientation to person, place, or time. three additional minor criteria were added. leukopenia (white blood cell count, !4000 cells/mm 3 ) resulting from cap has consistently been associated with excess mortality, as well as with an increased risk of complications such as acute respiratory distress syndrome (ards) [77, 79, [83] [84] [85] [86] [87] . in addition, leukopenia is seen not only in bacteremic pneumococcal disease but also in gram-negative cap [88, 89] . when leukopenia occurs in patients with a history of alcohol abuse, the adverse manifestations of septic shock and ards may be delayed or masked. therefore, these patients were thought to benefit from icu monitoring. the coagulation system is often activated in cap, and development of thrombocytopenia (platelet count, !100,000 cells/mm 3 ) is also associated with a worse prognosis [86, [90] [91] [92] . nonexposure hypothermia (core temperature, !36њc) also carries an ominous prognosis in cap [83, 93] . the committee felt that there was sufficient justification for including these additional factors as minor criteria. other factors associated with increased mortality due to cap were also considered, including acute alcohol ingestion and delirium tremens [79, 85, 94] , hypoglycemia and hyperglycemia, occult metabolic acidosis or elevated lactate levels [91] , and hyponatremia [95] . however, many of these criteria overlap with those selected. future studies validating the proposed criteria should record these factors as well, to determine whether addition or substitution improves the predictive value of our proposed criteria. with the addition of more minor criteria, the threshold for icu admission was felt to be the presence of at least 3 minor criteria, based on the mortality association with the curb criteria. selecting 2 criteria appears to be too nonspecific, as is demonstrated by the initial ats criteria [5] . whether each of the criteria is of equal weight is also not clear. therefore, prospective validation of this set of criteria is clearly needed. 9. in addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (moderate recommendation; level iii evidence.) the diagnosis of cap is based on the presence of select clinical features (e.g., cough, fever, sputum production, and pleuritic chest pain) and is supported by imaging of the lung, usually by chest radiography. physical examination to detect rales or bronchial breath sounds is an important component of the evaluation but is less sensitive and specific than chest radiographs [96] . both clinical features and physical exam findings may be lacking or altered in elderly patients. all patients should be screened by pulse oximetry, which may suggest both the presence of pneumonia in patients without obvious signs of pneumonia and unsuspected hypoxemia in patients with diagnosed pneumonia [42, 97, 98] . a chest radiograph is required for the routine evaluation of patients who are likely to have pneumonia, to establish the diagnosis and to aid in differentiating cap from other common causes of cough and fever, such as acute bronchitis. chest radiographs are sometimes useful for suggesting the etiologic agent, prognosis, alternative diagnoses, and associated conditions. rarely, the admission chest radiograph is clear, but the patient's toxic appearance suggests more than bronchitis. ct scans may be more sensitive, but the clinical significance of these findings when findings of radiography are negative is unclear [99] . for patients who are hospitalized for suspected pneumonia but who have negative chest radiography findings, it may be reasonable to treat their condition presumptively with antibiotics and repeat the imaging in 24-48 h. microbiological studies may support the diagnosis of pneumonia due to an infectious agent, but routine tests are frequently falsely negative and are often nonspecific. a history of recent travel or endemic exposure, if routinely sought, may identify specific potential etiologies that would otherwise be unexpected as a cause of cap (see table 8 ) [100] . 10. patients with cap should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (strong recommendation; level ii evidence.) the need for diagnostic testing to determine the etiology of cap can be justified from several perspectives. the primary reason for such testing is if results will change the antibiotic management for an individual patient. the spectrum of antibiotic therapy can be broadened, narrowed, or completely altered on the basis of diagnostic testing. the alteration in therapy that is potentially most beneficial to the individual is an escalation or switch of the usual empirical regimen because of unusual pathogens (e.g., endemic fungi or mycobacterium tuberculosis) or antibiotic resistance issues. broad empirical coverage, such as that recommended in these guidelines, would not provide the optimal treatment for certain infections, such as psittacosis or tularemia. increased mortality [80] and increased risk of clinical failure [81, 101] are more common with inappropriate antibiotic therapy. management of initial antibiotic failure is greatly facilitated by an etiologic diagnosis at admission. de-escalation or narrowing of antibiotic therapy on the basis of diagnostic testing is less likely to decrease an individual's risk of death but may decrease cost, drug adverse effects, and antibiotic resistance pressure. some etiologic diagnoses have important epidemiologic implications, such as documentation of severe acute respiratory syndrome (sars), influenza, legionnaires disease, or agents of bioterrorism. diagnostic testing for these infections may affect not only the individual but also many other people. although pneumonia etiologies that should be reported to public health officials vary by state, in general, most states' health regulations require reporting of legionnaires disease, sars, psittacosis, avian influenza (h5n1), and possible agents of bioterrorism (plague, tularemia, and anthrax). in addition, specific diagnostic testing and reporting are important for pneumonia cases of any etiology thought to be part of a cluster or caused by pathogens not endemic to the area. there are also societal reasons for encouraging diagnostic testing. the antibiotic recommendations in the present guidelines are based on culture results and sensitivity patterns from patients with positive etiologic diagnoses [102] . without the accumulated information available from these culture results, trends in antibiotic resistance are more difficult to track, and empirical antibiotic recommendations are less likely to be accurate. the main downside of extensive diagnostic testing of all patients with cap is cost, which is driven by the poor quality of most sputum microbiological samples and the low yield of positive culture results in many groups of patients with cap. a clear need for improved diagnostic testing in cap, most likely using molecular methodology rather than culture, has been recognized by the national institutes of health [103] . the cost-benefit ratio is even worse when antibiotic therapy is not streamlined when possible [104, 105] or when inappropriate escalation occurs [95] . in clinical practice, narrowing of antibiotic therapy is, unfortunately, unusual, but the committee strongly recommends this as best medical practice. the possibility of polymicrobial cap and the potential benefit of combination therapy for bacteremic pneumococcal pneumonia have complicated the decision to narrow antibiotic therapy. delays in starting antibiotic therapy that result from the need to obtain specimens, complications of invasive diagnostic procedures, and unneeded antibiotic changes and additional testing for false-positive tests are also important considerations. the general recommendation of the committee is to strongly encourage diagnostic testing whenever the result is likely to change individual antibiotic management. for other patients with cap, the recommendations for diagnostic testing focus on patients in whom the diagnostic yield is thought to be greatest. these 2 priorities often overlap. recommendations for patients in whom routine diagnostic testing is indicated for the above reasons are listed in retrospective studies of outpatient cap management usually show that diagnostic tests to define an etiologic pathogen are infrequently performed, yet most patients do well with empir-ical antibiotic treatment [42, 106] . exceptions to this general rule may apply to some pathogens important for epidemiologic reasons or management decisions. the availability of rapid point-of-care diagnostic tests, specific treatment and chemoprevention, and epidemiologic importance make influenza testing the most logical. influenza is often suspected on the basis of typical symptoms during the proper season in the presence of an epidemic. however, respiratory syncytial virus (rsv) can cause a similar syndrome and often occurs in the same clinical scenario [107] . rapid diagnostic tests may be indicated when the diagnosis is uncertain and when distinguishing influenza a from influenza b is important for therapeutic decisions. other infections that are important to verify with diagnostic studies because of epidemiologic implications or because they require unique therapeutic intervention are sars and avian (h5n1) influenza, disease caused by agents of bioterrorism, legionella infection, community-acquired mrsa (ca-mrsa) infection, m. tuberculosis infection, or endemic fungal infection. attempts to establish an etiologic diagnosis are also appropriate in selected cases associated with outbreaks, specific risk factors, or atypical presentations. 12. pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in the only randomized controlled trial of diagnostic strategy in cap has demonstrated no statistically significant differences in mortality rate or los between patients receiving pathogendirected therapy and patients receiving empirical therapy [108] . however, pathogen-directed therapy was associated with lower mortality among the small number of patients admitted to the icu. the study was performed in a country with a low incidence of antibiotic resistance, which may limit its applicability to areas with higher levels of resistance. adverse effects were significantly more common in the empirical therapy group but may have been unique to the specific antibiotic choice (erythromycin). the lack of benefit overall in this trial should not be interpreted as a lack of benefit for an individual patient. therefore, performing diagnostic tests is never incorrect or a breach of the standard of care. however, information from cohort and observational studies may be used to define patient groups in which the diagnostic yield is increased. patient groups in which routine diagnostic testing is indicated and the recommended tests are listed in table 5. blood cultures. pretreatment blood cultures yielded positive results for a probable pathogen in 5%-14% in large series of nonselected patients hospitalized with cap [104, 105, [109] [110] [111] . the yield of blood cultures is, therefore, relatively low (although it is similar to yields in other serious infections), and, when management decisions are analyzed, the impact of positive blood cultures is minor [104, 105] . the most common blood culture isolate in all cap studies is s. pneumoniae. because this bacterial organism is always considered to be the most likely pathogen, positive blood culture results have not clearly led to better outcomes or improvements in antibiotic selection [105, 112] . false-positive blood culture results are associated with prolonged hospital stay, possibly related to changes in management based on preliminary results showing gram-positive cocci, which eventually prove to be coagulasenegative staphylococci [95, 109] . in addition, false-positive blood culture results have led to significantly more vancomycin use [95] . for these reasons, blood cultures are optional for all hospitalized patients with cap but should be performed selectively (table 5). the yield for positive blood culture results is halved by prior antibiotic therapy [95] . therefore, when performed, samples for blood culture should be obtained before antibiotic administration. however, when multiple risk factors for bacteremia are present, blood culture results after initiation of antibiotic therapy are still positive in up to 15% of cases [95] and are, therefore, still warranted in these cases, despite the lower yield. the strongest indication for blood cultures is severe cap. patients with severe cap are more likely to be infected with pathogens other than s. pneumoniae, including s. aureus, p. aeruginosa, and other gram-negative bacilli [77-80, 95, 113, 114] . many of the factors predictive of positive blood culture results [95] overlap with risk factors for severe cap (table 4) . therefore, blood cultures are recommended for all patients with severe cap because of the higher yield, the greater possibility of the presence of pathogens not covered by the usual empirical antibiotic therapy, and the increased potential to affect antibiotic management. blood cultures are also indicated when patients have a host defect in the ability to clear bacteremia-for example, as a result of asplenia or complement deficiencies. patients with chronic liver disease also are more likely to have bacteremia with cap [95] . leukopenia is also associated with a high incidence of bacteremia [79, 95] . respiratory tract specimen gram stain and culture. the yield of sputum bacterial cultures is variable and strongly influenced by the quality of the entire process, including specimen collection, transport, rapid processing, satisfactory use of cytologic criteria, absence of prior antibiotic therapy, and skill in interpretation. the yield of s. pneumoniae, for example, is only 40%-50% from sputum cultures from patients with bacteremic pneumococcal pneumonia in studies performed a few decades ago [115, 116] . a more recent study of 100 cases of bacteremic pneumococcal pneumonia found that sputum specimens were not submitted in 31% of cases and were judged as inadequate in another 16% of cases [117] . when patients receiving antibiotics for 124 h were excluded, gram stain showed pneumococci in 63% of sputum specimens, and culture results were positive in 86%. for patients who had received no antibiotics, the gram stain was read as being consistent with pneumococci in 80% of cases, and sputum culture results were positive in 93%. although there are favorable reports of the utility of gram stain [118] , a meta-analysis showed a low yield, considering the number of patients with adequate specimens and definitive results [119] . recent data show that an adequate specimen with a predominant morphotype on gram stain was found in only 14% of 1669 hospitalized patients with cap [120] . higher psi scores did not predict higher yield. however, a positive gram stain was highly predictive of a subsequent positive culture result. the benefit of a sputum gram stain is, therefore, 2-fold. first, it broadens initial empirical coverage for less common etiologies, such as infection with s. aureus or gram-negative organisms. this indication is probably the most important, because it will lead to less inappropriate antibiotic therapy. second, it can validate the subsequent sputum culture results. forty percent or more of patients are unable to produce any sputum or to produce sputum in a timely manner [108, 120] . the yield of cultures is substantially higher with endotracheal aspirates, bronchoscopic sampling, or transthoracic needle aspirates [120] [121] [122] [123] [124] [125] [126] , although specimens obtained after initiation of antibiotic therapy are unreliable and must be interpreted carefully [120, 127, 128] . interpretation is improved with quantitative cultures of respiratory secretions from any source (sputum, tracheal aspirations, and bronchoscopic aspirations) or by interpretation based on semiquantitative culture results [122, 123, 129] . because of the significant influence on diagnostic yield and cost effectiveness, careful attention to the details of specimen handling and processing are critical if sputum cultures are obtained. because the best specimens are collected and processed before antibiotics are given, the time to consider obtaining expectorated sputum specimens from patients with factors listed in table 5 is before initiation of antibiotic therapy. once again, the best indication for more extensive respiratory tract cultures is severe cap. gram stain and culture of endotracheal aspirates from intubated patients with cap produce different results than expectorated sputum from non-icu patients [76, 120] . many of the pathogens in the broader microbiological spectrum of severe cap are unaffected by a single dose of antibiotics, unlike s. pneumoniae. in addition, an endotracheal aspirate does not require patient cooperation, is clearly a lower respiratory tract sample, and is less likely to be contaminated by oropharyngeal colonizers. nosocomial tracheal colonization is not an issue if the sample is obtained soon after intubation. therefore, culture and gram stain of endotracheal aspirates are recommended for patients intubated for severe cap. in addition to routine cultures, a specific request for culture of respiratory secretions on buffered charcoal yeast extract agar to isolate legionella species may be useful in this subset of patients with severe cap in areas where legionella is endemic, as well as in patients with a recent travel history [130] . the fact that a respiratory tract culture result is negative does not mean that it has no value. failure to detect s. aureus or gram-negative bacilli in good-quality specimens is strong evidence against the presence of these pathogens. growth inhibition by antibiotics is lower with these pathogens than with s. pneumoniae, but specimens obtained after initiation of antibiotic therapy are harder to interpret, with the possibility of colonization. necrotizing or cavitary pneumonia is a risk for ca-mrsa infection, and sputum samples should be obtained in all cases. negative gram stain and culture results should be adequate to withhold or stop treatment for mrsa infection. severe copd and alcoholism are major risk factors for infection with p. aeruginosa and other gram-negative pathogens [131] . once again, gram stain and culture of an adequate sputum specimen are usually adequate to exclude the need for empirical coverage of these pathogens. a sputum culture in patients with suspected legionnaires disease is important, because the identification of legionella species implies the possibility of an environmental source to which other susceptible individuals may be exposed. localized community outbreaks of legionnaires disease might be recognized by clinicians or local health departments because у2 patients might be admitted to the same hospital. however, outbreaks of legionnaires disease associated with hotels or cruise ships [132] [133] [134] are rarely detected by individual clinicians, because travelers typically disperse from the source of infection before developing symptoms. therefore, a travel history should be actively sought from patients with cap, and legionella testing should be performed for those who have traveled in the 2 weeks before the onset of symptoms. urinary antigen tests may be adequate to diagnose and treat an individual, but efforts to obtain a sputum specimen for culture are still indicated to facilitate epidemiologic tracking. the availability of a culture isolate of legionella dramatically improves the likelihood that an environmental source of legionella can be identified and remediated [135] [136] [137] . the yield of sputum culture is increased to 43%-57% when associated with a positive urinary antigen test result [138, 139] . attempts to obtain a sample for sputum culture from a patient with a positive pneumococcal urinary antigen test result may be indicated for similar reasons. patients with a productive cough and positive urinary antigen test results have positive sputum culture results in as many as 40%-80% of cases [140] [141] [142] [143] . in these cases, not only can sensitivity testing confirm the appropriate choice for the individual patient, but important data regarding local community antibiotic resistance rates can also be acquired. other cultures. patients with pleural effusions 15 cm in height on a lateral upright chest radiograph [111] should undergo thoracentesis to yield material for gram stain and culture for aerobic and anaerobic bacteria. the yield with pleural fluid cultures is low, but the impact on management decisions is substantial, in terms of both antibiotic choice and the need for drainage. nonbronchoscopic bronchoalveolar lavage (bal) in the ed has been studied in a small, randomized trial of intubated patients with cap [144] . a high percentage (87%) of nonbronchoscopic bal culture results were positive, even in some patients who had already received their first dose of antibiotics. unfortunately, tracheal aspirates were obtained from only a third of patients in the control group, but they all were culture positive. therefore, it is unclear that endotracheal aspirates are inferior to nonbronchoscopic bal. the use of bronchoscopic bal, protected specimen brushing, or transthoracic lung aspiration has not been prospectively studied for initial management of patients with cap [123] . the best indications are for immunocompromised patients with cap or for patients with cap in whom therapy failed [101, 145] . antigen tests. urinary antigen tests are commercially available and have been cleared by the us food and drug administration (fda) for detection of s. pneumoniae and l. pneumophila serogroup 1 [138, 140, [146] [147] [148] [149] . urinary antigen testing appears to have a higher diagnostic yield in patients with more severe illness [139, 140] . for pneumococcal pneumonia, the principal advantages of antigen tests are rapidity (∼15 min), simplicity, reasonable specificity in adults, and the ability to detect pneumococcal pneumonia after antibiotic therapy has been started. studies in adults show a sensitivity of 50%-80% and a specificity of 190% [146, 149, 150] . this is an attractive test for detecting pneumococcal pneumonia when samples for culture cannot be obtained in a timely fashion or when antibiotic therapy has already been initiated. serial specimens from patients with known bacteremia were still positive for pneumococcal urinary antigen in 83% of cases after 3 days of therapy [147] . comparisons with gram stain show that these 2 rapidly available tests often do not overlap, with only 28% concordance (25 of 88) among patients when results of either test were positive [140] . only ∼50% of binax pneumococcal urinary antigen-positive patients can be diagnosed by conventional methods [140, 150] . disadvantages include cost (approximately $30 per specimen), although this is offset by increased diagnosis-related group-based reimbursement for coding for pneumococcal pneumonia, and the lack of an organism for in vitro susceptibility tests. falsepositive results have been seen in children with chronic respiratory diseases who are colonized with s. pneumoniae [151] and in patients with an episode of cap within the previous 3 months [152] , but they do not appear to be a significant problem in colonized patients with copd [140, 152] . for legionella, several urinary antigen assays are available, but all detect only l. pneumophila serogroup 1. although this particular serogroup accounts for 80%-95% of communityacquired cases of legionnaires disease [138, 153] in many areas of north america, other species and serogroups predominate in specific locales [154, 155] . prior studies of culture-proven legionnaires disease indicate a sensitivity of 70%-90% and a specificity of nearly 99% for detection of l. pneumophila serogroup 1. the urine is positive for antigen on day 1 of illness and continues to be positive for weeks [138, 150] . the major issue with urinary bacterial antigen detection is whether the tests allow narrowing of empirical antibiotic therapy to a single specific agent. the recommended empirical antibiotic regimens will cover both of these microorganisms. results of a small observational study suggest that therapy with a macrolide alone is adequate for hospitalized patients with cap who test positive for l. pneumophila urinary antigen [156] . further research is needed in this area. in contrast, rapid antigen detection tests for influenza, which can also provide an etiologic diagnosis within 15-30 min, can lead to consideration of antiviral therapy. test performance varies according to the test used, sample type, duration of illness, and patient age. most show a sensitivity of 50%-70% in adults and a specificity approaching 100% [157] [158] [159] . advantages include the high specificity, the ability of some assays to distinguish between influenza a and b, the rapidity with which the results can be obtained, the possibly reduced use of antibacterial agents, and the utility of establishing this diagnosis for epidemiologic purposes, especially in hospitalized patients who may require infection control precautions. disadvantages include cost (approximately $30 per specimen), high rates of false-negative test results, false-positive assays with adenovirus infections, and the fact that the sensitivity is not superior to physician judgment among patients with typical symptoms during an influenza epidemic [157, 158, 160] . direct fluorescent antibody tests are available for influenza and rsv and require ∼2 h. for influenza virus, the sensitivity is better than with the point-of-care tests (85%-95%). they will detect animal subtypes such as h5n1 and, thus, may be preferred for hospitalized patients [161, 162] . for rsv, direct fluorescent antibody tests are so insensitive (sensitivity, 20%-30%) in adults that they are rarely of value [163] . acute-phase serologic testing. the standard for diagnosis of infection with most atypical pathogens, including chlamydophila pneumoniae, mycoplasma pneumoniae, and legionella species other than l. pneumophila, relies on acute-and convalescent-phase serologic testing. most studies use a microimmunofluorescence serologic test, but this test shows poor reproducibility [164] . management of patients on the basis of a single acute-phase titer is unreliable [165] , and initial antibiotic therapy will be completed before the earliest time point to check a convalescent-phase specimen. a new pcr test (bd probetec et legionella pneumophila; becton dickinson) that will detect all serotypes of l. pneumophila in sputum is now cleared by the fda, but extensive published clinical experience is lacking. most pcr reagents for other respiratory pathogens (except mycobacterium species) are "home grown," with requirements for use based on compliance with nccls criteria for analytical validity [166] . despite the increasing use of these tests for atypical pathogens [167, 168] , a 2001 review by the centers for disease control and prevention (cdc) of diagnostic assays for detection of c. pneumoniae indicated that, of the 18 pcr reagents, only 4 satisfied the criteria for a validated test [166] . the diagnostic criteria defined in this review are particularly important for use in prospective studies of cap, because most prior reports used liberal criteria, which resulted in exaggerated rates. for sars, several pcr assays have been developed, but these tests are inadequate because of high rates of false-negative assays in early stages of infection [169, 170] . a major goal of therapy is eradication of the infecting organism, with resultant resolution of clinical disease. as such, antimicrobials are a mainstay of treatment. appropriate drug selection is dependent on the causative pathogen and its antibiotic susceptibility. acute pneumonia may be caused by a wide variety of pathogens (table 6) . however, until more accurate and rapid diagnostic methods are available, the initial treatment for most patients will remain empirical. recommendations for therapy (table 7) apply to most cases; however, physicians should consider specific risk factors for each patient (table 8) . a syndromic approach to therapy (under the assumption that an etiology correlates with the presenting clinical manifestations) is not specific enough to reliably predict the etiology of cap [172] [173] [174] . even if a microbial etiology is identified, debate continues with regard to pathogen-specific treatment, because recent studies suggest coinfection by atypical pathogens (such as c. pneumoniae, legionella species, and viruses) and more traditional bacteria [120, 175] . however, the importance of treating multiple infecting organisms has not been firmly established. the majority of antibiotics released in the past several decades have an fda indication for cap, making the choice of antibiotics potentially overwhelming. selection of antimicrobial regimens for empirical therapy is based on prediction of the most likely pathogen(s) and knowledge of local susceptibility patterns. recommendations are generally for a class of antibiotics rather than a specific drug, unless outcome data clearly favor one drug. because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. other factors for consideration of specific antimicrobials include pharmacokinetics/pharmacodynamics, compliance, safety, and cost. although cap may be caused by a myriad of pathogens, a limited number of agents are responsible for most cases. the emergence of newly recognized pathogens, such as the novel sars-associated coronavirus [170] , continually increases the challenge for appropriate management. table 6 lists the most common causes of cap, in decreasing order of frequency of occurrence and stratified for severity of illness as judged by site of care (ambulatory vs. hospitalized). s. pneumoniae is the most frequently isolated pathogen. other bacterial causes include nontypeable haemophilus influenzae and moraxella catarrhalis, generally in patients who have underlying bronchopulmonary disease, and s. aureus, especially during an influenza outbreak. risks for infection with enterobacteriaceae species and p. aeruginosa as etiologies for cap are chronic oral steroid administration or severe underlying bronchopulmonary disease, alcoholism, and frequent antibiotic therapy [79, 131] , whereas recent hospitalization would define cases as hcap. less common causes of pneumonia include, but are by no means limited to, streptococcus pyogenes, neisseria meningitidis, pasteurella multocida, and h. influenzae type b. the "atypical" organisms, so called because they are not detectable on gram stain or cultivatable on standard bacteriologic media, include m. pneumoniae, c. pneumoniae, legionella species, and respiratory viruses. with the exception of legionella species, these microorganisms are common causes of pneumonia, especially among outpatients. however, these pathogens are not often identified in clinical practice because, with a few exceptions, such as l. pneumophila and influenza virus, no specific, rapid, or standardized tests for their detection exist. although influenza remains the predominant viral cause of cap in adults, other commonly recognized viruses include rsv [107] , adenovirus, and parainfluenza virus, as well as less common viruses, including human metapneumovirus, herpes simplex virus, varicella-zoster virus, sars-associated coronavirus, and measles virus. in a recent study of immunocompetent adult patients admitted to the hospital with cap, 18% had evidence of a viral etiology, and, in 9%, a respiratory virus was the only pathogen identified [176] . studies that include outpatients find viral pneumonia rates as high as 36% [167] . the frequency of other etiologic agents-for example, m. tuberculosis, chlamydophila psittaci (psittacosis), coxiella burnetii (q fever), francisella tularensis (tularemia), bordetella pertussis (whooping cough), and endemic fungi (histoplasma capsulatum, coccidioides immitis, cryptococcus neoformans, and blastomyces hominis)-is largely determined by the epidemiologic setting (table 8) but rarely exceeds 2%-3% total [113, 177] . the exception may be endemic fungi in the appropriate geographic distribution [100] . the need for specific anaerobic coverage for cap is generally overestimated. anaerobic bacteria cannot be detected by diagnostic techniques in current use. anaerobic coverage is clearly indicated only in the classic aspiration pleuropulmonary syndrome in patients with a history of loss of consciousness as a result of alcohol/drug overdose or after seizures in patients with concomitant gingival disease or esophogeal motility disorders. antibiotic trials have not demonstrated a need to specifically treat these organisms in the majority of cap cases. smallvolume aspiration at the time of intubation should be adequately handled by standard empirical severe cap treatment [178] and by the high oxygen tension provided by mechanical ventilation. resistance to commonly used antibiotics for cap presents another major consideration in choosing empirical therapy. resistance patterns clearly vary by geography. local antibiotic prescribing patterns are a likely explanation [179] [180] [181] . however, clonal spread of resistant strains is well documented. therefore, antibiotic recommendations must be modified on the basis of local susceptibility patterns. the most reliable source is state/provincial or municipal health department regional data, if available. local hospital antibiograms are generally the most accessible source of data but may suffer from small numbers of isolates. drug-resistant s. pneumoniae (drsp). the emergence of drug-resistant pneumococcal isolates is well documented. the incidence of resistance appears to have stabilized somewhat in the past few years. resistance to penicillin and cephalosporins may even be decreasing, whereas macrolide resistance continues to increase [179, 182] . however, the clinical relevance of drsp for pneumonia is uncertain, and few well-controlled studies have examined the impact of in vitro resistance on clinical outcomes of cap. published studies are limited by small sample sizes, biases inherent in observational design, and the relative infrequency of isolates exhibiting high-level resistance [183] [184] [185] . current levels of b-lactam resistance do not generally result in cap treatment failures when appropriate agents (i.e., amoxicillin, ceftriaxone, or cefotaxime) and doses are used, even in the presence of bacteremia [112, 186] . the available data suggest that the clinically relevant level of penicillin resistance is a mic of at least 4 mg/l [3] . one report suggested that, if cefuroxime is used to treat pneumococcal bacteremia when the organism is resistant in vitro, the outcome is worse than with other therapies [112] . other discordant therapies, including penicillin, did not have an impact on mortality. data exist suggesting that resistance to macrolides [187] [188] [189] and older fluoroquinolones (ciprofloxacin and levofloxacin) [180, 190, 191] results in clinical failure. to date, no failures have been reported for the newer fluoroquinolones (moxifloxacin and gemifloxacin). risk factors for infection with b-lactam-resistant s. pneumoniae include age !2 years or 165 years, b-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, and exposure to a child in a day care center [112, [192] [193] [194] . although the relative predictive value of these risk factors is unclear, recent treatment with antimicrobials is likely the most significant. recent therapy or repeated courses of therapy with b-lactams, macrolides, or fluoroquinolones are risk factors for pneumococcal resistance to the same class of antibiotic [181, 193, 195, 196] . one study found that use of either a b-lactam or macrolide within the previous 6 months predicted an increased likelihood that, if pneumococcal bacteremia is present, the organism would be penicillin resistant [196] . other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci [195, 197] . whether this risk applies equally to all fluoroquinolones or is more of a concern for less active antipneumococcal agents (levofloxacin and ciprofloxacin) than for more active agents (moxifloxacin and gemifloxacin) is uncertain [190, 197, 198] . recommendations for the use of highly active agents in patients at risk for infection with drsp is, therefore, based only in part on efficacy considerations; it is also based on a desire to prevent more resistance from emerging by employing the most potent regimen possible. although increasing the doses of certain agents (penicillins, cephalosporins, levofloxacin) may lead to adequate outcomes in the majority of cases, switching to more potent agents may lead to stabilization or even an overall decrease in resistance rates [179, 180] . ca-mrsa. recently, an increasing incidence of pneumonia due to ca-mrsa has been observed [199, 200] . ca-mrsa appears in 2 patterns: the typical hospital-acquired strain [80] and, recently, strains that are epidemiologically, genotypically, and phenotypically distinct from hospital-acquired strains [201, 202] . many of the former may represent hcap, because these earlier studies did not differentiate this group from typical cap. the latter are resistant to fewer antimicrobials than are hospitalacquired mrsa strains and often contain a novel type iv sccmec gene. in addition, most contain the gene for panton-valentine leukocidin [200, 202] , a toxin associated with clinical features of necrotizing pneumonia, shock, and respiratory failure, as well as formation of abscesses and empyemas. the large majority of cases published to date have been skin infections in children. in a large study of ca-mrsa in 3 communities, 2% of ca-mrsa infections were pneumonia [203] . however, pneumonia in both adults [204] and children has been reported, often associated with preceding influenza. this strain should also be suspected in patients who present with cavitary infiltrates without risk factors for anaerobic aspiration pneu-monia (gingivitis and a risk for loss of consciousness, such as seizures or alcohol abuse, or esophogeal motility disorders). diagnosis is usually straightforward, with high yields from sputum and blood cultures in this characteristic clinical scenario. ca-mrsa cap remains rare in most communities but is expected to be an emerging problem in cap treatment. outpatient treatment. the following regimens are recommended for outpatient treatment on the basis of the listed clinical risks. the most common pathogens identified from recent studies of mild (ambulatory) cap were s. pneumoniae, m. pneumoniae, c. pneumoniae, and h. influenzae [177, 205] . mycoplasma infection was most common among patients !50 years of age without significant comorbid conditions or abnormal vital signs, whereas s. pneumoniae was the most common pathogen among older patients and among those with significant underlying disease. hemophilus infection was found in 5%mostly in patients with comorbidities. the importance of ther-apy for mycoplasma infection and chlamydophila infection in mild cap has been the subject of debate, because many infections are self-limiting [206, 207] . nevertheless, studies from the 1960s of children indicate that treatment of mild m. pneumoniae cap reduces the morbidity of pneumonia and shortens the duration of symptoms [208] . the evidence to support specific treatment of these microorganisms in adults is lacking. macrolides have long been commonly prescribed for treatment of outpatients with cap in the united states, because of their activity against s. pneumoniae and the atypical pathogens. this class includes the erythromycin-type agents (including dirithromycin), clarithromycin, and the azalide azithromycin. although the least expensive, erythromycin is not often used now, because of gastrointestinal intolerance and lack of activity against h. influenzae. because of h. influenzae, azithromycin is preferred for outpatients with comorbidities such as copd. numerous randomized clinical trials have documented the efficacy of clarithromycin and azithromycin as monotherapy for outpatient cap, although several studies have demonstrated that clinical failure can occur with a resistant isolate. when such patients were hospitalized and treated with a b-lactam and a macrolide, however, all survived and generally recovered without significant complications [188, 189] . most of these patients had risk factors for which therapy with a macrolide alone is not recommended in the present guidelines. thus, for patients with a significant risk of drsp infection, monotherapy with a macrolide is not recommended. doxycycline is included as a cost-effective alternative on the basis of in vitro data indicating effectiveness equivalent to that of erythromycin for pneumococcal isolates. the use of fluoroquinolones to treat ambulatory patients with cap without comorbid conditions, risk factors for drsp, or recent antimicrobial use is discouraged because of concern that widespread use may lead to the development of fluoroquinolone resistance [185] . however, the fraction of total fluoroquinolone use specifically for cap is extremely small and unlikely to lead to increased resistance by itself. more concerning is a recent study suggesting that many outpatients given a fluoroquinolone may not have even required an antibiotic, that the dose and duration of treatment were often incorrect, and that another agent often should have been used as firstline therapy. this usage pattern may promote the rapid development of resistance to fluoroquinolones [209] . comorbidities or recent antimicrobial therapy increase the likelihood of infection with drsp and enteric gram-negative bacteria. for such patients, recommended empirical therapeutic options include (1) a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg daily]) or (2) combination therapy with a b-lactam effective against s. pneumoniae plus a macrolide (doxycycline as an alternative). on the basis of present pharmacodynamic principles, high-dose amox-icillin (amoxicillin [1 g 3 times daily] or amoxicillin-clavulanate [2 g 2 times daily]) should target 193% of s. pneumoniae and is the preferred b-lactam. ceftriaxone is an alternative to highdose amoxicillin when parenteral therapy is feasible. selected oral cephalosporins (cefpodoxime and cefuroxime) can be used as alternatives [210] , but these are less active in vitro than highdose amoxicillin or ceftriaxone. agents in the same class as the patient had been receiving previously should not be used to treat patients with recent antibiotic exposure. telithromycin is the first of the ketolide antibiotics, derived from the macrolide family, and is active against s. pneumoniae that is resistant to other antimicrobials commonly used for cap (including penicillin, macrolides, and fluoroquinolones). several cap trials suggest that telithromycin is equivalent to comparators (including amoxicillin, clarithromycin, and trovafloxacin) [211] [212] [213] [214] . there have also been recent postmarketing reports of life-threatening hepatotoxicity [215] . at present, the committee is awaiting further evaluation of the safety of this drug by the fda before making its final recommendation. inpatient, non-icu treatment. the following regimens are recommended for hospital ward treatment. level i evidence) 19. a b-lactam plus a macrolide (strong recommendation; level i evidence) (preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level iii evidence] as an alternative to the macrolide. a respiratory fluoroquinolone should be used for penicillin-allergic patients.) the recommendations of combination treatment with a blactam plus a macrolide or monotherapy with a fluoroquinolone were based on retrospective studies demonstrating a significant reduction in mortality compared with that associated with administration of a cephalosporin alone [216] [217] [218] [219] . multiple prospective randomized trials have demonstrated that either regimen results in high cure rates. the major discriminating factor between the 2 regimens is the patient's prior antibiotic exposure (within the past 3 months). preferred b-lactams are those effective against s. pneumoniae and other common, nonatypical pathogens without being overly broad spectrum. in january 2002, the clinical laboratory standards institute (formerly the nccls) increased the mic breakpoints for cefotaxime and ceftriaxone for nonmeningeal s. pneumoniae infections. these new breakpoints acknowledge that nonmeningeal infections caused by strains formerly considered to be intermediately susceptible, or even resistant, can be treated successfully with usual doses of these b-lactams [112, 186, 220] . two randomized, double-blind studies showed ertapenem to be equivalent to ceftriaxone [221, 222] . it also has excellent activity against anaerobic organisms, drsp, and most enterobacteriaceae species (including extended-spectrum b-lactamase producers, but not p. aeruginosa). ertapenem may be useful in treating patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy. however, clinical experience with this agent is limited. other "antipneumococcal, antipseudomonal" b-lactam agents are appropriate when resistant pathogens, such as pseudomonas, are likely to be present. doxycycline can be used as an alternative to a macrolide on the basis of scant data for treatment of legionella infections [171, 223, 224] . two randomized, double-blind studies of adults hospitalized for cap have demonstrated that parenteral azithromycin alone was as effective, with improved tolerability, as intravenous cefuroxime, with or without intravenous erythromycin [225, 226] . in another study, mortality and readmission rates were similar, but the mean los was shorter among patients receiving azithromycin alone than among those receiving other guideline-recommended therapy [227] . none of the 10 patients with erythromycin-resistant s. pneumoniae infections died or was transferred to the icu, including 6 who received azithromycin alone. another study showed that those receiving a macrolide alone had the lowest 30-day mortality but were the least ill [219] . such patients were younger and were more likely to be in lower-risk groups. these studies suggest that therapy with azithromycin alone can be considered for carefully selected patients with cap with nonsevere disease (patients admitted primarily for reasons other than cap) and no risk factors for infection with drsp or gramnegative pathogens. however, the emergence of high rates of macrolide resistance in many areas of the country suggests that this therapy cannot be routinely recommended. initial therapy should be given intravenously for most admitted patients, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. when an intravenous b-lactam is combined with coverage for atypical pathogens, oral therapy with a macrolide or doxycycline is appropriate for selected patients without severe pneumonia risk factors [228] . inpatient, icu treatment. the following regimen is the minimal recommended treatment for patients admitted to the icu. 20 . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level ii evidence) or a fluoroquinolone (level i evidence) (strong recommendation) (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) a single randomized controlled trial of treatment for severe cap is available. patients with shock were excluded; however, among the patients with mechanical ventilation, treatment with a fluoroquinolone alone resulted in a trend toward inferior outcome [229] . because septic shock and mechanical ventilation are the clearest reasons for icu admission, the majority of icu patients would still require combination therapy. icu patients are routinely excluded from other trials; therefore, recommendations are extrapolated from nonsevere cases, in conjunction with case series and retrospective analyses of cohorts with severe cap. for all patients admitted to the icu, coverage for s. pneumoniae and legionella species should be ensured [78, 230] by using a potent antipneumococcal b-lactam and either a macrolide or a fluoroquinolone. therapy with a respiratory fluoroquinolone alone is not established for severe cap [229] , and, if the patient has concomitant pneumococcal meningitis, the efficacy of fluoroquinolone monotherapy is uncertain. in addition, 2 prospective observational studies [231, 232] and 3 retrospective analyses [233] [234] [235] have found that combination therapy for bacteremic pneumococcal pneumonia is associated with lower mortality than monotherapy. the mechanism of this benefit is unclear but was principally found in the patients with the most severe illness and has not been demonstrated in nonbacteremic pneumococcal cap studies. therefore, combination empirical therapy is recommended for at least 48 h or until results of diagnostic tests are known. in critically ill patients with cap, a large number of microorganisms other than s. pneumoniae and legionella species must be considered. a review of 9 studies that included 890 patients with cap who were admitted to the icu demonstrates that the most common pathogens in the icu population were (in descending order of frequency) s. pneumoniae, legionella species, h. influenzae, enterobacteriaceae species, s. aureus, and pseudomonas species [171] . the atypical pathogens responsible for severe cap may vary over time but can account collectively for у20% of severe pneumonia episodes. the dominant atypical pathogen in severe cap is legionella [230] , but some diagnostic bias probably accounts for this finding [78] . the recommended standard empirical regimen should routinely cover the 3 most common pathogens that cause severe cap, all of the atypical pathogens, and most of the relevant enterobacteriaceae species. treatment of mrsa or p. aeruginosa infection is the main reason to modify the standard empirical regimen. the following are additions or modifications to the basic empirical regimen recommended above if these pathogens are suspected. pseudomonal cap requires combination treatment to prevent inappropriate initial therapy, just as pseudomonas nosocomial pneumonia does [131] . once susceptibilities are known, treatment can be adjusted accordingly. alternative regimens are provided for patients who may have recently received an oral fluoroquinolone, in whom the aminoglycoside-containing regimen would be preferred. a consistent gram stain of tracheal aspirate, sputum, or blood is the best indication for pseudomonas coverage. other, easier-to-treat gram-negative microorganisms may ultimately be proven to be the causative pathogen, but empirical coverage of pseudomonas species until culture results are known is least likely to be associated with inappropriate therapy. other clinical risk factors for infection with pseudomonas species include structural lung diseases, such as bronchiectasis, or repeated exacerbations of severe copd leading to frequent steroid and/or antibiotic use, as well as prior antibiotic therapy [131] . these patients do not necessarily require icu admission for cap [236] , so pseudomonas infection remains a concern for them even if they are only hospitalized on a general ward. the major risk factor for infection with other serious gram-negative pathogens, such as klebsiella pneumoniae or acinetobacter species, is chronic alcoholism. (moderate recommendation; level iii evidence.) the best indicator of s. aureus infection is the presence of gram-positive cocci in clusters in a tracheal aspirate or in an adequate sputum sample. the same findings on preliminary results of blood cultures are not as reliable, because of the significant risk of contamination [95] . clinical risk factors for s. aureus cap include end-stage renal disease, injection drug abuse, prior influenza, and prior antibiotic therapy (especially with fluoroquinolones [237] ). for methicillin-sensitive s. aureus, the empirical combination therapy recommended above, which includes a b-lactam and sometimes a respiratory fluoroquinolone, should be adequate until susceptibility results are available and specific therapy with a penicillinase-resistant semisynthetic penicillin or first-generation cephalosporin can be initiated. both also offer additional coverage for drsp. neither linezolid [241] nor vancomycin [238] is an optimal drug for methicillin-sensitive s. aureus. although methicillin-resistant strains of s. aureus are still the minority, the excess mortality associated with inappropriate an-tibiotic therapy [80] would suggest that empirical coverage should be considered when ca-mrsa is a concern. the most effective therapy has yet to be defined. the majority of ca-mrsa strains are more susceptible in vitro to non-b-lactam antimicrobials, including trimethoprim-sulfamethoxazole (tmp-smx) and fluoroquinolones, than are hospital-acquired strains. previous experience with tmp-smx in other types of severe infections (endocarditis and septic thrombophlebitis) suggests that tmp-smx is inferior to vancomycin [239] . further experience and study of the adequacy of tmp-smx for ca-mrsa cap is clearly needed. vancomycin has never been specifically studied for cap, and linezolid has been found to be better than ceftriaxone for bacteremic s. pneumoniae in a nonblinded study [240] and superior to vancomycin in retrospective analysis of studies involving nosocomial mrsa pneumonia [241] . newer agents for mrsa have recently become available, and others are anticipated. of the presently available agents, daptomycin should not be used for cap, and no data on pneumonia are available for tigecycline. a concern with ca-mrsa is necrotizing pneumonia associated with production of panton-valentine leukocidin and other toxins. vancomycin clearly does not decrease toxin production, and the effect of tmp-smx and fluoroquinolones on toxin production is unclear. addition of clindamycin or use of linezolid, both of which have been shown to affect toxin production in a laboratory setting [242] , may warrant their consideration for treatment of these necrotizing pneumonias [204] . unfortunately, the emergence of resistance during therapy with clindamycin has been reported (especially in erythromycinresistant strains), and vancomycin would still be needed for bacterial killing. clinicians should be aware of epidemiologic conditions and/ or risk factors that may suggest that alternative or specific additional antibiotics should be considered. these conditions and specific pathogens, with preferred treatment, are listed in tables 8 and 9. pathogen-directed therapy 23 . once the etiology of cap has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (moderate recommendation; level iii evidence.) treatment options may be simplified (table 9) if the etiologic agent is established or strongly suspected. diagnostic procedures that identify a specific etiology within 24-72 h can still be useful for guiding continued therapy. this information is often available at the time of consideration for a switch from parenteral to oral therapy and may be used to direct specific oral antimicrobial choices. if, for example, an appropriate culture reveals penicillin-susceptible s. pneumoniae, a narrowspectrum agent (such as penicillin or amoxicillin) may be used. this will, hopefully, reduce the selective pressure for resistance. the major issue with pathogen-specific therapy is management of bacteremic s. pneumoniae cap. the implications of the observational finding that dual therapy was associated with reduced mortality in bacteremic pneumococcal pneumonia [231] [232] [233] [234] [235] are uncertain. one explanation for the reduced mortality may be the presence of undiagnosed coinfection with an atypical pathogen; although reported to occur in 18%-38% of cap cases in some studies [73, 175] , much lower rates of undiagnosed coinfection are found in general [171] and specifically in severe cases [78] . an alternative explanation is the immunomodulatory effects of macrolides [244, 245] . it is important to note that these studies evaluated the effects of initial empirical therapy before the results of blood cultures were known and did not examine effects of pathogen-specific therapy after the results of blood cultures were available. the benefit of combination therapy was also most pronounced in the more severely ill patients [233, 234] . therefore, discontinuation of combination therapy after results of cultures are known is most likely safe in non-icu patients. oseltamivir or zanamivir is recommended for influenza a. (strong recommendation; level i evidence.) 25. use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for 148 h (level i evidence), but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia. (moderate recommendation; level iii evidence.) studies that demonstrate that treatment of influenza is effective only if instituted within 48 h of the onset of symptoms have been performed only in uncomplicated cases [246] [247] [248] [249] . the impact of such treatment on patients who are hospitalized with influenza pneumonia or a bacterial pneumonia complicating influenza is unclear. in hospitalized adults with influenza, a minority of whom had radiographically documented pneumonia, no obvious benefit was found in one retrospective study of amantadine treatment [250] . treatment of antigen-or culture-positive patients with influenza with antivirals in addition to antibiotics is warranted, even if the radiographic infiltrate is caused by a subsequent bacterial superinfection. because of the longer period of persistent positivity after infection, the appropriate treatment for patients diagnosed with only 1 of the rapid diagnostic tests is unclear. because such patients often have recoverable virus (median duration of 4 days) after hos-pitalization, antiviral treatment seems reasonable from an infection-control standpoint alone. because of its broad influenza spectrum, low risk of resistance emergence, and lack of bronchospasm risk, oseltamivir is an appropriate choice for hospitalized patients. the neuraminidase inhibitors are effective against both influenza a and b viruses, whereas the m2 inhibitors, amantadine, and rimantadine are active only against influenza a [251] . in addition, viruses recently circulating in the united states and canada are often resistant to the m2 inhibitors on the basis of antiviral testing [252, 253] . therefore, neither amantadine nor rimantadine should be used for treatment or chemoprophylaxis of influenza a in the united states until susceptibility to these antiviral medications has been reestablished among circulating influenza a viruses [249] . early treatment of influenza in ambulatory adults with inhaled zanamivir or oral oseltamivir appears to reduce the likelihood of lower respiratory tract complications [254] [255] [256] . the use of influenza antiviral medications appears to reduce the likelihood of respiratory tract complications, as reflected by reduced usage rates of antibacterial agents in ambulatory patients with influenza. although clearly important in outpatient pneumonia, this experience may also apply to patients hospitalized primarily for influenza. parenteral acyclovir is indicated for treatment of varicellazoster virus infection [257] recent human infections caused by avian influenza a (h5n1) in vietnam, thailand, cambodia, china, indonesia, egypt, and turkey raise the possibility of a pandemic in the near future. the severity of h5n1 infection in humans distinguishes it from that caused by routine seasonal influenza. respiratory failure requiring hospitalization and intensive care has been seen in the majority of the 1140 recognized cases, and mortality is ∼50% [258, 259] . if a pandemic occurs, deaths will result from primary influenza pneumonia with or without secondary bacterial pneumonia. this section highlights issues for consideration, recognizing that treatment recommendations will likely change as the pandemic progresses. more specific guidance can be found on the idsa, ats, cdc, and who web sites as the key features of the pandemic become clearer. additional guidance is available at http://www.pandemicflu.gov. the who has delineated 6 phases of an influenza pandemic, defined by increasing levels of risk and public health response [260] . during the current pandemic alert phase (phase 3: cases of novel influenza infection without sustained person-to-person transmission), testing should be focused on confirming all suspected cases in areas where h5n1 infection has been documented in poultry and on detecting the arrival of the pandemic strain in unaffected countries. early clinical features of h5n1 infection include persistent fever, cough, and respiratory difficulty progressing over 3-5 days, as well as lymphopenia on admission to the hospital [258, 259, 261] . exposure to sick and dying poultry in an area with known or suspected h5n1 activity has been reported by most patients, although the recognition of poultry outbreaks has sometimes followed the recognition of human cases [261] . rapid bedside tests to detect influenza a have been used as screening tools for avian influenza in some settings. throat swabs tested by rt-pcr have been the most sensitive for confirming h5n1 infection to date, but nasopharyngeal swabs, washes, and aspirates; bal fluid; lung and other tissues; and stool have yielded positive results by rt-pcr and viral culture with varying sensitivity. convalescent-phase serum can be tested by microneutralization for antibodies to h5 antigen in a small number of international reference laboratories. specimens from suspected cases of h5n1 infection should be sent to public health laboratories with appropriate biocontainment facilities; the case should be discussed with health department officials to arrange the transfer of specimens and to initiate an epidemiologic evaluation. during later phases of an ongoing pandemic, testing may be necessary for many more patients, so that appropriate treatment and infection control decisions can be made, and to assist in defining the extent of the pandemic. recommendations for such testing will evolve on the basis of the features of the pandemic, and guidance should be sought from the cdc and who web sites (http://www.cdc.gov and http://www.who.int). patients with confirmed or suspected h5n1 influenza should be treated with oseltamivir. most h5n1 isolates since 2004 have been susceptible to the neuraminidase inhibitors oseltamivir and zanamivir and resistant to the adamantanes (amantidine and rimantidine) [262, 263] . the current recommendation is for a 5-day course of treatment at the standard dosage of 75 mg 2 times daily. in addition, droplet precautions should be used for patients with suspected h5n1 influenza, and they should be placed in respiratory isolation until that etiology is ruled out. health care personnel should wear n-95 (or higher) respirators during medical procedures that have a high likelihood of generating infectious respiratory aerosols. bacterial superinfections, particularly pneumonia, are important complications of influenza pneumonia. the bacterial etiologies of cap after influenza infection have included s. pneumoniae, s. aureus, h. influenzae, and group a streptococci. legionella, chlamydophila, and mycoplasma species are not important causes of secondary bacterial pneumonia after influenza. appropriate agents would therefore include cefotaxime, ceftriaxone, and respiratory fluoroquinolones. treatment with vancomycin, linezolid, or other agents directed against ca-mrsa should be limited to patients with confirmed infection or a compatible clinical presentation (shock and necrotizing pneumonia). because shortages of antibacterials and antivirals are anticipated during a pandemic, the appropriate use of diagnostic tests will be even more important to help target antibacterial therapy whenever possible, especially for patients admitted to the hospital. time to first antibiotic dose for cap has recently received significant attention from a quality-of-care perspective. this emphasis is based on 2 retrospective studies of medicare beneficiaries that demonstrated statistically significantly lower mortality among patients who received early antibiotic therapy [109, 264] . the initial study suggested a breakpoint of 8 h [264] , whereas the subsequent analysis found that 4 h was associated with lower mortality [109] . studies that document the time to first antibiotic dose do not consistently demonstrate this difference, although none had as large a patient population. most importantly, prospective trials of care by protocol have not demonstrated a survival benefit to increasing the percentage of patients with cap who receive antibiotics within the first 4-8 h [22, 65] . early antibiotic administration does not appear to shorten the time to clinical stability, either [265] , although time of first dose does appear to correlate with los [266, 267] . a problem of internal consistency is also present, because, in both studies [109, 264] , patients who received antibiotics in the first 2 h after presentation actually did worse than those who retemperature р37.8؇c heart rate р100 beats/min respiratory rate р24 breaths/min systolic blood pressure у90 mm hg arterial oxygen saturation у90% or po 2 у60 mm hg on room air ability to maintain oral intake a normal mental status a note. criteria are from [268, 274, 294] . po 2 , oxygen partial pressure. a important for discharge or oral switch decision but not necessarily for determination of nonresponse. ceived antibiotics 2-4 h after presentation. for these and other reasons, the committee did not feel that a specific time window for delivery of the first antibiotic dose should be recommended. however, the committee does feel that therapy should be administered as soon as possible after the diagnosis is considered likely. conversely, a delay in antibiotic therapy has adverse consequences in many infections. for critically ill, hemodynamically unstable patients, early antibiotic therapy should be encouraged, although no prospective data support this recommendation. delay in beginning antibiotic treatment during the transition from the ed is not uncommon. especially with the frequent use of once-daily antibiotics for cap, timing and communication issues may result in patients not receiving antibiotics for 18 h after hospital admission. the committee felt that the best and most practical resolution to this issue was that the initial dose be given in the ed [22] . data from the medicare database indicated that antibiotic treatment before hospital admission was also associated with lower mortality [109] . given that there are even more concerns regarding timing of the first dose of antibiotic when the patient is directly admitted to a busy inpatient unit, provision of the first dose in the physician's office may be best if the recommended oral or intramuscular antibiotics are available in the office. with the use of a potent, highly bioavailable antibiotic, the ability to eat and drink is the major consideration for switching from intravenous to oral antibiotic therapy for non-icu patients. initially, ramirez et al. [268] defined a set of criteria for an early switch from intravenous to oral therapy (table 10). in general, as many as two-thirds of all patients have clinical improvement and meet criteria for a therapy switch in the first 3 days, and most non-icu patients meet these criteria by day 7. subsequent studies have suggested that even more liberal criteria are adequate for the switch to oral therapy. an alternative approach is to change from intravenous to oral therapy at a predetermined time, regardless of the clinical response [269] . one study population with nonsevere illness was randomized to receive either oral therapy alone or intravenous therapy, with the switch occurring after 72 h without fever. the study population with severe illness was randomized to receive either intravenous therapy with a switch to oral therapy after 2 days or a full 10-day course of intravenous antibiotics. time to resolution of symptoms for the patients with nonsevere illness was similar with either regimen. among patients with more severe illness, the rapid switch to oral therapy had the same rate of treatment failure and the same time to resolution of symptoms as prolonged intravenous therapy. the rapid-switch group required fewer inpatient days (6 vs. 11) , although this was likely partially a result of the protocol, but the patients also had fewer adverse events. the need to keep patients in the hospital once clinical stability is achieved has been questioned, even though physicians commonly choose to observe patients receiving oral therapy for у1 day. even in the presence of pneumococcal bacteremia, a switch to oral therapy can be safely done once clinical stability is achieved and prolonged intravenous therapy is not needed [270] . such patients generally take longer (approximately half a day) to become clinically stable than do nonbacteremic patients. the benefits of in-hospital observation after a switch to oral therapy are limited and add to the cost of care [32] . discharge should be considered when the patient is a candidate for oral therapy and when there is no need to treat any comorbid illness, no need for further diagnostic testing, and no unmet social needs [32, 271, 272] . although it is clear that clinically stable patients can be safely switched to oral therapy and discharged, the need to wait for all of the features of clinical stability to be present before a patient is discharged is uncertain. for example, not all investigators have found it necessary to have the white blood cell count improve. using the definition for clinical stability in table 10, halm et al. [273] found that 19.1% of 680 patients were discharged from the hospital with у1 instability. death or readmission occurred in 10.5% of patients with no instability on discharge, in 13.7% of patients with 1 instability, and in 46.2% with у2 instabilities. in general, patients in higher psi classes take longer to reach clinical stability than do patients in lower risk classes [274] . this finding may reflect the fact that elderly patients with multiple comorbidities often recover more slowly. arrangements for appropriate follow-up care, including rehabilitation, should therefore be initiated early for these patients. in general, when switching to oral antibiotics, either the same agent as the intravenous antibiotic or the same drug class should be used. switching to a different class of agents simply because of its high bioavailability (such as a fluoroquinolone) is probably not necessary for a responding patient. for patients who received intravenous b-lactam-macrolide combination therapy, a switch to a macrolide alone appears to be safe for those who do not have drsp or gram-negative enteric pathogens isolated [275] . most patients with cap have been treated for 7-10 days or longer, but few well-controlled studies have evaluated the optimal duration of therapy for patients with cap, managed in or out of the hospital. available data on short-course treatment do not suggest any difference in outcome with appropriate therapy in either inpatients or outpatients [276] . duration is also difficult to define in a uniform fashion, because some antibiotics (such as azithromycin) are administered for a short time yet have a long half-life at respiratory sites of infection. in trials of antibiotic therapy for cap, azithromycin has been used for 3-5 days as oral therapy for outpatients, with some reports of single-dose therapy for patients with atypical pathogen infections [276] [277] [278] . results with azithromycin should not be extrapolated to other drugs with significantly shorter half-lives. the ketolide telithromycin has been used for 5-7 days to treat outpatients, including some with pneumococcal bacteremia or psi classes уiii [211] . in a recent study, highdose (750 mg) levofloxacin therapy for 5 days was equally successful and resulted in more afebrile patients by day 3 than did the 500-mg dose for 7-10 days (49.1% vs. 38.5%; p p ) [276] . on the basis of these studies, 5 days appears to be .03 the minimal overall duration of therapy documented to be effective in usual forms of cap. as is discussed above, most patients become clinically stable within 3-7 days, so longer durations of therapy are rarely necessary. patients with persistent clinical instability are often readmitted to the hospital and may not be candidates for shortduration therapy. short-duration therapy may be suboptimal for patients with bacteremic s. aureus pneumonia (because of the risk of associated endocarditis and deep-seated infection), for those with meningitis or endocarditis complicating pneumonia, and for those infected with other, less common pathogens (e.g., burkholderia pseudomallei or endemic fungi). an 8-day course of therapy for nosocomial p. aeruginosa pneumonia led to relapse more commonly than did a 15-day course of therapy [279] . whether the same results would be applicable to cap cases is unclear, but the presence of cavities or other signs of tissue necrosis may warrant prolonged treatment. studies of duration of therapy have focused on patients receiving empirical treatment, and reliable data defining treatment duration after an initially ineffective regimen are lacking. drotrecogin alfa activated is the first immunomodulatory therapy approved for severe sepsis. in the united states, the fda recommended the use of drotrecogin alfa activated for patients at high risk of death. the high-risk criterion suggested by the fda was an acute physiologic and chronic health assessment (apache) ii score у25, based on a subgroup analysis of the overall study. however, the survival advantage (absolute risk reduction, 9.8%) of drotrecogin alfa activated treatment of patients in the cap subgroup was equivalent to that in the subgroup with apache ii scores у25 [92, 280, 281] . the greatest reduction in the mortality rate was for s. pneumoniae infection (relative risk, 0.56; 95% ci, 0.35-0.88) [282] . subsequent data have suggested that the benefit appears to be greatest when the treatment is given as early in the hospital admission as possible. in the subgroup with severe cap caused by a pathogen other than s. pneumoniae and treated with appropriate antibiotics, there was no evidence that drotrecogin alfa activated affected mortality. although the benefit of drotrecogin alfa activated is clearly greatest for patients with cap who have high apache ii scores, this criterion alone may not be adequate to select appropriate patients. an apache ii score у25 was selected by a subgroup analysis of the entire study cohort and may not be similarly calibrated in a cap-only cohort. two-organ failure, the criterion suggested for drotrecogin alfa activated use by the european regulatory agency, did not influence the mortality benefit for patients with cap [92] . therefore, in addition to patients with septic shock, other patients with severe cap could be considered for treatment with drotrecogin alfa activated. those with sepsis-induced leukopenia are at extremely high risk of death and ards and are, therefore, potential candidates. conversely, the benefit of drotrecogin alfa activated is not as clear when respiratory failure is caused more by exacerbation of underlying lung disease rather than by the pneumonia itself. other minor criteria for severe cap proposed above are similar to organ failure criteria used in many sepsis trials. consideration of treatment with drotrecogin alfa activated is appropriate, but the strength of the recommendation is only level ii. 35 . hypotensive, fluid-resuscitated patients with severe cap should be screened for occult adrenal insufficiency. (moderate recommendation; level ii evidence.) a large, multicenter trial has suggested that stress-dose (200-300 mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressor-dependent patients with septic shock who do not have an appropriate cortisol response to stimulation [283] . once again, patients with cap made up a significant fraction of patients entered into the trial. in addition, 3 small pilot studies have suggested that there is a benefit to corticosteroid therapy even for patients with severe cap who are not in shock [284] [285] [286] . the small sample size and baseline differences between groups compromise the conclusions. although the criteria for steroid replacement therapy remain controversial, the frequency of intermittent steroid treatment in patients at risk for severe cap, such as those with severe copd, suggests that screening of patients with severe cap is appropriate with replacement if inadequate cortisol levels are documented. if corticosteroids are used, close attention to tight glucose control is required [287] . 36 patients who do not require immediate intubation but who have either hypoxemia or respiratory distress should receive a trial of niv [114, 288, 289] . patients with underlying copd are most likely to benefit. patients with cap who were ran-domized to receive niv had a 125% absolute risk reduction for the need for intubation [114] . the use of niv may also improve intermediate-term mortality. inability to expectorate may limit the use of niv [290] , but intermittent application of niv may allow for its use in patients with productive cough unless sputum production is excessive. prompt recognition of a failed niv trial is critically important, because most studies demonstrate worse outcomes for patients who require intubation after a prolonged niv trial [288, 290] . within the first 1-2 h of niv, failure to improve respiratory rate and oxygenation [114, 289, 290] or failure to decrease carbon dioxide partial pressure (pco 2 ) in patients with initial hypercarbia [114] predicts niv failure and warrants prompt intubation. niv provides no benefit for patients with ards [289] , which may be nearly indistinguishable from cap among patients with bilateral alveolar infiltrates. patients with cap who have severe hypoxemia (pao 2 /fio 2 ratio, !150) are also poor candidates for niv [290] . 37. low-tidal-volume ventilation (6 cm 3 /kg of ideal body weight) should be used for patients undergoing ventilation who have diffuse bilateral pneumonia or ards. (strong recommendation; level i evidence.) distinguishing between diffuse bilateral pneumonia and ards is difficult, but it may not be an important distinction. results of the ardsnet trial suggest that the use of low-tidalvolume ventilation provides a survival advantage [291] . pneumonia, principally cap, was the most common cause of ards in that trial, and the benefit of the low-tidal-volume ventilatory strategy appeared to be equivalent in the population with pneumonia compared with the entire cohort. the absolute risk reduction for mortality in the pneumonia cohort was 11%, indicating that, in order to avoid 1 death, 9 patients must be treated [292] . other aspects of the management of severe sepsis and septic shock in patients with cap do not appear to be significantly different from those for patients with other sources of infection. recommendations for these aspects of care are reviewed elsewhere [293] . because of the limitations of diagnostic testing, the majority of cap is still treated empirically. critical to empirical therapy is an understanding of the management of patients who do not follow the normal response pattern. although difficult to define, nonresponse is not uncommon. overall, 6%-15% of hospitalized patients with cap do not respond to the initial antibiotic treatment [81, 84, 101, 294] . the incidence of treatment failure among patients with cap who are not hospitalized is not well known, because population-based studies are required. almirall et al. [295] described an overall hospitalization rate of 60% in a population-based study, but the rate of failure among the 30% of patients who initially presented to their primary care physician was not provided. the frequency of prior antibiotic therapy among medicare patients admitted to the hospital with cap is 24%-40% [95, 109] , but the percentage who received prior antibiotic therapy for the acute episode of pneumonia itself versus other indications is unclear. for patients initially admitted to the icu, the risk of failure to respond is already high; as many as 40% will experience deterioration even after initial stabilization in the icu [101] . mortality among nonresponding patients is increased several-fold in comparison with that among responding patients [296] . overall mortality rates as high as 49% have been reported for an entire population of nonresponding hospitalized patients with cap [76, 84, 101] , and the mortality rate reported in one study of early failure was 27% [81] . apache ii score was not the only factor independently associated with mortality in the nonresponding group, suggesting that the excess mortality may be due to factors other than severity of illness at presentation [101] . 38. the use of a systematic classification of possible causes of failure to respond, based on time of onset and type of failure (table 11) , is recommended. (moderate recommendation; level ii evidence.) the term "nonresponding pneumonia" is used to define a situation in which an inadequate clinical response is present despite antibiotic treatment. lack of a clear-cut and validated definition in the literature makes nonresponse difficult to study. lack of response also varies according to the site of treatment. lack of response in outpatients is very different from that in patients admitted to the icu. the time of evaluation is also important. persistent fever after the first day of treatment differs significantly from fever persisting (or recurring) at day 7 of treatment. table 11 provides a construct for evaluating nonresponse to antibiotic treatment of cap, based on several studies addressing this issue [76, 81, 84, 101] . two patterns of unacceptable response are seen in hospitalized patients [101] . the first is progressive pneumonia or actual clinical deterioration, with acute respiratory failure requiring ventilatory support and/or septic shock, usually occurring within the first 72 h of hospital admission. as is noted above, as many as 45% of patients with cap who ultimately require icu admission are initially admitted to a non-icu setting and are transferred because of deterioration [75] . deterioration and development of respira-tory failure or hypotension 172 h after initial treatment is often related to intercurrent complications, deterioration in underlying disease, or development of nosocomial superinfection. the second pattern is that of persistent or nonresponding pneumonia. nonresponse can be defined as absence of or delay in achieving clinical stability, using the criteria in table 10 [274, 294] . when these criteria were used, the median time to achieve clinical stability was 3 days for all patients, but a quarter of patients took у6 days to meet all of these criteria for stability [274] . stricter definitions for each of the criteria and higher psi scores were associated with longer times to achieve clinical stability. conversely, subsequent transfer to the icu after achieving this degree of clinical stability occurred in !1% of [297] . given these results, concern regarding nonresponse should be tempered before 72 h of therapy. antibiotic changes during this period should be considered only for patients with deterioration or in whom new culture data or epidemiologic clues suggest alternative etiologies. finally, nonresolving or slow-resolving pneumonia has been used to refer to the conditions of patients who present with persistence of pulmonary infiltrates 130 days after initial pneumonia-like syndrome [298] . as many as 20% of these patients will be found to have diseases other than cap when carefully evaluated [295] . two studies have evaluated the risk factors for a lack of response in multivariate analyses [81, 84] , including those amenable to medical intervention. use of fluoroquinolones was independently associated with a better response in one study [84] , whereas discordant antimicrobial therapy was associated with early failure [81] . in table 12, the different risk and protective factors and their respective odds ratios are summarized. specific causes that may be responsible for a lack of response in cap have been classified by arancibia et al. [101] (table 11) . this classification may be useful for clinicians as a systematic approach to diagnose the potential causes of nonresponse in cap. although in the original study only 8 (16%) of 49 cases could not be classified [101] , a subsequent prospective multicenter trial found that the cause of failure could not be determined in 44% [84] . management of nonresponding cap. nonresponse to antibiotics in cap will generally result in у1 of 3 clinical responses: (1) transfer of the patient to a higher level of care, (2) further diagnostic testing, and (3) escalation or change in treatment. issues regarding hospital admission and icu transfer are discussed above. an inadequate host response, rather than inappropriate antibiotic therapy or unexpected microorganisms, is the most common cause of apparent antibiotic failure when guidelinerecommended therapy is used. decisions regarding further diagnostic testing and antibiotic change/escalation are intimately intertwined and need to be discussed in tandem. information regarding the utility of extensive microbiological testing in cases of nonresponding cap is mainly retrospective and therefore affected by selection bias. a systematic diagnostic approach, which included invasive, noninvasive, and imaging procedures, in a series of nonresponding patients with cap obtained a specific diagnosis in 73% [101] . in a different study, mortality among patients with microbiologically guided versus empirical antibiotic changes was not improved (mortality rate, 67% vs. 64%, respectively) [76] . however, no antibiotic changes were based solely on sputum smears, suggesting that invasive cultures or nonculture methods may be needed. mismatch between the susceptibility of a common causative organism, infection with a pathogen not covered by the usual empirical regimen, and nosocomial superinfection pneumonia are major causes of apparent antibiotic failure. therefore, the first response to nonresponse or deterioration is to reevaluate the initial microbiological results. culture or sensitivity data not available at admission may now make the cause of clinical failure obvious. in addition, a further history of any risk factors for infection with unusual microorganisms (table 8) should be taken if not done previously. viruses are relatively neglected as a cause of infection in adults but may account for 10%-20% of cases [299] . other family members or coworkers may have developed viral symptoms in the interval since the patient was admitted, increasing suspicion of this cause. the evaluation of nonresponse is severely hampered if a microbiological diagnosis was not made on initial presentation. if cultures were not obtained, clinical decisions are much more difficult than if the adequate cultures were obtained but negative. risk factors for nonresponse or deterioration (table 12) , therefore, figure prominently in the list of situations in which more aggressive initial diagnostic testing is warranted (table 5) . blood cultures should be repeated for deterioration or progressive pneumonia. deteriorating patients have many of the risk factors for bacteremia, and blood cultures are still high yield even in the face of prior antibiotic therapy [95] . positive blood culture results in the face of what should be adequate antibiotic therapy should increase the suspicion of either antibiotic-resistant isolates or metastatic sites, such as endocarditis or arthritis. despite the high frequency of infectious pulmonary causes of nonresponse, the diagnostic utility of respiratory tract cultures is less clear. caution in the interpretation of sputum or tracheal aspirate cultures, especially of gram-negative bacilli, is warranted because early colonization, rather than superinfection with resistant bacteria, is not uncommon in specimens obtained after initiation of antibiotic treatment. once again, the absence of multidrug-resistant pathogens, such as mrsa or pseudomonas, is strong evidence that they are not the cause of nonresponse. an etiology was determined by bronchoscopy in 44% of patients with cap, mainly in those not responding to therapy [300] . despite the potential benefit suggested by these results, and in contrast to ventilator-associated pneumonia [301, 302] , no randomized study has compared the utility of invasive versus noninvasive strategies in the cap population with nonresponse. rapid urinary antigen tests for s. pneumoniae and l. pneumophila remain positive for days after initiation of antibiotic therapy [147, 152] and, therefore, may be high-yield tests in this group. a urinary antigen test result that is positive for l. pneumophila has several clinical implications, including that coverage for legionella should be added if not started empirically [81] . this finding may be a partial explanation for the finding that fluoroquinolones are associated with a lower incidence of nonresponse [84] . if a patient has persistent fever, the faster response to fluoroquinolones in legionella cap warrants consideration of switching coverage from a macrolide [303] . stopping the b-lactam component of combination therapy to exclude drug fever is probably also safe [156] . because one of the major explanations for nonresponse is poor host immunity rather than incorrect antibiotics, a positive pneumococcal antigen test result would at least clarify the probable original pathogen and turn attention to other causes of failure. in addition, a positive pneumococcal antigen test result would also help with interpretation of subsequent sputum/tracheal aspirate cultures, which may indicate early superinfection. nonresponse may also be mimicked by concomitant or subsequent extrapulmonary infection, such as intravascular catheter, urinary, abdominal, and skin infections, particularly in icu patients. appropriate cultures of these sites should be considered for patients with nonresponse to cap therapy. in addition to microbiological diagnostic procedures, several other tests appear to be valuable for selected patients with nonresponse: • chest ct. in addition to ruling out pulmonary emboli, a ct scan can disclose other reasons for antibiotic failure, including pleural effusions, lung abscess, or central airway obstruction. the pattern of opacities may also suggest alternative noninfectious disease, such as bronchiolitis obliterans organizing pneumonia. • thoracentesis. empyema and parapneumonic effusions are important causes of nonresponse [81, 101] , and thoracentesis should be performed whenever significant pleural fluid is present. • bronchoscopy with bal and transbronchial biopsies. if the differential of nonresponse includes noninfectious pneumonia mimics, bronchoscopy will provide more diagnostic information than routine microbiological cultures. bal may reveal noninfectious entities, such as pulmonary hemorrhage or acute eosinophilic pneumonia, or hints of infectious diseases, such as lymphocytic rather than neutrophilic alveolitis pointing toward virus or chlamydophila infection. transbronchial biopsies can also yield a specific diagnosis. antibiotic management of nonresponse in cap has not been studied. the overwhelming majority of cases of apparent nonresponse are due to the severity of illness at presentation or a delay in treatment response related to host factors. other than the use of combination therapy for severe bacteremic pneumococcal pneumonia [112, 231, 233, 234] , there is no documentation that additional antibiotics for early deterioration lead to a better outcome. the presence of risk factors for potentially untreated microorganisms may warrant temporary empirical broadening of the antibiotic regimen until results of diagnostic tests are available. vaccines targeting pneumococcal disease and influenza remain the mainstay for preventing cap. pneumococcal polysaccharide vaccine and inactivated influenza vaccine are recommended for all older adults and for younger persons with medical conditions that place them at high risk for pneumonia morbidity and mortality (table 13) [304, 305] . the new live attenuated influenza vaccine is recommended for healthy persons 5-49 years of age, including health care workers [304] . postlicensure epidemiologic studies have documented the effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infection (bacteremia and meningitis) among elderly individuals and younger adults with certain chronic medical conditions [306] [307] [308] [309] . the overall effectiveness against invasive pneumococcal disease among persons у65 years of age is 44%-75% [306, 308, 310] , although efficacy may decrease with advancing age [308] . the effectiveness of the vaccine against pneumococcal disease in immunocompromised persons is less clear, and results of studies evaluating its effectiveness against pneumonia without bacteremia have been mixed. the vaccine has been shown to be cost effective for general populations of adults 50-64 years of age and у65 years of age [311, 312] . a second dose of pneumococcal polysaccharide vaccine after a у5-year interval has been shown to be safe, with only slightly more local reactions than are seen after the first dose [313] . because the safety of a third dose has not been demonstrated, current guidelines do not suggest repeated revaccination. the pneumococcal conjugate vaccine is under investigation for use in adults but is currently only licensed for use in young children [314, 315] . however, its use in children !5 years of age has dramatically reduced invasive pneumococcal bacteremia among adults as well [314, 316] . the effectiveness of influenza vaccines depends on host factors and on how closely the antigens in the vaccine are matched with the circulating strain of influenza. a systematic review demonstrates that influenza vaccine effectively prevents pneumonia, hospitalization, and death [317, 318] . a recent large observational study of adults у65 years of age found that vaccination against influenza was associated with a reduction in the risk of hospitalization for cardiac disease (19% reduction), cerebrovascular disease (16%-23% reduction), and pneumonia or influenza (29%-32% reduction) and a reduction in the risk of death from all causes (48%-50% reduction) [319] . in longterm-care facilities, vaccination of health care workers with influenza vaccine is an important preventive health measure [318, 320, 321] . because the main virulence factors of influenza virus, a neuraminidase and hemagglutinin, adapt quickly to selective pressures, new vaccine formulations are created each year on the basis of the strains expected to be circulating, and annual revaccination is needed for optimal protection. 43 many people who should receive either influenza or pneumococcal polysaccharide vaccine have not received them. according to a 2003 survey, only 69% of adults у65 years of age had received influenza vaccine in the past year, and only 64% had ever received pneumococcal polysaccharide vaccine [322] . coverage levels are lower for younger persons with vaccine indications. among adults 18-64 years of age with diabetes, 49% had received influenza vaccine, and 37% had ever received pneumococcal vaccine [323] . studies of vaccine delivery methods indicate that the use of standing orders is the best way to improve vaccination coverage in office, hospital, or long-term care settings [324] . hospitalization of at-risk patients represents an underutilized opportunity to assess vaccination status and to either provide or recommend immunization. ideally, patients should be vaccinated before developing pneumonia; therefore, admissions for illnesses other than respiratory tract infections would be an appropriate focus. however, admission for pneumonia is an important trigger for assessing the need for immunization. the actual immunization may be better provided at the time of outpatient follow-up, especially with the emphasis on early discharge of patients with cap. patients with an acute fever should not be vaccinated until their fever has resolved. confusion of a febrile reaction to immunization with recurrent/superinfection pneumonia is a risk. however, immunization at discharge for pneumonia is warranted for patients for whom outpatient follow-up is unreliable, and such vaccinations have been safely given to many patients. the best time for influenza vaccination in north america is october and november, although vaccination in december and later is recommended for those who were not vaccinated earlier. influenza and pneumococcal vaccines can be given at the same time in different arms. chemoprophylaxis can be used as an adjunct to vaccination for prevention and control of influenza. oseltamivir and zanamivir are both approved for prophylaxis; amantadine and rimantadine have fda indications for chemoprophylaxis against influenza a infection, but these agents are currently not recommended because of the frequency of resistance among strains circulating in the united states and canada [252, 253] . developing an adequate immune response to the inactivated influenza vaccine takes ∼2 weeks in adults; chemoprophylaxis may be useful during this period for those with household exposure to influenza, those who live or work in institutions with an influenza outbreak, or those who are at high risk for influenza complications in the setting of a community outbreak [325, 326] . chemoprophylaxis also may be useful for persons with contraindications to influenza vaccine or as an adjunct to vaccination for those who may not respond well to influenza vaccine (e.g., persons with hiv infection) [325, 326] . the use of influenza antiviral medications for treatment or chemoprophylaxis should not affect the response to the inactivated vaccine. because it is unknown whether administering influenza antiviral medications affects the performance of the new live attenuated intranasal vaccine, this vaccine should not be used in conjunction with antiviral agents. other types of vaccination can be considered. pertussis is a rare cause of pneumonia itself. however, pneumonia is one of the major complications of pertussis. concern over waning immunity has led the acip to emphasize adult immunization for pertussis [327] . one-time vaccination with the new tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine-adsorbed (tdap) product, adacel (sanofi pasteur)is recommended for adults 19-64 years of age. for most adults, the vaccine should be given in place of their next routine tetanus-diphtheria booster; adults with close contact with infants !12 months of age and health care workers should receive the vaccine as soon as possible, with an interval as short as 2 years after their most recent tetanus/diphtheria booster. 46 smoking is associated with a substantial risk of pneumococcal bacteremia; one report showed that smoking was the strongest of multiple risks for invasive pneumococcal disease in immunocompetent nonelderly adults [328] . smoking has also been identified as a risk for legionella infection [329] . smoking cessation should be attempted when smokers are hospitalized; this is particularly important and relevant when these patients are hospitalized for pneumonia. materials for clinicians and patients to assist with smoking cessation are available online from the us surgeon general (http://www.surgeongeneral.gov/tobacco), the centers for disease control and prevention (http://www.cdc.gov/ tobacco), and the american cancer society (http://www .cancer.org). the most successful approaches to quitting include some combination of nicotine replacement and/or bupropion, a method to change habits, and emotional support. given the increased risk of pneumonia, the committee felt that persons unwilling to stop smoking should be given the pneumococcal polysaccharide vaccine, although this is not currently an aciprecommended indication. 48 . cases of pneumonia that are of public health concern should be reported immediately to the state or local health department. (strong recommendation; level iii evidence.) public health interventions are important for preventing some forms of pneumonia. notifying the state or local health department about a condition of interest is the first step to getting public health professionals involved. rules and regulations regarding which diseases are reportable differ between states. for pneumonia, most states require reporting for legionnaires disease, sars, and psittacosis, so that an investigation can determine whether others may be at risk and whether control measures are necessary. for legionnaires disease, reporting of cases has helped to identify common-source outbreaks caused by environmental contamination [130] . for sars, close observation and, in some cases, quarantine of close contacts have been critical for controlling transmission [330] . in addition, any time avian influenza (h5n1) or a possible terrorism agent (e.g., plague, tularemia, or anthrax) is being considered as the etiology of pneumonia, the case should be reported immediately, even before a definitive diagnosis is obtained. in addition, pneumonia cases that are caused by pathogens not thought to be endemic to the area should be reported, even if those conditions are not typically on the list of reportable conditions, because control strategies might be possible. for other respiratory diseases, episodes that are suspected of being part of an outbreak or cluster should be reported. for pneumococcal disease and influenza, outbreaks can occur in crowded settings of susceptible hosts, such as homeless shelters, nursing homes, and jails. in these settings, prophylaxis, vaccination, and infection control methods are used to control further transmission [331] . for mycoplasma, antibiotic prophylaxis has been used in schools and institutions to control outbreaks [332] . 49 . respiratory hygiene measures, including the use of hand hygiene and masks or tissues for patients with cough, should be used in outpatient settings and eds as a means to reduce the spread of respiratory infections. (strong recommendation; level iii evidence.) in part because of the emergence of sars, improved respiratory hygiene measures ("respiratory hygiene" or "cough etiquette") have been promoted as a means for reducing transmission of respiratory infections in outpatient clinics and eds [333] . key components of respiratory hygiene include encouraging patients to alert providers when they present for a visit and have symptoms of a respiratory infection; the use of hand hygiene measures, such as alcohol-based hand gels; and the use of masks or tissues to cover the mouth for patients with respiratory illnesses. in a survey of the us population, the use of masks in outpatient settings was viewed as an acceptable means for reducing the spread of respiratory infections [334] . for hospitalized patients, infection control recommendations typically are pathogen specific. for more details on the use of personal protective equipment and other measures to prevent transmission within health care settings, refer to the healthcare infection control practices advisory committee [335] . performance indicators are tools to help guideline users measure both the extent and the effects of implementation of guidelines. such tools or measures can be indicators of the process itself, outcomes, or both. deviations from the recommendations are expected in a proportion of cases, and compliance in 80%-95% of cases is generally appropriate, depending on the indicator. four specific performance indicators have been selected for the cap guidelines, 3 of which focus on treatment issues and 1 of which deals with prevention: • initial empirical treatment of cap should be consistent with guideline recommendations. data exist that support the role of cap guidelines and that have demonstrated reductions in cost, los, and mortality when the guidelines are followed. reasons for deviation from the guidelines should be clearly documented in the medical record. • the first treatment dose for patients who are to be admitted to the hospital should be given in the ed. unlike in prior guidelines, a specific time frame is not being recommended. initiation of treatment would be expected within 6-8 h of presentation whenever the admission diagnosis is likely cap. a rush to treatment without a diagnosis of cap can, however, result in the inappropriate use of antibiotics with a concomitant increase in costs, adverse drug events, increased antibiotic selection pressure, and, possibly, increased antibiotic resistance. consideration should be given to monitoring the number of patients who receive empirical antibiotics in the ed but are admitted to the hospital without an infectious diagnosis. • mortality data for all patients with cap admitted to wards, icus, or high-level monitoring units should be collected. although tools to predict mortality and severity of illness exist-such as the psi and curb-65 criteria, respectivelynone is foolproof. overall mortality rates for all patients with cap admitted to the hospital, including general medical wards, should be monitored and compared with severity-adjusted norms. in addition, careful attention should be paid to the percentage of patients with severe cap, as defined in this document, who are admitted initially to a non-icu or a high-level monitoring unit and to their mortality rate. • it is important to determine what percentage of at-risk patients in one's practice actually receive immunization for influenza or pneumococcal infection. prevention of infection is clearly more desirable than having to treat established infection, but it is clear that target groups are undervaccin-ated. trying to increase the number of protected individuals is a desirable end point and, therefore, a goal worth pursuing. this is particularly true for influenza, because the vaccine data are more compelling, but it is important to try to protect against pneumococcal infection as well. coverage of 90% of adults у65 years of age should be the target. 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prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis efficacy of an acellular pertussis vaccine among adolescents and adults cigarette smoking and invasive pneumococcal disease. active bacterial core surveillance team surveillance for legionnaires' disease: risk factors for morbidity and mortality sars in healthcare facilities an outbreak of multidrugresistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents azithromycin prophylaxis during a hospital outbreak of mycoplasma pneumoniae pneumonia respiratory hygiene/cough etiquette in health-care settings experiences with influenza-like illness and attitudes regarding influenza prevention-united states, 2003-04 influenza season guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee the committee wishes to express its gratitude to robert balk, christian brun-buisson, ali el-sohl, alan fein, donald e. low, constantine manthous, thomas j. marrie, joseph f. plouffe, and david a. talan, for their thoughtful review of an earlier version of the guidelines. supplement sponsorship. this article was published as part of a supplement entitled "infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults," sponsored by the infectious diseases society of america. key: cord-285898-rtqkvf63 authors: padberg, stephanie title: anti-infective agents date: 2014-09-29 journal: drugs during pregnancy and lactation doi: 10.1016/b978-0-12-408078-2.00007-x sha: doc_id: 285898 cord_uid: rtqkvf63 infections may be hazardous to the health of the mother, the course of pregnancy, and the unborn child. they can lead to premature labor or premature rupture of membranes and thereby increase the risk for spontaneous abortion and prematurity. furthermore, certain germs can pass to the unborn child and harm it directly. therefore, an anti-infective treatment which should be both effective and safe for the mother and the unborn child is often required. the use of penicillines and older cephalosporines is well documented and considered to be safe. consequently, they are the drug of choice during pregnancy. in selected cases of bacterial resistance or intolerance to first-line antibiotics, other anti-infective agents might be recommended. especially for life-threatening infections, a therapy with not so well-tried agents might be needed. the potential benefit of treatment in such cases most often outbalances the potential risk for the unborn child. infections may be hazardous to the health of the mother, the course of pregnancy, and the unborn child. they can lead to premature labor or premature rupture of membranes and thereby increase the risk for spontaneous abortion and prematurity. furthermore, certain germs can pass to the unborn child and harm it directly. therefore, an anti-infective treatment which should be both effective and safe for the mother and the unborn child is often required. the use of penicillins and older cephalosporins is well documented and considered to be safe. consequently, they are the drug of choice during pregnancy. in selected cases of bacterial resistance or intolerance to first-line antibiotics, other anti-infective agents might be recommended. especially for life-threatening infections, a therapy with not so well-tried agents might be needed. the potential benefit of treatment in such cases most often outbalances the potential risk for the unborn child. stephanie padberg 2.6 2.6.4 erythromycin and other macrolides pharmacology erythromycin and other macrolides inhibit bacterial protein synthesis and are bacteriostatic. macrolides are primarily applied in the treatment of infections with gram-positive germs, but are also effective against haemophilus influenzae and intracellular pathogens such as chlamydia. macrolides offer an alternative for patients with penicillin allergy. erythromycin is the oldest medication of this group. its resorption can be delayed in the third trimester. gastrointestinal side effects can lead to lower than therapeutic plasma concentrations, resulting in treatment failure (larsen 1998) . only 5-20% of the maternal erythromycin concentration is obtained in the fetus. therefore, erythromycin is not a sufficiently reliable drug for fetal or amniotic infections. the newer macrolide antibiotics azithromycin, clarithromycin, dirithromycin, josamycin, midecamycin, roxithromycin and troleandomycin have a similar antibacterial spectrum as erythromycin, but to some degree less gastrointestinal side effects. spiramycin is used for toxoplasmosis in the first trimester. telithromycin is the first ketolide antibiotic for clinical use. it is structurally related to erythromycin. erythromycin has always been considered a safe and effective antibiotic during pregnancy. data on several thousand first trimester exposures do not support an association between erythromycin and congenital malformations (e.g. czeizel 1999a ). however, an analysis of the data from the swedish birth registry showed a weakly significant increase in malformations in 1,844 children whose mothers took erythromycin in early pregnancy compared to offspring whose mothers used phenoxymethylpenicillin (källén 2005a ). this was based on an increased rate of cardiovascular malformations, especially ventricular and atrial septal defects. an update of the swedish data verified an association between the use of erythromycin during early pregnancy and cardiovascular defects (källén 2014 ). an increased incidence of pyloric stenosis was discussed by the same author (källén 2005a) . this observation after intrauterine exposure in the first trimester is biologically not plausible; but it should be mentioned that a link has been suggested between a neonatal treatment with erythromycin during the first two weeks and the development of pylorus stenosis (e.g. mahon 2001) . other studies have failed to find a higher rate of septum defects, pyloric stenosis or other malformations (bahat dinur 2013 , lin 2013 , romøren 2012 , malm 2008 , cooper 2002 , louik 2002 . in summary, the experiences argue against an increased embryo-and fetotoxic risk for erythromycin. there are several reports of maternal hepatotoxic changes when erythromycin estolate was administered in the second half of pregnancy. these women developed a cholestatic icterus during the second week of treatment that abated within weeks when the treatment was discontinued, without evidence of permanent damage or signs of fetal compromise (e.g. mccormack 1977) . azithromycin, clarithromycin and roxithromycin have also been studied in several publications without any indication of embryo-or fetotoxic effects (bar-oz 2012, bar-oz 2008 , chun 2006 , sarkar 2006 , drinkard 2000 , einarson 1998 ). in the case of clarithromycin, there was some 2.6 anti-infective agents 2 pregnancy initial concern as animal experiments demonstrated teratogenic effects, and for instance, in some studies cardiovascular defects were induced in rats. recently a danish cohort study based on a prescription register observed an increased risk of miscarriage after clarithromycin in early pregnancy, but no increased risk for major malformations (andersen 2013a) . experience with dirithromycin, josamycin, midecamycin, spiramycin, and troleandomycin is very limited (czeizel 2000b) . spiramycin has been used in many first trimesters for the treatment of toxoplamosis. although these reports did not focus on a possible teratogenic effect, numerous normal births after spiramycin exposure are reassuring. there is no published experience with the use of the ketolide telithromycin in the first trimester. the animal experiments did not show that this agent is teratogenic. a local treatment with macrolides is quite safe for the fetus. yet, because resistance develops quickly and allergies are frequent, macrolides should be used with some reservation. clindamycin and lincomycin belong to the lincosamide group. they inhibit bacterial protein synthesis and can be bactericidal or bacteriostatic depending on concentration and sensitivity. after an oral dose the resorption is almost complete. about half of the maternal concentration can be attained in the umbilical veins. there were no signs of embryo-or fetotoxic effects in several hundred pregnant women treated with lincomycin at different points in pregnancy (czeizel 2000c , mickal 1975 . there were also no problems found for clindamycin. pseudomembranous enterocolitis is a dangerous maternal complication of clindamycin treatment that may also happen after vaginal application. pregnancy complications due to bacterial vaginosis are not sufficiently preventable by vaginal clindamycin therapy (joesoef 1999) . it should be noted though, that other investigators found a reduction in late abortions and prematurity when treating several hundred patients with oral clindamycin for an abnormal vaginal flora (ugwumadu 2003) . recommendation. erythromycin, clarithromycin, azithromycin, and roxithromycin may be used in pregnancy when the resistance spectrum requires them, or in cases of an allergy to penicillin. because of hepatotoxicity, erythomycin estolate should not be given during the second and third trimester. spiramycin is the treatment of choice for toxoplasmosis in the first trimester. telithromycin and other makrolides should only be given during pregnancy when no alternatives are available. recommendation. clindamycin and lincomycin should only be used when penicillins, cephalosporins and macrolides have failed. clindamycin should not be routinely used after dental procedures. the bacteriostatic effect of tetracyclines is based on an inhibition of the bacterial protein synthesis. these broad-spectrum antibiotics, especially tetracycline itself, form stable chelates with calcium ions. the standard agent today is doxycycline. minocycline is especially lipophilic and displays a somewhat wider antibacterial spectrum than doxycycline. the older derivatives such as oxytetracycline and tetracycline are now rarely used as they are poorly resorbed. chlortetracycline, demeclocycline, and meclocycline are only used as local agents. tigecycline is a minocycline derivative that belongs to the glycylcyclines; it has a very broad-spectrum and is especially effective against multi-resistant pathogens such as mrsa. tetracyclines cross the placenta. according to current knowledge an increased risk of malformation is not expected when tetracyclines are used (cooper 2009 , czeizel 1997 . the results of a population-based case-control study suggested that oxytetracycline was associated with an increased incidence of congenital malformations (czeizel 2000d) . however, the number of cases in this study was small, and there are no other studies confirming this suspicion. a danish cohort study found an association between oral clefts and maternal tetracycline exposure in the second month, but this result was based on only two exposed cases (mølgaard-nielsen 2012) . from the sixteenth week of pregnancy when fetal mineralization takes place, tetracyclines can bind to calcium ions in developing teeth and bones. in the 1950s numerous publications described the brown/yellow discoloration of teeth in children who were prenatally exposed to tetracyclines. such dental discoloration is the only proven prenatal side effect of tetracyclines in humans. under discussion were also enamel defects leading to an increased risk of caries, inhibition of the growth of the long bones, specifically the fibula and further, cataracts due to depositions into the lens. as doxycycline has a weaker affinity to calcium ions than the older tetracyclines, the risk appears to be lower for doxycycline exposures. a discoloration of milk teeth is not to be expected prior to the sixteenth week of gestation. even thereafter, at worst, only the first molars of the permanent teeth would be affected when the usual therapeutic regimens if current dosings are adhered to. a bigger risk for the described development abnormalities can possibly expected with higher tetracycline doses during the second and third trimester that are necessary, for example, in malaria treatment. in the past, the use of tetracyclines, especially in high doses or via intravenous administration in the second half of pregnancy, has been associated with severe maternal hepatic toxicity (e.g. lewis 1991) . in most cases these were patients with kidney problems whose serum concentrations were markedly above the therapeutic range. no untoward effects have been described in pregnant women who applied tetracyclines locally during pregnancy. there is a lack of experience with tigecycline; no statement can be made about its tolerance in pregnancy. for local application silver sulfadiazine is used for burn injuries and sulfacetamide for eye infections. sulfonamides attain 50-90% of the maternal concentration in the fetus and compete with bilirubin for binding sites on albumin. today, sulfonamides are seldom used as monotherapy because their spectrum is limited and resistance develops rapidly. combined with a folate antagonist such as trimethoprim or pyrimethamine (section 2.6.16), sulfonamides are indicated among others in the treatment of toxoplasmosis and malaria. the fixed combination of the sulfonamide sulfamethoxazole and trimethoprim is available as co-trimoxazole. both agents in this combination are not subject to pregnancy-induced variation in clearance that would require dose modifications. trimethoprim is effective as a monotherapy in uncomplicated urinary tract infections with sensitive pathogens. to date, there are no indications that sulfonamides, trimethoprim, and their combinations have a teratogenic potential in humans (nørgård 2001 , czeizel 1990 ). an embryotoxic potential has been discussed from time to time, because antagonists to folic acid can lead to malformations in animal experiments, and in humans the spontaneous incidence of neural tube defects (spina bifida) can be decreased by the administration of folic acid during early pregnancy (chapter 2.18). the fact that human folic acid reductase is much less sensitive to trimethoprim than the bacterial enzyme, could explain that teratogenic problems have so far not been documented in humans when antibiotics with folic acid antagonists were used. trimethoprim has been used for many decades in pregnant women. at present, there is an ongoing discussion concerning the association between the use of folic acid antagonists and an increased risk of congenital malformations. a retrospective case-control study discusses the causal relationship between treatment with trimethoprim and other folic acid antagonists, and the development of neural tube defects, cardiovascular abnormalities, cleft lip and palate, and urinary tract anomalies (hernandez-diaz 2000) . authors' views on a preventative dose of multivitamin and folic acid preparations vary. additional case-control studies, some of them with notable methodological problems, found weakly recommendation. all tetracyclines are contraindicated after the fifteenth gestational week. prior to this, they are antibiotics of second choice. doxycycline should be preferred in such cases. inadvertent use of tetracyclines, even after the fifteenth week, is not an indication for termination of pregnancy (chapter 1.15). if really necessary, a local application to a small area may be conducted throughout pregnancy. tigecyclin is reserved for special situations when sufficiently tested antibiotic are not effective. significant evidence for the development of cardiovascular defects, urinary tract anomalies, anencephaly, limb defects, and orofacial clefts (e.g. mølgaard-nielsen 2012 , crider 2009 , czeizel 2001c ). an increased risk for preterm birth and low birth weight has also been observed after exposure to trimethoprim/sulfamethoxazole (santos 2011 , yang 2011 . a danish cohort study based on a prescription register found a doubling of the hazard of miscarriage after trimethoprim exposure in the first trimester (andersen 2013b ). based on the same prescription register, an increased risk of heart and limb defects was observed after preconceptional exposure (during the 12 weeks before conception) to trimethoprim (andersen 2013c) . beside methodological problems, such an association seems unlikely because a short-term therapy with trimethoprim does not usually lead to a relevant folic acid deficiency as a possible cause for birth defects. trimethoprim and sulfonamides are not drugs of first choice, but they exhibit no established teratogens. according to current knowledge the teratogenic risk of a trimethoprim and sulfonamide therapy is negligible. actually, there are no sufficiently convincing arguments to support the recommendation of an additional folic acid administration during an antibiotic therapy with the discussed medications, see chapter 2.18.8 for additional discussion concerning folic acid usage. extensive, generally reassuring experiences in the use of co-trimoxazole for common urinary tract infections during pregnancy, do not include the conclusion that this medication is safe when used at a much higher dose for opportunistic infections such as a pneumocystis pneumonia in the context of an hiv infection. so far, there have been no reports of malformations when such therapy was used in pregnant women. there are no systematic studies about the local application of sulfonamides during pregnancy. as sulfonamides compete with bilirubin for binding sites with plasma proteins, it has been argued that the risk of neonatal kernicterus is increased when sulfonamides are given at the end of gestation. with current surveillance, the danger of kernicterus is not tangible. however, a rise in bilirubin, especially in premature infants, cannot be excluded when sulfonamides have been used until birth. a danish population-based study could not find an association between sulfamethoxzole exposure near term and an increased risk of neonatal jaundice (klarskov 2013 ). quinolones inhibit the bacterial enzymes topoisomerase ii and iv that are important for the nucleic acid metabolism of bacteria. quinolones recommendation. sulfonamides, trimethoprim, and co-trimoxazole are antibiotics of second choice throughout pregnancy. if high dose co-trimoxazole is used for a pneumocystis pneumonia during the first trimester, based on theoretical grounds, folic acid should be supplemented and a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. if a premature birth is threatening, sulfonamides should be avoided in view of the bilirubin levels of the newborn. a short-term local treatment is acceptable, especially if the site is small. have a high affinity for cartilage and bone tissue which is highest in immature cartilage. pipemidic acid and nalidixid acid belong to the group of older quinolones. they have been displaced by the newer fluoroquinolones. the most important fluoroquinolones include ciprofloxacin, enoxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin. several substances have been removed from the market because of severe side effects. garenoxacin, lomefloxacin, pefloxacin, rosoxacin, and sparfloxacin are still available in some countries. gatifloxacin and nadifloxacin are only used as local agent. quinolones cross the placenta and are found in the amniotic fluid at low concentrations.when moxifloxacin is used about 8% of the maternal serum concentration can be measured in the amniotic fluid, and with lovofloxacin about 16% (ozyüncü 2010) . quinolones have not been found to be teratogenic in animals but severe, irreversible damage to joint cartilages was noted in young dogs treated after birth with quinolones (e.g. gough 1992 ). such alterations have not been described in prenatally exposed children. many publications failed to show indications of joint cartilage damage or an increased risk of malformations (bar-oz 2009 , cooper 2009 , larsen 2001 , loebstein 1998 , schaefer 1996 , berkovitch 1994 . one study expressed concern that the prenatal use of fluoroquinolones may be associated with an increased risk of bone malformations (wogelius 2005) . although not resembling each other, in three out of four birth defects the skeleton was affected. however, in this study of 130 women who redeemed a prescription for fluoroquinolones during the first trimester, or 30 days before conception, the total malformation rate was not increased (wogelius 2005) . in a prospective cohort study with 949 women who were exposed to a fluorquinolone during the first trimester, neither the rate of major birth defects, nor the risk of spontaneous abortion were increased compared to a control group (padberg 2014) . altogether, most data are available for norfloxacin and ciprofloxacin and, to a lesser extent, for levofloxacin, moxifloxacin, ofloxacin and pefloxacin. there are few or no data for the other fluoroquinolones. there have been no reports of undesirable side effects after topical use of quinolones during pregnancy. nitrofurantoin is a chemotherapeutic agent for drug-resistant urinary tract infections (utis) and for the prevention of recurrent utis. it acts as a bacteriostatic, but is also bactericidal at higher concentrations. details of its mechanism of action remain to be clarified. after an oral dose, therapeutic effective levels are attained only in the urinary tract. several publications do not support an association between nitrofurantoin and congenital malformations (nordeng 2013 , goldberg 2013 quinolones are antibiotics of second choice during pregnancy. in well-founded situations, when better studied antibiotics are ineffective, those quinolones that are well documented may be preferred such as norfloxacin or ciprofloxacin. a detailed ultrasound examination may be offered after exposure with the other fluoroquinolones during the first trimester. local treatment with quinolones is acceptable throughout pregnancy. czeizel 2001d , ben david 1995 , although in a number of studies, some of them with methodological faults, weakly significant findings were noted for craniosysnostosis, ophthalmic malformations, oral clefts, and cardiovascular defects (crider 2009 , källén 2005b , källén 2003 . a case-control study observed an increased risk of craniosynostosis after intrauterine exposure to nitrosatable drugs (gardner 1998) . as nitrofurantoin lowers the activity of glutathione reductase, discussions arise periodically as to whether an intrauterine exposure could trigger a fetal hemolysis. bruel (2000) reported a mature newborn with hemolytic anemia whose mother took nitrofurantoin during the last gestational month. nitrofurantoin is often used during pregnancy, and fetal hemolysis has not been commonly observed; therefore, a relevant risk is not likely. however, nordeng (2013) observed an increased risk of neonatal jaundice after maternal nitofurantoin treatment in the last 30 days before delivery. there is a case report of a pregnant woman who developed a toxic hepatitis after having been exposed to nitrofurantoin in her thirty-sixth week (aksamija 2009 ). in another case a woman took nitrofurantoin in her thirty-third week and was interpreted to present a gestational nitrofurantoin-induced pneumonia (mohamed 2007) . the nitrofurantoin derivative nifuroxazide is used for the treatment of diarrhea. there are no documented reports of its tolerance in pregnancy nor evidence of effectiveness. nifurtimox is a nitrofuran used for treatment of chagas disease. experience for pregnancy is very limited and the world health organization recommends that nifurtimox should not be taken by pregnant women (who 2013a). one study about safety included 14 pregnant women, but did not give information about the pregnancy outcome (schmid 2012) . for local treatment the nitrofurans furazolidone, nitrofural, and nifuratel are available. there has been no evidence of embryo-or fetotoxic risk in local applications. the use of local nitrofurans, especially as vaginal therapy, remains controversial and needs to be critically assessed not only during pregnancy. methenamine is a uti medication that releases the antiseptic formaldehyde into the urine. methenamine mandelate had been used for chronic utis due to e. coli and unproblematic germs. effectiveness and tolerance of the agent remain controversial. embryo-or fetotoxic problems have not been reported. there are no reports about the use of the hydroxy-quinolone derivative nitroxoline in pregnancy. fosfomycin is a broad-spectrum antibiotic that is bactericidal by inhibiting the synthesis of the bacterial cell wall. it is used as an intravenous injectable and as a reserve antibiotic in severe infections such as osteomyelitis. fosfomycin tromethamine is an orally taken salt of fosfomycin used for the treatment of uncomplicated utis. some authors also recommend the oral use during pregnancy (e.g. falagas 2010 , bayrak 2007 . these studies, however, are primarily focused on the effectiveness of fosfomycin tromethamine, not on the risk for the newborn. overall, the experience argues against a teratogenic and fetotoxic potential in humans. nitroimidazoles are effective bactericidal agents against anaerobes and protozoa. they are converted into metabolites that impede intracellular bacterial dna synthesis. the main representative of the nitroimidazoles is metronidazole. metronidazole is now being recommended by some investigators for the treatment of bacterial vaginosis in pregnancies at high risk for preterm delivery, as a strategy to decrease this risk (review by joesoef 1999) . others, however, failed to notice an improvement in the incidence of prematurity ( shennan 2006 , andrews 2003 , klebanoff 2001 . after oral and intravenous administration, concentrations as high as those in the mother are reached in the embryo/fetus. significant systemic absorption occurs after vaginal application, exposing the fetus as well. the pharmacokinetic profile of metronidazole did not change at the different time points assessed during pregnancy, and did not differ from nonpregnant patients (wang 2011) . like all nitroimidazoles, metronidazole displays an experimentally mutagenic and cancerogenic potential (review by dobias 1994) that has not been confirmed in humans. an investigation that ranged over 20 years did not show any indication of an increased risk of cancer when metronidazole was used (beard 1988) . on the basis of over 3,000 analyzed pregnancies, it can be stated that metronidazole has no teratogenic potential in humans (e.g. koss 2012 , diav-citrin 2001 , czeizel 1998 . suggestions from the hungarian malformation registry of a link between vaginal therapy with metronidazole and miconazole during the second and third month, and an increased appearance of syndactylies and hexadactylies have not been confirmed by other investigators (kazy 2005a) . nimorazole and tinidazole, both registered for the treatment of trichomonas infections, amebiasis, and bacterial vaginosis, cannot be evaluated sufficiently because of the lack of human data -the same applies to ornidazole. so far, there are no reports of human teratogenicity. the aminoglycoside antibiotics amikacin, framycetin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, ribostamycin, streptomycin, recommendation. nitrofurantoin can be given during pregnancy to treat urinary tract infections when the antibiotics of choice have been ineffective. if possible, it should be avoided towards the end of pregnancy. the use of nifuroxazide, nifurtimox, local nitrofurans, methenamine, and nitroxoline should be avoided during pregnancy. when the antibiotics of choice in pregnancy cannot be used, fosfomycin tromethamine may be used to treat urinary tract infections in pregnancy. the intravenous application of fosfomycin should be restricted to severe bacterial infections with problematic germs. recommendation. metronidazol may be used in pregnancy when indicated. a single oral dose of 2 g is preferable to vaginal administration spread over several days, particularly as there are doubts about the effectiveness of the vaginal application. a parenteral administration is only indicated for a serious anaerobic infection. metronidazole is to be preferred to the less examined nitroimidazoles. and tobramycin inhibit protein synthesis and are bactericidal primarily for gram-negative germs. after oral administration only a minimal portion of aminoglycosides is resorbed. after parenteral administration of about 20-40% of the maternal plasma concentration is detectable in the fetus. spectinomycin is an aminocyclitol antibiotic closely related to the aminoglycosides. oto-and nephrotoxic side effects are also known to occur in nonpregnant patients when aminolgycosides are used parenterally. there are case reports about the parenteral use of kanamycin and streptomycin during pregnancy describing auditory problems, even deafness, in children exposed in utero (e.g. jones 1973 , conway 1965 , robinson 1964 . a similar case was reported in connection with gentamicin (sánchez sainz-trápaga 1998). an investigation of the hearing ability of 39 children whose mothers had received gentamicin intravenously during pregnancy found no deficiencies. this argues against a major ototoxic risk of gentamicin when used in pregnancy (kirkwood 2007) . theoretically, a fetal nephrotoxic risk exists because aminoglycosides concentrate in the fetal kidneys. a case report about a connatal kidney dysplasia after maternal gentamicin therapy (hulton 1995) does not prove a clinically relevant human risk, nor does a case of a hydronephrosis and suspected stenosis at the uteropelvic junction with lethal outcome, where the mother had been treated for uti first with ciprofloxacin and then with gentamicin at weeks 4-5 (yaris 2004) . except for these case reports, studies argue against a high oto-or nephrotoxic risk of gentamicin in the fetus and newborn. there has been no increase in the observation of malformations (czeizel 2000e) . no untoward effects have been described with aminoglycosides as local treatment during pregnancy. experience with spectinomycin is insufficient to analyze a risk in pregnancy. glycopeptide and polypeptide antibiotics  glycopeptide antibiotics the glycopeptides vancomycin and teicoplanin are bactericidal only for gram-positive pathogens by inhibiting their cell wall synthesis. they are considered reserve antibiotics to be used against msra and multiresistant enterococci. to avoid the development of resistance, their application should be critically appraised, and possibly limited only to fighting problematic pathogens. oral glycopeptides are hardly resorbed. this is useful when treating pseudomembranous enterocolitis with vancomycin. however, in this situation metronidazole (section 2.6.10) should be considered as an alternative, as vancomycin therapy is more expensive, and to prevent the selection for vancomycin-resistant enterococci. vancomycin crosses the placenta reaching the fetus in relevant quantities (laiprasert 2007) . it has not shown teratogenic effects in animal studies. experience with treatment in human pregnancy is limited to a recommendation. aminoglycosides should only be used parenterally in life-threatening infections with difficult gram-negative pathogens and when firstchoice antibiotics fail. the serum levels need to be monitored regularly during the treatment. a risk-based termination of pregnancy or invasive diagnostic are not required (chapter 1.15). if the parenteral therapy had been extensive, renal function should be monitored in the neonate and an auditory test should be performed. if local or oral application of aminoglycosides is indicated, they can be given because systemic absorption is minimal by these routes. pregnancy few case reports. there were no observations of malformations, kidney damage, or hearing deficits (reyes 1989) . experience with teicoplanin and the new lipoglycopeptides dalbavancin, oritavancin and telavancin is insufficient to analyze a risk in pregnancy. in vitro telavancin crosses the human placenta, with fetal concentrations reaching less than 3% of maternal concentrations (nanovskaya 2012) . daptomycin belongs to a new class of cyclic lipopeptides and is effective exclusively against gram-positive bacteria. it works by interfering with the bacterial cell membrane and protein synthesis, and is indicated to treat complicated infections with difficult pathogens. in animal experiments, daptomycin crossed the placenta and was not teratogenic. two children whose mothers took daptomycin in the fourteenth and twentyseventh weeks were unremarkable (stroup 2010 , shea 2008 ). polymyxins belong to the polypeptide antibiotics that are bactericidal by interfering with the transport mechanism of the cell wall. while the polymyxin colistin is today mostly used locally, it can also be applied parenterally where there is an infection with multi-resistant gram-negative germs. in patients with mucoviscidosis it is used as an inhalative. enterally colistin is not resorbed; therefore its oral administration is used to selectively decontaminate the intestinal tract. the polypeptide antibiotics bacitracin, polymyxin b, and tyrothricin are used locally. only limited experience is available in the application of polypeptide antibiotics during pregnancy and do not indicate a substantial risk (kazy 2005b ). other antibiotics chloramphenicol and tiamphenicol inhibit bacterial protein synthesis and have bacteriostatic activity. chloramphenicol is relatively toxic, and can cause severe agranulocytosis. it crosses the placenta well and can reach therapeutic concentrations in the fetus. in premature and term births it may lead to the grey baby syndrome. chloramphenicol can reach toxic levels in the neonate even when only the mother has been treated. there have been no suggestions of malformations (czeizel 2000f ). recommendation. glycopeptides should only be used in cases of life-threatening bacterial infections; vancomycin should then be preferred. recommendation. the use of daptomycin is limited to cases of life-threatening bacterial infections. recommendation. the parental use of colistin is limited to cases of lifethreatening bacterial infections. the local and oral application of polypeptide antibiotics need to be critically assessed. experience with thiamphenicol is insufficient to analyze a risk in pregnancy. dapsone, used among other indications against leprosis, apparently has no teratogenic potential (e.g. lush 2000 , bhargava 1996 . however, cases of hemolytic anemia have been reported in mothers and newborns. as dapsone bears a structural similarity to the sulfonamides, it has been argued that it might compete with bilirubin for protein binding, and thus could lead to hyperbilirubinemia in the newborn. fidaxomicin is a macrocyclic antibiotic which is approved for the treatment of infections with clostridium difficile. enterally fidaxomicin is very poorly resorbed. no experiences have been reported about its use during pregnancy. linezolid is a member of the oxazolidinone class, a new group of antibiotics. it acts bactericidally by inhibiting bacterial protein synthesis and is indicated in the treatment of multi-resistant pathogens. there is just one case report about the use of linezolid during pregnancy. after intrauterine exposure from gestational weeks 14 to 18 a healthy infant was delivered at term (mercieri 2010 ). the antiprotozoal agent pentamidine, among others effective in pneumocystis pneumonia, has not been evaluated sufficiently in pregnancy to recommendation. the systemic use of chloramphenicol and thiamphenicol is contraindicated throughout pregnancy. exceptions are life-threatening maternal infections that do not respond to less toxic antibiotics. when systemic treatment is absolutely necessary before birth, it is important to observe the newborn for toxic symptoms. a local application is also to be avoided during pregnancy. recommendation. during pregnancy, dapsone should be reserved for specific indications. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. fidaxomicin should be avoided in pregnancy. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. with the lack of experience, linezolid should only be used for severe infections with problematic germs. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. pregnancy estimate its embryotoxic potential for humans. usually it can be replaced by other antibiotics, e.g. co-trimoxazole (section 2.6.7). rifaximin is an antibiotic to treat travelers' diarrhea. there is not enough experience regarding its use in pregnancy. minimal enteral resorption and negative animal testing suggest that a high embryotoxic risk is unlikely. streptogramins are a group of cyclic peptide antibiotics that inhibit, like macrolides and lincosamides, the synthesis of bacterial proteins. they are derivatives of the naturally occurring pristinamycin. the later developed derivatives quinupristin and dalfopristin are used in a fixed combination. streptogramins should only be applied as reserve antibiotics for infections with highly resistant gram-positive germs. reports about use in pregnancy have not been available. active tuberculosis (tb) requires treatment in pregnancy, as the disease endangers not only the mother, but also the fetus. pregnancy does not seem to affect the course of tb. the prevalence of congenital tb is less than 1% where no treatment is initiated. lin (2010) investigated 761 newborns of mothers who had received treatment for tb during the gestation. their children were smaller and had lower birth weights than the control group of children of healthy mothers. there are slight differences in the recommendations of the different organizations in the world, such as the who (2010a), the international union against tuberculosis and lung disease (iuatld), and several national organizations (e.g. blumberg 2003) . treatment considerations depend on disease status and drug resistance. first-line drugs for the treatment of tb during pregnancy are isoniazid (+pyridoxine), rifampicin, ethambutol and pyrazinamide. these standard medications have not shown teratogenic or fetotoxic effects in humans (e.g. bothamley 2001) . as far as we know today, tb drugs reach the fetus in relevant quantities. an increasing development of resistance makes it harder to choose the right medication in pregnancy. pregnant women with multidrugresistant tb (mdr-tb) may also require second-line antituberculous recommendation. pentamidine is to be reserved in pregnancy for special situations when better tested antibiotics are not effective. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. if possible, rifaximin should be avoided during pregnancy. recommendation. streptogramins are to be avoided during pregnancy. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. drugs; the necessity for treatment should be weighed against the risk for the fetus on an individual base. current experiences in the management of mdr-tb argue against a high risk of the reserve drugs for the newborn (drobac 2005 , shin 2003 . streptomycin, however, should be avoided because of its ototoxic potential. ethambutol is a bacteriostatic drug used against tuberculosis. it can cross the placenta, but the risk of congenital malformations when used during pregnancy appears to be low. there are no reports indicating that ethambutol can cause ocular toxicity in the fetus, as it does in adults, when given in higher doses. isoniazid (inh) has proven to be a highly effective drug against many strains of mycobacterium, and can be used for tuberculous prophylaxis and for treatment of an active disease during pregnancy. although inh can cross the placenta, it does not appear to be teratogenic, even when given during the first trimester. the older literature contains case reports of different malformations and neurological damages in prenatally exposed children. inh intake, lack of pyridoxine, co-medication, and even the tb disease itself was blamed. newer publications did not confirm a teratogenic risk (e.g. taylor 2013 . in summary, experiences speak against a major risk. inh increases pyridoxine metabolism, which may be responsible for cns toxicity. to prevent a possible vitamin b6 deficiency, inh should be given during pregnancy in combination with pyridoxine. pyrazinamide (pza) is an antibiotic with specific effectiveness against mycobacterium tuberculosis. as its structure resembles nicotinamide, it is assumed that it intervenes with the nucleic acid metabolism of the bacterial cell. pza has effective bactericidal properties. systematic studies of its tolerance in pregnancy are lacking. so far, there has been no evidence of embryo-or fetotoxic effects in humans. the use of pza during pregnancy is recommended in several guidelines (e.g. who 2010a). the american thoracic society recommends in its guidelines to hold pza as a reserve drug during pregnancy, as there are currently insufficient data about its teratogenicity (blumberg 2003) . if pza is not used, treatment may be prolonged. recommendation. ethambutol is a first-line drug for treatment of tuberculosis during pregnancy. recommendation. isoniazid is a first-line drug for treatment of tuberculosis during pregnancy. it needs to be given together with pyridoxine. rifampicin also called rifampin, inhibits bacterial rna polymerase and is effective as a bactericidal agent against different pathogens, particularly mycobacteria. rifampicin can cross the placenta. in animal experiments, teratogenic effects were seen with doses 5-10 times higher than in human treatment. because rifampicin inhibits dna-dependent rna polymerase, there has been concern that it might interfere with fetal development. until now, no reports in the literature have confirmed this fear. there is apparently no increased risk of malformations. a long-term therapy of the mother could result in inhibition of vitamin k synthesis, and result in a higher bleeding tendency in neonates. streptomycin is an aminoglycoside that is used parenterally in the treatment of tb. it is bactericidal, particularly affecting germs that proliferate extracellularly. its ototoxicity can also hurt the fetus (section 2.6.11). aside from the above discussed first-line drugs for tb, reserve medications are available and used in cases of resistance or intolerance. no systematic studies exist on the tolerance of 4-aminosalicylic acid (p-aminosalicylic acid; pas). so far, no evidence for embryo-or fetotoxic effects has been found in humans (e.g. lowe 1964) . capreomycin, ethionamide, protionamide, rifabutin, rifapentine, thioacetazone, and terizidone, a prodrug of cycloserine, are all second-line agents used internationally for mdr-tb. the extent of documented experiences in pregnancy is limited, and insufficient for a differentiated risk assessment. single case reports argue against a high teratogenic risk of these drugs (e.g. lessnau 2003 , drobac 2005 . for additional reserve drugs for multi-resistant tb such as amikacin, see section 2.6.11, and diverse quinolones, see section 2.6.8; for other anti-infective agents, view the relevant sections of this chapter. recommendation. pyrazinamide may be used during pregnancy to treat active tb. recommendation. rifampicin is a first-line drug for treatment of tuberculosis during pregnancy. when used near term the newborn should receive an extended vitamin k prophylaxis (chapter 2.9). regarding other infections such as mrsa, rifampicin should only be administered when the drugs of first choice for pregnancy cannot be used. recommendation. streptomycin is contraindicated during pregnancy because of its ototoxic properties. inadvertent exposure does not require risk-based termination of pregnancy or invasive diagnostic procedures, but hearing tests should be performed after birth (chapter 1.15). generally, each external antibiotic treatment needs to be examined carefully to see whether or not the bacterial infection is more effectively treated with systemic medication. the potential of local treatment is often overestimated. further, with topical therapy, sensitization and resistance development need to be considered. fusafungine has bacteriostatic and anti-inflammatory effects and is used as a spray for the treatment of infections of the nose and throat area. there is insufficient experience about its application in pregnancy. fusidic acid is an antibiotic that is almost exclusively used externally; its prenatal tolerance has not been examined systematically, although the medication has been available for a long time. it has a narrow spectrum of effectiveness against gram-positive bacteria (staphylococci) and is not recommended for an untargeted treatment. mupirocin is primarily bacteriostatic, affecting staphylococci and streptococci by inhibiting bacterial protein synthesis. it is especially used as a nasal ointment to eliminate mrsa. mupirocin has not been examined systematically, but there is no evidence of undesirable effects in pregnancy. retapamulin is the first representative of the pleuromutilins that is approved for human treatment. it is applied as an ointment for short-term treatment of superficial skin infections. retapamulin inhibits bacterial protein synthesis and is bacteriostatic, primarily for gram-positive germs. systemic resorption is minimal with topical use, but nevertheless, as experience in pregnancy has been limited, its application needs to be critically examined. taurolidine is an antimicrobial solution that can be used for lavage in peritonitis and for the prevention of infections with catheters. as a bactericidal agent, its mechanism of action is only partially clarified. there are no reported experiences in pregnancy. see the corresponding sections for the local application of aminoglycosides (section 2.6.11), chloramphenicol (section 2.6.13), quinolones (section 2.6.8), macrolides (section 2.6.4), nitrofurans (section 2.6.9), nitroimidazoles (section 2.6.10), polypeptide antibiotics (section 2.6.12), sulfonamides (section 2.6.7), and tetracyclines (section 2.6.6). apart from pregnant women living in malaria areas, pregnant women are increasingly traveling to tropical countries and need a suitable malaria prophylaxis. increased resistance of malaria pathogens make it more difficult to suggest a general recommendation. the guidelines of tropical medicine recommendation. the reserve drugs discussed here should only be used for multi-resistant tuberculosis when standard therapy is not indicated. an inadvertent exposure during pregnancy does not require a risk-based termination or invasive diagnostic, but a detailed ultrasound examination should be carried out (chapter 1.15). recommendation. externally used antibiotics are not suspected to be teratogenic. nevertheless, the application of local antibiotics needs to be critically assessed. antibiotics that are safe when used systemically may also be used locally. if another local antibiotic is absolutely necessary, it may be used in pregnancy. should be followed, also in pregnancy, according to the travel destination. especially difficult is the management of malaria tropica caused by plasmodium falciparum. pregnancy enhances the clinical severity of falciparum malaria, especially in the primiparous and non-immune woman. pregnancy alters a woman's immunity to malaria, making her more susceptible to malaria infection and increasing the risk of illness, severe anaemia, and death. maternal malaria increases the risk of spontaneous abortion, stillbirth, prematurity, and low birth weight, and thus results in excess infant mortality (e.g. bardaji 2011 , shulman 2003 . therefore, mosquito-bite prevention, prophylaxis, and treatment of malaria should not be shortened or omitted in an ongoing pregnancy. traveling to areas with multidrug-resistant malaria should be avoided if possible. the choice of drug for malaria prophylaxis and treatment during pregnancy depends on the local pattern of antimalarial drug resistance, the severity of the malaria, and the degree of pre-existing immunity. it is important to be well informed about the current recommendations for prophylaxis and treatment of malaria in the area to be visited. for travelers to malaria-endemic areas, a general recommendation is difficult because of increasing resistances. depending on the drug, the chemoprophylaxis must be continued for up to 4 weeks after leaving the malarial region. for women living in falciparum-endemic areas with stable transmission, the world health organization recommends the use of insecticide-treated nets (itns) and intermittent preventive treatment (ipt) with sulfadoxine-pyrimethamine during pregnancy (who 2013b , nyunt 2010 . ipt reduces maternal malaria episodes, maternal anaemia, placental parasitaemia, low birth weight, and neonatal mortality (review by mcclure 2013). a prompt diagnosis and effective treatment of malaria infections is vital. although data from prospective studies are limited quinine, chloroquine, proguanil, and clindamycin (section 2.6.5) are considered safe during early pregnancy. pregnant women in the first trimester with uncomplicated malaria tropica should be treated with quinine plus clindamycin (if available) (who 2010b). for the second and third trimester the world health organization recommends artemisinin derivatives. the choice of combination partner is difficult because of limited information. reserve medications include the following: amodiaquine, atovaquone, dapsone (section 2.6.13), lumefantrine, mefloquine, piperaquine, and pyrimethamine plus sulfadoxine. doxycycline is contraindicated after the sixteenth gestational week (section 2.6.6). halofantrine and primaquine should be avoided. see the relevant sections of this chapter about the specific active substrates. during gestation plasma concentrations of many antimalaria agents are lower and their elimination is enhanced. this can result in treatment failure. thus, in each patient dose and dose interval need to be assessed individually. recommendation. generally, the physician should discuss with a patient if the trip to a tropical region could be postponed (section 2.6.36). the risk of exposure can be reduced by long clothes, mosquito netting, and repellents. in no case should medications be denied for prophylaxis or treatment on behalf of a pregnancy, as the potential risk for the unborn child predominates. if medications with inadequate pregnancy experience are used in the first trimester, a detailed ultrasound examination should be offered. a risk-based termination is not justified when the above-described medications have been used in pregnancy (chapter 1.15). amodiaquine, like chloroquine, belongs to the group of 4-aminoquinolines. it can cause severe side effects such as liver damage and agranulocytosis, and for this reason, is unsuitable for prophylaxis. its use is limited as a reserve medication for malaria. there has been no evidence of tetatogenicity (review by thomas 2004) , but experiences are limited. with regard to early pregnancy, only single case reports have been published. one study found only mild maternal side effects in 450 pregnant women who had been treated in the second or third trimester. an increase in miscarriages, prematurity, stillbirth, or malformations was not observed (tagbor 2006 ). artemisinin and its derivatives artemether, artemotil, artesunate, and dihydroartemisinin, are increasingly used against malaria as plasmodium falciparum has developed resistance to other drugs. these compounds combine rapid blood schizonticide activity with a wide therapeutic index. artemisinins should be given as combination therapy to protect them from resistance. typical combinations of such artemisinin-based combination therapy (act) are artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, artesunate plus sulfadoxine-pyrimethamine, and dihydroartemisinin plus piperaquine first trimester experiences with the use of artemisinin derivatives are limited. a number of studies contain data of more than 250 pregnant women treated with an artemisinin derivative during the first trimester, without showing evidence of a teratogenic risk (mosha 2014 , adam 2009 , clark 2009 , who 2006 . manyando (2010) more commonly found umbilical hernias in an additional 140 children whose mothers had been treated with artemether and lumefantrine. after 12 months most of these hernias were not detectable anymore. there are experiences with more than 1,500 pregnant women who used artemisinin derivatives in the second and third trimester (e.g. piola 2010 , bounyasong 2001 , deen 2001 , mcgready 2001 , phillips-howard 1996 . in summary, these studies did not find an increased risk in miscarriages, stillbirths, and malformations. to some degree the artemisisin derivatives were better tolerated by pregnant women, and were more effective than treatments of the control group. as plasma levels of artemether are decreased during pregnancy, it has been suggested that the dose and the dose interval may have to be adjusted (e.g. tarning 2013, morris 2011). these reassuring data led the who (2010b) to recommend using artemisinin derivatives as medications of choice for malaria tropica in the second and third trimester. it does not specify what combination is recommended in the context of act. during the first trimester, based on a lack of experiences, the who views artemisinin derivatives as reserve medications that should not be withheld in an individual case where needed. recommendation. amodiaquine may be used as a reserve medication for the treatment of malaria. atovaquone is a broad-spectrum anti-protozoal drug that is also used in pneumocystis pneumonia. monotherapy quickly leads to resistance, thus it is combined with proguanil when used for malaria prophylaxis and treatment. experience with atovaquone is limited in pregnancy. a danish cohort study based on a prescription register with 149 women exposed during their first trimester to atovaquone, 93 of them exposed at any time in weeks 3 through 8 after conception, found no increased risk for birth defects (pasternak 2011) . when used in the second and third trimester, small studies observed no adverse effects (mcgready 2005 , na-bangchang 2005 . available data are insufficient for a differentiated risk assessment, but do not suggest a teratogenic risk. mcgready (2003) discusses the need of a dose adjustment as clearance increases and levels decrease during pregnancy. chloroquine, an antimalaria drug of the group of 4-aminoquinolines, works well and effectively as a schizonticidal drug against the erythrocytic forms of all types of plasmodia. today though, almost all pathogens of the potentially lethal malaria tropica have become resistant to this rather well tolerated, and for many decades, useful medication. resistance has also been noted for plasmodium vivax, the pathogen of the less severe malaria tertiana. plasmodium ovale and plasmodium malariae still remain mainly sensitive to chloroquine. chloroquine is not embryo-and fetotoxic when used at the usual dose for malaria prophylaxis or for a three-day treatment of a typical malaria attack (mcgready 2002 , phillips-howard 1996 . current evidence does not suggest fetal ocular toxicity when chloroquine was used as antimalarian medication during pregnancy (review by osadchy 2011). lee (2008) examined 12 pregnant women and nonpregnant controls, and did not find any changes in the pharmacokinetics or the serum level of chloroquine. the anti-inflammatory properties of chloroquine are used also for antirheumatic therapy (section 2.12.8). antirheumatic doses of chloroquine are higher than those used for malaria prevention. recommendation. artemisinin derivatives may be used in the second and third trimester. in the first trimester they are reserve medications for the treatment of malaria. recommendation. atovaquone may be used as a reserve medication for the treatment of malaria. recommendation. chloroquine may be used throughout pregnancy for the prophylaxis and treatment of malaria. if chloroquine resistance of the parasite is likely or has been demonstrated, other drugs must be used. halofantrine has a rapid schizonticidal effect upon the erythrocytic forms of those plasmodia that are resistant to chloroquine and other antimalarials. halofantrine prolongs the qt interval in the ekg. becauses it can provoke life-threatening cardiac arrhythmias in patients with heart disease, or in conjunction with other arrhythmogenic medications, halofantrine is no longer recommended. the limited experiences in pregnancy allow no differentiated risk analysis. lumefantrine belongs to the group of arylamine alcohols like quinine, mefloquine, and halofantrine. artemether plus lumefantrine is currently a popular artemisinin-based combination therapy. few experiences are available regarding its application in the first trimester without showing evidence of a teratogenic risk (e.g. mosha 2014) . for the second and third trimester, studies with several hundred patients have been reported and do not indicate a major risk (piola 2010 . manyando (2010) found only a mild increase in umbilical hernias in 140 children whose mothers took artemether and lumefantrine during the first trimester. most of these had disappeared when follow-up examination was conducted 12 months later. in summary, current experiences do not suggest a major embryo-or fetotoxic risk of lumefantrine. during pregnancy, the plasma concentration is lower and the elimination enhanced, thus increasing the risk of treatment failure (e.g. tarning 2009 ). mefloquine displays an effective and rapid activity against the erythrocytic forms of all plasmodia. current experiences with more than 2,000 treated pregnant women, several hundred of them in the first trimester, do not suggest a teratogenic or fetotoxic potential in humans (e.g. schlagenhauf 2012 , bounyasong 2001 , mcgready 2000 . one single study of the use of mefloquine has been debated as finding an increased rate of stillbirths. this study compared 200 pregnant women who received mefloquine for malaria, and found them to have a significantly higher rate of stillbirth than those who had been treated with quinine and other antimalarials (nosten 1999) . other studies, however, have not confirmed this risk, and mefloquine has been an established medication in pregnancy for some time. recommendation. halofantrine is only to be used in cases of acutely threatening malaria that cannot be managed with better tested and less toxic drugs. when cardiac problems are an issue, other antimalaria medications must be used. recommendation. lumefantrine may be used as a reserve medication for the treatment of malaria. recommendation. mefloquine may be used throughout pregnancy for the prophylaxis and treatment of malaria if there is no resistance. a fixed oral combination of the bisquinolone piperaquine and dihydroartemisinin (dhp) is a new and promising artemisinin-based combination therapy. the mechanism of action of piperaquine is unknown. an indonesian observational study detected a higher rate of abortion after first trimester exposure to dihydroartemisinin-piperaquine (poespoprodjo 2014) . this observation was based on five abortions among eight pregnancies (63%). the same study found a lower risk of perinatal mortality after dihydroartemisinin-piperaquine in the second and third trimester compared to quinine-based regimens. the limited experiences in pregnancy allow no differentiated risk analysis. no significant pharmacokinetic differences between pregnant and nonpregnant women were reported in two small studies , hoglund 2012 ). primaquine, an 8-aminoquinoline derivative, is effective against the intrahepatic permanent forms of plasmodium vivax and plasmodium ovale. it is used for the complete elimination of pathogens in combination with a blood schizontocide for the erythrocytic parasites. primaquine should not be used in pregnancy because of the potential risk of hemolytic effects in the fetus. as yet, there are no studies that permit a well-grounded risk assessment. however, there is no substantial evidence for a teratogenic potential in humans (phillips-howard 1996). proguanil, an older medication for malaria prophylaxis belonging to the folic acid antagonists, is experiencing a renaissance as it has become useful in the face of increasing chloroquine resistance. most often it is applied in combination with the synergistic atovaquone. there is no evidence of an embryotoxic potential in humans (e.g. pasternak 2011 , mcgready 2005 . mcgready (2003) discuss the need to adjust the dose as clearance is increased and blood levels decreased during pregnancy. pyrimethamine is an inhibitor of folic acid synthesis that is also used in the treatment of toxoplasmosis and pneumocystis pneumonia. in malaria recommendation. piperaquine may be used as a reserve medication for the treatment of malaria. recommendation. primaquine is not a therapeutic option during pregnancy. a prophylactic elimination of hepatic spores should usually be postponed for a time after birth. recommendation. proguanil may be used throughout pregnancy for prophylaxis and treatment of malaria provided there is no resistance. treatment it is only applied in combination with another folic acid antagonist such as sulfadoxine (section 2.6.7). this particular combination is used for intermittent preventive treatment (ipt) during pregnancy. however, increasing resistance has started to limit the effectiveness of this popular combination (newman 2003) . as animal experiments indicated embryotoxic effects, concerns had been raised about the use of these folic acid antagonists in early pregnancy. numerous investigations, however, have not demonstrated an increased malformation risk in humans (e.g. manyando 2010 , phillips-howard 1996 . some studies suggest that pregnancy adversely alters the pharmacokinetics of pyrimethamine and sulfadoxine (e.g. karunajeewa 2009 , green 2007 . as data are inconsistent, a general recommendation about dose adjustments in pregnancy is difficult. when sulfadoxine-pyrimethamine is given in early pregnancy, it should be supplemented by folic acid until the tenth week. the who recommends 0.4-0.5 mg per day, as a coadministration of high dose (5 mg daily) compromises the efficacy of sulfadoxine-pyrimethamine in pregnancy (who 2010b). quinine is the oldest antimalarial agent. it works well and effectively as a schizonticidal drug against the erythrocytic forms of all plasmodium species. despite a relatively high toxicity and a narrow therapeutic range, it is used again increasingly in the treatment of chloroquine-resistant malaria. in combination with clindamycin (section 2.6.5) its effectiveness is increased. concentrations in the fetus are just as high as in the mother, and are potentially toxic. in some case reports it was observed that children had auditory or visual defects after the use of quinine in pregnancy. however, in those cases considerably higher doses had been administered than currently in use. there is no evidence of an increased risk of abortion or preterm delivery with the use of a standard dosage of quinine for treatment of acute malaria (phillips-howard 1996) . these findings were confirmed by other studies with several hundred pregnant women exposed during the first trimester, where no increased rates of spontaneous abortion, congenital malformations, stillbirth or low birth weight were found (e.g. adam 2004b , mcgready 2002 . quinine increases the secretion of insulin (elbadawi 2011) . especially in the last part of pregnancy, severe maternal hypoglycaemia has been induced by quinine therapy. due to the risk of hypoglycemia, the who (2010b) guidelines prefer to use an artemisinin combination for the management of malaria tropica from the second trimester on. a study of the metabolism of quinine in pregnant and nonpregnant women failed to show significant pharmacokinetic differences. the authors concluded that dose adjustment is not necessary during pregnancy (abdelrahim 2007) . induction of contractions with high doses of quinine cannot be excluded. recommendation. pyrimethamine in combination with sulfadoxine may be administered for the treatment of malaria. for toxoplasmosis it is the drug of choice when combined with a long-term sulfonamide, especially after the first trimester. when pyrimethamine is given in early pregnancy, it should be supplemented with folic acid, see also chapter 2.18.8. quinine is a component of some analgesic compounds and of certain beverages, although in lower and apparently nonembryotoxic doses. azole antifungals azole derivatives inhibit the ergosterol biosynthesis, thereby causing disturbances in the permeability and functions of the fungal cell membrane. azole antifungals include two broad classes, imidazoles and triazoles. in animal experiments azole antifungals cross the placenta and are teratogenic at high doses. with regard to the use of the triazole derivative fluconazole in pregnancy, there was a report of three children (two of them siblings) with craniofacial, skeletal, and cardiac malformations, similar to those seen in animal studies (pursley 1996) . because of meningitis, their mother had used high doses of fluconazole (400-800 mg daily) through or beyond the first trimester on a long-term basis. additional case reports have described two births involving craniofacial, limb, and cardiac defects in two mothers who used fluconazole (lopez-rangel 2005 , aleck 1997 ). those cases shared some characteristics with the antley-bixler syndrome. however, there was no evidence of an increased risk of malformation in a prospective cohort study with 226 women exposed during the first trimester (mastroiacovo 1996) . in several other studies, first trimester exposure to low-dosage regimens of fluconazole for vaginal candidiasis did not appear to cause an increased risk of malformations (e.g. jick 1999 , campomori 1997 , inman 1994 . danish cohort studies based on a prescription register also could not find an increased risk of birth defects after first trimester exposure in several thousand pregnant women (nørgaard 2008 , sørensen 1999 ). an extended analysis of the danish data observed an increased risk for tetralogy of fallot based on seven cases (prevalence 0.1%) compared to unexposed pregnancies (or 3.16; 95% ci 1.49-6.71). the rate of major birth defects was not increased (mølgaard-nielsen 2013). in most cases the low and single dose consisted of 150 mg fluconazole usually used for a vaginal yeast infection. itraconazole is a triazole derivative with wide-spectrum activity. there has been no evidence of teratogenicity in prospective studies examining several hundred women with first trimester exposure (e.g. de santis 2009 , bar-oz 2000 ; most of the exposures were short-term. a danish register analysis did not find an increased risk of birth defects among 687 women with a first trimester prescription of itraconazole (mølgaard-nielsen 2013). recommendation. despite its toxicity, quinine belongs to the drugs of choice when dealing with chloroquine-resistant malaria tropica in pregnancy. in this situation the potential risk of treatment is much smaller for the fetus than the danger of a severe maternal disease. attention needs to be paid to possible maternal hypoglycemia. even though embryotoxic effects due to quinine in analgesic compounds are not to be expected, these agents should be avoided because they do not conform to good therapeutical practice. the same holds for the regular or excessive consumption of quinine drinks. the imidazole derivative ketoconazole is usually avoided in systemic use because it is poorly tolerated and has many suitable alternatives. ketoconazole is administered on occasion for the treatment of cushing syndrome as it inhibits steroid synthesis. theoretically, by decreasing testosterone synthesis, it might impede the sexual development of male foetuses; however, this has not been described. ketoconazole has been used in several cases in pregnancy with good maternal and fetal outcome (e.g. boronat 2011 , berwaerts 1999 , amado 1990 . a retrospective study from data of the hungarian malformation registry based on 18 exposed subjects shows no evidence of an increased risk of malformations after systemic use of ketoconazole (kazy 2005c ). an analysis of a danish register did not observe a significantly increased risk of birth defects among 72 pregnant women with a prescription for this agent during first trimester (mølgaard-nielsen 2013). for posaconazole and voriconazole which are used for aspergillosis and other invasive mycoses, information is lacking about use during pregnancy. there is only one published case report of a normal child, born after voriconazole treatment of the mother in the second and third trimester (shoai tehrani 2013). a multitude of poorly resorbed topical azole derivatives are available for the treatment of superficial fungal infections. the drugs of this group that had been introduced first, namely clotrimazole and miconazole, are most thoroughly investigated for use in pregnancy. regarding clotrimazole, there are extensive studies about the treatment of vaginal yeast infections that do not indicate an embryotoxic potential (e.g. czeizel 1999b , king 1998 . also, there is no suggestion that there is an increase in miscarriages. czeizel (2004a) noted a decrease in prematurity when vaginosis was treated locally with clotrimazole. experiences with several thousand pregnant women are available for miconazole (e.g. czeizel 2004b , mcnellis 1977 . a suggestion by the hungarian malformation registry about a link between vaginal therapy with miconazole plus metronidazole during the second and third gestational month, and an increase in syndactyly and hexadactyly, has not been substantiated by other studies (kazy 2005a ). an israeli report describes two cases of severe skeletonal anomalies after the use of bifonazole that are reminiscent of anomalies seen after systemic use of fluconazole. in the first case, bifonazole was taken orally from week 6 to 16, in the second case 500 mg/d vaginally throughout pregnancy and clearly at a higher dose than recommended (linder 2010) . at dose levels which are reached with nomally recommended topical application no teratogenic risks have been noted, yet systematic studies are lacking. for ketoconazole see above (azole antifungals for systemic use). recommendation. if a systemic treatment with an azole derivative becomes absolutely necessary, fluconazole and itraconazole are to be preferred as the better-tested medications. if possible, treatment should start after the first trimester. an inadvertent exposure during pregnancy does not require a risk-based termination or invasive diagnostic, but a detailed ultrasound examination should be carried out (chapter 1.15). clearly less experience has been collected about the local applications of butoconazole, croconazole, econazole, fenticonazole, isoconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, terconazole, and tioconazole. teratogenic effects have not been observed (king 1998) . this was confirmed for vaginal econazole treatment in a study of 68 pregnant patients (czeizel 2003a ). amphotericin b is a broad-spectrum antifungal agent of the polyene group. it binds to ergosterol at the cell membrane of fungi and disturbs cell wall permeability. it can be used intravenously, orally, and locally. with oral application, it is poorly resorbed and thus has only a local effect in the intestinal tract. conventional amphotericin b given parenterally has a number of side effects, primarily nephrotoxicity. newer lipid formulations of amphotericin b such as liposomal amphotericin b are characterized by a markedly better tolerance and less nephrotoxicity. amphotericin passes the placenta. relevant plasma concentrations could be measured in a newborn, although the mother had taken her last dose four months prior (dean 1994 ). this could be due to placental accumulation or delayed elimination by the fetal kidneys. several case reports do not indicate an increased risk of malformations with amphotericin b (e.g. costa 2009 , ely 1998 , king 1998 ). more than 10 pregnancy courses with liposomal amphotericin b also argue against an embryo-or fetotoxic risk (e.g. mueller 2006 , pagliano 2005 , pipitone 2005 ). these experiences are insufficient for a differentiated risk assessment. as resorption is minimal with oral or local use, a risk appears unlikely. echinocandins are a new antifungal medication group. these parenteral synthetic lipopeptides inhibit the synthesis of 1,3-β-d-glucan, a key ingredient of the fungal cell wall. anidulafungin, caspofungin, and micafungin are currently approved. in animal experiments echinocandins cross the placenta. there have been no reports of their use in pregnancy. yalaz (2006) described the successful postnatal application of caspofungin in a dystrophic premature newborn of the twenth-seventh gestational week. recommendation. clotrimazole and miconazole belong to the local antifungal medications of choice in pregnancy. the other azole derivates are antimycotic drugs of second choice. recommendation. amphotericin b should only be used parenterally in cases of serious disseminated fungal infections. the liposomal formulation may be preferred. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. oral and local use of amphotericin b is acceptable in pregnancy. flucytosine is effective against cryptococcus neoformans and many candida species. it inhibits the dna synthesis. within the mycotic cell flucytosine is partially converted into the cytostatic 5-fluorouracil. to a smaller degree this reaction has to be expected in humans as well. due to a high incidence of resistance, flucytosine should only be administered in combination with another antifungal drug such as amphotericin b. in animal experiment, fluycytosine has a teratogenic effect at doses below those used in humans. as yet, no malformations have been reported in humans; however, there is, as yet, no published experience with the use of flucytosine in the first trimester. case reports about application in the second and third trimester for dangerous disseminated cryptococcosis have not shown evidence of fetal damage (e.g. ely 1998). griseofulvin is an organically derived antifungal agent that is used orally for several weeks against fungal infections of the skin, hair and nails. as it is deposited within the keratin, it is especially suited for the management of fungal infections of nail mykoses. in animal experiments griseofulvin is teratogenic and, at high doses, cancerogenic. it crosses the placenta at term (rubin 1965) . one publication, based on birth defects data, reported two pairs of conjoined twins after the use of griseofulvin in early pregnancy (rosa 1987) . this observation could not be confirmed in other publications (knudsen 1987 , metneki 1987 . a population based case-control study with some 31 exposed pregnant women did not demonstrate an increased risk of malformations (czeizel 2004c ). these experiences are insufficient for a differentiated risk assessment. recommendation. as there is insufficient data regarding the use of echinocandins in pregnancy, they should only be used where no alternatives are available and the mycosis is life-threatening. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. flucytosine should only be used for life-threatening disseminated fungal infections during pregnancy. as it is not indicated as a monotherapy, it needs to be assessed critically if its use as a second mycotic drug is really necessary. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. as griseofulvin is not used to treat life-threatening fungal infections, its application in pregnancy should be avoided. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. terbinafine is used for both oral and topical treatment of fungal infections of the nails and other dermatophytoses. a prospective study reported on 54 pregnant women exposed to terbinafine which showed no evidence of a teratogenic potential (sarkar 2003) . of these women 24 were exposed during the first trimester and 26 had an oral exposure. these data are insufficient for a differentiated risk analysis. when used topically, less than 5% is resorbed making a risk unlikely. regarding the topical use of azole derivatives such as clotrimazole and miconazole, see section 2.6.17; for amphotericin b, section 2.6.18; and for terbinafine, section 2.6.22. nystatin is an antifungal drug from the polyene group. like the closely related amphotericin b it binds with ergosterol of the mycotic cell wall and interferes with its function. nystatin is an effective local antifungal drug for candidiasis of the skin or mucosa. when taken orally, it is poorly resorbed and only works locally in the intestinal tract. the indication for intestinal cleansing needs to be critically assessed in immunocompromized patients. nystatin is used frequently, and there is no evidence of embryo-or fetotoxic effects (e.g. king 1998) . a population-based case control study did not show an increased risk of malformation after first trimester exposure. when treatment was performed in the second and third trimester, slightly more cases of hypospadia were noted (czeizel 2003b ). however, a low resorption rate, methodological weaknesses of the study, and the low number of only 106 pregnant women place the result in question. a retrospective study of the hungarian malformation register, with 160 exposed subjects, did not reveal signs of an increased risk of malformation when natamycin was applied vaginally (czeizel 2003c) . based on the same register, a case-control study discussed a possible association between cardiovascular malformations and maternal use of tolnaftate in pregnancy (czeizel 2004d) . this observation was based on 26 exposed cases, of which four cases had varying types of cardiac defects (or 3.1, 95%; ci 1.0-9.7). these data are insufficient for a differentiated risk analysis. amorolfine, butenafine, ciclopirox, haloprogin, naftifin, and tolciclate are insufficiently investigated with regard to prenatal human toxicity. as yet, there is no substantial indication for an increased risk of malformations after local use. recommendation. terbinafine should be avoided during pregnancy as safety data are lacking and fungal nail infections do not require urgent treatment. if treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. a topical application is likely to be harmless. recommendation. nystatin, like clotrimazole and miconazole is an antifungal drug of choice during pregnancy. where possible, these drugs should be preferred. external treatment with amorolfine, butenafine, ciclopirox, haloprogin, natamycin, naftifin, tolciclate, and tolnaftate should be avoided during pregnancy. more than 2 billion people are infected with helminths worldwide. soil-transmitted helminths have been recognized as an important public health problem in many developing countries. severe hookworm and other helminth infections during pregnancy may cause anemia, reduced birth weight and increased perinatal mortality. a routine application of anthelmintics during the second and third trimester for women in areas endemic for hookworm infection has been suggested, with the argument that this may improve maternal anemia, birth weight, and neonatal mortility (e.g. who 2013c, christian 2004 ). however, a randomized placebo-controlled study showed no advantage for newborns whose pregnant mothers had received albendazole or praziquantel . recently, it has been discussed if routine anthelmintic treatment during pregnancy might lead to an increased risk for allergies in infancy (mpairwe 2011 ). the benzimidazole derivatives albendazole, flubendazole, mebendazole, thiabendazole, and triclabendazole inhibit the uptake of glucose and thereby kill the parasites. in animal experiments benzimidazole derivative with anthelmintic activity showed teratogenic effects. albendazole and mebendazole are poorly resorbed from the gastrointestinal tract, except when there is an inflammation. however, enteral absorption may be increased due to high-fat diet. mebendazole is a highly effective and well tolerated anthelmintic drug used against nematodes (such as pinworms, roundworms, whipworms, and hookworms). there have been reports describing children with various malformations after in utero exposure to mebendazole, but a distinct pattern of malformations could not be discerned (review by schardein 2000) . an increased risk of congenital malformations was not observed in a study of over 400 pregnant women exposed to mebendazole in the first trimester (de silva 1999) . this was confirmed in a controlled prospective study covering 192 first trimester exposed pregnant women (diav-citrin 2003) . another study with 48 first trimester exposures also found no increased risk for malformations or miscarriages ( mcelhatton 2007) . although numbers are too small for any definite conclusion, mebendazole does not appear to represent a major teratogenic risk. significantly more experience has been collected with exposure during the second and third trimester showing no evidence of a fetal risk (e.g. gyorkos 2006) . albendazole is a newer, highly effective broad-spectrum anthelmintic which combined with operative interventions has become the treatment of choice for alveolar and cystic echinococcosis. limited experience in the first trimester has not shown evidence of a major risk (gyapong 2003 , cowden 2000 . there are several thousand pregnancies with the use of albendazole in the second or third trimester without any obvious adverse reactions reported (e.g. , ndyomugyenyi 2008 . two abstracts from korea which reported the outcome of 16 pregnant women after the first trimester exposure to flubendazole showed no evidence of a teratogenic potential (choi 2008 (choi , 2005 . however, the data is insufficient for a differentiated risk assessment. there are no reports of thiabendazole and triclabendazole use during human pregnancies. ivermectin is a broad-spectrum anthelmintic agent which is mainly used in humans in the treatment of onchocerciasis (river blindness), lymphatic filiriasis and strongyloidiasis. it is also effective against other worm infections and some epidermal parasitic skin diseases, such as scabies. ivermectin is well resorbed after oral administration. animal experiments do not suggest a teratogenic potential, although at maternally toxic exposures malformations were noted in rodents. a number of case reports describing accidental treatments during the first trimester have not shown malformations in the children (gyapong 2003 , chippaux 1993 , pacque 1990 ). however, data are insufficient for a differentiated risk assessment. a study encompassing more than 100 women who took ivermectin during the second trimester found no significant anomalies in the newborns (ndyomugyenyi 2008 ). niclosamide is an anthelmintic that is effective against tapeworms (cestodes). it affects the energy metabolism of the parasites and is practically not resorbed by the intestinal tract. this agent had been used extensively in the past and is not suspected to cause malformations, but has not been systematically studied in humans. praziquantel is a highly effective broad-spectrum anthelmintic agent against many trematodes and cestodes. it is mainly used for the treatment of schistosomiasis (bilharziosis). no teratogenicity has been reported in animal studies. over the last decades millions of pregnant women have been inadvertently treated with praziquatel during routine anthelmintic programs without an obvious adverse reactions reported. a few publications recommendation. mebendazole may be used during pregnancy to treat relevant worm diseases. albendazole may be used in cases of echinococcosis. the other benzimidazole anthelmintics should only be used with a compelling indication, and when more established anthelmintics are ineffective. after first trimester exposure a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. with a compelling indication ivermectin may be used in pregnancy. after first trimester exposure a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. niclosamide may be given during pregnancy to treat relevant tapeworm infections. application in the first trimester needs to be critically assessed as tapeworm infections are generally not a great hazard to the mother or unborn child. after first trimester exposure, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. also found no evidence of a teratogenic potential after mothers had been treated in the first trimester (adam 2004a , paparone 1996 . in a study from uganda encompassing more than 1,000 pregnant women, treatment with praziquantel in the second and third trimester was not associated with an increase in adverse outcomes (ndibazza 2010) . the who (2002) recommends the use of praziquantel for schistosomiasis during pregnancy. pyrantel is a broad-spectrum anthelmintic that acts by inhibition of cholinesterase, causing spastic paralysis and subsequent death of the parasite. no teratogenicity has been reported in animal studies. pyrantel is poorly absorbed from the gastrointestinal tract. published experience on its use during pregnancy is not sufficient to determine risk. pyrvinium is effective against pinworms (enterobius). after oral administration it is hardly absorbed. therefore, it is unlikely to reach the fetus in relevant amounts. there are no reports of embryo-or fetotoxic effects. however, there has been no published experience with the use of pyrvinium during pregnancy. a danish cohort study based on prescription registers identified 1606 women redeeming a prescription for pyrvinium (449 during first trimester). the pregnancy outcome was not considered in this article (torp-pedersen 2012). diethylcarbamazine is used for the treatment of filiriasis and onchocercosis. no teratogenicity was reported in animal studies. no publications regarding its use during human pregnancies have been located. levamisole is used as anthelmintic and as an immunomodulator. a retrospective study with data from the hungarian malformation registry based on 14 subjects (four first trimester exposures), shows no evidence of an increased risk of malformations after use of levamisole (kazy 2004) . oxamniquine is used for the treatment of schistosomiasis. no experiences have been reported about its use during pregnancy. recommendation. praziquantel should be reserved for specific severe indications like schistosomiasis. usually for other indications better-established anthelmintics are available. after first trimester exposure a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. pyrantel should be avoided in pregnancy because better tested alternatives are available for all indications. after first trimester exposure a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. pyrvinium may be used during pregnancy. the standard agent of this group is acyclovir which is used against the varicella-zoster virus (vzv) and herpes simplex virus (hsv) type 1 and 2. the manufacturer's case collection contains over 1,000 women treated systemically with acyclovir during pregnancy, 756 of them during the first trimester; with no evidence of embryo-or fetotoxic risk (stone 2004) . a study of a danish registry with 1,561 women with prescriptions in the first trimester, showed no increased risk after acyclovir (pasternak 2010) . although these studies had some methodological weaknesses, the experiences argue against the risk of acyclovir in pregnancy. valacyclovir, the prodrug of acyclovir, is converted quickly and completely to acyclovir in the body. orally it is distinctly better resorbed than acyclovir of which only about 20% is resorbed. the manufacturer did not find an increased risk of malformation in 56 women who had received valacyclovir during pregnancy, 14 of these during the first trimester (glaxo wellcome 1997) . also, the above cited study of the danish registry did not show evidence of embryo-or fetotoxic risk in 299 pregnancies, in which the mother filled a prescription for valacyclovir during the first trimester (pasternak 2010) . ganciclovir and its prodrug valganciclovir are effective in cytomegalus virus infections (cmv). in animal experiment, teratogenic effects were only seen with plasma levels that were twice as high as those recommended in human therapy. there are a few case reports describing normal pregnancy outcome after the first trimester treatment during early pregnancy (pescovitz 1999) . puliyanda (2005) describes a successful oral treatment with ganciclovir for an intrauterine cmv infection after the 22nd week. these experiences are insufficient to evaluate the safety of ganciclovir in pregnancy. famciclovir is quickly converted after enteral resorption into the virostatic penciclovir. neou (2004) reported a newborn whose mother took 250 mg famciclovir daily in her fifth week. the boy who succumbed to a severe neonatal infection had a hypoplastic thymus, a mild stenosis of the pulmonary valve, an ostium secundum defect, and an enlarged liver with stenotic extrahepatic biliary ducts. a retrospective study of data from the danish birth registry contained 26 women who took oral famciclovir during the first trimester, and showed no increase in the malformation rate (pasternak 2010) . there is insufficient data about the use in pregnancy for brivudine, cidofovir, foscarnet, and fomivirsen. in animal experiments, small doses of foscarnet sodium trigger skeletal anomalies in rats and rabbits. no experience is reported for the combination therapy of dimepranol and inosine that is used to stimulate the immune system against viruses of the herpes group. recommendation. diethylcarbamazine, levamizole and oxamniquine should be avoided during pregnancy as better tested alternatives are available for most indications. after first trimester exposure a detailed ultrasound examination should be offered to ascertain the normal development of the fetus.  herpes medication for local use acyclovir, foscarnet, ganciclovir, idoxuridine, penciclovir, trifluridine, and tromantadine are locally applied in hsv infections. none of these agents has been suspected to give rise to teratogenic effects. acyclovir may be used in pregnancy systemically and is harmless in local application. in the above cited danish registry study 2,850 women had used acyclovir and 118 women penciclovir locally during the first trimester, and no increased malformation risk was noted (pasternak 2010) . the other agents lack studies about local application. docosanol is a newly approved agent for topical application in herpetic cold sores. the mechanism of action is unknown. there has been no experience about its use in pregnancy; however, a risk is unlikely with its minimal resoption. the local application of zinc sulfate and of patches containing hydrocolloid particles is harmless in pregnancy. antiviral drugs for hepatitis  antiviral drugs for hepatitis b nucleoside/nucleotide analogs and α-interferon (chapter 2.12) are used for the management of chronic hepatitis b. a general therapeutic recommendation cannot be made for pregnancy as data are inadequate. experience so far did not reveal serious signs of teratogenic or fetotoxic damage in humans. if there is a very active hepatitis b or cirrhosis, antiviral treatment might be considered. passive-active immunoprophylaxis of infants have reduced mother-to-child-transmissions. however, in high viremic mothers immunoprophylaxis might fail. no consensus has been reached if pregnant women who are hbsag positive, and highly viremic should be treated in the third trimester to prevent a perinatal transmission to the infant (e.g. pan 2012). for lamivudine and tenofovir see section 2.6.30. adefovir dipivoxil, the prodrug of adefovir, is an orally-administered nucleotide analog. no teratogenicity has been reported in animal studies. the antiretroviral pregnancy registry (2013) received reports of 48 births after a maternal adefovir dipivoxil regimen in the first trimester. no birth defects were observed in the infants. entecavir has shown teratogenic effects in animal studies where, in high doses, more vertebral and tail malformations occurred. of 55 recommendation. if an antiviral therapy is indicated for a severe maternal disease, or to protect the fetus from an intrauterine infection, acyclovir or valacyclovir should be used as the best evaluated medication whenever possible. the other antiviral agents are only indicated in infections where they have a therapeutic advantage over acyclovir. after the application of one of the less well examined drugs during first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. recommendation. where indicated, local remedies for herpes may be used during pregnancy. drying agents and patches for herpes are harmless. where possible, acyclovir should be preferred as the best evaluated antiviral drug. infants whose mothers were exposed to entecavir during first trimester, two babies were born with birth defects (no details available) (antiretroviral pregnancy registry 2013). one case report describes a healthy baby born after entecavir exposure for 32 days in the second trimester (kakogawa 2011) . telbivudine raised no suspicions for teratogenicity in animal experiments. among 86 pregnancies of women who received telbivudine before or in early pregnancy the abortion rate was 7.9%. fifty mothers delivered 52 infants. one pregnancy was terminated because of cleft lip and palate and one infant showed right ear accessories, no other birth defects were reported (liu 2013) . in the antiretroviral pregnancy registry (2013) no birth defects were observed in 10 infants after first trimester exposure to telbivudine. in a prospective study, 136 infants were born after maternal treatment with telbivudine in late pregnancy to prevent perinatal transmission. exposure took place from the twentieth to thirty-second gestational week until at least 1 month after delivery. there were no significant differences in infant outcomes compared to a control group. no serious adverse events were noted in the infants . there is an ongoing discussion as to whether telbivudine should be given to women with a high virus load during late pregnancy to prevent intrauterine transmission (review by deng 2012). the nucleoside analog ribavirin inhibits both dna-and rna-viruses, displaying a relatively broad antiviral spectrum experimentally. among other applications, it is used to treat respiratory syncytial virus (rsv) infections in infants, and, combined with α-interferon (chapter 2.12), against hepatitis c. ribavirin has teratogenic and mutagenic effects in animal experiments. nine women who were treated during the second half of pregnancy for severe measles delivered healthy infants (atmar 1992) . a woman treated for sars (severe acute respiratory syndrome) in the first trimester with ribavirin by injection for 3 days gave birth to a normal child (rezvani 2006) . in its pregnancy registry, the manufacturer noted eight women with ribavirin exposure in the first trimester, and 77 women with exposure within 6 months of the last menstrual period (roberts 2010) . the authors found no evidence of a teratogenic risk for humans. in summary, current data is insufficient for a risk assessment for ribavirin. an embryo-or fetotoxic risk is not apparent with the available case reports. the level of ribavirin is twice as high in seminal fluid as in sperm. there has been no increased risk of malformations after paternal ribavirin treatment and interferon in 20 pregnancies reported as case reports (review by hofer 2010), and 110 pregnancies of the ribavirin pregnancy registry (roberts 2010) . these numbers are inadequate to assess a possible risk after paternal exposure. the protease inhibitors boceprevir, simeprevir and telaprevir have been approved for the treatment of chronic hepatitis c. there are no experiences with their use in pregnancy. the same applies to sofosbuvira recently approved polymerase inhibitor for the treatment of chronic hepatitis c. amantadine enhances dopamine activity at the receptor and thus is also used as an antiparkinson drug. as an antiviral medication, it inhibits the membrane protein hampering the ability of the virus to enter the cell nucleus. because of rapid resistance and frequent neurologic side effects, it is not recommended any more as an antiviral agent. for amantadin in parkinson disease, see chapter 2.11. the neuraminidase inhibitors oseltamivir, peramivir and zanamivir are used to treat patients whose influenza requires therapy. oseltamivir has not shown teratogenic effects in animal studies. a prospective investigation at two japanese centers did not see an increase in malformations where 90 women had been treated in the first trimester (review by tanaka 2009 ). another study involving 137 exposed offspring, 18 of them in the first trimester, also did not find a higher risk (greer 2010) . the manufacturer, too, noticed no increased risk in 115 women who had used oseltamivir during pregnancy, 44 of these during the first 3 months (donner 2010) . one study with 81 pregnant women exposed to oseltamivir, 24 in the first trimester, found an increased risk of late transient hypoglycaemia compared to an unexposed control group. no other increased risks of adverse birth outcomes among the infants have been observed. one child had a ventricular septal defect. this was the only major malformation after exposure in the first trimester (svensson 2011) . another publication included 619 pregnant women exposed to oseltamivir, 159 of them in first trimester. the overall rate of major malformation after first trimester exposure was 1.3% (saito 2013) . in a french publication, a total of 337 mothers received at least one prescription of oseltamivir during pregnancy. one congenital heart defect was observed among 49 infants who were exposed during first trimester. no significant association between adverse fetal outcomes and exposure to oseltamivir during pregnancy could be found (beau 2014) . dunstan (2014) could also find no signs of embryo-or fetotoxic effects in 27 exposed pregnant women. no birth defects were observed in eight first trimester exposures. a population-based retrospective cohort study analyzed data from 1,237 women who received oseltamivir during pregnancy. compared to a control group, there were no associations between maternal use of oseltamivir with preterm birth and low apgar score. women who recommendation. ribavirin and the other antiviral agents discussed here should only be used during pregnancy when compellingly indicated. treatment during the first trimester is not a justification for a risk-based termination of pregnancy (chapter 1.15 ). in such a situation a detailed ultrasound examination should be offered to ascertain normal fetal development. pregnancy took oseltamivir during pregnancy were less likely to have a small for gestational age infant. however, birth defects and time of exposure were not mentioned (xie 2013) . two studies looked into the pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate during gestation. greer (2011) compared the pharmacokinetics of 10 pregnant women in each group during the last trimester and found no significant differences. beigi (2011) examined the pharmacokinetcs in 16 pregnant women (average gestational age 24.6 weeks) in comparison to 23 nonpregnant women, and found the pregnant group to have lower oseltamivir carboxylate level. however, it remains unclear if the dose needs to be adjusted during pregnancy. zanamivir is applied by inhalation and very little is resorbed. no teratogenicity was found in animal experiments. a case series study from japan reported 50 infants born after intrauterine zanamivir exposure, 15 of them were exposed in the first trimester. no malformations have been observed (saito 2013) . a prospective surveillance study did not provide a case that use of zanamivir in pregnancy is associated with an increased risk of adverse pregnancy outcomes among 180 women exposed to zanamivir during pregnancy. no major malformations were reported in 37 zanamivir first trimester exposures (dunstan 2014) . experience and the presence of low systemic concentrations, make it unlikely that there is an increased embryo-or fetotoxic risk. experience during pregnancy with peramivir is insufficient for a risk assessment. the aim of antiretroviral therapy (art) during pregnancy is the prevention of a vertical transmission of the human immunodeficiency virus (hiv) from mother to child, and also the optimal management of the hiv-infected mother, whereby unwanted side effects are to be kept at a minimum for her and the child. art in pregnancy has become an integral part in the prophylaxis of hiv transmission after data revealed the protective effect of perinatal prophylaxis, with the nucleoside analog reverse transcriptase inhibitor (nrti) zidovudine that could prevent a possible vertical transmission during the last trimester and labor (connor 1994) . national and international guidelines recommend a standard therapy for both nonpregnant and pregnant hiv-infected women take a combination of at least three antiretroviral medications (eacs 2013 , oarac 2012 , who 2010c . this highly active antiretroviral therapy (haart) typically consists of two nrtis and either a protease inhibitor (pi), or a non-nucleoside analog reverse transcriptase inhibitor (nnrti). the intention is that the suppression of the plasma hiv load (hiv-rna) should be as close to <50 copies/ml at least by the end of the pregnancy. when an effective haart is applied during pregnancy and lactation, the hiv rate of transmission can be decreased from its former levels of recommendation. if indicated, neuraminidase inhibitors oseltamivir and tanamivir may be used in pregnancy. peramivir should be avoided. amantadine is no longer recommended for the treatment of influenza. when used during the first trimester, a detailed ultrasound examination should be offered to ascertain normal fetal development. 20-30% to <1% (townsend 2008 , warszawski 2008 . the decision of what regimen to use is already complicated in nonpregnant patients, but more so in pregnancy. how to balance individual needs and risks should be considered, especially in view of the timing of the start of treatment, a possible interruption of therapy during the first trimester in women already under treatment, and the selection of appropriate antiretroviral medications. the risks from intrauterine exposure to combinations of antiretroviral agents are difficult to assess, as data are limited concerning the pharmakinetics and the developmental toxicity for most of the drugs. there is no data about the long-term toxicity of the exposure to intrauterine retroviral substances. information about the safety of retroviral drugs in pregnancy are limited to experiments in animals, single case reports, a few clinical studies, and analyses of registries such as the antiretroviral pregnancy registry (2013) in the usa that contains most of the information about the safety of antiviral substances in pregnancy. overview of the antiretroviral medications , darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. 4 . entry inhibitors: enfuvirtide and maraviroc. 5. integrase inhibitors: raltegravir, dolutegravir and elvitegravir. data currently available do not allow for a summarizing differentiated risk analysis for antiretroviral medications in pregnancy. with the exception of efavirenz, there have been no serious signs of teratogenic or fetotoxic damages in humans (e.g. watts 2011 , ecs 2003 . prospectively documented pregnancies do not demonstrate a higher risk of malformations and, like retrospective case reports, fail to reveal any distinct pattern of anomalies. when antiretroviral agents are used in the first trimester, the embryotoxic risk appears to be generally small (phiri 2014 , floridia 2013 , antiretroviral pregnancy registry 2010 , joao 2010 . nevertheless, substances that might be embryotoxic should be eschewed in early pregnancy. common side effects in children treated in utero or after birth with zidovudine or antiretroviral combinations consist of hematologic problems, especially anemias and neutropenias (dryden-peterson 2011 , feiterna-sperling 2007 , le chenadec 2003 . it is being debated if antiretroviral treatment with or without protease inhibitors favors prematurity (chen 2012 , patel 2010 , kourtis 2007 , cotter 2006 , tuomala 2005 . the maternal risks of therapy are discussed with the specific medications. the medical treatment of hiv infection during pregnancy is a prime example for the need to sometimes utilize insufficiently tested medications -because of the acute danger for mother and child. in individual cases it needs to be critically assessed if an ongoing or maternally indicated treatment is absolutely necessary during the time of embryogenesis, or if it can be temporarily suspended. data from clinical studies during pregnancy in women are available for abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. with the exception of didanosine, the nrtis showed comparable levels in the maternal serum, and the umbilical cord blood suggested an easy placental passage (pacifici 2005) . having an affinity to mitochondrial γ-dna polymerases, nrtis can induce mitochondrial dysfunction. the greatest risk for mitochondrial toxicity is exhibited in vitro for didanosine, stavudine, and zidovudine. the question if a perinatal nrti exposure could lead to mitochondrial problems in children is currently under discussion; a final consensus has not been reached (benhammou 2007 , blanche 1999 . lamivudine and zidovudine are the nrtis that should be preferred during pregnancy because of extensive experience. abacavir, emtricitabine and tenofovir are alternative nrtis which also might be used. didanosine and stavudine should only be used in special circumstances (oarac 2012). abacavir can lead to skeletal anomalies when given to rats at a high dosage. there is no evidence of teratogenicity in humans. abacavir readily crosses the placenta (chappuy 2004) . data from the antiretroviral pregnancy registry (2013) with 27 birth defects in 905 cases, indicate a malformation rate of 3.0% after exposure during the first trimester, similarly as seen in the general population of the usa. in animal experiments didanosine given at high doses did not show teratogenic effects. didanosine crosses the placenta only in limited recommendation. antiretroviral medications may be used in pregnancy. specific risks for the prophylaxis of transmission and the therapy of maternal hiv infection need to be observed. the choice of medication and the timing of treatment have to be decided on an individual basis. when choosing medications it should be noted that some of the retroviral substances should be avoided during pregnancy, if possible. this concerns efavirenz (teratogenic effects) and the combination stavudine/didanosine (lactic acidosis). for newer medications such as maraviroc, raltegravir and etravirine, few or no data are available concerning their use in pregnancy. caution is called for when nevirapine is used in women with cd4 cell counts of <250/mm mm 3 (hepatotoxicity). if nevirapine is used during pregnancy, transaminases need to be checked regularly, especially during the first 18 weeks of treatment; also, clinical symptoms are to be watched. the short-term use of nevirapine for transmission prophylaxis does not seem to carry a similar risk. when exposure occurs during the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. it is recommended that the pregnant patient is cared for in a specialized center. physicians should report pregnancies involving the use of hiv medications shortly after diagnosis to the antiviral pregnancy registry (www.apregistry.com). amounts (wang 1999) . the data of the antiretroviral pregnancy registry (2013) show a slightly increased malformation rate after first trimester exposure at 4.8% (20 of 416 births), in comparison to 2.7% in the general us population. however, no distinct pattern of birth defects has been discovered. in a study where 14 hiv infected women were treated at 26-36 weeks with didanosine, neither maternal nor neonatal side effects were noted (wang 1999) . cases of lethal lactic acidosis have been described in pregnant women treated with a combination of stavudine and didanosine (mandelbrot 2003 , sarner 2002 . due to the risk of fatal lactic acidosis, combination treatment with didanosine and stavudine should only be used in cases where no alternatives are available (bristol-myers squibb 2001) . emtricitabine has not shown evidence of teratogenicity in animal experiments or in humans. it crosses the placenta readily (stek 2012 , hirt 2009b ). among cases of first trimester exposures reported to the antiretroviral pregnancy registry (2013), the prevalence of birth defects was 2.4% (34 of 1,400 births), similar to the rate in the general us population. lamivudine, one of the best evaluated nrtis, is also approved for the treatment of chronic hepatitis b. levels measured in the umbilical cord blood correspond to those of the mother. data from the antiretroviral pregnancy registry (2013) indicate an unsuspicious malformation rate of 3.1% (136 of 4,360 births). a larger study to prevent perinatal transmission was conducted in france where 445 pregnant women received zidovudine and lamivudine after gestational week 31, and their newborns were also given the combination for 6 weeks ( mandelbrot 2001) . in this study newborns displayed significant side effects that included lethal mitochondriopathies. however, lamivudine and zidovudine are medications that are preferred in pregnancy because of extensive experience. there is no evidence that stavudine leads to teratogenic effects in animal experiments or humans. stavudine crosses the placenta easily ( chappuy 2004) . the malformation rate after exposure in the first trimester is 2.6% (21 of 805 births) according to data from the antiretroviral pregnancy registry (2013), thus similar as in the general us population (2.7%). good tolerance of a staduvine-lamivudine combination has been described in a small phase i/ii study with 14 mother-child pairs (wade 2004) . cases of lethal lactic acidosis have been described in pregnant women treated with a combination of stavudine and didanosine (mandelbrot 2003 , sarner 2002 . due to the risk of a fatal lactic acidosis, combination treatment with didanosine and stavudine should only be used in cases where no alternatives are available (bristol-myers squibb 2001). in animal experiments, offspring of monkeys that received high doses of tenofovir have a decreased fetal growth rate and diminished fetal bone density (tarantal 2002) . during pregnancy tenofovir crosses the placenta easily (flynn 2011 , hirt 2009a . there is no evidence that tenofovir is teratogenic in humans. according to the data of the antiretroviral pregnancy registry (2013) the malformation rate after exposure during the first trimester is 2.3% (46 of 1,982 births), similar to the 2.7 % rate in the general us population. in clinical studies hiv patients, primarily children, displayed decreased bone density when treated with tenofovir. the clinical significance of these findings is still unclear. one study did not reveal any risk for adverse effects of in utero tenofovir exposure in 141 pregnant women (gibb 2012 ). however, tenofovir should be used with caution during pregnancy, because of the risk of fetal bone changes and the paucity of other data about its pregnancy-related risks. zidovudine, also known as azidothymidine (azt), is the oldest antiviral drug used for antiretroviral therapy. it readily crosses the placenta. in rats, maternal toxic doses lead to an increased malformation rate during organogenesis, an effect not seen with lower doses. there are no signs of teratogenicity in humans. according to data from the antiretroviral pregnancy registry (2013) the malformation rate of 3.2% (129 of 4,000 births) was not significant higher than that of the general us population. the application of zidovudine has been well studied in pregnancy and is considered to be safe in regard to shortterm and medium-term toxicities. a common side effect, when zidovudine is used in the perinatal period, is a transient anemia in newborns (sperling 1998 , connor 1994 . a follow-up study of 234 children who had been exposed to zidovudine in utero did not display any physical, immunological, or cognitive anomalies. the median age of children at the time of last follow-up was 4.2 years (range, 3.2-5.6 years) (culnane 1999) . also, there was no evidence of an increased risk for neoplasia in more than 700 children after pre-and perinatal exposure (culnane 1999 , hanson 1999 . there are no data regarding long-term toxicity, especially for cancerogenicity. data from clinical studies about the safety in human pregnancy for nnrt is are limited. nevirapine is the agent that should be preferred if a nnrti is required during pregnancy. efavirenz might be used in special circumstances. for etravirine and rilpivirine the data are insufficient to recommend use during pregnancy (oarac 2012). delavirdine is not recommended as part of an initial therapy. delavirdine caused an increased incidence of ventricular septal defects in rats. experience in humans is limited to 11 births after first trimester exposure reported to the antiretroviral pregnancy registry (2013). although no birth defects have been observed, these data allow no differentiated risk analysis. most guidelines do not recommend delavirdine as a part of antiretroviral regimens for initial treatment of hiv infection because of inferior efficacy. in animal experiments efavirenz showed evidence of teratogenicity. three of 20 prenatally exposed cynomolgus monkeys showed malformations when plasma levels were similar to the therapeutic levels in humans. anencephaly with unilateral anophthalmia was observed in one fetus, microphthalmia in another, and cleft palate in a third. there are case reports in humans about neural tube defects in children whose mothers had received efavirenz during the first trimester (de santis 2002 , fundaro 2002 . according to the data of the antiretroviral pregnancy registry (2013) the malformation rate of 2.3% (18 of 766 births) after first trimester exposure is comparable to the background rate of 2.7% in the general us population. the 18 birth defects included one infant with myelomeningocele. another child was born with anophthalmia, severe facial cleft and amniotic banding. in total, the antiretrorviral pregnancy register received six retrospective reports of neural tube defects; four of them were exposed to efavirenz. a meta-analysis, including nine prospective studies together with 1,132 live births, did not detect an increased risk of overall birth defects after exposure to an efavirenz-containing regimen during the first trimester. including retrospective studies, one neural tube defect was reported in 1,256 live births (ford 2010 ). an update of this meta-analysis which included 181 additional subjects had similar results (ford 2011) . in contrast to these reassuring findings, another study analyzes data of 1,112 infants born between 2002 and 2007. a significantly increased risk of congenital anomalies after exposure to efavirenz during first trimester was observed. six of 47 infants with first trimester exposure to efavirenz had congenital anomalies (adj.or 2.84, 95%; ci: 1.13-7.16) (knapp 2012) . however, the six observed major and minor defects (patent foramen ovale, gastroschisis, postaxial polydactyly, arnold-chiari malformation, talipes equinovarus, plagiocephaly), do not present a distinct pattern. with the available published experience, the british hiv association guidelines panels concluded that there are insufficient data to support the former position and furthermore recommend that efavirenz can be both continued and commenced in pregnancy (taylor 2012) . however, the united state guidelines are more restrictive. they recommend that an efavirenz-based regimen may be continued in women who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (oarac 2012). animal experiments have not shown that etravirine is teratogenic. experience in pregnancy is limited to case reports (jaworsky 2010 , furco 2009 ). according to the data of the antiretroviral pregnancy registry (2013) no birth defects were reported in 39 infants born after first trimester pregnancy exposure to etravirine. experiences are insufficient to analyze a possible risk in pregnancy. there is no evidence in animal experiments or human experience that nevirapine is teratogenic. nevirapine crosses the placenta easily and attains levels in the neonate that correspond to those of the mother ( benaboud 2011 , mirochnick 1998 . according to the data of the antiretroviral pregnancy registry (2013) the malformation rate after first trimester exposure is 2.9% (31 of 1,061 births), which is no higher than that of the general us population. studies indicate that viral transmission is blocked when 200 mg p.o. nevirapine is given to the mother at the beginning of labor, and the newborn receives a single dose of 2 mg/kg 48 to 72 hours after delivery (guay 1999) . there is a high risk of developing viral resistance even after a single dose (low resistance barrier and long half-life of nevirapine), thus nevirapine should only be administered in a combination regimen. reports have been published describing single cases of liver toxicity in pregnant women who took nevirapine (e.g. knudtson 2003 ). this event is often rash-associated and potentially fatal. liver toxicity is primarily observed in patients with higher cd4 cell counts (>250/mm 3 ); in these patients the risk of symptomatic hepatic events is twelve times greater than in women with lower cd4 cell counts (<250/mm 3 ). studies indicate that pregnancy per se is a risk factor for liver toxicity. pregnant patients using haart that includes nevirapin have no higher risk of hepatotoxicity than those who use haart without nevirapine (ouyang 2010 , ouyang 2009 ). these data suggest that the risk of liver toxicity of nevirapine is similar in pregnant and nonpregnant patients. however, if nevirapine is used in pregnancy, physicians should be aware of hepatotoxicity. animal experiments failed to show that rilpivirine is teratogenic. in the antiretroviral pregnancy registry (2013) no birth defects were reported in 31 infants born after first trimester exposure to rilpivirine. one publication describes two healthy infants after rilpivirine exposure during pregnancy (colbers 2014) . experiences are insufficient to analyze a possible risk in pregnancy. pis are being used increasingly in pregnancy. they are recommended in regimens combined with two nrti drugs. pi therapy can lead to the disturbance of glucose tolerance and even to the manifestation or exacerbation of diabetes mellitus. it remains unclear if pregnancy itself increases the risk even further. generally, pis pass the placenta poorly ( gingelmaier 2006 , marzolini 2002 , mirochnick 2002 . therefore, fetal toxicity would seem to be unlikely. lopinavir/ritonavir and atazanavir with low-dose ritonavir boosting are the preferred pis during pregnancy. alternative pis include ritonavir-boosted saquinavir and darunavir. indinavir and nelfinavir should only be used in special circumstances. data is too limited to recommend the routine use of fosamprenavir and tipranavir in pregnant women (oarac 2012). atazanavir has not shown evidence of teratogenicity in animal experiments or human experience. according to the data of the antiretroviral pregnancy registry (2013), the malformation rate of 2.2% (19 of 878 births) after first trimester exposure is comparable to the rate of 2.7% in the general us population. a number of studies are available, including pharmacokinetic evaluations in pregnant women using haart with atazanavir , ripamonti 2007 . some experts recommend an increased dose in late pregnancy. the umbilical cord blood of neonates shows atazanavir levels of 13-16% of those seen in the maternal serum. atazanavir inhibits the uridin glucuronosyl transferase that metabolizes indirect bilirubin. thus, as a common side effect, atazanavir treatment may lead to higher indirect bilirubin levels. while case numbers are relatively small, investigations showed that neonates of atazanavir-treated mothers did not show pathological elevations of indirect bilirubin. , ripamonti 2007 ). darunavir did not demonstrate evidence of teratogenicity in animal experiments. some case reports demonstrated a limited placental transfer. like with other pis a reduction in plasma levels has been observed in late pregnancy (pinnetti 2010) . in the antiretroviral pregnancy registry (2013) five birth defects were reported in 212 infants born after first trimester exposure to rilpivirine (prevalence 2.4%). few experiences about its use in pregnancy are available (e.g. jaworsky 2010, ivanovic 2010). these data are insufficient for a differentiated risk assessment. in animal experiments no evidence was found that fosamprenavir leads to teratogenicity. human data about its use in pregnancy are very limited. transplacental passage analyzed in seven cases was relatively high compared to other pis. the authors detected a median ratio of 0.27 of cord blood to maternal amprenavir level (the active metabolite of fosamprenavir) (cespedes 2013) . one publication did not report adverse effects in nine infants after intrauterine exposure to fosamprenavir (martorell 2010) . two birth defects among 102 births were reported to the antiretroviral pregnancy registry (2013) after first trimester exposure to fosamprenavir. these data are insufficient for a differentiated risk assessment. evidence for teratogenicity is not evident for indinavir in animal experiments or human reports. little of indinavir crosses the placenta ( mirochnick 2002) . according to the data of the antiretroviral pregnancy pregnancy registry (2013) the malformation rate of 2.4% (7 of 289 births) after first trimester exposure is comparable to that in the general us population. these data are insufficient for a differentiated risk assessment. there is a theoretical concern that physiologic hyperbilirubinemia might be exacerbated due to indinavir. lopinavir is used in conjunction with its pharmacological booster ritonavir. in animal experiments with high doses of lopinavir, rats displayed evidence of embryotoxicity with an increased rate of miscarriages, less fetal viability, lower fetal weight, and skeletal changes. these problems were not apparent in rabbits. there is no evidence of teratogenicity in humans. like most pis, lopinavir/ritonavir crosses the placenta poorly (gingelmaier 2006) . according to the data of the antiretroviral pregnancy registry (2013) the malformation rate is 2.3% (26 of 1,125 births) after first trimester exposure, and thus not increased in comparison to the general us population. studies with hiv-infected pregnant women indicate that the treatment with lopinavir/ritonavir is well tolerated. pharmacokinetic investigations show lower plasma levels, primarilty in the last trimester (best 2010) . it is unclear if pregnant women require a higher dose or just a continuation of the pi standard therapy. a report of 50 infants who received lopinavir/ ritonavir after birth observed an association with transient adrenal dysfunction in the infants (simon 2011) . a systematic review about the safety and efficacy of lopinavir/ritonavir during pregnancy included nine studies involving 2,675 pregnant women. no concerns with the use of these agents were suggested (pasley 2013 ). nelfinavir did not display evidence of teratogenicity in animal experiments. according to the data of the antiretroviral pregnancy registry (2013), the malformation rate is 3.9% (47 of 1,211 births) after first trimester exposure which is a modest evaluation compared to the general population (2.7%). no distinct pattern of birth defects defects has been discovered. in studies with hiv-infected pregnant women it was noted that a small amount crosses the placenta (bryson 2008 , mirochnick 2002 . when nelfinavir is used as an unboosted pi in pregnant women who need treatment for hiv, it is inferior to newer, low-dose ritonavir boosted pis, but is useful as an alternative pi in combination with 2 nrtis for the prophylaxis of hiv transmission. however, nevirapine should only be used under special circumstances during pregnancy. ritonavir should be used in combination with other pis as a low-dose booster to increase levels of a second pi. only a small amount crosses the placenta (mirochnick 2002) . there is no evidence that ritonavir is teratogenic in animal experiments or humans. according to the data of the antiretroviral pregnancy registry (2013) the malformation rate is 2.3% (52 of 2,260 births) after first trimester exposure, thus similar to the general us population. saquinavir has not demonstrated evidence of teratogenicity in animal experiments or human experience. like with other pis only small amounts of the drug cross the placenta (mirochnick 2002) . pharmacokinetic studies indicate that the newer tablet formulation that has replaced the former capsule formulation, leads to plasma concentrations similar to nonpregnant patients (van der lugt 2009). thus, it is not necessary to adjust the doses in pregnancy. seven birth defects among 182 first trimester exposures were reported to the antiretroviral pregnancy registry (2013). these data are insufficient for a differentiated risk assessment. tipranavir shows no teratogenicity in animal experiments. there are no data about its ability to cross the placenta. aside from single case reports of pregnant patients with multiple resistances (weizsaecker 2011 , wensing 2006 , there are no other data about the use of tipranavir in pregnancy. no birth defects were reported to the antiretroviral pregnancy registry (2013) among four first trimester exposures to tipranavir. experiences are insufficient to analyze a possible risk in pregnancy. entry inhibitors are antiretroviral agents that inhibit viral binding or fusion of hiv to the cell, either by inhibition of the fusion of the viral capsule with the cell membrane or by blocking cd4-or co-receptors. data about the use of enfuvirtide or maravorioc during pregnancy are insufficient to recommend their use during pregnancy (oarac 2012). in animal experiments no evidence was observed that enfuvirtide is teratogenic. a number of single case reports suggest that enfuvirtide apparently does not cross the placenta (weizsaecker 2011 , brennan-benson 2006 . according to the data of the antiretroviral pregnancy registry (2013) no birth defects have been reported among 20 first trimester exposure to enfuvirtide. thus, it can be assumed that the risk of fetal toxicity is likely to be small. enfuvirtide may be used in pregnant women with multi-resistent hiv in combination with other potent agents as a therapeutic option, but current experience in pregnancy is very limited. maraviroc is a ccr5 inhibitor that is used to treat pretreated hivinfected adults in combination with other antiretroviral medications, when exclusively ccr5-tropic hiv type-1 have been proven to be present. animal experiments using rats and rabbits did not show evidence of teratogenicity for maraviroc. there are no data indicating to what degree pregnancy maraviroc crosses the placenta. while there has been no indication that the use of maraviroc leads to a higher rate of malignancy, a theoretical concern remains based on the method of its action. maraviroc should only be used when the benefit justifies the potential fetal risk. there is a lack of data about its application in pregnancy. among 13 cases with first trimester exposure reported to the antiretroviral pregnancy registry (2013) no birth defects have been observed. integrase inhibitors block integrase, a hiv-coded enzyme, and thereby hiv replication. the use of raltegravir during pregnancy can be considered in special circumstances when preferred and alternative agents cannot be used (oarac 2012) . there is insufficient data for the new integrase inhibitors dolutegravir and elvitegravir. in animal experiments no evidence was seen that dolutegravir is teratogenic. placental transfer has been described in animals. no experiences have been reported about its use during human pregnancy. there are also no reports about the use of dolutegravir to the antiretroviral pregnancy registry (2013). elvitegravir is combined with colbicistat which has no known antiretroviral activity. colbicistat is a pharmacokinetic enhancer which inhibits enzymes that metabolize elvitegravir. animal studies of elvitegravir have shown no evidence of teratogenicity. only one report about the use of elvitagravir during the first trimester has been reported to the antiretroviral pregnancy registry (2013). no birth defects were observed in this case. development studies in rats and rabbits did not show raltegravir to be teratogenic. however, there was a slightly increased incidence of supernumerary ribs in the offspring of rats that had received raltegravir at doses about 4.4 times higher than those recommended in human treatment. potential human risks are not known at this time. according to the few data about its use during pregnancy, raltegravir crosses the placenta well (mckeown 2010). in a case series of five women raltegravir was well tolerated (taylor 2011) . three birth defects were observed among 141 pregnant women with first trimester exposures reported to the antiretroviral pregnancy registry (2013). because experience is increasing, the united states guidelines recommend allowing a regimen including raltegravir in special circumstances, when preferred and alternative agents cannot be used (oarac 2012) . however, the data on the use of raltegravir during pregnancy allow no differentiated risk analysis. more than 30 years ago animal experiments demonstrated that an increase in the body temperature can cause malformations (review by graham 2005 , edwards 1995 , miller 2013 . this problem has also been discussed for humans. neural tube defects, in particular (suarez 2004 , shaw 1998 ), but also kidney, heart and abdominal wall defects (abe 2003 , chambers 1998 , have been reported in association with febrile infections in early pregnancy, even though the overall malformation risk is absent or only mildly increased. moretti (2005) performed a meta-analysis about the risk of neural tube defects and hyperthermia. they included 15 studies with 1,719 cases and found a significant correlation (or 1.9; 95%; ci 1.61-2.29), both in the nine case-control studies and the six cohort studies. lowering fever in pregnant women seems to reduce the risk (suarez 2004) . it has been debated if the use of sauna, electric blankets, or other factors that bring about a short-term increase in body temperature could lead to similar effects as high fever (suarez 2004) . in finland, where this issue had been investigated repeatedly, visits to saunas occur frequently during pregnancy and is considered safe. the use of electric blankets and heated water beds has not shown, in other investigations, that they are linked to an increased malformation risk. one study observed that children between the ages of 5 and 12 had more frequent emotional and cognitive deficits where there were reports about high fever during the second and third trimester (dombrowski 2003) . in summary, it appears that there is a slightly higher risk of malformations when high fever (>39°c and >24 hours) occurs, especially during the first 4 weeks after conception. during long-distance travel and flights during pregnancy, a number of potential risks need to be considered: □ prevention of infections (malaria prophylaxis, see section 2.6.16.; vaccinations, see chapter 2.7). □ the risk of other infections (fever, fluid loss), and required therapy. □ during long-distance flights: -risks of thrombosis -ionizing cosmic radiation recommendation. if there is an infection with high fever, especially during early pregnancy, the fever should be controlled with acetaminophen (paracetamol) or ibuprofen (chapter 2.1). ibuprofen should not be taken after 28 gestational weeks. non pharmacological measures of fever control such as cool wrappings, and sufficient fluid intake should also be considered. in cases of high fever episodes in early pregnancy, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. a fever episode does not justify a risk-based termination of pregnancy (chapter 1.15). visits to a sauna should be limited to less than 10 minutes, and hot or long baths need to be avoided as well as other sources that can overheat the body. -decrease of the partial oxygen pressure equivalent to an altitude of 2,500 m -dry air. □ physical and psychological stress. specific developmental anomalies have not been found in pregnant women undergoing vaccinations or recommended malaria prophylaxis, nor were such problems seen as a result of long-distance flights. however, it needs to be noted that the stress of a long-distance trip, especially in predisposed women, might increase the risk of miscarriage. also, aside from typical infectious diseases, "common" infections may be more prevalent due to altered hygienic standards in the destination country. the accompanying dehydration, fever, or other complications may also endanger the fetus. the dose of cosmic radiation on a long-distance flight varies markedlydepending on solar activity. yet, according to current knowledge, no doses are reached that are high enough to lead to an increased risk of malformations. pharmacokinetics of quinine and its metabolites in pregnant sudanese women with uncomplicated plasmodium falciparum malaria maternal febrile illnesses, medication use, and the risk of congenital renal anomalies is praziquantel therapy safe during pregnancy? safety of artemisinins during early pregnancy, assessed in 62 sudanese women quinine for chloroquine-resistant falciparum malaria in pregnant sudanese 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infancy: a randomised, double-blind, placebo-controlled trial pharmacokinetic profile in late pregnancy and cord blood concentration of tipranavir and enfuvirtide prevention of mother-to-child transmission of multi-drug resistant hiv-1 using maternal therapy with both enfuvirtide and tipranavir report of the who informal consultation on the use of praziquantel during pregnancy/ lactation and albendazole/mebendazole in children under 24 months assessment of the safety of artemisinin compounds in pregnancy guidelines for treatment of tuberculosis guidelines for the treatment of malaria antiretroviral drugs for treating pregnant women and preventing hiv infection in infants: recommendations for a public health approach who. chagas disease (american trypanosomiasis) malaria in pregnant women soil-transmitted helminth infections further analysis of the risk of adverse birth outcome after maternal use of fluoroquinolones infant outcomes among pregnant women who used oseltamivir for treatment of influenza during the h1n1 epidemic successful caspofungin treatment of multidrug resistant candida parapsilosis septicaemia in an extremely low birth weight neonate exposure to trimethoprim/sulfamethoxazole but not other fda category c and d anti-infectives is associated with increased risks of preterm birth and low birth weight gentamicin use in pregnancy. a renal anomaly key: cord-305327-hayhbs5u authors: gonzalez, jean-paul; souris, marc; valdivia-granda, willy title: global spread of hemorrhagic fever viruses: predicting pandemics date: 2017-09-19 journal: hemorrhagic fever viruses doi: 10.1007/978-1-4939-6981-4_1 sha: doc_id: 305327 cord_uid: hayhbs5u as successive epidemics have swept the world, the scientific community has quickly learned from them about the emergence and transmission of communicable diseases. epidemics usually occur when health systems are unprepared. during an unexpected epidemic, health authorities engage in damage control, fear drives action, and the desire to understand the threat is greatest. as humanity recovers, policy-makers seek scientific expertise to improve their “preparedness” to face future events. global spread of disease is exemplified by the spread of yellow fever from africa to the americas, by the spread of dengue fever through transcontinental migration of mosquitos, by the relentless influenza virus pandemics, and, most recently, by the unexpected emergence of ebola virus, spread by motorbike and long haul carriers. other pathogens that are remarkable for their epidemic expansions include the arenavirus hemorrhagic fevers and hantavirus diseases carried by rodents over great geographic distances and the arthropod-borne viruses (west nile, chikungunya and zika) enabled by ecology and vector adaptations. did we learn from the past epidemics? are we prepared for the worst? the ultimate goal is to develop a resilient global health infrastructure. besides acquiring treatments, vaccines, and other preventive medicine, bio-surveillance is critical to preventing disease emergence and to counteracting its spread. so far, only the western hemisphere has a large and established monitoring system; however, diseases continue to emerge sporadically, in particular in southeast asia and south america, illuminating the imperfections of our surveillance. epidemics destabilize fragile governments, ravage the most vulnerable populations, and threaten the global community. pandemic risk calculations employ new technologies like computerized maintenance of geographical and historical datasets, geographic information systems (gis), next generation sequencing, and metagenomics to trace the molecular changes in pathogens during their emergence, and mathematical models to assess risk. predictions help to pinpoint the hot spots of emergence, the populations at risk, and the pathogens under genetic evolution. preparedness anticipates the risks, the needs of the population, the capacities of infrastructure, the sources of emergency funding, and finally, the international partnerships needed to manage a disaster before it occurs. at present, the world is in an intermediate phase of trying to reduce health disparities despite exponential population growth, political conflicts, migration, global trade, urbanization, and major environmental changes due to global warming. for the sake of humanity, we must focus on developing the necessary capacities for health surveillance, epidemic preparedness, and pandemic response. infectious diseases have swept the world, taking the lives of millions of people, causing considerable upheaval, and transforming the future of entire populations. every year pathogens cause nearly 14 million deaths worldwide, mostly in developing countries. more than 350 infectious diseases have emerged between the 1940s and 2004 [1] . also among the 500 known arboviruses, only 50 are known to be human pathogens, while the others only infect wild animals and/or arthropods. to anticipate an epidemic one must identify the risk, prepare an appropriate response, and control the disease spread by first identifying the vulnerabilities of the population and circumscribing the potential space into which a disease will extend. when the epidemic expansion risk is identified, adequate information must be communicated to decision makers. ultimately, an appropriate response will depend on biosurveillance, prevention, sustained data processing, communication, strategic immunization campaigns, resilience, and mitigation strategies. the viral hemorrhagic fevers (vhfs) are a diverse group of human illnesses caused by rna viruses including approximately 50 species of the arenaviridae, filoviridae, bunyavirales, flavi viridae, and rhabdoviridae (table 1) . despite the efforts placed on early detection, viruses like dengue, ebola, lassa, crimean-congo hemorrhagic fevers continue to threaten the health of millions of people, mostly in areas where demographic changes, and political and socio-economic instability interrupt vaccination campaigns [2] . however, the threat of vhf to global health is increased by intercontinental travel and global trade. moreover, because of the high case fatality rate of some of these pathogens, such concerns extend to the potential use of these viruses by bio-terrorists [3] . global expansion of several diseases is exemplified by the spread of yellow fever from africa to the americas, the spread of dengue fever across continents, and recently, the spread of ebola virus from the democratic republic of the congo to western africa. the concept of an epidemic, as a disease affecting many persons at the same time and spreading from person to person in a locality where the disease was not previously prevalent, was not enunciated until 1854 when john snow produced his admirable demonstration of the emergence of an infectious disease in an urban area: the emergence of a cholera epidemic in london. at that time, none could clearly comprehend the mechanisms of emergence and spread since the existence of microbes had just been demonstrated by louis pasteur in the late 1830s and microbe transmission modes were more speculative than based on medical or scientific facts, until 1876 when robert koch demonstrated that bacteria can be transmitted and responsible for diseases. nowadays, it is extremely difficult to make a retrospective diagnosis of historical pandemics, there are currently 41 species in the orthohantavirus genus. the pathogeny of most of them is unknown during times when clinical descriptions were rare or lacking accuracy, and the extent of an epidemic was extremely subjective. thus, it is common to note that the first outbreak described in the western world was that of the plague of athens for which thucydides rather precisely reported the symptoms; today this epidemic has often been attributed to typhus through its clinical picture and epidemic profile [4] . the first historically recorded outbreaks due to viral agents date to antiquity when the roman armies were returning from distant countries bringing with them "exotic" diseases. indeed, the rise of a "new" virus is an extremely rare event. most often, in terms of pathogen emergence, a virus adapts through mutation and selection pressure to a human host causing disease. presumably, smallpox, measles, and influenza were among the plagues that struck the ancient latins in gusts of epidemics more or less severe. the antonin plague that extended from 167 to 172 ad in much of western europe, when the troops of emperor lucius verus returned from war against the parthians, is often attributed to a smallpox pandemic by historians. in the middle ages, it seems that smallpox made a return around 541 ad to france, germany, belgium, and the british islands [5] . the acute respiratory infections reported during the winter of 876-877 ad accompanying the return of the carolingian armies from italy have been attributed by historians to a flu epidemic. many soldiers of charlemagne died then. the disease returned regularly and fiercely in 927 and 1105 ad to the western european peninsula [6, 7] (table 2) . from the plague (sensu lato, including all transmissible diseases) of antiquity, to the severe acute respiratory syndrome that emerged on the eve of the third millennium, pandemics have followed in the history of mankind. as noted by mirko grmek, a historian of medicine, it seems that one pandemic will drive in another. if several diseases circulate concomitantly, one of them will take precedence over the other, an epidemic over the previous, and it is more likely that a pandemic will prevail [8] . plague temporarily replaced the leprosy that appeared in eurasia for over 50,000 years; during the first millennium, plague was manifested by successive pandemics that crossed continents. during the first half of the past millennium, syphilis started its expansions, crossed oceans, and became global. tuberculosis originated in europe more than 15,000 years ago, but it was only at the turn of the seventeenth century that it was considered a pandemic; smallpox was also manifest as epidemics and then was pandemic at its peak in the late nineteenth century, then smallpox persisted until the jenner area. although early medical records of smallpox are available (egypt, china, india), large and devastating epidemics were only identified in the late fifteenth century of the millennium. smallpox was introduced into the americas by spanish settlers in the caribbean island of hispaniola in 1492 and arrived in mexico in 1509. on hispaniola island, one third of a million of the inhabitants died of smallpox in the following 20 years. smallpox devastated the native amerindian population and was an important factor in the conquest of the aztecs and the incas by the spaniards [9] . in 1545, 8000 children died in goa, india, from a smallpox epidemic. in europe, smallpox was a leading cause of death in the eighteenth century, killing an estimated 400,000 europeans each year [10] . during the twentieth century, it is estimated that smallpox was responsible for 300-500 million deaths. the last known natural case of smallpox occurred in somalia in 1977 [11] . it is only at the end of the first millennium that all these pathologies were better understood and their infectious origins elucidated. the first pandemic of the twentieth century was attributed to the h1n1 spanish flu that emerged in kansas in 1918. however, this "flu pandemic" is now thought to have had subepidemic circulation earlier in france or germany or even prior emergence in china in 1916 or 1917 [12] , and to be exascerbated by concurrent bacterial infections. although it burned out quickly by 1920, it has been estimated that one third of the world's population was afflicted; 50 million people died, half of them in the first 25 weeks of the outbreak. since the 1960s, the frequency and magnitude of dengue fever epidemics increased dramatically as the viruses and the mosquito vectors have both expanded geographically in pandemic proportions [13] largely extending the pandemic to all the intertropical zone. in the early 1980s, human immunodeficiency viruses (hiv-1 and hiv-2) spread as an acquired immunodeficiency syndrome (aids), a pandemic that continues to take its terrible toll at the global level. since the emergence of aids, 78 organization updates, as of june 2015 only 17 million people were accessing antiretroviral treatment and among them, seven of ten pregnant women received treatment. in 2003, a severe acute respiratory syndrome, sars, inaugurated the twenty-first century as a first pandemic of the millennium, involving more than 24 countries with secondary epidemic chains in asia, europe, north america, south america, and a total of 8098 cases [14] . ultimately, one of the major characteristics that defines today's pandemics, apart from the introduction of the disease within several continents or the rapid expansion across the administrative borders of countries, is the initiation of locally active transmission of the pathogen. although, the first ebola virus disease outbreak of western africa was considered a pandemic and witnessed several exported cases with secondary epidemic chains in distant countries of the african continent (i.e., nigeria, mali), outside of africa, exported cases rarely sparked local transmission. emergence from a sporadic case to an outbreak, to an epidemic, and ultimately to a pandemic depends upon effective transmission among nonimmune hosts, host availability (density), characteristics of the vector (natural or human made) that would enable it to circumvent distances, and the pathogen infectiousness. all these dynamics are essential for an effective disease transmission and spread. an outbreak is a sudden increase in occurrences of a disease in a particular time and place, more localized than an epidemic. an epidemic occurs as the disease spreads to a large number of people in a given population within a short period of time. to spark an epidemic chain of transmission depends on factors like immune population density, virus infectiousness, promiscuity, vulnerability, etc., while the efficiency of such transmission depends on how many persons will be infected by one person (i.e., the reproductive ratio or r0). an epidemic event will therefore expand in space (beyond the first cluster of cases) and time (rapid spread). a pandemic is essentially spatial, and represents an epidemic of infectious disease that has spread through human populations across a large region, extensively across two or more continents, to worldwide. however, all these typologies harbor the same fundamentals: emergence from one index case, transmission from one host to another, and spatial expansion. altogether, an epidemic and a pandemic are respectively a local and a global network of inter connected infectious disease outbreaks (i.e., epidemic chains). ultimately, understanding how disease (i.e., pathogens) spread in the social system is fundamental in order to prevent and control outbreaks, with broad implications for a functioning health system and its associated costs [15] . also, after the last case occurs at the end of an epidemic, the goal is to control the risk of transmission for a 21-day time period. this three-week period represents an incubation when the infected subject does not transmit the virus and remains asymptomatic. the "21 days" is based on experimental methods use in virology to detect virus replication: influenza virus infected eggs should hatch in 21 days, there is a 21-day limit for an arbovirus to infect a living model (suckling mice, mice, rats, guinea pigs, cell lines). moreover, most viral infectious diseases have a maximal incubation period of 21 days, with few exceptions (e.g., hiv, and rabies). ultimately, such 21-day periods multiplied by the potential of a carrier to travel will produce the risk area for the emergence of secondary cases (from a walking distance to the long distances covered by commercial jets). however, it is important to clarify that many vhf including ebola virus can be carried by an asymptomatic host for several months [16, 17] . the mode of transmission profiles the epidemic pattern of a transmissible disease. it is extremely helpful when a disease emerges to rapidly surmise the mode of transmission and how to respond (e.g., water-borne disease, arthropod-borne disease, human-tohuman transmission). pathogen transmission can be interspecific or hetero-specific, direct or indirect. direct transmission occurs by close contact with infected biological products (e.g., blood, urine, saliva). indirect transmission occurs with intermediate hosts such as arthropod vectors (e.g., mosquito, tick) or mammalian vector/reservoir (e.g., rodent, chiropteran) or from infected environmental means (e.g., soil, water, etc.). mobility and transportation are the main factors for diseases dispersion, as an emblematic example, one can simply show how the 2013-2016 evd outbreak of western africa expanded due to the transportation of patients during their 21-day incubation periods, first by foot-paths, then by motorbike, then taxis and public transportation, finally becoming a global concern with patients traveling by boat or commercial airline [18, 19] . host population density and promiscuity, crowded places (like schools, markets, mass transportation system) also play an important role in the efficiency of transmission as well as the level of herd immunity (e.g., annual pandemic flu), altogether this gives us the level of population susceptibility (i.e., vulnerability). environmental factors can also be major drivers of pathogen expansion, for example the emergence of nipah encephalitis. the nipah virus, when it emerged for the first time in malaysia in 1998, was transported by its natural host, a frugivorous chiropteran. a year earlier, an immense forest fire affecting several indonesian islands had forced the escape of disease-carrying bats that took refuge in malaysian orchards, planted to nurture newly developed pig farms. both pigs and farmers became infected and nipah virus was discovered for the first time. another classical example, more associated with human environment and behavior, is the old story of the spread of dengue virus via the used tires carrying infected aedes aegypti eggs and transporting dengue across oceans and continents [20] . understanding the mechanisms of transmission and expansion of disease vectors with respect to the typology (epidemic pattern) of a disease is the ultimate challenge for controlling and preventing disease. typologies from human-to-human transmission, zoonotic diseases, arboviruses, water-borne diseases, and others play different roles in the rate of disease spread and need to be clearly understood. finally, while an epidemic pattern is driven intrinsically by the virus and its vector, the host population, the mode of transmission, and even the human environment (e.g., population density, urbanization, agricultural practices, health system, public health policies) as well as physical environment (season, meteorology, climate changing, latitude, altitude) factor into the rate of disease spread. with respect to pandemic risk (the rapidity and area covered by disease), the main characteristics of a virus are found in its environmental persistence while remaining infectious. environmental persistence depends on: virus structure, enveloped viruses are more sensitive than the naked viruses; its mode of entry into the body of the susceptible subject (transdermal, oral, respiratory); its ability to diffuse out of the body for a sufficient period of time which will, in turn, enable transmission to a greater number of subjects (r0). altogether these intrinsic factors link to the infectivity of the virus, indeed, viruses transmitted by aerosol possess certainly the most efficient way to spark an epidemic that increases with population density and vulnerability as well as with the resistance of the virus to environmental factors outside the host cells. the cycle of transmission shapes the epidemic in time and spatial dispersion. for example, animal to human zoonoses are dictated by chance encounters between host (population density, animal farming, pets, hunting) and, eventually transmission such as that observed between human and nonhuman primates [21] . vectortransmitted diseases (i.e., arthropod-borne diseases) depend on the vector ecology (ability to transmit, length of the intrinsic cycle of the virus, trophic preferences, vector density, seasonality, reproduction, breeding sites, food abundance for hematophagous arthropods). mobility of hosts/vectors that are part of the natural cycle will also play a role in the potential for disease expansion (e.g., mosquito-flying distance, cattle transhumance, human migration). also, other factors associated with the hosts will render a more efficient transmission: human behaviors like fear/social responses, nosocomial infections, super-spreaders); viruses having multiple natural hosts (vicariates) or vectors; vectors with multiple trophic preferences (e.g., biting cattle, birds, and primates); the incubation period in the vertebrate hosts as well as the intrinsic replication in the arthropod vectors will also intervene; ultimately subclinical infection is also an underestimated factor of virus dispersion and transmission that modifies the epidemiological pattern of disease. one can distinguish also a typology of communicable diseases that reflects the spatial and temporal mode of transmission including arthropod-borne transmission, human-to-human transmission, human-to-animal (and vice versa) transmitted diseases (i.e., zoopredicting hfv pandemics noses) including vector and nonvector transmitted diseases, and some other types of environmentally transmitted diseases. all of them represent unique types of transmission and risk of spread with a variable path of time, and also dependent on multiple factors (environment, climate, behavior, etc.). we have to consider territories as spaces where disease can potentially expand and that can be characterized by the fundamental factors of emergence and spread: the vulnerability of the population, the level of favorable transmission factors, and the probability for the population to be exposed to the virus. vhf are exemplary for their epidemic patterns of expansion dependent on the above reviewed factors (i.e., fundamentals of emergence) and their epidemiological characteristics (i.e., virus, host, environments). for example, let us consider the control of arenavirus spread by their strong host-species association. on a geological time scale, arenaviruses such as the agent for argentinian hemorrhagic fever (ahf) coevolved with their natural rodent host and then spread according to the expansion of the rodent host. one host-one virus ultimately produces a localized endemic cycle, the distribution of the disease overlaps the distribution of the rodent host while enzootic patterns appear naturally limited to an ecosystem (e.g., local rodent populations, behaviors, and environmental factors). hantaviruses also appear as a global complex, resulting from the coevolution of virus and rodent hosts and a global dispersion of generally localized enzootic diseases [22] [23] [24] . as for the pandemic risk associated with a natural virus reservoir, chiropterans are unique flying and migratory mammals that have been associated with filoviruses and other viruses of major public health importance [25] , their potential as vectors will eventually favor the spread of these viruses into new territories. also because there is potential for a long coevolution, epidemiological patterns are also dependent on virus-host spillover, host vicariate, and other environmental factors (e.g., climate change and man-made changes in land use). other arboviruses such as yellow fever virus, dengue virus, as well as west nile, chikungunya, or zika viruses show a pandemic risk associated with the existing distribution of their respective arthropod vector, vector density, and ability to transmit virus. investigating the fundamental factors of transmission and favorable territories for disease emergence are necessary to evaluate the risk, respond to the epidemic, and control its expansion from an index case to a pandemic. ultimately, when the fundamentals are understood and epidemic/pandemic risk identified, suitable emergency funding needs to be identified and made available in endemic areas to insure political willingness and community participation. ultimately, a suitable response will improve biosurveillance, data processing, communication, strategic immunization campaigns, and research for future risk prevention. several emblematic vhf and their original "epidemiological engineering" are presented in herein. vhf such as ebola virus disease, lassa fever, rift valley fever, or marburg virus disease are highly contagious and deadly diseases, with potential to become pandemics. remarkably, vhf are essentially caused by viruses of eight families; arenaviridae, filoviridae, hantaviridae, nairoviridae, peribunyaviridae, phenuiviridae, flaviviridae, and more recently rhabdoviridae [26] (table 3) . hemorrhagic fever viruses (hfv) have been classified as "select agents" because they are considered to pose a severe threat to both human and animal health due to high mortality rate, human-to-human transmission, and, in some cases, the potential to be aerosolized and used as bioweapons [27] . each of these hfv shares some common features that define the nosology of the vhf group, from virus structures to the clinical and epidemiological characteristics of their diseases. -hfv spread person-to-person through direct contact with symptomatic or asymptomatic patients, body fluids, or cadavers. -vhf can have a zoonotic origin, as when humans have contact with infected livestock via slaughter or consumption of raw meat, unpasteurized milk, bushmeat, inhalation or contact with materials contaminated with excreta from rodents or bats. -hfv can be vector-borne, i.e., transmitted via rodents, mosquitos, and ticks. -vhf are zoonotic diseases. accidental transmission from the natural host to humans can eventually lead to human-to-human transmission, human infection, and sporadic outbreaks. -with a few noteworthy exceptions (i.e., ribavirin), there is no cure or established drug treatment for vhf, while limited vaccines could be available, including yf, ahf, and rvf (the latter is for animals only). -vhf have common features: they affect many organs, they damage blood vessels, and they affect the body's ability to regulate itself. clinical case definitions describe vhf with at least two of the following clinical signs: hemorrhagic or purpuric rash; epistaxis, hematemesis, hemoptysis, melena, among other hemorrhagic symptoms without known predisposing host factors for hemorrhagic manifestations. in fact, during an epidemic, all infected patients do not show these signs and a specific case definition needs to be defined in accordance with the suspected or proven viral etiology of the disease [28]. also, vhf pathogenesis encompasses a variety of mechanisms including: (1) alteration of hepatic synthesis of coagulation factors, cytokine storm, increased vascular permeability, complement activation, disseminated intravascular coagulation. moreover, severe pathogenic syndrome is often supported by an ineffective immunity, high viral loads, and severe plasma leakage and co-infection with other pathogens [29] . the present chapter will mainly focus on the factors that can specifically and eventually contribute to a pandemic risk and how did we learn from historical spread of the vhf. the yellow fever disease pandemic is thought to have originated in africa, where the virus emerged in east or central africa and spread to western africa. in the seventeenth century, it spread to south america through the "triangular" slave trade, after which several major outbreaks occurred in the americas, africa, and europe [30, 31] . the yellow fever vaccine is a fantastic gift from pioneering vaccinology; it is efficient, affordable for developing countries, and protects for at least a decade or even life-long. however, yf remains a particular concern at the global level and the number of cases has unexpectedly increased this past decade. nowadays, yfv causes 200,000 infections and 30,000 deaths every year, with nearly 90% occurring in africa. nearly a billion people live in an endemic area [32] . although yfv is common in tropical areas of south america and africa, it has never been isolated in asia [33] . ultimately, the pandemic risk is there, from the uncontrolled epidemic as for example in the inland remote area of the brazilian mato grosso state, to the recent burst of epidemics in west and central africa including angola, drc, as well as imported cases in kenya and china [34, 35] . indeed, the risk of a pandemic exists if any imported case goes to an area where the fundamentals of emergence are present (i.e., aedes aegypti and a nonimmune human population). for years it has been stressed that yf coverage needs to be exhaustive in the endemic area, and the who international health regulations (ihr) need to be strictly respected when peoples are crossing frontiers to or from an endemic area [36] . even though the virus was known to actively circulate in asia, north america, and africa 200 years ago, a global pandemic of dengue fever began in southeast asia in the 1950s [37, 38] . dengue virus (denv) expansion was followed by the emergence of a dhf pandemic that occurred in the late twentieth century (see above, the "tire-mosquito larvae connection"). by the end of the century, dhf emerged in the pacific and the americas, and extended to all asian continents [32] . lately, in the 1980s, epidemic dengue fever occurs in africa, with a predominant activity in east africa, while sylvatic denv circulation was described in western africa [39] . the different dengue virus serotypes spread also independently to all continents. while it is remarkable that infection with one serotype does not provide cross-protective immunity against the others, epidemics caused by multiple serotypes became more frequent, and highly pathogenic denv were identified [40] . dengue fever to date has a global distribution with an estimated 2.5 billion people at risk. yearly, hundreds of thousands of dhf cases occur [32] . altogether, the requirements for a dhf pandemic are globally present [41] : the highly competent aedes aegypti and aedes albopictus denv vectors, the globally distributed denv serotypes and highly pathogenic strains, and finally, climate change that opens new breeding opportunities for these mosquitoes to expand and eventually transmit imported denv into new populations and territories [42] . mankind will have to live with this pandemic until the new denv vaccines can be implemented. in 1967, an unknown disease was reported by a group of laboratory workers in west germany and former yugoslavia [43] . over the course of 2 months, 31 cases and seven deaths occurred. conclusions made by treating physicians at the time (and published shortly thereafter) highlighted the following: high fatality rate, risk of relapse; risk of sexual transmission [38] . a connection was made to infected african primates, chlorocebus aethiops, when laboratory workers were exposed to their imported tissues. it took 43 years to effectively connect marburg virus, marv, to a bat, rousettus aegyptiacus, as a natural marv reservoir in central africa [44] . marv is considered to be extremely dangerous for humans, is classified as a risk group 4 pathogen, and also is listed as a select agent; however, the pandemic risk cannot be assessed because only four epidemics have occurred. although marv expansion appears to be limited to a few countries in africa, the recent emergence (estimated at a few decades ago) of a second human pathogenic marburgvirus known as ravn virus, and the widely distributed old world rousette fruit bats (rousettus spp.) serving as reservoir for both viruses [45] , are two factors that favor pandemic risk. although more than 35 years after its emergence from a remote area on the ebola river in the central african rain forest, ebola virus (ebov) remained hidden in a cryptic natural cycle. then a series of 23 outbreaks occurred in the large congolese rain forest of central africa [46] . the epidemic risk was always considered to be localized and circumscribed [47] . then, suddenly without warning, in the late months of 2013, ebov emerged for the first time in a remote area of western africa and sparked an outbreak more massive than ever witnessed before. more than 28,000 people were infected, ten countries recorded cases (transmitted or imported), the pandemic risk raised fear, and who declared it as an inter national health emergency that requires a coordinated global approach [48] . besides the lack of preparedness of national and international public health systems, the other major factor that played an immense role for the dispersion of evd in western africa was the extreme mobility of village populations. they followed the kissidougou forest foot-paths to the towns in guinea using motorbikes, cars, and other public transportation, then later evd traveled by plane to the global level. the evd epidemic went from outbreak to pandemic risk. like marburg virus, another member of the filoviridae, ebola virus, shares bats as a potential virus reservoir, human and nonhuman primates are highly sensitive to the virus, and inter-epidemic periods play an important role since the epidemic silences tend to diminish the attention of health services and increase epidemic risk. in this way, the first western african evd epidemic is exemplary for showing the hidden risks contained in the natural cycle of a virus, and the sudden emergence followed by an unprecedented velocity of spreading. in the absence of biosurveillance, a pandemic risk remains. hemorrhagic fever with renal syndrome, hfrs, appears first as a global concern of one virus family, several human pathogenic viruses of the genus orthohantavirus, multiple clinical presentations, and different epidemiological patterns [49] . hantaviruses and hfrs were first described in asia [50] ; nowadays, hantaviruses are the cause of zoonoses that are expanding worldwide. indeed, since 1993 when a previously unknown hantavirus was implicated in the first hantavirus pulmonary syndrome (hps) outbreak in the united states, several other hantavirus infections were reported in western europe, and then hantaviruses were described in south america. ultimately, after an early suspicion of the presence of the hanta viruses in africa [51] , a novel hantavirus, sangassou virus, was isolated in 2012 in guinea [52] . altogether we observed the emergence of the hantaviridae in the western hemisphere, from the old world to the new world, and recently discovered its first tentative steps on the african continent. with respect to the orthohantavirus genus, a real pandemic exists even when multiple viruses are involved. ultimately, as for the arenaviridae, hosts are specific and certainly the major vectors of virus dispersion. the arenaviridae includes 33 different viral species grouped as old or new world arenaviruses [53] , each is maintained by rodents of individual species as natural reservoir host and as vector for the viruses that are human pathogens. the rodent hosts are chronically infected without obvious illness and they pass virus vertically to their offspring. de facto, the distribution of the virus covers that of its natural hosts but is isolated in an ecosystem generally limited by natural barriers, e.g., mountains, river. a phenomenon in which rodent lineages are naturally infected by a virus and remain in such a limited environment is called "nidality" [54] . this is what it is observed for argentinian hf, venezuelan hf, bolivian hf, and lassa hf. regarding the pandemic risk of any of these hf, arenaviruses because of their strict association with their natural hosts, like the hantaviruses, have their expansion potential limited by their natural hosts even though the latter are widely spread and could certainly be infected. such risk lies in an unexpected encounter between infected and noninfected populations under the pressures of (as yet unknown) factors that favor their migration from enzootic to non-enzootic areas. in that matter, lymphocytic choriomeningitis virus, another member of the arenaviridae, has a worldwide distribution through its domesticated natural host, the ubiquitous house mouse, mus musculus. although crimean-congo hemorrhagic fever, cchf, is a widespread disease endemic to africa, the balkans, western asia, and asian countries south of the 50th parallel north, it is generally transmitted by ticks to livestock or humans and therefore geographically limited to regions where tick vectors feed on humans. although the competent ixodid vector is limited, as is the abundance of their natural hosts, climate change modifies the distribution and abundance of tick hosts (i.e., tick abundance) [55] . additionally the cchfv pandemic risk is limited by low mobility, geographical repartition, and seasonal activity, although its main natural hosts are widely dispersed from africa, to asia and europe [56] . ultimately, human-to-human transmission occurs from close contact with the blood, secretions, or other biological fluids of infected persons but these remain rare events with a r0 < 1. altogether, a cchf pandemic risk remains hypothetical but underlined by the risk of human-to-human transmission [57] . as for cchf, rift valley fever, rvf, is first a disease of cattle and illustrates a unique subcontinental zoonotic spread along the path of traditional herders. rvf became a transcontinental risk with trade and transportation when the virus spread from north east africa to western africa, and even to madagascar [58] . if one considers its pandemic risk, with respect to rvf epidemiology as a mosquito-transmitted disease, two factors have to play concomitantly: the presence of infected cattle (i.e., nonimmune) and competent mosquito abundance, both considered hazards, while concretizing the risks from human vulnerability (nonimmune; mosquito bite; direct exposure to infected blood). in order to streamline the prevention and the actions to reduce epidemic risk, the various elements involved in an outbreak are here considered from a systemic point of view, considering the risk as the convergence of a hazard and vulnerability: -the presence of the threat (or "hazard" pathogen, i.e., vector, virus reservoir) is considered to be a necessary-but not sufficient-condition for the development of a disease. it is often known only in terms of probabilities, sometimes very low and therefore often subject to significant random variability in time and space. we often seek to evaluate the spatial and temporal differences of this probability, trying to measure its significance. sometimes, it only uses one character necessary to the presence of the pathogen or vector (e.g., the presence of water, a minimum temperature, a type of vegetation). -the susceptibility of the host (which is essentially linked to individual characters, genetic, biological, such as immune status or age) is individual, and often given by a probability. -direct exposure of the host to the hazard is an element of active vulnerability, depending on the behavior of the host that increases the likelihood of contact between host and hazard by exposing it to an environment conducive to his presence (e.g., travel and contacts, professional activities). it also includes all the known "risk" behaviors that increase the likelihood of direct exposure to the hazard. -passive vulnerability of the host, which is not directly dependent on the pathology, is not even necessary nor sufficient for pathology, but influences the exposure of the host to the hazard or to protection from the pathology. this protection consists of prophylaxis, access to care, availability of care. it is independent of the real presence of the hazard; the host can be vulnerable without being exposed to the threat. the vulnerability is often defined by several levels (individual, context). it is very often "spatial" as linked to phenomena of segregation or spatial concentration. this is an area primarily studied by geography. ultimately, this vision can differentiate what is active, often subject to high variability, random in time and space (the emergence or the presence of hazards is often difficult if not impossible to control) from what is passive, generally situated among more stable population levels (sensitivities, exhibitions, behaviors, and vulnerabilities). this allows for better public health preventive actions, and also to understand rationally crisis situations by preemptively targeting the most important elements of the system in terms of vulnerability, and secondly by optimizing risk reduction (elimination of vectors, vaccinations, quarantine, etc.). in all cases, these actions must be adapted to social contexts to have a real impact on risk behaviors and vulnerabilities that they generate, hence the increasing role of anthropology in the field of health. to prevent or reduce the epidemic risk, it is necessary to act on each component of this system: -reducing the susceptibility of the host (e.g., immunization, vaccination, prophylaxis). -reducing host exposure to the pathogen (e.g., vector control, quarantine, exclusion zone). -eliminating the pathogen directly (e.g., animal slaughter, disinfection, hygiene), or indirectly (e.g., suppress transmission). -reducing host vulnerability (e.g., socio-economic, behavioral, access to health care system). -reducing host exposure to emergency condition (e.g., realtime data collection, warning systems for emergency, crisis management, implementation of treatment). the rapid detection of emergence is the key to controlling the spread of an epidemic. it requires comprehensive monitoring to trigger alerts and all other risk-reducing actions, in particular, reducing the exposure of the host to the pathogen and, if possible, the elimination of the pathogen. in parallel to the monitoring and warning systems, protocols must always take into account local characteristics of political power and decision-making bodies that could otherwise render ineffective year-long action plans or warning systems (for example, the management of the chikungunya epidemic in reunion island was largely impacted by bottlenecks related to local political system) [59] . biosurveillance and efficiency in data collection and management will be the technical keys for prevention (early detection of epidemic risk) and forecasting epidemic emergence and spread (i.e., analyzing the data in near real time taking into account the vulnerability of a given population). also, this can be achieved only by exhaustive capacity building (human and technical) mostly in the more vulnerable developing countries but also where the most advanced technology needs to be developed. networking biosurveillance systems are a major undertaking from regional to global, involving politics and diplomacy. taking in account the local characteristics of political structures and decision systems is fundamental. despite our current recognition of the risks posed by emerging and re-emerging infectious diseases to global public health and stability, reliable structured data remains a major gap in our ability to measure (and therefore manage) globally infectious diseases. who has long served as an information hub for infectious disease events worldwide; however, extracting quantitative data from who information bulletins (weekly epidemiological record and the more recent disease outbreak news alerts) proves to be a time-consuming effort with limited results in terms of operability, and exists more for the record and future analysis. the current proliferation of geospatial information tools (i.e., geographical information system, gis) and stepwise advances in data extraction capabilities have made it possible to develop robust, systematic databases facilitating anomaly detection (like clusters), infectious disease models (and model evaluation), and apples-to-apples comparisons of historic infectious disease events worldwide. however, biosurveillance capabilities-the key to global prevention and health securityremain inadequate to support true early detection and response. increased access to technology, rapidly developing communications infrastructures, smartphone usage for suspected-case reporting, and global networks of (formal and informal) disease surveillance practitioners provide an explosive opportunity to patch and improve surveillance networks. the challenge is to leverage all these developments, implement technical and capacity building where needed, before the next epidemic with global impact emerges. several organizations have developed systems to collect epidemic information and facilitate rapid response: who has the department of pandemic and epidemic diseases (ped) that develops mechanisms to address epidemic diseases, thereby reducing their impact on affected populations and limiting their international spread. among them some have self-explanatory titles: the battle against respiratory viruses (brave); early warning and response systems for epidemics in emergency (eware); emerging and dangerous pathogens laboratory network (edpln); international coordinating group for access to vaccines for epidemics (icg); global infection prevention and control network; (gipcn ); global influenza surveillance and response system (gisrs); global leptospirosis environmental action network (glean); meningitis environmental risk information technologies (merit); weekly epidemiological record (wer); emerging diseases clinical assessment and response network (edcarn). global commitment to these efforts will insure their readiness in times of need. most certainly and most importantly, any preparedness and response requires emergency funding [60] . it has been estimated that if the ebola virus disease response started 2 months earlier, it could have reduced the total number of deaths by 80% in liberia and sierra leone [61] . we learned from this last evd epidemic that in march 2015, the african union's minister of finance requested the african risk capacity (arc) agency to help member states to better plan, prepare, and respond to devastating outbreaks by developing new applications for financial tools, like insurance, that can significantly improve the speed of funds to affected countries and shorten the time between event and response. the agency is now developing an outbreak and epidemic insurance product primarily based on responsibly and timely budget reallocation; however, viruses do not wait. moreover, the world bank's pandemic emergency facility is designed to finance surge capacity and support international government partners to actively participate to the response. ultimately, epidemics are not one-off events, but rather demonstrate financial patterns similar to other natural catastrophes. as natural catastrophes, large epidemics can be insured by creating financial mechanisms to facilitate the movement of critical resources within affected countries and ultimately manage the spread of disease and minimizing macroeconomic impact [62] . classical tools and strategies for predicting epidemics encompass human disease surveillance (e.g., public health and hospital statistics) and, sometimes, environmental surveys (e.g., climate, el niño, earthquake, tsunami); also more recently complying with one health concept, human and veterinary health as well environmental risk factors have been reunited in a comprehensive approach of public health risk (i.e., outbreak, epidemic risks). however, this heuristic approach of health remains limited to specific diseases and territories and does not apply as a global predictor of pandemics. first, historical data is the only available objective view of past epidemics and pandemics, needs to be collected, formatted, corrected, and analyzed. this will be the foundation of the different tools and strategies described below. in that matter, with respect to the depth of the past data available, time series of disease observation, modern tools such as internet search data have actually led to the development of several specific sites (e.g., google flu and dengue) [63], whose search-term reports have correlated strongly with incidence estimates in several public health reports in europe, asia, and the u.s. however, even though such tools can complement classical disease surveillance, most of these sites are geographically limited and cannot be used for live monitoring of epidemic risk and for neglected tropical disease surveillance [64, 65] . however, from such historical and live-collected data, health alert systems can be implemented, and prediction models can be developed. moreover, thanks to the spatial analyses, combining multiple data sources will provide the ultimate tools for livemapping an outbreak, which will lead to an efficient response when tools and strategy have been specifically identified (i.e., sufficient and available in-country heath system resources and funding; identifying variations in pathogen sequences that contribute to ro and pathogenicity; monitoring population movement; etc.). the amount of data being digitally collected and stored is exponentially accumulating. it is estimated that, as of september of 2016, the world wide web reached 5.02 billion pages containing eight zettabytes of accessible data, and the accumulation of information is growing around 40% every year [66] . this situation has generated much discussion about how to use the unprecedented availability of information and computational resources and the sophistication of new analytic and visualization algorithms for decision-making to reduce the impact of infectious diseases. in fact, it is argued that the paradigm of "big data" will change not only the way business and research is done, but significantly improve the understanding of factors leading to the emergence of infectious diseases. big data could lead to the implementation of a decentralized biosurveillance enterprise allowing organizations and individuals to take full advantage of a large collection of disparate, unstructured qualitative, and quantitative datasets. with the proper integration and the right analytics, big data could find unusual data trends leading to better pathogen detection systems, as well as therapeutic and prophylactic countermeasures. however, the impact of these analyses and forecasts depends not only on how the data is collected, ingested, disambiguated and processed, but also on how it is relayed in different operational contexts to users with different backgrounds and understandings of technology. while impressive in data mining capabilities, real-time content analysis of social media data misses much of the factual complexity. quality issues within freeform user-provided hashtags and biased referencing can significantly undermine our confidence in the information obtained to make critical decisions about the natural versus intentional emergence of a pathogen. risk factors associated with a health event in a population are often linked to environmental factors (fig. 1) . they are also linked to spatial relationships between individuals, especially for infectious diseases. the geographical distribution of these phenomena reflects spatial relationships. beyond "classic" epidemiology mainly based on statistical analysis, using the location and spatial distribution is essential in the understanding of health events and analysis of their mechanisms. spatial analysis in epidemiology is a method to help determine the location (georeferenced) of risk factors. it allows one to identify the spatial and temporal differentiation in the distribution of events, using their location in time and space. when the location is available, with precision for each studied object (i.e., individuals or geographical units), it is possible to: -characterize the overall spatial distribution, using synthetic indices on the absolute position of an object, on the average spatial arrangement of objects or their values (grouping/ fig. 1 mapping environmental factors that have a major impact on insect vector population (i.e., mosquitoes and ticks). this map of laos constitutes the basis of a risk map showing part of the hazards contributing to virus vector density that could be matched with human density and pathogen prevalence leading to a risk map (spatial risk) and eventually extended through seasonality (temporal risk). mean temperature and mean rainfalls are interpolated as climatic conditions, as environmental factors influencing the presence of mosquitoes dispersion, spatial dependence, variogram measure of autocorrelation space). -look for characteristics of the overall shape of the phenomenon (tendency, shape), and search for a theoretical spatial distribution, or for a process to model the observed spatial distribution. -look for unusual places (geographical centers and source sites; aggregates; exclusions; hot spots, cold spots), and to study the spatial relationships at the individual level. -conduct spatiotemporal analysis: search index cases, reconstruction of paths, diffusion models, models of extinction, etc. -spatial analysis allows the development of applications for modeling epidemics, preparing warning systems, as well as crisis management systems, risk prevention and analysis systems, and vaccination campaigns. many tools for biomonitoring and prevention of epidemic risk have been developed (fig. 2) , as well as software tools to: (a) visualize spatial distributions. (b) synthesize and analyze position and spatial relationships between events (continuity, consolidation, attractionrepulsion, shape, centrality, displacement, diffusion processes). (c) to analyze the relationship between spatial distribution of attributed values and environmental characteristics of the phenomenon (environmental correlations). (d) to model the phenomena of emergence, dissemination, extinguishment of an epidemic. cluster detection, space-time analysis, and spatial integration with environmental and demographic data are widely used in such warning systems. multiple and complex factors are associated with the emergence and impact of pathogens in a given geographical area. therefore, public health analysts are confronted with the task to identify the likely, and unlikely, consequences and alternative critical outcomes of a given vhf outbreak. this requires the ability to monitor in near real time the dynamics of the geographical dissemination of these viruses in villages, cities, countries, continents, or the globe using new analytical techniques within the emerging field of genomicbased biosurveillance. this concept integrates microbial genotyping, next generation sequencing, metagenomics, big data and database analytics, and contextualized visualization to identify, characterize, and attribute known and unknown pathogens and generate estimates of how different contingencies will affect their impact [67] . a genomic-based biosurveillance system includes powerful microbial genomic characterization to rapidly identify a pathogen [67] . this characteristic makes a genomic-based biosurveillance a useful approach not only for public health but serves as a deterrence tool for intentional biological weapon development and deployment. the initial step consists of integration of signals generated by molecular-based assays and next generation dna sequencing and unbiased microbial characterization for pathogen source tracing, attribution and forensics. while each of these techniques has been discussed in the literature in detail [68] , the integration of this information can yield a more extended view of the scale of a pathogen outbreak. the development of high-throughput the exemplary case of the highly pathogenic avian influenza virus h5n1 in thailand. from the emergence of one imported case (red-filled circle), the pathway direction (arrowed green lines) of h5n1 infection in farms (yellow points) is reconstituted, using dates of infection and distance between farms. results show local spread with time-to-time medium distance jumps dna sequencing technologies (i.e., dna and cdna forms of rna viral genomes) is allowing the genomic characterization of previously unknown pathogens without relying on prior reference molecular information [69, 70] . this information is available within days, and even hours, of sample collection, and well before the development of animal infection models. because of their portability, this technology will become widely used in the next 5 years in routine clinical settings. however, to be clinically and epidemiologically relevant, dna sequences must be rapidly and effectively translated into actionable information defining pathogen characteristics (i.e., virulence or drug resistance), it must point to a source of origin, and discriminate a natural event from a manmade release [71] . while some government agencies are considering use of genomic information to develop next generation level-0 and level-1 detection/surveillance devices [72, 73] , there is no reference database where researchers can retrieve standardized genomic signatures and motif fingerprints to develop primer-, probe-, and antibody-based detection technology using reference moieties. the impact of genomic-based biosurveillance in public health and biodefense will not be fully realized until addressing the current impracticality of transferring the terabytes of genomic data generated by dna sequencing devices to a centralized architecture performing analysis operations, as that might take hours or even days. therefore, a new paradigm could emerge from encouraging the development of decentralized algorithms that first determine in situ the presence of pathogen-specific genomic signatures or motif fingerprints, summarize and relay the results into an operational biosurveillance metadata format for contextualized decision support. the localized data management, time, and space required for spatial analysis is performed by geographic information systems (gis). these are computer systems that manage large volumes of data and easily use the location to perform spatial analysis. most gis are not limited to data management functions, but also integrate multiple analysis tools, data transformation, and cartographic representation. these are for the most part complex applications with enormous features. the "gis" designation covers a wide variety of software projects built according to different technical options, functionality, and diverse performances. a gis is essentially a management tool (structure, organization, entry, storage), an analytical tool (statistical and geographical treatment, spatial analysis), and a communication tool (data visualization, descriptive mapping, thematic mapping, atlas). it is also a tool that allows the use of a spatial model for the simulation of a process, such as the development of an epidemic. gis facilitates the interface between modeling and simulation program, and the geographic database, and can ultimately take over the whole of access to spatial information needed by the modeling program. the gis should thus be at the heart of organizing the collection and processing of monitoring data. to ensure the management of this system, it is important to set up a body specifying all the collection, validation, processing and dissemination of information and results (alerts, risk modeling, near real-time dissemination of results). this body must be proposed and validated by political authorities, preemptively, to avoid further blockage and to ensure effectiveness in situations of epidemic crisis. mathematical modeling is a mathematical formulation of a parameter or risk; it depends on identified or hypothesized risk factors whose coefficients are determined by a statistical or heuristic analysis from historical or observed data with the use of r0, as a basic reproduction rate, to timely and spatially predict the spread-speed of an emerging outbreak. spatial-temporal modeling of health events can be seen as the final stage of the analysis. it is different from statistical modeling. despite using risk factors, it considers the epidemic phenomenon as a whole, taking into account the spatial relationships between agents (hosts, vectors, reservoirs, and pathogens), between individuals, and relationships between individuals and their environment. this model is thus useful for understanding and anticipating the epidemics, and can be generally used to classify individuals in different states (susceptible, infected, sick healed, immune) and to model the major phenomena that can change the state of an individual. however, when a model takes into account many phenomena, it can quickly become very complex. the vast majority of models are simplifications of assumed reality. two broad categories of methods are usually developed in modeling: -a deterministic approach, based on differential equations whose coefficients are adjusted from observed data, or monitoring data from epidemics. in this model, one can introduce stochastic types of components in the coefficients, studying the variability of observed data. taking no account of spatial relationships is difficult in these models, which deal in general populations, not individuals. -a nondeterministic approach, which is based on agents whose behavior is described by expertly determined rules (multiagent models). the status of each agent is calculated at each time step, from its behavior, environment, and relations between the agent and all other agents. these models take into account a more realistic description of the phenomenon, near the complex system finely describing reality. they allow us to consider spatial relationships in each time step. these models require intensive calculation, and their use is made possible by development of the power of computer calculations. let us first honestly address the fundamental questions about epdimeics and preparedness: what did we learn from all the past epidemics, what will we remember in times of need? are we prepared for the worst of these hypothetic pandemics abundantly illustrated in the cinema and unfortunately sometimes overwhelmed when reality goes beyond fiction? certainly, we are not "globally" prepared, unfortunately, at that scale, the immense natural and human disparities do not permit it, but we do our best in our own societies. the concept of disease emergence, born only at the end of the twentieth century, is a societal marker, our desire to be on alert, understand and predict epidemics. ultimately, there are a few, but necessary and difficult goals to reach for the prevention and control of any epidemic, also these goals are part of the development of our societies, as well as for education, they become part of the wellbeing for all: first, beyond understanding transmission, is needed a clear understanding of the epidemiological pattern and the spread of a given disease, before it is too late; then, which is certainly one of the more complex and costly things to achieve, is having an efficient health system to respond to an epidemic and an operational network to respond at the regional and global levels; and last but certainly not a least, having identified funding for any public health emergency will be crucial to changing our world. perhaps, in a shrinking global community, after too many ebola virus disease outbreaks, we will learn and be prepared for future epidemic challenges? the progress made, mostly by computer sciences in the overall analysis of health data, should serve as a tool in the prevention of major epidemics. let us ultimately use our predictions of pandemic risk to meet and unite beyond the current frontiers of political and social wills. epidemic predictions in an imperfect 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systems: challenges and opportunities biosurveillance observations on biowatch generation-3 and other federal efforts: testimony before the subcommittees on emergency preparedness, response, and communications and cybersecurity, infrastructure protection, and security technologies, committee on house homeland security, house of representatives congress. house (2012) committee on homeland security. subcommittee on emergency preparedness response and communications., united states. congress. house. committee on homeland security. subcommittee on cybersecurity infrastructure protection and security technologies., united states. government accountability office: biosurveillance observations on biowatch generation-3 and other federal efforts: testimony before the subcommittees on emergency preparedness, response, and communications and cybersecurity, infra structure protection, and security technologies, committee on house homeland security, house of representatives acknowledgments w.a. valdivia-granda has been funded by the department of homeland security and the department of defense. we are greatfull to sarah cheeseman barthel, director, data acquisition & management metabiota, inc., for her review and input of the section on "global surveillance and data collection." key: cord-353904-dieaqxmi authors: davies, m.; osborne, v.; lane, s.; roy, d.; dhanda, s.; evans, a.; shakir, s. a. title: remdesivir in treatment of covid-19: a systematic benefit-risk assessment date: 2020-05-12 journal: nan doi: 10.1101/2020.05.07.20093898 sha: doc_id: 353904 cord_uid: dieaqxmi background: there is a need to identify effective, safe treatments for covid-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. a systematic benefit-risk assessment was designed and conducted to strengthen the ongoing understanding of the benefit-risk balance for remdesivir in covid-19 treatment by using a structured method which uses all available data. methods: the benefit-risk action team (brat) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for covid-19 compared to standard of care, placebo or other treatments. we searched pubmed,google scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for covid-19. a value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance. results: several key benefits and risks for use of remdesivir in covid-19 compared to placebo have been identified. in one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, hr=1.23, 95% ci: 0.87, 1.75), although the study was underpowered. in another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). risk data were only available from one trial. this trial reported fewer serious adverse events in patients taking remdesivir (18%) comparted to the placebo group (26%), however more patients in the remdesivir group discontinued treatment as a result of an adverse event compared to those patients receiving placebo (12% vs 5%). conclusions: preliminary clinical trial results suggest a favourable benefit-risk profile for remdesivir compared to placebo, however there is limited safety data available at the current time. the current framework summarises the key anticipated benefits and risks for which further data are needed. ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment. coronaviruses are a cause of respiratory tract infections in humans [1] . a novel coronavirus emerged in wuhan, china in december 2019 [2] , subsequently called severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [3] . coronavirus disease (covid-19) is caused by sars-cov-2 [3] and since march 2020 this outbreak has been declared a pandemic by the world health organisation (who) [4] . fever, cough and shortness of breath are the main reported symptoms of covid-19 [5] but it also has a concerning case mortality rate among certain populations, such as older adults and those with underlying health conditions. currently, there is a need to identify effective, safe treatments for covid-19 as quickly as possible, due to the ongoing pandemic. one such proposed treatment is remdesivir, which is an investigational antiviral medicine with proven activity against rna viruses [6, 7] . remdesivir was originally developed for treatment of ebola virus disease and results from the phase 3 randomised clinical trial for this indication have been published [8] . it has been shown to have broad spectrum in-vitro activity against several coronaviruses, including sars-cov-2 [6, 9, 10] in-vivo activity against mers-cov in animal models [11, 12] , and has been made available for patients with covid-19 through compassionate use programmes [13, 14] . several clinical trials are ongoing to examine the effectiveness and safety of remdesivir in covid-19 in humans [15] [16] [17] [18] . most recently, remdesivir was granted an emergency use authorisation in covid-19 by the us food and drug administration. whilst there is considerable interest in the use of remdesivir for covid-19, there has not been a systematic benefit-risk assessment on the use of remdesivir for covid-19 treatment using a structured descriptive framework. the ongoing monitoring of the benefit-risk balance for remdesivir in covid-19 treatment is strengthened by use of a systematic assessment. the benefit-risk action team (brat) framework allows identification of the key benefits and risks of a product in a defined disease context within a structured descriptive framework; further quantitative assessments can then be applied and conducted according to the availability of relevant data at that time [19] . the brat framework was also specifically designed to assist communication with regulatory authorities [20] . the decision-making process is transparent due to the framework design, while any assumptions can be explored further by sensitivity analysis through a quantitative component [21] . this benefit-risk assessment has been conducted based on publicly available publications to date (data-lock april 30th 2020). it is however acknowledged that there is extremely limited data available at this timepoint. the benefit-risk assessment has been designed to be . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint implemented regardless of the quantity of data available, but the intention is that the framework will subsequently be readily available to repeat the assessment as further data arise, e.g. results from new and ongoing clinical trials, allowing for rapid decision-making. to examine the benefit-risk profile of remdesivir in covid-19 patients compared to standard of care, placebo or other treatments. the brat framework was used to assess the overall benefit-risk of using remdesivir as a treatment for covid-19 compared to standard of care, placebo or other treatments. brat uses a six step iterative process to support the decision and communication of a benefit-risk assessment: define decision context, identify outcomes, identify data sources, customise framework, assess outcome importance, and display and interpret key benefit-risk metrics [20, 21] . we identified three settings of interest for use of covid-19 treatments; treatment for severe disease, treatment of milder disease in the community, and prevention in health care professionals exposed to the virus. we have focused on the use of remdesivir for the treatment of severe covid-19 disease within this benefit-risk assessment. for the purposes of this study, we considered severe covid-19 to include any patient who was hospitalised as a result of the infection. the population of interest were patients with severe covid-19, while the exposure of interest was remdesivir. the comparators of interest were standard of care, placebo or other treatments for covid-19. regardless of importance, all potential benefits and risks related to remdesivir were initially identified. key benefits and risks were then selected by clinician judgement, which were those considered to drive the benefit-risk balance of remdesivir. the key benefits and risks were used to construct a value tree, ranking benefits and risks in order of considered importance. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint we searched pubmed, google scholar and government agency websites to identify suitable data for inclusion. the search strategy used was: remdesivir and (coronavirus or covid* or "sars-cov-2" or "2019-ncov") papers were included if they reported quantitative data on effectiveness and/or safety of remdesivir in patients with severe covid-19. case reports were excluded. results were restricted to english language only (abstracts in english language were acceptable where sufficient data was provided) and peer-reviewed publications (for pubmed and google scholar) since 2019 to 30th april 2020. where a control group was included, data were extracted for each benefit and risk, for both remdesivir and the comparator (standard of care, placebo or other treatments). a summary benefit-risk table was created to allow visualisation of the magnitude of each benefit and risk. risk differences and corresponding 95% confidence intervals (ci) were calculated for each outcome where both numerator (number of events) and denominator (number of patients at risk) were available for both the treatment group (remdesivir) and comparator group. due to paucity of data, a fully quantitative assessment was not undertaken. however, the risks and risk difference per 1000 patients were calculated for each benefit and risk. the outcomes identified in the value tree were ranked so that swing weighting can be applied in future assessments. the weighted net clinical benefit (wncb) can subsequently be calculated using these weights [21] [22] [23] . we would propose using the sutton et al method, where benefits have a positive contribution to the wncb and risks have a negative contribution [23] ; the overall wncb would be considered positive (benefit outweighs the risk) where wncb >0. a sensitivity analysis can also be used to examine the robustness of the assigned weights and whether significant changes would alter the benefit-risk profile [19] . analysis using wncb was not undertaken at this time due to the limited release of clinical trial data. figure 1 displays the value tree of the key benefits and risks related to remdesivir treatment in covid-19. the benefits included in the value tree include key endpoints included in clinical trial protocols for studies assessing the efficacy of remdesivir in severe covid-19 disease. as . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint remdesivir is currently not approved for use in any condition, it is acknowledged that its safety profile has not been completely characterised. for the purposes of identifying potentials risks associated with the use of remdesivir in covid-19 disease, safety data has been identified from currently available sources. these include studies reporting its use in the treatment of ebola virus disease [8] , cases series documenting the use of remdesivir in covid-19 disease [24] , and safety data included in the study by wang et al [25] . both the efficacy and safety outcomes have been presented in ranked numerical order according to perceived clinical significance. the . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint as remdesivir is an unapproved medicine in most countries, its safety profile has not yet been fully characterised. known key risks at the current time have been included in the value tree, identified from a variety of sources, including recently published clinical trial data in the context of covid-19 [25] . these have also been ranked according to perceived seriousness. cardiovascular outcomes including hypotension and arrhythmias have been documented following the use of remdesivir [8, 27, 24] , however the risk of cardiovascular outcomes with remdesivir remains largely unknown [28] . hypotension was reported in one patient in the phase 3 study investigating remdesivir in the context of ebola virus disease; this patient subsequently suffered a cardiac arrest, although the author states that this death could not readily be distinguishable from underlying fulminant ebola virus disease itself [8] . cardiac arrest was also reported in a further patient in the remdesivir group reported in the covid-19 study by wang et al [25] . multiple organ dysfunction, septic shock, acute kidney injury and hypotension have also been reported as adverse events amongst patients provided with remdesivir either on a compassionate-use basis, or in a clinical trial [24, 25] . respiratory failure or acute respiratory distress syndrome has been cited as an adverse event in patients taking remdesivir [25, 29] , and as such has been included here, although it is acknowledged that this may be related to underlying disease (covid-19), rather than to remdesivir. elevations in liver transaminases and gastrointestinal events, including diarrhoea, have also been reported with the use of remdesivir [13, 8, 24, 30] , in addition to reports of haemorrhage of the lower gastrointestinal (gi) tract [25, 31] . where available, clinical trial data relating to any efficacy or safety outcomes included in the value tree for both remdesivir and a comparator group were extracted and included in table 1 . based on this data, summary metrics including risks per 1000 patient years, and risk differences have been presented in table 2 . we identified 68 papers through literature searching from pubmed and 384 papers from google scholar. we also identified results from one clinical trial on the niaid website. after initial review, one paper and results from one clinical trial on the niaid website were included in the final benefit-risk assessment. in the wang et al trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, hr=1.23, 95% ci: 0.87, 1.75). in the niaid trial, a statistically significant shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days; p<0.001), with non-significant reduced mortality risk (8% vs 12%; p=0.059). other . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint non-significant benefit data were identified from the wang et al trial including invasive ventilation and oxygen use at day 28 (1% vs 4% and 12% vs 17%, respectively). risk data were only available from the wang et al trial, which reported fewer serious adverse events in patients taking remdesivir (18%) comparted to the placebo group (26%), however more patients in the remdesivir group discontinued treatment as a result of an adverse event compared to those patients receiving placebo (12% vs 5%). this benefit-risk assessment presented the currently known key benefits and risks for the use of remdesivir for severe covid-19 disease. the value tree provides a visual summary of these key benefits and risks, which have been ranked according to perceived clinical importance. as remdesivir is currently unlicensed in most countries, these include endpoints used in remdesivir clinical trials, and risks identified from available data sources. a literature search (including grey literature from government agency websites) identified relevant numerical data for these outcomes for both remdesivir, and comparator groups. recently, the first results from a randomised, double-blind, placebo-controlled clinical trial studying remdesivir in the context of covid-19 have been published [25] . the primary outcome suggested a reduction in the median time to clinical improvement, although this difference was non-significant (21 vs 23 days, hr=1.23, 95% ci: 0.87, 1.75). however, the planned sample size of 453 patients (151 on placebo and 302 on remdesivir) was not reached due to difficulties in enrolment, and therefore this study may have been underpowered to detect significant differences. nevertheless, multiple additional endpoints were included in this study, and these data have been presented in table 1 . whilst no statistically significant differences were observed between the remdesivir and placebo group [25] , the study reported generally improved outcomes in the remdesivir group compared to placebo, including reductions in mortality, risk of invasive and non-invasive ventilation, and need for supportive oxygen at day 28. data has also been presented for remdesivir and the placebo group included in the adaptive covid-19 treatment trial [26] . as of 29 th april 2020, limited data has been made available on the nih website [26] and suggested a statistically significant reduction in time to recovery from a median 15 days (placebo group) to 11 days (remdesivir group) (p<0.001). further study results provided suggested a non-significant reduced mortality risk amongst remdesivir patients (8.0%) vs. patients given placebo (11.6%), p=0.059, which equates to 40 fewer deaths per 1000 patients treated with remdesivir. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint key risks have been identified and included based on currently available evidence, however it is acknowledged that the safety profile of remdesivir has not been fully characterized. from risk data currently available, key risks were identified and ranked according to seriousness. the cardiovascular side effects of remdesivir are largely unknown; one patient in the study by wang et al was noted to have had a cardiac arrest. individual cases of multiple organ dysfunction syndrome and septic shock were also reported in this study [25] , whilst reports were also identified in patients receiving remdesivir on a compassion ate use basis [24] . in the latter case, reports of these events occurred in patients who were on invasive ventilation. whilst there were multiple reports of liver enzyme abnormalities in patients who received remdesivir in the study by wang et al [25] , three patients discontinued treatment as a result of liver enzyme elevation (two reports of raised alanine aminotransferase, one report of increased total bilirubin). reports of acute respiratory distress syndrome have also been reported as adverse events in patients taking remdesivir [25, 29] . sixteen patients experienced this outcome during treatment in the study by wang et al, [25] , which led to discontinuation in seven patients. finally, whilst fewer patients experienced an adverse event classified as serious in the remdesivir group (18%) compared to the placebo group (26%), a higher number of patients discontinued remdesivir as a result of an adverse event (12% vs. 5%) [25] . currently there would appear to be favourable efficacy results from patients treated with remdesivir in the context of severe covid-19 disease from these preliminary data available. the data in the study by wang et al [25] did not include any statistically significant results, although it is acknowledged that the study was underpowered. primary endpoint data available from the adaptive covid 19 trial [26] have also suggested a shorter time to recovery in patients treated with remdesivir, with non-significant reduced mortality risk. there is limited safety data available at the current time, although it is expected that this will increase as more clinical trial safety data becomes available. from the limited clinical trial safety data , it is unclear whether reports of serious adverse events are a function of the underlying severe covid-19 disease, or attributable to treatment with remdesivir. it is anticipated that both the efficacy, and the safety profile will be further strengthened in the coming months with the availability of additional clinical trial data. sample sizes for each outcome were limited to those available in the original studies and may not have adequate power to detect differences in risk between groups, especially where the outcomes examined were not the primary outcome of interest. the benefit-risk assessment is . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medrxiv preprint limited by the availability of data in the published literature. however, this assessment can be subsequently updated once further data from clinical trials are available. in addition, given the public health urgency of the covid-19 pandemic, it is important to provide a systematic assessment of the benefits and risks of remdesivir treatment with evidence available to date and establish a framework which can be used to rapidly update the assessment once further data become available. data quality is not reflected in this benefit-risk assessment, though all data was extracted from peer-reviewed manuscripts, with the exception of data included from the adaptive covid-19 treatment trial. these data were obtained from the niaid website, and included time to recovery and mortality data. since the full results of this clinical trial were not made available at the time of datalock (april 30 th 2020), a wncb analysis was not undertaken because there was a concern that only including efficacy outcomes from the adaptive covid-19 treatment trial may bias the wncb results. it is anticipated that such an analysis can be undertaken in the future when results are made available, to provide further evidence on the benefit-risk profile. confirmation of causality was not a requirement for inclusion of data in the brat assessment. patients may have been on other concomitant medications or had other medical conditions at the time of remdesivir treatment. finally, we considered hospitalisation of patients to reflect severe covid-19, but we acknowledge that severity of disease may vary regardless of hospitalisation. preliminary clinical trial results suggest a favourable benefit-risk profile for remdesivir compared to placebo, however there is limited safety data available at the current time. the current framework summarises the key anticipated benefits and risks for which further data are needed. ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. origin and evolution of pathogenic coronaviruses a novel coronavirus outbreak of global health concern naming the coronavirus disease (covid-19) and the virus that causes it who. who announces covid-19 outbreak a pandemic epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study pharmacologic treatments for coronavirus disease 2019 (covid-19): a review remdesivir is a direct-acting antiviral that inhibits rna-dependent rna polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. the journal of biological chemistry controlled trial of ebola virus disease therapeutics remdesivir, lopinavir, emetine, and homoharringtonine inhibit sars-cov-2 replication in vitro remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov prophylactic and therapeutic remdesivir (gs-5734) treatment in the rhesus macaque model of mers-cov infection summary on compassionate use: remdesivir gilead expanded access treatment protocol: remdesivir (rdv; gs-5734) for the treatment of sars-cov2 (cov) infection (covid-19) a phase 3 randomized study to evaluate the safety and antiviral activity of remdesivir (gs-5734â�¢) in participants with severe covid-19 study to evaluate the safety and antiviral activity of remdesivir (gs-5734â�¢) in participants with moderate coronavirus disease (covid-19) compared to standard of care treatment a phase 3 randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of remdesivir in hospitalized adult patients with mild and moderate covid-19 the (norwegian) nor solidarity multicenter trial on the efficacy of different anti-viral drugs in sars-cov-2 infected patients systematic benefit-risk assessment for buprenorphine implant: a semiquantitative method to support risk management a case study using the proact-url and brat frameworks for structured benefit risk assessment benefit-risk analysis: examples using quantitative methods a bayesian approach to evaluating net clinical benefit allowed for parameter uncertainty compassionate use of remdesivir for patients with severe covid-19 remdesivir in adults with severe covid-19: a randomised, double-blind, placebo-controlled, multicentre trial. the lancet national institute of allergy and infectious disease. nih clinical trial shows remdesivir accelerates recovery from advanced covid-19 cardiovascular complications in covid-19 position statement on the management of cardiac electrophysiology and cardiac implantable electronic devices in australia during the covid-19 pandemic gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe covid-19 care of patients with liver disease during the covid-19 pandemic: easl-escmid position paper journal of microbiology, immunology, and infection = wei mian yu gan ran za zhi death all-cause mortality -risk and time to death icu admission -invasive mechanical ventilation and/or ecmo, duration, time to icu clinical endpoints 5. other clinical outcomes -time to improvement or recovery, duration of hospitalisation 7. liver -elevations of transaminases renal -acute kidney injury, impaired renal function clinical endpoints 2. multiple organ dysfunction syndrome / septic shock viral load parameters -clearance rate (throat, sputum, nasopharyngeal swabs) 4. oxygen -number of patients requiring supplemental oxygen cardiovascular -arrhythmias, cardiopulmonary failure, hypotension non-invasive ventilation / high flow oxygen -duration, time to ventilation 8. gastrointestinal events -diarrhoea, haemorrhage of lower digestive tract 5. venous thromboembolism -pulmonary embolism, deep vein thrombosis 3. respiratory failure or acute respiratory distress syndrome 9 key: cord-356348-e7hefkd3 authors: kim, inho; lee, jia; lee, jihee; shin, eensuk; chu, chaeshin; lee, seon kui title: kcdc risk assessments on the initial phase of the covid-19 outbreak in korea date: 2020-04-17 journal: osong public health res perspect doi: 10.24171/j.phrp.2020.11.2.02 sha: doc_id: 356348 cord_uid: e7hefkd3 objectives: this study aims to evaluate the risk assessments of coronavirus 2019 (covid-19) in the korea centers for disease control and prevention (kcdc), from the point of detection to the provision of basic information to the relevant public health authorities. methods: to estimate the overall risk of specific public health events, probability, and impact at the country-level were evaluated using available information. to determine the probability of particular public health events, the risk of importation and risk of transmission were taken into consideration. kcdc used 5 levels (“very low,” “low,” “moderate,” “high,” and “very high”) for each category and overall risk was eventually decided. results: a total of 8 risk assessments were performed on 8 separate occasions between january 8(th) to february 28(th), 2020, depending on the detection and report of covid-19 cases in other countries. the overall risk of the situation in each assessment increased in severity over this period: “low” (first), “moderate” (second), “high” (third), “high” (fourth), “high” (fifth), “high” (sixth), “high” (seventh), and “very high” (eighth). conclusion: the kcdc’s 8 risk assessments were utilized to activate national emergency response mechanisms and eventually prepare for the pandemic to ensure the containment and mitigation of covid-19 with non-pharmaceutical public health measures. on december 31 st 2019, a cluster of pneumonia cases with unknown etiology was reported in wuhan city, china [1] . on january 11 th , 2020, the chinese authority identified a new type of coronavirus from 41 cases and isolated the nucleic acid of the pathogen [2] . the south china seafood market in wuhan city was thought to be the source of the outbreak, which remains under investigation. since then, the number of confirmed cases in china has rapidly increased, with the outbreak spreading to other countries. as of 5 th march 2020, a total of 89,253 confirmed cases of coronavirus-19 (covid-19), including 3,246 deaths, have been reported in 79 countries [3] . kcdc has officially established a risk assessment system since 2016 due to lessons learned from the 2015 middle east respiratory syndrome coronavirus (mers-cov) outbreak in korea. the initial format of the system was established using the overall structure of the european centre for disease prevention and control (ecdc) rapid risk assessment procedures, and updated and modified this based on the requirements of the institution. to estimate the overall risk of specific public health events, probability, and impact at the country-level were evaluated using the available information. for the probability of certain public health events, risk of importation and risk of transmission were taken into consideration. kcdc risk assessment was categorized into 5 levels ("very low," "low," "moderate," "high," and "very high"), and overall risk was determined [4] . the emergence of covid-19, which started as clusters of pneumonia with unknown etiology in china at the end of 2019, was unique and thus, a good example for kcdc to conduct a series of risk assessments to evaluate the potential risk of importation, transmission, and the impact at the country-level. the risk of importation and transmission were evaluated separately as covid-19 was a newly identified pathogen where information about the coronavirus was limited. predefined criteria triggered the kcdc risk assessment and enabled each risk assessment to be described in detail. since the beginning of the current covid-19 outbreak, 8 risk assessments have been conducted from january 8 th to february 19 th, 2020 ( figure 1 ; table 1 ). the first risk assessment was conducted on january 8 th , which was 8 days after the official date report of the outbreak in wuhan city. the overall risk of the situation was considered "low" in the first risk assessment. the risk of importation was estimated "very low" due to the immediate closure of the south china seafood market in wuhan on january 1 st . the risk of importation to korea was "low," but could not be excluded given the unknown nature of the respiratory pathogens and unknown human to human transmissibility. the impact of the outbreak was "low," as no fatal cases had been reported in china. the wuhan pneumonia task force was established on january 3 rd , and entry fever screening of flights from wuhan was initiated. a pancoronavirus laboratory diagnosis method was established on january 7 th . the second risk assessment was conducted on january 16 th , 9 days after the first assessment. the main triggers of this risk assessment were official reports of imported cases in thailand on january 13 th , and in japan on january 16 th . there was no evidence of human to human transmission until this time and no additional case had been officially reported in china since january 3 rd . the overall risk was escalated to "moderate" due to the increased risk of importation ("low" to "high") and transmission ("low" to "moderate"). the risk of importation was estimated as "high" because of the imported cases identified in thailand and japan, indicating a possibility of under-reporting of cases due to the unknown nature of the virus. the risk of transmission was also escalated due to the report of 1 potential family cluster in wuhan, and contact history with an unidentified pneumonia patient from japan. the impact was "low" as there had been only 1 fatal case who had underlying chronic conditions and the rest of the patients were in stable conditions. additionally, evidence of recovery of patients in japan and thailand also influenced the estimation. on january 11 th , the who confirmed that the pathogen was a novel coronavirus and a validated primer was distributed and diagnostic probe was made available from january 11 th . the third risk assessment was conducted on january 20 th , 4 days after the second risk assessment. beijing and shenzhen also reported confirmed cases. the risk of spread was not changed ("moderate") as no secondary transmission was officially confirmed. the impact was escalated to "moderate" as there was growing concern over the risk of additional cases, and human to human transmission. overall, the risk was escalated to "high" accordingly. meanwhile, updated case definitions were shared with provincial government and healthcare facilities on january 17 th . cluster of cases, the risk of infection in this specific province was evaluated and it was estimated as "very high" and also the risk of transmission to other provinces was "high." all other nationwide risk assessment results remained the same (risk of importation: "very high," risk of spread: "very high," impact: "high," overall risk: "high"). the last risk assessment was conducted on february 23 rd because of an exponential number of confirmed cases. as of this led to an increased impact on the risk estimation, and the overall risk was also increased to "very high" accordingly (risk of importation: "very high," risk of spread: "very high," impact: "very high," overall risk: "very high)." after this risk assessment, the national crisis management level was escalated to the highest level, level 4. risk assessment is one of the core functions of a national public health agency, and it has been conducted by many the elderly and those with underlying chronic illnesses are most susceptible to severe symptoms of the disease [5] . the risk of covid-19 ranged from "low" to "very high" in the risk assessments, based on the likelihood of transmission and the impact on society. given the available epidemiological and clinical characteristics, the korean population was deemed to be susceptible, and as more information became available, it was evident that virus transmission was rapid, and had the potential to be a major public health issue in korea. the rok risk assessment covered each phase of the outbreak, formats including social media, homepages, and press-releases. the ecdc evaluated the situation based on the chinese report, initially indicating a "low" likelihood of importation to europe [6] . the who indicated that the imported case in thailand did not prove human-to-human transmission as further information was required [7] . the key messages to the general public include prevention of infection and transmission, and preparation status of public health authorities. it also addresses multi-sectoral messages to relevant ministries/agencies and healthcare workers. communication can use all available formats including social media, homepages, and press-releases. ecdc evaluations are escalated when the likelihood of importation to europe is "low" to "moderate," and likelihood of importation to neighboring asian countries is "high," and human-to-human transmission cannot be excluded [8, 9] . the who's risk assessment showed that china's risk is "very high," while the risk of the asia region is "high," and human-to-human transmission is occurring [10] . to "moderate," and likelihood of importation to neighboring asian countries as "high." infection contracted in hospital was considered a "low" risk when appropriate infection prevention and control measures were in place [9] . the who evaluates risk in china as "very high" and the asia region's risk as "high." the who proposed that super-spread events may occur with human-to-human transmission among family members, and healthcare workers [10] . risk assessment 7 described a situation with distinct local outbreaks. there was sustained local transmission in korea. the objective was to mitigate the impact of the outbreak by decreasing general admissions to the hospitals and clinics to protect the general population from contracting the disease. in this situation, communication should be conducted daily. messages should be balanced and focused on prevention and treatment. it also provides detailed routes of confirmed cases ecdc evaluations are escalated from likelihood of importation to europe as "moderate" to "high," and the impact of the disease as "high," and human-to-human transmission may lead to widespread community transmission [11] . the who assesses the situation that several countries show local humanto-human transmission [10] . risk assessment 8 dealt with a situation with widespread sustained transmission in a korean province (daegu-gyeongbuk province) and distinct local outbreaks in other regions of korea. the healthcare system was overburdened. icu capacity was strained. the workers suffered from exhaustion, and staff numbers, ppe, and diagnostic testing capacity became insufficient. the objective was the same as risk assessment 7. at this stage, the communication of risk was to ensure close collaboration of the general public with public health authorities, and healthcare providers is essential. individual, religious, and societal concerns about death need to be considered. there are several limitations in this study. firstly, the information in the early phase of the covid-19 outbreak was preliminary and very limited, mainly since covid-19 was a new emerging disease, and data from the chinese government was the main source of information of this novel coronavirus. thus, we conducted several risk assessments with the ongoing available evidence, in a very short period of time as the situation evolved rapidly. therefore, the estimation was very likely to be subjective in nature. secondly, the risk assessment tool was not strictly applied to this novel pathogen as critical information was missing and had to be estimated with limited confirmed evidence. thus, initial evaluation of this virus pathogenesis was likely to be subjective, and was the one of major factors that needed to be considered when conducting the risk assessment. once more scientific evidence and knowledge becomes available after the end of this pandemic, overall review procedures and evaluation mechanisms need to be developed to improve and to minimize the limitations of the existing risk assessments by the korea cdc. there was no conflicts of interest to declare. notice of situation on pneumonia of unknown etiology novel coronavirus (ncov-2019) situation report-1 coronavirus disease (covid-19) situation report-45 risk assessment tool report of the who-china joint mission on coronavirus disease 2019 (covid-19) european centre for disease prevention and control novel coronavirus-thailand (ex-china) rapid risk assessment: cluster of pneumonia cases caused by a novel coronavirus risk assessment: outbreak of acute respiratory syndrome associated with a novel coronavirus novel coronavirus (2019-ncov) situation report-3 risk assessment: outbreak of severe acute respiratory syndrome coronavirus 2 (sars-cov-2): increased transmission beyond china -fourth update we acknowledge all the efforts and hard work of staff in the kcdc in responding to covid-19. key: cord-355118-w3l4h5y4 authors: sharif, ali; jendle, johan; hellgren, karl-johan title: screening for diabetic retinopathy with extended intervals, safe and without compromising adherence: a retrospective cohort study date: 2020-11-09 journal: diabetes ther doi: 10.1007/s13300-020-00957-0 sha: doc_id: 355118 cord_uid: w3l4h5y4 introduction: screening for diabetic retinopathy (dr) prevents blindness through the early detection of sight-threatening retinal microvascular lesions that respond to timely local treatment. however, the provision of easy and regular access to dr screening programs is currently being challenged by the increasing prevalence of diabetes. one proposed solution is to extend the screening interval for patients at low risk for progression of retinopathy. to date, most providers of screening programs have hesitated to implement a strategy of extended intervals due to the lack of data on whether adherence and safety are compromised when retinal examinations occur less frequently. in the study reported here, we investigated adherence to the screening program and progression of retinopathy in patients with type 2 diabetes participating in a dr screening program with extended intervals. methods: this was a retrospective study that included 1000 patients with type 2 diabetes mellitus who attended a screening program for dr. the patients were consecutively placed into a low-risk patient cohort with no retinopathy or into an intermediate-risk patient cohort with mild retinopathy (each cohort n = 500). screening intervals were 36 months for the low-risk cohort and 18 months for the intermediate-risk cohort. results: the 1000 subjects enrolled in the study had a median age of 68 (interquartile range 12) years and 60.4% were men. at the follow-up screening visit, data on 102 subjects were not included in the analysis of adherence rate due to death, severe systemic illness, other concurrent eye disease or migration. among the 898 remaining subjects, adherence to the screening program was 93.7% (413/443) in the 36-month group and 98.3% (449/455) in the 18-month group (p < 0.0001). non-adherence decreased with increasing age (odds ratio 0.92, 95% confidence interval 0.888–0.954, p = 0.0005). at follow-up, 65 subjects showed progression of retinopathy; none had worse than moderate retinopathy. risk factors for dr and treatment for hyperglycemia, hypertension and hyperlipidemia were compared among subjects in the low-risk cohort: non-adherent subjects did not differ from their adherent counterparts without progression of dr, but the former had a shorter duration of diabetes and higher diastolic blood pressure than adherent subjects with progression of dr (4.5 vs. 7.5 years, p = 0.007; and 80 vs. 75 mmhg, p = 0.02, respectively). conclusion: the results suggest that screening dr at extended intervals can be achieved with high adherence rates without compromising patient safety. however, younger subjects and those at higher risk of progression may require extra attention. methods: this was a retrospective study that included 1000 patients with type 2 diabetes mellitus who attended a screening program for dr. the patients were consecutively placed into a low-risk patient cohort with no retinopathy or into an intermediate-risk patient cohort with mild retinopathy (each cohort n = 500). screening intervals were 36 months for the lowrisk cohort and 18 months for the intermediaterisk cohort. results: the 1000 subjects enrolled in the study had a median age of 68 (interquartile range 12) years and 60.4% were men. at the follow-up screening visit, data on 102 subjects were not included in the analysis of adherence rate due to death, severe systemic illness, other concurrent eye disease or migration. among the 898 remaining subjects, adherence to the screening program was 93.7% (413/443) in the 36-month group and 98.3% (449/455) in the 18-month group (p \ 0.0001). non-adherence decreased with increasing age (odds ratio 0.92, 95% confidence interval 0.888-0.954, p = 0.0005). at follow-up, 65 subjects showed progression of retinopathy; none had worse than moderate retinopathy. risk factors for dr and treatment for hyperglycemia, hypertension and hyperlipidemia were compared among subjects in the low-risk cohort: non-adherent subjects did not differ from their adherent counterparts without progression of dr, but the former had a shorter duration of diabetes and higher diastolic blood pressure than adherent the increasing prevalence of diabetes places stress on screening programs for diabetic retinopathy (dr). a strategy of extended intervals in screening programs for dr would ease the workload, but there has been hesitation in implementation due to concerns of comprising patient adherence and safety. no previous study has reported on how subjects with diabetes adhere to dr screening at different interval lengths. what was learned from the study? there was high patient adherence to dr screening with extended intervals of up to 36 months. non-adherence decreased with increasing age. incidence and progression of dr was low among subjects in the screening program. stratifying patients to extended intervals based on absence/presence of mild dr appears to be a safe strategy. screening for diabetic retinopathy (dr) is recommended by the world health organization since such evaluations have been shown to prevent blindness through the timely detection of sight-threatening dr (stdr) that can respond to local eye treatment [1] . screening intervals of up to 1 or 2 years are generally recommended for patients with type 2 diabetes patients (t2dm) with mild or no dr [2, 3] , but it has been suggested that extending screening intervals beyond the recommended time spans would be cost-effective and help avoid unnecessary controls [4] [5] [6] [7] . however, a common concern among healthcare professionals has been that adherence may be poorer when intervals are longer than 1 year [8] [9] [10] [11] [12] , although to date no study has reported on how subjects adhere to screening at different interval lengths. taking into account that most diabetes patients have t2dm and that the majority of these individuals do not have retinopathy and are at low risk of progression to stdr [13] , extending control intervals for this population is likely to substantially reduce the workload in screening programs. we hypothesized that adherence to screening for dr in t2dm would be no worse for individuals at low risk of progression to stdr and scheduled for a longer screening interval than for those at intermediate risk and assigned to a shorter screening interval. to test our hypothesis, we accessed data on two representative cohorts with t2dm assigned to screening at a 36-or 18-month interval, respectively, based on the absence or presence of mild dr. this retrospective cohort study included 1000 patients participating in the screening program in värmland county, sweden. this program represents the only dr screening program performed in the county (population 280,000), where 16,000 individuals have been diagnosed with type 1 diabetes (t1dm) or t2dm. in this screening program, a patient with t2dm is assigned a 36-or 18-month screening interval based on the absence or presence of mild dr, in accordance with guidelines from the swedish national board of health and welfare [14] . the study followed the tenants of the declaration of helsinki and was approved by the regional ethical review board, uppsala, sweden (registry no. 2017-092). consent of participants to publish was not necessary as no patient-identifying data were presented. inclusion criteria were t2dm, age 18-79 years and no or mild dr. two cohorts (each n = 500) were consecutively selected from patients with t2dm participating in the screening program, with a follow-up visit planned during the same period. subjects in one cohort had no dr and were subsequently assigned a 36-month screening interval; this cohort was designated the low-risk cohort. subjects in the other cohort had mild dr and were subsequently assigned an 18-month interval; this cohort was designated the intermediate-risk cohort. the screening program is provided by region värmland which is responsible for the county's publicly funded health care. the program is open to all patients with diabetes from the age of 10 years. the screening is provided at multiple (four different access points) separate locations in the region, and the patients are generally allocated to the closest available screening location. each screening visit includes dilation of pupils and fundus photography, performed by a specially trained nurse using a topcon trc-nw8 retinal camera (topcon corp., tokyo, japan), which captures two redfree 45-50°images per eye centered on the fovea and the optic disc. the program uses a telemedicine platform, with images sent electronically to one center within the region for evaluation by trained graders using imagenet i-base software version 3.18.3 (topcon europe medical bv, essebaan, the netherlands). the images are graded according to the international clinical diabetic retinopathy (icdr) severity scale [15] . each patient's diabetologist/general practitioner receives feedback via the electronic medical records (emr) system on the current grade of the patient's retinopathy. any patient failing to attend a screening visit is sent a letter of reminder to schedule a new appointment. the treating diabetologist/general practitioner is also notified via emr, encouraging a mutual dialogue with the patient on diabetes and dr. the endpoint for our study was defined as the proportion of patients attending the followup screening appointment. attendance rate was calculated as the total proportion of subjects present at the follow-up screening visit, regardless of reasons for loss to follow-up. adherence rate was calculated after subtracting patients not attending due to the following specified reasons: death, severe systemic illness, rescheduling due to other concurrent eye disease or migration from the region. patients without these specified reasons for not attending were defined as non-adherent if they had failed to reschedule within 3 months after the first given appointment. the primary aim was to explore adherence rates in the two cohorts. secondary aims were to analyze whether the number of previous visits in the program was correlated to non-adherence and to analyze differences in risk factors for dr and treatment for diabetes and complications among non-adherent and adherent subjects. data on the level of retinopathy, the number of previous screening visits and the shortest travel distance from patients' residences to the allocated screening service were acquired from emr at the grading center. characteristics such as age, gender, diabetes duration, hemoglobin a1c (hba1c), systolic and diastolic blood pressure (bp) and treatment for diabetes and hypertension were acquired from the swedish national diabetes registry (ndr). the sample size was calculated to determine whether adherence at the follow-up visit was not poorer in the low-risk cohort than in the intermediate-risk cohort with an expected adherence of 90%, a power of 80%, a least detectable difference in adherence of 5% and an attrition rate of 10% [16, 17] . differences in baseline data between the main cohorts were analyzed using t tests or the mann-whitney u test. difference in adherence between the low-risk and intermediate-risk cohorts was tested using the chi 2 -test. a multiple logistic regression was performed to analyze if non-adherence was affected by the number of previous screening visits, controlling for demographic factors, including age, gender and distance to screening center. differences in risk factors for dr and treatment for diabetes, hypertension and hyperlipidemia between non-adherent subjects, adherent subjects without and adherent subject with progression of dr were analyzed using fishers exact test or kruskal-wallis test with holm-bonferroni correction of p values. where data is not normally distributed, values given are the median and interquartile range (iqr). p values of b 0.05 were considered to be significant. analyses were conducted using ibm spss statistics version 26.0 (ibm corp. armonk, ny, usa). the 1000 t2dm patients included in this study had a median age of 68 (iqr 12) years, and 60.4% were men. an hba1c value \ 7.0% (53 mmol/mol) was present in 57% of subjects. in total, 381 subjects were c 70 years, among whom 52.2% had a blood pressure (bp) \ 140/ 90 mmhg. of the remaining 619 subjects, 41.5% had a bp b 130/80 mmhg. compared to the patients in the intermediate-risk cohort, those in the low-risk cohort were younger (p \ 0.0001, mann-whitney u test), had shorter diabetes duration (p \ 0.0001), lower hba1c (p \ 0.0001) and less pharmacological treatment for diabetes (p \ 0.0001, chi 2 -test), hypertension (p = 0.0001) or hyperlipidemia (p \ 0.0001). baseline characteristics of the patients are presented in table 1 . of the 1000 patients enrolled in the study, 864 attended their follow-up screening visit, representing an overall attendance rate of 86%. of the 136 who did not attend their follow-up screening visit, 102 had specific reasons for nonattendance. despite the difference in time to follow-up between the low-risk and the intermediate-risk cohort, namely 36 versus 18 months, there was no significant difference between the cohorts in terms of the number of subjects with specified reasons for not attending follow-up (57/500 and 45/500, respectively; p = 0.21) (fig. 1 ). after adjusting for the specified reasons for non-attendance, 898 patients were eligible for further analysis of adherence; of these 34 were non-adherent and 864 were adherent, representing an overall adherence rate of 96.2% (864/898). in the low-risk cohort (n = 443), the proportion of adherent subjects was 415/443, corresponding to an adherence rate of 93.7% (95% confidence interval [ci] 0.91-0.958). in the intermediate-risk cohort (n = 455) the proportion of adherent subjects was 449/455, corresponding to an adherence rate of 98.7% (95% ci 0.972-0.995) (fig. 2a) . based on these findings, a smaller proportion of subjects were adherent in the lowrisk cohort compared to the intermediate-risk cohort (p \ 0.0001, chi 2 -test). too few subjects (6/455) were non-adherent in the intermediate-risk cohort to perform any further statistical analyses. the number of previous screening visits or the travel distance to the allocated screening center did not correlate to non-adherence ( table 2) . age was the only factor significantly associated with non-adherence. non-adherence decreased with older age (odds ratio [or] 0.92, 95% ci 0.888-0.954; p = 0.0005). the median age of non-adherent and adherent subjects was 52 (iqr 18) years and 65 (iqr = 13) years, respectively (fig. 2b) . both cohorts had their follow-up screening visit during the same 6-month period. on average, subjects in the low-risk cohort were screened 12 ± 42 days after the planned 3-year follow-up visit and subjects in the intermediaterisk group were screened 12 ± 39 days after the intended 18-month follow-up visit. one year after the scheduled follow-up, only two of the 34 non-adherent subjects had rescheduled a retinal examination. photographs taken at the follow-up visit were ungradable due to media opacities for only one subject in the intermediate-risk group. incidence/progression of dr had occurred in 65 patients. in the low-risk cohort, with no dr at baseline, retinopathy occurred in 40/415 subjects (9.6%), of whom 36 had mild and four had moderate dr; none of these 40 subjects exhibited any signs of diabetic macular edema. in the intermediate-risk cohort, with mild dr at baseline, progression of retinopathy was observed in 25/449 subjects (5.6%), with all 25 having progressed to moderate dr. in four of these 25 patients, hard exudates were evident in the macular region. at a subsequent evaluation, those subjects had normal visual acuity (20/20) , showed no evidence of retinal thickening and did not require local eye treatment. risk factors for dr and treatment for hyperglycemia, hypertension and hyperlipidaemia were compared among non-adherent subjects whose dr status was unknown, adherent subjects without dr and adherent subjects with dr, all in the low-risk cohort (table 3) . nonadherent subjects differed from adherent subjects with dr in terms of median diabetes duration (4.5 vs. 7.5 years, respectively; p = 0.009, kruskal-wallis test), median diastolic bp (80 vs. 75 mmhg, respectively; p = 0.009) and the proportion of subjects with anti-hyperlipidemic treatment (36 vs. 78%, respectively; p = 0.006). non-adherent subjects did not differ from adherent subjects in terms of hba1c level or systolic bp. adherent subjects with dr differed from those without dr in terms of duration of diabetes (median 7.5 vs. 5.0 years; p = 0.005) and hba1c (6.9 [52] vs 6.5% [48 mmol/mol], respectively; p = 0.01). extended intervals for dr screening have been extensively debated due to a lack of information on whether adherence is negatively affected if screening events are performed less frequently [8] [9] [10] [11] [12] . we investigated adherence in 1000 patients with t2dm participating in a dr screening program, applying extended intervals of 36 and 18 months for patients at low-or intermediate-risk of dr progression, respectively. the total adherence was 96.2%, and no patient showed progression to more than moderate non-proliferative dr. the results of this study refuted our hypothesis by showing that adherence was poorer in the low-risk cohort. nonetheless, our findings do demonstrate that dr screening with extended intervals can be performed on t2dm patients while safely achieving high adherence. this observation supports a transition to screening programs with a more favorable cost-utility profile in which unnecessary control visits are avoided. the adherence rates for the low-risk cohort (93.7%) and the intermediate-risk cohort (98.7%) are higher than rates observed in previous investigations, which range from 71 to 91% [16, [18] [19] [20] [21] . only two of the cited studies exclusively included patients with t2dm fig. 2 a the proportion of adherent (blue) and nonadherent (orange) patients participating in the diabetic retinopathy (dr) screening program. the majority of subjects were adherent, but the proportion of nonadherent patients was 5% higher in the low-risk cohort (without dr at baseline) assigned a 36-month screening interval compared to the intermediate risk cohort (with mild dr at baseline) assigned an 18-month screening interval. b violin plots with overlaid box plots of age in adherent (blue) and non-adherent (orange) patients in the low-risk cohort. compared to adherent subjects, the nonadherent subjects were younger (median age 52 vs. 65 years, respectively) [16, 20], but none of the subjects evaluated in those investigations had retinopathy. the authors of one of those two studies reported that 87% of subjects scheduled for annual examinations had at least one screening event over a 4-year period [20] , but they did not provide the specified reasons for non-attendance, which may partly explain the higher rate of adherence in our study. the second study used an extended screening interval of 3 years, and an adherence rate of 91% was observed [16] , which is close to that noted in our investigation. the high adherence rates we report from the screening program in our study may also be explained by having implemented a panel of interventions reported to be favorable for dr screening [22] . these interventions include facilitating retinal examinations by multiple access points, using telemedicine, giving feedback to diabetologists and general practitioners and sending reminders to patients who failed to attend their follow-up visit. furthermore, the ndr provides open access for benchmarking within the region and across the country [23] . although adherence at the follow-up visit was excellent in both cohorts, it was 5% lower data are presented as the median with the iqr in parenthesis or as a number with the percentage in parenthesis dr diabetic retinopathy indicates significant differences at p \ 0.05 between non-adherent subjects and adherent subjects with dr at follow-up. à indicates significant differences at p \ 0.05 between adherent subjects without dr and adherent subjects with dr in the cohort with a 36-month screening interval than in the cohort with an 18-month screening interval (93.7 vs. 98.7%). in our study, we assessed adherence at the next planned follow-up screening event, and it is possible that the difference in adherence rate will diminish over time, since the intermediate-risk cohort will have to adhere to the screening program twice as often as the low-risk cohort. the difference in adherence may also be explained by age and the absence or presence of retinopathy. our cohorts were defined based on the absence or presence of mild retinopathy, where those with mild retinopathy were slightly older. adherence to retinal examinations has been reported to be better in subjects with retinopathy than in those without this diabetic complication [21, 24, 25] . also, adherence has been found to be higher in patients of older age [19, 24, 26] . in line with these previous findings, we found that non-adherence decreased with older age. we also found no association between adherence and distance to screening center, which is similar to results previously reported, suggesting that the level of accessibility offered in our setting was acceptable [19, 21] . adherence was not found to be affected by the number of previous screening visits, suggesting that patients also comply alike to recurrent visits with extended intervals. the incidence of any retinopathy over the 3-year screening interval in the low-risk cohort was 9.6%, with none of the affected subjects showing disease progress to stdr. previous reports on screening dr in patients with t2dm have indicated the incidence of any dr to be between 16.7 and 28% over 3 years [5, 16] and 36% over 4 years [20] . glycemic control was only reported in one of these studies [16], and we compared our values with those cited in that investigation: in comparison, fewer patients in the present study were without glucose-lowering drug treatment and a majority of subjects met the treatment targets for glycemic control [27], thus possibly achieving better glycemic control. this may explain the lower incidence and non-occurrence of stdr in our study. furthermore, bp levels were not reported in any of the earlier studies, and almost half of the patients in our study met the targets for bp, indicating that these patients were well controlled [27] . our results indicate a very modest progression of retinopathy in both cohorts, suggesting that it can be possible to conduct a safe and effective screening program even with screening at intervals of [ 1 year . with regards to safety in the current healthcare environment, healthcare providers also need to consider risk factors for severe coronavirus disease 2019 infection as many patients with diabetes have multiple risk factors for covid-19, such as older age, male gender, obesity and hypertension [28] . in this perspective, extending intervals for screening dr may reduce unnecessary exposure of vulnerable patients to severe acute respiratory syndrome coronavirus 2 (sars-cov-2). our study had several strengths. first, the consecutive inclusion of patients provided a representative sample of patients. second, only subjects with t2dm were included, after considering differences between t1dm and t2dm with regards to demography, incidence of dr and intensity of diabetic treatment and monitoring [29] [30] [31] . third, a clear definition of nonadherence was used, determined as disregarding a screening visit and not making a new appointment within 90 days of the first scheduled follow-up appointment. as only 6% of the non-adherent subjects had re-entered the screening program 1 year after failing to attend their follow-up visit, the 90-day window for rescheduling reflected non-adherence for at least 1 year. fourth, assessed clinical parameters were from the ndr. these have high validity [32] . also, ndr data were complete at a level of [ 95% for any analyzed variable of patient characteristics. our findings should also be viewed in light of the limitations to the study. a retrospective design may suffer from selection bias, but such an effect may have been minimized in our study by the consecutive inclusion of patients in each cohort. to avoid any seasonal differences in accessibility to the screening program, the follow-up visits for the two cohorts were scheduled during the same period. we consider our catchment area as favorable in terms of minimizing selection bias because this region has only a single provider of dr screening to cover the population and also has a low migration rate [33] . regional differences in deprivation may also introduce bias, as indicated by previous reports showing poorer adherence to screening among patients with low socioeconomic status [21, 29, 34, 35] . public health in the studied region is similar or only slightly inferior to the swedish national average [36] ; therefore, we do not believe that the adherence rates in our investigation were overestimated due to socioeconomic and demographic differences. however, our data may not be representative for populations with poorer glycemic control. also, our study did not include patients with more severe retinopathy or t1dm, or elderly patients aged c 80 years, and hence it may be valuable to focus on these subgroups in future studies of adherence to dr screening. with an increasing prevalence of diabetes, effective and safe screening for dr is a pressing issue. considering that [ 90% of all individuals with diabetes have been diagnosed with t2dm, and the majority of these subjects have only mild or no retinopathy [13] , extending the screening intervals for these patients will have a substantial positive impact on the effectiveness and costs of screening programs. one strategy to accomplish this is to stratify patients based on retinopathy (i.e. such as the stratification used in the present study). another potential strategy is to optimize intervals based on individual risk using several risk factors for progression of dr [37, 38] . when such strategies are implemented, prospective studies controlling for age and risk factors for progression of dr could examine whether the length of intervals has any impact on adherence. it is plausible that earlier concerns that extended intervals lead to poorer adherence can turn out to be the opposite, with patients being less adherent if screening is performed too often. however, based on the present study in which real-life data from a well-established screening program were analyzed, it can be concluded that it is possible to screen for dr with extended intervals of up to 3 years and still achieve excellent adherence. disclosures. the authors ali sharif, johan jendle and karl-johan hellgren declare that they have nothing to disclose. compliance with ethics guidelines. the study followed the tenants of the declaration of helsinki and was approved by the regional ethical review board, uppsala, sweden (registry no. 2017-092).consent of participants to publish was not necessary as no patient-identifying data were presented. data availability. the datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. open access. this article is licensed under a creative commons attribution-noncommercial 4.0 international license, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated 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healthcare quality registries migration by region, age and sex divergent perceptions of barriers to diabetic retinopathy screening among patients and care providers factors determining uptake of diabetic retinopathy screening in oxfordshire public health agency of sweden. ö ppna jämförelser folkhälsa open comparisons public health 2019 (swedish) individual risk assessment and information technology to optimise screening frequency for diabetic retinopathy individualised variable-interval risk-based screening for sight-threatening diabetic retinopathy: the liverpool risk calculation engine the authors thank the swedish national diabetes register (ndr) and the department of ophthalmology, karlstad hospital, sweden, for contributing to the acquisition of data. authorship. all named authors meet the international committee of medical journal editors (icmje) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.authorship contributions. as organized the project, collected the data, analyzed the data, wrote the manuscript draft, edited the manuscript and approved the final draft. jj edited the manuscript and approved the final draft. k-jh accessed the data from the ndr, edited the manuscript and approved the final draft. jj and k-jh designed the project. k-jh is the guarantor of the study.prior presentation. parts of this work were presented at the 28th meeting of the european association for the study of diabetes eye complication study group, belfast, northern ireland, may 25-26th, 2018. key: cord-009729-69swjzic authors: nan title: scientific opinion on the public health hazards to be covered by inspection of meat from sheep and goats date: 2013-06-27 journal: efsa j doi: 10.2903/j.efsa.2013.3265 sha: doc_id: 9729 cord_uid: 69swjzic a risk ranking process identified toxoplasma gondii and pathogenic verocytotoxin‐producing escherichia coli (vtec) as the most relevant biological hazards for meat inspection of sheep and goats. as these are not detected by traditional meat inspection, a meat safety assurance system using risk‐based interventions was proposed. further studies are required on t. gondii and pathogenic vtec. if new information confirms these hazards as a high risk to public health from meat from sheep or goats, setting targets at carcass level should be considered. other elements of the system are risk‐categorisation of flocks/herds based on improved food chain information (fci), classification of abattoirs according to their capability to reduce faecal contamination, and use of improved process hygiene criteria. it is proposed to omit palpation and incision from post‐mortem inspection in animals subjected to routine slaughter. for chemical hazards, dioxins and dioxin‐like polychlorinated biphenyls were ranked as being of high potential concern. monitoring programmes for chemical hazards should be more flexible and based on the risk of occurrence, taking into account fci, which should be expanded to reflect the extensive production systems used, and the ranking of chemical substances, which should be regularly updated and include new hazards. control programmes across the food chain, national residue control plans, feed control and monitoring of environmental contaminants should be better integrated. meat inspection is a valuable tool for surveillance and monitoring of animal health and welfare conditions. omission of palpation and incision would reduce detection effectiveness for tuberculosis and fasciolosis at animal level. surveillance of tuberculosis at the slaughterhouse in small ruminants should be improved and encouraged, as this is in practice the only surveillance system available. extended use of fci could compensate for some, but not all, the information on animal health and welfare lost if only visual post‐mortem inspection is applied. following a request from the european commission to the european food safety authority (efsa), the panel on biological hazards (biohaz) was asked to deliver a scientific opinion on the public health hazards to be covered by the inspection of meat from sheep and goats. the panel was supported by the efsa panels on contaminants in the food chain (contam) and animal health and welfare (ahaw) in the preparation of this opinion. briefly, the main risks for public health that should be addressed by meat inspection were identified and ranked; the strengths and weaknesses of the current meat inspection system were evaluated; recommendations were made for inspection methods fit for the purpose of meeting the overall objectives of meat inspection for hazards currently not covered by the meat inspection system; and recommendations for adaptations of inspection methods and/or frequencies of inspections that provide an equivalent level of protection were made. in addition, the implications for animal health and animal welfare of any changes proposed to current inspection methods were assessed. sheep and goats were considered together, unless otherwise stated. decision trees were developed and used for priority ranking of biological and chemical hazards present in meat from sheep and goats. for biological hazards the ranking was based on the magnitude of the human health impact, the severity of the disease in humans and the evidence supporting the role of meat from sheep and goats as a risk factor for disease in humans. the assessment was focused on the public health risks that may occur through the handling, preparation for consumption and/or consumption of meat from these species. the term 'priority' was considered more appropriate than 'risk' for categorizing the biological hazards associated with meat from small ruminants, given that a significant amount of data on both the occurrence of the hazards and on the attributable fraction of human cases to meat from small ruminants were not available. risk ranking of chemical hazards into categories of potential concern was based on the outcomes of the national residue control plans (nrcps), as defined in council directive 96/23/ec for the period 2005-2010, and of other testing programmes, as well as on substance-specific parameters such as the toxicological profile and the likelihood of the occurrence of residues and contaminants in sheep and goats. based on the ranking for biological hazards, toxoplasma gondii and pathogenic verocytotoxinproducing escherichia coli (vtec) were classified as high priority for public health regarding meat inspection of small ruminants. the remaining hazards were classified as low public health relevance, based on available data, and were therefore not considered further. for chemical hazards, dioxins and dioxin-like polychlorinated biphenyls (dl-pcbs) were ranked as being of high potential concern owing to their known bioaccumulation in the food chain, their frequent findings above maximum levels (mls), particularly in sheep liver, and in consideration of their toxicological profile; all other substances were ranked as of medium or lower concern. it should be noted that the ranking into specific-risk categories of hazards is based on current knowledge and available data and therefore ranking should be updated regularly, taking account of new information and data and including 'new hazards'. the main elements of the current meat inspection system include analysis of food chain information (fci), ante-mortem examination of animals and post-mortem examination of carcasses and organs. the assessment of the strengths and weaknesses of the current meat inspection was based on its contribution to the control of the meat-borne human health hazards identified in sheep and goats. a number of strengths and weaknesses of the current inspection system were identified. currently, the use of fci for food safety purposes is limited for small ruminants because the data that it contains is very general and doesn't address specific hazards of public health importance. however, fci could serve as a valuable tool for risk management decisions and could be used for risk categorisation of farms or batches of animals. to achieve this, the system needs further development to include additional information important for food safety, including definition of appropriate and standardized indicators for the main public health hazards identified above. ante-mortem and post-mortem inspections of sheep and goats enable the detection of observable abnormalities and provide a general assessment of animal/herd health, which if compromised may lead to a greater public health risk. visual inspection of live animals and carcasses can detect animals heavily contaminated with faeces, which increase the risk for cross-contamination during slaughter and may constitute a food safety risk if the animals are carrying hazards of public health importance. if such animals or carcasses are dealt with adequately, this risk can be reduced. visual detection of faecal contamination on carcasses can also be an indicator of slaughter hygiene, but other approaches to verify this should be considered. post-mortem inspection can also detect non meat-borne hazards of public health significance, such as echinococcus granulosus, that can be present in carcasses or offal from small ruminants. ante-mortem and post-mortem inspection also have the potential to detect new diseases, which may be of direct public health significance. with regard to chemical hazards, it was noted that current procedures for sampling and testing are, in general, well established and coordinated, including follow-up actions subsequent to the identification of non-compliant samples. the regular sampling and testing for chemical residues and contaminants is an important disincentive for the development of undesirable practices and the prescriptive sampling system allows for equivalence in the control of eu-produced sheep and goat meat. the current combination of animal traceability, ante-mortem inspection and gross tissue examination can support the collection of appropriate samples for residue monitoring. the main weakness of ante-mortem and post-mortem inspection is that they are not able to detect any of the public health hazards identified as the main concerns for food safety. in addition, given that the current post-mortem procedures involve palpation and incision of some organs, the potential for crosscontamination of carcasses exists. for chemical hazards, a major weakness is that, with very few exceptions, presence of chemical hazards cannot be identified by current ante-/post-mortem meat inspection procedures at the slaughterhouse level and there is a lack of sufficient cost-effective and reliable screening methods. in addition, sampling is mostly prescriptive rather than risk or information based. there is limited ongoing adaptation of the sampling and testing programmes to the results of the residue monitoring programmes, with poor integration between the testing of feed materials for undesirable substances and the nrcps and sampling under the nrcps reflecting only a part of testing done by a number of mss, the results of which should be taken into consideration. as neither of the main public health hazards associated with meat from small ruminants can be detected by traditional visual meat inspection, other approaches are necessary to identify and control these microbiological hazards. a comprehensive meat safety assurance system for small ruminants, combining a range of preventive measures and controls applied both on the farm and at the slaughterhouse in a longitudinally integrated way, is the most effective approach to control the main hazards in the context of meat inspection. information on the biological risks associated with the consumption of meat from sheep or goats is sometimes scant and unreliable. in order to facilitate decision making, harmonised surveys are required to establish values for the prevalence of the main hazards t. gondii and pathogenic vtec at flock/herd, live animal and carcass level in individual mss. epidemiological and risk assessment studies are also required to determine the specific risk to public health associated with the consumption of meat from small ruminants. if these studies confirm a high risk to public health through the consumption of meat from sheep or goats, consideration should be given to the setting of clear and measurable eu targets at the carcass level. to meet these targets and criteria, a variety of control options for the main hazards are available, at both farm and abattoir level. flock/herd categorisation according to the risk posed by the main hazards is considered an important element of an integrated meat safety assurance system. this should be based on the use of farm descriptors and historical data in addition to batch-specific information. farm-related data could be provided through farm audits using harmonised epidemiological indicators (heis) to assess the risk and protective factors for the flocks/herds related to the given hazards. in addition, classification of abattoirs according to their capability to prevent or reduce faecal contamination of carcasses can be based on two elements: (1) the process hygiene as measured by the level of indicator organisms on the carcasses (i.e. process hygiene criteria); and (2) the use of operational procedures and equipment that reduce faecal contamination, as well as industry led quality systems. there are a variety of husbandry measures that can be used to control t. gondii on sheep and goat farms but at present these are impractical to implement in most farms. a number of post-processing interventions are effective in inactivating t. gondii such as cooking, freezing, curing, high pressure and irradiation treatments, although further research is required to validate these treatments in meat from small ruminants. there are also a variety of husbandry measures that can be used to reduce the levels of vtec on farms, but their efficacy is not clear in small ruminants. there are also a number of challenges that need to be overcome regarding the setting of targets for pathogenic vtec, including the difficulties in identifying husbandry factors that can be used to classify farms according to pathogenic vtec risk, the intermittent nature of shedding, and the problems with the interpretation of monitoring results for pathogenic vtec due to the difficulty to correctly identify pathogenic vtec. the main sources of vtec on sheep and goat carcasses are the fleece/hide and the viscera. to control incoming faecal contamination only clean animals should be accepted for slaughter. there are also a number of measures that can help reducing the spillage or leakage of digestive contents onto the carcass, as well as post-processing interventions to control pathogenic vtec are also available. these include hot water and steam carcass surface treatments. risk categorisation of slaughterhouses should be based on trends of data derived from process hygiene assessments and from hazard analysis critical control point programmes. improvement of slaughter hygiene through technological and managerial interventions should be sought in slaughterhouses with repeatedly unsatisfactory performance. fci can be improved by including information on participation in quality assurance schemes and by greater feedback to the primary producer, as this would likely result in the production of healthier animals. ante-mortem inspection assesses the general health status of the animals and helps to detect animals heavily contaminated with faeces on arrival at the slaughterhouse, so no adaptations for the existing visual ante-mortem inspection are required. routine post-mortem examination cannot detect the meat-borne pathogens of public health importance. palpation of the lungs, the liver, the umbilical region and the joints, and incision of the liver could contribute to the spread of bacterial hazards through cross contamination. for these reasons, palpation and incision should be omitted in animals subjected to routine slaughter. sheep and goat production in the eu is marked by being largely extensive in nature, involving frequent trading of animals and involving nomadic flocks. these differences in husbandry systems and feeding regimes result in different risks for the occurrence of chemical residues and contaminants. extensive periods on pasture or/as nomadic flocks and the use of slaughter collection dealerships may preclude detailed lifetime fci. it is recommended regarding chemical hazards, that fci should be expanded for sheep and goats produced in extensive systems to provide more information on the specific environmental conditions where the animals are produced and that future monitoring programmes should be based on the risk of occurrence of chemical residues and contaminants, taking into account the completeness and quality of the fci supplied, and the ranking of chemical substances into categories of potential concern, which ranking needs to be regularly updated. control programmes for chemical residues and contaminants should be less prescriptive, with sufficient flexibility to adapt to results of testing, should include 'new hazards', and the test results for sheep and goats should be separately presented. 'new' chemical hazards identified are largely persistent organic pollutants that have not been comprehensively covered by the sampling plans of the current meat inspection or which have not been included in such sampling plans. there is a need for an improved integration of sampling, testing and intervention protocols across the food chain, nrcps, feed control and monitoring of environmental contaminants. a series of further recommendations are made in relation to chemical hazards dealing with control measures, testing and analytical techniques and also on data collection and source attribution studies for biological hazards, as well as on methods of detection of viable t. gondii in meat and on assessing the effect of the omission of palpation and incision on the risk posed by non-meat-borne zoonoses. the implications for surveillance of animal health and welfare of the changes proposed to the current meat inspection system were evaluated quantitatively and qualitatively. the proposed changes related to biological hazards included shorter transport and lairage time, improved collection of food chain information, and omission of palpation and incision in animals subjected to routine slaughter at postmortem inspection. recommendations on chemical hazards included the ranking system for chemical substances of potential concern and its updating, the use of food chain information to help facilitate risk based sampling strategies, and the inclusion of 'new hazards' in control programmes for chemical residues and contaminants. from the quantitative assessment, a change to visual only inspection caused a significant reduction of the probability of detection of detectable cases of fasciolosis and tuberculosis in goats. with regard to exotic diseases, clinical surveillance had a greater sensitivity for detecting foot and mouth disease than slaughterhouse surveillance. a change in post-mortem protocol to a visual only system did not significantly reduce the detection of any welfare conditions. following the qualitative analysis, it was concluded that a change to visual inspection (which implies no palpation) would reduce detection effectiveness for tuberculosis. surveillance of tuberculosis at the slaughterhouse in small ruminants should be improved and encouraged, as this is in practice the only surveillance system available in these species. the detection of tuberculosis in small ruminants should be adequately recorded and followed at the farm level. moving to a visual only meat inspection system would decrease the sensitivity of inspection of fasciolosis at animal level, however it would be sensitive enough to identify most if not all affected herds. therefore the consequences of the change would be of low relevance. the feedback to farmers of fasciola hepatica detected at meat inspection should be improved, to allow farmer information to support rational on-farm fluke management programmes. qualitative analysis suggested that the proposal for shortened transport and lairage time would be beneficial to improving the welfare of small ruminants. food chain information should include animal welfare status in order to complement the slaughterhouse surveillance systems (ante-mortem and postmortem inspection) and the latter could be used to identify on farm welfare status. regulation (ec) no 854/2004 of the european parliament and of the council lays down specific rules for the organisation of official controls on products of animal origin intended for human consumption 4 . inspection tasks within this regulation include: checks and analysis of food chain information animal welfare specified risk material and other by-products laboratory testing the scope of the inspection includes monitoring of zoonotic infections and the detection or confirmation of certain animal diseases without necessarily having consequences for the placing on the market of meat. the purpose of the inspection is to assess if the meat is fit for human consumption in general and to address a number of specific hazards: in particular the following issues: transmissible spongiform encephalopathies (only ruminants), cysticercosis, trichinosis, glanders (only solipeds), tuberculosis, brucellosis, contaminants (e.g. heavy metals), residues of veterinary drugs and unauthorised substances or products. during their meeting on 6 november 2008, chief veterinary officers (cvo) of the member states agreed on conclusions on modernisation of sanitary inspection in slaughterhouses based on the recommendations issued during a seminar organised by the french presidency from 7 to 11 july 2008. the cvo conclusions have been considered in the commission report on the experience gained from the application of the hygiene regulations, adopted on 28 july 2009. council conclusions on the commission report were adopted on 20 november 2009 inviting the commission to prepare concrete proposals allowing the effective implementation of modernised sanitary inspection in slaughterhouses while making full use of the principle of the 'risk-based approach'. in accordance with article 20 of regulation (ec) no 854/2004, the commission shall consult efsa on certain matters falling within the scope of the regulation whenever necessary. efsa and the commission's former scientific committee on veterinary measures relating to public health have issued in the past a number of opinions on meat inspection considering specific hazards or production systems separately. in order to guarantee a more risk-based approach, an assessment of the risk caused by specific hazards is needed, taking into account the evolving epidemiological situation in member states. in addition, methodologies may need to be reviewed taking into account risks of possible cross-contamination, trends in slaughter techniques and possible new inspection methods. the scope of this mandate is to evaluate meat inspection in order to assess the fitness of the meat for human consumption and to monitor food-borne zoonotic infections (public health) without jeopardising the detection of certain animal diseases nor the verification of compliance with rules on animal welfare at slaughter. if and when the current methodology for this purpose would be considered not to be the most satisfactory to monitor major hazards for public health, additional methods should be recommended as explained in detail under points 2 and 4 of the terms of reference. the objectives of the current legal provisions aimed at carrying out meat inspection on a risk-based analysis should be maintained. in order to ensure a risk-based approach, efsa is requested to provide scientific opinions on meat inspection in slaughterhouses and, if considered appropriate, at any other stages of the production chain, taking into account implications for animal health and animal welfare in its risk analysis. in addition, relevant international guidance should be considered, such as the codex code of hygienic practice for meat (cac/rcp 58-2005) , and chapter 6.2 on control of biological hazards of animal health and public health importance through ante-and post-mortem meat inspection, as well as chapter 7.5 on slaughter of animals of the terrestrial animal health code of the world organisation for animal health (oie). the following species or groups of species should be considered, taking into account the following order of priority identified in consultation with the member states: domestic swine, poultry, bovine animals over six weeks old, bovine animals under six weeks old, domestic sheep and goats, farmed game and domestic solipeds. in particular, efsa, in consultation with the european centre for disease prevention and control (ecdc), is requested within the scope described above to: 1. identify and rank the main risks for public health that should be addressed by meat inspection at eu level. general (e.g. sepsis, abscesses) and specific biological risks as well as chemical risks (e.g. residues of veterinary drugs and contaminants) should be considered. differentiation may be made according to production systems and age of animals (e.g. breeding compared to fattening animals). 2. assess the strengths and weaknesses of the current meat inspection methodology and recommend possible alternative methods (at ante-mortem or post-mortem inspection, or validated laboratory testing within the frame of traditional meat inspection or elsewhere in the production chain) at eu level, providing an equivalent achievement of overall objectives; the implications far animal health and animal welfare of any changes suggested in the light of public health risks to current inspection methods should be considered. 3. if new hazards currently not covered by the meat inspection system (e.g. salmonella, campylobacter) are identified under tor 1, then recommend inspection methods fit for the purpose of meeting the overall objectives of meat inspection. when appropriate, food chain information should be taken into account. 4. recommend adaptations of inspection methods and/or frequencies of inspections that provide an equivalent level of protection within the scope of meat inspection or elsewhere in the production chain that may be used by risk managers in case they consider the current methods disproportionate to the risk, e.g. based on the ranking as an outcome of terms of reference 1 or on data obtained using harmonised epidemiological criteria (see annex 2) . when appropriate, food chain information should be taken into account. the scope of the mandate is to evaluate meat inspection in a public health context; animal health and welfare issues are covered with respect to the possible implications of adaptations/alterations to current inspection methods, or the introduction of novel inspection methods proposed by this mandate. issues other than those of public health significance but that still compromise the fitness of the meat for human consumption (regulation (ec) no 854/2004, 5 annex i, section ii, chapter v) are outside the scope of the mandate. examples of these include sexual odour or meat decolouration. transmissible spongiform encephalopathies (tses) are also outside the scope of the mandate. the impact of changes to meat inspection procedures on the occupational health of abattoir workers, inspectors, etc. is outside the scope of the mandate. additionally, hazards representing primarily occupational health risks, the controls related to any hazard at any meat chain stage beyond the abattoir, and the implications for environmental protection are not dealt with in this document. in line with article 20 of regulation (ec) no 854/2004 5 the european commission has recently submitted a mandate to efsa (m-2010-0232) to cover different aspects of meat inspection. the mandate comprises two requests: one for scientific opinions and one for technical assistance. the european food safety authority (efsa) is requested to issue scientific opinions related to inspection of meat in different species. in addition, technical assistance has been requested on harmonised epidemiological criteria for specific hazards for public health that can be used by risk managers to consider adaptation of the meat inspection methodology. meat inspection is defined by regulation 854/2004. the species or groups of species to be considered are: domestic swine, poultry, bovine animals over six weeks old, bovine animals under six weeks old, domestic sheep and goats, farmed game and domestic solipeds. taking into account the complexity of the subject and that consideration has to be given to zoonotic hazards, animal health and welfare issues and chemical hazards (e.g. residues of veterinary drugs and chemical contaminants), the involvement of several efsa units was necessary. more specifically, the mandate was allocated to the biological hazards panel (biohaz), which prepared this scientific opinion with the support of the animal health and welfare (ahaw) and contaminants in the food chain (contam) panels. in addition, the delivery of the technical assistance was allocated to the biological monitoring (biomo), scientific assessment support (sas), and dietary and chemical monitoring (dcm) units of the risk assessment and scientific assistance directorate. this scientific opinion therefore concerns the assessment of meat inspection in sheep and goats, and it includes the answer to the terms of reference proposed by the european commission. owing to the complexity of the mandate, the presentation of the outcome does not follow the usual layout. for ease of reading, main outputs from the three working groups (biohaz, contam and ahaw) are presented at the beginning of the document. the scientific justifications for these outputs are found in the various appendices as endorsed by their respective panels, namely biological hazards (appendix a), chemical hazards (appendix b), and the potential impact that the proposed changes envisaged by these two could have on animal health and welfare (appendix c). differentiation may be made according to production systems and age of animals (e.g. breeding compared to fattening animals). based on the priority ranking, the hazards were classified as follows: -toxoplasma gondii and pathogenic verocytotoxin-producing escherichia coli (vtec) 6 were classified as high priority for sheep/goat meat inspection. -the remaining identified hazards, bacillus anthracis, campylobacter spp. (thermophilic) and salmonella spp. were classified as low priority, based on available data. as new hazards might emerge and/or hazards that presently are not a priority might become more relevant over time or in some regions, both hazard identification and the risk ranking should be revisited regularly to reflect this dynamic epidemiological situation. particular attention should be given to potential emerging hazards of public health importance. a multi-step approach was used for the identification and ranking of chemical hazards. evaluation of the 2005-2010 national residue control plans (nrcps) outcome for sheep and goats indicated that only 0.41 % of the total number of results was non-compliant for one or more substances listed in council directive 96/23/ec. potentially higher exposure of consumers to these substances from sheep and goat meat takes place only incidentally, as a result of mistakes or non-compliance with known and regulated procedures. available data however, do not allow for a reliable assessment of consumer exposure. ranking of chemical residues and contaminants in domestic sheep and goats based on predefined criteria, relating to bioaccumulation, toxicological profile and likelihood of occurrence, and taking into account the findings from the nrcps for the period 2005-2010 was as follows: -dioxins and dioxin-like polychlorinated biphenyls (dl-pcbs) were ranked as being of high potential owing to their known bioaccumulation in the food chain, their frequent findings above mls, particularly in sheep liver, and in consideration of their toxicological profile. -stilbenes, thyreostats, gonadal (sex) steroids, resorcylic acid lactones and beta-agonists, especially clenbuterol, chloramphenicol and nitrofurans were ranked as being of medium potential concern, as they have proven toxicity for humans, are effective as antibacterial treatments for sheep/goats and as non-compliant samples are found in most years of the nrcps. -chloramphenicol and nitrofurans were ranked as being of medium potential concern, as they have proven toxicity for humans, they are effective as antibacterial treatments for sheep/goats and as non-compliant samples are found in most years of the nrcps. -non dioxin-like polychlorinated biphenyls (ndl-pcbs) bioaccumulate, and there is a risk of exceeding the mls, but they were ranked in the category of medium potential concern, because they are less toxic than dioxins and dl-pcbs. -the chemical elements cadmium, lead and mercury were allocated to the medium potential concern category taking into account the number of non-compliant results reported under the nrcps and their toxicological profile. -all other substances listed in council directive 96/23/ec were ranked as of low or negligible potential concern owing to the toxicological profile of these substances at residue levels in edible tissues or to the very low or non-occurrence of non-compliant results in the nrcps 2005-2010, and/or to the natural occurrence in sheep and goats of some of these substances. strengths -ante-mortem and post-mortem inspection of sheep and goats enable the detection of observable abnormalities. in that context, they are an important activity for monitoring animal health and welfare. they provide a general assessment of animal/herd health, which if compromised may lead to a greater public health risk. visual inspection of live animals and carcasses can also detect animals heavily contaminated with faeces. such animals increase the risk for cross-contamination during slaughter and may consequently constitute a food safety risk if carrying hazards of public health importance. if such animals or carcasses are dealt with adequately, this risk can be reduced. visual detection of faecal contamination on carcasses can also be an indicator of slaughter hygiene, but other approaches to verify slaughter hygiene should be considered. -post-mortem inspection can also detect non meat-borne hazards of public health significance that can be present in carcasses or offal from small ruminants. ante-mortem and post-mortem inspection also have the potential to detect new diseases if these have clinical signs, which may be of direct public health significance. weaknesses -currently, the use of food chain information (fci) for food safety purposes is limited for small ruminants, mainly because the data that it contains is very general and doesn't address specific hazards of public health importance. however, fci could serve as a valuable tool for risk management decisions and could be used for risk categorisations of farms or batches of animals. to achieve this, the system needs further development to include additional information important for food safety, including definition of appropriate and standardized indicators for the main public health hazards identified in section 2 of appendix a. -ante-and post-mortem inspection is not able to detect any of the public health hazards identified as the main concerns for food safety. it would therefore be expected that more efficient procedures might be implemented to monitor the occurrence of non-visible hazards. in addition, given that the current post-mortem inspection procedures involve palpation and incision of some organs, the potential for cross-contamination of carcasses exists. strengths of the current meat inspection methodology for chemical hazards are as follows: -the current procedures for sampling and testing are a mature system, in general well established and coordinated including follow-up actions subsequent to the identification of non-compliant samples. -the regular sampling and testing for chemical residues and contaminants in the system is an important disincentive to the development of undesirable practices. -the prescriptive sampling system allows for equivalence in the control of eu-produced sheep and goat meat. any forthcoming measures have to ensure that the control of imports from third countries remains equivalent to the controls within the domestic market. -the current combination of animal traceability, ante-mortem inspection and gross tissue examination can support the collection of appropriate samples for residue monitoring. weaknesses of the current meat inspection methodology for chemical hazards are as follows: -a weakness of the system is that presence of chemical hazards cannot be identified by current ante-/post-mortem meat inspection procedures at the slaughterhouse level, indicating the need for further harmonization of the risk reduction strategies along the entire food chain. -integration between testing of feed materials for undesirable contaminants and the nrcps in terms of communication and follow-up testing strategies or interventions is currently limited. moreover, a routine environmental data flow is not established and keeping habits for sheep and goats provides opportunities for feed coming in without a clear feed chain history. -under the current system, sampling is mostly prescriptive rather than risk-or informationbased. it appears that individual samples taken under the nrcp testing programme may not always be taken as targeted samples, as specified under council directive 96/23/ ec, but sometimes may be taken as random samples. -there is a lack of sufficient cost-effective and reliable screening methods and/or the range of substances prescribed/covered by the testing is sometimes limited. -there is limited flexibility to adopt emerging chemical substances into the nrcps and limited ongoing adaptation of the sampling and testing programme to the results of the residue monitoring programmes. in addition, sampling under the nrcps reflects only a part of testing done by a number of mss, the results of which should be taken into consideration. -sheep and goats may not be subject to surveillance over their lifetime at the same level as is the case for other food animal categories such as pigs, poultry and, to a large extent, bovine animals due to the traditional nomadic/outdoor farming systems. as shown in the comisurv assessment, a change to visual only inspection would cause a significant reduction in the probability of detection (i.e. non-overlapping 90% probability intervals) of detectable cases of fasciolosis and of tuberculosis in goats. small ruminants are usually not subjected to official tuberculosis eradication campaigns, and farm controls are only performed on premises where cattle and goats are kept together, or in flocks/herds that commercialise raw milk. surveillance for small ruminant tuberculosis at present relies on meat inspection of sheep and goats slaughtered for human consumption, or other limited diagnostic surveillance activities. as is the case with tuberculosis in bovines, the contribution of meat inspection surveillance of tuberculosis in small ruminants is to support the detection of flocks/herds with tuberculosis. detection of tuberculosis in individual animals is merely the first step in improving the effectiveness of flock/herd surveillance, and for any given flock/herd, the flock/herd sensitivity will increase with the number of animals slaughtered. in recent years tuberculosis has been reported in small ruminants in several eu countries and most information derives from recognition of tuberculous lesions at the slaughterhouse and from laboratory reports. although small ruminants are not considered to represent a significant reservoir of the disease for the persistence of bovine tuberculosis in cattle, it is still possible that infected sheep and goat herds could act as vectors of infection for other domestic and wild animals. therefore, surveillance and control of tuberculosis in domestic small ruminants does have consequences for the overall surveillance and control of tuberculosis. the feedback to farmers of fasciola hepatica detected at meat inspection is low at present and the real risk to animal health/welfare for this disease, caused by a change to a visual only meat inspection method, is probably low. implementation of welfare assessment protocols using appropriate animal based indicators during clinical and slaughterhouse (ami + pmi) surveillance system would improve the welfare of small ruminants. extended use of food chain information has the potential to compensate for some, but not all, of the information on animal health and welfare that would be lost if visual only post-mortem inspection is applied. food chain information is a potentially effective tool to perform more targeted ante-mortem and post-mortem inspection tasks in the slaughterhouse which may increase the effectiveness of those tasks in detecting conditions of animal health and animal welfare significance. the existing ineffective flow of information from primary production to the slaughterhouses and vice versa reduces the ability of detection of animal diseases and animal welfare conditions at the slaughterhouse and as a result it limits possible improvements on animal health and welfare standards at the farm as farmers will not be aware of the slaughterhouse findings. the conclusions and recommendations on chemical hazards were reviewed by the ahaw working group and none of them were considered to have impact on animal health and welfare surveillance and monitoring. as neither of the main public health hazards associated with meat from small ruminants can be detected by traditional meat inspection, other approaches are necessary to identify and control these microbiological hazards. a comprehensive meat safety assurance system for meat from small ruminants, combining a range of preventive measures and controls applied both on the farm and at the slaughterhouse in a longitudinally integrated way, is the most effective approach to control the main hazards in the context of meat inspection. information on the biological risks associated with the consumption of meat from sheep or goats is sometimes scant and unreliable. in order to facilitate decision making, harmonised surveys are required to establish values for the prevalence of the main hazards t. gondii and pathogenic vtec at flock/herd, live animal and carcass level in individual member states. epidemiological and risk assessment studies are also required to determine the specific risk to public health associated with the consumption of meat from small ruminants. in the event that these studies confirm a high risk to public health through the consumption of meat from sheep or goats, consideration should be given to the setting of clear and measurable eu targets at the carcass level. to meet these targets and criteria, a variety of control options for the main hazards are available, at both farm and abattoir level. flock/herd categorisation according to the risk posed by the main hazards is considered an important element of an integrated meat safety assurance system. this should be based on the use of farm descriptors and historical data in addition to batch-specific information. farmrelated data could be provided through farm audits using harmonised epidemiological indicators (heis) to assess the risk and protective factors for the flocks/herds related to the given hazards. classification of abattoirs according to their capability to prevent or reduce faecal contamination of carcasses can be based on two elements: (1) the process hygiene as measured by the level of indicator organisms on the carcasses (i.e. process hygiene criteria); and (2) the use of operational procedures and equipment that reduce faecal contamination, as well as industry-led quality systems. as mentioned in section 4.2 of appendix a, further studies are necessary to determine with more certainty the risk of acquiring t. gondii through consumption of meat from small ruminants. in addition, the lack of tests that can easily identify viable cysts in meat is a significant drawback. further, if there is a high prevalence in the animal population, this will hamper the development of systems based on risk categorisation of animals. for these reasons, the setting of targets for t. gondii is not recommended at the moment. there are a variety of animal husbandry measures that can be used to control t. gondii on sheep and goat farms but at present these are impractical to implement in most farms. a number of post-processing interventions might be effective in inactivating t. gondii such as cooking, freezing, curing and high-pressure and -irradiation treatments. however, most of the information available for these treatments originates from research in pigs, so further research is required to validate these treatments in meat from small ruminants. there are also a variety of animal husbandry measures that can be used to reduce the levels of vtec on infected farms, but their efficacy is not clear in small ruminants. in addition, there are a number of challenges that need to be overcome regarding the setting of targets for pathogenic vtec, including the difficulties in identifying husbandry factors that can be used to classify farms according to pathogenic vtec risk, the intermittent nature of shedding, and the problems with the interpretation of monitoring results for pathogenic vtec due to the difficulty to correctly identify pathogenic vtec. the two main sources of vtec on sheep and goat carcasses are the fleece/hide and the viscera. to control faecal contamination from the fleece or hide only clean animals should be accepted for slaughter, as currently required by eu legislation. there are also a number of measures that can help reducing the spillage or leakage of digestive contents onto the carcass, particularly rodding of the oesophagus and bagging of the rectum. post-processing interventions to control vtec are also available. these include hot water and steam pasteurization. risk categorisation of slaughterhouses should be based on trends of data derived from process hygiene assessments and from hazard analysis critical control point programmes. improvement of slaughter hygiene through technological and managerial interventions should be sought in slaughterhouses with repeatedly unsatisfactory performance. dioxins and dl-pcbs which accumulate in food-producing animals have been ranked as being of high potential concern. as these substances have not yet been comprehensively covered by the sampling plans of the current meat inspection (nrcps), they should be considered as 'new' hazards. in addition, for a number of chemical elements used as feed supplements and for organic contaminants that may accumulate in food-producing animals only limited data regarding residues in sheep and goats are available. this is the case, in particular, for brominated flame retardants, including polybrominated diphenylethers (pbdes) and hexabromocyclododecanes (hbcdds) and perfluorinated compounds (pfcs) including (but not limited to) perfluorooctane sulphonate (pfos) and perfluorooctanoic acid (pfoa). fci can be improved by including information on participation in quality assurance schemes and by giving greater feedback to the primary producer, as this would probably result in the production of healthier animals. ante-mortem inspection assesses the general health status of the animals and helps to detect animals heavily contaminated with faeces on arrival at the slaughterhouse. taking these factors into consideration, and given that current methods do not increase the microbiological risk to public health, no adaptations to the existing visual ante-mortem inspection procedure are required. although visual examination contributes by detecting visible faecal contamination, routine post-mortem examination cannot detect the meat-borne pathogens of public health importance. palpation of the lungs, the livers, the umbilical region and the joints and incision of the liver could contribute to the spread of bacterial hazards through cross-contamination. for these reasons, palpation and incision should be omitted in animals subjected to routine slaughter. sheep and goat production in the eu is marked by being largely extensive in nature, involving frequent trading of animals and nomadic flocks. this involves differences in husbandry systems and feeding regimes resulting in different risks for chemical substances and contaminants. extensive periods on pasture or/as nomadic flocks and the use of slaughter collection dealerships may preclude detailed lifetime fci. similarly, in these situations, the level of feedback from the slaughterhouse and authorities to farmers regarding the results of residue testing may be suboptimal. there is less concern about fci from dairy sheep and goats as they are reared under more intensive and controlled conditions. better integration of results from official feed control with residue monitoring seems essential to indicate whether monitoring of residues in slaughter animals needs to be directed to particular substances. therefore, there is a need for an improved integration of sampling, testing and intervention protocols across the food chain, nrcps, feed control and environmental monitoring. to provide a better evidence base for future risk ranking of hazards, initiatives should be instigated to: improve and harmonise data collection of incidence and severity of human diseases caused by relevant hazards; systematically collect data for source attribution; collect data to identify and risk rank emerging hazards that could be transmitted through handling, preparation and consumption of sheep and goat meat. source attribution studies are needed to determine the relative importance of meat and to ascertain the role of the different livestock species as sources of t. gondii and pathogenic vtec for humans. methods should be developed to estimate the amount of viable t. gondii tissue cysts in meat, especially in meat cuts that are commonly consumed. the effect of the omission of palpation and incision on the risk posed by non-meat-borne zoonoses such as echinococcus granulosus and fasciola hepatica should be assessed, particularly in those regions where these hazards are endemic. fci should be expanded for sheep and goats produced in extensive systems to provide more information on the specific environmental conditions where the animals are produced. it is recommended that sampling of sheep and goats should be based on the risk of occurrence of chemical residues and contaminants and on the completeness and quality of the fci supplied. regular updating of the ranking of chemical substances in sheep and goats as well as of the sampling plans should occur taking into account any new information regarding the toxicological profile of chemical residues and contaminants, usage in sheep and goat production, and actual occurrence of individual substances in sheep and goats. control programmes for chemical residues and contaminants should be less prescriptive, with sufficient flexibility to adapt to results of testing, should include 'new hazards', and the test results for sheep and goats should be separately presented. there is a need for an improved integration of sampling, testing and intervention protocols across the food chain, nrcps, feed control and monitoring of environmental contaminants. the development of analytical techniques covering multiple analytes and of new biologically based testing approaches should be encouraged and incorporated into the residue control programmes for prohibited substances, testing should be directed where appropriate towards the farm level and, in the case of substances that might be used illicitly for growth promotion, control measures, including testing, need to be refocused to better identify the extent of abuse in the eu. in addition, control measures for prohibited substances should not rely exclusively on nrcp testing, but should include veterinary inspection during the production phase and the use of biological methods and biomarkers suitable for the identification of abuse of such substances in sheep and goat production in the eu. data collected during clinical and slaughterhouse (ante-mortem and post mortem inspection) surveillance systems should be utilised more effectively to improve animal welfare at farm level. slaughterhouse surveillance of tuberculosis in small ruminants should be improved and encouraged, as this is in practice the only surveillance system available. the detection of tuberculosis in small ruminants should be adequately recorded and notified, followed by control measures at the farm level. lack of feedback of post-mortem inspection results to the farmer prevents instigation of a fluke management programme, which could be detrimental to animal health and welfare. an improvement in this feedback of information is recommended. welfare surveillance systems should become an integral part of the food chain information. an integrated system should be developed whereby food chain information for public health and for animal health and welfare can be used in parallel, more effectively provide farmers with background information on the animal diseases and welfare conditions of key concern that may affect their livestock and why it is important to provide this information to the slaughterhouse through the use of food chain information. following a request from the european commission, the panel on biological hazards (biohaz) was asked to deliver a scientific opinion on the public health hazards to be covered by inspection of meat for several animal species, with the contribution of the panel on contaminants in the food chain (contam) and the panel on animal health and welfare (ahaw). briefly, the main risks for public health that should be addressed by meat inspection were identified and ranked; the strengths and weaknesses of the current meat inspection were evaluated; and recommendations were made for inspection methods capable of meeting the overall objectives of meat inspection for hazards currently not covered by the meat inspection system, as well as recommendations for adaptations of inspection methods and/or frequencies of inspections that provide an equivalent level of protection. in addition, the implications for animal health and animal welfare of any changes proposed to current inspection methods were assessed. this opinion covers the inspection of meat from sheep and goats. the biohaz panel considered sheep and goats together 7 . a decision tree was used for priority ranking of meat-borne hazards present in meat from sheep and goats. the ranking was based on the magnitude of the human health impact, the severity of the disease in humans and the evidence supporting the role of meat from sheep and goats as a risk factor for disease in humans. the assessment was focused on the public health risks that may occur through the handling, preparation and/or consumption of meat from these species. the term 'priority' was considered more appropriate than 'risk' for categorizing the hazards associated with meat from small ruminants, given that a significant amount of data on both the occurrence of the hazards and on the attributable fraction of human cases to meat from small ruminants were not available. based on the priority ranking, the hazards were classified as follows: toxoplasma gondii and pathogenic vtec were classified as high priority for sheep/goat meat inspection. the remaining identified hazards, bacillus anthracis, campylobacter spp. (thermophilic) and salmonella spp., were classified as low priority, based on available data. as new hazards might emerge and/or hazards that presently are not a priority might become more relevant over time or in some regions, both hazard identification and the risk ranking should be revisited regularly to reflect this dynamic epidemiological situation. particular attention should be given to potential emerging hazards of public health importance. the main elements of the current meat inspection system include analysis of fci, ante-mortem examination of animals and post-mortem examination of carcasses and organs. the assessment of the strengths and weaknesses of the current meat inspection was based on its contribution to the control of the meat-borne human health hazards identified in sheep and goats. a number of strengths and weaknesses of the current system were identified. currently, the use of food chain information (fci) for food safety purposes is limited for small ruminants because the data that it contains is very general and doesn't address specific hazards of public health importance. however, fci could serve as a valuable tool for risk management decisions and could be used for risk categorisation of farms or batches of animals. to achieve this, the system needs further development to include additional information important for food safety, including definition of appropriate and standardized indicators for the main public health hazards identified above. ante-mortem and post-mortem inspections of sheep and goats enable the detection of observable abnormalities and provide a general assessment of animal/herd health, which if compromised may lead to a greater public health risk. visual inspection of live animals and carcasses can detect animals heavily contaminated with faeces, which increase the risk for cross-contamination during slaughter and may constitute a food safety risk if the animals are carrying hazards of public health importance. if such animals or carcasses are dealt with adequately, this risk can be reduced. visual detection of faecal contamination on carcasses can also be an indicator of slaughter hygiene, but other approaches to verify this should be considered. post-mortem inspection can also detect non meat-borne hazards of public health significance, such as echinococcus granulosus, that can be present in carcasses or offal from small ruminants. ante-mortem and post-mortem inspection also have the potential to detect new diseases, which may be of direct public health significance. the main weakness of ante-mortem and post-mortem inspection is that they are not able to detect any of the public health hazards identified as the main concerns for food safety. in addition, given that the current post-mortem procedures involve palpation and incision of some organs, the potential for crosscontamination of carcasses exists. as neither of the main public health hazards associated with meat from small ruminants can be detected by traditional visual meat inspection, other approaches are necessary to identify and control these microbiological hazards. a comprehensive meat safety assurance system for small ruminants, combining a range of preventive measures and controls applied both on the farm and at the slaughterhouse in a longitudinally integrated way, is the most effective approach to control the main hazards in the context of meat inspection. information on the biological risks associated with the consumption of meat from sheep or goats is sometimes scant and unreliable. in order to facilitate decision making, harmonised surveys are required to establish values for the prevalence of the main hazards t. gondii and pathogenic vtec at flock/herd, live animal and carcass level in individual mss. epidemiological and risk assessment studies are also required to determine the specific risk to public health associated with the consumption of meat from small ruminants. if these studies confirm a high risk to public health through the consumption of meat from sheep or goats, consideration should be given to the setting of clear and measurable eu targets at the carcass level. to meet these targets and criteria, a variety of control options for the main hazards are available, at both farm and abattoir level. flock/herd categorisation according to the risk posed by the main hazards is considered an important element of an integrated meat safety assurance system. this should be based on the use of farm descriptors and historical data in addition to batch-specific information. farm-related data could be provided through farm audits using harmonised epidemiological indicators (heis) to assess the risk and protective factors for the flocks/herds related to the given hazards. in addition, classification of abattoirs according to their capability to prevent or reduce faecal contamination of carcasses can be based on two elements: (1) the process hygiene as measured by the level of indicator organisms on the carcasses (i.e. process hygiene criteria); and (2) the use of operational procedures and equipment that reduce faecal contamination, as well as industry led quality systems. there are a variety of husbandry measures that can be used to control t. gondii on sheep and goat farms but at present these are impractical to implement in most farms. a number of post-processing interventions are effective in inactivating t. gondii such as cooking, freezing, curing, high pressure and irradiation treatments, although further research is required to validate these treatments in meat from small ruminants. there are also a variety of husbandry measures that can be used to reduce the levels of vtec on farms, but their efficacy is not clear in small ruminants. there are also a number of challenges that need to be overcome regarding the setting of targets for pathogenic vtec, including the difficulties in identifying husbandry factors that can be used to classify farms according to pathogenic vtec risk, the intermittent nature of shedding, and the problems with the interpretation of monitoring results for vtec due to the difficulty to correctly identify pathogenic vtec. the main sources of vtec on sheep and goat carcasses are the fleece/hide and the viscera. to control incoming faecal contamination only clean animals should be accepted for slaughter. there are also a number of measures that can help reducing the spillage or leakage of digestive contents onto the carcass, as well as post-processing interventions to control vtec are also available. these include hot water and steam pasteurization. risk categorisation of slaughterhouses should be based on trends of data derived from process hygiene assessments and from hazard analysis critical control point programmes. improvement of slaughter hygiene through technological and managerial interventions should be sought in slaughterhouses with repeatedly unsatisfactory performance. fci can be improved by including information on participation in quality assurance schemes and by greater feedback to the primary producer, as this would likely result in the production of healthier animals. ante-mortem inspection assesses the general health status of the animals and helps to detect animals heavily contaminated with faeces on arrival at the slaughterhouse, so no adaptations for the existing visual ante-mortem inspection are required. routine post-mortem examination cannot detect the meat-borne pathogens of public health importance. palpation of the lungs, the liver, the umbilical region and the joints, and incision of the liver could contribute to the spread of bacterial hazards through cross contamination. for these reasons, palpation and incision should be omitted in animals subjected to routine slaughter. a series of recommendations were made on data collection, source attribution studies, methods of detection of viable t. gondii in meat and on assessing the effect of the omission of palpation and incision on the risk posed by non-meat-borne zoonoses. assessing current meat inspection systems for sheep and goats with the aim of introducing improvements requires a common understanding of the term "meat inspection". however, as discussed previously (efsa, 2010 (efsa, , 2011 , it seems that there is no precise, universally agreed definition of meat inspection. the term meat inspection is not described specifically in current european union (eu) legislation (regulation (ec) no 854/2004) or in the codex alimentarius's code of hygienic practice for meat (cac/rcp 58-2005) 8 ; rather, there are references to elements of the inspection process for meat such as ante-and post-mortem inspections and food chain information. consequently, the current understanding of the term meat inspection is probably based more on its practical application, and somewhat intuitive, than on a specific, formal definition. the biohaz panel defined the main scope of this scientific opinion as identifying and ranking the most relevant public health risks associated with meat from sheep and goats, assessing the strengths and weaknesses of the current meat inspection system, proposing alternative approaches for addressing current meat safety risks, and outlining a generic framework for inspection, prevention and control for important hazards that are not sufficiently covered by the current system. outside of the scope of the opinion were: microbiological hazards representing only occupational health risks transmissible spongiform encephalopathies (tses) issues other than those of public health significance, but which still compromise fitness of meat for human consumption (for example quality issues such as dark firm and dry (dfd) meat). as the eu regulations do not include different inspection requirements for sheep and goats, both species are considered together, but any important differences between these species are considered when necessary. in this document, the term small ruminant is used to refer to a combination of sheep and goats. in order to evaluate any important differences in meat inspection procedures between countries and/or regions as well as between species, the biohaz panel was supported by input provided during a technical hearing on meat inspection of small ruminants, during which experts from several stakeholder organisations presented information that had previously been requested by means of a questionnaire. following the hearing, an event report was compiled (efsa, 2012). the conclusions from this report are referred to when relevant. chemical hazards and associated meat safety risks in small ruminants are considered in a separate part of this opinion (see appendix b). although highest priority is given to the public health aims of the improvements of the biological/chemical meat safety system, any implications for animal health and welfare of the proposed changes were assessed (see appendix c). furthermore, issues related to epidemiological indicators and associated sampling/testing methodologies for hazards dealt with in this opinion were addressed by the biological monitoring unit in a separate document (efsa, 2013). the structure of the eu small ruminants farming industry has already been described in an efsa opinion (efsa, 2004) . briefly, sheep farming takes place in many areas of europe because sheep are able to live in a wide range of environments, even those hostile for other animals. goats are generally reared in extensive systems, traditionally in less developed areas, such as mountains or arid regions, and are often reared with sheep, especially in southern europe. milk sheep and goats are reared in similar systems, either grazed near the farm or kept housed, with the milk used in most cases for cheese production. meat production in europe reflects the diverse farming systems. lamb 9 meat production originates from sheep milk farms or from farms raising meat breeds. in the mediterranean countries, the lambs from milk farms are slaughtered at approximately one month of age (suckling lambs, the same applies to goat kids). in some of these countries, lambs from meat breeds are generally slaughtered at 70-100 days of age and represent the majority of total national lamb meat production. in northern countries, the rearing systems usually produce heavier lambs that may be slaughtered at six or more months of age. the proportion of sheep raised for wool production has steadily decreased over time, but it is still significant in parts of the eu. sheep and goats at the end of their productive life can also be destined for meat production, with the resulting meat usually processed into meat products or exported. although the production and consumption of lambs have decreased in recent years, lamb meat continues to be a traditional product consumed in some countries of the eu such as the united kingdom, ireland and the mediterranean countries (spain, france, greece and italy). these countries have the largest populations of sheep in the eu. in general, the southern countries produce lighter carcasses (about 10 kg) than the northern ones (18-20 kg). sheep are relatively small animals, with a lower yield of meat per carcass and higher slaughter and processing costs per unit of meat produced. as a result, sheep meat is relatively expensive in the market compared with other protein sources. the co-products (e.g. hides, wool, offal, feet, tails, etc.) have a major effect on the prices received by producers, and the impact on the profitability of the enterprise is profound (byrne et al., 2011) . eurostat statistics show that sheep meat production in the eu was over 720 000 tonnes in 2011, with the united kingdom and spain as the greatest producers ( figure 1 ). goat meat production in the eu is concentrated in the southern european countries, especially greece and spain ( there are many forces instigating change in sheep and goat meat production. legislative forces present in the hygiene package and microbiological regulation have increased meat hygiene service costs through structural and food safety requirements as well as mandating the provision of traceability and food chain information (palmer c.m., 2008) . commercial considerations, such as lower coproduct returns, higher costs of by-product disposal and the sourcing policies of the multiple retailers (using their market power to control margins) have also put pressure on slaughterhouse profitability (palmer, 2008) . in spite of the eu being only about 80 % self-sufficient in sheep meat, the predictions are that eu sheep numbers are expected to continue to decline over the next 10 years. this problem of falling sheep supplies has led to an overcapacity in the processing sector (byrne et al., 2011) . the effect of this decline is most acute for large slaughterhouses, which can only be run profitably at certain levels of throughput. given the energy market expectations, greater environmental controls and the pressure on enforcement costs, relief from falling costs looks unlikely (palmer, 2008) . , 1999) . these variations, individually and their combinations, lead to between-slaughterhouse differences in process hygiene performance and, consequently, in the hygienic status of the final carcass. at the end of the slaughter line prior to chilling, process hygiene microbiological criteria, as defined in regulation (ec) no 2073/2005, verify the effectiveness of each plant's food safety management system (which includes ghp and good manufacturing practices (gmp) prerequisite programmes), based on the principles of hazard analysis and critical control points (haccp) systems. generally, smaller slaughterhouses process much smaller quantities of meat for localised markets and operate at a slower line speed. operators in such establishments tend to have a wider skill base than their counterparts in large establishments owing to the many varied roles they perform. however, small slaughterhouses have reduced investment capital for expenditure on premises, equipment and staff food safety management training. disposal of animal by-products and compliance with the microbiological testing regulation (ec) no 2073/2005 places further financial pressure on these lowthroughput businesses. to ameliorate the financial impact of this testing, article 4 in this regulation states that the frequency of this microbiological sampling may be adapted to the nature and size of the food business, based on a standardised risk assessment and authorised by the competent authority. larger slaughterhouses operate more efficiently, with greater separation of duties and better sampling and food safety oversight. these larger units have larger co-product/by-product markets and therefore produce less waste per animal processed. however, the requirement for high-volume throughput with increased slaughter line speed can impinge on operational hygiene and therefore food safety (food standards agency, 2007a; palmer, 2008) . such differences in structure and operational practices in the varying sized slaughterhouses can determine the effectiveness of the food safety management system (motarjemi, 2000). hazard identification and risk ranking 2.1. a hazard is defined by the codex alimentarius commission (cac) as a "biological, chemical or physical agent or property of food with the potential to cause an adverse health effect". the first step in the hazard identification carried out in this assessment focused on identifying biological hazards occurring in small ruminants and small ruminant meat that can be transmitted to humans, where they may cause disease. hazards were identified based on evidence found in peer-reviewed literature, textbooks, through reported data (e.g. eu summary reports on zoonoses), previous assessments and efsa opinions, and the biohaz panel's and working group's expert knowledge. from this "long" list of identified hazards, the panel excluded those hazards: for which no causal relationship between human infections and the handling, preparation and consumption of meat from small ruminants could be documented through targeted literature reviews. not presently found in the small ruminant population in the eu. the final "short" list of identified hazards to be included in the priority ranking consisted of hazards occurring in the eu and for which evidence could be found of foodborne transmission through the handling, preparation and/or consumption of sheep and goat meat. in the context of this opinion, when referring to handling and preparation this should be interpreted as handling of sheep and goat meat that occurs immediately prior to consumption, when these activities are carried out by consumers or professional food handlers. based on a review of the scientific literature, a wide range of biological hazards were identified as potential zoonotic hazards related to small ruminants (see table 1 ). from these, the majority were considered not to be small ruminant meat-borne pathogens, as no evidence could be found in the literature to support transmission through handling, preparation or consumption of small ruminant meat (for further information on hazards not included see annex 1, and section 2.2.3 in this appendix for those for which evidence for meat-borne transmission was documented). other potential pathogenic microorganisms were found not to be relevant as they are not considered to be currently present in small ruminants in europe (chandipura virus, cryptococcus neoformans var. neoformans and hepatitis e virus), or, if they are, consumption of meat is not considered a significant source of infection. the latter situation applies in particular to linguatula serrata, for which contact with the final host (canids) is the source for the human cases described in europe. for some of these hazards (e.g. extended-spectrum β-lactamase-(esbl-)/ampc-carrying escherichia coli), despite their presence in the animal reservoir, no studies have been conducted to establish whether there is a link between consumption of meat from small ruminants and disease in humans. the presence of mycobacteria has been previously reported in the small ruminant population in the eu (domenis et al., 2011; malone et al., 2003; marianelli et al., 2010; . despite these reports, evidence of meat-borne transmission of these pathogens to humans from small ruminants is lacking, so this potential pathway of infection remains unproven in the context of livestock processed through the eu meat inspection system. a more detailed discussion on the potential for meat-borne transmission of mycobacteria can be found in the scientific opinion dealing with bovines (efsa biohaz panel, 2013). the remaining hazards were considered eligible for further assessment and risk ranking ( table 2 ). the panel developed a decision tree that was used for the risk ranking of the small ruminant meatborne hazards according to their risk of causing infection in humans following the handling, preparation and/or consumption of sheep or goat meat ( figure 3 ). the cac defines risk as "a function of the probability of an adverse health effect and the severity of that effect, consequential to one or more hazards in a food". in other words, a foodborne risk is a product of the likelihood of occurrence of the hazard and the magnitude and severity of the consequences of the illness it causes on human health. this decision tree was adapted from that presented in the scientific opinion on poultry meat inspection (efsa panel on biological hazards (biohaz), efsa panel on contaminants in the food chain (contam) and efsa panel on animal health and welfare (ahaw), 2012). however, there are key differences as follows: carcass pathogen prevalence and source attribution are not considered as separate questions, or ranking steps, but these two questions are addressed together in a single step. this modification was considered appropriate as there was insufficient data at eu level for qualifying carcass prevalence and source attribution for the given hazards. furthermore, consumption of meat from small ruminants is both lower and unevenly distributed in the eu relative to that of meat from other animal species such as pigs or poultry. attribution at the population level, as applied in the previous scientific opinions on meat inspection (efsa panel on biological hazards (biohaz), efsa panel on contaminants in the food chain (contam) and efsa panel on animal health and welfare (ahaw), 2011, 2012), may not provide a sufficiently detailed perspective on the relative risk of different hazards in meat from small ruminants. the risk to consumers of meat from these species, rather than to the population as a whole, was therefore assessed. an added consequence is that the categorisation has been reduced from three to two categories (i.e. the medium category is not used in this opinion). the term "priority" has replaced the term "risk" used in the pork and poultry opinions. risk ranking requires a significant amount of data on both the occurrence of the relevant hazards and the fraction of cases of human disease caused by the different hazard-meat species combinations (i.e. source attribution). while there were sufficient data to perform a risk ranking of the hazards associated with pork and poultry, this was not the case for all potential hazards in small ruminants, for which eu-wide baseline surveys and harmonised monitoring do not exist and relevant studies published in the scientific and technical literature are often limited. the term "priority" was therefore considered more appropriate than "risk" for categorising the hazards associated with meat from small ruminants. based on this, the panel identified the following criteria to be important for determining the final priority category: step 1: identifying and excluding those hazards that are introduced and/or for which the risk for public health requires microbial growth during steps that take place after carcass chilling. the reasons for excluding such hazards from further assessment were that: (1) the scope and target of meat inspection are focused on the food safety risks of the carcasses at the end of slaughter when they are chilled but before they are further processed; and (2) hazards introduced and/or for which the risk relates exclusively to growth during post-chilling processes are better controlled later in the food production chain through, for instance, haccp programmes. step 2: to assess the magnitude of the human health impact, as measured by the reported incidence (notification rate) or number of cases. where data allowed, the estimated total number of cases was presented, i.e. adjusting for under-reporting. incidence was considered high if the notification rate in humans at eu level, as reported to ecdc, was equal to or higher than 10 cases in 100 000 population in any given year. step 3: to assess the severity of the disease in humans based on mortality. if necessary, severity was also evaluated by comparing disease burden estimates, expressed for example in disability-adjusted life-years (dalys) per 1 000 cases. the daly metric quantifies the impact of disease on the health-related quality of life of acute diseases and sequelae, as well as the impact of premature deaths. severity was considered high if mortality in humans at eu level, as reported to ecdc, was higher or equal to 0.1 % in more than one year. step 4: evidence supporting the role of meat from small ruminants as a risk factor for disease in humans. for this, the following sources of information were considered: 1. epidemiological link, based on a significant likelihood that the consumption of meat from the given species is a risk factor for human cases, or on outbreak data 2. carcass prevalence /farm level prevalence (prevalence studies) 3. comparative considerations for meat from related species 4. expert opinion that meat consumption is a risk factor. the final outcome of this process involved categorising each hazard as high or low priority, as follows: the priority was characterized as 'high' when a hazard was identified as causing a high incidence and/or severity of illness in humans, and when strong evidence existed for meat from sheep or goats being an important risk factor for human disease. considering the limitations of the data available for the priority ranking, this risk category could be regarded as combining both the medium and high risk categories of the risk ranking carried out in the poultry meat inspection opinion (efsa panel on biological hazards (biohaz), efsa panel on contaminants in the food chain (contam) and efsa panel on animal health and welfare (ahaw), 2012); the priority was characterized as 'low' when a hazard was identified as not associated with a high incidence and a high severity of human disease or if, despite the hazard causing a high incidence and/or severity in humans, the evidence available did not identify meat from sheep or goats as an important risk factor for human disease; all hazards placed in the low priority category were further evaluated to determine if this was low due to currently controls applied (i.e. any hazard specific control measure implemented at farm and/or slaughter level before chilling of the carcass, including meat inspection procedures). if this was not the case, the hazard was not considered further. however, if this was the case then the hazard was further considered and the effect of any recommendations regarding the removal of specific control measures or meat inspection activities on these hazards was assessed and the categorisation of the hazard was reconsidered. figure 3 : flowchart for priority ranking different public health hazards. 1 risk of infection by handling, preparation or consumption of sheep and/or goat meat. 2 current controls: any hazard-specific control measures implemented at farm and/or slaughterhouse level before chilling of the carcasses. for the hazards shortlisted (table 2) , data on the incidence and severity in humans and the prevalence of the pathogens in the carcasses of small ruminants were sought to allow the risk from these microbiological hazards to be ranked, based on the decision tree in figure 3 . see tables 3, 4, 5 and 6 for details. the data in table 3 were obtained from the european surveillance system (tessy), covering the years 2008, 2009, 2010 and 2011 . the data are officially reported to the european centre for disease prevention and control (ecdc) by eu mss; however, some countries do not report on certain diseases; these were specified. the data were supplied as aggregates from all reporting mss. data show notification rates of confirmed human disease cases as per 100 000 persons, and severity of illness in humans. cases include all reported confirmed occurrences of the disease, regardless of the origin of the infection. in fact, establishing the food-related origin of infection is often not possible and seldom reported. the data on severity include as a proxy the proportion of confirmed human cases that died. this information is usually only available in a small proportion of cases. finally, it has to be kept in mind that the surveillance systems are set up differently in the various eu mss, with different case definitions, national or restricted coverage, voluntary or compulsory reporting, focus, target groups, etc., in addition to the fact that only a small fraction of diseased patients is sampled and the casual organism typed and reported to the respective national health institutes. because of all these caveats, the incidence and severity figures quoted here are only approximate and must be considered with caution. n.a. h a eu population data based on individual ms population sizes reported in eurostat (data extracted: september 2012). when the given hazard was not reported by a ms to tessy, the population size reported by that ms was also taken out of the calculation of the overall eu population size. b calculated as the percentage of cases with fatal outcome over all cases of disease with known outcome, for a given hazard. c portugal, greece not reporting. d portugal not reporting. for a more detailed review of vtec (including serotype o157) incidence and severity in the eu see the recently published efsa opinion on vtec-seropathotype and scientific criteria regarding pathogenicity assessment (efsa panel on biological hazards, 2013). e portugal not reporting. f s. enterica subsp. enterica serovar typhi and s. paratyphi serovars not included; netherlands not reporting. g seroprevalence. belgium, denmark, greece, italy, netherlands, portugal and sweden not reporting; spain reporting through the sentinel system and thus not taken into account. france not reported in 2011 at the time of extraction of these data. h n.a. = not available. data presented in tables 4-6 are related to flock/herd and carcass prevalence of the hazards identified in sheep and goats. they were obtained from monitoring data as reported by the eu mss in the frame of the zoonosis directive (2003/99/ec), when available. data reported in the period from 2007 to 2010 were considered. no information was available at carcass level for goats. in these tables, data described as originating from suspect or selective sampling and from clinical investigations were excluded as they do not, in most cases, represent the actual epidemiological situation. food samples described as collected for haccp and own-check purposes were also excluded because the sampling scheme may be biased. samples included are described as originating from control and eradication plans and monitoring and surveillance; consequently they are supposed to represent the occurrence of the zoonotic agent in the reporting country over the years, based on objective sampling. however, it has to be noted that monitoring and surveillance systems for most of zoonotic agents are not fully harmonised between mss. furthermore, data may not necessarily be derived from sampling plans that have a sound statistical design, and may therefore not accurately represent the national situation regarding the true prevalence of zoonoses. data in tables 4 and 6 originate from samples taken from either farms or slaughterhouses, while for table 5 28.0 (0-100) a n.a., no data available. b includes those reported as human pathogenic and non-human pathogenic (i.e. no harmonised scheme to discriminate between both, and data available does not preclude that they are not human pathogenic). c seroprevalence. includes those reported as human pathogenic and non-human pathogenic (i.e. no harmonised scheme to discriminate between both, and data available does not preclude that they are not human pathogenic). c seroprevalence. includes those reported as human pathogenic and non-human pathogenic (i.e. no harmonised scheme to discriminate between both, and data available does not preclude that they are not human pathogenic). c seroprevalence. listeria monocytogenes and toxins of bacillus cereus, clostridium botulinum, clostridium perfringens and staphylococcus aureus were all considered to fall within the category of risk related to growth or introduction post-chilling, for different reasons: b. cereus, c. botulinum and c. perfringens and their spores and s. aureus are considered ubiquitous bacteria, and can be found in a variety of foods. their vegetative forms need temperatures above those used for refrigeration to grow in raw meat to concentration levels of relevance for public health and thus the risk of disease seems not to be correlated with occurrence in raw meat but rather with improper hygiene and storage that allows the production of toxins. illness caused by l. monocytogenes is usually associated with ready-to-eat products, in which contamination has occurred before or during processing followed by growth during storage at refrigeration temperatures. based on incidence and severity in humans (table 3) , flock/herd, animal and carcass prevalence (tables 4, 5 and 6) and other epidemiological evidence, the hazards in table 2 were ranked and categorised according to the flowchart in figure 3 , as described in section 2.2.1 above. a summary of the outcome is provided in table 7 at the end of this section. none of the hazards identified as low priority were found to be such owing to currently applied controls. this organism has a worldwide distribution, persisting in the soil in the form of extremely resistant spores for many years. infection is initiated with the introduction of the spore through a break in the skin or entry through the mucosa. after ingestion by macrophages at the site of entry, germination to the vegetative form occurs, followed by extracellular multiplication and capsule and toxin production. humans can acquire anthrax by exposure to infected animals, animal products or spores in the soil and, depending on the mode of transmission, can develop one of four distinct clinical forms: respiratory, cutaneous, gastrointestinal and oropharyngeal. human cases of pulmonary anthrax have been linked to the large-scale processing of hides and wool in enclosed factory spaces, where aerosolised anthrax spores may be inhaled. humans also acquire the cutaneous form of anthrax from handling contaminated animal products, such as hides, wool and hair. cases of gastrointestinal anthrax have resulted from the ingestion of raw or undercooked meat (spickler, 2007) and well-cooked beef from infected animals (centers for disease control and prevention, 2000) . recently, a case of anthrax possibly acquired through handling or consumption of contaminated beef in a household in romania has been reported (popescu et al., 2011) . consumption of meat (including sheep and goat meat) from carcasses of animals showing clinical signs of anthrax, or animals that have died from the disease, is the most reported common route of foodborne infection resulting in gastrointestinal anthrax. human incidence: based on eu data, low. anthrax has a low human prevalence in the eu (see table 3 for details). between 2008 and 2011, the number of anthrax cases reported to the ecdc ranged from two confirmed cases (2008) severity of disease: based on eu data, high. the severity of these infections is considered high, and this is supported by the mortality figures in table 3 . evidence for meat from small ruminants as an important risk factor: no. the organism causes a highly infectious notifiable disease in farmed and wild animals that have grazed on contaminated land or ingested contaminated feed (swartz, 2001) . the livestock species most susceptible, in descending order, are cattle, sheep, horses, pigs, goats and camels (fasanella et al., 2010a) . the disease is endemic in most countries in africa and asia (thurnbull, 1998) and in defined regions of other countries. flooding may often concentrate spores of b. anthracis in particular locations. in sheep and goats, the disease is usually peracute, or acute and rapidly fatal, with death occurring in some cases within hours and affected animals showing multiple haemorrhages from natural orifices. although most cases are found dead without showing premonitory signs, pyrexia with temperatures up to 42 c along with depression, congested mucosae and petechiae may be observed ante-mortem. post-mortem findings are characterised by incomplete rigor mortis, widespread ecchymotic haemorrhages and oedema, dark, unclotted blood and blood-stained fluid in body cavities and severe splenomegaly (quinn et al., 2002) . handling, or direct contact with such animals and carcasses is highly dangerous. anthrax is now rare in livestock in the eu. the major enzootic areas are greece, spain, france and southern italy (fasanella et al., 2005; fouet et al., 2002) . a severe outbreak of anthrax occurred in southern italy in (fasanella et al., 2010b . over 41 days, 81 cattle, 15 sheep, 9 goats, 11 horses and 8 deer died. also in italy, an outbreak of anthrax of similar magnitude was reported among cattle, sheep and horses in 2011 11 . given the low number of cases of anthrax in the small ruminant population in the eu, the risk of acquiring this disease through consumption of meat from these species can be considered very low. based on the data presented and on the above discussions, the biohaz panel concluded that b. anthracis was a low priority hazard with regard to meat inspection of small ruminants. this result is not due to current controls (i.e. any hazard-specific control measures implemented at farm and/or slaughter level before chilling of the carcasses, including current meat inspection procedures). human incidence: based on eu data, high. campylobacteriosis is the most frequently reported zoonotic illness in the eu with a reported incidence of 71.5 confirmed cases per 100 000 in 2011 (table 3) , and it is estimated that there are nine million cases of illness annually in the eu-27 (efsa panel on biological hazards, 2010). severity of disease: as the incidence is high, the severity does not need to be considered. campylobacter jejuni is common in the intestines of ruminants of sheep and lambs. the reported prevalence of campylobacter spp. in sheep and goats can be found in tables 4, 5 and 6. for sheep and at flock level, the prevalence was 8.1 %, while for goats it was 3.7 % (at individual animal level there were 2.7 % and 4.7 %). with regards to carcasses, no data were available for goats. for sheep, the batch prevalence was 0 %, and at individual sample level 1.8 %. information from the scientific literature also suggests that campylobacter spp. is often found in small ruminants, with a wide range of prevalences reported. in a study of lambs in the united kingdom campylobacter spp. was isolated from 92 % of the 360 samples taken from the small intestines (stanley et al., 1998) . on the other hand, sproston et al. (2011) found this bacterium in just 14 % of fresh faecal samples from 214 sheep on a farm in scotland. other studies have reported prevalences somewhere in between these two figures (milnes et al., 2008; ogden et al., 2009; oporto et al., 2011; schilling et al., 2012) . a seasonal variation in prevalence and the number of campylobacter spp. has also been reported in some studies (milnes et al., 2008; sproston et al., 2011) . several studies have investigated the presence of campylobacter spp. in carcasses or meat from small ruminants. garcia et al. (2010) investigated the presence of campylobacter spp. on 80 sheep carcasses, with a resulting prevalence of 90 %. the authors concluded that the prevalence on carcasses reflected the occurrence of campylobacter spp. in both wool and faeces. however, there is a significant reduction in detection following chilling, probably owing to both the low temperature and drying of the carcass (norwegian scientific committee for food safety, 2012). after swabbing of 100 cm 2 around the circum-anal incision of 60 lamb carcasses before chilling campylobacter spp. was isolated from eight (13.3 %) of the carcasses. after a relatively slow chilling process (the air temperature was never below 0 °c) campylobacter spp. was recovered from only one carcass ( for contact with sheep as a risk factor for human campylobacteriosis, but consumption of meat from these species was not considered a risk factor. an earlier case-control study in households with primary campylobacter spp. infection in the netherlands also failed to identify consumption of mutton as risk factor (oosterom et al., 1984) finally, people that had consumed mutton were less likely to become ill with campylobacter spp. infection in a prospective case-control study of campylobacteriosis carried out in norway (kapperud et al., 2003) . like their sensitive counterparts, antimicrobial-resistant campylobacter spp. involved in human disease are mostly spread through foods, especially poultry meat. as stated in a previous efsa opinion (efsa, 2008) , "a major source of human exposure to fluoroquinolone resistance via food appears to be poultry, whereas for cephalosporin resistance it is poultry, pork and beef that are important, these food production systems require particular attention to prevent spread of such resistance from these sources". there are no indications that resistant strains behave differently in the food chain compared with their sensitive counterparts, hence there is no need to consider these strains separately in the context of meat inspection. based on the presented data, it is concluded that campylobacter spp. are a low public health priority with regard to meat inspection of small ruminants. this ranking is not the result of current controls. verocytotoxin/shiga toxin (vt/stx)-producing e. coli (vtec/stec) are characterised by the ability to produce potent cytotoxins. pathogenic vtec usually also harbour additional virulence factors that are important for the development of the disease in human (efsa and ecdc, 2012, 2013b) . not all vtec strains have been associated with human disease and there is no single marker or combination of markers that defines a "pathogenic" vtec (efsa panel on biological hazards, 2013). while stx2and eae gene-positive strains are associated with a high risk of more serious illness, other virulence gene combinations and/or serotypes may also be associated with serious disease in humans. for the purposes of this opinion, pathogenic vtec are defined as vtec capable of causing disease in humans. human incidence: based on eu data, low. most reported meat-borne human vtec infections are sporadic cases. in 2010 (efsa and ecdc, 2012), the total number of confirmed vtec cases in the eu was 4 000, representing a 12.0 % increase compared with 2009, with a fatality rate of 0.39 %. table 3 includes data from tessy from 2008 to 2011 inclusive. in that period the incidence (all vtec serotypes) per 100 000 population varied between 0.86 and 2.56. the data are not easily comparable between eu countries, owing to underlying differences in the national surveillance systems. the concentration of laboratory testing on the o157 serogroup means that the proportion of non-o157 strains is largely under-reported (ecdc and efsa, 2011) . data for 2011 have to be interpreted with caution, as vtec o104:h4 caused a major outbreak which resulted in 4 321 confirmed cases, including 3 469 cases of vtec infection and 852 of acute renal failure, known as haemolytic-uraemic syndrome (hus), with 54 deaths reported in 14 eu countries, the united states and canada when the epidemic was declared to be over at the end of july 2011 (karch et al., 2012) . it has to be noted, however, that the source of the outbreak was sprouted seeds and not meat. severity of disease: based on eu data, high. pathogenic vtec infections can be severe, and are often associated with bloody diarrhoea, but there is a wide clinical spectrum in the association between specific subtypes of pathogenic vtec and the clinical outcome. bloody diarrhoea has been shown to be associated with an increased risk of developing hus and neurological injury, such as paralysis. hus develops in up to 10 % of patients infected with vtec o157 and is the leading cause of acute renal failure in young children (efsa and ecdc, 2012) . this is reflected in the severity figures in table 3 and the corresponding classification in table 7 , which are also supported by high daly (havelaar et al., 2012a) and quality-adjusted lifeyear (qaly) estimates (hoffmann et al., 2012) published in the literature. evidence for meat from small ruminants as an important risk factor: yes. pathogenic vtec can be found in the gut of numerous animal species, but ruminants have been identified as a major reservoir of vtec that are highly virulent to humans, in particular vtec o157. although cattle are considered to be the most important source of human infections caused by vtec o157, they have also been isolated from the intestinal contents of sheep and goats. food of small ruminant origin has been reported as a source for human vtec infections (kosmider et al., 2010; schimmer et al., 2008; werber et al., 2007) . transmission occurs through consumption of undercooked meat, unpasteurised dairy products, or water and vegetables contaminated by faeces of carriers. person-to-person transmission has also been documented (rey et al., 2006) . data reported in the frame of the zoonoses directive (2003/99/ec) from 2004 to 2011 can be found in tables 4-6. for all vtec serotypes, the reported prevalence was 11.6 % and 4.4 % for sheep at flock and individual animal level, respectively. for goats, the figures were 13.0 % and 10.9 %. prevalences for vtec o157 were much lower across the board. isolation of e. coli o157 from goats has been reported in studies from several countries, with isolation rates ranging between 2 % and 89 % (cortes et al., 2005; keen et al., 2006; orden et al., 2008; orden et al., 2003; schilling et al., 2012) . vtec strains have also been detected in sheep, with a similarly wide range of prevalence figures (milnes et al., 2008; oporto et al., 2008; prendergast et al., 2011; pritchard et al., 2009; schilling et al., 2012; sekse et al., 2011) . thus it is clear that small ruminants can play an important role by shedding these pathogens in the faeces (blanco et al., 2003; la ragione et al., 2009) . the prevalence can be influenced by the sampling and testing methodology, but these studies nevertheless clearly indicate that pathogenic vtec is present in the small ruminant population in the eu. table 5 includes data from official monitoring of sheep carcasses. the reported prevalence was 0 % at batch level and 0.8 % at individual carcass level (0.2 % for vtec o157). the scientific literature also indicates that sheep and goat carcasses or meat can be contaminated with vtec, albeit generally at lower levels compared with those in the animal reservoir. at the higher end of the range, barlow et al. (2006) in australia and zweifel et al. (2003) in switzerland reported prevalences around 40 % in carcasses and lamb cuts. brooks et al. (2001) reported a prevalence of 17 % in lamb cuts in new zealand and other, less recent, studies reported much lower prevalence-between 0 % and 4 % (doyle and schoeni, 1987; heuvelink et al., 1999; pierard et al., 1997; samadpour et al., 1994) . it has to be noted that this variation in prevalence could be a result of the different testing methodologies used (e.g. use of polymerase chain reaction (pcr) testing), and the fact that not all these vtec isolates would necessarily be pathogenic to humans. a case-control study on risk factors for human vtec in germany identified lamb as an important risk factor for human infection (werber et al., 2007) . consumption of dry cured sausages made with sheep meat was identified as the cause of an outbreak of vtec o103:h25 infection in humans (schimmer et al., 2008; sekse et al., 2009 ). in the latter study, bacteria with the same properties, including identical dna profiles, were found in five dry cured sausage products and sheep meat used as raw material in sausage production and were identical to the isolates from patients. e. coli with the same virulence genes, serotypes, biochemical characteristics and dna profiles as those found in patients from the e. coli o103:h25 outbreak, were detected in sheep from 29 of 491 farms in norway (brandal et al., 2010) . more recent research in norway and spain comparing virulence characteristics between strains isolated from humans and sheep has suggested that the latter can be an important reservoir for pathogenic vtec (brandal et al., 2012; sanchez et al., 2012) . the evidence arising from epidemiological or source attribution studies points to a minor role for meat from small ruminants as a source of human cases of vtec, although the model used in this study was found to underestimate the observed prevalence of vtec in lamb, so this attribution estimate should be interpreted with caution (kosmider et al., 2010) . based on the data (see table 7 ) and the assessment presented above, the biohaz panel concluded that pathogenic vtec can be considered to be of high priority for meat inspection of small ruminants given the relatively high prevalence of this hazard in the small ruminant population, the epidemiological links to outbreaks in humans and the severity of the disease in humans. human incidence: based on eu data, high. in the eu, s. enterica subsp. enterica serovar enteritidis and s. typhimurium are the serovars most frequently associated with human illness, although the number of reported cases of s. enteritidis has more than halved since 2006. human s. enteritidis cases are most commonly associated with the consumption of contaminated eggs and poultry meat, while s. typhimurium cases are mostly associated with the consumption of contaminated pig, poultry and bovine meat. human salmonellosis is the second-ranking foodborne disease reported in the eu and most european countries, exceeded only by campylobacteriosis (efsa, 2008; efsa and ecdc, 2013b) . a total of 94 264 confirmed cases were reported from 27 eu mss in 2011 through tessy, corresponding to a notification rate of 20.37 confirmed cases per 100 000 (table 3 , which also includes data on the severity of human disease). accounting for under-reporting, it is estimated that there are six million cases of this illness annually in the eu-27 (efsa, 2011; havelaar et al., 2012b) . severity of disease: as the incidence is high, the severity does not need to be considered. evidence for meat from small ruminants as an important risk factor: no. the common reservoir of salmonella spp. is the intestinal tract of a wide range of domestic and wild animals, which results in a variety of foodstuffs, of both animal and plant origin, as sources of human infections. the organism may be transmitted through direct contact with infected animals or between humans or from faecally contaminated environments. in animals, subclinical infections are common. the organism may easily spread between animals in a herd or flock without detection, and animals may become intermittent or persistent carriers. the variant, s. enterica subsp. diarizonae iiib 61.k:1,5, (7), which might be referred to as "the sheep variant" owing to its adaption to sheep, is endemic in sheep in several regions of the world such as the united kingdom (hall and rowe, 1980) and norway (norwegian scientific committee for food safety, 2008) in europe and canada (greenfield et al., 1973; pritchard, 1990 ) and the united states (weiss et al., 1986 ). however, the overall conclusion is that s. enterica subsp. diarizonae iiib 61.k:1,5, (7) is very rarely demonstrated as a cause of human infections, including in those areas in which the endemic prevalence in sheep is high such as the united kingdom and norway ((norwegian scientific committee for food safety, 2008). another salmonella spp. variant well adapted to sheep, causing abortion and death of ewes, is s. brandenburg, which is endemic in the south island of new zealand (sabirovic, 2002) , but its human health relevance seems to be limited. eu monitoring data for sheep and goats are presented in tables 4-6 , which contain data collected by mss from 2004 to 2011. the prevalence reported in both herds and individual animals is 7.2 % and 5.7 %, respectively, for sheep and 3.1 % and 1.5 % for goats. although salmonella spp. is commonly found in live sheep or goats at variable prevalence levels (bonke et al., 2012; duffy et al., 2009; duffy et al., 2010; hjartardottir et al., 2002; moriarty et al., 2011; zweifel et al., 2004) , there is a more limited number of studies looking at the occurrence of salmonella spp. in sheep and goats carcasses. a prevalence of 0. 3% was reported in individual sheep carcasses in the eu monitoring (see table 5 ). some outbreaks linked to meat from small ruminants can be found in the scientific literature (evans et al., 1999; hess et al., 2008; synnott et al., 1993) . these involved unusual consumption patterns (e.g. raw lamb liver) or cross-contamination of raw food ingredients (e.g. yoghurt relish contaminated with carcass blood), therefore it is unclear how significant these events are when assessing the role of sheep or goat meat as a source of salmonella spp. infection. data from epidemiological or source attribution studies suggest that the role of meat from small ruminants as a vehicle for salmonella spp. the occurrence of antimicrobial resistance among zoonotic salmonella spp. is an increasing problem. antimicrobial-resistant salmonella spp. involved in human disease are, like salmonella spp. in general, mostly spread through foods, predominantly poultry meat, eggs, pork and beef (hald et al., 2007) . as there are no indications that resistant strains behave differently from their sensitive counterparts in the food chain, there is no need to consider these strains separately in the context of meat inspection. fluoroquinolone and cephalosporin resistance are currently considered to be those of most public health concern. meat, particularly poultry meat and pork, is recognised as an important source of human exposure to fluoroquinolone-resistant salmonella spp., and high levels of esbl-/ampc-producing salmonella spp. have also been reported in poultry in some eu mss (efsa and ecdc, 2013a). such resistant strains may or may not be associated with a significant level of human infection, depending on the pathogenicity of the strains involved and the opportunity for them to contaminate the food chain (butaye et al., 2006; de jong et al., 2012; efsa panel on biological hazards, 2011c; rodriguez et al., 2012) . the control of antimicrobial-resistant bacteria in food including poultry meat is further complicated by the fact that resistance mechanisms can be located on mobile genetic elements such as plasmids and thereby be transferred between different bacterial species, for instance between generally apathogenic e. coli and salmonella spp. based on the data (see table 7 ) and the assessment presented above, the biohaz panel concluded that the risk arising from consumption of meat from small ruminants with regards to salmonella spp. is of low priority for meat inspection of small ruminants. this ranking is not the result of current controls. human incidence: based on eu data on congenital toxoplasmosis, low. toxoplasmosis can be contracted by the oral ingestion of oocysts present in cat faeces and the environment, or tissue cysts present in the meat of infected animals (tenter et al., 2000) . in pregnant women, the parasite can cause congenital infections (abortion, stillbirth, mortality and hydrocephalus in newborns or retinochoroidal lesions leading to chronic ocular disease) and complications (lymphadenopathy, retinitis or encephalitis) in immunocompromised individuals such as organ graft recipients and individuals with acquired immune deficiency syndrome (aids) or cancer (efsa, 2007b) . in immune-competent individuals, 80-90 % of cases of toxoplasma gondii infection are asymptomatic, and the majority of the remainder have only mild, self-limiting symptoms. thus, reports of acute symptomatic t. gondii infection (toxoplasmosis) do not provide a reliable basis for assessing overall disease incidence. given these limitations, the incidence of human disease caused by toxoplasmosis is rare ( table 3 ). the prevalence of antibodies to t. gondii in the general population provides an alternative for estimating the number of cases and disease burden (food standards agency, 2011). t. gondii seroprevalence is known to vary geographically and with age (montoya and liesenfeld, 2004). although antibodies are found in 20-40 % of adults in the united kingdom, seroprevalence is higher in central europe, and similar or lower in scandinavia (11-28 %). climate and consumption of raw meat, meat from animals farmed outdoors or frozen meat may be factors that contribute to these variations (kijlstra and jongert, 2008) . seropositivity also varies within countries, being highest in those from rural or small town backgrounds and lowest in those from urban or suburban areas (food standards agency, 2011). data showing the variation in seropositivity with age are available from a number of countries. for example, in the netherlands, it was found to range from 20 % at 25 years of age to 60 % at 50 years (efsa, 2007b; hofhuis et al., 2011) . there is evidence of a sharp decrease in seroprevalence over the last 40 years in many populations. for example, in 1960 there was a reported seroprevalence of 82 % in france, falling to 44 % in 2003 (afssa, 2005) . this decrease is in part attributable to a decrease in infection in childhood, probably associated with increased standards of living, and has also been linked to changes in meat husbandry and consumption. severity of disease: based on eu data for congenital toxoplasmosis, high. owing to the lifelong impact of symptoms related to toxoplasmosis, the burden of disease is high. mead et al. (1999) showed that t. gondii ranked fourth in hospitalisations and third concerning deaths when compared with other foodborne pathogens. more recent research ranked t. gondii among the highest in population burden estimates (daly or qaly) among 14 foodborne pathogens from both an individual and a population perspective (havelaar et al., 2012a; hoffmann et al., 2012) . evidence for meat from small ruminants as an important risk factor: yes. the relative role of t. gondii oocysts in the environment versus tissues cysts in meat and meat products as a source of infection for humans could not be determined by laboratory tests until recently. hill et al. (2011) have developed a test to identify a sporozite specific antigen which will be a useful tool in providing information on the relative importance of oocysts as the agent of infection. until this recent development, source attribution information came from epidemiological studies. in europe, three large case-control studies have pinpointed uncooked meat as the most important risk factor for pregnant women (baril et al., 1999; cook et al., 2000; kapperud et al., 1996) . with regard to the prevalence in the animal population, despite t. gondii infection being a major cause of abortion and stillbirth in sheep and goats in the eu, most infections exist subclinically in flocks/herds (dumetre et al., 2006) . in response to natural infection, seropositive sheep have been shown to harbour infectious parasites as tissue cysts (dubey et al., 2008; kijlstra and jongert, 2008; opsteegh et al., 2011) . antibodies to t. gondii and tissue cysts persist in infected sheep (dubey, 2009 ). this implies that serological tests can be used to estimate the number of animals carrying t. gondii tissue cysts in the meat and thereby indicate the risk for public health (opsteegh et al., 2010b) . seroprevalence increases with increasing age (dubey, 2009; halos et al., 2010) , and sheep and goats are identified as the main source of infected meat in southern european countries (berger et al., 2007; dumetre et al., 2006) . seroprevalence of t. gondii in sheep can range from 4 % to 92 % in certain european countries (efsa, 2007b) . limited data available in slaughtered sheep report seropositive rates of 16-66 % in europe (dumetre et al., 2006; tenter et al., 2000) . seroprevalence in farmed goats in europe ranges from 4 % to 77 % (efsa, 2007b) . no data have been published about seroprevalence in slaughtered goats in europe, but findings in goats in non-european countries range from 0 % to 40 % (efsa, 2007b; tenter et al., 2000) . data reported by eu member states under the zoonoses directive (2003/99/ec), showing a relatively high seroprevalence for this hazard in flocks/herds and individual animals, can be found in tables 4-6 . notwithstanding this, significant uncertainty remains regarding this hazard. the prevalence of toxoplasmosis in humans and its importance in terms of overall disease burden still requires research. despite the development of recent laboratory procedures, the proportion of human toxoplasmosis attributable to the consumption of sheep meat is unknown. furthermore, the relationship between seropositivity in sheep and the number of viable tissue cysts in edible tissue has yet to be established (food standards agency, 2011). these uncertainties hinder the development of control procedures for this hazard. with regard to the role of meat from small ruminants as a risk factor for human toxoplasmosis, a prospective case-control study designed to identify preventable risk factors for t. gondii infection in pregnancy, conducted in norway (kapperud et al., 1996) found eating raw or undercooked mutton to be independently associated with an increased risk of maternal infection (or = 11.4, p = 0.005). in the case-control study carried out by baril et al. (1999) , an odds ratio of 3.1 was estimated for the consumption of undercooked or raw mutton/lamb. the same odds ratio was obtained for the consumption of undercooked or raw mutton/lamb in the study carried out in 2000 (cook et al.) . in addition, raw or undercooked lamb meat is considered a delicacy in certain countries, such as france, and is therefore considered an important source of infection in that country (afssa, 2005) . this has been recently corroborated by a report of an outbreak of toxoplasmosis linked to the consumption of undercooked lamb (ginsbourger et al., 2012) . given its high seroprevalence in sheep and goat meat and the correlation of human infection to animal incidence, t. gondii in sheep and goat meat was considered by the panel to be of high priority for meat inspection of small ruminants within the eu (see table 7 ). based on the priority ranking, the hazards were classified as follows: t. gondii and pathogenic vtec were classified as high priority for sheep/goat meat inspection. the remaining identified hazards, b. anthracis, campylobacter spp. (thermophilic) and salmonella spp., were classified as low priority, based on the available data. as new hazards might emerge and/or hazards that presently are not a priority might become more relevant over time or in some regions, both hazard identification and the risk ranking should be revisited regularly to reflect this dynamic epidemiological situation. particular attention should be given to potential emerging hazards of public health importance that arise only in small ruminants. to provide a better evidence base for future risk ranking of hazards, initiatives should be instigated to: improve and harmonise data collection of incidence and severity of human diseases caused by relevant hazards. systematically collect data for source attribution. collect data to identify and risk rank emerging hazards that could be transmitted through handling, preparation and consumption of sheep and goat meat. protection of public health is the top priority objective of meat inspection. the origin of western european meat inspection goes back to the end of the 19th century, when it became obvious that meat could play a role in the transmission of disease, particularly tuberculosis, and that the trade in animals, meat and meat products needed some sort of safety and quality assurance (johnson, 2009; theves, 2002; von ostertag, 1892) . the first meat inspection act was drawn up in 1900 by professor ostertag at the university of berlin. there is no doubt that the meat inspection procedures were highly risk based at that time. ever since, an ante-mortem and post-mortem inspection has been carried out at individual animal level in cattle and it has been extended to other species. the ante-mortem inspection is a simple clinical examination aimed at identifying sick or abnormal animals, as well as assessing the level of cleanliness of the animals entering the slaughtering process. the post-mortem inspection is a pathological-anatomical examination aiming at detecting and eliminating macroscopic abnormalities that could affect the fitness of meat for human consumption. it is based on visual inspection, palpation, incision and, when required, laboratory examination. postmortem inspection is laborious and expensive. the previous situation of slaughtering a few animals originating from a farm has evolved into large numbers of uniform, relatively young and healthy animals presented for slaughter, which have a common genetic background and prior history. at the same time, it is common to find mixed batches of animals arriving at the slaughterhouse, having been assembled at markets and where several farms have each contributed a few animals. transport can also increase the level and/or duration of shedding of pathogens, as well as the surface contamination of animals with pathogens via animal-animal or animal environment-animal contacts in the vehicle, at the market or in the lairage. therefore, it can be assumed that the food/meat safety risks increase as the number/frequency of movements of animals between farm and slaughter increases (scientific committee on veterinary measures relating to public health (scvmph), 2003). the current state of meat inspection in the eu and six selected exporting countries outside the eu has been reviewed and summarised recently in an external report. 12 for further, more detailed information on the current eu meat inspection system, the reader is referred to that report. still, irrespective of the meat inspection procedures in place, it is well recognised that small ruminants presented at slaughter can be carriers of zoonotic microorganisms (see section 2.2.3 above), which cannot be detected during ante-and post-mortem inspections. in the following section, an assessment of the strength and weaknesses of the current practices for protection of public health will be given. the food chain information (fci) principle includes a flow of information from farm to slaughterhouse in order to help classify the batch of animals according to its expected food safety risk, so that slaughter procedures and/or decisions on fitness for consumption can be adapted to the health status and food safety risk presented by the batch of sheep or goats. regulation (ec) no 2074/2005 also requires the feedback of information from slaughterhouse to farmers, describing also the information that has to be provided (appendix to annex i of the regulation). fci is recorded at the flock/batch level and its minimum content is described in regulation (ec) no 853/2004. fci related to primary production of flocks or herds is based on a farmer's declaration. most mss have made available a standardised fci declaration form to farmers (e.g. ireland, the united kingdom, italy, france). fci must be checked for completeness and content as part of antemortem inspection. in theory, fci may be used to adapt ante-and/or post-mortem inspections. fci serves as a channel of communication between the primary producer and the inspectors at the slaughterhouse. this, theoretically, facilitates the process of evaluating the health of incoming batches and prevents sick or abnormal animals entering the slaughterhouse, by providing early data on probable disease conditions that may be present in the flock or herd. this is based on information related to the on-farm health status of the animals (occurrence of disease, veterinary treatments, specific laboratory testing). the main benefit of the food chain information is that it may create an awareness among primary producers of the need for high standards of animal health and welfare, proper identification of animals and appropriate use of medicines. by contributing to the overall health of the animals sent to slaughter, such a system should have a positive impact on public health by ensuring that the animals are less likely to carry hazards of public health importance. in practice, ante-or post-mortem inspections of sheep and goats are rarely adapted to take account of fci. the main reason that current fci is insufficiently utilised is because of the lack of adequate and harmonised indicators that could help in classifying the animals according to the risk to public health they may pose. the food safety relevance of fci is often limited because the data that it contains is very general and does not address specific hazards of public health importance. also, farmers might not be in a position to properly assess the presence of relevant hazards. feedback of the results of the meat inspection process to farmers is not implemented in all mss to the full extent foreseen in the legislation. the flow of information back to the farm is not straightforward in the absence of a fast and reliable animal movement tracing system, e.g. through the use of electronic individual animal identification linked to a database containing information on the movements of animals (e.g. change of farm, last farm). for example, in ireland between 15 % and 50 % of small ruminants come to the slaughterhouse from assembly centres or markets (efsa, 2012) . in this case, it is difficult to consider a batch of small ruminants as an epidemiological unit. good feedback to farmers also requires harmonisation of the reasons for condemnation and the systematic use of the same terminology for each reason for condemnation. the ante-mortem clinical examination is carried out to evaluate the health and welfare of the animals, and to prevent sick or abnormal animals entering the slaughterhouse. this is a visual-only inspection, consisting of the identification of clinical signs of a disease and an assessment of the cleanliness of the incoming animals. it is performed at the individual level in sheep and goats. the public health-related strengths of ante-mortem inspection include inspection of individual animals for signs of disease and animal identification. ante-mortem inspection also helps in identifying dirty animals, as required by current legislation. regulation (ec) no 852/2004, annex i requires primary producers to ensure the cleanliness of animals going to slaughter. regulation (ec) no 853/2004 annex ii, section ii states that food business operators, operating slaughterhouses, must have haccp-based intake procedures to guarantee that each animal or, where appropriate, each lot of animals accepted on to the slaughterhouse premises are clean. regulation (ec) no 854/2004, annex i, section ii, chapter iii states that animals with hides, skins or fleeces posing an unacceptable risk of contamination to meat during slaughter cannot be slaughtered for human consumption unless they are cleaned beforehand. adjustments can be made to the slaughter process depending on how dirty the batch of sheep or goats is. current pre-slaughter control procedures include: rejection of dirty lots, washing of animals, fleece/hide trimming or clipping (at the farm or at the slaughterhouse, either pre-or post-slaughter), and slaughter of dirty animals at the end of the day (byrne et al., 2007) . dirty animals that are presented for slaughter are rejected at ante-mortem inspection until their fleece/hide condition improves. suppliers are sometimes penalised financially through reduced price and the cost imposed by remedial actions required to improve fleece/hide condition. certain countries have adopted such measures as part of a "clean livestock policy". these policies were adopted to meet the requirements of the hygiene package and have proved to be effective in reducing the risk posed by dirty sheep (see section 4.4.2 below). from a public health perspective, ante-mortem examination is of no value in the detection of toxoplasmosis in small ruminants, as animals infected with this previously identified hazard do not show clinical signs. despite the haccp-based intake procedures guaranteeing the health, welfare and cleanliness of animals going for slaughter, it is difficult to identify animals infected with pathogenic vtec and other enteric pathogens. supplying clean animals reduces, but does not prevent, the possibility of introducing this invisible hazard as infected animals are asymptomatic transient shedders (duffy, 2003) . post-mortem inspection of carcasses is designed to detect and withdraw from the food chain any carcass or part thereof that has grossly identifiable abnormalities that could affect its meat safety or wholesomeness. the meat inspector examines external and internal surfaces of the carcass and internal organs after evisceration for disease conditions and contamination that could make all or part of the carcass unfit for human consumption. generally, inspection procedures include mainly visual examination of the carcass and offal. these procedures are described in annex i, section iv, chapter ii of regulation (ec) no 854/2004. palpation is compulsory for liver, lungs and their lymph nodes. in addition, palpation is mandatory for the umbilical region and joints in young animals. incision is currently required only for the gastric surface of the liver. this procedure can be reduced to a visual-only inspection for sheep less than a year old or goats less than six months of age, if certain conditions are met, as stated in regulation (ec) no 1244/2007, amending regulation (ec) no 2074/2005, in the spirit of a risk-based inspection. it is unclear to what extent this derogation is currently used as intended. a more thorough examination, involving palpation and incision of other organs, is performed if abnormalities are detected during visual inspection. table 1 in annex 2 summarises these requirements for post-mortem inspection. ultimately, the production of safe food is the responsibility of the food business operator (fbo) as defined by regulation ( post-mortem inspection enables, to a certain extent, detection of lesions related to animal health and welfare, which are not dealt with in this part of the document (see appendix c). for food safety concerns, post-mortem examination can detect visibly contaminated carcasses and offal, which might present an increased food safety risk and is an indication of a hygienically inefficient slaughter process. post-mortem inspection allows for an assessment of the general health status of the animal to be carried out, which could influence the likelihood of important meat-borne hazards to be present in the carcass. classic zoonotic diseases, such as tuberculosis, which can be detected by post-mortem examination, are now controlled in many areas where modern systems of animal husbandry, disease control and animal health care were introduced. hence, the ability of current post-mortem inspection to detect lesions caused by mycobacteria is only relevant in regions where they are present. post-mortem inspection can also detect other non meat-borne hazards of public health significance that can be present in carcasses or offal from small ruminants. examples of these hazards are echinococcus granulosus and trematode parasites such as fasciola hepatica. acquisition of these parasites by humans occurs when subjects inadvertently swallow eggs or cysts attached to tainted vegetation or by drinking contaminated water containing free-floating eggs (e. granulosus) or cysts (f. hepatica) (fried and abruzzi, 2010) . from the public health standpoint, only e. granulosus is still relatively important in some mss (efsa and ecdc, 2013b), while trematode parasites are less commonly reported in humans in the eu. meat inspection contributes to the monitoring of these parasites as they are routinely detected during post-mortem examination of sheep and goats. this also allows for appropriate disposal of infected organs, thus breaking the life cycle of the parasites. the extent to which meat inspection contributes to reducing the risk to human health posed by these parasites, compared with control measures elsewhere (e.g. anti-parasitic treatments of the final hosts) is not known, so it is difficult to assess the relative importance or effectiveness of this activity in protecting public health. nevertheless, the importance of meat inspection as a monitoring tool has been stressed previously (efsa, 2010). the slaughter of sheep involves greater challenges than the slaughter of cattle and pigs since the animal is relatively small and has a wool fleece increasing the risk of surface contamination at dehiding (buncic, 2006) . as mentioned in section 1.3 of this appendix, many challenges are posed by the processing procedure at the slaughterhouse, which has a direct effect on the final microbial disposition of the carcass (e.g. line speed, operational hygiene, equipment and training) (hansson, 2001; palmer, 2008) . in this context, the mandatory bacteriological analysis of carcasses to evaluate slaughter process hygiene is important. the maximum acceptable microbiological values are set in the phc for the indicators mentioned in regulation (ec) no 2073/2005. some risks determined at postmortem examination are under the direct influence of the processor and can be ameliorated by corrective action procedures. in the case of the identified hazard, pathogenic vtec, post-mortem corrective actions may include clipping after stunning and bleeding, adjustments to operational hygiene practices, slowing the slaughter line down and/or adding extra personnel at certain carcass dressing stations, with feedback to producers (see section 4.4.2 below). the competent authority also verifies the fbo's responsibility to produce safe food, as mandated by regulation (ec) no 178/2002, through audit and inspection of the slaughterhouse's food safety management system. in terms of the slaughter process, phc are end-product criteria. compliance with these criteria, in regulation (ec) no 2073/2005, is one aspect of system compliance verification carried out by the competent authority. more details about phc can be found in section 4.4.2.3. potential threats to public health associated with slaughtered sheep or goats including agents such as pathogenic vtec and t. gondii are carried by animals without signs or lesions. current meat inspection is not designed to detect or eliminate these agents. sometimes, cysts of t. gondii can be macroscopically visible but it is impossible to distinguish them from sarcocystis cysts, except cysts of s. ovifelis. visible meat quality-related abnormalities are detectable at post-mortem inspection, but these are not important for human health (see table 8 ). sometimes, septicaemia and conditions associated with foci of infection in tissue such as arthritis, bronchopneumonia, mastitis, pleuritis or abscesses can be detectable at post-mortem inspection. some of these are caused by pathogens that might have zoonotic implications (e.g. erysipelothrix rhusiopathiae, s. aureus), but, as explained in section 2 of this appendix, the risk to public health arising from these hazards is not considered to be important and is mostly related to occupational exposure or the way the meat is handled after it leaves the slaughterhouse. other conditions that result in condemnation of offal or carcasses are parasitic lesions. these parasites (c. tenuicollis, sarcocystis, fasciola, dicrocoelium, etc.) are not transmissible via meat consumption. in cases where these abnormalities are observed, the meat must be removed as unfit for human consumption on aesthetic or meat quality grounds. the potential for cross-contamination of carcasses exists whenever palpation and/or incision methods are used in the inspection process. palpation of the liver, the lungs, the umbilical region and the joints, and the incision of the gastric surface of the liver during the post-mortem examination of sheep and goats could contribute to the spread of the bacterial hazards of public health importance in small ruminants through cross-contamination. the importance of cross-contamination is not clear in small ruminants, although it has been considered important in other species (walker et al., 2000) . however, it should be borne in mind that incision is compulsory only for the liver, whereas in cattle and pigs incision of muscle is also required, so the level of contamination is likely to be smaller in small ruminants than in these species. current legislation foresees more detailed palpation and incision if abnormalities are detected during visual inspection. this could also facilitate cross-contamination of normal carcasses with microbiological hazards of public health importance. judgement of the fitness of meat for human consumption in current post-mortem inspection is based on the identification of "conditions making meat unfit for human consumption" but does not make a clear foodborne risk distinction between different subcategories i.e. between non-zoonotic conditions making meat unfit (inedible) on aesthetic/meat quality grounds (e.g. repulsive/unpleasant appearance or odour), non-zoonotic conditions making meat unfit in order to prevent spreading of animal diseases (e.g. foot and mouth disease), zoonotic conditions making meat unfit due to transmissibility to humans via the foodborne route (e.g. toxoplasmosis) and zoonotic conditions making meat unfit due to transmissibility via routes other than meat borne (e.g. brucellosis). the legislation on official controls on fresh meat from 2004 (regulation (ec) 854/2004, annex i) has a more horizontal approach than the former one (council directive no 432/1964 , amended by council directives no 497/1991 and no 498/1991 and has also in theory a risk-based approach. however, the main experiences are that alternative control regimes, such as visual control of young animals (sheep of less than a year old and goats less than six months old) are not implemented due to the fact that the gains are limited due to: the threshold in terms of implementation of quality assurance systems and extra procedures at herd level is too high logistical challenges connected to the post-mortem meat inspection procedures as some flocks/herds are certified for visual control while others are not due to the fact that alternative control methods are not accepted by some importing countries outside the eu. ante-mortem and post-mortem inspections of sheep and goats enable the detection of observable abnormalities. in that context, they are an important activity for monitoring animal health and welfare. they provide a general assessment of animal/herd health, which if compromised may lead to a greater public health risk. visual inspection of live animals and carcasses can also detect animals heavily contaminated with faeces. such animals increase the risk for cross-contamination during slaughter and may consequently constitute a food safety risk if carrying hazards of public health importance. if such animals or carcasses are dealt with adequately, this risk can be reduced. visual detection of faecal contamination on carcasses can also be an indicator of slaughter hygiene, but other approaches to verify slaughter hygiene should be considered. post-mortem inspection can also detect non meat-borne hazards of public health significance that can be present in carcasses or offal from small ruminants. ante-mortem and post-mortem inspection also have the potential to detect new diseases if these have clinical signs, which may be of direct public health significance. currently, the use of food chain information for food safety purposes is limited for small ruminants, mainly because the data that it contains is very general and doesn't address specific hazards of public health importance. however, fci could serve as a valuable tool for risk management decisions and could be used for risk categorisation of farms or batches of animals. to achieve this, the system needs further development to include additional information important for food safety, including definition of appropriate and standardised indicators for the main public health hazards identified above (section 2 of this appendix). ante-and post-mortem inspection is not able to detect any of the public health hazards identified as the main concerns for food safety. it would therefore be expected that more efficient procedures might be implemented to monitor the occurrence of non-visible hazards. in addition, given that the current postmortem procedures involve palpation and incision of some organs, there is potential for crosscontamination of carcasses. as identified by priority ranking earlier in this opinion, the principal biological hazards associated with meat from small ruminants are t. gondii and pathogenic vtec. the ranking presented in section 2 of this appendix classified all other hazards in the low-risk category. this ranking is provisional because of the limited information available for some of the hazards. neither of the principal hazards identified can be detected by traditional meat inspection, which is focused on identification of visible abnormalities and issues relating to the health and welfare of the animals on the farm, in transit and at the slaughterhouse before slaughter. detection and quantification of those hazards in/on sheep or goats and their carcasses is possible only through laboratory testing. the occurrence and levels of t. gondii and pathogenic vtec on carcasses are highly variable depending on various factors, including particularly: (i) their occurrence in the sheep and goat population before slaughter and the application and the effectiveness of related pre-slaughter controls strategies; (ii) the extent of direct and/or indirect faecal cross-contamination during slaughter line operation (this does not apply to t. gondii); and (iii) the application and the effectiveness of possible interventions to eliminate/reduce them on carcasses (e.g. decontamination). therefore, as far as the presence of these pathogens in/on carcass meat is concerned, the risk reduction strategies, and related controls, are focused on these three aspects. changes are therefore necessary to identify and control microbiological hazards, and this can be most readily achieved by improved use of fci and interventions based on risk. control measures for pathogenic vtec at the slaughterhouse are also likely to be effective against other enteric pathogens, as they would all be controlled by addressing faecal contamination of carcasses. a comprehensive meat safety assurance system for meat from small ruminants, combining a range of preventive measures and controls applied both on the farm and at the slaughterhouse in a longitudinally integrated way, is the most effective approach to control the main hazards in the context of meat inspection. the main responsibility for such a system should be allocated to fbos, whereby compliance is to be verified by the competent authority. the setting up of such a comprehensive meat safety assurance system at eu level is dependent on the availability of reliable information on the biological risks associated with the consumption of meat from these species. as indicated in the priority ranking section of this opinion (section 2 of this appendix), information on the biological risks associated with the consumption of meat from sheep or goats is sometimes scant and unreliable. consequently, in order to facilitate decision making, harmonised surveys are required to establish values for the prevalence of the main hazards t. gondii and pathogenic vtec at flock/herd, live animal and carcass level in individual mss. epidemiological and risk assessment studies are also required to determine the specific risk to public health associated with the consumption of meat from small ruminants. in the event that these studies confirm a high risk to public health through the consumption of meat from sheep or goats, consideration should be given to the setting of clear and measurable eu targets at the carcass level. eu targets to be reached at the national level are already in place for salmonella spp. in breeding flocks of gallus gallus and turkeys and production flocks of broilers, turkeys and laying hens. similar targets in primary production could also be considered for the main hazards of other species, including small ruminants. the use of specific hazard-based targets (i.e. pathogenic vtec or t. gondii related) for chilled carcasses provides: 1. measurable and transparent focus for the abattoir meat safety assurance system. ) on what has to be achieved at earlier steps in the food production chain. 3. information for the purpose of consumer exposure assessment for each hazard. 4. measurable aim for the meat industry in the context of global pathogen reduction programmes. for all these reasons, the chilled carcass targets have to be specific hazard based. this, however, may not be always practical (e.g. in very low hazard prevalence situations). therefore, proper functioning of meat safety quality assurance systems may not rely exclusively on hazard-based testing of the final carcass but on the general hygiene of the slaughter process. this issue is discussed further in the following sections. ). in addition, information on harmonised epidemiological indicators (heis) and related methodologies for the main hazards that can be used in studies to establish prevalence of the main pathogens to establish targets for carcasses and performance criteria for slaughterhouses, as well as targets for incoming small ruminant animals, is provided in the efsa report (efsa, 2013) . therefore, this opinion should be used in combination with that report. at farm level, the primary goal is reduction of risk for the main hazards, which can be achieved through preventive measures such as flock/herd health programmes, including biosecurity and good farming practices (gfps) that specifically address the hazards identified in section 2 of this appendix. husbandry practices will vary considerably for small ruminants, particularly, the intensity of the rearing system. so, although it is not possible to detect any of the main foodborne zoonotic infections visually at the farm, there are known risk factors that are likely to increase the risk of infection with the main hazards. an important element of an integrated meat safety assurance system is considered to be risk categorisation of flocks or herds based on the use of farm descriptors and data on clinical disease and use of antimicrobials, in addition to data provided by ongoing monitoring of high-risk hazards that constitute the fci. such data could be provided through farm audits using heis to assess the risk and preventive factors for the flocks or herds related to each of the prioritised microbiological hazards (see efsa report, (2013)). ongoing monitoring could be put in place for particular pathogens at eu level if, following the completion of the prevalence studies described earlier, these pathogens are identified as presenting a high risk. an assessment of the historical data over a time period could also be used for adjusting the sampling frequency of the main hazards in order to focus control efforts where the risk is highest. a structured approach to gathering more detailed farm information should become an additional farmrelated element of the fci that, in combination with the monitoring results for the main hazards, should form the basis for the risk categorisation of the farms. the frequency of monitoring in higher risk farms could be adapted in a cost-effective manner, e.g. there would be no need to sample every batch of animals to be slaughtered if the result is very likely to be "high risk" or "very low risk". thus, animals from higher risk farms could be systematically directed to, for example, logistic slaughter, or specific treatments such as decontamination at the slaughterhouse, until these high-risk farms demonstrated a decreased risk following the implementation of adequate on-farm measures. this system could act as an incentive for the primary producer to improve farm standards by means of reduced monitoring costs associated with low-risk status. at slaughterhouse level, the primary goal is risk reduction for the main hazards that can be achieved through integrated programmes based on gmp, ghp and haccp, including the use of phc: logistic slaughter based on the risk categorisation of the slaughtered batches; this could be slaughter of higher risk animals at the end of the day. hygienic practices and technology-based measures aimed at avoiding direct and indirect cross-contamination with the main hazards. interventions such as the scheduling of higher risk animals for carcass decontamination or for risk-reducing processes such as heat treatment to reduce pathogenic microorganisms or freezing-based treatments to eliminate parasites such as t. gondii. enteric pathogens are carried in the gastrointestinal tract and/or on the fleece of sheep and goats presented for slaughter, and carcass meat becomes contaminated as a result of direct or indirect crosscontamination that is highly dependent on slaughterhouse technology and the skills of the operators. technical aspects of individual steps of the slaughter process for small ruminants may vary considerably. the order of the processing steps at the slaughterhouse is generally as follows: transport/lairaging-stunning-bleeding-skinning-evisceration-chilling. each of these steps contributes differently to the final microbial load of the carcass. crosscontamination between animals can occur from transport and lairaging and during the slaughter process. contamination occurs particularly during skinning and evisceration. the slaughter of sheep involves greater challenges than the slaughter of cattle and pigs since the animal is relatively small and has wool. "during sheep de-pelting, it is difficult to achieve the low contamination rates capable of being achieved during cattle de-hiding, as the animal is smaller, the fleece is longer and there is a much greater chance of fleece inrolling and contacting the carcass. therefore, overall, de-skinning is a 'dirtier' procedure in small ruminants than in larger ones" (buncic, 2006) . chilling can help to control the numbers of pathogenic and spoilage microorganisms on carcasses. decontamination treatments for carcasses might be used to reduce the levels of enteric pathogens and can be divided into physical and chemical treatments. physical interventions include water-based treatments, irradiation, ultrasound or freezing. hot water, steam and irradiation effectively reduce the bacterial load. chemical interventions such as treatments with acetic and lactic acid reduce the bacterial load, as observed in poultry (loretz et al., 2010) . some combinations of treatments further enhance the reductions (loretz et al., 2010) . freezing and -irradiation can also be effective in eliminating t. gondii in carcasses. however, some of these methods are limited by their practicability, regulatory requirements or acceptability to consumers (acmsf, 2005) . thus, the best way to achieve reductions in carcass contamination is likely to come either from physical decontamination treatments or from technological developments in the process that are designed to improve hygiene, as long as they are acceptable to the industry and the consumer. each slaughterhouse can be viewed as unique, owing to differences in species slaughtered, logistics, processing practices, plant layout, equipment design and performance, standardised and documented procedures, personnel motivation and management, and other factors. these variations individually and in combination lead to between-slaughterhouse differences in risk-reduction capacity and, consequently, in the microbiological status of the final carcass. hansson (2001) indicated that there was a significantly greater amount of aerobic bacteria in ruminant carcasses slaughtered at lowcapacity slaughterhouses than in high-capacity slaughterhouses. this difference in carcass microbiological status can be accounted for by better separation of low-and high-risk areas, less variation in evisceration techniques, uniformity of the animals slaughtered, increased specialisation of labour and equipment, and improved measures taken to prevent contamination through effective operational hygiene practices in high-volume slaughter establishments (hogue et al., 1993; rahkio and korkeala, 1996) . consequently, a risk categorisation of slaughterhouses is also possible, based on the assessment of individual hygiene process performance. for that, a standardised methodology and criteria for the assessment of process hygiene is a prerequisite. in respect to process hygiene, differentiation of abattoirs in current eu regulation is based on the use of process hygiene criteria providing two categories: "acceptably" and "unacceptably" performing abattoirs. however, this differentiation is based solely on carcass testing, and so does not differentiate the abattoirs in terms of the processes but only the end products. more in-depth differentiation, even within each of the two global categories of abattoirs, would have been possible if improved process hygiene assessment methodology and indicators were used. the main guiding principle (koutsoumanis and sofos, 2004) in abattoir process hygiene differentiation is that abattoir phc need to address the initial level of a hazard and the reduction of that hazard during the production process. in the process of creating phc for abattoirs, the possibilities that need to be considered are whether they should be linked to individual stages of the process (e.g. reduction of occurrence/level of indicator organisms or hazards at a selected one or more specific steps along the slaughter line) or only related to the starting and the end point of the process (e.g. reduction of the occurrence/level in/on the final carcass meat compared with that in/on incoming animals). establishing the frequency of the official controls on the basis of pre-defined and objective criteria. carrying out the official controls using homogeneous criteria for plants with a comparable risk profile. these criteria take six parameters into account: food safety management systems can combine official control and supervision based on compulsory requirements prescribed by law (haccp, traceability, fci, etc.) , and private quality assurance schemes. besides those aspects included in the legislation, abattoirs can voluntarily implement their own quality requirements in the form of certification schemes. certification of production processes is based on the auditing and approval by accredited third-party organisations on an accredited standard. these schemes include official requirements but also pay attention to additional, more stringent, quality and safety aspects of the processes and products. at the slaughterhouse, standards are implemented for animal welfare and hygiene, slaughtering, dressing and evisceration, hygiene control, carcass quality and grading, storage conditions, carcass cutting and processing, etc. the adherence to certification schemes reassures stakeholders (suppliers, clients), government and consumers of the quality and safety of their products, with a view to meeting market demands and consumer satisfaction. retailers and manufacturers are increasingly demanding that their suppliers hold an approved certification. in this sense slaughterhouses are becoming increasingly important throughout supply chains in integrated food safety management systems. some examples of quality assurance schemes are the international standards organisation (iso) 22000, food safety system certification (fssc) 22000, international food standard (ifs), british retail consortium (brc) and globalgap. in summary, classification of abattoirs according to their capability to prevent or reduce faecal contamination of carcasses can be based on two elements: (i) the process hygiene as measured by the level of indicator organisms on the carcasses (i.e. process hygiene criteria); and (ii) the use of operational procedures and equipment that reduce faecal contamination (as described in section 4.4.2.2 above), as well as industry-led quality systems. information about the risk categorisation of slaughterhouses could be then considered with the fci when assessing the risk arising from incoming animals. herbivorous animals most likely contract t. gondii infection via ingestion of pasture, hay, forage, feed or surface water contaminated with oocysts shed by infected cats (skjerve et al., 1998; tenter et al., 2000) . oocysts are very resistant and can survive a range of temperatures in the environment. a continuous input of sporulated oocysts, originating from young infected cats, must be present to sustain the oocyst reservoir in the environment (kijlstra and jongert, 2008). the risk of environmental oocyst contamination can be addressed by using sterilised feed and bedding, and not allowing sheep and goats outdoor access; however, such husbandry practices are not economically viable in most eu commercial sheep and goat enterprises (kijlstra and jongert, 2009). removing cats from the farm surroundings, or vaccinating cats, could theoretically lead to a reduction of the oocyst load in the neighbourhood of the farm. in reality, most of these measures would not be practical to implement in most situations at the moment. (dubey, 1996; kijlstra and jongert, 2008) . moreover, the vaccine may revert to a pathogenic strain and is, therefore, not suitable for human use (hiszczynska-sawicka et al., 2011 ). an oral vaccine composed of live bradyzoites from an oocyst-negative mutant strain (t-263) has been effective in preventing oocyst shedding by cats in experimental trials but a vaccine for cats is not yet commercially available (innes et al., 2009) . while the s48 strain vaccine remains the only one commercially available, there has been significant progress over the last 15 years in the development of vaccines against toxoplasmosis due to technological advances in molecular biology (kur et al., 2009) . a cocktail dna vaccine has been shown to prime the immune system of animals against toxoplasmosis with increased immune responses being observed after experimental challenge (hoseinian khosroshahi et al., 2011) . in principle, an effective recombinant vaccine against both sexual and asexual stages of the parasite should be able to address all three targets listed above, but this is hampered by stage-specific expression of t. gondii proteins (jongert et al., 2009) . for this reason, the development of vaccines that prevent t. gondii infection in ruminants and/or cats is recommended. surveillance and monitoring of t. gondii in animals preharvest is essential in the control of this parasite, something that is currently not addressed effectively within the eu (efsa, 2007b; opsteegh et al., 2010b) . the most feasible surveillance method is the use of indirect serological tests (e.g. enzyme-linked immunosorbent assay, elisa) on live sheep and goats for the detection of t. gondii antibodies, as seropositivity has been correlated with tissue cyst presence in non-vaccinated animals (buxton, 1998; conde de felipe et al., 2007; dubey, 2009; opsteegh et al., 2010b) . however, a more practical solution is taking a blood sample during bleeding of the animal at the slaughterhouse, or even freezing a piece of meat and collecting the meat juice during thawing. studies have indicated regional differences in seroprevalence in small ruminants which can be accounted for by differences in environmental contamination or by factors that influence the level of exposure of sheep to the environment, such as age and farm management (alvarado-esquivel et al., 2012; opsteegh et al., 2010b) . monitoring programmes could help in the risk assessment and categorisation of small ruminants with regard to t. gondii at the slaughterhouse as part of the fci provided. for more details on the different options for indicators of the presence of t. gondii we refer the reader to the technical specifications on harmonised epidemiological indicators for biological hazards to be covered by meat inspection of small ruminants (efsa, 2013). with this background of high t. gondii prevalence in the national flocks and herds of small ruminants, a more realistic approach could be to focus the efforts in setting up a system to identify negative flocks/herds instead. for example, animals raised exclusively indoors and under controlled husbandry conditions (which would need to include for example the exclusion of cats from the farms and the absence of contamination of feed, bedding and water with t. gondii oocysts) would present a much lower risk with regards to t. gondii. when these husbandry conditions are combined with serological testing and the selection of young animals for slaughter, the production of t. gondii-free meat should be a feasible goal. this meat could be then used for either subpopulations at greater risk (e.g. pregnant women or immunocompromised people), or for the elaboration of particular dishes that require little cooking of the meat (e.g. agneau rosé in france). at the moment, this system might be practical to implement only for some intensive farms dedicated to milk or cheese production in some mss. a more detailed explanation about how harmonised epidemiological indicators could help setting up this system is provided in the accompanying report on these indicators mentioned above (efsa, 2013). there is no way to distinguish t. gondii-infected meat carcasses from uninfected carcasses during meat inspection (dubey et al., 2002) . similarly, current process hygiene criteria do not address the risk arising from this hazard (or any non-enteric hazard). the presence of t. gondii tissue cysts can be determined only by laboratory methods, particularly by using serological methods. this can be done on farm or at the slaughterhouse. studies on pcr methods to detect and quantify t. gondii in meat samples have shown promise with detection sensitivities comparable to those of bioassay (opsteegh et al., 2010a) . studies using such laboratory techniques allow epidemiological studies to be conducted to determine the seroprevalence of toxoplasmosis in ovine meat and the risks such meat poses to human health (efsa, 2007b; opsteegh et al., 2010b) . additional information on sampling and testing methodologies to detect t. gondii can be found in the efsa report on harmonised epidemiological indicators for sheep and goats (2013). given that t. gondii cannot be horizontally transmitted between ruminants, there is no issue of between-animal cross-contamination with t. gondii at slaughter, and therefore separating sheep and goats from negative and positive flocks or herds during transport, lairage and on the slaughter line would not have any impact on the levels of t. gondii. studies have indicated that t. gondii tissue cysts in meat are susceptible to various physical procedures that can take place at the abattoir or beyond. these include heat treatment, freezing, irradiation, high pressure treatment and curing (addition of salt combined with drying) (table 9 ). heat treatment is the most secure method to inactivate the parasite; however, freezing would probably be the most practical risk management option to control t. gondii for the meat industry (kijlstra and jongert, 2008). most of the information available for these treatments originates from research in pigs, so further research is required to validate these treatments in meat from small ruminants. these treatments would be particularly appropriate for meat cuts that are intended to be consumed rare. the ranking presented in section 2 of this appendix classified pathogenic vtec as high risk. however, it is important to note that measures aimed at controlling this hazard will also probably be effective in reducing the level of other enteric pathogens such as salmonella spp. or campylobacter spp. control of pathogenic vtec at farm level is complicated by the fact that animals are asymptomatic carriers of these organisms, thus without an active monitoring programme there is no way of knowing which animals are infected and/or shedding at any given time. control activities must therefore be directed at the flock or herd. good management practices such as maintaining stable rearing groups, keeping a closed herd and preventing young animals from having contact with older animals all decrease the spread of vtec on and between farms. a number of studies have reported reductions in bacterial contamination and, in particular, in e. coli o157:h7 levels on carcasses by reducing the level of fleece/hide contamination (hadley et al., 1997; longstreeth and udall, 1997) . in this context, the provision of a dry lying area for sheep improves hygiene. in outdoor rearing systems, this is achieved by access to sheltered free-draining land, avoiding access to wet or boggy areas. the housed rearing environment is more easily controlled by the producer. the shelter provided, in addition to the effect of good-quality bedding and the ability to influence access to food/water in the housed system, result in pre-slaughter housing being recommended as a clean fleece policy control measure (food standards agency, 2007b) . other husbandry practices such as internal parasite control, effective mineral supplementation, regular dagging/crutching and the planned pre-slaughter preparation by the producer can have an impact on the on-farm clean sheep policy (food standards agency, 2007b; pugh and baird, 2011) . although no such information is available for goats, it is probably safe to assume that these principles would also work in this species. controlling diet and feeding before slaughter to minimise digestive upset is essential in ensuring that animals are clean prior to slaughter. the provision of a high-fibre, nutritionally balanced diet, with easily digestible protein, helps develop good faecal consistency (collis et al., 2004; pugh and baird, 2011) . lush grass, contaminated water sources, overfertilised grassland, excessive concentrate supplementation and root/forage crop consumption prior to slaughter are dietary causes of fleece contamination (food standards agency, 2007b ). in addition, in a recent review, pointon et al., (2012), considered the impact of pre-slaughter feed curfews of cattle, sheep and goats on food safety and carcass hygiene in australia. the authors examined the ecology of salmonella spp. and e. coli and the efficacy of on-farm withholding of feed, carried out to reduce soiling during transport, in terms of microbial reduction. they suggested that, to minimise carcass contamination with salmonella spp. and generic e. coli, the animals should be fasted before transport only for a period sufficient to complete faecal expulsion, i.e. 24 hours, but not exceeding 48 hours, and they concluded that the implementation of these practices as good agricultural practice is likely to improve the effectiveness in terms of reducing pathogens on the carcasses. good management of animal waste is also essential to prevent spread and cross-infection of other animals. animal waste from animals housed indoors generally accumulates as slurry or farmyard manure. vtec survive for extended periods in faecal, slurry, soil and water environments (besser et al., 2001; bolton et al., 1999; bolton et al., 2012; fremaux et al., 2008; himathongkham et al., 1999; hutchison et al., 2005a; hutchison et al., 2005b; islam et al., 2004; mcgee et al., 2001; o'neill et al., 2011) . current control measures to reduce the pathogen risk in animal waste can be applied before, during or after spreading manure. pre-spreading controls include the provision of proper storage facilities for animal waste to prevent leakage of waste into ground water, and keeping animals away from slurry pits or dung heaps. spreading should not take place in conditions where contamination of a water course is more likely to occur. after manure is spread, the land should not be used for grazing for a certain amount of time (at least one month or until all visible signs of animal waste have disappeared in the case of grazing (hutchison et al., 2000) . despite there being a range of on-farm measures to control vtec at farm level, the efficacy of such measures in reducing the prevalence (or load) of pathogenic vtec in small ruminants is not clear. transport has also been identified as a risk factor for hide cleanliness (animalia, 2007; byrne et al., 2007; food standards agency, 2007b) . in compliance with council regulation (ec) no 1/2005 on the protection of animals during transport and related operations, livestock should be carried in wellventilated, clean vehicles, at the correct stocking density, with the provision of shelter, bedding and access to food and water where appropriate. these measures, particularly relating to vehicle facilities, design and journey distances directly affect fleece/pelt cleanliness. industry standards on stocking densities during transport and lairage also facilitate the requirements of clean livestock policies (anonymous, 2009; minihan et al., 2003) . section 4.2.1 above indicated that categorisation of flocks or herds according to risk can be an important element of an integrated meat safety assurance system. however, for pathogenic vtec there are a number of challenges that need to be overcome for this approach to be feasible, including the difficulties in identifying husbandry factors that can be used to classify farms according to pathogenic vtec risk, the intermittent nature of shedding, and the problems with the interpretation of monitoring results for vtec due to the difficulty of correctly identifying pathogenic vtec. the two main sources of enteric bacteria on sheep and goat carcasses are the fleece/hide and the viscera, but contamination from the former is more common. a number of studies have established a relationship between the dirtiness of sheep at the time of slaughter and the amount of contamination, and therefore the amount of pathogenic bacteria transferred to the carcass during skinning (duffy et al., 2000; gerrand, 1975; hauge et al., 2011a; longstreeth and udall, 1997) . this relationship is addressed by legislation at the production and processing level, within the hygiene package, as previously mentioned in section 3.3.2. to meet this requirement for clean fleece/hides, some mss have adopted formalised "clean livestock policies" to categorise livestock including sheep and goats at ante-mortem examination, thereby placing the responsibility of presenting clean animals for slaughter with the producer and the processor (byrne et al., 2007; hauge et al., 2011a) . pre-slaughter washing of sheep is widely used in new zealand (biss and hathaway, 1995) , together with routine shearing at high-risk sites. the clean livestock policy adopted by the food standards agency in the united kingdom has had considerable success in meeting the requirements of the hygiene package. it is based on a visual inspection during unloading or lairaging and the categorisation of the animals as acceptable for slaughter, acceptable for slaughter following shearing or clipping (conducted at the primary producers expense), and unsuitable for slaughter. extra time spent in lairage, clipping, subsequent reduction in slaughter line speed, separate processing or excessive trimming and rejection of animals all incur additional costs to producers and processors (food standards agency, 2007b) . similarly, in 2006, the norwegian meat industry also adopted national guidelines for good hygiene slaughter practices regarding the categorisation of fleece cleanliness for sheep (hauge et al., 2011a) . the policy coordinators, in both the united kingdom and norway, communicate the risk of contaminated sheep to the sheep producer, suggesting various husbandry practices, handling methods and pre-slaughter preparation to limit contamination prior to slaughter (animalia, 2007; food standards agency, 2007b) . as part of the norwegian clean sheep policy, developed by the associations of producers and slaughterers, sheep are shorn in the slaughterhouses. if they do not become visually clean after shearing or they are already shorn on farm and are contaminated after shearing, the carcasses of these animals are processed in a separate line. this separate processing may include heat treatment of meat products and processing into a restricted range of products, with the farmers receiving a lower price (a reduction of 10-15 % in the carcass value). hauge et al. (2011a) demonstrated that the measures taken as part of the norwegian policy decreased the risks posed by carcasses and thereby validated the use of such clean sheep policies. the influence of animal cleanliness on small ruminant carcass contamination was investigated by several authors in australia, canada, new zealand, ireland and norway (biss and hathaway, 1996a , 1996b , 1996c duffy et al., 2000; gill, 2004; hauge et al., 2011a; sumner et al., 2003) , but there is contradictory evidence on the impact of measures to improve fleece cleanliness on microbiological contamination of lamb carcasses. roberts (1980) and field et al. (1992) found no effect of shearing of sheep on carcass contamination. some more recent studies have reported that shearing of sheep decreased carcass surface bacterial counts (biss and hathaway, 1996a; collis et al., 2004; schroder and ring, 1998) . in a study carried out in norway by hauge et al. (2011a) a significantly lower level of aerobic plate count (apc) and e. coli was found on carcass surfaces from shorn lambs when compared with unshorn lambs at skinning. at this sampling point, shearing proved to be effective for reducing microbial loads on carcasses. results in this study showed a trend of increasing contamination of carcasses with increasing duration of the time between shearing and slaughter. sheep shorn immediately before slaughter yielded carcasses with the lowest microbial loads with respect to apc. the e. coli results were less definitive, but a similar trend was demonstrated. biss and hathaway (1996b), investigating the effect of pre-slaughter washing of lambs on the microbiological and visible contamination of the carcasses at four slaughterhouses in new zealand, showed that total aerobic bacteria and e. coli contamination was greater on carcasses that had been washed before slaughter, irrespective of wool length, and it was generally higher on carcasses derived from woolly lambs than those derived from shorn lambs. other researchers have found that pre-slaughter washing of sheep will only have positive effects if the washed animals are allowed sufficient time to dry before they are slaughtered (newton et al., 1978; patterson and gibbs, 1978) . many studies have reported difficulties in making valid microbiological comparisons associated with differences in slaughter hygiene due to individual operators, uneven distribution of microorganisms on carcasses, variations between groups of animals, day-to-day variations, and seasonal variations (biss and hathaway, 1996b; hauge et al., 2011a; ingram and roberts, 1976) . this may explain the conflicting results obtained in relation to the effect of shearing or washing on carcass contamination in such studies. irrespective of this conflicting evidence about how to best ensure that incoming animals are clean, it seems necessary to continue accepting only clean animals for slaughter as currently required by eu legislation, as it can be assumed that the dirtier the animals are in terms of faecal material, the higher the risk of cross-contamination of the slaughterline environment, including the carcasses. as mentioned above, a second source of enteric bacteria on carcasses are the viscera. during carcass dressing, bacteria are transferred from the gastrointestinal tract to the carcass directly by contact with gut spillage or indirectly via contaminated hands, knives, other equipment and the air. in general, prerequisite gmp and ghp implemented to reduce bacterial contamination will also prevent or reduce carcass contamination with pathogenic vtec, salmonella spp. and other pathogens. during evisceration, the abdominal cavity is opened using a knife and the connective tissue joining the bung and the viscera to the carcass is cut. rodding (sealing the oesophagus with a crocodile clip, plastic ring or starch cone) may be performed to prevent leakage. the spread of faecal material from the rectum can be prevented or reduced by bagging and tying the bung. the current throat sticking practice in halal slaughter (cutting of blood vessels, oesophagus and trachea) 15 limits the effect of rodding as the leakage from the oesophagus occurs before rodding can be applied. if a sticking method such as chest sticking is applied, the effect of rodding will be greater as the oesophagus remains intact, with reduced leakage from the oesophagus until rodding is performed as one of the first steps after bleeding. using this method, contamination from the oesophagus of wool, skinned surfaces and the abdominal and chest cavity, in addition to the operator's hands, equipment, walls and floor, will be avoided to a high degree. the effect of bagging on the level of e. coli on sheep carcasses has been previously investigated (norwegian scientific committee for food safety, 2012). although the numbers of carcasses were limited, based on relevant 100-cm 2 sampling sites (circum-anal incision and pelvic duct), it could be concluded that the use of the plastic bag technique during circum-anal incision and removal of the rectum results in a 1 to 2 log reduction in e. coli (figure 4 ). if a plastic bag is not used and the rectum is inserted in the abdomen, the chances of contamination are larger. the hygienic effect of rodding and bagging will depend on the operator's experience at these critical hygienic positions. skinning and evisceration may also be designated as critical control points (ccps) as part of the haccp programme, the critical limit for both being zero visible faecal contamination on the carcasses. monitoring occurs at the trimming stand where every carcass is visually inspected. this inspection may be facilitated using the online monitoring system described by tergney and bolton (2006) . when faeces or faecal stains are detected they are immediately removed by trimming. the cause of the breach in hygiene should also be investigated, and secondary corrective actions require retraining of personnel, replacement of knives, etc. setting and using indicators/criteria for "process hygiene" of slaughterhouses is an integral part of the meat safety assurance system, which targets specifically contamination of the carcasses with enteric pathogens. according to the regulation on microbiological criteria, a microbiological criterion means a criterion defining the acceptability of a product, a batch of foodstuffs or a process, based on the absence, presence or number of microorganisms, and/or on the quantity of their toxins/metabolites, per unit(s) of mass, volume, area or batch. phc included in regulation (ec) no 2073/2005 are defined as criteria indicating the acceptable functioning of the production process. they give guidance on the acceptable implementation of pre-requisite programmes (gmp/ghp) and haccp-based systems to ensure hygienic functioning of slaughterhouse processes and are applicable only to the product at the end of the manufacturing process (final carcass after dressing but before chilling), and not to products placed on the market. in eu countries, phc involve the evaluation of indicators of overall contamination (total viable count of bacteria), indicators of contamination of enteric origin (enterobacteriaceae) and salmonella spp. prevalence. bacteriological analysis of carcasses, as outlined in this regulation, is carried out by the fbo. it involves pooled samples from four risk-assessed sampling sites on each of five sampled carcasses. this must be carried out weekly or, depending on the previous results, once a fortnight. phc set an indicative microbial contamination value above which corrective actions are required by the fbo in order to maintain the hygiene of the process in compliance with eu food law. these corrective actions should include the improvement of slaughter hygiene and the review of process controls. the phc communicate the expected outcome of a process, but they neither characterise nor differentiate between the processes themselves. process compliance must be verified by audits of haccp plans and inspections of processing procedures. the competent authority carries out this role on behalf of the member state as defined by regulation (ec) no 854/2004. as phc verifies the hygienic functioning of the process rather than the safety of the product, it does not require validation by independent sampling on behalf of the competent authority. microbiological testing alone may convey a false sense of security due to the statistical limitations of sampling plans, particularly in the cases where the hazard presents an unacceptable risk at low concentrations and/or low and variable prevalences. in addition, for pathogens other than enteric hazards (e.g. t. gondii), phc does not provide any information about risk. sampling and testing, as required by regulation (ec) no 2073/2005, is only part of the verification process of systems in place. these criteria should not be considered without other aspects of eu food legislation, in particular haccp principles and official controls to fbos' compliance (efsa, 2007c) . with current eu legislation, one element of the phc indicates the maximum acceptable prevalence of salmonella spp. on carcasses at the end of the slaughter line. the inclusion of this pathogen as a process hygiene criterion for carcasses highlights the importance of salmonella spp. as a foodborne pathogen in the eu and the need for good hygiene measures for controlling it in the abattoir. however, the use of this hazard presents some problems, because the salmonella spp. occurrence on carcasses depends not only on process hygiene performance of a given abattoir, but also on the salmonella spp. carriage by incoming animals (or lack of it). hence, when slaughtering batches that are salmonella spp. free or that have a low prevalence, such phc will be satisfied even if the actual process hygiene is inadequate-and vice versa. on the other hand, the current eu salmonella-based process hygiene criterion partly has the nature of a salmonella-related target to be achieved by abattoirs. the important difference is that with the current eu phc the hazard is measured on the carcass before chilling, while with the target-based concept the hazard is measured on the chilled carcass (i.e. just before dispatch onwards to the meat chain). however, the chilled carcass is better suited for assessing consumer exposure, and for the hazard-related target concept, as the prevalence/levels of microbial hazards on the carcass may change during chilling. furthermore, these current salmonella-related eu criteria for chilled carcasses are not clearly linked to other salmonellarelated criteria/targets at preceding and/or consecutive steps of the meat chain. in addition, current eu-legislated phc for abattoirs actually do not provide information on ratios between initial contamination associated with incoming animals versus final contamination associated with carcasses, i.e. on the actual capacity of the process to reduce the incoming contamination, but only on the process outcomes. when the main purpose is to microbiologically characterise the abattoir process itself, which is the subject of this subsection and a prerequisite for related differentiation of abattoirs, this is a significant weakness of the current eu-legislated phc. these shortcomings could be addressed by the setting of specific targets for pathogenic vtec, as described in section 4.2 above, instead of using salmonella spp. in phc. in addition, to measure the performance of the slaughter line, phc based on indicator organisms should be implemented, measuring microbial loads in at least two stages of the processing line. this would allow determination of the ratio between indicator organisms on pre-chill carcasses and those found in incoming animals, for a given batch. the phc is considered to be a key component of the proposed meat safety assurance system so, in that context, careful consideration would need to be given to issues such as the number of samples taken per week, the areas where those samples are taken from (both in carcasses and incoming animals) and the need for regulatory auditing of the process hygiene assessment (which may include microbial testing, as well as record verification). this more accurate information based on trends of data derived from process hygiene assessments and from haccp programmes would enable differentiation ("risk categorisation") of abattoirs with respect to pathogenic vtec which, in turn, would enable different risk management options for different risk categories of abattoirs to be used, including: optimisation of balancing pathogenic vtec risk categories of small ruminants with risk categories of abattoirs where they are to be slaughtered. optimisation of the decision whether/where additional pathogenic vtec risk-reducing interventions are to be applied (e.g. carcass decontamination step). more stringent requirements for monitoring/verification/auditing programmes for higher risk abattoirs. more reliable feedback to the farm of origin on the root of problems with pathogenic vtec on carcasses of small ruminants. clearer identification of slaughterhouses where improvement of the slaughtering practices and/or technology is needed. small ruminants represent a reservoir of enteric pathogens. in that context, the slaughtering of sheep involves greater challenges because the animal is relatively small and has a wool fleece, thus increasing the risk of surface contamination at dehiding (buncic, 2006) , which might result in suboptimal hygiene during slaughtering compared with the slaughtering of cattle. technological and operational shortcomings, such as a too high line speed, no rodding and bagging and the use of seasonal workers not sufficiently trained for the purpose, are reported as additional challenges in some abattoirs (norwegian scientific committee for food safety, 2012). accordingly, interventions such as surface pasteurisation using hot water might be considered as one of several options to reduce the bacterial contamination on carcasses. hot water at 72-85 °c achieves a 1.0 to 2.8 log 10 reduction in colony-forming units (cfus)/cm 2 in salmonella spp. on beef carcasses (arthur et al., 2008; cutter and rivera-betancourt, 2000) . in a study by hauge et al. (2011b) 210 lamb carcasses were subjected to hot water pasteurisation at 82 °c for eight seconds. the reduction in e. coli just after pasteurisation was 99.5 %, corresponding to 1.85 log cfus/cm 2 , and after 24 hours' storage 2.02 log cfus/cm 2 . accordingly, surface pasteurisation of sheep carcasses might represent an important and efficient step (ccp) to reduce vtec on the carcasses and the risk of disease among consumers. an automatic surface pasteurisation step is easy to control by measurement of time/temperature, and these results, together with the quality of the process water, might be documented on display and/or on hard copy. the pasteurisation step might be recognised as a ccp in a haccp concept. steam treatment is also allowed in the eu and has been found to reduce bacterial contamination in sheep carcasses by a log 10 cfus/cm 2 , both in enterobacteriaceae (milios et al., 2011) and aerobic plate counts (james et al., 2000) . greater reductions of up to 4.0 log 10 cfus/cm 2 have been described when using a combination of steam and a hot water wash in sheep carcasses (dorsa et al., 1996) . similar effects have been observed with salmonella spp. counts in beef carcasses, achieving reductions of < 0.7 to 4.8 log 10 cfus/cm 2 (phebus et al., 1997; retzlaff et al., 2005) . surface pasteurisation can also be achieved by manual steam vacuum technology. however, the use of this technology depends on skilled and responsible operators, and will require close supervision in order to ensure the pasteurisation procedure is correctly applied to the whole carcass. the use of manual steam vacuum was evaluated in a norwegian slaughterhouse, showing a real reduction (median of 1.10 log cfus/cm 2 )(hassan, 2008). surface pasteurisation of ruminant carcasses is an option that allows dealing with carcasses presenting greater risk, such as emergency slaughtered carcasses or unclean carcasses, without the need, for example, to apply a heat treatment on these carcasses. although not permitted in the eu, a range of specific interventions are applied in us slaughter plants targeting enteric pathogens such as pathogenic vtec and salmonella spp. these include the application of organic acids. the application of acetic acid to beef carcasses will reduce e. coli counts by 1.0-3.7 log 10 cfus/cm 2 (sofos and smith, 1998) . significant reductions achieved with lactic acid have also been described (efsa panel on biological hazards, 2011). as neither of the main public health hazards associated with meat from small ruminants can be detected by traditional meat inspection, other approaches are necessary to identify and control these microbiological hazards. a comprehensive meat safety assurance system for meat from small ruminants, combining a range of preventive measures and controls applied both on the farm and at the slaughterhouse in a longitudinally integrated way, is the most effective approach to control the main hazards in the context of meat inspection. information on the biological risks associated with the consumption of meat from sheep or goats is sometimes scant and unreliable. in order to facilitate decision making, harmonised surveys are required to establish values for the prevalence of the main hazards t. gondii and pathogenic vtec at flock/herd, live animal and carcass level in individual mss. epidemiological and risk assessment studies are also required to determine the specific risk to public health associated with the consumption of meat from small ruminants. in the event that these studies confirm a high risk to public health through the consumption of meat from sheep or goats, consideration should be given to the setting of clear and measurable eu targets at the carcass level. to meet these targets and criteria, a variety of control options for the main hazards are available, at both farm and abattoir level. flock/herd categorisation according to the risk posed by the main hazards is considered an important element of an integrated meat safety assurance system. this should be based on the use of farm descriptors and historical data in addition to batch-specific information. farm-related data could be provided through farm audits using heis to assess the risk and protective factors for the flocks/herds related to the given hazards. classification of abattoirs according to their capability to prevent or reduce faecal contamination of carcasses can be based on two elements: (i) the process hygiene as measured by the level of indicator organisms on the carcasses (i.e. phc); and (ii) the use of operational procedures and equipment that reduce faecal contamination, as well as industry-led quality assurance systems. as mentioned in section 4.2, further studies are necessary to determine with more certainty the risk of acquiring t. gondii through consumption of meat from small ruminants. in addition, the lack of tests that can easily identify viable cysts in meat is a significant drawback. furthermore, if there is a high prevalence in the animal population, this will hamper the development of systems based on risk categorisation of animals. for these reasons, the setting of targets for t. gondii is not recommended at the moment. there are a variety of animal husbandry measures that can be used to control t. gondii on sheep and goat farms but at present it would not be practical to implement them on most farms. a number of post-processing interventions might be effective in inactivating t. gondii such as cooking, freezing, curing and high-pressure and -irradiation treatments. however, most of the information available for these treatments originates from research in pigs, so further research is required to validate these treatments in meat from small ruminants. there are also a variety of animal husbandry measures that can be used to reduce the levels of vtec on infected farms, but their efficacy is not clear in small ruminants. in addition, there are a number of challenges that need to be overcome regarding the setting of targets for pathogenic vtec, including the difficulties in identifying husbandry factors that can be used to classify farms according to pathogenic vtec risk, the intermittent nature of shedding, and the problems with the interpretation of monitoring results for vtec due to the difficulty of correctly identifying pathogenic vtec. the two main sources of vtec on sheep and goat carcasses are the fleece/hide and the viscera. to control faecal contamination from the fleece or hide only clean animals should be accepted for slaughter, as currently required by eu legislation. there are also a number of measures that can help to reduce the spillage or leakage of digestive contents onto the carcass, particularly rodding of the oesophagus and bagging of the rectum. post-processing interventions to control pathogenic vtec are also available. these include hot water and steam pasteurisation. risk categorisation of slaughterhouses should be based on trends of data derived from process hygiene assessments and from hazard analysis critical control point programmes. improvement of slaughter hygiene through technological and managerial interventions should be sought in slaughterhouses with repeatedly unsatisfactory performance. source attribution studies are needed to determine the relative importance of meat, as well as to ascertain the role of the different livestock species as a source of t. gondii and pathogenic vtec. methods should be developed to estimate the amount of viable t. gondii tissue cysts in meat, especially in meat cuts that are commonly consumed. recommend adaptation of inspection methods that provide an equivalent protection for current hazards the main rationale behind the concept of fci is that animals sent for slaughter can be categorised into different risk groups based on relevant information from the flock/herd of origin. this enables appropriate measures to be put in place during slaughter to deal with the level of risk identified. although regulation (ec) no 853/2004 mentions the basic requirements for fci, these are very general and as a consequence the information reported in fci is rarely used as described above (section 3.2.3 of this appendix). there are a number of ways in which fci could be improved. as explained in section 4.2.1 above, more specific information about the main hazards could be used for assessing the risks associated with batches of animals arriving at the slaughterhouse, resulting in a classification according to these risks. to achieve this, the system needs further development to include additional information important for food safety, including the definition of appropriate and standardised indicators for the main public health hazards identified in section 2 of this appendix. in addition, membership of quality assurance schemes and certification systems can have a positive impact on public health by contributing to the overall health of the animals sent to slaughter. certification procedures at farm level are voluntary tools to ensure compliance with given standards and regulations in the quality assurance system. they are aimed at achieving continuous improvement in production standards by monitoring quality assurance standards or criteria. audits or inspections of farms ensure that the animal (final product) is being raised and handled in accordance with the standards or guidelines, which producers should adhere to. the main areas covered by the standards include usually animal health, welfare and hygiene, identification and traceability, adequate and prudent use of medicines and chemicals at farm level, safety of feed and water, environmental guidelines, hygiene of personnel, processes and infrastructure, and preparation of animals for slaughter. the standards should be regularly updated in line with changes in legislation and with scientific developments. certifications are issued by independent agencies or bodies which confirm that an auditing process has been passed. farmers can also adopt other schemes such as the guides to good farming practices, recommendations of best practice published by international bodies (i.e. world organisation for animal health (oie) and the food and agriculture organization of the united nations (fao)). adherence to such quality schemes and guidelines at farm level has multiple benefits, providing slaughterhouse operators with useful information about animals intended to be slaughtered and could be integrated in the fci. it also increases farmers' responsibilities and has a beneficial influence on meat safety and quality. schemes such as the beef and lamb quality assurance scheme in ireland cover a broad area, relating to animal identification and animal health and welfare, and contribute to ensuring that healthy animals enter the slaughterhouse. farmers should be encouraged to participate in these schemes, and information on whether or not a primary producer is a member should be included in the fci. eu regulations (ec) no 854/2004 and (ec) no 2074/2005 already require that information gathered during meat inspection is fed back to the primary producer. the main value of such feedback relates to animal health and welfare and production-related diseases, such as liver fluke and pneumonia. however, as mentioned previously, use of this information to produce healthier animals would have indirect benefits for public health. from discussions with stakeholders, it is clear that feedback to the producers is very limited in most mss and that there is considerable room for improvement in that area (see the report from the technical hearing on meat inspection of small ruminants 16 ). ante-mortem inspection assesses the general health status of the animals on arrival at the slaughterhouse. meat for human consumption should be derived from the slaughter of healthy animals. inspection of animals on arrival at the slaughterhouse will help to enforce acceptable standards of transport and handling. this might indirectly contribute to the maintenance of operating standards that minimise the general risk associated with unhygienic and stressful management of food-producing animals. stress has been shown to be an important factor in the excretion of enteric pathogens such as pathogenic vtec, salmonella spp. and campylobacter spp., so inspection procedures that prevent stress are likely to be beneficial (efsa panel on biological hazards, 2011b). measures to keep the transport-lairaging period as short as possible may be beneficial in terms of reducing crosscontamination with these enteric pathogens. the ante-mortem procedure will help to detect animals heavily contaminated with faeces and other material. measures to prevent excessively dirty animals from entering the slaughter line will help to prevent contamination of the carcasses and may reduce the level of enteric pathogens. taking these factors into consideration, and given that current methods do not increase the microbiological risk to public health and have considerable benefits in relation to the monitoring of animal health and welfare, no adaptations for the existing visual ante-mortem inspection are proposed. in the inspection procedure for sheep and goats, as set out in eu regulation (ec) no 854/2004, carcasses are subject to visual inspection only. incision is mandatory for the gastric surface of the liver. palpation is mandatory for the lungs, bronchial and mediastinal lymph nodes, the liver and its lymph nodes. in addition, palpation is mandatory for the umbilical region and joints of young animals. palpation of lungs, liver, umbilical region and joints, and incision of the liver could contribute to the spread of bacterial hazards through cross-contamination. although the importance of such crosscontamination has not been studied in small ruminants, it has been considered important in other species ( the pathogens of importance for public health cannot be detected by routine post-mortem examination. consequently, palpation of liver, lungs, the umbilical region and joints and incision of the gastric surface of the liver do not contribute to preventing the risk to public health arising from the meat-borne hazards identified in this opinion. for these reasons, palpation and incision should be omitted in animals subjected to routine slaughter. visual examination contributes by detecting visible faecal contamination and/or spilled intestinal contents, although it is unclear how sensitive the current system is or what contribution this detection makes towards preventing public health risk. the current legislation foresees palpation and incision if abnormalities are detected during visual inspection. it is recommended that these procedures, if necessary, are carried out separately from the routine inspection of carcasses to prevent cross-contamination. elimination of abnormalities on aesthetic/meat quality grounds can be ensured through a meat quality assurance system and not through the official meat safety assurance system including meat inspection. any handling should be performed on a separate line and accompanied by laboratory testing as required. palpation and incision currently assist in the identification of zoonootic pathogens that are not meat borne, such as echinococcus granulosus, fasciola hepatica (although cysts are usually visible before incisions are made) and mycobacterium bovis. the removal of palpation and incision as a requirement in the post-mortem procedure in small ruminants could have a significant effect on monitoring echinococcus, in particular, as meat inspection is the principal method of detection of this pathogen (efsa, 2010) . in countries where hazards such as echinococcus are present it might be appropriate to conduct a risk assessment to evaluate the benefits to public health of stopping cross-contamination through palpation and incision of viscera with those obtained through monitoring of these non-meatborne zoonotic hazards. fci can be improved by including information on participation in quality assurance schemes and by giving greater feedback to the primary producer, as this would probably result in the production of healthier animals. ante-mortem inspection assesses the general health status of the animals and helps to detect animals heavily contaminated with faeces on arrival at the slaughterhouse. taking these factors into consideration, and given that current methods do not increase the microbiological risk to public health, no adaptations to the existing visual ante-mortem inspection procedure are required. although visual examination contributes by detecting visible faecal contamination, routine postmortem examination cannot detect the meat-borne pathogens of public health importance. palpation of the lungs, the liver, the umbilical region and the joints and incision of the liver could contribute to the spread of bacterial hazards through cross-contamination. for these reasons, palpation and incision should be omitted in animals subjected to routine slaughter. the effect of this omission on the risk posed by non-meat-borne zoonoses such as e. granulosus, f. hepatica and m. bovis should be assessed, particularly in those countries where these hazards are prevalent. conclusions tor 1 identify and rank the main risks for public health that should be addressed by meat inspection at eu level. general (e.g. sepsis, abscesses) and specific biological risks as well as chemical risks (e.g. residues of veterinary drugs and contaminants) should be considered. differentiation may be made according to production system and age of animals (e.g. breeding compared to fattening animals). based on the priority ranking, the hazards were classified as follows: -t. gondii and pathogenic verocytotoxin-producing escherichia coli (vtec) were classified as high priority for sheep/goat meat inspection. -the remaining identified hazards, b. anthracis, campylobacter spp. (thermophilic) and salmonella spp., were classified as low priority, based on the available data. as new hazards might emerge and/or hazards that presently are not a priority might become more relevant over time or in some regions, both hazard identification and the risk ranking should be revisited regularly to reflect this dynamic epidemiological situation. particular attention should be given to potential emerging hazards of public health importance. assess the strengths and weaknesses of the current meat inspection methodology and recommend possible alternative methods (at ante-mortem or post-mortem inspection, or validated laboratory testing within the frame of traditional meat inspection or elsewhere in the production chain) at eu level, providing an equivalent achievement of overall objectives; the implications for animal health and animal welfare of any changes suggested in the light of public health risks to current inspection methods should be considered. ante-mortem and post-mortem inspection of sheep and goats enable the detection of observable abnormalities. in that context, they are an important activity for monitoring animal health and welfare. they provide a general assessment of animal/herd health, which if compromised may lead to a greater public health risk. visual inspection of live animals and carcasses can also detect animals heavily contaminated with faeces. such animals increase the risk for cross-contamination during slaughter and may consequently constitute a food safety risk if carrying hazards of public health importance. if such animals or carcasses are dealt with adequately, this risk can be reduced. visual detection of faecal contamination on carcasses can also be an indicator of slaughter hygiene, but other approaches to verify slaughter hygiene should be considered. post-mortem inspection can also detect non-meat-borne hazards of public health significance that can be present in carcasses or offal from small ruminants. ante-mortem and post-mortem inspection also have the potential to detect new diseases if these have clinical signs, which may be of direct public health significance. currently, the use of food chain information (fci) for food safety purposes is limited for small ruminants, mainly because the data that it contains is very general and doesn't address specific hazards of public health importance. however, fci could serve as a valuable tool for risk management decisions and could be used for risk categorisation of farms or batches of animals. to achieve this, the system needs further development to include additional information important for food safety, including definition of appropriate and standardised indicators for the main public health hazards identified in section 2 of this appendix. ante-and post-mortem inspection is not able to detect any of the public health hazards identified as the main concerns for food safety. it would therefore be expected that more efficient procedures might be implemented to monitor the occurrence of non-visible hazards. in addition, given that the current post-mortem procedures involve palpation and incision of some organs, there is potential for cross-contamination of carcasses. if new hazards currently not covered by the meat inspection system (e.g. salmonella, campylobacter) are identified under tor 1, then recommend inspection methods fit for the purpose of meeting the overall objectives of meat inspection. when appropriate, food chain information should be taken into account. as neither of the main public health hazards associated with meat from small ruminants can be detected by traditional meat inspection, other approaches are necessary to identify and control these microbiological hazards. a comprehensive meat safety assurance system for meat from small ruminants, combining a range of preventive measures and controls applied both on the farm and at the slaughterhouse in a longitudinally integrated way, is the most effective approach to control the main hazards in the context of meat inspection. information on the biological risks associated with the consumption of meat from sheep or goats is sometimes scant and unreliable. in order to facilitate decision making, harmonised surveys are required to establish values for the prevalence of the main hazards t. gondii and pathogenic vtec at flock/herd, live animal and carcass level in individual member states. epidemiological and risk assessment studies are also required to determine the specific risk to public health associated with the consumption of meat from small ruminants. in the event that these studies confirm a high risk to public health through the consumption of meat from sheep or goats, consideration should be given to the setting of clear and measurable eu targets at the carcass level. to meet these targets and criteria, a variety of control options for the main hazards are available, at both farm and abattoir level. flock/herd categorisation according to the risk posed by the main hazards is considered an important element of an integrated meat safety assurance system. this should be based on the use of farm descriptors and historical data in addition to batch-specific information. farmrelated data could be provided through farm audits using harmonised epidemiological indicators (heis) 17 to assess the risk and protective factors for the flocks/herds related to the given hazards. classification of abattoirs according to their capability to prevent or reduce faecal contamination of carcasses can be based on two elements: (i) the process hygiene as measured by the level of indicator organisms on the carcasses (i.e. process hygiene criteria); and (ii) the use of operational procedures and equipment that reduce faecal contamination, as well as industry-led quality assurance systems. as mentioned in section 4.2 of appendix a, further studies are necessary to determine with more certainty the risk of acquiring t. gondii through consumption of meat from small ruminants. in addition, the lack of tests that can easily identify viable cysts in meat is a significant drawback. furthermore, if there is a high prevalence in the animal population, this will hamper the development of systems based on risk categorisation of animals. for these reasons, the setting of targets for t. gondii is not recommended at the moment. there are a variety of animal husbandry measures that can be used to control t. gondii on sheep and goat farms, but at present these would not be practical to implement on most farms. a number of post-processing interventions might be effective in inactivating t. gondii such as cooking, freezing, curing and high-pressure and -irradiation treatments. however, most of the information available for these treatments originates from research in pigs, so further research is required to validate these treatments in meat from small ruminants. there are also a variety of animal husbandry measures that can be used to reduce the levels of vtec on infected farms, but their efficacy is not clear in small ruminants. in addition, there are a number of challenges that need to be overcome regarding the setting of targets for pathogenic vtec, including the difficulties in identifying husbandry factors that can be used to classify farms according to pathogenic vtec risk, the intermittent nature of shedding, and the problems with the interpretation of monitoring results for vtec due to the difficulty of correctly identifying pathogenic vtec. the two main sources of vtec on sheep and goat carcasses are the fleece/hide and the viscera. to control faecal contamination from the fleece or hide only clean animals should be accepted for slaughter, as currently required by eu legislation. there are also a number of measures that can help to reduce the spillage or leakage of digestive contents onto the carcass, particularly rodding of the oesophagus and bagging of the rectum. post-processing interventions to control vtec are also available. these include hot water and steam pasteurisation. risk categorisation of slaughterhouses should be based on trends of data derived from process hygiene assessments and from hazard analysis critical control point programmes. improvement of slaughter hygiene through technological and managerial interventions should be sought in slaughterhouses with repeatedly unsatisfactory performance. tor 4 recommend adaptations of inspection methods and/or frequencies of inspections that provide an equivalent level of protection within the scope of meat inspection or elsewhere in the production chain that may be used by risk managers in case they consider the current methods disproportionate to the risk, e.g. based on the ranking as an outcome of terms of reference 1 or on data obtained using harmonised epidemiological criteria (see annex 2 18 ). when appropriate, food chain information should be taken into account. fci can be improved by including information on participation in quality assurance schemes and by giving greater feedback to the primary producer, as this would probably result in the production of healthier animals. ante-mortem inspection assesses the general health status of the animals and helps to detect animals heavily contaminated with faeces on arrival at the slaughterhouse. taking these factors into consideration, and given that current methods do not increase the microbiological risk to public health, no adaptations for the existing visual ante-mortem inspection are required. although visual examination contributes by detecting visible faecal contamination, routine post-mortem examination cannot detect the meat-borne pathogens of public health importance. palpation of the lungs, the liver, the umbilical region and the joints, and incision of the liver could contribute to the spread of bacterial hazards through cross-contamination. for these reasons, palpation and incision should be omitted in animals subjected to routine slaughter. to provide a better evidence base for future risk ranking of hazards, initiatives should be instigated to: improve and harmonise data collection of incidence and severity of human diseases caused by relevant hazards systematically collect data for source attribution collect data to identify and risk rank emerging hazards that could be transmitted through handling, preparation and consumption of sheep and goat meat. source attribution studies are needed to determine the relative importance of meat, as well as to ascertain the role of the different livestock species, as a source of t. gondii and pathogenic vtec for humans. methods should be developed to estimate the amount of viable t. gondii tissue cysts in meat, especially in meat cuts that are commonly consumed. assessment of the importance of the hazards in table 1 with regard to their potential as zoonotic agents that can be transmitted via consumption of meat from small ruminants. these bacteria are considered zoonotic, although this characteristic has only been documented in fish. transmission via consumption of meat from small ruminants has not been reported, despite aeromonas being detected in lamb and meat products and having the potential to be a foodborne pathogen (daskalov, 2006) . these obligate intracellular bacteria are found in sheep, cattle, horses and dogs, as well as deer and rodents in europe (kalinova et al., 2009), and although they cause human disease, this illness is rare (scharf et al., 2011) . they are transmitted by ticks of the genus ixodes, therefore they do not present a risk to humans via consumption of sheep meat. arcobacter spp. the genus arcobacter includes species that can be defined as aerotolerant campylobacter-like organisms. they were first isolated from aborted bovine foetuses. information on the real prevalence and clinical importance of arcobacter is limited because of the absence of routine testing protocols and the fact that most laboratories do not use appropriate culture conditions or do not identify isolates to species level. small ruminants have been found to be carriers of these bacteria (de smet et al., 2011) in europe. recent reports suggest that arcobacters, especially a. butzleri, may be involved in human enteric disease, although the evidence is not conclusive (houf, 2009 ). there are no specific epidemiological data establishing a link between arcobacter infection with consumption of meat from small ruminants. in addition, the public health significance of arcobacter remains unclear. borrelia are transmitted by ticks of the genus ixodes, and infect a wide range of hosts including sheep, although their contribution to the maintenance of b. burgdorferi is still not clear (mannelli et al., 2012) . although present throughout europe, currently there is no evidence that borrelia can be transmitted via consumption of meat. sheep and goat brucellosis is a zoonotic infection. brucellosis is caused by some bacterial species belonging to the genus brucella. of the six species known to cause disease in humans b. melitensis affects goats and sheep, their specific animal reservoir. humans are usually infected from direct contact with infected animals or via contaminated food, typically raw milk, cheese made thereof or other milk products such as cream and ice cream. meat is not considered a source of infection since muscle tissue contains low concentrations of brucella organisms and the survival time in meat seems extremely short. the number of organisms per gram of muscle is small and rapidly decreases as the ph of the meat drops. brucella spp. die off rapidly when incubated at 37º c in a medium at ph < 5 (icmsf (international commission on microbial specifications for food), 1996). an exception in survival behaviour seems to be frozen carcasses, in which the organism can survive for years. c. abortus is known to be transmissible from animals to humans, causing significant zoonotic infections. c. abortus causes the enzootic abortion of ewes (ovine enzootic abortion), which has become recognised as a major cause of loss in sheep (and goats) in europe, north america and africa. (pospischil, 2006) . most cases of c. abortus infection are directly associated with exposure to infected sheep or goats, with transmission most probably occurring by mouth following the handling of an infected ewe or lamb or of contaminated clothing (longbottom and coulter, 2003) . the role of meat from small ruminants in the epidemiology of human infection with c. abortus is nevertheless unclear. c. difficile is a species of anaerobic, spore-forming gram-positive bacteria that causes severe diarrhoea and other intestinal disease when competing bacteria in the gut flora have been eliminated by antibiotic treatment. there are reports of c. difficile being isolated from small ruminants (hunter et al., 1981; koene et al., 2012; rieu-lesme and fonty, 1999; saif and brazier, 1996) . however, there is to date no indication of meat-borne transmission to humans. c. pseudotuberculosis is the causative agent of caseous lymphadenitis in small ruminants. these bacteria are commonly found in europe in the ruminant population. cases of human lymphadenitis have been described previously (peel et al., 1997) , although transmitted via occupational exposure and not through consumption of meat. c. burnetti has been isolated from a large range of animals including farm animals (e.g. cattle, sheep and goats), wildlife and arthropods. it has a near-worldwide distribution. c. burnetti causes q fever in humans, in whom it was traditionally considered an occupational disease in farm and abattoir workers. airborne transmission is also important, and has played a major role in recent outbreaks. the meatborne transmission route has so far not been identified as a possibility (georgiev et al., 2013) . erysipelothrix rhusiopathiae e. rhusiopathiae is a ubiquitous bacterium which can cause polyarthritis in sheep and lambs. it can also infect humans, in whom it causes either cutaneous (localised or general) or septicaemic disease (wang et al., 2010) . humans usually acquire the infection through contact with infected animals, i.e. erysipelas is considered an occupational disease. meat from small ruminants has not been identified as a vehicle for human infection. esbls may be defined as plasmid-encoded enzymes found in the enterobacteriaceae that confer resistance to a variety of ß-lactam antibiotics, including penicillins, and second-, third-and fourthgeneration cephalosporins. in contrast, ampc β-lactamases are intrinsic cephalosporinases found on the chromosomal dna of many gram-negative bacteria, which confer resistance to penicillins, second-and third-generation cephalosporins, including β-lactam/inhibitor combinations, and cefamycins (cefoxitin), but usually not to fourth-generation cephalosporins. a growing number of these ampc enzymes are now plasmid-borne (efsa panel on biological hazards, 2011c). a targeted literature search found references that reported the presence of esbl/ampc-gene carrying enterobacteriaceae (geser et al., 2012; snow et al., 2011) in small ruminants but none indicated transmission of these enzymes to humans via consumption of meat from sheep or goats. helicobacter pylori h. pylori was previously known as campylobacter pylori (it is taxonomically related to campylobacter spp. and belongs to the family helicobacteraceae). infection of the stomach by h. pylori is associated with several alterations in gastric mucosal cell proliferation, and disorders such as chronic gastritis, gastric ulcers, duodenal ulcers and stomach cancer. colonisation of the stomach by h. pylori is well established and the bacterium is able to withstand digestive enzymes and concentrated hydrochloric acid. h. pylori is believed to be transmitted orally but no food has been as yet identified as a source. no reservoir other than the human gastric mucosa has been identified for h. pylori. plonka et al. (2006) suggest a zoonotic link to sheep, but no evidence of meat-borne transmission is presented. although the isolation of k. pneumoniae from small ruminants' meat has been described (brahmbhatt, 2000; sharma et al., 2003) , no evidence for meat-borne transmission of this pathogen to humans could be found. l. spiralis has been reported in the small ruminant population in europe and elsewhere (bisias et al., 2010; savalia et al., 2008; seixas melo et al., 2010) ; however, although it has been considered a potential occupational hazard (heuer et al., 2010) , there is no current evidence that it can be transmitted to humans via consumption of meat from small ruminants. mycobacterium avium subsp. paratuberculosis m. avium subsp. paratuberculosis (map), which causes chronic enteritis in all ruminants, is the most prevalent mycobacterium found in small ruminants within the m. avium complex (mac). mac includes eight mycobacteria species and several subspecies with different degrees of pathogenicity, a broad host range and environmental distribution in numerous biotopes including the soil, water, aerosols, etc. (alvarez et al., 2011; biet et al., 2005) . a link between map and the human chronic enteritis, crohn's disease, has been speculated and supported by several lines of evidence, such as the demonstration of map-specific sequences in crohn's disease-affected tissues. however, at present, there is no agreed consensus on any aetiological role for map in crohn's disease (chiodini, 2000; waddell et al., 2008; wagner et al., 2013) and no evidence that it presents a risk via consumption of meat or meat products. the presence of mycobacteria has been previously reported in the small ruminant population in the eu (domenis et al., 2011; malone et al., 2003; marianelli et al., 2010; . despite these reports, evidence of meat-borne transmission of these pathogens to humans from small ruminants is lacking, so this potential pathway of infection remains unproven in the context of livestock processed through the eu meat inspection system. mrsa has been isolated from most food-producing animals and from most meats, as well as from milk including sheep and lamb meat. where mrsa cc398 prevalence is high in food-producing animals, people in contact with these live animals (especially farmers and veterinarians, and their families) are at greater risk of colonisation and infection than the general population. food may be contaminated by mrsa (including cc398): eating and handling contaminated food is a potential vehicle for transmission. there is currently no evidence for increased risk of human colonisation or infection following contact or consumption of food contaminated by cc398 both in the community and in hospital (efsa, 2009). streptococcus spp. have been isolated in small ruminants, most commonly in milk or mastitis samples (pisoni et al., 2009; zdragas et al., 2005) . zoonotic transmission has been described (poulin and boivin, 2009), but there is no evidence to date that it can cause meat-borne disease in humans. foodborne yersiniosis is caused primarily by yersinia enterocolitica, with y. pseudotuberculosis representing a low fraction of isolates (less than 1 %) from human cases reported (efsa and ecdc, 2013b). the majority of isolates of y. enterocolitica isolated from food and environmental sources are non-pathogenic types, and therefore discrimination between pathogenic and non-pathogenic strains for humans is necessary. no reports of y. pseudotuberculosis have been published of isolates in food items tested during -2011 (efsa and ecdc, 2012 , 2013b . pigs are considered to be the primary reservoir for the human pathogenic types of y. enterocolitica, and they can be isolated from the oral cavity, the submaxillary lymph nodes, the intestine and faeces (nesbakken, 2006) . y. enterocolitica is found in small ruminants, and is considered to be responsible for certain infections in sheep and goats such as enteritis (arnold et al., 2006; fearnley et al., 2005; fredriksson-ahomaa et al., 2006; fukushima et al., 1993; gourdon et al., 1999; krogstad, 1974; mcnally et al., 2004; milnes et al., 2008; philbey et al., 1991; slee and button, 1990; slee and skilbeck, 1992; soderqvist et al., 2012; wojciech et al., 2004) . mcnally et al. (2004) investigated the relationship between livestock (sheep, cattle and pigs) carriage of y. enterocolitica and human disease with inconclusive results. the majority of the strains isolated from animal reservoirs differ from clinical strains found in humans, biochemically and serologically. so far pigs are the only species pinpointed as being significant reservoirs for pathogenic y. enterocolitica. there is no evidence that sheep and goats are important animal reservoirs for strains involved in human cases, although slee and button (1990) reported the infection of an animal attendant in connection with an outbreak of y. enterocolitica infection in a goat herd in norway. no evidence that yersinia spp. present a risk via consumption of meat or meat products from sheep or goats is currently available. c. albicans is a fungus that is the causal agent of opportunistic oral and genital infections in humans and has also been isolated from sheep and goats, for example in milk samples of goats suffering from mastitis (langoni et al., 2006) or from sheep droppings (nardoni et al., 2002) . no evidence to date could indicate transmission of this fungus to humans via consumption of meat. cryptococcosis is a rare disease in animals in europe. a few cases have been described in sheep and goats (lung and mammary gland) in australia. the source of microorganisms is largely environmental. no cases of transmission from animal to animal or from animal to man or from man to man (except corneal transplant) have been described (acha and szyfres, 2001). c. neoformans is therefore currently considered not relevant in the eu sheep and goat population and not transmissible via meat. species of microsporidia infecting humans have been identified in water sources as well as in wild, domestic, and food-producing farm animals, raising concerns for waterborne, foodborne, and zoonotic transmission (didier, 2005) . no evidence could be found in the literature of meat-borne transmission of this hazard from small ruminants to humans. enterocytozoon bieneusi e. bieneusi, the species now known to be the most frequent in microsporidial infections of humans, was not discovered until 1985. e. bieneusi has recently been found in the faeces of animals, including pigs, rhesus macaques, cats and cattle. however, the potential reservoirs and the mode of transmission of this pathogen are still unknown (dengjel et al., 2001) . phylogenetic analysis revealed the lack of a transmission barrier between e. bieneusi from humans and animals (cats, pigs and cattle). thus, e. bieneusi appears to be a zoonotic pathogen." (dengjel et al., 2001 ). however, no evidence could be found in the literature for meat-borne transmission of this hazard from small ruminants to humans. parasites of the genus ascaris have very occasionally reported in sheep. however, the transmission of these parasites to humans is via ingestion of eggs that are excreted in faeces of the definite hosts (e.g. in pigs a. sum and in and humans a. lumbricoides), therefore there is currently no evidence of a link between human ascariasis and the consumption of ruminant meat. babesia spp. are vector-mediated parasites, and are transmitted by hard ticks (e.g. ixodes, dermacentor, rhipicephalus and hyaloma spp.). in europe, they are found in cattle and rodents, although they have also been reported in sheep ( (sreter et al., 2005) . human babesiosis is rare in europe, and only transmitted via tick bites, i.e. there have been no reports of meat-borne transmission to humans from animals. cerebral coenurosis is caused by the metacestode stage of the cestode t. multiceps, which has canids as the final host. both humans and sheep are intermediate hosts in the life cycle of this parasite, which is present in parts of europe (scala and varcasia, 2006) . infection occurs by ingestion of vegetables or water contaminated with the tapeworm eggs shed by the final host. meat has not been recorded as being involved in transmission of this parasite. cryptosporidiosis in humans is usually linked to consumption of contaminated water or contact with infected animals, mainly cattle but also young sheep and goats. although its presence in meat is considered possible, a quick review of the literature did not reveal any evidence describing the isolation in meat or any outbreaks caused by consumption of meat from small ruminants. c. ovis and c. tenuicollis are the larval stages of taenia ovis and taenia hydatigena respectively, found in the intestines of canids. humans can act as intermediate hosts for these cysticerci, but cases are very rare. consumption of meat is not associated with the transmission of these parasites, but they are targeted during meat inspection because cysticerci are visible and render the meat unfit for human consumption on quality grounds. ) . humans are a dead-end host and may become infected through accidental ingestion of the eggs, shed in the faeces of infected dogs or other canids. this usually occurs via the ingestion of contaminated food (especially vegetables) or water, and also through accidental soil ingestion or by acquiring the eggs directly from the coat of the definitive host. meat, however, has not been identified as a vehicle for transmission of e. granulosus. the trematode fasciola is a parasite of herbivores that can infect humans accidentally, and is commonly found in europe. humans can become infected by ingesting freshwater plants or water containing metacercariae (fried and abruzzi, 2010). there is currently no evidence of meat-borne transmission of this parasite to humans. g. intestinalis is a ubiquitous protozoan parasite with global distribution, which infects humans as well as a wide range of other mammals. g. intestinalis is excreted in faeces, and it is transmitted to humans via contaminated water or fresh vegetables. no evidence is available for a role for meat from small ruminants in transmitting this parasite to humans. virus of the family astroviridae are associated with gastroenteritis in birds and mammals, including small ruminants and humans. although a potential zoonotic link has been suggested (jonassen et al., 2001) , information available in the scientific literature does not point at potential transmission of astroviruses to humans via consumption of meat. bdv infections can result in neurological disease that mainly affects horses and sheep in certain areas of germany (bilzer et al., 1996; durrwald, 1993; grabner and fischer, 1991; ludwig et al., 1985) . the endemic area also includes areas of switzerland, austria and the principality of liechtenstein (caplazi et al., 1999; weissenbock et al., 1998) . bdv received worldwide attention when it was reported that sera and/or cerebrospinal fluids from neuropsychiatric patients can contain bdv-specific antibodies. as infected animals produce bdv-specific antibodies only after virus replication, it was assumed that the broad spectrum of bdv-susceptible species also includes man. however, reports describing the presence of other bdv markers, i.e. bdv-rna or bdv-antigen, in peripheral blood leucocytes or brain tissue of neuropsychiatric patients are highly controversial and, therefore, the role of bdv in human neuropsychiatric disorders is questionable (richt and rott, 2001) . in any case, no evidence of meat-borne transmission has been found. there is a lack of clarity in relation to the taxonomy of bovine enterovirus (bev). while it appears that bev may be zoonootic, based on a serological survey in turkey, and that sheep and goats in europe are infected, it is likely that the main source of infection for humans is contact with infected animals and/or material contaminated with faeces of infected animals. on the basis of the information obtained from the scientific literature, it is proposed that bev should not be considered for risk ranking. chandipura virus, a member of the rhabdoviridae family and vesiculovirus genus, has recently emerged as a human pathogen associated with a number of outbreaks of acute encephalitis in different parts of india (basak et al., 2007) . the virus closely resembles the vesicular stomatitis virus, and there are reports of antibody detection in small ruminants, also in india (joshi et al., 2005) . there are no reports of this virus being present in the eu or being able to be transmitted to humans via food. the information available in the scientific literature for this virus in the small ruminant reservoir is very limited. cchf is a tick-borne disease that can also be transmitted to humans through contact with infected tissues or blood from affected (viraemic) livestock, including sheep. cases of cchf have been reported in butchers and abattoir workers (ergonul, 2006) as well as health care workers, therefore it can be considered an occupational disease. currently, there is no evidence of meat-borne transmission, and it has been reported that "meat itself is not a risk because the virus is inactivated by post slaughter acidification of the tissues and would not survive cooking in any case." (ergonul, 2006) . hev has been found in both livestock, especially pigs, and humans in europe. the epidemiology of hev is complex, and a foodborne transmission of hev from animal products (e.g. pork and pork products) to humans is an emerging concern. however, only very few systematic studies have been performed so far, therefore the importance of specific food items has not been sufficiently substantiated. although the presence of hev antibodies in sheep has been previously reported in europe (peralta et al., 2009), there is no evidence that meat from small ruminants has played a role in transmitting the virus to humans (efsa panel on biological hazards, 2011a). the presence of influenza virus has been occasionally reported in small ruminants (abubakar et al., 2008; shukla and negi, 1984; zupancic et al., 1992) . although no information is available for small ruminants, the safety of meat from pigs infected with influenza has been previously assessed, and it was found that these viruses are not known to be transmissible to humans through the consumption of meat (fao/who/oie, 2009). orf, also known as contagious ecthyma, is caused by a parapoxvirus and is commonly found in the small ruminant population in europe. this virus is transmitted to humans through direct contact with infected animals and thus is considered an occupational disease (uzel et al., 2005) . meat-borne transmission has not been reported to date. small ruminants are susceptible to infection with rabies virus, which is present in the wild animal reservoir in europe (mainly in bats and wild canids). cases of rabies in sheep and goats have been occasionally reported in europe (maciulskis et al., 2005; mudura et al., 2007) , and although experimental oral transmission has been described (bell and moore, 1971; fischman and ward, 1968) , transmission of this virus to humans through the consumption of meat from small ruminants has not been reported to date. this rna virus of the family bunyaviridae causes disease in cattle, sheep and goats, and is transmitted to humans by a wide range of mosquitoes, as well as by handling diseased animals (davies and martin, 2006) . contact with and consumption of meat, as well as other animal products, has been identified as a risk factor for human infection (anyangu et al., 2010; mohamed et al., 2010) . the presence of this virus has not been reported in europe so far (efsa panel on animal health and welfare (ahaw), 2013). rotaviruses are responsible for causing enteritis and diarrhoea in young livestock, including sheep and goats, as well as in humans. some studies that used gene sequencing point to a common evolutionary origin for rotavirus strains found in small ruminants and those found in humans (ghosh et al., 2010; matthijnssens et al., 2009 ). this could suggest that there is potential for zoonotic transmission between livestock and humans, or at least that some exchange of viruses has occurred in the past (nakagomi et al., 1992) . it is, however, unclear if meat-borne transmission is possible, as there are no data in the literature reporting this possibility. tbe is an infection caused by flavivirus found in both wild and domestic animals in europe, including small ruminants. humans acquire the infection following the bite of an infected tick. transmission via aerosol and direct contact is also possible, as well as by consuming fresh milk from infected animals. however, transmission via consumption of meat has not been described (krauss et al., 2003) . objective of meat inspection is to ensure that meat is fit for human consumption. historically, meat inspection procedures have been designed to control slaughter animals for the absence of infectious diseases, with special emphasis on zoonoses and notifiable diseases. the mandate that meat needs to be fit for human consumption, however, also includes the control of chemical residues and contaminants that could be potentially harmful for consumers. this aspect is not fully addressed by the current procedures. the efsa panel on contaminants in the food chain (contam panel) was asked to identify and rank undesirable or harmful chemical residues and contaminants in meat from sheep and goats. such substances may occur as residues in edible tissues from the exposure of the animals to contaminants in feed materials as well as following the possible application of non-authorised substances and the application of authorised veterinary medicinal products and feed additives. a multi-step approach was used for the ranking of these substances into categories of potential concern. as a first step, the contam panel considered substances listed in council directive 96/23/ec and evaluated the outcome of the national residue control plans (nrcps) for the period 2005-2010. the contam panel noted that only 0.41 % of the total number of results was non-compliant for one or more substances listed in council directive 96/23/ec. potentially higher exposure of consumers to these substances from sheep and goat meat takes place only incidentally, as a result of mistakes or noncompliance with known and regulated procedures. the available aggregated data indicate a low number of samples that were non-compliant with the current legislation. however, in the absence of substance-and/or species-specific information, such as the tissues used for residue analysis and the actual concentration of a residue or contaminant measured, these data do not allow for a reliable assessment of consumer exposure. independently from the occurrence data as reported from the nrcps, other criteria used for the identification and ranking of chemical substances of potential concern included the identification of substances that are found in other testing programmes and that bio-accumulate in the food chain, substances with a toxicological profile of concern, and the likelihood that a substance under consideration will occur in sheep and goat carcasses. taking into account these criteria, the individual compounds were ranked into four categories denoted as being of high, medium, low and negligible potential concern. dioxins and dioxin-like polychlorinated biphenyls (dl-pcbs) were ranked as being of high potential concern owing to their known bioaccumulation in the food chain, the frequent findings above maximum levels (mls), particularly in sheep liver, and in consideration of their toxicological profile. the following substances were ranked in the category of medium potential concern: stilbenes, thyreostats, gonadal (sex) steroids, resorcylic acid lactones and beta-agonists (especially clenbuterol) because of their toxicity for humans, their efficacy as growth promoters in sheep and goats and the incidence of non-compliant results; chloramphenicol and nitrofurans because they have proven toxicity for humans, are effective as antibacterial treatments for sheep/goats and non-compliant samples are found in most years of the nrcps; non-dioxin-like polychlorinated biphenyls (ndl-pcbs) because, while they bioaccumulate and there is a risk of exceeding the mls, they are less toxic than dioxins and dl-pcbs; and the chemical elements cadmium, lead and mercury because of the number of non-compliant results reported under the nrcps and their toxicological profile. residues originating from other substances listed in council directive 96/23/ec were ranked as of low or negligible potential concern. the contam panel emphasises that this ranking into specific categories of potential concern is based on the current knowledge regarding toxicological profiles, usage in sheep and goat production and occurrence as chemical residues and contaminants. where changes in any of these factors occur, the ranking might need amendment. the contam panel was also asked to assess the main strengths and weaknesses of current meat inspection protocols within the context of chemical hazards. it was noted that current procedures for sampling and testing are, in general, well established and coordinated, including follow-up actions subsequent to the identification of non-compliant samples. the regular sampling and testing for chemical residues and contaminants is an important disincentive for the development of undesirable practices and the prescriptive sampling system allows for equivalence in the control of eu-produced sheep and goat meat. the current combination of animal traceability, ante-mortem inspection and gross tissue examination can support the collection of appropriate samples for residue monitoring. nevertheless, a major weakness is that, with very few exceptions, presence of chemical hazards cannot be identified by current ante-/post-mortem meat inspection procedures at the slaughterhouse level and there is a lack of sufficient cost-effective and reliable screening methods. in addition, sampling is mostly prescriptive rather than risk or information based. there is limited ongoing adaptation of the sampling and testing programmes to the results of the residue monitoring programmes, with poor integration between the testing of feed materials for undesirable substances and the nrcps and sampling under the nrcps reflecting only a part of testing done by a number of mss, the results of which should be taken into consideration. the contam panel was also asked to identify and recommend inspection methods for new hazards. as dioxins and dl-pcbs have not yet been comprehensively covered by the sampling plans of the current meat inspection, they should be considered as 'new' hazards as they have been ranked as being of high potential concern. moreover, for other organic contaminants that may accumulate in foodproducing animals and for a number of chemical elements used as feed supplements, only limited data regarding residues in sheep and goats are available. this is the case, in particular, for brominated flame retardants, including polybrominated diphenylethers (pbdes) and hexabromocyclododecanes (hbcdds) and perfluorinated compounds (pfcs) including (but not limited to) perfluorooctane sulphonate (pfos) and perfluorooctanoic acid (pfoa). the contam panel concludes that sheep and goat production in the eu is marked by being largely extensive in nature, involving frequent trading of animals and nomadic flocks. these differences in husbandry systems and feeding regimes result in different risks for the occurrence of chemical residues and contaminants. extensive periods on pasture or/as nomadic flocks and the use of slaughter collection dealerships may preclude detailed lifetime food chain information (fci). the contam panel recommends that fci should be expanded for sheep and goats produced in extensive systems to provide more information on the specific environmental conditions where the animals are produced and that future monitoring programmes should be based on the risk of occurrence of chemical residues and contaminants, taking into account the completeness and quality of the fci supplied and the ranking of chemical substance into categories of potential concern, which needs to be regularly updated. control programmes for chemical residues and contaminants should be less prescriptive, with sufficient flexibility to adapt to results of testing, should include 'new hazards', and the test results for sheep and goats should be separately presented. there is a need for an improved integration of sampling, testing and intervention protocols across the food chain, nrcps, feed control and monitoring of environmental contaminants. the development of analytical techniques covering multiple analytes and of new biologically based testing approaches should be encouraged too and incorporated into the residue control programmes. for prohibited substances, testing should be directed where appropriate towards the farm level and, in the case of substances that might be used illicitly for growth promotion, control measures, including testing, need to be refocused to better identify the extent of abuse in the eu. meat inspection in the eu is specified in regulation (ec) no 854/2004. 19 the main objective of meat inspection is to ensure that meat is fit for human consumption. historically, meat inspection procedures have been designed to control slaughter animals for the absence of infectious diseases, with special emphasis on zoonoses and notifiable diseases. the mandate that meat needs to be fit for human consumption, however, also includes the control of chemical residues and contaminants in meat that could be potentially harmful for consumers. this aspect is not fully addressed by the current procedures. for the purposes of this document 'chemical residues' refer to chemical compounds which result from the intentional administration of legal or illegal pharmacologically active substances while 'chemical contaminants' refer to chemical compounds originating from the environment. this document aims to identify undesirable or harmful chemical residues and contaminants that may occur in meat from sheep and goats taking into account the current legislation and the results from the national residue control plans (nrcps) implemented in line with council directive 96/23/ec. 20 these findings, together with the characteristics of the individual substances and the likelihood that a substance will occur in meat from sheep or goats were used to rank chemical residues and contaminants into categories of potential concern. four categories were established constituting a high, medium, low or negligible potential concern. in the second part, the main strengths and weaknesses of current meat inspection protocols were assessed within the context of chemical hazards. the ultimate aim is an overall evaluation of the current strategies for sampling and analytical testing, resulting in recommendations for possible amendments to the current meat inspection protocols. in this opinion, where reference is made to european legislation (regulations, directives, decisions), the reference should be understood as relating to the most current amendment, unless otherwise stated. sheep (ovis aries) were domesticated from ancestral subspecies of wild mouflon approximately 9 000 years ago in south-west asia, and by 5 000 years ago, sheep had been transported throughout europe. today, over 850 sheep breeds are recognised worldwide, and europe supports a greater number of breeds than any other continent. sheep are raised for three main purposes: meat, milk and wool. therefore, a range of different breeds have been developed over centuries to suit the land and weather and husbandry conditions in different areas of the eu. in mountain and arid areas, for example, sheep are bred for hardiness and self-reliance (e.g. scottish blackface). they must be able to survive poor weather and thrive on poor grazing. lowland or grassland breeds, on the other hand (e.g. suffolk and texel), usually do not cope as well with bad weather or poor-quality feed, but produce higher numbers of lambs that are often better suited for meat production. most lambs are born in late winter or spring. many lambs are born outside, particularly those in mountain flocks. indoor lambing is also common, particularly for lowland flocks. good housing facilities and management are important in order to prevent disease and heat stress problems. most meat-breed sheep are slaughtered and presented for meat inspection as younger stock "lambs" from ten weeks up to one year. in accordance with commission regulation (ec) no 1244/2007, 21 a "young ovine animal" means an ovine animal of either gender, not having any permanent incisor teeth erupted and not older than 12 months. sheep have also been raised for milk production for thousands of years. the east friesian type is one of the most common and productive breeds of dairy sheep. europe's commercial dairy sheep industry is concentrated in the countries on or near the mediterranean sea. most of the sheep milk is used to produce cheese, such as feta, ricotta, manchego and pecorino romano. in france, the lacaune is the breed of choice for making roquefort cheese. dairy sheep kept on small farms are milked seasonally by hand but more modern sheep dairies use sophisticated machinery for milking. ewes are milked once or twice per day. sheep are also widely kept for wool production, particularly in the united kingdom and spain. wool may range from fine or medium fibre diameter to specialised breeds producing wool for carpets. some flocks may be kept for both meat and wool production purposes. meat from older sheep carcasses (mutton), derived from cull adult sheep from the dairy or wool industries, is tougher and is not as widely consumed as fresh meat, but may also be used in sausage production. goats have been associated with man in a symbiotic relationship for up to 10 000 years. the goat eats little, occupies a small area and each produces enough milk to sustain a family. in europe, goat farming is strongly oriented towards milk production, which is mostly used for cheese production. it has been estimated that the eu has 1.6 % of the world's goat population, but it produces 13.2 % of goat milk and 2.0 % of goat meat generated in the world annually (casey, 2005) . during the last ten years, the overall eu goat count has diminished. in france, greece and spain, annual goat milk production is 580, 510, and 420 million litres, respectively, which comprises 83 % of the total goat milk produced in the eu. france produces a great number of goat's milk cheeses, especially in the loire valley, with examples of french chèvre including bucheron. like sheep, dairy goats kept on small farms are milked seasonally by hand but modern goat dairies use more sophisticated machinery for milking. does are milked once or twice per day. goats produced for fibre are not common in europe, but small local flocks occur in many member states (mss). the fibre taken from an angora goat breed is called mohair. a single goat produces between four and five kilograms of hair per year, shorn twice a year. cashmere is the valuable fine undercoat found to varying degrees and qualities on all goats, except the angora. it grows as a winter down which is shed in early spring, when it is harvested by either shearing or combing. goat meat or chevron is not widely consumed in the eu. specialised larger goat meat breeds such as the boer goat are currently only held in small local herds, but crosses of a boer sire and a cashmeretype breed dam can also be used to provide a suitable carcass. these meat-line goats can grow to slaughter weight (25-30 kg) in approximately six to nine months on low-quality feeding. again, the meat from older goat carcasses derived from the cull goats from dairy or fibre industries tends to be very tough. meat from older male goats ('billy' goats) can have an offensive odour. the extensive farming practices and generally low economic value of sheep and goats mean that veterinary treatment of individual animals is often limited. sheep and goats are often exposed to parasites, which explain the necessary use of anti-parasitic programmes for the flocks. other veterinary interventions follow normal clinical practice, such as the use of registered mastitis treatments for milking animals, with appropriate withdrawal periods and residue monitoring. it is important to note that, despite recent developments towards large milking goat holdings, sheep and goat production in the eu largely remains extensive 22 in nature, involving frequent trading of animals and nomadic flocks. this involves varied husbandry systems and feeding regimes resulting in different risks for chemical substances and contaminants. sheep and goat populations in the eu as reported by eurostat are presented in table 1 . in accordance with annex i of regulation (ec) no 854/2004 all animals should be inspected prior to slaughter (ante-mortem inspection) as well as after slaughter and evisceration (post-mortem inspection). there are concerns about slaughter outside licensed premises where animals are not subject to appropriate meat inspection. since january 2010, a mandatory identification of small ruminants has been implemented in the eu by regulation (ec) no 21/2004. 23 domestic sheep and goats may be presented for slaughter in small numbers or even as individuals. visual ante-mortem inspection is carried out at the level of the individual animal. extensive periods on pasture or as nomadic flocks, sale at open markets of many sheep and goats, and the presence of slaughter collection dealerships that may combine small numbers of animals purchased from several farmers, means that there is a level of concern that food chain information (fci) shared between farmers and the slaughterhouse (where residue data are managed), may be suboptimal. similarly, in these situations, the level of feedback from the slaughterhouse and authorities to farmers regarding the results of residue testing may be suboptimal. here the individual identification of animals, which has now become mandatory, may contribute to more transparency in the future. there is less concern about fci from dairy sheep and goats as they are reared under more intensive and controlled conditions. fci is the animal's life history data from birth, through all stages of rearing, up to the day of slaughter. in particular, the food business operator (fbo) at the slaughterhouse should receive information related to the veterinary medicinal products (vmps) or other treatments administered to the animals within a relevant period prior to slaughter, together with their administration dates and their withdrawal periods. moreover, any test results for samples taken from the animals within the framework of monitoring and control of residues should also be communicated to the slaughterhouse operators before the arrival of the animals. based on regulation (ec) no 854/2004, post-mortem inspection was, and still is, directed primarily at the detection of lesions due to infections, based on observation, palpation, and incision. an exception is the mandatory sampling of adult animals for transmissible spongiform encephalopathies (tses). in contrast to bovine animals, tse testing is not directed at individual animals, but is based on a region and animal stock related monitoring system. visual inspection of the carcass (and offals) may allow, in some cases, for the identification of gross alterations in carcass conformation (e.g. abscesses or deposits) and organ-specific lesions in kidneys, liver, lungs or other organs that might be indicative of recent use of vmps (with the possibility of noncompliance with withdrawal periods) or acute or chronic exposure to toxic substances. in most cases, exposure to chemical compounds does not result in typical organ lesions. hence it needs to be considered that evidence for the presence of chemical residues and contaminants will in most cases not be apparent during the visual inspection of ovine and caprine carcasses. therefore, the meat inspection approach based on "detect and immediately eliminate", used for biotic (microbiological) hazards in slaughterhouses, is generally not applicable to abiotic hazards. while monitoring programmes (council directive 96/23/ec, described in section 1.3) may provide a gross indication of the prevalence of undesirable chemical residues and contaminants in ovine and caprine carcasses, the sole intervention at abattoir level is the isolation of a suspect carcass as potentially unfit for human consumption, pending results of residue testing. council directive 96/23/ec prescribes the measures to monitor certain substances and residues thereof in live animals and animal products. it requires that mss adopt and implement a national residue monitoring programme, also referred to as the national residue control plan (nrcp, for defined groups of substances. 24 mss must assign the task of coordinating the implementation of the controls to a central public body. this public body is responsible for drawing up the national plan, coordinating the activities of the central and regional bodies responsible for monitoring the various residues, collecting the data and sending the results of the surveys undertaken to the commission each year. the nrcp should be targeted; samples should be taken on-farm and at abattoir level with the aim of detecting illegal treatment or controlling compliance with the maximum residue limits (mrls) for vmps according to commission regulation (eu) no 37/2010, 25 with the maximum residue levels (mrls) for pesticides as set out in regulation (ec) no 396/2005, 26 or with the maximum levels (mls) for contaminants as laid down in commission regulation (ec) no 1881 this means that in the national monitoring plans, the mss should target those groups of animals/gender/age combinations in which the probability of finding residues is highest. this approach differs from random sampling, in which the objective is to gather statistically representative data, for instance to evaluate consumer exposure to a specific substance. the minimum number of animals to be checked for all kind of residues and substances must be at least equal to 0.05 % of sheep and goats over three months of age slaughtered the previous year, with the following breakdown (further details on group a and b compounds is presented in section 2. group a: 28 0.01 % of total samples -each sub-group a must be checked each year using a minimum of 5 % of the total number of samples to be collected for group a. the balance is allocated according to the experience and background information of the ms. group b: 0.04 % of the total samples -30 % must be checked for group b1 substances -30 % must be checked for group b2 substances -10 % must be checked for group b3 substances. the balance must be allocated according to the situation of the ms. in the case of imports from third countries, chapter vi of council directive 96/23/ec describes the system to be followed to ensure an equivalent level of control on such imports. in particular it specifies (i) that each third country must provide a plan setting out the guarantees which it offers as regards the monitoring of the groups of residues and substances referred to in annex i to the council directive, (ii) that such guarantees must have an effect at least equivalent to those provided for in council directive 96/23/ec, (iii) that compliance with the requirements of and adherence to the guarantees offered by the plans submitted by third countries shall be verified by means of the checks referred to in article 5 of directive 72/462/eec 29 and the checks provided for in directives 90/675/eec 30 and 91/496/eec, 31 and (iv) that mss are required to inform the commission each year of the results of residue checks carried out on animals and animal products imported from third countries, in accordance with directives 90/675/eec and 91/496/eec. in accordance with article 8 of council directive 96/23/ec, the mss are requested, as a follow-up, to provide information on actions taken at regional and national level as a consequence of non-compliant results. the commission sends a questionnaire to the ms to obtain an overview of these actions, for example when residues of non-authorised substances are detected or when the maximum residue limits/maximum levels established in eu legislation are exceeded. in summary, this means that the term 'suspect sample' applies to a sample taken as a consequence of: non-compliant results, and/or suspicion of an illegal treatment, and/or suspicion of non-compliance with the withdrawal periods. non-compliant results for a specific substance or group of substances or a specific food commodity should result in intensified controls for this substance/group or food commodity in the plan for the following year. article 16 it should be noted that targeted sampling as defined by council directive 96/23/ec aims at monitoring certain substances and residues thereof in live animals and animal products across eu mss. in contrast to monitoring, under suspect sampling, a 'suspect' carcass has to be detained at the abattoir until laboratory results confirm or deny conformity with legislative limits for chemical residues. based on the test results, the carcass can be declared fit or unfit for human consumption. in the first scenario, the carcass is released into the human food chain whereas in the second case the carcass is disposed of. in addition to the minimum testing requirements which form part of the nrcps, council directive 96/23/ec also establishes the requisites for self-monitoring and co-responsibility on the part of operators. in accordance with article 9, chapter iii of council directive 96/23/ec, mss shall ensure that the owners or persons in charge of the establishment of initial processing of primary products of animal origin (slaughterhouses) take all necessary measures, in particular by carrying out their own checks, to: accept only those animals for which the producer is able to guarantee that withdrawal times have been observed satisfy themselves that the farm animals or products brought into the slaughterhouse do not contain residue levels which exceed maximum permitted limits and that they do not contain any trace of prohibited substances or products. farmers and food processors (including slaughterhouses) must place on the market only: animals to which no unauthorised substances or products have been administered or which have not undergone illegal treatment animals for which, where authorised products or substances have been administered, the withdrawal periods prescribed for these products or substances have been observed. tor 1: identification, classification and ranking of substances of potential concern 2.1. in the current eu legislation, chemical residues and contaminants in live animals and animal products intended for human consumption are addressed in as one of the objectives of this assessment of current meat inspection protocols is the identification of chemical substances of potential concern that may occur as residues or contaminants in sheep and goats, but have not been specifically addressed in council directive 96/23/ec, a more general grouping of chemical substances was chosen, resulting in the following three major groups: substances that are prohibited for use in food-producing animals, corresponding to group a substances in council directive 96/23/ec veterinary drugs, also denoted vmps, corresponding to groups b1 and b2 substances in council directive 96/23/ec and contaminants, corresponding to group b3 substances in council directive 96/23/ec. the first group of chemicals that may occur in edible tissues as residues are those substances prohibited for use in food-producing animals; these substances correspond largely with group a substances in council directive 96/23/ec. there were different rationales for banning these substances for application to animals and the list of group a substances comprises compounds that are of toxicological concern (including vmps for which an acceptable daily intake (adi) could not be established), as well as substances having anabolic effects and pharmacologically active compounds that may alter meat quality and/or affect animal health and welfare. a second group of chemicals that may be a source of residues in animal-derived foods are vmps (including antibiotics, anti-parasitic agents and other pharmacologically active substances) and authorised feed additives used in the health care of domestic animals; these substances correspond largely with group b1 and b2 substances in council directive 96/23/ec. these substances have been subjected to assessment and pre-marketing approval by the with regard to antibacterial agents, it is important to state that the ranking of substances of concern in this part of the document considers only toxicological concerns related to the presence of residues. other aspects, such as the emergence of antimicrobial resistance is considered by the efsa panel on biological hazards (biohaz panel) in a separate part of this opinion (see appendix a of the biohaz panel). a third group of chemical substances that may occur in edible tissues of sheep and goats are contaminants that may enter the animal's body mainly via feed, ingested soil, drinking water, inhalation or direct (skin) contact; these substances include the group b3 substances in council directive 96/23/ec. feed materials can contain a broad variety of undesirable substances comprising persistent environmental pollutants, toxic metals and other elements as well as natural toxins, including toxic secondary plant metabolites and fungal toxins (mycotoxins). feed producers have to act in compliance with commission directive 2002/32/ec, 35 listing the undesirable substances in feed and feed materials and presenting maximum content in feed materials or complete feedingstuffs. in a recent re-assessment of these undesirable substances in animal feeds, the contam panel reevaluated the risk related to exposure to these substances for animals. special attention was given to toxic compounds that accumulate or persist in edible tissues, including meat, or that are directly excreted into milk and eggs. 3.12.2011, pp. 18-23. 38 the term "dioxins" used in this opinion refers to the sum of polychlorinated dibenzo-p-dioxins (pcdds) and polychlorinated dibenzofurans (pcdfs). as an early warning tool, the european commission has set action levels for dioxins and dl-pcbs in food through commission recommendation 2011/516/ec. 40 owing to the fact that their sources are generally different, separate action levels for dioxins and dl-pcbs were established. the action levels for meat and meat products of sheep are 1.75 pg who-teq/g fat for dioxins and 1.75 pg who-teq/g fat for dl-pcbs. in cases where levels of dioxins and/or dl-pcbs in excess of the action levels are found, it is recommended that mss, in cooperation with fbos, initiate investigations to identify the source of contamination, take measures to reduce or eliminate the source of contamination and check for the presence of ndl-pcbs. maximum residue levels for certain elements in sheep and goats are also laid down in regulation (ec) no 396/2005 of the european parliament and of the council on maximum residue levels of pesticides in or on food and feed of plant and animal origin, related to the use of copper-containing and mercury-containing compounds as pesticides. for copper, the maximum residue levels are each 5 mg/kg for meat and fat and 30 mg/kg each for liver, kidney and edible offal. for mercury compounds (sum of mercury compounds expressed as mercury), the maximum residue levels are 0.01 mg/kg each for meat, fat, liver, kidney and edible offal. a multi-step approach was used for ranking the potential concern of the three groups of substances that are presented in sections 2.1 and 2.2. the steps are: evaluation of the outcomes of the nrcps indicating the number of results that are noncompliant with the current legislation evaluation of the likelihood that specific residues or contaminants, including 'new hazards', may be present in sheep and goat carcasses consideration of the toxicological profile for chemical substances. data from the nrcps are published annually and these data were considered as the first step for hazard ranking. aggregated data for the outcome of the nrcps for targeted sampling of sheep and goats from 2005 to 2010 are presented in tables 3-5 results from suspect sampling are not included, as these results are considered not to be representative of the actual occurrence of chemical residues and contaminants. as stated above, suspect sampling arises as (i) a follow-up to the occurrence of a non-compliant result, and/or (ii) on suspicion of illegal treatment at any stage of the food chain, and/or (iii) on suspicion of non-compliance with the withdrawal periods for authorised vmps (articles 5, 11 and 24 of council directive 96/23/ec, respectively). a non-compliant result refers to an analytical result exceeding the permitted limits or, in the case of prohibited substances, any measured level with sufficient statistical certainty that it can be used for legal purposes. 41 it should be noted that information on the number of total analyses performed for an individual substance is only transmitted by those mss that were reporting at least one non-compliant result for that substance. therefore, it is not possible to extract from the data supplied complete information on the individual substances from each sub-group tested or the number of samples tested for an individual substance where no non-compliant result is reported. in addition, in some cases the same samples were analysed for different substance groups/sub-groups and therefore the number of substance groups/sub-groups tested is higher than the total number of samples collected from sheep and goats. it is to be noted that there is a lack of harmonisation regarding details provided on non-compliant results for the nrcps from mss. this hampers the interpretation and the evaluation of these data. moreover, in some cases, no information is available on the nature of the positive samples (i.e. whether this refers to muscle, liver, kidney, skin/fat or other samples) and these results often give no indication of the actual measured concentrations of residues or contaminants. as a result, in the absence of substance-specific information and the actual concentration of a residue or contaminant measured, these data do not allow for an assessment of consumer exposure. in addition, particularly in the case of prohibited substances, much of the testing may be done in matrices such as urine, faeces and hair and so no data on residue levels in edible tissues are available. another problem with interpreting the data provided arises from the failure to clearly identify in all cases (i) the proportion of total samples tested that are of sheep and that are of goat and (ii) whether a particular non-compliant result refers to a sample from a sheep or from a goat. in spite of the limitations highlighted above, an overall assessment of these data indicates that the percentage of non-compliant results is of a low order of magnitude compared with the total number of samples tested. ( (3) 11 407 32 (6) 11 715 50(9) 12 320 antibacterials (unspecified) c published at http://ec.europa.eu/food/food/chemicalsafety/residues/control_en.htm a summary of the data presented in the previous tables (tables [3] [4] [5] shows that 619 of the 152 143 (0.41 %) samples analysed in the eu nrcps during the period 2005-2010 were non-compliant for one or more substances listed in annex i of council directive 96/23/ec. further details are presented in table 6 . as mentioned above, one sample can be non-compliant for multiple substances, so that the number of non-compliant results is higher than the number of non-compliant samples. for example, for b3 substances, there were 207 non-compliant results in 176 non-compliant samples. one sample can be non-compliant for more than one substance. b published at http://ec.europa.eu/food/food/chemicalsafety/residues/control_en.htm c some of the samples were analysed for several substances in different subgroups (e.g. same sample analysed for b3a, b3b and b3c), this total represents the total number of samples analysed for at least one substance in the group. it should be noted that the data in tables 3-5 provide the results for sampling and testing carried out by mss under the terms of council directive 96/23/ec within the nrcps. however, there may be other chemical substances of relevance for control in sheep and goats, particularly in the case of contaminants, which are not included in the nrcps at all or which are not systematically covered by the nrcps. some of these substances are addressed further under tor 3 of this opinion ('new hazards'). of the total number of samples taken for analysis during the period 2005-2010, 5.5 % were taken at farm level while the remaining 94.5 % were taken at slaughterhouse level. no information on the types of animals sampled is readily available. results indicate that: 0.41 % of the total samples were non-compliant for one or more substances, with 0.64 %, 0.24 % and 0.86 % being non-compliant for group a, group b1/b2 and group b3 substances, respectively. 0.35 % of all samples taken at farm level were non-compliant for one or more substances, with 0.06 %, 0.79 % and 0.48 % being non-compliant for group a, group b1/b2 and group b3 substances, respectively. 0.41 % of all samples taken at slaughterhouse level were non-compliant for one or more substances, with 0.74 %, 0.22 % and 0.88 % being non-compliant for group a, group b1/b2 and group b3 substances, respectively. the highest proportion of non-compliant results overall (0.86 %) was for group b3 substances, contaminants, representing largely exceedances of the mls/mrls specified for these substances. the proportions of non-compliant results overall for group a, prohibited substances (0.64 %), and for group b1/b2 substances, vmps (0.24 %) represent largely illicit use of prohibited substances and exceedances of the mrls specified for vmps, respectively. an analysis of the results for sampling at farm level compared with slaughterhouse level indicates that for prohibited substances (group a) the rate of non-compliant results determined for sampling at farm level is considerably lower than that for sampling at slaughterhouse level. the majority (90 %) of samples found to be non-compliant for prohibited substances relate to those having anabolic effects (thyreostats, steroids, zeranol, beta-agonists) and only a minority (10 %) were non-compliant for substances such as chloramphenicol, nitrofurans and nitroimidazoles. while the incidence of noncompliant results from farm level sampling is low, such sampling is an integral component of the system for controlling illicit use of prohibited substances in food-producing animals, particularly in the case of substances having anabolic effects. in the case of vmps (group b1/b2) the rate of non-compliant results determined at farm level is markedly higher than for sampling at slaughterhouse level. however, slaughterhouse-level sampling is more appropriate for identifying non-compliant samples for vmps, based on compliance with or exceedance of the specified mrls in edible tissues. in the case of contaminants (group b3) the rate of non-compliant results determined for sampling at slaughterhouse level is almost twofold higher than for sampling at farm level. indeed, sampling for group b3 substances is more appropriate, generally, at slaughterhouse level where identification of non-compliant results, based on compliance with or exceedance of specified mrls/mls in edible tissues, can be made. it should be noted also that a direct comparison of data from the nrcp over the years is not entirely appropriate as the test methods used and the number of samples tested for an individual residue varied between mss, and the specified mrls/mls for some substances may change over time. in addition, there are ongoing improvements in analytical methods, in terms of method sensitivity, accuracy and scope (i.e. number of substances covered by the method), which affects inter-year and inter-country comparisons. therefore, the cumulative data from the nrcps provide only a broad indication of the prevalence and nature of non-compliant samples. in conclusion, this compilation of data clearly indicates the low prevalence of abiotic hazards (residues and contaminants) in edible tissues of sheep and goats. only 0.41 % of the total number of analysed samples was non-compliant for one or more substances listed in annex i of council directive 96/23/ec. based on these results, it can be concluded that potentially higher exposure of consumers to these substances from edible tissues of sheep and goats takes place only incidentally, as a result of mistakes or non-compliance with known and regulated procedures. the available aggregated data indicate the number of samples that were non-compliant with the current legislation. however, in the absence of species-and substance-specific information, such as the tissues used for residue analysis and the actual concentration of a residue or contaminant measured, these data do not allow for a reliable assessment of consumer exposure. while the data from the annual nrcp testing by mss indicate a relatively low incidence of noncompliant results for sheep and goats, there may be human health concerns regarding certain contaminants. for example, an evaluation undertaken by efsa (efsa contam panel, 2011b) on the risk to public health related to the presence of high levels of dioxins and dioxin-like pcbs in liver from sheep (and deer) concluded that regular consumption of sheep liver would result, on average, in an approximate 20 % increase of the median background exposure to dioxins and dioxin-like pcbs (dl-pcbs) for adults. the study also concluded that on individual occasions, consumption of sheep liver could result in high intakes exceeding the tolerable weekly intake (twi), and that the frequent consumption of sheep liver, particularly by women of child-bearing age and children, may be a potential health concern. independent from the occurrence data as reported from the nrcps, each substance or group of chemical substances that may enter the food chain was also evaluated for the likelihood that potentially toxic or undesirable substances might occur in sheep and goat carcasses. for prohibited substances and vmps/feed additives, the following criteria were used: the likelihood of the substance(s) being used in an illicit or non-compliant way in sheep and goats (suitability for sheep and goat production; commercial advantages) the potential availability of the substance(s) for illicit or non-compliant usage in sheep and goat production (allowed usage in third countries; availability in suitable form for use in sheep and goats; non-authorised supply chain availability ('black market'); common or rare usage as a commercial licensed product) the likelihood of the substance(s) occurring as residue(s) in edible tissues of sheep and goats based on the kinetic data (pharmacokinetic and withdrawal period data; persistence characteristics; special residue issues, e.g. bound residues of nitrofurans) toxicological profile and nature of hazard and the relative contribution of residues in sheep and goats to dietary human exposure. for contaminants, the following criteria were considered: the prevalence (where available) of occurrence of the substances in animal feeds/forages and pastures, and of the specific environmental conditions in which the animals are raised the level and duration of exposure, tissue distribution and deposition including accumulation in edible tissues of sheep and goats toxicological profile and nature of hazard and the relative contribution of residues in sheep and goats to dietary human exposure. considering the above mentioned criteria, a flow-chart approach was used for ranking of the chemical residues and contaminants of potential concern. the outcome of the nrcps (indicating the number of non-compliant results), the evaluation of the likelihood that residues of substances of potential concern can occur in sheep and goats and the toxicological profile of the substances were considered in the development of the general flow chart, presented in figure 1 . ml, maximum level; mrl, maximum residue limits; nrcp: national residue control plan. a contaminants from the soil and the environment, associated with feed material, are considered to be part of the total feed for the purposes of this opinion. b potential concern was based on the toxicological profile and nature of hazard for the substances. c the contam panel notes that the ranking of vmps/feed additives was carried out in the general context of authorised usage of these substances in terms of doses, route of treatment, animal species and withdrawal periods. therefore, this ranking is made within the framework of the current regulations and control and within the context of a low rate of exceedances in the nrcps. d see definitions as provided in the next section 2.3.5. figure 1 : general flow chart used for the ranking of residues and contaminants of potential concern that can be detected in sheep and goats. outcome of the ranking of residues and contaminants of potential concern that can occur in sheep/goat carcasses four categories were established resulting from the application of the general flow chart: substance irrelevant in sheep/goat production (no known use at any stage of production); no evidence for illicit use or abuse in sheep/goats; not or very seldom associated with exceedances in mrls in nrcps; no evidence of occurrence as a contaminant in feed for sheep/goats. vmps/feed additives which have an application in sheep/goat production, residues above mrls are found in control plans, but substances are of low toxicological concern; 45 contaminants and prohibited substances with a toxicological profile that does not include specific hazards following accidental exposure of consumers and which are generally not found or are not found above mls in sheep/goats. contaminants and prohibited substances to which sheep/goats are known to be exposed and/or with a history of misuse, with a toxicological profile that does not entirely exclude specific hazards following accidental exposure of consumers; evidence for residues of prohibited substances being found in sheep/goats; contaminants generally not found in concentrations above the mrl/mls in edible tissues of sheep/goats. contaminants and prohibited substances to which sheep/goats are known to be exposed and with a history of misuse, with a distinct toxicological profile comprising a potential concern to consumers; evidence for ongoing occurrence of residues of prohibited substances in sheep/goats; evidence for ongoing occurrence and exposure of sheep/goats to feed contaminants. 2.4.2.1. substances classified in the category of high potential concern 2.4.2.1.1. contaminants: dioxins, dioxin-like polychlorinated biphenyls (dl-pcbs) in the high potential concern category are dioxins and dioxin-like polychlorinated biphenyls (dl-pcbs) as the occurrence data from the monitoring programmes show a number of incidents due to contamination of feed, such as illegal disposal of dioxin-and dl-pcb-containing waste materials into feed components, or open drying of feed components with dioxin-containing fuel materials. dioxins are persistent organochlorine contaminants that are not produced intentionally and have no targeted use, but are formed as unwanted and often unavoidable by-products in a number of thermal and industrial processes. because of their low water solubility and high lipophilic properties, they bioaccumulate in the food chain and are stored in fatty tissues of animals and humans. the major pathway of human dioxin exposure is via consumption of food of animal origin which generally contributes more than 80 % of the total daily dioxin intake (efsa, 2010) . a number of incidents in the past 15 years were caused by contamination of feed with dioxins. examples are feeding of contaminated citrus pulp pellets, kaolinitic clay containing potato peel or mixing of compound feed with contaminated fatty acids. all these incidents were caused by grossly negligent or criminal actions and led to widespread contamination of feed and subsequently to elevated dioxin levels in the animals and the foodstuffs produced from them. monitoring programmes also demonstrated that certain food commodities, such as sheep liver can have high dioxin levels even when not affected by specific contamination sources. in 2011, the contam panel delivered a scientific opinion on the risk to public health related to the presence of high levels of dioxins and dl-pcbs in liver from sheep and deer (efsa contam panel, 2011b). efsa evaluated, inter alia, the dioxin and pcb results from 332 sheep liver and 175 sheep meat samples submitted by eight european countries. almost all sheep meat samples were below the relevant mls set by regulation (ec) no 1881/2006. however, the corresponding liver samples from the same sheep in more than half of the cases exceeded the relevant maximum levels considerably. this finding is likely to be associated with differences in the level of biotransformation enzymes in sheep compared with bovine animals. dioxins have a long half-life and are accumulated in various tissues. the findings of elevated levels in food are of public health concern owing to their potential effects on liver, thyroid, immune function, reproduction and neurodevelopment (efsa, 2005a (efsa, , 2010 . the available data indicate that a substantial part of the european population is in the range of or already exceeding the twi for dioxins and dl-pcbs. a report on "monitoring of dioxins and pcbs in food and feed" (efsa, 2012) estimated that between 1.0 % and 52.9 % of individuals were exposed above the twi of 14 pg teq/kg body weight (b.w.) for the sum of dioxins and dl-pcbs. in addition to milk and dairy products and fish and seafood, meat and meat products also contributed significantly to total exposure. owing to the high toxic potential of dioxins and the incidence of samples of sheep meat and sheep liver exceeding the maximum limits, efforts need to be undertaken to reduce exposure where possible. in summary, based on the high toxicity and the low maximum levels set for meat and fat of sheep (see table 1 ) and considering that food of animal origin contributes significantly (> 80 %) to human exposure, dioxins have been ranked in the category of substances of high potential concern. (b) dioxin-like polychlorinated biphenyls (dl-pcbs) in contrast to dioxins, pcbs had widespread use in numerous industrial applications, generally in the form of complex technical mixtures. due to their physicochemical properties, such as nonflammability, chemical stability, high boiling point, low heat conductivity and high dielectric constants, pcbs were widely used in industrial and commercial closed and open applications. they were produced for over four decades, from 1929 onwards until they were banned, with an estimated total world production of 1.2-1.5 million tonnes. according to council directive 96/59/ec, 46 mss were required to take the necessary measures to ensure that used pcbs are disposed off and equipment containing pcbs is decontaminated or disposed of at the latest by the end of 2010. earlier experience has shown that illegal practices of pcb disposal may occur resulting in considerable contamination of animals and foodstuffs of animal origin. on the other hand, monitoring programmes also demonstrated that certain food commodities, such as sheep liver can have high pcb levels even when not affected by specific contamination sources. this was demonstrated by efsa in its scientific opinion on the risk to public health related to the presence of high levels of dioxins and pcbs in liver from sheep and deer (efsa contam panel, 2011b). efsa evaluated, inter alia, the dioxin and pcb results from 332 sheep liver and 175 sheep meat samples submitted by eight european countries. for sheep liver, the mean upper bound concentration for dl-pcbs (expressed as who-teq 1998 ) was 11.2 (range: 0.10-198.2) pg who-teq/g fat. the corresponding levels in sheep meat were considerably lower: 1.29 (range: 0.08-11.29) pg who-teq/g fat (efsa contam panel, 2011b). based on structural characteristics and toxicological effects, pcbs can be divided into two groups. one group consists of 12 congeners that can easily adopt a coplanar structure and have the ability to bind to the aryl hydrocarbon (ah) receptor, thus showing toxicological properties similar to dioxins (effects on liver, thyroid, immune function, reproduction and neurodevelopment). this group of pcbs is therefore called "dioxin-like pcbs". the other pcbs do not show dioxin-like toxicity but have a different toxicological profile, in particular with respect to effects on the developing nervous system and neurotransmitter function. this group of pcbs is called "non dioxin-like pcbs" (see below). as dl-pcbs, in general, show a comparable lipophilicity, bioaccumulation, toxicity and mode of action as dioxins (efsa, 2005a) , these two groups of environmental contaminants are regulated together in european legislation and are considered together in risk assessments. based on the high toxicity, widespread use and potential for improper disposal practices of technical pcb mixtures, dl-pcbs have been ranked in the category of substances of high potential concern. 2.4.2.2. substances classified in the category of medium potential concern 2.4.2.2.1. prohibited substances: stilbenes, thyreostats, gonadal (sex) steroids, resorcylic acid lactones, beta-agonists, chloramphenicol and nitrofurans (a) stilbenes the toxicity of stilbenes is well established (for review see waltner-toews and mcewen, 1994) and this has led to their prohibition for use as growth promoters in animals in most countries, based also on their involvement in the baby food scandal in the late 1970s (loizzo et al., 1984) . in particular, diethylstilbestrol is a proven human genotoxic carcinogen (group i iarc (international agency for research on cancer)) (iarc, 2012), while sufficient evidence for hexestrol and limited evidence for dienestrol for carcinogenicity in animals were found (iarc, 1979) . diethylstilbestrol is associated with cancer of the breast in women who were exposed while pregnant, and also causes adenocarcinoma in the vagina and cervix of women who were exposed in utero; finally, a positive association has been observed between exposure to diethylstilbestrol and cancer of the endometrium, and between in utero exposure to diethylstilbestrol and squamous cell carcinoma of the cervix and cancer of the testis. in 1981, the use of stilbenes in all species of food-producing animals was prohibited in the european community by directive 81/602/eec. 47 diethylstilbestrol, and other stilbenes such as hexestrol and dienestrol, are likely to be available on the black market and, therefore, might be available for illicit use in sheep and goats. no non-compliant results for stilbenes in sheep and goat samples have been reported from the european nrcps 2005-2010, indicating that abuse of stilbenes in sheep and goat production in the eu is unlikely. considering that stilbenes have proven toxicity for humans, these substances are ranked as of medium potential concern. however, considering that there is no evidence for current use of stilbenes in sheep and goat production and that no non-compliant results have been found over a number of years of nrcp testing, control measures for stilbenes might be focused on identifying any potential future abuse of these substances in sheep and goat production in the eu. thyreostats are a group of substances that inhibit the thyroid function, resulting in decreased production of the thyroid hormones triiodothyronine (t3) and thyroxine (t4). enlargement of the thyroid gland has been proposed as a criterion to identify illicit use of these compounds (vos et al., 1982; vanden bussche et al., 2009) . they are used in human and in non-food-producing animal medicine to deal with hyperthyroidism. the use of thyreostats for animal fattening is based on weight gain caused by filling of the gastrointestinal tract and retention of water in muscle tissues (courtheyn et al., 2002) . synthetic thyreostats include thiouracil, methylthiouracil, propylthiouracil, methimazole, tapazol (methylmercaptoimidazole) and mercaptobenzimidazole (mbi). use of synthetic thyreostats in food-producing animals has been prohibited in the eu since 1981 (council directive 81/602/ec). naturally occurring thyreostats include thiocyanates and oxazolidine-2-thiones, which are present as glucosinolates in plant material such as in the seeds of cruciferae, like rapeseed (efsa, 2008b; vanden bussche et al., 2009) . evidence for the occurrence of thiouracil in urine of cattle fed on a cruciferous-based diet has been demonstrated (pinel et al., 2006) . thyreostats are very widely available on the black market so there is the possibility for illicit use in sheep/goat production. the results from the european nrcps 2005-2010 show that sheep/goat samples were found to be non-compliant for thyreostats (17 non-compliant results out of the total 1 958 samples analysed for thyreostats). however, it has been shown that the source of the generally low levels of thiouracil determined in urine samples may be from exposure of animals through their diet (le bizec et al., 2011) . some mss reporting the highest numbers of non-compliant samples for thiouracil state that "the presence of thiouracil in low concentrations may be due to the animals eating cruciferous plant material" and "in line with scientific evidence, the competent authority has concluded that the residues resulted from dietary factors". thyreostats have been considered to be carcinogenic and teratogenic. while the in utero exposure to methimazole or propylthiouracil has been associated with aplasia cutis and a number of other congenital defects (löllgen et al., 2011; rodriguez-garcia et al., 2011) , an iarc evaluation found inadequate evidence in humans, but limited evidence (in the case of methimazole) and sufficient evidence (in the case of thiouracil, methylthiouracil and propylthiouracil) in experimental animals for carcinogenicity (iarc, 2001; efsa 2008b) . thyreostats are prohibited substances owing to their potential toxicity to humans and their efficacy as growth promoters in sheep/goats, but considering that the non-compliant results that have been found in most years of nrcp testing have been attributed largely to a dietary source, these substances are ranked as of medium potential concern. control measures for thyreostats might focus on identifying potential abuse of these substances in sheep and goat production in the eu. (c) gonadal (sex) steroids a broad range of steroids derived from oestrogens, androgens and progestagens are available and have been used as growth-promoting agents in food-producing animals. there is an extensive body of animal production research demonstrating the efficacy of anabolic steroids, often in combination treatments of an oestrogen and an androgen (or progestagen), as growth promoters. all use of steroids as growth-promoting agents in food-producing animals is banned according to council directive 96/22/ec, as amended by directives 2003/74/ec 48 and 2008/97/ec. 49 the latter included 17βoestradiol in the list of prohibited substances owing to its demonstrated tumour-promoting (epigenetic) and tumour initiating (genotoxic) properties (russo et al., 2003) . certain uses of 17β-oestradiol, progesterone and medroxyprogesterone acetate in sheep and/or goats are allowed for therapeutic or zootechnical purposes only (commission regulation (eu) no 37/2010). there is evidence that anabolic steroids are of economic value for farmers as animals respond to their application with increased growth rate and feed conversion efficiency. anabolic steroids are widely available on the black market so there is the possibility for illicit use in sheep and goat production. 318, 28.11.2008, p. 9-11. an accurate estimate for the level of abuse of anabolic steroids in european sheep and goat production from these data. there are divergent views on the potential adverse effects for the consumer from residues of anabolic steroids in edible tissues of treated animals. there is concern regarding the carcinogenic effects of oestrogenic substances, and the long-term effects of exposure of prepubescent children to oestrogenic substances. in 1999 the scientific committee on veterinary measures relating to public health (scvph) performed an assessment of the potential risks to human health from hormone residues in bovine meat and meat products (scvph, 1999 (scvph, , 2000 (scvph, , 2002 , particularly as regards the three natural hormones (17β-oestradiol, testosterone, progesterone) and the three synthetic analogues (zeranol, trenbolone acetate, melengestrol acetate) that may be legally used as growth promoters in third countries. it was concluded that, taking into account both the hormonal and nonhormonal toxicological effects, the issues of concern include neurobiological, developmental, reproductive and immunological effects, as well as immunotoxicity, genotoxicity and carcinogenicity. in consideration of concerns relating to the lack of understanding of critical developmental periods in human life as well as uncertainties in the estimates of endogenous hormone production rates and metabolic clearance capacity, particularly in prepubertal children, no threshold level and therefore no adi could be established for any of the six hormones. according to iarc, 17β-oestradiol and steroidal oestrogens are classified as proven human carcinogens (group 1), androgenic (anabolic) steroids as probably carcinogenic to humans (group 2a); for most progestagens, evidence for human carcinogenicity is inadequate while that for animals varies from sufficient to inadequate (iarc, 2012) . notwithstanding the toxicological profile of gonadal (sex) steroids, owing to the low prevalence of non-compliant samples from confirmed illicit use in the nrcps, these substances are ranked as of medium potential concern. (d) resorcylic acid lactones (rals) in the eu, zeranol was evaluated together with other hormonal growth promoters by the scvph (scvph 1999 (scvph , 2000 (scvph , 2002 . in these scientific opinions it was concluded that, taking into account both the hormonal and non-hormonal toxicological effects, no adi could be established for any of the six hormones, including zeranol. use of zeranol as a growth promoter in cattle production was widespread in some mss prior to its prohibition in europe in 1985. zeranol is widely available as a commercial product and is used extensively in third countries. hence it is readily available on the market and there is the possibility for its illicit use in cattle production in the eu. zeranol is derived from, and can also occur as, a metabolite of the mycotoxin zearalenone, produced by fusarium spp. the results from the european nrcps 2005-2010 show sheep/goat samples non-compliant for resorcylic acid lactones (a total of seven non-compliant results out of the total 3 283 samples analysed). however, it has been shown that the source of the generally low levels of zeranol and its metabolites determined in these samples may be from exposure of sheep/goats to the mycotoxin zearalenone through their diet (efsa, 2004a) . some mss reporting non-compliant results for zeranol and its metabolites state that "the residue was found to be as a result of feed contamination on the farm" and it was "probably attributable to mycotoxin contamination of feed". rals are prohibited substances owing to their potential toxicity to humans and their efficacy as growth promoters in sheep and goats, but considering that the non-compliant results that have been found in some years of nrcp testing have been attributed largely to a dietary source, these substances are ranked as of medium potential concern. control measures for rals might focus on identifying potential abuse of these substances in sheep and goat production in the eu. (e) beta-agonists beta-agonists, or β-adrenergic agonists, have therapeutic uses as bronchodilatory and tocolytic agents. a wide range of beta-agonists have been developed, such as clenbuterol, salbutamol, cimaterol, terbutaline, ractopamine, etc., and all of these are prohibited for use as growth-promoting agents in food-producing animals in the eu. salbutamol and terbutaline are licensed human medicines indicated for treatment of asthma and bronchospasm conditions and for prevention of premature labour, respectively. one of the beta-agonists, clenbuterol, is licensed for therapeutic use in cattle (as a tocolytic agent) and in the treatment of obstructive airway conditions in horses (commission regulation (eu) no 37/2010). other beta-agonists, such as ractopamine, have been approved for use in food-producing animals in a number of third countries. treatment of sheep with beta-agonists, such as clenbuterol, results in increased muscle mass and increased carcass leanness (baker et al., 1984) . the commercial benefits of using beta-agonists in sheep and goat production, particularly lambs, combined with the availability of these substances, indicates that illicit use of beta-agonists as growth promoters cannot be excluded. an outbreak of collective food poisoning from the ingestion of lamb meat containing residues of clenbuterol has been reported in portugal; symptoms shown by the intoxicated people may be generally described as gross tremors of the extremities, tachycardia, nausea, headaches and dizziness (barbosa et al., 2005) . in the light of the known adverse biological effects of beta-agonists in humans, particularly clenbuterol, and the efficacy of such drugs as repartitioning agents in sheep/goats, but considering that no non-compliant results for sheep/goats have not been found in the nrcps since 2005, these substances currently are ranked as of medium potential concern. (f) chloramphenicol chloramphenicol is an antibiotic substance, first used for the treatment of typhoid in the late 1940s. chloramphenicol may produce blood dyscrasias in humans, particularly bone marrow aplasia, or aplastic anaemia, which may be fatal. there is no clear correlation between dose and the development of aplastic anaemia and the mechanism of induction of aplastic anaemia is not fully understood (watson, 2004) . although the incidence of aplastic anaemia associated with exposure to chloramphenicol is apparently very low, no threshold level could be defined (emea, 2009 ). in addition, several studies suggest that chloramphenicol and some of its metabolites are genotoxic (fao/who, 1988 emea, 2009) . considering the available evidence from in vitro experiments and from animal studies, as well as from a case-control study conducted in china, in which there was evidence for the induction of leukaemia in patients receiving a long-term treatment with chloramphenicol, iarc classified chloramphenicol as group 2a (probably carcinogenic to humans) substance (iarc, 1990) . based on these evaluations, the use of chloramphenicol in food-producing animals is prohibited within the eu to avoid the exposure of consumers to potential residues in animal tissues, milk and eggs. consequently, chloramphenicol is included in table 2 until its prohibition, chloramphenicol was used on food-producing animals, including sheep and goats, for treatment of salmonella infections and for prevention of secondary bacterial infections. currently, chloramphenicol, which is licensed for use as a broad-spectrum bacteriostatic antibacterial in pets and non-food-producing animals in the eu, is used also in some third countries for foodproducing animals. hence, chloramphenicol may be available on the black market for illicit use in sheep/goat production. however, the availability for use on food-producing animals of related substances with similar antibacterial properties, thiamphenicol and florfenicol (with no toxicological concern), should mitigate the illicit use of chloramphenicol in sheep/goat production as these alternative drugs are available as prescription medicines. non-compliant results for chloramphenicol in sheep/goats have been reported in most years' results from the european nrcps 2005-2010 (11 non-compliant results), indicating that abuse of chloramphenicol in sheep/goat production in europe may be a continuing occurrence. chloramphenicol has proven toxicity for humans and is effective as an antibacterial treatment for sheep/goats but, considering that lower numbers of non-compliant results have been found in recent years of the nrcp testing, chloramphenicol currently is ranked as of medium potential concern. (g) nitrofurans nitrofurans, including furazolidone, furaltadone, nitrofurantoin and nitrofurazone, are very effective antimicrobial agents that, prior to their prohibition for use on food-producing animals in the eu in 1995, were widely used on livestock (cattle, sheep/goats, pigs, sheep and goats), in aquaculture and in bees. various nitrofuran antimicrobials are still applied in human medicine particularly for the treatment of urinary tract infections. a characteristic of nitrofurans is the short half-life of the parent compounds and the formation of covalently bound metabolites which, under the acidic conditions of the human stomach, may be released as active agents (hoogenboom et al., 1992) . these covalently bound metabolites are used as marker residues for detecting the illicit use of nitrofurans in animal production. it should be noted that the metabolite semicarbazide (sem) has been shown not to be an unambiguous marker for abuse of the nitrofuran drug nitrofurazone because the sem molecule may occur from other sources (hoenicke, et al., 2004; sarnsonova et al., 2008; bendall, 2009 ). nitrofurans are effective in treatment of bacterial and protozoal infections, including coccidiosis, in food-producing animals. although prohibited for use on food-producing animals in many countries, nitrofurans are likely to be available on the black market for illicit use in sheep/goat production. noncompliant results for nitrofurans in sheep/goats have been reported in most years' results from the european nrcps 2005-2010, indicating that abuse of nitrofurans in sheep/goat production in europe is a continuing occurrence. a metabolite of furazolidone that can be released from covalently bound residues in tissues has been shown to be mutagenic and may be involved in the carcinogenic properties of the parent compound (emea, 1997a). nitrofurans have proven toxicity for humans and are effective as antibacterials for sheep and goats but, considering that non-compliant results, other than for the marker residue sem, are found only sporadically in the nrcp testing, these substances currently are ranked as of medium potential concern. 2.4.2.2.2. contaminants: non dioxin-like pcbs (ndl-pcbs), chemical elements and mycotoxins (a) non dioxin-like pcbs (ndl-pcbs) the non dioxin-like pcbs (ndl-pcbs) show a different toxicological profile to the dl-pcbs. in 2005, the contam panel performed a risk assessment on ndl-pcbs in food (efsa, 2005a) . in the final conclusion, the contam panel stated that no health-based guidance value for humans can be established for ndl-pcbs because simultaneous exposure to dioxin-like compounds hampers the interpretation of the results of the toxicological and epidemiological studies, and the database on effects of individual ndl-pcb congeners is rather limited. there are, however, indications that subtle developmental effects, caused by ndl-pcbs, dl-pcbs, or polychlorinated dibenzo-pdioxins/polychlorinated dibenzofurans alone, or in combination, may occur at maternal body burdens that are only slightly higher than those expected from the average daily intake in european countries. in its risk assessment the contam panel decided to use the sum of the six pcb congeners (-28, -52, -101, -138, -153 and -180) as the basis for their evaluation, because these congeners are appropriate indicators for different pcb patterns in various sample matrices and are most suitable for a potential concern assessment of ndl-pcbs on the basis of the available data. moreover, the panel noted that the sum of these six indicator pcbs represents about 50 % of total ndl-pcbs in food (efsa, 2005a because of their somewhat lower toxicity than that of dl-pcbs, ndl-pcbs are classified in the medium potential concern category. (b) chemical elements (heavy metals: cadmium, mercury and lead) among the chemical elements, heavy metals traditionally have gained attention as contaminants in animal tissues, as they may accumulate in certain organs, particularly in kidneys over the lifespan of an animal. kidney tissue from sheep forms a specific dietary component in many european cultures. exposure of animals is commonly related to contaminated feed materials, despite older reports of accidental intoxication of animals from other sources (paints, batteries). the contam panel has issued within the framework of the re-evaluation of undesirable substances in animal feeds according to directive 2002/32/ec several opinions addressing heavy metals and arsenic in feed materials and the transfer of these elements from feed to edible tissues, milk and eggs. cadmium (efsa, 2009a) is a heavy metal found as an environmental contaminant, both through natural occurrence and from industrial and agricultural sources. cadmium accumulates in humans and animals, causing concentration-dependent renal tubular damage. older animals are expected to have higher concentrations of cadmium accumulated in the kidneys. most of the non-compliant results were for kidney samples with some non-compliant results for muscle and liver being reported. mercury (efsa, 2008a , efsa contam panel, 2012a exists in the environment as elemental mercury, inorganic mercury and organic mercury (primarily methylmercury). methylmercury bioaccumulates and biomagnifies along the aquatic food chain. the toxicity and toxicokinetics of mercury in animals and humans depends on its chemical form. elemental mercury is volatile and mainly absorbed through the respiratory tract, whereas its absorption through the gastrointestinal tract is limited (10-30 %). following absorption, inorganic mercury distributes mainly to the kidneys and, to a lesser extent, to the liver. the critical effect of inorganic mercury is renal damage. in contrast, in animals, as in humans, methylmercury and its salts are readily absorbed in the gastrointestinal tract (> 80 %) and rapidly distributed to all tissues, although the highest concentrations are also found in the kidneys. data from mss indicated the presence of mercury in animal feeds, but the measured concentrations remained below the maximum content for feed materials ( lead (efsa contam panel, 2010) is an environmental contaminant that occurs naturally and, to a greater extent, from anthropogenic activities such as mining and smelting and battery manufacturing. lead is a metal that occurs in organic and inorganic forms; the latter predominate in the environment. human exposure is associated particularly with the consumption of cereal grains (except rice), cereal and cereal-based products, potatoes, leafy vegetables and tap water. the contribution of sheep and goat meat and offal to human exposure is limited. given the toxicological profile of these elements and the fact that cadmium accumulates in animals and humans, these three elements have been allocated to the group of substances of medium potential health concern. 2.4.2.3. substances classified in the category of low potential concern 2.4.2.3.1. prohibited substances: nitroimidazoles, chlorpromazine (a) nitroimidazoles the 5-nitroimidazoles, dimetridazole, metronidazole and ronidazole, are a group of drugs having antibacterial, antiprotozoal and anticoccidial properties. owing to the potential harmful effects of these drugs on human health (emea, 1997b)-carcinogenicity, mutagenicity, genotoxicity and the occurrence of covalent binding to macromolecules of metabolites with an intact imidazole structuretheir use in food-producing animals is prohibited in the eu, united states, china, and other countries. nitroimidazoles had been used as veterinary drugs for the treatment of cattle, pigs and sheep and goats. although prohibited for use on food-producing animals, not only in the eu but also in many third countries, nitroimidazoles are likely to be available on the black market for illicit use in animal production, particularly as drugs such as metronidazole are readily available as human medicines. however, there are no clinical conditions in sheep/goats for which nitroimidazoles are particularly appropriate. non-compliant results (two) for nitroimidazoles in sheep/goats have been reported only in one year and from one ms from the european nrcps 2005-2010, suggesting that abuse of nitroimidazoles in sheep/goat production in europe is not widespread. considering that nitroimidazoles have proven toxicity for humans and that they may be effective as antibacterial/antiprotozoal treatments for sheep/goats, these substances might be ranked as of medium potential concern. however, as only occasional non-compliant results have been found over a number of years of nrcp testing, nitroimidazoles currently are ranked as of low potential concern. (b) chlorpromazine chlorpromazine is a sedative and is also used against motion sickness and as an anti-emetic in pets. its use is banned in food-producing animals, including sheep/goats. chlorpromazine is likely to be available as a black market substance for illicit use in sheep/goat production. no non-compliant results for chlorpromazine were reported from the nrcp for the period 2005-2010, indicating that the substance may not be rarely used illicitly in sheep/goat production in the eu. chlorpromazine is used as an antipsychotic drug in human therapy and has long-term persistence in humans and numerous side effects, including the more common ones of agitation, constipation, dizziness, drowsiness, etc. (emea, 1996) . chlorpromazine may be effective as a tranquilliser for sheep/goats but, since no non-compliant results have been found over a number of years of nrcp testing, chlorapromazine currently is ranked as of low potential concern. 2.4.2.3.2. contaminants: organochlorine pesticides, organophosphorus compounds, and natural toxins (a) organochlorine compounds organochlorine pesticides, such as dichlorodiphenyltrichloroethane (ddt) and its metabolites, hexachlorocyclohexanes (hchs), dieldrin, toxaphene and others have been assigned to the category of contaminants of low potential concern. occurrence of residues of these substances has declined over the years, because of their long-standing ban, and relatively low levels in animal products can be expected, as shown by results from the nrcps 2005-2010, which indicate that 17 results out of the total of 8 007 samples tested for the category of organochlorine compounds were non-compliant for organochlorine pesticides. organophosphorus compounds are classified in council directive 96/23/ec as group b3b contaminants, although they may be used also as vmps for the therapy of parasitic infestations of sheep and goats. however, their probably infrequent use and short half-life results in these compounds being assigned to the category of low potential concern, or even negligible potential concern where mrls are not exceeded. results from the nrcps from 2005-2010 indicate that 5 results out of the total of 5 766 samples tested for the category of organophosphorus compounds were non-compliant. (c) natural toxins: mycotoxins and toxic plant secondary metabolites (c.1) mycotoxins mycotoxins comprise a chemically diverse group of secondary metabolites of moulds which may induce intoxication in humans and animals following ingestion of contaminated food or feed materials. mycotoxins evaluated by the contam panel as undesirable contaminants in animal feeds, including aflatoxins (efsa, 2004b ), deoxynivalenol (efsa, 2004c , fumonisins (efsa, 2005b) and zearalenone (efsa, 2004a) , t-2 toxin (efsa contam panel, 2011c), ergot alkaloids (efsa contam panel, 2012b) may pose a risk for animal health and productivity when present in feed materials that are used for sheep and goat animals over an extended period of time. however, most of the known mycotoxins are efficiently degraded by the rumen microflora and have a short biological half-life. hence, even if residues of mycotoxins are occasionally detected in animal tissues (monogastric animal species) they do not contribute significantly to human exposure, which is mainly related to the consumption of cereal products, nuts and spices. considering that some mycotoxins like aflatoxins have proven toxicity for humans, some of these substances might be ranked as of medium potential concern. however, since non-compliant results have been found incidentally (two out of 1 655 samples) over a number of years of nrcp testing, these substances currently are ranked as of low potential concern. (c. (efsa, 2008f) . although for several of these substances potential concerns for animal health could be identified following ingestion with feed, none of these natural toxins appeared to accumulate in edible tissues. the limited data on the kinetics of these metabolites does not preclude in all cases a transfer from the feed into animal tissues under certain circumstances of exposure. for example, residues of gossypol in meat of cattle (and sheep) were demonstrated under experimental conditions (feeding of cotton meal as the main feed component), but such residues are not expected under the conditions of european farming, where cotton seeds or cotton seed by-products are infrequently used and only with limited inclusion rates in feed (efsa, 2008e) . other natural substances, such as the fungal metabolite (mycotoxin) zearalenone, are intensively metabolised in the rumen and following absorption in the liver and other animal tissues, and this may explain certain noncompliant analytical results. zearalanol (zeranol) is one of these metabolites and which is used in certain third countries as a growth-promoting agent owing to its oestrogenic activity (see section 2.3.5.2.1 (d) ). this applies also to certain thiocyanates and oxazolidinethiones, originating from glucosinolates produced by a broad variety of plants of the brassicaceae family. they target different steps in the synthesis of thyroid hormones, leading eventually to hypothyroidism and enlargement of the thyroid gland (goitre) (efsa, 2008b) . again, these natural products may explain some of the noncompliant results found in nrcp testing where treatment of animals with antithyroid agents (thyreostats) has been suspected. recently, an increasing use of herbal remedies, given as so-called alternatives to antibiotics for animals, has been reported also in ruminants. many of the herbal products contain biologically active substances that are also addressed in the list of undesirable plant metabolites. however, the remedies are given in low concentrations (lower than the larger amount that could be ingested with feed), and for a limited period. although specific data are lacking, it seems unlikely that residues of these compounds may be found in edible tissues of slaughtered animals. such substances, therefore, are placed in the category of low potential concern within the current classification. vmps, such as antimicrobials, anti-coccidials and anti-parasitics, are used commonly on sheep and goats for prophylactic purposes, particularly prior to turning animals out to grazing (anti-parasitic treatments). therapeutic use of vmps, particularly antimicrobials, may occur in response to diagnosis of infection in individual animals or in the flock. in general, vmps, except the substances allocated to annex table 2 of regulation (ec) no 37/2010, are categorised as being of low potential concern because they have all been subjected to premarketing approval which specifies adis, and mrls, with the aim of guaranteeing a high level of safety to the consumer. where exceedances of mrls are found in the residue monitoring programmes (i.e. 203 non-compliant results out of the 63 500 samples analysed for antibacterials, 28 non-compliant results for anthelmintics out of the 17 151 samples analysed, and eight non-compliant results out of the 4 318 samples analysed for anti-coccidials), these are typically of an occasional nature that is not likely to constitute a concern to public health. despite only two non-compliant results being reported out of the 3 534 samples analysed for corticosteroids, there is concern about their potential illicit use, particularly in fattening lambs. in the negligible potential concern category are the dyes and the prohibited substances, colchicine, dapsone, chloroform and aristolochia spp. 2.4.2.4.1. prohibited substances: colchicine, dapsone, chloroform and aristolochia spp. colchicine is a plant alkaloid that has been used in veterinary medicine to treat papillomas and warts in cattle and horses by injection at the affected area. a possible contamination of food with colchicine has been identified through consumption of colchicum autumnale in forage by animals such as cattle or sheep and, in this context, colchicine has been determined in milk of sheep after exposure to c. autumnale (hamscher et al., 2005) . colchicine is genotoxic and teratogenic and may have toxic effects on reproduction. no non-compliant results for colchicine in sheep/goats have been reported from the european nrcps 2005-2010; however, it is probable that testing for this substance may not be included in monitoring programmes in many countries. in the absence of the absence of evidence for use of colchicine in sheep/goats colchicine currently is ranked as of negligible potential concern. (b) dapsone dapsone is a drug used in humans and formerly in veterinary medicine: in human medicine it is used for treatment of leprosy, malaria, tuberculosis and dermatitis; and in veterinary medicine it is used as an intramammary treatment for mastitis, for oral treatment of coccidiosis and for intra-uterine treatment of endometriosis. following scientific assessment by the committee for medicinal products for veterinary use (cvmp), a provisional mrl of 25 µg/kg parent drug was established for muscle, kidney, liver, fat and milk for all food-producing animals (emea, 1999) . further information on teratogenicity and reproductive effects for dapsone was required but, when this was not provided, the substance was recommended for inclusion in annex iv to council regulation (eec) no 2377/90 (now annex, table 2 , of commission regulation (ec) no 37/2010). more recently, the cvmp has reviewed the alleged mutagenicity of dapsone in the context of its occurrence as an impurity in vmps containing sulphonamides and concluded that it is not genotoxic (cvmp, 2012) , and efsa has issued a scientific opinion on the product as a food-packaging material (compound 15267), proposing an acceptable level of 5 mg/kg food (efsa, 2005c) . in the absence of evidence for use of dapsone in sheep and goats, dapsone currently is ranked as of negligible potential concern. (c) chloroform and aristolochia spp. in the negligible potential concern category are the prohibited substances, chloroform and plant remedies containing aristolochia spp., as these are not relevant to sheep/goat production and there is no evidence for use of these substances in sheep/goat production. vmps used in sheep and goat production but with no evidence for residues above mrls being found in monitoring programmes and vmps irrelevant for sheep and goat production are ranked as of negligible potential concern. (a) carbamates and pyrethroids carbamates and pyrethroids are used in animal houses and occasionally in animals including sheep for control of environmental infections, such as lice eggs in buildings. there are no recent incidents of non-compliant results reported in nrcp testing in sheep and goats during the period 2005-2010, resulting in these substances being assigned to the category of negligible potential concern. (b) sedatives a range of sedative substances including barbiturates, promazines, xylazine and ketamine, are licensed for use in sheep, goats and other animal species for sedation and analgesia during surgical procedures or for euthanasia. they are rarely used in sheep and goats. no non-compliant results were found in the nrcp testing for the period 2005-2010. due to their rapid excretion, these substances generally do not have detectable residues in muscle and so do not have mrls registered in the eu. animals euthanised with these substances are not allowed to enter the food chain. however, it should be noted that testing for this category of substances is not required under the provisions of council directive 96/23/ec. there are no indications for use of dyes such as (leuco-)malachite green in sheep and goat animals. testing of sheep and goat animals for this group of substances is not required under council directive 96/23/ec2. a summary of the outcome of the ranking is presented in table 7 . dioxins dl-pcbs mrl, maximum residue limit; nrcp, national residue control plan; psm, plant secondary metabolite; vmp, veterinary medicinal product. the ranking into specific categories of potential concern of prohibited substances, vmps and contaminants presented in this section applies exclusively to sheep and goats and is based on current knowledge regarding the toxicological profiles, usage in ovine animal production, and occurrence as residues or contaminants, as demonstrated by the data from the nrcps for the 2005-2010 period. where changes in any of these factors occur, the ranking might need amendment. another element of future aspects is the issue of 'new hazards'. in this context, new hazards are defined as compounds that have been identified as anthropogenic chemicals in food-producing animals and derived products and in humans and for which occurrence data are scarce. it does not imply that there is evidence for an increasing trend in the concentration of these compounds in food or in human samples. examples are brominated flame retardants, such as polybrominated diphenyl ethers (pbde) and hexabromocyclododecanes (hbcdds) or perfluorinated compounds (pfc), such as perfluorooctane sulphonate (pfos) and perfluorooctanoic acid (pfoa). in 2011, efsa performed a risk assessment on polybrominated diphenyl ethers (pbdes) in food (efsa contam panel, 2011e) . pbdes are additive flame retardants which are applied in plastics, textiles, electronic castings and circuitry. pbdes are ubiquitously present in the environment and likewise in biota and in food and feed. eight congeners were considered by the contam panel to be of primary interest: . the highest dietary exposure is to . toxicity studies were carried out with technical pbde mixtures or individual congeners. the main targets were the liver, thyroid hormone homeostasis and the reproductive and nervous system. pbdes are not genotoxic. the contam panel identified effects on neurodevelopment as the critical endpoint, and derived benchmark doses (bmds) and their corresponding lower 95 % confidence limit for a benchmark response of 10 %, the bmdl 10 , for a number of pbde congeners: bde-47, 309 μg/kg b.w.; bde-99, 12 μg/kg b.w.; bde-153, 83 μg/kg b.w.; bde-209, 1 700 μg/kg b.w. owing to the limitations and uncertainties in the current database, the panel concluded that it was inappropriate to use these bmdls to establish health based guidance values, and instead used a margin of exposure (moe) approach for the health risk assessment. as the elimination characteristics of pbde congeners in animals and humans differ considerably, the panel used the body burden as the starting point for the moe approach. the contam panel concluded that for bde-47, -153 and -209 current dietary exposure in the eu does not raise a health concern. for bde-99 there is a potential health concern with respect to current dietary exposure. the contribution of ovine meat and ovine-derived products to total human exposure is currently not known. as these compounds bioaccumulate in the food chain, they deserve attention and should be considered for inclusion in the nrcps. in 2011, efsa delivered a risk assessment on hbcdds in food (efsa contam panel, 2011f) . hbcdds are additive flame retardants, primarily used in expanded and extruded polystyrene used as construction and packing materials, and in textiles. technical hbcdd consists predominantly of three stereoisomers (α-, βand γ-hbcdd). also δ-and ε-hbcdd may be present but at very low concentrations. hbcdds are present in the environment and likewise in biota and in food and feed. data from the analysis of hbcdds in 1 914 food samples were provided to efsa by seven european countries, covering the period from 2000 to 2010. the contam panel selected α-, β-and γ-hbcdd as of primary interest. as all toxicity studies were carried out with technical hbcdd, a risk assessment of individual stereoisomers was not possible. main targets were the liver, thyroid hormone homeostasis and the reproductive, nervous and immune systems. hbcdds are not genotoxic. the contam panel identified neurodevelopmental effects on behaviour as the critical endpoint, and derived a bmdl 10 of 0.79 mg/kg b.w. owing to the limitations and uncertainties in the current data base, the contam panel concluded that it was inappropriate to use this bmdl to establish a healthbased guidance value, and instead used an moe approach for the health risk assessment of hbcdds. as the elimination characteristics of hbcdds in animals and humans differ, the panel used the body burden as the starting point for the moe approach. the contam panel concluded that current dietary exposure to hbcdds in the eu does not raise a health concern. the occurrence data reported to efsa have shown that hbcdds could be detected in a limited number of meat samples. as the total number of sheep and goat meat samples analysed for hbcdds are sparse and thus the current knowledge about the prevalence and their levels in edible tissues of ovine animals is limited, their inclusion into nrcps even as a temporary measure should be considered. perfluorinated compounds (pfcs), such as pfos, pfoa and others have been widely used in industrial and consumer applications including stain-and water-resistant coatings for fabrics and carpets, oil-resistant coatings for paper products approved for food contact, fire-fighting foams, mining and oil well surfactants, floor polishes, and insecticide formulations. a number of different perfluorinated organic compounds have been widely found in the environment. in 2008, efsa delivered a risk assessment on pfos and pfoa in food (efsa, 2008g) . the contam panel established a tdi for pfos of 150 ng/kg b.w. per day, and a tdi for pfoa of 1.5 μg/kg b.w. per day. a few data indicated the occurrence of pfos and pfoa in meat samples. however, owing to the low number of data, it has not been possible to perform an assessment of the relative contribution from different foodstuffs to human exposure to pfos and pfoa. a recent study in which contaminated feed was fed to sheep demonstrated the transfer of pfos, pfoa and various other pfcs with different chain lengths into milk and meat of the sheep (kowalczyk et al., 2012) . as pfcs have found widespread use and ubiquitous distribution in the environment, but representative data on their occurrence in meat are still limited, an intensified monitoring of these compounds in tissues as well as feed should be considered. besides the heavy metals discussed in section 2.4.2.2.2, attention should be given also to those compounds that may be used as feed supplements (e.g. copper, selenium, zinc). the correct use of these supplements cannot be guaranteed. although supplementary feeding to sheep and goats at pasture with trace elements is practised, supplements for sheep are not permitted to contain copper. however, the risk of copper supplementation cannot be ruled out on mixed livestock farms where supplements containing copper for other livestock, e.g. pigs or calves, may be given in error to sheep, resulting in undesirable residues in animal organs, such as the liver. sheep are particularly susceptible to copper toxicity; goats appear to be able to tolerate higher intakes (underwood and suttle, 1999) . in the absence of supplementation, the main source of copper is the pasture, the uptake of which is a complex interaction between the copper, molybdenum and sulphate levels in the plants and the grass plants themselves. for example, sheep that consume excess subterranean clover (trifolium spp.) will develop chronic copper accumulation in their tissues as a result of the copper/molybdenum balance in the clover (radostits et al., 2007) . there are also large differences between breeds in susceptibility to copper toxicity (underwood and suttle, 1999) . a closer communication of results from official feed control seems essential to decide whether or not analytical monitoring of residues in slaughter animals needs to be directed to these substances that might be overused or mistakenly used in sheep or goat feeds. in light of the existing regulations and the daily practice of the control of residues/chemical substances in sheep/goat carcasses, the strengths and weaknesses of the current meat inspection methodology can be summarised as follows: the strengths of the current meat inspection methodology for chemical hazards are as follows: the current procedures for sampling and testing are a mature system, well established and coordinated, and subject to regular evaluation that is in place across eu mss, with residue testing that is based on common standards for method performance and interpretation of results (commission decision 2002/657/ec), laboratory accreditation (iso/iec 17025) and quality assurance schemes. the residue monitoring programmes are supported by a network of eu and national reference laboratories and by research in the science of residue analysis that serves to provide state-of-the-art testing systems for control of residues (see annex 1). there are well-developed systems and follow-up actions subsequent to the identification of non-compliant samples. as indicated in section 1.4, follow-up on non-compliant samples is typically through intensified sampling (suspect sampling), withholding of slaughter and/or of carcasses subject to positive clearance as compliant, and on-farm investigations potentially leading to penalties and/or criminal prosecutions. the regular sampling and testing for chemical residues is a disincentive for the development of bad practices. there is constant development of new approaches in sampling and testing methodologies, particularly in the area of prohibited substances, directed at identifying illicit use of such substances in animal production; for example, use of samples other than edible tissues, such as excreta, eyes, fibre, etc. that demonstrate enhanced residue persistence characteristics, and use of indirect testing procedures, such as genomics, proteomics and metabolomics, to identify treated animals. the prescriptive sampling system allows for equivalence in the control of eu-produced sheep/goat meat. any forthcoming measures have to ensure that the control of imports from third countries remains equivalent to the controls within the domestic market (this issue is addressed further in tor 4). the current combination of animal traceability, ante-mortem inspection and gross tissue examination can support the collection of appropriate samples for residue monitoring. however, any indication of misuse or abuse of pharmacologically active substances through visual assessment needs to be confirmed by chemical analysis for potential residues. the weaknesses of the current meat inspection methodology for chemical hazards are as follows: presence of chemical hazards cannot be identified by current ante-/post-mortem meat inspection procedures at the slaughterhouse level, indicating the need for further harmonisation of the risk reduction strategies along the entire food chain. at present, there is poor integration between the testing of feed materials for undesirable contaminants and the nrcps in terms of communication and follow-up testing strategies or interventions. moreover, a routine environmental data flow is not established and keeping habits for sheep and goats provide opportunities for feed coming in without a clear feed chain history. under the current system, sampling is mostly prescriptive rather than risk or information based. it appears that individual samples taken under the nrcp testing programme may not always be taken as targeted samples, as specified under council directive 96/23/ec, but sometimes may be taken as random samples. there is a lack of sufficient cost-effective and reliable screening methods and/or the range of substances prescribed/covered by the testing is sometimes limited. there is limited flexibility to adopt new chemical substances into the nrcps and limited ongoing adaptation of the sampling and testing programme to the results of the residue monitoring programmes. the sampling under the nrcps reflects only a part of testing done by a number of mss and, therefore, data from the nrcps may not provide the most complete information for certain categories of substances. sheep and goats may not be subject to surveillance over their lifetime at the same level as is the case for other food animal categories such as pigs, poultry and, to a large extent, bovine animals owing to their traditional nomadic/outdoor farming systems. current monitoring of residues and contaminants in edible tissues of slaughter sheep/goats is based on council directive 96/23/ec. in turn, risk ranking as presented under tor 1 is also based largely on the chemical substances listed in council directive 96/23/ec. the outcome of the ranking showed that only a small number of compounds are considered to constitute a high potential concern for consumers. however, considering the recent information available from the re-assessment of undesirable substances in the food chain, covered by more recent efsa opinions from the contam panel, additional compounds have been identified that require attention. prominent examples of such substances are and dl-pcbs, which were identified as compounds of high potential concern as they bioaccumulate in the food chain, are likely to be found in sheep/goat carcasses and have a toxicological profile that points towards public health concerns even at low (residue) concentrations. in addition, it has been shown that these substances are found in edible tissues of sheep, particularly in sheep liver. other halogenated substances such as brominated flame retardants, including polybrominated diphenylethers (pbdes) as well as hexabromocyclododecanes (hbcdds) and perfluorinated compounds (pfcs), such as pfos and pfoa have a different toxicological profile. these compounds bioaccumulate in the food chain and deserve attention, as currently the knowledge about the prevalence and level of residues of these compounds in edible tissues of sheep and goats is limited. chemical elements, such as copper, selenium and zinc, given as feed supplements may be mistakenly provided to sheep and goats resulting in undesirable residues in animal organs, such as the liver. inclusion of these various substances in the nrcps (even as a temporary measure) should be considered together with an intensified monitoring of feed materials for the presence of these compounds, to support forthcoming decisions on whether or not these substances require continued monitoring either in feed materials and/or in slaughter animals. due to the nature of the husbandry systems applied, sheep and goats are more likely to be exposed to environmental contaminants than other livestock. therefore, any incident giving rise to contamination of the environment may be noted primarily in animals kept outdoors, i.e. in sheep and goats. it is important to note that sheep and goat production in the eu is marked by being largely extensive in nature, involving frequent trading of animals and nomadic flocks. this involves differences in husbandry systems and feeding regimes resulting in different risks from chemical substances and contaminants. extensive periods on pasture or/as nomadic flocks, sale at open markets of many sheep and goats, and the presence of slaughter collection dealerships that may combine small numbers of animals purchased from several farmers, means that there is a level of concern that fci shared between farmers and the slaughterhouse (where residue data is managed), may be suboptimal. similarly, in these situations, the level of feedback from the slaughterhouse and authorities to farmers regarding the results of residue testing may be suboptimal. here the individual identification of animals, which has now become mandatory, may contribute to more transparency in the future. there is less concern about fci from dairy sheep and goats if they are reared under more intensive and controlled conditions. fci should be expanded for sheep and goats produced in extensive systems to provide more information on the specific environmental conditions where the animals are produced. it is recommended that sampling of sheep and goats should be based on the risk of occurrence of chemical residues and contaminants and on the completeness and quality of the fci supplied. to achieve this, better integration of results from official feed control with residue monitoring seems essential to indicate whether monitoring of residues in slaughter animals needs to be directed to particular substances. it should be noted that for the small ruminant chains more environmental information should be provided. therefore, there is a need for an improved integration of sampling, testing and intervention protocols across the food chain, nrcps, feed control and monitoring of environmental contaminants. moreover, the combination of data from both sheep and goats into one data set is based on the assumption that both food chains are identical. in many cases such an assumption is not justified. a separation of records for both species is recommended. in addition, there is a need to develop new approaches to chemical residues and contaminants testing. recent developments in chemical analytical techniques allow the simultaneous measurement of a broad range of substances. analytical techniques covering multiple analytes should be encouraged too and incorporated into feed quality control and national residue control programmes. application of such validated methods for multi-residue analyses comprising veterinary drugs, pesticides and natural and environmental contaminants should be encouraged. for prohibited substances, testing should be directed towards the farm level. one of the limitations of the currently applied analytical strategies is the generally poor sensitivity of some screening methods, resulting in the potential failure to detect residues in the low µg/kg range and, therefore, to identify non-compliant samples. new approaches including molecular biological techniques for the identification of indirect biomarkers of exposure in animals, as well as the development of reliable in vitro assays based on the biological action(s) of the compounds under analysis, are considered to be of additional value. such approaches may help in detecting molecules of unknown structure or that are not included in the nrcps but share a common mechanism of action, thereby better orienting and rationalising the subsequent chemical analysis. in the case of many of the substances that might be used illicitly for growth-promoting purposes in sheep and goat production, the results of nrcp testing show no non-compliant results (e.g. stilbenes) or indicate that reported non-compliant results may be attributable to dietary sources (e.g. thyreostats, zeranol) or are the result of endogenous production (e.g. gonadal (sex) steroids). therefore, future nrcp testing relating to such substances needs to be reduced and/or refocused, in terms of the range of analytes tested and the appropriateness of samples taken for testing, to better identify the extent of abuse of growth-promoting substances in sheep and goat production in the eu. in addition, control measures for such substances must not rely exclusively on nrcp testing, but should include veterinary inspection/police activities along the food chain directed at identifying abuse of such substances in sheep and goat production in the eu. finally, it should be noted that any measures taken to improve the efficacy of meat inspection protocols also need to address the compliance of imports to the eu with these strategies. where eu meat inspection would move to a risk-based approach, particular attention to the achievement of equivalent standards of food safety for imported food from third countries will be required. currently, within the prescriptive system for meat inspection and residue monitoring applying in the eu, third countries exporting food products of animal origin to the eu need to demonstrate that they have the legal controls and residue monitoring programmes capable of providing equivalent standards of food safety as pertains within the eu. if eu meat inspection moves to a risk-based approach, particular attention will need to be paid to the achievement of equivalent standards of food safety for imported food from third countries. the risk-ranking appropriate within the eu in relation to veterinary drugs and contaminants might not be appropriate in third countries to achieve equivalent standards of food safety. rather than requiring that a risk-based monitoring programme applying within eu mss should be applied similarly in the third country, an individual risk assessment for each animal product(s)/third country situation may be required, which should be updated on a regular basis. this section contains conclusions derived from the material discussed in the document, together with recommendations for improvements to meat inspection with regard to chemical hazards within the eu. tor 1 to identify and rank the main risks for public health that should be addressed by meat inspection at eu level. general (e.g. sepsis, abscesses) and specific biological risks as well as chemical risks (e.g. residues of veterinary drugs and contaminants) should be considered. differentiation may be made according to production systems and age of animals (e.g. breeding compared to fattening animals) as a first step in the identification and ranking of chemical substances of potential concern, the contam panel considered the substances listed in council directive 96/23/ec and evaluated the outcome of the national residue control plans (nrcps) 2005-2010. the contam panel noted that only 0.41 % of the total number of results was non-compliant for one or more substances listed in council directive 96/23/ec. potentially higher exposure of consumers to these substances from sheep and goat meat takes place only incidentally, as a result of mistakes or non-compliance with known and regulated procedures. the available aggregated data indicate a low number of samples that were non-compliant with the current legislation. however, in the absence of substance-and/or species-specific information, such as the tissues used for residue analysis and the actual concentration of a residue or contaminant measured, these data do not allow for a reliable assessment of consumer exposure. other criteria used for the identification and ranking of chemical substances of potential concern included the identification of substances that that are found in other testing programmes and that bioaccumulate in the food chain, substances with a toxicological profile of concern, and the likelihood that a substance under consideration will occur in sheep and goat carcasses. taking into account these criteria the individual compounds were ranked into four categories denoted as being of high, medium, low and negligible potential concern. the highest overall proportion of non-compliant results under the nrcps were for group b3 substances, contaminants (0. 86 %) representing largely exceedances of the maximum residue limits/maximum levels (mrls/mls) specified for these substances. the proportion of noncompliant results overall for group a substances, prohibited substances (0.64 %) and for group b1/b2 substances, veterinary medicinal products (vmps) (0.24 %) represent largely illicit use and exceedances of the mrls, respectively. dioxins and dioxin-like polychlorinated biphenyls (dl-pcbs) were ranked as being of high potential concern owing to their known bioaccumulation in the food chain, their frequent findings above mls, particularly in sheep liver, and in consideration of their toxicological profile. stilbenes, thyreostats, gonadal (sex) steroids, resorcylic acid lactones and beta-agonists, especially clenbuterol, were ranked as being of medium potential concern because of their toxicity for humans, their efficacy as growth promoters in sheep and goats and the incidence of non-compliant results. chloramphenicol and nitrofurans were ranked as being of medium potential concern, as they have proven toxicity for humans, they are effective as antibacterial treatments for sheep/goats and as non-compliant samples are found in most years of the nrcps. non-dioxin-like polychlorinated biphenyls (ndl-pcbs) bioaccumulate, and there is a risk of exceeding of the mls, but they were ranked in the category of medium potential concern, because they are less toxic than dioxins and dl-pcbs. the chemical elements cadmium, lead and mercury were allocated to the medium potential concern category taking into account the number of non-compliant results reported under the nrcps and their toxicological profile. residues originating from other substances listed in council directive 96/23/ec were ranked as of low or negligible potential owing to the toxicological profile of these substances at residue levels in edible tissues or to the very low or non-occurrence of non-compliant results in the nrcps 2005-2010, and/or to the natural occurrence in sheep and goats of some of these substances. the low potential concern category includes nitroimidazoles chlorpromazine, organochlorine pesticides, organophosphorus compounds, natural toxins, as well as and vmps exceeding mrls. in the negligible potential concern category are the prohibited substances colchicine, dapsone, chloroform and aristolochia spp., the dyes, as well as vmps occurring below mrls. the contam panel emphasises that this ranking into specific categories of potential concern is based on the current knowledge regarding toxicological profiles, usage in sheep and goat production and occurrence as contaminants or chemical residues, as demonstrated by the data from the nrcps for the 2005-2010 period. future monitoring programmes should be based on the system for the ranking of chemical compounds into potential concern categories as presented in this document. regular updating of the ranking of chemical compounds in sheep and goats as well as of the sampling plans should occur, taking into account any new information regarding the toxicological profile of chemical residues and contaminants, usage in sheep and goat production, and actual occurrence of individual substances in sheep and goats. tor 2 to assess the strengths and weaknesses of the current meat inspection methodology and recommend possible alternative methods (at ante-mortem or post-mortem inspection, or validated laboratory testing within the frame of traditional meat inspection or elsewhere in the production chain) at eu level, providing an equivalent achievement of overall objectives; the implications for animal health and animal welfare of any changes suggested in the light of public health risks to current inspection methods should be considered strengths of the current meat inspection methodology for chemical hazards are as follows: the current procedures for sampling and testing are a mature system, in general well established and coordinated including follow-up actions subsequent to the identification of non-compliant samples. the regular sampling and testing for chemical residues and contaminants in the system is an important disincentive to the development of undesirable practices. the prescriptive sampling system allows for equivalence in the control of eu-produced sheep and goat meat. any forthcoming measures have to ensure that the control of imports from third countries remains equivalent to the controls within the domestic market. the current combination of animal traceability, ante-mortem inspection and gross tissue examination can support the collection of appropriate samples for residue monitoring. weaknesses of the current meat inspection methodology for chemical hazards are as follows: a weakness of the system is that presence of chemical hazards cannot be identified by current ante-/post-mortem meat inspection procedures at the slaughterhouse level, indicating the need for further harmonisation of the risk reduction strategies along the entire food chain. integration between testing of feed materials for undesirable contaminants and the nrcps in terms of communication and follow-up testing strategies or interventions is currently limited. moreover, a routine environmental data flow is not established and keeping habits for sheep and goats provides opportunities for feed coming in without a clear feed chain history. under the current system, sampling is mostly prescriptive rather than risk or information based. it appears that individual samples taken under the nrcp testing programme may not always be taken as targeted samples, as specified under council directive 96/23/ ec, but sometimes may be taken as random samples. there is a lack of sufficient cost-effective and reliable screening methods and/or the range of substances prescribed/covered by the testing is sometimes limited. there is limited flexibility to adopt emerging chemical substances into the nrcps and limited ongoing adaptation of the sampling and testing programme to the results of the residue monitoring programmes. in addition, sampling under the nrcps reflects only a part of testing done by a number of ms, the results of which should be taken into consideration. sheep and goats may not be subject to surveillance over their lifetime at the same level as is the case for other food animal categories such as pigs, poultry and, to a large extent, bovine animals owing to their traditional nomadic/outdoor farming systems. meat inspection systems for chemical residues and contaminants should be less prescriptive and should be more risk and information based, with sufficient flexibility to adapt the residue monitoring programmes to results of testing. if new hazards currently not covered by the meat inspection system (e.g. salmonella, campylobacter) are identified under tor 1, then recommend inspection methods fit for the purpose of meeting the overall objectives of meat inspection. when appropriate, food chain information should be taken into account dioxins and dl-pcbs which accumulate in food-producing animals have been ranked as being of high potential concern. as these compounds have not yet been comprehensively covered by the sampling plans of the current meat inspection (nrcps), they should be considered as 'new' hazards. in addition, for a number of chemical elements used as feed supplements and for organic contaminants that may accumulate in food-producing animals only limited data regarding residues in sheep and goats are available. this is the case, in particular, for brominated flame retardants, including polybrominated diphenylethers (pbdes) and hexabromocyclododecanes (hbcdds) and perfluorinated compounds (pfcs) including (but not limited to) pfos and pfoa. control programmes for residues and contaminants should include 'new hazards' and take into account information from environmental monitoring programmes which identify chemical hazards to which animals may be exposed. provide an equivalent level of protection within the scope of meat inspection or elsewhere in the production chain that may be used by risk managers in case they consider the current methods disproportionate to the risk, e.g. based on the ranking as an outcome of tor 1 or on data obtained using harmonised epidemiological criteria. when appropriate, food chain information should be taken into account sheep and goat production in the eu is marked by being largely extensive in nature, involving frequent trading of animals and nomadic flocks. this involves differences in husbandry systems and feeding regimes resulting in different risks for chemical substances and contaminants. extensive periods on pasture or/as nomadic flocks and the use of slaughter collection dealerships may preclude detailed lifetime fci. similarly, in these situations, the level of feedback from the slaughterhouse and authorities to farmers regarding the results of residue testing may be suboptimal. there is less concern about fci from dairy sheep and goats as they are reared under more intensive and controlled conditions. better integration of results from official feed control with residue monitoring seems essential to indicate whether monitoring of residues in slaughter animals needs to be directed to particular substances. therefore, there is a need for an improved integration of sampling, testing and intervention protocols across the food chain, nrcps, feed control and environmental monitoring. fci should be expanded for sheep and goats produced in extensive systems to provide more information on the specific environmental conditions where the animals are produced. it is recommended that sampling of sheep and goats should be based on the risk of occurrence of chemical residues and contaminants and on the completeness and quality of the fci supplied. there is a need for an improved integration of sampling, testing and intervention protocols for domestic sheep and goats across the food chain, nrcps, feed control and environmental monitoring. the development of analytical techniques covering multiple analytes and of new biologically based testing approaches should be encouraged and incorporated into feed quality control and chemical residue/contaminants testing in the nrcps. the combination of data from both sheep and goats into one data set assumes that both food chains are identical, which is not the case. a separation of test records for both species is recommended. for prohibited substances, testing should be directed where appropriate towards the farm level. future nrcp testing relating to substances that might be used illicitly for growth promoting purposes needs to be refocused to better identify the extent of abuse in the eu. in addition, control measures for prohibited substances should not rely exclusively on nrcp testing, but should include veterinary inspection during the production phase and the use of biological methods and biomarkers suitable for the identification of abuse of such substances in sheep and goat production in the eu. commission decision 2002/657/ec specifies the performance criteria for methods, including recovery and accuracy, trueness and precision. the decision specifies, also, the validation required to demonstrate that each analytical method is fit for purpose. in the case of screening methods, validation requires determination of the performance characteristics of detection limit, precision, selectivity/specificity and applicability/ruggedness/stability. for confirmatory methods, in addition to determination of those performance characteristics, validation requires, also, determination of decision limit and trueness/recovery. the analytical requirements for the determination of dioxins, dl-pcbs and ndl-pcbs are laid down in commission regulation (ec) no 252/2012. 50 following a criteria approach analyses can be performed with any appropriate method, provided the analytical performance criteria are fulfilled. while methods, such as gc-ms and cell-and kit-based bioassays are allowed for screening purposes, the application of gc/high-resolution ms is mandatory for confirmation of positive results. screening methods include a broad range of methods, such as elisa, biosensor methods, receptor assays, bioassays and biomarkers for the presence of residues of concern. these screening methods generally use specific binding of the molecular structure of the residue(s) by antibodies or other receptors to isolate and measure the presence of the residues in biological fluids (urine, plasma) or sample extracts. more recently, biomarkers for the use of prohibited substances such as hormonal growth promoters have been identified as potential screening methods for these substances. physicochemical methods, such as lc or gc with various detectors, may be used, also, as screening methods. in the particular case of antimicrobials, microbiological or inhibitory substance tests are widely used for screening. in such tests, using multiple plates/organisms or kit formats, the sample or sample extract is tested for inhibition of bacterial growth. if, after a specific period of incubation, the sample inhibits the growth of the bacteria, it is considered that an antibacterial substance is present in the sample, but the specific substance is not identified. given that this is a qualitative analytical method, a misinterpretation of the results cannot be ruled out, and some false-positives can occur. microbiological methods are screening methods that allow a high sample throughput but limited information is obtained about the substance identification and its concentration in the sample. when residues are found in a screening test, a confirmatory test may be carried out, which normally involves a more sophisticated testing method providing full or complementary information enabling the substance to be identified precisely and confirming that the maximum residue limit has been exceeded. with the significant developments in liquid chromatography and in mass spectrometry over the last decade, confirmatory methods are largely ms-based, using triple quadrupole, ion trap, and other ms techniques. indeed, with current methodology in a modern residue laboratory with good ms capability, much of the two-step approach of screening followed by confirmatory testing has been replaced by single confirmatory testing. this has been made possible by the greatly-enhanced separation capability of ultra-high-performance liquid chromatography (uplc), coupled with sophisticated ms detection systems. the parallel growth in more efficient sample extraction/clean-up methods is an integral part of these advances in confirmatory methods and such chemistries produce rapid, sometimes (semi)-automated procedures providing multi-residue capability. techniques based on highly efficient sorbent chemistries for solid-phase extraction and techniques such as quechers are examples of these advances. such combinations of uplc-ms/ms methods with appropriate sample extraction/cleanup technologies allows for unequivocal, quantitative determination of a broad spectrum of substances in a single analytical method. particularly in the area of prohibited substances, the power of ms techniques is being applied to identify hitherto unknown compounds and to identify exogenous from endogenous substances. for example, time-of-flight ms provides accurate mass capability and may allow for retrospective analysis capability from the ms data. the technique of gc-combustion-isotope ratio ms has been utilised to study the 13 c/ 12 c ratio of substances in urine samples, where, for example, such 13 c/ 12 c ratio differs significantly between endogenous (or natural) testosterone and exogenous (or synthetic) testosterone. liver examination at slaughter is the most direct, reliable, and cost-effective technique for the diagnosis of fasciolosis. moving to a visual only meat inspection system would decrease the sensitivity of inspection of fasciolosis at the animal level; however, it would be sensitive enough to identify most if not all affected herds. therefore the consequences of the change would be of low relevance. the feedback to farmers of fasciola hepatica detected at meat inspection should be improved, to allow farmer information to support rational on-farm fluke management programmes. quantitative analysis indicated that the proposed changes to the meat inspection system would not affect detection of welfare conditions; however, for leg and foot disorders and sheep scab a combination of the two surveillance components (clinical surveillance and meat inspection) were found to be more effective than either one of the surveillance component on its own. qualitative analysis suggested that the proposal for shortened transport and lairage time would be beneficial to improving the welfare of small ruminants. food chain information should include animal welfare status in order to complement the slaughterhouse surveillance systems (ante-mortem and post-mortem inspection) and the latter could be used to identify on-farm welfare status. other recommendations on biological and chemical hazards would not have a negative impact on surveillance of animal diseases and welfare conditions. in this mandate, the ahaw panel and the ad hoc working group (wg) are focusing on the implications for animal health and welfare of any changes to the current meat inspection (mi) system, as proposed by biological hazards (biohaz) and contaminants in the (contam) panels. "implications for animal health and welfare" relates specifically to monitoring and surveillance of animal diseases and welfare conditions during mi (that is, inspection at the slaughterhouse before and after slaughter, in this document referred to as ante-mortem (ami) and post-mortem (pmi) inspection, respectively). therefore, the objective of this work was to identify possible effects and to assess the possible consequences on surveillance and monitoring of animal diseases and welfare conditions if the proposed changes in the mi system were applied. apart from its contribution to assuring public health, current mi also contributes to surveillance and monitoring of animal diseases and welfare conditions (efsa, 2003) , and may be an important component of the overall monitoring and surveillance system. further, mi offers the only opportunity for monitoring some diseases and welfare conditions at certain stages of a control and eradication programme. therefore, any change in mi system that could lead to a loss of sensitivity (reduced probability of detection) may compromise the surveillance efficacy. in the case of animal welfare, ami and pmi also play a role in surveillance and monitoring of the welfare of farmed animals, and, moreover, it is the only place to assess poor welfare during the transport of animals to the slaughterhouse. small ruminants are subjected to different periods of feed and water restriction, handling and transport prior to arrival at the slaughterhouse. ami begins with the observation of animals at the time of unloading from the transport vehicle and the purpose is to determine whether animal welfare has been compromised in any way on the farm and during handling and transport. welfare conditions such as fitness to travel, prevalence of injury, lameness and exhaustion, and the cleanliness of the animals are ascertained during ami. certain other welfare conditions such as bruising may not always be detectable during ami, but become visible during routine pmi. welfare conditions related to foot and leg disorders would be detectable only if the animals are observed during walking, e.g. unloading or moving to lairage pens, and are also less likely to be detected by visual examination during pmi. when mi detects apparent defects or abnormalities, incision of the relevant joints, tendons and/or muscles could be necessary to determine the presence as well as the severity of foot and leg disorders. implications for surveillance and monitoring for small ruminant health and welfare of changes to meat inspection as proposed by the biohaz panel the proposed modifications to the mi system that may have implications for animal health and welfare (see biohaz appendix a for full details), include: shorter transport and lairaging, which may be beneficial in terms of reducing crosscontamination of pathogens salmonella spp. and human pathogenic escherichia coli (see biohaz appendix a, section 5.2). the changes to address prioritised hazards not currently detected by mi will focus on improved collection and use of relevant food chain information (fci), including the use of harmonised epidemiological indicators, to provide information for categorisation of farms, which can be used for, for example, risk-based ami, logistic slaughter and/or decontamination (see biohaz appendix a, sections 4 and 5.1). omission of palpation and incision in animals subjected to routine slaughter at pmi. if abnormalities are detected during visual inspection, palpation and incision should be carried out separately from the routine inspection of carcasses to prevent cross-contamination) (see biohaz appendix a, section 5.3). to assess the impact of proposed changes to the current mi on the overall sensitivity for surveillance and control of animal diseases and welfare conditions, a quantitative assessment was performed based on expert opinion and modelling. an external consortium (comisurv), under the provision of an efsa procurement, performed this work. the detailed methodology, as well as results and conclusions, together with assumptions and limitations of the modelling, can be found in the comisurv report for small ruminants mi (hardstaff et al., 2012) . these limitations include: the parameters for the probability of detection were based on expert opinion and therefore there is uncertainty as to the true range of these values. limited number of experts to cover the different subjects needed for the assessment. variations in the epidemiological situation of the disease and welfare conditions between countries. a brief description of the methodology that was applied is given below. an initial long list of small ruminant diseases and welfare conditions relevant to the eu was established, based on general textbooks, references, and expert opinion. wg experts filtered this list using a decision tree, following previous methodology and criteria developed for previous opinions (efsa biohaz, contam and ahaw panels, 2011, 2012) . a disease or condition was retained on the list by the wg experts using the following criteria: a high likelihood of detection of a disease or welfare condition at mi, at the age that animals are presented at the slaughterhouse (if likelihood was medium, low, or the condition was undetectable, it was excluded from the list). the disease or welfare condition is considered relevant to the eu (conditions not occurring in eu member states (ms) were omitted). the condition is relevant to animal health and welfare (conditions mainly relevant to public health were not retained, as they should be dealt with by the biohaz panel). the slaughterhouse surveillance component (ami + pmi) provided by mi is significant for the overall surveillance of the disease or welfare condition (if there are other surveillance or detection systems much more effective and highly preferable to mi, the conditions were removed from the list). the final list of conditions established by the wg experts to be assessed by the comisurv consortium is shown in table 1 . a total of twenty conditions (eleven diseases and nine welfare conditions) were included in this list. a stochastic model to quantify the monitoring and surveillance effectiveness of mi in small ruminants was developed. a definition of a typical and a mild case for each of the diseases and welfare conditions listed in table 1 was provided by the comisurv experts. typical cases were by definition detectable cases and express more developed clinical signs than mild cases. typical cases were defined as the clinical signs and/or lesions that are expected to be observed in more than 60 % of affected or infected small ruminants arriving at slaughter. the mild case of a disease or welfare condition is the form that could be seen at the early stages of the disease or at some point between the subclinical (and without pathological lesions that are observable through the meat inspection process) and the fully developed form (i.e. "typical" form). a mild case is neither typical nor non-detectable. the animal will probably present more subtle signs than in the typical case. as an example, a typical case of echinococcosis would show hydatid cysts in the liver and in the lungs, and a mild case would have a low number of small cysts in liver and lungs. the proportion of affected animals presenting as typical or mild cases, as well as the non-detectable fraction was estimated (see comisurv report for details). the most likely detection probability, as well as 5th and 95th percentiles (the probability intervals) of the output distribution of ami, pmi, and ami and pmi combined were derived for each of the conditions in table 1 , both prior to and following suggested changes to the mi system as proposed by the biohaz panel. the inspection protocols in the current and visual only systems are compared in table 2 . the probability of detection was calculated for both detectable cases (mild and typical), and for all cases (referred to as stage 2 in the comisurv report). mastitis x a stage 2-all diseases and welfare conditions listed were evaluated with regards to their probability of being detected at mi. b stage 3-for selected diseases and welfare conditions, surveillance by mi was to be compared with clinical surveillance. as inspection tasks aimed to detect orf do not change in a visual-only system, orf was not further discussed. in addition, for three of the selected diseases and two welfare conditions, considered to be more adversely affected in terms of probability of detection following the proposed changes to the mi system, further modelling was implemented to quantify the effectiveness of monitoring and surveillance in the overall monitoring and surveillance system, both prior to and following suggested changes to the mi system (referred to as stage 3 in the comisurv report). the objective for exotic diseases (i.e. foot and mouth disease (fmd), was to evaluate the probability of detecting at least one infected case of infected small ruminants by slaughterhouse inspection relative to other surveillance system components (component sensitivity), which for the purpose of this opinion was clinical surveillance. for endemic diseases (fasciolosis, lower respiratory tract infection) and welfare conditions (leg and feet disorders including foot rot, sheep scab) the objective was to calculate the case-finding capacity i.e. the proportion of infected or affected animals detected by the surveillance components (detection fraction) during both slaughterhouse and clinical surveillance. note that the word surveillance as used in this opinion does not imply that any action is taken to capture, or act upon, the information that is collected. it merely points to the potential of these systems to be used for such purposes. the detection probability for each disease and condition using the current mi system and the visual only system is shown in table 3 (detectable cases) and table a of annex 1 (all cases, including subclinical cases not detectable at slaughterhouse). a change to visual only inspection caused a significant reduction in the probability of detection (i.e. non-overlapping 90 % probability intervals, stage 2) during mi of detectable cases of fasciolosis (with a 28 % reduction in detection probability) and tuberculosis (tb) in goats (24 %) ( table 3 ). when all cases were considered (see annex 1, table a) , the change to a visual only pmi protocol resulted in a clear reduction in the detection probability of three diseases, tb in goats (with a 30 % reduction in detection fraction), fasciolosis (28 %) and pulmonary adenomatosis/maedi-visna (15 %)), although none of these reductions was significant when the overlap of probability intervals was considered. values for the probability of detection at ami and for the two proposed pmi scenarios for all cases (detectable and non-detectable cases combined) were also determined for welfare conditions (table 3 and annex 1, table a , respectively). the probability of detection was significantly higher for ami than pmi for broken bones, diarrhoea, leg and foot disorders, partial prolapses/hernias and sheep scab. a change in pmi protocol to a visual only system did not significantly reduce the detection of any welfare conditions. pmi had a significantly higher probability of detection than ami for mastitis. combined slaughterhouse probabilities of detection were higher for detecting cases of many welfare conditions than when the slaughterhouse inspection components were considered separately (table 3 and annex 1, table a ). where this was not the case, i.e. the detection probability of the combined mi process yielded equal values as either ami or pmi on its own. this was due to the fact that the experts had agreed that the respective welfare condition could not be detected at all with the one of the two mi steps. therefore the results of the combined mi are solely based on the results of either ami or pmi. for three welfare conditions (arthritis, broken bones and poor body condition), the pmi of detectable cases with visual only protocol also reduced the detection probability, although this was not significant. when considering all cases (annex 1, table a ), the probability of detection for the combined inspection was lower than for detectable cases. the change in pmi protocols led to a slight reduction in the detection probability of two welfare conditions (arthritis and poor body condition), yet none of these reductions were significant when the overlap of probability intervals was considered. the probability of detection for all detectable cases of diseases and welfare conditions at ami, pmi (two proposed scenarios-current and visual) inspection scenarios with the most likely (ml), 5th and 95th percentiles. shaded rows indicate diseases identified as having a significant reduction in detection probability in the visual-only scenario. for the two welfare conditions (leg and foot disorders and sheep scab) included in the overall surveillance analysis (stage 3), a combination of the two surveillance components (clinical surveillance and mi) was found to be more effective (detecting a higher fraction of affected animals) than either one of the surveillance component on its own. however, the change in pmi protocol did not greatly affect the detection fraction of these welfare conditions (table 4) . with regard to epizootic diseases, clinical surveillance (detection of clinical signs) had a greater sensitivity for detecting fmd than slaughterhouse surveillance, and the sensitivity increased with an increase in population size (table 5 , stage 3). a change to a visual only system would not have a negative impact on sensitivity of detection. a qualitative assessment was conducted, based on a literature review and expert opinion from the wg members, for the diseases identified as having a significant reduction in detection probability of detectable cases in the quantitative assessment of the comisurv report (tb in goats and fasciolosis) and welfare conditions. therefore routine inspection, unlike inspection for btb in the bovine, does not differ substantially from the visual only mi being proposed. information regarding the presence of tb is not specifically recorded at pmi. the comisurv report relating to the contribution of meat inspection to animal health surveillance in sheep and goats investigated the probability of detection of specific diseases and welfare conditions for three scenarios: one for inspection tasks as currently required by the legislation; one with visual inspection only; and one in which risk categorisation based on a hypothetical public health risk formed the basis for subsequent inspections. according to the comisurv report, the most likely values for the proportion of non-detectable, mild and typical cases elicited by experts for tb in goats were 0.35, 0.45 and 0.20, respectively. the pmi had a significantly higher probability of detection of tb in goats than ami for detectable cases and all cases, and the reduction in the probability of detection of tb in goats was significant for visual only pmi. the probability of detection (most likely values) of tb in goats (table 3 for detectable cases and annex 1, table a for all cases) for combined ami and pmi was 0.84 (0.47 for all cases) changing to 0.64 (0.40 for all cases) for visual only, which represents a 24 % reduction. as is the case with btb in bovines, the contribution of mi surveillance of tb in small ruminants is to support the detection of flocks/herds with tb, and the detection of individual animals with tb is merely the first step in improving herd surveillance. since more than one sheep or goat per flock/herd is likely to be slaughtered per time period (e.g. per year), the flock/herd probability of detection is a function of the individual animal sensitivity, the number of animals slaughtered from the herd and the within-herd prevalence of tb. for any given flock/herd, the flock/herd sensitivity will increase with the number of animals slaughtered. officially tuberculosis free (otf) status, however, is not available for small ruminants as it is for bovine herds, so the herd status is important in controlling tb in small ruminants, but not in substantiating freedom from tb. for tb in goats, the results from the comisurv report suggest that a change from the current inspection to visual only will reduce the probability of detection for detectable cases. a qualitative risk and benefit assessment for visual only pmi of cattle, sheep, goats and farmed/wild deer, commissioned by the uk food standards agency (fsa) (fsa, 2013a), considered the absolute and relative animal health risk of tb in small ruminants as negligible when moving to a visual only pmi system when compared with the current legal requirements of inspection for sheep and goats (regulation (ec) 854/2004). the main reason to reach this conclusion is that the current legal pmi requirements for small ruminants are mainly visual and do not require the incision of the lungs. incision of lymph nodes are required if in doubt after the initial visual inspection. considering that the majority of positive submissions to government labs in the united kingdom are associated with lesions in the mediastinal and bronchial lymph nodes, it is likely that the most frequent tb-like lesions in small ruminants (as described above) are not detected under the current traditional pmi requirements, which are initially visual, and therefore nor would be by visual only inspection. this lack of sensitivity is aggravated by the current commercial speed of slaughtering lines and the limited time available to carry out the inspection of carcases and offal. in the united kingdom, tb in non-bovine farmed animals is rare. small ruminants are not considered to represent a significant reservoir of the disease for other animals or to be of any significance in the persistence of btb in cattle. although small ruminants are considered as spillover hosts, it is still possible that severely infected sheep and goats could act as vectors of infection for other domestic and wild animals. in these circumstances, on-farm identification of possible sick small ruminants by farmers and a differential diagnosis from other respiratory disease and necropsy examination of lungs and relevant lymph nodes by farm veterinarians are the most effective control activities. fasciolosis (liver fluke) in small ruminants has a world wide distribution and is caused by the trematode parasite, fasciola hepatica. the direct losses due to fasciolosis are mortality, liver condemnation and reduced growth rate. disease results from the migration of large numbers of immature flukes through the liver, from the presence of adult flukes in the bile ducts, or both. liver fluke can infect all grazing animals, but is most pathogenic in sheep (armour, 1991) . the incidence of liver fluke is inextricably linked to high rainfall and is particularly prevalent in years when summer rainfall is high, which facilitates the survival and proliferation of the snail intermediate host and infective parasite stages present in the environment (ollerenshaw, 1959) . changes in recent epidemiological patterns, due to climate change, have resulted with increasing prevalence in northern european countries and the survival of fluke on pasture over winter, exposing sheep to infection for long periods (daniel and mitchell, 2002) . there have been increasing reports of liver fluke disease over the last decade in countries such as the united kingdom and ireland, most likely due to higher than average rainfall and temperatures through the seasons, and greater stock movements (taylor, 2012) . in southern european regions, for example in spain, the infection of snails could occur throughout the year, with a higher infection rate at the end of summer-autumn and at the end of the winter, and sheep eliminating eggs throughout the year (manga et al., 1990) . prevalence studies in the north-west of spain have indicated a liver fluke infection rate of approximately 56 % of sheep flocks (ferre et al., 1995) . regulation (ec) 854/2004 requires that domestic sheep and goats going for human consumption must have visual inspection of the liver and the hepatic lymph nodes, palpation of the liver and its lymph nodes, and incision of the gastric surface of the liver to examine the bile ducts. liver examination at slaughter is the most direct, reliable, and cost-effective technique for diagnosis of fasciolosis (urquhart et al., 1996) . reliance upon clinical signs to diagnose fasciolosis may result in low detection rates (rojo-vázquez et al., 2012) . mi is a convenient means of confirming a suspected herd or flock infestation, assessing the extent of infestation or determining the effectiveness of anthelmintic treatment (kissling and petrey, 1989) . pmi can confirm acute and sub-acute liver damage with liver enlargement, caused by the presence of immature flukes. animals suffering from chronic fasciolosis show a deterioration of the carcass, cholangitis, biliar occlusion and hepatic fibrosis with adult fluke present in bile ducts. besides the liver, other organs and structures can be found damaged, such as periportal and mesenteric lymph nodes that are enlarged and exhibit a brownish colour (rojo-vázquez et al., 2012) . mckenzie's study (1987) compared the new zealand inspection procedure (observation and palpation of livers) with the european community procedure (observation and incision through the gastric surface of liver to examine the bile ducts) and found that the new zealand method detected fewer truly infected livers, but misdiagnosis by inspectors gave more false-positives. the gastric surface incision procedure has a specificity of 100 % and sensitivity of 93.08 % to 99.42 % (kissling and petrey, 1989) . this underlines their importance in animal disease surveillance and the importance of the present mi technique in liver fluke surveillance. effective disease monitoring systems are essential to the provision of reliable information on diseases to producers, thereby protecting a nation's agricultural system and its potential for production (glosser, 1988) . information on fluke infestation at herd level allows farmers to develop and implement control programmes that can attempt to reduce risk factors and recommend the use of drugs in a more strategic fashion (fairweather, 2011) . edwards et al., (1999) demonstrated that one-third of farmers would improve their animal husbandry if informed of the mi findings for their lambs. the comisurv report on the contribution of mi to animal health surveillance determined that there would be a significant difference in detection rates between the current and the visual only mi techniques (a probability of 0.96 of all detectable cases by current method compared with 0.69 by the visual only method). a reduction in liver fluke surveillance by the use of a less sensitive mi procedure will reduce the quality of information available for producers and thereby directly impact animal health and welfare. the quantitative analysis (see comisurv report) of detection levels for welfare conditions indicated that none of them will be significantly affected by the proposed changes to mi. however, the results also revealed that when both ami and pmi were considered, the probability of detection was high for most welfare conditions. it was also evident that detection of two welfare conditions, i.e. leg and foot disorders (including foot rot) and sheep scab, would be more effective when a combination of clinical and slaughterhouse surveillance systems are used. leg and foot disorders in sheep are caused by either infectious conditions, i.e. interdigital dermatitis (also known as scald), foot rot, contagious ovine digital dermatitis, or non-infectious conditions such as white line disease (shelly hoof), granulomas, foot abscesses, interdigital fibromas, and foreign bodies such as thorns, wire or soil balls (kaler and green, 2008; conington, et al., 2010a conington, et al., , 2010b fawc, 2011) . overgrown and misshapen hooves are also attributed to lameness in sheep and erysipelas can cause outbreaks of lameness in lambs. the importance of routine feet examination in sheep health management is well documented (hodgkinson, 2010) . the farm animal welfare council (fawc) suggested that there is adequate legal protection for sheep suffering from lameness as the european transport regulation ec/1/2005 53 prohibits the transport of unfit animals, and specifically includes those that are "injured or present physiological weaknesses or pathological processes" and, in particular, are "unable to move independently without pain or to walk unassisted". the fawc also recommended that the surveillance of lameness in sheep should be undertaken by the uk government, in conjunction with farm assurance schemes, to determine trends in lameness over time, which would also apply to other mss where the prevalence of lameness is high (e.g. more than 2 % of flocks being affected at national level). lameness in dairy goats is also a common welfare problem and abnormalities detected in the united kingdom were horn separation, white line lesions, slippering, abscess of the sole, foreign bodies and granulomatous lesions (hill et al., 1997) . interdigital dermatitis has also been reported to be the cause of lameness in goats kept indoors in greece (christodoulopoulos, 2009 ). sheep scab is a skin disease caused by the mite psoroptes ovis and has been widely prevalent in europe. it is a major animal welfare, husbandry and economic problem (bisdorff et al., 2006; bisdorff and wall, 2008) . the objectives of the ami in the current hygiene legislation, regulation (ec) 854/2004, are to determine: conditions that may might adversely affect human or animal health, paying particular attention to the detection of zoonotic diseases and animal diseases for which animal health rules are laid down in eu legislation, and whether there is any sign that welfare has been compromised. 53 council regulation ( implementation of welfare assessment protocols using appropriate animal based indicators during clinical and slaughterhouse (ami + pmi) surveillance systems would improve the welfare of small ruminants. these welfare surveillance systems should become an integral part of the food chain information (fci). sheep are thought to be tolerant of being transported and deprived of food and water for long periods (knowles et. al., 1998) . it is a common practice by farmers to withdraw food on the farm for several hours prior to transport of sheep / lambs to auction markets or slaughterhouses, primarily to reduce soiling. however, dehydration can be a welfare problem during long transport distances/times, especially in high ambient temperatures (knowles, 1998) . recovery from the effects of food and water deprivation is a very slow process and therefore lairage appears to be of very little benefit. in this regard, full recovery from 14 hours of transport has been shown to take up to 144 hours (knowles, 1998) . owing to these, the biohaz panel's proposal for shortened transport and lairage time would be beneficial to animal welfare. the eu regulation (ec) no 852/2004 54 on the hygiene of foodstuffs requires slaughterhouse operators to request fci declarations to ensure animals entering the food chain are safe for human consumption. fci is also a good source of information to facilitate the detection in the slaughterhouse of abnormalities indicative of animal health and welfare conditions. fci is recorded at the flock/herd level, and its minimum content is described in regulation (ec) no 853/2004. fci related to primary production of small ruminant herds/flocks is based on a farmer's declaration. most mss have made available to farmers a standardised fci declaration form. a whole-chain approach to food safety, animal health and animal welfare requires slaughterhouse operators to be provided by livestock producers with information about their animals consigned to slaughter. based on the fci provided food business operators (fbos) can assess potential hazards presented by the animals and are required to act upon any information recorded on the fci declaration as part of their hazard analysis and critical control point (haccp) plan. this helps the slaughterhouse operator to organise slaughter operations and to ensure that no animals affected by disease or certain veterinary medicines enter the food chain. quality assurance schemes at primary producer level are voluntary tools operated by independent agencies or bodies to ensure compliance with given standards and regulations. these schemes increase farmers' responsibilities with regard to animal health and welfare and have potential for integration within the fci provided (oie, 2006) . the fci also assists risk management to determine the required inspection procedures and should be analysed by risk management and used as an integral part of the inspection procedures. the value of the fci in guiding risk management to discriminate between animals subsequently going through different types of inspection procedures should be evaluated. as for any evaluation of (pre-) screening procedures, the sensitivity and specificity of the classification should be estimated. priority should be given to improving test sensitivity, noting that (pre-) screening tests should preferably produce few false negative classifications for the sake of animal disease detection and surveillance. test specificity will largely be an economical parameter, since the subsequent inspection of all "fcipositive" animals or groups should detect any false positives not correctly identified during the fci pre-screening. regulation (ec) no 854/2004 requires that data from the ami and pmi at the slaughterhouse is delivered back to the farmer/producer when the inspections reveal the presence of any disease or condition that might affect public or animal health, or compromise animal welfare. currently this feedback of information to primary producers is not fully implemented in all mss (efsa biohaz, contam and ahaw panels, 2011 concludes that the effective and efficient flow of information provides valuable information to both the farmer and the fbo and allows more targeted and effective inspection procedures in the slaughterhouse and effective interventions on the farm that should contribute to a cycle of continuous improvement with positive implications for animal health and welfare. the effectiveness of this information cycle depends on a reliable animal identification and recording system at the slaughterhouse and an information transfer system to the primary producer. the collection and communication of slaughterhouse inspection results is an opportunity to collect and use data and knowledge applicable to disease control and the effectiveness of interventions, animal production systems, food safety and animal health/welfare (garcia, 2012) . at national and eu level such data can contribute to disease surveillance (for the detection of exotic diseases, monitoring of endemic diseases and identification of emerging diseases) and targeted animal health and welfare interventions. therefore fci, if consistently and effectively implemented as enshrined within the hygiene package, will form an integral part of a risk-based mi system. extended use of fci has the potential to compensate for some, but not all, of the information on animal health and welfare that would be lost if visual only pmi is applied. for the fci to be effective it should include species-specific indicators for the occurrence of disease and welfare conditions. fci for public health purposes may not have an optimal design for the surveillance and monitoring of disease and welfare conditions; therefore, an integrated system should be developed whereby fci for public health and for animal health and welfare can be used in parallel, more effective. the conclusions and recommendations from the contam panel refer to areas such as the ranking system for chemical substances of potential concern and its updating, the use of fci to help facilitate risk-based sampling strategies; the inclusion of new hazards in control programmes for chemical residues and contaminants (see contam appendix b, for full details). none of these were considered to have an impact on animal health and welfare surveillance and monitoring. as shown in the comisurv assessment, a change to visual only inspection would cause a significant reduction in the probability of detection (i.e. non-overlapping 90 % probability intervals) of detectable cases of fasciolosis and of tuberculosis in goats. clinical surveillance had a greater sensitivity for detecting fmd than slaughterhouse surveillance following the assessment by comisurv, although the sensitivity of meat inspection increased with an increase in population size. a change to a visual only system would not have a negative impact on sensitivity of detection. as shown in the comisurv assessment, the proposed changes to meat inspection would not greatly affect the probability of detection of any of the welfare conditions analysed. from the comisurv assessment, for two welfare conditions (leg and foot disorders and sheep scab), a combination of the two surveillance components (clinical surveillance and meat inspection) were shown to be more effective (detecting a higher fraction of affected animals) than either one of the surveillance components on its own. according to regulation (ec) 854/2004, current inspection in small ruminants includes visual inspection and palpation of the lungs and respiratory lymph nodes. a change to visual inspection would imply that palpation is abandoned. small ruminants are usually not subjected to official tuberculosis eradication campaigns, and farm controls are only performed on premises where cattle and goats are kept together, or in flocks/herds that commercialise raw milk. surveillance for small ruminant tuberculosis at present relies on meat inspection of sheep and goats slaughtered for human consumption, or other limited diagnostic surveillance activities. as is the case with tuberculosis in bovines, the contribution of meat inspection surveillance of tuberculosis in small ruminants is to support the detection of flocks/herds with tuberculosis. detection of tuberculosis in individual animals is merely the first step in improving the effectiveness of flock/herd surveillance, and for any given flock/herd, the flock/herd sensitivity will increase with the number of animals slaughtered. results of two recent risk assessments (comisurv report; fsa, 2013a) show that a change from the current inspection to visual only will reduce the probability of detection of tuberculosis in small ruminants. however, the consequences for animal health were considered as negligible in the fsa assessment, due to the fact that current meat inspection does not prescribe routine incision of lymph nodes, and the only inspection task omitted will be palpation of lungs and respiratory lymph nodes. in recent years tuberculosis has been reported in small ruminants in several eu countries and most information derives from recognition of tuberculosus lesions at the slaughterhouse and from laboratory reports. although small ruminants are not considered to represent a significant reservoir of the disease for the persistence of bovine tuberculosis in cattle, it is still possible that infected sheep and goat herds could act as vectors of infection for other domestic and wild animals. therefore, surveillance and control of tuberculosis in domestic small ruminants does have consequences for the overall surveillance and control of tuberculosis. liver examination at slaughter is the most direct, reliable, and cost-effective technique for diagnosis of fasciolosis. moving to a visual only meat inspection system would decrease the sensitivity of inspection at animal level for fasciolosis, however it would be sensitive enough to identify most, if not all, affected herds. therefore the consequences of change are low (charleston et al., 1990) . the feedback to farmers regarding fasciola hepatica detected at meat inspection is low at present and the real risk to animal health/welfare for this disease, caused by a change to a visual only meat inspection method, is probably low. implementation of welfare assessment protocols using appropriate animal based indicators during clinical and slaughterhouse (ami + pmi) surveillance systems would improve the welfare of small ruminants. extended use of food chain information has the potential to compensate for some, but not all, of the information on animal health and welfare that would be lost if visual only post-mortem inspection is applied. food chain information is a potentially effective tool to perform more targeted ante-mortem and post-mortem inspection tasks in the slaughterhouse which may increase the effectiveness of those tasks in detecting conditions of animal health and animal welfare significance. the existing ineffective flow of information from primary production to the slaughterhouses and vice versa reduces the ability of detection of animal diseases and animal welfare conditions at the slaughterhouse and as a result it limits possible improvements on animal health and welfare standards at the farm as farmers will not be aware of the slaughterhouse findings. the conclusions and recommendations on chemical hazards were reviewed by the ahaw working group and none of them were considered to have impact on animal health and welfare surveillance and monitoring. data collected during clinical and slaughterhouse (ante-mortem and post mortem inspection) surveillance systems should be utilised more effectively to improve animal welfare at farm level. slaughterhouse surveillance of tuberculosis in small ruminants should be improved and encouraged, as this is in practice the only surveillance system available. the detection of tuberculosis in small ruminants should be adequately recorded and notified, followed by control measures at the farm level. lack of feedback of post-mortem inspection results to the farmer prevents instigation of a fluke management programme, which could be detrimental to animal health and welfare. an improvement in this feedback of information is recommended. welfare surveillance systems should become an integral part of the food chain information. an integrated system should be developed whereby food chain information for public health and for animal health and welfare can be used in parallel, more effectively provide farmers with background information on the animal diseases and welfare conditions of key concern that may affect their livestock and why it is important to provide this information to the slaughterhouse through the use of food chain information. all cases: the combination of detectable cases (mild and typical) and non-detectable cases. case-finding capacity: characteristic of a surveillance system for endemic disease, describing the ability of the system to identify infected or affected herds or individuals, so that a control action can (potentially) be taken. the detection fraction is a measure of the case-finding capacity. case type: includes detectable (mild or typical cases) and non-detectable cases. clinical surveillance: surveillance based on clinical observations in the field. combined inspection: taking into account ante-mortem and post-mortem inspection. component sensitivity: the probability that one or more infected animals will be detected by the surveillance component during a specified time period, given that the disease is present at a level defined by the design prevalence. a risk assessment of shiga toxin-producing escherichia coli (stec) in the norwegian meat chain with emphasis on dry-cured sausages. panel on biological hazards, norwegian scientific committee for food safety norwegian scientific committee for food safety konsekvenser for dyr og mennesker norwegian scientific committee for food safety great hygienic effects from more strict requirements for the sheep slaughter campylobacter excreted into the environment by animal sources: prevalence, concentration shed, and host association comparative studies on the survival of verocytotoxigenic escherichia coli and salmonella in different farm environments epidemiological investigations on campylobacter-jejuni in households with a primary infection escherichia coli o157 : h7 and non-o157 shiga toxin-producing e-coli in healthy cattle, sheep and swine herds in northern spain genetic diversity among campylobacter jejuni isolates from healthy livestock and their links to human isolates in spain direct detection and genotyping of toxoplasma gondii in meat samples using magnetic capture and pcr a quantitative microbial risk assessment for meatborne toxoplasma gondii infection in the netherlands evaluation of elisa test characteristics and estimation of toxoplasma gondii seroprevalence in dutch sheep using mixture models a longitudinal study of verotoxinproducing escherichia coli in two dairy goat herds prevalence and characterization of vero cytotoxin-producing escherichia coli isolated from diarrhoeic and healthy sheep and goats liver distomatosis in cattle, sheep and goats of northeastern iran subtilase cytotoxin encoding genes are present in human, sheep and deer intimin-negative, shiga toxin-producing escherichia coli o128:h2 studies on the reservoir status of leptospirosis in gujarat updates on morphobiology, epidemiology and molecular characterization of coenurosis in sheep distinct host species correlate with anaplasma phagocytophilum anka gene clusters sheep and goat medicine zoonotic agents in small ruminants kept on city farms in southern germany outbreak of haemolytic uraemic syndrome in norway caused by stx2-positive escherichia coli o103:h25 traced to cured mutton sausages minimising the bacterial count on lamb carcases by means of slaughtering methods scvmph (scientific committee on veterinary measures relating to public health) 2003. opinion on revision of meat inspection in veal calves. european commission, health and consumer protection directorate-general. directorate c-scientific opininos main aspects of leptospira sp infection in sheep an outbreak of escherichia coli o103:h25-bacteriological investigations and genotyping of isolates from food potentially human-pathogenic escherichia coli o26 in norwegian sheep flocks tuberculosis in goats on a farm in ireland: epidemiological investigation and control study on prevalence of klebsiella pneumoniae in meat and meat products and its enterotoxigenicity a study of the sero-prevalence of influenze-a viruses in sheep and goats risk factors for the presence of antibodies to toxoplasma gondii in norwegian slaughter lambs enteritis in sheep and goats due to yersinia enterocolitica infection epidemiology of yersinia pseudotuberculosis and y. enterocolitica infections in sheep in australia investigation of the presence of esbl-producing escherichia coli in the north wales and west midlands areas of the uk in 2007 to 2008 using scanning surveillance yersinia enterocolitica in sheep -a high frequency of biotype 1a nonacid meat decontamination technologies: model studies and commercial applications temporal variation and host association in the campylobacter population in a longitudinal ruminant farm study babesia microti and anaplasma phagocytophilum: two emerging zoonotic pathogens in europe and hungary seasonal variation of thermophilic campylobacters in lambs at slaughter attribution of campylobacter infections in northeast scotland to specific sources by use of multilocus sequence typing microbial contamination on beef and sheep carcases in south australia current concepts -recognition and management of anthrax -an update an outbreak of salmonella mikawasima associated with doner kebabs diagnosis of human visceral pentastomiasis pathogenicity of yersinia enterocolitica biotype 1a procedures in the current meat inspection of domestic sheep and goats 128 2.4. criteria used for the evaluation of the likelihood of the occurrence of residues or contaminants in sheep and goats 2. weaknesses of the current meat inspection methodology for chemical hazards tor 4: adaptation of inspection methods use of a β-adrenergic agonist to alter muscle and fat deposition in lambs food poisoning by clenbuterol in portugal semicarbazide is non-specific as a marker metabolite to reveal itrofurazone abuse as it can form under hofmann conditions special issue plenary papers of the 8th international conference on goats recent developments in the use and abuse of growth promoters regulation (ec) no 726/2004 for dapsone as an impurity in veterinary medicinal products containing sulphamethoxazole or other sulphonamides scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to zearalenone as undesirable substance in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to aflatoxin b 1 as undesirable substance in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to deoxynivalenol (don) as undesirable substance in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to the presence of non dioxin-like polychlorinated biphenyls (pcb) in feed and food scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to fumonisins as undesirable substances in animal feed opinion of the scientific panel on food additives, flavourings, processing aids and materials in contact with food (afc) on a request related to a 9th list of substances for food contact materials scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to pyrrolizidine alkaloids as undesirable substaces in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission related to cyanogenic compounds as undesirable substances in animal feed mercury as undesirable substance in animals feed-scientific opinion of the panel of contaminants in the food chain glucosinolates as undesirable substances in animal feed-scientific opinion of the panel of contaminants in the food chain scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission on tropane alkaloids (from datura spp.) as undesirable substances in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission on theobromine as undesirable substances in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission on gossypol as undesirable substances in animal feed scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission on ricin (from ricinus communis) as undesirable substances in animal feed opinion of the scientific panel on contaminants in the food chain (contam panel) on perfluorooctane sulfonate (pfos), perfluorooctanoic acid (pfoa) and their salts cadmium in food -scientific opinion of the panel of contaminants in the food chain (contam panel) scientific opinion of the panel of contaminants in the food chain (contam panel) on request from the european commission on saponins in madhuca longifolia l. as undesirable substances in animal feed results of the monitoring of dioxin levels in food and feed update of the monitoring of dioxins and pcbs levels in food and feed scientific opinion on lead in food efsa panel on contaminants in the food chain (contam), 2011a. statement on tolerable weekly intake for cadmium scientific opinion on the risk to public health related to the presence of high levels of dioxins and dioxin-like pcbs in liver from sheep and deer scientific opinion on the risk for animal and public health related to the presence of t-2 and ht-2 toxin in food and feed scientific opinion on pyrrolizidine alkaloids in food and feed scientific opinion on polybrominated diphenyl ethers (pbdes) in food scientific opinion on hexabromocyclododecanes (hbcdds) in food scientific opinion on the risk for public health related to the presence of mercury and methylmercury in food scientific opinion on ergot alkaloids in food and feed emea (the european agency for the evaluation of medicinal products) emea (the european agency for the evaluation of medicinal products), 1997a. committee for veterinary medicinal products emea (the european agency for the evaluation of medicinal products), 1997b. committee for veterinary medicinal products emea (the european agency for the evaluation of medicinal products), 1999. committee for veterinary medicinal products. dapsone (1) committee for veterinary medicinal products expert committee on food additives. chloramphenicol -toxicological evaluation of certain veterinary drug residues in food evaluaion of certain veterinary drug residues in food agriculture organization of the united nations/world health organization expert committee on food additives), 2011. safety evaluation of certain contaminants in food who food additives series, 63. who/jecfa monographs 8, who determination of colchicine residues in sheep serum and milk using high-performance liquid chromatography combined with electrospray ionization ion trap tandem mass spectrometry depletion of protein-bound furazolidone metabolites containing the 3-amino-2-oxazolidinone side-chain from liver, kidney and muscle tissues from pigs formation of semicarbazide (sem) in food by hypochlorite treatment: is sem a specific marker for nitrofurazone abuse? monographs on the evaluation of carcinogenic risks to humans. sex hormones (ii) iarc monographs on the evaluation of carcinogenic risks to humans. pharmaceutical drugs iarc monographs on the evaluation of carcinogenic risks to humans. some thyrotropic agents iarc monographs on the evaluation of carcinogenic risks to humans transfer of perfluoroctanoic acid (pfoa) and perfluoroctane sulfonate (pfos) from contaminated feed into milk and meat of sheep: pilot study towards a criterion for suspect thiouracil administration in animal husbandry italian babyfood containing diethylstilbestrol -3 years later aplasia cutis congenita in surviving co-twin after propylthiouracil exposure in utero evidence that urinary excretion of thiouracil in adult bovine submitted to a cruciferous diet can give erroneous indications of the possible illegal use of thyreostats in meat production diseases associated with inorganic and farm chemicals aplasia cutis congenita and other anomalies associated with methimazole exposure during pregnancy estrogen and its metabolites are carcinogenic agents in human breast epithelial cells the identification of potential alternative biomarkers of nitrofurazone abuse in animal derived food products opinion on the risk assessment of dioxins and dioxins-like pcbs in food. cs/cntm/dioxin/20 final opinion of the scientific committee on veterinary measures relating to public health on assessment of potential risks to human health from hormone residues in bovine meat and meat products, adopted on review of specific documents relating to the scvph opinion on 30 april 99 on the potential risks to human health from hormone residues in bovine meat and meat products opinion of the scientific committee on veterinary measures relating to public health on review of previous scvph opinions of the mineral nutrition of livestock analysis of thyreostats: a history of 35 years the 2005 world health organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds weight increase of the thyroid gland as a tentative screening parameter to detect the illegal use of thyreostatic compounds in slaughter cattle residues of hormonal substances in foods of animal origin: a risk assessment pesticide, veterinary and other residues in food quantitative assessment of the impact of changes on meat inspection on the effectiveness of the detection of animal diseases and welfare conditions (comisurv report) implications for surveillance and monitoring for small ruminant health and welfare of changes to meat inspection as proposed by the contam panel and has also zoonotic implications. the pathological and histological findings in sheep and goats are similar to those seen in cattle these reports highlight the possible role of domestic goats and sheep as reservoirs of tb, and the need to re-evaluate the evidence for m. bovis (and m. caprae) transmission among cattle and small ruminants described the main pathological lesions in goats in the lungs in the form of abscesses (2-10 cm in size) with yellowish white, caseous or caseocalcareous lesions. lesions are also seen in the retropharyngeal, mediastinal or mesenteric lymph nodes and in liver, spleen and udder. lesions is sheep are very similar to those in goats, ranging from encapsulated soft, caseous lesions and encapsulated, calcified tubercles are also present in the lungs and liver in general, small ruminants are not subjected to official tb eradication campaigns; however, sheep and goats may undergo a bovine tuberculin skin test for detecting tb infection if located on premises where btb has been confirmed in cattle (subject to findings of a veterinary risk assessment), or if m. bovis infection has been confirmed in the sheep/goat flock/herd itself. if goats are kept together with cows, such goats must be inspected and tested for tb. furthermore, given that milk has it involves a visual inspection of the lungs, trachea and oesophagus, with palpation of the lungs and the bronchial and mediastinal lymph nodes both m. bovis and m. caprae cause tuberculosis in bovines and other species, including humans. further in the text, only m. bovis is mentioned regulation (ec) no 853/2004 of the european parliament and of the council of 29 april 2004 laying down specific hygiene rules for food of animal origin oj l 139 interference of paratuberculosis with the diagnosis of tuberculosis in a goat flock with a natural mixed infection elevation of mycobacterium tuberculosis subsp. caprae aranaz et al. 1999 to species rank as mycobacterium caprae comb. nov., sp. nov liver fluke morphopathology of caprine tuberculosis. i. pulmonary tuberculosis. anales de veterinaria de murcia prevalence and regional distribution of scab, lice and blowfly strike in great britain control and management of sheep mange and pediculosis in great britain liver fluke (fasciola hepatica) in slaughtered sheep and cattle in new zealand, 1984-85 foot lameness in dairy goats contribution of meat inspection to animal health surveillance in sheep and goats characterisation of white line degeneration in sheep and evidence for genetic influences on its occurrence foot health in sheepprevalence of hoof lesions in uk and irish sheep tb in goats caused by mycobacterium bovis fasciolosis in cattle and sheep outbreak of tuberculosis caused by mycobacterium bovis in golden guernsey goats in great britain scientific opinion of the panel on biological hazards (biohaz) on a request from the commission on tuberculosis and control in bovine animals: risks for human health strategies scientific opinion on the public health hazards to be covered by inspection of meat (swine) scientific opinion on the public health hazards to be covered by inspection of meat (poultry) reducing the future threat from (liver) fluke: realistic prospect or quixotic fantasy? veterinary parasitology seroprevalence of fasciola hepatica infection in sheep in northwestern spain a qualitative risk and benefit assessment for visual-only postmortem inspection of cattle, sheep, goats and farmed/wild deer an evaluation of food chain information (fci) and collection and communication of inspection results (ccir) for all species the use of data mining techniques to discover knowledge from animal and food data: examples related to the cattle industry back to the future: the animal health monitoring system -a political necessity being addressed in the united states differentiation by molecular typing of mycobacterium bovis strains causing tuberculosis in cattle and goats lameness and foot lesions in adult british dairy goats the importance of feet examination in sheep health management naming and recognition of six foot lesions of sheep using written and pictorial information: a study of 809 english sheep farmers comparison of new zealand and european community ovine liver inspection procedures a review of the road transport of slaughter sheep effects of stocking density on lambs being transported by road evaluation of the gammainterferon assay for eradicaiton of tuberculosis in a goat herd cost-effective meat inspection: the scientific basis. surveillance kinetics of fasciola hepatica egg passage in the faeces of sheep in the porma basin a case of generalized bovine tuberculosis in a sheep tuberculosis due to mycobacterium bovis and mycobacterium caprae in sheep guide to good farming practices for animal production food safety the ecology of the liver fluke (fasciola hepatica) tuberculosis in goats aranaz a and spanish network on surveillance monitoring of animal tuberculosis, 2012. a database for animal tuberculosis (mycodb.es) within the context of the spanish national programme for eradication of bovine tuberculosis update on trematode infections in sheep tuberculosis in goats on a farm in ireland: epidemiological investigation and control concurrent outbreak of tuberculosis and caseous lymphadenitis in a goat herd emerging parasitic diseases in sheep 1996. fasciolidae. in: veterinary parasitology mycobacterium bovis causing clinical disease in adult sheep meat inspection, comprising both ante-mortem and post-mortem inspection, is recognised as a valuable tool for surveillance and monitoring of animal diseases and welfare conditions, and helps in the recognition of outbreaks of existing or new disorders or disease syndromes, in situations where clinical signs are not detected on-farm. meat inspection represents a practical way to evaluate the welfare of small ruminants on-farm, and the only way to evaluate their welfare during transport and associated handling. changes in the meat inspection system may negatively affect the efficiency of the surveillance and monitoring of animal diseases and welfare conditions. the focus of the animal health and welfare (ahaw) panel was to assess the implications for surveillance of animal health and welfare of the changes proposed to the current small ruminants meat inspection system by the biological hazards (biohaz) and contaminants in the food chain (contam) panels. briefly, the recommendations of the biohaz panel were related to (i) shorter transport and lairaging, (ii) improved collection of food chain information to provide information for categorisation of farms, which can be used for e.g. risk-based ante-mortem inspection, logistic slaughter and/or decontamination, (iii) omission of palpation and incision in animals subjected to routine slaughter at post-mortem inspection (if necessary, detailed inspection with potential use of palpation and incision should be carried out separately). the contam panel recommendations included (i) the ranking system for chemical substances of potential concern and its updating, (ii) the use of fci to help facilitate risk-based sampling strategies, and (iii) the inclusion of new hazards in control programmes for chemical residues and contaminants.to assess the impact of proposed changes to the current meat inspection on the overall sensitivity for surveillance and control of animal diseases and welfare conditions, the results and conclusions of a quantitative assessment, carried out by an external consortium (comisurv) under an efsa procurement, were analysed. this report assessed the impact of a change from the current small ruminant meat inspection to a visual only system in terms of detection efficiency of a list of twenty selected diseases and welfare conditions of sheep and goats. additional information from scientific literature and other recent assessments were also taken into account by experts to assess the impact of proposed changes on the detection probability and overall surveillance of animal diseases and welfare conditions.a change to visual only inspection caused a significant reduction in the probability of detection (i.e. non-overlapping 90 % probability intervals) of detectable cases of fasciolosis and tuberculosis in goats (stage 2).with regard to exotic diseases, clinical surveillance (stage 3) had a greater sensitivity for detecting foot and mouth disease than slaughterhouse surveillance, and the sensitivity increased with an increase in population size. this indicates that for those countries in europe with a large sheep population, clinical surveillance is highly effective for detecting at least one case of foot and mouth disease in an infected sheep. for countries with high slaughter numbers of sheep, slaughterhouse surveillance would be almost equally efficient in detecting the disease. a change in post-mortem protocol to a visual only system did not significantly reduce the detection of any welfare conditions.in recent years tuberculosis has been reported in small ruminants in several eu countries and most information derives from recognition of tuberculosus lesions at the slaughterhouse and from laboratory reports. according to regulation (ec) 854/2004, current inspection in small ruminants aimed at detecting tuberculosis includes visual inspection and palpation of the lungs and respiratory lymph nodes. a change to visual inspection would imply abandoning palpation, which is the reason for this reduced detection. surveillance of tuberculosis at the slaughterhouse for small ruminants should be improved and encouraged, as this is in practice the only surveillance system available. the detection of tuberculosis in small ruminants should be adequately recorded and followed at the farm level. detectable cases: cases that are detectable by routine meat inspection procedures. they will express a range of combinations of clinical and pathological signs. a proportion of detectable cases will fit the definition of the typical case and a proportion will be milder cases.detection effectiveness: the proportion of animals with lesions (i.e. detectable by visual inspection, palpation and/or incision) that are actually detected.detection fraction: the proportion of infected or affected units that are successfully detected by the surveillance system.mild cases: the mild case of a disease or condition is the form that could be seen at the early stages of the disease or at some point between the subclinical and the fully developed (i.e. "typical") form. a mild case is neither typical nor subclinical. the animal will probably present more subtle signs than in a typical case. mild cases fit the mild case definition validated by experts.monitoring: investigating samples or animals in order to obtain information about the frequency of disease or infection as it varies in time and/or space.non-detectable cases: cases that are beyond the detection capacity of current meat inspection protocols. these will often be early cases at a stage where distinct clinical signs have not yet developed, but they can be cases with mild infection that leads to only subclinical conditions, without pathological lesions detectable by meat inspection.non-overlapping probability intervals: indicates that scenarios differ significantly from each other.overall surveillance system: includes several components, such as slaughterhouse surveillance and clinical surveillance. stage 2: assessment of the probability of detection at meat inspection. the objective of stage 2 modelling was to estimate case type-specific (for typical and mild cases) as well as overall probabilities of detection at meat inspection.stage 3: assessment of the relative effectiveness of meat inspection within the overall surveillance system by comparing meat inspection with other available surveillance methods.typical cases: cases that are, by definition, detectable cases and express more developed clinical signs than mild cases. they fit the typical case definition provided by the experts, which is defined as signs and/or lesions that are expected to be observed in more than 60 % of affected or infected of animals seen at the slaughterhouse. key: cord-350959-bsbz3a1l authors: dovey, zachary; mohamed, nihal; gharib, yasmine; ratnani, parita; hammouda, nada; nair, sujit; chakravarty, dimple; stanislaw, sobotka; lantz, anna; wiklund, peter; kyprianou, natasha; tewari, ash title: impact of covid-19 on prostate cancer management: guidelines for urologists date: 2020-06-16 journal: nan doi: 10.1016/j.euros.2020.05.005 sha: doc_id: 350959 cord_uid: bsbz3a1l abstract context the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) pandemic has resulted in a global health emergency, the like of which has never been seen before. prostate cancer (pca) services across the globe have been on hold due to changing medical and surgical priorities. there is also epidemiological evidence that pca patients have increased incidence and mortality from sars-cov-2 infection due to gender differences, age, and higher propensity for risk factors (eg, respiratory disease, obesity, hypertension, and smoking status). objective to contribute to the emerging body of knowledge on the risks of sars-cov-2 infection to pca patients and, in the face of pca treatment delays, provide evidence-based recommendations for ongoing management of specific pca patient groups. evidence acquisition a literature search was performed using all sources (medline, embase, sciencedirect, cochrane libraries, and web of science) as well as the media to harness emerging data on the sars-cov-2 pandemic and its influence on pca. eligibility criteria were originality of data and relevance to pca management. the authors note that during these unprecedented times, retrospective data are constantly being updated from multiple sources globally. evidence synthesis a total of 72 articles and data sources were found initially. owing to repetition, lack of originality, or nonrelevance, six articles were rejected, leaving 23 retrospective studies, seven basic science research articles, 15 societal and journal guidelines, and 21 epidemiological data sources, from countries at different stages of sars-cov-2 pandemic. these were analyzed qualitatively to produce evidence-based guidelines for the management of pca patients at different stages of the patient journey, with strategies to reduce the risk of viral spread. conclusions pca patients may have an increased risk of sars-cov-2 infection as well as morbidity and mortality if infected. once appropriately triaged, and to reduce viral spread, pca patients can have surveillance by telemedicine, and institute lifestyle changes and social quarantining measures. if risk stratification suggests that treatment should be planned, androgen deprivation therapy can be started, or potentially surgery or radiation therapy is possible on a case-by-case basis. patient summary prostate cancer patients can be followed up remotely until the severe acute respiratory syndrome coronavirus 2 pandemic resolves, but higher-risk cases may have treatment expedited to limit any negative impact on prostate cancer outcomes. the subfamily coronavirinae, which contains positive-sense single-stranded rna, and genus betacoronavirus [5] [6] [7] . covs are pathogenic in humans and animals, causing disease syndromes of varying severity affecting mainly respiratory, but also the liver, gastrointestinal, and central nervous systems [7] . other notable covs were sars-cov, which caused a human epidemic of severe acute respiratory syndrome in 2003, with a patient mortality rate of 10% [8] , and mers-cov, which impacted the middle east in 2012, with a mortality rate of approximately 35% [9] . sars-cov-2 most likely arose from bats, based on genetic sequencing similarities [7] , with sars-cov-2 sharing 79.5% genetic sequence with sars-cov but 96.2% with a bat cov (batcov ratg13) [5] . as yet, the intermediate host from the bats to humans is not known [7] . structurally, the virion has an envelope spike (s) protein that drives entry of sars-cov-2 into target host cells by engaging the cellular receptor angiotensin-converting enzyme-2 (ace2) [10, 11] . this step is accompanied by activation of cellular tmprss2, a type-ii transmembrane serine protease [12] . the tmprss2 protein interaction is of major mechanistic significance in pca, as the androgenically regulated tmprrs2/erg fusion has been found in approximately 50% of pca patients. the incubation period for sars-cov-2 is around 5 d, varying from 1 to 14 d, and the main mode of transmission is human to human, via direct contact or aerosol spread, or through fomites [13, 14] . according to the cdc, infected patients have a low risk of being contagious until the onset of symptoms, most commonly in the 2nd week of illness, but as a precaution, it recommends limiting contact until 10 d after the illness has resolved [15] . examining the aerosol and surface stability, in comparison with sars-cov, sars-cov-2 remained stable in the aerosol drops for hours and on surfaces for days (depending on the amount of virus shed), the worst surfaces being stainless steel and plastic [14] . this means that the virus can spread at large-scale events, page 6 of 36 j o u r n a l p r e -p r o o f nosocomially exacerbating its pandemic potential [14] . the important epidemiological impact of the sars-cov-2 pandemic presents challenging questions to urologists and pca patients as to how long it will take for services hubei province following suit days after [7, 16] , and only recently did china announce plans to lift the lockdown on april 8, 2020 [17] . the presumption will be that once "lockdown" is lifted and social quarantining restrictions relaxed, hospitals will resume normal services. this timeline is in keeping with a statistical model recently developed by zhao and chen [16] , who predicted an end to the wuhan and hubei epidemic at the end of march 2020. based on this timeline, it seems unlikely that normal urological services will resume in affected countries until 3-6 mo following the onset of government restrictions. this means that pca patients awaiting biopsy or treatment may be in a triage system for up to 6 mo, with possibly starting androgen deprivation therapy (adt) to defer treatment until the pandemic is resolved. compelling epidemiological evidence suggests that pca patients have increased susceptibility to sars-cov-2 based on their male gender, age, and associated comorbidities. gender disparity has been reported for the sars-cov-2 pandemic, with some sources quoting twice as many men as women affected, although there is clear j o u r n a l p r e -p r o o f geographical variation (tables 1 and 2 ). in china, as of february 11, 2020, examination of 44 672 confirmed cases found that the male to female ratio was from 0.99 to 1 in wuhan, 1.04 to 1 in hubei, and 1.06 to 1 in the country [18] . another chinese study with a smaller cohort of 1099 confirmed cases has shown that 58% of those infected were men [19] . beyond asia, for the italian outbreak, livingston and bucher [20] also found that 58% of 22 512 confirmed cases were men (table 1 ). further evidence suggests that morbidity and mortality rates in confirmed cases are worse for men than for women [1] , with reports in chinese cohorts, albeit with small numbers, showing that 73% of patients are admitted to hospital [21] , 67% of patients are admitted to intensive treatment unit (itu), and 66% of mortalities in itu occur in male patients [22] (table 3) . similarly, another chinese cohort found that of 99 patients developing pneumonia, 67% were male [23] . in keeping with previous sars and mers outbreaks, older men with chronic morbidities and impaired immunity seem to be at maximum risk, once infection has taken hold [24] (summarized in tables 2 and 3 ). smoking rate, which is also associated with worse outcomes, may be a factor in male preponderance, and certainly in china, smoking is significantly more common in men than in women [23] . the potential role of ace2 in gender and ethnic disparity in sars-cov-2 infection has also been suggested, and although ace2 expression is similar in asians, caucasians, men, women, old, and young, it is much higher in asian smokers than in non-asian smokers [23] . the clinical syndrome of sars-cov-2 infection ranges from asymptomatic disease to pneumonia, multiorgan failure, and death. published retrospective studies, mainly from china, report symptoms in decreasing order of frequency page 8 of 36 j o u r n a l p r e -p r o o f as fever, cough, fatigue, arthralgia and myalgia, headache, hemoptysis, and diarrhea [19, 21] . in a chinese retrospective study, 78.7% of patients had mild disease, while 15.7% progressed to severe disease and 6.1% required itu admission [19] . there is also geographical variation, based on more virulent strains of sars-cov-2, with the italian epidemic showing higher rates of more severe disease [20] . ace2 expression (potential for sars-cov-2 infectivity) has been shown in 4% of proximal convoluted cells in the kidney and 2% of bladder urothelium [25] . this may cause acute kidney injury (aki) in 3-9% of cases [ 26, 27] . other urological abnormalities such as hematuria and proteinuria may be seen in up to 44% of admitted patients, as well as abnormal serum creatinine in 15.5% and blood urea in 14.1% [26, 27] . significantly, the development of an aki has been an independent risk factor for fatality [ 26, 27] . a clinical diagnosis may be made in a patient who has coryzal symptoms with fever, dyspnea, and signs of pneumonia [28] . chest x-ray may show interstitial consolidation, more common at the lung periphery, seen more clearly on a computed tomography (ct) scan [28] . laboratory diagnosis hinges on viral nucleic acid identification and viral isolation in respiratory tract specimens as well as in blood and feces [28] , primarily by reverse transcription polymerase chain reaction (rt-pcr) [7] , with detection rates improving with additional sars-cov-2 igg and igm serology [ 29] . the guidelines to urologists for the general approaches and clinical management of pca patients during the covid-19 pandemic are summarized in table 4 . smoking is associated with chronic obstructive pulmonary disease), which increases the risk and severity of sars-cov-2 infection. furthermore, smoking with vaping may independently increase sars-cov-2 infection risk and morbidity as well [30] . smokers have a 1.4 increased risk of sars-cov-2 infection and a 2.4 increased risk of icu admission, mechanical ventilation, and death [31] . a meta-analysis of 4202 smokers out of 22 549 pca patients revealed that the smoking status was associated with an increased risk of biochemical recurrence (bcr), progression to metastasis, and pcaspecific mortality [31] . as yet, there is no evidence on whether the combined effects of smoking and sars-cov-2 in pca patients will have a cumulative deleterious effect, but clearly a sensible recommendation on both counts is smoking cessation. retrospective studies from china revealed that patients with diabetes or hypertension were more likely to be admitted to itu [22] , and ace2 expression is increased in diabetics and also in patients treated with ace inhibitors and angiotensin receptor blockers (arbs) [32] . as shown in table 2 , pca patients with either diabetes or hypertension should seek advice from their physicians to optimize their treatment, especially if this includes ace inhibitors or arbs [32] , to reduce their risk of sars-cov-2 infection and morbidity. the human herpes family) showed a higher likelihood of a psa rise than controls, but the absolute change was small (only 5.9% with a rise of >0.50 ng/ml). they also found that patients with nonspecific systemic viral infections were more likely to have a psa rise than controls, but only >0.2 ng/ml [33] . in addition to the specific viral prostate infection, the effects of a viral immune response with systemic inflammation may affect local vascular permeability or prostate epithelium, resulting in psa elevation. thus, a systemic viral infection may produce a small rise in psa in pca patients in active surveillance or watchful waiting programs, but no such inference can be made on postradical prostatectomy patients. for those urologists who perform transrectal biopsies, there is evidence that sars-cov-2 may also be transmitted by fecal-oral route. a clinical study reported that over half of patients with sars-cov-2 infection had viral genome in the stool, and in just under a quarter, this viral shedding continued beyond when the virus was cleared from the respiratory tract, potentially as a result of ace2 expression within the gastrointestinal tract [34] . as discussed earlier, both renal proximal convoluted tubular cells and bladder urothelium express ace2 [25] ; however, reports of viral urinary shedding are conflicting. one study found urine samples to be negative for sars-cov-2 viral rna [35] , but another showed that 6.9% of infected patients had viral rna in their urine, which stayed positive until after their throat swabs were cleared [35] . if biopsy is the sars-cov-2 pandemic has caused widespread cancellations of pca surgeries, due to reduced anesthesiology cover, bed and resource availability, staffing levels, and policies aimed at reducing viral spread [3] . at the authors' institution, there is a triage system in place, where patients awaiting robotic-assisted radical prostatectomy (rarp) for national comprehensive cancer network (nccn) high-risk pca are assessed on a case-by-case basis, depending on wait time prior to suspension of surgery and individual disease parameters (summarized in table 5 ). a number of recent studies have examined the influence of delay between diagnosis of pca and surgical treatment on outcomes [36] [37] [38] [39] . a single-institution study of over 2600 patients undergoing radical prostatectomy with an average of 56 mo of follow-up found, despite a trend toward higher bcr rates after surgery, that this was significant for only nccn high-risk groups beyond 12 mo [36] . gupta et al [39] examined nearly 1250 patients with unfavorable intermediate-and high-risk pca, and found no difference in outcomes between groups waiting for <3 or 3-6 mo after diagnosis, with up to 10 yr of follow-up. loeb et al [37] studied delaying surgery for patients with gleason 6 pca, who under current guidelines will be in active surveillance programs, and park et al [38] evaluated open and minimally invasive radical prostatectomy performed before and after 4 wk following diagnosis of prostate biopsy, which is too short a time frame to influence the decision for expedited surgery in this context. optimization of operating room (or) times means that procedures should be performed by experienced prostatectomists with no training for page 12 of 36 j o u r n a l p r e -p r o o f residents or fellows during this period, and the number of trained or staff in the room should be kept to a bare minimum [40] . patients being considered for surgery should have a sars-cov-2-negative nasal swab pcr and potentially a ct thorax to rule out parenchymal lung infection, in case of a false negative nasal swab pcr. studies have shown that the pcr test is affected by technique and timing within disease course, with a false negative rate of 15-25%, and there are reports of negatively tested patients transmitting the disease [41] . at the authors' institution, nasal swab pcr is mandatory, but ct thorax is not; however, given the possibility of false negative results, full precautions should apply regardless. the primary risk of anesthesia relates to intubation as an aerosol-generating procedure, increasing the risk of acute respiratory virus infection in the staff [42] . for those involved, environmental and ppe control protocols are important, and intubation should be performed, if possible, under airborne isolation conditions and ors with negative pressure environments [43] . in patients for whom rarp is planned, or recommendations for minimally invasive surgery are available from a number of sources including erus, rcs, rcog, sages, american association of gynecologic laparoscopists (aagl), and aorn [44] . the putative risk is viral presence in the co2 plume, putting or staff at risk, based on prior evidence of hpv, hepatitis b, and hepatitis a smoke contamination [45] ; without evidence, this also applies to the sars-cov-2 virus. nevertheless, the prudent approach is a cautious one, with the procedural aim of limiting co2 and smoke release into the environment. this can be achieved by the lowest possible intra-abdominal pressure and closed systems with ultra-low penetrating air filters for plume evacuation to 0.01 m in size; sars-cov-2 size is 0.06-0.14 m) [43] . in addition, the ports should be closed when possible, instrument movement should be limited, intra-abdominal smoke should be kept to a minimum by suction, and smoke production should be reduced by avoiding the use of ultrasonic sealing and using low electrocautery power and bipolar vessel sealing, and sutures and clips whenever possible [40, 46, 47] . or personnel should also wear full protective equipment including masks with goggles or visors, and the console should be cleaned between cases [40, 46, 47] . radiation reduces white cell counts, but whether this increases the risk of sars-cov-2 for patients is not clear [48] . recently, a radiation oncology panel (from the usa and uk) published a systematic review with recommendations on how to manage pca patients safely during sars-cov-2 pandemic, applying a "rads framework" referring to remote visits, avoidance, deferment, and shortening of radiotherapy (rt) protocols [49] . for pca patients with nccn low-risk and favorable intermediate-risk disease, avoidance is recommended until the pandemic resolves (tables 4 and 5 ). for nccn unfavorable intermediate-risk, high-risk, and locally advanced disease, treatment can be deferred with the start of adt, depending on how the pandemic develops; however, if adt cannot be given, the risks of treatment for cure should be weighed against the risks of sars-cov-2 infection [49] . patients considered for adjuvant rt after surgery should have salvage rt instead, and the "rads framework" will also apply to patients referred for palliative rt (fig. 1 ). presently, there is no evidence that adt directly increases the risk of viral infection, so patients could be treated safely with luteinizing hormone-releasing hormone agonists, abiraterone, or enzalutamide [50] , unless convincing evidence emerges to the contrary. however, adt may exacerbate comorbidities such as obesity, diabetes, and hypertension, which may increase the risk of sars-cov-2 infection and complications [32, 51] . if present, patients should be advised regarding lifestyle changes and should be assessed by their internists on adt to optimize diabetic and hypertensive treatments (table 5) . sars-cov-2 requires tmprss2 as well as ace2 for cellular uptake, and it is known that upregulation of tmprss2 is caused by androgenic hormones in pca cells [12, 52] . given that sars-cov-2 has this novel mechanism of pathogenicity, further research is required to determine accurately the risk of sars-cov-2 infection in patients on adt. in the meantime, we must optimize comorbidities and monitor for adt complications, while adhering to government regulations to limit the risk of sars-cov-2 infection during progression to metastatic disease (fig. 1 ). advanced pca patients on chemotherapy treatments such as taxotere, carboplatin, or cabazitaxel may have an increased risk of sars-cov-2 infection. cancer patients undergoing chemotherapy, including taxanes, have been shown to have an increased risk of viral infections, specifically influenza, which may worsen their morbidity and mortality as a result of immunosuppression caused by the chemotherapy itself [53, 54] . although there are no data examining pca chemotherapy during the sars-cov-2 epidemic, a recent retrospective study by yu et al [55] reports on 1524 cancer patients treated at a center in wuhan during the chinese sars-cov-2 epidemic. less than 50% of the patient cohort was receiving active treatment, but all had regular hospital visits and besides the food and drug administration-approved autologous, active cellular immunotherapy sipuleucel, and checkpoint inhibitors ipilumab and nivolumab, which are used to treat metastatic castration-resistant prostate cancer [56] , most immunotherapies for different pca patient subpopulations with advanced disease will be given as a part of a clinical trial and will be suspended during the sars-cov-2 pandemic. telehealth and other technologies that facilitate remote patient interactions have previously been discussed as a means of providing healthcare in times of disaster [57] . the literature has focused on specific care for patients who are victims of the disaster (eg, those infected with sars-cov-2 during the viral pandemic), but there is much to be learnt for allied specialties in the current period of "lockdown." in the usa, over 50 large healthcare institutions have the digital telemedicine infrastructure in place, and from a urological perspective, the priority is triage of patients who are suitable compared with those who are not [58] . for pca clinic appointments, these can be screened and categorized as urgent or nonurgent (eg, a high suspicion of high-risk pca or uncomplicated active surveillance follow-up, respectively). nonurgent patients described as "well" can have telemedicine follow-up consultations as an alternative (table 4 ). any (table 4 ). the sars-cov-2 pandemic offers an opportunity to gain widespread experience of telehealth and associated technologies, and although all research in the usa is currently on hold, retrospective data will emerge, allowing the urological community to assess the success of these triage systems for both outpatient and inpatient care. one small silver lining to covid-19 is the opportunity to assess whether telemedicine has any real potential for providing pca clinical services over the long term. covid-19 as a pandemic has three phases: presurge, surge, and postsurge. table 4 deals with recommendations for the surge phase, but as hospitalization numbers gradually come down, the pandemic will enter the postsurge phase. however, given the predictions for more waves of the virus, the lines between the pre-and postsurge phases may become blurred. during these phases, stocks of ppe should be refilled, and departments should ensure that staff are fully cognizant of covid-19 guidelines. where possible, telemedicine infrastructure should be developed to allow remote followup, and all patients on treatment waiting lists should be meticulously stratified according to nccn risk guidelines and according to comorbidities and covid risk stratification [44] . during pandemic surge, nccn risk groups 5 and 6 (high and very high risk) may be offered surgery or alternatively adt according to their choice and their assessed risk of covid-19 infection due to comorbidities. after the surge, departments can work their way down through risk groups according to local capacity, preparing for subsequent pandemic waves as described above. similarly, patients with bcr or metastatic disease can be assessed according to table 4 and be referred for therapy as appropriate. these are extraordinary times, and there is much that is unknown. as just-in-time information is processed to improve understanding on how the pandemic should be managed at clinical, social, and economic levels, critical questions need to be asked so that lessons are learnt [3] . in affected countries, the aim has been to transfer pca services from predominantly hospitals to community-based systems, and surgeries have been delayed or cancelled. the questions are how long this will last and how long urological services can be put on hold. many countries have government-imposed targets for pca investigation and treatment from the point of referral, including italy and the uk [3] . at the best of times, urology departments find meeting these targets challenging, but clear guidance are now needed on how to manage delays in patients under diagnosis and treatment for pca, how long patients can wait to be seen, what red flags during initial assessment should expedite management, and how to deal with patients (and their families) who have suffered negative outcomes as a result of these delays. other direct effects of sars-cov-2 also need to be considered. service reductions and banning of group meetings necessarily have a deleterious effect on training and education. research efforts, both basic science and clinical, have generally been put on hold (barring local guidelines), and ramifications of interrupting projects and withholding grants will have long-term economic effects on institutional research programs and funding mechanisms, notwithstanding a negative impact on patient care. finally, although sars-cov-2 predictions point to that it will pass following containment, there is the potential for recurrence, and also emergence of mutant viruses with enhanced sensitivity. the question then arises whether formal guidelines be put in place for viral there is emerging evidence that patients with cancer have increased susceptibility to sars-cov-2 infection and potentially worse outcomes [84, 85] . general recommendations for pca patients waiting for treatment, under as, or after treatment should exercise ppe, social distancing, and quarantining according to local guidelines [83] . smoking cessation and optimization of comorbidities to reduce risk and severity of infection should be recommended to all [30] [31] [32] . lifestyle changes, physical 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patients with cancer have a poorer prognosis of covid-19? an experience in impact of covid-19 on prostate cancer management: guidelines for urologists tewari prostate cancer (pca) patients may have an increased risk of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection and mortality. most can be followed up remotely until the pandemic resolves, but, once appropriately triaged, higher-risk cases can have treatment key: cord-339188-apgdzgfz authors: lewis, thomas j; huang, jason h; trempe, clement title: reduction in chronic disease risk and burden in a 70-individual cohort through modification of health behaviors date: 2020-08-26 journal: cureus doi: 10.7759/cureus.10039 sha: doc_id: 339188 cord_uid: apgdzgfz introduction health risk factors, including lifestyle risks and health literacy, are known to contribute to the chronic disease epidemic. according to the centers for disease control and prevention (cdc), chronic diseases account for 90% of healthcare costs, morbidity, and mortality. in the united states, healthcare providers attempt to modulate a limited set of risks. however, chronic diseases continue to proliferate despite expansion of wellness programs and drugs to manage and prevent chronic conditions. pandemics, exemplified by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), show that people in good health suffer mortality rates at 10% the rate compared to those with pre-existing chronic conditions. healthcare costs and morbidity rates often parallel mortality rates. new root-cause risk and health tools that accommodate low health literacy and are linked to personalized health improvement care plans are needed to reverse the chronic disease epidemic. reported here is a study on 70 manufacturing employees in the midwest us using a personalized and group approach to chronic disease reversal and prevention which may also find utility in pandemic severity and policy decisions. methods health, lifestyle, behavior, and motivation data were collected on 70 individuals at the beginning of a nine-month disease reversal and prevention program. the data were updated every two to six months over the period. inputs included information from a novel health risk assessment, serum biomarkers specific for chronic disease, and traditional medical information. using all these data we generated robust, personalized, and modifiable care plans that were implemented by the participant and guided by a care team including health coaches and medical providers. periodic renewal of profile data and biomarkers facilitated adjustment of care plans to optimize the path toward health goals set mutually by the participant and the care team. results ninety percent of participants experienced a favorable reduction in chronic disease biomarkers. the reduction in serum biomarkers coincided with a reduction in disease and risk attributes based on medical chart data and before and after interviews. hemoglobin a1c, for example, lowered in all but one participant concomitant with reported improved energy and reduced need for medications in the majority of participants. markers of inflammation lowered across the population. most importantly each individual reported improvement in their overall health. conclusions this simple, inexpensive, root-cause based risk and health approach generates a “do no harm” action plan that guides a care team, including the participant, on a path to improved health. the data demonstrate that changes in a novel risk calculator score coincide with changes in sensitive biomarkers for chronic disease. when the risks of an individual are reduced, the biomarkers reflect that change with self-reported wellbeing also improved. this program and process may be of value to society plagued with escalating levels of chronic disease and merits further study and implementation. developed nations, and particularly the united states, continue to confront a chronic disease crisis. the world health organization (who) reported that in 2010, non-communicable chronic diseases including: cardiovascular diseases, diabetes, cancers, and chronic respiratory diseases, accounted for 2/3 of deaths worldwide [1] . the institute of medicine reported that america is less healthy compared to high income nations in obesity, diabetes mellitus, heart disease, chronic lung disease, and disability [2] . the organization of economic cooperation and development (oecd) tracks the health of 36 developed nations. the u.s. scores in the lower half among these 36 nations on all major indicators of health, and longevity. when considering that the per person per year cost of healthcare in the united states is more than two and a half times that of the oecd nation average, yet our residents live 2.5 years less, a health paradox exists in the united states. this u.s. paradox is the worst cost-to-value benefit for chronic disease outcomes compared to the average of 35 other developed nations. the chronic disease management system is failing people at both ends of the health spectrum. a root of the problem is that health and prevention recommendations currently supported by the major medical societies have proven ineffective at reversing or preventing chronic diseases. laboratory tests in common use remain of limited scope and provide little insight into chronic health status. pharmaceuticals prescribed based on test results have poor absolute statistical success at preventing or reversing disease. these assertions are borne out since 90% of the nation's nearly $4 trillion in annual health care expenditures are for chronic conditions per the cdc. and the situation is not improving, for example, cardiovascular disease mortality, managed with statin drugs, blood pressure medications, and other usual care approaches across broad members of the u.s. population, increased nationally by 4.3% between 2011 and 2016 [3] . on average, residents of the united states with five or more chronic conditions spend 14 times more on health services than people with no chronic conditions [4] . as of 2014, 60% of u.s. adults had at least one chronic condition, and 42% had more than one chronic condition. five percent of the population accounts for an estimated 49%-53% of total health care expenses [5] . the 15 most expensive health conditions account for 44% of total health care expenses. the financial and productivity costs impact our corporations, who fund over half of the national healthcare at a price of roughly 4% of their gross revenues. and much of this cost is segmented in high-cost beneficiaries where, for example, the top 1% of claimants cost $150,000/y compared to the population mean of $5800/y. in a report compiled by the health care cost institute, there is a surprising large turnover from year to year among the highest cost healthcare spenders. three out of five top spenders in any given year were low or moderate spenders in the prior year. in 2015, only 39% of the top 5% of spenders were in the top 5% of spenders in 2014. moreover, this trend was consistent in each year from 2009 to 2015. there is a need for better predictive analytics to determine who is and, more importantly, will be in this significantly high-cost segment of any population as a current tool, claims data, lacks predictive power. in pandemics, standard tests provide little information on projected outcomes, rather they simply indicate exposure and potential immunity. healthy people are much less likely to die compared to unhealthy or older people. physiological health, the main concern of practicing clinicians, is not well characterized through these tests. further, the main cause of death appears to be cytokine storm syndrome which is driven by innate, not adaptive immunity [6] . thus, antibody testing does not adequately describe disease risk or severity. validated data on severe respiratory viral diseases and the correlation between mortality, immunocompromised status and existing chronic conditions in infected individuals indicate that a broad set of blood-based biomarkers may best serve to stratify risk and to set policy on containment strategies in populations [7] . currently, the policy is being established with an incomplete set of evidence. in vivo blood biomarker analysis offers considerable opportunities for individual and population risk measurement. these tests afford fast analytical turn-around time, quantitative measurement, accessibility, serial monitoring and ready availability. in some instances, rapid and continuous monitoring is available. the measurement of and changes to a broad range of modifiable risk factors, and biomarkers connected to immune system activity through cytokine surrogates, offers the most important opportunity for the prediction of disease and improvement in global chronic and pandemic disease status. most industries recognize the value of early problem intervention. in the waste management industry, for example, there is a clear hierarchy of: 1. source reduction, 2. recycling, 3. treatment, and 4. land disposal. in healthcare, there is also a potential for a four-tiered approach to health maintenance: 1. prevention, 2. mitigation of asymptomatic disease in people with elevated predictive biomarkers, 3. mitigation upon the earliest detectable signs of early disease (dry macular degeneration is an example), and 4. advanced root-cause mitigation approaches within disease management approaches. most of the efforts in today's healthcare is on disease management with usual care which is only a small part of this suggested four-tiered approach. the who addressed major causes of chronic diseases with modifiable risk factors being: unhealthy diet; physical inactivity; and tobacco use. in addition, the who stated "these causes are expressed through the intermediate risk factors of raised blood pressure, raised glucose levels, abnormal blood lipids, overweight and obesity. the major modifiable risk factors, in conjunction with the non-modifiable risk factors of age and heredity, explain the majority of new events of heart disease, stroke, chronic respiratory diseases and some important cancers. the relationship between the major modifiable risk factors and the main chronic diseases is similar in all regions of the world." studies show that the u.s. experiences the same risks as exist globally. dietary factors, alone, are associated with nearly half of all cardiometabolic deaths. the highest proportions of cardiometabolic deaths were estimated to be related to excess sodium intake, insufficient intake of nuts/seeds, high intake of processed meats, and low intake of seafood omega-3 fats. dramatic changes in disease rates among migrating populations indicate that the primary determinants of these diseases are not genetic but environmental factors, including diet and lifestyle [8] . studies on twins separated at a young age corroborate that chronic disease is much more related to environmental factors. expansion of the depth and breadth of risk assessment and concomitant prevention and disease amelioration programs represent an unmet healthcare need. a well-studied disease prevention arena is corporate wellness programs. most of these programs rely on "usual care" that includes: basic dietary recommendations, weight loss, smoking, alcohol consumption and metabolic and lipid index targets. a broad-based team of wellness professionals and academics evaluated workplace wellness programs. they unanimously concluded that few wellness programs meet expectations and most are abysmal failures. what separates bad, good, and great programs is "a combination of good design built on behavior change theory, effective implementation using evidence-based practices, and credible measurement and evaluation." to further support the need for more thorough risk assessment, in a global study of 84 risks, the authors concluded "increasingly detailed understanding of the trends in risk exposure and the relative risks for each risk-outcome pair provide insights into both the magnitude of health loss attributable to risks and how modification of risk exposure has contributed to health trends [9] . these types of data clearly illustrate a path to improved health outcomes through broader and deeper precision and personalized assessment. the risk evaluation tool used in this study, the chronic disease assessment™ (cda), is an on-line health risk assessment and mitigation tool and involves answering approximately 120 questions that probe deeply into lifestyle and environmental sources of risks, behaviors, health attitudes, readiness to change, current and past complaints, problems and diagnoses. the output of the cda is an overall risk score and then sub-sets of scores by risk categories, and a score for each question/answer combination. the overall raw risk score is converted into a letter "grade" reflecting the extent of the individual's risk "portfolio." the letter grade is provided to participants as an easily understood value for their risks, to overcome a lack of health literacy that especially impacts high risk populations. in addition, the cda output generates a series of actions that provide personalized education and actionable solutions to each risk in a participant's risk portfolio. finally, a health revival care plan™ is generated from the risk portfolio, and adjusted by the health coach and the participant, to create a simplified, personalized roadmap to overcome risks and improve health. a major impediment to health improvement is low health literacy. the de facto intervention perpetuating this problem is a prescription for symptom management that requires little knowledge by the patient. deficits in health literacy are associated with poorer health outcomes and higher health-related costs for both individuals and systems. improved health literacy has been associated with reductions in risk behaviors for chronic disease, and decreased rates of hospitalization [10] . health literacy is a critical and under-examined component of health disparities. according to the national assessment of adult literacy, over a third of u.s. adults have basic or below basic health literacy and have difficulty managing common health-related tasks. limited health literacy poses a significant economic burden to our society, with national estimates indicating that low health literacy costs the u.s. healthcare system from $106 to $238 billion each year in 2007 healthcare dollars [11] . the nexus of this program, including the cda risk portfolio, actions, care plans, and health coaching, is designed to meet and exceed the united states department of health and human services national action plan to improve health literacy's three goals: ensuring equitable access to health information; creating 'person-centered health information and skills' and supporting the development of the skills needed to attain and maintain good health. a final important aspect of this process, not articulated by the action plan, is illumination of the connection of risks to problems and complaints. the cda collects and reports risks, problems, and complaints together. thus, participants are able to "connect the dots" between risks and problems, like oral health and joint pain or carbohydrate intake and fatigue, as examples. these upstreamdownstream connection realizations improve health literacy and stimulate more sustainable change which manifests in the adoption of actions and plans to eliminate the risks as a solution to their problems as opposed to the usual care option of a drug to control symptoms. this process empowers individuals to be a participant in their own health improvement through recognition of their control over causes and outcomes. within this study, health coaches interacted face-to-face and electronically with participants and groups of participants to implement care plans. coaching activates patients to change through collaborative learning and social support. patient engagement and 4p medicine, defined as predictive, preventive, personalized and participatory, is an increasingly important component of strategies to prevent and reverse chronic disease, at least within the functional and integrative medical communities. interventions that tailor support to the individual's level of activation, and that build skills and confidence, are effective in increasing patient activation. more highly activated people are more likely to engage in healthy behavior such as eating a healthy diet and getting regular exercise while avoiding health-damaging behavior such as smoking and illegal drug use. these behavioral changes have led to lower rates of hospitalizations and emergency department visits, compared to less activated patients [12] . a bridge between risk factors and modification in certain intermediate factors like blood pressure and obesity are changes to blood-based biomarkers, which are more objective measures of health. the most routinely performed tests in usual care are for the assessment of kidney and liver health, blood chemistry, lipid markers and metabolic markers. heart disease continues to be the number one cause of morbidity and mortality in the u.s. and globally despite the broad use of cardiovascular disease medications for both prevention and intervention. a study of 136,905 patients hospitalized with a heart attack between 2000 and 2006 showed that almost 75% had ldl cholesterol levels within guidelines [13] . these data imply there is room for testing to augment evaluation of cardiovascular risk and cause. in older populations, "concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the framingham risk score do not" [14] . in healthy men, adding creactive protein levels to traditional risk factors, the reynolds risk score, improved cardiovascular risk prediction. the intermountain risk score uses common blood measures and assesses risk from the group of markers to develop a risk score. although limited in application, this scoring system has been reported to be predictive of increased mortality risk and provides patients with a more definable goal, the improvement of the score. more comprehensive assessments for risk and disease are emerging including the "allostatic load" and "inflammaging" concepts. each of these approaches considers a broader molecular view, rather than an organ system view of disease. according to mcewen, "when these (our body's) adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. however, there are a number of circumstances in which allostatic systems may either be over-stimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation" [15] . diabetes is a relevant example, where insulin production is frequently elevated in response to regular highly absorbable carbohydrate intake. claudio franceschi coined the term "inflammaging" in 2000 to describe the concept of low-grade chronic inflammation and its impact on health. inflammaging was described as an extension of the "network theory of aging" [16] . similar to the allostatic load, a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are considered the major characteristics of the inflammation aging process and susceptibility to premature disease and mortality. biomarkers for inflammaging are readily available and inexpensive but seldom obtain in usual care, especially in the implementation disease prevention strategies. according to gay et al., the allostatic load leads to dysregulation of the neuroendocrine system and subsequent elevation in inflammatory markers, leading to metabolic syndrome and chronic diseases such as cardiovascular disease [17] . thus, the allostatic load and inflammaging are both measured, at least in part, with inflammatory markers like c-reactive protein, cortisol levels, glycosylated hemoglobin, white blood cell counts, and fibrinogen as examples. independent of inflammatory markers, multiple biomarkers, in general, improve the predictive power of a panel. in a study of 3209 people assessed with 10 biomarkers, persons with multi-marker scores in the highest quintile as compared with those with scores in the lowest two quintiles had elevated risks of death and major cardiovascular events of 4.08 and 1.84 (adjusted hazard ratios), respectively [18] . this far exceeds the predictive hazard ratio for cholesterol which varies from 0.89 to 1.25 depending upon the study [19] . a hazard ratio of < 1 means cholesterol levels were determined to be protective and stave off early mortality. numerous studies and reviews consistently show the value of multiple markers in real-world prediction of disease events and premature mortality. the chronic disease temperature™ (cdt) risk scale used in this study combines emerging concepts for improving the evaluation of disease risk and measurement of active disease. the significant attributes of the cdt scale are: 1. consideration of multiple biomarkers, 2. selection of markers based on traditional and new predictive markers based on inflammaging and the allostatic load, 3. harmonizing each marker to a standard endpoint -increase in early mortality risk, 4. consideration of risk contribution based on log-linear deciles of marker levels and individual marker hazard ratios for mortality, and 5. combination of the risk values from each marker into a single number score to accommodate limited health literacy and to set an understandable objective target for health improvement. the aggregate cdt score is an indicator of early mortality and associated total morbidity, while the values for each marker reflect both mortality risk and disease risk based on the association of a given marker to disease. this single number may be an important bridge to better health literacy as most patients do not understand the meaning of their current lab values. the cdt does not constitute a medical diagnosis of disease any more than does any individual marker, like homocysteine, but does statistically afford better predictive capability and measurement of disease progression or regression. the cdt output promotes the concept that health and disease lie on a log-linear continuum rather than being an on/off switch. in this study, the implementation of risk assessment, health and disease measurement, care plans, and frequent measurement leading to continuous improvement represents a needed response to challenges society faces from chronic diseases. this "systems approach" is designed to better connect across fragmented divisions in healthcare without bias of discipline. that is, fundamentally, most chronic diseases are connected at root-cause physiological processes. the ultimate goal is to create new risk/plan/action/outcome connections that facilitate learning opportunities and iterative advancement in treatment and preventative methods for chronic disease. another consideration is the order applied to the interventions including "in series" or "in parallel". an example is diabetes that needs to be managed for the prevention of heart disease, yet these diseases lie in different medical silos. the final objective ensures that workup of any individual patient, regardless of the presumed scope of the illness, embraces all possible causal factors. the purpose of this study was to assess the effectiveness and safety of this novel care model for the prevention and reversal of a broad spectrum of chronic diseases and complaints over a nine-month period. primary endpoints to assess the effectiveness of the intervention were changes in health risk assessment scoring, changes in documented health complaints, changes in medication usage, changes in vital signs, changes to individual blood-based biomarkers designed to measure chronic health, and changes to the multiple marker risk score, the cdt. we conducted an open-label, randomized, controlled, before-and-after nine-month study of a high intensity remote and on-site care intervention named a health revival process (hrp). participants included a group of 70 individuals who, at the time, were employed by a mid-west fortune 1,000 manufacturing company with approximately 1,000 employees at that site. no formal control group was established but non-participant health status over the period was tracked using claims data for diagnoses, complaints, medication use, and healthcare spending. participation was voluntary and recruitment started in november of 2016, implemented by our company and the employer, focused on higher claims and more chronically sick individuals who were motivated to overcome unresolved chronic health issues. no rigid participation inclusion criteria were used other than each individual had at least one diagnosed chronic condition, was formerly or currently on a medication for a chronic disease, and was a high healthcare claimant (> $5000/year currently or within the past three years) if that data was available. not all participants had claims data from previous years mainly due to their health plan and choice or employment history with the company. from those interested in the program and met the criteria, retrospective health data (medical claims) were reconciled to finalize the 70-person cohort without consideration for a specific type of condition. although not a formal clinical study, all procedures performed in the program involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. ethical oversight was provided by the existing primary care clinic management organization, but not under any formal written agreement other than to monitor for patient safety. informed consent, medical releases, and participation contracts were obtained from all participants included in the program. these documents were completed after each participant was provided detailed information about the program. all data were acquired in strict conformance with health data privacy laws by medical personnel and all stored data were contained on a health insurance portability and accountability act (hipaa) compliant cloud. the health revival process: participants in the health revival process (hrp) underwent medical history review, completed a 120 +/-question online health risk assessment (chronic disease assessment™ (cda)) and laboratory testing for 55 serum-based biomarkers (chronic disease temperature™ (cdt)). participants without a medical exam within the past 6 months had one perform by our doctor, to determine their baseline health and risk status. all data obtained on participants, including problems, diagnoses, health complaints, reconciled medications, vitals, food journal, and other measurements were entered into our proprietary health revival software. upon qualifying, hrp participants began one-on-one health coaching encounters. the initial coaching session included active listening by the coach and reconciliation between the output of the cda risk assessment and health concerns, problems, and information articulated by the participant at that first encounter. any discrepancy between the responses to the cda questions and information presented to the health coach were verified and the cda was appropriate updated and annotated. the health coach, using the recommendations promoted by the up-to-date hrp software record, developed a personalized health roadmap referred to as a person's health revival care plan™ (hrcp). our medical doctor reviewed and finalized that document and then conferred with the coach on next steps appropriate for the participant. our doctor and the non-hrp medical doctors ensured that the recommendations and suggestions made by the health coach did not violate the health coaches license to provide advice. there was reasonable fidelity to the hrp delivery as everyone saw the same coach and doctor over the same time period. however, participants experienced different levels of coaching and doctor intensity based on the extent of their risk portfolio and medical needs. participants had continuous access to their health information, suggestions, and progress within the hrp software which maintained much of their personal health information. specifically, a participant could follow, track, and monitor changes in health measures and interact with specific, personalized content (written, audio, and video) curated automatically by the hrp system based on their personalized health information inputs including, their cda risk assessment, cdt markers, and vital signs recorded in the system. in addition, the participant portal included their personalized hrcp that created the structure for their hrp. participants were able to work with their health coach on the plan, follow the plan through a selfguided process, or some hybrid between the two paths. the health coach was able to monitor the self-guided process through system feedback that included reports on system logins and completed "actions" and "goals." completed actions occurred after a participant accessed content relevant to a health risk determined by the hrcp and choose a selection after reviewing the information like "completed" or "deferred." most participants relied on the health coach for structure, direction, and motivation. figure 1 shows features of the patient portal health revival dashboard. participants in the hrp retained their existing providers for acute disease management and routine medical checkups. care coordination between existing providers and hrp care team occurred as needed. in particular, the hrp doctor and pcp discussed any possible interactions between supplements, lifestyle changes, and current medications. of frequent concern was a need to change the dose or use of insulin, other diabetic medications, blood pressure, cholesterol, and corticosteroid medications as the participant's health improved through lifestyle modification. frequency and type of biomarker tracking, beyond the before-and-after cdt labs, were individualized by the hrp doctor on the basis of care needs and progress as recorded by participants in updated cdas and health coaches in updated hrcps and coaching notes. participants on insulin were contacted at least weekly to assess any potential for hypoglycemia. either the pcp or the hrp doctor made medication modifications. chronic disease assessment: the cda was available electronically through a web browser and included 120+/-questions through a series of shorter surveys, with the participant able to stop and restart the survey at any point where they left off. each question included fixed answer choices from a single option to as many as 30 options depending upon the scope of the question. in some instances, a question allowed for multiple answer selections while in others, only a single response could be recorded. each question/answer combination was given a risk score and assigned one or more attributes of risk based on our study of the medical literature for potential outcomes associated with the specific behavior attribute. the cda included consideration of common risks and disease root causes determined from our own clinical experience and published clinical case studies, population and randomized clinical trials. for example, the cda gave considered to oral health, gut health, eye health status, macro-and micronutrient imbalances, and indications of chronic and occult infection. the output of the cda was a raw score that converted to a letter "grade" reflecting the extent of the risk "portfolio" determined by the assessment. each letter grade, a-f, spanned a range of raw scores. the purpose of the letter grade was to convert a numeric value into a more meaningful and recognizable risk level. in addition, the software interface outputted an action or a series of actions for many of the question/answer pairs, through if/then/else logic. the actions are those known or believed to lead to a reduction in that risk based on peer-reviewed published studies or our own experience. the actions are bundles of content that explain the risk or potential risks and offer suggestions to ameliorate the risk. all this content was made available to participants through their health revival dashboard (hrd). example questions from the cda are provided in figure 2 . chronic disease temperature: routine labs and the cdt biomarker panel were drawn at the on-site clinic by non-hrp technicians working for the primary care provider company. the labs drawn on each individual and the thresholds for chronic health considerations are described elsewhere [20] . in summary, reference intervals were not used to determine health status and risk. instead, our team of biostatisticians reviewed the medical literature to determine the threshold level or levels for each biomarker, they indicated a statistically significant increase in early mortality associated with that marker. each marker was assigned escalating risk based on log-linear curve fitting to published information on mortality risk and biomarker raw value. many of the cdt biomarkers are common biomarkers with some being less commonly obtained in usual care. the ordering doctor of record was held responsible for ensuring any participant with an abnormal lab value, based on usual care reference intervals, notified the participant and arranged for appropriate care to correct the abnormal value. the "tighter" thresholds used as part of the cdt labs were used only by the hrp doctor and not used for making a medical diagnosis. instead, this more sensitive scale of normal vs abnormal lab values was used to measure changes in participant's physiology concomitant with lifestyle changes. this more sensitive scale for each biomarker and the overall cdt value, helped assess participant's health trends by recognizing that disease is not an on/off switch, but rather a continuum. for example, and hba1c level of 6.3%, although not a diagnosis for type 2 diabetes, is a strong indicator of future type 2 diabetes. a goal value of < 5.0% was established for all participants to optimize insulin sensitivity and avoid future diabetes risk, assuming that value was obtained through lifestyle improvement and not pharmaceutical intervention. this logic was applied to all cdt markers. the interventions affected by the hrp through the hrcp were individualized to each participant and included a consideration of the participant's readiness to change and the likely sustainability of any given change as determined by their responses to chronic disease assessment questions and discussions with their health coach. the intensity of coaching was predetermined, but not fixed, by the cda grade. the coaching time allotted to each participant based on the cda grade is provided in table 1 . doctor time allocation was approximately 1/10th coaching time. the main risk considerations were a reduction in inflammation through: more movement, increased nutrient density of foods, improvement in digestion/absorption by improving gut balance and activity, increasing probiotic and prebiotics foods, elimination of high glycemic foods, better oral health maintenance, increased intake of healthy fats and omega-3 fatty acids, increased micronutrients to support hormone production, stress reduction, brain health through reducing whole-body inflammation, and consumption of greater amounts of fat-soluble vitamins, as examples. no specific nutrition program was recommended to the participants as a whole. instead a simple process of substitution of one food, considered of low nutrient value for another of higher value, was made as recommended by the health coach. recommendations were made on an individualized basis based on participant preferences, to affect a gradual and sustainable change from the standard american diet (sad) that was prolific throughout the cohort, to a new food consumption pattern with increased micronutrient density, fiber, and fat with less carbohydrate and sugar consumption. short term (one to three months) nutritional ketosis was suggested for a few highly insulin resistant and diabetic patients but no participants fully achieved nutritional ketosis during the nine-month period. however, these participants achieved a significant reduction in total carbohydrate consumption with a shift to low glycemic index food and those containing higher concentrations of marine, monounsaturated, and saturated fats. supplements were provided as part of the program and compliance with supplementation was near 100% based on self-reporting and resupply orders. at the outset of the program, after evaluation of cdt labs, cda reported dietary information, and food journals, the participants were provided any or all of the following supplements based on individually assessed deficiencies: multivitamin/mineral (1 qd); vitamin d3 (2000-10,000 iu, qd); cod liver oil (5-15 g, qd); magnesium glycinate ( 100-400 mg, qd); vitamin k2 (50 mcg, qd); probiotic (20-70 billion organisms, qd). supplements were provided only when deemed appropriate by the hrp doctor and were phased in then phased out over the nine-month period as the doctor determine that nutritional deficiencies or insufficiencies were being mitigated by the program. the purpose of the supplements was to quickly overcome apparent nutritional deficiencies. as part of the hrcp, foods that contained nutrients provided by the supplements were recommended and, when adopted, enabled the gradual elimination of supplementation without compromising nutritional needs. the main behavioral change strategy, executed by the doctor and coach care team, was to slowly and gradually ease a participant into change. the frequency of coaching sessions, dictated by the need of the participant (cda letter grade), including their burden or disease and risk, and their motivation, was adjusted to improve compliance. most participants suffered from some health ailment that impacted their daily wellbeing. improvement in general wellbeing, which started to be noticed by participants by the end of month 1, provided the motivation to continue to adopt gradual modifications to lifestyle. to help participants understand that the hrp is not a quick fix, our coaches explained that we have determined a general "rule of thumb" for the time required to improve health significantly. if a disease, like diabetes, has been slowly developing over five years, it will take at least five months of effort to reverse the disease, assuming the interventions are appropriate. outcome measures: in-clinic vital signs, health risk assessment (cda) risk score and list, and biomarkers were obtained at baseline and at the end of the 9-month program. problems, complaints and medications were reconciled at each health coaching and doctor encounter. fasted and non-fasted blood draws were obtained by clinic pcp staff using routine procedures. samples were provided to and analyzed by quest diagnostics using standard operating procedures. primary outcomes were: changes in biomarker values; risk scores; reported diagnoses; vital signs; weight; and medication use. secondary outcomes included reported complaints, for example, lack of energy, chronic pain, sleeplessness, mood issues, and general lack of wellbeing. the baseline demographics of the final 70 hrp participants are presented in table 2 . all participants were caucasian of european heritage. at baseline, 96% of hrp participants were actively taking pharmaceuticals for a medical problem and 98% were diagnosed with at least 1 chronic condition. this reflects a substantially higher percentage of chronically ill individuals compared to the u.s. national average of 60% of u.s. adults having at least one chronic condition. on average, the group was taking 2.3 prescriptions per person. the major class of medications included: diabetes medications, injectable insulin, statins, blood pressure lowering, pain, mood (ssris), bisphosphonates, steroids, thyroid hormone, and proton pump inhibitors. the final participant number of 70 was established after 10 left the program. two were dismissed from the program for compliance reasons, four left early to join a weight loss program, two left because of the time commitment, and two left due to potential interactions between current medications and supplements as encouraged by their pcp, for a total of 12.5%. there was no clear demographic trend between those who remained in the program versus those who dropped out. chronic disease assessment™ (cda): on average, the 70-participant cohort lowered their cda score by 31 points (27%) from a raw value of 115 to a new value of 84 over six months. each point lowered reflected a reduction in a disease risk or resolution of a health problem or complaint. risks were scored on a 1-10 scale, with 1 representing a minor risk or problem and 10 representing a major risk or problem. the initial population cda grade was d+, assigned based on a range of raw numeric scores calculated from the survey, and the final grade after 6 months of the hrp was c+. ninety-four percent of the group experienced an improvement in their risks while 6% of the cohort experienced a worsening of their cda grade ( figure 3) . participants did not have their initial cda answers to refer to when they retook the assessment six months into the program. chronic disease temperature™ (cdt): on average, the 70-participant cohort lowered their cdt score from 102.1 to 100.8. the cdt is based on a 7 "degree" scale calculated by adding the risk contribution from each biomarker to 98.6 to arrive at the participant's cdt. the average chronic disease risk reduction in cdt was 39% (figure 4 ). all 6% of participants whose cda grade worsened also experienced an adverse change in their cdt score. three participants improved their reported cda grade but witnessed an adverse change in their cdt. the cdt included several markers that are classified as "acute phase" reactants. in "acute-phase proteins and other systemic responses to inflammation," the authors explain that markers of chronic systemic inflammation are also subject to change acutely [21] . for example, c-reactive protein elevates during the acute phase of pneumococcal pneumonia. c-reactive protein has an acute phase relaxation half-life of approximately one day upon removal of the insult whereas the half-life of fibrinogen is about one week. two of the three participants with an improved cda but worsened cdt experienced adverse physiological changes due to documented acute circumstances. retest was not available during the nine-month program to confirm our suspicion about the cause of the elevation. one recently underwent surgery and was recovering slowly. another participant was receiving ongoing treatment for a complex acute condition managed by the patient's pcp. other participants whose cdt worsened were in the hrp and a calorie-restricting weight loss program administered by third parties. the weight loss program was calorie counting-based with no guidance provided on macro and micronutrients. these individuals, although in the hcp, were less flexible to our coach's dietary suggestions because of the calorie restriction. for example, a participant refused to take cod liver oil because each capsule contributed approximately 10 calories to their daily calorie allotment. our results demonstrated, in this small subgroup, that people in poor health and with a highly elevated cdt, confirming their health status objectively, may be contraindicated for a sustained calorie restriction program without nutritional guidance. although the literature is rich in studies suggesting that calorie restriction improves lifespan and reduces inflammatory markers, emerging studies emphasize that calorie restriction must be implemented without malnutrition that comes from low nutrient-dense foods processed foods. macro-and micronutrient intake of all participants was monitored with a food journal. worsening in cdt markers in people on a calorie-restricted diet correlated to micronutrient malnutrition exacerbated by reduced total calorie intake. malnutrition status was established in these individuals by determining their daily nutrient recommendation from the dri calculator for healthcare professionals provided by the usda and comparing the results to nutrients consumed based on available nutritional labels for foods consumed. there are numerous studies on the association between lifestyle behaviors and chronic disease risk. in large prospective studies, like the nurses' health study, vague conclusions are made about the association of smoking, regular physical activity, maintaining normal body mass index, eating a healthy diet and chronic disease proliferation [22] . the individualized cda risk values potentially increase the precision, personalization, and accuracy of risk-to-disease relationship measurement. figure 5 provides a view of the change in the cda risk score and its relationship to the cdt value for the biomarker panel at the beginning and end of the 9-month hrp program for the entire population. the same data are presented in figure 6 as bubble chart with the before and after data superimposed on the same scale. temperature score) before and after six months of the hrp program notable is the reasonably smooth relationship between the two risks scores, the subjective cda and the more objective cdt. we conclude, from these data, reducing the most basic health risks, over time, may lead to a reduction in cytokine burden with often concomitant change in diagnosed chronic diseases. increasing the "n" in our database and making appropriate adjustments to assigned subjective risk values within the algorithm offers the potential to improve the correlation between determinants of health risks and physiological health status. the individualized statistics for the cda, cdt, and biomarkers comprising the cdt to evaluate participants health and risk are provided in table 3 . score mean before mean after mean difference standard deviation t test value cdt is the chronic disease temperature biomarker score as a relative value with 98.6 considered optimal and elevated values indicating chronic risk; hba1c is expressed as a %; glucose is expressed as mg/dl; nlr is the neutrophil to lymphocyte ratio; hs-crp is high sensitivity c-reactive protein or c-reactive protein, cardiac expressed as mg/l; insulin is expressed as uiu/ml; hdl is expressed as mg/dl; triglycerides are expressed as mg/dl; vitamin d is expressed as ng/ml; uric acid is expressed as mg/dl; wbc is the white blood cell count expressed as cells/ul; rdw is the red blood cell distribution width expresses as a %; ab neutrophils are neutrophils (absolute) expressed as cells/ul; esr is the sedimentation rate-westergren expressed in mm/hr; fibrinogen is fibrinogen activity expressed as mg/dl; homocysteine is expressed as umol/l; and aip is the atherogenic index of plasma expressed as the log(triglycerides/hdl) glycosylated hemoglobin (a1c): a1c, a 120-day retrospective average of blood glucose, contributes to an assessment of metabolic risk along with fasting glucose and insulin. a current therapeutic goal in usual care is to lower the a1c value of diabetics, those with a1c values above 6.4%, with pharmaceuticals. the accord study shows that tight pharmaceutical control of blood sugar in those with severe insulin resistance suffer a significant increase in adverse cardiovascular events and mortality compared to those with less tight control [23] . lifestyle interventions offer another approach to glycemic control and does so without risk of hypoglycemia and other side effects of the pharmaceutical approach. in the cohort of 70, none had optimal a1c levels, defined as 4.2%-5.2%. even a 0.5% increase in a1c above 5% increases the 6year risk for diabetes (odds ratio >1.5) and the risk of diabetes increases exponentially with a1c. in the 70participant cohort, at the end of the hrp, 98% (all but 1) lowered their a1c value ( insulin is the most sensitive marker for early metabolic risk because it increases first as an individual becomes insulin resistant. even values slightly above normal, and well below a diagnosis of diabetes, contribute to serious chronic diseases in the future, including alzheimer's and cardiovascular disease. type 2 diabetes is associated with increased risk of cancer. hyperinsulinemia (elevated insulin levels) and insulin resistance are apparently the link. in a 15-year mortality study, individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality and a 161% higher risk of gastrointestinal cancer mortality [24] . the authors of this study concluded that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and metabolic syndrome. in the 70-person cohort, 38 participants (54%) were at elevated metabolic and associated chronic risk. six of the 38 (16%) experienced a double digit drop in fasting insulin, 8 of 9 (89%) dropped from the high-risk category to a lower risk level, 17 (52%) lowered insulin levels sufficiently to reduce their cancer risk severity category, 11 (33%) changed little and stayed in the same risk category and 2 move up one risk category ( [25] . in the 70-person cohort, 56% of participants who were at high risk for cardiovascular disease, based on hs-crp level >5, lowered that risk ( table 6) . [19] . the aip average value before the hrp was 0.26 and lowered to 0.20 at the end of the hrp. conventionally the rdw test, which is a part of a complete blood count, is used to help determine anemia status. however, it is also a marker of inflammation and often tracks with crp. red blood cells elongate and deform when flowing through capillaries, which may explain the association between red blood cell widths, vascular inflammation, and increased cardiovascular morbidity and mortality. in the 70-person cohort, 92% of participants at elevated risk for cardiovascular disease based on rdw levels lowered their risk ( table 7) . white blood cell counts (wbc) is a predictor of strokes, heart attacks, and fatal heart disease. in the women's health initiative involving 72,242 women from 50-79 years of age, those with approximately 6,700 white cells per ml had more than double the risk of fatal heart disease than women with 4700 cells per ml [26] . white blood cell counts in the normal range for acute indications are now more widely recognized as a predictor of adverse chronic outcomes. in the 70-person cohort, three individuals had high cardiovascular disease risk based on wbc levels, and 100% lowered that risk through lifestyle modifications. in addition, 54% of those with moderate risk moved to either low or very low risk as assessed by risk quartiles for wbc. in general, 80% of participants moved from a high to a lower risk status ( table 8) . multiple studies show a significant inverse relationship between 25-hydroxy vitamin d (d3) status and cancer mortality. in a fifteen-year study of nearly 50,000 participants, an increment increase of 10 ng/ml was associated with a 17% reduction in total cancer incidence, 29% reduction in total cancer mortality and statistically significant reductions in colorectal, pancreatic, esophageal, oral, and pharyngeal cancer mortality [27] . for cancer, optimal d3 levels are above 55 ng/ml. at the start of the program, eight participants had optimal levels and that number increased to 35 by the end of the program. insufficient vitamin d, as defined for bone health are values below 30 ng/ml. initially there were 14 participants insufficient for blood d3 and none were insufficient at the end of the program. the population d3 levels went from 38 to 60 ng/ml, on average, by the end of the hrp. these data indicate a high degree of compliance with the program recommendations as the increase in d3 status was largely attributable to consistent supplementation. in general, the increase observed required daily supplementation of 5000 iu d3 daily ( table 9 ). the neutrophil-to-lymphocyte ratio (nlr) is reported to be a robust outcome prognosticator in existing solid tumor cancers. in a study on breast cancer, patients with an nlr > 3.3 had substantially higher oneyear and five-year mortality rates compared to those with an nlr < 1.8. the nlr value has similar predictive ability for cardiovascular mortality [28] . in the cohort of 70, 20 had nlr above the threshold for adverse cancer outcomes. sixteen of 20 (80%) saw their nlr ratios return to very low risk (normal values) by the end of the program ( and associated changes to cancer and cardiovascular mortality prognosis medication prescription reduction was achieved as part of the outcome measurement. the cohort experienced a 32% reduction in medication usage, reduction in dose in 8%, and an avoidance of two costly medications. the prices included in table 11 , below, where the actual pharmacy costs realized by the health plan and did not include any co-pay. the cohort experienced a reduction in chronic disease burden. chronic disease reduction was determined by changes in any of the following: actual change to a medical diagnosis, elimination of a medication associated with an existing diagnosis, changes in a vital sign that indicated a migration out of a diagnosis that was affected without the use of a medication, or change in a biomarker value or values that were initially used to make the diagnosis into a "normal" range without the use of medications (table 12) . this participant presented with major risk factors and complaints including lack or exercise, fast food diet, high carbohydrate diet, daily high fructose corn syrup containing beverage consumption, use of omega-6 containing oils in cooking, statin drug daily prescription for primary cardiac event prevention, severe arthritis, psoriasis, and cataract. the severity of the psoriasis and her job function put her at risk of imminently going on disability. she had seen multiple specialists, was placed on antihistamines and topical steroids but her psoriasis condition continued to worsen. the next treatment option for her was to be etanercept which she declined pending the outcome from the hrp. she indicated that she had not washed her hands without pain in over a year. the hrp included 45-minute semi-monthly health revival coaching following the participant and care team agreed upon care plan. cholesterol-lowering drug usage was eliminated in the first month as directed by our medical director. health coaching focused mainly on food substitutions, increasing activity, value and use of supplements, a limited set of supplements, and additional care to her oral hygiene. after six months of intensive health revival coaching, many risk factors and complaints, revealed on her cda report, were either removed or reduced including nagging chronic pain. her main complaint, debilitating psoriasis slowly, but completed resolved in five months ( figure 7) . however, the first signs of improvement in her psoriasis condition did not appear until month 4 of the program. normally, in the case of autoimmune diseases like psoriasis, food sensitivities or allergies must be addressed. this participant was unwilling to eliminate some of the common allergens like gluten and dairy. she was placed on a modest supplement regiment based on nutritional deficiencies determined from food journaling, including: cod liver oil (5 g/day); vitamin d3 (5,000 iu/day) and a multivitamin/mineral supplement (taken per label instruction), and the other general supplements included in the "methods" section. positive changes in lab values included: 25-hydroxy vitamin d status (24 to 55 ng/ml); white blood cell counts (6,200 to 5,500) ; rdw (14.6% to 13.0%); and fibrinogen (339 to 282 mg/dl). case 2: rheumatoid arthritis and type 2 diabetes -62-year-old male factory worker with a high school education (table 14) . over the first five months, the participant lost 25 pounds through a reduction in carbohydrate consumption, but with no significant change in daily calorie intake. the participant embarked on a substitution diet where, over five months, gluten-containing foods were removed from his diet and replaced with vegetables and marine-and animal-based fats. he was also put on a modest supplementation program including cod liver oil (10 g/day); vitamin d3 (5000 iu/day); magnesium glycinate (400 mg/day); vitamin k2 (50 mcg/day) and a multivitamin/mineral (per label instruction). his type 2 diabetes was reversed as illustrated by his a1c dropping from 8.8% to 5.4% and his fasting glucose dropping from 180 to < 90 mg/dl. his pain was substantially eliminated, based on a subjective pain score of 8/10 initially, to 0/10. his ra improved to enable him to be able to bend his fingers into a full fist for the first time in over five years (figure 8 ). this participant reported with a severe autoimmune disease, polychondritis, that produced monthly painful flares in cartilage above her shoulders including her ears and eyes. long-term use of steroidal antiinflammatories were implicated in the cataracts and a breast lump that was removed surgically. the cataracts had progressed sufficiently to cause her to be on disability and be unable to drive a car. cataract surgery was not an option due to the severity and unpredictability of eye flares that could cause extremely adverse outcomes if they coincided with surgery. she had seen several specialists including local rheumatologists, natural doctors, and doctors from cleveland clinic with no relief to her condition. she had researched polychondritis on her own, prior to joining this program and eliminated gluten and dairy from her diet but this change did not alter the disease severity or frequency. this participant had made significant changes in her lifestyle prior to this program as reflected in her cda grade, but these changes were insufficient to improve her blood biomarkers indicated by the high cdt value of 104.1, indicative of serious health risk and poor prognosis. our health revival process guided her to continued better choices and involved semi-monthly 45-minute lifestyle coaching. the main changes made over a six-month period included: increasing healthy fats, reducing carbohydrate intake, increasing micronutrient density, stopping nicotine dependence, improving digestive health with optimizing food choices including increasing stomach acid status, and repopulating gut microflora. at month 6 in the program, her eye and ear flares had subsided sufficiently to allow for a meaningful reduction in eye and oral steroids, (50 mg/day to 5 mg/day prednisone). in addition, she was able to have successful cataract surgery which enable her to start driving again, and return to work, both of which were curtailed over one year. the polychondritis may never be cured, however, with appropriate lifestyle management, it is no longer impacting her quality of life. prevention and reversal of chronic and non-communicable diseases continue to be a largely unmet need. a fresh approach is clearly warranted to curb this global scourge. one impediment is the lack of precision and personalization of risk with "poor diet" as an example. and there is a lack of measurement of a broad array of minor, yet important, risks that can easily be overcome. the same suite of risks is continually presented to individuals who historically have not been able to modify or overcome them, with smoking or alcohol consumption as examples. according to khullar in, "we're bad at evaluating risk, how doctors can help," a broader approach involves helping patients systematically identify what's important to them, and based on these goals and preferences, suggesting to them how to think about their options [29] . this logic is best applied across the entire time-line that defines the slow and insidious development of chronic disease. it starts with lifestyle decisions and habit development early in life that perpetuate into mid-life and then into old age. measurement and a proper medical "workup" regardless of presumed health status is a key strategy and potential motivating factor that is currently lacking. changes in chronic disease biomarkers in asymptomatic people may afford an early warning sign of stealth changes to which many may respond. pathology changes, identified with advanced diagnostics, which generally develop after a long incubation period detectable with proper biomarker evaluation, may facilitate change in the more recalcitrant. each individual has their own motivations. thus, providing patients with an array of choices and recommendations along the health/disease continuum has a higher probability of inciting action and improving outcomes or preventative actions. this study evaluated a new population risk and health assessment and mitigation system where measurements of risk and disease were made across the disease continuum by using finely tuned biomarkers and risk assessment. the output was a broad-reaching care plan assembled through integration of current health survey results, biomarkers, problems, complaints, medications, vital signs, verbal input from the participant to the health coach, and contributions from the care team. the remediation path to improved health developed as a consensus between the participant and care team, of agreed upon steps and actions, that were malleable as the process moved forward. adjustments were made based on participant preferences, success and failures, a solid health data. according to khullar, "patients need to understand their values but also their possible futures. the idea is not to reduce uncertainty, but to help patients clearly envision what life would look like in one outcome versus another, and to better prepare them for the various futures that might unfold." this program was designed to give participants options beyond the management of disease once it has struck. and it included regular monitoring and concomitant course adjustments to help participants attain their goals. this study prospectively observed adults with chronic conditions and unresolved health complaints that remained unresolved under usual care management and treatment. following six months of hrp, participants achieved subjective and objective improvement in health status with 90% seeing a reduction in multiple blood-based biomarkers and 94% achieving a reduction is a broad measure of determinants of health risk factors. concurrently participants reported weight loss (34% of the total and 80% of those with a reported weight loss goal), reduction in reported pain, sleeplessness, memory issues, heartburn, skin rashes, migraines, and daily fatigue. the diabetics in the program had all progressively worsen over the previous two years, as measured by fasting glucose, hba1c, and medication usage and all improved under the hrp program. hrp meaningfully improved hba1c, fasting insulin, neutrophil-to-lymphocyte ratio, hs-crp, vitamin d, white blood cell counts, red blood cell distribution width, absolute neutrophils -all part of the cdt panel. in addition, hdl, fasting glucose, triglycerides, gfr, atherogenic index of plasma (aip) liver enzymes, and blood pressure improved is most participants with initial abnormal values. aip is emerging as a valuable representation of increased mortality risk. improvement in this lab value ratio was consistent with previous studies using carbohydrate-restricted interventions. however, although the hrp included some level of carbohydrate restriction, this was not a mandate and carbohydrate consumption goals were not set. instead, participants were afforded broader options that met each at their level of readiness to change and did not overwhelm anyone with unachievable objectives. in general, small swap-out suggestions were agreed upon at each encounter. the "pure" study reports are a set of studies that describe components of the nutritional approach used in the hrp. in "fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (pure): a prospective cohort study," fruit, vegetable and legume consumption recommendations were 375-500 g/day to achieve maximum benefit at reducing non-cardiovascular and total mortality [30] . the hrp coaches encouraged consumption of three to four servings of these foods per day, focusing on lowest glycemic index choices. in "associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (pure): a prospective cohort study," healthy fats were found to be indicated for a reduction of total mortality risk and saturated fats were shown to be inversely associated to stroke risk. the hrp coaches guided participants to swap out carbs, sugars, and some protein in favor of healthy fats in foods and cooking oils with emphasis on increasing saturated, mono-saturated, and marine fats. obtaining nutritional ketosis for a two to three months window was suggested for all the diagnosed type 2 diabetics; however, none achieved sustained ketosis but their metabolic markers indicated improvement of their diabetic conditions during the 6-month hrp. this suggested that the broader, more personalized risk reduction approach of this hrp, compared to strict carbohydrate restriction, affords metabolic profile results without the potential risks associated with carbohydrate starvation in insulinresistant subjects. reducing whole body inflammation was the primary objective of each encounter, not just reducing the glycemic value of food. examples included switching out proinflammatory for anti-inflammatory cooking oils, lowering glycemic value and load of substituted foods, reducing frequency of fast food consumption, improving oral hygiene, managing stress, establishing better sleep and rest patterns, enhancing hydration, improving micronutrient density of foods consumed, establishing more frequent movement routines, and consuming more gut-supporting foods. the regular health coach encounters that included reviewing risk factors, vitals, and medication usage, with doctor supervision, may have provided behavior reinforcement. further, it is plausible that this multi-risk amelioration care model allowed from both broader and greater adoption and improvements compared to interventions focused on fewer factors. in this hrp we effectively leveraged credible measurement and evaluation, linked these findings to participant's unresolved and nagging health complaints, and facilitated behavioral change leading to health improvement in most participants. the program did not rely only on usual care measures of health. participants were not confronted with high hurdles to health improvement that often discourage engagement. instead, the program centered around meeting a person at their level of readiness and capitalizing on small triumphs that eventually led to measurable health improvements recognized by the individual that led to a cycle of improvement rather than deterioration. no episodes of adverse events were attributable to the hrp. one insulin-dependent type 2 diabetic participant showed a sudden increase in fasting insulin, from 1.8 to 53 μu/ml, which was reported to his pcp for medication adjustment. several participants reported dizziness and either the hrp or pcp lowered their blood pressure medication dose that, in all cases, resolved the complaint. prior studies have demonstrated favorable cost reductions in broad-based wellness and disease management programs. most of the cost-saving and health maintenance were attributed to the management of existing disease rather than prevention and required a strong evidence-based approach. a strength of this hrp was an emphasis on root-causes of and reversal of disease rather than just case management. additionally, this study reflected a real-world workplace environment with a distribution of both white-and blue-collar workers participating and with a range of diseases and aliments. weaknesses included a lack of a representative control group, single location and participants were mostly caucasian. the study was not of sufficient size and duration to measure hard endpoints including mortality and adverse health events. future studies of this nature could include multisite randomized controlled trials with greater racial and ethnic diversity, and longer duration. this highly personalized and scalable health revival study protocol demonstrated that a broad array of chronic health complaints and problems can be controlled and reversed by methodically eliminating seemingly small lifestyle-induced health risks. it also demonstrated that the lifestyle risk tool, the chronic disease assessment™, and the biomarker panel, the chronic disease temperature™, that were used to develop care plans, changed in correspondence with participant-and medical staff-reported health improvements. therefore, these tools may be valuable for the measurement and mitigation of chronic disease risk and chronic diseases generally. importantly, the implementation of this program is low cost, using inexpensive on-line survey tools, biomarkers, and health coaching. additionally, this program is well suited to be implemented in large populations through surveying, obtaining labs through national networks, and performing group coaching sessions based on common risks identified through the risk assessment tool. more studies using this overall hrp approach are required to validate the measurement methods, processes, and outcomes. this approach offers a potentially important health delivery modality in a world with escalating chronic disease morbidity and mortality. acquired in strict conformance with health data privacy laws by medical personnel and stored and managed in a hipaa compliant emr. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. global status report on noncommunicable diseases. world health organization (ed): world health organization the us health disadvantage relative to other high-income countries: findings from a national research council/ institute of medicine report heart disease strikes back across the u.s even in healthy places multiple chronic conditions in the united states consistently high turnover in the group of top health care spenders the cytokine storm and pre-cytokine storm status in covid-19 -a model for managing population risk for pandemics and chronic diseases association between platelet parameters and mortality in coronavirus disease 2019: retrospective cohort study. platelets. 2020 disease control priorities in developing countries. 2nd edition. the international bank for reconstruction and development/the world bank global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the global burden of disease study effects of health literacy on health status and health service utilization amongst the elderly is patient activation associated with future health outcomes and healthcare utilization among patients with diabetes lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines use of framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study stress and the individual: mechanisms leading to disease . arch internal med network theory of aging meeting physical activity guidelines is associated with lower allostatic load and inflammation in mexican americans multiple biomarkers for the prediction of first major cardiovascular events and death atherogenic index of plasma and triglyceride/high-density lipoprotein cholesterol ratio predict mortality risk better than individual cholesterol risk factors, among an older adult population quarterback your own health -how to take and lower your chronic disease temperature acute-phase proteins and other systemic responses to inflammation diet, lifestyle, biomarkers, genetic factors, and risk of cardiovascular disease in the nurses' health studies the association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the accord study insulin resistance/hyperinsulinemia and cancer mortality: the cremona study at the 15th year of follow-up rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity c-reactive protein: rationale and design of the jupiter trial leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the women's health initiative observational study prospective study of predictors of vitamin d status and cancer incidence and mortality in men the predictive value of elevated neutrophil to lymphocyte ratio for long-term cardiovascular mortality in peripheral arterial occlusive disease we're bad at evaluating risk. how doctors can help . the new york times fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (pure): a prospective cohort study the authors thank the invaluable assistance of dr. michael l. carter, dr. trent austin, and jasmin lewis 2020 human subjects: consent was obtained by all participants in this study. neco irb issued approval 7669t.the neco irb has approved this study as it was conducted in conjunction with routine clinical practice. all procedures performed in the program involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. ethical oversight was provided by the existing primary care doctors who were not part of the program. informed consent, medical releases, and participation contracts were obtained from all participants included in the program. these documents were completed after each participant was provided detailed information about the program. all data was key: cord-318061-xe8lljz0 authors: overgaauw, paul a.m.; vinke, claudia m.; van hagen, marjan a.e.; lipman, len j.a. title: a one health perspective on the human–companion animal relationship with emphasis on zoonotic aspects date: 2020-05-27 journal: int j environ res public health doi: 10.3390/ijerph17113789 sha: doc_id: 318061 cord_uid: xe8lljz0 over time the human–animal bond has been changed. for instance, the role of pets has changed from work animals (protecting houses, catching mice) to animals with a social function, giving companionship. pets can be important for the physical and mental health of their owners but may also transmit zoonotic infections. the one health initiative is a worldwide strategy for expanding collaborations in all aspects of health care for humans, animals, and the environment. however, in one health communications the role of particularly dogs and cats is often underestimated. objective: evaluation of positive and negative one health issues of the human–companion animal relationship with a focus on zoonotic aspects of cats and dogs in industrialized countries. method: literature review. results: pets undoubtedly have a positive effect on human health, while owners are increasing aware of pet’s health and welfare. the changing attitude of humans with regard to pets and their environment can also lead to negative effects such as changes in feeding practices, extreme breeding, and behavioral problems, and anthropozoonoses. for the human, there may be a higher risk of the transmission of zoonotic infections due to trends such as sleeping with pets, allowing pets to lick the face or wounds, bite accidents, keeping exotic animals, the importation of rescue dogs, and soil contact. conclusions: one health issues need frequently re-evaluated as the close human–animal relationship with pet animals can totally differ compared to decennia ago. because of the changed human–companion animal bond, recommendations regarding responsible pet-ownership, including normal hygienic practices, responsible breeding, feeding, housing, and mental and physical challenges conforming the biology of the animal are required. education can be performed by vets and physicians as part of the one health concept. the one health initiative or concept is a worldwide strategy that recognizes that public health is connected with animal health and the environment. it concerns multidisciplinary collaboration between physicians, veterinarians, environmental scientists, public health professionals, wildlife experts, and many others [1, 2] . with a multisectoral and transdisciplinary approach, public health threats can be better monitored and controlled. the resulting synergism enhances the knowledge of how diseases, known as zoonotic diseases, can be shared between animals and people with the goal of this article is based on an existing post-graduate course for veterinarians, vet technicians, family doctors, midwifes, and specialists such as pediatricians which explores healthy human-animal relationships. the existing evidence-based knowledge contained in this course has been actualized by performing a literature search to add new relevant publications. a literature search was conducted through 2 march 2020, using the national library of medicine's pubmed for the terms "one health" and "companion animals"; "pet ownership"; "households" and "pets"; "dogs" or "cats" or "pets" and "mental" or "physical health" or "children"; "animal assisted therapy"; "dogs" or "cats" and "nutritional problems" or "overweight" or "obesity" or "homemade" or "raw meat diets"; "dogs" or "cats" and "behavior problems" or "aggression" or "fear" or "anxiety" or "abnormal repetitive behavior"; "dogs" or "cats" and "breeding" or "genetic problems"; "dogs" or "cats" and "zooanthroponoses"; "pets" and "anthropomorphism"; "dogs" or "cats" or "exotic animals" or "rescue dogs" or "soil" and zoonoses. for some topics the internet was accessed and used as reference if additional information was not available as scientific publication. the authors selected articles that described pivotal and novel insights in the different topics. all searches were carried out without filters. the titles of all found articles were screened for relevance to the topic, and appropriate titles were assessed and selected based on their abstracts. if a selected article was a review, it was read and relevant citations were used to find primary literature on the subject. additional studies were found using the bibliographies of selected articles. occasionally, reviews were directly used as sources, mostly to convey background information that is not in the core focus of this article. original articles in english and different national languages (dutch, german, french, spanish, if available) were included. specific searches were made for citations dated after the year 2000 to ensure more recent literature on the topic had not been missed. a pet or companion animal is an animal that lives in or around the house and is fed and cared for by humans. until the 1960s, pets were mainly kept as utility animals, for example as draft dogs or watch dogs or for pest control when it comes to cats. due to major changes that have taken place in society since the second world war, such as increased leisure time and prosperity, but also individualization of humans, animals are nowadays kept as pets and are regarded by many owners as valued family members, e.g., over 90% in the united kingdom [13] . pet ownership is still increasing in many industrialized countries and these animals are more often considered a member of the family [5] . even in china, a country where pets were banned in urban areas until 1992, pet ownership has grown quite rapidly in the major cities. the rate of pet ownership of all usa households increased from 57.6% to 59% in 2018. dogs continue to dominate in popularity among american households. approximately 38% of households nationwide owned a dog, bringing the population of pet dogs to nearly 77 million, while 25% of households owned cats, with a total population of 58 million [14] . in 2018, an estimated 80 million european households owned at least one pet animal; 24% of households owned dogs and 25% owned cats [15] . there are 85 million pet dogs and 104 million pet cats in europe which is a 15% increase of dogs within 8 years (74 million dogs in 2010) and a 22% increase of cats (85 million in 2010) [16] . pet cats in europe thereby are more popular than dogs. an explanation of the higher popularity of cats may be the number of single-person households in the eu that rose on average by 2.0% per annum between 2006 and 2016 to 32.5%, and the growth of two-family households grew by 1% to 31% in this period [17] . also, dual-earner families are widespread as a result of quite a steep growth in female employment over the past two decades [18] . when animals live with humans, they too benefit from human interaction. over the past decades, animal welfare has evolved to recognize that animals are sentient beings capable of experiencing positive and negative emotions. the social and ethical dimensions of animal welfare, which are concerned with how human society morally regards and treats non-human animals, are also increasingly being recognized [19] . in dutch law, the intrinsic value of kept animals is expressly incorporated and used as a guiding ethical principle that forms the basis of any further legislation. the intrinsic value is thereby defined that animals are sentient beings that can feel pain and discomfort. therefore, they should be kept free of stress, pain, disease, hunger, thirst, and should be able to show natural behavior known as the five freedoms of r. brambell 1965 [20] . in industrialized countries animal keepers, their owners, are legally required to provide such circumstances and can be prosecuted if they infringe the law. of course, in the field there is animal abuse, negative animal welfare conditions, and animal diseases. however, in general, caretaking for companion animals is nowadays performed at a high level. new insights into animal behavior has had its influence on the general public. for example, owners are aware or are told by vets and pet shops that rabbits should not be kept alone but at least in pairs due to their need for social contact [21] . there are various reasons to keep pets, such as love, warmth, and companionship. companion animals have an important emotional value, and promote the socialization of the lonely elderly because they facilitate additional contact with people. pets form a goal in life, reduce stress, and ensure that the owner keeps physically active. around 95% of dog owners and 93% of cat owners expressed that owning their pet makes them happy and 44% of owners selected this as one of the reasons they got their pet in the first place [22] . however, the function of companion animals consists of more than just providing a socializing being. studies show other benefits of having a pet, such as the positive effect on individuals' mental and physiological health status. most research addressing the health benefits of pet ownership show reductions in distress and anxiety, decreases in loneliness and depression, and increases in physical condition [23] . the positive benefits to human health from interacting with animals, focusing on the companion animal, have also be described with the term "zooeyia" [24] . in fact, 63% of owners agreed that having a pet makes them physically healthier, with dog owners more likely to agree, most probably because dog owners exercise more (85% agreeing, compared to 41% of cat owners). besides, 84% of owners agreed that having a pet makes them mentally healthier. expressed reasons are the non-judgmental nature of their pets, their playfulness, or physical contact [22] . another demonstrated positive influence is the blood pressure and heart rate lowering effects that occurs when stroking a friendly-looking dog or even being in the presence of a friendly animal, while it is not necessary to own a pet to obtain these stress-moderating benefits [23] . many studies have demonstrated the association between pet ownership and cardiovascular health and dog owners appear to have a significantly greater chance of survival after a heart attack compared to people without pets [25] [26] [27] . pets can therefore play an important role in reducing absenteeism and visits to family doctors or the hospital [28] . it has been estimated that pet ownership saved australia $1 billion in 1994 [29] , while it may reduce the use of the national health service (nhs) in the uk to the value of £2.45 billion per year [30] . dogs also play an increasing role as co-therapist or as supporter for people with psychological or physical disabilities. the benefits of these animal-assisted activities are improved mood, decreased physiological distress, depression, dementia, and loneliness [31, 32] . examples include resident or visiting dogs in prisons, nursing homes [33] , mental institutions, and hospitals where they can reduce patient anxiety in a hospital emergency department [34] , reduce pain perceptions in children after surgery [35] , or calm young patients at a pediatric dental clinic [36] . since dogs have extremely sensitive noses, they are used for several purposes such as tracking, bomb detection, and search and rescue. in recent years, canine olfaction has also been more recognized as a diagnostic tool for identifying pre-clinical disease status, such as diabetes (ketones), different forms of cancer, and infections from biological media samples [37] . animal-assisted therapies can act as co-therapies to facilitate psychotherapy or to provide specific types of therapeutic interventions such as improving motor skills or behavior [23] . such interventions were effective in improving the state of children or adults with or at risk of developing mental disorders such as attention deficit hyperactivity disorder (adhd), post-traumatic stress disorder (ptsd), or autism spectrum disorder (asd) [38] [39] [40] , and for the treatment of ptsd in military veterans [41, 42] . assistance or service animals are trained to perform tasks for the benefit of individuals who have disabilities such as hearing loss, physical disabilities, emotional disabilities, seizure disorders, or diabetes [23] . finally, a wide range of emotional health benefits from childhood pet ownership has been identified, particularly for those suffering from low self-esteem and loneliness. there is evidence of an association between pet ownership and educational and cognitive benefits, increased social competence, social networks, social interaction, and social play behavior [43, 44] . significantly less absenteeism from school through sickness among children who live with pets has also been reported [13] . having a dog or cat in the house during the first year of life may protect against childhood asthma and allergy [45, 46] . it can therefore be concluded that companion animals contribute significantly toward the public health, but also increasingly, the health of individually challenged persons through animal-assisted interventions [47] . providing companion animals with feed by humans, has been considered an advantage for companion animals in their relationship with humans. however, the feeding practices can also have a negative impact on companion animals [48, 49] . obesity in cats and dogs is a disease which is rapidly increasing with significant and lifelong implications for animal welfare. although no universally accepted definition of canine and feline obesity exists, the american veterinary medical association defined obesity being more than 30% above the ideal weight of an animal. overweight is defined as 10%-20% above the ideal weight. using body condition scores, it has been estimated that in the united states, 54% of dogs and 59% of cats are obese or overweight. a study in the united kingdom reported 65% of adult dogs and 37% of juvenile dogs as being obese or overweight [50, 51] . overweight dogs are more likely to be diagnosed with, e.g., urinary tract diseases. obese and overweight dogs are at risk developing orthopedic disorders and hypothyroidism [52, 53] . obese cats are at higher risk for developing urinary tract disease, diabetes mellitus, and neoplasia [54, 55] . other diet-related problems in companion animals can be caused by the changed feeding behavior of humans, e.g., by providing companion animals with bone and raw feed (barf) or vegan diets. risks for companion animals associated with barf or vegan diets are the presence of microbial hazards, insufficient nutrition, and in raw meat diets the presence of risk materials like thyroid tissue. through contact with their animals, it is possible that risks could even develop for owners. there could be an increased risk of human salmonellosis because of the presence of salmonella spp. in the diet which can spread to humans through diet leftovers or by contact with animal feces. recently a review was published on the risks of barf feeding [56] . the authors concluded that the data for the nutritional, medical, and public health risks of raw feeding are fragmentary, but they are increasingly forming a compelling body of formal scientific evidence. publications were found reporting the presence of escherichia coli o157, salmonella typhimurium, campylobacter spp., and antibiotic resistant bacteria in the feed. nutritional problems, such as calcium/phosphorous imbalances and specific vitamin deficiencies [57] are also reported. moreover, homemade diets are inherently susceptible to nutritional imbalances and deficiencies [58] . awareness about climate change, public health and animal welfare has incited a major change in dietary choices among many individuals. the number of vegans in the world keeps growing, even quadrupling from 150,000 to 600,000 individuals between 2014 and 2019 in affluent countries such as the uk [59] . the popularity of veganism goes beyond the scope of the human diet, as more people are interested in the possibility of feeding their companion animal a vegan diet than ever before. to create animal-free complete cat food requires replacing nutrients in animal-based materials with plant-based materials. different sources are used such as corn, rice, peas, soy, potato, and different oils and seeds. any further nutrients that are missing from plant-based materials, such as taurine and carnitine, are replaced with synthetically produced versions [60, 61] . feeding trials using vegan animal food are either not performed due to testing costs or kept private due to the highly competitive vegan pet food market [62] . additionally, they reported testing 24 vegetarian diets for cats and dogs and found that one was lacking protein and six did not meet all amino acid concentration requirements. vegan animal food may not contain meat, but it does contain grains, soy, and corn. plant-based products, such as grains, can be a source of health problems because of the presence of mycotoxins, for example [63] . warm, humid storage conditions can lead to the formation of mycotoxins such as aflatoxins, produced by the fungi aspergillus flavus and aspergillus parasiticus. many regular animal feeds also contain plant-based products, therefore the negative impact of feeding vegan diets to companion animals, especially obligate carnivores such as the cat or the ferret, seems therefore more related to diet insufficiency than to microbial health risks. additionally, addressing behavioral problems, the "free" provision of food might fulfil the consumptive part of feeding behavior of our companion animals but does not fulfil the appetitive phase. especially this phase of feeding patterns can have consequences for the companion animals' mental health and may result in behavioral problems if appetitive physical and mental challenges remain chronically absent in the human-animal relationship. in the human-companion animal bond, pets may develop abnormal behavior, including excessive aggression, fear and anxiety, or even abnormal repetitive behavior. abnormal repetitive behavior (arbs) were first noticed in zoo-, shelter-, and laboratory animals: all animals housed under stimulus-poor conditions and with limited space. however, companion animals can develop arbs as well, if the individual's adaptive capacity is exceeded due to, e.g., a lack of social contact, physical exercise, mental challenges, and in uncontrollable and unpredictable environments (e.g., separation, mistreatment, or inadequate application of cages). arbs can either be classified in stereotypies or compulsive disorders [64] with stereotypies generally defined as unvarying repetitive behavior patterns with no obvious goal or function [65] . the terminology of compulsive disorders is preferably chosen for repetitive behavior patterns that are goal-directed and show variability in the repetitive (motor) patterns [66, 67] . under chronic conditions without possibilities to adapt (cope), companion animals may develop stereotypies or compulsive disorders like, e.g., tail chasing, polyphagia, compulsively self-directed licking and/or biting the coat [68] , or feather pecking in parrots [69] . self-directed patterns can result in serious degrees of alopecia, lick granuloma, or even self-inflicted injuries (auto-mutilation) with a risk of infection. two main reasons underlie the development of arbs in our companion animals. first of all, a lot of companion animals are social species eager for social contact. in the human-companion animal bond, the need for social contact with either conspecifics and/or humans [70, 71] can remain unfulfilled if owners work from nine to five, five days a week with the pet staying alone at home on a daily basis. on the other hand, a cat which is originally a solitary hunter with a complex dynamic social structure may start overgrooming or house soiling in the presence of another cat in the territory. such situations might occur in multi-cat households, in the presence of neighboring cats, and in in-stable grouped housing conditions in shelters [72, 73] . secondly, most companion animals are species that are eager for mental and physical challenges on a daily basis. the lack of foraging opportunities, the appetitive phase of feeding behavior [74] might be another reason for the possible development of arbs in companion animals. foraging is often regarded as a high priority behavior [75, 76] , i.e., an internally motivated behavioral pattern that should be performed, or otherwise may induce a state of chronic stress, which may result in behavioral pathology like arbs as described in many other animal species [77] [78] [79] . foraging patterns may include walking, running, jumping, nose pushing, digging, and overseeing the area, all active patterns that imply the daily need for physical exercise and mental challenges in most of our companion animals. nonetheless, our pets mostly, if not always, get their food for free with minimal foraging challenges, except for going out 3-5 times a day. for some individuals (and especially some dog breeds, e.g., malinois, border collies, and pit bull terriers) [80, 81] , situations and contexts with limited challenges can make them more vulnerable to the development of arbs. as well as arbs, other problematic behavior may develop in our companion animals, and the prevalence of some of this behavior is even higher than that of arbs, for example excessive interspecific and/or intraspecific aggression, fear, and anxiety. at what moment, and which type of problem behavior may develop, depends on the intermingled factors of, e.g., genetics, early life experiences (maternal-child bonding, weaning, socialization [82] ), daily environment, and multiple factors in and around the human-companion animal bond. the history of breeding animals goes back to a time when humans and animals shared each other's habitat. dogs originally have been selectively bred to support human needs, such as hunting, herding, obedience, guarding, rescuing, and for companionship. this artificial selection has generated a large number of dog breeds, displaying a large variation of behavior, size, head shape, coat color, and coat texture [83, 84] . unfortunately, in the last 100 years, intensive selection for extreme looks and a narrow gene pool of many breeds has interfered in the genetic make-up of dogs, leading to unfavorable anatomy (extreme large, or extreme "teacup" small), and genetic predisposition to numerous health, welfare, and behavioral problems [85] . over 700 inherited disorders and traits have already been described in the domestic dog [86] . one type of dog with a distinct dysmorphology is the brachycephalic dog. brachycephalic dogs are characterized by a large head and round face due to a shortened muzzle, a high and protruding forehead, and widely spaced large eyes. these facial features fit the concept of baby schema ("kindchenschema") proposed by konrad lorenz [87] . infantile (cute) faces are biologically relevant stimuli for rapidly and unconsciously capturing attention and eliciting positive or affectionate behavior, including the willingness to care [88] . the appeal of brachycephalic animals has led to specimens that are the so-called "over-typed" dogs and cats with a too short nose, excessively protruding eyes, too straight angulations, etc. breeding animals with this type of severe skull and muzzle abnormalities leads to physical and physiological hardship and limits their natural behavior [89, 90] . this violates their integrity and is a big risk for their welfare. selectively breeding animals in order to express specific traits does not only alter existing animals, but also creates new ones, turning animals into an instrument for human use [91] . the bambino sphynx cat is an example of so called "mutant breeding", where breeders deliberately stack in two steps the recessive inheriting mutations, which leads to hairlessness in sphynx cats, on the dominant inheriting (lethal) mutation responsible for the shortened legs of the munchkin cat. the lack of hair in combination with short legs interferes with the normal physiology of the cat with regard to the manner of movement, thermoregulation, and skin health. one may argue that artificial selection in exchange for money, status, or aesthetic reasons violates the animal's dignity and integrity [92] . conclusively, artificial selection for excessive traits can have direct consequences for individual health and welfare, may obstruct and prevent a pet from fulfilling its behavioral needs, and conflicts with the current moral way of thinking on animal dignity and integrity. pet animals are not only perceived in 80%-90% as family members or partners but are almost treated like humans. in one study, up to 62% of owners agreed with the statement "my dog is more important to me than any human being" [93] . this kind of behavior is the result of the attribution of human cognitive processes and emotional states to animals, such as feelings of happiness, love, or guilt. people believe that animals have awareness, thoughts, and feelings. this behavior is called anthropomorphism, personification, or humanization and can also be applied to plants, gods, or objects. anthropomorphism appears to be caused by the perceived similarity between humans and animals and the extent to which people have developed an affectionate bond with their dogs and cats [94] . human empathy provides the basis for the attribution of empathy to other animals, as well as attributions of the communicative ability of other animals [95] . anthropomorphistic behavior can be harmless, such as talking to pets, which many owners do and one of the reasons for this may be the unique ability of humans to recognize facial expressions. talking to pets is also found to be linked to social intelligence [94] . however, it can lead to animal welfare problems when the feelings of owners no longer match the needs and the intrinsic values of their animal. examples of this are designer dog clothes, animal perfumes, and jewelry, thought the use of protective coats in colder climates for small, short-haired breeds, e.g., chihuahuas, is considered useful. the large number of obese pets can also be partly attributed to anthropomorphism. studies from north america, europe, and australia to determine what proportion of animals, mainly dogs, are overweight or obese reported prevalences of between 22%-44% [96] . in 2018, an estimated 60% of cats and 56% of dogs in the usa were overweight or obese [50] . when the owner takes a treat with coffee, it is believed that the dog should also get it. even chocolate treats are given, when these are potentially fatal for dogs and cats. this also applies to a good meal that is shared with the pet. dog owners who did not consider obesity to be a disease, maybe because the facial features of their pets fit the concept of baby schema [87] , were more likely to have obese dogs [97] . an often-unrecognized risk for pets is reverse zoonotic disease transmission, the so-called zooanthroponosis. a review on this subject reported 56 articles dealing with human to animal disease transmission [98] . most of the articles dealt with bacterial pathogens but also viral, parasitical, and fungal pathogens were studied in these publications. animals reported to have been infected or inoculated with human diseases included wildlife, livestock, companion animals, and other animals or animals not explicitly mentioned. the majority of the studies focused on human to wildlife transmission with an emphasis on mycobacterium spp. for companion animals, mrsa-infection was especially reported but m. tuberculosis, influenza a, and candida albicans were also discussed. for all groups of animals, microsporum spp. and trichophyton spp. were identified as infectious agents originating from humans [99] . recent publications report a different kind of zooanthroponosis: the transmission of high-risk, multidrug-resistant pathogens from humans to animals [100] . a major issue mentioned is the transmission of high-risk clones of extended-spectrum beta-lactamase (esbl) producing bacteria including escherichia coli, enterobacter cloacae, and klebsiella pneumonia [100, 101] . the transmission of carbapenem-resistant ndm-5 producing e. coli from previously hospitalized humans to dogs has also been suggested [102] . transmission of hospital acquired antibiotic resistant bacteria from human patients to their pets has been confirmed, such as the vim-2 producing pseudomonas aeruginosa st233 strain in brazil [103] . this increased transmission of high-risk multidrug-resistant pathogens from humans to animals was related to the closer relationships between humans and companion animals. some authors doubt the generalized pet-effect on human mental and physical health because of conflicting results that are prevalent in this area of science and the lack of publication of negative results [13, [104] [105] [106] . the majority of research evidence was also considered inconclusive due to methodological limitations such as reliance on self-reports, small sample sizes that may not be representative of the general population, homogeneous populations, varying research designs, narrow range of outcome variables that were examined, and the use of cross-sectional designs that do not consider long-term health outcomes [107] [108] [109] . other studies found for example that pet ownership was associated with a higher incidence of heart attacks and readmissions in heart attack patients instead of a lower incidence [110] or that pet owners had higher diastolic blood pressure than those without pets [111] . müllersdorf (2010) showed that pet owners had better general health but suffered more from mental problems such as anxiety, insomnia, and depression, than those who did not own pets [112] . other studies failed to support earlier findings that pet ownership is associated with a reduced use of general practitioner services [113] or psychological or physical benefits on health for community dwelling older people [114] . negative effects of pet ownership include dog and cat bites or scratches, the spreading of disease (zoonoses), and fall injuries, caused by falling or tripping over dogs and cats [115] . allergic reactions may be a consequence of animal contact and affect 15%-30% of individuals (often genetically) predisposed [116] . allergies relating to more uncommon pets such as fish, birds, and amphibians seem to be increasing in prevalence [117] . other studies prove that pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6-10 years. therefore, advice to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given [118] . there are also less-positive effects that pets can have on health. more excessive forms of anthropomorphism became clear in our study for the presence of zoonotic parasites in healthy dogs and cats. fifty percent of owners allow pets to lick their faces. sixty percent of the pets visit the bedroom; 45-60% (dogs-cats) are allowed on the bed, and 18-30% (dogs-cats) sleep with their owner in bed. six percent of pets always sleep in the bedroom. of the cats, 45% are allowed to jump onto the kitchen sink [119] . this means that in addition to the detected zoonotic parasites (the hazard), there was a significant potential exposure to these pathogens. in addition to parasites, other pathogens such as bacteria, viruses, and fungi can also be transmitted by animals by direct contact through biting, licking, scratching, sneezing or coughing, handling pets or their body fluids or secretions and by indirect contact through contaminated bedding, food, water, or bites from an arthropod vector [120] . not every individual will develop symptoms after being infected with a zoonosis. this is the result of various factors such as the causative pet species, housing, the degree of contact and contamination, the ability of a micro-organism to cause disease in humans and animals, but especially due to the degree of immunity of the recipient. in order to assess the risk of disease transmission from pets it is important that the nature and frequency of contacts between pets and their owners or other people are evaluated [120] . we traditionally know that young children (age < 5 years), the elderly (age ≥ 65 years), patients with an impaired immunity, and pregnant women that carry a fragile fetus are at more than average risk of becoming ill after an infection. moreover, they may have more severe disease, have symptoms for a longer duration, or develop more severe complications compared to other patients. young children (notably those aged 3-5 years) and some people with developmental disabilities often have suboptimal hygiene practices or higher risk contact with animals which further increases risk [121] . in children, hand-to-mouth behavior is part of their natural development and they mouth their fingers and other objects. in a meta-analysis, the average indoor hand-to-mouth frequency ranged from 6.7 to 28.0 contacts/hour and the average outdoor frequency ranged from 2.9 to 14.5 contacts/hour. the lowest value was attributed to the 6-to 11-year-olds and the highest to the 3-to < 6-month-olds [122] . fifteen percent of dog owners and 8% of cat owners always wash their hands after contact with the animals [119] . in addition, due to improved healthcare in recent decades, the group of immunocompromised patients has increased sharply. this includes, for example, patients with diabetes, post-splenectomy, after placement of implants and patients being treated with chemotherapy or immunosuppressants. the risk groups are also referred to as yopis (young, old, pregnant, and immune suppressed). patient surveys and epidemiological studies suggest that the occurrence of pet-associated zoonotic disease is low overall [121] . many of these pathogens are not reportable and presumably underdiagnosed or not recognized by family doctors due to the general, mostly flu-like, symptoms. therefore, any reported frequency of such infections is likely underestimated. to get a better picture of zoonotic risks, a risk analysis is required where a risk score can be calculated using exposure, contagiousness of the infection, and its consequences in the human. in addition, the disease burden of an infection for the population can be calculated and expressed in disability adjusted life years (dalys). this quantifies the health loss based on two components: the life years lost due to premature death and secondly the proportional loss of quality of life as a result of the disease. there is a trend towards closer physical contact between owners and their pets or their environment which poses an increased risk of transmission of zoonotic pathogens. these trends (a general direction in which something is developing or changing) will be explained. our publication [119] showed that a high percentage of pets were allowed in the bedroom and in bed, with 6% always sleeping in bed with their owner. is that a problem? already from a hygienic point of view, it is not advisable to sleep with animals or take them into bed. they do not pay attention to where they are walking outside and do not wipe their feet after arriving home. dogs like to roll in carcasses and both dogs and cats regularly lick the anus and thereafter the fur. in a pilot study with 28 healthy dogs and 22 healthy cats that slept with their owners, we tested 68% of the dogs (19) and 32% of the cats (7) positive for enterobacteriaceae on the fur or footpads. fleas and flea larvae were found on 14% of pets [123] . as a result of our publication, chomel investigated in 2011 whether transmission of infections by sleeping with pets and licking the face could be found in literature. he reported that also in the usa, france and the uk, a relatively large number of pets slept in bed with their owner (14%-33% of dogs and 45%-60% of cats) [124] . similar results of sleeping with pets were also reported from canada (26% of pets slept with children), the czech republic (45%), and qatar (63.3%) [125] [126] [127] . chomel found bacterial infections such as yersinia pestis (plague), bartonella henselae (cat scratch disease), methicillin-resistant staphylococcus aureus, and sometimes fatal bite wound infections such as capnocytophaga canimorsus and pasteurella multocida. furthermore, parasite infections such as cheyletiella spp. were reported. feline cowpox is a rare viral infection, but it can be transferred to the human after direct contact. both animals and humans reveal local exanthema on arms and legs or on the face. in most cases the disease is self-limiting, but immunosuppressed patients can develop a lethal systemic disease resembling smallpox [128] . it can be concluded that, although uncommon with healthy pets, the risk of transmission of zoonotic agents by close contact between pets and their owners through bed sharing is real and has even been documented for life threatening infections such as plague [129, 130] . although pets do not transmit arthropod-borne diseases to people (e.g., lyme borreliosis, ehrlichiosis, anaplasmosis), they do bring zoonotic disease vectors such as ticks and fleas, in close proximity to people, e.g., when they are sleeping with their animals [121] . while fleas are considered a vector of bartonella henselae (the causative agent of cat scratch disease) tickborne diseases are reported as increasing as ticks expand their ranges [131, 132] . with an estimated 65,000 cases a year, lyme borreliosis is responsible for the largest disease burden of any vector-borne disease in the european union [133] . another increased risk associated with close contact with fur is when it is contaminated with zoonotic parasite eggs. especially with echinococcus multilocularis (fox tapeworm) or e. granulosus (hydatid worm, or dog tapeworm). these eggs are immediately infective and may cause serious health problems in the human, many years post infection [134, 135] . despite a low prevalence of infectious (embryonated) eggs of toxocara spp. on dog's fur, the potential zoonotic risk should not be disregarded [136] . the same risk is applicable for the persistence of sporulated toxoplasma gondii oocysts in dogs' fur [137] . in relation to this, it is noteworthy that many publications report striking increases of ringworm, a common zoonotic fungal skin infection in mainly children caused by microsporum spp., trichophyton spp. or arthroderma spp., where the presence of pets is always mentioned [94] . however, nowhere has it been suggested that close contact with infected pets in bed increases the infection risk [138, 139] . rodents or rabbits are mainly infected with t. mentagrophytes, while m. canis is primarily found in dogs and cats. infection occurs by direct or indirect contact with infected hair, scales, or materials. infected animals may be asymptomatic carriers without clinical signs. examples are 16% m. canis carriage in a study of european cats [140] , 27% in suspected brazilian cats [141] , and the isolation of t. mentagrophytes dermatophytes from 4% of clinically healthy rabbits and 17% of guinea pigs in dutch pet shops [142] . licking the face of humans by mainly dogs is an expression of their naturally submissive, positive social behavior. the owner is recognized by the dog as the dominant superior in the ranking. in a pack of dogs, submissive dogs lick their dominant counterparts at the corners of the mouth from a typical submissive attitude [143, 144] . owners apparently allow this as a token of affection from their pet. such behavior is more common in young animals and has been considered as attention-seeking or care-soliciting gestures. it indicates to the owner the strength of the social bond between dogs and people [120] . licking or nudging of veterans by service dogs may help take their mind off any negative thoughts, emotions, or memories that they might be experiencing [145] . on the internet, many images can be found of mainly dogs, but also cats and even rats licking their owner's face. various studies show that around 40%-50% of owners allow this [119, 120] . the question is whether this is harmful due to the potential transmission of infections. the review by chomel (2011) shows in the literature that infections, especially pasteurella spp. and capnocytophaga canimorsus, were reported to have transmitted to humans by dogs, cats, kittens, and rabbits [124] . pasteurella multocida meningitis has been reported in 36 infants where 87% had been exposed directly or indirectly to the oropharyngeal secretions of household dogs or cats through licking or sniffing [146] . zoonotic transmission via this route is also assumed for various other pathogens such as gastric helicobacter spp. [147] , periodontal pathogens [148] , and bartonella henselae the etiological agent in cat scratch disease. the b. henselae bacteria may cause ocular complications, including parinaud oculoglandular syndrome, a severe eye infection. the route of infection is unknown, although direct conjunctival inoculation, most likely with infected flea feces, seems to be most plausible [149] . knowing, however, that b. henselae is present in up to 40% of cat saliva [150] , it is more plausible that salivary fluid could be rubbed directly into the eye from the skin after been licked by a cat. there are several anecdotal reports of infections in mainly young children that were transmitted by being licked. one recent example is an 8-month-old baby that presented with fever and preseptal cellulitis with purulent discharge. the causative agent was surprisingly corynebacterium bovis, a bacterium that is normally found in bovine mastitis. it became clear that the dog was frequently allowed to lick the baby's face and was fed on raw meat [151] . there is an ineradicable belief among a large part of the public that the licking of human wounds by dogs can disinfect them and that the saliva thereby has healing properties [152] . in addition, it is regularly reported that a dog's tongue is believed to be sterile. this is of course not the case and the oral flora of a dog comprises hundreds of species (including pathogenic) bacteria, fungi, and viruses [153, 154] . various wound healing saliva components have indeed been demonstrated in human and animal studies [155, 156] . the bactericidal effects of male and female dog saliva facilitate the hygienic function of maternal licking of the mammary and anogenital areas by protecting newborns from fatal coliform enteritis caused by e. coli and neonatal septicemia caused by streptococcus canis. however, the saliva is only slightly, and non-significantly, bactericidal against wound bacteria such as coagulase positive staphylococci and pseudomonas aeruginosa [157] . capnocytophaga canimorsus and pasteurella multocida are common commensals in the oral cavity of dogs, cats, and other species [158, 159] . transmission has been reported after the licking of mucous membranes or open wounds [160] [161] [162] . in patients at high risk, severe wound infections, sepsis, disseminated intravascular coagulation, or death can occur. patients with immunodeficiency, splenectomy, or alcohol dependence are at a particularly increased risk of infection with c. canimorsus [159] . even immunocompetent persons who have been licked by a dog can develop fatal sepsis [163] . a further negative effect of companion animal ownership is, of course, accidents inflicted on humans by these animals. these accidents can involve tripping over a cat or being dragged by an enthusiastic dog, but in literature, most evidence points towards biting and scratching incidents. dog biting and cat scratching incidents can cause physical health problems both at the time of infliction but also afterwards by triggering trauma-related secondary infections. dog biting incident reports are numerous, and numbers vary from country to country. in the uk, 18.7 dog bites per 1000 population per year were reported [164] , while a commission in the netherlands reported in 2008, 150,000 bite accidents per year in a population of 16 million (9 events per 1000 inhabitants) [165] . children are especially vulnerable to dog bites. the majority of dog bites occurred in children 5 years of age or younger (68.0%) and almost all (89.8%) of the dogs were known to the children [166] . recently, a systematic review has been published that analyzed more than 26,000 bites from the literature of the past 30 years about the risk of bites relative to specific breeds of dogs, combining bite incidence with bite severity [167] . the analysis by breed revealed that pit bulls were responsible for the highest percentage of reported bites across all studies (22.5%), followed by mixed breed (21.2%), and german shepherds (17.8%). dog bite incidents can result in medical treatment, hospitalization and even death. in the netherlands it was calculated that from the 150,000 dog bite victims per year, around 50,000 seek medical attention and 230 are hospitalized [165] . between 3% and 30% of dog bites become infected and complications become more severe when infection occurs. more than 100 species of bacteria have been isolated from bacterial infections of dog bites, suggesting that most oral flora of dogs have the potential to be pathogenic [168] . the top 3 pathogens found are pasteurella, staphylococcus, and streptococcus. in literature, specific attention is given to wound infections caused by capnocytophaga canimorsus, because this bacterium is seen as the relatively deadliest pathogen. it was suggested that only 2% of dog bite wounds contained capnocytophaga spp. [154] while others reported infection percentages of 4.2% [169] . wound infection with this bacterium can lead to severe complications like septicaemia, meningitis, osteomyelitis, peritonitis, endocarditis, pneumonia, purulent arthritis, and disseminated intravascular coagulation. c. canimorsus septicaemia has been associated with 30% mortality. the true number of c. canimorsus infections is probably largely underestimated due to the fastidious growth of the organism. however, infected dog bites in predisposed persons should be taken seriously especially after splenectomy [170] . cat bite incidents occur less frequently. in only 5%-10% of reported bite incidents in australia, cats are to blame. the long incisor teeth inflict less severe superficial wounds but because of the penetrating effect, joint and tendon infections more easily occur. in a review it is reported that 28%-80% of cat bites become infected mostly by pasteurella multocida [169] . the bacterium bartonella henselae can also be transmitted by cats through biting incidents but the transmission of this bacterium is much more related to a cat scratch accident. even less frequently reported animal biting incidents are those inflicted by rodents (2% of cases in australia). these bites have an infection rate of approximately 10%. this could result in rat bite fever in humans, an infection with streptobacillus monoliformis or spirillum minus, characterized by the triad of fever, rash, and arthritis [169] . cat scratch disease (csd) was first described in a french boy in 1931 and is a common, often self-limited, disease that usually presents as tender lymphadenopathy caused by bartonella henselae [171] . the cat is considered the primary reservoir for this bacterium, with infected fleas and ticks serving as vectors and humans and dogs as accidental hosts. vector transmission of this bacterium occurs via two primary routes: inoculation of bartonella contaminated arthropod feces via animal scratches, most often cat scratches, or by self-inflicted contamination of wounds induced by the host scratching arthropod bites [172] . immunocompromised human hosts (kidney transplant patients or patients with hiv) are especially susceptible to infection. in these individuals, the disease may be present as a more disseminated form with hepatosplenomegaly, meningoencephalitis, or angiomatosis [173] . an increasing number of pocket pets and exotic pets are kept by humans. numbers of ornamental birds in europe are estimated as 50 million, fish tanks 15.5 million (300 million ornamental fish), small mammals 27 million, and reptiles 8 million [15] . these animal species can also be a source of many zoonotic diseases, especially in young children and immunocompromised individuals. most cases of these conditions are not serious, and deaths are very rare but some of these diseases can be life threatening, such as rabies, rat bite fever infections, and plague [174] . however, there is also a trend to keep more unusual exotic animals, legally or illegally. these are "wild" animals that are kept in the home such as bats, foxes, skunks, raccoons, meerkats, prairie dogs, kinkajous, sloths, monkeys, apes, prosimians (mammals), parrots, mynah birds, finches (birds), crocodiles, turtles, tortoises, lizards, snakes (reptiles), frogs, toads, newts, salamanders (amphibians), fish, eels, rays (fish), crabs, crayfish, snails, insects, spiders, and millipedes (invertebrates) [175] . even fruit bats are kept as pets [176] and it is known that bats harbor a higher proportion of zoonoses than all other mammalian orders, including rabies-like viruses that are highly pathogenic for people. [177] . another example of a zoonosis is monkeypox following the importation of prairie dogs in the usa [178] . most reptiles and amphibians such as turtles, lizards, and frogs carry salmonella bacteria in their gut, in most cases without visible signs of infection. the infection may cause symptoms of sickness, diarrhea and fever in humans [179] . zoonotic transmission of salmonella infections causes an estimated 11% of salmonellosis annually in the united states. in cases involving pet turtles, almost half (45%) of infections occurred in children younger than 5 years [180] . salmonella infections are often transferred by feeder rodents [181] and outbreaks highlight the importance of improving public awareness and education in countries who receive imported reptiles [182] . it is advised to exclude reptiles, amphibians, rodents, exotic species, baby poultry, and raw animal-based pet food items from the households of patients at high risk. in lower risk households, an understanding of the risk of salmonellosis and other pet-associated zoonoses and preventive hygiene measures is needed. the pet trade in general, with its high turnover and diversity of available species, creates a reservoir for pathogens originating from all over the globe. reptiles account for approximately 10% of live animal shipments imported to the united states [182] . importation of live reptiles and amphibians for commercial purposes is for a great part unregulated at eu level except cites and customs regulations [176] . in a risk assessment study, the five pathogens with the highest public health risk caused by the import of exotic animals were salmonella spp., crimean-congo hemorrhagic fever virus, west nile virus, yersinia pestis, and arenaviruses. the risk via legally imported animals was considered low, but substantial for illegally imported animals due to the unknown health status of the animals [183] . avoiding exposure to exotic pet pathogens in the home is difficult and best achieved by not keeping them in the first place. otherwise, it is advised to always wash the hands immediately and thoroughly after contact with exotic pets and after handling raw (including frozen or defrosted) mice, rats and chicks. children should be supervised so that they do not put their mouths close to or kiss exotic animals. reptiles and other animals should be kept out of rooms in which food is prepared and eaten. the number of abandoned and homeless dogs and cats in europe is estimated to be over 100 million. countries with more than 1 million abandoned animals are italy, romania, russia, and ukraine [184] . there is an increasing trend to rescue and import dogs from countries with stray animal problems, in europe often from southern or eastern europe and in the us from puerto rico, the dominican republic, mexico, the middle east, turkey, china, and korea [185] . many charities and independent groups are involved to rescue dogs and seek adoption in more animal-friendly countries [186] . new owners primarily choose to adopt from abroad based on a desire for a particular dog they had seen advertised and on concern for its situation, while some were motivated by previously having been refused dogs from local rescues [187] . in the usa 85% of all household dogs were neutered and today there are no longer enough dogs being born in the usa annually to replace the approximately 8 million dogs that die each year. developing countries have hundreds of millions of street dogs available for export, for example egypt has an estimated 15 million, india, 30 million, and afghanistan, 100 million [188] . in 2006, more than a decade ago, the centers for disease control (cdc) estimated annual dog imports at around 287,000. today the number of imported dogs is estimated to be more than a million a year [189] . imported dogs are reintroducing diseases and parasites that were previously eliminated in the usa [190] . in the usa new and lethal strains of distemper and canine influenza as a result of imported rescue dogs were reported as well as canine brucellosis, rabies, and vector-borne diseases like ehrlichiosis, heartworm, babesiosis, and leishmaniasis [188, 191] . in many southern european countries, there is also a risk of exposure to diseases not encountered in the northern, importing, countries. animals could be infected with anaplasma phagocytophilum, babesia canis, brucella canis, borrelia burgdorferi, dirofilaria immitis (heartworm), dirofilaria repens (subcutaneous worm), echinococcus multilocularis (fox tapeworm), echinococcus granulosus (hydatid or dog tapeworm), ehrlichia canis, hepatozoon canis, leishmania infantum, linguatula serrata (tongue worm), onchocerca lupi, rabies, rickettsia conorii, strongyloides stercoralis, and thelazia callipeda. except b. canis, e. canis, and h. canis, the infections are zoonotic and regularly reported [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] . most of these are transmitted by ticks, sand flies, or mosquitoes that are non-endemic in the receiving countries, but a reservoir of infections has been created and the risk is that vectors will become present as result of climate change. [203] . animals that are infected with rabies or echinococcus spp. may infect people directly. the importation of dogs from endemic, predominantly mediterranean, regions to northern europe, as well as travelling with dogs to these regions carries a significant risk of acquiring an infection. pet owners are therefore advised not to travel with dogs and to seek the advice of their veterinarian prior to importing a dog from an endemic area or travelling to such areas [193] . for this reason, esccap developed maps on their website featuring european countries and regions with advice on endemic parasites, diseases and recommended treatments when travelling with dogs [204] . a three-year european union funded project entitled callisto (companion animal multisectorial interprofessional and interdisciplinary strategic think tank on zoonoses), has investigated zoonotic infectious diseases transmitted between companion animals and humans and food producing animals [176] . the committee advised that special attention should be given to stray cats and dogs. stray dogs, in particular, may pose serious health and welfare problems for humans and animals [81] , including the transmission of zoonotic diseases such as rabies. consideration should be given to controlling companion animal movement between areas of the eu endemic for particular zoonoses and areas that are not currently endemic for that disease. reliable figures are not available, probably because of the fact that many voluntary organizations are responsible for saving and transporting these rescue animals. such data are essential in order to be able to quantify the actual risks of zoonotic diseases attributable to companion animals and to develop sustainable interventions to prevent transmission to humans and livestock [176] . as long as there are no official guidelines, to prevent the spread of (zoonotic) diseases to new countries, the time, expense, disease risk, and the implications of adopting a dog from abroad should all be carefully considered before importation. as an alternative, the conditions for native dogs could be improved by supporting local charities to organize neutering campaigns and rehoming programs, to build local animal shelters and to improve attitudes towards dogs and their living conditions [205] . cats and dogs harbor the enteric nematodes toxocara canis and toxocara cati, and cats are the final host for the protozoal parasite toxoplasma gondii. these parasites can be transmitted to humans because they have an oral-fecal transmission cycle. humans can be infected by ingestion of infective toxocara spp. eggs or toxoplasma oocysts from contaminated soil (gardens, sandpits, and playgrounds) [206, 207] . a recent meta-analysis of data from published records indicates that public places are often heavily contaminated with a pooled global prevalence of toxocara eggs of 21% [208] . both parasites are considered by cdc as part of five neglected parasitic infections. these infections are considered neglected because relatively little attention has been devoted to their surveillance, prevention, and/or treatment. the diseases that they cause have been targeted as priorities for public health action based on the number of people infected, the severity of the illnesses and the ability to prevent and treat them [209] . tens of millions of people worldwide are estimated to be exposed to, or infected with, toxocara spp. and recent findings suggest that the effect of toxocarosis on human health is increasing in some countries. almost one fifth (19%; 1.4 billion individuals) of the world's human population is seropositive to toxocara. the highest seroprevalence rates were found in africa (mean: 37.7%) and the lowest in the eastern mediterranean region (mean: 8.2%) [210] . toxocara larvae migrate into the body of the human to several organ systems with a preference for the central nervous system (brain, eyes). human toxocarosis can manifest itself as syndromes known as visceral larva migrans, ocular larva migrans, neurotoxocarosis, and covert or common toxocarosis [211] . asthma is one of the most common chronic respiratory diseases worldwide, with a negative impact on the quality of life and socio-economic status of patients. two decades ago, the first evidence was published that suggested that toxocara infection is a neglected risk factor for childhood asthma [212] . the finding that children infected with toxocara spp. are more likely to have asthma compared to non-infected children was recently confirmed in a systematic review and meta-analysis [213] . cognitive or developmental delays in children or young adults who become infected is of particular concern. toxocarosis appears to be associated with decreased cognitive function [214, 215] . the annual toxoplasma oocyst burden measured in community surveys has been reported as up to 434 oocysts per square foot (4670 per square meter) and is greater in areas with loose soil, that cats like to use to cover their feces in gardens, children's play areas, and especially sandboxes, also called sandpits and sand piles [207] . because a single oocyst can possibly cause infection, this oocyst burden represents a major potential public health problem. an estimated one third of the world's population harbor anti-toxoplasma antibodies. due to keeping pigs indoors, more education and awareness, the prevalence of the disease in the usa and europe declined by 50% over the last decades [216] . during an acute invasion of toxoplasma parasites there is mild to major tissue damage without clinical symptoms (latent toxoplasmosis). the most important form is congenital toxoplasmosis when a woman receives her first exposure to toxoplasma during pregnancy. in early pregnancy, this can lead to abortion or to malformations that are not compatible with life shortly after birth. congenital infections may also be characterized by mental retardation and ocular defects. acquired infection after birth may result in clinical symptoms such as lymphadenitis, fever, and malaise and probably leads to a clinically symptomatic disease state more frequently than the congenital condition, with an estimated incidence of 30% of all ocular toxoplasmosis cases [216] . playing in a sandbox is also found to be a predominant risk factor for s. typhimurium salmonellosis in children aged 4-12 years [217] . this can be the result of fecal contamination of the sand by dogs and cats that have been fed raw meat (see section 5.1.1.). young children are especially at risk as they put their hands or other objects in their mouths every 2-3 min [208] . it has also been reported that children ingest a median of 40 mg of soil per day and that one child consumed 5-8 g of soil per day on average [218] . it is therefore advisable not to let children play in public places or on playgrounds with loose sand, but only in sandboxes that can be covered. furthermore, washing hands after playing outside is important and fingernails must be trimmed to prevent sand being left behind. in this context, a strange trend can be observed as young children play in mud baths on 29 june "as a way to connect and celebrate the natural joys of playing in the mud". this international mud day originated in 2008 and was initiated by an australian pedagogue who had observed this phenomenon during a visit to nepal [219] . if the origin of the soil needed for producing the mud is unknown, there is of course an infection risk for the above discussed parasites. to prevent the transmission of zoonotic diseases from pets, risk analysis is of great value. this starts with an assessment of the potential zoonoses in an area, depending on the endemicity (the hazard, h). hazard characterization also includes prevalence in animals (the reservoir), virulence for man, transmission routes, and survival of the agent in the environment. the second step is exposure assessment (e). who is exposed to the potential hazard and for how long or how often? how much of the potential pathogen is needed to become a health risk? this inevitably is directly related to human behavior in relation to their pets. the third step is to assess the impact of getting infected (i). how serious is the disease, what is the chance of complications, and what economic consequences may be expected (e.g., labor hours lost)? each of the parameters can be ranked in classes from negligible to the most serious possibility. ranking is based on literature data, own observations (measuring), or experts' opinions. the final risk assessment can be achieved by multiplying the outcome of hazard characterization, exposure assessment and impact (h × e × i = a number). the outcome can be compared with other zoonotic agents and a ranking of significance can be made [220] . there is one important parameter to reduce the risk of contracting a zoonotic infection that can directly be influenced, which is exposure. recommendations are particularly targeted to households with very young children, the elderly, pregnant women, or immunocompromised patients. they are based on reducing exposure to hazards and involve four categories of advice (table 1) . table 1 . recommendations to prevent the transmission of zoonotic pathogens from pets [121, 221] . • washing the hands thoroughly -after animal contact, at least before eating and drinking and before preparing food or drinks -after handling raw pet food -after handling pet habitats or equipment -after cleaning up feces -after removing soiled clothes or shoes reflecting on the changed human-companion animal bond, it can be concluded that pets undoubtedly have a positive effect on human health. conversely, the human-pet bond seen nowadays is facing many challenges, putting pet welfare under more pressure due to issues such as anthropomorphism, which mainly results in obesity, breeding on extreme appearance rather than health, behavioral problems connected to unfulfilled species specific mental and physical needs, and the provision of inadequate food because owners mistakenly think they feed more naturally. with regard to the negative effects of pets this article attempts to give an impression of increasing trends in the human-companion relationship that can be observed in society, which appears to increase the risk of transmission of infection between pets and humans. it is mainly a consequence of the increasing contacts between humans and pets and with pathogens secreted by animals in the shared environment. more than 6 out of every 10 known infectious diseases in people can be spread from animals, and 3 out of every 4 new or emerging infectious diseases in people come from animals [222] . the recent pandemic of the covid19 coronavirus (sars-cov-2), that may be originated from bats, is a good example of a recent emerging zoonotic infectious disease. a few cats and dogs have tested positive but are not considered as a source of infection for people. the proportion of zoonotic human disease that is attributable to pets is largely unknown. reports about the frequency of such infections are likely underestimated [120] ; however, the risk of infection is relatively small for many zoonoses and the severity of the disease is often limited. a person's age and health status may affect their immune system, and thereby increase his or her chances of getting a disease from animals. pregnant women should avoid contact with pet rodents, reptiles, cat feces, and raw meat to prevent infection of the unborn child, abortion, or birth defects. if symptoms occur in immunocompetent, non-pregnant persons between 5 and 64 years of age, these are mainly of a general nature such as diarrhea or flu-like symptoms. physicians do not regularly ask about the presence of pets or pet contact, nor do they discuss the risks of zoonotic diseases with patients, regardless of the patient's immune status, which means that many cases of zoonotic diseases go undiagnosed. the general public and people at high risk of pet-associated disease are not aware of the risks associated with high risk pet practices or recommendations to reduce them. since unfamiliarity with hazards reinforces fear, communication plays an important role in this. veterinarians play a key role in education regarding risk reduction by giving advice about responsible pet ownership and the required preventive hygiene. healthcare providers such as family doctors, school doctors, and pediatricians can also provide information about safe pet ownership. physicians should ask as part of the medical history about eventual contact with pets, particularly with patients at high risk [120] . the "one health" initiative aims to reduce this professional gap between vets and physicians [2] . when giving recommendations to prevent zoonotic transmission, one of the often-made remarks is that people nowadays are already too hygienic. it is assumed that there is a protective influence of postnatal infection and that it might be lost in the presence of modern hygiene. this belief is based on the hygiene hypothesis that was formulated in 1989 [223] . it was observed that hay fever in young adults was inversely related to the number of siblings in their family. this hypothesis focused exclusively on allergic conditions as a result of the modern way of life and the assumption that modern hygiene was reducing contact with bacteria. another view is that some chronic inflammatory disorders have increased over the last decades as a result of decreased frequency of infections due to pathogenic organisms [224] . another related theory is the "old friends" mechanism that is based on the positive influence of gut parasites, non-pathogenic environmental bacteria (saprophytes, pseudocommensals), and gut commensals or microbiota. however, decreased exposure to these microorganisms is not the only reason for the increasing frequency of allergies and chronic inflammatory disorders in industrialized countries. nowadays there is more information about the immunological roles of skin, oral mucosa, and gut microbiota as well as helminths and the influence these have on the immune system [225] . gut flora may be modified due to diet, obesity, hygiene, antibiotics, but also to psychological stress, vitamin d deficiency, and pollution [225] [226] [227] . pollution also has a significant effect on the development of several respiratory problems and diseases. not only due to outdoor pollution such as fine dust, harmful solids, liquids, or gases [228] , but also due to indoor molds as result of insufficient ventilation in energy efficient homes [229] . finally, there is a clear increase in the allergen production of house dust mites and pollen leading to more exposure and sensitization in susceptible individuals [230] . all together it must be clear that there is much more known about other causes of increasing allergies worldwide than simply excessive cleanliness as suggested in the hygiene hypothesis. regarding field infections with helminths such as trichuris trichiura in early life, these are associated with a reduced prevalence of allergies later in life and infants of helminth-infected mothers have a reduced prevalence of eczema. hookworm infections in developing countries are associated with a reduced prevalence of asthma [231] . the rate of eczema in such countries was found to be about five times higher in infants whose mothers had never had helminths compared with persistent helminth-infected mothers [232, 233] . helminths are nowadays even used under controlled conditions to stimulate immunity. examples are trichuris suis therapy for crohn's disease and necator americanus larvae to treat crohn's disease and other autoimmune disorders [234] . there are no clinically apparent childhood infections found to be associated with protection from allergic disorders [235] . it can even result in an opposite effect in the case of toxocara infection by children after soil contact. a recent meta-analysis showed that children infected with toxocara spp. are more likely to have asthma compared to non-infected children [213] . this parasite and asthma both have elevated immunoglobulin e (ige) levels and eosinophilia in common. that means that precautions should be taken in children to prevent soil contact not only to prevent toxocara infection, but also to prevent acquired ocular toxoplasmosis. there is no need, therefore, to stimulate the contraction of pathogenic bacteria or helminths to achieve a healthy gut microbiota and to reduce allergic conditions. recommendations based on the hygiene hypothesis should preferably be based on results from controlled studies to prevent unintentional negative effects. it is both humans and companion animals who experience negative effects of a changed human-companion animal bond. the education given by vets to their clients should therefore also focus on preventing these negative health and behavioral effects. for instance, by giving science-based advice on feeding practices. in general, regulating authorities should encourage the development of enforcement criteria for breeding dogs and cats to reduce health and welfare risks. pets undoubtedly have a positive effect on human health and well-being, while owners are increasingly aware of pet health, welfare, and well-being. anthropomorphism, also resulting in behavioral problems and breeding on appearance rather than health, and trends such as keeping exotic animals and importing rescue dogs may result in an increased risk of contracting zoonotic infections. recommendations regarding responsible pet ownership, including normal hygienic practices, responsible breeding, feeding, housing, and mental and physical challenges conform the biology of the animal, are key in preventing such negative aspects of the human-animal bond. there is no need to stimulate unhygienic practices following the hygiene hypothesis. education can be performed by vets and physicians as 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friends' hypothesis metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment current understanding of the human microbiome environmental and health impacts of air pollution: a review. front. public health 2020, 8, 14 abridged version of the awmf guideline for the medical clinical diagnostics of indoor mould exposure house dust mite allergy under changing environments interactions between helminth parasites and allergy the impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood immunologic profiles of persons recruited for a randomized, placebo-controlled clinical trial of hookworm infection an update on the use of helminths to treat crohn's and other autoimmune diseases infections presenting for clinical care in early life and later risk of hay fever in two uk birth cohorts this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors declare no conflict of interest. key: cord-338889-7hd3iibk authors: solbakk, jan helge; bentzen, heidi beate; holm, søren; heggestad, anne kari tolo; hofmann, bjørn; robertsen, annette; alnæs, anne hambro; cox, shereen; pedersen, reidar; bernabe, rose title: back to what? the role of research ethics in pandemic times date: 2020-11-03 journal: med health care philos doi: 10.1007/s11019-020-09984-x sha: doc_id: 338889 cord_uid: 7hd3iibk the covid-19 pandemic creates an unprecedented threatening situation worldwide with an urgent need for critical reflection and new knowledge production, but also a need for imminent action despite prevailing knowledge gaps and multilevel uncertainty. with regard to the role of research ethics in these pandemic times some argue in favor of exceptionalism, others, including the authors of this paper, emphasize the urgent need to remain committed to core ethical principles and fundamental human rights obligations all reflected in research regulations and guidelines carefully crafted over time. in this paper we disentangle some of the arguments put forward in the ongoing debate about covid-19 human challenge studies (chis) and the concomitant role of health-related research ethics in pandemic times. we suggest it might be helpful to think through a lens differentiating between risk, strict uncertainty and ignorance. we provide some examples of lessons learned by harm done in the name of research in the past and discuss the relevance of this legacy in the current situation. these are uncertain times-for all, wherever one lives, and whatever one aspires to know about the covid-19 pandemic. at present, there are so many things we do not (yet) know: how it will evolve and spread, when, if ever, it will end, how and why it started, whether infected persons develop permanent immunity, whether safe and effective cures and vaccines will be possible to develop, and last, but not least, what impact the pandemic will have on each and every one; be it individuals, families, societies, nations, regions, or globally. the aim of this paper is to address the ongoing debate about covid-19 chis and discuss the concomitant role of medical and health-related research ethics in the present situation the word pandemic comes from two ancient greek words (pan 'all' + dēmos 'people'), so literally speaking 'pandemic' means all the people, all the world. where there is an urgent need for developing effective methods of detection, treatment, and prevention to cope with the covid-19 pandemic and notably in ways that minimize harm and that benefit all human beings. although at present all attention and focus is on the covid-19 pandemic, it is key not to forget there have been pandemic surprises in the past and that future, unknown pathogens may lead to crises with unprecedented implications. the issues we discuss here are therefore relevant beyond the covid-19 pandemic; above all they concern how we should navigate (research ethics) in times of great threats to individual, public and population health and under conditions where different forms of uncertainty still prevail. 1 the british medical association's report on biomedical research and human rights states: «research is driven by a desire to understand the causes of disease or dysfunction and find effective methods of prevention and treatment." 2 however, the report continues, "even such humanitarian aims can be risky", in particular under circumstances perceived as extreme or exceptional. 3 in the report, nine risk-factors for abusive research are identified, of which three are of particular relevance in the present context: (1) the perception of an urgent and overriding scientific need; (2) the perception of a national necessity or government pressure to conduct research; and (3) the situation of contingent populations chosen as research subjects. 4 table 1 covid-19 and three forms of uncertainty (risk, strict uncertainty and ignorance) a goldstein and burstyn (2020) b sethuraman et al. (2020) c mutambudzi et al. (2020) d mcintosch et al. (2020) e hofmann (2020) f mcintosch et al. (2020) g yelin et al. (2020) h european group in ethics in science and technology (2020) i mcintosch et al. (2020) j hofmann (2020) k yelin et al. (2020) l kalil (2020) risk a,b,c,d (known outcomes and known probability distributions) test accuracy (sensitivity, specificity, predictive values) for the various tests in different contexts effects and side effects of new treatments prevalence of disease the risk of healthcare workers versus the risk of non-essential workers testing positive for covid-19 strict uncertainty e,f,g,h (known outcomes and unknown probability distributions) basic reproduction number (r) case fatality rate/infection fatality rate the precise interval during which an individual with sars-cov-2 infection can transmit infection the pathogenic effect of the sars-cov-2 in different age groups the extent to which transmission occurs from a-symptomatic or pre-symptomatic subjects and how much it contributes to the pandemic whether all infected patients mount a protective immune response and how long any protective effect will last reinfection how long sars-cov-2 can persist on surfaces whether pre-existing immune responses impact the risk or the severity of covid-19 and whether they will influence sars-cov-2 vaccine responses long-term sequelae and late-stage consequences of covid-19 ignorance i,j,k,l (unknown outcomes and unknown probability distributions) in a recent letter to the editor of the american journal of bioethics, stoeklé and hervé state that now is not the right time for ethics reflection, but rather for political action and for "indisputable confidence in medical care staff and scientists, not only in france, but everywhere around the world". 5 in a response to this view, and notably with the opposite title, the respondents state 6 : in times of crisis, like the current pandemic of covid-19, the perception that ethical standards can be relaxed due to the urgent need for solutions is growing, according to stoeklé and hervé. for them, ' ethics is only useful if you have the time, and right now, time is exactly what we do not have.' it is a misperception without any doubts. ethics has always preserved its identity as a rationalization of human action. therefore, ethical reflections to take decisions are useful all the time and must be reinforced in times of pandemic. another way of visualising this tension is by differentiating between the epistemological ethos of doing biomedical research, such as developing knowledge and skills for effective diagnostic, treatment and prevention, versus the ethical ethos of the same enterprise; the attempt to protect the interests and wellbeing of patients and healthy individuals involved in such research. ethos is here used in the meaning of 'accepted standards.' in research, two such normative standards or rules of play are used: epistemological rules of play (such as truth, probability, coherence, relevance, fruitfulness, interestingness, and utility), and ethical rules of play (such as autonomy, informed consent, justice, beneficence, non-maleficence, truthfulness, dignity, trust, vulnerability, and solidarity). the tension between these two normative standards is permanent, and one that probably never can be fully resolved. but in times of perceived urgency, the danger is increased tension, or worse, a disregard and violation of epistemological as well as ethical standards, and that shortsighted expediency with questionable results will ensue. in the pages to follow we argue in favour of an ethics of precaution, with particular emphasis on the role of research ethics in particularly challenging situations, such as pandemics. that is, we will analyse and critically assess the epistemological and ethical justification of several research initiatives that have been implemented or are at the planning stage. we claim that in the current situation of a palpable sense of medical and scientific urgency, and of national and global necessity, there should be no room for epistemological or ethical exceptions or shortcuts. on the contrary-and perhaps more than ever-there is a need to conduct biomedical and health-related research in compliance with existing rules of play and fundamental human rights commitments. faced with the "toxic brew of uncertainty" 7 the pandemic has caused, we suggest it would be helpful to differentiate between three different forms of uncertainty: risk, strict uncertainty, and ignorance or non-knowledge. risk represents a form of uncertainty with known potential outcomes, and, where the probability distribution is known. the plethora of uncertainties that the covid-19 pandemic are causing cannot, however, be addressed within this narrow framework of risk estimation; uncertainty considerations of the two additional kinds mentioned above should also be included. strict or fundamental uncertainty is a form of uncertainty where possible outcomes are known, but the probability distribution is unknown, while ignorance or nonknowledge represents forms of uncertainty where only some possible outcomes are known while the statistical likelihood of each of them is unknown. 8 the relevance of differentiating between these three forms of uncertainty in the present context is visualized in table 1 . in the aftermath of another global disaster, world war ii, several normative initiatives were taken to prevent a similar catastrophe to recur, such as the establishment of the united nations and the development of the universal declaration of human rights. in addition, more robust ethical standards for biomedical research were crafted in order to avoid inhuman research in the future-not the least in crisis-situations. the then first lady of the usa, eleanor roosevelt, served as the first chair of the un commission on human rights, which drafted the universal declaration of human rights (1948). the first paragraph in the declaration's preamble states that "the foundation of freedom, justice, and peace in the world" is the "recognition of the inherent dignity and of the equal and inalienable rights of all members of the human family". 9 of the 30 articles in the declaration article 1 and 5 are of particular relevance for research ethics; article 1 restates the freedom and equality of all human beings in terms of 5 stoeklé and hérve (2020) . 6 hellmann et al. (2020) . 7 outka (2020). 8 wynne (1992) , rørtveit and strand (2001) , nielsen and sørensen (2017) and hofmann (2020). 9 https ://www.ohchr .org/en/udhr/pages /udhri ndex.aspx. dignity and rights, and article 5 emphasizes the right to be protected from torture or cruel, inhuman or degrading treatment or punishment. the essence of these normative statements harkens back to the ethical code of medical research issued by the war crimes tribunal at nuremberg the previous year, in 1947. 10 of the 10 standards laid down in this code, and with which physician-researchers must comply when carrying out experiments on human subjects, standard 5, in particular, has become highly relevant these days due to pressure from influential medical stakeholders, agencies and bioethicists to permit the conduct of controlled human infection studies (chis), also labeled human challenge trials (hcts), or challenge studies (css) to possibly shorten the development time of vaccines to protect against covid-19 caused by the sars-cov-2 virus. 11 in the next paragraph of this paper we will examine and critique in detail four position statements advocating the epistemological and ethical justifiability of conducting covid-19 chi-studies: p. singer and r.y. chappell's, pandemic ethics: the case for experiments on human volunteers 12 ; the report, key criteria for the ethical acceptability of covid-19 human challenge studies, issued by a working group set up by who 13 ; the policy forum statement, ethics of controlled human infection to study by shah, miller, darton et al.; 14 and jamrozik and selgelid's statement, in addition, we will consider other recent papers advocating the use of covid-19 chis studies. in table 2 below we have made a summary of prevalent arguments for and against such studies. standard 5 of the nuremberg code reads: no experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 16 while repeating (in the first clause of article 7) that no one shall be subjected to torture or to cruel, inhumane or degrading treatment or punishment, the legally binding 1966 un international covenant on civil and political rights adds a second clause that "in particular, no one shall be subjected without his free consent to medical or scientific experimentation". 17 the prohibition is intended to prevent the recurrence of atrocities such as those that took place during wwii and the first decades after the war. even though this prohibition is implicit in the first clause, the matter was deemed so important as to require a specific and precise provision. 18 during the drafting of the covenant, there was a proposal that compulsory measures might be taken "in the interest of community health", but the proposal was rejected on the grounds that this might lead to abuse. 19 the consent requirement is thus formulated as absolute, without any exceptions. the human rights committee has reaffirmed what is already explicitly mentioned in article 4 (2), that even in situations of public emergency, no derogation from article 7 is allowed. 20 controlled human infection studies (chis) "are clinical studies that, as part of the protocol, deliberately expose trial participants to an infectious pathogen. these studies are often done in the context of vaccine development, with trial candidates exposed to a pathogen after being immunized with an experimental vaccine". 21 the main advantages of chis compared to large field trials are that they can generate data much faster, they are much less expensive and they do not require thousands of research participants, normally only between 10 and 50 participants. 22 the four position statements on chis referred to above all suggest that suitable candidates for such studies are "young people without underlying medical 13 who (2020). 14 shah et al. (2020) . 15 jamrozik and selgelid (2020a callaway (2020) , eyal (2020), eyal et al. (2020) , jamrozik and selgelid (2020a, b) , plotkin and caplan (2020) , schaefer et al. (2020) , shah et al. (2020) , , who (2020) and wolemonwu (2020) . 12 . the urgency of the current pandemic gives substantial weight to a challenge study j the endemic argument the probability of dying or developing disability if infected would be smaller in a chi trial k the risks in question do not entail a major net increase in risk (in light of background risks of infection) l participants face a background risk of infection in the community m only people with an especially high baseline risk of getting exposed during or soon after the trial period should be recruited (e.g., people residing in areas with high transmission rates) n the risk and safety argument participation in a covid 19-chi trial would be less risky than joining a standard efficacy trial for the same vaccine o covid-19 chis have a much higher risk than the minor risk threshold. p for a live sars-cov-2 challenge there are deadly risks q currently, we lack sufficient knowledge of sarscov-2 pathogenesis to inform inclusion and exclusion criteria for a sars-cov-2 chim r the medical benefit argument the probability of averting death in the event of infection would be substantially better inside a chi trial than outside s the altruistic argument it might seem that anybody volunteering to participate in such a study lacks capacity for rational decision-making. but humans do many important things out of altruism t volunteers who participate in the challenge trials should be motivated to advance human health and wellbeing rather than driven by their economic needs u the social value argument benefits to the subject + benefits to society > risks to the subject v,w given the risks to participants, sars-cov-2 challenge studies would need to demonstrate very substantial social value before proceeding. arguably, this bar might already be met given the high death toll and severe disruption caused by the pandemic x covid-19 chis could help prioritize among the almost 100 investigational vaccines and over 100 experimental treatments for covid-19 currently in development y young healthy adults may not generalize to older individuals and those with comorbidities who would most benefit from effective vaccines z conditions" 23 /"healthy young volunteers" 24 /"young healthy adults". 25 the last part of standard 5 of the nuremberg code deserves particular attention in this context because it rejects high risk experiments with human beings be they young or old, "except perhaps", in cases where physician researchers are willing to conduct such experiments on themselves. the proponents of starting such studies all admit that there remains "significant uncertainty" with regard to the pathogenic effects of sars-cov-2 in both elderly and young people, and that high or significant risk is involved in such studies with the potential of causing severe harm, or death. 26 even if the recommendations of the nuremberg code of letting researchers themselves serve as participants had been followed strong caution is still warranted for at least six reasons. first, as uncertainty still surrounds the pathogenic effect of the sars-cov-2 in different age groups, challenge-studies would not be justified because of the lack of robust knowledge and understanding of the short term consequences of the sars-cov-2, 27 and because of the almost complete absence of data on the long term effects of the virus. 28 for these reasons it would be very difficult to justify the inclusion even of the most knowledgeable individuals in such studies, i.e. covid-19 researchers, because even the most knowledgeable are currently deeply ignorant. 29 it is worth noting here that in a document on a eyal (2020) and callaway (2020) b the international alliance for biological standardization (2019), jamrozik and selgelid (2020a, b) , menikoff (2020) , eyal et al. (2020 eyal et al. ( , pp. 1753 eyal et al. ( -1754 who (2020) and jamrozik and selgelid (2020a) . 26 eyal (2020) , who (2020) . 27 in a recent paper reviewing and synthesizing available evidence on asymptomatic sars-cov-2 infection, subclinical lung abnormalities was found even among asymptomatic persons (for this see oran 2020) . 28 this additional form of uncertainty is admitted by jamrozik and selgelid (2020a, p. 4) . 29 jamrozik and selgelid (2020a, p. 4 ) briefly address the question whether "the permissibility of high-risk human challenge studies" would increase if researchers used themselves as research participants, but they warn against this, and notably for the reason that "clinical and research staff might feel pressure to participate". 23 shah et al. (2020) . 24 . challenge-studies for vaccine development adopted in 2016 by who's expert committee on biological standardization there is no talk about accepting such studies if the risk is of the size referred to in the who-working group's report of this year; i.e. "high" risk with the potential of causing "severe harm". 30 on the contrary, in the 2016 document emphasis is on "minimizing risks to subjects" and reference is made to "situations in which there may be greaterthan-minimal risk", or risks "…considerably greater than minimal", but still manageable as "…e.g. accepting that they [the trial candidates] will develop an acute, but manageable, disease that will resolve but in the meantime may cause considerable morbidity, such as severe diarrhea managed with fluid and electrolyte replacement". 31 however, risks "considerably greater than minimal" are still far from being equal to high risk with the potential of causing severe harm. further down the same paragraph of the 2016 who expert committee document the following is added: "however, accepting such risks requires absolutely that the elements of voluntary consent are based on truly being informed". 32 it is, however, difficult to see how it would be possible to comply with this condition when so much is still unknown with regard to both the short and long-term pathogenic effects of the sars-cov-2. a valid informed consent is a legally binding absolute human rights requirement. second, if something goes wrong after infecting healthy young volunteers with the virus, the treatment options at present are limited. accepting such studies in relation to the sars-cov-2 would therefore not be in compliance with two of the core conditions in current ethical frameworks for challenge studies: namely that the pathogen studied does not induce infections that may cause severe harm, or for which there exist no effective treatment. 33 despite this, challenge studies for covid-19 are proceeding and the recruitment of health volunteers has exceeded 30,000. 34 if something goes wrong, compensation to participants ought to be a major consideration for these trials. in a recent publication, carl elliot argues that although the focus of challenge studies is to recruit healthy volunteers, if the model is based on remunerating these volunteers, the studies may attract economically vulnerable volunteers who view participation as a means to an end. 35 and as stated by ruth macklin 36 : …given standard practice, it is virtually certain that monetary payment-which may be considerable-will serve as an inducement to enroll. the likely result is that a disproportionate number of volunteers would come from lower-income brackets, including many people who lost their jobs because of the pandemic. it is also likely that many volunteers would be members of racial and ethnic minorities, raising a serious question of social justice. economically vulnerable volunteers who become injured or "permanently disabled" may not receive compensation, especially in the us. 37 in contrast to other developed countries, research sponsors in the us are not under any legal obligation to pay for the medical care of research participants who become injured or ill, hence, few do. 38 furthermore, the us national vaccine injury compensation program excludes payment for experimental vaccines. 39 research participants in the us can therefore be left without compensation for injury caused by their participation in a challenge study. third, the technical label 'controlled human infection studies' is unfortunate, because it might give healthy young volunteers and other non-experts the impression of a kind of control that is misleading. fourth, at present one does not know whether controlled infections studies conducted with young and healthy adults (or covid19-researchers) will provide results that enhance survival and/or healing-rates of those most affected by sars-cov-2, i.e. old fragile persons with comorbidities. 40 hence, there is a significant problem of external validity. fifth, the argument that participants "might benefit from controlled infection and/or vaccination if they become immune to virus" 41 is also undermined by major uncertainty, as openly admitted by the proponents of such studies. 42 sixth, and, perhaps, most important, such studies violate the core ethical principle of human subjects research; i.e. the priority of the individual principle. this principle emerged as a normative response to the medical horrors that had been practiced during wwii in concentration camps in nazi germany and in japan. yet in spite of the universal declaration of human rights and the nuremberg 33 lynch (2020) . 34 cohen (2020)-for this, see also guarino and johnson (2020) . 35 elliott (2020) . 36 macklin (2020) . 37 elliott (2020) . 38 ibid. 39 ibid. 40 jamrozik and selgelid (2020a) . this concern is also raised by deming et al. (2020) , and by schaefer et al. (2020) . 41 shah et al. (2020) . 42 shah et al. (2020) , who (2020, note 27, p. 13 code, several ethically compromised studies involving vulnerable groups have been conducted after wwii. to underscore this point, and analyze their implications, allow us to describe two such examples. first, the hepatitis studies, conducted from 1953, at willowbrook state school, an institution for mentally disabled children on staten island, new york. more than 700 children, predominantly african-american and puerto-rican, were included in these studies, and a subgroup of almost 100 non-infected children were fed a suspension with the local strains of the hepatitis virus prepared from the stool of six children collected "during the first 8 days of recognized jaundice". 43 written consent from the parents of these children had been obtained by the chief investigator, dr. krugman. but later investigations indicated that the parents' consent might have been based on indirect coercion since volunteering their children to the infection study was allegedly put forward as a condition for admitting the children to care at willowbrook state school. krugman defended the contested infection and immunization studies his whole life with reference to their scientific merits; the "confirmation of two types of hepatitis, a and b, with different infection pathways (oral versus close contact), and the preparation of a "crude vaccine" containing the hepatitis b virus. 44 in a letter to the editor of the lancet in 1971 he justified the exposure of "a small number of newly admitted children to the willowbrook strains" of the hepatitis virus with reference to: (1) inevitability; the children were "bound to be exposed" to the same virus strains "under the natural conditions existing in the institution", (2) safety; they would be admitted to "a special, well-equipped and well-staffed unit", thus shielding them from exposure to other prevalent infectious diseases in the institution, (3) immunity; "they were likely to have a subclinical infection followed by immunity", and (4) informed consent; "only children with parents who gave their informed consent would be included". 45 the second study worth mentioning is the cancer injection study that took place in the early 1960s at the jewish chronic disease hospital in brooklyn, new york. the chief investigator, dr. chester m. southam, had since 1953 conducted research on the role of the immune system in protecting against cancer, using two different groups of research participants who were injected with a suspension of foreign cancer cells to study the difference in immunological rejection of the cells between the two groups. the first group was a cohort of patients at memorial hospital in ohio, in total 300, with different forms of widespread cancer, and the second group consisted of 300 healthy individuals from the ohio state penitentiary 46 ; i.e. a prison in downtown columbus, ohio. these studies documented that healthy individuals rejected the injected cancers cells faster than the cancer patients (4-6 weeks versus 6 weeks to 3 months). 47 in his presentation of southam's studies john d. arras labeled the second group of research subjects "healthy prison volunteers", and notably, without any reflection whatsoever either about the ethical justifiability of recruiting prisoners for a study that would not benefit them, or whether it is appropriate to consider prisoners to be free to volunteer. 48 on this point southam himself seems to have been, at least, partly aware of the dilemma of recruiting incarcerated individuals. in an interview in science he admitted that, although there was no theoretical likelihood that the injections would produce cancer, he had nonetheless been unwilling to inject himself, or his colleagues, when there was a group of normal volunteers at the ohio penitentiary fully informed about the experiment and its possible risks and nonetheless eager to take part in it: "i would not have hesitated", southam said, "if it had served a useful purpose. but to me it seemed like false heroism, like the old question whether the general should march behind or in front of his troops. i do not regard myself indispensable-if i were not doing this work someone else would be-and i did not regard the experiment as dangerous. but, let's face it, there are relatively few cancer researchers, and it seemed stupid to take even the little risk". 49 southam persuaded the then director of the jewish chronic disease hospital, emmanuel e. mandel, to permit, as a third part of his immune reaction studies, the injection of foreign cancer cells into 22 old patients with other debilitating chronic diseases than cancer. the scientific justification for this study was to get "direct evidence" that it was the cancer disease that caused the delay in rejection of the foreign cancer cells, and not the fact that most of the cancer patients he had studied were elderly, debilitated and with additional chronic diseases. 50 such evidence, he maintained, would be possible to establish by doing the same immune reaction study in a group of elderly patients with other chronic and debilitating diseases than cancer. in the letter southam wrote to mandel on july 5, 1964, he also discussed whether consent ("written permission") from the patients was warranted, something which he warned against, for two reasons; first, at memorial hospital they considered it a "routine study, much less hazardous than other routine procedures", and second, the only risk related to the use of cancer cells in these injections was the "phobia and ignorance surrounding the word "cancer". 51 in the same letter southam informed mandel that with regard to the 300 prisoners, "signed permits" had been obtained, but this, according to southam, was "because of the law oriented personalities of these men, rather than for any medical reason". 52 in 1966 the two doctors were found guilty of fraud, deceit and unprofessional conduct, and they were, in particular, criticized for assuming they were entitled to perform any kind of research without consent as long as the research in question was scientifically justified. two years later, however, southam, was elected president of the american association for cancer research for the period of 1968-1969. in 2001 miller and grady proposed a way of evaluating the ethical justifiability of planned challenge-studies by locating each candidate along a continuum from legitimate studies to clearly unacceptable ones. in the "border zone" between these two extremes they locate studies that are neither indisputably justifiable nor clearly unacceptable. among legitimate ones they count studies for common cold, cholera 53 and malaria, 54 while chi-models for lyme disease or helicobacter pylori are labeled "more controversial". 55 finally, among clearly unacceptable studies they mention two examples; hiv-chi-studies or chi-studies for hepatitis c virus. 56 their arguments for labeling these two chi-models unacceptable were twofold; "non-existent or ineffective" treatment, and "intolerable symptoms and/or the likelihood of serious morbidity or mortality". 57 two additional possible studies deemed unacceptable are referred to in cioms' commentary on guideline 4 of the international ethical guidelines for health-related research involving humans 58 : for example, a study that involves deliberately infecting healthy individuals with anthrax or ebola-both of which pose a very high mortality risk due to the absence of effective treatments-would not be acceptable even if it could result in developing an effective vaccine against these diseases. therefore, researchers, sponsors, and research ethics committees must ensure that the risks are reasonable in light of the social and scientific value of the research, and that the study does not exceed an upper limit of risks to study participants. an additional example-deemed unacceptable at the time of the evaluation-was a zika virus-chi-study. 59 the nih ethical review committee's reasons for deciding against the study were with reference to three kinds of uncertainty; uncertainty of the risk to research participants as well as to third parties (fetus and sexual contacts), uncertainty about the duration of protection needed, and, third, uncertainty of the study's societal value. 60 viewing the studies conducted by drs. krugman and southam in the light of miller and grady's differentiation between legitimate, more controversial and clearly unacceptable challenge-studies, and in view of current ethical standards pertaining to such studies, calls for reflection, not only for historical reasons; they may also be of help in investigating where the arguments in favor of chi-studies in the current context of the covid-19-pandemic differ from those of krugman and southam, and where these arguments seem to overlap. when it comes to locating the studies under discussion along the ethical line of decreasing permissibility proposed by miller and grady, southam's immune reaction studies on elderly, debilitated subjects arguably deserve the label ethically unacceptable, in spite of their scientific merits, for at least three reasons: (a) no consent was obtained, (b) 53 a chi-study in 197 healthy volunteers contributed to the development and licencing of the live oral cholera vaccine cvd 103-hgr study in 1993. for this, see: roestenberg et al. (2018, p. 4) . 54 in 2015, the first malaria vaccine allegedly achieved through the use of chi-studies gained ema approval. for this, see roestenberg et al. (2018, p. 4) . for this, see also: european medical agency: https ://www.ema.europ a.eu/en/docum ents/medic ine-outsi de-eu/mosqu irixsumma ry-publi c_en.pdf. 55 for such a study, see: graham et al. (2004) . 56 grady (2001, p. 1032) . 57 ibid., p. 1032. 58 cioms (2016, p. 10). 59 the international alliance for biological standardization (2019, p. 88). 60 ibid., p. 88. for a similar verdict concerning a zika chi-trial, see recommendation 2 in shah et al. (2017, p. 27) : "whether a zika virus human challenge trial has sufficient social value to proceed depends on the reasons for doing it and whether there are alternative ways to obtain the information. the most compelling rationale for conducting a zika virus human challenge trial, given the risks and uncertainty, would be if field trials were prohibitively difficult to conduct in light of a waning epidemic. this rationale is not currently met, but it could come to pass in the future. another valuable reason to conduct a challenge trial would be to accelerate the development of a vaccine that could prevent congenital zika infection. this rationale must be accompanied with strong evidence that results from a zika virus human challenge trial would be used by stakeholders (e.g., indication from regulatory agencies that finding a correlate would speed up the licensing of a vaccine). the committee did not hear sufficient evidence that this rationale is currently met. finally, using a challenge trial solely to learn about the pathogenesis and natural history of zika infection is unlikely to justify the risk involved given the alternative ways to obtain similar information". 51 southam in his letter to mandel. 52 ibid. the element of deceit involved and (c) the fact that participants did not stand to benefit in any ways from the studies. southam's reluctance against using himself and colleagues as study subjects was based on two considerations: first, exposure to possible risks caused by the injection of foreign cancer cells; second, since neither he nor his colleagues were physically debilitated they were unsuitable candidates for the study. in two of the position statements referred to above reservation is expressed against using researchers as studysubjects in covid-19 cih-studies, although for a different reason; "clinical and research staff might feel pressure to participate", 61 and "such individuals could feel pressured to participate (thereby undermining the voluntariness of informed consent". 62 krugman's challenge studies at willowbrook are more difficult to locate and label according to miller and grady's linear differentiation, not least because his defense of the studies has several striking similarities with arguments used in favor of conducting chi-studies to speed up the development of efficient vaccines against the sars-cov-2 virus. first the reference to the studies' scientific merit; the "confirmation of two types of hepatitis, a and b, with different infection pathways, and the preparation of a "crude vaccine" containing the hepatitis b virus. 63 a similar type of argument is used by and shah, miller, darton et al. 64 : for example, chis could clarify dynamics of infection, viral pathogenesis, and risk of vaccine pathogenesis or identify correlates of protection-all of which could inform the development and implementation of vaccines. second, their high social value. in his letter to the editor of the lancet in 1971 krugman emphasized the high social value beyond willowbrook of his studies: "it is unnecessary to point out the additional benefit to the world-wide population which have been plagued by an insoluble hepatitis problem for many generations". 65 in support of such arguments, shah, miller, darton et al. argue 66 : sars-cov-2 chis could have high social value in several ways. for example, they could help prioritize among the almost 100 investigational vaccines and over 100 experimental treatments for covid-19 cur-rently in development. chis could help identify the most promising agents, which would inform the design of larger trials, guide decisions to scale up manufacturing early, and thereby accelerate product development and implementation. in a similar vein, singer and chappel refer to the high social value, or in their wording-"the broader humanitarian benefits"-of such studies. 67 third, the exposure of a small number of individuals to risk for the sake of benefits to the rest. different versions of this argument are used in the four position statements, 68 and also by the international alliance for biological standardization. 69 fourth, the endemic argument-the children were "bound to be exposed" to the same virus strains "under the natural conditions existing in the institution". 70 two 2020-versions of the same argument read: "the risks in question do not entail a major net increase in risk (in light of background risks of infection", 71 and "participants face a background risk of infection in the community". 72 fifth, the safety-and better care argument. in krugman's wording the study subjects would be admitted to "a special, well-equipped and well-staffed unit", 73 to minimize risks to study personnel, participants should be in inpatient isolation, with contact reduced to the extent possible and robust personal protective equipment provided. and who's working group highlights the importance of "supportive care, including critical care" and "long-term follow-up" as two crucial risk-minimization strategies. 75 sixth, the immunity-argument; krugman argued that the children involved in his studies "were likely to have a subclinical infection followed by immunity" 76 , while who's working group refers to "[i]mmunity induced by experimental vaccines" as a potential benefit of study participants. 77 jamrozik and selgelid combine the safety-/better care argument with the immunity argument 78 : …potential direct benefits of being infected with sars-cov-2 in the course of human challenge studies would include participants being exposed to less infection-related risk than if they are infected in the community (e.g. because of early diagnosis and medical care) and gaining immunity to future infection in the context of a high background risk. seventh, and last but not least, krugman as well as the authors of the four position statements referred to above all emphasize the importance of informed consent. 79 this comparison between krugman's arguments and the arguments in the four position statements here subject of detailed analysis and in other recent papers advocating the use of covid-19 chis shows that their overall views are pretty much the same. in fact, the only difference in terms of substance is the use of vulnerable individuals or groups as study-participants which two of the four position statements warn against. 80 singer and chappel do not address this issue, while the authors behind the fourth position statement, jamrozik and selgelid, in a recent paper on cih studies in endemic settings, argue that sometimes it may be justifiable, in fact "ethically important" to include vulnerable populations: "…especially where the results of research in other populations are not likely to be generalisable to the vulnerable populations in question. this is one consideration that sometimes favours conducting (more) hcs in low-middle income countries (lmics)". 81 so where does all this lead us? should we accept the 'neo-krugman'ian' views advocated by proponents of covid-19 chis, or should we rely on the normative principles that were formulated as a reaction to the kind of studies southam and krugman had conducted? of these principles the priority of the individual principle is the most fundamental. the original formulation of this principle in biomedical research ethics occurred in the first, i.e the 1964-version of the declaration of helsinki as basic principle 5 and reads 82 : every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. concern for the interests of the subject must always prevail over the interests of science and society. this principle has been maintained in all versions of the declaration. in the latest version (wma 2013) it is included as general principle 8: while the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects. whereas the declaration of helsinki is a professional ethics norm, the principle was restated in article 3 of the une-sco universal declaration on bioethics and human rights, which was adopted by all member states of the united nations in october 2005, and notably with reference in the first section of the article to human dignity, human rights and fundamental freedoms: the interests and welfare of the individual should have priority over the sole interest of science or society. in their position statement singer and chappell claim that current research-ethical principles are based on "assumptions developed in calmer times when much less was at stake". 83 this claim is historically wrong, as this is not the first time the world has faced a public health crisis since the development of the core principles of research ethics. we have managed to live through those less calm times without 77 who (2020, p. 8). for the immunity argument, see also eyal (2020, p. 30) . 78 jamrozik and selgelid (2020a, p. 3) . a slightly different version of this argument reads thus: "in short, if researchers conducting challenge trials act as recommended, admittedly, the probability of getting infected would remain larger inside a challenge trial than either outside any trial or in a standard efficacy trial; but the probability of death or disability is likely to be much smaller inside a challenge trial than in these alternative scenarios. overall, a × b could be smaller for any individual inside the challenge trial than either outside any trial or in a standard efficacy trial. what the individual would lose in the probability of averting infection (with that probability rising) she could gain in better protection from death" (eyal 2020, p. 27) . 79 krugman (1971, p. 967) : informed consent by proxy; shah et al. (2020, p. 3): "robust consent"; jamrozik and selgelid (2020a, p. 4): "proper" or "adequate consent"; who, 220, p. 15: "sars-cov-2 challenge studies must involve rigorous informed consent". for this, see also bambery et al. (2020, pp. 97-98) , eyal (2020, p. 29 ), plotkin and caplan 2020, p. 3987), schaefer et al. (2020), and wolemonwu (2020, p. 3) . 80 shah et al. (2020, p. 3): «sites should be selected for sound scientific reasons while avoiding especially vulnerable populations"; who (2020, p. 13): "those whose background risk is high as a result of social injustice should be excluded from participation because their inclusion could be considered unethical exploitation (i.e., taking advantage of those who have already been wrongly disadvantaged. any prospective participants who could reasonably be perceived to be vulnerable in other ways that would undermine their consent or put them at greater risk (for example as a result of the mental health strain of inpatient isolation during the study) should also be excluded". 81 jamrozik and selgelid (2020b, p. 11 ). 82 https ://www.cirp.org/libra ry/ethic s/helsi nki/. 83 infringing those principles, and we have no particular reason to overstep them now. so to conclude our analysis and critique of controlled human infection studies (chis) with sars-cov-2: there is a consistent, historical line of research ethical principle from nuremberg, through the revisions of the helsinki declaration, and the successive un human rights declarations and other normative documents. this principle is that the interests of the individual research participant is paramount in research ethics, i.e. that if there is a conflict between the interests of society (e.g. in speeding up vaccine development) and the interests of the participants (e.g. in not dying or being permanently harmed) then the interests of society has to yield to the interests of the participant. there is no exception for times of crisis, or for instances where societal interests are large. one might argue against this principle, and some have done so, but well-founded and sustainable ethical principles can't be disregarded just because they seem inconvenient at a certain point in time. the concern here is not just an abstract philosophical principle, but a part of the normative core of all existing research ethics processes. if we take this principle seriously it prohibits the conduct of sars-cov-2 challenge studies at the present time where the challenge virus would be the native virus with full virulence and where there is no rescue treatment yet available. in a policy forum statement in science alex london and jonathan kimmelman, warn against "pandemic research exceptionalism" and against using crises as an excuse for lowering scientific standards. 84 they focus on five epistemological conditions of "informativeness and social value" that research should embody, even in times of emergency: first, importance 85 : trials should address key evidence gaps…as of this writing, more than 18 clinical trials enrolling more than 75,000 patients have been registered in north america for testing various hydroxychloroquine regimens for covid-19. this massive commitment concentrates resources on nearly identical clinical hypotheses, creates competition for recruitment, and neglects opportunities to test other clinical hypotheses. second, rigorous design. third, analytical integrity: "designs should be pre-specified in protocols, prospectively registered, and analyzed in accordance with pre-specification". fourth, complete reporting: "trials should be reported completely, promptly, and consistently with pre-specified analyses". fifth, and last, feasibility: "studies must have a credible prospect of reaching their recruitment target and being completed within a time frame where the evidence is still actionable". 86 similar warnings against research exceptionalism, and notably with reference to things that went wrong in the past when arguments in favor of this were used, are made by deborah doroshow, scott podolsky and justin barr 87 : the coronavirus disease 2019 (covid-19) pandemic has incited remarkable disruption in biomedical research. at academic institutions worldwide, laboratories have been forced to halt all but the most critical activities. clinical trials of novel agents for such diseases as cancer are temporarily suspended, limiting access to potentially life-prolonging medications […] although this boom has already begun to transform our response to the pandemic for the better, medical and scientific responses to past crises suggest that urgency may also result in compromised research quality and ethics, which may in turn jeopardize public faith in government and science, waste precious resources, and lead to the loss of human life. another problem with knowledge-production of the covid-19 pandemic has been the lowered standards of quality assurance of published research. it has been documented that the peer review process has been rushed ("express" or "opinion based peer review") 88 and so far (october 28, 2020) 37 research papers about covid-19 have been retracted. 89 a stunning example of this is an observational study based on the health records of almost 100,000 patients around the world published in the prestigious journal lancet in may 2020, which indicated that hydroxy-chloroquine had a sharply higher risk of death and heart problems compared to those who did not receive the drug, and that hydroxychloroquine did not provide any benefit. 90 on june 4, 2020 this study was retracted by the authors due to doubts about 84 london and kimmelman (2020, pp. 476-477) . 85 ibid., p. 476. 86 ibid, p. 477. 87 doroshow et al. (2020) . 88 ioannidis (2020) . 89 retraction watch. retracted coronavirus (covid-19) papers. https ://retra ction watch .com/retra cted-coron aviru s-covid -19-paper s/. 90 mehra et al. (2020a) . the veracity of the data used and the analyses conducted. 91 on june 16, 2020 preliminary clinical trial results from the recovery study of the university of oxford were broadcasted all over the world suggesting that a commonly used drugdexamethasone-reduced deaths among the sickest covid-19 patients by a third. 92 hopefully, the published study will prove this claim to be justified, but it is unfortunate when covid-19 researchers start "doing science by press release" 93 instead of following generally accepted publication procedures. as stated by dr. atul gawande at brigham and women's hospital in boston 94 : typically, researchers extensively detail their work in scientific journal articles. before publication, other scientists take an in-depth look at how the study was designed, who the patients were and whether any potential side effects were uncovered-a process called peer review. it takes time-weeks or months in some cases-for independent, unbiased experts to pore over the manuscripts, looking for any concerns. taking epistemic shortcuts inevitably produces poor evidence and often leads to bad decisions with potentially severe consequences for vulnerable persons. although tempting, we should avoid epistemic shortcuts, as high-quality evidence is needed in exceptional times, as otherwise. when taking chances, we must consider the risks of harm, not only the benefits. one such risk worth mentioning here is that persons selected for testing emergent vaccines become victims of enhanced disease, i.e. presenting worse symptoms from the effects of an unproven vaccine compared to persons catching e.g. the covid-19 flu through usual paths of contagion. potential covid-19 vaccine volunteers might e.g. end up with life-threatening complications (such as irreversible and untreatable clogged lungs) whereas, in the current situation most unvaccinated patients display only mild flu-indicators, if infected. as there as yet does not exist any known therapy, the perils these volunteers risk is ethically unacceptable. 95 two examples of enhanced disease precipitated by insufficiently proven vaccines occurred in connection with the inoculation of children against rsv (respiratory syncytial virus in the late 1960s. 96 similarly, from october 1976 to january 1977 more than 40 million adult citizens in the usa were vaccinated with a swine influenza virus vaccine. during the same period more than 500 vaccinated persons fell ill with a rare neurological illness (guillain-barré syndrome) and 25 of them died. 97 these unexpected events led to immediate cancellation of the vaccination program indicating that the effects of an insufficiently tested vaccine in some cases cause greater harm than benefit. hence, ethical reflection and compliance with epistemological rules of play are needed more than ever. in a paper reflecting on what might be learned from the 1976 swine flu vaccination program, sencer and millar warn against politicization of scientific information in a way that is well worth listening to also for today's public health leaders and their political peers 98 : while all decisions related to niip [the national influenza immunization program] had been reached in public sessions (publishing of the initial virus findings in cdc's weekly newsletter, the morbidity and mortality weekly report (mmwr); new york times reporter harold schmeck's coverage of the acip [the advisory committee on immunization practices of the united states public health service] sessions, the president's press conference, and 4 congressional hearings), effective communication from scientifically qualified persons was lacking, and the perception prevailed that the program was motivated by politics rather than science. in retrospect (and to some observers at the time), the president's highly visible convened meeting and subsequent press conference, which included pictures of him being immunized, were mistakes. these instances seemed to underline the suspicion that the program was politically motivated, rather than a public health response to a possible catastrophe. mehra et al. (2020b) . 92 university of oxford. dexamethasone reduces death in hospitalised patients with severe respiratory complications of covid-19. june 16, 2020. accessible at: https ://www.ox.ac.uk/news/2020-06-16dexam ethas one-reduc es-death -hospi talis ed-patie nts-sever e-respi rator y-compl icati ons. on october 16, 2020, who reported that "dexamethasone is the only effective drug for coronavirus". this information is accesible at: https ://www.aa.com.tr/en/lates t-on-coron aviru s-outbr eak/who-dexam ethas one-only-effec tive-drug-for-coron aviru s/20091 14. 93 the expression "doing science by press release" we have borrowed from an interview about the study with dr. george anesi, director of the medical critical care bioresponse team at the hospital of the university of pennsylvania. accessible at: https ://www.nbcne ws.com/healt h/healt h-news/scien ce-press -relea se-docto rs-view-covid -19-drug-resul ts-excit ement -n1231 183. 94 nbc news. doctors view dexamethasone results on covid-19 with excitement and skepticism. accessible at: https ://www.nbcne ws.com/healt h/healt h-news/scien ce-press -relea se-docto rs-view-covid -19-drug-resul ts-excit ement -n1231 183. 95 macklin (2020) . 96 acosta et al. (2015) . 97 langmuir (1979, p. 660) . 98 sencer and millar (2006) . rounding them should be communicated'. 99 this goal is much better accomplished if the explanations are communicated by those closest to the problem, who can give authoritative scientific information. scientific information coming from a nonscientific political figure is likely to encourage skepticism, not enthusiasm. another function of research ethics is to provide guidance on the "compassionate use" of drugs unapproved for covid-19. in the past months we have read about compassionate use access of covid-19 patients to hydroxychloroquine and remdesivir. 100 by compassionate use (otherwise known as expanded access), we refer to 101 : …a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. in principle compassionate use must have regulatory oversight and, in some countries such as the us, spain, and italy, research ethics committee approval as well. 102 us regulations as well as those of individual eu member states stipulate the requirements before an investigational drug can be offered to either an individual, a limited group, or a wider population. 103 but what exactly is the role of research ethics? compassionate use is therapy in the sense that the purpose of it is to cure. however, compassionate use is not only therapy. 104 it is, after all, the provision of a drug with yet-to-be determined levels of efficacy and safety. considering the not very impressive success rate of an investigational drug of only 14% (i.e., from phase 1 to successfully being licensed for market distribution), 105 the risks of compassionate use, especially when doctors cannot be provided with definitive guidance on dosage or exclusion criteria, can actually be worse than the risks of a controlled clinical trial. this being the case, research ethics guidance is imperative for access to investigational drugs via compassionate use. also, faced with a surge of sick patients suffering from a new unknown disease, well-motivated clinicians and investigators all over the world, including drug companies and funding agencies, should adopt "a more integrated approach to learning while doing", and they should join forces, i.e. engage in collaborative efforts so as to increase the "exploitation/exploration trade-offs", and, hopefully, shorten "the period until effective treatments are discovered and implemented". 106 one of the tenets of research ethics is the provision of the benefits of research to the intended patient population. all major international ethics guidelines for research have provisions with different degrees of specifications. the declaration of helsinki article 34, for example, requires clinical trial "sponsors, researchers, and host country governments" to ensure post-trial provisions to participants who, at the end of the trial, might still need the trial intervention that has been "identified as beneficial in the trial". 107 unesco's universal declaration on bioethics and human rights provides more specificity and directive. article 15 says the following 108 : benefits resulting from any scientific research and its applications should be shared with society as a whole and within the international community, in particular with developing countries. in giving effect to this principle, benefits may take any of the following forms: (a) special and sustainable assistance to, and acknowledgement of, the persons and groups that have taken part in the research; (b) access to quality health care; (c) provision of new diagnostic and therapeutic modalities or products stemming from research; (d) support for health services; (e) access to scientific and technological knowledge; (f) capacity-building facilities for research purposes; (g) other forms of benefit consistent with the principles set out in this declaration. guideline 2 of cioms' international ethical guidelines for health-related research involving humans provides a similar specification in terms of provision of the fruits of research to the population or community where the research was carried out, most especially for research conducted in low-resource settings. 109 then, on guideline 20, it stipulates the applicability of guideline 2 for research during disaster and disease outbreaks. 110 during the covid-19 pandemic, we see these principles tested again and again. there were moments filled with high spirits and solidarity. the sequencing of the genome of sars-cov-2, as well as the identification of relevant proteins and enzymes, happened at lightning speed because of spontaneous collaboration between universities from different countries. 111 we also saw how public funds were earmarked covid-19 research and therapy development. 112,113,114 at the same time, we saw how public funds were used to secure advanced orders of potential covid-19 vaccines originally researched using public funds 115 and how pharmaceutical companies played hardball with the public for covid-19 testing kits. 116 there were real reasons to be worried, most especially if pharmaceutical companies continue to be granted free rein in pricing, which usually means paying "a small fortune" for new interventions. 117 to address potential access concerns brought about by patent market exclusivity, 118 costa rica spearheaded what is now the who solidarity call for a covid-19 technology access pool. 119 specifically, this is a call for "key stakeholders and the global community to voluntarily pool knowledge, intellectual property and data necessary for covid-19". 120 it was this same spirit of solidarity that spurred the sequencing of the genome of the sars-cov-2 and it is this same spirit of pooling, collaboration, and sharing of benefits that provides hope for timely and equitable access to much needed interventions. 121 research ethics has provided this foundation, as we saw above, and it remains research ethics' task to ensure that covid-19 drug discovery and development take this course. to date, 38 countries have signed the who solidarity call, which countries such as the us and the uk have yet to become signatories. the role of research ethics in research on and with those most vulnerated by the covid19-pandemic: the case of elderly people in nursing homes older people in nursing homes are among the most vulnerable in contemporary society. this has become very clear in several countries during the covid19-pandemic. in may 2020 a report from bergen (one of the largest cities in norway) revealed that 87% of the city's covid-19 deaths stemmed from patients living in nursing homes. 122 and in sweden nursing home residents account for nearly half of deaths linked to 123 while future estimates in england are that more than half of coronavirus-related deaths will affect people living in care homes. 124 research on how to prevent deaths in nursing homes during a pandemic, and ways of minimizing the risk of contagion represent issues of great ethical and health political urgency. there are, however, several research ethical challenges related to the inclusion of nursing home residents in research projects because the pandemic has rendered them victims of additional vulnerability. 125 the more vulnerable 109 'cioms' stands for council for international organizations of medical sciences. for this, see cioms (2016). 110 ibid. 111 editorial in nature. everyone wins when patents are pooled. nature, 2020; 581: 240. 112 aj impact/europen union (2020). 113 novavax (2020). 114 cnbc (2020a). 115 cnbc (2020b). 116 dutchnews.nl (2020). 117 lazarus (2020) . 118 hoen (2020) . 119 covid-19 technology access pool, 2020. https ://www.who.int/ emerg encie s/disea ses/novel -coron aviru s-2019/globa l-resea rch-onnovel -coron aviru s-2019-ncov/covid -19-techn ology -acces s-pool. 120 ibid. 121 emanuel et al. (2020) . 122 bergens tidende: accessible at: https ://www.bt.no/nyhet er/lokal t/i/70vxd 4/26-av-30-doede -var-sykeh jemsb eboer e. 123 bbc news. accessible at: https ://www.bbc.com/news/world -europ e-52704 836. 124 the guardian. accessible at: https ://www.thegu ardia n.com/socie ty/2020/jun/07/more-than-half-of-engla nds-coron aviru s-relat ed-death s-will-be-peopl e-from-care-homes . 125 the differentiation between vulnerability and being vulnerated is important to distinguish between on the one hand persistent and on the other variable forms of vulnerability (solbakk 2011, pp. 228-238) . the persistent form of vulnerability we all share, is part of the human condition, while the second form of vulnerability is contextdependent, in the sense that some people because of disease, poverty, lack of freedom etc. are vulnerated, i.e. harmed or wounded. this distinction points to the need for a differentiation between at least two distinct regimes of protection. firstly, a human rights-based regime aimed at protecting persistent or universal vulnerability. this regime requires negative action on the part of the state, in the sense that its responsibility is to guarantee basic liberties by securing a just social order that gives equal protection to the vulnerability of each citizen. these protective measures are, however, in need of being supplemented by additional measures of protection-of affirmative actionto cope with accidental states and situations when human vulnerabil-a research participant is, the greater the risk of causing harm. furthermore, the inherent asymmetric power relation between the researcher and his/her patients fuels powerimbalance, about which we as researchers should be ever more concerned, many older and vulnerable nursing home patients, many of whom either lack the competency to consent, or are verbally deficient. the principle of consent is one of the most basic research principles. the un human rights committee notes that special protection is warranted when including persons not capable of giving valid consent. 126 in some cases a next of kin may consent on behalf of the patient, but since we cannot be sure whether this consent reflects the wishes of the patient him/herself, this poses a problem. we should therefore be aware of both verbal and non-verbal signs and reactions from the participants' signs of discomfort and resistance throughout the research process. here we will argue that researchers need a moral sensitivity, not only to avoid physical harm or risks, but also to avoid psychological and social damage. 127 it is not sufficient to conform to "procedural ethics" at the onset of a researchproject or to gain/secure approval from a research ethical committee. moral sensitivity in research may be even more important during pandemics, when research protocols seem to be "rushed" and misgivings ignored. in addition to moral sensitivity as researchers, we may also argue for a kind of ethical calmness or what guillemin and gillam refer to as "ethical reflexivity" 128 throughout the research process. the arguments presented above suggest that the role of research ethics in pandemic times is exceptionally important, but not only in the sense of deviating from hard won core ethical and epistemological principles in the wake of wwii. on the contrary, perhaps more than ever, it is vital to restate the importance of human dignity, human rights and fundamental freedoms as the normative bedrock on which medical research involving human subjects should rely. there is no alternative pathway for research ethics that is viable; returning to the core values and principles enshrined in the universal declaration of human rights is urgently needed. we therefore share the views expressed by the european group on ethics in science and new technologies in a statement on the covid-19 pandemic 129 : it is natural in these circumstances of deep uncertainty to focus on immediate action and speed of measures. this must not, however, lead to a continuous suspension of rights and liberties. we therefore call for vigilance about the necessity, evidence, proportionality of any policy and technological intervention that, even temporarily, suspends fundamental rights. consideration needs to be given to the immediate and lasting impacts that such measures have on our societies. funding open access funding provided by university of oslo (incl oslo university hospital). open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. for the scientific merit argument, see also bambery for this argument, see also eyal jamrozik and selgelid performing chi is a way to learn and test, while minimizing the number of subjects for this argument, see also eyal also eyal (2020, p. 26) highlights the importance of covid-19-chi-trial participants having "access to standardof-care life-sustaining treatments accessible at: https ://www. pharm acyti mes.com/news/fda-annou nces-two-drugs -appro ved-forcompa ssion ate-use-in-treat ing-covid -19; and, fda is allowing two drugs to be used for here's what that means publi c-healt h-focus /expan ded-acces s. for this, see also reference is here made to: department of health and human services. annex 11: pandemic influenza response and preparedness plan brief history and characterization of enhanced respiratory syncytial virus disease aj impact/europen union. 2020. eu may deploy emergency funds in covid-19 vaccine race optimizing the trade-off between learning and doing in a pandemic the jewish chronic disease case article 7 (prohibition of torture, or other cruel, inhuman or degrading treatment or punishment) ethics, reflexivity, and "ethically important moments" in research. qualitative inquiry statement on european solidarity and the protection of fundamental rights in the covid-19 pandemic footnote 125 (continued) fallen vulnerability" is a metaphor that has been suggested to designate such situations ethical criteria for human challenge studies in infectious diseases ethics review in compassionate use the medical profession & human rights. handbook for a changing agenda should we infect healthy people with coronavirus? international ethical 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1976 swine flu vaccination program interpreting diagnostic tests for sars-cov-2 ethical considerations for zika virus human challenge trial ethics of controlled human infection to study covid-19 the principle of respect for human vulnerability and global bioethics pandemic ethics: the case for experiments on human volunteers covid-19: act first, think later the international alliance for biological standardization infectious hepatitis. studies of its natural history and prevention declaration of helsinki human challenge trials for vaccine development: regulatory considerations key criteria for the ethical acceptability of covid-19 human challenge studies human challenge trials for a covid-19 vaccine: should we bother about exploitation? uncertainty and environmental learning-reconceiving science in the preventive paradigm long-term consequences of covid-19: research need key: cord-331885-8zmuhebu authors: xu, xiuyan title: risk factor analysis combined with deep learning in the risk assessment of overseas investment of enterprises date: 2020-10-02 journal: plos one doi: 10.1371/journal.pone.0239635 sha: doc_id: 331885 cord_uid: 8zmuhebu to evaluate the overseas investment risks of enterprises and expand the application and development of deep learning methods in risk assessment, 15 national clusters are utilized as samples to analyze and discuss the overseas investment risk indicators of enterprises. first, based on the indicator system of overseas investment risks, five major types of investment risks are identified. second, the deep neural network (dnn) is introduced; a risk evaluation model is constructed for enterprise overseas investment. finally, the investment attractiveness index in the fraser risk assessment learning label is adopted as the evaluation results of the model. according to the classification of risks, the model is trained and its performance is tested. the results show that the major source of overseas investment risks includes basic resources, political systems, economic and financial development, and environmental protection. the corresponding risk score is high. north american country clusters and oceanian country clusters have lower investment risks, while the investment risks in africa, latin america, and asia are affected by multiple factors of the specific cities. this is closely related to the resources and legal systems possessed by the country clusters. this is of great significance for enterprises to conduct risk assessment in overseas investment. in the overseas investment activities of enterprises, risk is the most critical problem and challenge [1, 2] . especially, for mining enterprises, their overseas investment projects are affected by multiple factors such as long periods and various uncertainties. the impact on the ecological environment is large. under the action of multiple factors, there is a greater degree of uncertainty between the investment expenditure of mining enterprises and the expected benefits. therefore, the application of scientific and effective solutions to assess the investment risks has great significance in reducing losses of enterprises and ensuring the utilization of overseas resources and energy. the assessment of investment risks has been extensively discussed by researchers. researched the risk management strategy of chemical industry clusters and found that when unexpected losses increased, enterprises were more inclined to adopt high-level investment strategies [3] . for the difficulty in calculating the a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 weight of risk assessment indicators in traditional investment risk assessment models, ren and du (2018) constructed an industrial investment risk assessment indicator system from the levels of systemic risks and non-systematic risks; on this basis, they proposed a support vector machine (svm)-based industrial investment risk assessment model for the marine foreign trade and economic zone; the results suggested that the model could assess risks through empirical analysis [4] . liu and zeng (2017) adopted the system dynamics method to analyze and discuss the investment risks of renewable energy projects,' the results revealed that policy risks, technical risks, and market risks had greater impacts [5] . yao et al. (2017) proposed a tactical exploration framework that applied grammar-based genetic planning to the generation and evolution of tactics in combat-level simulations, which could effectively reduce investment risks [6] . due to its unique advantages, deep learning has been widely used in many fields [7] . the applications of deep learning methods in the field of risk or investment have been researched extensively. xie et al. (2020) analyzed and discussed the application of deep learning in financial data processing, investment model, and investment strategy establishment, which had reference value for improving investors' investment strategy and rate of return [8] . sohangir et al. (2018) explored the application of convolutional neural network (cnn) in stock market investment forecasting; they found that deep learning models could be effectively applied to financial analysis, and cnn had the best effect [9] . liu (2019) believed that the prediction accuracy and portfolio optimization of financial risks were very important and compared the performance of support vector machines (svm) and long short term memory recurrent neural networks (lstm-rnns) in classification; the results suggested that the latter had better performance, which was of great significance for maximizing investment profits [10] . kim and won (2018) proposed a new hybrid lstm model and found that the model could be applied to the prediction of stock market volatility [11] . the above research indicates that investment assessment and investment risks have been discussed a lot. at the same time, deep learning methods have been widely adopted in market forecasting and investment. meanwhile, the assessment of overseas investment risks is less researched, let alone the applications of deep learning methods in overseas investment risk assessment. the effective assessment of risks is influential. to build a risk assessment model for overseas investment of enterprises and evaluate investment risks scientifically and effectively, the deep neural network (dnn) based on deep learning is introduced, which is an innovation. the built risk assessment model is built to provide a reference for enterprises to assess investment risks and reduce risks. from the perspective of enterprises, overseas investment risks are affected by multiple factors, and the function of each influencing factor is very unclear. it is widely recognized that the overseas investment risks of enterprises are a huge and complex system. therefore, it is necessary to design and construct an investment risk assessment system. during the entire process of constructing the assessment system, determining the construction principles and the composition of the investment risk influencing factors are the key links, which helps refining the influencing factors and indicators. on this basis, the review of literature, on-site inspections, and expert consultation are the means of model construction; in the meantime, the construction principles of scientificity, reliability, and comparability are persisted. the assessment system is divided into risk categories, project components, and risk factors. for the evaluation of venture capital, common methods include variance method [12] , coefficient and capital asset pricing model [13] , "a" scoring method [14] , value-at-risk evaluation model [15] , and comprehensive risk index model [16] . due to the complexity of different country clusters, the comprehensive risk index evaluation method is adopted. the risks in the overseas investment assessment system are divided into basic resources, economics and finance, political systems, environmental protection, and resources and energy. then, these five categories are refined. under the category of basic resources, the investment goal is to improve the infrastructure equipment in the process of overseas investment and resource development of enterprises; specifically, it includes health care, basic communications, power energy, and land resources [17] . the category of economic and finance is correlated to the economic development and financial system in the destinations of overseas investment. the investment goal of this category is to promote the optimization of enterprise profits. the risk can be evaluated by the inflation rate and gdp. here, this risk category is refined into economic growth, financing, changes in interest rates and exchange rates, inflation, credit systems, and total tax rates [18] . the risk category of political systems mainly characterizes the degree of political influences, as well as the stability of a particular country. this is a key factor in assessing the diplomatic situation, which also includes the level of rule of law and policy support. in particular, the major risk factors of the political system include regime alternation, contradictions and conflicts among surrounding powers, law system, social credit, foreign shareholding, and partners [19] . the risk factor category of environmental protection is essential for investment enterprises. when enterprises make overseas investments, they will always consider environmental protection factors, such as the legal requirements of environmental protection, the environmental law enforcement level of the investment destinations, and the impact of natural factors on environmental protection. specifically, this category, a major risk factor, is refined into environmental law enforcement and environmental expenditures [20] . the risk factor category of resources and energy includes the development and utilization of minerals and other resources. specifically, this category is refined into resource application potential and development conditions [21] . an overseas investment risk assessment system of enterprises including five major categories is thereby built. the details of categories are shown in table 1 below. of late years, deep learning technology has developed rapidly. dnn has been applied in image recognition, text detection, and other fields. compared with previous machine learning methods, deep learning technology has better performance in data fitting of complex factors [22, 23] . therefore, the deep learning method is adopted to build the overseas investment risk assessment model of enterprises. the overall construction idea includes three steps: preliminary model construction, model training, and analysis and characterization of model performance. deep learning technology includes a variety of models, for dnn, strong feature extraction ability, easy training, fast convergence speed, and simple structure composition are its characteristics [24] . considering the characteristics of investment risk assessment, dnn is applied to the construction of the enterprise overseas investment risk assessment model. in deep learning neural network models, the structure of dnn is different from traditional neural network models. it consists of the input layer, the hidden layer, and the output layer [25] . a basic model y k corresponding to dnn can be expressed as: in (1), x i represents the neural unit node of the dnn, w ik b k represents the value of the weight, b k represents the bias, and y k represents the activation function. the training process of dnn is shown in fig 1 below . on this basis, the input and output of dnn in overseas investment risk assessment are defined. x is utilized as the input value of the evaluation model, and the above five table 1 . the composition of the risk assessment indicator system for overseas investment of enterprises. basic resources health care a1 -health care (+), risk ( categories of investment risks are converted into corresponding risk indicators. first, the evaluation model is input into the sample feature dataset, which is represented by the following equation: in (2), f represents the number of features corresponding to each data, which corresponds to the risk factor indicator in the assessment model; l represents the number of labeled data, which corresponds to the investment destination in the assessment model and the training sample; u represents the number of unlabeled data, which also corresponds to the test sample. if y is the output value of the evaluation model, it will also correspond to the sample risk label dataset. in (3), c represents the number of categories corresponding to the sample label. refined into the investment risk assessment, the investment risks are divided into five different levels; level i indicates that no investment can be made, level ii indicates that the investment risk is serious, level iii indicates that the investment risk is high, level iv indicates that the investment risk is average, and level v indicates that the investment risk is low. these five different risk levels correspond to five label categories and the realization of the labeling rules, which can be expressed as: for the sample dataset in the input investment risk assessment model, feedforward calculation should be utilized to judge and express the input data features. after successive propagation throughout the layers, the data dimensionality is finally reduced. in this process, the corresponding data are constantly becoming abstract, and finally, the result can be predicted. the risk assessment model of enterprise overseas investment built here is actually a process of reducing multidimensional data to five dimensions. to solve this problem, the feedforward propagation of information in dnn can be expressed as: in (5), z (p) represents the specific state of the eigenvalues corresponding to the p-tier investment risk assessment, w (p) represents the weight matrix, f p represents the activation function corresponding to the eigenvalues of the p-tier investment risk assessment, and b (p) is the offset. the information is passed successively throughout the layers in dnn, and finally, the output of the network can be obtained. considering that data can have limitations in the target countries or regions for enterprises investment overseas, the application of labeled data can play an important role in the training of the network. if there is a set of data samples (x (i) , y (i) ): the corresponding output of the neural network after the feedforward propagation is f(x|w, b): then, the corresponding objective function o(•) can be expressed as: in (8), w represents the weight matrix corresponding to each layer, and b represents the bias vector corresponding to each layer in the neural network. based on the goal of minimizing investment risk output, the gradient descent method is applied to realize the iteration and update of parameters. the corresponding calculation is: in (9), δ represents the update rate corresponding to the parameter, and λ represents the parameter. furthermore, the error term is defined as: in (10), � represents the dot product operator of vectors. after obtaining the error term corresponding to each layer, the gradient value corresponding to each layer parameter can be obtained. according to above analysis, the entire training process of dnn is achieved through the calculation of the state and activation value of each layer, as well as the calculation of the error corresponding to each layer in the neural network, which helps update the relevant parameters. the expression level of dnn also plays an extremely important role, which can be achieved by the introduction of nonlinear activation functions. the logistic function, tanh function, and relu function are the most commonly used activation functions in traditional neural network models. however, the first two activation functions have the problem of gradient disappearance during neural network training [26] . therefore, in the proposed model, relu is used as the activation function, and its corresponding equation is: compared with the other two activation functions, the gradient calculation corresponding to the relu function can be expressed as: ( this makes the problem of gradient disappearance in the entire backpropagation process alleviated. to test the effectiveness of the dnn-based enterprise overseas investment risk assessment model, the fraser risk assessment is chosen as the learning label. this risk assessment includes multiple countries and regions [27, 28] . here, countries and regions that have continuity in the fraser risk assessment learning label from 2018 to 2019 are selected as the research samples. specifically, a total of 15 countries are included as the target countries. besides, president xi jinping of china has visited all the included countries, sharing close cooperative relations with china. in addition, the selected countries have rich resources such as minerals. the five risk assessment levels proposed above are utilized to analyze and characterize the proposed dnn-based enterprise overseas investment risk assessment model. the selected research samples are shown in table 2 table 1 above. furthermore, for output y of the risk assessment model, the investment attractiveness index of the target country or region in the fraser risk evaluation learning label is adopted as the evaluation result of the model. in addition, the corresponding label of the model output is divided into five risk levels according to the corresponding scores. therefore, the model is trained and its performance is tested. during 2018-2019, the selected overseas investment risk assessment indicators for north american country clusters and latin american country clusters are shown in fig 2a-2d below. data analysis shows that the risk assessment indicators of the two countries in north america, the united states and canada, show different indicators among the five risk levels. however, because the united states and canada have richer reserves of resources and energy, coupled with a higher level of economic development, better political systems, and sound infrastructure, the overall investment environment is better, and the overall investment risks are also lower. in contrast, however, several countries in latin america have different levels of investment risks. this is mainly due to differences in the level of economic development between countries, as well as the differences in the supply of basic resources and the rule of law system. during 2018-2019, the selected overseas investment risk assessment indicators for asian country clusters are shown in fig 3a and 3b below. data analysis shows that asian countries have richer resources and energy reserves. however, due to multiple factors, such as the development level of industries, professional skills, and capital supply, generally, these countries show higher investment risks. this is inseparable from a country's political development trends and geographic location. during 2018-2019, the selected overseas investment risk assessment indicators for african country clusters are shown in fig 4a and 4b below. analyzing the risk assessment indicators of each risk level shows that african country clusters also have abundant resources and energy reserves. however, because the overall level of economic development is poor, these countries are highly dependent on mineral resources and energy exports. in addition, the political system are often traditional so that the degree of implementation is also poor. the political situation in africa is generally stable but partially turbulent, leading to a higher level of investment risk. during 2018-2019, the selected overseas investment risk assessment indicators for european and oceanian country clusters are shown in fig 5a and 5b below. changes in the risk indicators show that the overall resource and energy reserves of the european country clusters are general; however, the basic resources, such as infrastructure, are sound and complete. the overall macroeconomic development level is lower. the overall risks at all levels are lower in several cities. australia, a representative country of oceania, has abundant minerals, coal, and other natural resources, with independent legislation among states, stable political trends, and sound infrastructure; therefore, the overall investment environment is good. the above analysis suggests that a country's infrastructure, health care conditions, economic development level, environmental protection conditions, and political system are the key components that affect its risks of enterprise overseas investment [29, 30] . in contrast, north american countries are more favorable target countries for overseas investment, which are inseparable from their resources and energy, health care conditions, economic development, and political systems. among the investment risks, the biggest disadvantage of the north american clusters is that if the investment is associated with mining, due to the high requirements for environmental protection, the labor factors and other issues must be considered. meanwhile, in latin american clusters, the main problems are the level of economic development and the imperfections of infrastructure and legal construction. in the meantime, considering the actual situation during the current covid-19 (corona virus disease 2019) pandemic, the situations in the united states and other countries are severe, which also needs to be noted in investment. asian countries have abundant resources and energy reserves; besides, the overall political development situation is stable [31] . however, the policies for investment are not perfect and stable enough. changes in leadership will trigger adjustments and changes in policies; therefore, problems in the efficiency and concepts of the government have led to an increase in investment risks. in the meantime, the presentation of the final result of investment risks is inseparable from a country's geographic location. in terms of development stage, africa is still in the initial period of industrialization. although the momentum of development in recent years has become stronger, the overall facilities and systems need to be improved. in addition, the health care conditions in africa are backward. natural disasters and infectious diseases occur frequently. this is a concrete manifestation of the risks of african country clusters in overseas investment, which is also an aspect that needs attention. the enterprise overseas investment risks of european and oceanian clusters also illustrate the important role of several risk factors in investment. a total of 15 country clusters with different geographical locations are chosen as the research objects. based on risk factor analysis, the dnn-based enterprise overseas investment risk assessment model is tested. the results suggest that the investment risk indicators can clearly show the level of investment risks. the investment risk level of each country is comprehensively affected by basic resources and energy, political systems, and economic and financial development levels. the above results have provided basic data support for the risk assessment of enterprises overseas investment. however, the assessment of enterprise investment risks is still in the exploratory stage. affected by multiple objective factors, the sample data only include the risk indicators during 2018-2019. as the research continues to be expanded, the sample data will be increased in the future to obtain more valuable results. supporting information s1 data. 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based natural language processing deepsurv: personalized treatment recommender system using a cox proportional hazards deep neural network hierarchical modeling of molecular energies using a deep neural network deep binary reconstruction for cross-modal hashing health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: a survey study anticipated health behaviour changes and perceived control in response to disclosure of genetic risk of breast and ovarian cancer: a quantitative survey study among women in the uk overseas direct investment and exports in korea: a time series approach the influence of investor-centered values in the operation of political risk insurance risk and opportunity assessment for water cooperation in transboundary river basins in south asia resources: xiuyan xu. writing -review & editing: xiuyan xu. key: cord-332051-yw5zlucc authors: aghababaei, soodabeh; bashirian, saeed; soltanian, alireza; refaei, mansoureh; omidi, tahereh; ghelichkhani, samereh; soltani, farzaneh title: perceived risk and protective behaviors regarding covid-19 among iranian pregnant women date: 2020-09-18 journal: middle east fertil soc j doi: 10.1186/s43043-020-00038-z sha: doc_id: 332051 cord_uid: yw5zlucc background: despite the vulnerability of pregnant women, few studies have been conducted on their perceived risk and protective behaviors during the covid-19 pandemic. the present cross-sectional study aims to investigate the perceived risk and protective behaviors regarding covid-19 among pregnant women, in hamadan, iran. using a two-stage cluster sampling method, 225 pregnant women referring to the health centers completed the questionnaires. data were analyzed using the kruskal-wallis and spearman correlation tests as well as a stepwise linear regression model at 95% confidence level. results: 93.8% of pregnant women had a high level of knowledge, 97.3% had a high performance in protective behaviors, and 72.9% had a moderate level of risk perception related to covid-19. the highest mean score of knowledge was observed in women who had a history of influenza in their previous pregnancies (90.97 ± 5.94). the mean score of protective behaviors was significantly higher in women with a high economic level (97.78 ± 5.11), and the highest level of risk perception was observed in nulliparous women (59.97 ± 9.80). risk perception was an independent predictor of protective behaviors related to covid-19 (p < 0.05). conclusions: pregnant women had a high level of knowledge, high performance in protective behaviors, and a moderate level of risk perception related to covid-19. history of influenza in previous pregnancies, high economic level, and nulliparity were associated with higher levels of knowledge, protective behaviors, and risk perception, respectively. risk perception of pregnant women regarding covid-19 can predict their protective behaviors. in the last days of 2019, an unknown outbreak of pneumonia was reported in eastern china, which was recognized by the world health organization as covid-19 [1] . the most important route of transmission agreed by all is respiratory droplets or direct human-to-human contact [2] [3] [4] . covid-19, which has now become a pervasive epidemic, is a serious public health emergency that is deadly, especially in vulnerable populations and communities where health systems are not sufficiently prepared to manage the infection [4] . pregnant women and their fetuses are at high risk during the outbreak of infectious diseases [5] . in general, physiological and mechanical changes during pregnancy increase susceptibility to infections. researchers have shown that emerging infections have a significant impact on pregnant women and their fetuses [6] . previous data from sars and mers infections show that clinical findings during pregnancy can range from mild symptoms to severe illness and death [7] . it seems that coronavirus infection in the third trimester of pregnancy increases the risk of premature rupture of the membranes, preterm labor, fetal tachycardia, and fetal distress [8] [9] [10] . therefore, it is important that pregnant women and their families, as well as health care providers, receive as much accurate information as possible. during the corona epidemic, it is recommended that pregnant women take care of personal and social hygiene and avoid unnecessary trips, crowded places, public transportation, and contact with sick people [9] . pregnant women have different attitudes toward the recommendations of health care providers. some evaluate the given instructions based on their views and experiences and change them if they do not feel useful, but some women carefully follow the treatment plans and welcome health care to reduce the risk [11] . in pandemic diseases, perceived risk encourages people to engage in protective behaviors to reduce potential risks [12] . globally, risk is defined as the probability of loss and is thought to be composed of two components: probability and severity of negative outcomes [13, 14] . meanwhile, risk perception is defined as a person's expectation of a particular event occurring [15] . risk perception as an important determinant of healthy behaviors plays an important role in designing interventions to change behaviors [16] . in the study of ackerman et al. on the iranian pregnant women, the higher fear of covid-19 was associated with higher preventive behaviors. covid-19 pandemic is the most intense and emotional experience of pregnant women's lives. in this regard, health care providers should pay more attention to pregnant women who have health concerns at the same time about themselves and their fetuses. currently, the mortality rate from covid-19 is lower than previous epidemics such as sars and mers. however, stress and anxiety may be the most important challenge in the covid-19 pandemic [17] . transmitting large amounts of information and overuse of the media can lead to overreaction, irrational fear, and overperception of risk, which in turn might affect pregnant women's behaviors [18] . psychobehavioral surveillance is critical during communicable disease outbreaks because it affects risk awareness strategies targeting high-risk groups such as pregnant women [19] . measuring the level of risk perception as well as its determinants in pregnant women is essential for the transmission of information and health protocols. despite the vulnerability of pregnant women during the covid-19 pandemic, few studies have been conducted on their risk perception and protective behaviors. the present study aims to investigate the perceived risk and protective behaviors regarding covid-19 among iranian pregnant women. this cross-sectional study was conducted on 225 pregnant women referring to the health centers to receive prenatal care in hamadan, iran, 2020. the inclusion criteria included normal singleton pregnancies, without medical or obstetrical complications, and the ability to read and write. pregnant women who did not answer more than 10% of the questionnaire items were excluded from the study. considering the standard deviation of the knowledge of covid-19 in women (about 16.58), 96% confidence level, and maximum error equal to 15% standard deviation, the sample size was calculated to be 225 pregnant women. the sample was drawn through a two-stage cluster sampling method. first, hamadan city was divided into four geographical regions (north, south, east, and west), and then two health centers were randomly selected from each region using the list of health centers (8 health centers in total). thirty eligible pregnant women were randomly selected from each center, and after obtaining the informed consent of the participants, the self-administered questionnaires were completed with observing health protocols. the questionnaire consisted of 4 sections including the following: 1. socio-demographic and obstetrics characteristics: including age, education level, place of residence, housing status, economic situation, gestational age, parity, pregnancy status, history of abortion, number of children, history of influenza in the previous pregnancies, and sources of information about covid-19. 2. covid-19-related knowledge (16 items): the items were designed based on the health protocols by the world health organization [20] , as well as the ministry of health and medical education, iran ( table 1 ). the aspects of knowledge included etiology, symptoms, transmission, and public prevention. correct answers were assigned 1 point, and incorrect answers or "i do not know" were assigned 0 points. the total score was converted into a percentile. a score ≥ 75% was designated as high, 50-75% as moderate, and ≤ 50% as low level of knowledge. 3. covid-19-related risk perception (7 items): using the visual scale measure [21, 22] , perceived risks of maternal infection, fetal infection, fetal anomalies, abortion or fetal death, preterm delivery, hospitalization the newborn in the neonatal intensive care unit, and maternal death due to coronavirus infection were measured. responses were given based on a lickert range from 0 (no perceived risk) to 10 (high level of perceived risk). the total score, which was between 0 and 70, was calculated from the score of 100. in this study, a score of less than 40 was considered the low perceived risk, a score between 40 and 60 was considered the moderate perceived risk, and a score higher than 60 was considered the high perceived risk. the items were designed based on the health protocols by the world health organization [20] , as well as the ministry of health and medical education, iran ( table 1 ). the aspects of preventive behaviors included social distancing, personal hygiene and frequent hand washing, public transportation, out-of-home prepared foods, and shopping. responses were "yes" or "no," and the participant was assigned 1 point for each appropriate behavior and 0 point for inappropriate behaviors. the total score was converted into a percentile. a score ≥ 75% was designated as high, 50-75% as moderate, and ≤ 50% as low level of knowledge. the validity of the questionnaire was assessed using different experts' opinions, and its reliability was calculated using the cronbach α coefficient (0.89). statistical analysis was performed using spss/24.0, at the 5% significance level. using the kolmogorov-smirnov test, none of the major outcomes followed a normal distribution and was analyzed using the kruskal-wallis and spearman correlation tests. stepwise multivariate linear regression analysis was performed to determine the most predictive indicator for preventive behaviors. the frequencies and percentages were computed for categorical variables, and the means and standard deviations were calculated for numerical variables. a total of 240 pregnant women were enrolled in this study, and 225 people responded to the questionnaires. the mean age of women was 30.24 years. the majority of participants had college education (36.4%), were unemployed (90.2%), had a moderate economic situation (72.9%), and lived in their personal houses (49.8%). the mean gestational age was 25.71 weeks. the majority of participants were primigravida (45.8%), had a wanted pregnancy (79.6%), had regular prenatal care (95.6%), and did not have a history of abortion (78.2%) or influenza in the previous pregnancy (96%); 71.1% of pregnant women said that television was the main source of their information about covid-19. table 1 shows the distribution of participants' responses to the items of knowledge and preventive behaviors related to covid-19. the average of correct answers was 84.54% in the knowledge section. the lowest scores pertained to q9 (children do not get the disease), q14 (everyone in the community should wear a mask), q15 (coronavirus can be treated with common antiviral drugs), q16 (the flu vaccine can be given every year to prevent the coronavirus). in the preventive behaviors section, the average of correct answers was 95.8%. the lowest score (89.3%) pertained to "i keep my distance from others at home." according to the results, 93.8% of pregnant women had a high level of knowledge related to covid-19. 97.3% of the participants had high performance in preventive behaviors, and 72.9% of pregnant women had a moderate level of risk perception related to the disease ( table 2 ). the mean score of knowledge in women who had a university education, their source of information was an obstetrician, had two or more children, and had a history of influenza in the previous pregnancy was significantly higher (p < 0.05) ( table 3) . the highest mean score of knowledge was observed in women who had a history of influenza in their previous pregnancies (90.97 ± 5.94), and even in these women, the average level of risk perception and preventive behavior was higher than in pregnant women who did not have a history of influenza. the mean score of preventive behaviors was significantly higher in women with a high economic level (p < 0.05), so the highest score of preventive behaviors (97.78 ± 5.11) also belonged to this group of women. the mean score of risk perception in nulliparous women and those without a history of abortion was significantly higher (p < 0.05). the highest level of risk perception was observed in nulliparous women (59.97 ± 9.80), and the lowest level was observed in pregnant women who experienced two or more abortions (42.54 ± 8.28). the spearman correlations between knowledge, protective behaviors, and risk perception related to covid-19 are presented in table 4 . risk perception was positively associated with protective behaviors (r = 0.146, p = 0.031). the knowledge negatively associated with protective behaviors, but this relationship was not statistically significant (r = − 0.125, p = 0.069). we also performed a linear regression analysis considering all studied risk factors to determine the most predictive indicator for protective behaviors. in table 5 , we present the final multivariate linear regression model. stepwise multivariate linear regression analysis revealed that risk perception was an independent predictor of protective behaviors (β = 0.146, p = 0.029). although the effect of covid-19 on pregnant women is still unclear, there are concerns about its potential impact on maternal and perinatal outcomes due to suppression of the immune system during pregnancy [23] . however, few studies have been conducted on perceived risk and protective behaviors among pregnant women during the covid-19 pandemic. the present study addressed this important issue and measured the level of risk perception, knowledge level, and protective behaviors of pregnant women, as well as the relevant determinants. the present study showed that the level of knowledge related to the covid-19 and its transmission and mann-whitney u value *significant at the level of p < 0.05 prevention was high among pregnant women, so this level of awareness about the symptoms of the disease, and in particular the ways in which it is transmitted, has been almost above 95%. it seems that the awareness of pregnant women, both through the mass media and by health care providers, has increased significantly. in a study by nwafor et al., 60.9% of pregnant women had sufficient knowledge of preventive measures against covid-19 [24] . yassa et al., in their study on pregnant women near childbirth, found that pregnant women have a positive attitude toward quarantine. at the same time, they expressed their progressive anxiety and concern for the pregnancy and the baby due to the pandemic and also believed that they had been given insufficient counseling or limited information about the relationship between pregnancy and pandemic [25] . in the present study, the majority of pregnant women [about 62%] believed that the general population should use masks to prevent disease; nearly 29% opposed it, and about 10% said they were unaware. it should be acknowledged that the unknown nature of covid-19, and even its transmission, along with the different policies of different countries on disease protection, can have a significant impact on people's responses. besides, researchers have noted the sensitivity and concern of pregnant women about their vulnerability to infectious diseases. for example, an interview study conducted during the h1n12009 influenza pandemic revealed that the individuals most concerned for the possibility of getting infected or transmitting the virus to others were pregnant women and those with young children [26, 27] . in the present study, 32% of pregnant women did not know that children could also develop covid-19. about 40% of women did not know that the disease could not be treated with common antiviral drugs, and about 45% of pregnant women thought that the flu vaccine could be given every year to prevent the covid-19. while the clinical evidence was growing rapidly, this data may guide to perceive what accurate information should be provided to pregnant women. our results showed that more than half of pregnant women obtained their information through tv. similar to our findings, other studies reported that participants usually obtained their information about infectious diseases through the internet and watching tv. olapegba and ayandele in a study in nigeria reported that traditional media [tv/radio] was the source of information regarding covid-19 for more than 93.5% of people [28] . in a similar manner, sasaki et al. found that television, the internet, and newspapers were the most common sources of information about the h1n1 outbreak [29] . according to our study, women with a university education were significantly more aware of the disease than women with less education. in the recent study of nwafor et al., one of the factors associated with inadequate knowledge of preventive measures regarding covid-19 was no formal education [24] . the level of knowledge of pregnant women who had more children was significantly higher, and although nonsignificant, their risk perception was lower and their preventive behavior was better. contrary to our study, in the study of nwafor et al., pregnant african women who had given birth five or more times had lower levels of awareness about preventive measures related to covid-19 [24] . the greater awareness of pregnant women with a previous history of influenza in the present study can be related to the increased sensitivity of this group of women to the risk of contracting viral diseases during pregnancy and its complications. pregnant women in our study reported high levels of protective behaviors related to covid-19. it seems that during acute conditions such as epidemics, due to extensive training and information transition, high preventive behavior can be expected from individuals. in the usa, over the course of a few days, people became increasingly aware of the dangers of covid-19 and performed well on protective behaviors [30] . in our study, pregnant women with better economic status had better protective behaviors. in a study by chandrasekaran et al. [31] , knowledge and behavior related to zika disease were lower in women with poor economic status compared to women with moderate to high status. therefore, special attention should be paid to women with low economic status, especially during pandemics. nulliparous women in our study had a higher level of risk perception related to covid-19 than multiparous women. similar to the risk perception in other fields, pregnancy risk perception is highly individualized and several factors may influence the perception of pregnancy risk [17] . risk perception is the subjective response based on previous life experiences, coping strategies, the context in which the risk occurs, and the degrees the risk obtained from a variety of sources [32] . little is known about how risk impacts a woman's perception and experience of pregnancy [33] . however, it seems that the experience of pregnancy and childbirth can reduce the perceived risk. the results of the present study showed that risk perception can predict preventive behaviors significantly. in contrast to our study, taghrir et al., in the recent study on the medical students, reported a negative correlation between preventative behaviors and risk perception related to covid-19 [34] . risk perception as a determinant of protective behaviors is often positively associated with preventative behaviors, although in some cases negative interactions with preventive behaviors have been shown, for example, when the perception of risk is high, but the chance of success in dealing with it is considered low, preventive behaviors are reduced [35] . the main strong point of the present study is addressing pregnant women as a vulnerable group during the covid-19 pandemic. yet, the causal relationships among the variables could not be assessed due to the cross-sectional design of the study. iranian pregnant women had a high level of knowledge, high performance in protective behaviors, and a moderate level of risk perception related to covid-19. history of influenza in previous pregnancies, high economic level, and nulliparity were associated with higher levels of knowledge, protective behaviors, and risk perception, respectively. risk perception of pregnant women can predict their protective behaviors against covid-19. the results of the present study, as one of the first study on the risk perception and protective behaviors of iranian pregnant women during the covid-19 pandemic, can be used by researchers and health planners in similar future crises. abbreviation covid-19: coronavirus disease of 2019 a novel coronavirus from patients with pneumonia in china transmission of 2019-ncov infection from an asymptomatic contact in germany epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study coronavirus disease 2019 (covid-19) coronavirus disease 2019 (covid-19) pandemic and pregnancy public health approach to emerging infections among pregnant women coronavirus disease 2019 (covid-19) and pregnancy: what obstetricians need to know novel corona virus disease (covid-19) in pregnancy: what clinical recommendations to follow? experience of clinical management for pregnant women and newborns with novel coronavirus pneumonia in tongji hospital, china analysis of the pregnancy outcomes in pregnant women with covid-19 in hubei province factors influencing pregnant women's perceptions of risk the effects of social media use on preventive behaviors during infectious disease outbreaks: the mediating role of selfrelevant emotions and public risk perception risk perception among women at risk for hereditary breast and ovarian cancer the risk perception paradox--implications for governance and communication of natural hazards perceptions of risk characteristics of earthquakes compared to other hazards and their impact on risk tolerance risk perceptions and health behavior the novel chinese coronavirus (2019-ncov) infections: challenges for fighting the storm data for understanding the risk perception of covid-19 from vietnamese sample behavioral responses to the influenza a (h1n1) outbreak in malaysia world health organization (2020) coronavirus disease (covid-19) advice for the public psychometric testing of the perception of pregnancy risk questionnaire difference in perception of pregnancy risk in two maternal age groups clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study okedo-alex in (2020) pregnant women's knowledge and practice of preventive measures against covid-19 in a low-resource african setting near-term pregnant women's attitude toward, concern about and knowledge of the covid-19 pandemic understanding the school community's response to school closures during the h1n1 2009 influenza pandemic the psychological impact of quarantine and how to reduce it: rapid review of the evidence survey data of covid-19-related knowledge, risk perceptions and precautionary behavior among nigerians. data brief 30:105685 attitudes about the 2009 h1n1 influenza pandemic among pregnant japanese women and the use of the japanese municipality as a source of information changes in risk perception and protective behavior during the first week of the covid-19 pandemic in the united states socioeconomic disparities in knowledge and behaviors of zika virus in pregnant women how can doctors communicate information about risk more effectively? high-risk pregnancy after perinatal loss: understanding the label covid-19 and iranian medical students; a survey on their related-knowledge, preventive behaviors and risk perception factors associated with preventive behaviors regarding lyme disease in canada and switzerland: a comparative study the authors sincerely appreciated the financial support from the research deputy of hamadan university of medical sciences. in addition, all participants and personnel in health care centers who helped in the research process are appreciated.authors' contributions sa and fs contributed to the proposal development, interpretation of the data, and drafting of the manuscript. sb and mr contributed to the preparation of the manuscript draft. sgh gathered the data. as and so analyzed the data and contributed to the manuscript development. all authors read, commented, and approved the final manuscript. this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. received: 15 july 2020 accepted: 8 september 2020 the authors declare that they have no competing interests. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-350023-7wx5v9b8 authors: tautenhahn, a.; merle, r.; müller, k. e. title: factors associated with calf mortality and poor growth of dairy heifer calves in northeast germany date: 2020-09-24 journal: prev vet med doi: 10.1016/j.prevetmed.2020.105154 sha: doc_id: 350023 cord_uid: 7wx5v9b8 a cross-sectional study was conducted on fifty german dairy farms to identify risk factors for high mortality and poor growth in calves. between 2012 and 2014, farm visits took place and a questionnaire on farm management practices was completed by in-person interview. in addition, heart girth measurements of calves around weaning were performed to estimate average daily weight gain. furthermore, blood and faecel samples of calves were collected and a score addressing calf welfare was determined. the epidemiological associations between risk factors and high mortality and poor growth were estimated using two regression models. the factors significantly associated with high calf mortality (> 5%) were a high rate of calves with failure of passive transfer (> 25%) and the metaphylactic use of halofuginone lactate. a small amount of concentrates consumed around weaning, relocating calves more than twice until weaning and a low incidence risk of milk fever (< 5%) were found to be significantly associated with poor growth (median: 675 grams). although the fifty farms cannot be considered as a representative sample for north-east germany, the results indicate that the farm management has a big impact on growth and survival of dairy calves and needs to be addressed more thoroughly when raising the future dairy cow. defence, by improvement of colostrum management and nutrition as well as minimizing stress by professional stockman ship in animal handling and by reducing the number of pathogens in the calf's environment (lago et al., 2006; windeyer et al., 2014; al mawly et al., 2015; urie et al., 2018b) . previous studies reported average calf mortality rates between 3.3% and 5.3% for norway, canada, switzerland, united states and the netherlands (gulliksen et al., 2009; bleul, 2011; windeyer et al., 2014; urie et al., 2018a; santman-berends et al., 2019) . few current data is available on calf mortality rates in germany. zitzmann et al. (2019) reported an average calf mortality rate of 7.7% for thuringia in , hoedemaker (2018 8.1% for lower saxony in 2016 and sanftleben (2009) 6,4% for mecklenburg-western pomerania in 2007. no data is available on growth rates of preweaned dairy calves and calf rearing practices on german dairy farms. identifying risk factors for high dairy calf mortality and poor growth, will contribute to improve housing, feeding and management strategies on german dairies. therefore, the objective of the present study was to identify factors associated with high mortality (> 5%) in dairy calves during the first six months of life and with poor growth in calves in the first three months of life. the study was designed as an observational study and consisted of two models. in both models, the herd was the unit of concern. in the model "risk factors associated with high calf mortality", a cross-sectional study was j o u r n a l p r e -p r o o f conducted with calf mortality, defined as mortality of calves between the second day and sixth month of life, as the dependent variable. at herd level calf mortality was not normally distributed and was therefore dichotomized in herds with high risk of calf mortality (> 5%) and herds with a low risk (≤ 5%). the classification of herds was based on the median calf mortality in the study population in 2012, which is in agreement with the target value for calf mortality of 5% proposed by roy (1990) . in the model "risk factors associated with median adg from birth to weaning", average daily weight gain (adg) of calves from birth until twelve weeks of life was the dependent variable at herd level. due to the limited study period and resources, we decided to enrol a total of 50 dairy herds in the study. for logistical reasons farms had to be located in northeastern germany (brandenburg, saxony, lower saxony and mecklenburg-western pomerania). inclusion criteria for the study were an average herd size of ≥ 50 dairy cows and in-house rearing of calves and heifers. most farms were enrolled in the projects "brandenburger testherden" of the cattle breeders' association brandenburg (visited/contacted: n=20/58) and "veredelungsland sachsen 2020" of the state control association of saxony (visited/contacted: n=10/10) and were invited to participate in the study by letter (müller et al., 2016) . additional farms belonged to the clientele of the clinic for ruminants and swine of the some of these farms have been working together with the clinic for several years; others contacted the clinic due to problems with calf rearing. we offered them to participate in the study as a first diagnostic step. during the study visits no other investigations than on the purpose of this study were made. in october 2013, members of the project "brandenburger testherden" and of the educational and experimental institution for animal husbandry echem were asked for help with farm acquisition. between october 2013 and october 2014 the remaining 33 farms were visited. overall, 88 farms were invited to participate in the study. in detail, 68 farms were contacted by letter and 20 farms by phone with a response rate of 44% and 100%, respectively. the overall response rate was 57%, which can be considered a high response rate. all farms entered the study voluntarily. each herd was visited on a single occasion by the same veterinarian (corresponding author) between september 2012 and october 2014. a questionnaire on farm management practices, morbidity and calf mortality was completed by in-person interview. in addition, blood und faecel samples were obtained to evaluate for failure of passive transfer (fpt), selected metabolic parameters (serum albumin, globulin) and enteropathogens often observed in calves with ncd. heart girth measurements were conducted around weaning (12th week) to estimate adg from birth to weaning. additionally, a score addressing calf welfare (animal needs index by winckler et al. (1994) ) was determined. all variables were collected and retrieved on farm by a single investigator at a single farm-visit. this made a separate data collection of exposure and outcome variables impossible and therefore rules out blinding of the study. this could lead to biased data what should be in mind when interpreting the results of this study. the questionnaire was created hypothesis driven and corresponding to literature (taffe et al., 2006; schäffer et al., 2007; bundesministerium, 2009; lorenz et al., 2011a; lorenz et al., 2011b) in this study we applied the centimetre scale. as described by heinrichs et al. (1992) , heart girth measurements were carried out and the described formula was used to estimate life weight in kilograms for the breed german holstein. one herd kept mainly the breed jersey and was excluded from the model "risk factors associated with median adg from birth to weaning", because the calculation of adg is not suitable for this breed. colostral antibody transfer was estimated on basis of serum total protein levels the test was carried out following the operating instructions. for evaluation of husbandry conditions with respect to calf welfare a modified version of the animal needs index 94 for calves (tiergerechtheitsindex 94 für kälber) described by winckler et al. (1994) was applied. the animal needs index (ani) for calves covers seven areas of influence: movement behavior, feeding behavior, social behavior, resting behavior, comfort behavior, hygiene and supervision. in each area of influence, several parameters are graded using a score. a farm can achieve calf mortality risk was calculated as follows: the average birth weight of 43 kg refers to trilk and münch (2008) , who determined the birth weights for the breed german holsten in northern germany. data at individual calf level from blood and faecel testing as well as from heart girth measurements were transformed into data at herd level using the herd median or percentage of calves. the cut-off value for fpt and successful antibody transfer was set at < 55 g/l and ≥ 55 g/l, respectively, as recommended by vandeputte et al. (2011) when the biuret-test for serum total protein examination is applied. at herd level, the percentage of calves with fpt was used for further analyses. serum albumin levels in calves around the twelfth week of life was used to evaluate appropriate nutrition and health status before weaning. the authors assumed a threshold value of < 33 g/l serum albumin to be an indicator for malnourishment (and chronic disease) of preweaned calves. at herd level, the percentage of calves with low serum albumin was used for further analyses. after execution of the ani, the results were transferred into score values for each area of influence. at herd level results were expressed as percentage of the achieved score from maximum possible score value in each area of influence. for example: a farm with 13 points in the area of influence "supervision" (maximum possible score value: 20 points) achieved 65% of all possible points in this area of influence. due to possible information bias, we excluded the incidence risks of ncd, brd and navel-ill as outcome variables. diseases were treated at very different degrees of severity and most farmers estimated all incidence risks freely. others counted the cases out of the treatment register (herd management program or stable book) and calculated incidence risks by dividing counted cases by the number born alive calves for ncd, brd and navel-ill and by the number of calvings for milk fever and ketosis in the past j o u r n a l p r e -p r o o f twelve month before farm visit. because of the importance of these variables for the outcome variables calf mortality and adg we kept them in these models. due to the convenience sampling strategy of farms selection bias cannot be ruled out. confounding was controlled by including potential confounders in the multivariable regression models. before statistical analyses the data set was revised by using data cleaning techniques as removing duplicate data and correcting or marking obviously incorrect data. missing or incorrect data was marked as missing values. all statistical analyses were performed using the software spss (version 20.0, spss inc. 2012, usa). for the investigation of associations between potential risk factors with calf mortality and adg from birth to weaning a multivariable model each was built. at first, the large data set was reduced. therefore, descriptive analyses of all data at herd level were performed. continuous not normally distributed data was dichotomized or categorized. potential risk factors were eliminated from further analyses if they were lacking variance (< 5% observations per category in binary outcomes), were missing biological causality or had too many missing values (> 20%, except for "amount of concentrates consumed around weaning in kg" in the model for poor growth). then all variables were tested for correlation using the spearman's rank correlation coefficient. if the correlation coefficient was above 0.6, only the factor with the better biological plausibility was selected for further analyses. the remaining potential risk factors as well as categories and observed j o u r n a l p r e -p r o o f frequencies are summarized in table 1 . table 1 is displayed in the supplements of this article. the associations of calf mortality (binary: ≤ 5%, > 5%) with potential risk factors (n = 52) were tested in univariable analyses. candidate variables with binary outcome were tested using chi-square-test and those with categorical or continuous outcome using logistic regression. factors with a p-value ≤ 0.2 (n = 16) qualified for multivariable analysis. due to a limited number of herds (n = 50) in the study the number of candidate variables was reduced according to the p-value to a maximum of seven candidate variables. in the first step, the multivariable logistic regression model was reduced by using a manual stepwise backward procedure, with p < 0.1 as criterion for retention. in the second step, excluded variables were reentered one by one. the final model only included variables that were significant at a significance level of p < 0.05. confounding and interaction effects were considered in the model. in the end, no confounders were discovered in the model and none of the two-way interactions were significant in the model and therefore, all interaction terms were removed. variables with binary outcome were tested using student's t-test, those with categorical outcome using analysis of variance (anova) and with continuous outcome using linear regression. factors with a p-value ≤ 0.2 (n = 25) qualified for multivariable analysis. as described in the previously model a maximum of seven candidate variables were included in a multivariable linear regression model. the potential risk factor "amount of concentrates consumed around weaning" was used in the model with an adjusting factor to weight the observations, to account for heteroscedasticity of the data (weighting was done using "weighted least squares"). further analysis was performed as described above. in the model "risk factors associated with median adg from birth to weaning", the fit of the model was evaluated with the adjusted r-squared and by assessing the residuals. plots of the standardized residuals against the predicted values were observed for their pattern and distribution and for outliers. herd size ranged from 70 to 1414 cows (median: 419 cows) with a median milk yield of 9800 kg per cow and year (range: 7680 -12000 kg). median calf mortality risk in 2012 was 5.0% (range: 0.0% -17.7%). herd characteristics of low and high mortality herds are presented in table 2 . median herd level incidence risk for ncd, brd and navel-ill in calves (treatment) was 12.0% (range: 0.0% -90.0%, q 25%: 5.0%; q 75%: 27.0%), 17.5% (range: 0.1% -90.0%, q 25%: 9.4%; q 75%: 30.0%) and 1.6% (range: 0.0% -30.0%, q 25%: 1.0%; q 75%: 4.2%), respectively. median herd level incidence risk for milk fever and ketosis treatment of dairy cows j o u r n a l p r e -p r o o f was 4.6% (range: 1.0% -35.0%, q 25%: 3.0%; q 75%: 6.7%) and 3.1% (range: 0.5% -46.0%, q 25%: 1.5%; q 75%: 6.6%), respectively. with fpt compared to farms visited in winter (p = 0,077). serum albumin, total protein and globulin levels were determined in 518 calves around weaning with a herd median of 34.7 g/l (range: 29.5 g/l -37.4 g/l), 60.9 g/l (range: 52.0 g/l -72.1 g/l) and 25.5 g/l (range: 18.7 g/l -37.6 g/l), respectively. 40.0% of the herds had at least 25% calves per herd with a serum albumin concentration < 33.0 g/l. the authors assume a threshold value of ≥ 33 g/l serum albumin to be an indicator for malnourishment of preweaned calves. respectively. relevant descriptive data of the questionnaire and the ani is presented in a summarized form in table 1 . results from univariable analyses are presented in table 3 . seven of these variables were introduced to the model "risk factors associated with high results from univariable analyses are presented in table 5 . seven of these variables were introduced into the model "risk factors associated with median adg from birth to weaning" selected by the lowest p-value in univariable analyses. after manual backward selection, the variables "amount of concentrates consumed around weaning" (p < 0.001), "frequency of relocation of calves between birth and weaning" (p < 0.001) and "incidence risk of milk fever" (p = 0.001) remained in the final multivariable linear regression model (table 6 ) and explained 72.8% of the variance between herds (adjusted r-squared). the amount of consumed concentrates around weaning was associated with adg until weaning. median adg increased by 160 grams (95% confidence interval 107 -213) at herd level. frequent relocation of calves turned out to be a risk factor for poor growth until weaning. calves that were relocated on the same farm more than twice from birth until weaning gained 119 grams per day less until weaning than calves that were relocated not more than twice (95% confidence interval -172 --67). farms with a high incidence risk of milk fever treatment in periparturient cows (> 5%) had 115 grams more adg until weaning than farms with a lower incidence risk (95% confidence interval 55 -175). fpt of more than 25% of the neonatal calves in a herd was associated with high calf mortality. this finding is in accordance with results of previous studies demonstrating that total serum protein levels below 55 g/l in j o u r n a l p r e -p r o o f neonatal calves are a risk factor for lethal outcome (rea et al., 1996; tyler et al., 1998; torsein et al., 2011) . in the present study, cryptosporidium parvum was detected in faecel samples obtained from calves on 49 (98%) farms with a median percentage of 72.7% of calves between 5 and 28 days of age. halofuginone lactate was administered to all neonatal calves on nearly half (46%) of the farms visited. farms on which routine administration of halofuginone lactate was performed had 10.0 times higher odds for calf mortality risk above 5%. similar observations were made by fourichon et al. (1997) , who observed a higher mortality in neonatal calves on farms applying medical prevention for digestive disorders. one explanation could be that farms with high risk of calf mortality due to ncd use halofuginone lactate more often than farms with less problems with ncd. in contrast to these observations, other researchers demonstrated the beneficial effect of metaphylactic halofuginone treatment (keidel and daugschies, 2013) . a toxic effect of halofuginone lactate as reason for increased calf mortality is unlikely as villacorta et al. (1991) observed toxic side effects at much higher dosages (500 µg/kg bw) than those recommended by producers (5-10 µg/kg). risk factors that did not remain in the multivariable model for high calf mortality, but showed a significant (p < 0.05) association with calf mortality, are discussed in this section. the risk factor "age at first offer of hay" did not remain in the model although no offer of hay in the first days of life compared to early supply was associated with higher calf mortality in the univariable analysis (p = 0.033). j o u r n a l p r e -p r o o f torsein et al. (2011) and perez et al. (1990) observed lower calf mortality rates on farms that offered roughage to calves from the first week of life onwards compared to those farms that offered roughage shortly before weaning. perez et al. (1990) assumed that the supply of roughage to neonatal calves enhances early rumen development. in practice, feeding concentrates to young calves is preferred to offering hay as concentrates were proven to enhance rumen development more efficiently than hay (noci, 2010 ). in addition, hay feeding was shown to reduce the amount of concentrates consumed (žitnan et al., 1998) . early supply of high amounts of concentrates without any roughage was shown to cause hyperkeratosis and clumping of rumen papillae. to this end, the hay provided is thought to prevent hyperkeratosis of rumen papillae by evoking a scratching effect on the rumen epithelium (suárez et al., 2007; noci, 2010) . promoting solid feed intake of calves during the pre-weaning period has a positive effect on rumen development and facilitates the transition from milk to solid feed at weaning (khan et al., 2011b) . the intake of high amounts of concentrates in the pre-weaning period was associated with high adg until weaning (+ 130 adg per kg concentrates). this is in line with the results of relocating calves more than twice from birth until weaning was related to lower adg. corresponding observations were made by mormède et al. (1990) and siegel and latimer (1975) in rats and chickens. as a result of repeated regrouping and relocation, animals showed signs of chronic stress such as aggression against herd mates and insufficient adg. veissier et al. (2001) did not observe adverse effects on adg due to regrouping and relocating of calves but measured an increased stress response compared to controls. they suspected a negative effect of regrouping and relocation on adg and calf health under field conditions when more than two calves form a group. more research is needed to confirm their assumptions. the association between incidence risk of milk fever in dairy cows and adg in calves was an unexpected result. calves showed higher adg on farms with a higher milk fever incidence risk. this result is in contrast to former publications that describe significant health implications for both dams and calves on farms with a high milk fever incidence risk, among these, dystocia and the weak calf syndrome (gröhn et al., 1989; houe et al., 2001; wilhelm et al., 2017) . weak calves consume less first colostrum, fall ill more often and have reduced adg (besser et al., 1990; wittum and perino, 1995; weaver et al., 2000) . one explanation for our findings could be a higher percentage of cows with ≥ 3 parities on farms with higher incidence risk of milk fever treatment. milk fever is usually a disease of dairy cows in their third lactation or beyond (correa et al., 1993) . at the same time multipara j o u r n a l p r e -p r o o f have richer first colostrum (tyler et al., 1999; scholz et al., 2011) and therefore their offspring has a decreased risk of fpt, sickness and reduced adg (robison et al., 1988; wittum and perino, 1995; windeyer et al., 2014) . risk factors that did not remain in the multivariable model for median adg, but showed a significant (p < 0.05) association with adg, are discussed in this section. as expected the risk factors "time per day without staff at the farm" (p = 0.024) and "maximal time interval between calving and harvesting first colostrum of the dam" (p = 0.019) were associated with adg. a precondition for early first colostrum harvesting is that staff members are present to take over the latter task. in our study, collecting first colostrum within two hours after calving at maximum versus a more extended period was associated with better growth in neonatal calves. several studies proved before, that a delay in first colostrum harvesting leads to reduced immunoglobulin g concentrations due to the diluting effect of milk synthesis in the freshly calved cow (moore et al., 2005; morin et al., 2010; scholz et al., 2011) . calves that consume first colostrum with low concentrations of immunoglobulin g have a higher risk of fpt (besser et al., 1991) and thus are at risk for diseases and poor growth (robison et al., 1988; wittum and perino, 1995; windeyer et al., 2014) . feeding at least three litres of first colostrum at first meal was associated with higher weight gains before weaning (p = 0.031). this finding is in accordance with observations by others (faber et al., 2005 ; trotz-williams j o u r n a l p r e -p r o o f beam et al., 2009) . early and sufficient colostrum supply is one of the main protective factors against fpt, which is connected to poor growth, as described above. farms that started offering concentrates to calves beyond two weeks of life had lower adg from birth to weaning than farms that fed concentrates earlier (p = 0.015). most of the study farms reared their calves with a restricted milk feeding routine und tried to wean calves as early as possible to reduce feeding costs. in particular, calves fed restricted depend on early rumen development for sufficient growth. therefore, concentrates that are supposed to be the most effective feed for early rumen development need to be offered to calves as early as possible (tamate et al., 1962; forbes, 1971; noci, 2010) . farms that abandoned hay from the diet of preweaned calves had higher adg in this study than farms that fed hay unchopped and separately (p = 0.025). this result is in line with studies (warner et al., 1956; jahn et al., 1970; kertz et al., 1979) in which calves were exposed to a restricted milk feeding routine. pre-ruminant calves consumed less concentrates when they were fed hay separately. the authors concluded that limited rumen capacity in young calves determines the amount of solid feed intake. to this end, the simultaneous offer of hay and concentrates would reduce adg due to the lower energy density of hay compared to concentrates. in further studies, pre-ruminant calves were fed chopped hay either separately, or mixed with concentrates (coverdale et al., 2004; suárez et al., 2007; khan et al., 2011a) . none of these authors could show a negative effect of hay on adg. taking the protective effect of hay on calf mortality into account hay feeding to calves seems to be recommendable. evaluating the data from the animal needs index, we observed higher adg on those farms that fulfilled the requirements of calves more efficiently than farms with insufficient adg. farms with more than 65% of points in the area of influence "supervision" in the animal needs index had higher adg than farms with less points (p = 0.002). differences between farms relied mainly on differences in documentation of symptoms and treatment of diseases. this corresponds to the results of lundborg et al. (2005) . they found a positive correlation between proper documentation and good calf health and draw the conclusion that thoroughness in documentation reflects a good quality of calf raising management. in our study, we found a strong positive correlation of median serum albumin concentrations and adg until weaning (p < 0.001). at herd level, each onegram increase in serum albumin concentration was associated with a rise in adg by 46 grams. low serum albumin levels are a constant finding in malnourished and underweight children (clarke et al., 2006; cripps et al., 2008) . in piglets and calves, the predictive capacity of serum or plasma albumin concentrations has been examined in the context of different rearing intensities (restricted vs. ad libitum feeding) in the first month of life (hammon et al., 2002; liu et al., 2015; maccari et al., 2015) . a positive association between body weight and plasma albumin concentration was detected in mature humans by jeejeebhoy et al. (2015) . although in individual animals low serum albumin concentrations can be the j o u r n a l p r e -p r o o f consequence of either malnutrition or a variety of disorders (protein loosing enteropathy, liver degeneration), on herd level, we consider low serum albumin (< 33 g/l) as predicting indicator for malnourishment or for an elevated proportion of calves with chronic diseases leading to insufficient adg from birth to weaning. its suitability as indicator, however, has to be investigated in subsequent studies. our statistical analyses included dealing with data challenges such as multicollinearity, finding associations 'due to chance alone', confounding and interaction effects (dohoo et al., 1997) . we used techniques to reduce the number of independent variables and to select for variables with the highest explanatory power before inserting them into multivariable models. furthermore, confounding and interaction effects were considered for in the models. due to the limited number of farms in this study, the number of independent variables per final multivariable regression model had to be reduced to a maximum of seven variables to reduce the possibility to find associations just due to chance alone. since more than seven risk factors may effect multifactorial diseases in calves, we had to select the variables carefully. the results of the present field study indicate that high calf mortality (> 5%), fpt in the neonate (serum protein < 55 g/l) and low adg from birth to weaning (< 700 g/day) are still a problem on dairy farms under livestock production conditions in northeast germany. as the welfare of food producing animals and in particular of young stock comes more and more j o u r n a l p r e -p r o o f into the focus of society, the management of calf rearing should be systematically evaluated and improved in the light of recent insights into nutrition, husbandry conditions, animal handling and disease prevention. especially colostrum and feeding management routines on most farms need to be revised and checked more frequently. feeding routines should focus on high rates of adg until weaning. offering water and concentrates right from the start enables calves to consume sufficient amounts of concentrates at weaning and leaves them prepared for the milk deprivation at weaning. animal handling and husbandry conditions should be reviewed from an animal perspective to reduce unnecessary stressful routines as frequent relocating of calves until weaning. connected with the funding associations, helped with the farm acquisition and supervised the corresponding author in this study. the author roswitha merle supported the study with the development of the assessment strategy and by performing data analysis. all examinations and sample collections were performed in line with legal regulations on the performance of experiments on animals (bundesministerium, 2010) . in conduct with this research quality standards like standard operating 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health organization influence of dietary concentrate to forage ratio on the development of rumen mucosa in calves risk factors for calf mortality influence the occurrence of antibodies against the pathogens of enzootic bronchopneumonia the study was supported by the cattle breeders' association brandenburg "brandenburger testherden", the managers of the project "veredelungsland sachsen 2020" of the state control association of saxony and the educational and experimental institution for animal husbandry echem by helping with the farm acquisition. the authors thank the participating farmers for their interest and support. declarations of interest: none. key: cord-349415-q0g0uqj6 authors: commodari, elena; la rosa, valentina lucia title: adolescents in quarantine during covid-19 pandemic in italy: perceived health risk, beliefs, psychological experiences and expectations for the future date: 2020-09-23 journal: front psychol doi: 10.3389/fpsyg.2020.559951 sha: doc_id: 349415 cord_uid: q0g0uqj6 since march 2020, many countries throughout the world have been in lockdown in response to the covid-19 pandemic. in italy, the quarantine began on march 9, 2020, and containment measures were partially reduced only on may 4, 2020. the quarantine experience has a significant psychological impact at all ages but can have it above all on adolescents who cannot go to school, play sports, and meet friends. in this scenario, this study aimed to provide a general overview of the perceived risk related to covid-19 and the psychological experience of quarantine in a large sample of italian adolescents. nine hundred and seventy eight adolescents (males = 339; females = 639) living in 13 italian regions and attending upper secondary school (age range: 13–20, m = 16.57, sd = 1.20), responded to an internet-based questionnaire about perceived health risk related to covid-19, knowledge and information on measures to control the pandemic, beliefs and opinions on stage two of the quarantine, and psychological experiences related to quarantine. 31.1% of the participants lived in “red zones,” which are places where the government has imposed stricter measures of containment due to exponential and uncontrolled growth in contagion cases compared to other areas in italy. according to our results, italian adolescents had a low perception of risk of covid-19. perceived comparative susceptibility and perceived seriousness were also very low. however, they were aware of the restriction measures necessary to contain the spread of the virus, and they agreed with the limitations imposed by the government. females and adolescents living in a “red zone” showed more significant psychological negative feelings about the quarantine experience. however, no significant differences were found about the regions where the teenagers of our sample live and the other variables related to the covid-19 experience. this is very interesting data, leading us to hypothesize that the participants’ negative feelings may be more related to the adolescent period than to the pandemic itself. since march 2020, many countries throughout the world have been in lockdown in response to the covid-19 pandemic. in italy, the quarantine began on march 9, 2020, and containment measures were partially reduced only on may 4, 2020. people had to stay at home. all social and sporting activities were canceled, and many work activities were forbidden; schools were closed and will reopen only with the new academic year. many countries around the world have temporarily closed educational institutions to contain the spread of the covid-19 pandemic. according to the united nations educational, scientific and cultural organization (unesco), school closures have impacted over 90% of the world's student population (unesco, 2020) . italy and several other countries have used educational technologies, including online platforms, radio, television, and texting, to support access to remote learning during the covid-19 pandemic, and so guarantee the students' right to education (unesco, 2020) . changes in life caused by the pandemic were dramatic for people of all ages. however, the revolution of behavioral routines caused by quarantine can have been particularly hard to accept for young people who could not go to school, play sports, and meet friends. usually, adolescents spend much of their waking time in school or other social contexts, such as gyms or recreational spaces (mahoney et al., 2009 ). now they have had to stay home all day for months, with online relationships only with peers and adults, such as their teachers, except the persons that live with them. moreover, their home has become a "school." for these reasons, there was an extensive debate between scientists on the effects of quarantine, limitations of freedom, and school closures on adolescents' emotional and affective states. previous studies on the effect of quarantine, which is the separation and restriction of movement of people who can be potentially exposed to a contagious disease, report common psychological effects (brooks et al., 2020) . research conducted on the severe acute respiratory syndrome (sars) epidemic (hawryluck et al., 2004; mihashi et al., 2009; liu et al., 2012) reported a high prevalence of symptoms of psychological distress, such as insomnia, irritability, anger, and other mood disorders. however, although the risk for psychological disorders related to changes in life caused by an epidemic is largely documented, there is evidence that several sociodemographic and psychological variables influence the emotional responses to behavioral limitations (hawryluck et al., 2004) . in particular, the perceived health risk for disease affects the emotional responses to the prevention measures and the acceptance of limitations of behavior (tang and wong, 2003; commodari, 2017) . health-related perceived risk depends on perceived "seriousness" and perceived "susceptibility" to a disease. risk perception is one of the key drivers of health behavior (brewer et al., 2004; ibuka et al., 2010; commodari et al., 2020) and influences the adoption of precautionary measures. perceived seriousness refers to how at risk a person considers himself to develop a disease, while perceived susceptibility concerns the perceived probability of getting a disease. perceived susceptibility can be differentiated into perceived personal susceptibility, which is the perceived probability that one will be harmed by a hazard (rogers, 1983) , and perceived comparative susceptibility, which is the perceived probability that a hazard will hurt one compared with other people of the same age and gender. research on health-related risk perception in young people has shown that adolescents engaged in risky behavior do not have a complete appreciation of their exposure to harm (johnson et al., 2002) . however, there are no previous studies on the health risk perception for pandemic diseases and the psychological experiences related to quarantine in this stage of the life span. based on these considerations, the main goal of this study was to investigate the perceived risk related to covid-19 and the psychological experiences of adolescents during the pandemic. in particular, the purpose of the study was to analyze the perceived seriousness of and susceptibility to covid-19, the beliefs of adolescents in the first phase of quarantine and their opinions on the stage two of quarantine, during which a partial reduction of behavioral measures was hypothesized. moreover, the study explored adolescents' moods, emotions, and feelings, with attention to expectations for the immediate future. more specifically, the study intended to verify the following hypotheses: hypothesis 1 (h1): living in an area with more restrictions than in other areas of the country contributes significantly to increasing the disease's perception of risk. hypothesis 2 (h2): living in an area with more restrictions than in other areas of the country significantly contributes to accentuating the negative psychological impact of the quarantine experience. hypothesis 3 (h3): other sociodemographic variables influence health risk perception and psychological experiences of the adolescents in the sample. in particular, a higher perception of risk and a greater concern of contracting covid-19 were expected to predict more negative feelings during the quarantine. conversely, it was expected that higher adherence to government measures to contain the infection and greater confidence in the information received on covid-19 were predictors of positive emotions. participants were 978 adolescents (males = 339; females = 639) who attended upper secondary school (age range: 13-20, m = 16.57, sd = 1.20), which corresponds to the international standard classification of education level 3. the participants lived in 13 of the 20 italian regions which are the first-level constituent entities of the italian republic. five hundred and seventy four of the respondents lived in a provincial seat, while 404 lived in towns that are not the provincial seat. teachers and some students collaborated in the recruitment of the participants, sharing an online survey on the leading social networks and inviting students to respond to the questionnaire. data were collected using an internet-based questionnaire. in total, the questionnaire consisted of 81 multiple-choice and open-ended questions. participation was voluntary, and the questionnaire required approximately 10-15 min to complete. the survey collected sociodemographic information, such as age, gender, area in which the respondents live, type of upper secondary school, academic grade, number of persons in the household, and other information. moreover, it explored perceived health risk related to covid-19, knowledge and information on measures to control the pandemic, beliefs and opinions on stage two of the quarantine, routines and habits of life that adolescents miss most (such as going out with friends, meeting boyfriend or girlfriend, going to visit their relatives, for a total of six items), and psychological experiences related to quarantine. the survey also collected information on e-learning experiences during quarantine, but this subject is beyond the scope of this article. perceived seriousness, perceived personal susceptibility, and perceived comparative susceptibility to covid-19, which are the main dimensions of risk perception related to health, were investigated using an adjustment of the italian version (commodari, 2017) of the risk perception of infectious diseases questionnaire (brug et al., 2004) . participants responded to questions using a five-point likert-type scale. the participants were invited to report (a) how serious it would be for them to get the disease, (b) how likely they think they are to contract the disease, (c) whether they would have a smaller or larger chance of getting the disease before summer, compared with their peers of the same age and gender, and (d) if they believed that students could be a category particularly at risk of contracting the virus. the original version of the risk perception of infectious diseases questionnaire was developed during the sars epidemic, and it was translated into several languages (de zwart et al., 2010) . its psychometric characteristics are good (cronbach's α = 0.79), and many international studies have used this measure in different contexts (de zwart et al., 2009 (de zwart et al., , 2010 commodari, 2017) . in this regard, a recent study by commodari (2017) used the italian adjustment of this questionnaire to investigate the risk perception of flu and the role of sociodemographic and psychological variables on perceived risk. a confirmatory factor analysis was run to assess the validity of this adapted version and a good model fit was obtained [χ 2 (5) = 21.5; p < 0.001; rmsea = 0.05; srmr = 0.03; cfi = 0.945; tli = 0.95]. the reliability is also good (cronbach's α = 0.80). regarding their opinions and beliefs, participants were asked to indicate whether they agreed with statements of reported information on covid-19 and quarantine (e.g., "there are some categories of people at higher risk for covid-19 than the general population"; "in stage two of the quarantine it is necessary to avoid the use of public transport to reduce the risk of contagion and to avoid a new increase in the epidemic, " and others). regarding feelings, emotions, and moods, participants were asked to complete a likert-type scale that focused on the personal feelings about one's cognitive, physiological, and behavioral state. participants indicated their level of agreement with several statements using a five-point likert-type scale (e.g., "in this period in which i have to stay at home, i feel well physically"; "in this period in which i have to stay home i am tense and i feel tight"). the scale measured two aspects: "negative feelings" and "positive feelings." a high score corresponded to high perception of negative or positive feelings, respectively. a cfa was also performed to assess the validity of these scores. regarding the model for the "negative feelings, " although the chi-square statistic resulted to be statistically significant [χ 2 (27) = 165; p < 0.001], the other values were indicative of a good model fit (rmsea = 0.07; srmr = 0.04; cfi = 0.943; tli = 0.95). the same result was obtained also for the model of the "positive feelings" [χ 2 (9) = 40.6; p < 0.001; rmsea = 0.05; srmr = 0.03; cfi = 0.932; tli = 0.96]. both the scales showed a good reliability (negative feelings: cronbach's α = 0.81; positive feelings: cronbach's α = 0.78). the scores were converted into z scores for the purpose of statistical analyses. finally, participants were asked to answer questions about their routines and habits of life they missed most, and to complete, without a word limit, the sentence "in this period in which i have to stay home, i think my summer will be. . .". participants completed the online survey between april 22 and may 1, 2020. the statistical package for the social sciences (spss) version 25.0 (ibm corporation, armonk, ny, united states) was used for the statistical analyses. quantitative data were expressed as frequencies and percentages in the case of categorical and ordinal variables and as mean and standard deviation in the case of continuous variables. independent-samples t-test were run and the magnitude of the differences between the means were assessed using hedges's g formula (hedges, 1981) to calculate effect size (es), with 0.20 indicating a small es, 0.50 a medium es, and 0.80 a large es (cohen, 1988) . besides, two multiple regression analyses were calculated to investigate the impact of sociodemographic variables and risk perception on positive and negative feelings experienced during the lockdown. for this purpose, the main sociodemographic variables and risk perception values were the independent variables, and the "positive feelings" and "negative feelings" scores were the dependent variable. qualitative data were coded and analyzed to show emerging themes. the thematic coding structure's development and confirmation was an iterative process involving two researchers conducting individual, recursive reading of the textual data and group meetings to discuss and test the emerging themes. discrepancies were resolved by consulting specific instances in the data, discussing their relationship to establish themes, and reaching consensus as a group (corbin and strauss, 2014) . the participants' responses to some items were free, and these could be single words or full sentences. codification was realized using "thought unit, " also denoted "sense unit" or "unit of meaning." the units comprised one idea communicated, whether it was expressed as a sentence, a verb-object sequence, or a single word. the responses were first categorized into 55 categories. then, these categories were progressively reduced. finally, the responses were coded in 52 categories (srnka and koeszegi, 2017) . the study was performed following the ethical standards of the 1964 declaration of helsinki and followed the ethical code for italian psychologists (l. 18.02.1989, n. 56), italian law for data privacy (dlgs 196/2003) , and the ethical code for psychological research (march 27, 2015) approved by the italian psychologists association. no sensitive data that could identify the participants was collected. the schools involved in the research had previously informed the students' parents to consent to the study's participation. the chair of school and family psychology, disfor, university of catania, approved this study. table 1 shows the sociodemographic characteristics of the participants. participants lived in 13 of the 20 italian regions. covid-19 was not diffused equally throughout italy. the regions in which participants lived reported on may 3 different levels of contagion, with a broader spread of the virus in the regions of northern italy. of the student participants, 31.1% lived in "red zones, " which were places in which the government has imposed stricter measures of containment due to an exponential and uncontrolled growth in cases of contagion compared to other areas in italy. regarding the number of persons with whom respondents were spending quarantine, 20.1% reported that the size of their household was more than four people, including themselves; 46.5% reported four persons; 24.9%, three persons; 7.6%, two persons; and 0.8% reported living alone during the quarantine. five of the respondents (0.5%) had been or was currently suffering from covid-19, while 0.8% of the respondents reported that they were uncertain about having had this disease; 3.1% of respondents reported that one or more family members living with them had been or was currently suffering from covid-19. furthermore, 10.2% of the sample had at least one family member who worked with people affected by covid-19 (health care or other essential services). table 2 reports data on the perceived health risk in the sample. in general, adolescents considered the possibility of getting covid-19 before summer to be low: 60.3% responded that their probability was very low or low, while only 4.5% think that this probability was high or very high (27.7% very low; 32.6% low; 33.9% neither low nor high; 3.7% high; and 0.8% very high). furthermore, most subjects believed they had a low or very low probability of contracting the virus before the summer compared to peers of the same age and gender (20.7% very low; 33.7% low; 39.7% neither low nor high). only 4.3% of the sample thought that this probability was high and 0.9% very high. regarding the perceived seriousness of the disease, 36% of the sample believed that contracting the virus could be serious or very serious (30.4% serious and 5.6% very serious), and 31.1% believed that it was neither serious nor not serious. only a limited there were no differences by regions in perceived health risk, although some of these regions were the most affected by the disease. moreover, the presence of parents or other family members who had been or was currently suffering from covid-19 did not influence risk perception. interestingly, both the perceived susceptibility (family member working with people who had covid-19: m = 2.61, sd = 0.92; no family member working with people who had covid-19: m = 2.13, sd = 0.89; t = 3.36; p = 0.001; g = 0.53) and comparative susceptibility (family member working with people who had covid-19: m = 2.71, sd = 0.97; no family member working with people who had covid-19: m = 2.26, sd = 0.85; t = 4.91; p < 0.001; g = 0.52) were higher in those adolescents whose parents or other relatives worked with persons sick with this disease and the es was medium. to better analyze the perception of the risk for covid-19, students were also invited to report how frightened they were of getting covid-19. the majority of the sample was not particularly afraid of contracting covid-19. there were no significant differences in the responses of the students by region. the students who lived in the regions with higher diffusion of the disease did not show greater fear of the disease than their peers. however, the students who lived in a red zone were more fearful of covid-19 than their peers with a medium es (red zone: m = 2.91, sd = 1.32; non-red zone: m = 2.22, sd = 1.20; t = 2.71; p = 0.007; g = 0.55) ( table 3) . ninety three percent of respondents believed that there were categories of people more at risk of getting covid-19, but, interestingly, 76.2% of the respondents did not consider students as a category at risk for covid-19. the remaining participants (21.9%) believed that students were an at-risk category for this disease. these students motivated their response with the argument that the school setting does not permit social distancing. the remaining 1.9% did not answer the question. a significant percentage of the respondents reported having confidence in the information that they received on the disease (56.1% trust enough; 18.3% trust a lot; 0.2% trust very much). moreover, the most critical information the adolescents would have liked to receive on covid-19 concerned on how to cure the disease (42.8% of the respondents). interestingly, only 17.2% of respondents were interested in how to prevent the infection. furthermore, 11.2% wanted information on the likelihood of contracting the virus in an area of residence, 10.6% how to recognize the symptoms of the disease, 3% the geographical areas where the virus is most present, and only 0.2% would have liked to have been more informed about how the virus was transmitted. regarding adolescents' opinions of the behavioral measures that could be useful to maintain in stage 2 of quarantine, during which there was a partial reduction of containment measures, a very high percentage of respondents (89.1%) agreed on the need to avoid public transport, such as trains or busses, as well as to confined spaces such as bars, restaurants, cinemas, theaters, and school classrooms (91.8%). similarly, 90.2% of the respondents agreed with the need to avoid going into shops if not necessary and only with personal protective equipment, such as a face mask. further, 84.4% of the respondents agreed with the need to avoid going to gyms or swimming pools, and 72.5% considered it useful to avoid medical consultations if possible. however, adolescents did not think it will be necessary to maintain social distancing in the second quarantine stage. most respondents did not agree on the need to avoid staying with persons who are not cohabiting (57.0%), and 82.6% think that it is not necessary to avoid staying in open places such as parks. data are summarized in table 4 . interestingly, adolescents showed a high awareness of the particularity of the moment in which italy was living. the vast majority of the sample reported having no difficulty complying with the government's restrictive provisions (73.1%), and they substantially agreed with the restrictions imposed on citizens due to the pandemic (81.9%). the majority of the adolescents interviewed said they had more homework than before due to the remote school activities (66.8%), and a significant percentage of them (40.5%) reported having little free time. however, a large percentage was coping with quarantine by dedicating at least 1 h a day to a hobby (61.5%), watching television or playing video games (42.4%), or spending much more time on social networks such as facebook or instagram (62.3%). more specifically, males tended to devote themselves to hobbies ( differences were small or approaching to medium. furthermore, adolescents living in a red zone tended to watch tv or play video games more than peers who did not live in a red zone but the difference was small (red zone: m = 3.20, sd = 1.34; no red zone: m = 2.97, sd = 1.41; t = 2.44; p = 0.015; g = 0.16) ( table 5) . as for what the teenagers in the sample missed most in this time of restrictions, the majority of the participants stated that they especially missed being able to meet friends (55.8%) and relatives (62.5%) and staying out later in the evening due to the closure of premises such as restaurants, pubs and discos and the prohibition to go out except for reasons of absolute necessity (52%). to confirm this, a large majority of the sample said they found significant support from family (81.1%) and friends (65.3%) to face this time when they had to stay home. the responses of the adolescents show heterogeneous psychological reactions to the experience of quarantine. to better investigate the specific emotion and feeling they perceived, the responses to some of the more relevant items were first examined. this analysis aimed to capture a snapshot of the emotional state of adolescents during the quarantine. the majority of those interviewed stated that they stayed physically well (68.7%). males felt better than females but the difference was small (males: m = 3.32, sd = 1.17; females: m = 2.97, sd = 1.16; t = 4.54, p < 0.001; g = 0.30). however, quarantine influenced their sense of security and self-confidence: 43.1% of the students reported feeling less secure than in the past. females were less self-confident than males with a medium es (females: m = 2.50, sd = 1.23; males: m = 3.18, sd = 1.14; t = 8.58, p < 0.001; g = 0.56) while there were no significant differences by age, the area in which the person lived, and other socio-demographic variables. concerning psychological status, about 40% of students reported feeling tenser and sadder (42.6%) and more irritable table 5 . interestingly, the responses of the students showed their great empathy and interest in socialization. a high percentage of respondents said they were not bored listening to others' problems (46.7%) and reported being able to manifest their emotions (41.5%). these results agree with the findings discussed in the previous section, which showed that the things and situations students missed most were meeting friends, staying with relatives, and being out late in the evening. multiple regression analyses were performed to investigate the impact of sociodemographic and perceived health risk variables on the psychological outcomes (positive and negative feelings z scores). sociodemographic variables, perceived health risk, and adherence to government restrictive measures were used as independent variables while positive and negative feelings z scores were the dependent variable. all regression assumptions were checked. there was linearity as assessed by partial regression plots and a plot of studentized residuals against the predicted values. there was independence of residuals, as assessed by a durbin-watson statistic of 1.9. there was homoscedasticity, as assessed by visual inspection of a plot of studentized residuals versus unstandardized predicted values. there was no evidence of multicollinearity, as assessed by tolerance values greater than 0.1. there were no studentized deleted residuals greater than ±3 standard deviations, no leverage values greater than 0.2, and values for cook's distance above 1. the assumption of normality was met, as assessed by a q-q plot. regarding positive feelings, a significant regression equation was found (f = 6.995, p ≤ 0.001), with an r square of 0.11. more specifically, significant predictors of positive feelings were gender (t = −5.851, p < 0.001, std β = −0.185), region (t = 2.326, p = 0.02, std β = 0.074), confidence in the information received on covid-19 (t = 2.631, p = 0.009, std β = 0.084), perceived susceptibility (t = −2.386, p = 0.017, std β = −0.089), ease in respecting government measures (t = 4.698, p < 0.001, std β = 0.152), and belief that the government measures were justified (t = 2.480, p = 0.013, std β = 0.082). according to these results, females reported less positive feelings than males on average as well as adolescents living in northern italy. furthermore, higher confidence in the information received on covid-19, higher perceived susceptibility, higher ease in respecting government measures and higher beliefs that these measures are justified were predictive of positive feelings. table 6 shows the significant results of the regression analyses and the contribution of each predictor to the dependent variable. regarding negative feelings, the regression model was significant (f = 11.103, p < 0.001), with an r square of 0.16. more in detail, significant predictors of negative feelings were gender (t = 9.291, p < 0.001, std β = 0.284), age (t = 3.900, p < 0.001, std β = 0.119), living in a red zone (t = 2.905, p = 0.004, std β = 0.090), perceived seriousness (t = 2.690, p = 0.007, std β = 0.085), fear of getting covid-19 (t = 2.809, p = 0.005, std β = 0.091), and compliance with government measures (t = −3.281, p = 0.001, std β = 0.152). according to these results, females and older adolescents reported more negative feelings than males and younger adolescents on average. furthermore, living in a red zone, a higher perceived seriousness, a higher fear of getting covid-19 and a lower compliance with government measures were predictive of negative feelings. table 6 presents the significant results of the regression analyses and shows the contribution of each predictor to the dependent variable. in summary, the model showed a moderate but significant impact of both the sociodemographic and the health risk perception variables related to covid-19 experience on the perception of negative and positive feelings. participants' expectations for the immediate future were also investigated through an open-ended question about how they imagined the upcoming summer holidays. data were codified according to the modality described in the procedure section. we first categorized the responses into 55 categories and then progressively reduced these categories. the adolescents were aware that the experience of quarantine would continue to produce effects during the summer period. in this regard, a significant percentage of the adolescents in the sample said that their summer would be "different" or would have "different limitations" (24.1%). uncertainty and doubt were widespread feelings, as expressed by these answers: "my summer will be full of anguish, doubts, and perplexity, but my friends are enough for me to feel good"; "i am very worried because i cannot imagine how it will be but i look forward to it as much as every year." in addition, 26.3% of the sample thought that summer would be sad, boring, or horrible, as demonstrated by the following quotes: "if transportation does not reopen, my summer will be wasted, the collapse of different dreams and projects that have so far pushed me to go on and resist a very dense pool of mud in which i will struggle so much not to sink"; "like a prison, locked between the walls and between the screams, as if it were winter or autumn, without being able to see the seawater, which is freezing or boiling." in some cases, quarantine only highlighted pre-existing difficult situations, such as in this case: "it will be the usual summer in which it is amplified that i have no friends and that no one ever invites me to go out and i will spend the day in my pajamas eating food at will and watching netflix and sky until i vomit." however, 8.9% thought summer would still be interesting and fun: "interesting, i have high school exams, a girl, and too many friends to share my life with. i'm curious to see how everything will evolve." in general, the teenagers in the sample looked to the future with the hope of overcoming the difficult period of the pandemic and resuming a normal life, even if different from the previous one: "i don't care what my summer will be like, i just hope that we will be able to get out of this situation with a new unitary spirit, i hope people understand that we are one family in one house"; "meeting again, with the necessary restrictions, my friends, my grandparents, will be difficult as if we had to learn to live in a different way from what we were used to until a couple of months ago. it will be exciting!". this study aimed to provide a general overview of the psychological experience of quarantine in a large sample of italian adolescents. according to other recent studies conducted on this topic in the italian population, the covid-19 emergency was a very difficult experience from an emotional point of view, and several categories such as health professionals have undergone significant stress with a consequent negative impact on their psychological well-being (ramaci et al., 2020) . to the best of the knowledge, this is the first study investigating the experience of the covid-19 pandemics in italian adolescents and with such a large number of subjects. first, the perceived seriousness and susceptibility to covid-19 were evaluated, as well as the impact of sociodemographic variables on the perception of health risk. according to the study results, italian adolescents had a low perception of risk of covid-19. perceived comparative susceptibility and perceived seriousness in italian adolescents were also very low. these results show that young people think that covid-19 is not a potentially severe disease for them. indeed, there is some evidence that young people are less vulnerable to the effects of the new coronavirus sars-cov-2 (kolifarhood et al., 2020) , although the possibility of getting the disease depends on the diffusion within the population. they underestimate the probability of getting the disease and show a very high trust in their good health, neglecting that the probability of being infected, albeit slight, is similar to that of their peers and people of other age groups. interestingly, as hypothesized, teenagers residing in a red zone reported higher perceived seriousness and susceptibility than those who did not reside in these zones. furthermore, females showed a higher perceived seriousness than males. in both cases, the medium effect size suggests a role of these variables in influencing health risk perception. therefore, living in an area with more restrictions than in other areas of the country may have contributed significantly to increase the perception of risk about the disease. also, this information seems consistent with several studies demonstrating that women tend to have a higher perception of risk than men, thus avoiding risky behaviors to a greater extent (harris et al., 2006) . despite underestimating their risk of infection, however, the italian teenagers who participated in this study were aware of the restriction measures necessary to contain the spread of the virus and they agreed with the limitations imposed by the government. these responses show high awareness of the potential danger of covid-19 and acquire more value when considering that young people were conscious that they were not at serious risk, but that the risk was high for society as a whole. the study also wanted to investigate the emotional and psychological impact of the quarantine period on the youth population in italy. as underlined in the literature on this topic, prolonged school closure and home confinement during an epidemic can have a detrimental effect on children's and adolescents' physical and psychological well-being (brooks et al., 2020; wang et al., 2020) . according to the results, this study also shows that italian adolescents suffered the psychological effects of this quarantine period. indeed, they had more marked negative feelings. more specifically, females and adolescents residing in the red zones with more restrictions showed higher levels of negative feelings related to the quarantine, in accordance with the study's hypotheses. in this regard, effect sizes approaching to medium indicate a possible role of these variables in determining negative feelings in the adolescents of the sample, even if these feelings may be likely influenced also by other variables not considered in the study. however, it is essential to emphasize that these feelings are subjective perceptions rather than a psychopathological state. indeed, quarantine did not reduce the empathy and sociability of young people. in this regard, the adolescents who participated in this study reported that they engaged in school activities remotely and carried out the assigned homework. furthermore, they continued to listen to the problems of others and to express their emotions. no significant differences related to the regions where the teenagers lived were found. this is very interesting data, leading to hypothesize that the negative feelings reported by the participants may be more related to the adolescent period than to the pandemic itself. the results also showed a moderate but significant impact of both the sociodemographic and the health risk perception variables related to the covid-19 experience in the perception of negative and positive feelings. more specifically, being male, living in a region with less virus spread, reporting low levels of perceived susceptibility and high compliance and agreement with government measures were all variables associated with the perception of positive feelings. on the contrary, being female and older, living in a red zone, reporting high levels of perceived seriousness and fear of getting covid-19, and being less compliant with government measures were associated with more negative feelings. as recently underlined by wang et al. (2020) , the adverse effects on psychological well-being are more significant when children and adolescents are confined to their homes without the possibility of carrying out activities outside and meeting peers. in confirmation of these considerations, this study showed that the majority of teenagers interviewed suffered in particular from not being able to meet friends and relatives, as well as from not being able to go out and stay out late in the evening. the results also confirmed the literature data demonstrating that when children and teenagers do not go to school and stay home, they are physically less active, are exposed to much more screen time, and have irregular sleep patterns. similarly, the teenagers in the sample had difficulty falling asleep and spent more time watching television, playing video games, or using social networks. however, a significant percentage stated that they dedicated at least an hour a day to playing a musical instrument, dancing, exercising, acting, or drawing. in light of these insights, it is important to promote healthy habits and lifestyles in adolescents to reduce psychosocial stress and improve the psychological and physical well-being of the young population. finally, the quarantine experience was also associated with a widespread sense of uncertainty about the near future in the adolescents interviewed in this study. although some participants were convinced that the virus would disappear during the summer, allowing a return to normal life, most believed that their near future would be unpredictable or different due to the various health and social distancing rules that must be respected. in this regard, it is important to support the youth population in addressing the uncertainties related to the period following the quarantine to ensure better adherence to the limitations that will have to be faced to avoid a new outbreak of the epidemic. this study has some important strengths. as already underlined, this is one of the first studies conducted in italy about the perceived seriousness and susceptibility for covid-19 as well as the effects of school closures and home confinement on the physical and psychological well-being of adolescents. another strength is certainly the large sample size, with almost 1000 italian teenagers interviewed from north, central, and south italy. however, there are also several limitations. first, this is a cross-sectional study so an exact causal relationship between the variables could not be established. secondly, an internetbased questionnaire with self-reported measures was used, so it was not possible to ascertain the accuracy of the answers to the questions and the possible influence of selfreport bias on the results. finally, not all italian regions are represented in the sample; however, it is representative of the three main areas in which italy is generally divided (north, central, and south). this study has several social and psychological implications. in particular, the results underline that the covid-19 emergency has undoubtedly had a significant impact on the lifestyle and psychological well-being of italian adolescents. in light of these findings, the physical and mental impact of the covid-19 epidemic on children and adolescents is a matter of fundamental importance both for governments and families and cannot be neglected, especially in this phase of a progressive resumption of ordinary life. therefore, it is necessary to prepare adequate strategies to support the youth population in addressing the uncertainty associated with the pandemic and the quarantine period to reduce the psychological impact of school closures and home confinement as much as possible and guarantee adequate support to deal with the return to school. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by chair of school and family psychology, disfor, university of catania. written informed consent to participate in this study was provided by the participants, and where necessary, the participants' legal guardian/next of kin. ec designed the study, analyzed the data, and wrote the first draft. vllr revised the manuscript. both authors contributed to the article and approved the submitted version. risk perceptions and their relation to risk behavior the psychological impact of quarantine and how to reduce it: rapid review of the evidence sars risk perception, knowledge, precautions, and information sources, the netherlands statistical power analysis for the behavioral sciences the role of sociodemographic and psychological variables on risk perception of the flu health risk perceptions in the era of the new coronavirus: are the italian people ready for a novel virus? a cross sectional study on perceived personal and comparative susceptibility for infectious diseases basics of qualitative research : techniques and procedures for developing grounded theory, 4 edn perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey monitoring of risk perceptions and correlates of precautionary behaviour related to human avian influenza during 2006 -2007 in the netherlands: results of seven consecutive surveys gender differences in risk assessment: why do women take fewer risks than men? sars control and psychological effects of quarantine distribution theory for glass's estimator of effect size and related estimators the dynamics of risk perceptions and precautionary behavior in response to 2009 (h1n1) pandemic influenza risk involvement and risk perception among adolescents and young adults epidemiological and clinical aspects of covid-19; a narrative review depression after exposure to stressful events: lessons learned from the severe acute respiratory syndrome epidemic adolescent out-of-school activities predictive factors of psychological disorder development during recovery following sars outbreak social stigma during covid-19 and its impact on hcws outcomes cognitive and physiological processes in fear appeals and attitude change: revised theory of protection motivation from words to numbers: how to transform qualitative data into meaningful quantitative results an outbreak of the severe acute respiratory syndrome: predictors of health behaviors and effect of community prevention measures in hong kong. china covid-19 educational disruption and response mitigate the effects of home confinement on children during the covid-19 outbreak the authors wish to thank the united network europe for the fundamental support in the diffusion of the online survey and dr. giulia carnemolla and dr. jessica parisi for the help in the data collection. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 commodari and la rosa. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-328442-mnlzj1ly authors: barattucci, massimiliano; chirico, alice; kuvačić, goran; de giorgio, andrea title: rethinking the role of affect in risk judgment: what we have learned from covid-19 during the first week of quarantine in italy date: 2020-10-02 journal: front psychol doi: 10.3389/fpsyg.2020.554561 sha: doc_id: 328442 cord_uid: mnlzj1ly due to covid-19 spreading in italy, on march 11 the prime minister of italy declared a lockdown and imposed severe restrictive measures impacting citizens’ freedom at several levels. people were required to stay at home and go out only to satisfy basic needs. several risk models have postulated a link among online searching behavior, affect, anxiety, and complaints by individuals toward government restrictions (gr), which emerged as also related to an increased perception of knowledge toward risk. however, to date, no study has addressed how these key risk-related aspects (i.e., affect, anxiety, perceived knowledge on risk, and risk dimensions) can act jointly to orient online health information-seeking behavior, and people’s complaints toward gr imposed during the lockdown. this study investigated the mechanisms underlying online health information-seeking behavior and people’s complaints toward the government’s restrictions during a covid-19 emergency in the italian population. drawing from the health belief model (hbm), which postulates a link between sociodemographic variables, risk, and affect dimensions in emergency, we assumed risk factors as predictors of affect and anxiety, which, in turn, were posited as mediators between risk dimensions, online health information-seeking behavior, and complaints toward gr. participants (1,031) were involved during the first week of the quarantine (march 11–18) and completed an online survey composed of (i) an adapted version of the italian risk perception questionnaire; (ii) the italian positive (pa) and negative affect (na) schedule (panas-10); (iii) the state anxiety scale (stai-y1); (iv) ad hoc personal knowledge measure about novel coronavirus; (v) ad hoc item measuring information search behavior regarding the novel coronavirus; (vi) ad hoc measure of the complains regarding gr; and (vii) sociodemographic questions. general linear models and structural equation modeling (sem) were carried out to test the model. sociodemographic and cognitive factors predicted the participants’ affect and anxiety, which, in turn, motivated and fully mediated both information search behavior and complaint toward gr. this research can offer useful suggestions for policy-makers during the covid-19 emergency, and it advanced the knowledge on the risk–emotion link in emergency situations. in december 2019, a cluster of pneumonia cases of unknown etiology was detected in the city of wuhan, hubei province, central-eastern china. this initial phenomenon turned into a novel coronavirus (zhu et al., 2020) , which is named sars-cov-2 (i.e., severe acute respiratory syndrome), and which caused a disease named covid-19 (qu et al., 2020) . even though symptomatology has been defined clearly, it is still hard to define how long it will last and if a cure is possible (porcheddu et al., 2020; wangping et al., 2020) . recently, the infection has caused enough deaths to be considered as a pandemic by the world health organization (who) (onder et al., 2020; sohrabi et al., 2020) . in italy, the outbreak spread on february 20, and after an ad hoc decree of the president of the council of ministers (dpcm), a lockdown was imposed on italians (i.e., 20 days after the first recognized patient). all italians were required to stay home if they were not involved in jobs or tasks involved in other people's survival. since march 11 in italy, restrictive and severe measures have been gradually implemented (from march 11 to 18) (de giorgio, 2020a,b) . according to the health belief model (hbm) (janz and becker, 1984; carpenter, 2010 )-well-established theoretical frameworks in health-related behavior research-often, the psychological counterpart of disease-related emergencies can entail an increased risk perception (bults et al., 2011) modulated also by sociodemographic variables (e.g., vaughan, 2011; clifton et al., 2016) . this cognitive perception of risk can have significant implications on individuals' emotional states on the short and on the long-term (cafagna and barattucci, 2019) . moreover, it would be closely related to the intention to adopt protective behaviors (leppin and aro, 2009; goodwin et al., 2011) as well as to personal susceptibility (lin et al., 2020) . however, hbm has never been used to investigate the mechanisms underlying all these variables in a pandemic situation. moreover, no data on the italian population's risk perception have been reported yet. crucially, no studies have investigated the impact of risk cognition and emotional response on research behavior and compliance with government actions. this last aspect can be far more relevant if considering that cognitive perception of risk is sensitive to peculiar emergencyrelated environmental factors. for instance, italians were forced to stay home, thus changing their normal habits related to work and leisure activities. confined at home, italians tended to rely more on the internet to remain up-to-date on pandemic progress in a safe way. crucially, online information searching regarding health issues is not a neutral task since it can influence people's affective states, especially anxiety (jutel, 2017) . to investigate the joint impact of cognitive risk dimensions, affect, and anxiety on online searching behavior and compliance toward government restrictions (gr), in the peculiar context of the italian pandemic emergency, we drew from the hbm to formulate and test a novel explicative model. first, we posed the first day of lockdown (march 11, 2020) as the trigger event and the online health information on covid-19 searching behaviors as the main outcome. then, we built and tested a novel model including sociodemographical factors, risk cognitions, behaviors, and affect as mediators between the trigger event and the main outcome of the online health information searching behaviors (figure 1) . elucidating this mechanism can be crucial also because information-seeking behaviors can influence the population' general compliance with government decisions (clifton et al., 2016) . therefore, these data can provide the government with useful indications regarding which online communication strategies would be the most effective in an emergency situation (liao et al., 2020) . the term "risk" represents the possibility of suffering damage connected to foreseeable circumstances. in essence, it is consequently a variable connected to the frequency (or probability) of the occurrence of the damage and the magnitude that the latter can cause in the individual (slovic, 2000) . this universally recognized definition may look as reducible to a mere mathematical formula. however, its subjective dimension suggests a deeper complexity. indeed, a plethora of approaches have been developed to capture all the key aspects related to risk perceptions, as well as its main consequences on people' behavior. among the main subjective dimensions of risk, cognitive factors emerged as playing a key role (slovic, 2000; leppin and aro, 2009) . risk perception would be determined by a complex series of cognitive factors: (i) the perceived possibility of having damage to health; (ii) the subjective importance that the damage is more or less possible; (iii) by personal uncertainty associated with the exposure to a specific risk factor (slovic et al., 2004) . in the case of general risk or infection or disease, personal knowledge negatively affects the perception of risk danger (shook et al., 2019) . in turn, risk perception impacts behaviors (sjöberg, 2000) , specifically between different risk dimensions regarding infection, perceived fatality, severity, vulnerability, and uncontrollability, and are proven to have effects on protective conduct . in regard to pandemic-related risk perceptions, two main factors emerged as relevant, that is, vulnerability (a person's subjective perception of the risk of acquiring an illness or disease) and severity (a person's feelings on the seriousness of contracting an illness or disease) of harm (carpenter, 2010) . however, despite that it has been repeatedly shown that risk perception can affect behavior (brewer et al., 2007; vaughan, 2011; shook et al., 2019) , the underlying mechanism still needs to be elucidated. specifically, antecedents of cognitive dimensions of risk should be still clarified. with this regard, demographic factors/variables emerged as playing a key role in shaping pandemic risk perception and subsequent behaviors (see e.g., vaughan, 2011) . for instance, women resulted as more avoidant, fearful, and vulnerable in terms of pandemic risk perception, with lower risk acceptance scores when compared to men (see e.g., de zwart et al., 2009) . conversely, age often leads to an increased perception of control on infection risk, lower susceptibility, avoidance, and higher acceptance of risk (see e.g., clifton et al., figure 1 | the first week of lockdown in italy: epidemiological and variable trends. all variables have been standardized. due to the numerical difference of epidemiological data between northern and southern italy, we divided the real values by 1,000 and have thus reported them in the y-axis. 2016). conversely, the level of education was negatively related to the risk of infection and contagion (i.e., vulnerability) (gidengil et al., 2012) . lower income and urbanization positively affected vulnerability and perceived infection risk (brewer et al., 2007; de zwart et al., 2007; gidengil et al., 2012) . another factor, which would act as a mediator, should be included between risk perception and behavior, that is, affect. affect, such as fear, is related to a general amplification of the perception of the danger of risky events, while anger would be significantly associated with underestimation of dangers (slovic, 2000; brown, 2014) . moreover, the degree of emotional involvement in the perceived consequences of different risks, or specific personality dimensions that determine emotional attitudes, is associated with different aspects of risk perception (among all, vulnerability, and severity) (slovic, 2000; brown, 2014) . crucially, among the stimuli triggering emotional states, also online searching information should be included, which could also lead to a phenomenon of large-scale emotional contagion (hatfield et al., 1993) . emotions expressed via the internet, and mainly through social media, can lead to a longterm psychological impact (arapakis et al., 2008; fowler and christakis, 2008; coviello et al., 2014; kramer et al., 2014; ferrara and yang, 2015; mui et al., 2018) including also a simple health information search (gadahad et al., 2013) . specifically, both general and specific discrete emotional states can orient people's online search for information on health issues (wissow, 2007; myrick and willoughby, 2019) . emotions and affect act as motivators of specific survival behaviors (frijda et al., 1989) , and this definition could hardly be more appropriate than in this worldwide emergency. in this case, one key survival behavior motivated by affect could consist of online health information seeking or avoidance (savolainen, 2014) . while positive affect (pa) resulted in determining people's attitudes toward information avoidance, negative affect (na) predicted individuals' attitudes toward information seeking (yang and kahlor, 2013) . on the other hand, searching for information about symptoms or specific illnesses can increase people's distress and anxiety about their health (graffigna et al., 2017) . crucially, na and anxiety have often resulted in closely positively intertwined affective states (crawford and henry, 2004) , even though they can be considered as clear, distinguishable constructs (watson and kendall, 1989; clark and watson, 1991) . according to the tripartite model of anxiety and depression, high levels of na underlie both anxiety and depression, while na would act as a central risk factor of anxiety (clark and watson, 1991) . na has also often been considered an early predictor of anxiety in several domains (crawford and henry, 2004; cisler et al., 2010) . during the lockdown, the internet became one of the most important sources of health-related information; thus, it would be crucial to analyze antecedents of this behavior as well as its potential impact on compliance with gr. to date, the literature regarding risk perception and behavior on worldwide pandemics has focused mainly on general population's or on healthcare workers' punctual psychological responses immediately after the end of isolation (wilder-smith and freedman, 2020). acute stress/posttraumatic disorders, as well as higher propensity to live state anxiety, emerged as serious issues (leppin and aro, 2009) . crucially, no data on the italian population's risk perception have been reported yet. moreover, no studies have investigated the role of risk cognition and emotional response to research behavior and compliance with government actions. in this study, we aimed to advance previous studies on covid-19 at two levels. first, we elucidated the link between cognitive and emotional risk dimensions in a pandemic, then, we built and tested a novel model linking cognitive, emotional, and sociodemographic factors to a peculiar behavior enacted in this emergency, which would be probably increasingly adopted in the future, that is, online searching behavior of health-related information. moreover, we also used the hbm, for the first time, as a general explicative framework in a pandemic situation. health belief model posits a cognitive appraisal framework, in which perception of the risk for individual health affects emotions and protective behavior (roseman, 1996) . more specifically, when referring to the hbm framework (janz and becker, 1984) and adapting recent theoretical models (watson and spence, 2007; keller et al., 2012; lemée et al., 2019) , the present research model considers sociodemographics as antecedents of risk cognition and emotion as a buffering factor between risk perception and behavior (figure 2 ). this novel model proposes that two different risk cognition aspects have independent effects on pa and na. perceptions regarding specific pandemic and perceived knowledge of risk (champion and skinner, 2008; carpenter, 2010) can act differently on contingent affect, which can have an impact on both information search behavior and complaints regarding government action. in a situation of physical and social constraint, i.e., quarantine, the sudden perceptions of the risk would depend mainly on mass media, social media, and word of mouth information (jung et al., 2015) . this growing information impacting the emotional state can, in turn, act as both a search trigger for further infection information and a facilitator of compliance with the government's restrictions (goodwin et al., 2011; rolison and hanoch, 2015) . in line with hbm and literature, major evidence linking cognitive risk dimensions and affect keller et al., 2012) , this study aimed to explore the following hypotheses: sociodemographic factors have an impact on risk perception and perceived risk knowledge (hp1); more precisely, the research expects that age (hp1a) and education (hp1b) will negatively affect risk perception and positively risk knowledge; thus, it is hypothesized that women will have a worse perception of pandemics and less perceived knowledge compared to men (hp1c). the research assumed that risk perception would positively impact on na (hp2a) and negatively on pa (hp2b); on the contrary, it expected that risk knowledge would negatively impact on na (hp3a) and positively on pa (hp3b). moreover, the research intends to elucidate whether the differential effect of na (hp4a) and pa (hp4b) on search behavior and a complaint is mediated by state anxiety (hp4). in order to test all the mentioned hypotheses thoroughly, we tested this novel model by means of structural equation modeling (sem) (figure 2 ). one thousand thirty-one participants from italy voluntarily took part to this study (mean age = 38.34; sd = 13.02, range = 18-82). after removing the data of the participants who did not answer all the survey questions, we analyzed 998 participants, of which 739 were females (mean age = 37.01; sd = 12.39) and 259 were males (mean age = 42.15; sd = 14). their marital status was as follows: 37.68% were engaged in a relationship, 32.57% were married, 23.75% were single, 5.42% were divorced, 0.6% were widowed; 23.75% reported living in central big city areas, 20.4% were living in the suburb of a big city, 36.07% reported living in a small town (i.e., less than 50,000 inhabitants), and 20.14% reported living in the countryside; 57.52% resided in northern italy, 17.33% resided in central italy, 17.64% resided in south italy, and 7.52% resided in the islands; 20.44% were students, 2.51% were retired, 25.35% were freelance, 11.72% were temporary workers, and 30.96% were full-time employees with a permanent position; and 52.93% reported having no children, 17.13% reported having two children, 16.43% reported having one child, and 0.6% reported having more than three children. regarding schooling, 3.71% reported having a middle school diploma, 31.16% declared having a high school degree, 18.84% reported having a bachelor's degree, 24.15% reported having a master's degree, and 21.64% reported having a ph.d. this study was conducted in accordance with apa ethical standards and with the declaration of helsinki. participants: (i) were fully informed in regard to institutional affiliations of the researchers and research scope; (ii) continued the survey only if they were adult (>18 years old); (iii) gave information that could not allow their identification; (iv) had the right to refuse to participate in the study and withdraw at any time; (v) filled an anonymous questionnaire and confirmed the understanding of instructions and voluntary participation. participants completed an online survey between march 11, the first day of quarantine and national lockdown, and march 18. the research design relied on snowball sampling (chain referral process). participants were recruited through flyers, social networks, and by word of mouth. the questionnaire answering began in the evening (march 11) when the dpcm decree was issued. first, participants completed the part of the questionnaire created to gather sociodemographic information. second, the following questionnaires were then completed: 1. italian risk perception questionnaire (cafagna and barattucci, 2019) : originally developed by savadori et al. (1998) . based on literature indications (keller et al., 2012) , the study deduced that the pandemic risk could generally be identified as terrifying, uncontrollable, fatal, and dangerous for future generations, and widespread in terms of exposure. hereupon, the researchers built a tool that measures five single-item dimensions of risk infection, on a seven-point scale ranging from 1 to 7: severity, vulnerability, uncontrollability, terror, and danger for future generation (item examples: "considering the scale below (1 'not fatal' to 7 'fatal'): in your opinion, when the virus infects a subject, how likely are the consequences of being fatal?" "considering the scale below (1 'not exposed' to 7 'totally exposed'), in your opinion, to what extent do you think you are exposed to the coronavirus risk?" 2. italian short version of the positive and negative affect schedule (terraciano et al., 2003 (agresti and kateri, 2011) . moreover, regarding the residence area, we operationalized the "residence area" into two different variables. the former "residence area" refers to how far from the city center a person lives: (i) city center; (ii) suburb of a city; (iii) town; (vi) countryside, and (v) the latter, "residence area in italy" refers to a zone of residence from the north to the south of italy and islands, which also coincides with the distance from the first epidemic center of diffusion (i.e., codogno) in northern italy. a comprehensive structural equation model with amos22 was used to test the proposed theoretical model and the main hypotheses. commonly reported fit statistics were: comparative fit index (cfi), tucker-lewis index (tli), normed fit index (nfi), goodness of fit index (gfi), incremental fit index (ifi), root mean square error of approximation (rmsea), plus standardized root mean square residual (srm) for measurement model fit. research has sought to reduce response bias and common-method variance problems utilizing suggested methods (podsakoff et al., 2012) : scales were visually divided, and different formats and endpoints were used for each different measure. psychological impact on anxiety, negative affect, risk dimensions, and search behavior all factors are reported in table 1 with significant regression coefficients and wald statistics. all omnibus models were residency: countryside note. "male" as category of "gender"; "single" as a category of "status"; "ph.d,/ms" as a level of "education"; "three or more children" as "number of children"; "city center" as a level of "residency"; "islands" as a level of "residency in italy" were not reported since they are a redundant levels. marital status was transformed into a dummy variable (engaged vs. single). a the predictor was significant, but the omnibus model was not. ci95, conventional 95% confidence interval; pa, positive affect; na, negative affect; sb, search behavior; knw, knowledge; vul, vulnerability; con, control; sev, severity; ter, terrifying; dfg, damage for future generations; com, compliance. significant except for the model with "knowledge, " i.e., a risk dimension, as the predicted variable. we reported results for each of the dependant variables (anxiety, pa, na, sb, knw, vul, con, sev, ter, dfg, com) in relation to all predictors taken together (gender, marital status, education, number of children, residency, residency in italy). only b values useful for explaining results were reported in order to avoid redundancies. younger , not engaged, significantly positively predicted the perception of being vulnerable against risk. a lower education (beta decreased positively from high school to elementary school) and being older (b = 0.016) significantly positively predicted the perception of control over the risk associated with the pandemic. being female, with a lower level of education, and with no to one child and older led to a significantly higher perception of risk severity. being less educated and younger led to a significantly higher perception of risk as terrifying. being female, with lower education, and an increasing number of children (from no to two children) led to a significantly higher perception of risk damage associated with new generations. females with lower education and younger tended to report more compliance toward the government's measures. descriptive statistics for all the measures and zero-order correlations between them are described in table 2 . with the aim of exploring a measurement model and construct validity, a confirmatory factor analysis (cfa) was conducted comparing four nested models from one factor to a final model composed of the four principal latent factors (risk perception, na, pa, and anxiety). table 3 represents chi-square and goodness of fit indices for the four measurement models developed. considering that risk perceptions were all measured with single items, and despite the final cfa indexes not being optimal, there was an evident amelioration of all indices from the first to the final model. therefore, the measurement model can be profitably used in further testing of the proposed structural model. thus, we tested through sem the proposed structural model (figure 2) : the five risk perception dimensions (fatality, vulnerability, uncontrollability, terrifying) and risk knowledge as (correlated) antecedents, with direct relationships with both na and pa as intermediate variables, which themselves have direct links with state anxiety that fully mediates information search behavior. the proposed model exhibited optimal goodness of fit: chi-square = 112.812 (df = 23; p < 0.000), rmsea = 0.063, cfi = 0.966, ifi = 0.967, nfi = 0.958, gfi = 0.980, tli = 0.919. consequently, we tested the same model deleting nonsignificant relationships (severity, vulnerability, and terrifying with pa; risk knowledge with na) and some correlations between antecedents (vulnerability and danger for future generations, with terrifying risk, risk dimensions, and risk knowledge). consistent with our hypothesized relationships, the model showed excellent goodness of fit: chi-square = 129,737 (df = 33; p < 0.000), rmsea = 0.054, cfi = 0.964, ifi = 0.964, nfi = 0.952, gfi = 0.977, tli = 0.94, with all significant relationships (p < 0.001). regression weights are presented in table 4 , while the path diagram of the final model is shown in figure 3 . as hypothesized (hp2a), each dimension of risk perception is positively related to na. in contrast, only two dimensions (uncontrollability and danger for future generations) are significantly linked to pa, not confirming what was expected (hp2b); conversely, confirming hypotheses hp3a but not hp3b, risk knowledge is only positively related to pa. results confirmed that the expected differential effect of na (hp4a) and pa (hp4b) on search behavior and on a complaint is fully mediated by state anxiety (pa indirect effect on search behavior: β = −0.051, p < 0.001; na indirect effect on search behavior: β = 0.142, p < 0.001). overall, the relationships expressed in the model explained 17% of the variance for na, 18% for pa, 82% for state anxiety, 10% for search behavior, and 7% for complaint in government actions. the present research carried forward the literature regarding the fact that cognitive factors predict population affect that, in turn, motivate and fully mediate information search behavior and complaints about government actions, overturning contributions that proposed that risk behavior is driven by affects (kahan, 2008; leppin and aro, 2009; wu et al., 2018) . considering our sample of participants, results showed that being female and younger with a lower level of education led to more anxiety, na, a higher risk perception as terrifying, and higher complaint regarding gr. moreover, pa increased significantly in older males and those with a decreasing number of children (less than two). younger people or those who were not engaged or married tended to look for information online about the covid-19 more frequently. older females with a lower education level (from middle to elementary school) were more prone to perceive themselves as competent regarding their acquired knowledge on covid-19. being engaged or married acted as a protective factor regarding the perceived vulnerability against covid-19. older people with lower levels of education (from high school to elementary school degree) tended to feel more able to control the gravity of risks associated with this pandemic. older females having from one to no children, and with high-school to elementary school degree, tended to perceive the covid-19-associated risk as more severe. females who have a higher number of children (from no child to two children) and with a lower level of education (this effect increased from bachelor to elementary school) tented to perceive an increased risk associated with covid-19 for future generations. younger females with lower education tended to report more compliance toward the government's measures. in this study, we elucidated two crucial phenomena in emergency: general na and its link with anxiety. na and anxiety have often resulted in closely positively intertwined affective states (crawford and henry, 2004 ) even though they can be considered as clear, distinguishable constructs (watson and kendall, 1989; clark and watson, 1991) . the tripartite model of anxiety and depression confirmed that high levels of na underlie both anxiety and depression, while na acts as a predictor of anxiety (clark and watson, 1991) . specifically, na has been often considered as an early predictor of anxiety in several domains (crawford and henry, 2004; cisler et al., 2010) . the model tested in this study confirmed the direction of this link. emotions and affect also act as motivators of specific survival behaviors (frijda et al., 1989) , and this definition could hardly be more appropriate than in this worldwide emergency. in this case, affect can trigger behaviors such as online health information seeking or avoidance (savolainen, 2014) . while pa resulted in playing a pivotal role in determining people's attitudes toward information avoidance, the negative one predicted individuals' attitudes toward information seeking (yang and kahlor, 2013) . on the other hand, searching for information about symptoms or specific illnesses can increase people distress and anxiety about their health following a reinforcing spiral to the extent that a new term has been coined to refer to this condition, i.e., "cyberchondria" (te poel et al., 2016) . indeed, people with high health anxiety (i.e., fears stemming when individuals exaggerate in interpreting their bodily symptoms as an indicating severe illnesses) (mcmullan et al., 2019) trend to increase their negative responses related to the likelihood of suffering from a given disease now and in the future (baumgartner and hartmann, 2011) . the present result showed that anxiety triggered by na acted as a strong predictor of people's searching behavior regarding health. in other words, italians were motivated by anxiety stemming from na and triggered by their risk perception on the controllability and vulnerability regarding sars-cov-2 spread and health searching behavior. overall, results provided support for the cognitive appraisal framework in risk perception keller et al., 2012) and the main hypotheses. risk perception and knowledge acted with different mechanisms on emotions: risk perception mainly contributed to having an effect on negative affect, while knowledge influenced only positive affect. furthermore, in line with our hypotheses, emotions fully mediated the relation among risk cognition, complaint, and information search behavior (champion and skinner, 2008; carpenter, 2010; jung et al., 2015) . risk perception and affective response to pandemics can be crucial factors for managing population behaviors, thus ensuring the best adherence to prescription and safety norms (poletti et al., 2011; merino, 2014; shook et al., 2019) . moreover, the efficiency of prevention behaviors in pandemics by the government is related to population cooperation, which is highly related to risk perception (leppin and aro, 2009; goodwin et al., 2011) . exploring risk perception during pandemics is fundamental because misperceptions can often cause inadequate responses (poletti et al., 2011; merino, 2014) . in particular, perceptions regarding infection can lead people to take safer actions, to reduce exposure, and to increase protective conducts (e.g., vaccination, social distancing, hygiene, search for information; shook et al., 2019) . these individual behaviors can significantly influence the disease progression at a system level (de zwart et al., 2007; jiang et al., 2009) . since emotion and behavior are closely related (loewenstein et al., 2001; slovic and peters, 2006; brown, 2014) , beliefs and perceptions regarding risk represent core predisposing factors to predict people reactions. therefore, it would be crucial to promote public order and right risk communication and to prevent counterproductive behaviors linked to bad information and fake news (brug et al., 2004; voeten et al., 2009; shook et al., 2019) . the risk controllability is one of the most important factors that need to be considered since pa can reduce anxiety and, consequently, affect complaint and informational search behavior. in italy, especially during the first days of the epidemic (from the end of february), there was too much conflicting information (e.g., "this virus is very similar to normal flu."/"please, pay attention, it is a very dangerous virus; it is not like normal flu."). it is crucial to evidence that too much information, especially if conflicting (or worse, fake news), can cause confusion in the population, and this, in turn, can affect emotional states (bawden and robinson, 2009 ). politicians should act on proper information dispersion procedures regarding specific risk, as perceived knowledge may act on search behavior and complaint. our results can suggest more tailored strategies of communication for prevention to be implemented by the government, not just in pandemic emergency (smith, 2006) . research regarding the way the population appraised hazards acquired significant scientific attention, and different approaches and paradigms to the perception of risk have been discussed (leppin and aro, 2009; keller et al., 2012) . recent contributions have conformed on the emotional appraisal of risk perception (loewenstein et al., 2001; wu et al., 2018) . thus, results from our study could offer evidence in favor of the hypothesis that the analytic system (i.e., risk judgment) would precede the emotional one, at least in a pandemic emergency. covid-19 is having, and is predicted, to have a substantial impact on the world economy, both due to the effect on national health systems, and on the slowdown of business activities through lockdowns and measures of social distancing. the economic impact would be even more substantial in developing countries, due to both difficulties related to social distancing in the slums and in the suburbs, as well as for the absence of stable health systems, welfare measures, and smart-working policies, and for the access to the various forms of institutional communication and to the mass media. the literature concerning the other pandemics has clearly shown that the perception of risk has a strong cultural component; thus, communication strategies should be tailored according to the peculiarities of each country . in this regard, the proposed model can indicate a priority of all the variables capable of influencing preventive behavior or adherence to restrictions directly, which must be taken into account when planning communication to the general public. for instance, accurate and clear communication should clarify the danger for future generations, the terror aroused, and the degree of exposure to the pandemic (van bortel et al., 2016) . furthermore, the proposed model evidenced also perceived knowledge of risk as another key variable to be considered in mass communication. finally, communication in developing countries should consider that people living in precarious economic conditions could give less weight to the health consequences of covid-19, in a cost-benefit assessment process that could overestimate economic costs to the detriment of those for health and economics (leppin and aro, 2009 ). given the novelty and relevance of this study, some limitations should be discussed. first of all, the cross-sectional design of the research limits the generalizability of its findings. although results should be interpreted, especially concerning the specificity of both the contagion risk and the quarantine situation, useful indications on the mechanism that operates between cognitions, emotions, and behaviors in situations of high stress and forced captivity can be provided. moreover, due to the recruitment type (i.e., online), and despite a large number of participants, this sample cannot be considered as fully representative of the italian population (26% males, 57% in northern italy). almost 50% of the participants filled out the survey in the first 2 days (maybe caused by people's reactions to the lockdown). 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role of affect in information seeking and avoidance china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china ad and mb conceived and designed the experiments. mb and ac done through questionnaires to target groups investigation.mb, ac, and gk analyzed the data. ad contributed the analysis tools. mb, ac, and ad wrote the manuscript. ad and gk critically reviewed the manuscript. all authors contributed to the article and approved the submitted version. key: cord-335960-biwnqa3f authors: luke, anthony; d'hemecourt, pierre title: prevention of infectious diseases in athletes date: 2007-07-31 journal: clinics in sports medicine doi: 10.1016/j.csm.2007.04.006 sha: doc_id: 335960 cord_uid: biwnqa3f the sports medicine physician may face challenging issues regarding infectious diseases when dealing with teams or highly competitive athletes who have difficulties taking time off to recover. one must treat the individual sick athlete and take the necessary precautions to contain the spread of communicable disease to the surrounding team, staff, relatives, and other contacts. this article reviews preventive strategies for infectious disease in athletes, including immunization recommendations and prophylaxis guidelines, improvements in personal hygiene and prevention of spread of infectious organisms by direct contact, insect-borne disease precautions, and prevention of sexually transmitted diseases. a special emphasis on immunizations focuses on pertussis, influenza, and meningococcal prophylaxis. i nfections in sports can be serious medical problems. they can affect individual athletes, resulting in morbidity and decreased performance [1] . they can also be spread to other athletes, putting them at risk for similar disease and complications. the sports medicine physician may face challenging issues regarding infectious diseases when dealing with teams or highly competitive athletes who have difficulties taking time off to recover. one must treat the individual sick athlete and take the necessary precautions to contain the spread of communicable disease to the surrounding team, staff, relatives, and other contacts. the authors aim to translate recommendations in public health to practice in a sports medicine setting. sports physicians have an opportunity to see athletes during adolescence and adulthood who might not come in for routine health maintenance except when related to their sports. primary prevention of infectious disease, the ideal goal, deals with avoiding the development of the disease before infection occurs. immunizations are an example of primary prevention and have been the most successful public health programs for disease prophylaxis. secondary prevention for infection control involves prevention of spread to others. athletes are often exposed to many different people, travel to compete in various environments locally and internationally, and engage in higher-risk activities, often in close contact with others [2] . the authors discuss the preventive strategies for infectious disease in sport, including (1) a review of immunization recommendations and prophylaxis guidelines, (2) improvements in personal hygiene and prevention of spread of infectious organisms by direct contact, (3) insect-borne disease precautions, and (4) prevention of sexually transmitted diseases (stds). a special emphasis on immunizations focuses on pertussis, influenza, and meningococcal prophylaxis. athletes may share personal items (eg, towels, water bottles, and soap) and equipment (eg, weights). they may live in dormitories or in hotel rooms while traveling, which leads to close contact and high exposure to teammates. they participate in higher-risk activities [2, 11] . fewer athletes practice safe sex, which can lead to stds in homosexual and in heterosexual individuals. athletes also use more illicit drugs and alcohol, which can place them at risk of intravenous needle exposure [12, 13] . steroids, hormones, and vitamins are other substances that some athletes are injecting [14, 15] . tattoos are popular among athletes, which are another source of needle infection risk. active immunization involves the administration of all or part of a microorganism or a modified product of that microorganism, such as an antigen or protein. this administration stimulates an immune response to develop protection against future exposure to the infection [16] . although most vaccines are over 90% effective, they are not guaranteed to promote immune protection [16] . immunizations typically involve inactivated vaccines or live, attenuated viruses. inactivated vaccines include killed virus or bacterial proteins to stimulate one's immune system to develop antibodies to any similar virus or bacteria. more side effects are associated with the live, attenuated viruses-typically local pain and, rarely, hypersensitivity reactions to vaccine constituents. a mild febrile illness, a recent exposure to an infectious disease, pregnancy, breastfeeding, nonspecific allergies, and family history of an adverse event after immunization, including seizures, are not contraindications for immunization [16] . sports medicine physicians need to consider the following indications for immunizations (tables 1 and 2) : (1) routine health maintenance; (2) catch-up immunizations for failed or missed immunizations; (3) immunizations of high risk groups (ie, splenectomy, chronic disease, immunocompromised); (4) travel to an endemic area; (5) close contact with an infected individual, or (6) recent potential exposure to an infectious agent. when doing preparticipation physical examinations, it is sometimes assumed that athletes have received all their immunizations. proof of immunizations is required by schools and colleges, although exceptions can be given to individuals refusing to receive immunizations. in a study surveying 69,115 minnesota children who entered kindergarten in 1992, by 19 months of age, 73% of students had received the measles, mumps, and rubella (mmr) vaccine, and only 39% had received their fourth dose of diphtheria, tetanus, and pertussis vaccine (dtap) [17] . vaccination rates can vary substantially by age, race/ethnicity, and neighborhood [17] . white, non-hispanic students usually have higher vaccination rates than children of other racial/ethnic groups. it has been estimated that 79% of whites, 76% of hispanics, and 71% of african americans are fully immunized [18] . although mmr vaccines have been administered for many decades and incidences of disease are presently low [7] , the diseases can still occur in the adult population. between 1986 and 1989, 6% of the measles cases occurred in college students [19] . enzyme-linked immunosorbent assay tests for antibodies to mmr are available to detect for immunization status [19] . in a series of 256 students, 53 (21%) were found to be seronegative to measles alone, 13 (5%) were seronegative to rubella alone, and 5 (2%) were seronegative to measles and rubella. eighty-six percent of the individuals seronegative to measles had previously received a dose of measles vaccine. following a second injection, conversion to seropositive status rose to 97% and 100% for measles and rubella, respectively. these data support the need for a two-dose vaccine schedule [19] . pneumococcal vaccine is administered to prevent streptococcus pneumoniae infections. a conjugate heptavalent is given to during the first 2 years of life. a polysaccharide vaccine is provided to high-risk individuals older than 2 years against 23 types of streptococcus pneumonia that account for 90% of invasive disease [20] . high-risk groups include patients who have asplenia, sickle cell disease, diabetes mellitus, cirrhosis, immunocompromised states, chronic cardiac or pulmonary disease, or age 65 years or older. immunity following vaccination is successful for periods of 5 to 10 years, requiring booster injections [20] . hepatitis b is a blood-borne virus transmitted through sexual contact and parenteral exposure to blood and blood components [14] . hepatitis b has a greater risk for transmission in sports than hiv. the risk of hiv transmission is estimated to between 1 in 1 million games and 1 in 85 million games [14, 21] . the risk arises if bleeding and skin exudates from an infected individual come into contact with open wounds in another athlete, particularly during contact and collision sports. there are no confirmed cases of spread of hiv through sports [14] ; however, 5 out of 10 high school sumo wrestlers at one club developed hepatitis b [22] . another case series reported on 11 of 65 american football players who developed hepatitis b over a period of 19 months [23] . contact through open wounds, cuts, and abrasions were the suspected routes of transmission. although hepatitis a is a considered immunization in athletes who are traveling to endemic areas, routine vaccination for hepatitis b is recommended for all individuals after birth using single or combination vaccines [24] . a three-dose immunization schedule is typically used after 18 years of age, with injections at 0 months, 1 month, and 6 months, although there is an optional four-dose schedule [25] . the licensed vaccines have had 90% to 95% efficacy of preventing hepatitis b, with immunity lasting 15 years or longer [25] . immunizations for hepatitis b should be checked during the preparticipation physical examination, and catch-up immunizations recommended to the individual (see table 2 ). if individuals are uncertain about their immunization status, serologic testing for antibody to hepatitis b surface antigen can determine immunity. when athletes are known to be infected with hepatitis b, secondary prevention includes education on personal hygiene, appropriate management of open wounds, proper use of protective equipment, safe sex practices using a condom, and avoidance of intravenous blood transmission (eg, through needle sharing and illicit drug use). bordetella pertussis, which is responsible for whooping cough, is a gram-negative coccobacillus transmitted by way of airborne droplets [26] . although tetanus and polio have been controlled well with the use of vaccines [7] , the rate of pertussis cases has been increasing in adolescents and adults despite routine immunizations [27] . most cases occur in patients 10 years or older [28] . the infection is most concerning for infants because immunity is not complete until older ages. the spread to infants is typically from adults. pertussis usually presents with nonspecific upper respiratory tract infection symptoms for 1 to 2 weeks (catarrhal stage), after which the paroxysmal and sometimes uncontrollable cough develops [26] . the cough is not necessarily always followed by the classic ''whooping'' sound, and pertussis should be considered with any persistent, prolonged cough. the whole-cell pertussis vaccine is estimated to be approximately 85% effective [29] . this vaccine is still recommended for use in the routine immunization of young children; however, the immunity provided begins to decline at 4 to 12 years following vaccination, which makes adolescents and adults susceptible [27] . rare adverse reactions from the vaccine include hypotonic, hyporesponsive episodes, high fever, seizures, and anaphylaxis [26] . two acellular vaccines have been introduced that are as effective as whole-cell vaccines and have fewer adverse reactions [30] . these vaccines are combined with tetanus toxoid and reduced diphtheria toxoid (dtap). the centers for disease control and prevention (cdc) recommends use of these dtap boosters rather than the tetanus-diptheria (td) booster starting after 11 to 12 years of age [31] . for pertussis, individuals are most contagious during the first 1 to 2 weeks during the catarrhal stage but should be considered contagious until 3 weeks after the paroxysmal stage ends or after taking antibiotics for 5 days [32] . diagnosis of pertussis infection is best performed through polymerase chain reaction assay (sensitivity, 94%; specificity, 97%) or through direct fluorescent antibody testing (sensitivity, 52%; specificity, 98%). nasal swab cultures (sensitivity, 15%; specificity, 100%) are routinely performed; however, they have high false negative rates and take 7 to 12 days to yield results [33] . physicians in the united states are legally required to report cases of pertussis to state public health departments [26] . it is estimated that 80% of susceptible household contacts will be infected after close contact [26] . antibiotic prophylaxis is recommended for close contacts of persons who have pertussis to prevent outbreaks [34] . preferred drugs are azithromycin for 5 days, clarithromycin for 7 days, or trimethoprim-sulfamethoxazole or erythromycin for 14 days, which are similar for prophylaxis and treatment [34] . influenza presents with constitutional symptoms of fever, chills, malaise, fatigue, and myalgia in addition to upper respiratory tract symptoms of a sore throat, cough, and rhinitis. rarely, more serious conditions can occur, including encephalopathy, transverse myelitis, myocarditis, and pericarditis [9] . immunogenicity is determined by hemaglutinins and neuraminidases on the virus surface. antigenic drift can occur that can mutate the virus into different strains. transmission occurs by way of respiratory droplets. the virus has an incubation period of usually 2 days (range, 1-4 days), and adults are infectious from the day before symptoms begin to approximately 5 days after the illness starts [9] . symptoms usually last a week, although less likely, symptoms can last longer than 2 weeks. these symptoms can be very disruptive for treatment and challenging for the athlete to keep training and competing. a case series of 81 students, mostly healthy adolescents at a ski school in austria, reported a severe outbreak of influenza a, leading to an attack rate of 49%, with 69% becoming ill within 2 days of the outbreak. two students were hospitalized with pneumonia and 1 died [35] . influenza vaccines contain strains of antigenically equivalent strains of influenza similar to those annually recommended: influenza a (h3n2), influenza a (h1n1), and a b virus. depending on the emergence and spread of new strains, other virus strains can be added to update the vaccine [9] . the efficacy of influenza vaccine is approximately 70% to 90% for individuals under age 65 years [36] . vaccination for influenza should occur in the fall (october or november), at the beginning of the flu season (box 2) [9] . antibodies develop approximately 2 weeks after vaccination [9, 37] . inactivated influenza vaccine is generally appropriate for all populations requiring influenza vaccine. three influenza vaccines were available in the united states for the 2006 to 2007 season: fluzone (manufactured by sanofi-pasteur); fluvirin (manufactured by novartis); and fluarix (manufactured by glaxosmithkline). the typical dose is 0.5 ml administered intramuscularly, usually in the deltoid muscle. live, attenuated influenza vaccine (laiv) is approved for use in healthy, nonpregnant individuals aged 5 to 49 years. the laiv is administered by way of a nasal spray once in each nostril (flumist, manufactured by medimmune). individuals who have a hypersensitivity or anaphylactic reaction to components of the flu vaccine or to eggs should not be vaccinated [9] . adults reported having a 19% reduction in severe febrile illnesses after laiv compared with placebo [38] . side effects from laiv increased in adults within 7 days of immunization compared with placebo and consisted mainly of nasal congestion (44.5% versus 27.1%) and sore throat (27.8% versus 17.1%), which lasted, on average, 2 days. less common complaints were tiredness, cough, and chills. there was no significant difference in the number of mild febrile illnesses between immunization and placebo groups [39] . injections can be scheduled to occur at the optimum time during the athlete's competitive schedule to minimize concern about side effects. when inactivated influenza vaccine shortages occurred in previous years, the vaccine was recommended for high-risk groups as priority; however, the general recommendation now is to offer the immunization annually to anyone who wishes to reduce the likelihood of being ill with influenza or transmitting the virus if they should become infected [9] . although this policy cannot be directly translated into a benefit for the athlete, depending on the level of athlete, the use of the laiv may also be beneficial to prevent lost time from sport. influenza vaccine has been suggested for competitive athletes and essential personnel, especially before international events occurring during the influenza season [4, 40] . treatment with antiviral medications can reduce the duration of uncomplicated influenza a and b illness by approximately 1 day when administered within 2 days of illness onset [41, 42] . recommended antiviral treatment should be given for 5 days [9] . four antiviral agents are currently available: amantadine, rimantadine, zanamivir, and oseltamivir [9] . the influenza a virus, however, has become resistant to amantadine and rimantadine, which are presently not recommended to be used as first-line drugs [43] . zanamivir (ralenza, dry powder taken by orally inhaled route) and oseltamivir (tamiflu, capsule or oral suspension) are neuraminidase inhibitors and can be used to treat patients and to control influenza outbreaks in closed settings. although typically used in nursing homes, an outbreak in a dormitory may require chemoprophylaxis [9] . there are limited data to suggest that serious complications from influenza, such as lower respiratory tract infections, may be reduced [44] . the use of antiviral medications for prophylaxis of influenza is unclear and is not yet recommended for routine seasonal control [45] . the use of oseltamivir, however, has been recommended in specific cases, especially if there is high risk of spread such as household contacts and if individuals have not been immunized [46] . oseltamivir was used to treat 36 of 188 patients, including 13 athletes during the 2002 salt lake city winter olympics, with medications given to close contacts, which was believed to limit the spread of influenza [47] . clinical history and physical examination are still the mainstays for diagnosing influenza. rapid swab tests are available and take approximately 30 minutes to detect the influenza virus. the tests are less sensitive (72%-95%) and specific (76%-86%) than the traditional viral cultures [48] . they have moderate sensitivities for influenza antigens and are more likely to produce false negative rather than false positive results [48, 49] . direct and indirect fluorescent antibody staining tests are also available, but they are ordered more in hospitals because they take 2 to 4 hours to obtain results [49] . viral cultures are still the ''gold standard'' for confirming the presence of influenza and identifying the strains and subtypes [9] . neisseria meningitides is a serious concern, especially for the adolescent and college populations. an alarming trend during the 1970s demonstrated an increase in meningitis deaths in college students, with living in dormitories being a risk factor. the disease can be spread by asymptomatic carriers. students living in dormitories were 9 to 23 times more likely of getting infected than those living in other types of accommodations [50] . freshmen who lived in dormitories had an elevated risk of meningococcal disease (odds ratio, 3.6; 95% confidence interval, 1.6-8.5; p â¼ .003) compared with other college students [51] . aside from the risk of death, 11% to 19% of survivors of meningitis have serious sequelae such as neurologic disability, limb loss, and hearing loss [50] . routine vaccination with meningococcal vaccine is recommended for college freshmen living in dormitories and for other populations at increased risk. the cdc advisory committee on immunization practices recommends routine vaccination of young adolescents (11-12 years old) with meningococcal vaccine (mcv4) at the preadolescent health care visit [50] . therefore, sports medicine physicians may be faced with higher frequency of checking for meningococcal immunization status for high school and college athletes. a tetravalent conjugate vaccine (menactra, sanofi pasteur) is available against neisseria meningitidis isolates a, c, y, and w-135 in a 0.5-ml single-dose vial. over the age of 11 years, 75% of the meningococcal infections are caused by strains c, y, or w-135 (cdc, unpublished data, 2004) [50] . another vaccine, menomune (aventis pasteur limited), has been licensed since 1981 and has a similar immunogenicity profile to menactra and is delivered subcutaneously as a 0.5-ml dose. menactra and menomune have serum bactericidal protection ranging from 89.4% and 94.4% for strain w-135 and 73.5% and 79.4% for strain y, respectively [50] . revaccination may be necessary for individuals at high risk after 5 years [52, 53] . common side effects with mcv4 were local pain in just over 50% of patients, followed by swelling, induration, and redness in approximately 10.8% to 17.1%. fever was reported in 5.1% of children 18 years old or younger and in 1.5% of adults [50] . close contacts are at high risk and should be treated with chemoprophylaxis ideally within 24 hours of identifying the index patient [50] . the goal of treatment is to reduce nasopharyngeal carriage of n meningitidis. after more than 14 days after the onset of illness in the index patient, chemoprophylaxis is not necessary [50] . a single dose of ciprofloxacin (500 mg orally) or ceftriaxone (250 mg by intramuscular injection), or rifampin (600 mg twice a day for 2 days) is recommended for adults. children between 1 month and 18 years old may take rifampin (10 mg/kg every 12 hours for 2 days), or ceftriaxone (125 mg intramuscularly) if younger than 15 years [50] . one dose of azithromycin (500 mg) was also shown to eradicate n meningitidis and may represent another treatment option [54] . human papillomavirus (hpv) is associated with 99% of cervical cancers and anogenital, head and neck, and nonmelanoma skin cancers. it is an std and can be diagnosed by abnormal cervical cell changes seen on pap smear [55] . this is a common infection, especially in sexually active adolescents and university students [56] . primary prevention is now possible with two new vaccines: a bivalent vaccine against hpv types 16 and 18 and a quadravalent vaccine against types 6, 11, 16, and 18. the vaccines have a three-dose schedule: 0, 1, and 6 months (bivalent vaccine) and 0, 2, and 6 months (quadravalent vaccine). at 4.5 years, the bivalent vaccine was effective for producing a persistent antibody response against hpv 16 and 18, with more than 98% seropositivity and 96.9% effectiveness (95% confidence interval, 81.3-99.9) in reducing the number of reported abnormalities on pap smear, colposcopy, or both [57] . routine vaccination with three doses of quadrivalent hpv vaccine is recommended for girls 11 to 12 years old but can be started in girls as young as 9 years. girls and women aged 13 to 26 years who have not been vaccinated previously or who have not completed the full vaccine series are recommended to receive a catch-up series. the vaccine is intended to be administered before potential exposure to hpv through sexual contact [58] . secondary prevention involves checking the affected individual's partners for signs of genital warts and other stds. regular cervical screen is recommended. use of condoms and education on spread is important. hpv infection persists for life; however, the degree and duration of contagiousness is yet unknown [59] . athletes traveling need to consider the endemic diseases in the geographic location where they are competing. they should be aware of risks of acquiring common diseases, their accommodations (urban versus rural), local foods, and customs. immunizations should ideally be planned 4 or more months in advance to allow for adequate time to administer vaccines (table 3 ). there are many resources for information about prevention of infectious diseases for travelers (table 4) . mosquito-borne disease a number of arthropods, such as mosquitoes and ticks, can transmit diseases. mosquito-vector diseases include west nile virus, yellow fever virus, and dengue virus. west nile virus, a flavivirus, has demonstrated a seasonally endemic epidemiology with geographic variation in the united states, especially in california, arizona, and colorado [7, 61] . this disease typically presents between july and october, although cases have presented between april and december. the prevention of mosquito bites is the cornerstone of prevention. an athlete in an endemic area should wear an insect repellant such as deet (n,n-diethyl-mtoluamide), picaridin (kbr-3023), or oil of lemon eucalyptus (p-menthane-3,8 diol). deet and permethin may be applied to the clothing [62] . if a sunscreen is used concomitantly, the insect repellant should be applied on top of this and removed at the end of the day. long-sleeved shirts that are tucked into long pants are also useful. tick-borne diseases include rickettsial diseases, lyme disease, babesiosis, tickborne relapsing fever, and occasionally, tularemia and q fever (table 5) . certain athletes who participate in rural outdoor activities are more susceptible to tick bites. these sports include cross-country running, training in multiple sports in rural areas, and recreational outdoor sports such as fishing and hiking. children are more at risk to tick bites. three more common rickettsial illnesses are rocky mountain spotted fever, human monocytotropic ehrlichiosis, and human granulocytotropic anaplasmosis [60] . the infectious organisms responsible for these illnesses maintain their lifecycles in mammals and ticks. their prevalence reflects the geographic locations and the seasonality of the tick abundance. their season is usually from april to september, but they can present throughout the year. newer rickettsial diseases are emerging. these potentially lethal diseases are difficult to diagnose because they often mimic viral syndromes. as many as 60% to 75% of patients are initially misdiagnosed [63, 64] . with rocky mountain spotted fever, more than 50% of cases are reported in the five states of north carolina, south carolina, tennessee, oklahoma, and arkansas [65] . the presentation most often manifests as a sudden febrile illness with headache, myalgia, and a maculopapular rash that spreads in a centripetal pattern. rickettsia rickettsii has a predilection for endothelial cells and can cause a diffuse vasculitis and an untreated mortality of 10%. the diagnosis is based on clinical presentation, with epidemiologic, geographic, and seasonal considerations. laboratory testing may be supportive with thrombocytopenia and mild liver enzyme elevation. serologic testing is supportive only on a delayed basis with acute and convalescent titers. human monocytotropic ehrlichiosis and human granulocytotropic anaplasmosis can also present with acute headache, fever, and myalgia. laboratory evaluation often demonstrates leukopenia, thrombocytopenia, and transaminase elevation. common tick-borne illnesses that have been reported in the northeast united states are lyme disease and babesiosis, which are transmitted by the tick ixodes scapularis [66] . babesiosis can cause a febrile illness and possibly life-threatening anemia and thrombocytopenia. lyme disease is a rickettsial disease caused by borrelia burgdorferi. as such, concurrent disease may be caused by the same tick bite (see table 4 ). there are no proven vaccines for these tick-borne illnesses, but all are preventable by careful vigilance and protection. the key to prevention is to understand the regional epidemiology and seasonality of the diseases. vaccination for lyme disease (lymerix) was originally approved; however, the manufacturer took the vaccine off the market due to declining sales. there was a 49% efficacy after two doses and a 76% efficacy after three doses [67] ; however, the protection diminished after 2 years. ticks thrive in a wooded environment and at the edge of woods with surrounding high vegetation. ticks are uncommon in well-mowed lawns. relative tick-free zones can be created by placing wood chips or gravel around recreational areas to separate the woods [68] . other landscape management tips include removing clippings and leaves, keeping stone walls clean of leaves, and restricting the use of groundcover, such as pachysandra, where pets and children may play. widening woodland trails andkeeping in the center of the trail while walking may be helpful. when traveling in wooded areas, light-colored clothing is helpful to identify the tick. long pants tucked into tightly woven socks and closed shoes minimize exposure. deet at 10% to 25% should be applied to the skin. permethrin may be applied only to the clothing. clothes should be removed and cleaned and dried after exposure. the clothes dryer is effective in killing ticks. one should carefully check for ticks in the nymphal phase that may be the size of a pin head. careful inspection should be done of the hair, ears, axilla, belly button, and legs. children and pets should also be checked. it is also important to monitor pets that may travel in the woods and return indoors. the technique of tick removal is critical. tweezers with fine tips should be used close to the skin and pulled directly away. squeezing the body may allow contamination of the disease into the host [69] . lyme disease is not contracted until at least 24 hours of tick adherence [70] ; however, ehrlichiosis may transmit in less than 24 hours. preventive antibiotics are generally not indicated because less than 5% of bites are lyme infected, especially with a flat tick. after a high-risk exposure (when the tick has been engaged for more than 24 hours and is engorged), a single dose of 200 mg of doxycycline is believed to be effective [71] . most infectious diseases are spread from contact with the microorganism directly or indirectly from the infected individual. athletes frequently interact with teammates, coaches, athletic trainers, and physicians and share equipment, water bottles, towels, and supplies. this interaction is particularly a concern, with the recent outbreaks of methicillin-resistent staphylococcus aureus (mrsa) infections among sports teams [72, 73] . three categories of potential risk factors for spreading infection have been suggested: ''sharing'' (sharing soap/towels/water bottles with teammates), ''skin injury'' (cuts, abrasions), and ''close contact'' (locker adjacent to infected teammate, living on-campus) [74] . good personal hygiene can help reduce colonization of bacteria. bacterial counts can range from 5000 to 5 million colony-forming units per square centimeter on the hands [75] . universal body fluid precautions-for example, using disposable gloves when examining the oral cavity or wounds and frequent hand washing-can reduce the risk of infection. mrsa is transmitted from an infected patient to the gloves of a health care worker in approximately 17% (9%-25%). physicians, in particular, have a low compliance for using gloves and washing their hands [76] . proper surgical hand washing is recommended to be 15 to 30 seconds with soap, a 30-second rinse with water, followed by complete drying with a towel. the use of rinses and gels with concentrations of 50% to 95% alcohol take 15 seconds to use and are effective at killing organisms [75] . the use of chlorhexidine soap has been useful for reducing mrsa infections. viruses and bacteria can exist on equipment. mrsa was found in the taping gel and whirlpool in the training facilities of a professional football team [72] . using diluted bleach (1 part bleach in 9 parts water) to cleanse training areas and equipment is recommended [8] . routine cleaning schedules for shared equipment should be established and recorded. for upper respiratory tract infections, isolation of those who have had close contact with someone who has a confirmed or suspected infection, especially those who have active symptoms such as persistent fever and cough, is an effective and practical method of avoiding contact [8] . any athlete who has a scratch, abrasion, or laceration or who has potentially infectious skin lesions such as vesicular or weeping skin lesions should be removed from play until the area can be securely covered with occlusive bandages or dressings to prevent leakage of blood or serous fluid [77] . uniforms with fresh blood should be removed and replaced immediately after stopping any bleeding. bleach diluted with tap water in a 1:10 ratio can be used to wash equipment that has had contact with blood or body fluid. body substance precautions should be taken by health care professionals at all times when treating open wounds. one type of bacteria that has become more common in the hospital and a community-acquired infection is mrsa. although contact sports such as wrestling and football have been commonly associated with mrsa spread, this infection has also been discovered in minimal-contact sports such as fencing [78] . three factors are associated with mrsa spread in sports. first, even with sports that have minimal contact, there are often abrasions and chaffing from clothing and hot environments. second, equipment is often shared and there is potential for transmission of bacteria. third, many sports have sufficient skin-to-skin contact to transmit organisms. subsequently, health care providers should strongly encourage good overall and hand hygiene in addition to covering all wounds and limiting shared equipment. it is crucial to have an ample supply of soap and water and alcohol-based hand cleansers. athletes, staff, and coaches should be educated in proper first aid for wounds, in recognition of wounds that are potentially infected, and in seeking medical attention for lesions that have concerning signs, especially large pustules or boils. athlete's foot, tinea pedis, is a common ailment not only during the hot summer months but also during the winter months with indoor sports. a number of prevention items include washing feet daily; drying between the toes; wearing cotton, nonsynthetic socks; wearing bathing shoes in public showers; and wearing sandals in warmer weather. jock itch, tinea cruris, is best prevented by showering immediately after athletic endeavors and wearing cotton briefs. a good talc powder may be used for prevention of athlete's foot and jock itch. ring worm, tinea corporis, is best prevented by avoiding contact. contact athletes such as wrestlers should not participate until any lesions have cleared or can be safely and effectively covered. athletes may manifest risk-taking behavior and subsequently be at increased risk for stds [2] . the preparticipation examination affords the opportunity for the clinician to address these concerns. the cdc has emphasized the five intervention strategies [79] , which include education on sexual behavior, identification of asymptomatic individuals, diagnosis and treatment of infected individuals, counseling of sexual partners of persons who have an std, and pre-exposure vaccination when applicable. individuals at risk should be questioned about partners regarding number and same or opposite sex. information about the type of sexual activity, the use of protection, and history of previous stds should also be identified. preventive measures for an std include abstinence if an individual or partner is actively infected and undergoing treatment. pre-exposure prophylaxis is relevant in several situations. hepatitis b vaccine is recommended in all individuals potentially exposed to stds. hepatitis a vaccine is recommended for all men who have sex with men or users of illicit drugs (injectable and noninjectable). for girls and women aged 9 to 26 years, the new quadrivalent vaccine for hpv types 6, 11,16, and 18 is recommended due to the higher associated risk of cervical cancer. most condoms are made of latex and are quite effective in std prevention. in one study of partners of hiv-infected individuals, partners were 80% less likely to seroconvert than those who did not use condoms [80] . the male condom can also reduce the transmission of gonorrhea, chlamydiosis, and trichomiasis [81] . there may be some added protection against herpes simplex virus 2 and a 70% reduction of hpv transmission [82, 83] . when an individual is allergic to latex, certain polyurethane condoms are likely just as effective, although they may break more readily. conversely, natural-membrane condoms such as lambskin are too porous to be used for std prevention. only water-based lubricants should be used with latex condoms because oil bases will weaken the latex. the female condom is a double-ringed polyurethane sheath that is used vaginally and during anal receptive intercourse that is effective in limited trials in preventing hiv/stds [84, 85] . spermicides and nonbarrier contraception have no role in std prevention. finally, providers should encourage patients who have stds to notify their partners. often, this notification is pursued by the public health department. in the event of exposure to hiv by sexual exposure or needle stick, hiv prophylaxis is often undertaken and should be immediate. prophylactic treatment usually involves the hospital infectious disease division to determine the best combination therapy. education is paramount in public health and in the prevention of infectious diseases. athletes are a high-risk population often due to their 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rickettsial infection in patients with unexplained fever and recent history of tick bite in central north carolina the epidemic of west nile virus in the united states laboratory evaluation of mosquito repellents against aedes albopictus, culex nigripalpus, and ochierotatus triseriatus (diptera: culicidae) physician knowledge of the diagnosis and management of rocky mountain spotted fever: mississippi rocky mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases rocky mountain spotted fever in the united states, 1993-1996 endemic babesiosis in another eastern state: new jersey vaccination against lyme disease with recombinant borrelia burgdorferi outer-surface lipoprotein a with adjuvant. lyme disease vaccine study group prevention of lyme disease effect of tick removal on transmission of borrelia burgdorferi and ehrlichia phagocytophila by ixodes scapularis nymphs duration of tick bites in a lyme disease-endemic area prophylaxis with single-dose doxycycline for the prevention of lyme disease after an ixodes scapularis tick bite a clone of methicillin-resistant staphylococcus aureus among professional football players methicillin-resistant staphylococcus aureus in a high school wrestling team and the surrounding community recurring methicillin-resistant staphylococcus aureus infections in a football team on washing hands an investigation of contact transmission of methicillin-resistant staphylococcus aureus transmission of blood-borne pathogens during sports: risk and prevention methicillin-resistant staphylococcus aureus infections among competitive sports participants-colorado sexually transmitted diseases treatment guidelines effectiveness of condoms in preventing sexually transmitted infections a randomized controlled trial to reduce hiv transmission risk behaviors and sexually transmitted diseases among women living with hiv: the willow program effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women condom use and the risk of genital human papillomavirus infection in young women use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women use of reality ''female condoms'' for anal sex by us men who have sex with men. hivnet vaccine preparedness study protocol team key: cord-344252-6g3zzj0o authors: farooq, junaid; bazaz, muhammad abid title: a novel adaptive deep learning model of covid-19 with focus on mortality reduction strategies date: 2020-07-21 journal: chaos solitons fractals doi: 10.1016/j.chaos.2020.110148 sha: doc_id: 344252 cord_uid: 6g3zzj0o we employ deep learning to propose an artificial neural network (ann) based and data stream guided real-time incremental learning algorithm for parameter estimation of a non-intrusive, intelligent, adaptive and online analytical model of covid-19 disease. modeling and simulation of such problems poses an additional challenge of continuously evolving training data in which the model parameters change over time depending upon external factors. our main contribution is that in a scenario of continuously evolving training data, unlike typical deep learning techniques, this non-intrusive model eliminates the need to retrain or rebuild the model from scratch every time a new training data set is received. after validating the model, we use it to study the impact of different strategies for epidemic control. finally, we propose and simulate a strategy of controlled natural immunization through risk based population compartmentalization (pc) wherein the population is divided in low risk (lr) and high risk (hr) compartments based on risk factors (like comorbidities and age) and subjected to different disease transmission dynamics by isolating the hr compartment while allowing the lr compartment to develop natural immunity. upon release from the preventive isolation, the hr compartment finds itself surrounded by enough number of immunized individuals to prevent spread of infection and thus most of the deaths occurring in this group are avoided. o an effective strategy to minimize the number of deaths through controlled natural immunization in absence of availability of vaccination at mass level. covid-19 is a highly contagious epidemic disease caused by novel coronavirus (sars-cov-2) that originated in wuhan, hubei province of china in late december 2019. world health organization (who) declared covid-19 as a pandemic on 12th march 2020 [1] . researchers are policy makers are working round the clock to find solutions and design strategies to control the pandemic and minimize its impact on human health and economy. the transmission of sars-cov-2 in humans is mostly through respiratory droplets (sneezing, coughing and while talking) and through contaminated surfaces [2] . the most significant property of sars-cov-2 is that it can persist on a variety of surfaces from hours to 9 days at room temperature which makes its transmission more rapid [3] . this virus can cause acute respiratory distress syndrome (ards) or multiple organ dysfunction, which may lead to physiological deterioration and death of an infected individual [4] . mathematical modeling of infectious diseases and epidemics has been employed as an important tool for analysis of disease characteristics and investigation of disease spread ever since the ground breaking work of kermack and mckendrick in 1972 [5] . it plays a useful role in efficient decision making and optimal policy framing. different models have been developed to analyse the transmission dynamics of many infectious diseases like malaria (ronald ross model) [6] , cholera (capasso and pareri-fontana model, 1979) [7] , gonorrhea (hethcote and yorke model, 1984) [7] , ebola [8] , h1n1 [9] etc. in this work, we employ deep learning to propose an artificial neural network (ann) based real-time online incremental learning technique to estimate parameters of a data stream guided analytical model of covid-19 to study the transmission dynamics and prevention mechanism for sars-cov-2 novel coronavirus in order to aid in optimal policy formulation, efficient decision making, forecasting and simulation. modeling and simulation of such problems poses an additional challenge of continuously evolving training data in which the model parameters change over time depending upon external factors. our main contribution is that in a scenario of continuously evolving training data, unlike typical deep learning techniques, this model eliminates the need to retrain or rebuild the model from scratch every time a new training data set is received. using a data science approach, model parameters are intelligently adapted to the new ground realities. to the best of our knowledge, this paper develops for the first time a deep learning model of epidemic diseases with data science approach in which parameters are intelligently adapted to the new ground realities with fast evolving infection dynamics. the covid-19 data from india has been taken as the case study. the first case of covid-19 in india was reported on 30th january 2020 originating from wuhan, china [10] . as on 13 june 2020, the total number of cases reported in india is 308,993 with 154,330 recoveries and 8,884 deaths [11] . hence the number of active cases is 145,779. the government of india imposed a country wide complete lockdown on 24th march 2020 with strict restrictions on the movement of people while allowing only the essential services to operate under the supervision of administration and health officials. the lockdown was renewed thrice on 14 april, 3 may and 18 may 2020 and has been relaxed since 8 june 2020 [12] . india is the second largest populated country in the world with a total population of around 1.35 billion. the health care facilities in india are considered poor with 0.55 hospital beds per thousand people of the population [13] . therefore, the covid-19 pandemic has emerged as a major challenge for the people, health workers and policy makers of the country. using a control theory approach, we analyze the stability of different disease prevention strategies. finally, we propose a strategy of controlled natural immunization of the population by dividing it in low risk and high risk compartments based on various risk factors like age and comorbidities. the two groups are treated separately and subjected to different disease mechanics with the aim to minimize the total number of deaths given the fact that the probability of death is very high in the high risk group as compared to the low risk group. the two compartments are isolated from each other for a certain period of time. the low risk compartment is allowed to fully brace the infection with maximum speed and develop immunity owing to its very low death rate while as the high risk compartment is put under preventive isolation till the infection growth curves fatten for the low risk group. upon release from the preventive isolation, the high risk group finds itself surrounded by enough number of immunized individuals to prevent spread of infection and thus most of the deaths occurring in this group are avoided. we simulate this strategy in matlab environment to establish its effectiveness in significant reduction in the number of deaths while demonstrating the usefulness of the deep learning based mathematical model. to the best of our knowledge, such an approach to reduce mortality has not been modeled and simulated earlier by the scientific community. sirvd refers to susceptible, infected, recovered, vaccinated and deceased states of individuals in a population going through an epidemic. the pioneer work in development of mathematical models for infectious diseases was carried out by by [5] known as the susceptible-infectious-recovered (sir) model. as one of the most classical models, it has been used by many researchers to study and analyse many infectious diseases like seasonal flu [14, 15] , pandemic flu [16, 17] , hiv/aids [18] , sars [19, 20] etc. these studies have shown that sir models are reliable for analysis of the infectious disease spread and evaluation of the impact of prevention schemes in different scenarios. the basic sir model is described by the following differential equations: where s , i and r are functions of time representing the number of susceptible, infected and recovered individuals in a population of size n at time t. β is the rate of transmission and γ is the rate of recovery of infected individuals. it is assumed that those recovered develop immunity and do not catch the infection again in the time span of interest. the basic sir model can be modified in various ways to accommodate different scenarios. a modified sir model known as sird (susceptible-infected-recovered-deceased) model is of our interest here and is based on the following assumptions: (i) this model is fatal unlike a typical non-lethal sir model which means that there is a positive probability of an infected person dying, p(death) = δ and δ ≥ 0. (ii) a typical sir model assumes that the recovered group gains full immunity from reinfection. however, this model accommodates the possibility of a recovered person being reinfected with probability of reinfection, p(rein f ection) = σ and σ ≥ 0. (iii) the impact of new births and unrelated deaths in ignored and the total population remains constant, n = constant ∀ t. (iv) the population is distributed randomly over the area. therefore, there are four classes of individuals: susceptible (s), infected (i), recovered (r) and deceased (d) as described by the following equation: where β = rate of infection, σ = rate of susceptibility, γ = rate of recovery and δ = rate of death. since the final cure for covid-19 pandemic is the successful discovery and optimal administration of the vaccine in the population, therefore we introduce the effect of vaccination with a given rate of vaccination under resource limited settings. this is achieved by adding a new class of individuals called vaccinated (v) in the population. it can be fairly assumed that there is no limit on the total number of vaccines produced as all the available resources for vaccine production are employed to eliminate the epidemic. however, the vaccine production capacity will have some limit based on availability of resources and facilities. therefore, there will be a limited number of vaccines available at a particular point of time. thus, it is assumed that the per capita rate of vaccination, α < where is a constant. it is assumed that the vaccination imparts long term immunity against the disease in the vaccination individuals. based on these assumption, we propose a final model as described by the following first order ordinary differential equations (ode's) and it illustrated by figure 1 : it must be noted here that the process of mass action transmission is described by the non-linear term βs i/n where β = number of contacts per unit time by a person in group i required to transmit the disease to a person in group s, n − 1 ≈ n = total number of possible contacts of a person, s /n = the fraction of possible contacts of a person that are from group s, i = the number of infected persons at time t, therefore βs i/n = number of people transmitted from group s to group i per unit of time. the next task is to to learn the model parameters which can be quite challenging in an epidemic scenario like covid-19 as the the model parameters are supposed to change with time. this section proposes an artificial neural network (ann) based adaptive incremental learning technique (annail) for online learning of the sirvd model parameters with the following assumptions: (i) the rate of vaccination α as a function of time (t) is set by the vaccine production capacity decided by availability of skilled labour, resources and facilities and by vaccination policy as well. maximum vaccine production capacity α max has been assumed to be constant indicating that there is no change in vaccine production infrastructure, technology or facilities. (ii) the rate of infection β as a function of time (t) is the major challenge for parameter learning. it is affected by external factors like degree of social distancing, lockdown etc. in case of a lockdown β decreases exponentially. therefore, in order to take into account both the lockdown and no lockdown scenarios, β has been modelled as: where t l is the time when the lockdown begins. therefore, the learning algorithm has to learn 3 parameters (β 0 , β 1 , τ β ) to find β. (iii) the rate of reinfection σ has been assumed to be zero for covid-19 disease as the human body develops antibodies to prevent re-infections in future against such a virus [21] . (iv) rate of recovery γ and rate of death δ are affected by factors like change in health care facilities, possible overcrowding of hospitals, development of new drugs to manage or treat the disease etc. both of these have been assumed to be constant in this paper. for a typical neural network or any other technique of model parameter estimation, the training data is required first to train the model before applying it on future scenarios. however, in case of an epidemic like covid-19, the training data is continuously evolving with time and the model needs to be trained and executed at the same time as the model parameters may change over time based on different external factors like government policies, social distancing etc which can be known only from newly arriving data sets. therefore, we propose a technique for the model to learn these parameters from new data sets in an adaptive manner while continuously updating the old models without the need to build the model from scratch every time a new training data set is received. deep learning and other machine learning techniques stand out in solving problems of data based model parameter estimation due to their state-of-the-art results. however, they face the problem of catastrophic forgetting which reduces their performance as new training data becomes available with time. this is because the typical neural networks require the entire dataset to update the model each time a new training data set becomes available as in case of an epidemic modelling problem where the training data becomes available incrementally with time. to address such issues, different incremental learning algorithms have been suggested in the literature [22, 23, 24] . incremental learning refers to an online learning technique of continuous model adaptation under a scenarios of continuously evolving training data. therefore, storage or access to the previously observed data is not required each time a new data set is received, as in case of an epidemic like covid-19. in order to adapt the model parameters in light of new data, it is not needed to use all the previously accumulated data for developing the model from scratch. rather, the learning network modifies the previous hypothesis to adapt to the new data chunk. in this paper, we propose hypothesis generation via an artificial neural network (ann). let d j−1 be the data set received between time t j−1 and t j , and h j−1 be the hypothesis generated on this data set. the hypothesis h j for a new data set d j received between time t j and t j+1 is a function of d j and h j−1 only as under: the experience gained from this step is stored and integrated to support in future adaptation process. thus the objective here is to integrate the previously learned knowledge into the new raw data set to adapt the model parameters accordingly; and to accumulate this experience over time to increase the model efficiency, accuracy and flexibility. the proposed framework for the above problem is shown in figure 2 . the ann is based on a non-linear activation function for successful regression analysis. the hidden layers are represented by the function f nn . with the continuous data stream, the weight distribution functions are generated to describe the learning capability of the ann where the decision boundary is adjusted to focus especially on the hard to learn data examples. the algorithm for this framework is given in algorithm 1. , where x i represents the input vector and y i represents the output. -associated mapping function output: where f nn is the ann defined mapping function. (ii) apply hypothesis h t−1 to d t , and find the pseudo-error (vi) repeat the above procedure for d t+1 . the final hypothesis is: where t is the set of incrementally developed hypotheses in the learning life. this algorithm is run in a top-down and horizontal signal flow, as shown in figure 2 . the adaptive nature of this algorithm is due to the mapping function based on ann which estimates the initial distribution functionφ t−1 for d t while providing a quantitative approach to indicate the learning power of the new data set based on previously trained model.φ t−1 is applied to the new data set to find pseudo-error, υ. thus a hard to learn example will have higher υ in step (iii) of the learning procedure, and will in turn receive higher weight in step (iv). this ensures the adaptive nature of the algorithm. mapping function connects the past experiences to the new data in an adaptive fashion. there can be many ways to design the mapping function. however, we implemented the nonlinear regression by an ann based approximation of mapping function owing to its flexibility. any such neural network based function approximation technique can be used. as in illustration we take the multilayer perceptron (mlp) in this paper. this is shown in figure 3 . the input is an n-dimensional vector (for example, number of infections, deaths, recoveries in an epidemic) of example i. the distribution function is currently estimated as j t−1 , w represents the weights of a layer. backpropagation is used to tune the weights w of different layers, where error function is defined as where k is the training epoch of the backpropagation. the neural network gives the following output: where h f represents the input to fth hidden node while as g f represents its output, υ is the input to the final node, n h is number of hidden neurons, and n is the total number of inputs. weights on the ann are updated by applying the above defined backpropagation strategy as explained below. backpropagation: weight adjustment for the hidden to out similarly, weight adjustments for the input to hidden layer is described as: where α(k) describes the learning rate. estimation of initial distribution functionφ t for d t required only the feedforward path of the mlp. this model was validated for covid-19 in india where the first 80% of data was used for training and the remaining 20 % was used for testing as shown in figure 4 . it is clearly evident from the plots shown in the figure that the results given by the model during testing are very close to the actual data. the inputs and outputs in this algorithm were: inputs : number of new infections, deaths and recoveries; rate of vaccination (α). outputs : β 0 , β 1 , τ β , δ, γ these outputs are fed to the analytical sirvd model at every time instant when a new set of input data is received to simulate and forecast different scenarios. in this section, we analyse three possible strategies to combat an epidemic like covid-19: (i) herd immunity, (ii) complete vaccination, (iii) complete lockdown and finally our proposed (iv) controlled natural immunization through risk based population compartmentalization is discussed in the next section. however, following definitions are needed beforehand: definition 1. (stability) if the jacobian matrix j for a system of n differential equations has eigenvalues λ 1 , λ 2 , ..., λ n , for a trivial steady state equilibrium at (0,0,...,0), then the stability of the solution is determined as following: .., n then the system has uniform and asymptotic stability (uas). .., n and the algebraic multiplicity equals the geometric multiplicity whenever λ i = 0 for any i, then the system has uniform stability (us). (iii) if re(λ i ) > 0 for any i and the algebraic multiplicity is greater then the geometric multiplicity whenever λ i = 0 for any i, then the system has instability. since the impact of new births and unrelated deaths has been fairly ignored for the purpose of this study and it has been assumed that the total population n stays constant throughout the epidemic, therefore the system of odes (8 -12) describing the model satisfies the following two conditions: this shows that a state of equilibrium always exists in the system. definition 2. (dfe) a disease free equilibrium (dfe) is defined as a state of equilibrium according to (25, 26) in which the number of infected and recovered individuals equal to zero such that there are no further deaths (i → d), infections (s → i) or reinfections (r → i): which gives us the following from the system of odes (8 -12) : we take the jacobian matrix of the above system to evaluate its stability. however, the fifth differential equation (representing d) is uncoupled from the first four differential equations and it can be derived from the first four equations using (25, 26) , therefore we consider the jacobian for the first four equations only which is given as: given below is the investigation of dfe stability for different epidemic control strategies. herd immunity is the idea that a virus cannot spread easily after enough people develop immunity against it. this reduces the chances of the virus transmitting from person to person and infecting those who haven't been infected yet [25] . such an immunity can be induced artificially by a vaccine, however it can also be developed naturally by the infection itself as the immune system of the body develops antibodies against the virus which prevent reinfection in future. this is based on the fact that the human body produces a non-specific innate response to a viral infection initially using neutrophils, macrophages, and dendritic cells. however, this is followed by a more specific adaptive response in the form of development of proteins called immunoglobulins which act as antibodies specifically binding to the virus. this is coupled with the formation of t-cells which generate cellular immunity by identifying and eliminating the cells that are infected with the virus. generally, sufficient presence of such antibodies in collaboration with cellular immunity prevents reinfection after recovery. although every recovered patient may not develop complete immunity, but that is the case for the most of them [21] . in case of covid-19, although research is till going on to reach a conclusive opinion, promising studies suggest that nearly all the recovered patients develop such antiviral immunoglobulin-g (igg) antibodies and are immune to reinfection [26] . this lays the basis for mass serological testing for covid-19 being practised by many governments across the world in which the blood samples of people are tested for the presence of these antibodies indicating present or past covid-19 infection. further, the data on reinfection, even if rare, is not available. therefore, the idea of herd immunity is to let the infectious disease take its natural course of action and let the population naturally develop immunity against the disease after most of the population gets infected. the dfe after herd immunity has the following form: where d 0 is the total number of deaths at the time of dfe and thus r = n − d 0 . since there is no vaccination, therefore α = 0 and v = 0. further, the rate of reinfection σ is zero as well, meaning recovered people cannot catch the infection again. using these values in (32), the jacobian at the dfe after herd immunity is given as: equating characteristic equation for this jacobian to zero gives: therefore, the eigenvalues of this system are: thus, all the eigenvalues have real parts less or equal to zero: re(λ i ) ≤ 0 ∀ i = 1, 2, ..., n and d 0 ∈ r ∩ [0, n]. hence, according to definition 1, the dfe for herd immunity possesses uniform stability (us). in this case, there are no chances of retriggering of the disease after the dfe has been reached. however, this approach has been criticised as dangerous as it will result in a large number of deaths [27] . to develop herd immunity for covid-19 in the population, roughly 70 % or more of the population needs to have gone through the infection [28] . the current death rate in india due covid-19 is around 3 % which means that if this death rate is maintained, nearly 2.1 % of the population will die till 70 % gets infected. this leads to nearly 28 million deaths. the actual number of deaths would be more than this, because with rapid growth of the infectious disease, hospitals would be over-flooded and health care infrastructure will not be able to cater to the demands of high number of patients leading to increase in the death rate. the growth of disease in india is shown in figure 5 if the disease is allowed to take its natural course without any intervention and control. the strategy of complete lockdown focuses on minimization of mobility and contact among the population with maxi-mum possible social distancing. therefore, it minimizes β (the rate of infection). the dfe under complete lockdown has the following form: where d 0 is the total number of deaths at the time of dfe and thus s = n − d 0 . since there is no vaccination, therefore α = 0 and v = 0. using these values in (32), the jacobian at the dfe under complete lockdown is given as: furthermore, equating characteristic equation for this jacobian to zero gives: therefore, the eigenvalues of this system are: thus, real part of one of the eigenvalues is always grater than zero: re(λ 3 ) > 0 ∀ d 0 ∈ r ∩ [0, n]. hence, according to definition 1, the dfe under complete lockdown is always unstable. thus, whenever a dfe is reached in this case, the tendency for the disease to be triggered again is always there. even a single case of infection can restart the disease. apart from the chances of reemergence of the disease, the time taken by the system to reduce the number of active infections to zero may be large enough to make the total lockdown unsustainable and practically impossible. the impact of lockdown on the disease growth in india is shown in figure 6 . it has been assumed that the lockdown ends on day 250 of the disease after it starts on day 55. it can be compared with figure 5 which shows the disease growth in case no preventive measures are taken. these results confirm that the infection plots shoot up as soon as the lockdown is lifted and there is no significant difference in terms of total number of infections or deaths. the only benefit of lockdown, as can be seen from these plots, is that the peak of infection is delayed which can be useful for the administration to buy some time to prepare the healthcare infrastructure of the country to brace for the full blown impact of the disease. researchers and health industries worldwide are working around the clock to discover a vaccine against sars-cov-2 [29]. moderna, a pharmacological company had started clinical testing of its mrna-based vaccine (mrna-1273) just 2 months after the complete sequencing of covid 19 was done and published by different research groups [30] . the most potential candidate for the vaccine development would be to induce our immune system to synthesize neutralizing antibodies against the viral spike protein which block its entry via ace2 receptors [31] . the dfe with vaccination of all living members of the population n has the following form: where d 0 is the total number of deaths at the time of dfe and thus v = n − d 0 as the rest of population has been vaccinated and is now immune to the disease. using these values in (32), the jacobian at the dfe with full vaccination is given as: furthermore, equating characteristic equation for this jacobian to zero gives: therefore, the eigenvalues of this system are: thus, all the eigenvalues have real parts less or equal to zero: members of the population is the way to completely eliminate the disease and its chances of re-triggering as well. however, successful development of a vaccine for sars-cov-2 has still a long way to go. further, a vaccination rate of 10 million per day is highly ambitious for a country like india. therefore, elimination of the current wave of covid-19 epidemic and minimization of number of deaths by vaccination is practically impossible as the successful development and mass administration of a vaccine is expected to take more than a year, at least. however, vaccination may still be necessary to prevent new waves of the disease in future. the strategy of herd immunity discussed in the previous section aims at minimizing the number of s (susceptible) and maximizing the number of r (recovered) people who are supposed to have developed the immunity. this will minimize the the factor β s i n in the sirvd model ode's discussed in section 2. however, this strategy results in the maximum number of deaths. the strategy of complete lockdown aims to minimize the rate of infection (β) by reducing the mobility of people. however, this strategy is not sustainable in the long term as discussed. the strategy of complete vaccination is an ideal solution to the problem. it aims at maximizing the number of people falling in v (vaccinated group) through artificial immunization. however, as discussed, the successful development of a vaccination and its administration in the population is expected to take enough time to cause a large number of deaths. in this section we propose a strategy of minimizing the number of deaths by controlled natural immunization by compartmentalization of the population in two groups: low risk and high risk. high risk group comprises of the people having co-morbidities or are aged above 50 years and as a result have high probability of death under covid-19 infection. the aim of this strategy is to minimize the number of deaths caused by covid-19 disease: the death rate (δ) is very high in the high risk group while as it is very low in the low risk group. the most prevalent comorbidity for covid-19 is hypertension, followed by diabetes with mean age of around 48.9 years [32]. in india, the percentage of population above 50 years of age is 19.28% while as the percentage above 60 is nearly 8% [33] . most of the people having comorbidities are expected to fall in above 50 age group. in this study, the high risk group has been assumed to be 20% of the population. it is proposed that these two population groups be subjected to different disease mechanics. the high risk group is subjected to a preventive quarantine or isolation wherein they are isolated from the low risk group by placing them in separate rooms or sections in homes with minimum contact with the low risk group. whatever necessary contact is required, it should be done with maximum preventive measures like wearing of face masks, sanitization etc. very high risk individuals may be placed in designated care centers where their health needs are met by medical professionals. therefore, for the high risk compartment, β is reduced to minimum as in the case of a lockdown. meanwhile, the low risk group is subjected to maximum mobility and contact among its members effectively increasing β to the maximum possible value. there should be no social distancing and other preventive measures for this group. as a result, the infection will spread very quickly in the low risk group and its members shall develop the immunity and transfer from s to r having gained the immunity naturally with a very low death rate. once this is achieved or in other words once the disease curves are flattened for the low risk group, the high risk group is released from the preventive isolation and allowed to mix with the low risk group. since most of the population (70 -80 %) is already immune and the value of s and i is low, the chances of the high risk group receiving infection from the low risk is very low because the factor β s i n has already been reduced to minimum. during pc, β is minimum for high risk group while as after pc, s i is minimum. after pc, the mobility and the contact in the population, represented by β, should be kept moderate. since, α and σ are zero, therefore: here, β represents the rate of infection which depends upon the mobility and contact among the population. due to the lockdown, this can be considered the lowest possible β in india. we have simulated the pc strategy with different values of β l ranging from 2 to 5 times of β given above to account for high mobility and contact during pc. β h = 0.2β to assume that the isolation of high risk individual is at least 5 times stronger than than the social distancing practised by the whole population during the nation wide lockdown. δ and γ are complementary in the sense that an individual either recovers or dies from the infection. to distribute the current death and recovery rate in low and high risk groups: integrating the equations of sirvd model for this case: where s (t 0 ) and i(t 0 ) are initial states. this is true for both low and high risk groups. however, for high risk group, s h (t 0 ) = i h (t 0 ) = 0 while as for low risk group; where t f is the time when pc ends and the two groups are allowed to remix. after pc: δ and γ have been restored to original values while as β has been multiplied by a factor of 2 to signify higher level of mobility and contact than lockdown albeit with social distancing. the stability analysis and eigenvalues for this case are same as that of herd immunity i.e, it posses uniform stability. this strategy was simulated using the model proposed in section 1 and 2. the results of the simulation are shown in figure (9 -10) . in all these figures, black line represents the number of deaths, blue is the total number of cases, red is the active number of infections while as green line represents the number of recovered people. in figure 9 , the preventive quarantine or compartmentalization of the population is done from day 130 after the start of the population till day 200 while as in in figure 10 the same is continued till day 300. the rate of infection β is shown as a multiple of the average rate of infection during the nation wide lockdown from 24 march to 08 june, 2020 which was the minimum possible. increase of β is achieved by increase of contact and mobility among the population, for example β = 5x means five times mobility and contact as compared to the days of nation wide lockdown. if no preventive measures are taken, then as per the current trend in the disease growth we may expect more than 55 million deaths in the country if all the population gets infected. this is shown in figure 8 . 55 million deaths is not surprising even if linear growth of the disease is assumed with 2.8% death rate for a population of 1.35 billion. different hypothetical experiments were simulated and their results are given in table 1 . as discussed earlier, β is supposed to be kept on lower side after the end of pc and social distancing is advised. these results show that the total number of deaths can be reduced to 1.3 million from 55 million, if mobility and contact is made 5 times to that of the lockdown period and pc is ended on day 300 of the pandemic while as after the end of pc, the mobility is reduced to two times. the growth of disease in such a scenario is shown in figure 11 . in this work, we developed an analytical epidemiological model for covid-19 pandemic where model parameters are continuously updated to intelligently adapt to new data sets using an ann based adaptive online incremental learning technique. in a scenario of continuously evolving training data, unlike typical deep learning techniques, the model eliminates the need to retrain or rebuild the model from scratch every time a new training data set is received. the model was validated and different scenarios were simulated to demonstrate its usefulness and significance. india was taken as a case study. however, this model can be applied to any population in the world and would be a useful tool for policy makers, health officials and researchers in improving decision making efficiency, policy formulation and forecasting. the simulation work was carried out in matlab environment. using this model, we simulated preventive measures like lockdown, vaccination and herd immunity to study their impact on the evolution of covid-19 disease. finally we proposed an effective method to significantly reduce the number of deaths caused by the pandemic in case a vaccine is not available at the mass level. this technique aims to develop natural immunity in the low risk group of the population by subjecting them to the full blown impact of sars-cov-2 virus while as subjecting the high risk group to preventive isolation during this time period. once the low risk group develops natural immunity and its disease curves are flattened, the high risk group is released from the preventive isolation. upon release, the high risk group doesn't find enough infected or susceptible people in the environment to catch the infection at a high rate and in this way the maximum number of deaths are avoided in the high risk group. the impact of this strategy has been simulated and it has been shown the the number of deaths can be reduced from 55 million to 1.3 million if the population compartmentalization starts tomorrow and ends on day 300 of the pandemic in india. during this period, the mobility and contact in low risk group has to be made five times as compared to the lockdown period and upon remixing of the two groups the mobility and contact should be reduced to 2 times from 5. the novelty of this paper lies in the use of real-time online incremental learning technique in epidemic disease modeling. many machine learning techniques have been used in epidemic disease modeling [36], however this paper is the first instance of development of an incremental learning algorithm as a real-time adaptive deep learning technique for parameter estimation of an epidemiological model thus providing the model with the capability to work online i.e, unlike typical machine learning techniques, it doesn't require to rebuild or retrain the model from scratch every time a new data set is received but intelligently adapts the model to ever changing infection dynamics. since the model is non-intrusive, adaptive, intelligent, real-time and online in nature, therefore it can be employed to monitor, forecast and simulate the growth of any infectious disease over a large sized population without losing accuracy, fidelity or com-putational performance due to limitations like run-time duration, size of training data, computational complexity, change in transmission dynamics due to mutations in virus or bacteria, change in prevention mechanisms or government policies. even if the epidemic continues for decades in the whole world, the model will keep working efficiently on daily basis without any decay in performance or rte (run-time environment). further, to the best of our knowledge, population compartmentalization to achieve natural immunity against an infectious disease while significantly reducing the mortality has been modeled and simulated for the first time in this paper. these findings could be highly useful to policy makers around the world to reduce the number of deaths in any country in case a vaccine is not readily available and lockdown is not sustainable economically. further, this is a demonstration of the usefulness and efficiency of deep learning based incremental learning algorithm in model parameter estimation and simulation of different epidemic scenarios. the doctoral research funding from ministry of human resource development, government of india, in favor of the first author is duly acknowledged. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. detail/who-director-general-sopening-remarks-at-the-mission-briefing-on-covid aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 covid-19 ards: clinical features and differences to "usual" pre-covid ards contributions to the mathematical theory of epidemics mathematical biology: 1. an introduction modeling influenza epidemics and pandemics: insights into the future of swine flu (h1n1) covid-19 covid-19 pandemic 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impact of non-pharmaceutical interventions on covid-19 in 11 european countries covid-19 vaccine tracker draft landscape of covid-19 candidate vaccines immune responses in covid-19 and potential vaccines: lessons learned from sars and mers epidemic ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒the authors declare the following financial interests/personal relationships which may be considered as potential competing interests: key: cord-328747-bf687r6j authors: st‐denis, xavier title: sociodemographic determinants of occupational risks of exposure to covid‐19 in canada date: 2020-07-13 journal: can rev sociol doi: 10.1111/cars.12288 sha: doc_id: 328747 cord_uid: bf687r6j the activities performed by canadian workers in some occupations may increase the risk of exposure to infectious diseases such as covid‐19. this research note explores how occupational exposure risks vary by labor force characteristics using publicly available canadian data in combination with a data set providing information on the level of physical proximity and frequency of exposure to infections or diseases faced by workers in different occupations. the results show important sociodemographic differences. first, women work in occupations associated with significantly higher average risks of exposure to covid‐19 than men. this is driven by their overrepresentation in high‐risk broad occupational categories such as health occupations. second, older workers (65 years or more), a group vulnerable to covid‐19, appear to work in occupations requiring performing activities characterized by a lower level of physical proximity than their younger colleagues, with minimal differences in the frequency of exposure to diseases or infections. finally, workers in low‐income occupations are employed in occupations that put them at greater risk of exposure to covid‐19 than other workers. this is especially the case for women, immigrants, and members of visible minority groups in low‐income occupations. more broadly, this research note provides insights into the health‐related dimension of the literature on occupational tasks and labor market stratification. les tâches effectuées par les travailleurs canadiens dans certaines professions peuvent augmenter le risque d'exposition à des maladies infectieuses tel que la covid-19. cette note de recherche explore la variation dans les risques d'exposition à la covid-19 selon les caractéristiques des travailleurs en se basant sur des données publiques canadiennes combinées à une base de données fournissant de l'information sur le niveau de proximité physique et la fréquence d'exposition à des infections ou maladie auxquels font face les personnes occupant différentes professions. les résultats démontrent d'importantes différences entre catégories sociodémographiques. premièrement, les femmes travaillent dans des professions associées à des niveaux moyens de risques d'exposition à la covid-19 significativement plus élevés que les hommes, qui s'explique en partie par leur surreprésentation dans des grandes catégories professionnelles à haut niveau de risque tel que les professions du secteur de la santé. deuxièmement, les travailleurs âgés (65 ans et plus), un groupe vulnérable à la covid-19, semblent travailler dans des professions demandant d'effectuer des tâches menant à un niveau plus faible de proximité physique que leurs plus jeunes collègues, alors que les différences d'exposition à des maladies ou infections sont limitées. finalement, les personnes travaillant dans des professions à faible revenu tendent également à travailler dans des professions plus à risque d'exposition à la covid-19 que les autres travailleurs, ce qui est particulièrement le cas pour les femmes, les immigrants et les personnes membres minorités visibles travaillant dans des professions à faible revenu. de manière plus générale, cette note de recherche explore les implications en matière de santé de la littérature sur les tâches professionnelles et la stratification du marché du travail. a number of inequalities have become visible among workers since the beginning of the covid-19 pandemic. most notably, publicfacing sectors such as accommodation, food services, retail trade, tourism, and recreation have been highly impacted, translating into important industry differences in job losses in the period immediately following the start of the outbreak (statistics canada 2020a). in addition, low-wage workers are more likely to experience financial difficulties as a result of job losses or absence from work. relatedly, recent analyses have highlighted how some occupations require completing activities that increase the risk of infection with covid-19. these include the level of physical proximity to other individuals and the frequency of exposure to diseases or infections (of all kinds). occupations in food processing and health care are examples of such jobs, as highlighted by data on covid-19 clusters from news reports (the new york times 2020). the objective of this empirical research note is to explore the distribution of occupational exposure risks in the canadian workforce and to identify the sociodemographic characteristics associated with high or low occupational exposure risk scores (note that the concept of risk of exposure does not allow to directly estimate the risk of infection the same way epidemiological data does). the results presented below show an unequal distribution of occupational characteristics associated with a higher risk of exposure to covid-19 (level of physical proximity with other individuals, and frequency of exposure to diseases or infections) across different groups of the workforce. first, women appear to face higher occupational risks of exposure to covid-19 than men. this is driven to a large extent by the fact that women are over-represented in broad occupational categories that have substantially higher average risk scores, such as health occupations. second, i also find important differences by aboriginal identity. in contrast, there are only limited differences by immigration status and visible minority status. third, outside of health occupations, workers with a bachelor's degree or more tend to face significantly lower occupational risks of exposure. importantly, older workers (55-64 years and 65 years or more), a group at high risk of infection, hospitalization, and complications, including death (public health agency of canada 2020), do not appear to work in occupations that have a higher physical proximity score than younger workers. those between 15 and 24 years score the highest. disaggregated results show that this pattern is found across occupations except in the two highest scoring broad occupational categories, where there is no significant age difference. meanwhile, the mean score for frequency of exposure to diseases or infections is lower for 15-to 24-year-old workers compared to all other groups, but the median is the highest. workers aged 65 or more have a lower mean but higher median score than those between 25 and 64 years. among workers in health occupations more specifically, an occupational category with extreme values for the exposure to diseases or infections score, 55-to 64-year-old and 65+ year-old workers are at higher risk of exposure than their younger colleagues by several points. however, age differences in mean frequency of exposure to infections or diseases are not statistically significant in regression analyses. finally, i find that workers in low-income occupations are more likely to be employed in occupations in the top half of both exposure risk score distributions when compared to those not working in a low-income occupation. this pattern is especially visible among women, immigrant, and visible minority workers. this is consequential to the extent that low-income workers may face financial disincentives for absence even if they are sick or vulnerable, increasing the risk of workplace transmission. this finding is especially significant if no measures are taken to close establishments and to provide income support to employees who are absent from work. this paper provides evidence on which groups of the labor force are at greater risk of exposure to covid-19 based on the characteristics of their occupation. in addition to providing evidence of important sociodemographic differences in exposure risks, it shows that gender and education sorting into different occupations is an important driver of disparities in health-related outcomes at work. in other words, the findings suggest that there are repercussions to gender-and education-based occupational sorting into jobs that bundle tasks differently beyond income and socioeconomic outcomes. a health-related dimension of "life chances" or "life conditions" is not frequently investigated in the sociological literature on occupations and stratification (weeden and grusky 2005; wodtke 2017) , and is gaining visibility as the risk of workplace transmission of covid-19 is discussed by the public and in public health policy-making circles. while the results presented in this paper contribute to our understanding of exposure risks at work in the context of the covid-19 pandemic, it can also be used more broadly to highlight certain sociodemographic determinants of the occupational risks of exposure to other types of infections or diseases at work. the paper relies solely on publicly available data sources in order to ensure a quick turnover. at the time of writing, access to scientific-use canadian microdata was not possible. further analyses building on this paper can contribute to a better understanding of which worker characteristics are associated with a high degree of occupational risk of exposure or of actual infection to covid-19 or other infectious disease in order to guide public health decisions at the intersection of occupational safety and health. occupations play an important role in social stratification. differences in earnings across detailed occupational categories explain a large proportion of the variance in earnings (mouw and kalleberg 2010; weeden et al. 2007; williams 2013) , and a number of studies find that occupationlevel task content and skill intensity account for a substantial portion of the relationship between education and income (carbonaro 2007; liu and grusky 2013; simard-duplain and st-denis 2020) . important theoretical statements and empirical studies in sociology emphasize the importance of stratification and class structuration at the level of detailed occupations (weeden and grusky 2012) . however, in many other cases measuring job task and skill content at the occupational level is a matter of convenience and data availability. this is especially true given the existence of the o*net data set and its predecessor, the u.s. dictionary of occupational titles, which provides a comprehensive profile of the work activities and features of the work context of detailed u.s. occupations. more specifically, the o*net database is administered by the u.s. department of labor since 1998, and disseminated online. it collects standardized information on the activities and tasks workers in 974 occupations 1 are required to perform as part of their jobs (as well as the knowledge, skills, and abilities requirements), typically using ordinal scales. this information is gathered regularly through surveys of u.s. workers in each occupation and occupational experts. this yields occupation-level scores that can be matched to observations from other data sources that include compatible occupational codes. in economics, o*net data on the task content of occupations has been used in studies of occupational employment losses related to the risk of automation (autor, levy, and murnane 2003; frey and osborne 2017) and the relationship between occupational task content and offshoring risks (blinder 2009 ). sociologists have used this data for similar purposes, especially in studies of occupation-level drivers of earnings disparities (carbonaro 2007; farkas, england, vicknair, and kilbourne 1997; grodsky and pager 2001; liu and grusky 2013; weeden 2002; williams and bol 2018) . in the context of the covid-19 pandemic, o*net occupational tasks and work activities data has proven relevant in a different way. o*net data can be used to construct measures of occupational risks of exposure to covid-19. accordingly, gamio (2020) has combined u.s. labor force data with two variables from the o*net database to measures differences in the risk of exposure to covid-19 across occupations. in canada, results based on this approach were also published by vu and malli (2020) . the o*net variables are (1) the level of physical proximity to other people, and (2) the frequency of overall exposure to diseases and infections. these two variables do not directly measure the risk of infection to covid-19. the first measure provides information about close physical proximity with other people, which is an important channel for contracting covid-19, and the second measure provides more direct information on the frequency of exposure to individuals who have infections or diseases. in the context of an infectious disease epidemic, occupations scoring high on this second measure could be considered as facing a higher probability of interaction in the workplace with individuals infected by the covid-19. note that the same methodology can be used to study occupational risks of exposure to other infectious diseases following similar transmission mechanisms than covid-19. in this paper, i leverage this approach to ask how occupational risks of exposure to covid-19 vary across sociodemographic characteristics (gender, age, education, immigration status, visible minority status, and aboriginal identity). this approach does not rely on epidemiological data, and the results cannot be used to infer population-level probabilities or rates of infection, especially to the extent that transmission also occurs in settings other than workplaces, and among nonemployed individuals. 2 the approach is nevertheless justified by the fact that while public health data allow to investigate differences in rates of infection, hospitalization or death by gender and age (public health agency of canada 2020; purdie et al. 2020) , the absence of a systematic collection of measures of education, employment status, and job characteristics in covid-19 epidemiological data means that limited statistical evidence exists on the role of work-related factors in those disparities at the population level. 3 the occupational scores should be interpreted as capturing the level of risk of exposure to covid-19 (or other similar infectious diseases) at work that results from close physical interaction with colleagues, customers, or other individuals, and from exposure to diseases or infections (in this case, . without physical distancing and other prevention measures, these characteristics are likely to increase the risk of transmission. importantly, the scores do not account for the impact of physical distancing measures or other adaptation in the organization of workplaces, or the degree of compliance of different establishments with public health guidelines. instead, the results may be used to better target interventions by governments and employers aimed at decreasing risks of transmission of infectious diseases such as covid-19 during different phases of an epidemic (including the progressive lifting of emergency measures mandating workplace closures). on a more theoretical level, the objective of this paper is to contribute to an understanding of the health repercussions of the occupation-level bundling of job tasks in order to shed light on this understudied healthrelated dimension of the stratification literature. for example, occupational sorting plays an important role in explaining the gender wage gap in canada (schirle 2015; waite 2017) and the u.s. (blau and kahn 2017; england 2010) . accordingly, i also ask whether sociodemographic differences in occupational exposure risks are driven by sorting into broad occupations with different average scores. the two variables used in this paper are based on simple questions that ask respondents to rate their work activities along ordinal scales. the score of respondents are averaged, and the variables available from the o*net database are continuous scores from 0 to 100 that can be mapped 2. differences between groups in rates of hospitalization, admission to intensive care units, and death are likely to be driven to significant extent by epidemiological risk factors such as chronic health conditions (public health agency of canada 2020), which cannot be inferred from data on occupational risks of exposure. for such reasons, estimates of the distribution of occupational risks of exposure to covid-19 by gender and age may not match epidemiological data. onto the ordinal response categories. the physical proximity variable is based on the following question: "to what extent does this job require the worker to perform job tasks in close physical proximity to other people?" with results reported a scale from going from 0 "i don't work near other people (beyond 100 ft.)" to 100 "very close (near touching)" with a total of five ordinal response categories divided by equal intervals of 25 points. the exposure to disease or infections variable asks "how often does this job require exposure to disease/infections?" on a scale from 0 "never" to 100 "everyday" designed with the same cutoff values at 25 points intervals. the unweighted correlation between the two scores at the four-digit occupation level is 0.5320. more details on the content of these variables and the construction of the scores based on ordinal scales is available in table 1 . in addition to the two o*net-derived occupational scores, i compute a "composite occupational risk score" combining both measures using a method proposed in kikuchi and khurana (2020) . this is an additive score that assumes independence in the impact of each work activity. each detailed canadian occupation coded using the 2016 national occupational classification system (noc 2016) can be matched to an o*net score from a corresponding u.s. occupation for both measures, using a correspondence table developed by the brookfield institute on innovation and entrepreneurship (vu 2019) . this crosswalk was constructed manually, based on the correspondence in the content of the o*net and noc 2016 occupation descriptions. 4 while the o*net data set is u.s.-specific, i assume that most occupations in canada and the u.s. share similar characteristics, especially in terms of physical proximity and exposure to infection or diseases. in making that assumption, i follow several canadian studies that adopted a similar approach to map o*net occupational scores onto noc 2011 and noc 2016 occupational codes. for example, a mapping of o*net scores on the labor force survey noc 2011 classification was used to study the relationship between o*net manual and cognitive job task requirements and job match quality in canada (summerfield 2014 (summerfield , 2016 , and a mapping on the national household survey noc 2011 classification was developed by statistics canada in studies of the job skill intensity of different groups of the canadian population frank 2017, 2018) . finally, the crosswalk used in this paper was leveraged in a report on the composition of the canadian tech workforce (vu, lamb, and zafar 2019) . o*net scores were also mapped on data from all european countries included in the european labor force survey from 1993 to 2006 to study the drivers of job polarization (goos, manning, and salomons 2009) . the results presented in this paper are based on public-use data estimates from the canadian long-form census of population, 2016. 5 at the time of writing, this was only the available source of data with the sufficient level of disaggregation (four-digit occupations). 6 it requires assuming that the composition of the workforce in 2020 (occupations, labor force characteristics) is similar to the reference period for data collection (occupation in may 2016, or last occupation for jobless individuals). the sample includes all individuals who were at least 15 years old on census day (may 10, 2016) and reported employment income for the fiscal year 2015 (worked any number of hours, part-year or full-year). the data set observations are population-weighted frequencies of respondents reporting nonzero employment income in 2015 in each fourdigit noc 2016 occupation, broken down by the following sociodemographic characteristics: sex, immigration status (other tables used in this paper instead include a variable on members of a visible minority group or on aboriginal identity), 7 age group (15-24, 25-54, 55-64, and 65 down by the same sociodemographic characteristics. the data set is used to produce descriptive cross-tabulations and to estimate ordinary leastsquare regression models of the association between sociodemographic characteristics and the three occupational exposure risk measures. the data do not include measures of detailed job characteristics (nonstandard employment contract, firm size, etc.) because these variables are not collected in the 2016 long-form census. the scale for each variable an ordinal scale mapped onto a continuous scale ranging from 0 to 100, with five distinct cutoff points each corresponding to an ordinal response category that guides respondent answers. table 1 presents the distribution of occupational scores weighted by the number of employees in each occupation, based on the ordinal scale ratings. each category includes all occupations with a score falling in a 25 points band around the cutoff point (±12.5 points around the cutoff value, with the bottom and top categories censored in one direction), meaning that occupational scores are rounded to the nearest cutoff value. in the top panel of table 1 , i show that the majority of canadian workers are in occupations that require being slightly close (51.8 percent), such as sharing an office. in addition, another 39.0 percent are in occupations that require working in moderately close proximity to other people (at arm's length, or below the physical distancing covid-19 requirements). in other words, 90 percent of workers in canada work in occupations that require some physical proximity. an additional 7.2 percent are in occupations that require being very close (near touching). this is evidence that establishment closures or job redesign may be necessary to avoid covid-19 transmission at work. meanwhile, approximately half (49.2 percent) of canadian workers are in occupations where they are never exposed to infections or diseases, and 8.3 percent are in occupations where they are exposed at least every week. the remaining 42.5 percent are in occupations that require being exposed to diseases or infections once a month or less. this means that small but nonnegligible share of the canadian workforce is employed in occupations likely to involve frequent contacts with individuals infected by covid-19. due to the concentration of the responses into a few categories, the remainder of this paper reports average occupational scores and other distributional statistics relying on continuous scores, in order to identify if certain segments of the workforce experience higher occupational risks of exposure to covid-19. histograms showing the full distribution of the scores, weighted by occupational employment, are included in the appendix. table 1 also reports counts. note that due to the treatment of missing values, the exclusion of workers without employment income in 2015, as well as random rounding to 0 for small cells, the total population count may differ across tables in this paper. distributional statistics for the numerical occupational scores by sociodemographic category are presented in tables 2 to 4. table 4 also reports the population distribution across groups (based on census weighted frequencies, which are estimates of population counts). the distributional statistics for different groups are weighted by the variable reporting the number of employed respondents in that group in 2015 in each occupation. the results show important gender differences. tables 2 and 3 show that on average, men work in occupations that have both lower physical proximity score (−4.2 points) and lower exposure to disease or infections scores (−12.3 points, or approximately 50 percent of the value for women). similarly, large gender differences are found for median scores, and an important gap is found between the 75th percentile score values. note that the distribution for the second variable is skewed to the left with several outliers with high values (in health occupations), translating into large differences between the mean and median score. the results for both scores yield a large average composite risk score difference between men and women (see table 4 ). there are little systematic differences in the average values for all scores between canada-born and immigrant workers. similarly, limited percentile distribution differences are found, with immigrant workers scoring 3.7 points lower on the median risk of exposure to diseases or infections than canadian-born workers. this small difference is meaningful given the compressed distribution of the score on this variable. however, the values for the 75th percentile are the same on that measure, at 29.0, suggesting that the share of workers in occupations at frequent risk of exposure to infections or diseases (more than every year, approximately) is similar in both groups. the same pattern is found when comparing members of visible minority groups with those who are not. in contrast, distributional statistics for first nations people, métis and inuit, each show higher average and median physical proximity and exposure to disease and infection scores than those with a non-aboriginal identity (one exception is the gap between inuit and non-aboriginal physical proximity scores, which is visible at the median but not the mean). gaps are especially large for the risk of occupational exposure to diseases or infections. this translates into gaps in mean and median composite scores as well. table 2 shows that younger workers (15-24 years) are employed in occupations that have a higher average physical proximity score than other age groups, at 66.2 points. prime-age workers score at 60.6. the values for the older age groups (55-64 years and 65 or more years) are slightly below 60 points. younger workers also have the highest median physical proximity occupational score, at 68.5 points (a gap of 10 points or more with workers in all other age groups). differences are visible at the 25th percentile and to a lesser extent at the 75th percentile as well. on the other hand, table 3 shows that younger workers have a slightly lower average exposure to disease or infections score than other age groups (−1.3 to −1.9 difference compared to older age groups). in contrast, they have a higher median occupational score, alongside 65-year-old or more workers, suggesting that the share of young workers in occupations with very high scores is small, although the overall distribution may lean towards higher scores. these patterns translate into a 2.8 to 4.0 negative difference in average composite risk score between younger workers and workers in other age groups, as reported in table 4 , and similar differences in median composite risk scores. this means that results based on the composite risk score may mask important dynamics such as the contrasting relationship between age and the two scores. i find meaningful differences in occupational risk scores by education. first, those with a university certificate, diploma, or degree at bachelor level or above have a lower average physical proximity score than all other groups by two to three points (table 2) . differences in median scores are substantially larger, suggesting the presence of certain high-scoring occupations among otherwise low-scoring occupations for highly educated workers (also see the larger interquartile range in the last two columns of table 2 ). workers with no certificate, diploma, or degree, those with apprenticeship or trades certificate or diploma, and with college, cegep, or other nonuniversity certificate or diploma have substantially higher mean and median scores. second, there is a positive relationship between educational attainment and occupational exposure to disease or infections score (table 3) . college, cegep, and university-educated workers have a higher average risk score, likely associated with working in a health care sector job. education-related differences in median scores are smaller, and percentile distribution differences are mostly visible in the values for the 75th percentile value, meaning that more highly educated workers are more likely to work in occupations that are among those requiring the most frequent exposure to diseases or infections. again, the contrasting patterns for the two measures translate into little difference by education in the mean composite risk score and lower median values (but no difference at the 75th percentile) for more educated workers, as shown in table 4 . finally, results by broad occupational categories (one-digit) are reported. table 2 shows that health occupations have very high mean and median physical proximity scores relative to other occupations, at 86.5 points compared to an average of 61.1 points for all workers (first row of table 2 ). the interquartile range bounds (25th and 75th percentiles are also very high, with 75 percent of workers in health occupations scoring above 85.5 points, above at least 75 percent or workers in any other occupation (the 75th percentile of all other occupations is below 85 points). sales and services occupations and occupations in education, law and social, community, and government services also have high mean and median scores, while professional occupations (management, business, finance, and administration, and natural and applied sciences occupations) score the lowest. table 3 shows that health occupations also score very high on exposure to diseases or infections with a mean score of 82.2 and a median score of 86.3 points. the 25th percentile value indicates that at least 75 percent of workers in health care occupations are exposed to diseases or infections at least once a week, consistent with what one would expect for workers in such occupations. the gap in median and mean scores with other occupations is of 50 points or more. occupations in education, law and social, community, and government services, and sales and services occupations again have the second and third highest mean and median scores. those in manufacturing and utilities occupations score the lowest (most workers are almost never exposed). the occupational patterns are relatively consistent for both scores, translating into similar results for the composite risk score. the distributional statistics reported above provide evidence of important differences in occupational risks of exposure to infectious diseases such as covid-19 by gender, age, aboriginal identity, education, and broad occupational category. in order to distinguish the net role of each variable in driving occupational exposure risk differences across the labor force, i provide estimates from multivariate analysis (ordinary least square regressions) in table 5 . this method is used to identify the net association between worker characteristics and average occupational risk scores because different worker characteristics may be correlated. the standard tables used in this analysis are available at the aggregate level rather than as microdata. therefore, the data set is formed of cells of individual-level observations aggregated into all sex-age group-education-immigration status configuration 8 for each four-digit noc occupations. this yields a data set of 47,450 observations. each cell is weighted using its population frequency estimates. the dependent variables are the three o*net occupation risk of exposure scores attributed to each four-digit noc occupation. in the first set of models, each occupational risk score is regressed on gender, immigration status, age group, and highest degree attained. these models are under the first column under each score type (models 1, 3, and 5). the estimates are consistent with descriptive results, with large gender differences and little differences by immigration background for all occupational scores. no statistically significant age difference is found for the exposure to disease or infections risk score, and younger workers (15-24 years) have a substantially and significantly higher average occupational physical proximity risk score than the three other age groups. that pattern is also found, muted, in the composite risk score estimates. lastly, the estimates by highest degree attained are also consistent with the patterns identified in the descriptive analysis. the physical proximity score of workers with apprenticeship or trades certificate or diploma is significantly higher than those with no certificate, diploma, or degree, while it is significantly lower for those with a university certificate, diploma, or degree at bachelor level or above. in contrast, the exposure to infections or diseases score is higher for more educated workers than those without a certificate, diploma, or degree, although the difference is only significant for those with a college, cegep, or other nonuniversity certificate or diploma, and with a university certificate or diploma below bachelor level. overall, statistical significance is low or null for most education estimates, suggesting little net role for this variable. 8. additional results presented in tables a5 and a6 report estimates based on aggregate data allowing sex-age group education visible minority and sex-age group education aboriginal identity configurations, respectively. these are reported separately because publicly available data do allow configurations combining immigration status, visible minority status and aboriginal identity together. a categorical variable capturing the one-digit broad occupational category of each observation is introduced in the second set of regression models. these models are reported in the second column under each score type (models 2, 4, and 6). they accomplish the following two objectives. first, they provide estimates of the net association between different occupations and the risk scores. second, they provide some evidence on the role of occupational differences as a mechanism driving other group differences. more specifically, if the regression coefficients on gender, immigration, age, and education decrease in size, i conclude that those group differences are explained by the sorting of workers with different characteristics in broad occupations with different average scores. results for these models show that the coefficients for women decrease by a substantial amount (by two thirds for physical proximity and 75 percent for exposure to infections or diseases, approximately), while the coefficients for age in models using physical proximity and the composite score as a dependent variable become less negative. this means that gender and age differences are partially explained by the fact that women and younger workers are employed in broad occupational categories with higher average occupational risk scores. most notably, the second and third rows of the last column of tables a1 to a4 show that women are strongly overrepresented in the three broad occupational categories with the highest occupational risks of exposures (60 percent of workers in those occupations or more), while men are overrepresented in the remaining occupations. the results for education are also noteworthy in the case of the model using exposure to diseases and infections as a dependent variable. the coefficients for workers with a college or university education change sign (from positive to negative), meaning that when controlling for occupations, workers with a higher level of education have a lower risk of exposure to diseases or infections than those without a secondary degree. the differences between models 3 and 4 can be interpreted as showing that although workers with a higher level of education work in broad occupations that have a higher average exposure to diseases or infections risk score (likely health care sector occupations), within each broad occupational categories they are in four-digit occupations that have a lower average risk score than less educated workers. finally, note that the coefficients on the one-digit occupations dummies are almost all statistically significant and negative (results are relative to sales and services occupations, which is used as the reference category), and estimates for health occupations are large and positive. these results are consistent with the distributional statistics reported in the previous section. 9 9. note that the r 2 are substantially higher in models controlling for one-digit occupations, meaning that variation in average occupational risks of exposure between one-digit noc codes explains a large share of the overall variation in occupational risk of exposure to covid-19 between four-digit noc codes and sociodemographic groups. because of the high score on the exposure to diseases and infections in health occupations, i report specific regression results in table 6 for the 1.2 million canadians who work in health occupations 10 (noc 2016 onedigit code 3). i do the same for two other occupational groupings that score high on all measures of occupational exposure risks: occupations in education, law and social, community, and government services (noc 2016 one-digit code 4), and sales and services occupations (noc 2016 onedigit code 6). results for the seven residual broad occupational categories grouped together are also reported in table 6 . occupational risk of exposure scores are regressed on gender, immigration status, age, and education separately for each of these four occupational groupings. for the residual, other noc codes subsample, a model with controls for broad occupational category is also estimated. distributional statistics for each subsample are reported in tables a1 to a4 . first, the results show that gender differences are muted for both scores, consistent with the findings from the previous section. no statistically significant difference between men and women is found in health occupations (table a1 shows high score values across all distributional statistics in these occupations). in the residual occupations subsample ("other noc" column), women have a lower physical proximity score than men by three points, while the opposite pattern is found in noc 4 and noc 6. these results suggest that the gender gap in physical proximity score is explained by the fact that high-risk occupations are also highly feminized. the same interpretation can be applied to the regression results for the exposure to infections or diseases score, although no statistically significant gender difference is found in any of the three high-risk occupational groupings. meanwhile, outside of the three high-risk occupations, physical proximity is higher in male-dominated occupations (one-digit broad occupational categories), as shown when comparing the second column for the residual subsample (other noc, 2) with the first column for the residual subsample regression. once controlling for occupations, the difference between men and women is approximately 0 and is not statistically significant. this may be explained by the higher share of men in the higher scoring occupations of the residual category such as trades, natural resources, agriculture, and manufacturing occupations. the opposite is true for exposure to infections or diseases: in the other noc subsample, the score for women is higher by five points, a statistically significant and substantial gap, given the intercept estimate of 12.1 (constant). second, the age gradient in physical proximity scores distinguishing younger workers (15-24 years) from others in aggregate results reported in table 5 is not visible in health occupations (noc 3) or occupations in education, law and social, community, and government services (noc 4). on the other hand, older workers have a higher score than other age groups for frequency of exposure to diseases or infections by four to five points, suggesting that older workers in health occupations, including the approximately 260,000 workers aged 55 or more (20 percent of workers in health occupations), are at higher risk of exposure to the covid-19 based on that measure. the age difference is only statistically significant when comparing older workers (65 years or more) to the youngest age group (15-to 24year-old workers). older workers also score higher in noc 4 and noc 6 although the differences with 15-to 24-year-old workers are generally not statistically significant. in the other noc subsample, prime-age workers (25-54 years) score the lowest, with a statistically significant difference with 15-to 24-year-old workers of more than two points. third, workers with any type of university degree have a lower occupational risk of exposure compared to less educated workers across both measures and all occupational groupings, except for health occupations and, in the case of physical proximity scores, for sales and services occupations. following a social closure and social constructionist approach (attewell 1990; collins 1979; grusky and weeden 2001) may help understanding how health occupations requiring a higher level of education are associated with a high frequency of exposure to diseases or infections and high level of physical proximity while the opposite is true outside for other occupations. proximity with patients with poor health such as the one required for surgeons or other medical specialties is central to the occupational identity of health care professionals and to boundary definitions and closure among health care professionals. meanwhile, exposure to diseases or infections may simply represent an occupational health and safety risk in other occupations, which high-status (more highly educated) occupational incumbents are able to avoid. lastly, separate results by occupational groupings do not show any statistically significant difference between immigrants and canadianborn workers, with the exception of exposure to infections or diseases in the other noc subsample, where immigrants are found to have a lower score than canada-born workers. 11 11. in addition, table a1 shows that immigrants in health occupations have a slightly higher mean occupational risk of exposure to diseases or infections than canadian-born workers (1.2 point), but a substantially lower median value (by 3.8 points). this suggests an overall distribution towards higher occupational scores among immigrants, but an underrepresentation of immigrants among the highest scoring occupations, namely nurses, physicians, and other health care professionals with frequent interactions with patients. this is possibly due to the fact that those occupations have high barriers to the international transfer of credentials, limiting the ability of immigrants educated abroad in those professions to enter them in canada. a similar difference in median gap is observed for women, the last set of findings reported in this paper focus on workers in lowincome occupations. low-income workers may be at greater risk of infection to covid-19 and subsequent complications than other workers because they are likely to face strong financial disincentives to be absent from work (low savings and precarious financial situation) even if they contract the virus or if they are in a group at higher risks of mortality following an infection to covid-19 (older individuals, those with chronic health conditions or respiratory diseases, etc.). this is especially true in cases where they do not have access to paid sick leaves (the data do not include any measure of access to sick leaves however, and provinces such as ontario do not mandate paid sick leaves; self-employed workers such as those employed in the gig economy also lack employer-sponsored paid sick leaves) or other forms of income support in cases of absence from work for health-related reasons. in the absence of public-use individual-level employment income microdata with detailed measures of occupations, median occupational employment income is used as a proxy for being in a low-income job. table 7 reports the distribution of workers in low-income and non-low-income occupations in the overall quartile distribution for the three different risk scores. low-income occupations are occupations with median annual employment income below 50 percent of the canadian median annual employment income value ($37,231 among all those who were employed at any time in 2015). in other words, workers in an occupation with a median annual employment income value below $18,615.50 are classified as working in a low-income occupation. no adjustment is made for annual work hours because part-time or part-year employment status is an aspect of economic precarity (this paper is not focusing on the labor market returns to specific skills and for that reason, differences in hourly wages are less important than differences in annual earnings). the results in table 7 show that 1,730,835 canadian workers in the sample are in a low-income occupation, or 10.4 percent of all sample observations. a much higher share of workers in low-wage occupations work in occupations at the top of the physical proximity score distribution. more specifically, more than 95 percent of low-income workers are in jobs in the top half of the physical proximity score distribution. meanwhile, only 43.1 percent of workers who are not in a low-income occupation are in the top half of that distribution. a similar pattern is found for the exposure to infections or diseases score, although in a more muted way, possibly because possibly driven by the lower score of some female-dominated health occupations. note that within health occupations for example, physicians, dentists, and veterinarians have an average exposure to diseases or infections score of 93.7, while it is 30 points below at 63.5 for therapy and assessment professionals. therefore, heterogeneity in occupational risks of exposure is also found within broad occupational groupings. higher paying health occupations are overrepresented in the top half of the distribution. the composite score results show that 29.9 percent of all low-income workers are in the bottom half of the distribution, while a little more than 50 percent of workers not in a low-income occupation are in the bottom half of the distribution. estimates are also reported separately for men and women in table 7 . the higher overall occupational exposure risk scores for women reported in previous sections translate in a greater share of women in the highest quartile both inside and outside of low-income occupations. strikingly, 57.8 percent of women in low-income occupations are in the top quartile of the physical proximity score distribution. results in tables a7 to a9 show a higher share of workers in low-income occupations in the fourth quartile of the physical proximity score distribution among immigrant than canadian-born workers and among members of visible minority groups than workers who are not. for first nations people and métis, a higher concentration of workers in the fourth quartile of the exposure to infections or diseases score distribution is found among workers who are not in low-income occupations than non-aboriginals. the same pattern is found when comparing inuit and non-aboriginal workers in low-income occupations. otherwise little difference is found between non-aboriginal and aboriginal people working in low-income occupations. these results highlight the association between socioeconomic status and occupational-level work activities that may increase the risk of exposure to covid-19, and more so among women, immigrants, and members of visible minority groups. this matters in terms of baseline risk of exposure, but also highlights the importance of preventive measures against contraction and transmission in the workplace, such as ensuring that workers who suspect they may have been infected or who tested positive do not face disincentives to stay at home in isolation. while this study considers occupational risks of exposure to covid-19 using measures of job tasks and activities at the detailed level, it faces some limitations. importantly, employers have reacted in at least two ways to the pandemic, in line with public health guidelines and directives as well as with the impact of the pandemic on the economy. first, a large number of establishments have ceased their activities, as a result of a decrease in demand and of the subsequent establishment closures mandated by provincial governments across the country. as a consequence, workers in a large number of occupations are absent from work or on layoff or furlough (statistics canada 2020b). therefore, the 2016 data used for this study do not account for the recent developments in that area since the beginning of the pandemic, which may compound the impact of differences over time in the composition of the workforce on the estimates presented in this study. further analysis with data from the labor force survey could allow the estimation of the impact of mandated establishment closures and various forms of cessation of activities on the aggregate distribution of occupational risk of exposure as well as on group differences. despite this limitation, the results presented in this note have important longer term implications. as emergency measures mandating establishment closures in specific sectors are progressively lifted without a complete eradication of covid-19 in the population, this note shows which workers are likely to face higher risks of exposure when (or if) returning to work. these segments of the workforce may especially benefit from enhanced preventive, protective, and adaptative measures by governments and employers in that context. the ability to identify the high-risk occupations is therefore important to determine what type of workplaces may require greater monitoring, efforts at physical distancing and other measures during all phases of a pandemic. second, a large number of employers have implemented policies allowing employees to work from home, and survey evidence shows that 3.3 million employed canadians who usually work outside of their home completed most of their work hours from home during the week of april 12, 2020 (statistics canada 2020b). the relationship between physical proximity requirements (as measured by o*net) and the ability to work from home is not straightforward because existing technology allows online face-to-face discussion through teleconferencing software as well as a broad range of other forms of live communication and interactions. nevertheless, a few approaches have been used to measure the feasibility of remote work across occupations (dingel and neiman 2020; gascon 2020), which may allow future research to estimate the impact of an unevenly distributed shift to remote work on disparities in occupational risks of exposure to covid-19. note that the redesign of occupational task content in reaction to the covid-19 pandemic cannot be fully accounted for using a static database such as o*net, and more timely data on transition to remote work may be necessary. finally, addressing the impact of these recent labor market trends on occupational task content and on the distribution of those tasks will be instrumental in achieving a more accurate understanding of the risk of occupational exposure to covid-19 in the workplace across different segments of the labor force. nevertheless, the job design and task allocation of employees who perform similar work can vary substantially across organizations (appelbaum et al. 2000; cohen 2013) . in fact, variation in the ability of different organizations to adapt, transform, and reassemble jobs may be observable across dimensions other than occupations. while the ability to redesign jobs towards remote work may depend on certain occupational characteristics, studies of the impact of organizational reactions to the covid-19 pandemic (job reassembly/redesign) on the exposure risk of workers may gain to take into account these other sources of variation. in this paper, i use data on occupational work activities from the o*net combined with canadian 2016 census data to show that approximately 45 percent of canadian workers are in occupations that require performing duties in relatively close physical proximity to others (at arm's length or closer). a smaller share of workers is in occupations with a regular frequency of exposure to diseases or infections (around 8 percent of them are in occupations with exposure once a week or more). these measures are used as indicators of the risk of exposure to covid-19 in the workplace for canadians working in various occupations. the methods and findings can also be relevant for studies of occupational risks of exposure to other infectious diseases similar to covid-19 that may be transmitted when individuals are in close physical proximity. i find important disparities by sociodemographic characteristics, notably by gender, age, education, and broad occupational category. in addition, workers in low-income occupations are found to be especially vulnerable to covid-19 exposure and transmission. these results contribute to identify which workers are at higher risk of exposure to covid-19 in the workplace and help policy-makers formulate decisions about the design of specific public health and occupational health and safety interventions, the closure of certain establishments, and the creation of related incomesupport measures in reaction to the current pandemic. following bignamivan assche et al. (2020) , this study highlights the importance of focusing on age differences when considering government interventions focusing on essential workers and confinement. the evidence showing lower risks of exposure among universityeducated workers compared to less educated workers in most nonhealth occupations (as well as college, cegep, and other nonuniversity postsecondary-educated workers in some broad occupational groupings) also has the potential to contribute to the literature on the educationhealth gradient (zajacova and lawrence 2018) . at the same time, the absence of an education risk of exposure gradient among the (higher paid) health occupations point at the existence of "pockets of complexity" in this relationship (schieman and koltai 2017) . the initial findings reported in this research note can be leveraged in future studies on the relationship between different measures of socioeconomic status and health focusing specifically on covid-19 or other similar infectious 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tech workers? toronto: brookfield institute for innovation + entrepreneurship anything but static: risks of covid-19 to workers in canada postgraduate wage premiums and the gender wage gap in canada why do some occupations pay more than others? social closure and earnings inequality in the united states the case for a new class map the three worlds of inequality social class and earnings inequality occupations and british wage inequality occupations and the wage structure: the role of occupational tasks in britain social relations, technical divisions, and class stratification in the united states: an empirical test of the death and decomposition of class hypotheses the relationship between education and health: reducing disparities through a contextual approach figure key: cord-314275-twjaq5do authors: diwekar, u.; amekudzi-kennedy, a.; bakshi, b.; baumgartner, r.; boumans, r.; burger, p.; cabezas, h.; egler, m.; farley, j.; fath, b.; gleason, t.; huang, y.; karunanithi, a.; khanna, v.; mangan, a.; mayer, a.l.; mukherjee, r.; mullally, g.; rico-ramirez, v.; shonnard, d.; svanström, m.; theis, t. title: a perspective on the role of uncertainty in sustainability science and engineering date: 2020-09-09 journal: resour conserv recycl doi: 10.1016/j.resconrec.2020.105140 sha: doc_id: 314275 cord_uid: twjaq5do the trans-atlantic research and development interchange on sustainability workshop (tardis) is a meeting on scientific topics related to sustainability. the 2019 workshop theme was "on the role of uncertainty in managing the earth for global sustainability." this paper presents the perspectives on this topic derived from talks and discussions at the 2019 tardis workshop. there are four kinds of uncertainties encountered in sustainability ranging from clear enough futures to true surprises. the current state-of-the-art in assessing and mitigating these uncertainties is discussed. the demands of humans on the earth have grown considerably with the human population and the increase in per capita consumption of all kinds (fuels and energy, food, water, minerals, etc.). consider that while the earth and its energy budget from the sun have remained roughly constant over the past 4000 years, the human population has risen from approximately 7 million around 4000 bce to more than 7 billion (worldmeters, 2020) at present. the value of the global economic activity, as measured by the world gross product, a proxy for consumption, had risen from approximately us$1 billion around 4000 bce to about us$78 trillion (wikipedia 2020; worldbank 2015) by 2014, both in 1990 international us dollars. about 94% of the population increase and almost 100% of the rise in the world gross product have happened since 1500 bce. these conditions create an unprecedented planet-wide situation where humanity has the imperative of managing the earth within very tight constraints with little margin for error. this requires that humans be able to: (1) accurately assess the current condition of the earth, (2) forecast future trends as accurately as possible, and (3) develop effective management strategies. uncertainty poses significant difficulties for all three efforts. the concept of sustainability is closely related to that of sustainable development, but the two are different. sustainability is about ensuring that the earth can meet the material and energy needs to support complex systems including humanity over the long term. this has economic dimensions because the rate of resource consumption heavily depends on economics, and it has social dimensions because the ultimate goal is to support human society. sustainable development provides a vision of how human society could develop sustainably, and it adds a stronger focus on social dimensions such as intergenerational equity. sustainability is, therefore, a basic concept oriented to making the survival of civilized human existence on earth feasible. the focus of tardis is mostly on sustainability. however, we did not attempt to create our own formal definition of sustainability. we merely used the aforementioned framework as a working definition of sustainability to focus on discussions. the trans-atlantic research and development interchange on sustainability (tardis) workshop is a three-day study session on scientific topics related to sustainability, stimulated by presentations, and discussion. the workshop involves participants from the united states, europe, and other parts of the world in the multidisciplinary field of sustainability. the 2019 tardis group included the participation of experts from engineering, mathematical sciences, physics, ecology, economics, decision sciences, and political science fields. the theme of the 2019 workshop was "on the role of uncertainty in managing the earth for global sustainability." this paper presents the summary perspectives on this topic derived from talks and discussions at the 2019 tardis. sustainability and uncertainty: the problems involved in understanding, modeling, assessing, and managing for sustainability, fall under what rittel and weber (1973) call "wicked problems". for example, a recent study by the world bank (damania et al., 2019; steffen et al., 2015) that focuses on threats to global water quality concludes that the uncontrolled release of reactive nitrogen (nr) into rivers, lakes, and estuaries presents us with the "largest global externality" that threatens human health and ecosystem stability at a scale that is not fully recognized by the governments of the world. as often happens with such "wicked" problems, solutions are confounded by interconnected positive and negative impacts that are difficult or impossible to unravel. for instance, reactive nitrogen in the environment is intertwined with several of the un sustainable development goals: zero hunger (2), good health and well-being (3), clean water and sanitation (6), affordable and clean energy (7), industry, innovation, and infrastructure (9), sustainable cities and communities (11), responsible consumption and production (12), climate action (13), life below water (14), and life on land (15). actions taken to address the role of nr in any one of these goals may exacerbate nrrelated impacts in the others. multiple stakeholders and their conflicting perspectives also generate wicked sustainability-related problems. one of the major challenges in the sustainability system, which results in wicked problems is the problem of uncertainties. some examples of uncertainties in sustainability include definition and quantification of various objectives, impact assessment methods and models, forecasting future, and unexpected events. in a broad sense, uncertainty may be defined simply as limited knowledge about future, past, or current events (walker et al., 2003) . fig. 1 shows four different quadrants of information leading to uncertainty. this diagram is the focal point in business strategy and planning literature (marshall et al., 2019) . sustainability systems and issues extend to all four quadrants of information, whether the problem is of community sustainability, manufacturing sustainability, sustainable economics, regional or global sustainability, as described in the various sections below. the paper is divided into the following sections. section 2 presents types of uncertainties followed by a section on systemic risks, precautionary principle, and normative risks. section 4 talks about the effect of uncertainties on the environmental policy, followed by a section related to sustainable economics and uncertainty. section 6 is devoted to community sustainability and uncertainty. sustainable manufacturing and sustainability assessment sections follow that. decision making under deep uncertainty is section 9, followed by global sustainability and stochastic processes. section 11 is devoted to the communication of uncertainties in sustainability education. the summary section is last. the literature related to uncertainty defines two kinds of uncertainties, namely epistemic uncertainty and aleatory uncertainty. epistemic uncertainty is a lack of knowledge on underlying fundamentals and characterized by alternative models. aleatory uncertainty refers to the inherent uncertainty due to the probabilistic variability. these uncertainties are characterized by a probability distribution. sustainability problems are difficult because they involve deep uncertainties. a recent open book on decision making under deep uncertainty divides uncertainties into four types. • level 1 uncertainty represents situations in which one admits that one is not absolutely certain, but one does not see the need for or is not able to measure the degree of uncertainty in any explicit way (hillier and lieberman 2001) . these are generally short-term uncertainties (clear enough futures) where historical data can be used to predict the future. sensitivity analysis can be used to address these types of uncertainties. • level 2 uncertainty can be described in terms of probability distributions, probability bounds, interval methods, or fuzzy information. these uncertainties are useful where system models are reasonably closer to the real world. most of the manufacturing uncertainties fall into these categories. • level 1 and 2 uncertainties are observed for known unknowns. according to knight (1921) , levels 1 and 2 uncertainties come under the category of "risks" and are often associated with optimality, unlike levels 3 & 4, which involve "robustness." • level 3 uncertainties involve situations in which there are a limited set of plausible futures, system models, outcomes, or weights, and types of information: known-knowns are known to exist, and information is available, known-unknowns are known to exist, but no information is available, unknown-knowns are not included in the analysis but the information is possible if they did, and unknown-unknowns are not known to exist, and no information is available if they did (marshall et al., 2019) . probabilities cannot be assigned to them-so the tools of neither level 1 nor level 2 are appropriate. in these cases, traditional scenario analysis is usually used. long-term assessment of sustainability (also comes under level 4 uncertainty) comes under this category. • level 4 uncertainty represents the deepest level of recognized uncertainty. this is called deep uncertainty. there are two types of deep uncertainties: the uncertainty where there are many possible futures and outcomes, and there are unknown futures and unknown outcomes. deep uncertainties are related to decreasing confidence in our ability to anticipate correctly future technological, economic, and social developments, future changes in the system we are trying to improve, or the multiplicity and time-varying preferences of stakeholders regarding the system's outcomes, or handling low probability but high impact events (black swans (taleb 2010) ) like a natural disaster, a pandemic, a financial crisis, a terrorist attack, or truly novel events for which there is no historical experience. (unknown knowns and unknown unknowns, true surprises). systemic risk, ontological uncertainty, and time-dependent uncertainties come under this category of level 4 uncertainty. dealing with these kinds of uncertainties involve monitoring the present and adaptations over time. the precautionary principle and options theory are two widely used methods to deal with these uncertainties. uncertainty, as well as the precautionary principle, take a prominent place within the scientific debate on sustainable development in general and on managing systemic risks specifically (renn 2008; becker 2014) . against the backdrop of the many meanings of systemic risks within the scientific discourse, we argue that the precautionary principle is only a negative or threshold criterion and that it is worthwhile to add positive normative criteria to inform management of systemic risks. however, we introduce the concept of normative uncertainty adding up to epistemic uncertainty in dealing with systemic risk. systemic risks are a relatively new type of risk concept (renn, 2016) . according to predominant understanding, the occurrence of an event would not simply lead to harm but to a breakdown of the system (kaufman and scott 2003; smaga, 2014) . in other words, the system would go beyond its resilience level and would no longer be able to execute its functions. with some probability the "event" climate change can, for example, lead to a breakdown of the earth's life-supporting functions; or a global financial crisis can be accompanied by major banks going bankrupt which in turn would severely undermine their functions supporting the economy potentially leading to a breakdown of the economy. such risks display new characteristics in comparison to traditional risks such as droughts, hailstorms, a car traveling, or smoking. whereas the latter are computable, systemic risks are not. it is neither possible to estimate the probability of occurrence of the triggering events, nor is it possible to assess the related harm (and to bring that into a cost-benefit analysis). these come under level 3 and level 4 types of uncertainties. risk assessments are always accompanied by epistemic uncertainties. the results of measuring frequencies of events or modeling the complexity of systems together with assessing potential harm are normally given within ranges expressing possible limitations. however, uncertainties related to systemic risks do not express a given range of likelihood. they represent the mode "we do not know," due to its character as not being computable. we can, for example, not give a reasonable likelihood estimation for whether the financial crisis in 2008 and the thread of big banks potentially collapsing would have led to a breakdown of the economic system. the issues are just too complex to come up with estimations. the possibility that it could and would bring about a huge amount of harm by a breakdown of the economy was seen as sufficiently reasonable to take action. the motivating principle, according to actions, is known as the precautionary principle (gardiner 2006) . it does not claim that you should not take risks. it rather says (in case of the financial crisis in 2008): we do not know whether the collapse of system-relevant banks will lead to a breakdown of the economic system. however, the level of risk resulting from such a breakdown is sufficient to intervene and not to let those banks go bankrupt. the precautionary principle is an action-guiding principle where the occurrence of events could have the effect that a threshold (or resilience) level of a major system supporting societal functions will trespass. however, the precautionary principle only indicates not to take a specific path. in contrast, it cannot inform positively decision making for "doing x," e.g., deciding that saving exposed banks whose activities brought about the crisis is the best decision to take. additional criteria are needed in order to make a positive decision. according to relevant theories in political economy and philosophy (renn 2009; stirling 2007; kaul and mendoza 2003) , public decisions should (ideally) primarily be motivated by taking public or common goods as well as the overall goal of human well-being into account. hence, the negatively oriented precautionary principle should be accompanied by a positive criterion on public goods and human wellbeing. together they build a sound basis for decision making regarding systemic risks, nowadays prominently expressed by the agenda 2030 and its 17 sustainable development goals. when tackling systemic risks from a perspective of societal goals, alternative options to deal with, as well as different outcomes of the crisis, come into the picture. specifically, it substantiates and rationalizes so-called 'pro-active intervention strategies' to systemic risks, such as adaptation and transformation (irgc 2018), scenario discovery approach (bryant and lampert, 2010) , etc. however, although such a positive approach offers a productive evaluative basis for assessing first what systemic risks are and what goods have to be taken into account, in strategies for dealing with (avoiding) systemic risks, this opens up a broad space of interpretation. this happens because there is not one single understanding of what constitutes public goods or belongs to human well-being. this points to another field of uncertainties, i.e., normative uncertainty (e.g., mazouz 2003) . it is by far not the case that anything goes when talking about justice or sustainable development. philosophy, social sciences, and economics provide a number of well-established approaches to frame justice (cf. miller 2017). we have a variety of options producing a range of normative claims and assessments (cf. burger 2018 for types of sustainability conceptions). as we have to learn to deal with epistemic uncertainties, the sciences additionally need to improve their understanding of normative uncertainties when dealing with systemic risks like climate change. lastly, in this overview of uncertainty types, we consider the role of ontological uncertainty (nielsen and ulanowicz 2011) , which refers to the emergence of new unpredictable or un-"pre-statable" types (kauffman 2019). any system that exhibits requisite complexity will have novel behaviors from the interactions of the agents within the system. for example, simple combinatorics tells us that the interactions of 80 distinguishable components will offer approximately 80! =~7 × 10, 118 possible configurations. yet, given the age of the universe, estimates are that there have only been~10, 110 quantum level events (elsasser and staude 1978) . in other words, there will be surprise events and other events that will never materialize. this level of uncertainty, which challenges the old school determinism, has manifest itself in many 20th century theories as given in table 1 (examples are taken from nielsen et al., 2020, p. 30) . the realization of ontic uncertainty is not inherently negatively consequential, but rather has benefits as it implies ontic openness that potentially brings new opportunities to any complex adaptive system, including humans striving for sustainable development. of course, this also reinforces the importance of applying the precautionary principle as prudent guidance into an unknown future. as in most areas of policy, environmental and sustainability policy must often contend with scientific uncertainty when prescribing actions and identifying targets (bradshaw and borchers 2000) . depending on the problem, scientific uncertainties in policymaking can be of any one of the four types described earlier. policymakers often grant implementing agencies considerable discretion to modify their actions in response to new information or understandings, but there are limits to how much discretion can be accommodated before policies must be rewritten (woods and morey 2008; lind-riehl et al., 2016) . at some point, when the language and concepts used in laws, regulations, and policies no longer relate to the state of knowledge in the field, these prescriptions must be amended. the us endangered species act or esa is one such example of science moving beyond the legal terminology. as implied by its title, the esa is a law that protects species from extinction. enacted in 1973, the esa is one of the most stringent environmental laws in the world, saving thousands of species from extinction and enabling the recovery of dozens of well-known and unique species (suckling et al., 2016) . when faced with a species in decline, the two enforcement agencies, the us fish and wildlife service and the national marine fisheries service, must first determine whether the species meets the esa's criteria for being listable. one of these criteria includes the distinctiveness of that species, subspecies, or population from other more common species. advancements in genetic technology and taxonomic science have complicated the boundaries between species, making it more difficult to use the esa to protect biodiversity from threats faced by land-use change, pollution, invasive species, and climate change (ritchie et al., 2018 ). an increasing number of lawsuits and petitions call on wildlife agencies to delist or downlist species from the esa, based on new information that calls the species' distinctiveness into question. one such example is the coastal california gnatcatcher (polioptila californica), a small, nonmigratory songbird that inhabits the rapidly urbanizing region of southern california and northern baja california peninsula in mexico (mayer, forthcoming) . the protection of this northern-most subspecies of california gnatcatcher has been constantly challenged by development industries in california, mainly over the scientific uncertainty of its distinctiveness from other subspecies. although ecological and morphological evidence continues to indicate that the coastal california gnatcatcher is substantially different from california gnatcatchers further south in mexico, genetic evidence has been more equivocal and contentious (mccormack and maley 2015; patten 2015; zink et al., 2013 zink et al., , 2016 . difficulties in determining the clarity of boundaries between species and subspecies are not unique to the california gnatcatcher, but rather are inherent in the concept of a species (zachos 2018) . species are continuously evolving over time and can and do hybridize with closely related species as they evolve, blurring their genetic and morphological distinctiveness. the difficulty of species delineation, and ongoing disagreements over concepts and methods among scientists, translates into difficulty for policy decision-making, even with considerable discretion for implementing agencies. insight into the roles of ambiguity, uncertainty, and discretion in the interaction between the scientific process and policy process can improve policy implementation and outcomes (doremus 1997; bradshaw and borchers 2000; cairney et al., 2016; wilhere 2017) . perhaps the first work applying financial decision-making models to environmental issues relevant to sustainability was by weisbrod (1964) . weisbrod considered the case of the sequoia national park, for which demand is infrequent and uncertain (i.e., many people consider going, but few actually go). he imagines a private owner who is able to price discriminate in charging entrance fees and thus capture the entire consumer surplus for himself. even under these conditions, however, entrance fees do not cover the full costs of running the park. ignoring all non-recreation benefits of the ecosystem in question, a rational owner might choose to irreversibly convert the area to other more profitable uses (e.g., chop down the forests and build condominiums). however, when demand is infrequent and uncertain, there is a certain value people give to retaining the option to visit the park even if they never do so. this value is a pure public good: as long as the park is there, the option itself is non-excludable and non-rival, and there are no non-coercive mechanisms for charging consumers for this option value. if enough people benefit from this option value, it would be socially efficient to keep the park open even if privately inefficient. the solution may be public ownership or subsidies. cicchetti and freeman (1971) have shown that weisbrod's option value will be positive when there is uncertainty in either demand or supply, and it has the same effect on decisions as risk aversion. arrow and fischer (1974) examined a slightly different situation, in which there is an opportunity to irreversibly convert an ecosystem to some other use, such as damming a river or converting a forest to housing developments. they look at the situation in which decisions this period change the expected values of conversion and/or non-conversion in the next period. for example, society might learn about a valuable service provided by the ecosystem, or a new medicinal plant, if it is left unconverted. they concluded that these unknown values created a quasi-option value that again increases the value of avoiding irreversible outcomes, acting the same as risk aversion. conrad (1980) later showed that the quasi-option value is equivalent to the expected value of information, while the option value is equivalent to the expected value of perfect information. however, in financial decision making, and in the models described above, unknown outcomes are of a very restricted variety: possible outcomes are known, as are the probabilities of each. knight (1921) referred to this type of unknown outcome as a risk. in the highly complex ecological-economic systems that humans want to sustain, it is often impossible to make objective assessments of the probabilities of different outcomes, and therefore impossible to model expected values. in many cases, we cannot even guess at possible outcomes. for example, human activities change ecosystems in ways that generate new evolutionary pressures on the species within them. humans react to their self-created changes through cultural evolution, including the development of new technologies. both evolution and technological advances can lead to entirely unpredictable outcomes, in which not even possible outcomes can be objectively assessed. this type of unknown outcome has been referred to as surprise (schneider et al., 1998; casti, 1994; faber et al., 1992; kates, 1985) novelty (faber and proops,1998) and ignorance (faber et al., 1992; daly and farley, 2003) . how to deal with ignorance and uncertainty in modeling sustainability is a serious challenge. this is within the area of deep uncertainty. in reality, due to the aforementioned uncertainties, we suffer table 1 examples of uncertainty and indeterminacy in the modern understanding of nature (nielsen et al., 2020) . creative destruction as part of the cyclic process jørgensen heisenberg extended to ecosystems kauffman continuous evolution into the possible adjacent states u. diwekar, et al. resources, conservation & recycling 164 (2021) 105140 profound ignorance about the most serious problems we currently face in our rapidly evolving system. it is a characteristic of complex systems that if we ramp up the value of a critical parameter beyond some critical point, the system can "flip" into an alternate regime about which we know very little and from which it can be difficult or impossible to return to the previous state (hughes et al., 2013; lenton et al., 2008; lenton and williams, 2013; pearce, 2007) . we are currently ramping up the value of innumerable critical parameters, both ecological and economic, simultaneously. climate change, biodiversity loss, nutrient flows, and land-use change are a few of the most egregious ecological examples (rockstrom et al., 2009; steffen et al., 2015) . financial systems regularly experience explosive growth followed by crisis. stocks are now held on average for some 30 s, down from 8 years in the 1960s (hudson 2011) . over half the value of stocks in the us are owned by the richest 1% of the population (wigglesworth 2020). the s&p 500 increased by 260% from 2009 to 2019, vs. a 35% increase in gdp, and by more than 12 times as much as gdp in 2019, contributing to an explosive increase in inequality. since over the counter foreign exchange trading first appeared in the early 1980s, transactions have soared to $6.6 trillion per day nearly 30 times greater than global gdp, with purchases also held for only seconds on average (hudson 2011) . we are often uncertain precisely which parameters are critical, can only guess when they will reach critical thresholds, and remain profoundly ignorant about new regimes into which our system may flip. as has been eloquently (taleb 2010) pointed out, the most consequential events in history have been black swans: extremely rare events with very high impacts that could not have been predicted ahead of time. the previous experience provides little to no guidance in predicting novel events. another major source of uncertainty is the reflexive nature of social systems and social science (soros, 2013) . societies develop beliefs and norms that affect their members' behavior. for example, social scientists develop theories to explain how people behave and how social systems function, but it is widely believed, the theories themselves can affect human behavior. theories can be self-fulfilling or self-negating. for example, even prior to the covid-19 crisis, many pundits were predicting a recession. if producers believe predictions, they will stop investing in new productive capacity, reducing the creation of new jobs if consumers believe that as well, they will start saving their money, reducing aggregate demand, leading producers to lay off workers, who respond by saving even more money in a positive feedback loop. these are the actions that can trigger a recession. in contrast, before the financial crisis that exploded in 2007, ben bernanke and other influential economists claimed we had achieved a 'great moderation' and no longer had to fear financial crisis (bernanke 2004; stock and watson 2002) . this very likely stimulated excessive risk-taking, and that precipitated the crisis, as predicted by minsky's financial instability hypothesis (minsky 1977) . several community environmental quality problems fall under wicked problems because depending on the stakes one has, the problem formulation -different characterizations of the problem that emerge when viewed from the perspectives of different stakeholders -can be very different: industry stakeholders whose primary objective is usually economic optimization within environmental regulation standards; communities that seek to balance socioeconomic welfare through access to jobs while reducing associated environmental contaminants -if they are dependent on jobs from the contaminating industries; more affluent communities that would rather have polluting industries removed or distanced from their communities to optimize environmental quality and public health, and government agencies whose primary objective is to administer regulations at the nexus of these competing demands. the triple bottom line does come into play here, but the relative importance of the different types of capital pertaining to the problem situation can be very different -sometimes reflected in long drawn out battles over community environmental contamination issues (brackett, 2019) . these multiple objectives bring in uncertainties as some objectives are well defined and can be quantified reasonably as others cannot be quantified accurately. use of multi-objective programming (mop) under uncertainty (fu et al., 2001; diwekar, 2012) or many objective robust decision making (mordm) (kasprzyk et al., 2013; singh et al., 2015) methods are useful in this context. the methods are suitable for level 2 as well as level 3 & 4 types of uncertainties. environmental contamination in local communities is a pervasive problem that affects sustainable development and public health at the local level, judging from the news and social media reporting. the popular media has intermittently reported on environmental contamination in various communities around the country where residents have been unaware of such contamination and its impact on their health for extended periods of time. examples include ethylene oxide emissions in the states of georgia and illinois, and the flint water crisis in michigan (goodman and miller, 2019; lutz, 2019; 11 alive news, 2019; abc-7 chicago, 2019; scalia, 2019; bowles, 2018) . communities that have been unknowingly exposed to environmental contaminants for relatively extended periods tend to develop a distrust of the public officials responsible for environmental quality (goodman and miller, 2019; lutz, 2019; 11 alive news, 2019; abc-7 chicago, 2019) . notable uncertainty exists concerning community exposure to environmental contaminants in the air, water, and soil, and there are several synthetic compounds in use today in various consumer products that have not been reviewed for safety by any government agency (asce, 2006) . therefore, uncertainties abound with local environmental contamination, both known unknowns and unknown unknowns. the emergence of lower-cost environmental quality sensors offers a growing opportunity for communities to engage in crowd science, partnering with universities and government officials, to develop a better understanding of their local environmental risks and begin to monitor and contribute to managing the most critical of them. how can emerging sensor technologies be adapted to monitor various critical contaminants in a community's risk profile in a cost-effective manner, and what is the feasibility and cost of large-scale deployments? the news media report that thousands of people around the country are beginning to measure air quality as climate change reports become increasingly dire, wildfires tear across the american west, and trust in the federal government's air quality oversight fades (un, 2015) . the purpleair map (2020), for example, is available to the public via the internet, and air quality monitoring network built on a new generation of "internet of things" sensors being used by individuals and communities. developed on the concern that local air contamination was higher than indicated, purpleair monitors are now being used by several individuals and communities around the world with air particulate data being fed in real-time over wi-fi to a public visual display online. coupling standard public domain reporting with organized crowd science efforts to monitor critical environmental contaminants, such technology can allow communities to initiate a new level of data-driven engagement with public officials. this can go a long way in fostering bottom-up approaches to balance the top-down approaches to environmental quality management at the local level. wicked problems that have persisted across years, decades, and centuries may have possible solution pathways that begin with the education of local communities to understand the profile of risks they are contending within their communities. it can then continue with communities partnering with universities, government officials, and other stakeholders to address such long-standing problems -leveraging emerging technologies and gathering relevant data to engage in smart governance. a recent case study in colorado presents a stake-holder-focused approach to local government sustainability planning to explicitly link u. diwekar, et al. resources, conservation & recycling 164 (2021) 105140 bottom-up and top-down approaches to environmental management (hopton et al., 2010; dubinsky and karunanithi, 2017a, b) . the deliberative process was intertwined with different types of uncertainties. during the stakeholder engagement phase, social values, competing interests, and points of view, trade-offs and choices would constitute different forms of uncertainties. the participation of community members introduced local context and local knowledge, which provided clear roadmaps for the construction of robust, meaningful, and realistic scenarios. it also facilitated the knowledge transfer process and ensured that locally defined sustainability benchmarks would be emphasized. it is highly recommended that the stakeholder-centric methodology be used in any future local governance sustainability projects. in a second case study, a multidisciplinary team evaluated a suite of six metrics of urban performance (ecological footprint, green net product, net energy, human wellbeing index, fisher information, emergy) linked to an agent-based simulation model to explore current conditions and trends in greater chicago. it was found as cronin (1991) suggested, that chicago and other urban systems are not static but constantly evolving. this poses the question of evolving uncertainties. the question for sustainability then is not whether an urban system (or any system) is sustainable at a given point in time, but rather whether that system has the capability and capacity to successfully evolve and adapt to the conditions that it will encounter in the future. manufacturing sustainability has become a global issue, especially in developed and fast-developing countries. an improved corporate sustainability performance does not automatically lead to an improved sustainability performance of the systems within which a company is embedded. a comprehensive assessment framework is needed to analyze whether an improved corporate sustainability performance can positively contribute to sustainable development on a global level. this includes first-order and second-order performance measurements (baumgartner, r. j., & korhonen, j., 2010; baumgartner and rauter, 2017) . the former assesses the direct sustainability impacts and usually focuses on narrow issues of efficiency, while second-order sustainability performance focuses on systemic effectiveness and covers sustainability impacts on society and nature in total, i.e., the entire system. this problem is usually posed as a multi-objective optimization problem (moradi and huang 2016 , liu and huang 2012 , 2013 , z. 2015 . however, there are not only uncertainties associated with each performance measure, but deciding the weights for different objectives presents significant uncertainties in solutions. there are both the aleatory and epistemic uncertainties that appear in various types of manufacturing sustainability problems. the uncertainties in secondorder performance measures are much higher than in first-order measures, and this needs to be balanced. this is because of the long-term nature of the performance objectives. this is obvious in the example of plastics (plastics europe, 2017; plastics europe 2020; geyer et al., 2017; shonnard et al., 2019; benavides et al., 2017; gracida, 2019; closed loop partners, 2019), and environmental impacts by the disposal of plastic from municipal solid waste. landfilling and leakage to the environment (as opposed to recycling or re-use) are thought to be the largest end-of-life fates for plastics that are used in packaging, which is the most common use of plastics. plastic packaging exhibits the shortest lifetime between its production and appearing at its end-of-life as waste in need of management. a circular economy for these polymeric materials, rather than a linear economy, is proposed as a solution to the responsible management of waste plastics. however, large-scale implementation of a circular economy for plastics is not well-understood with respect to economic costs and benefits, environmental impacts, and societal effects relative to business-as-usual linear management. a systems analysis for sustainability for a circular economy of plastics is difficult because of several problems related to uncertainties related to the definition of goals and knowledge gaps on current and future recycling processes. sustainable manufacturing often uses life cycle analysis for sustainability assessment. given the importance of life cycle assessment in sustainability, we have devoted a special section below on life cycle assessment and uncertainty. increasing awareness of environmental degradation and resource depletion has led to the incorporation of environmental sustainability considerations in engineering design and analysis. one such widely popular technique is the environmental life cycle assessment (graedel and allenby, 2019) , which aims to model and quantify the environmental impacts of products and systems over their entire life cycle (rebitzer et al., 2004) . by assessing the entire life cycle of the system of interest, one can evaluate the environmental impact of released emissions or of materials and energy used during various stages (material extraction, manufacturing, usage, disposal) of the product or system of interest. lca methods tend to focus heavily on emissions and their impact and resource use. it is also important to include ecosystem goods and services as well as societal benefits and impacts in lca to move towards sustainable development. however, ecosystem services and societal implications are either not accounted for or not well represented in most life cycle methods. some recent lca approaches have been developed for the purpose of assessing the role of ecosystem services in process and input-output life cycles (eco-lca) (zhang et al., 2010) . however, these have been limited in their scope, and placeholders exist for many ecosystem goods and serviced. these placeholders in lca (known unknowns) can lead to wrong policies. in "frames in toxicity controversy," arnold tucker (tucker, 1999) presents a case study where researchers had to advise the dutch government about the choice of incineration technology. however, lca at that time lacked fate modeling and could not provide any certainty about the choice. the researchers used the precautionary principle and asked for more research. however, the politicians did not have time or money to carry out the research, and it resulted in the wrong policy. these placeholders represent known unknowns and are part of level 3 uncertainties. as an example, consider the critical ecosystem service of pollination provided by insects. a lack of this service would be a significant detriment to not only ecosystem biodiversity and function, but also to various industrial sectors, agriculture, and the world economy (potts et al., 2016; klein et al., 2007) . in the united states, insectmediated pollination of crops accounts for between us$ 14-23 billion of pollination-dependent crop production alone, making this ecosystem service a highly valuable asset to the nutritional and economic welfare of the agricultural sector (chopra et al., 2015) . in addition, there are upstream and downstream industry sectors that rely upon pollinationdependent crop production (fertilizers, pesticides) as well as nonagricultural industrial sectors (pharmaceutical, fuel) that share linkages with crop production and agricultural sectors, leading to intricate indirect dependence upon pollination service mediated by insects. although this example is specific to insect pollination service, there are numerous other ecosystem goods and services that are being exploited at unsustainable rates and facing severe degradation (carpenter et al., 2006) . while the economic valuation of ecosystem goods and services provides an elegant framework highlighting their importance for society and human welfare, there is a need to explicitly account for their contribution when designing and developing products and services. data and models are needed at multiple scales to account for the contribution of ecosystem goods and services in environmental sustainability assessments and engineering design. at the process scale, recent work has attempted to account for the role of nature and specific ecosystem goods and services for the sustainable design of engineered u. diwekar, et al. resources, conservation & recycling 164 (2021) 105140 systems (carpenter et al., 2006; gopalakrishnan et al., 2016; charles et al., 2020) . from the lca perspective, new environmental impact categories will need to be developed for a comprehensive accounting of ecosystem goods and services. for example, the use of process-based models such as invest (sharp et al., 2018) could be integrated into life cycle frameworks. environmentally-extended input-output models have shown promise for an accounting of ecosystem goods and services, but they are also fraught with uncertainty associated with data and aggregation, which can hinder detailed assessments (zhang et al., 2010) . some of these challenges could be addressed with hybrid approaches (suh et al., 2004) . a more accurate valuation of ecosystem goods and services and their inclusion in human and engineering decision-making has the potential to motivate and guide conservation, revitalization efforts, and policy decision-making. recent efforts have focused on explicitly accounting for the role of ecosystems in supporting human activities by the framework of techno-ecological synergy (tes) . the goal of this framework is to determine the extent of ecological overshoot from specific activities for each ecosystem service and to encourage mutually beneficial designs of technological and ecological systems. several case studies indicate the potential environmental and economic benefits of establishing such synergies (bakshi, 2019; hanes et al., 2017; r.j. 2018; gopalakrishnan et al., 2016 gopalakrishnan et al., ,2017 gopalakrishnan and bakshi, 2018; martinez-hernandez et al., 2017; hernandez et al., 2019) . however, these studies are based on simplified models that do not account for the dynamics of technological and ecological systems, which can be quite different. technological systems are usually designed to have low variability and predictable behavior. thus, such systems tend to stay around a "set point" and exhibit homeostasis. in contrast, ecosystems tend to be intermittent and are not predictable. they exhibit "homeorhesis." benefiting from tes requires designs that combine the desired homeostasis of technologies and human-designed systems with the homeorhesis of nature. our hypothesis is that tes designs are more resilient than conventional techno-centric designs. exploring this hypothesis requires approaches for quantifying resilience. various approaches may be relevant for this task, depending on the nature of information available about the designed systems. ecological network analysis relies on information about the flow between nodes in a network. it relies on information-theoretic metrics that are useful for understanding the character of ecological and economic systems (ulanowicz et al., 2009) . if time-series data from the system are available, methods such as fisher information (eason et al., 2014 ) may be used. if more details such as dynamic models of the system, then mathematical approaches based on viability theory (béné, and doyen, 2018 ) may be applied. various approaches have been developed to account for the effect of uncertainties in network analysis (guesnet et al., 2015; hines et al., 2018) the effect of uncertainties may be included in the stochastic models used in these methods (de lara et al., 2009 ) and by the use of robust and stochastic optimization methods (sahinidis, 2004; diwekar, 2010) . the merriam-webster dictionary defines decision making as the act or process of deciding something, especially with a group of people. decision making under uncertainty methods are around for some time and is the topic of several books (e.g., morgan and henrion 1990; bedford and cooke 2001) . however, these methods do not deal with deep uncertainties that are present in regional as well as global sustainability models. dmdu methods are a topic of intense research in recent literature. dmdu methods are not based on the 'predict-then-act" paradigm, but that aims to prepare and adapt. according to a recent book on dmdu , there are four methods to deal with decision making under deep uncertainties. these include robust decision making (rdm), dynamic adaptive planning (dap), dynamic adaptive policy pathways (dapp), and engineering options analysis (eoa). while the first three involves hybrid approaches and described briefly below, eoa is quantitative in nature and is discussed in next section. for details of these methods, please refer to marchau et al., 2019. rdm draws from scenario analysis the concept of organizing information about the future into a small number of distinct cases that help people engage with, explore, and communicate deep uncertainty. however, rdm is different from scenario analysis that it uses computer simulations to generate large ensembles of future states of world as compared to a small number of cases in scenario analysis. rdm involves four steps 1 consider diverse plausible futures 2 seek strategies which are robust across a wide range of plausible futures 3 employ adaptive strategies to achieve robustness 4 use humans and computers alternatively to test each other's conclusions about futures and strategies. dap is a dmdu approach for designing a plan that explicitly includes provisions for adaptation as conditions change and knowledge is gained. dap approach involves 1 specifying a set of objectives and constraints 2 designing short-term actions initial plan 3 establish a framework to guide future (contingent) actions. dapp explicitly includes decision making over time. it is proactive and dynamic planning. it involves adaption pathways for multiple futures. dapp supports the design of a dynamic adaptive strategy that includes initial actions, long-term options, and adaptation signals to identify when to implement the long-term options or revisit decisions. also, central to the approach is the concept of adaptation tipping points. the adaptation tipping point (atp) approach was developed in the netherlands in response to a desire of the national government for a planning approach less dependent on any particular set of scenarios. dmdu approaches have been used for regional sustainability assessment and policy analysis. for example, molina-perez et al. (2019) studied how to design adaptive plans (rdm) for water supply infrastructure under deep uncertainty to ensure sustainable development in montreal, mexico. groves et al. (2019) presented a case study of the application of rdm to long-term water resources planning for the colorado river basin. vincent et al. (2019) used dap to derive innovative traffic safety technology in the netherlands. in a chapter, lawrence et al. (2019) describes how flood risk managers at a regional level in new zealand applied the dapp approach to managing deep uncertainty around flood frequency associated with changing climate, and examines the lessons learned from taking dapp theory into practice. hamarat et al. (2014) applied multi-objective simulation-based optimization with rdm to study how the european union can achieve its carbon reduction target under deep uncertainty. trindade et al. (2019) proposed deeply uncertain pathways for multicity regional water supply infrastructure investment and portfolio management. shi et al. (2019) proposed two adaptive screening procedures to identify when comprehensive decision analysis methods, such as dmdu methods introduced here, should be implemented. mathematical models featuring the critical components of a real ecosystem can aid in the formal study of sustainability. the first such comprehensive model for studying global sustainability is the model from the club of rome (meadows et al., 1972; meadows, 2014) called the world model. this model has components like the human u. diwekar, et al. resources, conservation & recycling 164 (2021) 105140 population, natural resources, pollution, industrial production, and agricultural land use. the results of this model established growth patterns and limits for the first time. models accounting for processes such as resource extraction, waste assimilation, recycling, and pollution in an integrated ecological, economic framework have also been proposed in the literature (van den bergh, 1996) . in recent years, the united global metamodel of the biosphere (gumbo) (boumans et al., 2002) was developed to include dynamic feedbacks among human technology, economic production and welfare, and ecosystem goods and services. the model was calibrated using time series data for 14 key variables from 1900 to 2000. recently, the model predictions were compared with data from 2000 to 2018 (boumans, 2019) . there are a number of planetary integrated assessment models available in the literature (wilson et al., 2017) to study global phenomena such as global climate change. a model that deals with food-energy nexus for global sustainability is recently proposed by kotecha et al. (2013) . since these models are dealing with long-term sustainability, they face the problem of time-dependent uncertainties (deep uncertainty). for example, fig. 2 shows how the global temperature change over the time span of 400 years. we can see that there is significant uncertainty in global warming and is changing with time. we cannot describe these uncertainties using static probability distributions. these are time-dependent uncertainty. financial literature abounds with such uncertainties and hence, as a result, provided a way to deal with such uncertainties using real options theory. real options theory uses stochastic processes to represent the time-dependent uncertainties. a stochastic process is one that evolves over time in an uncertain way. stochastic processes do not have time derivatives in the conventional sense, and, as a result, they cannot be manipulated using the ordinary rules of calculus as needed to solve the stochastic optimal control problems. ito (1951 ito ( , 1974 provided a way around this by defining a particular kind of uncertainty representation based on the wiener process as a building block. the wiener process, also known as brownian motion, is a continuous limit of the random walk and is a continuous-time stochastic process. a wiener process (continuous or discrete) can be used as a building block to model an extremely broad range of variables that vary continuously and stochastically through time. examples of ito processes are simple brownian motion, geometric brownian motion, mean-reverting process, etc. in the real options analysis (roa), dixit and pindyck (1994) used stochastic calculus (ito's lemma) coupled with dynamic programming to study investment decisions under uncertainty. this approach uses ito's lemma, which is called the fundamental theorem of stochastic calculus and allows us to differentiate and to integrate functions of stochastic processes. however, for deep uncertainties involved in sustainability, we need to consider the engineering options analysis. the difference between eoa and roa is that eoa considers multiple options with a range of possibilities. however, the mathematical methods used for roa and eoa are similar. recently, diwekar (diwekar, 2008; rico-ramirez et al., 2003; rico-ramirez and diwekar, 2004) presented basic concepts for dealing with time-dependent uncertainties modeling. these concepts are derived from the financial and economics literature and engineering optimal control theory. these concepts could be extended to studying sustainability as presented in the recent literature (shastri and diwekar, 2008; shastri et al., 2008a,b; diwekar and shastri, 2010; diwekar, 2012b diwekar, , 2015 doshi et al., 2015 , rodriguez-gonzalez et al., 2019 . although the tardis workshop of 2019 focused on the role of uncertainty in sustainability science and engineering, it was also discussed whether attempts to accurately assess the current condition of the earth and forecast future trends as accurately as possible are in fact in themselves symptoms of the underlying problem and reflects an anthropocentric view of human exemption, dominance, and omnipotence. effective management strategies might, therefore, focus also on fostering new approaches that reflect a more humble and flexible human-nature relationship. a recent article in pnas (steffen et al., 2018) argued that the "social and technological trends and decisions occurring over the next decade or so could significantly influence the trajectory of the earth system for tens to hundreds of thousands of years and potentially lead to conditions inhospitable to current human societies and to many other contemporary species." despite the best efforts of scientists to qualify their interventions and acknowledge that their scenarios are "mediating tools to communicate vulnerabilities, perceptions of risk or possible consequences, they often become taken as statements of the future" (yusoff and gabrys, 2011) . transformation is a way of reflecting on existing practices and imagining new ways of doing and knowing (duncan et al., 2018) , the capacity to collectively envision and meaningfully debate realistic and desirable futures (milkoreit, 2017) . transformations, however, involve "systems change and because of the political nature of change are subject to contestation" (hebinck et al., 2018) . norgaard (norgaard, 2018) suggests that while we have made significant progress in developing an ecological imagination through advances in climate science, we have made much less progress in actually changing course. the gap between responses to climate change and the socio-political realities of contemporary life have led to inaction, but the further problem is that we do not know and cannot know what changes are in motion (nightingale et al., 2019). beck's world risk society idea and its attendant uncertainty capture the sense that the speed and complexity of interactions blur cause and effect, creating the escalating potential for cascading catastrophic risks and a vision of the future characterized by chaos (rickards et al., 2014) . living with uncertainty is characterized "as the continuous emergency of its own emergence" (rickards et al., 2014) captured in the idea of the 'long emergency' (kunstler, 2005) . there is growing experimentation with participative and deliberative designs adapted from innovative governance mechanisms, e.g., citizens assemblies for national dialogues on climate change as a method for engaged research. the focus is very much on facilitating the active participation of local communities and civil society actors to explore the relationship between probable, preferable, and plausible futures (ellyard, 2011) . faced by growing societal demand for urgent action on climate change, e.g., extinction rebellion and the global climate strikes inspired by greta thunberg, there is an opportunity for more meaningful engagement between science and society. yet this is not straightforward and poses very particular challenges in preparing u. diwekar, et al. resources, conservation & recycling 164 (2021) 105140 present and future generations of researchers and professionals with the tools that are fit for the purpose of addressing these challenges. it is increasingly claimed that we are living in a world that is so complex, interconnected and uncertain, and that many of the situations that professionals, for example, engineers, have to deal with should be seen and treated as 'wicked problems' (an early description of such problems was provided by rittel & webber in 1973 . andersson et al. (2014 talk about societal systems as wicked, featuring properties that make them a combination of complicated and complex, using their terminology. farrell & hooker (2013) talk about all realworld science and engineering problems as wicked and describe three sources of wickedness: (1) finitude of cognitive abilities, (2) complexity of the problems, and (3) normativity in problem understanding and resolution. again, we can take the example of reactive nitrogen to describe the wickedness of problems. reactive nitrogen encompasses biologically and radiatively active, and chemically reactive nitrogen compounds. on a global scale, human activities now create approximately two-fold more nr than natural continental ecosystems. in the united states, nr creation by human activity is about 5-fold larger than natural processes by: (1) the haber-bosch process to generate ammonia (nh3) for synthetic nitrogen fertilizer and industrial feedstocks, (2) the enhancement of biological nitrogen fixation (bnf) in crop cultivation (e.g., legumes), and (3) the combustion of fossil fuels. the first two anthropogenic activities form nr on purpose; the last one forms nr as an unwanted pollutant. comparing these three sources, haber-bosch nr is by far the largest (epa et al., 2011) . anthropogenic creation of nr provides essential benefits for humans-first and foremost, in meeting human dietary needs. a large fraction of the human population of the earth could not be sustained if fertilizers containing haber-bosch (nr) did not augment food production significantly. there are, however, costs associated with these benefits. essentially all of the nr created by human activities is lost to the environment, often with negative, unintended consequences. there it circulates between, and accumulates within, environmental systems and contributes to a number of adverse public health and environmental effects. in an educational context, the collaboration of haber (a chemist) and bosch (a chemical engineer) is often presented as a triumph of science, and the ideal model for technological advancement. few at the time could foresee the unintended consequences of nr proliferation; indeed, perhaps these consequences were not foreseeable-the fields of environmental science and engineering, ecology, and environmental chemistry were at best immature, and the widely perceived vastness of earth lent it an aura of immutability. as hardin points out in his seminal essay "the tragedy of the commons" (hardin, 1968) , the concept of "waste" is relatively modern; humankind evolved on earth where almost all natural cycles were closed-loop systems-wastes simply did not exist. in many ways, our education paradigm is just emerging from its siloed past in which insular disciplinary approaches reigned supreme. the need for a new paradigm of convergent education is now widely recognized (nsf, 2017) . so, what approaches are more useful for dealing with wicked problems? porter & córdoba (2009) describe three different approaches to systems thinking. functionalist approaches are made from a scientific, systems analytic perspective and with a reductionist worldview. interpretive approaches, on the other hand, view systems as "mental constructs of observers" and explicitly explore normative assumptions behind the problem definition. complex adaptive systems approach instead recognize systems as not only complex, but also "adaptive," characterized by self-organization, emergence, and bottom-up change and thereby suggest that conflicts may be ultimately unresolvable and that there may not be definitive solutions to sustainability problems -or even a "best way of getting things done." if real-world problems are actually wicked, the third approach should be more useful, and it is then a problem that professionals are not properly trained to deal with such contexts. jonassen (2000) , for example, argues that engineering students are primarily trained to solve "story problems", using functionalist approaches. this is likely a result of the predominant culture in science and engineering based on objectivism, positivism, and reductionism and with a lack of recognition and discussions of the usefulness of alternative views. in an attempt to guide engineering education towards approaches that recognize the wickedness of real-world problems, lönngren et al. (2017; ) developed a description of and educational elements for developing such approaches. the description contains five 'structural' aspects related to the ability to deal with wicked problems, that focus on the interconnection between problems parts, improvement measures and secondary problems, but also five 'referential' aspects that focus on local contexts and stakeholders and their spheres of influence as well as the importance of lack of information and uncertainties. these latter five try to capture a new type of relationship to problem-solving, or rather to the management of situations, as wicked problems do not really have solutions. our relationship to what we know -and more importantly, what we do not know -requires mechanisms and tools that prepare researchers and professionals to foster adaptive relationships to the dynamics of complex socio-ecological systems. the challenges addressed here are akin to those identified by bai et al. " to find ways to live and act without knowing the future…science needs to have closer and different relations with practice, …where science not only informs practice but also learns from practice" (bai et al., 2016) . at its most basic core, sustainable development is an effort by humans to make institutions and choices to ensure that the earth can support our continued presence for the indefinite future. this is a difficult challenge given the size of the human population, the level of human activity, and the finite size of the earth. this brings humanity to a situation where it has to learn to manage the earth out of simple necessity. this is a difficult challenge because: (1) there are multiple aspects that must be considered and acted on, including policy, economics, manufacturing, environmental impacts, and education to name but a few, and (2) the knowledge necessary to effectively conduct the management action comes with substantial uncertainty which can be specific to some aspect or systemic and is often time-dependent. further, the challenges to the earth system can fall into any of the four known categories, where the most difficult one is that unknown unknowns, i.e., issues that are not even known to exists. here we have explored the challenges and made an effort to frame approaches that can be reasonably expected to lead to effective solutions or least management approaches. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. the vision for civil engineering in 2025. based on the summit on the future of civil engineering -2025 sustainable engineering: principles and practice techno-ecological synergy: a framework for sustainable engineering strategic perspectives of corporate sustainability management to develop a sustainable organization sustainability science: managing risk and resilience for sustainable development probabilistic 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(dap): the case of intelligent speed adaptation. in decision making under deep uncertainties defining uncertainty: a conceptual basis for uncertainty management in model based decision support collective consumption services of individual consumption goods the role of scientists in statutory interpretation of the u.s. endangered species act in: evaluating process-based integrated assessment models of climate change mitigation. laxenbur, austria. international institute for applied systems analysis working paper uncertainty and the endangered species act the world bank databank climate change and the imagination new) species concepts, species delimitation and the inherent limitations of taxonomy accounting for ecosystem services in life cycle assessment, part ii: toward an ecologically based lca phylogeography of the california gnatcatcher (polioptila californica) using multilocus dna sequences and ecological niche modeling: implications for conservation geographic variation, null hypotheses, and subspecies limits in the california gnatcatcher: a response to mccormack and maley foundation under the grant cbet 1854519. key: cord-355171-oi3ezlsl authors: macintyre, c. r.; seale, h.; yang, p.; zhang, y.; shi, w.; almatroudi, a.; moa, a.; wang, x.; li, x.; pang, x.; wang, q. title: quantifying the risk of respiratory infection in healthcare workers performing high-risk procedures date: 2013-12-05 journal: epidemiol infect doi: 10.1017/s095026881300304x sha: doc_id: 355171 cord_uid: oi3ezlsl this study determined the risk of respiratory infection associated with high-risk procedures (hrps) performed by healthcare workers (hcws) in high-risk settings. we prospectively studied 481 hospital hcws in china, documented risk factors for infection, including performing hrps, measured new infections, and analysed whether hrps predicted infection. infection outcomes were clinical respiratory infection (cri), laboratory-confirmed viral or bacterial infection, and an influenza infection. about 12% (56/481) of the study participants performed at least one hrp, the most common being airway suctioning (7·7%, 37/481). hcws who performed a hrp were at significantly higher risk of developing cri and laboratory-confirmed infection [adjusted relative risk 2·9, 95% confidence interval (ci) 1·42–5·87 and 2·9, 95% ci 1·37–6·22, respectively]. performing a hrp resulted in a threefold increase in the risk of respiratory infections. this is the first time the risk has been prospectively quantified in hcws, providing data to inform occupational health and safety policies. healthcare workers (hcws) are at increased risk of healthcare-associated infections due to the front-line nature of their work. transmission of highly infectious diseases from infected patient to other patients and hcws occurs constantly in hospitals and healthcare centres and has been well documented [1] [2] [3] . although hcws are aware of infection control measures, low levels of compliance with standard precautions by this group are frequent [4, 5] . hcws are less willing to adhere to infection-control practices when they work for extended hours [6] , with probable reasons for low compliance being insufficient time, scarcity of equipment, lack of knowledge and low perception of risk [5] . the three principal routes of transmission of respiratory pathogens are contact transmission (direct and indirect), droplet transmission, and airborne transmission. for any pathogen, more than one transmission route may occur, but many pathogens are known to be transmitted by one predominant mode. in droplet transmission, pathogens or droplets which are larger than 5 μm, such as influenza virus and bordetella pertussis are transmitted from an infected patient to hcws through breathing, talking, coughing, sneezing, as well as through performing high-risk procedures (hrps) [2, 7, 8] . however, influenza virus has also been documented to be transmitted by the airborne route, which results in infectious particles being present in the air for longer periods of time [9] [10] [11] [12] . respiratory infectious diseases, even those with limited airborne transmission, are more likely to be transmitted from patients to hcws during hrps such as suctioning and intubation which generate respiratory aerosols [13] . many studies suggest that both invasive and non-invasive procedures are likely to increase the probability of hcws being infected [13, 14] . some studies have reported that non-invasive positive pressure ventilation (nppv) can be a risk of severe acute respiratory syndrome (sars) transmission to hcws [15] [16] [17] . cardiopulmonary resuscitation, manual ventilation, bronchoscopy and suctioning have also been documented to increase the risk of hcws being infected with sars and tuberculosis (tb) [18] [19] [20] [21] , while tracheal intubation has been significantly associated with risk of sars transmission to hcws [17] . while it has been well documented that tb and sars can be transmitted to hcws during aerosol-generating procedures, there are some data suggesting h1n1 can transmit via such procedures [13] . seasonal influenza also causes outbreaks in healthcare settings [22] . hcws are one of the most vulnerable groups likely to be infected with influenza infection in acute-care facilities due to the high exposure rates in such settings [23] . an attack rate of nosocomial influenza could reach 11-59% in hcws in a healthcare environment [24] . as such, hcws are a priority group for preventive strategies such as influenza vaccination [25, 26] . although various guidelines and policies for infection control measures are implemented in healthcare settings worldwide, the risk of transmission of infectious diseases while performing hrps has not been well quantified. this study aims to describe the range of exposure to hrps in hcws and to quantify the risk of respiratory infections occurring in hcws who perform hrps. we prospectively studied 481 hospital hcws from wards including emergency and respiratory wards from nine hospitals in beijing, china over a 5-week period from 1 december 2008 to 15 january 2009. these 481 subjects were a control group in a larger study [27] . the hospital wards were selected as high-risk settings in which repeated and multiple exposures to respiratory infections are expected. participants were hospital hcws aged 518 years and who were provided with written information about the study. staff who agreed to participate provided informed consent and a copy of the information sheet with the participants' initials was retained as documentation [27] . the study protocol was approved by the institutional review board and human research ethics committee of the beijing ministry for health. participants were asked to record on a daily basis whether they had performed one of the following: provision of nebulizer medications, suctioning, intubation, aerosol-generating procedures and chest physiotherapy. the following information was also collected: number of hours worked, estimated number of daily contacts with patients, number of daily contacts with influenza-like illness (ili) patients, and hand-washing adherence. the use of personal protective equipment such as gloves, gowns, eye shields, foot/hair covers was documented by study participants in a daily selfreport diary, and details of clinical and demographics were also recorded. all study participants were followed up for a period of 31 days and monitored daily for the onset of respiratory symptoms. if any symptom developed, combined nasal and throat swabs (double rayon-tipped, plastic-shafted swab) were taken and tested for respiratory viral or bacterial infection (fig. 1) . the nose and throat swabs were tested at the laboratories of the beijing centres for disease control and prevention. viral dna⁄rna was extracted from 300μl of each respiratory specimen using the viral gene-spin ™ kit (intron biotechnology inc., korea) according to the manufacturer's instructions [27] . we tested nose and throat swabs for the following: adenoviruses, human metapneumovirus (hmp), coronaviruses 229e/nl63 and oc43/hku1, parainfluenza viruses 1, 2 and 3, influenza viruses a and b, respiratory syncytial virus (rsv) a and b, and rhinovirus a/b by nucleic acid testing using a commercial multiplex polymerase chain reaction (pcr), with the seeplex® rv12 detection kit (seegen inc., korea). details of laboratory methods have been described in a previous publication [27] . we also tested for bacterial colonization. a multiplex pcr (seegen inc.) was used to detect streptococcus pneumoniae, mycoplasma pneumoniae, b. pertussis, legionella spp, chlamydophilia and haemophilus influenza type b. after preheating at 95°c for 15 min, 40 amplification cycles were performed under the following conditions in a thermal cycler (geneamp pcr system 9700, applied biosystems, usa): 94°c for 30 s, 60°c for 1·5 min, and 72°c for 1·5 min. amplification was completed at the final extension step at 72°c for 10 min. the multiplex pcr products were visualized by electrophoresis on an ethidium bromide-stained 2% agarose gel. the controls represent hcws in their usual working conditions, without any interventions. this study is a post-hoc analysis of data collected during the primary trial on hrps in the control arm. the prospective data collection and measurement of clinical endpoints in a group of hcws working under usual conditions afforded the opportunity to measure the association of incident infection with hrps. the primary outcomes of the study were: clinical respiratory infection (cri)presence of two or more respiratory symptoms or one respiratory symptom (e.g. cough, runny nose, shortness of breath, sore throat) and one systemic symptom (e.g. fever, lethargy, chills); laboratory-confirmed viral infection (influenza a and b, parainfluenza, rsv, coronavirus, hmp virus, adenovirus, rhinovirus); laboratoryconfirmed viral or bacterial infection (and of the above viruses or a bacterial infectionpertussis, hib, pneumococcus, mycoplasma, legionella); and influenza a or b (categorized as 'influenza' if either strain were present). the outcomes were tested against predictor variables such as age, education, category of hcw, influenza vaccination uptake, and performance of hand washing and hrps. the total number of hrps performed over the study period was calculated. a binary variable defining whether or not hcws performed any hrps during the study period was created and analysed with other predictor variables against incident infection during the study period. poisson regression was used for the analysis of the outcomes, using egret software (cytel, usa). a p value of 40·05 was considered significant in the analysis. a total of 481 hcws were recruited into the study. demographic characteristics of study participants are described in table 1 . of these, 369 (76·7%) were females; and 52% (252/481) of the participants were aged 535 years. the breakdown of participants by area was: respiratory ward 75 (16%); emergency department 72 (15%); respiratory clinic 16 (3·3%); paediatric department 15 (3·1%); infection fever clinic 6 (1·2%); and other wards 297 (62%). of the 481 hcws, 236 (49%) were doctors and 245 (51%) were nurses and others. during the study period, the uptake of influenza vaccine in hcws was low in both 2007 and 2008 (19·3% and 18·1%, respectively). fifty-six (11·6%) out of 481 hcws performed at least one hrp during the study, with the most common activity being airway suctioning (66%, 37/56). figure 2 shows the number of days on which a hcw reported performing a hrp. thirty-four (61%) out of 56 hcws, reported performing a hrp more than once during the study period. the aggregated number of days a hrp was performed was 264. in addition, hcws on the respiratory ward (33%) were more likely to perform hrps than those in the emergency department (16·7%). nurses and other hcws (16%, 39/245) were significantly more likely than doctors (7%, 17/236) to perform hrps (p < 0·01). the weekly incidence of cri was 18/1000 hcws, for viral or bacterial infection, 16/1000; for any viral infection, 6/1000; and for influenza, 2·5/1000. hcws who performed hrps had a significantly higher risk of cri [relative risk (rr) 2·5, 95% (ci) 1·3-6·5, p < 0·01) and laboratory-confirmed viral or bacterial infection (rr 2·6, 95% ci 1·4-5, p < 0·01) than those who did not perform hrps (table 2) . by poisson regression analysis, adjusting for other variables, only hrps determined the risk of an infection outcome, as shown in tables 3-5. the relative risk for cri in hcws who performed a hrp was 2·9 (95% ci 1·42-5·87, p < 0·01) ( table 3 ). the rr for a laboratory-confirmed pathogen (viral or bacterial) in symptomatic hcws was 2·9 (95% ci 1·37-6·22, p = 0·01), in those who performed a hrp (table 4 ). for the outcome of any respiratory viral pathogen, the rr was 3·3 (95% ci 1·01-11·02, p = 0·05) ( table 5 ). hand washing, influenza vaccination and use of surgical or cloth face masks did not affect the risk of infection outcomes. we also tested for other variables, e.g. number of hours worked, number of patients the hcw was in contact with during the study period, and number of contacts with patients with ili; however, none of these had a significant association with infection outcomes. there were no significant association between laboratory-confirmed influenza and hrps (data not shown); but the numbers of influenza-positive cases were low (six cases) in the study. we examined the association between hrp and the risk of respiratory infection in hcws. our findings demonstrated that hcws who perform a hrp have a greater risk of respiratory infections than those who did not perform a hrp. this is consistent with observational findings of other studies [15, 16, 18, 21, 28] ; however, we have been able to quantify the magnitude of this risk in our study as a threefold increase in risk. many factors influence the nosocomial spread of infectious diseases, and hcws are the initial point of contact with patients in both acute and long-term healthcare settings. our findings suggest that targeted interventions and policies are warranted to offer greater protection to hcws who perform hrps. this has occupational health and safety implications for hcws routinely engaged in hrps. more than 10% of hcws performed a hrp during a 1-month period, and the majority of those performed more than one hrp. this suggests that interventions to reduce transmission of respiratory infections may be more efficient if targeted to hcws performing hrps. there may be certain settings such as emergency wards, intensive-care units and respiratory wards where hrps are more commonly performed, making these important targets for interventions. there are some limitations to our study. our study was conducted in china, so the results, particularly around frequency of performing hrps, may not be generalizable to different hcw populations in other contexts. there are variations in infection control practices from hospital to hospital, even within china. however, the quantification of risk for hcws who perform hrps has implications for hcws everywhere. the fact that this was a control group in a larger trial is a strength, rather than a limitation, in that this group had rigorous follow-up and documentation of incident infection as well as risk factors (including hrps). this provides more robust data than, for example, an observational study such as a case-control study, because it was prospective and measured infection in a group that went about usual practice. to date, there is much policy debate and direction about hrps, but no data whatsoever to inform the actual risk associated with hrps. despite the limitations of the analysis, we believe that the data we present in this paper are a useful addition to current knowledge. hcws are at higher risks of contracting respiratory infections, and are subject to generic guidelines around infection control. these include hand hygiene before and after the patient care; wearing of personal protective equipment such as gowns, goggles, gloves, n95 respirators or surgical masks; presence of minimum number of hcws when performing a procedure in a single room; and in addition, it is recommended that such procedures should be performed in a sterilized room [13, 29, 30] . we have shown in two large randomized controlled trials that the risk of respiratory infection in hcws can be reduced with the use of n95 respirators [27, 31] . we also show that in highrisk wards, targeted use in situations of self-identified risk, such as when performing hrps or barrier nursing a patient, is less effective than continuous use of a respirator in that ward while on shift [31] . this suggests that hcws are unable to identify all situations of risk when left to decide whether or not they should wear a respirator. this is the first time the risk of hcws performing hrps has been prospectively quantified, and this finding has important occupational health and safety implications for hcws, particularly in settings such as emergency and respiratory wards where hrps are frequently performed. the traditional approach to hospital infection control has not consistently categorized staff in terms of whether they perform hrps in order to apply guidelines. we found that the majority (89%) of hcws do not perform hrps. this proportion may vary in different country, hospital and ward settings; our study suggests that categorizing hcws by whether or not they perform hrps in their work may serve as a useful classification in order to tailor guidelines appropriately or increase the attention to adherence with existing guidelines. the minority of hcws performing hrps should receive optimal respiratory protection, and high-risk wards should have guidelines in place to minimize the risk to hcws. transmission of bacterial infections to healthcare workers during intubation and respiratory care of patients with severe pneumonia the 2003 sars outbreak and its impact on infection control practices healthcare workers and health care-associated infections: knowledge, attitudes, and behavior in emergency departments in italy practices and an assessment of health care workers' perceptions of compliance with infection control knowledge of nosocomial infections compliance with universal precautions among health care workers at three regional hospitals transmission of influenza virus via aerosols and fomites in the guinea pig model guideline for isolation precautions: preventing transmission of infectious agents in health care settings high humidity leads to loss of infectious influenza virus from simulated coughs detection of infectious influenza virus in cough aerosols generated in a simulated patient examination room airborne transmission of influenza: implications for control in healthcare and community settings influenza virus in human exhaled breath: an observational study interim guidance on infection control measures for 2009 h1n1 influenza in healthcare settings, including protection of healthcare personnel should noninvasive ventilation be considered a high-risk procedure during an epidemic? transmission of severe acute respiratory syndrome during intubation and mechanical ventilation illness in intensive care staff after brief exposure to severe acute respiratory syndrome aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review the transmission of tuberculosis in confined spaces: an analytical review of alternative epidemiological models possible sars coronavirus transmission during cardiopulmonary resuscitation a practical approach to airway management in patients with sars occupational tuberculous infections among pulmonary physicians in training influenza in the acute hospital setting requiring influenza vaccination for health care workers: seven truths we must accept vaccination against classical influenza in health-care workers: self-protection and patient protection acip recommendations: introduction and biology of influenza, 2010-11 influenza prevention & control recommendations world health organisation a cluster randomized clinical trial comparing fit-tested and non-fit-tested n95 respirators to medical masks to prevent respiratory virus infection in health care workers which preventive measures might protect health care workers from sars? infection prevention and control during health care for confirmed, probable, or suspected cases of pandemic (h1n1) 2009 virus infection and influenza-like illnesses epidemic and pandemic prone acute respiratory diseases -infection prevention and control in health care a randomised clinical trial of three options for n95 respirators and medical masks in health workers dr seale is in receipt of an nhmrc australian-based public health training fellowship (1 012 631) . professor macintyre receives funding from influenza vaccine manufacturers gsk and csl biotherapies for investigator-driven research. dr seale has received funding from sanofi pasteur, gsk and csl biotherapies for investigator-driven research and for conference presentations. key: cord-028564-sltofaox authors: gutiérrez-spillari, lucia; palma m., geovani; aceituno-melgar, jorge title: obesity, cardiovascular disease, and influenza: how are they connected? date: 2020-07-06 journal: curr trop med rep doi: 10.1007/s40475-020-00207-0 sha: doc_id: 28564 cord_uid: sltofaox purpose of review: to better understand the impact of obesity and cardiovascular diseases on influenza a infection. recent findings: this infection could have detrimental outcomes in obese patients with cardiovascular diseases, such as an increased risk, length of hospitalization, disease severity, morbidity, and mortality. nevertheless, there also might be some cardioprotective benefits associated with influenza vaccination, such as a reduced mortality, hospitalization, and acute coronary syndromes, in patients with coronary heart disease and/or heart failure. summary: obesity negatively impacts immune function and host defense. recent studies report obesity to be an independent risk factor for increased morbidity and mortality following infection. obese patients might need special considerations in the treatment; however, there is not enough evidence to fully comprehend the mechanisms behind the reduced immunocompetence when influenza a infection occurs. future studies should focus on special consideration treatments when the patients have not been vaccinated and have cardiovascular diseases. this review focuses on how obesity and cardiovascular disease impact influenza response. retrospective studies demonstrate that during the 2009 h1n1 pandemic, obesity was identified as a risk factor for hospitalization, mechanical ventilation, and mortality upon infection. these data must be highlighted since it is projected that nearly 50% of the worldwide population is going to be obese by 2050. several case studies have identified possible effects of obesity on viral replication in the deep lung, progression to viral pneumonia, and prolonged viral shedding [1] . therefore, management of the influenza infection in this at-risk population has to have special consideration given that they may not respond optimally to vaccination [2] . excessive fat accumulation that results in obesity impairs health for adults [3] . its low-grade chronic inflammatoryinduced state negatively impacts immune function and host defense [2] , as shown during the 2009 influenza a virus h1n1 pandemic, where obesity resulted to be an independent risk factor for severe disease, hospitalization, mechanical ventilation, and mortality upon infection [1] . it is well known that influenza a virus infection is characterized by fever, myalgia, rhinorrhea, sore throat, and sneezing. these symptoms peak 3-5 days post-infection, with viral shedding peaking at days 2-3. usually, it is limited to the upper respiratory tract; however, in severe cases, the lower respiratory tract, including the lungs, can be affected and often requires hospitalization. this progression is more common in obese patients, leading to diminish infection resolution when compared with non-obese patients [1] . obesity also plays a role in the outcome of critical complications from influenza this article is part of the topical collection on metabolism in tropical medicine a/pdmh1n1 infection and is associated with longer mechanical ventilation for severe acute respiratory distress syndrome and shock [4] . a higher body mass index (bmi) and metabolic syndrome in patients with influenza have shown an increased risk and length of hospitalization [4] [5] [6] , increased disease severity, morbidity, and mortality during lower respiratory tract infections. this might be explained in part by increased lung permeability during infection, found in mice studies. obese mice have an increased protein leakage from the lung into the bronchoalveolar lavage fluid when compared to lean mice. additionally, lung edema and oxidative stress are also increased, which emphasizes the multiple etiologies of increased lung pathology in the obese host and the impairment in wound repair [1, 4] . the obesogenic state can also affect the influenza a virus evolution. it is well known that obese individuals are malnourished besides their excess in fat; they might also present nutrient deficiencies, such as vitamins [7] , minerals, and trace elements [8] . there are a variety of mechanisms by which nutritional imbalances could alter within-host viral evolution [8] . studies have shown that such imbalances prolong infections, delay clearance, and increase shedding (42% longer than non-obese) [9] , all of which potentially increase viral transmission [1] . in addition to the decreased immunocompetence mechanisms, other potential factors might contribute to its increased susceptibility to infection in the hospital setting. some examples, which are underlying diseases that affect mobility, can also increase risk for skin problems, prolonged visits at hospitals and nosocomial infections, alteration in the pharmacokinetics of some drugs, and an increased susceptibility to postsurgery infections [2] . thus, it is a complex problem that needs further evidence to develop better treatments for this increasing population. obesity causes a chronic state of inflammation in a generalized and constant way with negative effects on immunity. obese people have delayed immune responses to influenza virus infection and experience slower recovery from the disease. in addition, the efficacy of the treatment and the vaccine is reduced in this population causing an alteration of the viral life cycle and, coupled with an already weakened and delayed immune response, leading to a more serious condition. poor initial and adaptive responses to infection and vaccination create an impaired ability to respond appropriately to infection. the efficacy of the vaccine may decrease in obese humans; however, more studies are needed to better understand how the obese state affects infection control [1] . previous studies suggest that the severity of influenza virus infection is multifactorial and may be related to lung spread and repair, the formation of extracellular concentrates of neutrophils at the lung level; however, this mechanism in individuals is unknown [10] . the efficacy of the vaccine in human groups has shown that initial seroconversion rates are high in the obese population, but that over time there is a greater decrease in efficacy than that observed in non-obese populations [11] . influenza vaccine as a method of prevention is formulated each year, typically containing both influenza a and b. a study conducted in 2013-2015 aimed at evaluating whether obesity was associated with an increased risk of influenza for influenza and influenza-like illness among vaccinated obese and nonobese adults, finding that, among the obese, 9.8% had confirmed influenza or influenza-like illness compared with 5.1% of healthy weight participants. compared with the vaccinated healthy weight, obese participants had twice the risk of developing influenza or influenza-like illness (relative risk = 2.01, 95% ci 1.12, 3.60, p = 0.020); therefore, in this risk group, in the same way, vaccination is very important [12] . although it appears that in high-risk groups, such as the obese and overweight population, vaccination may not provide optimal protection, and because of the growing trend of obesity worldwide, the efficacy of the vaccine should be improved [10] . among cardiovascular disease patients, there is compelling evidence that shows lower risk of major adverse cardiovascular events, reduced hospitalization, and mortality [13] [14] [15] , being the greatest treatment effect was seen among the highestrisk patients with more active coronary disease [15] . the recent recommendation advocates the priority of vaccination against influenza in obese patients; a vaccination program should be fully evaluated in obese adults. high-dose vaccines designed to vaccinate people over 65 can also be used in the obese population [9, 10] . in the twentieth century during influenza epidemics, there has been an excess of mortality from cardiovascular disease [16] . a recent study that included 364 hospitalizations for acute myocardial infarction demonstrated an increased risk of acute myocardial infarction within one week after influenza virus infection to a risk that was six times higher than the risk during the year before or after the onset of infection [17] . cardiovascular complications associated with influenza infection include myocarditis, pericardial effusion, myopericarditis, right and left ventricle dysfunction, myocardial infarction, heart failure, stroke, and circulatory failure due to septic shock [13, [18] [19] [20] . the risk of myocardial infarction after mild respiratory infection returns to baseline within approximately 5 weeks, but in the case of pneumonia complicated by sepsis the risk persists up to 10 years after the infection [16] [21] . infectious agents (including influenza virus) have been implicated in the etiology of atherosclerosis [22] . there have been described several mechanisms by which influenza increases the risk of cardiovascular events; they may be related to pro-inflammatory mediators, sympathetic stimulation, and the activation of the coagulation cascade [19] . according to the fourth universal definition of myocardial infarction, there are 5 types of myocardial infarction based on clinical, electrocardiographic, and laboratory evaluation [23] . influenza infection can trigger type 1 and type 2 myocardial infarctions [16] . type 1 myocardial infarction is defined as myocardial ischemia caused by atherothrombotic coronary artery disease, and it is usually precipitated by atherosclerotic plaque disruption that can be rupture or erosion [23] . it is important to remember that atherosclerotic plaques also contain inflammatory cells, and pro-inflammatory cytokines, such as interleukins 1, 6, and 8, and tumor necrosis factor α are generated as a response of infection. these inflammatory cytokines can activate inflammatory cells in atherosclerotic plaques [16] [24] . acute influenza infection is associated to a procoagulant state that increases the risk of coronary thrombosis at sites of plaque disruption [16] [25, 26] . infection with influenza virus is associated with expression of genes that have been linked to platelet activation: h1n1 exposure increases platelet gene expression signature, which is associated with myocardial infarction [25] . type 2 myocardial infarction might be considered with a rise and/or fall of cardiac troponin values and evidence of an imbalance between myocardial oxygen supply and demand unrelated to coronary thrombosis. [23] . influenza infection produces a systemic inflammatory response with a resulting increase in heart rate and shortens the filling time during diastole compromising in that way, the coronary blood supply. if septic shock occurs, it may have a substantial adverse effect on coronary perfusion. in older patients with chronic coronary plaques, systemic inflammation causes cardiac metabolic mismatch increasing the risk of myocardial infarction [16, 18] . influenza infection is also associated with increased mortality in patients with heart failure [27] and is vulnerable to influenza-associated complications [28] [29] . this type of patients has limited cardiac and respiratory reserves and may not tolerate the metabolic demand and hypoxemia, exacerbating underlying cardiac disease probably due to an increased sympathetic nervous system activity, hypoxemia, and renal dysfunction that can lead to volume overload [28] . in a healthy heart, severe acute influenza infection produces pro-inflammatory cytokine level elevations that can cause acute myocarditis [28] [18] , characterized by a broad spectrum of symptoms that go from asymptomatic courses to signs of myocardial infarction to devastating illness with cardiogenic shock [30] [31] . myocarditis often results from common viral infections and post-viral immune-mediated responses [30] . in acute myocarditis, there is a high incidence of wall motion abnormalities. during influenza epidemics, 15% of the patients admitted to a military hospital with influenza infection had wall motion abnormalities on echocardiogram [18] . this becomes important, due to the fact that the myocardium inflammatory disease is regarded as a precursor of dilated cardiomyopathy [30] [32] . the electrocardiographic findings in patients with myocarditis range from nonspecific t-wave and st segment changes to st segment elevation resembling an acute myocardial infarction; supraventricular and ventricular arrhythmias can also be present. electrocardiographic findings that are related to poor clinical outcome include a qtc prolongation at 440 ms, an abnormal qrs axis, and ventricular ectopic beats [30] . a recent study developed to evaluate the incidence and hemodynamic consequences of right ventricular and left ventricular dysfunction in patients with h1n1 infection demonstrated that on admission 72% had abnormal ventricular function (46% had isolated left ventricular abnormalities and 39% had isolated right ventricular dysfunction) and 14% had biventricular dysfunction. on the follow-up, right ventricular function tended to worsen during hospitalization, but left ventricular function tended to normalize. however, patients with ventricular dysfunction needed more aggressive therapy and of rescue ventilatory strategies, such as inhaled nitric oxide, prone positioning, and extracorporeal membrane oxygenation [18] . during influenza epidemics, hospitalizations for cerebrovascular diseases increase [33] . an increase in incidence of ischemic stroke within 2 weeks after influenza infection has been suggested [34, 35] . protein c pathway and endogenous fibrinolysis are mechanisms associated with cerebrovascular ischemia and influenza infection [19] . influenza infection develops a prothrombotic state by increasing tissue factor expression and decreases fibrinolytic capacity by increased plasminogen-activator inhibitor-1 (pai-1) expression. this results in an unbalance between coagulation and anticoagulant pathways [36] . as in myocardial infarction, the relationship between systemic inflammation and stroke pathophysiology has shown that stroke often occurs in a pre-existing state of inflammation due to atherosclerosis, obesity, or infection [37] . the sixth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice recommend that annual influenza vaccination can be considered in patients with established cardiovascular disease (class iib, level c) [38] , based on the fact that the risk of a cardiovascular event (myocardial infarction or stroke) is more than four times higher after a respiratory tract infection, with the highest risk in the first 3 days after infection [39] . there have been developed several studies that demonstrate that influenza vaccination reduces mortality, hospitalization, and acute coronary syndromes in patients with coronary heart disease and/or heart failure [13] . the mechanisms by which acute inflammation affect the risk of vascular events include the following: endothelial dysfunction, procoagulant state, and inflammatory changes in atherosclerotic plaques [39, 40] . it is also known that persistent systemic inflammatory activity is a risk of factor for cardiovascular disease, and higher interleukin-6 blood levels increase cardiovascular mortality at one year after pneumonia infection [41] . this systemic inflammatory response can be reduced by vaccination [13] . when estimating the cost and benefit of interventions to prevent pneumonia, the association of pneumonia with cardiovascular disease risk should also be considered [40] . patients with chronic heart failure are vulnerable to influenza-related complications (including secondary infections, such as pneumonia and acute heart failure exacerbations). recently, the paradigm-hf trial assessed associations between receiving influenza vaccine and cardiovascular death or heart failure hospitalizations, all-cause hospitalizations, and cardiopulmonary or influenza-related hospitalizations, concluding that vaccination was associated with reduced risk for death [42] . there have been described two possible mechanisms by which influenza vaccination may reduce cardiovascular events: unspecific and specific effects [13] . the unspecific mechanism is based on the fact that influenza infection causes a systemic inflammatory response, endothelial dysfunction, and a procoagulant state. these factors have negative effects on patients with previous cardiovascular diseases, such as ischemic heart disease and heart failure, causing acute heart failure, pulmonary edema, or destabilization of chronic ischemic heart disease, leading to myocardial infarction or sudden cardiac death [13] [15] . influenza vaccination reduces the risk fig. 1 possible cardioprotective mechanisms of influenza vaccination of infection and inflammation by decreasing the secretion of pro-inflammatory mediators, such as cytokines (that cause reduced myocardial contractility) and metalloproteinases (that cause adverse cardiac remodeling and plaque rupture); influenza vaccination also causes inhibition of platelet activation and cloth formation [13] [43] . the specific mechanism takes into account the immunological properties of the vaccine. the protective effect of the influenza vaccine has been demonstrated in multiple studies. to explain the pleiotropic effect of the influenza vaccine, the "antigen mimicry" between atherothrombotic plaque and influenza virus has been proposed [22] . it has also been proposed that there is an autoimmune "cross-reaction" between influenza and atherosclerosis [13] [44] . figure 1 summarizes the possible cardioprotective mechanism of influenza vaccination [13] . it is well studied that obese patients can develop cardiovascular diseases; however, it is less known that the lowinflammatory chronic state might affect host defense and immune cell dysfunction and infections, such as influenza a, could have detrimental outcomes in such patients, such as an increased risk, length of hospitalization, disease severity, morbidity, and mortality. cardiovascular diseases, such as ischemic heart disease and heart failure combined with influenza a infection, can trigger acute heart failure exacerbations that increase the overall mortality in a hospitalized setting. cardiovascular complications associated with influenza infection include myocarditis, pericardial effusion, myopericarditis, right and left ventricle dysfunction, myocardial infarction, heart failure, stroke, and circulatory failure due to septic shock. there have been described several mechanisms by which influenza increases the risk of cardiovascular events; they might be related to pro-inflammatory mediators, sympathetic stimulation, and activation of the coagulation cascade. while influenza vaccination is associated with a significant reduction in all-cause mortality risk in patients with heart failure, this cardioprotective mechanism may not function as intended in the obese population since they do not always respond optimally to vaccination. therefore, in an effort to prevent these complications and in the absence of special consideration treatments for this population, we strongly suggest a weight-loss approach. future studies should focus on developing targeted treatments that can combat the reduced immunocompetence that excess adiposity causes to the patient. particular interest, published recently, have been highlighted as: • of importance impact of obesity on influenza a virus pathogenesis, immune response, and evolution the impact of obesity on the immune response to infection immunity to influenza: impact of obesity high body mass index as a risk factor for hospitalization due to influenza: a case-control study epidemiology of severe influenza outcomes among adult patients with obesity in detroit association between vitamin deficiency and metabolic disorders related to obesity rna virus evolution, population dynamics, and nutritional status obesity increases the duration of influenza a virus shedding in adults obesity outweighs protection conferred by adjuvanted influenza vaccination obesity is associated with impaired immune response to influenza vaccination in humans increased risk of influenza among vaccinated adults who are obese cardioprotective effect of influenza and pneumococcal vaccination in patients with cardiovascular diseases influenza vaccines for preventing cardiovascular disease association between influenza vaccination and cardiovascular outcomes in high-risk patients acute infection and myocardial infarction acute myocardial infarction after laboratoryconfirmed influenza infection myocardial dysfunction during h1n1 influenza infection beneficial effects of vaccination on cardiovascular events: myocardial infarction, stroke, heart failure. cardiol cardiovascular manifestations associated with influenza virus infection severe infections and subsequent delayed cardiovascular disease influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies fourth universal definition of myocardial infarction diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary tree: a histopathologic study of patients dying of acute myocardial infarction gene expression profiles link respiratory viral infection, platelet response to aspirin, and acute myocardial infarction. schulz c, editor sepsis, thrombosis and organ dysfunction relation of concomitant heart failure to outcomes in patients hospitalized with influenza association of influenza-like illness activity with hospitalizations for heart failure: the atherosclerosis risk in communities study decreased immune responses to influenza vaccination in patients with heart failure update on myocarditis current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european society of cardiology working group on myocardial and pericardial diseases management of myocarditis-related cardiomyopathy in adults influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly temporal relationship between influenza infections and subsequent first-ever stroke incidence influenza-like illness as a trigger for ischemic stroke influenza and stroke risk: a key target not to be missed? influenza virus infection aggravates stroke outcome european guidelines on cardiovascular disease prevention in clinical practice. the sixth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts. developed with the special contribution of the european association for cardiovascular prevention & rehabilitationg ital cardiol (rome) risk of myocardial infarction and stroke after acute infection or vaccination association between hospitalization for pneumonia and subsequent risk of cardiovascular disease inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis influenza vaccination in patients with chronic heart failure: the paradigm-hf trial from vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part ii influenza vaccine as prevention for cardiovascular diseases: possible molecular mechanism publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-339341-c2o42b5j authors: matibag, gino c.; igarashi, manabu; la porte, ron e.; tamashiro, hiko title: advocacy, promotion and e-learning: supercourse for zoonosis date: 2005-09-01 journal: environmental health and preventive medicine doi: 10.1007/bf02897702 sha: doc_id: 339341 cord_uid: c2o42b5j this paper discusses the history of emerging infectious diseases, risk communication and perception, and the supercourse lectures as means to strengthen the concepts and definition of risk management and global governance of zoonosis. the paper begins by outlining some of the key themes and issues in infectious diseases, highlighting the way which historical analysis challenges ideas of the ‘newness’ of some of these developments. it then discusses the role of risk communication to public accountability. the bulk of the paper presents an overview of developments of the internet-based learning system through the supercourse lectures that may prove to be a strong arm for the promotion of the latest medical information particularly to developing countries. we live in a dangerous world. yet it is also a world far safer in many ways than it has ever been. diseases that only recently were mass killers have been all but eradicated. advances in public health, medicine, environmental regulation, food safety, and worker protection have dramatically reduced many of the major risks we faced just a few decades ago. governance refers to how societies structure responses to the challenges they face. analyses of emerging and re-emerging infectious diseases (eids) have made it clear that national and international societies are confronting increased microbial threats (1) (2) (3) . whether the focus is bioterrorism, hiv/aids, severe acute respiratory syndrome (sars), or avian influenza, germs increasingly pose dangers to human societies. germ governance concerns how societies, both within and beyond national borders, structure their responses to pathogenic challenges (4) . the global nature of the microbial threat requires that governance address the borderless challenges presented by infectious diseases. the emergence of sars is a major global public health threat that requires a coordinated global response in terms of continued and improved surveillance and of research into a number of important public health issues. while much has been learnt about sars since it was brought to international attention in march 2003, there remain many unanswered questions about where it came from, how it spreads, and the effectiveness of public health and other measures employed to control the disease. the overall goal of the "supercourse for zoonosis" is to show the most recent development in the knowledge of sars and other zoonotic diseases such as avian influenza and bovine spongiform encephalopathy (bse), inter alia, which have significant global impact not only on health but also on the economy. the specific objectives of "supercourse for zoonosis" are to develop a set of educational materials for the control of zoonotic diseases, to disseminate them effectively via the internet, to facilitate their use in the prevention and control of the diseases, and to promote human health while minimizing their economic impact. in the light of all these advances, it is most appropriate that all countries remain vigilant, not only with sars, but also to all zoonotic diseases that may toll the productivity of human, animal, ecological, and economical sectors of our daily lives. emerging infections (eis) can be defined as infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range (5) . re-emerging and resurging infections are those that existed in the past but are now rapidly increasing either in incidence or in geographical or human host range (2) . the term deliberately emerging refers to both naturally occurring microbial agents such as anthrax (3) , and to bioengineered microorganisms such as those created by the insertion of genetic virulence factors that produce or exacerbate disease. about 15 million (more than 25%) of 57 million annual deaths worldwide are estimated to be related directly to infectious diseases; this figure does not include the additional millions of deaths that occur as a consequence of past infections (for example, streptococcal rheumatic heart disease), or because of complications associated with chronic infections, such as liver failure and hepatocellular carcinoma in people infected with hepatitis b or c viruses (6) . the burden of morbidity (ill health) and mortality associated with infectious diseases falls most heavily on people in developing countries (7), and particularly on infants and children (about three million children die each year from malaria and diarrheal diseases alone (6)). in developed nations, infectious disease mortality disproportionately affects indigenous and disadvantaged minorities (8) . bacteria and viruses existed long before humans evolved, and bacterial diseases probably co-evolved with each species. many bacterial diseases that we see today have been around for as long as we have, others may have developed later. many examples can be cited in addition to the black death and the 1918 influenza pandemic, such as certain biblical pharaonic plagues and the unidentified plague of athens, which heralded the end of greece's golden age (9) . importation of smallpox into mexico caused 10-15 million deaths in 1520-1521, effectively ending aztec civilization (10, 11) . with the beginning of microbiology, pathogens became apparent. the establishment of the germ theory and the identification of specific microbes as the causative agents of a wide variety of infectious diseases (12) (13) (14) led to enormous progress, notably in the development of vaccines and ultimately of antimicrobials (14) . by the 1950s, which had witnessed the widespread use of penicillin, the development of polio vaccines and the discovery of drugs for tuberculosis, complacency had set in (15) , and in 1967, the us surgeon general stated that the war against infectious diseases has been won (16) . some experts remained skeptical, aware of the current lessons from history. they were less persuaded by successes than alarmed by failures, such as the lack of progress against infections in the developing world and the global spread of antimicrobial resistance. the emergence of aids led to renewed appreciation of the inevitability and consequences of the emergence of infectious diseases (17) (18) (19) (20) (21) (22) (23) . in the past 25 years, some of the factors that resulted in aids have also led to the re-emergence of historically important diseases such as cholera, diphtheria, trench fever and plague. many re-emergences have been catalyzed by wars, loss of cohesion, and natural disasters such as earthquakes and floods, indicating the importance not only of microbial and viral factors, but also of social and environmental determinants (17) (18) (19) (20) (21) (22) (23) . these infections are those that have not previously been recognized in man. many diverse factors contribute to their emergences (table 1) . numerous microbial, host and environmental factors interact to create opportunities for infectious agents to evolve into new ecological niches, reach and adapt to new hosts, and spread more easily between them. at the end of 2004, an estimated 39.4 million (range 35.9-44.3 million) people around the world were living with hiv, including the 4.9 million (range 4.3-6.4 million) people who acquired hiv in 2004. the epidemic claimed an estimated 3.1 million (range 2.8-3.5 million) lives in 2004. sub-saharan africa remains the most affected region and is home to about 65% of the total number of people living with hiv worldwide (18) . before jumping to humans an estimated 60-70 years ago (24) , perhaps through consumption of 'bush meat' from nonhuman primates, hiv-1 and hiv-2 had ample opportunity to evolve in hosts that were genetically similar to man (the chimpanzee, pan troglodytes, and the sooty mangabey, cercocebus atys). but hiv/aids may never have emerged had it not been for disruptions in the economic and social infrastructure in postcolonial sub-saharan africa. increased travel, the movement of rural populations to large cities, urban poverty and a weakening of family structure, all these promoted sexual practices such as promiscuity and prostitution that facilitate hiv transmission (24) (25) (26) (27) . infections in animals that are transmitted to humans (zoonoses), and those transmitted from one vertebrate to another by an arthropod vector (vector-borne diseases), have repeatedly been identified as ranking among the most important eis (17, 18) . viruses in these groups have co-evolved with specific rodent species whose contact with humans has increased as a result of modern environmental and human behavioral factors. farming, the keeping of domestic pets, hunting and camping, deforestation and other types of habitat destruction all create new opportunities for such infectious agents to invade human hosts (17) (18) (19) (20) (21) (22) (23) . examples include the arenavirus hemorrhagic fevers (argentine, bolivian, venezuelan and lassa hemorrhagic fevers) and hantavirus pulmonary syndrome (hps). variant creutzfeldt-jakob disease (vcjd) is another example of a zoonotic disease emerging in humans. it is caused by the human-adapted form of the prion associated with the emerging epizootic (large-scale animal outbreak) of bovine spongiform encephalopathy (bse), commonly known as mad cow disease. the new bse prion has become uncharacteristically promiscuous: unlike most known prions, it readily infects multiple species in addition to humans. this suggests the possibility of further emerging diseases associated with prions with currently unknown transmissibility to humans (28) . infectious agents indirectly transmitted to or between humans by way of human-modified environments account for other emerging zoonoses. legionnaire's disease, first identified in 1976, is caused by legionella pneumophilia, whose emergence as a human pathogen might not have occurred were it not for the environmental niche provided by air-conditioning systems (18) . campylobacter jejuni and escherichia coli infect agricultural animals, gaining access to humans through food, milk, water or direct animal contact. other enteric pathogens, such as the vibrios which cause classic cholera and the zoonotic protozoa cryptosporidium parvum and cyclospora cayetanensis (18), seem to have come from environmental or animal organisms that have adapted to human-to-human 'fecal-oral' transmission through water. some eis come from microorganisms that once caused familiar diseases, but which now cause new or previously uncommon diseases. streptococcus pyogenes caused a fatal pandemic of scarlet and puerperal fevers between 1830 and 1900 (29) . scarlet fever, then the leading cause of death in children, is now rare, but has largely been supplemented by other streptococcal complications such as streptococcal toxic shock syndrome, necrotizing fasciitis and re-emergent rheumatic fever (31) . streptococcus pyogenes has been studied more extensively, but the basis of severe disease emergence seems to be more complex. many factors associated with streptococcal virulence have been identified in strains bearing the m1 surface protein as well as in other m protein strains, among them bacteriophage-encoded superantigen toxins and a protein known as sic (streptococcal inhibitor of complement), which seems to be strongly selected by human host mucosal factors. several lines of evidence suggest that changes in streptococcal virulence reflect genetic changes associated with phage integration, large-scale chromosomal rearrangements and possibly the shuffling of virulence cassettes (clusters of genes responsible for pathogenicity), followed by rapid human spread and immune selection (31, 32) . infectious agents that are associated with chronic diseases are one of the most challenging categories of newly emerging (or at least newly appreciated) infections. examples include the associations of hepatitis b and c with chronic liver damage and hepatocellular carcinoma, of certain genotypes of human papillomaviruses with cancer of the uterine cervix, of epstein-barr virus with burkitt's lymphoma (largely in africa) and nasopharyngeal carcinoma (in china), of human herpesvirus 8 with kaposi sarcoma, and helicobacter pylori with gastric ulcers and gastric cancer (33) (34) (35) . some data even suggest infectious etiologies for cardiovascular disease and diabetes mellitus (36) , major causes of death and disability worldwide. other associations between infectious agents and idiopathic chronic diseases will inevitably be found. re-emergence is caused by some of the factors that allow for newly emerging infectious diseases, factors such as microbial evolutionary vigor, zoonotic encounters and environmental encroachment. re-emergences or at least cyclical resurgences of some diseases may also be climate-related-for example, the el niño/southern oscillation (enso) phenomenon is associated with resurgences of cholera and malaria (37) . travel has an important role in bringing people into contact with infectious agents (38) . an increase in travelassociated importations of diseases was anticipated as early as 1933, when commercial air travel was still in its infancy (39) . this has since been demonstrated dramatically by an international airline hub-to-hub pandemic spread of acute hemorrhagic conjunctivitis in 1981 (40), by epidemics of meningococcal meningitis associated with the hajj, and more recently by the exportation of epidemic sars (a newly emerging disease) from guangdong province, china, to hong kong, and from there to beijing, hanoi, singapore, toronto and elsewhere (41) . plasmodium falciparum malaria was neglected for several decades, but is now among the most important re-emerging diseases worldwide. years of effective use of dichlorodiphenyltrichloroethane (ddt) had led to the abandonment of other mosquito-control programs, but the insecticide fell into disuse because of mosquito resistance and concerns about the insecticide's potentially harmful effects on humans and wildlife. consequently, malaria has re-emerged, and the situation has been worsened by the development of drug resistance to chloroquine and mefloquine (42) . research efforts focus on the development of vaccines and new drugs, and on re-establishing public health measures such as the use of bed nets (43) . the remarkable re-emergence of tuberculosis was fuelled by the immune deficiencies of people with hiv infection, which greatly increases the risk of latent mycobacterium tuberculosis infections progressing to active disease, and being transmitted to others. inadequate courses of anti-tuberculosis therapy compound the problem, leading to the emergence and spread of drug resistant and multidrug-resistant strains, and a need for more extensive treatment strategies such as directly observed therapy (44) . it has been known for over a century that tuberculosis is a disease of poverty, associated with crowding and inadequate hygiene. the continuing expansion of global populations living in poverty makes tuberculosis more difficult to control. drug resistance, another factor causing microbial and viral re-emergence, may result from mutation or from bacterial acquisition of extraneous genes through transformation or infection with plasmids. sequential emergences of staphylococcus aureus that are resistant to sulpha drugs (1940s), penicillin (1950s), methicillin (1980s) and to vancomycin in 2002 (45)-a last line of antibiotic defense for some multiply drug-resistant bacteria-are troubling. nosocomial enterococcus faecalis became fully resistant to vancomycin by 1988, and then apparently transferred vana resistance genes to co-infecting staphylococci (46) . methicillin-resistant staphylococci are now being isolated from livestock that have been fed with growthpromoting antibiotics (45) , possibly contributing to resistance problems in humans. immune deficiency associated with hiv infection, and with chemotherapy for cancer, immune-mediated diseases and transplantation, has contributed to an enormous global increase in the numbers of immunosuppressed people over the past few decades (probably more than 1% of the world's population), setting the stage for the re-emergence of many opportunistic infections. hiv, which has infected more than 60 million people globally (47) , is the largest single cause of human immune deficiency and markedly increases vulnerability to a wide range of opportunistic pathogens, including pneumocystis carinii, various fungi, tuberculosis, protozoa and herpesvirus (48) . the simultaneous 1999 emergences of encephalitis due to west nile virus (wnv) in the united states and russia (49, 50) reflect abundances of eclectic vector mosquitoes and avian hosts in these locations. both were probably connected to endemic sites by virus carriage in migratory birds and travelers. the remarkable geographical spread of wnv in the five years since its introduction into the western hemisphere reflects an unfortunate confluence of viral promiscuity and ecological diversity (51) . although humans are dead-end hosts for wnv, the risk of infection is greatly increased by marked zoonotic viral amplification and persistence in the environment. although wnv is now a major epidemiological concern in the developed world, dengue remains the most significant and widespread flavivirus disease to have emerged globally (52) . usually transmitted by aedes aegypti mosquitoes, dengue has recently been transmitted by aedes albopticus-a vector switch of potential significance with respect to dengue reemergence (52) . dengue re-emergence is further complicated by disturbing increases in a serious and formerly rare form of the disease, dengue hemorrhagic fever (dengue shock syndrome being its highly fatal form). these severe complications are thought to result from the evolution of dengue viruses to escape high population immunity, seen in increased viral virulence and human immunopathogenesis due to antibody-dependent enhancement of viral infection (53) . cholera is also of interest, not only as an important cause of mortality, but also because of the complexity of factors that determine its re-emergence. both virulent and avirulent strains of these zoonotic bacteria are maintained in the environment and are rapidly evolving in association with phyto-and zooplankton, algae and crustaceans. such environmental strains seem to act as reservoirs for human virulence genes and to undergo gene transfer events that lead to new strains containing further virulence gene combinations (54) . thus, although cholera has appeared to be clinically and epidemiologically stable at least since the third pandemic (in the 1840s), modern evidence suggests that such apparent stability masks aggressive bacterial evolution in complex natural environments. influenza a viruses, which are endemic gastrointestinal viruses of wild waterfowl, have evolved elaborate mechanisms to jump species into domestic fowl, farm animals and humans. periodic gene segment reassortments between human and animal viruses produce important antigenic changes, referred to as 'shifts'. these can lead to deadly pandemics, as occurred in 1888, 1918, 1957 and 1968 (55, 56) . in intervening years, shifted viruses undergo continual but less dramatic antigenic changes called 'drifts,' which allow them partially to escape human immunity raised by previously circulating influenza viruses. influenza drift is an evolutionary success story for the virus. influenza a has a seemingly inexhaustible repertoire of mutational possibilities at several critical epitopes surrounding the viral hemagglutinin site that attaches to human cells. deliberately emerging microbes are those that have been developed by humans, usually for nefarious use. they include microorganisms or toxins produced in a form that would cause maximal harm because of ease of dissemination, enhanced infectivity or heightened pathogenicity (57) . two modern attacks have been well documented. in 1984, an oregon religious cult spiked restaurant salad bars with salmonellae in an attempt to sway a local election (58) . a 2001 anthrax attack (59) , in which a terrorist mailed anthrax-sporefilled letters to prominent figures, including two us senators, resulted in illness in at least 18 people and the death of five of these individuals. the united states, the united kingdom, the russian federation and other nations once had sophisticated offensive bioweapons programs that included the production of weaponized anthrax spores (57) . in japan, the doomsday sect, aum supreme truth, carried out a nerve-gas attack on the tokyo subway in 1995, and made a trial run on an anthrax weapon, using harmless vaccine bacteria as a test (60) . bioterror agents have been grouped into three categories (a, b and c) according to risk (61) . the six category a agents (anthrax, smallpox, plague, tularaemia, viral hemorrhagic fevers and clostridial botulinum toxin) are given top priority because they are highly lethal and readily deployed as weapons. category b and c agents include food-borne and water-borne organisms that incapacitate but usually do not kill. risk is the probability that exposure to a hazard will lead to a negative consequence (62) . risk communication is an interactive exchange of information and opinion on risk among risk assessors, risk managers, and other interested parties (63) . humans tend to fear similar things, for similar reasons. scientists studying human behavior have discovered psychological patterns in the subconscious ways we "decide" what to be afraid of and how afraid we should be. any given risk has a set of identifiable characteristics that help predict what emotional responses that risk will trigger. people's perceptions of the magnitude of risk are influenced by factors other than numerical data (64) . the factors influencing risk perception are summarized in table 2 . merely disseminating information without regard for communicating the complexities and uncertainties of risk does not necessarily ensure effective risk communication. wellmanaged efforts will help ensure that messages are constructively formulated, transmitted, and received and that they result in meaningful actions. the seven cardinal rules of risk communication are demonstrated in table 3 . the fundamental goal of risk communication is to provide meaningful, relevant and accurate information, in clear and understandable terms, targeted to a specific audience (63) . the goals of risk communication are summarized in table 4 . it may not resolve all differences between interested parties, but may working in earthquake-prone areas hormone replacement therapy 4. risks perceived to be fairly distributed are more accepted than risks to be unfairly distributed. gun shots (in japan) traffic accidents 5. risks perceived to be natural are more accepted than risks perceived to be manmade. radiation from mobile phones radiation from the sun 6. risks perceived to be statistical are more accepted than risks perceived to be catastrophic. eaten by a shark (catastrophe) heart disease (statistics) 7. risks perceived to be generated by a well-known source are more accepted than risks perceived to be generated by a less known source. private industry government 8. risks perceived to be familiar are more accepted than risks perceived to be exotic. 9. risks perceived to affect adults are more accepted than risks perceived to affect children. asbestos exposure for children asbestos exposure in workplace 10. risks perceived with less uncertainty are more accepted than risks with high uncertainty. new technology conventional technology 11 . risks perceived that could directly affect others are more accepted than risks that could affect oneself. table 3 seven cardinal rules of risk communication* 1. accept and involve the public as a partner. the goal is to produce an informed public, not to defuse public concerns or replace actions. different goals, audiences, and media require different actions. 3. listen to the public's specific concerns. people often care more about trust, credibility, competence, fairness, and empathy than about statistics and details. 4. be honest, frank, and open. trust and credibility are difficult to obtain; once lost, they are almost impossible to regain. 5. work with other credible sources. conflicts and disagreements among organizations make communication with the public much more difficult. 6. meet the needs of the media. the media are usually more interested in politics than risk, simplicity than complexity, danger than safety. 7. speak clearly and with compassion. never let efforts prevent acknowledging the tragedy of an illness, injury, or death. people can understand risk information, but they may still not agree; some people will not be satisfied. * from: covello v and allen f. 1988. (reference no. 67) lead to a better understanding of those differences. it may also lead to more widely understood and accepted risk management decisions. effective risk communication should have goals that build and maintain trust and confidence. it should facilitate a higher degree of consensus and support by all interested parties for the risk management options being proposed. many considerations for effective risk communication, especially those involving the public, can be grouped in a sequence following the systematic approach of the risk communication process. this starts with gathering background and needed information, followed by the preparation and assembly of the message and its dissemination and distribution, with a follow-up review and evaluation of its impact (63) . the general considerations for effective risk communication are demonstrated in table 5 . risk communication efforts and programs need to be evaluated both regularly and systematically to determine their effectiveness and to provide for change when needed. communication aims and objectives need to be clearly stated if an evaluation is to be effective. this could include the proportion of at-risk population to be reached, adoption of appropriate risk reduction practices, and the extent of resolution of the crisis. it is important to learn from both positive and negative risk communication experiences, in order to adjust and improve ongoing communication activities. only through systematic evaluations, which are performed throughout the communication process, can that process be strengthened (63) . globalization of disease prevention lectures, through the supercourse prevention project, is funded by the us national institutes of health (nih). the supercourse is an internet library of lectures on prevention, shared for free by 10,000 table 4 goals of risk communication* 1. promote awareness and understanding of these specific issues under consideration during the risk analysis process, by all participants; 2. promote consistency and transparency in arriving at and implementing risk management decisions; 3. provide a sound basis for understanding the risk management decisions proposed or implemented; 4. improve the overall effectiveness and efficiency of the risk analysis process; 5. contribute to the development and delivery of effective information and education programs, when they are selected as risk management options; 6. foster public trust and confidence in the safety of the food supply; 7. strengthen the working relationships and mutual respect among all participants; 8. promote the appropriate involvement of all interested parties in the risk communication process; and, 9. exchange information on the knowledge, attitudes, values, practices and perceptions of interested parties concerning risks associated with food and related topics. table 6 . japan has associated with the global health network through supercourse japan (66) where a series of lectures in health, environment and sustainable development, epidemiology for decision-making, and zoonosis have so far been developed. the supercourse on health, environment and sustainable development was designed to provide an overview on health and environment in the context of sustainable development for public health students around the world, as well as decision makers, community leaders, scientists and professionals in government and non-governmental organizations, who are interested in health and environmental linkages in sustainable development (66) . the supercourse on epidemiology for decision-making provides a learning resource for students of environmental and occupational epidemiology, and its main purpose is to promote the understanding and application of epidemiology in the prevention of environmental and occupational disease and the promotion of health (66) . the supercourse on zoonosis aims to disseminate rapidly the latest information on animal diseases transmittable to humans. severe acute respiratory syndrome (sars) and bovine spongiform encephalopathy (bse) are some of the lectures discussed which will help in information sharing to developing countries (66) . a joint action plan through the 'the pacific islands forum' was created in 2003. its five priority policy targets are: 1) enhancement of security in the pacific region, 2) creation of a safer and more sustainable environment, 3) improvement in education and human resources development, 4) improvement in health, and 5) promotion of more vigorous and continued trade and economic growth. the countries in the pacific region face a contradictory dilemma: some of the poorest countries have the most expensive telecommunications, yet information and telecommunication technology (ict) need to be extensively utilized. in these circumstances telemedicine, such as for remote clinical and pathological diagnosis, is too expensive and technically demanding to be widely used. since information in the future will be technology-and network-based, it is imperative for "supercourse asia" to fully exploit the potential of ict for health education and health service development in the region. the advantages of this approach are to use the most appropriate, inexpensive, opensource, and low-band ict, and to operate it through active national networking. the supercourse asia network (scan) is an offshoot of this initiative and aims that all children and adults will have equal access to health and education of sufficient quality to empower them to break the poverty cycle, to improve their quality of life (qol), and to participate effectively in national development. the mission is to alleviate poverty and improve health and qol of developing countries in the pacific region through advances in a cost-effective ict-based health educational system. the internet is the most inexpensive and speed efficient means to penetrate the remote places such as the pacific islands. japan, a leader of modern technology in the region, is in the best position to provide these technological and educational tools to contribute to the well-being of people in the region. the scan is a group of primarily academics, united by a common belief: the internet is the best way to disseminate knowledge, especially knowledge about health promotion and prevention. they are working towards facilitating the dissemination of health-related information over the internet and improving teaching in the field of education, social/preventive medicine, public health and epidemiology. the members are voluntary professionals in academia, healthcare, telecommunications, the government, ngos, and other public and private sector organizations who will work together towards developing "supercourse asia." they are not only active members of the scan but also the main contributors of "supercourse asia" lectures, reviewers, translators, and its major user group. the challenges for the scan are 1) how to effectively utilize the national networks among the participating countries and within each participating country that may be geographically remote, 2) how to evaluate the effects of the scan on the advancement of health and qol, and the alleviation of poverty though "supercourse asia" in the region, and 3) how to sustain the network activities for many years to come. currently, the public has become concerned with information and safety, however, gaps between the understanding of safety and assurance are widening. health advocacy and promotion through e-learning are becoming more important in the framework of risk communication for the community. the supercourse lectures will serve as an international platform for sharing information, lectures, and ideas. understand the public perception of the risk through such means as risk surveys, interviews and focus groups expect different people to see the risk differently. preparation/assembly 1. avoid comparisons between familiar risks and new risks, as they may seem flippant and insincere unless presented properly. 2. recognize and respond to the emotional aspects of risk perceptions. speak with sympathy and never use logic alone to convince an audience characterized by emotion express risk in several different ways, making sure not to evade the risk question explain the uncertainty factors which are used in risk assessment and standard setting maintain an openness, flexibility, and recognition of public responsibilities in all communication activities accept and involve the public as a legitimate partner by describing risk/benefit information and control measures in an understandable way. 2. share the public's concern rather than deny it as not legitimate or as unimportant. be prepared to give people's concerns as much emphasis as the risk statistics be honest, frank, and open in discussing all issues if explaining statistics derived from risk assessment, explain the risk assessment process before presenting the numbers coordinate and collaborate with other credible sources evaluate the effectiveness of risk messages and communication channels. 2. emphasize action to monitor, manage, and reduce risk plan carefully and evaluate efforts it is based on the open source model, which allows free redistribution, shows the source code, and allows modifications and derived works this is especially useful for developing countries and minority populations with limited access to resources it aims to overcome the digital divide by improving access in places with low bandwidth internet connection it is a teaching support system -differing from a traditional distance education system it provides timely information for action -one of the greatest advantages of having a regional faculty base with varied areas of expertise which are very important in the field of public health (e.g., lectures on sars from the members in china and singapore, where it is most rampant) it is a "hyper-text comic book format hypertext links from text, images, tables, and pictures take the reader to other relevant supercourse lectures, images, or other websites on the internet oaks sc editors. emerging infections; microbial threats in the united states world health organization. removing obstacles to healthy development global defence against the infectious disease threat. world health organization globalisation of prevention education: a golden lecture factors in the emergence of infectious diseases threats to global health and survival; the growing crises of tropical infectious diseasesan unfinished agenda emerging infectious diseases among indigenous peoples epidemiology of the plague of athens the columbian exchange: biological and cultural consequences of 1492. greenwood, westport: connecticut princes and peasants. smallpox in history. chicago: univ untersuchungen über bacterien. v. die aetiologie der milzbrand-krankheit, begründet auf die entwicklungsgeschichte des bacillus anthracis spreading germs: diseases, theories, and medical practice in britain the greatest benefit to mankind: a medical history of humanity from antiquity to the present the evolution and eradication of infectious diseases infectious diseases: considerations for the 21st century oaks sc editors. emerg infect. microbial threats to health in the united states lederberg j editors. microbial threats to health in the united states: emergence, detection and response emerging and re-emerging infectious diseases: a multidisciplinary perspective emerging and re-emerging infectious diseases emerging infectious diseases in the 21st century emerging and re-emerging infectious diseases the origins of acquired immune deficiency viruses: where and when population migration and the spread of types 1 and 2 human immunodeficiency viruses the aids knowledge base slowing heterosexual hiv transmission variant creutzfeldt-jakob disease and the acquired and transmissible spongiform encephalopathies severe streptococcal infections in historical perspective emerging infections group a streptococcus: allelic variation, population genetics, and hostpathogen interactions genome sequence of a serotype m3 strain of group a streptococcus: phage-encoded toxins, the highvirulence phenotype, and clone emergence identification if herpesvirus-like dna sequences in aids-associated kaposi's sarcoma microbes and malignancy: infection as a cause of human cancers helicobacter pylori-associated diseases current clinical topics in infectious diseases el niño and health island epidemics epidemiology in relation to air travel acute hemorrhagic conjunctivitis: dealing with a newly emerging disease the severe acute respiratory syndrome two worlds of malaria research toward vaccines against malaria the global situation of mdr-tb methicillin (oxacillin)-resistant staphylococcus aureus strains isolated from major food animals and their potential transmission to humans centers for disease control prevention. staphylococcus aureus resistant to vancomycin-united states joint united nations programme on hiv/aids. aids epidemic update surveillance for aids-defining opportunistic illnesses, 1992-1997. mmwr 48. cdc surveillance summary no. ss-2 the outbreak of west nile virus infection in the new york city area in 1999 outbreak of west nile virus infection west nile virus: epidemiology and ecology in north america dengue and dengue hemorrhagic fever antibody-dependent enhancement of infection and the pathogenesis of viral disease molecular ecology of toxigenic vibrio cholerae the next influenza pandemic: lessons from hong kong a molecular whodunit the chilling true story of the largest covert biological weapons program in the world-told from the inside by the man who ran it a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars investigation of bioterrorism-related anthrax, united states, 2001: epidemiologic findings japanese sect was close to bioterrorism journal says: live anthrax found at office threats in bioterrorism: i. cdc category a agents risk: a practical guide for deciding what's really safe and what's really dangerous in the world around you world health organization. the application of risk communication to food standards and safety matters, a joint fao/ who expert consultation supercourse: epidemiology, the internet, and global health seven cardinal rules of risk communication key: cord-351373-a21453gz authors: mowbray, n. g.; ansell, j.; horwood, j.; cornish, j.; rizkallah, p.; parker, a.; wall, p.; spinelli, a.; torkington, j. title: safe management of surgical smoke in the age of covid‐19 date: 2020-05-03 journal: br j surg doi: 10.1002/bjs.11679 sha: doc_id: 351373 cord_uid: a21453gz background: the covid‐19 global pandemic has resulted in a plethora of guidance and opinion from surgical societies. a controversial area concerns the safety of surgically created smoke and the perceived potential higher risk in laparoscopic surgery. methods: the limited published evidence was analysed in combination with expert opinion. a review was undertaken of the novel coronavirus with regards to its hazards within surgical smoke and the procedures that could mitigate the potential risks to healthcare staff. results: using existing knowledge of surgical smoke, a theoretical risk of virus transmission exists. best practice should consider the operating room set‐up, patient movement and operating theatre equipment when producing a covid‐19 operating protocol. the choice of energy device can affect the smoke produced, and surgeons should manage the pneumoperitoneum meticulously during laparoscopic surgery. devices to remove surgical smoke, including extractors, filters and non‐filter devices, are discussed in detail. conclusion: there is not enough evidence to quantify the risks of covid‐19 transmission in surgical smoke. however, steps can be undertaken to manage the potential hazards. the advantages of minimally invasive surgery may not need to be sacrificed in the current crisis. the 2020 pandemic of the novel coronavirus, covid-19, has raised concerns about the risk of virus transmission to staff in the operating room. this relates not just to intubation and extubation of the airway during anaesthesia, but also to the release of potential infectious particles in laparoscopic smoke or plume. the risks of laparoscopic smoke, or plume, have been recognized for a long time, but the advent of covid-19 has brought its importance into sharp relief 1 . the society of american gastroenterology and endoscopic surgeons updated their advice on 30 march 2020 2 : 'although previous research has shown that laparoscopy can lead to aerosolization of blood-borne viruses, there is no evidence to indicate that this effect is seen with covid-19, nor that it would be isolated to mis [minimally invasive surgery] procedures. nevertheless, erring on the side of safety would warrant treating the coronavirus as exhibiting similar aerosolization properties. for mis procedures, use of devices to filter released co 2 for aerosolized particles should be strongly considered'. a rapid, joint publication from italian and chinese surgeons 3 has shared excellent advice based on their experiences in the preceding months. the uk and ireland intercollegiate board has also continued to update its guidance. it moved from a statement that 'laparoscopy should generally not be used' to its most recent guideline on 27 march 2020 4 , which states: 'laparoscopy is considered to carry some risks of aerosol-type formation and infection and considerable caution is advised. the level of risk has not been clearly defined and it is likely that the level of ppe [personal protective equipment] deployed may be important. advocated safety mechanisms (filters, traps, careful deflating) are difficult to implement. consider laparoscopy only in selected individual cases where clinical benefit to the patient substantially exceeds the risk of potential viral transmission in that particular situation'. this expeditious advice is a pragmatic response to the widespread anxiety surrounding possible virus transmission in the operating room. this article reviews the best available evidence to understand the risk of transmission of covid-19 in laparoscopic smoke, and what steps, based on physical properties of the virus, may be best placed to reduce this and justify continuing laparoscopic surgery under strict safety guidelines. there is currently no evidence that covid-19 is transmissible through surgical smoke. previous studies have, however, demonstrated the presence of different viruses in surgical smoke, including: corynebacterium, human papillomavirus (hpv), poliovirus, human immunodeficiency virus (hiv) and hepatitis b 5 -8 . the aerosol produced by laparoscopic or robotic surgery, particularly when using low-temperature ultrasonic devices, may not effectively deactivate the cellular components of a virus 3 . the possibility of disease transmission through surgical smoke does exist in humans, but documented cases are rare 9 . hpv transmission during anogenital surgery is the most widely reported in the literature. this is most likely due to the direct contact of electrocautery on an infected field. liu and colleagues 9 outlined four articles 10 -13 linking surgical smoke to the transmission of hpv (types 6, 11 and 13), progressing to oropharyngeal squamous cell carcinoma. these cases occurred in otherwise fit healthcare professionals performing gynaecological surgery with no other risk factors for the disease. another study 14 found that one in five surgeons, and three in five nurses, tested positive for hpv after performing operations for laryngeal and urethral papillomas 14 . the hpv genotypes in the infected healthcare professional were identical to those identified in the patient. in addition to hpv transmission, baggish and co-workers reported that hiv proviral dna was captured in the inner lumen of smoke evacuation tubing after in vitro laser vaporization of cultured hiv cells 15 . kwak et al. 16 further revealed that hepatitis b virus (hbv) was present in surgical smoke 16 . in this study, surgical smoke was collected during laparoscopic or robotic surgery in 11 patients. hbv was detected in ten of the 11 samples of surgical smoke, including that from non-hepatic surgery. this suggests that bloodborne viruses may be present within surgical smoke. although the transmission of covid-19 is, at present, felt to occur primarily through respiratory droplets, there remains a theoretical risk of virus aerosolization during minimal access surgery 17, 18 . it is essential to understand the physical properties of the virus in order to predict the risk of transmission and the effectiveness of preventative measures. the correct term for the virus causing covid-19 is sarbecovirus severe acute respiratory syndrome coronavirus 2 (sars-cov2), which is a member of the betacoronavirus family (subgenus sarbecovirus). like its close relatives, middle east respiratory syndrome coronavirus (mers-cov) and sars-cov, it is believed to have its origins in bats. sequence analysis from cases around the world strongly indicate that the pandemic resulted from a single recent emergence of the virus from an animal reservoir. sars-cov2 is a positive-sense single-stranded rna virus, containing a linear genome of approximately 30 kb. like other members of the coronavirus family, the virion is typically around 120 nm in diameter, although this can vary from 50 to 200 nm 19 . as an enveloped virus, the rna genome is contained within a lipid bilayer containing several proteins: the n protein binds and stabilizes the rna genome, and the envelope (e), membrane (m) and spike (s) proteins make up the envelope. like other members of the sars family, the virus uses the heavily glycosylated, extended spike protein to mediate initial cellular engagement and begin the process of infection 20 . the s protein of sars-cov2 engages the angiotensin-converting enzyme 2 receptor (ace2) as a high-affinity primary attachment receptor 21 . ace2 expression is abundant on human airway epithelial cells, consistent with efficient transmission occurring via respiratory droplets. other co-receptors may also be involved in cellular infection, including cd147 (basigin, bsg) and cd26 20, 22 . in each case, the interaction is thought to occur with the s protein, which appears pivotal for cellular tropism. the extended s protein is a trimeric protein, each monomer being approximately 1100 amino acids in length. the structure of the protein (based on protein data bank (pdb) 6crv) is depicted in fig. 1a ,b. binding of ace2 to s protein occurs at the apical domain. although the overall net virion charge has not yet been evaluated, it is possible to assess the surface electric potential of individual capsid proteins where structures have been elucidated, as depicted for the s protein in fig. 1c ,d. fig. 1d shows the full surface electric potential of the spike protein, as viewed towards the virion. areas of both positive and negative charge are visible in approximately equal abundance, although the central depression, where ace2 is thought to bind, and one of the few regions of the s protein that is devoid of glycosylation, is seen to be relatively negatively charged. excellent theatre discipline and the use of checklists is highly recommended to minimize the risk of surgery and anaesthesia, regardless of surgical approach. expert recommendations from china suggest using a designated operating theatre for covid-19-positive patients 23 . this allows patient movements to be planned, limiting the contamination of other clinical areas. the flow of theatre staff can also be mapped to create designated areas for donning and doffing full personal protective equipment. the minimum number of staff should be present in the operating theatre, with the minimum amount of equipment. a runner can acquire further stock as required, but should be mindful to minimize the number of entries into the operating theatre. in deciding which operating theatre to use, the theatre ventilation system should be considered. negative pressure ventilation can limit the contamination of surgical smoke into neighbouring areas through doors and vents. during the sars outbreak in hong kong in 2004, chow and colleagues 24 described how they converted existing systems into negative pressure systems. this may not always be feasible, and so the recommendations from the uk and ireland surgical colleges are that positive pressure ventilation should be halted during the procedure and for at least 20 min after the patient has left theatre 4 . the risks of positive pressure ventilation, however, have not been quantified. if the virus is present in laparoscopic smoke, it must make its way to the edge of the theatre and then must have an uplift in theatre corridors at a concentration sufficient to be infective. any virus load is likely to be diluted massively by the time this happens. unidirectional air flow (laminar flow) systems remain controversial in their ability to decrease surgical-site infections and so are not recommended by the who 25, 26 . they produce a continuous flow of highly filtered ultraclean air and can display 99⋅97 per cent efficiency in removing airborne particles of 0⋅3 μm and larger 27 . this would imply an effectiveness in clearing covid-19, but it is also necessary to consider having multiple theatres available as sufficient downtime between procedures is essential to ensure full decontamination. if smoke is a risk factor, in a laminar flow theatre it will be pushed to the floor, away from staff, and the inhalation risk diminished. there is a limited amount of evidence related to the choice of tissue-cutting energy device used. monopolar electrocautery using teflon ® (chemours, delaware, usa) blades and a feedback mechanism to automatically reduce the voltage produces less surgical smoke 28 . the main laparoscopic alternatives to electrocautery are the ultrasonic energy devices such as harmonic scalpel (ace ® ; ethicon endo-surgery, cincinnati, ohio, usa). although such devices can add efficacy and speed to some laparoscopic procedures, more viable cells have been detected in the smoke from ultrasonic energy devices 29 . the operating room ventilation system is not the only method of smoke extraction; protection from surgical smoke can also be achieved by local extraction at the site of surgery or by the use of personal filtration masks. there are several benefits to using smoke extractors; they keep the surgical field clear, prevent corrosion of equipment due to released chemical, and reduce odour. however, for the purpose of this review, the main benefit is that they capture the smoke close to the source of emission, therefore minimizing exposure of healthcare professionals to potential contaminants and maintaining a safer environment. for this reason, the surgical colleges in the uk currently recommend their use 4 . the particulate removal capability of smoke evacuator devices is, by design, limited to the efficiency and size of their filters. other factors to consider include: the minimum flow rate (at least 0⋅012 m 3 /s), the ability to vary both the flow rate and noise level (ideally below 60 db), ergonomic features, portability, cost-effectiveness and ease of maintenance 30 . there are a number of types of filter available. charcoal filters use activated charcoal; they can absorb both gas and vapour, and can eliminate strong-smelling gases. coconut shell charcoal is better at absorbing particulate matter than wood-based charcoal owing to its greater internal pore area 31 . high-efficiency particulate air filters act to filter suspended compounds. they can retain particles larger than 0⋅3 μm at an efficiency rate of 99⋅97 per cent 32 . ultralow particulate air (ulpa) filters retain 99⋅9 per cent of particles at 0⋅1 μm and are a depth filter, filtering matter by different methods depending on the particle size 32 . this makes them ideal for removing the particles created in electrosurgical and laser procedures. the association of perioperative registered nurses guidelines 33 state that perioperative personnel should use ulpa filters routinely for surgical smoke. currently the most effective smoke evacuation system is the triple-filter system, which includes a prefilter that captures large particles, a ulpa filter, and a special charcoal that captures the toxic chemicals found in smoke. triple-filter systems often have variable suction volume capacity to accommodate various levels of smoke production. most commonly these filters are used in portable evacuation machines, but in some instances a filter can be used in the wall suction system to safely capture small amounts of smoke. depending on the environment, these filters may require replacement after each use or each day. most of the evacuation devices have an inbuilt alarm or an indicator light to signal a required change. a change of filter is mandated when the suction pressure decreases or there is a lingering odour in the air. the contaminated filter may be considered as infectious or regulated waste depending on the waste disposal protocol of the facility 34 . table 1 summarizes the currently available smoke evacuation devices. choi and colleagues 36 assessed surgical smoke from 20 patients undergoing transperitoneal laparoscopic nephrectomy for renal cell carcinoma. surgical smoke (prefilter) was collected 20 min after the electrocautery device was first used during the procedure and 2 h after the filter had been applied. the sample was analysed by gas chromatography-mass spectroscopy. strong carcinogens were eliminated by more than 85 per cent by using the activated carbon fibre filter. seipp and co-workers 37 tested the efficiency of portable smoke evacuation systems and found that filtration reduced surgical smoke by up to 99 per cent. however, this was accompanied by high noise levels that exceeded recommended limits. despite recommendations from various professional organizations advocating the use of smoke extraction devices in operating rooms, these measures are not being used widely because of excessive noise, high cost, equipment maintenance issues, large bulky devices, and resistance or complacency from clinical staff 38 -40 . abdominal wall and allowing the inadvertent escape of pressurized carbon dioxide from the pneumoperitoneum. this is an obvious area of concern in a covid-19-positive patient, and remains a risk throughout the procedure as displacement of the port is not uncommon. pressurized intraperitoneal aerosol chemotherapy (pipac) delivers aerosol chemotherapy under pressure during laparoscopy for the treatment of peritoneal carcinomatosis. by its very nature, the procedure has necessitated a high level of investigation into ways of mitigating the risk of gas leakage during surgery. both experimental and human models have shown that, with the development of standard operating procedures (sops) for laparoscopy, the risk of contamination of the operating theatre environment with potentially harmful chemotherapy agents is negligible 41 . the authors propose that these procedures could be applied to minimally invasive surgery on covid-positive patients, similarly negating the risk of virus escape during surgery. open hasson umbilical port insertion may result in a larger defect in the fascia than is required for the port, allowing pressurized carbon dioxide to escape around the trocar. pipac surgeons frequently use either off-midline open cutdown or alternative first entry techniques (veress, optical insertion), which result in a fascia defect that is more snug around the port, reducing the risk of gas leakage at this site. pipac sops recommend the use of balloon ports. balloon-secured trocars reduce the chance of inadvertent displacement of the trocar during instrument changes, thus reducing the risk of loss of pneumoperitoneum to the operating theatre environment. trocars also contain a valve preventing gas leakage when an instrument is passed through into the peritoneum; surgeons should be aware of the inherent risks if the valve should become damaged. in addition, the authors believe that, when the balloon is inflated inside the peritoneum and traction is applied against the posterior rectus sheath, a more secure seal is achieved around the body of the trocar, therefore reducing the risk of gas leakage. ten-millimetre ports should be closed under direct vision once the pneumoperitoneum has been safely evacuated using techniques described elsewhere in this article. the authors recommend against the use of devices such as endoclose™ (medtronic, dublin, ireland), which require maintenance of the pneumoperitoneum to facilitate closure, as this will increase the risk of gas leakage. pneumoperitoneum should be maintained throughout the procedure at the lowest possible pressure. at the end of the procedure, the pneumoperitoneum should be removed in a controlled fashion by first switching off the insufflation, and then aspirating the pneumoperitoneum using a suction device (preferably passed through a filter mechanism) 42 . if specimen extraction is required, the pneumoperitoneum should be decompressed safely as above before making an incision for specimen extraction. the ultravision™ system (alesi surgical, cardiff, uk) removes smoke and particulate matter produced during electrosurgical procedures, as an aid to maintaining a clear visual field. active throughout surgery, the system prevents the build-up of smoke by electrostatically precipitating particulate matter generated within the peritoneal cavity during the use of electrosurgical tools. it has been shown to negate the periprocedural venting of insufflation gas to facilitate clearance of smoke 43 . the principle on which the ultravision™ system operates is derived from electrostatic precipitators that are widely used to remove fine particulate matter from exhaust gases produced during, for example, the commercial manufacture of cement and paper. the system comprises a generator and a single-use electrode that together create negative ions in the abdominal cavity. these ions impart a transient negative charge to the particles of surgical smoke as they are created. the electrostatically charged particles are attracted to the patient tissue owing to the presence of the standard patient return electrode used during surgery. the charge is neutralized as each particle precipitates on to the surface of the peritoneal wall, where it remains unchanged physically and chemically 44, 45 . ultravision™ has also been used to enhance safety in pipac 46 . the functionality of the system is not restricted by particle size, and it has been demonstrated to remove over 99 per cent of all smoke particulates larger than 7 nm in size 47 . there is not enough evidence available to allow a balanced risk estimation for the infectious nature of surgical smoke. it is unclear whether laparoscopic smoke represents a greater risk than that created during open surgery. given the novel status of the covid-19 pathogen, and the evidence of other viruses being present in surgical smoke, maximizing intraoperative precautions at this time would seem prudent. there has never been a time when knowledge and guidelines are changing on an almost daily basis as a result of the unprecedented worldwide communication and information sharing. minimal access surgery offers advantages to patients in terms of hospital stay. with strict locally agreed theatre protocols aligned to evidence-based protective measures, it may be possible to continue to offer minimal access surgery to those who might benefit most. disclosure j.t. holds stock in alesi surgical and has received educational grants from medtronic and ethicon. the authors declare no other conflict of interest. is surgical smoke harmful to theater staff? a systematic review 2 society of american gastroenterology and endoscopic surgeons. sages and eaes recommendations regarding surgical response to covid-19 crisis minimally invasive surgery and the novel coronavirus outbreak: lessons learned in china and italy intercollegiate general surgery guidance on covid-19 update microbiologic activity in laser resurfacing plume and debris chemical composition of smoke produced by high-frequency electrosurgery in a closed gaseous environment. an in vitro study human immunodeficiency virus-1 (hiv-1) in the vapors of surgical power instruments risk of acquiring human papillomavirus from the plume produced by the carbon dioxide laser in the treatment of warts awareness of surgical smoke hazards and enhancement of surgical smoke prevention among the gynecologists laryngeal papillomatosis with human papillomavirus dna contracted by a laser surgeon laryngeal papillomatosis -first recognition in germany as an occupational disease in an operating room nurse hpv positive tonsillar cancer in two laser surgeons: case reports virus-induced cancers of the skin and mucosa: are we dealing with 'smoking guns' or 'smoke and mirrors' in the operating theatre transmission of human papillomavirus dna from patient to surgical masks, gloves and oral mucosa of medical personnel during treatment of laryngeal papillomas and genital warts presence of human immunodeficiency virus dna in laser smoke detecting hepatitis b virus in surgical smoke emitted during laparoscopic surgery modes-oftransmission-of-virus-causing-covid-19-implications-foripc-precaution-recommendations [accessed virological assessment of hospitalized patients with covid-2019 supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy emerging wuhan (covid-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human cd26 structural basis for the recognition of sars-cov-2 by full-length human ace2 sars-cov-2 invades host cells via a novel route: cd147-spike protein chinese society of anesthesiology, chinese association of anesthesiologists. perioperative management of patients infected with the novel coronavirus:recommendation from the joint task force of the chinese society of anesthesiology and the chinese association of anesthesiologists conversion of operating theatre from positive to negative pressure environment operating room ventilation with laminar airflow shows no protective effect on the surgical site infection rate in orthopedic and abdominal surgery guidelines for the prevention of surgical site infection operating theatre quality and prevention of surgical site infections electrocautery devices with feedback mode and teflon-coated blades create less surgical smoke for a quality improvement in the operating theater analysis of surgical smoke produced by various energy-based instruments and effect on laparoscopic visibility guideline implementation: surgical smoke safety surgical smoke in dermatology: its hazards and management filter collection guideline summary: surgical smoke safety surgical smoke: risk assessment and mitigation strategies society of american gastroenterology and endoscopic surgeons. resources for smoke and gas evacuation during open, laparoscopic and endoscopic procedures activated carbon fiber filters could reduce the risk of surgical smoke exposure during laparoscopic surgery: application of volatile organic compounds efficiencies and noise levels of portable surgical smoke evacuation systems comparison of current and past surgical smoke control practices physiologic and other effects and compliance with long-term respirator use among medical intensive care unit nurses behind the mask: determinants of nurse's adherence to facial protective equipment pressurized intraperitoneal aerosol chemotherapy (pipac): occupational health and safety aspects advices to minimize the potential aerosol spread during laparoscopy electrostatic precipitation is a novel way of maintaining visual field clarity during laparoscopic surgery: a prospective double-blind randomized controlled pilot study field evaluation of a new particle concentrator-electrostatic precipitator system for measuring chemical and toxicological properties of particulate matter the effect of electrostatic precipitation by the ultravision system on surgical smoke in vivo feasibility of electrostatic precipitation as an adjunct to pressurized intraperitoneal aerosol chemotherapy (epipac) a study of the ability of the innervision electrostatic precipitator to clear the particulate matter produced by energy-based surgical instruments: expert report prepared for alesi surgical limited key: cord-329614-deh5bidx authors: fielding, helen r.; mckinley, trevelyan j.; delahay, richard j.; silk, matthew j.; mcdonald, robbie a. title: effects of trading networks on the risk of bovine tuberculosis incidents on cattle farms in great britain date: 2020-04-22 journal: r soc open sci doi: 10.1098/rsos.191806 sha: doc_id: 329614 cord_uid: deh5bidx trading animals between farms and via markets can provide a conduit for spread of infections. by studying trading networks, we might better understand the dynamics of livestock diseases. we constructed ingoing contact chains of cattle farms in great britain that were linked by trading, to elucidate potential pathways for the transmission of infection and to evaluate their effect on the risk of a farm experiencing a bovine tuberculosis (btb) incident. our findings are consistent with variation in btb risk associated with region, herd size, disease risk area and history of previous btb incidents on the root farm and nearby farms. however, we also identified effects of both direct and indirect trading patterns, such that connections to more farms in the england high-risk area up to three movements away from the root farm increased the odds of a btb incident, while connections with more farms in the england low-risk area up to eight movements away decreased the odds. relative to other risk factors for btb, trading behaviours are arguably more amenable to change, and consideration of risks associated with indirect trading, as well direct trading, might therefore offer an additional approach to btb control in great britain. trading animals between farms and via markets can provide a conduit for spread of infections. by studying trading networks, we might better understand the dynamics of livestock diseases. we constructed ingoing contact chains of cattle farms in great britain that were linked by trading, to elucidate potential pathways for the transmission of infection and to evaluate their effect on the risk of a farm experiencing a bovine tuberculosis (btb) incident. our findings are consistent with variation in btb risk associated with region, herd size, disease risk area and history of previous btb incidents on the root farm and nearby farms. however, we also identified effects of both direct and indirect trading patterns, such that connections to more farms in the england high-risk area up to three movements away from the root farm increased the odds of a btb incident, while connections with more farms in the england low-risk area up to eight movements away decreased the odds. relative to other risk factors for btb, trading behaviours are arguably more amenable to change, and consideration of risks associated with indirect trading, as well direct trading, might therefore offer an additional approach to btb control in great britain. trading connections among farms can generate vast networks of animal movements [4] , which have been implicated in disease transmission [5, 6] . network epidemiology uses these networks as a framework on which to model the spread of infection [7] and measures describing the centrality of a farm in a trading network and the nature of its contact chains (describing temporal connectedness) can be useful in assessing an individual farm's risk of acquiring infection [8] . mycobacterium bovis causes bovine tuberculosis (btb) in cattle but can infect a wide range of mammalian species [9] . despite intense study and significant resources invested in control measures, the infection remains endemic in large parts of great britain [10] . among other factors, wildlife reservoirs of infection, most notably in badgers meles meles, and undetected infections and movements of cattle have been shown to contribute to disease persistence and spread. a dynamic transmission model using british cattle movement and btb testing data from 1996 to 2011 predicted that the movements of cattle alone accounted for 13% of btb incidents and played a further role in multifactorial btb incidents [11] . modelling by green et al. [12] suggested that in 2004, 16% of herd infections occurred as a result of cattle movements and that local effects were more important. the effects of cattle movements on patterns of btb incidence in great britain have varied across regions [13, 14] and over time as new policies have been implemented [15] . however, in spite of the introduction of pre-movement and, in some limited circumstances, post-movement testing for animals leaving high-incidence areas [15] [16] [17] , studies using data from 2006 to 2013 still suggested that there was an increased risk of btb incidents for herds that had purchased cattle from high-risk regions of england and wales [17] [18] [19] . when compared to other risk factors for btb incidents, such as location and herd type, cattle movements represent an activity that might be more amenable to management, for example, by the use of risk-based trading, regulation or legislation. while the role of direct cattle movements in the transmission of btb in great britain has been well-documented, the risks associated with indirect movements arising from trade have not yet been quantified or explored in detail. second-order contacts (i.e. contacts of contacts) in farm networks have been shown to improve the estimates of simulated epidemic size in models of disease in the british cattle herd [20] and, in italy, influence the roles of individual farms in disease transmission [21] . in order to interrogate the farm trading network beyond first-order, direct contacts, data on the sequential purchases of cattle can be used to construct temporally explicit contact chains among farms. the ingoing contact chain (icc) represents the source farms that may contribute infection to the root farm, while the outgoing contact chain represents those farms to which the root farm might transmit infection. the magnitude of ingoing contact chains has been associated with the risk of btb in french cattle [8] and was used to inform risk-based targeting of farms for surveillance of bovine coronavirus and bovine respiratory syncytial virus in sweden [22] . we have previously constructed contact chains for all cattle herds in great britain and found that a large proportion of herds have remarkably extensive chains, extending to tens of thousands of other farms within 12-month periods [4] . in the present study, we hypothesize that farms with larger numbers of farms in their iccs are at greater risk of exposure and acquisition of infection. we predict that infection risks might therefore be greater for farms with iccs that include more risky trading partners, such as those that have experienced a recent btb incident or that are located in regions with high incidence rates. we also predict that the closer a farm is to the root farm, both in terms of geographical proximity and trading proximity, the more impact it will have on disease risk on the root farm. it has been established that risk factors are likely to vary across different geographical regions [14, 23] . therefore, we performed multiple analyses using subsets of data from specific regions. overall, our study aimed to assess the importance of new parameters from contact chains based on trading networks, alongside established risk factors, on the risk of btb incidents on cattle farms in great britain. we obtained btb surveillance and farm information data collated in the cattle tracing system (cts) by the animal and plant health agency (apha). study farms were active premises (i.e. registered cattle holdings with a birth, death or movement) between 1 january 2012 and 31 december 2014 with full btb testing and location data, resulting in a final dataset comprising 71 096 cattle farms. annual herd size was derived from the mean daily number of cattle on the premises. we took the mean of these annual herd sizes across the three years of the study. herd type was defined using cts data, first by the predominant breed type (dairy, beef or dual purpose) and then sex of animals on the farm (as outlined in [4] ). farms were allocated to btb risk areas for england based on the designated risk area of their county parish defined royalsocietypublishing.org/journal/rsos r. soc. open sci. 7: 191806 by apha in 2015 [24] (electronic supplementary material, methods and figure s1). a farm was defined as having had a btb incident if its officially tuberculosis free (otf) status was withdrawn (otf-w) or suspended (otf-s) on one or more days during the time period in question, i.e. for assessing previous btb history this period was 2010-2014, and for our response variable, it was 2015-2016. otf status is suspended (otf-s) if at least one animal tests positive (or returns two inconclusive test results) for m. bovis, using either of the statutory live tests: the single intradermal cervical comparative tuberculin (sicct) test or the gamma interferon test, and is withdrawn (otf-w) upon finding post-mortem pathology characteristic of m. bovis or isolation of the bacteria by culture. both types of incident were included in the analysis in order to maximize the power of tests of the association between infection in the contact chain and subsequent incidents. two additional analyses were performed with each type of incident as the response variable (otf-s and otf-w), but final outcomes did not change substantially and so the simpler, combined analysis is presented here. a single-directed network was calculated for each of the three study years, representing farms as nodes and with farm-to-farm movements of at least one animal represented by edges, weighted by the number of animals traded between those farms in the study year (electronic supplementary material, methods). betweenness centrality was calculated for each root farm in each network, providing a centrality measure of the importance of the farm in connecting together different parts of the network [25] . iccs are comprised of farms linked by movements of animals onto farms in a chronological sequence, such than at least one animal from a movement could have potentially seeded an infection that could, in principle, be passed on in a subsequent movement of animals from that farm. any farm that may have contributed to infection on the root farm (via movements) within the study period is included in the chain as a 'source farm'. the 'level' for each source farm corresponds to the minimum number of movements away from the root farm at which they appear in the ingoing contact chain. to avoid any seasonal effect of starting the chain in a specific month, we calculated 24 iccs at one month intervals, each spanning 12 months of movements. we then grouped the source farms from each of the 24 iccs. where farms appeared more than once in the chain in any one year, we included them at the closest (minimum) level to the root farm and removed other instances. each chain was curtailed at eight levels away from the root farm due to computational limitations (electronic supplementary material, methods). for each root farm, we quantified how many source farms from each region were at each level of the contact chain and how many source farms at each level experienced a btb incident from 2010 to 2014. we used cumulative counts across the different levels, e.g. the number of source farms at level one, the sum of the number of source farms at levels one and two, etc., up to the eighth level. we recorded the mean distance between each root farm and all of their source farms at each level. to incorporate btb risks from local farms, we calculated the proportion of farms that had experienced a btb incident between 2010-2014, within a radius of 0-2 km, 0-4 km, 0-6 km, 0-8 km and 0-10 km of the root farm. location was defined by the (x, y) coordinates associated with a particular holding identity (county parish holding number) in the apha data. there are limitations with this proxy for farm location because, in some cases, the point location of the cph does not lie within farmland where cattle are mostly located. however, there is no known systematic spatial bias to these locations, sample size is very large and there are no validated alternatives at this scale. thus, this is the best proxy to use, and it has been used in previous studies [13, 18] . we selected baseline variables for a regression model based on previously identified risk factors [19, 23] listed in table 1. we specified a multivariable regression model using a baseline set of variables (table 1) with the binary response of whether the root farm experienced a btb incident in 2015 or 2016, i.e. immediately after the period over which the iccs had been calculated. various risk factors could be specified at different lags (e.g. distances or levels of the network). however, the inclusion of multiple variables corresponding to a single-risk factor specified at different lags results in high multicollinearity and thus model instability. instead, we chose a single representative variable within each set of lagged variables by adding each lagged variable in turn to this baseline model and choosing the one with the lowest value of the akaike information criterion (aic) [26] . this avoided the inclusion of a large number of highly correlated variables and problems with inference caused by singularity errors in the design matrix, while preventing excessive model selection and therefore reducing bias in the estimated coefficients of the model [27] . as an example, to select the most suitable lag for the risk of btb from the local area, we ran five multivariable regression models including each distance with the baseline risk factors described above (electronic supplementary material, figure s2 ). the model with the lowest royalsocietypublishing.org/journal/rsos r. soc. open sci. 7: 191806 table 1 . effect sizes of explanatory variables on the odds of a bovine tuberculosis incident on the root farm in 2015-2016. odds ratios with 95% confidence intervals are from our multivariable logistic regression analysis using the full great britain dataset. odds ratios of continuous variables are standardized as the odds associated with the difference between the 10th and 90th percentiles of the raw data. aic included the proportion of farms with btb during 2010-2014 within a radius of 8 km from the farm, and so this term was included in the final model. this process was repeated to select representative variables from two sets of contact chain variables; those we expected to be associated with increased or decreased risk of a btb incident on the root farm (electronic supplementary material, figure s3 ). the final model included all baseline explanatory variables, the proportion of farms in a radius of 0-8 km with a recent btb incident and the selected representative source farm variables: the number of farms located in the england high-risk area at levels 1-3, and the number of farms located in the england low-risk area at levels 1-8 of the icc (table 1) . to capture potential differences in aetiology between different regions, we grouped our root farms by their region (electronic supplementary material, figure s1 ) and performed the same multivariable analysis, only removing region as an explanatory variable. to aid comparison of odds ratios (ors) between variables specified on different scales, we re-scaled the coefficients for continuous variables such that each estimate corresponds to the or for a variable changing from the 10th percentile to the 90th percentile of the observed data (table 1; electronic supplementary material, table s2 ). to make it clear that these do not relate to a per-unit increase odds ratio, we henceforth refer to them as standardized ors (note that these are not standardized in the usual statistical sense (using standard deviations), which would not be sensible here due to high asymmetry in the distributions of some of the explanatory variables). model performance was assessed (electronic supplementary material, figure s4 ) and we tested for overfitting of the final model using bootstrapping [27] . given the size of the dataset, the model showed negligible evidence of any overfitting, so we chose to present the unadjusted results here. all analysis was performed using r [28] ; network measures were calculated in 'igraph' [29] , contact chains were calculated using 'epicontacttrace' [30] , and regression was performed using 'lme4' [31] . the majority of source farms were located within the same btb risk area or region as the root farm. however, the mean distance between root and source farms increased with the number of levels in the icc (electronic supplementary material, figure s5 ). an average root farm in the england edge area, england low-risk area or in wales had about 20-25% of its source farms located in the england high-risk area ( figure 1) . also, 21% of root farms in scotland had over 20% of source farms located in the england high-risk area (figure 1). apart from scotland, all regions had some farms that had almost all of their source farms located in other regions (figure 1). the maximum number of farms at each level increased up to level 3 and declined thereafter, likely demonstrating a saturation effect where farms connecting at 'higher' levels in the chain had already been counted at 'lower' levels and, therefore, did not increase the total number of farms in the chain. by contrast, the median values for the number of farms increased at each level up to level 8, likely demonstrating an overall amplification effect where the presence of more farms at each level allowed more farms to connect at the next (figure 2). in 2015-2016, 12.9% of root farms experienced a btb incident, of which 78.5% were classified as otf-w (electronic supplementary material, table s1). proportions of btb incidents classified as otf-w or otf-s in the england high-risk area and wales mirrored those in great britain as a whole, whereas in the england edge area the relative proportions of these classifications were more equal and in the england low-risk area and scotland, there were more btb incidents classed as otf-s than otf-w (electronic supplementary material, table s1). characteristics of the root farm and local btb history were major risk factors associated with the likelihood of a btb incident. in selecting our variables, model performance was better (i.e. a lower aic) when we included the number of source farms in the england high-risk area, than those in the england edge area, wales or the number of source farms with a btb incident in the last 5 years (electronic supplementary royalsocietypublishing.org/journal/rsos r. soc. open sci. 7: 191806 material, figure s3) . a root farm with more farms in the england high-risk area at levels 1-3 of their icc had 1.11 (1.07-1.15) times higher odds of having a btb incident (table 1). we found that having more farms in lower incidence areas at any level of the icc was associated with a decreased risk of btb incident on the root farm, specifically root farms had lower odds of a btb incident in 2015-2016 (or = 0.69, 0.58-0.83; table 1) if they had more source farms located in the england low-risk area at levels 1-8 of their icc. the odds of having a btb incident were 1.23 (1.12-1.34) times higher when purchasing cattle direct from the england high-risk area compared to not purchasing cattle from the england high-risk area (figure 3). our regional analyses showed broadly similar effect sizes to those obtained using the entire great britain dataset; however, there were key differences in the effect sizes for btb history on root farms and neighbouring farms (table 1; electronic supplementary material, table s2 royalsocietypublishing.org/journal/rsos r. soc. open sci. 7: 191806 area decreased the odds of a btb incident more for root farms in the england low-risk area than for farms in the full great britain dataset. in terms of previously established risk factors, the odds of having a repeat btb incident on root farms in the england low-risk area and in scotland following an incident in the preceding 5-year period were over fifteen times greater than those for farms which experienced no btb incident in that period. similarly, the odds of btb incidents on farms in the england low-risk area were almost five times greater if they had experienced a previous incident. for root farms in the england high-risk area, england edge area and in wales, a repeat incident had more than twice the odds of occurring than a first-time incident. larger herds had at least thirteen times the odds of experiencing a btb incident than smaller farms in all regions. compared to other herd types, dairy with previous btb incidents was associated with almost eight times higher odds (electronic supplementary material, table s2 ). the effect was lower for farms in the england low-risk area and scotland, where very few farms had neighbouring farms with recent btb incidents. after accounting for known risk factors, we have revealed additional influences on the risks of a new btb incident on cattle farms arising from the characteristics and btb history of indirect trading partners in the extensive trading networks of british cattle farms. the risk of a btb incident increased where there were more farms from the england high-risk area at levels 1-3 in the icc, while having more farms located in the england low-risk area at any level in the icc was associated with a decreased risk. our study covers the period 2010-2016, 4 to 10 years after the introduction of comprehensive premovement testing, and selective post-movement testing, and indicates that there remains an increased risk of btb incidents associated with direct and indirect trading with farms in the england high-risk area (including trades within the england high-risk area). while we found a modest effect (or = 1.23) of having made a direct purchase from the england high-risk area, our results suggest that there is scope for further reductions in the risks of acquiring btb through trading links. for herds with nonnegligible levels of infection, the sicct test has reasonable sensitivity when considered as a herd-level test [32] ; however, when used for pre-and post-movement testing on small batches of cattle (the median number of animals per trade between 2002 and 2015 was 2 with an interquartile range of 1-4 [4] ), its sensitivity is likely to be much lower [33] , resulting in frequent false negatives and the undesirable movement of truly infected animals. although farms tend to trade directly most often within their regions [34] and pre-and post-movement testing has been shown to deter movements between regions [17] , we show that extensive inter-regional connections are quickly formed in the contact chains of many farms. we observed that within a few movements, large areas of great britain might be traversed by cattle movements and that farms can be connected to many farms outside of their risk area or geographical region. while relatively few of these connections are likely to transmit infection, those that do may be effective in translocating disease into new areas [35] . the use of more sensitive diagnostics such as the gamma interferon assay [36] in movement-associated testing, both within and out of annually tested areas, might serve to deter purchase of animals from the england high-risk area, due to higher costs, and also to reduce transmission between farms, as the risk of moving infected animals would be reduced. risk-based trading protocols, including those that quantify direct trading risk, have been outlined elsewhere [37] , and including an estimate of the risk associated with indirect trading, using the locations and numbers of source farms might lead to better understanding of the totality of risk associated with each purchase. data used in this study are readily available for authorities to calculate indirect trading chains of each farm, perhaps to a lesser extent than practiced here, in order to reduce computational time (e.g. up to three movements away from the root farm) and could be then made available to farmers, for example, using an existing application such as the online ibtb tool [38] . clearly, btb status is only one of many factors taken into consideration when purchasing stock, if indeed it is considered at all [39] . focussing solely on sourcing animals based on particular diseases might also unintentionally result in an increased risk of others [40] . therefore, in addition to btb specific government controls, holistic measures that reduce the risk of all diseases, such as reducing trade connections and quarantine measures are likely to contribute effectively to herd biosecurity. results of the present study show that having more farms in the icc was initially associated with increased risk, as observed in a similar study of cattle contact chains in france [8] . however, unlike the french study, the number of source farms was not associated with a large increase in the risk of experiencing a btb incident, suggesting that trade in cattle might play a different role in predicting btb incidents in the two countries. bovine tuberculosis prevalence is much lower in france than in england and wales and there is a comparatively low force of infection from the local environment. this likely results in overall trading strategies being more important, relative to the specific identity of trading partners in the movement network. our analysis in britain showed that in terms of btb incident risk, the location of source farms was more important than the total number of source farms. we predicted that trading with farms that had a history of btb incidents would be a more accurate predictor of risk than trading with farms from the england high-risk area, as reported by green et al. [12] . however, we also found that trading with farms in the england high-risk area was more royalsocietypublishing.org/journal/rsos r. soc. open sci. 7: 191806 informative in predicting a subsequent btb incident on the root farm. this may suggest that past btb incidents do not fully describe btb risk and that undisclosed infections in herds and/or environmental sources of infection, such as wildlife, present a risk that is captured by being in the england high-risk area but not detected through routine testing [41] . spatial proximity to farms with recent btb incidents increased the risk of a btb incident on the root farm in the full great britain model and regional models except for scotland. we expected that farms closest (i.e. 0-2 km) to the root farm would have the greatest effect on this risk as this would encompass potential contacts of cattle on shared boundaries and the risks from infected local wildlife [42] . however, the variable which best explained this risk was the proportion of farms with a btb incident within a radius of 8 km. this could potentially be related to the additional effects of unrecorded local cattle movements [12] , the spreading of infected slurry [23] and movement of cattle among fragmented land parcels [42] . that this proxy measure still has a large effect size after accounting for other major factors suggests that some or all of these factors may be important drivers of local risk. notwithstanding the low number of repeat btb incidents in scotland (n = 21) and the england low-risk area (n = 60) and broad confidence intervals of this variable, the effect of previous incidents in the preceding 5 years (2010-2014) on the risk of a later incident in scotland or in the england low-risk area was considerably greater than the effect of prior history in the higher risk areas of england and wales. as the environmental force of re-infection in non-endemic areas is likely to be low, this suggests that a small number of herds in scotland and the england low-risk area may have had otf status restored without having fully eliminated infection [41] , or alternatively, that there is a repeated external source of infection not accounted for in our study. for example, we have not included cattle imports from outside great britain and may therefore have underestimated the risk of btb on farms that import animals from northern ireland and the republic of ireland [19] , where btb infection is also endemic in cattle. an advantage of the regression framework employed in the present study is that it is more straightforward to fit these models to complex data than it would be to fit a fully mechanistic infectious disease model [11, 41] . however, while we included approximations for risk based on region and local btb occurrence, we were unable to fully disentangle the relationships between movements, regions and finer scale spatial risk or the complex interactions between trading, behaviours, herd type and size. it may be that the impact of the network dynamics is more evident if explicit trading paths are modelled, for example, through the use of a compartmental network-based epidemic model [11] . the effects of trading patterns in our study were relatively small compared to other known risk factors such as herd size [43, 44] and prior btb history [8, 12, 44] . nevertheless, the major risk factors identified in this and previous studies tend to reflect fixed characteristics of farms (location, past disease history) and those that are difficult, costly or slow to change (herd type). by contrast, elements of trading behaviour, and particular purchasing decisions, might be more amenable to modification, through regulation and incentivization with support from industry and policy-makers. although certain trading behaviours are clearly related to business type (e.g. dairy, fattening, etc.) [4] , careful consideration of existing trading behaviours and potential purchases could result in more robust and safer acquisition and sales of livestock. the present study reinforces the importance of direct trading links but highlights the additional risks associated with indirect trading links, revealed by a more thorough examination of the movement network, as necessary factors to consider in strategies to reduce btb transmission in great britain. in the specific context of btb and trading, raising awareness of trading risks might prompt farmers to seek more information about their potential trading partners and encourage industry and government to facilitate sharing of this kind of data. given the computational complexities of interrogating such a dense movement network in real time, the next challenge will be in determining how best these sources of risk might be integrated into current management policies and evaluating how farmers might respond to them. further methodological information, figures and tables supporting this article have been uploaded as part of the electronic supplementary material. data accessibility. underlying data consist of every movement of cattle between all farms in great britain and their disease history. aside from the size of the dataset, there are substantial issues of confidentiality (locations, trading practices) and commercial sensitivity in these data. they are collated and managed by defra, via the animal and plant health agency, who grant access to the data with specific permissions for specific studies. in practice, this means that the data can be used for the stated purpose only, and making the data publicly accessible would not conform to the licence the authors have been granted to use these data. with the agreement of the journal's editorial office, the authors will not be able to make the dataset available on this occasion, but encourage readers, referees and editors to contact the animal and plant health agency data manager for data access requests. at the time of submission, the data royalsocietypublishing.org/journal/rsos r. soc. open sci. 7: 191806 superspreading and the effect of individual variation on disease emergence disease spread through animal movements: a static and temporal network analysis of pig trade in germany stochastic spatio-temporal modelling of african swine fever spread in the european union during the high risk period disease dynamics over very different timescales: foot-and-mouth disease and scrapie on the network of livestock movements in the uk network analysis of dairy cattle movement and its implication on bovine tuberculosis spread and control in emerging dairy belts of ethiopia social network analysis. review of general concepts and use in preventive veterinary medicine role of cattle movements in bovine tuberculosis spread in france between mycobacterium bovis infections in domesticated non-bovine mammalian species. part 1: review of epidemiology and laboratory submissions in great britain bovine tuberculosis in britain and ireland -a perfect storm? the confluence of potential ecological and epidemiological impediments to controlling a chronic infectious disease a dynamic model of bovine tuberculosis spread and control in great britain estimates for local and movement-based transmission of bovine tuberculosis in british cattle cattle movements and bovine tuberculosis in great britain herd-level risk factors of bovine tuberculosis in england and wales after the 2001 foot-and-mouth disease epidemic impact of regulatory perturbations to disease spread through cattle movements in great britain pre-movement and post-movement testing of cattle in great britain impact of changes in cattle movement regulations on the risks of bovine tuberculosis for scottish farms risk factors for bovine tuberculosis in low incidence regions related to the movements of cattle risk-based strategies for surveillance of tuberculosis infection in cattle for low-risk areas in england and scotland is r 0 a good predictor of final epidemic size: foot-and-mouth disease in the uk network analysis of italian cattle trade patterns and evaluation of risks for potential disease spread application of network analysis parameters in risk-based surveillance -examples based on cattle trade data and bovine infections in sweden herdlevel risk factors for bovine tuberculosis: a literature review bovine tuberculosis in great britain -surveillance data for 2015 & historical trends. project sb4500. addlestone, uk: animal and plant health agency using social network measures in wildlife disease ecology, epidemiology, and management model selection and multimodel inference: a practical information-theoretic approach regression modeling strategies r: a language and environment for statistical computing the igraph software package for complex network research epicontacttrace: an r-package for contact tracing during livestock disease outbreaks and for risk-based surveillance fitting linear mixed-effects models using lme4 herd-level interpretation of test results for epidemiologic studies of animal diseases evaluating the health status of herds based on tests applied to individuals characteristics of cattle movements in britain -an analysis of records from the cattle tracing system introduction of bovine tuberculosis to north-east england by bought-in cattle meta-analyses of the sensitivity and specificity of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis in the uk and ireland development of risk-based trading farm scoring system to assist with the control of bovine tuberculosis in cattle in england and wales developing a risk-based trading scheme for cattle in england: farmer perspectives on managing trading risk for bovine tuberculosis assessing the impact of tailored biosecurity advice on farmer behaviour and pathogen presence in beef herds in england and wales estimating the hidden burden of bovine tuberculosis in great britain farm characteristics and farmer perceptions associated with bovine tuberculosis incidents in areas of emerging endemic spread herd size and bovine tuberculosis persistence in cattle farms in great britain identifying genotype specific elevated-risk areas and associated herd risk factors for bovine tuberculosis spread in british cattle 2020 data from: effects of trading networks on the risk of bovine tuberculosis incidents on cattle farms in great britain manager is andy mitchell (andrew.mitchell@apha.gov.uk) . code used to run our analysis is available at dryad digital repository: https://dx.doi.org/10.5061/dryad.k0p2ngf56 [45] . competing interests. we declare we have no competing interests. funding. hrf was funded by an industrial case studentship from the bbsrc grant bb/m015874/1, in partnership with the apha.acknowledgements. the authors gratefully acknowledge stefan widgren, andy mitchell and the apha data and epidemiology teams for providing data and assisting with data interpretation. key: cord-328522-ef4xg3q0 authors: kelen, gabor d; kraus, chadd k; mccarthy, melissa l; bass, eric; hsu, edbert b; li, guohua; scheulen, james j; shahan, judy b; brill, justin d; green, gary b title: inpatient disposition classification for the creation of hospital surge capacity: a multiphase study date: 2006-11-30 journal: lancet doi: 10.1016/s0140-6736(06)69808-5 sha: doc_id: 328522 cord_uid: ef4xg3q0 background: the ability to provide medical care during sudden increases in patient volume during a disaster or other high-consequence event is a serious concern for health-care systems. identification of inpatients for safe early discharge (ie, reverse triage) could create additional hospital surge capacity. we sought to develop a disposition classification system that categorises inpatients according to suitability for immediate discharge on the basis of risk tolerance for a subsequent consequential medical event. methods: we did a warfare analysis laboratory exercise using evidence-based techniques, combined with a consensus process of 39 expert panellists. these panellists were asked to define the categories of a disposition classification system, assign risk tolerance of a consequential medical event to each category, identify critical interventions, and rank each (using a scale of 1–10) according to the likelihood of a resultant consequential medical event if a critical intervention is withdrawn or withheld because of discharge. findings: the panellists unanimously agreed on a five-category disposition classification system. the upper limit of risk tolerance for a consequential medical event in the lowest risk group if discharged early was less than 4%. the next categories had upper limits of risk tolerance of about 12% (iqr 8–15%), 33% (25–50%), 60% (45–80%) and 100% (95–100%), respectively. the expert panellists identified 28 critical interventions with a likelihood of association with a consequential medical event if withdrawn, ranging from 3 to 10 on the 10-point scale. interpretation: the disposition classification system allows conceptual classification of patients for suitable disposition, including those deemed safe for early discharge home during surges in demand. clinical criteria allowing real-time categorisation of patients are awaited. the ability to provide medical care during sudden increases in patient volume during a disaster or other highconsequence event is a substantial concern for health-care systems. history has shown that during disasters and epidemiological outbreaks, hospitals take the burden of caring for the sick and injured. [1] [2] [3] [4] [5] [6] in most major city hospitals, inpatient capacity is constrained on a daily basis. [7] [8] [9] thus, hospitals are concerned about maintenance of inpatient capacity during normal operating conditions, and they are developing methods to improve resource capabilities during surges. 10, 11 several measures have been suggested for the creation of hospital surge capacity. [12] [13] [14] [15] [16] these include: cancellation of elective admissions and operations; redesign of current inpatient space to accommodate more beds when needed; opening of unlicensed or unstaff ed beds; rapidly outfi tting temporary nearby space, such as cafeterias or outpatient facilities; or deployment of temporary portable inpatient units. all these possibilities present unique operational challenges, such as imposition of unpractised routines in the context of rapid incremental demand for inpatient census. furthermore, most options need hospital staffi ng to be increased at a time when the case-mix index can also be expected to increase. however, during some publichealth emergencies, especially those of a com municable nature, hospitals are likely to have substantial reductions in available staff , as happened during the severe acute respiratory syndrome outbreak. [17] [18] [19] thus, for acute-care hospitals, a means to achieve maximum availability of capacity resources to allow for the care of victims of a disaster is a priority. 20 one novel approach to capacity management during disasters is reverse triage, which includes the safe discharge of current inpatients and refocus of hospital resources to those in even greater need. patients might be discharged home, to facilities set up to care for less acute inpatients (eg, public-health contingency stations 21 specifi cally designed for this purpose), nursing homes, or other acute-care facilities. thus, a need exists to develop an easy method to categorise hospital patients for safe discharge to suitable venues (including early discharge home), taking into account the existence and competence (or lack thereof) of available external resources. we report the fi rst phase in the development of inpatient disposition criteria for the creation of hospital surge capacity during catastrophic or high-consequence events. the aim of this phase was to develop a disposition classifi cation system (reverse triage) based on risk tolerance of a consequential medical event as a result of discharge; assuming that critical interventions were withdrawn or withheld. we focus on the main components of the fi rst phase: (1) conceptualisation of the disposition classifi cation system; (2) development of operational defi nitions of consequential medical events and critical interventions; and (3) derivation of risk estimates related to early discharge from a multidisciplinary panel of experts. subsequent phases of this project will use clinical data obtained from nearly 4000 hospital patients to examine the validity of the classifi cation system to correctly identify those who can be discharged early. we used evidence-based materials combined with an expert panel consensus that was approved by the institutional review board on human subjects research. we hosted a warfare analysis laboratory exercise, 22 which was developed by the johns hopkins applied physics laboratory in 2004. the exercise uses networked computers that allow anonymous participation through streaming comments entered into individual laptops by panellists. 39 expert panellists (27 clinicians or practitioners, 12 nonclinicians, or non-practising clinicians) took part in the 8-h exercise. conference organisers determined the composition and the variety of desirable backgrounds of the panel members, who were then identifi ed and specifi cally invited. all panellists were involved in health care, but represented diverse perspectives, including those of nonclinicians. the composition of the expert panel is shown in panel 1. 31 of the participants were from various components of the johns hopkins medical institutions, and eight were from outside agencies and institutions. almost all the local panellists had experience in other health systems in the usa, and four had experience in other countries. those from the home institution represented three distinctly diff erent establish ments: a major academic health centre, an affi liate teaching centre, and a community hospital. four of the authors participated in the panel discussions. individual panellists received a detailed manual of background information on the day's proceedings, goals, objectives, and expectations from the expert panel. need for written informed consent for participation was waived by the institutional review board on human subjects research because all written comments and risk estimates made by the panellists were anonymous and could not be linked back to an individual. the warfare analysis laboratory is a specialised facility equipped with a network of 53 laptop computers, an integrated audio and visual infrastructure with six large-screen, high-resolution, interactive three-dimensional computer graphics display monitors, a designated data-analysis station, and a 50-seat observation gallery. plans, defi nitions, and assumptions can be displayed on large-screen monitors at the front of the room. one or more of the screens can be dedicated to continuous display of anonymous comments from panellists on each networked computer in real time. items that need opinions or need to be voted on can also be processed and displayed in real-time. computer comments are numbered consecutively to help with responses to specifi c statements. the exercise is a formally defi ned process and is further described elsewhere. 22 the warfare analysis laboratory has a professional team that oversees the process. a trained facilitator guides the process, allowing for discussion of key issues, and maintaining the focus on the day's objectives. before the exercise was started, eight consensus panel organisers held two separate full-day rehearsals for the conference, to ensure that presentations, discussion, and voting would go smoothly. on the day of the exercise, panellists were shown how to use the facility and computer data-gathering techniques with presimulations unrelated or indirectly related to the planned session. panellists were then exposed to short formal presentations on disaster management, surge-capacity concepts (fi gure), notions of risk and risk tolerance in health care, an overview of the project, and rationale and specifi c objectives. evidencebased information was presented about decision-making devices (eg, patient outcomes research team [port] and acute physiology and chronic health evaluation [apache] iii), peer-reviewed publications, and data for adverse events, readmission rate of discharged patients, and iatrogenic events related to being in hospital. the tasks of the expert panel during the exercise were to: (1) develop an evidence-based disposition classifi cation system for discharge or transfer based on tolerance for the occurrence of a consequential medical event or the need for a critical intervention during the ensuing 72 h after discharge or transfer; (2) develop consensus defi nitions of consequential medical event and critical intervention; (3) assign, for each category of the system, the panel's tolerance for a subsequent consequential medical event, or need for an in-hospital critical intervention; and (4) compile a list of (6), psychiatry (1), infectious diseases (1), obstetrics/gynaecology (2), oncology (1), paediatrics (2), paediatric emergency medicine (2), general surgery, paediatric surgery (1), critical care/anaesthesiology (2), cardiology (1), nephrology (1), trauma surgery (1), ear nose and throat (1), military surgery (1), military emergency medicine (2), military psychiatry (1) obstetrics and gynaecology (1), psychiatry (1), internal medicine (1), emergency medicine (1), surgery (2), paediatrics (1), military (2), oncology (1) disaster management (8), disaster and military triage (3), hospital epidemiology (3), research methodology (4), risk management (3), hospital administration (6), home health services (1), social work (1), medical law (1), medical ethics (1), patient safety (6), data analysis (5), military public health (3), city and state public health (3), public health (10), public health preparedness and response (10), homeland security (9), prehospital care (1), international health care (7) numbers in each category are shown in parentheses. some physicians and experts are included in more than one specialist area. critical interventions that would imply the need for continued stay in an acute-care hospital. discussions were held of assumptions to be used for defi nition of the disposition classifi cation system. panellists were presented with proposed assumptions developed by the project leaders and were invited to criticise and include additional assumptions. final assumptions under which the conference proceeded are shown in panel 2. panellists were shown examples of classifi cation systems used for clinical decision making. [23] [24] [25] [26] the notion and number of categories were discussed by panellists both via open comment and anonymous computer input. discussion focused on dispositions that defi ne severity of illness and likelihood of treatable complications. the process also included a discussion on the language used to defi ne the categories to help with assignment of tolerance of risk for a consequential medical event. consensus was reached about the number of categories based on tolerance for a consequential medical event. to determine into which category of the disposition classifi cation system a patient falls requires the assessment of risk for a consequential medical event. assessment of risk took into account the possibility of medical deterioration, a new medical event, or the untoward eff ect of the withdrawal of a continuing treatment (ie, withdrawal of a critical intervention). the consensus defi nition of consequential medical event developed by the panellists was: unexpected death, irreversible impairment, or reduction in function within 72 h of hospital discharge for which an in-hospital critical intervention would be initiated to stabilise or ameliorate the medical disorder or disorders. panellists reasoned that medical events were consequential only if acute in-hospital treatment or intervention was needed. thus, when the probability of a consequential medical event was determined, the panellists agreed that likelihood should be judged on the basis of need for a new or continuing in-hospital treatment, termed critical intervention. thus, failure to initiate or continue a critical intervention risked a consequential medical event. to orientate panellists with respect to tolerance of risks taken in daily medical care, panellists were presented data for: 3-day and 15-day readmission rates taken from 26 000 adult discharges during 1 year (2003) for various medical services from one of our hospitals (unpublished data), as well as data of baseline inpatient hospital errors from the institute of medicine. 27 risk, consequential medical event, and the defi nition of critical intervention were then discussed in detail. after the defi nitions had been decided on, the panellists voted to defi ne the upper limit of acceptable risk for the occurrence of a consequential medical event (ie, need for critical intervention), for each of the categories of the disposition classifi cation system. voting was on a scale of 0-100%, with votes given to one decimal point. results of the fi rst vote were revealed and further discussion ensued. a second (and fi nal) consensus vote was then taken. after discussion, a consensus defi nition of critical interventions was formed and became embedded in the defi nition of consequential medical event, as noted above. panellists were then presented with a list of critical interventions to consider, and asked to validate or criticise each in view of the consensus defi nition. a list of possible candidate critical interventions was initially developed by the conference organisers. all panellists were allowed to suggest and add interventions to the list. panellists with clinical experience or responsibilities were then asked to rank on a likert scale of 1 to 10 (whole numbers only), how likely, in their opinion, the withholding or withdrawal of • panellists should think globally and not specifi cally about their facilities • the hospital will remain functional (ie, not a target of terrorist threat or disaster) • government and other disaster response will occur • disaster plans will exist • health-care system will recover or be aided within 48-72 h • assume ability to smoothly discharge or transfer patients (specifi c logistical issues will be considered separately). • a model to compare risk profi les of competing new patients requiring hospital resources exists • hospital liability protection exists or is not an issue • inpatient beds could be redistributed across various services • quality of care will not be compromised • only basic (non-professional or family) care will be available to patients discharged into the community (relatives, shelters, or home) • hospital patients with dismal prognosis will be considered separately • other eff orts to improve surge capacity will be continuing each of the listed critical interventions would lead to a consequential medical event. a score of ten was deemed to be synonymous with certainty of a consequential medical event, whereas a score of one implied virtually no associated risk with withholding or withdrawing the specifi c critical intervention. panellists without clinical experience or responsibilities participated in discussions, but did not vote. separate votes were taken for withholding and withdrawing the critical intervention. data generated by these votes were presented. after further discussion, a fi nal vote was taken. data were recorded and stored in a database and were then tabulated. only the fi nal votes were used for analysis. data only from clinicians were used for those questions requiring clinical expertise (clinicians could be identifi ed because they logged on as "clinician" rather than "nonclinician"). because the warfare analysis laboratory exercise requires anonymity in recording participant responses, subgroup analyses by medical specialty were not possible. the study sponsor had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report. the corresponding author had full access to all data in the study and had fi nal responsibility for the decision to submit the paper for publication. the panellists agreed that a fi ve category disposition classifi cation system was optimum, for the intended task (table 1) . consensus was reached on the understanding and wording of the categories. the upper limit of risk tolerance for a consequential medical event for the fi rst category was less than 4%. this category represented patients who the panellists judged to be at low risk of a consequential medical event if discharged early; on the assumption that no skilled medical care was available outside the hospital setting. an example would be a patient admitted for intravenous antibiotics for uncomplicated cellulitis, who could readily be discharged and switched to oral medication. the next categories had upper limits of risk tolerance of about 12%, 33%, 60%, and 100% respectively. the panellists agreed that category 2 represented those patients who, although at some risk of a consequential medical event, might nonetheless warrant discharge if surge capacity was needed for victims of a disaster; especially if incoming victims are at higher risk of consequential medical event than those patients considered for discharge. panellists also agreed that this category of patients could warrant discharge in certain biothreat or other contagion situations in which spread of disease in hospitals would present a substantial added risk. an example would be a patient with acute coronary syndrome with no evidence of high risk for adverse events. category 3 represented patients who were potentially suitable for transfer to another medical facility. as a group, the risk was judged too high for simple discharge home. an example would be a stable elderly patient who is progressing well 3 days after hip-fracture surgery. category 4 patients were those at substantial risk and judged likely to need continued acute-hospital resources. examples of such patients include those in need of emergency surgery, those in need of pressors, and those in active labour. finally, category 5 patients were those who might be too unstable or critically ill even for transfer to another appropriate facility. most of these patients would require specialised medical care. most patients in intensive-care units would be in this category. table 2 shows the consensus list of critical interventions that if withdrawn would result in a consequential medical event. less than half the critical interventions were assessed as 7 or higher (on a scale of 1-10). only two-thirds were ranked higher than 5. for every situation, panellists' scoring for critical interventions that were withdrawn compared with those that were not available or withheld was much the same as that for critical interventions that were withheld. we have proposed the notion of in-hospital disposition classifi cation scheme (reverse triage) of inpatients to deal with increased hospital demand during high consequence disasters. a system of patient categorisation based on risk tolerance developed by an expert panel provides a context for further work to determine which patients can be safely discharged early at the time of overwhelming need for hospital-based resources. mean upper limit of tolerance for consequential medical events (iqr) high consequent events are disasters that overwhelm local or regional infrastructure including the health system. the need to plan for and increase hospital capacity during high consequence disasters is now a standard recommendation. 11, 28 many techniques have been suggested, such as cancellation of elective admissions and surgeries, opening of licensed but unstaff ed beds, use of other spaces that can be readily converted for clinical use, and triage and treat off site as many victims as possible. most of these techniques need increased staffi ng at a time when either staff are not available, staffi ng is degraded because of the disaster itself, or staff are co-opted by the public-health system for other needs. volunteer staff who are unfamiliar with hospital routine, remain an untested resource, and have yet to be shown as valuable for augmenting hospital capacity in any disaster. thus, other ideas for increasing or preserving capacity become important. much has been written about the appropriate triage of disaster victims. the focus is to concentrate resources on the most severely injured or ill who are likely to survive with defi nitive medical care. [29] [30] [31] one way to create hospital surge capacity-through reverse triage-has received scant attention. in military terms, reverse triage refers to treating those who are not seriously injured fi rst to allow them to return to the battlefi eld sooner. here, we expand the notion to the civilian medical model and include consideration of early discharge of the least sick. with present constraints on hospital capacity, making the most of available resources, rather than hoping that plans to augment them can be implemented, becomes an important consideration. patients are generally not discharged from hospitals if a consequential medical event is potentially foreseeable. however, a zero risk policy, although desirable, is not feasible. forster and colleagues 32 report that up to 19% of discharged patients have an adverse event in the immediate (3 week) post-discharge period. despite a strong patientsafety movement today, zero risk for an out of hospital consequential medical event as a condition of discharge is not attainable, and must be balanced against risk tolerance for various medical adverse events, including iatrogenic ones. 27, [32] [33] [34] [35] [36] despite the accepted risks discussed, our experienced panellists were reluctant to ascribe a substantially higher risk to the category 1 patients. even the risk tolerance assigned for category 2 patients can be regarded as conservative in view of the complex issues faced in major disasters. if a 12% risk of a consequential medical event is accepted, as was the consensus for category 2, the rate is still much less than the adverse event rate reported by forster. 32 the iqr for votes on categories 1, 2, and 5 were fairly narrow, indicating a cohesive consensus. however, the iqr for categories 3 and 4 were quite wide. categories 3 and 4 would be unlikely to be discharged. this report represents the fi rst part of a multiphase study. once the categories are established, the next step will be to derive a system that allows classifi cation of individual hospital patients in real time. to accomplish this, measurable outcomes and prognostic variables are required. the panel initially defi ned critical interventions as a means to understand the notions of risk. however, the consensus critical interventions will also serve as the outcome measures in subsequent studies. what constitutes a consequential medical event is subjective. thus, the critical interventions that are the outcome proxy measures were weighted for likely importance. future analysis will consider the accuracy of such weighting. the ultimate goal is to produce a disposition classifi cation system that guides clinical decision making during a disaster in a manner similar to the use of the apache score 24, 26 or port score 23 in everyday clinical practice. in view of the increasing trend toward electronic medical data, prognostic variables of potential interest-eg, vital signs, key laboratory values, diagnostic considerations, co-morbid conditions-could be captured and continuously updated in real-time. thus, in the event of a disaster, patients would be predesignated for the lowest risk disposition options, through the use of a system such as the one proposed here. if such a system were in place, each patient would have a continuously, updated reliable risk score to assist in disposition making. starting with those with the lowest risk, discharges would take place in an ascending order of risk. furthermore, in the future when prognostic scoring of risk for pre-hospital or emergency-department based disaster triage are developed and reliable, the entire demand for inpatient resources from all sources can be simultaneously ascertained and decisions made accordingly. the value of such a device is not only to augment surge capacity, but also to help with rapid decisions when complete or part hospital evacuations are required, such as happened during hurricanes katrina and rita, and the severe acute respiratory syndrome epidemic in toronto. a further and potentially important value of the development of a risk-based disposition classifi cation system is that it is also designed for everyday hospital use. emergency departments in many parts of the world are often overcrowded, mainly as a result of severely restricted in-patient capacity. thus, on a small, but real scale, disaster-like settings arise every day. the device being developed here could have a substantial eff ect on the safe management of hospital capacity on a routine daily basis. in fact, preliminary data from the next phase of the study, available at this time, show that such a device might prove useful for such dual purpose. simulating a disaster, we randomly sampled non-intensive-care unit adult patients from 50 medical units in our three-hospital system during 19 weeks. 37 of the 4781 patients sampled, 786 (16%) were discharged routinely on the day of the disaster. of the remaining patients, 2797 (70%) either had no critical interventions or were discharged in any event during the next 72 h. although full analysis remains to be completed, these data are consistent with those reported by davis and colleagues. 38 physicians and nurses in this study opined that about 50% of patients were dischargeable during 72 h. when controlling for patients in intensivecare, the proportion of capacity is similar to ours. finally, a study from a tertiary-care teaching hospital in the uk, also using opinion survey of nurses showed that more than a third of inpatient beds (including those in intensive-care units) could be made available within 4-12 h of a disaster if increased care were available in the community. 39 the fundamental problem with estimation of capacity on the basis of opinion surveys is absence of evidence that the estimates would result in safe practice. furthermore, as in the case of the uk study, which called for aug mentation of community resources, it is unclear whether these resources could reasonably be increased during catastrophic events. our approach is to establish the scientifi c basis for a practice that can be modifi able for use both daily and during catastrophic events. comments are needed on concerns that might be raised about the work presented here. the expert panellists were from a wide array of professions. although many of the panellists have varied geographic and institutional experience, we did not attempt to ensure that every hospital structure and size was represented by all disciplines. thus, inherent geographic or regional bias in the established ranges of risk tolerance could have occurred. however, as noted, about 25% of the panel were not from our system, and most of the panellists had other national and international experience. even so, the model described is suffi ciently robust that risk tolerance notions can be scaled to an individual hospital and even an individual service. if adopted for daily routine use, risk tolerances for categories 1 and 2 might change or be subject to local customs. we did not consider patient or lay perspectives, but again, the variables of the proposed device can be modifi ed in those settings that wish to consider such views. also, simulations used here might not represent reality, but most disaster planning is based on simulated exercises due to an absence of empirical data. furthermore, other systems have been developed on the basis of clinical judgment, in the absence of empirical data. one example is the abbreviated injury scale, 40, 41 which was originally based on clinical-judgment ratings, and has subsequently been shown to be both valid and reliable in measuring injury severity. more recently, hick and o'laughlin, 42 using a less structured consensus format, developed an ethical framework for the distribution of scarce intensive-care-unit resources during disasters. the 48-72 h period of concern is not arbitrary. generally local resources are highly stressed for this duration in the aftermath of a severe and sudden disaster. 43, 44 in fact, the us joint commission on accreditation of healthcare organizations position on hospital preparedness states that hospitals should "ensure a 48-72 hour stand-alone capability through the appropriate stockpiling of necessary medications and supplies." 11 other systems for augmenting surge capacity resources, including those defi ned by the national incident management system, 45 are activated within our period of concern. thus, external validation of our approach by the general community is needed, and this report serves as an appropriate foundation for such discussions. the next step is to derive a real-time decision rule or scoring system based on clinical variables that allows accurate categorisation of individual patients, followed by prospective validation. the experience of st vincent's hospital, manhattan two new york city hospitals' surgical response to the emergency department impact of the oklahoma city terrorist bombing severe acute respiratory syndrome and critical medicine: the toronto experience tornado: assessment of the trauma system response and the resulting injuries emergency department visits for home medical device failure during the 2003 north america blackout the role of public hospitals in urban health hospital and emergency department crowding in the united states emergency department overcrowding following systematic hospital restructuring: trends at twenty hospitals over ten years us government accountability offi ce. hospital preparedness: most urban hospitals have emergency plans but lack certain capacities for bioterrorism response health care at the crossroads: strategies for creating and sustaining community-wide emergency preparedness systems health care facility and community strategies for patient care surge capacity bioterrorism preparedness i: the emergency department and hospital lessons learned from the evacuation of an urban teaching hospital impact of a major hurricane on surgical services in a university hospital lessons learned from a nightclub fi re: institutional disaster preparedness clinical course and management of sars in health care workers in toronto: a case series an outbreak of severe acute respiratory syndrome among hospital workers in a community hospital in hong kong sars in three categories of hospital workers implications of hospital evacuation after the northridge, california, earthquake us centers for disease control and prevention. fiscal year 2006 justifi cation of estimates for appropriations committee the walex process a prediction rule to identify lowrisk patients with community-acquired pneumonia modeling the severity of illness of icu patients: a systems update a new simplifi ed acute physiology score (saps ii) based on a european/north american multicenter study the apache iii prognostic system. risk prediction of hospital mortality for critically ill hospitalized adults institute of medicine committee on quality of health care in america health care system surge capacity recognition, preparedness, and response casualties treated at the closest hospital in the madrid report of the events and the prehospital emergency response can external signs of trauma guide management? lessons from suicide bombing attacks in israel the incidence and severity of adverse event aff ecting patients after discharge form the hospital incidence of adverse events and negligence in hospitalized patients: results of the harvard medical practice study i the nature of adverse events in hospitalized patients: results of the harvard medical practice study ii institute of medicine medical error fi gures are not exaggerated deaths due to medical errors are exaggerated in the institute of medicine report creation of health system surge capacity by the immediate discharge of inpatients hospital bed surge capacity in the event of a mass-casualty incident accelerated discharge of patients in the event of a major incident: observational study of a teaching hospital rating the severity of tissue damage: i. the abbreviated scale rating the severity of tissue damage: ii. the comprehensive scale concept of operations for triage of mechanical ventilation in an epidemic state and regional responses to disasters: solving the 72-hour problem learning from disaster: the role of federalism and the importance of grassroots response national incident management system this study was sponsored by funding from the agency for healthcare research and quality (u01 hs14353-01). data in this manuscript were presented, in part, at the 14th world congress of disaster and emergency medicine, may 14, 2005, edinburgh, scotland. key: cord-334353-nc2jhemz authors: murphy, thérèse; whitty, noel title: is human rights prepared? risk, rights and public health emergencies date: 2009-05-08 journal: med law rev doi: 10.1093/medlaw/fwp007 sha: doc_id: 334353 cord_uid: nc2jhemz nan public health security is . . . the activities required, both proactive and reactive, to minimize vulnerability to acute public health events that endanger the collective health of national populations. global public health security widens this definition to include acute public health events that endanger the collective health of populations living across geographical regions and international boundaries . . . .[g]lobal health security, or lack of it, may also have an impact on economic or political stability, trade, tourism, access to goods and services and, if they occur repeatedly, on demographic stability. 3 the other term that requires some explanation is 'public health emergency legal preparedness'. stated shortly, this is all about having the right laws in place and then using them in the right way in a time of public health emergency. 4 in other words, it is about both legal preparedness for, and response to, public health emergencies -it is both proactive and reactive. more generally, it can be said to be an essential part of both public and global public health security, and a subset of public health emergency preparedness. having identified these basics, we move to the purpose of this article. the aim is to present a human rights lawyer's perspective on both public health emergency preparedness and, more generally, the turn towards securing public health through securitisation. we develop this perspective by asking the following question: is human rights prepared for public health emergency preparedness? we are not confident that it is. in what follows, we explain why we take this view and we also sketch out a preliminary agenda designed to encourage greater human rights preparedness. we focus in particular on the importance of thinking through how risk and its relationship to rights is being framed, and also how this relationship ought to be framed. one response to public health emergency preparedness might go as follows: even if there is an abundance of new terms, there is nothing new about the link between health and security. the detailed version 3 ibid., at 1. 4 220 medical law review [2009] of this response would run as follows: focusing first on national security, the effect of disease on military strength and preparedness is, without doubt, an age-old concern. infectious diseases can also be a source of indirect harm to national security given their potential to cause 'political and economic damage in countries in which a state has vital security, foreign policy, and trade interests'. 5 turning next to economic security, it is clear that here too there is a longstanding link to health. the first international health regulations (1969) and their predecessors, the international sanitary regulations (1951) , were explicit about this link: they aimed to 'ensure the maximum security against the international spread of diseases with a minimum interference with world traffic'. 6 finally, a third, more general, link between health and security arises from the fact that infectious diseases can 'erode governance capacities' and undermine 'a population's confidence and trust in the political leadership and system'. 7 clearly, then, there are longstanding connections between health and security. but that does not mean that the contemporary linkage between health and security is nothing new. to explain why we think there is something new in play, and to provide background for our argument in the latter parts of the article, this section sketches a history of the relationship between security and health. in particular, drawing on recent developments in international law and policy, it aims to show that health has come to be 'looked at through a new lens'. 8 we begin in 1994, the year in which the united nations development programme (undp) called for attention to be directed towards the achievement of 'human security', 'an idea . . . likely to revolutionize society in the 21st century'. 9 for undp, traditional concepts of security were, on the one hand, too focused on protecting states from 'external aggression, or as protection of national interests in foreign policy or as global security from the threat of nuclear holocaust' and, on the other, not focused enough on 'the legitimate concerns of ordinary people who sought security in their daily lives'. 10 undp saw 'human security' as a way to address this imbalance. it argued that human security could help to protect people from both chronic threats (such as hunger) and sudden, harmful disruptions of their daily lives. 11 six years later, in 2000, another less-than-conventional definition of security emerged. this time it came from a more surprising source: the un security council, which held a session in january 2000 on peace, security and hiv/aids, focusing in particular on the impact of aids in africa. 12 the security council's conjunction of peace, security and hiv/aids was novel. so too was its depiction of security and its explicit reference to the pioneering nature of its own position: it emphasised that by discussing hiv/aids as a security threat, it was 'exploring a brand-new definition of world security' and establishing 'a precedent for security council concern and action on a broader security agenda'. 13 11 september 2001 (or 9/11) is the next crucial date in this short history. as lucia zedner has explained, '[t]he events of that day alter the landscape of security irrevocably'. 14 very shortly thereafter, anthrax letters, sent using the us postal service, affected 22 people, of whom five died. as a core component of its response to the events of 2001, the united states committed to a range of legislative and regulatory activity designed to improve the preparedness of its public health law. for example, within weeks of september 11, the centers for disease control and prevention (cdc) had commissioned a draft model state emergency health powers act and, as of 2009, the united states is scheduled to have its first national health security strategy, designed to augment the extant strategies covering, respectively, the national security of the united states and homeland security. 15 strongly worded rhetoric on health and security has run alongside these reforms. typically, this rhetoric invokes the importance of experienced an outbreak of plague, causing 56 reported deaths; and second, a cholera epidemic killed up to 50,000 of the approximately 700,000 refugees who had fled to the democratic republic of the congo to escape the crisis in rwanda: see, respectively, dt dennis, 'plague in india ' (1994) the united states is only one among numerous jurisdictions pursuing public health emergency preparedness. put bluntly, 'vulnerability is universal '. 17 in 2003, another global health security concern emerged: severe acute respiratory syndrome (sars), a new and serious infectious disease. sars began to spread internationally in february 2003, approximately two months after the global outbreak alert and response network (goarn)-a multi-partner network of agencies and technical institutions established by who 18 -had detected a confirmed influenza outbreak in the guangdong province of china. on 12 march 2003, who issued its first global alert about the new infectious disease. three days later, it issued a second alert, naming the disease, offering guidance to health professionals and public health authorities, and alerting international travellers to the spread of the disease. within four months, however, transmission of sars had been interrupted in all affected countries and, on 5 july 2003, who announced that the outbreak had been contained. in total, 8,098 cases of sars were recorded in 26 countries, with 774 documented deaths (hospital staff were most affected). there were also serious financial implications due to disruption of travel, tourism, trade and production; who's estimate is that the outbreak cost us $12.3 billion in the asian countries affected. 19 the sars outbreak and its containment produced a range of responses. 20 china, for example, was criticised for its delay in reporting 16 cases and an initial lack of cooperation with who. who was criticised by canada for its unilateral issuance of travel advice to persons proposing to travel to toronto, the city outside asia worst affected by the outbreak. 21 meanwhile, in canada, delays and wrangling between the ontario government and the federal government over funding to provide compensation for individuals may have undermined the quarantine scheme by leaving people with financial incentives to break quarantine. 22 as part of quarantine and isolation measures, some jurisdictions, including canada, adopted policies involving heavy limitations on individual rights. 23 who has said that these control schemes were responsible for the interruption of transmission of the disease within four months of the announcement of the outbreak, but the use of measures that severely restricted individual freedoms was deeply controversial. the year 2003 is, however, notable for more than the sars outbreak and its containment. it was also the year in which the commission on human security, co-chaired by sadako ogata and amartya sen, issued its final report. 24 the commission labelled illness, disability and avoidable death as 'critical pervasive threats' to human security; more generally, it harnessed the language of security to highlight the ongoing neglect of social and economic rights. one year on, in 2004, 'comprehensive collective security'-described as a 'new and broader understanding' of international security-provided the overall vision behind the report of the un secretary general's high-level panel on threats, challenges and change. 25 the panel prescribed an improvement in public health systems, arguing that: ur best defence against this danger lies in strengthening public health' and he seemed to indicate that he supported an expanded role for the security council in the event of an 'overwhelming outbreak of infectious disease that threatens international peace and security'. 29 a few months later, in may 2005, the world health assembly, the highest decision-making body of who, adopted a revised set of international health regulations (ihr (2005)). 30 these regulations were welcomed by the then director general of who as a 'major step forward for international health'. 31 they took effect in june 2007, 32 binding who member states on an opt-out basis. 33 they contain 66 articles, organised across ten parts, and a total of nine annexes, and, crucially, they are significantly different from their predecessors, the international health regulations (1969). the new regulations take what has been described as an '"all risks" approach', 34 encompassing any emergency with repercussions for international health security, including 26 ibid., at para 47. 27 ibid., at para 19. 28 ibid., at para xx. 29 outbreaks of emerging and epidemic-prone diseases, outbreaks of food borne disease, natural disasters, and the accidental or deliberate release of pathogens, or chemical or radio-nuclear materials. 35 their purpose is to: prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade. 36 to give effect to this, they place obligations on member states with respect to surveillance and response capacities; states are also obliged to notify who of events within their territories that may constitute a 'public health emergency of international concern'. 37 but what of human rights? do they feature in the new ihr? put shortly, the answer is yes. article 3(1) contains the first reference to human rights: it states that the implementation of the ihr is to be 'with full respect for the dignity, human rights and fundamental freedoms of persons'. thereafter, human rights crop up in a number of articles. article 42, for example, provides that all health measures must be applied in a transparent and non-discriminatory way. informed consent and information privacy feature in several articles, including article 23 which provides that states parties must not apply health measures such as vaccination, medical examination or isolation to international travellers without 'prior express informed consent', save in circumstances where there is 'evidence of an imminent public health risk'. 38 article 45(1) provides that states parties must treat personal health information in a confidential manner 'as required by national law'. more generally, the new ihr feature requirements concerning any limitations on rights that are familiar from international human rights law. so, for example, who recommendations to states parties, and health measures implemented by states parties in response to identifiable risks, must be 'no more invasive or intrusive to persons than reasonably available alternatives that would achieve the appropriate level of health 35 see article 1 for definitions of the terms 'public health risk' and 'public health emergency of international concern'. 36 article 2. article 3(4), however, emphasises that states parties have 'the sovereign right to legislate and to implement legislation in pursuance of their health policies', noting that in so doing they should uphold the ihr. 37 see, respectively, articles 5, 13 and annex 1, and article 6 and annex 2. 38 if there is such evidence, then international travellers may be advised or compelled to submit to control measures such as vaccination, quarantine and isolation. protection'. 39 the ihr also give who a new power to use information about disease outbreaks provided by unofficial sources (for example, non-governmental organisations or individual scientists). 40 significantly, who has described this new power as a 'revolutionary departure from previous international conventions and regulations'. 41 so, how should a human rights lawyer respond to the panoply of new linkages between health and security and, more specifically, the increasing focus on public health emergency preparedness? in this section of the article, we outline two possible responses. we use broad strokes, not close detail: the aim is to provide a sense of the most likely human rights responses and to flag up why, in our view, they point to a need for greater human rights preparedness. the first possible human rights response to public health emergency preparedness is to embrace it, even acclaim it. this response will see public health being brought 'in from the cold'-its profile raised and increased resources directed towards it-as a result of the new linkage between health and security. preparedness, it will suggest, is a 'win-win'. specifically, investment in countering biothreats offers not just the possibility of protection against bioterrorism, but also enhanced public health given that 'the more research in weaponized diseases that takes place, the more innovations for disease prevention will be found'. 42 investment in hospitals, it will argue, should also receive a boost as a result of the new focus on preparedness: after all, 'if a bioweapon is released and people get sick, they will go to hospital first'. 43 faced with historical evidence of abuse committed in the name of public health, and of a traditionally hands-off response by the judiciary when faced with challenges to public health measures, 44 this first response is likely to counter-claim that human rights have been explicitly built-in as part of the ihr. it may also argue that states parties 39 article 43(1) re states parties; see also articles 23 and 31. as regards who recommendations, see article 17. 40 see articles 9, 10 and 11. who is required to seek official verification from the state concerned before taking action. it can share the information with other states if the affected state does not cooperate with verification and control efforts, 'when justified by the magnitude of the public health risk'. 41 above n 2, at xv. 42 jackson, above n 16, at 8. 43 ibid., at 17. 44 this first response will probably also argue that the overall response to hiv/aids shows that the linkage between health and human rights is now both accepted and embedded as best practice. the ascent of human rights in the popular imagination and in national, and international, legal and political orders might also be invoked. and, linked to this, it is likely that emphasis will be placed not just on the emergence of a 'right to human security' but also the fact that, today, neither states nor private actors (such as pharmaceutical companies) can afford to ignore human rights. putting that another way, this first response will point out that, today, rights are a potential risk for states and private actors. we think that this first response will also make claims focused on 'what works'. two particular claims spring to mind. the first addresses international co-operation: it will counter the argument that state sovereignty is an insurmountable obstacle to co-operation with evidence from the sars outbreak in 2003-in particular, who's unilateral issuance of a travel advisory and, relatedly, the fact that canada was 'a model of transparency in its reporting and public information, of determination in its contact tracing'. 46 in short, and in the words of the then executive director of communicable diseases at who, the argument will be that: the outbreak of sars in 2003 and its successful global containment are testimony to a new way of working internationally for the public good. 47 there is another possible version of the 'what works' argument, which focuses on drawing-out the rights potential of the language of security. it will run as follows: if, as seems to be the case in the counter-terrorism context, security and human rights are increasingly represented as in 45 conflict, with rights struggling to maintain popular confidence, why not use security-specifically, a right to security-as a way to bolster human rights? this argument will then go on to emphasise that states' obligations vis-à -vis positive rights (that is, economic, social and cultural rights) could also be bolstered by emphasising the importance of human security. there is though a second, very different, human rights response to public health emergency preparedness and the wider securitisation of health. as we see it, its defining stance will range from anxiety to outright opposition, and it absolutely will not share the optimism of the first response. for instance, faced with the latter's claims on 'win-win', its position is likely to be that preparedness distorts public health priorities, with negative consequences everywhere, but especially in developing states. securitisation, it will argue, compromises the public's health as it clambers after public health as security. moreover, even if one accepts the skewing of attention towards preparedness, isn't it the case-it will argue-that the preparedness project is out of balance? why does investment in neglected diseases continue to lose out so heavily in terms of funding? and, if hospital 'surge capacity' is a core issue, why hasn't there been more investment in public hospitals? claims of a new, co-operative world order will also be met with incredulity. co-operation on preparedness is essential and is embedded in the ihr, but it is also incredibly fragile, as was made clear in 2006 -07 when indonesia temporarily stopped sharing samples of the human avian influenza virus with who. 48 the cessation was prompted by the indonesian government's anger at what it saw as the commercial exploitation of developing countries. the catalyst for this was the announcement by an australian pharmaceutical company that it had developed a vaccine and could manufacture enough to protect the australian public within six months. the company was one of a number that had received indonesian samples from who. indonesia pulled out of sample-sharing with who, insisting that who change the rules to stop commercial abuse of poorer countries. it also allegedly entered into an arrangement with a us-based pharmaceutical company to provide samples in return for affordable access to any vaccine that might be developed. it is very likely that this second grouping of human rights advocateslet us call them linkage-sceptics-will also take a very different stance on the contemporary standing of human rights. it is true, the sceptics will agree, that human rights are built into the ihr. ultimately, however, article 3 of the ihr reserves the sovereign right of states parties to legislate for the public good, upholding the purpose of the ihr and sound science. moreover, the human rights provisions in the ihr have 'little to say about protection of livelihoods and food security, or potential health impacts that might result from the distortion of public health priorities towards global surveillance'. 49 the linkage-sceptic is also likely to point to a problem arising from a less obvious source: the health and human rights movement itself. this movement encompasses two different approaches to public health and human rights, one that forthrightly acknowledges the potential tension between public health necessity and human rights, and another that rejects the assumption of such a tension and instead sees the pursuit of public health and human rights as inextricably linked. one consequence of this has been vigorous intra-movement debate about the extent and inevitability of conflicts and trade-offs between public health and liberty. 50 this debate is both inevitable and deeply useful, but there is a problem in that, in an 'age of preparedness', robust debate amongst rights advocates about the pros and cons of trade-offs could be read in a way that puts rights at risk. threats to human rights-and indeed, human rights as a threat-are nothing new. the hype, or 'myth', of rights is a claim that is familiar from empirical socio-legal work on rights. problems with rights have also been emphasised by rights-sceptics. 51 the point though is that, lately, a new link between human rights and risk has emerged, largely as a result of post 9/11 rhetoric about life in a 'time of crisis'. its position, in crude terms, is that exceptional times mandate exceptional measures to deal with risk. as liora lazarus and benjamin goold have pointed out, 'the idea that certain human rights can be "turned off" when necessary' has acquired remarkable power; it is now widely regarded as a 'thoroughly reasonable reaction to the dangers allegedly faced by democratic societies'. 52 and, as they go on to emphasise: the exceptionalism argument has become pivotal, so much so that liberals and human rights organisations must either rebut claims 49 in this environment, human rights advocates debating the relationship between public health and human rights need to be extremely careful. 54 the ascent of post 9/11 exceptionalism is also reason to be deeply wary of upbeat, optimistic assessments concerning the relationship between security and human rights. for the linkage-sceptic, the hope that has been invested in the idea of a 'right to security' is misplaced, not least because this right could take shape as an argument against human rights. think, for example, of the claim that human rights are no more than a tool used and abused by 'minorities', especially 'dangerous, violent minorities'. this tends to be accompanied by another claim: namely, it is the right to security of 'law-abiding, decent people' to live safe and secure from crime and violence that has been neglected and needs shoring up. 55 moreover, these claims do not crop up only in the context of terrorism. as jonathan montgomery has pointed out, in the uk, discussions on the criminalisation of disease transmission have been fed by metaphors of disease carriers 'as markedly different from "normal" members of society', encouraging 'people to think of the transmission of disease as the province of evil criminals, not people like them'. specifically: those being prosecuted are [now] demonized less for their disease status than as sexual predators, and coverage shows a strong racial overtone. . . . aids is no longer presented as a gay plague but an african one. even more clearly the protection of victims from aggressors has emerged as the rationale for criminalization, obscuring public health issues. the innocence of the victims and the evil of the aggressor are stressed. 56 in our view, the sceptic's argument makes a great deal of sense. put bluntly, amidst the new 'rights revolution', which is characterised by a 53 ibid. med.l.rev. defensiveness in human rights advocacy and, its correlate, an anti-rights sentiment that queries the legitimacy of rights in a time of alleged crisis, there are no guarantees that the securitisation of public health, the right to security or human security will be good for human rights. 57 moreover, we know from history that, in the past, terrible abuses have been committed in the name of public health. 58 we have a potential problem, however, because in addition to agreeing with the sceptic's argument, we also agree with at least some of the optimist's argument. in particular, we cannot see how being 'against security' is a viable stance. in what follows, we try to address our split reaction by thinking through how human rights could engage more effectively with security. in this section, we focus on moving towards human rights preparedness in the 'age of preparedness'. in particular, we focus on risk, an increasingly common thread in contemporary debates about security. we ask: how does the identification and management of public health risks, tied explicitly in the ihr to the use of scientific principles and evidence, fit with human rights? we argue that, in order to answer this, human rights advocates need to direct greater critical attention towards prevailing interpretations of the relationship between risk and rights. 59 we propose two frames of enquiry: first, risk within rights and, secondly, rights as risk. thinking through these frames is, we suggest, an essential foil to the now-conventional mode of thinking about risk and rights which fixates on risk versus rights. as its name suggests, the first frame-risk within rights-emphasises risk as a component of human rights law. it emphasises, in particular, that the prevention of (future) harm can be interpreted within the existing framework of human rights. 60 risk-emerges from a now-dominant feature of contemporary governance: the assessment and management of risk. governments and organisations (whether national or international, and public, private or public-private in character) are expected to identify and prioritise the range of risks (financial, legal, political, reputational, regulatory, etc.) to which they are exposed. the particular point we want to draw out from this is that managing risk means managing the risk of rights. moreover, this risk is not limited to legal risk, that is, ( potential) claims and litigation for violation of human rights obligations. rather, because human rights are more than human rights law, rights as risk also encompasses the potential for human rights consciousness (as manifested, for example, in a public campaign) to disrupt the interests and overall standing of governments and organisations. a. risk within rights in many respects, 'risk' is not new ground for human rights lawyers. the terminology of risk was not widely used in the past, but analysing how threats to public health could be dealt with in a manner compatible with the normative frameworks of human rights instruments is an exercise that should be familiar to human rights lawyers. international instruments, including the 1950 european convention on human rights (echr) and the 1966 international covenant on civil and political rights (iccpr), enable states parties to derogate from certain human rights in the event of public emergencies that threaten 'the life of the nation'. 61 at other times, limitations on non-absolute rights are permitted, provided certain conditions are met. for example, interference with article 8 echr on the right to privacy is justified if it is legally prescribed, serves a legitimate purpose and can be proved to be 'necessary in a democratic society'. for the european court of human rights, the principle of proportionality is a key component of the latter 'democratic necessity' test. 62 more broadly, although the intensity of review in individual contexts (for example, interference with the right to liberty or privacy), and the exact legal terminology and method used, will differ, common judicial approaches towards questions of justification must recognize that liberty is part of our communal interests, along with public health . . . .' 61 as regards the iccpr, see also the 1984 siracusa principles on the limitation and derogation provisions in the iccpr. see, also, the 'intervention ladder' proposed by the nuffield council on bioethics in its recent report on public health, above n 23. 62 or necessity can be found across jurisdictions. 63 it is simply not correct therefore to claim that human rights law fails to deal with risk, or that a choice always has to be made between risk and rights. it is possible to identify-through the structure and interpretive principles of human rights instruments-the means to mediate the relationship between risk and rights. putting that another way, the framework of human rights law can, and already does, address issues of risk. until very recently, however, the identification of a 'risk within rights' approach did not register either among human rights lawyers or in the public imagination more generally. one explanation for this is that, for understandable reasons, lawyers did not pay much attention to the meaning, and role, of risk. 64 it was not a focus of critical concern (even though it was present in 'everyday' legal contexts-for example, identifying risk factors and making predictive judgements in relation to detention, imprisonment, mental health, child protection, asylum or deportation). instead, it was for the most part accepted as an uncontroversial component of the expert, scientific evidence put forward in support of one's legal arguments. 65 but a change has taken place due to the new societal emphasis on (in)security and public protection. significantly, in some jurisdictions, the new post 9/11 national security context has generated strong demand for greater prioritisation of risk 66 -even if this comes at the expense of established human rights norms. 67 the risk and rights relationship, in other words, is being framed as risk or rights-and rights seem to be at a substantial disadvantage. there is though a new critical counter-terrorism scholarship which is fighting this dangerous turn. in our view, its arguments need to be read very closely by those working on public health emergency preparedness, not least because of the effect that a 'risk or rights' approach 63 could have on the interpretation, and use, of the ihr and the design, interpretation and use of national preparedness measures. three insights from critical counter-terrorism scholarship merit particular attention. first, it should not be assumed that the human rights argument has been won: the reasons why human rights need to be protected have to be explained again and again, without fail. arguments, especially official ones, which insist that human rights norms have no place in times of emergency mean that counter-argument needs to be seen as constant requirement. 68 secondly, defending human rights in an era of heightened security-consciousness entails not just closer engagement with the contemporary politics of security, but also recognition of the value of security. 69 and, thirdly, a human rights spotlight on the language and practices of risk assessment and management is essential in order to evaluate the legitimacy of responses to public health threats. in thinking about risk within rights in the context of public health emergency preparedness, these points suggest a range of strategies. for example, the use of coercive measures-such as quarantine-requires particularly strong justification. these measures infringe liberty and privacy rights and, if mistakes are made, healthy individuals are put at serious risk of infection. the threat of quarantine can lead individuals to delay seeking diagnosis and treatment. it can also provoke or compound discrimination and stigmatisation of particular individuals and groups. and, as lucia zedner has pointed out, the use of risk categories to target certain groups can create a further problem: at one level, it makes perfect sense to target security measures at those deemed most to threaten. yet an inherent danger of selectivity is that precisely because it imposes restrictions only on targeted sections of the population, it is less likely to invoke the natural political resistance generated by burdens that affect us all. med.l.rev. critical counter-terrorism scholarship should also be seen as relevant in developing an account of risk-based evidence and its relationship to human rights. some public health commentators, discussing coercive measures, have begun to advocate a direct linkage between risk expertise and human rights standards: an approach, which might enable the formulation of a body of public health ethics acceptable to human rights jurisprudence is to introduce into the language of ethics and rights the notion of evidence-based assessment of risk. 71 this approach, they argue, could help to bring consistency and coherence to the 'balancing [of ] the common public health good with individual rights'. 72 for this to be true, critical counter-terrorism scholarship suggests that two particular problems will need to be addressed: the first concerns the terminology of balance; the second concerns the nature and role of risk-based evidence in legal processes. the metaphor of balance-which is now widely used in debates about appropriate legal responses to the risk of terrorism-has the potential to undermine human rights. as andrew ashworth has argued, the imagery of balancing assumes a 'hydraulic relationship between human rights safeguards and the promotion of security': specifically, 'as one goes up the other must go down, and vice versa'. 73 balancing, unlike proportionality, 'involves a broad brush, and sometimes opaque, analysis aimed at a resolution of the interests at stake and the rights involved'. it uses a 'utilitarian analysis of the rights and public interest goals in question, giving no significantly greater weight to rights than to security measures'. 74 proportionality, in contrast, is more protective of human rights: specifically, under the proportionality approach, there is a presumption that rights restrict public interest goals. rights outweigh goals that are not legitimate and, where goals are legitimate, any measures giving effect to them must be suitable, the least restrictive possible, and proportionate between the effects of the measures and the objectives to be achieved. 75 71 coker and others, above n 59, at 612. 72 ibid., at 613 (emphasis added). the second issue is risk-based evidence. a striking feature of contemporary security debates, in the terrorism and public health fields, is the increased reliance on risk-based evidence and expertise. human rights scholars have argued that, if risk evidence is to be used to justify limitations on rights, the evidence of threats to security must be disclosed and scrutinised according to identifiable legal norms. 76 clearly, where there is litigation, it is the judges' approaches to risk that will be crucial. historically, many types of expert evidence pertaining to public or national security were viewed as non-justiciable. and, where judicial intervention did occur, the actual level of scrutiny was often minimal and deferential to government assertions and experts. 77 today, however, what we have labelled as 'risk within rights' is beginning to be openly articulated by the judiciary in security contexts. specifically, in some jurisdictions, in response to concerns about the nature, and direction, of recent antiterrorism legislation and practice-including preventative detention, surveillance and deportation of suspected individuals-judges have started to engage openly, and more critically, with the relationship between risk and human rights. 78 this is a welcome development. but a wider and deeper engagement will be needed in order to dislodge the zero-sum representation of risk and human rights, and among other things this will require an exploration of the tendency to think of risk as an expert, rational or scientific knowledge, and human rights as a value-based legal knowledge. 79 we shift now to the complex terrain of 'rights as risk'. as noted earlier, the prompt for this second frame is that risk management has become a pre-eminent concern for governments and organisations (whether public, private or public -private in character)-to quote michael power, we are in the midst of 'the risk management of everything'. 80 in this section, we focus on organisational risk, emphasising that this includes management of the risk of rights, and we consider what this might mean for the project of human rights preparedness. 81 as we explain below, we take the view that a human rights engagement with 'rights as risk' is both necessary and undeniably complex. organisational risk is an umbrella term covering the possible risks affecting an organisation (including, for example, government departments, regulatory bodies and pharmaceutical companies). the organisational risks that have to be managed vary widely and are generally classed as reputational, financial, legal, political and operational in nature. the regulatory space in which the organisation operates will be a key factor. influences, demands and obligations can be exerted from numerous directions-for example, from international institutions, governments, state regulatory bodies, courts, professional associations, corporations, shareholders, trades union, litigants, ngos, the public and the media. 82 human rights are a particularly complex organisational risk. they encompass, but are not limited to, legal risk: that is, ( potential) claims and litigation for human rights law violations. rather, because human rights are more than human rights law, rights as an organisational risk are also about the capacity of human rights consciousness (as manifested, for example, in community group protests) to adversely affect the interests of the organisation. furthermore, for an organisation, risks exist in both engaging with, and rejecting, human rights. michael likosky, discussing the imperative of governments and private companies to manage human rights risks in joint projects, emphasises that organisations' risk-mitigation strategies will vary. for example: do they address the underlying human rights problem itself, making a project more respectful of human rights? do they discredit the ngo or community group campaign? do they negotiate with one ngo but not with another? do they assuage the concerns 80 in the public health emergency field, a wide range of influences, demands and obligations have the capacity to lead to the construction of rights as a risk. indeed, the cross-sector and cross-jurisdiction nature of public health emergencies (especially those of 'international concern') creates an especially complex governance landscape: distinct histories, cultures and agendas will be colliding in times of crisis when immediate responses are expected. in what follows, we outline a range of reasons why, from an organisational risk perspective, rights are likely to seen as a risk in the field of public health emergency preparedness. one obvious source of risk is the mounting number of human rights instruments and, as a result of increased litigation and the migration of legal arguments, the worldwide expansion of human rights-referencing case law. 84 the campaign to expand corporate liability for human rights violations is another source: although corporate opposition to new legally binding duties persists, this campaign has encouraged companies to commit to improved self-regulation. 85 another source is the human rights demands found within the conditional loan agreements between international organisations (such as the world bank) and recipient governments, or within the contractual and public procurement rules relating to the providers of public goods and services. 86 global health governance is also characterised by an increasingly influential role for hybrid and non-state actors, including ngos (such as médecins sans frontières), public-private partnerships (such as the global alliance for vaccines and immunisation (gavi)), and private foundations (such as the gates foundation). indeed, in evidence to a uk parliamentary committee, david fidler stated that: increasingly, the gates foundation is the first place people will pick up the phone to call; not the who. in fact, someone told me -and i do not know if this is true -that bill gates is now going to fly to indonesia to help intervene in that controversy over virus sharing. something has changed here. 87 in federal states, the legal relationship between federal and local government may constitute rights as a risk in the public health emergency field. on the one hand, a strong states' rights tradition can hamper, or be used as an excuse by, federal government in developing particular national preparedness measures. on the other hand, however, where federal government seeks aggressively to assert its power and interfere with protected human rights, a tradition of strong states' rights could be a bulwark against such abuse. 88 the levels of public trust in a particular national culture will also influence rights as risk perspectives. 89 lesley jacobs, in a study of the divergent uses of quarantine in hong kong, shanghai and toronto during the sars crisis, attributes the more extensive use of quarantine in toronto to the particular legal consciousness of senior public health officials: 'health security was weighed much more heavily than rights concerns . . . whereas in hong kong and shanghai there was much more of an even balance'. 90 but, even though there was dissent in toronto, courts and human rights bodies were not used to raise concerns about rights violations. one federal public health official has speculated that: the belief that the decisions about sars by senior public officials, provided that they had a legal basis, would be made fairly was so deeply ingrained among the public that there was little need to question or scrutinize those decisions. 91 jacobs's explanation for the non-use of courts is that legal avenues of redress might not be seen as appropriate 'where the health security of the community is at stake'. 92 from an organisational risk perspective, this phenomenon could be used as a reason to dismiss rights as a risk and, more specifically, to downgrade the need for rights protection in 87 house of lords select committee, above n 45, at 381. 88 medical law review [2009] preparedness planning and implementation. this, however, would be counter-productive. as james childress and ruth gaare bernheim have argued, 'public justification, deliberation, and other relationshipbuilding activities may be more important for biopreparedness than state power because they maintain and nurture civic ideals, cooperation, and trust'. 93 moreover, childress and gaare bernheim's argument can be extended to encompass the role of the private sector in sustaining public trust during an emergency. to give just one example: an employer's policy on matters such as job security has a very real capacity either to aid or to hinder the extent of voluntary compliance with quarantine requirements. but it is not just national cultures that merit attention in thinking about rights as risk: organisational cultures also 'shape how human rights are framed, interpreted and institutionalised'. 94 article 3(1) of the ihr states that implementation of the regulations is to be 'with full respect for the dignity, human rights and fundamental freedoms of persons'. the extent of internalisation of human rights within who is, therefore, crucial. little, however, is known about this as the organization has not been the focus of human rights or, indeed, regulation scholarship. 95 but it is obvious that the range of internal staff responses will play a significant role in the design, implementation and monitoring of any human rights-based policies. we can also speculate that any internal divisions on human rights will both increase who's own exposure to organisational risk and affect the handling of the specific human rights matter in question. consider, for example, galit sarfaty's study of interpretations of human rights at the world bank. comparing world bank investment projects relating to hiv/aids prevention in russia and saint lucia, sarfaty speculates on the reasons why different framings of the human rights dimension were adopted in each case: one reason may be that the project team was dominated by staff who prefer a cost-benefit analysis to a legal approach, and who concluded that funds would be better spent on other preventative projects. she also highlights two different core approaches to human rights among world bank staff: she labels the first 'instrumental' and the second 'intrinsic'. staff who adopt an intrinsic framework draw on either moral or legal imperatives and, overall, they see human rights in normative terms as an end in themselves. the instrumentalists, in contrast, see rights as a means to an end, using a functionalist, economics-driven rationale to determine whether, and how, human rights have value in any given case. we believe that thinking about 'rights as risk' should be a key aspect of human rights preparedness. human rights advocates need to recognise the growing significance of organisational risk and, in particular, the ways in which organisational culture intertwines with risk and rights. in addition, human rights needs to reflect on the emergence, from within its ranks, of the 'human rights risk strategist'. likosky, discussing public -private partnership infrastructure projects in different countries, highlights how governments and other organisations may aim to 'advance human rights interests for their own ethical or strategic reasons', and may therefore enter into negotiations and alliances with certain ngos. 97 human rights 'risk consultants', drawn from legal and other backgrounds, may also be employed by governments and organisations, to offer expertise on particular projects and human rights campaigns. looking specifically at the public health emergency context, it can be argued that who's new power under the ihr to use information about disease outbreaks provided by unofficial sources gives governments an added incentive to work with ngos and this, in turn, gives ngos increased influence. the end result is likely to be a mixture of human rights agendas, including-and this is the key point-human rights advocates adopting instrumentalist strategies and language (for example, urging the need to avoid 'business risk') in order to promote human rights protection. there is a lot for human rights advocates to address here. one question that needs to be asked is: are human rights risk strategists at work in public health preparedness projects and, if so, in what ways? are they, for example, picking up on the argument made by francis that it is not merely questions of justice within pandemic planning that demand attention but also the justice of pandemic planning: the triage choices in pandemic planning for the distribution of vaccines and antivirals are open, coordinated, and institutionally adopted. perhaps this is one reason why they have drawn so much attention. . . . no doubt there are other explanations, too, for the apparent assumption that devoting resources to pandemic planning is just. . . . nonetheless, there are serious questions of justice to be asked about the allocation of extensive resources to pandemic threats. 98 and, as they go on to point out, questions concerning the 'justice of' and 'justice within' pandemic planning are not unrelated. put shortly, if basic health care infrastructure is in a state of neglect or unavailable, if health professionals are in short supply or are not trusted by the population, and if there is inequality in access to primary care, then global surveillance, surge capacity and, more generally, preventing and coping with a pandemic will be all the more difficult. 'pandemic myopia', in other words, is a seriously flawed approach to pandemic planning 99 -which is surely something that human rights advocates (whether they see themselves as 'risk strategists' or not) need to be arguing as strongly and clearly as possible. there are other, broader questions too. these stem from the fact that rights as risk is not home-ground for human rights advocacy. put bluntly, it smacks of bad faith, of working on 'their' terms, not on 'ours'. being 'at the table', if that course is chosen, is not likely to be at all easy in practice. the counter-argument to this is that human rights advocacy has always been complex. 100 think, for example, of the diversity of human rights advocates (such as the us christian right at the united nations using human rights to argue against rights to sexual and reproductive health). 101 and it cannot be denied that human rights 'victories' have sometimes had unexpected, negative consequences: on occasion, they have been used by governments as a basis from which to claim that action has been taken and no further governmental action is required. it can also be argued that if deeper engagement with human rights by governments and other organisations (even if primarily through the lens of risk management) is a significant contemporary dynamic, then human rights advocates have little choice but to respond in some fashion. and it should not be forgotten that risk-based indicators and compliance strategies have also been growing areas of interest within human rights work. 102 lastly, there is, of course, the possibility that an organisation that starts out with an instrumentalist mindset towards human rights might ultimately internalise them to beneficial effect. overall, then, human rights advocates should not-and probably cannot-avoid engaging with rights as risk. one of the conclusions in the report of a recent uk parliamentary committee on infectious diseases and global health governance is that who needs additional funding 'if it is to be able to respond effectively to threats on behalf of the international community'. 103 this statement is a reminder of the importance, and the fragility, of public health emergency preparedness. it is likely that it will also be read, at least by some, as a rebuke to individuals, like us, who set out to critique preparedness when it is currently so precarious in practice. critiquing public health emergency preparedness is undeniably hard. who, in the end, would choose to be 'against preparedness'-especially when one considers the extreme human costs of recent public health emergencies? we are not against it, however. our argument throughout has been that critique is essential to preparedness and that, to date, critique from a human rights perspective has been in short supply. we have suggested a preliminary agenda to address the human rights gap, focusing in particular on the frames 'risk within rights' and 'rights as risk', and we assigned the name 'human rights preparedness' to the project as a whole. we concluded by turning inwards, emphasising that this project carries risks for human rights itself. specifically, critiquing preparedness could well involve self-critique as human rights advocacy works towards a more differentiated analysis of how security should be engaged and what it means to do human rights today. putting that another way, human rights preparedness-and, in particular, engagement with 'rights as risk'-is likely to be human rights without a safety net. human rights, terrorism and risk: the role of politicians and judges civil liberties law: the human rights act era see the discussion of uk and canadian national security cases in t poole regulation and administrative constitutionalism designs on nature: science and democracy in europe and the united states risk and human rights: ending slopping out in a scottish prison legal knowledges of risk' in law commission of canada risk, rights and public health emergencies infrastructure and human rights (cup a common law of human rights? transnational judicial conversations on constitutional rights the un human rights norms for corporations: the private implications of public international law between light and shadow: the world bank, the international monetary fund and international human rights law the new corporate accountability: corporate social responsibility and the law (cup risk, rights and public health emergencies pandemic planning and distributive justice in health care on the need to take account of social justice in pandemic planning, especially the needs and interests of the most disadvantaged, see the bellagio statement of principles globalizing family values: the christian right in international politics risk, rights and public health emergencies key: cord-348249-zhfrgaxf authors: osborne, v.; davies, m.; dhanda, s.; roy, d.; lane, s.; evans, a.; shakir, s. a. title: systematic benefit-risk assessment for the use of chloroquine or hydroxychloroquine as a treatment for covid-19: establishing a framework for rapid decision-making date: 2020-05-12 journal: nan doi: 10.1101/2020.05.07.20093989 sha: doc_id: 348249 cord_uid: zhfrgaxf objectives: given the current pandemic, there is an urgent need to identify effective, safe treatments for covid-19 (coronavirus disease). a systematic benefit-risk assessment was designed and conducted to strengthen the ongoing monitoring of the benefit-risk balance for chloroquine and hydroxychloroquine in covid-19 treatment. methods: the overall benefit-risk of the use of chloroquine or hydroxychloroquine as a treatment for covid-19 compared to standard of care, placebo or other treatments was assessed using the benefit-risk action team (brat) framework. we searched pubmed and google scholar to identify literature reporting clinical outcomes in patients taking chloroquine or hydroxychloroquine for covid-19. a value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance. results: several potential key benefits and risks were identified for use of hydroxychloroquine or chloroquine in covid-19 treatment. for the benefit of virological clearance, three studies were identified. a significant risk difference (rd) between hydroxychloroquine and the comparator group (standard of care) was found for only one study (rd=0.58, 95% ci: 0.17, 0.98). the risk difference was not significant for the other two studies (rd=-0.07, 95% ci:-0.75, 0.61 and rd=0.08, 95% ci:-0.74, 0.91). in addition, no significant risk difference between hydroxychloroquine and the comparator group (standard of care) was identified for the risk of abnormal liver function tests (lfts) (rd=0.07, 95% ci: -0.28, 0.41). conclusions: overall, no conclusion can be made on the benefit-risk profile of hydroxychloroquine or chloroquine in the treatment of covid-19 compared to standard of care, placebo or other treatments at this time. whilst the availability of comparative data are limited, the current framework summarises the key anticipated benefits and risks. as further data from clinical trials and real world use on these benefits and risks becomes available, this can be incorporated into the framework for an ongoing benefit-risk assessment. coronaviruses have circulated among humans and animals for many years, of which several strains are highly transmissible and pathogenic in humans [1] . severe acute respiratory syndrome (sars) emerged in 2002 and 2003, while middle east respiratory syndrome coronavirus (mers-cov) emerged 10 years later [1] . in december 2019, a novel coronavirus emerged in wuhan, china [2] , subsequently called severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [3] . sars-cov-2 causes coronavirus disease coronaviruses predominantly cause respiratory tract infections in humans [1] . specifically, the main symptoms of covid-19 have been reported as fever, cough and shortness of breath [5] , with a less abrupt onset of symptoms compared to sars [6, 7] . data are still emerging regarding the epidemiology of covid-19, though initial reports estimate a transmission rate (basic reproduction number, r0) of 2.2 [8] and a case fatality rate that increases among older adults [9] . given the current pandemic, there is an urgent need to identify effective, safe treatments for covid-19. two such proposed treatments are chloroquine and hydroxychloroquine, which are well-established medications predominantly used to treat malaria, lupus and rheumatoid arthritis. in vitro studies have shown that chloroquine and hydroxychloroquine are effective at inhibiting sars-cov-2 infection, with the latter appearing to have more potent antiviral activity [10, 11] . thus, repositioning of these drugs as antiviral therapies for covid-19 is of global interest, however clinical data are limited and inconclusive. currently, there are multiple ongoing clinical trials for use of these treatments in covid-19, while the us food and drug administration (fda) has issued an emergency use authorization (eua) for oral formulations of chloroquine phosphate and hydroxychloroquine sulfate for patients hospitalised with covid19 [12] . to date, whilst there have been many publications which have described the main effectiveness and safety concerns with these treatments, there has not been a systematic benefit-risk assessment on the use of chloroquine or hydroxychloroquine for covid-19 treatment using a structured descriptive framework. a systematic benefit-risk assessment strengthens the ongoing monitoring of the benefit-risk balance for chloroquine or hydroxychloroquine in covid-19 treatment. for this assessment, the benefit-risk action team (brat) framework is highly applicable as it allows identification of the key benefits and risks of a product in a defined disease context within a structured descriptive framework; further quantitative assessments can then be applied and conducted according to the availability of relevant data at that time [13] . the brat framework was also specifically designed to assist communication with regulatory authorities [14] . the decision-. cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093989 doi: medrxiv preprint making process is transparent due to the framework design, while any assumptions can be explored further by sensitivity analysis through a quantitative component [15] . given the public health urgency with the covid-19 pandemic, this benefit-risk assessment has been conducted based on publicly available information to date (data-lock april 7 th 2020). it is however acknowledged that there is extremely limited data available from ongoing clinical trials at this timepoint. to inform the debate expeditiously the benefit-risk assessment has been designed to be implemented regardless of the quantity of data available. the intention is that the framework will subsequently be readily available to repeat the assessment as further data arise, e.g. results from new clinical trials, allowing for rapid decision-making. to examine the benefit-risk profile of chloroquine or hydroxychloroquine in covid-19 patients compared to standard of care, placebo or other treatments. the overall benefit-risk of the use of chloroquine or hydroxychloroquine as a treatment for covid-19 compared to standard of care, placebo or other treatments was assessed using the brat framework. brat uses a six step iterative process to support the decision and communication of a benefit-risk assessment: define decision context, identify outcomes, identify data sources, customise framework, assess outcome importance, and display and interpret key benefit-risk metrics [14, 15] . three settings of interest were identified for use of these treatments in covid-19; treatment for severe disease, treatment of milder disease in the community, and prevention in health care professionals exposed to the virus. for the purposes of this benefit risk assessment, we have focused on the use of chloroquine or hydroxychloroquine for the treatment of severe covid-19 disease. the population of interest were patients with severe covid-19, while the exposure of interest was hydroxychloroquine or chloroquine. the comparators of interest were standard of care, placebo or other treatments for covid-19. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093989 doi: medrxiv preprint initially, all potential benefits and risks related to hydroxychloroquine or chloroquine, regardless of importance, were identified. from these the key benefits and risks associated with hydroxychloroquine and chloroquine use were selected by clinician judgement. key benefits and risks were those which were considered to drive the benefit-risk balance of the drug. a value tree was constructed using these key benefits and risks, all of which were ranked in order of considered importance. we searched pubmed and google scholar to identify suitable data for inclusion. in both databases, we searched for papers on: (((((((((chloroquine* and sars*)) or (chloroquine* and covid*)) or (chloroquine* and coronavirus))))) or (((chloroquine* and 2019-ncov)))) (((((((((hydroxychloroquine* and sars*)) or (hydroxychloroquine* and covid*)) or (hydroxychloroquine* and coronavirus))))) or (((hydroxychloroquine* and 2019-ncov)))) papers were included if they reported quantitative data on effectiveness and/or safety of chloroquine or hydroxychloroquine in patients with severe covid-19. case reports were excluded. results were restricted to english language only (abstracts in english language were acceptable where sufficient data provided) and peer-reviewed publications since 2019 to 7 th april 2020. data were extracted for each benefit and risk, for hydroxychloroquine, chloroquine and the comparator (standard of care, placebo or other treatments), where available. eudravigilance (up to 4 th april 2020) and faers spontaneous reporting data (up to 31 st december 2019) for hydroxycholoroquine and chloroquine were also examined. a summary benefit-risk table was created to allow visualisation of the magnitude of each benefit and risk. risk differences and corresponding 95% confidence intervals (ci) were calculated for each outcome where both numerator (number of events) and denominator (number of patients at risk) were available for both the treatment group (hydroxychloroquine or chloroquine) and comparator group. no appropriate comparator groups were identified in eudraviligance for hydroxychloroquine or chloroquine because there are no established treatments for covid-19 at this time. consequently, spontaneous reports are not included in the benefit-risk table and are presented in the text only. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093989 doi: medrxiv preprint due to lack of data, a fully quantitative assessment was not undertaken. however, the outcomes identified in the value tree were ranked so that swing weighting can be applied in future assessments. the weighted net clinical benefit (wncb) can subsequently be calculated using these weights [15] [16] [17] . we would propose using the sutton et al method, where benefits have a positive contribution to the wncb and risks have a negative contribution [17] ; the overall wncb would be considered positive (benefit outweighs the risk) where wncb >0. a sensitivity analysis can also be used to examine the robustness of the assigned weights and whether significant changes would alter the benefit-risk profile [13] . the value tree reflecting the key benefits and risks related to hydroxychloroquine or chloroquine treatment in covid-19 is displayed in fig 1. data for these outcomes are presented in the data extraction table and key benefit-risk summary table (tables 1 and 2, respectively). from literature searching we identified 71 papers from pubmed and 379 results from google scholar for chloroquine. we also identified 29 papers from pubmed and 158 results from google scholar for hydroxychloroquine. after initial review and removal of duplicates, 15 papers were reviewed further to determine if they met all inclusion criteria; 3 papers were included in the final benefit-risk assessment. a reduction in the risk of death from covid-19 is considered to be a key benefit of treatment with chloroquine or hydroxychloroquine compared to standard of care, placebo or other treatments. we found no comparative data were available for this key benefit. a reduction in the risk of icu admission was identified as a key benefit, though no comparative data were found in the existing literature. another key benefit identified was reduction in the risk of non-invasive ventilation. no data comparing hydroxychloroquine or chloroquine to standard of care, placebo or other treatments was identified. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093989 doi: medrxiv preprint secondary clinical outcomes were also considered key benefits as they refer to anticipated clinical endpoints as a result of chloroquine or hydroxychloroquine treatment, which reflect potential reductions in disease progression, such as development of pneumonia or acute respiratory distress syndrome (ards). no comparative data were found in the existing literature for these outcomes. a further key benefit identified was a reduction in the number of patients requiring supplemental/high flow of oxygen. no comparative data was identified. viral load parameters were considered a surrogate endpoint in this benefit risk assessment context, with outcomes such as virological clearance reflecting the benefit of recovery from covid-19. in the study by gautret et al [18] , the authors examined virological clearance . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. no comparative data were identified for cardiac toxicity. in eudravigilance, there were 13 reports of qt prolongation, one report of ventricular arrythmia, one report of atrioventricular (av) block, one fatal cardiac arrest and one non-fatal cardiac arrest in patients using hydroxychloroquine for coronavirus infection. in addition, there were 6 reports of qt prolongation, one report of tachyarrhythmia, and one report of ventricular tachycardia in patients using chloroquine for coronavirus infection. no comparative data were identified on immune reactions among patients using hydroxychloroquine or chloroquine for covid-19 treatment. no comparative data on ocular events among patients using hydroxychloroquine or chloroquine for covid-19 treatment were identified. no comparative data were identified on serious skin reactions among patients using hydroxychloroquine or chloroquine for covid-19 treatment. in the study by chen j et al [19] , abnormal liver function was reported for four patients in the hydroxychloroquine group (risk=0.27) and three patients in the comparator group (risk=0.20). there was no significant difference in risk between the two groups (rd=0.07, 95% ci: -0.28, 0.41). in eudravigilance, there were two reports of liver injury and one report of hepatocellular injury in patients using hydroxychloroquine for coronavirus infection. in addition, there was one report of hepatocellular injury in a patient using chloroquine for coronavirus infection. no comparative data were identified on severe hypoglycaemia among patients using hydroxychloroquine or chloroquine for covid-19 treatment. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093989 doi: medrxiv preprint no comparative data were identified for adverse haematological events. in eudravigilance, there were two reports of neutropenia in patients using hydroxychloroquine for coronavirus infection. no comparative data were identified on drug interactions with chloroquine or hydroxychloroquine. in eudravigilance, one potentiating drug interaction was reported in a patient using chloroquine for coronavirus infection; the patient experienced qt prolongation and was also taking lithium carbonate and quetiapine fumarate. several potential key benefits were identified with use of hydroxychloroquine or chloroquine in covid-19 treatment: reduction in risk of death, reduction in icu admission, reduction in non-invasive ventilation, reduction in secondary clinical outcomes, reduction in use of oxygen and improved viral load parameters (e.g. virological clearance). the key benefits were outcomes highlighted from currently ongoing clinical trials. in addition, several potential key risks were also identified; cardiac events, immune reactions, ocular events, skin events, liver events, severe hypoglycaemia, blood events and drug interactions. cardiac toxicity is of particular importance for covid-19 patients. both potentially the disease itself and anticipated treatment strategies with chloroquine or hydroxychloroquine pose significant risk of cardiac arrhythmias [21] . short term use, as expected for the treatment of covid-19, is likely to pose a lower risk of cardiac toxicity, nevertheless the risk cannot be overlooked as patients are expected to be on higher doses, possibly concomitantly taking other qt prolonging agents, in addition to having a potentially elevated risk due to the disease itself. one of the most serious toxic effects of hydroxychloroquine/ chloroquine are ocular side effects, notably retinopathy [22] [23] [24] [25] [26] , although the risk for hydroxychloroquine is considered to be lower [27] . both duration of use and weight-based dosing (dose per kg) are important parameters for the risk of developing retinopathy [26] . the risk of retinal damage over a short time period may be negligible even with high doses [25] . however, given the seriousness of the outcome we have identified this as a key risk in the benefit-risk framework. in addition, whilst the most robust evidence for safety concerns associated with chloroquine and hydroxychloroquine is with longer term use, although rare, there have been case reports after . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093989 doi: medrxiv preprint weeks as opposed to longer duration of use, with respect to adverse hepatic and haematological effects, and hypoglycaemia [28] [29] [30] . very few studies were identified that compared benefits and risks between those using hydroxychloroquine or chloroquine and those receiving standard of care, placebo or other treatments. data were only identified for one benefit (viral load parameters) and one risk (liver events). for the benefit of virological clearance, three studies with very small sample sizes were identified. these studies examined virological clearance at different time points as their primary outcome, meaning results from these studies could not be pooled. only one study revealed a significant risk difference between hydroxychloroquine and the comparator group (standard of care), though given the small sample size and biases in the study design this should be interpreted with caution. for the risk of abnormal lfts, only one studied was identified with a small sample size. no significant risk difference between hydroxychloroquine and the comparator group (standard of care). whilst there is a paucity of comparative data from the literature search at this stage, we identified a number of reports in eudravigilance. the following data was obtained from eudravigilance for patients taking chloroquine or hydroxychloroquine: qt prolongation (n=19), ventricular arrythmia (n=1), atrioventricular (av) block (n=1), non-fatal cardiac arrest (n=1), fatal cardiac arrest (n=1), tachyarrhythmia (n=1), ventricular tachycardia (n=1), liver injury (n=2), hepatocellular injury (n=2), neutropenia (n=2), drug interaction (n=1). these data can be used in future benefit-risk assessments once an appropriate treatment comparator has been identified, which should be an established treatment for covid-19. given the paucity of available data on benefits and risks with hydroxychloroquine or chloroquine compared to standard of care, placebo or other treatments, we chose not to undertake a fully quantitative assessment of the benefit-risk balance at this time. instead, all available comparative data for key benefits and risks are presented in a summary table. further data from clinical trials and observational studies are required in order to determine whether the benefit-risk profile of hydroxychloroquine or chloroquine in treating covid-19 is favourable. an important point for discussion regardless of the benefits and risks of hydroxychloroquine and chloroquine for covid-19 treatment is the availability of these medicines. inadequate . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . supply and shortages have already been reported [31] , meaning availability is not guaranteed for those using these treatments for licensed indications or covid-19. this must be taken into consideration in addition to the benefit-risk assessment, since there can be no benefit from a medication which is unobtainable. sample sizes for each outcome were limited to those available in the original studies and may not have adequate power to detect differences in risk between groups, especially where the outcomes examined were not the primary outcome of interest. the benefit-risk assessment is limited by the availability of data in the published literature. however, this assessment can be subsequently updated once further data from clinical trials are available. in addition, given the public health urgency of the covid-19 pandemic, it is important to provide a systematic assessment of the benefits and risks of hydroxychloroquine and chloroquine treatments with evidence available to date and create a framework which can be used to rapidly update the assessment when further data are available. data quality is not reflected in this benefit-risk assessment, though all data included were extracted from peer-reviewed manuscripts. of note, a statement was issued by the international society of antimicrobial chemotherapy [32] regarding the gautret et al paper published in the international journal of antimicrobial agents [18] . the paper was not considered to meet the society's expected standards and though it was peer-reviewed, the editor-in-chief was not involved in this process [32] . confirmation of causality was not a requirement for inclusion of data in the brat assessment. patients may have been on other concomitant medications or had other medical conditions at the time of hydroxychloroquine or chloroquine treatment. finally, we considered hospitalisation of patients to reflect severe covid-19, but we acknowledge that severity of disease may vary regardless of hospitalisation. overall, no conclusion can be made on the benefit-risk profile of hydroxychloroquine or chloroquine in the treatment of covid-19 compared to standard of care, placebo or other treatments at this time. whilst the availability of comparative data are limited, the current framework summarises the key anticipated benefits and risks. as further data from clinical trials and real world use on these benefits and risks becomes available, this can be incorporated into the framework for an ongoing benefit-risk assessment. . cc-by-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. no data origin and evolution of pathogenic coronaviruses a novel coronavirus outbreak of global health concern covid-19) and the virus that causes it epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study covid-19: what is next for public health? a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia estimates of the severity of coronavirus disease 2019: a model-based analysis in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro systematic benefit-risk assessment for buprenorphine implant: a semiquantitative method to support risk management a case study using the proact-url and brat frameworks for structured benefit risk assessment benefit-risk analysis: a proposal using quantitative methods a bayesian approach to evaluating net clinical benefit allowed for parameter uncertainty hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial a pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (covid-19) treating covid-19 with chloroquine clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china hydroxychloroquine and chloroquine retinopathy: screening for drug toxicity hydroxychloroquine dosing in immunemediated diseases: implications for patient safety effects of chloroquine on viral infections: an old drug against today's diseases? covid-19 and chloroquine/hydroxychloroquine: is there ophthalmological concern? recommendations on screening for chloroquine and hydroxychloroquine retinopathy -2016 covid-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient treated for ra fulminant hepatic failure secondary to hydroxychloroquine a case of thrombocytopenia associated with the use of hydroxychloroquine following open heart surgery a rush to judgment? rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for covid-19 statement on ijaa paper | international society of antimicrobial chemotherapy key: cord-354936-do0bmpxt authors: chatterjee, ranit; bajwa, sukhreet; dwivedi, disha; kanji, repaul; ahammed, moniruddin; shaw, rajib title: covid-19 risk assessment tool: dual application of risk communication and risk governance date: 2020-06-02 journal: nan doi: 10.1016/j.pdisas.2020.100109 sha: doc_id: 354936 cord_uid: do0bmpxt abstract risk awareness is the best way to prevent and slow-down the transmission of the covid-19 pandemic. risk awareness is achieved through communication of risk assessment. effective risk communication is an important measure to control the infodemic. most risk assessment tools focus on either tracking the affected patients or diagnosing a probable health condition through symptoms. rika india introduces an innovative risk assessment tool which goes beyond the symptom detection and patient tracking. it includes four factors in assessment of risk: health, behaviour, exposure and social policy. each of these four factors have sub-factors which help to assess the overall risk in a more comprehensive way and also present it to the user in a simplified way. the paper discusses the importance of the risk assessment tool for awareness generation and decision making. further, the datasets generated through the tool have been analysed to understand the key intervention areas for covid-19 response and management. j o u r n a l p r e -p r o o f and specifically for covid-19 pandemic. it undertakes a review of existing risk assessment and information tools available online in the form of apps and surveys. the second part concentrates on key features of rika"s covid19 risk assessment tool and discusses the methodology used for development of the tool. the third part focusses on data analysis based on the responses of the risk assessment tool. the data analysis uses pearson"s correlation coefficient to understand if there exists any linear relation between two variables and also to identify the strength of such relationship, if it exists. the analysis is followed by key inferences and conclusion. risk assessment is an important step in disaster risk reduction where it enhances the understanding of risk and allows information to decide on adequate preventive and mitigation measures. core methodologies for disaster risk assessment include hazard, exposure and vulnerability assessment. risk assessment is also widely used in the context of health, safety and environment. it involves evaluation of existing conditions of vulnerability, the impending hazard, existing exposure and current capacities for prevention (unisdr, 2009 ). risk models specify the factors which are needed to assess risk and the relationship among those factors, producing a sort of template for risk assessors to use in their assessments. health risk assessment tools have been developed to assess individual risk for particular diseases. [1] points out the need to have a proper risk assessment including factors of health risk, governance, exposure and citizen behaviour. to strengthen the community level response, a coordinated approach of disaster risk governance from sendai framework point of view is needed to manage this public health emergency. in the case of china, emerging technologies like artificial intelligence (ai), big data, 5g technologies, drones, automated vehicles, robotics etc were used to track, monitor and support logistics in management of covid19 [ibid] . technological risk assessment models can quickly analyze irregular symptoms and other similar red flags and thus alarm the community and the healthcare authorities. this helps to improve the planning, and awareness activities for patients on an evidence-based model. further it helps to provide faster decision making, which is cost-effective. such tools can help analyze the extent of infection spread by this virus by identifying the clusters and hot spots and can successfully do the contact tracing and monitor of the individuals [7] . covid-19 is as much a pandemic as it is an infodemic [5] . who information network for epidemics (epi-win) [8] was launched as a new information platform to share customized information with specific target groups. the data on covid-19 is dynamic and changing at a fast pace. covid-19 hotspots (areas with affected cases of covid19) are changing dynamically. this makes a control of information difficult. social media in this regard tends to be flooded with messages many of which are not verified. as per [5] , the media use for information access for the covid-19 increased tremendously. however, the right information is the key to success in mitigation measures. the chinese and singapore government in this regard have checked the fake news and kept control on rumour spreading. 1 . infermedica [13] identifies coronavirus symptoms and provides further information regarding covid-19 concerns. health engine [14] it asks questions on following parameters and provides analysis of risk:  travel history  corona positive patient contact history  symptoms of fever etc 3. henryford [15] it asks questions on symptoms, with travel history and contact to provide risk analysis 4. docsapp it is an online doctor consultation app to provide information on symptoms and whether to consult a doctor. 5. who mass gathering religious addendum risk assessment tool in the context of covid-19  it is an offline risk assessment tool for organisers and planners  it includes mitigation checklist for planning mass gatherings and events. humandx.org [16] it asks questions on age, travel history, symptoms, being in healthcare profession and co-morbidities. the assessment summary provides information on preventive steps, the need to visit doctor, get tested etc. 7. arogya setu [17] the app verifies symptoms and notifies the users if they are in vicinity of a diagnosed positive patient. tracking is done via bluetooth and a j o u r n a l p r e -p r o o f location-generated graph that charts proximity with anyone infected. the app also provides self-quarantine instructions. 8. tracetogether [17] it is a contact tracing app that uses bluetooth to track infected people and notify those who were in close proximity to them during the past 15 days. 9. covidwatch [17] it uses bluetooth signals to detect users when they are in proximity to each other and alerts them anonymously if they were in contact with someone who has tested positive. one unique feature of the app is that any third party, including the government does not have access to the data of who was exposed by whom. 10. hamagen [17] this is launched by the health ministry of israel. it uses contact tracing to contain the spread of the deadly contagion. the app allows users to know if in the past 15 days they were close to anyone who has been diagnosed with the virus. 11. the corona dataspende [17] it is a german smartwatch app which monitors the spread of coronavirus by collecting symptoms like pulse rate, body temperature, sleep patterns to detect any early signs of warning. it is done through wearing a smartwatch or a fitness tracker. 12. pedulilindungi [17] it is developed by the indonesian government. it enables users to compile data related to the spread of covid-19 in the community and helps confirmed and suspected cases. it cross-references data stored on mobile device through bluetooth. it enables an anonymous exchange of identities when in vicinity of another positive patient. 13. covid safe the australian app helps state and territory health officials to quickly contact people who may have been exposed to covid-19. the covid safe app speeds up the current manual process of finding people who have been in close contact with someone with covid-19. the above-mentioned risk assessment tools are mostly based on the premise of either tracking the affected patients or diagnosing a probable condition through symptoms. these tools and apps help the government as well as the community in knowing if they have been in contact with an affected person. amidst the concerns for privacy, many private apps have come up to aid in individual assessment of risk and contact tracing. the rika"s covid-19 risk assessment tool goes beyond the symptom detection and patient tracking. it intends to provide information on social behaviour and also assesses the people"s compliance for the government advisory. the risk assessment score also includes the exposure of people through the type of residence, the behaviour of hand-washing and wearing mask as well as the current implementation status of restricted movement guidelines of the government. in comparison to the arogya setu app by government of india, the covid-19 risk assessment tool, provides awareness information in the form of questions which are also used to assess the risk based on behaviour and social compliance. further, the covid-19 risk assessment tool generates information on anxiety levels to understand the need for psychosocial care as part of overall response. the inclusion of smoking as a risk behaviour is also not considered in arogya setu app or any other risk assessment tool available in asia or in the other continents. another unique feature is the assessment of exposure based on residential type which is again missed in other available applications and tools. j o u r n a l p r e -p r o o f 6 free to use. the simplicity of the app lies in the fact that there is minimal data entry. the tool prominently includes questions related to awareness behavior of the user in order to inculcate awareness. key questions on whether social distancing is being maintained reiterate the importance of such measures. the tool ensures the implementation of risk communication to the end users. further, the tool presents the analysis of risk in a visual format which is more appealing to the people. the tool assesses the prevalence of co-morbidities in the users which might increase their risk. as per [18] , underlying diseases (comorbidities), including hypertension, respiratory system disease and cardiovascular disease could be the risk factors for severe patients compared with non-severe patients of covid-19. [1] notes that pandemic is global but its response is local. it is also pointed out that a major part of the response depends upon the culture and citizen behavior [19] . [ibid], also notes that in japan, people with colds, flu, or allergic, wear surgical masks as a cultural norm to prevent others from getting sick. the japanese do not have emotional resistance to wearing masks, whereas people in other countries need to be informed on the need of wearing mask to prevent themselves as well as others. the survey assessment tool assesses the people"s behavior in wearing masks and can help overcome emotional resistance to adhering to government guidelines on restricted movements and sanitation practices. the study of [6] demonstrated that although knowledge is important for performing sars-preventive behaviours, social norm is also an important factor. the assessment tool allows the users to take adequate measures with respect to the risk outcomes of high, moderate and low. the assessment tool also allows the measurement of risk perception through the level of anxiety shown by the user in the current scenario. the risk assessment tool fights the infodemic. it shares the personalized risk assessment information. the data analysis can also provide insights into how many people are taking hand-washing seriously. it can detect the need for mental health risk assessment through anxiety level. the tool is a low-cost technology-based solution to provide assessment of individual risk as well as increase community awareness. the tool is customizable in various languages and is currently available in seven languages. the tool also adheres to the privacy norm by not collecting any personal information of the user like phone number or email id. the covid-19 risk assessment tool is broadly based on four major factors of health, exposure, behavior and social policy. each of these factors have sub-factors which are based on findings from studies conducted in china and italy [27] . the various parameters used to develop the assessment tool can be categorized as shown in table 2 below. each of the parameters are assigned linear weights based on the responses in the given options (annex-1 for details). the given weights for each parameter except for health are summed up and then average is calculated. the calculation is listed in table 3 below. the basic premise for calculation is that age and health is the inherent individual vulnerability that is being exacerbated due to individual exposures and individual behavioral elements. gender has also been found to be a prevalent determiner of risk to covid-19. the behaviour factor be5 and be6 are not scored for calculation of risk. based on the above weightage the risk is calculated as: risk= (hr*0.5) +(be*0.2) +(ex*0.2) +(sp*0.1) the output based on the above calculation gives us three different scenarios of risk as depicted at the end of the assessment: low, moderate and high risk along-with a general information advisory (figure 1 below) this application has been deployed on amazon web services (aws). aws simple storage solution (s3) is used to host the user interface (web site). the user interface has been developed using angularjs and responsive web design. to distribute the web site content aws cloudfront (content distribution network, cdn) is used so that customers across the world can access it with low latency and high transfer speed. survey data is submitted from https://www.covid19risk.net web site to aws api gateway, which internally calls aws lambda function to store the survey data into amazon dynamodb database. entire application is serverless and it scales out and scales in automatically based on the usage. the cost associated with this kind of architecture is very minimal. further, the geotagged locations for each respondent are plotted on a map to show the respondents the probable risk around that location and also the pre-identified hotspots by the government. the covid-19 risk assessment tool was launched in india on 11 th april 2020. between 11 th april and 4 th may 2020, a total of 2,216 responses were recorded. of these, the data of test users and users with identified repetition was excluded to have unique response. this was done by application of filters in the data set using spss software. two filters: ip address and names were used to exclude the duplicate entries. as a result, a total of 1,293 respondents" data is used to analyse the emerging trends and patterns. the statistical analysis used spss software (ibm statistics 20) to sort the data and understand relationship between variables using percentages, graphs and pearson correlation. the pearson correlation analysis was used so as to understand the linearity between variables. as observed in [22] , the pearson correlation can provide understanding on the relationship between variables. the assessment measured the variables of behaviour across different age groups, between variables of behaviour with each other, between social policy and behaviour, between behaviour and exposure, between co-morbidities and age and other different combinations to understand and quantify the relationship of variables. pearson's correlation coefficient was calculated to compare quantitatively the similarity between tow variables and to indicate quantitative discrepancies in the similarity. pearson's correlation coefficient (ranging from -1 to +1) is a measure of the strength of the association between the two variables. a value of +1 is the result of a perfect positive relationship between these variables. annexure-2 presents a summary of the results obtained from applying the correlation coefficient for different variables. the correlation coefficient is studied as per [24] . if the coefficient value lies between ± 0.50 and ± 1, then it is said to be a strong correlation. if the value lies between ± 0.30 and ± 0.49, then it is said to be a moderate correlation. when the value lies below ±.29, then it is said to be a weak correlation. there is no correlation when the value is zero. a spoke and wheel propagation strategy were adopted for disseminating the tool. the tool was shared with various groups through whatsapp, facebook and through personal networks over email. further, it was requested for the users to share it further within their own networks. the featuring of the tool on international science council and gdfrr newsletter gave it wider audience and credibility. the limitations of the study pertain to limited sample size of analysis with 1293 samples. further, the data from the survey tool may not be equally represented from each state, thus giving partial spatial analysis. the study uses the weighted variable to understand trends and patterns in place of absolute numbers. this is because the tool is meant to categorise risk based on the information and not for the survey as a primary objective. the covid-19 risk assessment tool has been promoted and widely used in india. india, the second most populous country, currently has 90,000 active cases of the covid-19 as on may 15, 2020 [20] . the string of measures taken by the indian government have so far proved successful in containing the spread of the disease. a timeline series analysis of the measures and increase in cases is as given in figure 2 below. as observed, despite the strict measures, the cases of affected patients are still on a rise. a total of 2,216 respondents used the tool across various states in india between its launch and 4 th of may 2020. a majority of the respondents fall in the age group of 10-39 followed by 40-49. this is possibly due to the access to mobile phone usage being especially high among the youth and young professionals (table-4 ). further, it suggests that the tool can thus be possibly enhanced as a mobile based application owing to the vast use of mobile phone devices. the mobile based application and a greater number of users would aid to crowd-sourcing of vital details to map the high-risk areas. the number of entries from foreign countries is 12.5%. this implies that the tool has wide application where one can use it not only in india but also by non-resident indians (nris) keen to check on the status of their friends and families in india. in addition, the tool can be used to take multiple surveys for family members who stay distantly. this is applicable to aged population who are not technology savvy and would need assistance of their children or other family members to fill up the survey. as per [27] , there is an increased mortality rate among males in comparison to females as have been observed among the covid-19 patients. from the analysis of the data, only 12 people among the respondents featured in high risk and 11 of them are male, and one being the other gender. the findings are consistent with immune system variance among male, female and other gender [35] . the other gender has high risk due to compromised immune system. further, 585 respondents fall within the medium risk category. within this category also, the total constitution of men and other gender stands at 91%. the third category i.e. low risk has 696 of the respondents. within this category the percentage of men stands at 68%. thus, it re-establishes that females are comparatively at lower risk as they do not feature in high-risk category and in moderate risk also their percentage is only 9%. within the high-risk category, all the respondents are found to be above the age of 60 years. as per [ibid], the risk increases with an increase in age as observed in cases from china and south korea. for germany, italy and spain, the crude-case fatality increases particularly after the age of 60 years. however, there is an exception, where there are three cases in the age-group of 0-9 who fall under the medium risk. this is largely due to their residential type of an informal settlement and low compliance on behavior factor of wearing mask, handwashing and sanitizing hands before touching face. further, there are three cases of individuals aged 80 years and above falling in medium risk. this is attributed to higher compliance of behavioral factors and low co-morbidity score. spatially, maximum data entries have been received from the states of uttar pradesh, followed by maharashtra, west bengal and gujarat (figure 3 ). while writing this paper, the state of maharashtra has the highest number of covid-19 affected cases with its capital mumbai being the worst hit. spatial analysis allows to identify areas which have maximum cases of the covid-19 diseases and also allow the maps which are generated from crowdsourced data to be more representative in nature. the findings on the individual behavior suggest that 89% people use mask and 87% people use sanitiser every time after coming home (figure 4a and 4b) . however, when it comes to sanitising hands before touching eyes, nose and mouth, 63% people are practicing it ( figure 4c ). it is often seen that we inadvertently tend to touch our face while being engaged in other tasks. as per the data reports, social distancing at individual level is being well-followed with 88% complying to it (figure 4d). considering that there is no confirmed cure for the covid-19 diseases, risk preventive behaviour is the key to mitigate and contain the spread of the disease. 14 locality (i.e. scoring for be5 in level 1), within the medium risk category, 36.92% people have reported similar levels of anxiety and within the low risk category, 25.67% have reported to be anxious. this states that there is more anxiety within high risk category people followed by medium and low risk categories. in terms of effectiveness of lockdown, 75% of people have reported it to be followed with maximum compliance (figure 7a ). in terms of mask wearing and maintenance of social distancing, 47% reported more than 80% people are following it while % people responded that some people (50-80%) are following it (figure 7b) . hence, while effectiveness of lockdown is being ensured, the community level compliance of wearing mask and maintenance of social distance needs to be improved. with respect to respondent data regarding the type of residence, 40% reported it from detached houses, 30% from high rise complexes, 21% from mohalla/chawl/shared accommodations and 8% from informal settlements ( figure 8 ). as suggested in [28] building types have direct impact on the risk of spread of pandemic. the informal settlements and shared accommodations are at most risk. the high-rise apartments also increase the aggregation of people in less space. the exposure component is also measured in terms of occupation type (figure 9a ). it is observed that maximum respondents (48%) did not fall in high risk occupation types (medical and emergency professionals). closely followed are the essential service providers (41%) who are at risk of exposure. another important variable of exposure is the travel history including use of public transport or chauffeur driven cab and attendance of public meeting, mass congregation or wedding/conference.the 90% of the respondents have not been involved in any of these activities in the last 14 days (figure 9b) . the table 5 below depicts the important correlation aspects as observed from the pearson"s correlation analysis (annex-2). the factors of age and co-morbidities has shown a positive and moderate correlation with coefficient of 0.434. as per [29] ageing population tends to be more affected by multiple morbidities. the same result is depicted by a negative correlation coefficient of -0.420 age-group with no disease factor. this relationship between age-group and co-morbidities is an important risk factor for covid-19 disease too as it places the elderly population with existing disease at a higher risk of mortality. as observed, the age-group and total risk depict a strong positive correlation with coefficient of 0.835. similarly, comorbidities and total risk also have strong correlation with a coefficient of 0.678. within the co-morbidities, hypertension stands-out most with a moderate positive correlation of coefficient 0.418. diabetes also has a moderate positive correlation with a coefficient of 0.400. this means hypertension and diabetes are two important factors which increase the overall health risk. the tool gives maximum weightage to health factor in assessing the risk and this is also shown with a strong positive correlation coefficient of 0.98 between health and total risk. with respect to individual behaviour, wearing of mask and following of social distancing norm has a weak correlation with a coefficient of 0.298. this depicts that while one may practice social distancing but might not comply with mask wearing or vice versa. however, washing hands and compliance of social-distancing has a slightly higher correlation coefficient of 0.364. the gender and behaviour show negligible correlation with a coefficient of 0.017 which means behaviour factors are not dependent on gender. similarly, age-group and behaviour have negligible correlation with a coefficient of 0.048. the study [27] states the need to reduce smoking as a possible preventable determinant of the covid-19. hence, the tool places smoking habit at a higher risk and as observed from correlation coefficient of 0.302, there is a moderate positive correlation between smoking and total risk. there are two components considered in social policy factor: effective lockdown and community compliance of wearing of mask and practicing social distancing. ideally, the two factors should have a strong positive correlation. however, as observed, there is a positive moderate correlation with a coefficient of 0.363 between the two factors. further, the social policy and individual behaviour also depict a positive and moderate correlation with a coefficient of 0.266. effective risk communication measures can result in increasing the awareness and creating social trust in the authorities [30] . providing the right information can result in risk preventive behaviour and enhance risk governance mechanisms [ibid]. the covid-19 risk assessment tool is aimed at awareness generation, risk communication and aiding in decision-making. as per [23] , increase in information gathering with respect to google searches on hand-washing and wearing masks correlated with lowering the speed of covid-19. the role of technology has emerged as of great importance in emergency management specially for risk communication. the important issue is how the technology can be used with proper governance mechanisms so as to enhance the capacity of the decision-makers in government set-up. the study has shown that the risk assessment tool is majorly being used via mobile devices and can thus be possibly enhanced as a mobile based app. further, as per [31] the younger population are more likely to own a phone than the adults. this also features in the higher number of entries received from the age-group pf 10-39 than the other agegroups. the study has re-iterated the characteristics of the covid-19 pandemic as mentioned in [1] by showing strong correlation of total risk with age and co-morbidities. in terms of comorbidities, hypertension followed by diabetes has appeared to be major factor in adding to the total risk. as per [32] , there is a high prevalence of hypertension, with almost one in every three indian adults affected. in addition to it, smokers are found to be more at risk with a moderate correlation between smoking and total risk. this finding corroborates with the study in [27] which portrays smoking as a risk factor contributing to the covid-19 fatalities. in terms of gender, males remain more susceptible than female in high risk category. anxiety in general has appeared as a major cause of concern and adequate mental health counselling measures are needed to be in place especially in areas where cases have been detected. as the paper states, the covid-19 risk assessment tool goes beyond the medical symptoms and considers factors of individual behaviour and social policy. in this regard, it is observed that there is a weak correlation between individual behaviour and social policy. also, there is weak correlation between individual behaviour of wearing mask and practicing social distancing. [6] states the importance of social behaviour in contribution to the risk of contracting the disease as observed in the case of sars. thereby, a weak correlation between individual behaviour and social policy compliance depicts a gap in the governance and implementation mechanism. this implies that there is a need for more awareness generation amongst community. since a major part of response of pandemic depends on culture and citizen behavior [19] , the decision-makers need to design targeted intervention policies for creating the risk preventive behavior and increasing the community compliance of the social policy measures. the finding regarding the lower age group (0-9 years) being in moderate risk category depict that there is a need to educate children about touching the face without sanitizing their hands as they might do it more frequently than adults. further, children specific risk communication means can be developed so as to ingrain the preventive behavior. as noted in [33] people"s behaviour is influenced by social norms: what they perceive that others are doing or what they think that others approve or disapprove of. risk perception can be changed by promoting public messages reinforcing positive healthpromoting norms [ibid] . public knowledge of risk allows for change in perspective and more social compliance in terms of adoption of risk preventive behavior. the interventions can focus on targeting well-connected individuals and making their behavior change visible and salient for others to copy. as only 8% people have responded from informal settlements, this depicts a wide gap in digital divide in the country. many of the respondents living in informal settlements reflect the bottom most layer of the social and income structure. inequalities in access to resources affect not only who is at greatest risk of infection, developing symptoms or succumbing to the disease, but also who is able to adopt recommendations to slow the spread of the disease. such communities may be more likely to be wary about the public health information they receive, less willing to adopt recommended safety measures and potentially more susceptible to "fake news" [ibid] . in this regard, community-oriented tools of risk awareness need to be more popularized so that risk communication reaches the last mile. [19] mentions a humancentric society where technology connects people and tries to reduce the barrier of digital divide. the covid-19 risk assessment tool is multi-lingual tool which helps the communities to access the advisory and understand the individual risk in a simplified way. this is particularly helpful for migrants who need to understand the risk in their own language. citizens might also be wary of using the government supported tools and apps for the concerns of privacy. lack of national data privacy laws and non-transparency in governance of such data collected are some of the issues flagged by people as part of resistance to use the arogya setu app of government of india [34] . rika"s covid-19 risk assessment tool addresses the concern by not collecting any personal data like mobile number or accessing the location history of the user. artificial intelligence has been used for emergency data management, especially for managing social networks and big data. the people are using digital technologies to support disaster management. crowdsourcing is helping to add vital details to maps of disaster areas. citizen science is becoming more popular and effective before, during, and after disasters. grassroots or demand-driven innovation has been practiced in many countries in recent years. in this aspect, the covid-19 risk assessment tool presents itself as an innovative approach of using science and technology for enhancing community preparedness. the crowd-sourced data and maps generated allow the stakeholders like government agencies and ngos to plan the response and interventions. the risk assessment tool is flexible and it has a simple userinterface. this allows it to be contextualised to cater to any target community with specific need. this adaptability of the tool places it as a unique innovation coming from the citizen science approach. the two-way data interface in the form of feedback mechanism provides platform for participation of citizens in decision-making for the response strategies. as observed from findings, 51% people have marked for the need of new measures to control the pandemic. this paves way for a more participatory approach for the decision-makers in planning an intervention at the local level. to re-iterate [1] the pandemic is global but the response is local, this tool allows for a more contextualised and community specific response. while writing this paper, the number of affected cases in india is still on a rise while countries like singapore, south korea, china and a few other are expecting a second wave of pandemic. in this backdrop, the preventive measures need to be strengthened at all costs and citizen"s behaviour as has been seen in south korea and japan is an important factors to break the chain. for a populous country like india, where it is difficult for the current health infrastructure to accommodate and treat an exponential increase number of the patients as had been seen also in italy, china and united states of america for treatment, it is best to follow the preventive strategies. rika"s covid-19 risk assessment tool can be used to reach the last mile community, ascertain the individual behaviour, social compliance and exposure factors in order to find out relevant areas of intervention and at the same time increase awareness generation among the community. as rightly pointed out by [4] , the management of covid-19 pandemic is interwoven within the global governance, technology and risk communication. this pandemic is witnessing a change in the social norm and a new normal is being established. this is also an opportunity for new innovative technologies to break the digital divide and increase the resilience of the most vulnerable communities through democratic information access and participatory decision-making to develop a local level response strategy. degree of correlation: perfect: if the value is near ± 1, then it said to be a perfect correlation: as one variable increases, the other variable tends to also increase (if positive) or decrease (if negative). high degree: if the coefficient value lies between ± 0.50 and ± 1, then it is said to be a strong correlation. moderate degree: if the value lies between ± 0.30 and ± 0.49, then it is said to be a medium correlation. low degree: when the value lies below ±.29, then it is said to be a small correlation. no correlation: when the value is zero. ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐the authors declare the following financial interests/personal relationships which may be considered as potential competing interests: as journal pre-proof governance, technology and citizen behavior in pandemic: lessons from covid-19 in east asia 3 13). who officials rethink epidemic messaging amid pandemic debate identifying research trends and gaps in the context of covid-19 (under 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(under publication) government of india: available at the relationship between indoor and outdoor levels of pm10 and its chemical composition at schools in a coastal region in spain google searches for the keywords of "wash hands" predict the speed of national spread of covid 19 outbreak among 21 countries telecom regulatory authority of india covid-19) pandemic: increased transmission in the eu/eea and the uk -seventh update covid-19: lessons for an urban(izing) world ageing and the epidemiology of multimorbidity initial impacts of global risk mitigation measures taken during the combatting of the covid-19 pandemic mobile connectivity in emerging economies prevalence of hypertension among indian adults: results from the great india blood pressure survey centre must address privacy concerns, and ensure greater transparency on aarogya setu effects of sex and gender on adaptation to space: immune system innovative responses to covid-19: collection of approaches from the republic of korea risk assessment: a neglected tool for health, safety, and environment management available at: world health organisation health emergency and disaster risk management framework thirty years of science, technology, and academia in disaster risk reduction and emerging responsibilities coronavirus disease 2019 (covid-19) pandemic: increased transmission in the eu/eea and the uk -seventh update fear and stigma: the epidemic within the sars outbreak public attitudes toward sars and their implications for societal preparedness for other emerging infections patterns and temporal trends of comorbidity among adult patients with incident cardiovascular disease in the uk between 2000 and 2014: a population-based cohort study the centre for evidence-based medicine develops, promotes and disseminates better evidence for healthcare concept, methodology, writing sukhreet bajwa: analysis and writing disha dwivedi: analysis and writing repaul kanji: methodology inputs moniruddin ahammed: system development rajib shaw: concept, methodology and writing we thankfully acknowledge the inputs from prof. emily chan, professor and associate director (external affairs and collaborations); head, division of global health and humanitarian medicine jc school of public health and primary care centre. we acknowledge mr. amit chowdhury, mr. tushar kumawat and mr. dipanjan bhowmik and the team of profecia links for the survey page design. key: cord-294916-xc9ozxyn authors: oehmen, josef; locatelli, giorgio; wied, morten; willumsen, pelle title: risk, uncertainty, ignorance and myopia: their managerial implications for b2b firms date: 2020-07-31 journal: industrial marketing management doi: 10.1016/j.indmarman.2020.05.018 sha: doc_id: 294916 cord_uid: xc9ozxyn abstract rare events are common: even though any particular type of ‘rare event’ a world war, global economic collapse, or pandemic for that matter should only occur once every 100 years, there are enough of those types of ‘rare events’ that overall, they commonly occur about once every 10 years. as we are currently experiencing with the covid-19 pandemic, we do not sufficiently leverage the rich toolset that risk management offers to prepare for and mitigate the resulting uncertainty. this article highlights four aspects of risk management, and their practical and theorical implications. they are: 1) risk (in the narrower sense), where possible future outcomes can be captured through probability distributions. 2) a situation of uncertainty, where there is transparency regarding what is not known, but probability distributions are unknown, as well as causal relationships influencing the outcome in question. 3) a situation of ignorance, where there is no understanding that certain possible future developments are even relevant. and finally: 4) the emergence of organizational and inter-organizational myopia as an effect of risk, uncertainty and ignorance on collective human behaviour. the outbreak of the current covid-19 pandemic was not a practically unforeseeable 'black swan event', as regularly claimed by media and online pundits (bloomberg tv, 2020) . not only is a general pandemic preparedness (typically for a much more severe pandemic influenza) part of standard government's emergency planning, but it has been communicated as a practical near-future certainty in expert forums and the general public alike (gates, 2015) . even a scenario worryingly close to what is currently unfolding (though with much higher mortality rates) was role-played by an international team of health experts in the fall of 2019 at the center for health security at johns hopkins university. their resulting recommendations (center for health security, 2019) mirror precisely the shortcomings we are experiencing today. sadly, their findings and those of earlier similar exercises collected dust in various drawers around the world. taking a step back, disruptive global events are not as rare as they may seem. the world is exposed to a significant amount of "1 in a 100 year" events, so that they occur with some regularity. they include for example : world war i (1914 ), spanish flu (1918 , the great depression (1929 ), world war ii (1939 , the cuban missile crisis (1962) , opec oil embargo (1973) , us-on-soviet union nuclear attack false alarm (1983) , collapse of the soviet union and the iron curtain several events, such as the cuban missile crisis of 1962, the false alarm regarding a nuclear attack in 1983, or the global near-collapse of the financial system in 2007/2008, were near-misses that could have just as easily rewritten the social and economic history of the world. the collapse of the soviet union in 1989 did change history, and in hindsight we easily forget the tensions that existed when the cold war status-quo was changing to some unknown future state. more generally speaking, the management of risk is an acknowledged challenge in managing business partnerships (zhang & banerji, 2017) . organizations (governments, companies and even universities) have little influence on the occurrence of these "exogenous shocks" (hartmann & lussier, 2020) , nor can the occurrence of any one specific event be pinpointed to an exact point in time in the future. nevertheless, there exists a rich toolbox of risk management practices to support decision-makers across organizations. as the economic impact of the current covid-19 disruption demonstrates, these tools are not leveraged effectively. one fundamental barrier to successful use of risk management practices is that risk and risk management is a highly diverse field, and for better or worse, under constant debate and development. moreover, decision-makers do not think in terms of risk, mostly because they have not been educated in those terms. they think in terms of cost-benefit analysis, a mental framework that is appropriated for simple short-term decisions but can lead to "organizational myopia" to long term, more complex decisions. this article briefly illuminates the broader field of risk management and highlights practical and theoretical research challenges. we believe that all of them are relevant for businesses today during the covid-19 crisis. we can broadly discern four contexts where organizations and decision makers face risk. contexts 1-3 are characterized by decreasing level of knowledge regarding the future: 1) risk (in the narrower sense), where possible future outcomes can be captured through probability distributions. a typical response is risk management (section 2). 2) a situation of uncertainty, where there is transparency regarding what is not known, but probability distributions are unknown, as well as causal relationships influencing the outcome in question. robust decision making is a possible response (section 3). 3) a situation of ignorance, where there is no understanding that certain possible future developments are even relevant. we discuss resilience as an organizational response (section 4). the fourth managerial context emphasizes not just the level of available knowledge, but how organizations culturally react to the resulting uncertainty: 4) the emergence of 'organizational myopia' (including inter-organizational myopia) as an effect of risk, uncertainty and ignorance on collective human behaviour. as a possible response, we discuss organizational mindfulness (section 5). in this article, we consider situations of 'practical' risk, uncertainty, and ignorance, i.e. we do not discuss if certain information would have theoretically been knowable at a certain point in time, but if it was practically known by decision makers. in that sense, the current pandemic falls into the category of "ignorance" for many organizations, although technically, it was a well understood, described and quantified risk. lastly, the discussion of organizational myopia illuminates the practical effects on the organizational level. table 1 summarizes the key theoretical and practice challenges. there are a multitude of competing definitions on what 'risk' is (aven, 2012 (aven, , 2016 . a definition following knight (1921) understands risk as uncertainty that can be modelled and quantified monetarily: risk is uncertainty that can for example be expressed as a probability distribution. as such, risk can be effectively insured against, or be weight and traded off against other risks and opportunities. to what extent this category is truly relevant in managerial practice is debated (aven, 2012 (aven, , 2017 ward & chapman, 2003) , but it is firmly established in organizational practice. examples include the already mentioned insurances, resource allocation, or the design and optimization of investment portfolios. the iso 31000 standard (iso, 2018) defines risk more broadly as the 'effect of uncertainties on objectives', generalizing from financial impacts to impacts on any type of stakeholder value (including, for example, well-being or reputation). this general definition and understanding of risk promotes professionalization of risk management practice (olechowski, oehmen, seering, & ben-daya, 2016) and underpins many existing practitioner standards for risk management -from domains such as systems engineering (incose, 2015) , to finance (allen, 2012) , to supply chain management (de oliveira, marins, rocha, & salomon, 2017; zsidisin & ritchie, 2008) , to project management (pmi, 2019) and of course data analytics (jaynes, edwin, & bretthorst, 2003) . despite multiple established standards in the field, there remain considerable foundational challenges. very simply, for example, consider situations with unclear or conflicting objectives-what are 'risks' under those circumstances (aven, 2012) . it is an interesting paradox that risk management focusses on uncertainty and its potential impact, yet the prescriptions found in the risk management literature can be shrouded in uncertainty and hidden assumptions (willumsen, oehmen, stingl, & geraldi, 2019) . in practice, risk management ranges from gut-feeling-based risk matrices with illdefined (or undefined) evaluation scales for probability and impact (cox jr., 2009) , to highly sophisticated quantitative models (allen, 2012; jaynes et al., 2003) . these foundational issues in risk management create challenges for practitioners. for example, risk management should be customized (iso, 2018; oehmen et al., 2014) as different risk management practices vary in their ability to create value in different contexts (willumsen, oehmen, stingl, & geraldi, 2019) . the clear implication for the current covid-19 crisis (that arguably affects all companies), there will be no 'one size fits all' risk management solution. one such difference relates to the availability and quality of data, which heavy influences if a method is applicable (tegeltija, 2018) . hubbard, (2009) has shown that using inappropriate risk management methods can be worse than doing nothing, as it leads decision makers towards a false sense of certainty. a common challenge is using expert judgement in the assessment of probability distributions of outcomes, or in simpler applications, in the estimation of probability-impact pairs for the occurrence of specific events. expert judgement can provide valuable insight in situations where available data is lacking (cooke, 1991; renn, 1998; zio, 2009 ). however, careful consideration of multiple factors such as level of expertise, confidence and subjective bias is needed (cooke, 1991; fortin & gagnon, 2006) . given the current scarcity of 'hard facts' during the covid-19 pandemic, expert judgement plays a significant role in decision making. the challenge of operationalizing risk management in practise extends to determining the maturity of such systems in their context (chapman, 2019) . having 'more' risk management does not necessarily improve the management of risk (oehmen et al., 2014) . rather, the contextual fit of risk management systems is of such importance that traditional process maturity scales falls short (tegeltija, 2018) . a number of challenges exist regarding risk management theory. as mentioned, the definition of risk itself is an ongoing debate, and no consensus has been reached. similarly multiple conceptualizations and interpretations of uncertainty exist, as discussed in the following sections. the different conceptualizations of uncertainty require different approaches in terms of modelling and management, and research into these foundational challenges is ongoing (aven, 2012 (aven, , 2016 tegeltija, 2018) . when studying the empirical research it becomes clear that the management of uncertainty and risk stretches beyond the risk management process in a narrow sense. for example, other processes in a company might serve to manage risk, such as stakeholder or knowledge management (neves, da silva, salomon, da silva, & sotomonte, 2014; xia, zou, griffin, wang, & zhong, 2018) , making it challenging to understand how risks are actually managed (szczepański & światowiec-szczepańska, 2012) . there are reports of a discrepancy between theory and practice (ahlemann et al., 2013; kutsch & hall, 2010) . according to kutsch and hall (2009) ; kutsch, browning, and hall (2014) there is limited research about how risks are managed or not managed in practice, and why. the strict probabilistic interpretation of uncertainty discussed above as 'risk' makes several axiomatic and practical assumptions that are easily violated in application. these include the fundamental assumption of measurability of uncertainty (bernardo & smith, 1994) , the identification and quantification of causal links influencing uncertainty (renn, klinke, & van asselt, 2011) , the availability of data (including quantitative data, expert judgement and experience) to evaluate uncertainty (klinke & renn, 2002; lough, stone, & tumer, 2009) , an infinite mental capacity to process information and draw factual conclusions (simon, 1990) , and an absence of ambiguity, i.e. divergence in the interpretation of identical factual information by different stakeholders (klinke & renn, 2002) . this is an area of significant ongoing research and debate (aven & cox, 2015; aven & zio, 2011; flage, aven, zio, & baraldi, 2014; zio, 2009) . for simplicities sake, we refer to 'uncertainty' as opposed to 'risk' for situations where we do not have a probabilistic quantification of the uncertainty, but we are aware that (not probabilistically quantified) uncertainty exists. this is a common challenge when dealing with novel situations such as the covid-19 pandemic: we know that there are a lot of factors in play, and we are aware of some relationships and some of the data -but we also know that we do not fully understand their interact, or how reliable our data is, or how to model the future with some sufficient quality. currently, significant resources are expended to better understand what impact what combination of non-pharmaceutical interventions has on reproduction numbers, or what the medium-and long-term economic effect of these actions is going to be for what part of the economy. this continues to the firm level, where we know that we are facing some supply chain disruptions and demand changes, but when, and where, and how bad, and with what exact consequences is difficult to pinpoint. a host of methods and approaches exist to deal with this wide range of limitations: bayesian statistics builds a bridge between 'risk' and 'uncertainty' by explicitly modelling both aleatoric (i.e. stochastic) uncertainty, as well as epistemological uncertainty, i.e. uncertainty due to a lack of knowledge. both are expressed in the language of probabilities (bernardo & smith, 1994) . the domain of imprecise probability (walley, 1991) extends the treatment of epistemic uncertainty, e.g. coherent upper and lower boundaries (colyvan, 2008; kozin, 1996) that relaxes one of the central assumptions of bayesian statistics by not requiring a single additive probability measure. it has found technical applications in the field of artificial intelligence and safety risk assessment. the dempster-shafer theory of evidence (beynon, curry, & morgan, 2000; dempster, 1967) allows to also model ambiguity by accounting for the weight of evidence. again, applications are mostly in technical domains such as facial recognition or medical diagnosis (yen, 1989) . there are specific risk communication approaches that extend classic probabilistic methods, e.g. the nusap scheme (funtowicz & ravetz, 1990) . the nusap scheme was originally developed to facilitate the communication of probabilistic models in climate science to a non-expert audience. it addresses the question of how to communicate the complexities that underly a risk or uncertainty assessment by not only communicating the (n)umber, (u)nit and (s)pread (i.e. the basic probabilistic information), but also qualitative information through the (a)ssessment, describing quality of the underlying the information (i.e. epistemic uncertainty), and the (p)edigree, i.e. an overall assessment of the quality of the applied method and result. while currently not in wide-spread use, descriptive schemes like nusap are very promising to better communicate the quality (and inherent uncertainty) of assessments. this richer communication helps resolve latent issues that decision makers face when they need to decide what information to trust or consider in a decision. this is a common occurrence in the current covid-19 situation, as executives are evaluating projections of spread of infection, associated government action, market reactions, and supply chain impact. finally, there is a class of methods based on the concept of exploratory modelling, where computational experiments are used to develop plausible future scenarios, and evaluate current decision options against those scenarios. the core idea is not to identify the 'optimum' solution to address uncertainties, as that solution may be very sensitive to assumptions (that had to be made due to a lack of table 1 summary of theoretical and practice challenges in risk management. theoretical challenges practice challenges • risk: possible outcomes with known probabilities (knight, 1921) • risk management: coordinated activities to direct and control an organization regarding its risks (iso, 2018) • conflicting definitions of 'risk' and 'risk management' (aven, 2012 (aven, , 2016 aven & renn, 2019) • articulation of organizational value of risk management (willumsen, oehmen, stingl, & geraldi, 2019) • one-size-fits-all expectation of risk management standards vs. need for customization (oehmen, olechowski, robert kenley, & ben-daya, 2014) • idealized formal risk management neglects actual risk management (including its informal aspects) (ahlemann, el arbi, kaiser, & heck, 2013; elmar kutsch & hall, 2010) • choice of appropriate risk management methods for given decision context and data quality (tegeltija, 2018) 2. management of uncertainty (section 3) • uncertainty: possible outcomes with unknown probabilities (knight, 1921) • robust decision making: assessing performance across a broad range of possible futures to minimize regret (walker, haasnoot, & kwakkel, 2013) • delineation of uncertainty and risk (aven, 2012; flage, aven, zio, & baraldi, 2014) • development of some mathematically very advanced reasoning into actionable methods, while maintaining rigor (tegeltija, 2018) • incorporation and communication of uncertainty in decision making (funtowicz & ravetz, 1990) • implementing and operationalizing novel uncertainty management methods (tegeltija, 2018) 3. management of ignorance (section 4) • ignorance: unknown outcomes with unknown probabilities (michael smithson, 1989) • resilience: the ability to resist or recover from unexpected events without foresight (holling, 1973) • theoretically sound operationalization of resilience concepts into organizational practice (wied, koch-ørvad, welo, & oehmen, 2020) • reconciliation of expectation of productivity with need for resilience (r. l. martin, 2019) • articulation of specific and explicit resilience strategies for organizations (wied et al., 2020) • orchestrate cultural shift from 'predict and plan' to 'monitor and react' (hall, turner, & kutsch, 2015; rolstadås, hetland, knowledge). instead, they seek to 'minimize regret', i.e. ensure that a decision avoids unacceptable outcomes under all plausible future scenarios, thus limiting the worse case scenario. all acceptable options can then for example be evaluated regarding their cost. a prominent example of such a method is robust decision making (rdm) (dewar, builder, hix, & levin, 1993; lempert, 2002; walker, haasnoot, & kwakkel, 2013) . rdm has been used to decide on climate change adaptation actions (lempert, 1996) or economic policy (seong, popper, & zheng, 2005) . the possible benefits of such a method for business decisions are obvious: instead of attempting to 'maximize value' with little more than educated guesses, an approach of 'minimizing regret' emphasizes the survival of the organization under all plausible circumstances, while explicitly acknowledging the uncertainties surrounding the decision. approaches such imprecise probabilities or exploratory modelling require new quantitative modelling capabilities and corresponding maturity in the decision making processes. however, if organizations honestly want to address the novelty, uniqueness, and first-of-a-kind challenges that covid-19 entails, they cannot rely on classic probabilistic approaches alone (gidel, gautier, & duchamp, 2005) . on the academic side, work remains to apply and validate these more advanced methods of uncertainty modelling in business practice (tegeltija, 2018; tegeltija, oehmen, & kozin, 2017) . at the same time, foundational discussions continue on the nature of risk and uncertainty, and how to coherently conceptualize them in the field of risk management (flage, aven, zio, & baraldi, 2014) . we are ignorant about the future when we do not know possible future outcomes (including their probabilities of occurring). as knight (1921) already pointed out, that is the common state of affairs in most real-world situations. typically, the number of possible outcomes (and combinations of them) is vast and practically infeasible to enumerate, and there is no historical basis for assigning statistical probabilities to all of them, and have them sum neatly to 1. under ignorance, rolstadås et al. (2011) likened navigating the future to crossing an eight-lane city street packed with vehicles of all kinds, moving at varying speeds, and in both directions. here, any detailed plan of crossing would likely be obsolete before making it across the first lane. instead, all we can do is to broadly outline a general direction, try one lane at the time, and respond to whatever unfolds (see wied et al. (2020) for an in-depth discussion of the relevant literature). resilience is an organization's ability to manage ignorance. holling (1973) first used the term to describe the ability to resist or recover from unexpected events, without the necessity of foresight. from a resilience perspective, ignorance is not the problem. rather, the problem is unrecognised, unpopular, or wilfully denied ignorance. this is when we think we know the future (or pretend to), but we really do not (taleb, 2007) . when this happens, we irreversibly commit to overspecialized plans and businesses models (specialized for an expected future), and over-confidently head out into oncoming traffic. this may be a sentiment that managers can relate to in the current covid-19 situation. in the words of holling (1973) , specialization is an adaptive response to a stable environment, whereas resilience is an adaptive response to a dynamic environment. while risk management, and to some lesser extent, management approaches focused on uncertainty, rely on a 'predict and plan' mindset (e.g. van poucke, matthyssens, van weele, & van bockhaven, 2019), resilience builds capabilities to 'monitor and react' (hall et al., 2015) : this includes building capabilities in four areas: 1) preparation, financially and operationally, for unexpected disruption (sheffi, 2017) ; 2) resistance, the immediate crisis management that moves the organization out of its denial and complacency, and minimizes the negative impact without delay (henry & ramirez-marquez, 2016) ; 3) recovery, when the organization works to regain pre-crisis performance by repairing damage, improvising, and making do; and 4) learning, implementing new solutions refining them than possibly surpassing precrisis performance (taleb, 2013) . or to paraphrase the intrepid explorer roald amundsen: preparation is called 'luck', whereas lack of necessary precautions is called 'bad luck'. during the covid-19 pandemic, we have to give our organizations a chance to 'be lucky' during and after a disruption. as the covid-19 situation evolves, disruptions will keep emerging across the value chain, and resilience will remain a core necessity. looking at instances of 'luck' during the covid-19 epidemic, this is a virtual manifesto against over-specialization and towards local adaptation. in the first days of the crisis, long outmoded ventilators were brought out of storage (and dumpsters), and animal hospital ventilators were rapidly adapted for human patients. a range of medical professionals were brought in and retrained in their use (hersher, 2020) . whiskey manufacturers switched to distilling batches hand sanitizer (c. levenson, 2020) . 3d printer hobbyists churned out face masks (brooks, 2020) . super markets and drug stores became door-todoor delivery services overnight despite the health risks (randle, 2020) . public and private spaces were re-organized for social distancing (tavares & stevens, 2020). churches, schools, and concert halls became online-only entities within a few weeks (freedman, 2020) . there is much to learn from these creative outbursts, outlining both practical and theoretical challenges for businesses. in the past, crises were followed by complacency (ayotte, gerberding, & morrison, 2019) . when normality returns, resilience thinking will, once again, be swimming against the steady current of specialization and optimization. at no point are uncertainty and ignorance harder to imagine than in predictable times (taleb, 2005) . already, detailed 'post-crisis' plans are potentially obscuring the view to a future that is, essentially, no less surprising than before (weick & sutcliffe, 2007) . denial, nostalgia and arrogance of past successes quickly reassert themselves (hamel & välikangas, 2003) , now amplified by survivorship and hindsight bias. preserving and harnessing the creative, flexible, imaginative, engaged, 'one-day-at-a-time' state of alertness (hall et al., 2015) will be a major challenge for businesses. preparing for the next surprise will involve remaining in the sweet spot between complacency and panic (henderson, 2020) . theoretically, the challenge is to move beyond a probabilistic and 'event-specific' understanding of risk, and towards a paradigm of 'general preparedness' (aven, 2017b) . in this respect, there is some way to go to reconcile holling's attitude of socratic humility about the future (holling, 1973) with the necessity of specialization, optimization and regular risk management. it is challenging to appreciate the value of 'post surprise' strategies like multi-functionality, redundancy, reversibility, incremental learning, modifiability and opportunism (wied et al., 2020) , before they are actually needed. importantly, resilience thinking does not preclude sophisticated anticipatory planning, but encourages us to prepare for even our best-laid plans to be wrong. despite all guidelines, mathematical models and software, risk management remains a human-centric activity. it is people deciding if and which risk management perspective and process to adopt, which scenarios or inputs to analyses, and what to with the results (discussed for example by cui, su, feng, & hertz, 2019 in the context of servitization). these human-centric activities are subject to several limitations, that can be analysed at two different levels: individual and organizational. at the individual level, humans dealing with risk, suffer from the socalled "cognitive bias". the term cognitive bias was popularized by the work of tversky and kahneman (1974) which identified cognitive biases as errors in thinking stemming from heuristics. these heuristics are principles which are used to reduce the complexity of decision making leading to errors in an individuals thoughts. pohl (2004) imagines cognitive biases as illusions that can cause an individual's thoughts, memories or judgements to deviate from reality. cognitive biases usually tend to affect complex decisions and individuals are not usually aware of the presence of such biases in their decision making. according to reyna, chick, corbin, and hsia (2014) experienced individuals were more likely to display cognitive biases in their decision making when compared to the group of inexperienced people. as the covid-19 situation unfolds, we can individually reflect on our own thinking and decision making biases, particularly in the early phases of the pandemic. cognitive biases, such as optimism bias, have been popularized in project and risk management literature by flyvbjerg's books and papers claiming that cognitive biases are key reasons why for example largescale projects are often delivered over budget and late (flyvbjerg, 2006; flyvbjerg, garbuio, & lovallo, 2009 ). however, the idea of cognitive biases in project and risk management is at least 20 years old. mccray et al. (2002) highlight the significant effect that cognitive biases may have on complex projects where project managers tend to rely on prior experience or rules of thumb (heuristics) that they have created over the years in order to deal with project complexity. the number of cognitive biases described in the literature is in the order of 100. one bias that is relatively infrequently discussed, but very relevant for our discussion, is the dunning-kruger effect. the term was first coined in 1999 when david dunning and justin kruger first observed the effects of incompetence on self-judgement (kruger & dunning, 1999) ; in addition to making wrong decisions, incompetent people are also unable to realize their incompetence. kruger and dunning (kruger & dunning, 1999) called this the "dual burden of incompetence". this poses a particular challenge in the covid-19 pandemic: in order to recognize the competence of other people in a specific domain, an individual should possess a certain level of competence in that domain as well; since an incompetent person will not be able to judge their performance correctly, that person will tend to overestimate their ability, e.g. in performing an appropriate risk analysis. advancing to the organizational level, humans dealing with risk suffer from "collective myopia", also called organizational and interorganizational myopia (chikudate, 2002) . organizational myopia received less attention and research than cognitive bias but is no less important. "collective myopia is a […] condition where the sensemaking capabilities among the members in collectivities are limited to their contexts. emerging orders or patterns are like the flocks of sheep that are nicely organized. each sheep knows how to behave and watch out for each other in a collectivity. but none observes their collective behaviours as a whole. […] the sense-making of these members is, thus, confined to the limited context of their own concerns in certain organizations or communities." (chikudate, 2015, p16) . the concept of collective myopia has been associated with the studies of ethics in organizational practices (chikudate, 2002) , where the ethical judgement of the individuals are suppressed by an overarching perspective from the organization. in this "ethical blindness" individuals, as part of an organization, might act unethically without being aware of it. they become ethically blind (palazzo, krings, & hoffrage, 2012) . this blindness has implications for risk management and decision making, like in the emblematic cases of the ford pinto (gioia, 1992) and fukushima daiichi (chikudate, 2015) where misjudged risk analyses had dramatic consequence on people, business and the environment. it is starting to become evident in the context of covid-19, when for example certain groups start discussing very matter-of-factly how we should deliberately sacrifice vulnerable populations for the greater good, completely oblivious of their ethical transgressions and proximity to eugenics (jones, 2020) . at individual level cognitive bias and, at an organizational level, collective myopia can at least in part explain how educated and intelligent people consistently failed to appreciate and take actions to mitigate a pandemic risk its implications. the risk management models reflected the bias and myopia of the people preparing them, and miserably failed. myopia, and ethical blindness, are major barriers in developing successful interorganisational relationships, as they push the organization to develop a tunnel vision. the organization loses its ability to develop empathetic relationship with its stakeholders, including understanding what represents "value" for them, greatly diminishing their ability to address the various forms of risk. the organization might even fail to recognize key stakeholders that can support the organization in achieving its objectives and responding to risk, uncertainty and ignorance. a way for addressing organizational myopia is "organizational mindfulness" (sutcliffe et al., 2016) . organizations can address the issues organizational myopia by closely monitoring failures (own failures and failures from other organizations), paying attentions to frontline operations, resist the temptation to oversimplifying the interpretations of events and situation privileging expertise over hierarchy (catino, 2013) . the case of the uk government failing to procure personal protective equipment (ppe) for its healthcare system is an exemplar case of how myopia undermined the interorganisational relationships, and it is discussed in the following section. on april 28, 2020, the bbc opened with a dramatic headline "the government failed to buy crucial protective equipment to cope with a pandemic" (bbc, 2020d). for the bbc, this news article was quite unique, as it showed two rare characteristics: (i) an almost alarmist tone, reminiscent of a tabloid, in stark contrast with the bbc's usually softer tone; and (ii) the headline being a direct attack on the uk government. however the situation was dramatic: "the consequence of not planning; not ordering kit; not having stockpiles is that we are sending into the front line doctors, nurses, other health workers and social care workers without the equipment to keep them safe". according to the government minister victoria atkins, "like every other country in the world, [the virus] is unprecedented and the requirements for [personal protection equipment] ppe have risen exponentially and we are doing our absolute best to address those needs and will continue to do so throughout this crisis" (bbc, 2020d). the nhs is the uk's national health care system. the nhs offers medical care across the uk to all those who reside there, including first aid, short and long-term hospital stay, and specialist services such as dental services. it came into operation on july 5, 1948. most of the services are tax financed, and as such, free of direct cost for patients. the issues related to the provision of ppe originated even before the covid-19 was recognised by the world health organization (who). a bbc report "found that vital items were left out of the stockpile when it was set up in 2009 and that the government subsequently ignored a warning from its own advisers to buy missing equipment. […] the expert committee that advises the government on pandemics, the new and emerging respiratory virus threats advisory group (nervtag), recommended the purchase of gowns last june. gowns are currently one of the items in shortest supply in the uk and they are now difficult to source because of the global shortage of ppe. doctors and nurses have complained that there are also shortages of the life-saving ffp3 respirator masks. panorama has discovered that millions of ffp3 respirator masks are unaccounted for. there were 33 million on the original 2009 procurement list for the stockpile, but only 12 million have been handed out. the government refuses to explain where the other masks have gone." (bbc, 2020d) . while many of these facts were knowable (or known to someone), the central decision makers were largely in positions of ignorance. what caused the later escalation of the situation is that the general level of resilience -a sufficient capability of preparation and ability to resist, recover and learn from an incident, in our case specifically escalation ppe demand -was very low. even the easiest option, stockpiling of cheap but critical items such as ppe, had not been realized. during the early phase of the outbreak, very little statistically relevant information was available that could have informed classic probabilistic risk assessments, but it was known that a novel virus was spreading. decision makers were no longer operating under conditions of ignorance, but significant uncertainty: according to who (2020c), on the 31st of december 2019 chinese authorities reported a group of cases of pneumonia in wuhan. a new coronavirus was recognised. shortly thereafter, on the 4th of january 2020, the who reported the news about a cluster of pneumonia cases with no deaths in wuhan. the following day the who distributed the first disease outbreak news about the virus. this type of announcement, intended for media, scientific and public health community, includes a risk assessment section, concluding that "there is limited information to determine the overall risk" (who, 2020a) -summarizing that decision makers are indeed operating under conditions of uncertainty, not risk. we can observe several actions taken under these conditions to 'minimize regret', i.e. actions minimizing the impact of a worst-case scenario. for example, on the 10th of january, the who issued a comprehensive package of technical guidance online with advice to all countries on how to detect, test and manage potential cases, based on what was known about the virus at the time. this guidance was shared with who's regional emergency directors to be shared with who representatives in countries. it is reasonable to assume that by the 10th of january, uk authorities were informed about the new virus, but it is not obvious that aggressive actions were taken to strengthen national capabilities. by january 12, china had publicly shared the genetic sequence of covid-19 to facilitate scientific endeavours for diagnosis, treatment and vaccination. on the 22nd of january, the department of health and social care and public health england published the first government statement. after another 9 days (31st of january), there are the first two cases of covid-19 confirmed in the uk. a few days later (3rd of february), the who releases the 28 page 'strategic preparedness and response plan' (who, 2020b) to support states with weaker health systems. it includes an updated risk assessment, now being based on over 10′000 confirmed cases globally, confirmed human-to-human transmission, and robust quarantine and lockdown measures being taken in china. arguably, the situation evolved into a scenario where larger amounts of data are becoming available, enabling probabilistic risk assessments. it is accompanied by increasingly aggressive eu-level activities to procure critical ppe. on the 31st of january four uk countries (not including the uk) suggest a need for ppe "in case of an expanding situation in the eu". (the guardian, 2020b) . on the 28th of february the eu launches its first joint procurement of £1.2 m worth of gloves and gowns/overalls. the procurement fails due to a lack of suitable suppliers. it is relaunched on 15 march -the uk was not involved in either (the guardian, 2020b) . one very visible turning point in the engagement with risk-based models was the publication of the so-called 'imperial model' by a research group from imperial college london on march 16 (ferguson et al., 2020) . based on some of the most detailed modelling to-date and the latest known characteristics of the covid-19 spread, it projected mortality figures for the uk and the us, which triggered the first significant actions in both countries in the following days regarding nonpharmaceutical interventions. as the covid-19 situation evolved, instances of organizational myopia became more and more apparent: for example, by the 11 of february there were eight confirmed covid-19 cases in the uk, but steve oldfield, chief commercial officer at the department of health and social care, reassured staff that the "nhs and wider health system are extremely well prepared for these types of outbreaks" (financial times, 2020) . only two days later uk dentists started to discuss the potential lacking of ppe (express, 2020) . in another instance, on the 24th of february (two days after the first major lockdowns in italy occurred), a meeting of officials, to which the uk was invited, hears an update from the european commission on the joint procurement of ppe. commission officials call on countries to confirm "their exact needs latest today … to move forward with next steps". no representative from the uk attends the meeting (the guardian, 2020b) . two days later emergency units in the uk start to be overcrowded and patients have to be looked after in hospital corridors (the guardian, 2020a) . on the 4th of march there is the 100 officially recognised victims in italy, and the following day there is the first victim of coronavirus in the uk (bbc, 2020a). over the next two weeks the number of victims in italy increases to more than 3000 and the italian healthcare system is, in the most affected zone, collapsing. however, still on the 18th of march (two days after the publication of the 'imperial model'), the uk prime minister boris johns declared "we have stockpiles of ppe equipment and we're proceeding in accordance with the best scientific advice." (bbc, 2020c). the uk is still largely operating 'business as usual' with children going to schools and pubs and restaurants opened (almost one month after the first lockdowns italy). on the 19th of march the uk eventually takes up an invitation to join the eu joint procurement agreement steering committee, which makes decisions on mass purchases. the uk does not join a procurement for laboratory supplies that is put out to tender on the same day (the guardian, 2020b). the following day, in a unique historic escalation of the uk's response to the outbreak, the uk prime minister boris johnson orders all gym, restaurants, pubs, churches and other social venues across the uk to stay closed indefinitely (the independent, 2020). on the 23rd of march, almost three months after the outbreak in china became public knowledge, the health secretary, matt hancock, confesses there have been "challenges" with suppling ppe after complaints by nhs staff (including doctors and nurse) from across the country. the uk army is drafted into the effort to support the distribution (the guardian, 2020b). while the presented case presents a rough progression from conditions of ignorance to those of uncertainty and risk, this cannot be generally assumed. as is the case in the example, this progression is also specific to each issue at hand. furthermore, the role that organizational myopia plays as the behavioural reaction to risk, uncertainty and ignorance evolved as the situation evolved. it is important to distinguish between ignorance and myopia, which are two distinct, yet complementary phenomena. at the beginning the government displayed prevalently ignorance. before the crisis started there was already a shortage of ppe. the government ignored the warning coming from nervtag, bill gate's now-famous ted talk (gates, 2015) and more generally the various expert assessments of possible future pandemics. at the time, the uk government was focused on the issues related to the exit of the uk from the european union ('brexit'). although these insights were technically knowable by uk department of health and social care (and most likely known by some), they were not considered for or implemented in the design of the healthcare and broader response system. however, after the who alerts and the first deaths in italy and spain, the situation progresses from ignorance to uncertainty. the uk government 'knows' about covid-19 but, for a long time, was refusing to acknowledge its relevance, that the system was poorly prepared, and the need for taking appropriate actions. instead, it propagated an increasingly untenable narrative that the nhs was well prepared to face the pandemic, ignoring available facts. myopia reduces the number of options assessed by decision makers making them rely on their own bounded rationality. the "big picture" is lost and future opportunities are missed (czakon & kawa, 2018) . in march, organizational myopia reaches a level where the government pretends to have ppe that does not exist. still in may, the nhs is struggling to access basic ppe (bbc, 2020b). arguably, organizational myopia was a moderating factor that negatively influenced uk government capability to adequately address all three conditions -risk, uncertainty and ignorance. as a result, prudent preparation where not taken, the lack of those preparations was ignored, timely steps to 'minimize regret' were not taken, and ultimately, even the increasing amount of scientific evidence and more advanced models only led to tangible action after significant delay. we can draw a number of managerial implications from the previous discussion (see fig. 1 ): first, it is important to note that the most widely used approach, risk management, is typically not geared towards providing meaningful responses to high-impact, low-probability events, such as the current covid-19 pandemic. these events in the 'fat tail' of the probability distribution typically do not meet threshhold criteria for taking substantial action, as standard cost-benefit tradeoffs fail to appropriately capture low likelihood events, or events expected to occur in the 10+ year future. an obvious task is to revise risk management procedures to adequately prioritize mitigation actions for this type of event. second, we have to acknowledge that rare events are characterized -by their nature -by less available data. our approaches to characterize those events must be chosen appropriately. if a quantitative risk assessment is not meaningful, organizations must employ methods that are appropriate for these situations, such as robust decision making, or resilience thinking. third, related to the previous point, decision makers have to reflect on the level of (practically) available knowledge, and actively discuss their current decision making context. in situations of significant uncertainty, or where we can reasonably expect a large degree of ignorance regarding future devleopments, managers should again emphasize resilience (i.e. general preparedness for noticing, resisting, recovering, and learning from distruptions), and robust decision making-type actions (e.g. minimizing regret under plausible future scenarios). fourth, the factual basis that is available to decision makers is only part of the equation. equally, if not more, important are the cultural and behavioural actions at the individual and organizational level. these have to be understood and reflected in the way that decisions are made and communicated. these implications are broadly supported by the ongoing discussions in the risk management domain, specifically regarding the need to tailor our responses to specific contexts (tegeltija, 2018) , as well as the discussions surrounding the relationship and integration of various models of and responses to uncertainty (aven, 2018) . the uk national risk register of civil emergencies was last updated in 2017. in contains a detailed description of what would happen during a pandemic, the impact on the uk, and what actions would need to be taken. it was ranked as the highest risk in the catalogue (national risk register of civil emergencies, 2017), with a near-certain probability of occurrence during our lifetimes. reports of that kind existed for practically all governments. the failure to take action to mitigate an obvious risk is not just the failure of our governments, it is also the failure of (most) major corporations, and us as individuals. we are paying a very high price for having neglected risk management in all its facets, as briefly laid out in this article. even articulating what we mean by 'risk management' is difficult. we suggest to use resilience -for example as 'resilient organizations' and 'resilient inter-organizational relationships' -as a shorthand to summarize the goal of the much needed transformation. if interpreted in a wider sense, the preparation phase inherent in resilience can accommodate all necessary risk and uncertainty 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vedder, daisy; baniaamam, milad; tausche, anne-kathrin; gerritsen, martijn; nurmohamed, michael t title: cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout date: 2020-09-01 journal: lancet rheumatol doi: 10.1016/s2665-9913(20)30221-6 sha: doc_id: 337487 cord_uid: 1lbopaso the increased risk of cardiovascular morbidity and mortality in rheumatoid arthritis and gout has been increasingly acknowledged in past decades, with accumulating evidence that gout, just as with rheumatoid arthritis, is an independent cardiovascular risk factor. although both diseases have a completely different pathogenesis, the underlying pathophysiological mechanisms in systemic inflammation overlap to some extent. following the recognition that systemic inflammation has an important causative role in cardiovascular disease, anti-inflammatory therapy in both conditions and urate-lowering therapies in gout are expected to lower the cardiovascular burden of patients. unfortunately, much of the existing data showing that urate-lowering therapy has consistent beneficial effects on cardiovascular outcomes in patients with gout are of low quality and contradictory. we will discuss the latest evidence in this respect. cardiovascular disease risk management for patients with rheumatoid arthritis and gout is essential. clinical guidelines and implementation of cardiovascular risk management in daily clinical practice, as well as unmet needs and areas for further investigation, will be discussed. cardiovascular disease is the most frequent cause of death worldwide. the 2017 global burden of disease study showed that 17·8 million people died of cardiovascular disease globally, accounting for 21% of all deaths. 1 well established, traditional risk factors for cardiovascular dis ease comprise age, sex, race, hypertension, diabetes, smok ing, and hyperlipidaemia, all of which are included in various prediction models. however, over the past 20 years several nontraditional risk factors, such as chronic inflam mation, have emerged as amplifiers of cardiovascular disease risk. 2 rheumatoid arthritis is the most common auto immune arthritis, with a prevalence of up to 1%, 2 and is char acter ised by a symmetrical polyarthritis with pos sible sys temic manifestations. rheumatoid arthritis is an accepted independent risk factor for cardiovascular disease, driven by the underlying chronic inflammatory pro cess. however, traditional cardiovascular risk factors remain important. 3 gout is the most common crystalinduced, auto inflammatory joint disease with a prevalence of between 0·1% and 10·0%. 4 gout occurs when monosodium urate crystals are deposited in joints and soft tissues. hyperuricaemia-defined by a serum urate concentra tion above the saturation point (ie, ≥0·41 mmol/l [≥6·8 mg/dl])-results predominantly from reduced renal excretion of uric acid, which is a consequence of genetics, comorbidities, and therapies. a continuum has been sug gested, from asymptomatic hyperuricaemia to asympto matic subclinical crystal deposition detectable only by ultrasound or dualenergy ct, to the clinical inflammatory state of gout flares, to chronic gouty arthritis with tophi and gouty bone erosions. 5 if not treated adequately, gout is a debilitating disease with systemic manifestations, such as monosodium urate crystal deposition in organs and worsening of cardiorenal function. 6, 7 in addition to gout flares, patients with gout frequently have a high burden of cardiovascular comorbidities, which might explain, in part, the high cardiovascular mortality when compared with the general population. 8 during the past 20 years, gout has been shown to be an independent cardiovascular risk factor, with higher cardiovascular mortality than in the general population. 9 in this review, we will discuss epidemiological data on cardiovascular disease in rheumatoid arthritis and gout, not only for atherosclerotic disease but also for venous thrombotic disease and heart failure, as clinical and subclinical prevalence of the two diseases is higher than previously thought. the underlying pathophysiology of increased cardiovascular risk relevant to inflammatory arthritis, as well as the observed effect of antiinflammatory and disease modifying treatments such as uratelowering therapies in gout, will be reviewed and discussed. increased cardiovascular risk in patients with inflam matory arthritis necessitates cardiovascular risk assess ment and current management guidelines and their practical implications will be discussed. finally, we con sider topics that need further research with the aim to decrease the cardiovascular burden of patients. patients with rheumatoid arthritis have up to a twotimes higher risk of developing atherosclerotic cardiovascular disease than the general population, similar to patients with diabetes. 10 the risk of ischaemic heart disease is increased in patients with early rheumatoid arthritis and symptom duration of less than 1 year, and probably even in the subclinical stage. 11 the risk of cerebrovascular incidents is increased by about 50% (relative risk 1·48, 95% ci 0·70-3·12), whereas the risk of myocardial infarction is doubled (relative risk 2·00, 1·23-3·29). 11 moreover, patients with rheu matoid arthritis have almost twice the risk of developing congestive heart failure (rate ratio 1·7, 95% ci 1·3-2·1), including both heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. 12 several factors contribute to increased cardiovascular risk, including comorbidities such as diabetes, dyslipidae mia, and hypertension; 13 albeit the data for hypertension are somewhat conflicting. 14 lipids seem to have paradoxi cal associations with cardiovascular risk in rheumatoid arthritis. during active disease, low total cholesterol and ldl cholesterol are associated with increased cardio vascular risk (the socalled lipid paradox). 15 effective anti rheumatic therapies resulting in reduced disease activity of rheumatoid arthritis reverse the cholesterol reduction, thus leading to increased lipid concentra tions, 16 and lipid concentrations in well controlled rheumatoid arthritis are generally stable and similar to those in the general population. 11, 15, 17 furthermore, patients with rheu ma toid arthritis also have more than a two times increased risk of venous thrombotic disease compared with the general population (cumulative inci dence of 6·7% [se 1·7] vs 2·8% [1·1], p=0·005). 18 studies show that allcause mortality among patients with rheumatoid arthritis was 54% higher than in the general population, primarily because of cardiovascular disease (32%), 19 with a median shortened life expectancy of 6-7 years. 20 in one study, the estimated standardised cardiovascularmortality ratio was 1·2 (95% ci 1·05-1·43), 21 which is substantially less than reported in earlier studies. the improvement in cardiovascular mortality in patients with rheumatoid arthritis over the past 20 years could be attributed to the early initiation of more effective anti rheumatic treatments (conventional synthetic and biologi cal diseasemodifying antirheumatic drugs [dmards]). 22 decreased disease activity following effec tive therapy is associated with a lower cardiovascular risk, and vice versa, whereas cardiovascular risk remains unchanged in patients who do not respond to biological dmards. 23 however, it should be noted that about 50% of increased cardiovascular disease risk in patients with rheuma toid arthritis is associated with traditional cardiovascular risk factors. 24 a large retrospective database study in the uk (8386 patients with gout vs 39 766 without gout) showed that the prevalence of hypertension in patients with gout at baseline was twice as high compared with the control group (36% vs 17%). patients were also more often obese (60% vs 44%) and hyperlipidaemic (6% vs 3%) with more prevalent use of statins (34% vs 26%). 25 a high prevalence of these traditional risk factors was also seen in the large national health and nutrition examination survey 2007-08, including 7·7 million us patients with gout. moreover, the national health and nutrition examination survey showed that 26% of patients with gout had diabetes compared with almost 8% in the nongout population (or 2·36, 95% ci 1·5-3·7). 26 in a large retrospective dutch cohort of primary care patients with gout, 796 (30%) of 2655 patients already had established cardiovascular disease at cohort entry compared with 1557 (20%) of 7891 in the nongout control group. after 3 years of followup, 154 (8%) of 1859 patients with gout had developed cardiovascular disease, compared with 318 (5%) of 6334 in the nongout control group. 13 there was an even higher incidence of cardiovascular disease (47%) in patients managed by rheumatologists, possibly explained by a higher portion of severe gout seen in this setting. 8 gout is an independent risk factor for cardiovascular disease; however, the strength of the association of hyper uricaemia and gout with other traditional cardio vascular risk factors makes distinguishing the isolated influence of gout on that risk difficult. 27 although atherosclerotic disease, hypertension, and chronic kidney disease are associated with elevated serum urate concentrations, the causal relationship and direction of association between urate and these disorders is still under debate. 28 29, 30 in the past decade, several observational studies have suggested an association between hyperuricaemia, gout, and congestive heart failure. a crosssectional study of 15 722 patients in the usa found the prevalence of congestive heart failure to be 10% in patients with gout versus 2% in patients without gout. 31 another study in patients with coronary artery disease showed that patients with gout had a higher prevalence of congestive heart failure (500 [36%] of 1406) than those without gout (3847 [25%] of 15 795). 32 furthermore, individuals with asymptomatic hyperuricaemia already have an increased risk of con gestive heart failure, 33, 34 and there appears to be a linear relationship with serum urate concentrations. gout increases the risk of mortality from cardiovascular disease (hazard ratio [hr] 1·29, 95% ci 1·14-1·44). 35 during a mean followup of 4 years among 706 patients with gout, 38 (59%) of 64 deaths had a cardio vascular attribution. 36 looking for trends and possible improvement of cardiovascular mortality in gout, analysis of a medical record database representative of the uk compared cumulative mortality rates of individuals with gout versus nongout between 1999-2006 and 2007-14. the investi gators found that the high mortality in patients with gout remained unchanged, whereas mortality rates for rheumatoid arthritis have improved over the same time period. this mortality gap might be related to suboptimal gout care (insufficient allocation of medication, insufficient treat ment, and low drug adherence), as well as insufficient management of cardiovascular comorbidities. gout speci fic character istics that are associated with high cardio vascular risk are elevated serum urate concentrations (>0·55 mmol/l [>9·1 mg/dl]), longer disease duration (≥2 years), oligo articular or polyarticular disease, and review joint damage and tophi, which all reflect a more severe disease state. 8 although rheumatoid arthritis and gout have different pathogenic stimuli (not known for rheumatoid arthritis; monosodium urate crystal deposition for gout), different immune pathways (eg, antibodymediated in rheumatoid arthritis; interleukin [il]1 driven in gout flares), and in most cases different clinical presentation (more chronic symmetric synovitis in rheumatoid arthritis; mostly mono arthritic gout flares with asymptomatic periods), imaging studies have shown that in gout, subclinical inflamma tion and synovitis are present, even during asymptomatic periods. 37 importantly, persistent inflammation is known to be a key mechanism in the development of cardiovascular disease. 38, 39 cardiovascular disease in patients with gout and rheumatoid arthritis can be divided into three main categories: atherosclerosis, thromboembolism, and cardiac dysfunction (figure 1). the pathophysiological mechanisms of these diseases are different. however, the inflammatory processes of gout and rheumatoid arthritis in the develop ment of cardiovascular diseases partly overlap. postulated shared mechanisms of rheumatoid arthritis and gout are systemic inflammation, reactive oxygen species (ros)induced oxidative stress, and endothelial dysfunction, all of which lead to atherosclerosis (figure 2). the pathways of inflammation in rheumatoid arthritis and gout share some components of the innate and adaptive immune system, including activated neutrophils. exaggerated neutrophil activation has been linked to auto immunity and autoinflammation in rheumatoid arthritis and gout. one of the supposed links is the formation of neutrophil extracellular traps (nets). netosis involves a neutrophil cell death process in which dna is extruded, together with cytoplasmic and granular contents, to trap and eliminate extracellular pathogens and neutralise inflammatory cytokines. this process, which was first described in gout by schauer and col leagues, 40 could explain the selflimiting character of gout flares. extra cellular dna exerts cytotoxic and pro thrombotic effects and might be a causal link between inflammation and coagulation. moreover, complexes of presumably net borne dna stimulate vascular plasma cytoid dendritic cells, with a strong interferon type 1 response, promoting atherogenesis. 41 nets might also directly cause endothelial dysfunction by activation and induction of damage to endothelial cells, illustrated by the establishment of nets in atherosclerotic lesions and arterial thrombi in humans. 42 in addition to neutrophils, different proinflammatory cytokines play a central role in the pathogenesis of rheumatoid arthritis and gout. in rheumatoid arthritis, the reason for immune system activation has not been completely elucidated. however, proinflammatory cyto kines, such as tumour necrosis factor (tnf), il6, and il1, are important in the inflammatory process. in gout, the central inflammatory pathogenic process is assumed to be hyperuricaemia, leading to monosodium urate crystal deposition. 43 these crystals provoke a host response, result ing in recurrent gout flares by acting as a danger signal for the innate immune system through activation of the nlrp3 inflammasome with the immedi ate release of mature il1β by resident macrophages, as well the release of other cytokines. 44 the nlrp3 inflammasome has an important role in the initiation of a gout flare. inflam masome activity causes oxidative stress, mito chondrial dysfunction, endoplasmic reticulum stress, and lysosome rupture, which are all important events in atherogenesis and could lead to atherosclerotic plaque instability and ultimately rupture. 42 ros are a group of small reactive species that play crucial roles in the regulation of biocellular processes. the balance between ros and antioxidant species is essential to maintain cellular homoeostasis. hence, an imbalance in oxidant and antioxidant mechanisms leads to a state of oxidative stress. in several chronic diseases, including rheumatoid arthritis, there is abundant oxidative stress. 45 although essential for vascular homoeostasis, an excess of ros might lead to vascular injury. vascular injury being the result of a complex cascade, including oxidative modification of lipoproteins, endothelial activation, and leucocyte migra tion and differentiation resulting in accelera tion of atherogenesis. 46 oxidative stress might also link gout with cardiovascular disease. although soluble urate has antioxidant properties, during urate generation the catalytic enzyme xanthine oxidase produces substantial amounts of ros that affect biocellular mechanisms. there is some experimental evidence that in patients with gout, higher activity of xanthine oxidoreductase (xo) is associ ated with larger amounts of ros. indirectly, it was shown that inhibiting endotheliumbound xo resulted in reduced ros with favourable effects on vascular function. 47, 48 endothelial dysfunction is a maladaptive state with disruption of vascular homoeostasis resulting from a proinflammatory state. by expressing adhesion molecules and inflammatory cytokines, endothelial cells amplify an inflammatory cascade facilitating monocyte infiltration in the subendothelial layer. ldl cholesterol accumulates in the subendothelial space and is oxidised, which is essential for the development of atherosclerotic plaques. 46 endo thelial dysfunction is the earliest phenomenon in the development of atherosclerosis and was first described in rheumatoid arthritis in 2002; 49 it has been observed in patients with early rheumatoid arthritis without traditional risk factors and in those with longstanding disease. in rheumatoid arthritis, systemic inflammation with pro inflammatory mediators, such as il1β and tnf, is assumed to play a role in the development of endothelial dysfunction, as shown in rodent models. 50 impaired endotheliumdependent arterial responsive ness has been observed in patients with untreated gout, compared with individuals without gout, with the degree of impairment related to both serum urate and high sensitive creactive protein concentrations. 51 there are published case series and case reports of urate crystal deposition in the spine and solid organs in histological samples fixed with alcohol (no dissolution of crystals). 52 a current observational study investi gated alcoholfixed specimens of coronary arteries from explanted hearts with polarisation microscopy and detected strongly birefringent urate crystals in about 10% of coronary arteries. 53 whether or not crystal deposition in the vessels with subsequent local inflammation con tributes to a higher cardiovascular risk in these patients is not known. the immune system and coagulation system are linked to increased activity of the fibrinolytic system in patients with inflammatory joint diseases. tissue factor initiates the extrinsic coagulation cascade and is found on extravascular cells, such as monocytes and neutrophils. creactive protein, tnf, il6, and com ple ment activation might amplify tissue factor synthesis in monocytes and endo thelial cells, and high concen trations of tissue factor have been found in patients with rheumatoid arthritis, particularly in those with a high disease activity. 54 conse quently, increased concentrations of coagulation factors were shown in patients with rheumatoid arthritis. 54 the role for tnf seems plausible, as in the general population this cytokine might induce an imbalance between clotting and fibrinolysis, resulting in a hypercoagu lable state. further more, a role for il6 was suggested by a randomised trial in patients with rheumatoid arthritis that showed that il6 receptor blockade reduced coagulation activation parameters by more than 40% compared with placebo. 55 to date, data on the role of cytokines in the develop ment of thromboembolism in gout are not available and observational data suggests that gout is an independent risk factor for the development of deep vein thrombosis and pulmonary embolism. 56 in addition to extensive neutrophil activation in gout, increased platelet reactivity has been detected. this finding might serve as one explanation for a prothrombotic state and association with thromboembolism in gout. 57 initially, cardiac dysfunction in patients with rheumatoid arthritis was assumed to be secondary to ischaemic heart disease. however, the incidence of congestive heart failure (heart failure with preserved ejection fraction and heart failure with reduced ejection fraction) cannot be explained by atherosclerotic disease alone. a casecontrol study showed that patients with rheumatoid arthritis had a rapidly increasing risk of developing nonischaemic conges tive heart failure after clinical onset. 58 congestive heart failure was seen more frequently in patients with rheuma toid arthritis compared with patients with osteo arthritis (adjusted risk 3·9% [95% ci 3·4-4·3] for rheumatoid arthritis vs 2·3% [1·6-3·3] for osteoarthritis). 59 patients with rheumatoid arthritis treated with tnf blocking agents had significantly less congestive heart failure than those who were not receiving antitnf treatment. 59 another study found an increased prevalence of heart failure with preserved ejection fraction in patients with rheumatoid arthritis, which correlated primarily with disease activity and with antiinflammatory treat ments (ie, conventional synthetic dmards and biological dmards). 60 in addi tion, patients with rheumatoid arth ritis are susceptible to more rapid subclinical changes in diastolic func tion than are the general population. 61 altogether, these studies suggest that systemic inflam matory activity and cardiac dys function cannot be attrib uted to athero sclerosis alone. chronic systemic inflammation has two distinct path ways in the development of cardiac dysfunction ( figure 3) . first, chronic systemic inflammation leads to myo cardial review remodelling, and, specifically, to diastolic dysfunc tion. this process starts with inflammationinduced microvascular dysfunction, 63 leading to deposition of collagen with subsequent stiffness and hypertrophy of cardio myocytes and a decreased ability of the myocardium to contract and relax, which might evolve into heart failure with preserved ejection fraction. 64 second, systemic inflam mation and traditional cardiovascular risk factorinduced coronary microvascular dysfunction and activation lead to athero sclerosis with ischaemic heart disease. this ischaemia leads to autophagy, apoptosis and necrosis of cardio myocytes, and collagen deposition in the interstitial space giving rise to systolic ventricular dysfunction. in severe cases, heart failure with reduced ejection fraction might develop. 62 several studies have assessed the effect of anti inflammatory therapy on cardiac function in rheumatoid arthritis, and a systematic review revealed that biological dmard therapy probably has favourable effects on cardiac dysfunction in rheuma toid arthritis. 65 remarkably, the pathogenesis of cardiac dysfunction in hyperuricaemia and gout has not been adequately investigated to date. 66 previous studies showed an associ ation between serum urate concentration and inflamma tion, thus suggesting a comparable pathogenesis with rheumatoid arthritis. 67 furthermore, increased serum urate concentration and higher activity of rosgenerating xo in gout might lead to endothelial dysfunction with decreased nitric oxide production. 68 hypertension might also have a causal role because gout and hyperuricaemia are independent predictors of developing hyperten sion. one interventional study assessing uratelowering therapy in patients with heart failure did not find signifi cant beneficial effects of allopurinol, probably because there was already advanced structural myocardial damage and multimor bidity in the patient population. 69 studies with early urate lowering inter ventions are needed to answer the ques tion of whether, and to what extent, urate concentration and the associated inflam ma tion in gout con stitutes an independent risk factor for cardiac dysfunction. 70 most nonsteroidal antiinflammatory drugs (nsaids), including the cyclooxygenase inhibitors, are associated with about a twotimes increased cardiovascular risk. 71 the excep tion is probably naproxen, although the pub lished literature is conflicting in this respect. 72 cardio vascular risk is associated with cox2 selectivity, and the lower cox2 selectivity of naproxen than of other nsaids (eg, cyclooxygenase inhibitors) is assumed to translate into a lower cardiovascular risk. 73 in clinical practice, weighing the benefits of these drugs against cardiovascular risk is often difficult. the first risk model that could aid in clinical decision making regarding the use of these drugs was published in 2019. 74 this model was based on the precision trial, 75 a large randomised controlled trial in which patients with osteoarthritis or rheumatoid arthritis were random ised to naproxen, ibuprofen, or celecoxib. 75 a major toxicity risk calculator was developed from easily accessible cardiovas cular risk factors (ie, age, gender, diabetes, cardio vascular disease, hypertension, current smoking, statin use, serum creatinine, rheumatoid arth ritis, and haemato crit) to calculate a 1year risk score yielding three risk categories: low (<1%), inter medi ate (1-4%), or high risk (>4%). however, external validation is necessary before such a calculator can be implemented in daily clinical practice. there has been a longstanding debate on whether steroids (eg, low dose of prednisolone, <10 mg daily) have unfavourable cardiovascular effects in an inflammatory situation. this effect is suggested by observational studies, but these data are confounded by indication because of high disease activity and should therefore be inter preted with caution. 76 hopefully this debate can be settled by the gloria trial (nct02585258), a multicentre, 2year trial assessing the safety and effectiveness of a daily 5 mg dose of prednisolone versus a matching placebo added to standard of care in older patients (aged ≥65 years) with rheumatoid arthritis. systemic inflammation with elevated concentrations of circulating cytokines, such as il-6 and tnf, induce oxidative stress and endothelial activation. consequently, presentation of adhesion molecules (vcam-1 and e-selectin) by endothelial cells leads to monocyte infiltration in the myocardium. these monocytes produce tgf-β, resulting in the differentiation of fibroblasts into myofibroblasts, with subsequent deposition of collagen in the interstitial space. in addition, intracellular oxidative stress results in disrupted crosstalk between endothelial cells and cardiomyocytes, leading to stiffness and hypertrophy of cardiomyocytes with a subsequent decreased ability to contract and relax. these processes ultimately lead to preclinical diastolic ventricular dysfunction, which might evolve into heart failure with preserved ejection fraction. ischaemia, mostly secondary to atherosclerosis, leads to autophagy, apoptosis, and necrosis of cardiomyocytes, and deposition of collagen in the interstitial space. this condition can give rise to systolic ventricular dysfunction, which in severe cases can lead to heart failure with reduced ejection fraction. adapted from paulus and tschöpe, 62 one of the first studies suggesting that cardiovascular mortality risk in rheumatoid arthritis could be reduced by methotrexate was published in 2002. 77 of 1240 patients with rheumatoid arthritis with a mean followup of 6 years, 191 (15%) patients had died, 84 (44%) of which were cardiovascular deaths. methotrexate use was associ ated with a 70% reduction in cardiovascular mortality (hr 0·3, 95% ci 0·2-0·7). methotrexate also has favourable effects on nonfatal cardiovascular events, with metaanalysis showing a risk reduction of 28% in comparison with treatment without methotrexate. 78 other conventional synthetic dmards, such as sulfasalazine, might also have favourable cardio vascular effects. 79 in addition to beneficial effects on the lipid profile, hydroxychloroquine has been associated with a reduc tion in cardiovascular events in patients with rheumatoid arthritis. 80 the recent association of highdose hydroxy chloroquine with qt prolongation in patients with covid19 has raised questions about the use of hydroxy chloroquine in patients with rheumatoid arthritis. 81 as such, it is important to note that disease activity of rheumatoid arthritis itself is associated with qt prolonga tion. 82 furthermore, there have been no published reports indicating that the use of hydroxychloquine in patients with rheumatoid arthritis is associated with an increased risk for qt prolongation. hence, there is no indication to restrict the use of hydroxychloroquine in people with rheumatoid arthritis to require baseline electrocardiograms. the first largescale investigation that compared the effect of antitnf agents versus conventional synthetic dmards on cardiovascular mortality in patients with rheu matoid arthritis found an adjusted hr for death of 0·65 (95% ci 0·46-0·93). 83 the risk of acute coro nary syndrome in rheumatoid arthritis was studied in 7704 patients from a swedish registry (32 621 patientyears) compared with the general population; 84 the hr for acute coronary syndrome was 2·0 (95% ci 1·8-2·3) for patients who were previously untreated with biolo gics and 1·6 (1·4-1·9) for patients using tnf inhibitors. a metaanalysis of 28 studies with 236 525 patients with rheumatoid arthritis investigated the reduction in cardio vascular events with methotrexate and tnf inhibitors in comparison with patients previously untreated with these agents. 85 5410 cardiovascular events were observed and the relative risk was 0·72 (95% ci 0·57-0·91) for metho trexate and 0·70 (0·54-0·90) for tnf inhib itors. hence, favourable cardiovascular effects might be mediated through an overall reduction in inflammation and are not drug specific. in 2017, janus kinase (jak) inhibitors were suggested to be associated with an increased risk of thromboembolic disease 86 and concerns have been reported by the us food and drug administration (fda) about the safety of tofacitinib. these concerns emerged from a postmarketing trial evalu ating the safety of tofacitinib at two doses (5 mg twice daily and 10 mg dose twice daily) versus a control group given a tnf inhibitor. 87 there was an increased inci dence of pulmonary embolism and an increased overall mortality in patients taking 10 mg tofacitinib twice daily. 88 subse quently, a warning was issued indicating that tofacitinib 10 mg twice daily is contraindicated in patients who have an increased thromboembolic risk. in view of these events, it is important that the prescribed dose for the treatment of rheumatoid arthritis is restricted to 5 mg twice daily. the trial programme for baricitinib, the other jak inhibitor currently licensed for rheumatoid arth ritis, identified more thromboembolic events in the 4 mg group in comparison with the placebo group, 89 and as a result the 4 mg dose was not approved in the usa. by contrast, a warning was issued in europe, indicating that the 4 mg dose should not be used in patients with rheumatoid arthritis with an increased risk of venous thrombo embolism. further studies are needed to investi gate and to differentiate between the potential adverse effect of jak inhibitors and the hypercoagulable character of rheumatoid arthritis. firstline treatment of gout flares is usually with an nsaid or cyclooxygenase inhibitor. the duration of treatment, in general, is short, as gout flares in the early stages of disease are often limited to a few days. whether or not this treatment increases cardiovascular risk is not known. furthermore, there are no data on the cumulative yearly dose of nsaid or cyclooxygenase inhibitor intake for patients with recurrent gout flares, as these drugs are often available without prescription. in advanced gout in particular, chronic use of these drugs might be relevant with respect to adverse cardiovascular effects. colchicine is frequently used for treatment of acute gout flares and is also given as a lowdose regimen to prevent gout flares during initiation of uratelowering therapy. colchicine was first used as an antiinflammatory treatment in cardiovascular disease. a 2018 narrative review showed that colchicine has beneficial effects on athero sclerosis with plaque stabilisation, reduction of cardiovascular damage, and reduction in recurrence of acute coronary syndromes. 90 colchicine might also have protective effects in stable coronary artery disease. 91 two retrospective cohort studies in patients with gout showed a lower incidence of combined cardiovascular out comes in patients treated with colchicine. 92, 93 by contrast, a trial showed that shortterm lowdose colchicine does not improve endothelial function in patients with coronary artery disease. 94 however, an exploratory analysis indicated that endothelial function was significantly improved in the subgroup of patients with leucocyte activation, further indicating the important role of inflammation in athero sclerosis. 94 ongoing trials, such as the colcot trial (nct02551094), will hopefully settle the debate about the efficacy of lowdose colchicine for secondary preven tion in patients with coronary disease. in patients with gout, more research is needed to establish the effects of colchicine on cardiovascular risk. gout flares that do not respond to nsaids, cyclo oxygenase inhibitors, or colchicine are frequently treated with steroids, either systemically or by intraarticular injec tion. as data on patients with gout are scarce, one can only speculate as to whether the typically short treatment duration has any unfavourable cardiovascular effects. in 2013, the antiil1β antibody canakinumab was approved by the fda and the european medicines agency for gout inflammation refractory to conven tional antiinflam matory treatment. 95 a 2019 trial of the il1 receptor antagonist, anakinra, showed efficacy in controlling inflammation during gout flare without cardio vascular safety issues. 96 the cantos trial, 97 which investi gated antiinflammatory therapy with canakinumab for secon dary cardiovascular prevention in patients with myocar dial infarction, showed only a modest decrease in recurrent cardiovascular events (about 15%) compared with placebo, and this result was independent of lipid lowering effects. whether patients with gout had a cardio vascular bene fit from il1βblocking therapy was not answered by this trial. in patients with diagnosed gout, uratelowering therapy with a treattotarget strategy to reduce serum urate below 0·36 mmol/l (6 mg/dl) is an essential therapeutic intervention recom mended by current gout guidelines. 98 the efficacy of a treattotarget approach on regression of tophi, frequency of gout flares, and mridetected synovitis has been shown. 99 to reach the serum urate target, patients could be treated with uratelowering drugs such as xo inhibitors (eg, allopurinol), uricosurics (and combination with xo inhibitors-eg, benzbromaron), or a recombinant uricase (eg, rasburicase). uratelowering therapy should, in theory, reduce the risk of cardiovascular disease in gout. this therapy could decrease the risk by directly lowering urate concentration or indirectly through xo inhibition, with a subsequent reduc tion in oxidative stress and improvements in endothelial function. a systematic review and metaanalysis of randomised controlled trials 100 revealed that uratelowering therapy with allopurinol, a purine xo inhibitor, lowered the incidence of major cardiovascular events (or 0·65, 95% ci 0·41-1·05), total cardiovascular events (or 0·57, 0·46-0·72), myocardial infarction or the need of urgent revas cularisation (or 0·38, 0·17-0·83), and new or worsening hyper tension (or 0·32, 0·18-0·58) in patients with various cardiovascular conditions versus the control group, but did not affect overall or cardiovascular mortality. these effects were not observed with nonpurinelike xo inhib itors, such as febuxostat. 100 however, febuxostat lowered the composite event rate (cerebral, cardiovascular, and renal events, as well as all deaths) in patients with hyper uricaemia who were at risk of cerebral, cardio vascular, or renal disease compared with a nonfebuxostat group (hr 0·75, 95% ci 0·59-0·95). 101 in a systematic review and metaanalysis in patients with gout uratelowering therapy with an xo inhibitor was not shown to reduce cardiovascular events compared with placebo. 102 in addition, another systematic review and metaanalysis showed that there was no significant association between allcause mortality and allopurinol use in patients with gout, albeit the number of studies was small. 103 finally, a trial of nurseled gout care in a primary care setting consisting of extensive patient education and involvement, as well as a treattotarget strategy, was shown to be superior in reach ing a serum urate con centration of less than 0·36 mmol/l (6 mg/dl) compared with standard care (95% vs 30%, risk ratio 3·18, 95% ci 2·42-4·18, p<0·0001). 104 fewer deaths were observed in the nurseled care group, but numbers were too small to draw firm con clusions. to date, data regarding the effect of uricosurics or uricase treatment on cardiovascular risk in gout are absent. in general, available evidence is not sufficient to draw definite conclusions and further studies are needed. in 2019, the fda issued a public safety alert with a warning of increased risk of death with febuxostat compared with allopurinol. 105 this warning was based on results from the cares trial. although febuxostat was shown to be noninferior to allopurinol for the primary outcome (a composite of death and major cardiovascular events; hr 1·03, upper limit of the onesided 98·5% ci 1·23, p=0·002 for noninferiority), the incidence of secondary outcome measures, including death from any cause (hr 1·22, 95% ci 1·01-1·47) and cardiovascular death (hr 1·34, 1·03-1·73), was significantly higher with febuxostat than with allopurinol. 106 definite conclusions from this trial are difficult to draw: first, no significant difference was observed in the primary outcome of the trial, second, there was a very high rate of discontinuation of therapy, with the majority of deaths occurring after stopping the drug, and finally, a control group without a xo inhibitor was absent. 106 the fda therefore first mandated febuxostat not to be used in patients with cardio vascular disease but thereafter restricted the approved use to patients who could not be treated effectively or had severe sideeffects with allopurinol. important data will come from the fast trial, comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia (eudract number: 2011-001883-23, isrctn72443728). the recognition of an increased cardiovascular disease risk in arthritis prompted the european league against rheumatism (eular) to set out evidencebased recom mendations for the management of cardiovascular disease risk in inflammatory arthritis, and these guidelines were updated in 2017. 107 rheumatoid arthritis is also now accepted as an independent cardiovascular disease risk factor by the european society of cardiology guidelines. 108 to reduce the risk of cardiovascular disease in patients with rheumatoid arthritis, optimal disease control is neces sary, and cardio vascular disease management should be the responsibility of the rheumatologist. risk assessment review should be done at least once every 5 years, and should be reassessed following major changes in dmard therapy. cardiovascular risk management is also important for patients with gout, since gout is associated with a high rate of traditional cardiovascular risk factors and is also considered an independent risk factor for cardiovascular disease and associated mortality. in the 2016 update of eular's evidencebased recommendations for the management of gout, two overarching principles were that every patient with gout should receive advice regarding lifestyle and that they should be screened for cardiovascular comorbidities and cardiovascular risk factors. how ever, no specific recommenda tions for cardiovascular risk management were given. 109 this omission was one of the main reasons for the assembly of a eular taskforce to develop recommenda tions for the management of athero sclerotic cardiovascular risk in rheu matic and musculo skeletal diseases, including sys temic lupus erythematosus, antiphospholipid syn drome, vasculitis, and gout. 110 in europe, the systematic coronary risk evaluation calculator is used for cardiovascular disease risk pre diction. this model estimates the 10year risk of cardio vascular mortality and includes age, gender, smoking status, total cholesterol to hdl cholesterol ratio, and systolic blood pressure. however, systematic coronary risk evaluation was developed solely for the general popula tion and therefore underestimates the cardio vascular risk in patients with rheumatoid arthritis. to correct for this underestimation, eular recommends use of a multi plication factor of 1·5. 107 importantly, eular advises screening for cardiovascular disease risk in all patients with inflammatory arthritis and states that the rheumatol ogist is responsible for its initiation. subse quently, several prediction models for cardiovascular disease risk, such as qrisk3, have incorporated rheu matoid arthritis in their risk model. 111 the expanded risk score in rheumatoid arthritis is derived from the corrona registry and includes rheumatoid arthritis specific features (laboratory data are not needed). 74 this risk score appears to perform as well as qrisk3. 112 the the table shows the characteristics of these algorithms. thus far, no goutspecific cardiovascular risk scores have been developed, probably because of an absence of con sistent data on cardiovascular outcomes. statins reduce cholesterol concentrations and cardio vascular disease in patients with rheumatoid arthritis to a similar extent as in the general population. furthermore, statins are not associated with more adverse events in comparison to the general population. the trace ra study compared the effect of 40 mg atorvastatin with placebo in patients with rheumatoid arthritis and found a significant reduction in ldl cholesterol in the atorvastatin group. 113 in this group, ldl concentrations were similar to those observed in the general population. a risk reduction of 34% in major cardiovascular events compared with placebo was observed, although this difference did not reach statistical significance possibly due to a lower than expected event rate. furthermore, statins have anti inflammatory properties that might translate into further reductions in cardiovascular disease risk as well as a modest reduction in rheumatic disease. a metaanalysis has shown the pleiotropic effects of statins, with a decline in inflammation markers (oestrogen receptor, creactive protein), proinflammatory cytokines (tnf, il1, and il6), and fewer tender and swollen joints. 114 the eular recommendations for gout advise syste matic screening and care in terms of cardiovascular diseases and risk factors. 98 this strategy can be complicated because many drugs targeting comorbidities can aggravate hyperuricaemia and gout by lowering renal excretion of uric acid-eg, antihypertensive drugs such as β blockers, nonlosartan angiotensin 2 receptor blockers, thiazides, and loop diuretics. 115 this is also true for lowdose aspirin, but as the effect is very modest, use of lowdose aspirin for cardioprotective reasons should not be precluded in highrisk patients with gout. 116 statins (atorvastatin and simvastatin), and also fenofibrate, have uratelowering effects by increasing renalurate excre tion. 117 the effects of dietary measures in rheumatoid arthritis are still uncertain because of an absence of adequately powered studies. observational studies show that diet, exercise, and stress are associated with outcomes such as inflammation or disease activity. therefore, eular recom mends a general healthy lifestyle for all patients with rheumatoid arthritis, defined as a healthy diet (mediterranean), regular exercise, and smoking cessation. exercise improves cardiorespiratory fitness and decreases cardiovascular risk in patients with rheumatoid arthritis. 120 there is lowtomoderate quality evidence for beneficial effects of weight loss with respect to lowering serum uric acid, achieving serum uric acid targets, and preventing flares in patients with gout. 121 the eular guideline recom mends that patients with gout receive advice regarding lifestyle that includes avoidance of alcohol and sugar sweetened drinks, and discourages excessive intake of meat and seafood (purinelow diet). in addition to purines, the intake of fructose is also associated with an increase in uric acid production and should be avoided. guidance on smoking cessation is similar to the general population as smoking has multiple adverse effects, such as increasing the risk of cardiovascular disease, respir atory disease, and cancer. smoking also seems to have a pathogenic role in rheumatoid arthritis, promoting disease activity and reducing response to antirheumatic therapy. in contrast to rheumatoid arthritis, a relationship between smoking and the development of gout has not been found. 122 many studies have indicated poor adherence to cardio vascular disease risk, management in rheumatoid arth ritis. for example, in a crosssectional study 282 (71%) of 400 patients with rheumatoid arthritis had hypertension, of which 171 (61%) were treated with antihypertensive medications. moreover, despite treatment, many of these patients had suboptimal blood pressure. 123 also, hyper cholesterolaemia is under diagnosed and undertreated in patients with rheumatoid arthritis. 124 notwithstanding guidelines for the implementation of cardiovascular risk, management in clinical practice is often difficult. 125 nevertheless, successful implementation of cardiovascular disease risk management was shown in a dutch programme for cardiovascular disease care. 126 this programme included a collaboration between primary care and secondary care professionals with a shared laboratory system for primary care physicians and rheumatologists, in which primary care physicians received reimbursement for additional costs from health care insurance companies. lipid screening (as a proxy for cardiovascular disease risk management) was done in 454 (72%) of 600 patients with rheumatoid arthritis and increased to almost 90% after primary care physicians were sent reminder letters. implementation of cardiovas cular risk management for patients with gout has not been syste matically studied and to what extent it has been applied in either primary or secondary care is unknown. unfortunately, despite several guidelines for cardiovas cular disease risk management, implementation in daily clinical practice is still poor. a study in the uk confirmed this in a group of 673 patients with gout in primary care. monitoring of lipids (34 [5%]), blood pressure (178 [26%]), and glucose (43 [6%]) within 1 month after their first gout consultation was infrequently recorded. 127 this finding indicates the urgent unmet need for optimisation of cardiovascular risk management in these patients. at the same time, we should not forget that patients often also have other comorbid conditions. optimal preven tive treatment requires attention to these comorbidities, which are commonly seen in inflammatory arthritis and include osteoporosis, fatigue, and depression. the rationale is that the underlying mechanisms of these common comor bidities, particularly in rheumatoid arth ritis, overlap. in our view, such a multi morbidity, holistic approach is the optimal way to achieve substantial improvement in the quality of life of these patients. lastly, further randomised controlled trials with cardiovascular end points are needed, especially in gout, to ascertain optimal serum urate concentrations to improve the cardiovascularrisk profile. another relevant question is whether early uratelowering therapy-in case of asympto matic hyper uricaemia and evidence of crystal deposi tion by ultrasound or dual energy ct-has favourable cardio vascular effects, as shown for early treat ment intervention in patients with rheumatoid arthritis. rheumatoid arthritis and gout-two inflammatory joint diseases with different underlying causes-are associated with about a 50-70% increased risk of cardiovascular disease compared with the general population. these patients not only have inflammation of joints but also experience systemic effects, including cardiovascular and haematological manifestations. different underlying pathophysiological mechanisms, such as systemic inflam mation, elevated oxidative stress, endothelial dysfunction, and changes in lipid profiles, might contribute to a substantially higher cardiovascular risk in these patients. the increased cardiovascular risk includes not only a higher rate of ischaemic cardiovascular disease but also subclinical heart failure, which seems far more prevalent than previously thought. early therapeutic intervention with current antirheumatic treatment in rheumatoid arthritis has shown favourable effects on cardiovascu lar disease risk. unfortunately, in gout, evidence that uratelowering therapy has consistent beneficial effects review on cardiovascular outcomes is still scarce. following the recognition that inflammation has an important causative role for cardiovascular risk in gout, anti inflammatory therapy and uratelowering therapies are expected to reduce the cardiovascular burden of these patients. therefore, optimal antiinflammatory control of patients with rheumatoid arthritis and effective urate lowering therapy in patients with gout are the main treatment goals to date. in addition to adequate control of disease activity, attention of the treating physician should be given to the treatment of concomitant cardio vascular diseases and management of risk factors-eg, adequate control of hypertension and dislipidaemia. for individual cardio vascular risk estimation in patients with rheumatoid arthritis and gout, the use of estab lished cardiovascular risk scores (eg, systematic coronary risk evaluation) could be implemented in daily assess ments. the inclu sion of a multiplication factor for gout in cardiovascular risk scores, as already accepted for rheumatoid arthritis, should be considered. all authors searched and screened references. the figures were constructed by mb and dv. the drafts were cowritten by rh, dv, mb, akt, mg, and mtn. all authors contributed to the final writing and editing of the submitted manuscript. dv has received speaker fees from novartis. akt has received speaker fees from berlinchemie menarini, novartis, and pfizer; personal fees and nonfinancial support from astrazeneca; and personal fees from grünenthal, outside the submitted work. mg has received speaker fees from sobi and roche, and research support from berlinchemie menarini and grünenthal. mtn received consulting fees from abbvie, celgene, celltrion, eli lilly, janssen, and sanofi; speakers fees from abbvie, bristolmyers squibb, eli lilly, roche, and sanofi; and research funding from abbvie, bristolmyers squibb, celgene, eli lilly, janssen, msd, mundipharma, novartis, pfizer, roche, and sanofi. all other authors declare no competing interests. we followed the main steps in writing a narrative review, and mtn formulated cardiovascular research questions addressing epidemiological and pathophysiological aspects of rheumatoid arthritis and gout, cardiovascular effects of drug treatment, and management of cardiovascular risk. references for this review were identified through searches of pubmed with the terms "rheumatoid arthritis", "gout", "hyperuricemia", "gouty", "arthritis, "gouty", "atherosclerosis", "cardiovascular disease", "cardiovascular event", "myocardial ischemia", "cerebrovascular disease", "stroke", "angina pectoris", "coronary disease", "coronary artery disease", "coronary arterial disease", "peripheral artery disease", "peripheral arterial disease", "congestive heart failure", "cardiac dysfunction", and "cardiovascular risk management" from jan 1, 1998, to april 1, 2019. articles were also identified through searches of the authors' own files. only papers published in english were reviewed. the final reference list was generated on the basis of originality and relevance to the broad scope of this review. 2 van der woude d, van der helmvan mil ahm. update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis cardiovascular disease in patients with rheumatoid arthritis global epidemiology of gout: prevalence, incidence and risk factors hyperuricaemia and gout: time for a new staging system gout as a systemic disease. manifestations, complications and comorbidities of hyperuricaemia hyperuricaemia and crystalassociated disease network (gcan) consensus statement regarding labels and definitions of disease states of gout crystalproven gout and characteristic gout severity factors are associated with cardiovascular disease association between gout and allcause as well as cardiovascular mortality: a systematic review rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a crosssectional study, the carre investigation cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis the risk of congestive heart failure in rheumatoid arthritis: a populationbased study over 46 years gout and rheumatoid arthritis, both to keep in mind in cardiovascular risk management: a primary care retrospective cohort study hypertension in rheumatoid arthritis changes in lipid levels with inflammation and therapy in ra: a maturing paradigm lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events how many life years are lost in patients with rheumatoid arthritis? secular causespecific and allcause mortality in rheumatoid arthritis, and their predictors in a longterm australian cohort study trend in and predictors for cardiovascular mortality in patients with rheumatoid arthritis over a period of 15 years: a prospective cohort study decreased cardiovascular mortality in patients with incident rheumatoid arthritis (ra) in recent years: dawn of a new era in cardiovascular disease in ra? reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to antitumor necrosis factor alpha therapy: results from the british society for rheumatology biologics register impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the uk clinical practice research datalink comorbidities of gout and hyperuricemia in the us general population: nhanes 2007-2008 uric acid and cardiovascular events: a mendelian randomization study no causal effects of serum urate levels on the risk of chronic kidney disease: a mendelian randomization study uric acid is a strong risk marker for developing hypertension from prehypertension: a 5year japanese cohort study elevated serum uric acid increases risks for developing high ldl cholesterol and hypertriglyceridemia: a fiveyear cohort study in japan independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality association of gout with longterm cardiovascular outcomes among patients with obstructive coronary artery disease uric acid and risk of heart failure: a systematic review and metaanalysis gout and the risk for incident heart failure and systolic dysfunction increased cardiovascular mortality associated with gout: a systematic review and metaanalysis tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout the burden of subclinical intraarticular inflammation in gout inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout inflammation beyond the joints: rheumatoid arthritis and cardiovascular disease aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines neutrophil extracellular traps in atherosclerosis and atherothrombosis presence of luminal neutrophil extracellular traps in atherosclerosis monosodium urate crystals generate nucleaseresistant neutrophil extracellular traps via a distinct molecular pathway gout is a chronic inflammatory disease in which high levels of interleukin8 (cxcl8), myeloidrelated protein 8/myeloidrelated protein 14 complex, and an altered proteome are associated with diabetes mellitus and cardiovascular disease increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis oxidative stress in atherosclerosis xanthine oxidase induces foam cell formation through lox1 and nlrp3 activation monosodium urate crystals induce oxidative stress in human synoviocytes endothelial dysfunction in rheumatoid arthritis: mechanistic insights and correlation with circulating markers of systemic inflammation impaired arterial responsiveness in untreated gout patients compared with healthy nongout controls: association with serum urate and creactive protein the anatomical pathology of gout: a systematic literature review prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system effect of interleukin6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: measure, a randomised trends of venous thromboembolism risk before and after diagnosis of gout: a general populationbased study increased platelet reactivity as measured by plasma glycoprotein vi in gout association between rheumatoid arthritis and risk of ischemic and nonischemic heart failure heart failure in rheumatoid arthritis: rates, predictors, and the effect of antitumor necrosis factor therapy increased prevalence of diastolic heart failure in patients with rheumatoid arthritis correlates with active disease, but not with treatment type fiveyear changes in cardiac structure and function in patients with rheumatoid arthritis compared with the general population a novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the ipower study cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction the effect of biological dmards on the risk of congestive heart failure in rheumatoid arthritis: a systematic review impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options uric acid in chronic heart failure: a marker of chronic inflammation uric acidinduced creactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (exacthf) study the role of uratelowering treatment on cardiovascular and renal disease: evidence from cares, fast, allheart, and feather studies cardiovascular safety of nonsteroidal antiinflammatory drugs: network metaanalysis risk of acute myocardial infarction with nsaids in real world use: bayesian metaanalysis of individual patient data clinical pharmacology and cardiovascular safety of naproxen derivation and validation of a major toxicity risk score among nonsteroidal antiinflammatory drug users based on data grom a randomized controlled trial cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis confounding by indication probably distorts the relationship between steroid use and cardiovascular disease in rheumatoid arthritis: results from a prospective cohort study methotrexate and mortality in patients with rheumatoid arthritis: a prospective study protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a metaanalysis of the literature data diseasemodifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and metaanalysis qt prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in covid19: a systematic review marked qtc prolongation and torsades de pointes in patients with chronic inflammatory arthritis treatment with tnf blockers and mortality risk in patients with rheumatoid arthritis the risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study the effects of tumour necrosis factor inhibitors, methotrexate, nonsteroidal antiinflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta analysis olumiant clot signal echoes xeljanz experience fda responds to safety signal reported in required postmarketing trial for xeljanz restrictions in use of xeljanz while ema reviews risk of blood clots in lungs cardiovascular safety during treatment with baricitinib in rheumatoid arthritis the beneficial therapy with colchicine for atherosclerosis via antiinflammation and decrease in hypertriglyceridemia colchicine in stable coronary artery disease colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with medicare claims effect of shortterm colchicine treatment on endothelial function in patients with coronary artery disease canakinumab for the patient with difficulttotreat gouty arthritis: review of the clinical evidence anakinra for the treatment of acute gout flares: a randomized, doubleblind, placebocontrolled, activecomparator, noninferiority trial antiinflammatory therapy with canakinumab for atherosclerotic disease updated european league against rheumatism evidencebased recommendations for the diagnosis of gout what is the evidence for treattotarget serum urate in gout? xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and metaanalysis of randomized controlled trials febuxostat for cerebral and cardiorenovascular events prevention study cardiovascular effects of uratelowering therapies in patients with chronic gout: a systematic review and metaanalysis mortality in patients with gout treated with allopurinol: a systematic review and metaanalysis efficacy and costeffectiveness of nurseled care involving education and engagement of patients and a treattotarget uratelowering strategy versus usual care for gout: a randomised controlled trial fda adds boxed warning for increased risk of death with gout medicine uloric (febuxostat) cardiovascular safety of febuxostat or allopurinol in patients with gout eular recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update european guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the european association for cardiovascular prevention & rehabilitation (eacpr) updated eular evidencebased recommendations for the management of gout eular recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases (including sle and the antiphospholipid syndrome) development and validation of qrisk3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study the expanded risk score in rheumatoid arthritis (ersra): performance of a diseasespecific calculator in comparison with the traditional prediction scores in the assessment of the 10year risk of cardiovascular disease in patients with rheumatoid arthrit a multicenter, randomized, placebocontrolled trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis the impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a metaanalysis antihypertensive drugs and risk of incident gout among patients with hypertension: population based casecontrol study lowdose aspirin use and recurrent gout attacks effect of fenofibrate on uric acid and gout in type 2 diabetes: a posthoc analysis of the randomised, controlled field study impact of statin therapy on plasma uric acid concentrations: a systematic review and metaanalysis statin use and mortality in gout: a general populationbased cohort study individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis weight loss for overweight and obese individuals with gout: a systematic review of longitudinal studies association between smoking and gout: a metaanalysis prevalence and associations of hypertension and its control in patients with rheumatoid arthritis marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis suboptimal cardiovascular risk management in rheumatoid arthritis patients despite an explicit cardiovascular risk screening programme implementation of the eular cardiovascular risk management guideline in patients with rheumatoid arthritis: results of a successful collaboration between primary and secondary care prescription and comorbidity screening following consultation for acute gout in primary care key: cord-332533-iqe6sdq2 authors: grant, william b.; lahore, henry; mcdonnell, sharon l.; baggerly, carole a.; french, christine b.; aliano, jennifer l.; bhattoa, harjit p. title: evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths date: 2020-04-02 journal: nutrients doi: 10.3390/nu12040988 sha: doc_id: 332533 cord_uid: iqe6sdq2 the world is in the grip of the covid-19 pandemic. public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. this article reviews the roles of vitamin d in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and covid-19, and how vitamin d supplementation might be a useful measure to reduce risk. through several mechanisms, vitamin d can reduce risk of infections. those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. several observational studies and clinical trials reported that vitamin d supplementation reduced the risk of influenza, whereas others did not. evidence supporting the role of vitamin d in reducing risk of covid-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin d (25(oh)d) concentrations are lowest; that the number of cases in the southern hemisphere near the end of summer are low; that vitamin d deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(oh)d concentration. to reduce the risk of infection, it is recommended that people at risk of influenza and/or covid-19 consider taking 10,000 iu/d of vitamin d(3) for a few weeks to rapidly raise 25(oh)d concentrations, followed by 5000 iu/d. the goal should be to raise 25(oh)d concentrations above 40–60 ng/ml (100–150 nmol/l). for treatment of people who become infected with covid-19, higher vitamin d(3) doses might be useful. randomized controlled trials and large population studies should be conducted to evaluate these recommendations. the world is now experiencing its third major epidemic of coronavirus (cov) infections. a new cov infection epidemic began in wuhan, hubei, china, in late 2019, originally called 2019-ncov [1] the general metabolism and actions of vitamin d are well known [7] . vitamin d 3 is produced in the skin through the action of uvb radiation reaching 7-dehydrocholesterol in the skin, followed by a thermal reaction. that vitamin d 3 or oral vitamin d is converted to 25(oh)d in the liver and then to the hormonal metabolite, 1,25(oh) 2 d (calcitriol), in the kidneys or other organs as needed. most of vitamin d's effect arises from calcitriol entering the nuclear vitamin d receptor, a dna binding protein that interacts directly with regulatory sequences near target genes and that recruits chromatin active complexes that participate genetically and epigenetically in modifying transcriptional output [8] . a well-known function of calcitriol is to help regulate serum calcium concentrations, which it does in a feedback loop with parathyroid hormone (pth), which itself has many important functions in the body [7] . several reviews consider the ways in which vitamin d reduces the risk of viral infections [9] [10] [11] [12] [13] [14] [15] [16] [17] . vitamin d has many mechanisms by which it reduces the risk of microbial infection and death. a recent review regarding the role of vitamin d in reducing the risk of the common cold grouped those mechanisms into three categories: physical barrier, cellular natural immunity, and adaptive immunity [16] . vitamin d helps maintain tight junctions, gap junctions, and adherens junctions (e.g., by e-cadherin) [18] . several articles discussed how viruses disturb junction integrity, increasing infection by the virus and other microorganisms [19] [20] [21] . vitamin d enhances cellular innate immunity partly through the induction of antimicrobial peptides, including human cathelicidin, ll-37, by 1,25-dihdroxyvitamin d [22, 23] , and defensins [24] . cathelicidins exhibit direct antimicrobial activities against a spectrum of microbes, including gram-positive and gram-negative bacteria, enveloped and nonenveloped viruses, and fungi [25] . those host-derived peptides kill the invading pathogens by perturbing their cell membranes and can neutralize the biological activities of endotoxins [26] . they have many more important functions, as described therein. in a mouse model, ll-37 reduced influenza a virus replication [27] . in another laboratory study, 1,25(oh) 2 d reduced the replication of rotavirus both in vitro and in vivo by another process [28] . a clinical trial reported that supplementation with 4000 iu/d of vitamin d decreased dengue virus infection [29] . vitamin d also enhances cellular immunity, in part by reducing the cytokine storm induced by the innate immune system. the innate immune system generates both pro-inflammatory and anti-inflammatory cytokines in response to viral and bacterial infections, as observed in covid-19 patients [30] . vitamin d can reduce the production of pro-inflammatory th1 cytokines, such as tumor necrosis factor α and interferon γ [31] . administering vitamin d reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages ( [17] and references therein). vitamin d is a modulator of adaptive immunity [16, 32] ; 1,25(oh) 2 d 3 suppresses responses mediated by the t helper cell type 1 (th1), by primarily repressing production of inflammatory cytokines il-2 and interferon gamma (infγ) [33] . additionally, 1,25(oh) 2 d 3 promotes cytokine production by the t helper type 2 (th2) cells, which helps enhance the indirect suppression of th1 cells by complementing this with actions mediated by a multitude of cell types [34] . furthermore, 1,25(oh) 2 d 3 promotes induction of the t regulatory cells, thereby inhibiting inflammatory processes [35] . serum 25(oh)d concentrations tend to decrease with age [36] , which may be important for covid-19 because case-fatality rates (cfrs) increase with age [37] . reasons include less time spent in the sun and reduced production of vitamin d as a result of lower levels of 7-dehydrocholesterol in the skin [38] . in addition, some pharmaceutical drugs reduce serum 25(oh)d concentrations by activating the pregnane-x receptor [39] . such drugs include antiepileptics, antineoplastics, antibiotics, anti-inflammatory agents, antihypertensives, antiretrovirals, endocrine drugs, and some herbal medicines. pharmaceutical drug use typically increases with age. vitamin d supplementation also enhances the expression of genes related to antioxidation (glutathione reductase and glutamate-cysteine ligase modifier subunit) [40] . the increased glutathione production spares the use of ascorbic acid (vitamin c), which has antimicrobial activities [41, 42] , and has been proposed to prevent and treat covid-19 [43] . moreover, a former director of the center for disease control and prevention, dr. tom frieden, proposed using vitamin d to combat the covid-19 pandemic on 23 march 2020 (https://www.foxnews.com/opinion/former-cdc-chief-tomfrieden-coronavirus-risk-may-be-reduced-with-vitamin-d). influenza virus affects the respiratory tract by direct viral infection or by damage to the immune system response. the proximate cause of death is usually from the ensuing pneumonia. patients who develop pneumonia are more likely to be < 5 years old, > 65 years old, white, and nursing home residents, to have chronic lung or heart disease and a history of smoking, and to be immunocompromised [44] . seasonal influenza infections generally peak in winter [45] . cannell et al. hypothesized that the winter peak was due in part to the conjunction with the season when solar uvb doses, and thus 25(oh)d concentrations, are lowest in most mid-and high-latitude countries [46] , extended in [47] . mean serum 25(oh)d concentrations in north and central regions of the united states are near 21 ng/ml in winter and 28 ng/ml in summer, whereas in the south region, they are near 24 ng/ml in winter and 28 ng/ml in summer [48] . in addition, the winter peak of influenza also coincides with weather conditions of low temperature and relative humidity that allow the influenza virus to survive longer outside the body than under warmer conditions [49] [50] [51] . ecological studies suggest that raising 25(oh)d concentrations through vitamin d supplementation in winter would reduce the risk of developing influenza. table 1 presents results from randomized controlled trials (rcts) investigating how vitamin d supplementation affects risk of influenza. the rcts included confirmed that the respiratory tract infection was indeed derived from influenza. only two rcts reported beneficial effects: one among schoolchildren in japan [52] , the other among infants in china [53] . an rct in japan that reported no beneficial effect did not measure baseline 25(oh)d concentration [54] and included many participants who had been vaccinated against influenza (m. urashima; private communication). the two most recent rcts included participants with above average mean baseline 25(oh)d concentrations [55, 56] . a comprehensive review of the role of vitamin d and influenza was published in 2018 [15] . it concluded that the evidence of vitamin d's effects on the immune system suggest that vitamin d should reduce the risk of influenza, but that more studies are required to evaluate that possibility. large population studies would also be useful, in which vitamin d supplementation is also related to changes in serum 25(oh)d concentration. note: 95% confidence interval (95% ci); day (d); hazard ratio (hr); inflammatory bowel disease (ibd); months (mos); not available (n/a); relative risk (rr); upper respiratory tract infection (urti); week (wk); years (yrs). an observational study conducted in connecticut on 198 healthy adults in the fall and winter of 2009-2010 examined the relationship between serum 25(oh)d concentration and incidence of acute rtis (artis) [57] . only 17% of people who maintained 25(oh)d >38 ng/ml throughout the study developed artis, whereas 45% of those with 25(oh)d < 38 ng/ml did. concentrations of 38 ng/ml or more were associated with a significant (p < 0.0001) twofold reduction in risk of developing artis and with a marked reduction in the percentage of days ill. eight influenza-like illnesses (ilis) occurred, seven of which were the 2009 h1n1 influenza. the first step in developing a hypothesis is to outline the epidemiological and clinical findings regarding the disease of interest and their relationship with 25(oh)d concentrations. from the recent journal literature, it is known that covid-19 infection is associated with the increased production of pro-inflammatory cytokines [58] , c-reactive protein [30] , increased risk of pneumonia [58] , sepsis [59] , acute respiratory distress syndrome [59] , and heart failure [59] . cfrs in china were 6%-10% for those with cardiovascular disease, chronic respiratory tract disease, diabetes, and hypertension [37] . two regions hard hit by covid-19 are regions of high air pollution in china [60] and northern italy [61] . the possible roles of vitamin d for the clinical and epidemiological characteristics of diseases associated with the increased risk of covid-19 cfr are given in table 2 . most of the beneficial effects of vitamin d given in table 2 are from observational studies of disease incidence or prevalence with respect to serum 25(oh)d concentrations. rcts comparing outcomes for participants treated or given a placebo are preferred to establish causality related to health outcomes. however, most vitamin d rcts have not reported that vitamin d supplementation reduced the risk of disease [62, 63] . reasons for the lack of agreement between observational studies and rcts seems to be due to several factors, including enrolling participants with relatively high 25(oh)d concentrations and using low vitamin d doses and not measuring baseline and achieved 25(oh)d concentrations. previous studies proposed that rcts of nutrients such as vitamin d be based on nutrient status, such as 25(oh)d concentration, seeking to enroll participants with low values, supplementing them with enough agent to raise the concentration to values associated with good health, and measuring achieved concentrations as well as cofactors such as vitamin c, omega-3 fatty acids, and magnesium [64, 65] ,. two recently completed rcts reported significantly reduced incidence in the secondary analyses for cancer [66] and diabetes mellitus [67] . table 2 . how vitamin d is related to the clinical and epidemiological findings for incidence and case-fatality rates. clinical severe cases associated with pneumonia inverse correlation for cap [68, 69] increased production of pro-inflammatory cytokines such as il-6 inverse correlation [70, 71] increased crp inverse correlation [72, 73] increased risk of sepsis inverse correlation [74, 75] risk of ards inverse correlation [76, 77] risk of heart failure inverse correlation [78, 79] risk of diabetes mellitus inverse correlation [67, 80] epidemiological began in december 2019 in china, spread mainly to northern midlatitude countries low 25(oh)d values in winter [48, 81] males have higher incidence and much higher cfrs than females smoking reduces 25(oh)d [82] cfr increases with age chronic disease rates increase with age; vitamin d plays a role in reducing risk of chronic diseases [83] higher cfr for diabetics diabetics may have lower 25(oh)d [84] higher cfr for diabetics lower 25(oh)d associated with increased risk of incidence [85] higher cfr for hypertension lower 25(oh)d may be associated with increased risk of incidence [86] higher cfr for cardiovascular disease lower 25(oh)d associated with increased risk of incidence and death [87] higher cfr for chronic respiratory disease for copd patients, 25(oh)d inversely correlated with risk, severity, and exacerbation [88] found at higher rates in regions with elevated air pollution air pollution associated with lower 25(oh)d concentrations [89] note: 25-hydroxyvitamin d ((25(oh)d); acute respiratory distress syndrome (ards); community-acquired pneumonia (cap); case-fatality rate (cfr); interleukin 6 (il-6); chronic obstructive pulmonary disease (copd); c-reactive protein (crp); vitamin d deficiency (vdd). table 3 lists some findings for vitamin d supplementation in reducing the clinical effects of covid-19 infection found from treating other diseases. treatment of cap with vitamin d did not significantly result in complete resolution. baseline 25(oh)d was 20 ng/ml. achieved 25(oh)d in the treatment arm was 40 ng/ml. [90] increased production of pro-inflammatory cytokines such as il-6 reduces concentration of il-6 [11] increased crp reduces crp in diabetic patients [91] increased risk of sepsis no reduction in mortality rate found for adults with sepsis supplemented with vitamin d. most trials included participants with 25(oh)d <20 ng/ml; vitamin d 3 doses between 250 and 600 thousand iu. [92] risk of ards vitamin d deficiency contributes to development of ards [77, 93] acute respiratory distress syndrome (ards); community-acquired pneumonia (cap); case-fatality rate (cfr); interleukin 6 (il-6); chronic obstructive pulmonary disease (copd); c-reactive protein (crp); vitamin d deficiency (vdd). a possible reason for the monotonic increase in cfr with increasing age could be that the presence of chronic diseases increases with age. for example, the global prevalence of diabetes mellitus increases from about 1% below the age of 20 years, to~10% at 45 years and to 19% at 65 years, decreasing to 14% by 95 years [94] . invasive lung cancer incidence rates for females in the united states in 2015 increased from 1.1/100,000 for those aged 30-34 years, to 51.0/100,000 for those aged 50-54 years, 204.1/100,000 for those aged 65-79 years, and 347.3 for those aged 75-79 years [95] . several studies report that people with chronic diseases have lower 25(oh)d concentrations than healthy people. a study in italy reported that male chronic obstructive pulmonary disease patients had mean 25(oh)d concentrations of 16 (95% ci, 13-18) ng/ml, whereas female patients had concentrations of 13 (95% ci, 11-15) ng/ml [96] . a study in south korea reported that community-acquired pneumonia (cap) patients had a mean 25(oh)d concentration at admission of 14 ± 8 ng/ml [97] . a study in iran reported that hypertensive patients had lower 25(oh)d concentrations than control subjects: males, 13 ± 11 vs. 21 ± 11 ng/ml; females, 13 ± 10 vs. 20 ± 11 ng/ml [98] . another factor that affects immune response with age is reduced 1,25-dihydroxyvitamin d (1,25(oh) 2 d, or calcitriol), the active vitamin d metabolite, with increased age. parathyroid hormone (pth) concentration increases with age. a u.s. study was based on 312,962 paired serum pth and 25(oh)d concentration measurements from july 2010 to june 2011. for participants with 20-ng/ml 25(oh)d concentration, pth increased from 27 pg/ml for those <20 years to 54 pg/ml for those >60 years [99] . serum calcitriol concentrations are inversely related to pth concentrations. in a study conducted in norway on patients with a mean age of 50 (sd, 21) years, calcitriol decreased from 140 pmol/l for those aged 20-39 years to 98 pmol/l for those >80 years despite an increase in serum 25(oh)d from 24 ng/ml for those 20-39 years to 27 ng/ml for those >80 years [100] . the seasonality of many viral infections is associated with low 25(oh)d concentrations, as a result of low uvb doses owing to the winter in temperate climates and the rainy season in tropical climates-such as respiratory syncytial virus (rsv) infection [101, 102] ,. this is the case for influenza [45, 46] , and sars-cov [103] . however, mers showed a peak in the april-june quarter [104] , probably affected by both hajj pilgrims gathering and the fact that 25(oh)d concentrations show little seasonal variation in the middle east [105] . in the tropics, seasonality is related more to rainy periods (low uvb doses), for example, for influenza [106] . considerable indirect evidence is inferred from effects found for other enveloped viruses. table 4 presents the findings from various studies. table 4 . findings regarding the associations and effects of vitamin d on enveloped viral infections. dengue vitamin d mechanisms discussed [107] dengue inverse association between 25(oh)d concentration and progression of disease state [108] dengue vitamin d supplementation trial with 1000 and 4000 iu/d. 4000 iu/d resulted in higher resistance to denv-2 infection. mddcs from those supplemented with 4000 iu/d showed decreased mrna expression of tlr3, 7, and 9; downregulation of il-12/il-8 production; and increased il-10 secretion in response to denv-2 infection [29] hepatitis c 1,25-hydroxyvitamin-d3-24-hydroxylase, encoded by cyp24a1 gene, is a key enzyme that neutralizes 1,25(oh) 2 d. this study found that alleles of cyp24a1 had different effects on risk of chronic hepatitis c infection. [109] chb 25(oh)d concentrations were lower in chb patients than that of healthy controls and inversely correlated with hbv viral loads [110] kshv found that cathelicidin significantly reduced ksvh by disrupting the viral envelope. [111] hiv-1 review of 29 clinical studies of vitamin d supplementation showed there was a decrease in inflammation. in 3 of 7 studies, cd4+ t cell count increased, but effect on viral load was inconclusive since most patients were on cart. [112] in a lung epithelial cell study, calcitriol treatment prior to and post infection with h9n2 influenza significantly decreased expression of the influenza m gene, il-6, and ifn-β in a549 cells, but did not affect virus replication. [113] rsv demonstrated that the human cathelicidin ll-37 has effective antiviral activity against rsv in vitro and prevented virus-induced cell death in epithelial cultures, [114] rsv performed a laboratory study that identified the mechanism by which vitamin d reduced risk of rsv. [28] rsv found that the t-allele of the vitamin d receptor has a lower prevalence in african populations and runs parallel to the lower incidence of rsv-associated severe alri in african children, 1 year. [115] rotaviral diarrhea found serum 25(oh)d <20 ng/ml associated with an odds ratio of 6.3 (95% ci, 3.6 to 10.9) for rotaviral diarrhea [116] note: acute respiratory tract infection (alri); combination antiretroviral therapy (cart); chronic hepatitis b (chb); dengue virus-2 (denv-2). human immunodeficiency virus 1 (hiv-1); kaposi's sarcoma-associated herpesvirus (kshv); monocyte-derived dendritic cells (mddcs); respiratory syncytial virus (rsv). one way that covs injure the lung epithelial cells and facilitate pneumonia is through increased production of th1-type cytokines as part of the innate immune response to viral infections, giving rise to the cytokine storm. a laboratory cell study reported that interferon γ is responsible for acute lung injury during the late phase of the sars-cov pathology [117] . pro-inflammatory cytokine storms from cov infections have resulted in the most severe cases for sars-cov [118] and mers-cov [119] . however, covid-19 infection also initiated increased secretion of the th2 cytokines (e.g., interleukins 4 and 10) that suppress inflammation, which differs from sars-cov infection [30] . an example of the role of vitamin d in reducing the risk of death from pandemic respiratory tract infections is found in a study of cfrs resulting from the 1918-1919 influenza pandemic in the united states [120] . the u.s. public health service conducted door-to-door surveys of 12 communities from new haven, connecticut, to san francisco, california, to ascertain incidence and cfrs. the canvasses were made as soon as possible after the autumn 1918 wave of the epidemic subsided in each locality. a total of 146,203 people, 42,920 cases, and 730 deaths were found. as shown in their table 25 , fatality rates averaged 1.70 per 100 influenza cases but averaged 25.5 per 100 cases of pneumonia. the percentage of influenza complicated by pneumonia was 6.8%. the pneumonia cfr (excluding charles county, md, because of inconsistencies in recording cause of death) was 28.8 per 100 for whites and 39.8 per 100 for "coloreds". as shown in table 23 , "coloreds" in the southeastern states had between a 27% and 80% higher rate of pneumonia compared to whites. as discussed in an ecological study using those cfr data, communities in the southwest had lower cfr than those in the northeast because of higher summertime and wintertime solar uvb doses [121] . previous work suggested that higher uvb doses were associated with higher 25(oh)d concentrations, leading to reductions in the cytokine storm and the killing of bacteria and viruses that participate in pneumonia. african americans had much higher mortality rates than white americans for the period 1900-1948 [122] . the reasons cfrs were higher for "coloreds" than whites may include that they have higher rates of chronic diseases, are more likely to live in regions impacted by air pollution, and that with darker skin pigmentation, blacks have lower 25(oh)d concentrations. a clinical trial involving postmenopausal women living on long island, ny with mean baseline 25(oh)d concentration 19 ± 8 ng/ml found that supplementation with 2000 iu/d resulted in significantly fewer upper respiratory tract infections, including influenza, than a placebo or supplementation with 800 iu/d [123] . see, also, references in [11] . an analysis of serum 25(oh)d concentrations by race for 2001-2004 indicated mean 25(oh)d concentrations for people over 40 years: non-hispanic whites,~25-26 ng/ml; non-hispanic blacks, 14-17 ng/ml; mexican-americans, 18-22 ng/ml [124] . a reason proposed for the higher mortality rates in some communities during the 1918-1919 influenza pandemic was that they were near to coal-fired electricity generating plants [125] . recent studies have confirmed that air pollution, from combustion sources, increases the risk of influenza [126, 127] . the highest concentration of these plants is in the northeast, where solar uvb doses are lowest. [93] . in a follow-on pilot trial involving 30 mechanically ventilated critically ill patients, 500,000 iu of vitamin d 3 supplementation significantly increased hemoglobin concentrations and lowered hepcidin concentrations, improving iron metabolism and the blood's ability to transport oxygen [128] . hospitals are a source of rtis for both patients and medical personnel. for example, during the sars-cov epidemic, a woman returned to toronto from hong kong with sars-cov in 2003 and went to a hospital. the disease was transmitted to other people, leading to an outbreak among 257 people in several greater toronto area hospitals [129] . during the 2014-2015 influenza season, 36% of health care workers in a german hospital developed influenza infection [130] . working in a hospital dealing with covid-19 patients is associated with increased risk of covid-19 infection. for example, 40 of 138 hospitalized covid-19 patients in wuhan in the zhongnan hospital from 1 to 28 january were medical staff, and 17 more were infected while in the hospital [58] . it was announced on february 14, 2020, that more than 1700 chinese health workers were infected by covid-19 and six had died (https://www.huffpost.com/entry/chinese-health-workers-infected-by virus_n_5e46a0fec5b64d860fc97c1b). vitamin d supplementation to raise serum 25(oh)d concentrations can help reduce hospitalassociated infections [131] . concentrations of at least 40-50 ng/ml (100-125 nmol/l) are indicated on the basis of observational studies [132, 133] . during the covid-19 epidemic, all people in the hospital, including patients and staff, should take vitamin d supplements to raise 25(oh)d concentrations as an important step in preventing infection and spread. trials on that hypothesis would be worth conducting. the data reviewed here supports the role of higher 25(oh)d concentrations in reducing risk of infection and death from artis, including those from influenza, cov, and pneumonia. the peak season for artis is generally when 25(oh)d concentrations are lowest. thus, vitamin d 3 supplementation should be started or increased several months before winter to raise 25(oh)d concentrations to the range necessary to prevent artis. studies reviewed here generally reported that 25(oh)d concentrations of 20-30 ng/ml reduced the risk of artis [134] . one reason for that result may be that the studies included few participants with higher 25(oh)d concentrations. however, one observational study reported that 38 ng/ml was the appropriate concentration to reduce the risk of cap [57] . although the degree of protection generally increases as 25(oh)d concentration increases, the optimal range appears to be in the range of 40-60 ng/ml (100-150 nmol/l). to achieve those levels, approximately half the population could take at least 2000-5000 iu/d of vitamin d 3 [135] . various loading doses have been studied for achieving a 25(oh)d concentration of 30 ng/ml. for example, one study used a weekly or fortnightly dose totaling 100,000-200,000 iu over 8 weeks (1800 or 3600 iu/d) [136] . however, to achieve 40-60 ng/ml would take higher loading doses. a trial involving canadian breast cancer patients with bone metastases treated with bisphosphonates but without comorbid conditions reported that doses of 10,000 iu/d of vitamin d 3 over a four-month period showed no adverse effects, but did unmask two cases of primary hyperparathyroidism [137] . a study involving 33 participants, including seven taking 4000 iu/d of vitamin d 3 and six who took 10,000 iu/d of vitamin d 3 for 8 weeks, reported that 25(oh)d concentrations increased from 20 ± 6 to 39 ± 9 for 4000 iu/d and from 19 ± 4 to 67 ± 3 for 10,000 iu/d and improved gut microbiota with no adverse effects [138] . thus, from the literature, it is reasonable to suggest taking 10,000 iu/d for a month, which is effective in rapidly increasing circulating levels of 25(oh)d into the preferred range of 40-60 ng/ml. to maintain that level after that first month, the dose can be decreased to 5000 iu/d [135, 139, 140] . when high doses of vitamin d are taken, calcium supplementation should not be high to reduce risk of hypercalcemia. a recent review suggested using vitamin d loading doses of 200,000-300,000 iu in 50,000-iu capsules to reduce the risk and severity of covid-19 [43] . the efficacy and safety of high-dose vitamin d supplementation has been demonstrated in a psychiatric hospital in cincinnati, ohio [141] . the age range was from 18 to 90 years. half of the patients were black, and nearly half were white. all patients entering since 2011 were offered supplementation of 5000 or 10,000 iu/d vitamin d 3 . for 36 patients who received 5000 iu/d for 12 months or longer, mean serum 25(oh)d concentration rose from 24 to 68 ng/ml, whereas for the 78 patients who received 10,000 iu/d, mean concentrations increased from 25 to 96 ng/ml. no cases of vitamin d-induced hypercalcemia were reported. this article includes a brief review of other high-dose vitamin d studies, including the fact that vitamin d doses of 60,000-600,000 iu/d were found to treat and control such diseases as asthma, rheumatoid arthritis, rickets, and tuberculosis in the 1930s and 1940s. those doses are much higher than the 10,000-25,000 iu/d of vitamin d 3 that can be made from solar uvb exposure [142] . however, after reports of hypercalcemia associated with use of supra-physiological doses of vitamin d surfaced, e.g., [143] , high-dose vitamin d supplementation fell out of favor. a recent article on a high-dose vitamin d supplementation trial in new zealand involving 5110 participants reported that, over a median of 3.3 years, monthly supplementation with 100,000 iu of vitamin d 3 did not affect the incidence rate of kidney stone events or hypercalcemia [144] . unfortunately, most countries do not have guidelines supporting vitamin d supplementation doses and desirable serum 25(oh)d concentrations that would deal with wintertime rtis. guidelines for many countries consider 20 ng/ml (50 nmol/l) adequate. according to the statement from the european society for clinical and economic aspects of osteoporosis, osteoarthritis, and musculoskeletal diseases, "attainment of serum 25-hydroxyvitamin d levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed" [145] . this statement, published in 2017, is no longer correct since a number of vitamin d supplementation studies have reported that long-term vitamin d supplementation has health benefits without adverse health effects, e.g., 2000 iu/d for cancer risk reduction [66, 146] and 4000 iu/d for reduced progression from prediabetes to diabetes [67] . a recent review on the status of vitamin d deficiency worldwide stated that because of inadequate evidence from clinical trials, "a 25(oh)d level of >50 nmol/l or 20 ng/ml is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold" [147] . a companion article in the same issue of the journal stated, "although 20 ng/ml seems adequate to reduce risk of skeletal problems and artis, concentrations above 30 ng/ml have been associated with reduced risk of cancer, type 2 diabetes mellitus, and adverse pregnancy and birth outcomes" [148] . however, on the basis of the findings in several studies discussed here, as well as recommendations for breast and colorectal cancer prevention [149] , the desirable concentration should be at least 40-60 ng/ml. the u.s. institute of medicine issued vitamin d and calcium guidelines in 2011 [150] . the institute recommended vitamin d supplementation of 600 iu/d for people younger than 70 years, 800 iu/d for those older than 70 years, and a serum 25(oh)d concentration of 20 ng/ml (50 nmol/l) or higher. that recommendation was based on the effects of vitamin d for bone health. the institute recognized that no studies had reported adverse effects of supplementation with less than 10,000 iu/d of vitamin d, but set the upper intake level at 4000 iu/d, partly out of concerns stemming from observational studies that found u-shaped 25(oh)d concentration-health outcome relationships. however, later investigation determined that most reports of j-or u-shaped relationships were from observational studies that did not measure serum 25(oh)d concentrations and that the likely reason for those relationships was a result of enrolling some participants who had started taking vitamin d supplements shortly before enrolling [151] . moreover, in 2011, the endocrine society recommended supplementation of 1000-4000 iu/d of vitamin d and a serum 25(oh)d concentration of 30 ng/ml or higher [152] . those guidelines were for patients. it appears that anyone with chronic disease should be considered in that category. the u.s. institute of medicine noted that no adverse effects of vitamin d supplementation had been reported for daily doses <10,000 iu/d [150] . measuring serum 25(oh)d concentration would be useful to determine baseline and achieved 25(oh)d concentrations. a recent article recommended testing for groups of people who were likely to have low concentrations and could benefit from higher concentrations, such as pregnant women, the obese, people with chronic diseases, and the elderly [148] . part of the rationale for testing was to increase awareness of actual 25(oh)d concentrations and the benefits of higher concentrations. in addition, increases in 25(oh)d concentration with respect to vitamin d supplementation depend on various personal factors, including genetics, digestive system health, weight, and baseline 25(oh)d concentration. for about half the population, taking 5000 iu/d of vitamin d 3 or 30,000-35,000 iu/wk would raise 25(oh)d concentration to 40 ng/ml. taking 6235-7248 iu/d as proposed to ensure that 97.5% of the population has concentrations >20 ng/ml [153] would not exceed the 10,000-iu/d threshold. vitamin d supplementation is required for many individuals to reach 25(oh)d concentrations above 30 ng/ml, especially in winter [154] . however, vitamin d fortification of basic foods such as dairy and flour products [83, 155] can raise serum 25(oh)d concentrations of those members of various populations with the lowest concentrations by a few ng/ml. doing so can result in reduced risk of artis for individuals with extreme vitamin d deficiency [134, 156] . however, for greater benefits, daily or weekly vitamin d supplementation is recommended [134] , as is the annual determination of serum 25(oh)d concentration for those with health risks [148] . magnesium supplementation is recommended when taking vitamin d supplements. magnesium helps activate vitamin d, which in turn helps regulate calcium and phosphate homeostasis to influence the growth and maintenance of bones. all the enzymes that metabolize vitamin d seem to require magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys [157] . the dose of magnesium should be in the range of 250-500 mg/d, along with twice that dose of calcium. the hypothesis that vitamin d supplementation can reduce the risk of influenza and covid-19 incidence and death should be investigated in trials to determine the appropriate doses, serum 25(oh)d concentrations, and the presence of any safety issues. the rct on vitamin d supplementation for ventilated icu patients conducted in atlanta, georgia, is a good model [93] . a recent review stated: "although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. micronutrients with the strongest evidence for immune support are vitamins c and d and zinc. better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection." 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daniel; schliebner, alexandra; hegewald, janice; seidler, andreas title: the age-related risk of severe outcomes due to covid-19 infection: a rapid review, meta-analysis, and meta-regression date: 2020-08-17 journal: int j environ res public health doi: 10.3390/ijerph17165974 sha: doc_id: 355905 cord_uid: av03suua increased age appears to be a strong risk factor for covid-19 severe outcomes. however, studies do not sufficiently consider the age-dependency of other important factors influencing the course of disease. the aim of this review was to quantify the isolated effect of age on severe covid-19 outcomes. we searched pubmed to find relevant studies published in 2020. two independent reviewers evaluated them using predefined inclusion and exclusion criteria. we extracted the results and assessed seven domains of bias for each study. after adjusting for important age-related risk factors, the isolated effect of age was estimated using meta-regression. twelve studies met our inclusion criteria: four studies for covid-19 disease severity, seven for mortality, and one for admission to icu. the crude effect of age (5.2% and 13.4% higher risk of disease severity and death per age year, respectively) substantially decreased when adjusting for important age-dependent risk factors (diabetes, hypertension, coronary heart disease/cerebrovascular disease, compromised immunity, previous respiratory disease, renal disease). adjusting for all six comorbidities indicates a 2.7% risk increase for disease severity (two studies), and no additional risk of death per year of age (five studies). the indication of a rather weak influence of age on covid-19 disease severity after adjustment for important age-dependent risk factors should be taken in consideration when implementing age-related preventative measures (e.g., age-dependent work restrictions). the first cluster of cases of coronavirus disease 2019 (covid19) was reported in wuhan (huban province, china) in december 2019. only a little more than two months later, on 12 march 2020 the world health organization (who) announced the covid-19 outbreak to be pandemic. due to the high number of increasing cases and deaths, research identifying the risk factors for covid-19 disease severity is being published at a high rate. an increase in covid-19 disease severity with increased patient age has been widely noted [1] [2] [3] [4] . national health institutions such as the robert koch institute (rki) in germany and the centers for disease control (cdc) in the united states routinely report covid-19 cases and deaths stratified by age. they have described an increase in mortality with increasing age. in its covid-19 informational report, the rki states "the risk of severe diseases increases steadily from 50 to 60 years of age" [5] . due to these observations, several governments have recommended older workers, mostly starting at the age of 60, to abstain from going into the workplace during the pandemic because of the increased risk of complications due to covid-19. after the lockdown and in the course of the relaxation of restrictions, the federal state of lower saxony in germany stated that because teachers over the age of 60 (together with persons with chronic diseases) are considered a risk group, they may be able to work from home after the presentation of a medical certificate [6] . in general, the classification of people over 60 years of age as risk persons can significantly reduce the chances of older unemployed people finding a job or make them "targets" for layoffs. there is a major drawback in relying on the age-stratified data of disease severity for the individual assessment of the risk of a severe outcome of a disease: considering only the age-dependency of the disease course could result in a distorted picture. other risk factors, such as cardiovascular diseases, respiratory diseases, and conditions that result in a weakened immunity, also increase with increasing age, and must be taken into account to uncover the isolated effect of age. the largest report on risk factors for death due to covid-19 so far is based on 44,672 confirmed cases from the cdc in china [7] . along with a case fatality rate (cfr) of 2.6% in people older than 59 years, a 6% cfr was reported for patients with hypertension, 7.3% for patients with diabetes, 10.5% for patients with cardiovascular diseases, 6.3% for patients with chronic respiratory diseases, and 5.6% for cancer patients. in addition, there is increased evidence of an increased risk of negative covid-19 outcomes with obesity [8, 9] . a recent review names smoking as a likely risk factor for adverse covid-19 outcomes [10] . it is therefore of utmost importance to quantify the isolated effect of age in the risk for covid-19 disease severity. the aim of this study was to do exactly this. for this purpose, we performed a systematic rapid review of the studies investigating age and covid-19 adverse outcomes. on 15 may 2020, we searched pubmed using the search strings "covid-19" and "age". we applied no language, region, or time restrictions. articles in chinese were translated automatically with the help of google translate. following the population, exposure, comparator, outcome, study design (pecos) scheme for the eligibility criteria of the studies (table 1 ), we considered cross-sectional, case-control, and cohort studies on the general population infected with covid-19. we defined the outcome of interest, "disease severity due to covid-19", as hospitalization, admission to an intensive care unit (icu), intubation, or death due to covid-19. persons from the same study population with non-severe covid-19 could be used as a comparison group, and the definition of non-severity could depend on the definition of the outcome considered. we only considered studies which estimated the adjusted risk of age on disease severity, meaning that studies which only reported age-stratified results or univariate analysis were excluded. the resulting titles and abstracts were screened by two independent scientists to disqualify the studies which were unrelated to the defined research question. in case of disagreement on inclusion, a consensus decision was sought between the two scientists. if there was still no agreement, the decision was made by a third reviewer. the full texts of the remaining studies were again independently examined by two reviewers to determine if the inclusion criteria for this specific review were met. likewise, in case of disagreement, a consensus decision was sought between the two reviewers, and in case of no consensus, the decision was made by third reviewer. additionally, a manual search was performed to find additional relevant articles by screening the reference lists of key articles. the data extraction was done by one reviewer. we tried to obtain the missing or unclear information through personal communication with the authors. the data extraction form included information on the first author and publication year, country of origin, study population, outcome, confounding, and study results. for each included study, we evaluated the overall risk of bias as "low", "high", or "unclear". the overall risk of bias was based on seven domains of bias, following the example used by ijaz and colleagues [11] , and considering the criteria described by sign (scottish intercollegiate guidelines, 2012 [12] and casp (critical appraisal skills programme [13] ): a low-risk study should have avoided selection bias by ensuring an adequate recruitment method, such as randomized sampling. the response rate should be 50% or more, and if not achieved, a non-participation analysis should be performed. for cohort studies, if the loss to follow-up was below 20% and there was no substantial difference between the comparison groups, the risk of bias for this domain was rated as low. similarly, for a case-control study to be rated as having a low risk of bias for this section, both cases and control subjects should have had a response of 50% or more, and if this number was not achieved, the substantial differential selection of cases and controls should have been excluded by a non-participation analysis. if the exposure (age) was accurately measured and finely categorized (i.e., in per year categories), the domain for the study was considered to have a low risk of bias. if the age was measured in large categories, such as ≥65 years vs. <65 years, the domain was considered as having a high risk of bias. if the outcome was objectively measured to minimize bias, such as through hospital or medical records and the assessment was similar for the comparison groups, the domain was considered as having a low risk of bias. the following major age-dependent factors (which might at least partly mediate the influence of age on the course of disease) should have been considered for this domain to have a low risk of bias: (1) diabetes, (2) hypertension, (3) coronary heart disease/cerebrovascular disease, (4) compromised immunity/cancer, (5) previous respiratory disease, and (6) renal disease. other known risk factors of disease severity with no or little age-dependency (sex, obesity, smoking) were not considered as major age-dependent risk factors. if the adequate statistical models were used to reduce bias and control for confounding, this domain was considered as having a low risk of bias. if the risk factors were included in the model which reflected covid-19 infection (in other words, an over-adjustment on the model), this domain was regarded as having a high risk of bias. this was assessed in two areas: the sources of funding and the involvement of the funding body in the research. if a study was funded by non-profit organization(s) and it was not affected by sponsors, the domain was rated as having a low risk of bias. if the sponsoring organization participated in the data analysis or the study was probably affected by the sponsors, the domain was considered as having a high risk of bias. if the authors reported not having a conflict of interest, the domain was rated as having a low risk of bias. if one author had a conflict of interest, the domain was considered as having a high risk of bias. from the seven domains described, we considered the domains described in section 2.2.1-section 2.2.5 as major domains for a risk of bias, while sections 2.2.6 and 2.2.7 were minor domains. a "high risk" or "unclear risk" rating in any of the major domains would result in an overall "high risk of bias" assessment for each study. when studies used either the same population or a subset of another study's population and investigated the same outcomes, we chose the study with more precise age categories (i.e., per year of age) for the risk of bias assessment and for the subsequent meta-analysis. we used stata version 14.2 [14] for all statistical analyses. to obtain a precise pooled age-related risk, we decided a priori to conduct a meta-analysis if at least two studies were present with similar outcomes, exposures, and evaluating risk per year of age. we assessed statistical heterogeneity with the i 2 statistic and assessed publication bias by observing the funnel plot asymmetry and by performing egger's test (metabias). since we deem adjustment for age-dependent risk factors essential for determining the isolated risk of age on disease severity, we performed a meta-regression (metareg) to obtain the effect of the number of important age-dependent risk factors (0-6) used in the study models (diabetes, hypertension/cardiovascular disease, compromised immunity, respiratory disease) on the relative risk. in a sensitivity analysis, we included a bivariate factor (0 = no, 1 = yes) in the model, representing whether there was an over-adjustment in the model-meaning that the model included variables which already reflected a possible covid-19 infection (e.g., fever, dyspnea, neutrophil to lymphocyte ratio, c-reactive protein). through the database and manual search, 546 studies identified were screened, resulting in 57 full-text articles assessed for eligibility ( figure 1 ). from these, 45 articles were excluded for the following main reasons: the risk of age was not calculated, only the crude (unadjusted) risk of age was reported, irrelevant subject, unclear methodology, and unclear outcome definition. finally, twelve studies met our inclusion criteria. we assessed statistical heterogeneity with the i 2 statistic and assessed publication bias by observing the funnel plot asymmetry and by performing egger's test (metabias). since we deem adjustment for age-dependent risk factors essential for determining the isolated risk of age on disease severity, we performed a meta-regression (metareg) to obtain the effect of the number of important age-dependent risk factors (0-6) used in the study models (diabetes, hypertension/cardiovascular disease, compromised immunity, respiratory disease) on the relative risk. in a sensitivity analysis, we included a bivariate factor (0 = no, 1 = yes) in the model, representing whether there was an over-adjustment in the model-meaning that the model included variables which already reflected a possible covid-19 infection (e.g., fever, dyspnea, neutrophil to lymphocyte ratio, c-reactive protein). through the database and manual search, 546 studies identified were screened, resulting in 57 full-text articles assessed for eligibility ( figure 1 ). from these, 45 articles were excluded for the following main reasons: the risk of age was not calculated, only the crude (unadjusted) risk of age was reported, irrelevant subject, unclear methodology, and unclear outcome definition. finally, twelve studies met our inclusion criteria. the study characteristics are summarized in tables 2-5 and below. all studies originated in china and were retrospective cohort studies, using hospitalized patients as the study population. eight studies categorized and analyzed the patients' age by year [15] [16] [17] [18] [19] [20] [21] [22] , three studies constructed larger age categories for their analyses [23] [24] [25] , and one study did both [26] . the study characteristics are summarized in tables 2-5 and below. all studies originated in china and were retrospective cohort studies, using hospitalized patients as the study population. eight studies categorized and analyzed the patients' age by year [15] [16] [17] [18] [19] [20] [21] [22] , three studies constructed larger age categories for their analyses [23] [24] [25] , and one study did both [26] . seven studies evaluated the risk of patients' mortality [18] [19] [20] [21] [22] [23] [24] , four evaluated the covid-19 disease severity by building a composite index comprising of admission to the icu, invasive ventilation, or death [15, 17, 25, 26] , and one study evaluated the admission to icu [16] . there were studies that used the same study population or a subset of the other's study population. an example of this is the population from guan et al. 2020 [26] and chen, r et al. 2020 [23] , and liang, w. [17] et al., where all three studies used the same data from 1590 participants across 575 hospitals in mainland china. another example is that of zhou et al. 2020 [18] and du et al. 2020 [24] . in this case, both studies used data in a similar timeframe from a subset of hospitals included in the previous large study by guan and colleagues [26] , and therefore we considered these two studies [18, 24] to have used a subset of the guan et al. 2020 population [26] . a summary of the studies investigating disease severity by a composite index can be found in table 3 . the largest study in china was a retrospective cohort study from guan and colleagues [26] , which included the clinical data of 1590 laboratory-confirmed hospitalized covid-19 cases from 575 hospitals in china, representing almost a third of the certified hospitals in china for admitting patients with covid-19 between 11 december 2019 and 31 january 2020. after adjustment for malignancy, chronic obstructive pulmonary disease (copd), diabetes, hypertension, and smoking, every year of age increased the risk of severe outcome by 3.6% (hr = 1.036, 95% ci 1.022-1.050). because this study did not consider all the necessary risk factors into its analysis (coronary heart disease/cerebrovascular and renal disease missing), it was considered to have a high risk of bias (table 4 ). this study was included in our meta-analysis. liang et al. 2020 [17] investigated the above study's [26] same population and outcome and performed a similar analysis using somewhat different confounders, including biomarkers that were reflective of covid-19 infection. the study yielded similar results (per year of age hr = 1.03, 95% ci 1.01-1.05) as guan et al. 2020 [15] , but we preferred to use guan et al. 2020 in our meta-analysis, since liang et al. 2020 [17] used markers reflective of infection in their analysis. chen c. et al. 2020 [15] was a retrospective cohort made up of 150 patients admitted to the fever ward in tongji hospital. after adjustment for confounders, each year of age elevated the risk of severe disease by 1.9% (hr = 1.019; 95% ci 0.963-1.077), although the result was not statistically significant. this study did not consider all the necessary risk factors (diabetes, compromised immunity, respiratory disease missing). it also used several biomarkers reflective of covid-19 infection in its analysis, so it was evaluated as having a high risk of bias. this study was included in our meta-analysis. meng et al. 2020 [25] investigated chen c. and colleagues' [15] study population, but used large age categories (0-59, 60-79, ≥80 years) for the analysis. they found a higher risk of death in older patients than in those younger than 60 years. because of the broad age categories used, it was not used for the risk of bias or meta-analysis and chen c. et al.'s [15] analysis was instead preferred. the reasons for the exclusion of any study from our risk of bias assessment and meta-analysis are given in table 4 . again, we avoided having more than one study using the same population, and studies investigating the age effects per year of age were preferred to the studies using large age categories, such as <65 yrs. vs. ≥65 yrs. therefore, lian et al. 2020 [17] and meng et al. 2020 [25] were excluded, and guan et al. 2020 [26] and chen c et al. 2020 [15] were included in the risk of bias assessment and in the meta-analysis. figure 2 summarizes the risk of bias (rob) for composite endpoints of disease severity. because all important age-dependent risk factors were not considered, both included studies [15, 26] had a high risk of bias. in addition, chen c. et al. included all the factors indicating an infection and this study was further marked down. are given in table 4 . again, we avoided having more than one study using the same population, and studies investigating the age effects per year of age were preferred to the studies using large age categories, such as <65 yrs. vs. ≥65 yrs. therefore, lian et al. 2020 [17] and meng et al. 2020 [25] were excluded, and guan et al. 2020 [26] and chen c et al. 2020 [15] were included in the risk of bias assessment and in the meta-analysis. figure 2 summarizes the risk of bias (rob) for composite endpoints of disease severity. because all important age-dependent risk factors were not considered, both included studies [15, 26] had a high risk of bias. in addition, chen c. et al. included all the factors indicating an infection and this study was further marked down. the pooled effect of both studies [15, 26] indicates a 4% increase in the risk of severe disease per year of age (95% ci 2%-5%), figure 3 . the corresponding funnel plot indicates no evidence of publication bias (results not shown). the pooled effect of both studies [15, 26] indicates a 4% increase in the risk of severe disease per year of age (95% ci 2%-5%), figure 3 . the corresponding funnel plot indicates no evidence of publication bias (results not shown). the meta-regression from both studies [15, 26] indicated an intercept of 1.052 (95% ci 1.026-1.078) and a slope (ß) of 0.996 (95% ci 0.987-1.006). an estimate of the age-related relative risk by the number of important risk factors considered in the adjustment models can be found in table 6 . the unadjusted age effect was a 5.2% increase in disease severity per age year. the maximum number of important risk factors adjusted for by the studies was five, which resulted in a 3.5% increase in disease severity per age year. the meta-regression from both studies [15, 26] indicated an intercept of 1.052 (95% ci 1.026-1.078) and a slope (ß) of 0.996 (95% ci 0.987-1.006). an estimate of the age-related relative risk by the number of important risk factors considered in the adjustment models can be found in table 6 . the unadjusted age effect was a 5.2% increase in disease severity per age year. the maximum number of important risk factors adjusted for by the studies was five, which resulted in a 3.5% increase in disease severity per age year. because there were only two studies, a sensitivity analysis of the effect of both the important risk factors and the inclusion "over-adjustment" variables in the multivariate model could not be done. a summary of the studies investigating death due to covid-19 can be found in table 4 . chen r et al. [23] used the same study population as guan et al.'s (n = 1590) [26] , but studied mortality (table 4 ). they used broad age categories (<65, 65-74, and ≥75 years) for their analysis. after adjusting for coronary heart disease, cardiovascular disease, and for several biomarkers, there was an increased risk of mortality for older patients (≥75 years hr 7.86, 95% ci 2.44-25.35; 65-74 years because there were only two studies, a sensitivity analysis of the effect of both the important risk factors and the inclusion "over-adjustment" variables in the multivariate model could not be done. a summary of the studies investigating death due to covid-19 can be found in table 4 . chen r et al. [23] used the same study population as guan et al.'s (n = 1590) [26] , but studied mortality (table 4 ). they used broad age categories (<65, 65-74, and ≥75 years) for their analysis. after adjusting for coronary heart disease, cardiovascular disease, and for several biomarkers, there was an increased risk of mortality for older patients (≥75 years hr 7.86, 95% ci 2.44-25.35; 65-74 years hr 3.43, 95% ci 1.24-9.5). it was not included in the meta-analysis because no other study used comparable age categories. zhou et al. 2020 [18] investigated death in 191 covid-19 patients from two hospitals which were included as part of chen r et al. 2020 [23] and guan's study population and in similar timeframes. several of the risk factors of interest were missing from the analysis (diabetes, weakened immunity, and respiratory disease). after the adjustment for confounders, an increased risk of death was found for each year of age (or = 1.10; 95% 1.03-1.17). since "per year of age" analyses were done, the zhou et al. study was included in the risk of bias and meta-analysis for death as an outcome. we evaluated the study as having a high risk of bias because not all age-related risk factors were considered, and because biomarkers which were already reflective of covid-19 disease severity were used for the risk analysis. wang d. et al. 2020 [19] studied 107 patients hospitalized at zhongnan hospital of wuhan university and at xischui hospital. after adjusting for sex, hypertension, cardiovascular disease, and creatinine concentration, each increased year of age resulted in an 11% increased risk of mortality (or = 1.11; 95% ci 1.042-1.184). because not all important age-related risk factors were included in the analysis, and because they adjusted for biomarkers which were reflective of disease severity/covid-19 infection, the study was rated as having a high risk of bias. wang d. et al. 2020 [19] was included in our meta-analysis. in another retrospective study, wang k. et al. 2020 [20] studied 305 patients hospitalized in first people's hospital of the jiangxia district in wuhan from 7 january to 11 february 2020. after adjustment for hypertension and fever, there was a 9% increased mortality for every year of age (or = 1.09; 95% ci 1.054-1.14). due to the lack of age-related risk factors included in the analysis and the adjustment for fever, which is reflective of covid-19 infection/disease severity, this study was determined to have a high risk of bias. this study was included in our meta-analysis. shi et al. 2020 [21] studied the patients admitted to renmin hospital of wuhan university from 1 january to 23 february 2020, using a retrospective cohort design. they used two models: model 1 considered sex, hypertension, diabetes, coronary heart disease, chronic renal disease, cerebrovascular disease and several biomarkers as categorical variables. model 2 used sex and the same chronic diseases as model 1, but with the biomarkers as continuous variables. when model 1 was used, there was a 1% increased risk of death per year of life (or = 1.01; 95% ci 0.98-1.05) which was borderline statistically significant. model 2 resulted in a 4% increased risk of death per year of life (or = 1.04; 95% ci 1.00-1.07), also borderline statistically significant. we evaluated this study as having a high risk of bias, because not every important age-related risk factor was considered and because it used variables which may reflect covid-19 disease severity. shi et al. 2020 [21] was included in our meta-analysis. sun et al. 2020 [22] identified 244 patients over the age of 60 years of the sino-french new city branch of tongji hospital between 29 january to 5 march 2020. only patients who were 60 years or older were enrolled. after adjustment for sex, hypertension, previous respiratory diseases and other confounders, there was a 12% increase risk of death per year of life was observed (or = 1.12; 95% ci 1.01-1.25). this study received a high risk of bias rating because only patients older than 60 years of age were considered, because of missing risk factors, and because biomarkers were used that might indicate a covid-19 infection/disease severity. sun et al. 2020 [22] was included in our meta-analysis. the reasons for the exclusion of any study from our meta-analysis/risk of bias assessment for death are summarized in table 4 . in summary, five studies (zhou et al. 2020 [15] , wang d et al. 2020 [19] , wang k et al. 2020 [20] , shi et al. 2020 [21] , and sun et al. 2020 [22] ) were included in the risk of bias assessment and meta-analysis. all the studies included in the meta-analysis for mortality were rated as having a high risk of bias because not all age-dependent risk factors were considered and because the variables used in the analysis may have already indicated covid-19 disease severity. in addition, sun et al. 2020 [22] only investigated people over the age of 60, and therefore it received a high-risk in the recruitment procedure domain. the pooled effect of the five studies [18] [19] [20] [21] [22] indicates an 8% increase in the risk of death per year of age (95% ci 3-13%) when shi et al.'s [21] model with categorized values for the biomarkers was used (figure 4) . the effect remains similar with slightly narrower confidence intervals when model 2 was used with continuous values (rr = 1.08; 95% ci 1.06-1.11). the corresponding funnel plot indicates no evidence of publication bias (egger's test p = 0.21), see figure 5 for funnel plot). the pooled effect of the five studies [18] [19] [20] [21] [22] indicates an 8% increase in the risk of death per year of age (95% ci 3-13%) when shi et al.'s [21] model with categorized values for the biomarkers was used (figure 4) . the effect remains similar with slightly narrower confidence intervals when model 2 was used with continuous values (rr = 1.08; 95% ci 1.06-1.11). the corresponding funnel plot indicates no evidence of publication bias (egger's test p = 0.21), see figure 5 for funnel plot). the pooled effect of the five studies [18] [19] [20] [21] [22] indicates an 8% increase in the risk of death per year of age (95% ci 3-13%) when shi et al.'s [21] model with categorized values for the biomarkers was used (figure 4) . the effect remains similar with slightly narrower confidence intervals when model 2 was used with continuous values (rr = 1.08; 95% ci 1.06-1.11). the corresponding funnel plot indicates no evidence of publication bias (egger's test p = 0.21), see figure 5 for funnel plot). the meta-regression from five studies resulted in an intercept of 1.134 (95% ci 1.110-1.158) and a slope of β = 0.978 (95% ci 0.967-0.989). table 6 shows the estimates of the relative risk by the number of important risk factors adjusted for. the unadjusted age effect resulted in a 13.4% increase in mortality per age year. the maximum number of risk factors used by the studies was five, which would result in a 1.4% increase in death per age year. the sensitivity analysis shows a statistically non-significant decrease in the relative risk (0.979; 95% ci 0.923-1.039) with over-adjustment; meaning including variables which reflect a current infection (probably due to in the regression model will decrease the calculated relative risk by a factor of 0.979 (table 7 ). chen j. et al. 2020 [16] studied 249 patients at shanghai public health clinical center between 20 january and 25 february 2020 (table 5 ). after adjusting for sex, cardiovascular and cerebrovascular diseases, endocrine system diseases, digestive system diseases, respiratory system diseases, hepatitis b, malignant tumor, and several biomarkers, there was an increased, borderline statistically significant risk per year of age on the admission to the icu (or = 1.06; 95% ci 1.00-1.12). because the study [16] did not adjust for all the important risk factors and because it used biomarkers that may be indicative of a covid-19 infection or covid-19 severe disease, it was assessed as having a high risk of bias. no meta-analysis could be done for this outcome due to the lack of studies. according to the meta-regression of five studies, the effect estimate of age on mortality risk decreases with an increasing adjustment for important age-related risk factors. a maximum of five age-dependent risk factors were adjusted for in the included studies. after the adjustment for these five risk factors, the risk per age year decreases from 13.4% (unadjusted value) to 1.4% per year. this translates to about a 20% higher risk of death for a 60 year-old person compared to that of a 50 year-old person due to the (almost) isolated effect of age. nonetheless, no studies adjusted for all six important risk factors, which would further decrease the age-related risk. to illustrate our point more clearly, figure 6 shows how the effect estimate of disease severity and death decreases with the inclusion of the important age-dependent risk factors. looking at only disease severity (blue line) and death (orange line), the following is shown: the age-related risk decreases with adjustment for each age-related risk factor (i.e., age-related comorbidities). if we were to extrapolate to the scenario where all six age-dependent risk factors were adjusted for, there would be a 3.2% increased risk per age year for disease severity, and almost no age-related risk for death. figure 6 also depicts the effect of over-adjustment in the model, when the models use variables (usually biomarkers) that are already indicative of infection. in this case, the effect estimate is even lower than when just adjusting for the important age-dependent risk factors. such a scenario is also undesirable, since it leads to a considerable underestimation of the effect. our results show an increased age-related risk of covid-19 disease severity, admission to icu, and death. however, our risk of bias analysis show that these pooled results are biased: not one study adjusted for all the necessary age-dependent risk factors to obtain the isolated effect of age on covid-19 disease severity. further analysis attempting to correct for this bias shows that if important age-related risk factors are taken into account, there is a 2.7% increased risk per age year for disease severity (based on two studies), and almost no age-related risk for death (based on five studies). it appears that age-related comorbidities have a more important weight than age itself. to our knowledge, this is the first review to investigate the isolated age-associated risk for a covid-19 disease severity or death. the main strengths of our research methods were the systematic literature search, and the independent appraisal of titles, abstracts, and full text by two scientists. our formal risk of bias assessment for the included studies was integrated into the meta-analysis and interpretation of our results. we only included the studies published in peer-reviewed journals, although we included the studies available as a pre-print only due to the time criticality of the research question on hand. there was no indication of publication bias for the risk of severe outcomes or death. in our meta-regression, we assumed that the effect of each risk factor on the risk reduction was the same and that no interactions were present, which might not be the case. however, it was our wish to illustrate the general consequence of not adjusting for all (known) age-dependent risk factors when estimating the effect of age on covid-19 disease severity or death. future studies need to apply models that appropriately incorporate all relevant risk factors. in our risk of bias analysis, we assessed all the included studies to have biased results, mostly because none included all the important age-related risk factors necessary to estimate the isolated effect of age on disease severity. we therefore stress that future studies control for all of these factors in their analysis. the most common reason for study exclusion was that only the unadjusted risk of age was reported-meaning that only univariate analysis or age-stratified results were reported. the data might be indeed available already-but it has just not been adequately analyzed and published. in addition, studies might also have used different definitions of certain conditions, such as hypertension, or the collective terms such as "cardiovascular disease", or "renal disease". furthermore, most studies used biomarkers or disease markers reflective of an infection such as covid-19 in their analysis. our sensitivity analysis indicated that the use of those markers would lead to a (statistically not significant) decrease in the relative risk, underestimating the real age-related risk of death. further studies should restrain from including such variables in their models when studying covid-19 disease severity to avoid over-adjustment. all studies used hospitalized patients as the study population, which may not be reflective of the general population. therefore, the results of this study refer to the risk of covid-19 disease severity in hospitalized patients. in order to study the risk of disease severity in covid-19 infection, it is necessary to study the general population infected with covid-19 and to determine their outcomes with a prospective cohort study. it is necessary to accurately define and target risk groups for covid-19 disease severity for any prevention measures considered. taking the example of one of the included studies investigating disease severity [26] , the results show that the unadjusted risk of a 50 year old person is compared to that of a 60 year old person, the risk increase is comparable to the risk observed for diabetes, smoking or hypertension (or per 10 yrs. = 1.65). however, when a more isolated age effect is calculated by adjusting for other important age-related risk factors, the risk due to age decreases by almost a third, this time being lower than the risk caused by diabetes, smoking, hypertension, malignancy or copd. this way, one could make individualized risk profiles to set more transparent and logical recommendations in the case of a lockdown. one could for instance compare the risk of a 45 year-old person suffering from diabetes to the risk of a 60 year old person with no underlying illnesses and come to the conclusion that the younger person with diabetes would have a higher risk for covid-19 disease severity. thus, it is particularly important at this time that the general population is aware of their underlying conditions and to continue to attend health screenings and medical check-ups. policy makers should in turn promote screenings at this time. overall, it seems arbitrary to target persons over the age of 60 years as a high-risk group, solely based on age. there are estimates that up to 20-30% of people between the age of 60 and 65 have no underlying chronic disorders [27] . even if this estimate were lower, targeting solely by age group would bring potentially unnecessary and unjustified consequences. this undifferentiated classification may encourage the discrimination of older people in society at large, which has already been reported during the covid-19 pandemic [28] . serious negative repercussions can result for older people, including biographical constraints, psychological problems, and economic hardship [28] [29] [30] . in terms of the older worker, such undifferentiated classification would also be difficult to reconcile with the declaration of the council of the european union of july 2012, which, under the heading "prevention of age discrimination" [31] , cites "refraining from using age as a decisive criterion for assessing whether a worker is fit for a certain job or not". since age is an essential and inevitable characteristic of a person, particular caution seems necessary when defining age-specific exclusion criteria for certain jobs. in this respect, it should be pointed out that the social isolation often associated with the selective absence of older employees from the workplace can in principle lead to depressive and post-traumatic stress symptoms [32] . the indication of a rather weak influence of age on covid-19 disease severity and death after adjustment for important age-dependent risk factors should be taken in consideration when implementing age-related preventative measures. clinical characteristics and outcomes of older patients with coronavirus disease 2019 (covid-19) in wuhan clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study disparities in age-specific morbidity and mortality from sars-cov-2 in china and the republic of korea estimates of the severity of coronavirus disease 2019: a model-based analysis informationen und hilfestellungen für personen mit einem höheren risiko für einen schweren covid-19-krankheitsverlauf schule in corona-zeiten. leitfaden für schulleitungen lehrkräfte und pädagogische fachkräfte an schulen the 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research, and medical education: a cross-sectional study an evaluation of tweets about older adults and covid-19 recovering from the covid-19 pandemic: a focus on older adults aging in times of the covid-19 pandemic: avoiding ageism and fostering intergenerational solidarity council declaration on the european year for active ageing and solidarity between psychosoziale folgen von quarantänemaßnahmen bei schwerwiegenden coronavirus-ausbrüchen: ein rapid review this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license funding: this research received no external funding. the authors declare no conflict of interest. key: cord-318363-1mv5j4w2 authors: zvolensky, michael j.; garey, lorra; rogers, andrew h.; schmidt, norman b.; vujanovic, anka a.; storch, eric a.; buckner, julia d.; paulus, daniel j.; alfano, candice; smits, jasper a.j.; o'cleirigh, conall title: psychological, addictive, and health behavior implications of the covid-19 pandemic date: 2020-08-27 journal: behav res ther doi: 10.1016/j.brat.2020.103715 sha: doc_id: 318363 cord_uid: 1mv5j4w2 • the public health impact of covid-19 on psychological symptoms and disorders, addiction, and health behavior is substantial and ongoing. • an integrative covid-19 stress-based model could be used to guide research focused on the stress-related burden of the pandemic. • this work could provide a theoretical and empirical knowledge base for future pandemics. around some of the most clinically important psychological disorders, addictive behaviors, and health behaviors for well-being. in the first section, we describe the covid-19 implications for mental health focusing on (a) anxiety/stress and mood disturbance, (b) obsessive compulsive symptoms and disorders, and (c) posttraumatic stress. such mental health problems, although certainly not exhaustive of the scope of psychological disorders impacted by covid-19, are some of the most common mental health issues in the general population and are frequently comorbid with chronic illness. in the second section, we focus on addictive behaviors, including (d) tobacco (combustible and electronic), (e) alcohol use and misuse, and (e) cannabis. these forms of drug use represent the most prevalent types of substance use and are frequently associated with chronic illness and premature death. in the third section, we spotlight health behavior and chronic illness by discussing the role of (f) sleep health and behavior, (g) chronic illness using the example of hiv/aids as an illustrative model, and (h) physical activity. health behaviors represent vital targets for the mitigation of covid-related disease and may play a key role in psychological adjustment and recovery. in the final section, we highlight sociocultural factors (e.g., race/ethnicity, economic adversity), developmental considerations, and the role of individual difference factors for psychological, addictive, and health behavior and chronic illness. we conclude by offering an integrative covid-19 stress-based model that could be used to guide research focused on the stress-related burden of the pandemic. fear is an adaptive defense mechanism that is fundamental for survival and involves several psychological and biological processes of preparation for a response to potentially j o u r n a l p r e -p r o o f threatening events. covid-19 represents a true threat, with many unknowns. if you are infected, there is a chance you could die, regardless of your current age, sex, or health status. as such, fear is a natural and adaptive response to this pandemic. on the other hand, every year tens of thousands die from influenza as well as many other preventable or unexpected causes. this raises the key question regarding the degree to which we should be anxious and fearful of . how much anxiety is reasonable? since even basic knowledge about covid-19 is undeveloped, it will be difficult to clearly discriminate between normal, adaptive fear responses and less adaptive responses. that said, such an overarching true threat and the concomitant stressors such as social isolation, economic uncertainty and so forth could in fact recalibrate what is considered a normal level of anxiety in the general population. research has demonstrated that trait levels of anxiety have increased in the us in recent decades, though the cause of such increases is unknown (twenge, 2000) . the covid-19 pandemic is likely to contribute to these basic levels of trait anxiety, thus creating a "new normal" level of anxiety. if we consider the likely general increase in anxiety and stress in the context of diathesisstress conceptualizations of mental illness, we expect that such a salient and broad reaching stressor to increase the incidence of pathological anxiety. anxiety conditions are already highly prevalent (bandelow & michaelis, 2015) , and we may see an increased incidence of anxiety psychopathology if the pandemic serves to push vulnerable individuals toward the expression of maladaptive levels of anxiety. moreover, those with preexisting conditions are likely to have their symptoms intensify. one could further speculate that forms of pathological anxiety will increase. first responders and hospital personnel, particularly in affected areas are already showing troubling signs of stress and psychopathology (joob & wiwanitkit, 2020) . it is highly j o u r n a l p r e -p r o o f likely that we will see increased rates of generalized anxiety and posttraumatic stress related to the pandemic and its sequelae. beyond the somewhat vague notion of covid-19 acting as a stressor to increase both normal and pathological anxiety, it is interesting to consider the specific mechanisms that play a role in this process. there are several well-established parameters that relate to the genesis and maintenance of anxiety that seem highly relevant to the current situation. these processes include perceptions relating to predictability/certainty and controllability of threat (barlow, 2004) . coming across a shark while swimming is quite different from viewing the same shark in an aquarium since a potential threat in the wild is far less predictable or controllable than one in an enclosure. historically, epidemics and pandemics were considered divine punishments that were essentially uncontrollable. although medical understanding of pathogens has advanced, globalization now facilitates the spread of pathological agents, which diminishes the degree to which we can control them. similarly, naturally occurring mutations and adaptation of viruses ensure that novel pathogens like covid-19 will emerge and spread. these conditions leave us in a state of uncertainty, except that we can be certain that covid-19 and other infectious agents will persist. thus, covid-19 affects many of the core anxiety generating mechanisms since it leads to a sense of diminished predictability and controllability along with increased uncertainty relating to a true threat. ultimately, the covid-19 pandemic creates an ideal environment for the onset, maintenance, and exacerbation of anxiety symptoms and syndromes. the dsm-5 posttraumatic stress disorder (ptsd) criterion a (american psychiatric association [apa] , 2013, p.271) defines trauma as "exposure to actual or threatened death." individuals who are closer to that exposure --providing healthcare to those infected, witnessing j o u r n a l p r e -p r o o f the deleterious and perhaps deadly effects of the virus on patients or loved ones, enduring losses of patients, family, or friends --might experience the crisis as potentially traumatic. people on the frontlines of the pandemic, including healthcare personnel, first responders, grocery store clerks, and other essential workers, encounter the threat of possible exposure to the virus regularly and on an ongoing basis. similarly, incarcerated populations and those who might feel compelled, financially or otherwise, to work in close quarters without adequate personal protective equipment (e.g., factory workers) may be exposed to the covid-19 virus for extended periods without perceived or actual recourse and suffer negative mental health repercussions as a result. covid-19 survivors, particularly those who might have struggled through various medical procedures and prolonged hospitalizations, may emerge with unique or shared constellations of mental health reactions from risk to resilience. additional high-risk groups include healthcare professionals or first responders who may have experienced significant moral injuries (jinkerson, 2016; joannou, besemann, & kriellaars, 2017; williamson, stevelink, & greenberg, 2018 ) as a result of making unfathomable decisions on the job (e.g., providing admission or ventilator access to one patient at the sacrifice of another). yet, in addition to considering direct impacts of the novel covid-19 virus on our population, it is imperative to understand the secondary potentially traumatic effects of the pandemic on individuals and communities. the combination of prolonged stress, close quarters, and self-isolation guidelines has increased risk of domestic violence, child abuse, and substance use (abramson, 2020; national institute on drug abuse, 2020; santhanam, 2020; taub, 2020) . indeed, physical and sexual violence may escalate without the regular societal checks provided by employers, schools, and loved ones. furthermore, such violence may stem from and/or intensify more unbridled substance use (carter et al., 2020) emerging from a context where j o u r n a l p r e -p r o o f uncertainty and unpredictability are high, practical stressors (e.g., unemployment, financial stress, food insecurity) may be difficult to problem-solve, and social supports may be distant. furthermore, in this pandemic, issues of grief and loss are inevitably interwoven with those of potential trauma. spiritual and emotional grief processes to honor and emotionally mourn the losses of loved ones may be interrupted by this pandemic, potentially exacerbating or prolonging grief, traumatic bereavement, or ptsd reactions. to understand the effects of covid-19 on the mental health of those who experience it as potentially traumatic, we need to recognize first that the impacts of trauma may not be fully determined nor completely recognizable until after the traumatic stressor has concluded. the covid-19 crisis is going to have a long, yet undetermined course, and thus our ongoing reactions to it are dynamic but indicative of peri-traumatic rather than post-traumatic coping (bell, boden, horwood, & mulder, 2017; lapid pickman, greene, & gelkopf, 2017) . based upon decades of research, we can expect the majority of the population, regardless of level of proximity to or interaction with covid-19, to demonstrate resilience and to recover psychologically in the aftermath of the pandemic (alisic et al., 2014; kilpatrick et al., 2013) . a relative minority, the proportions of which are unknown, may emerge from the crisis with clinical or subclinical ptsd or with exacerbation in pre-existing ptsd symptoms and related mental health conditions (e.g., depression, substance use disorder). women are at heightened risk of ptsd following potentially traumatic events (gaffey et al., 2019; rattel et al., 2019) and racial/ethnic minority populations may be especially impacted due to socioeconomic inequities and health-related disparities with regard to financial security and access to healthcare and treatment (asnaani & hall-clark, 2017; cross et al., 2018; sibrava et al., 2019) . the intersections of trauma and the covid-19 pandemic are complex. many constellations of interweaving risk and protective factors, learning histories, and life circumstances can affect how trauma histories and potentially traumatic experiences during the covid-19 crisis can affect individual journeys of recovery. for example, more unbalanced, negative individual interpretations of the covid-19 crisis and related changes in beliefs about oneself, others, or the world may have lasting deleterious effects (e.g., "i am damaged"; "people cannot be trusted"; "the world is dangerous and unsafe"; beierl, böllinghaus, clark, glucksman, & ehlers, 2019; bernardi & jobson, 2019; köhler, goebel, & pedersen, 2019; losavio, dillon, & resick, 2017; scher, suvak, & resick, 2017) . similarly, avoidance of thoughts or emotions related to the covid-19 crisis may increase the risk of developing ptsd symptoms and/or exacerbating or maintaining pre-existing trauma-related symptoms (e.g., orcutt, reffi, & ellis, 2020) . additional risk factors for the development or exacerbation of ptsd symptoms include a prior history of trauma or mental health disturbances, depressed or anxious mood, significant concurrent life stressors (e.g., financial problems, job loss, relationship stress), low social connectedness or support, sleep disturbance, substance use, and emotional numbing or detachment (colvonen, straus, acheson, & gehrman, 2019; cusack et al., 2019; germain, mckeon, & campbell, 2017; hancock & bryant, 2018; shalev et al., 2019; steenkamp et al., 2017; vujanovic & back, 2019) . navigating the covid-19 crisis requires a tolerance of uncertainty that is challenging for all, but especially trauma survivors who may have endured, sometimes over months or years (e.g., combat, childhood abuse), unfathomable circumstances that were, by definition, unpredictable and uncontrollable (e.g., raines, oglesby, walton, true, & franklin, 2019; vujanovic & zegel, 2020) . undoubtedly, social connection and a sense of community and collectivism, hope, psychological awareness, and healthy coping will j o u r n a l p r e -p r o o f differentiate risk versus resilience trajectories during and after this crisis (bernardi & jobson, 2019; long & gallagher, 2018; thompson, fiorillo, rothbaum, ressler, & michopoulos, 2018) . learning who suffers long-term negative effects of the covid-19 pandemic, why, and under what circumstances will help us to understand how to intervene most effectively to psychologically support trauma survivors in the aftermath of this and future societal crises. indeed, reactions of trauma survivors to the covid-19 crisis are also likely to be as diverse as the traumas and individuals themselves with the possibility of emergent themes. theoretically, individuals with histories of being directly impacted by natural disasters, people recovering from severe medical conditions, and those with histories of imprisonment or captivity may feel especially emotionally reactive to the large community-level impact, the social distancing and quarantining aspects of weathering covid-19, and the continual perceived health threat inherent to the pandemic. individuals with interpersonal trauma histories may experience a solidification or exacerbation of maladaptive beliefs relevant to trust, safety, or power. others may feel increased social detachment or engage in increased harmful, self-injurious, or suicidal behaviors, particularly those with mood or substance use disorders. for some trauma survivors, following social distancing and self-quarantine guidelines may lead to less frequent exposure to trauma-related reminders in the outside world and/or a lower perceived interpersonal threat due to social-isolation, but increased trauma-related avoidance during the covid-19 crisis in turn may exacerbate ptsd symptoms in the long-term. a high-risk subset may emerge who are slow or reluctant to heed public health guidelines due to a reaction against efforts to control, an increased risk-taking propensity, all-or-none thinking, or helplessness resulting from a history punctuated by traumatic, uncontrollable events. this may lead to incessant attempts, by some, to attain perceived control via closely monitoring news, stockpiling food, or supplies, and maintaining constant vigilance. for those affected by trauma prior to and/or during the covid-19 crisis, the current, chronically stressful global atmosphere where uncertainty reigns may feel especially overwhelming. for others, this crisis may foster growth and resilience as they endure and overcome a crisis of epic and unimaginable proportions. obsessive-compulsive disorder (ocd) is a common (1-2% incidence; (nestadt, bienvenu, cai, samuels, & eaton, 1998; ruscio, stein, chiu, & kessler, 2010) , disabling mental health condition characterized by presence of obsessions and/or compulsions (american psychiatric association, 2013; markarian et al., 2010) . symptoms present in a heterogeneous fashion across a number of dimensions, including contamination/cleaning, taboo obsessions (i.e., sexual, aggressive content), symmetry/repeating/ordering, and checking (mckay et al., 2006) . childhood onset occurs in over 50% of cases and symptoms run a chronic course without adequate intervention (pinto, mancebo, eisen, pagano, & rasmussen, 2006) . clinical presentation is further characterized by frequent comorbidity (stein et al., 2019) and variable degrees of insight (hamblin, park, wu, & storch, 2017) . the covid-19 pandemic is likely to have a number of effects on those with ocd, as well as those at risk. this includes the potential for symptom exacerbation and increased incidence of ocd cases, as well as having implications for assessment and treatment post-covid-19. patients with ocd commonly present with contamination obsessions and associated cleaning compulsions (mataix-cols, do rosario-campos, & leckman, 2005; pinto et al., 2006) . some individuals with contamination related ocd have reported that their symptoms have worsened in light of public health recommendations for increased cleaning behaviors (e.g., washing, wearing masks) and other safety behaviors (e.g., social distancing, wearing masks), j o u r n a l p r e -p r o o f which may be difficult for some patients to maintain within recommended guidelines. covid-19 has become a feared outcome for many patients with contamination-related ocd similar to other what has been observed with other infectious diseases (e.g., hiv). outside of contamination-focused symptomology, other obsessive-compulsive symptoms may be affected such as harm obsessions whereby someone fears that they may have unintentionally spread covid-19. stress has an established relationship with worsened obsessive-compulsive symptoms (adams et al., 2018; brander, perez-vigil, larsson, & mataix-cols, 2016) , and availability of coping strategies is taxed for many; this may further impact ocd symptom presentation as well as comorbidity patterns. although systematic data have not been presented, clinical accounts support symptom worsening for some affected individuals while, on balance, many others have not experienced negative symptomatic change. beyond worsening of symptoms in those with ocd, there is the possibility that there will be increased cases in the near future. this may involve those with subclinical symptoms or other risk factors experiencing onset or worsening of symptoms. the behavioral cycle of ocd/anxiety highlights the role of negative reinforcement in which rituals/avoidance are reinforced by distress reduction and creating a cognitive sense of control (i.e., not getting covid-19 is due to compulsions; rector, wilde, & richter, 2017) . in this scenario, a person with or at risk for ocd may engage in rituals/safety behaviors in response to obsessional distress which in turn reduces anxiety and is perceived as reducing the risk. reduction in distress may motivate further safety behaviors which, for some at risk, could begin to exceed recommended guidelines. while ordinary levels of risk have risen requiring increased hygiene, it remains to be seen what happens when risk levels decline. that is, do cleaning behaviors likewise decline or remain at elevated states thereby impacting diagnosis rates? assessment approaches should continue to capture j o u r n a l p r e -p r o o f obsessive-compulsive symptoms that are impairing, distressing and excessive relative to current risk levels and not count symptoms that reflect behaviors consistent with accepted public health standards. there are also treatment implications. the gold standard psychological treatment for adult and childhood ocd is cognitive behavioral therapy with exposure and response prevention (erp; mcguire et al., 2015; olatunji, davis, powers, & smits, 2013) . this treatment involves gradual exposure to triggers that evoke obsessive-compulsive symptoms while refraining from completing rituals or other avoidance behaviors. a core element to this treatment is that exposure to triggers involves exposure to 'ordinary' levels of risk. covid-19 understandably has shaken what is perceived as ordinary; fortunately, adept therapists have shifted their practice to utilize exposures that reflect this new normal such as relying on imaginal exposures or exposures targeting rituals in excess of public health agency recommendations. at the same time, some clinicians have negative attitudes towards exposure (meyer, farrell, kemp, blakey, & deacon, 2014) which is related to reduced practice of this core therapeutic technique (farrell, deacon, kemp, dixon, & sy, 2013) . it will be critical to provide guidelines established by expert erp clinicians for how providers integrate realistic covid-19 concerns into their ongoing practice, as well as that in the future. a concerning possibility is that erp treatment post-covid-19 is diluted by virtue of therapists not practicing exposures to the actual level of risk. cigarette smoking remains the leading cause of preventable death and disability globally. smoking may confer worse covid-19 outcomes given extensive evidence for the negative impact of smoking on lung health and respiratory function (tonnesen, marott, nordestgaard, j o u r n a l p r e -p r o o f bojesen, & lange, 2019). indeed, emerging evidence has identified smoking as a possible risk factor for adverse covid-19 prognosis and disease progression (patanavanich & glantz, 2020; vardavas & nikitara, 2020) . in the largest study of covid-19 patients, 16.9% of severely affected patience were current smokers relative to 11.8% of non-severe patients (guan et al., 2020 ). an inverse pattern emerged with non-smokers such that a greater proportion of nonsevere patients identified as a non-smoker relative to severe patients. moreover, 25.5% of covid-19 patients who either needed mechanical ventilation, were admitted to an intensive care unit, or died from complications related to the disease were current smokers relative to 11.8% of those not experiencing these outcomes. similar disparities in covid-19 severity across smoking status have been observed in other samples (w. j. zhang et al., 2020) . thus, these data, albeit preliminary and limited by sample size, indicate that smoking is a risk factor for covid-19 progression (w. . taking a biological perspective to understand why smokers are more susceptible to severe covid-19 symptoms, recent research has proposed that smoking and covid-19 susceptibility and symptom severity may be related to an upregulation of the angiotensin-converting enzyme-2 (ace2) receptor (brake et al., 2020) . ace2, a membrane-bound aminopeptidase that plays a vital role in cardiovascular and immune systems, is highly expressed in the heart and the lungs (turner, hiscox, & hooper, 2004; wang, luo, chen, chen, & li, 2020) . studies have established that ace2 is a receptor for the covid-19 virus (j. , and greater ace2 gene expression has been observed in smokers compared to non-smokers (brake et al., 2020; cai, 2020; emami, javanmardi, pirbonyeh, & akbari, 2020; tian et al., 2020; wan, shang, graham, baric, & li, 2020; zhao et al., 2020; . the upregulation in ace2 creates an environment that allows greater potential for covid-19 to j o u r n a l p r e -p r o o f infect human cells among smokers through more opportunity to bind to this receptor (olds & kabbani, 2020; zuluaga, montoya-giraldo, & buendia, 2020) . in part, this biological mechanism may help explain observed sex differences in covid-19. specifically, covid-19 symptom severity and mortality rates in china indicate worse outcomes for men than for women, where 52.1% of men and 2.7% of women are current smokers (parascandola & xiao, 2019; sun et al., 2020) . it is possible that the elevated smoking rates among men in china, and therefore greater upregulation in ace2, contributed to significant gender difference in covid-19 incidence and severity (j. . in addition to combustible cigarette smoking, there also is growing concern for the impact of electronic cigarette (e-cigarette) use on covid-19 infection and disease progression (lewis, 2020) . although it is believed that the worldwide distribution and adoption of ecigarettes has the potential to increase population-level vulnerability to respiratory infecting diseases (olds & kabbani, 2020) , such as covid-19, no studies have assessed e-cigarette use among covid-19 patients (farsalinos, barbouni, & niaura, 2020) . given evidence for the impact of various e-cigarette formulations on lung health and functioning (viswam, trotter, burge, & walters, 2018) as well as the fact that most e-cigarette users are former or current combustible cigarette users (mirbolouk et al., 2018) , it is possible that product use will critically impact the course of covid-19 among users. additionally, similar to combustible cigarette use, it has been theorized that e-cigarette use may engage an upregulation in ace2 that parallels that of combustible cigarette use and increases the likelihood of covid-19 infection (brake et al., 2020) . further research on these products and their influence on covid-19 outcomes is urgently needed. a final point to consider is the effect that the covid-19 pandemic itself has on smoking. one of the leading reasons for smoking is stress management (baker, piper, mccarthy, majeskie, & fiore, 2004; garey et al., in press) . the psychological effect of the current global environment, characterized by feelings of fear, uncertainty, isolation, and stress (mertens, gerritsen, salemink, & engelhard, 2020) , coupled with limited availability of adaptive coping tools due to regulations and consequences of covid-19 (i.e., social distancing, financial hardship) likely increases the risk for smoking onset, increased intensity, and relapse (patwardhan, 2020; stubbs et al., 2017) . smoking initiation and severity, in turn, increase susceptibility for covid-19 and worse disease-related outcomes. behavioral scientists must engage in targeted efforts to support current smokers and former smokers in achieving and maintaining cessation during this particularly challenging time. there are promising initial findings from smoking cessation programs implemented in smokers managing other infectious disease that may help guide some of these initiatives . as more is learned about covid-19, it is imperative that health care providers assess smoking (and e-cigarette) use status as well as relapse potential among former users and provide appropriate education and intervention to help mitigate the potential risk of this health behavior on disease infection and course. the (mis)use of alcohol is a leading risk factor for global disease burden and preventable death (degenhardt et al., 2018; organization, 2019) . alarmingly, alcohol use, high-risk drinking, alcohol use disorder (aud), and alcohol-related deaths were increasing before the covid-19 pandemic (grant et al., 2017; white, castle, hingson, & powell, 2020) . despite the widespread belief that moderate alcohol consumption may confer health benefits (diaz et al., 2002; j o u r n a l p r e -p r o o f et al., 2007) , more recent work suggests that any alcohol consumption is associated with health risks (griswold et al., 2018) . in fact, given the immunosuppressing effects of alcohol both generally and in the respiratory system specifically (molina, happel, zhang, kolls, & nelson, 2010; szabo & mandrekar, 2009) , it is germane to consider the role that alcohol consumption, whether chronic or in acute response to the ongoing crisis, may have on contraction of the covid-19 virus. in addition to the direct physiological impact of alcohol consumption on the body, the disinhibiting properties of alcohol (kumar et al., 2009; oscar-berman & marinković, 2007) may put individuals at risk for other risky/poor decisions (george, rogers, & duka, 2005) . for example, those under the influence of alcohol may be more likely to violate social distance protocols, exhibit poor hand washing procedures, or refuse/forget to wear a face covering in public, leading to potential exposure to and/or spreading of the virus. importantly, impulsivity has reciprocal relationships with alcohol such that consumption increases impulsive behaviors and individuals with greater trait impulsivity (mis)use alcohol to a greater extent (dick et al., 2010) . moreover, the effects of impulsivity on alcohol (mis)use can be amplified by other factors, such as stress, to confer greater risk for alcohol (mis)use (fox, bergquist, gu, & sinha, 2010) . it is well-documented that stress, both acute and chronic, is a trigger for alcohol (mis)use (becker, lopez, & doremus-fitzwater, 2011; blaine & sinha, 2017) . the covid-19 pandemic has brought about both acute (e.g., work displacement, limited availability of cleaning supplies) and chronic stress (e.g., financial difficulty, isolation) that likely will contribute to alcohol (mis)use for coping. it also is reasonable to expect that alcohol (mis)use will worsen during the crisis in response to the stress and uncertainty. for example, during the 2008-2009 economic recession, although there was a decrease in prevalence of alcohol use overall (i.e., increase in j o u r n a l p r e -p r o o f abstainers), there was an increase in prevalence of binge drinking (bor, basu, coutts, mckee, & stuckler, 2013) . this suggests that there may be a realignment/concentration of problematic drinking such that a greater segment of those who do consume alcohol may be doing so in a maladaptive or harmful way. although sales to restaurants and events have reduced markedly during the pandemic, sales of online and to-go alcohol have skyrocketed (nielsen, 2020) . given shelter in place orders and limits on socializing, it is possible that greater amounts of alcohol are being consumed at home/solitarily relative to social contexts. solitary drinking can, in some circumstances, lead to greater alcohol consumption than social drinking (kuendig & kuntsche, 2012) and is associated with greater alcohol-related consequences overall (christiansen, vik, & jarchow, 2002) . for many, the covid-19 pandemic has led to significant social isolation with in-person socializing virtually eliminated and many working from home (if at all). these conditions may also exacerbate a common reason for alcohol-related relapse: boredom (levy, 2008) . without other adaptive ways to manage stress, socialize, or simply occupy one's mind, it is possible that craving for alcohol may intensify. finally, there are important treatment implications for alcohol (mis)use during covid-19. individuals already report numerous barriers to seeking drug/alcohol treatment (mcgovern, xie, segal, siembab, & drake, 2006) . in the wake of the pandemic additional barriers may arise such as the perception that one's treatment is not a priority during a 'life or death' pandemic or not worth the risk of leaving one's home. alternatively, for those seeking treatment, there may simply not be local resources available or treatment facilities may have waitlists. although the use of telehealth services are growing in general (dorsey & topol, 2016) , there is more work to be done, with specific considerations for low-income individuals (e.g. recently unemployed) who j o u r n a l p r e -p r o o f may be reluctant to spend money on treatment, perceive treatment to be a luxury, or not have technological resources or a private location to engage in telehealth. affordable computer-based treatments without the need for a provider that focus on stress and alcohol use (paulus, gallagher, neighbors, & zvolensky, 2020) could be particularly pertinent during this pandemic. administration center for behavioral health statistics and quality, 2019) presumably due at least in part to legalization of recreational and/or medical marijuana at the state level (johnston, o'malley, miech, bachman, & schulenberg, 2015) . notably, cannabis users report using more cannabis during times of heightened distress following national disasters such as the september 11, 2001 terrorist attacks, a pattern that was especially prominent among individuals who experienced post-traumatic stress disorder and depression (vlahov et al., 2002) . it therefore follows that cannabis use and associated problems may increase during the covid-19 pandemic. cannabis use increases during times of distress to manage negative affect. in support of this contention, cannabis users report relaxation and tension relief as one of the most common reasons for use (copeland, swift, & rees, 2001; hathaway, 2003; reilly, didcott, swift, & hall, j o u r n a l p r e -p r o o f 1998). data from experimental studies support these self-reports. to illustrate, current cannabis users were randomly assigned to an anxiety-induction or non-anxious control condition and cannabis craving increased from before to during the task among participants in the anxiety condition, but not among those in the control condition (buckner, ecker, & vinci, 2013) . these data indicate that cannabis users were especially vulnerable to wanting to use cannabis during an anxiety-provoking situation, which has direct implications for the covid-19 pandemic characterized by heightened stress. notably, this effect was specific to cannabis craving and was not observed for craving for alcohol or cigarettes in this sample of cannabis users. coping motives are the most common reasons cited for wanting to use during laboratory-induced anxiety (buckner, zvolensky, ecker, & jeffries, 2016) . prospective data collected via ecological momentary assessment also confirm that anxiety is positively, significantly related to cannabis craving at the momentary level, and is related to greater subsequent craving (buckner, crosby, silgado, wonderlich, & schmidt, 2012) . further, although positive and negative affect were greater immediately prior to cannabis use compared to non-use episode, negative affect increased at a significant rate prior to cannabis use, and decreased at a significant rate following cannabis use; changes in positive affect were not significantly related to use (buckner et al., 2015) . further, the stress associated with the covid-19 pandemic may serve as trigger for lapse and/or relapse among individuals undergoing a cannabis quit attempt. in a qualitative interview following cannabis quit attempts, situations involving negative affect and exposure to others smoking cannabis were among the most difficult situations individuals reported in which to abstain (hughes, peters, callas, budney, & livingstone, 2008) . among cannabis users undoing a self-guided quit attempt, data from ecological momentary analysis indicated that although positive and negative affect were significantly higher during cannabis lapse episodes compared j o u r n a l p r e -p r o o f to non-use episodes, when negative and positive affect were analyzed simultaneously, negative affect, but not positive affect, remained significantly related to lapse (buckner, zvolensky, & ecker, 2013) . again, the most common reason for use cited during lapse episodes was to cope with negative affect. not only could covid-19 increase cannabis use, but cannabis use may exacerbate covid-19 symptoms given that smoking cannabis damages the lungs. respiratory toxins (including carcinogens) in cannabis smoke are similar to that of tobacco smoke but notably the smoking topography for cannabis leads to higher per-puff exposures to inhaled tar and gases (tashkin & roth, 2019) . further, respiratory symptoms such as chronic cough, sputum, and airway mucosal inflammation are also similar between cannabis smokers and tobacco smokers. the impact on respiratory functioning of cannabis smoke has led for the consideration of cannabis use as a pre-exiting condition that could increase the likelihood of more severe complications should one contract covid-19 (national institute on drug abuse, 2020). sleep is a fundamentally restorative process, but it is also highly responsive to stress (irwin, 2015) . during times of increased stress, sleep, quite paradoxically, serves both as a major line of defense and as a source of heightened vulnerability. these relationships derive from the fact that sleep and immunological functioning are reciprocally related: sleep promotes healthy immune responses and healthy immune responses (e.g., to infectious agents) promote deeper, more restorative sleep (opp, 2005) . precise mechanisms are of course complex, but several specific links are noteworthy. immune-signaling proteins called cytokines, such as tumor necrosis factor (tnf) and interleukin-1 (il-1) directly target infection and inflammation but are j o u r n a l p r e -p r o o f also known to promote sleepiness and non-rapid eye movement (nrem) sleep (jewett & krueger, 2012) . the hormone melatonin, which provides an endogenous marker of circadian phase peaks during the nocturnal sleep period but also has important immunomodulatory effects. conversely, the hypothalamus-pituitary-adrenal (hpa) axis and the sympathetic nervous system (sns), two primary stress response systems, are down-regulated during sleep, decreasing immune-regulating cortisol levels (besedovsky, lange, & born, 2012) . however, when sleep is inadequate or disrupted, alteration in these systems is readily observable. experimental sleep research provides overwhelming evidence for the detrimental effects of chronic sleep disruption on immune responses including increases in multiple inflammatory markers such as c-reactive protein, diminished immune response to vaccination, and enhanced susceptibility to bacteria and toxins (besedovsky et al., 2012) . rather than representing enhanced immunity, elevated levels of inflammation are associated with a range of health risks including cardio-pulmonary disease (libby, 2006) . sleep's inextricable role in human immunological functioning clearly place it at the forefront of critical behaviors during a pandemic. unfortunately, multiple aspects of the covid-19 pandemic threaten healthy sleep patterns which in turn endanger both physical and mental health. widespread uncertainty, 24-hour media coverage (including misinformation), fear for one's own health and the health of loved ones, and potential loss of employment/wages are but a few of the significant sources of stress present during these unprecedented times. heighted psychological and physiological arousal elicited by such stress falls in direct odds with a calm, quiescent state necessary for sleep onset and maintenance. further, common behaviors aimed at managing increased stress and anxiety such as smoking, alcohol consumption, and decreased physical activity can give rise to or worsen sleep disruption via known negative effects on sleep j o u r n a l p r e -p r o o f duration and quality (irish, kline, gunn, buysse, & hall, 2015) . moreover, sleep deprivation can amplify inflammatory responses (bollinger, bollinger, oster, & solbach, 2010) , increasing the risk for poor outcomes in covid-19 as unrestrained inflammation is implicated in the pathophysiology of the disease (gamaldo, shaikh, & mcarthur, 2012) . although predisposing (e.g., genetics) and precipitating (e.g., trauma) factors play a role, stress is considered a primary cause of insomnia (morin, rodrigue, & ivers, 2003 ) and among insomniacs, perceived inability to sleep often becomes a major source of stress in its own right. studies that have systematically examined incidence and severity of insomnia symptoms during a global pandemic are unavailable despite ubiquitous anecdotal reports and cautions from health professional regarding the immunosuppressive effects of poor sleep. however, in a recentlypublished study conducted between january 29 and february 3, 2020, c. zhang et al. (2020) surveyed medical staff responding to the covid-19 pandemic in china using the insomnia severity index (isi; morin, belleville, bélanger, & ivers, 2011) . more than a third of workers (36.1%) endorsed symptoms indicative of clinical insomnia and those with insomnia reported elevated levels of depression. insomnia is well-known to herald the onset of depression both acutely and years later even among those who have never been depressed (baglioni et al., 2011) . studies directed at uncovering precise mechanisms of affective risk during the covid-19 pandemic must therefore consider the presence and severity of insomnia symptoms. the covid-19 pandemic also has upended daily routines and associated 'cues' that serve to maintain regular sleep schedules. working from home, altered mealtimes, increased sedentary behavior, social distancing, and increased "screen time" are only some of the changes that hold potential to disrupt circadian rhythms that govern sleep-wake patterns. other factors such as social activities also can affect sleep-wake patterns. the human internal circadian clock j o u r n a l p r e -p r o o f runs slightly longer than 24 hours and therefore needs to be 'entrained' to the 24-hour day via internal and external cues (czeisler et al., 1999) . sunlight is the most potent exogenous cue that aligns our internal rhythm to the external environment, but quarantine measures and greater time spent indoors means that many individuals are receiving inadequate dosages of light exposure. although public health guidelines center on sufficient sleep duration (watson et al., 2015) , sleep timing is equally critical for overall health and well-being. misalignment of the sleep period with the body's 'biological night' is routinely linked with a host of serious risks, including anxiety, depression, suicide, cardiac events, and several forms of cancer (baron & reid, 2014) . healthcare workers who are working long hours and night shifts during the covid-19 pandemic are therefore a particularly high-risk group for circadian shifts and associated comorbidities. considering sleep's role in immunological function, this represents an area of priority for future research. the intersection of covid-19 with pre-existing chronic medical illness (e.g., cardiovascular disease, diabetes, hiv) raises additional challenges to the patient for managing multiple treatment cascades. these challenges are exacerbated by the poorer survival and disease course for patients with underlying medical conditions (emami et al., 2020) which in turn seems to be driving, in part, the alarming covid-19 racial disparity (laurencin & mcclinton, 2020) . the overlapping epidemic of covid-19 with hiv, for example, presents unique challenges for hiv access to care, hiv treatment engagement, and prevention. infection or if it exacerbates the likelihood of poor covid-19 outcomes. however, people living with hiv may have other comorbidities, such as cardiovascular disease and chronic lung disease, j o u r n a l p r e -p r o o f that increase the risk for a more severe course of covid-19 illness (guaraldi et al., 2011; guo et al., 2020) . there is also a concern that individuals who are immunocompromised, such as those with hiv, may be at greater risk for severe covid-19 symptoms (cdc, 2020a; duffau et al., 2018) . in the u.s., most people living with hiv (plwh) are tested, linked to hiv care, well engaged in antiretroviral treatment, and achieve hiv viral suppression thus ensuring their optimal health and protecting the public health by containing onward transmission (cdc, 2020b). however, structural and individual barriers to treatment and prevention create enduring inequalities and significantly increase the risk of infection, reduce access to, and engagement in, hiv care, and compromise participation in hiv biobehavioral prevention among particular risk groups. gay and bisexual men (particularly hispanic and african american men) are most impacted by hiv and account for nearly 70% of new hiv cases. hiv incidence rates in the u.s. are also significantly higher for those who are homeless or living in poverty (denning & dinenno, 2020) . with respect to individual barriers to care, plwh are disproportionally affected by traumatic life experiences, anxiety, depression, and substance use (brandt et al., 2017; nanni, caruso, mitchell, meggiolaro, & grassi, 2015; c. o'cleirigh, magidson, skeer, mayer, & safren, 2015) . each of these also have been associated with poorer engagement in hiv care, worse antiretroviral medication adherence, and poorer hiv disease course. their co-occurrence and interaction significantly increases both the risk for hiv infection (mimiaga et al., 2015) and poorer hiv disease management among those already infected (harkness et al., 2018; pantalone, valentine, woodward, & o'cleirigh, 2018) . these mental health barriers to full engagement in hiv care may well be exacerbated by increased levels of covid-19 specific anxieties and j o u r n a l p r e -p r o o f increases in general health-related anxieties. the requirements of social distancing also may contribute to feelings of isolation and loneliness which may in turn contribute to increased depression or depression-related withdrawal. both anxiety-related avoidance and depressive related withdrawal will likely have negative consequences for self-care generally and for hiv care specifically. these increases in distress will occur at a time when access to behavioral health services is already severely restricted. some plwh who become co-infected with covid-19 will already be struggling with hiv disease management (e.g., missed medical appointments, sub-optimal medication adherence) and may require additional supports to manage care and treatment at a time when many routine supports may not be available due social distancing and lack of routine medical services. protecting access to care and treatment among those already struggling with the complexities of the hiv care cascade who must now manage the additional burdens of the covid-19 illness is a robust clinical concern. here, we underline the importance of community (carrico et al., 2020) and health worker based approaches (operario, king, & gamarel, 2020) to hiv treatment and protecting access to care through innovative and virtual care models. many of those at risk for being lost to care during this covid-19 pandemic also may be vulnerable to perceived stigma (krier, bozich, pompa, & friedman, 2020; logie, 2020 ). many will have multiple stigmatized identities with respect to hiv status, covid-19 status, substance use, sexual or gender minority status, and others. keeping our community members and peers involved in our service delivery will help ensure our treatments are delivered in stigma-free contexts. empirical support for integrated treatment platforms that address mental health (ironson et al., 2013; safren, o'cleirigh, skeer, elsesser, & mayer, 2013) and substance use issues (mimiaga et al., 2019; safren et al., 2012) to protect engagement in hiv treatment and j o u r n a l p r e -p r o o f prevention (mayer et al., 2017; conall o'cleirigh et al., 2019) are available to guide these initiatives. in addition, protecting access and supporting engagement (virtual or otherwise), to mental health and substance use treatment will be critically important. these approaches may be particularly key for protecting access to hiv prevention services (i.e., hiv testing, access to preexposure prophylaxis [prep]) for those at risk for hiv. access to these services may be particularly important for those whose behavioral risk profiles and risk appraisals may be disturbed because of the impact of social distancing on usual patterns of substance use or sexual behavior. although much remains unknown about covid-19 and the mental health consequences of the pandemic, it is likely that regular physical activity offers protective effects. regular physical activity reduces risk of and helps manage conditions that appear to increase risk of adverse outcomes of covid-19 (e.g., obesity, cardiovascular disease, diabetes; lee et al., 2012) , and improves immune function (nieman & wentz, 2019) which likely positively affects the progression of covid-19. it also buffers the effect of stressors and (in part thereby) can prevent the onset of mental health conditions (harvey et al., 2018; jacquart et al., 2019) . further, diminished physical activity can disrupt sleep quality (buman & king, 2010; youngstedt & kline, 2006) , which increases susceptibility to infection and mental and physical illness (see sleep section). hence, establishing or maintaining a regular physical activity habit has the potential to mitigate the impact of the pandemic both at a personal and societal level. establishing and maintaining a regular physical activity habit has proven to be challenging. indeed, only 24% of adults meet the guidelines set forth by the department of health and human services (whitfield et al., 2019) . the covid-19 pandemic has impacted j o u r n a l p r e -p r o o f several factors, including a change in the daily routine and increased stress and anxiety, that can affect the intent of or ability to engage in behavior change. it is important to acknowledge the relationship between factors such as stress or changes in routine and physical activity participation can vary in strength or direction (i.e., negative or positive) depending on the individual and their context. for example, for some routine changes have created barriers for exercise participation, while for others changes to the daily structure have opened opportunities to engage in regular exercise. similarly, stress and anxiety at the "right" level can be motivating for some make exercise part of their daily routine, but when stress and anxiety become overwhelming, automated emotion action tendencies often cause people to move away from healthy (coping) behaviors such as exercise (otto et al., 2016) . importantly, such relationships may further vary within and across individuals depending on other individual difference variables (e.g., risk factors, protective factors, [mental] health diagnosis) and contextual factors (e.g., job loss, financial stress, isolation). research aimed at understanding the relationship between covid-19 and physical activity mostly likely will benefit from considering the importance of individual differences and the influence of contextual factors. comprehensive assessment batteries and statistical models that include the testing of these complex moderation effects are key. this perspective that acknowledges nuance in the relationship between covid-19 (pandemic) and physical activity also will aid efforts to develop or fine-tune intervention programs for physical activity uptake. the covid-19 pandemic, although still ongoing and presently under investigated from a behavioral health perspective, is apt to impart acute and potentially chronic exacerbations in psychological symptoms and disorders, addictive behavior, and health behavior and chronic j o u r n a l p r e -p r o o f illness. across various phenotypes overviewed in the current essay, previous scientific work and theoretical models predict covid-19, regardless of acquisition of the virus, has and will continue to have a strong negative psychological impact on negative mood states, various forms of substance use, and sleep, chronic illness, and physical activity. although many of these relations would be expected, theoretically, to be negative, select subgroups will certainly adaptively respond to covid-19 related stress (e.g., improve their physical fitness, improve self-care routines, quit/reduce maladaptive behaviors that place them at risk). in this final section of the paper, we discuss sociocultural considerations, developmental issues, and the role of individual difference factors for covid-19-related psychological, addictive, health behavior and chronic illness. we conclude by offering an integrative covid-19 model that could be used to guide research focused on the stress-related burden of the pandemic. certain subpopulations and contextual factors (e.g., loss of work) are likely to signify a vulnerability gradient for covid-19 in terms of mental health, addictive behavior, and health behavior. although there are numerous possible sociocultural factors that could be relevant, we highlight first responders and medical professionals, economic adversity, and racial/ethnic factors as three prototypical factors of public health importance. of all the sectors of the population, first responders and front-line healthcare professionals are arguably at the greatest risk for at least acute disruptions in anxiety, stress, and negative mood. first responders and healthcare professionals at the front line of the covid-19 pandemic have at their core mission to protect and preserve life (prati & pietrantoni, 2010) . these groups, although engaging in a diverse range of specific occupational activities (e.g., direct medical care, transport, public safety j o u r n a l p r e -p r o o f enforcement), share in common that they are among the first to respond to the covid-19 crisis and take primary responsibility for attending to covid-19 related health issues. first responders and healthcare professionals are undoubtedly experiencing emotionally challenging and unpredictable situations that can place their lives in danger. the acute emotional effects of managing covid-19 cases is likely to be amplified by heavy work schedules and reduced access to and isolation from social support systems (e.g., self-isolation after finishing a shift). it is likely that first responders and healthcare professionals working with covid-19 cases in hospitals will be exposed to potentially traumatic events, the greater-than-usual experience of life-threatening situations, working with emotional strain related to isolation of patients from their families (e.g., compassion stress in the form of offering emotional support to patients in a manner that family or caregiver of patients would typically offer), and exposure to the struggle to life and death. these experiences are apt to challenge the coping resources of even the most seasoned professionals, which can result in higher degrees of anxiety, stress, and depressed mood (lafauci schutt & marotta, 2011) . such elevated stress levels are likely to be related to changes in cognition and physical health, including emotional exhaustion, fatigue, sleep dysfunction, and problems with interpersonal relationships (kronenberg et al., 2008; lane, lating, lowry, & martino, 2010) . cognitive-based beliefs about personal safety and health can be altered and memories of potentially traumatic events engrained (setti & argentero, 2014) . collectively, the covid-19 related stress burden, as discussed in several sections of the current essay, will have a high likelihood of being related to increased risk of anxiety and depression for first responders and medical professionals working at the front line. moreover, consistent with past literature of these populations, the regulation of affect will be associated with addictive and health behavior to modulate such affect (e.g., physical activity, substance j o u r n a l p r e -p r o o f use). although some regulatory behavior will be adaptive (e.g., increasing sleep where possible to aid in recovery, engaging in regular physical exercise), others may be less adaptive (e.g., smoking to reduce stress) and promote the risk for other health problems (e.g., physical illness). economic adversity. economic hardship related to covid-19 is already evident at numerous levels of analysis, including job loss, reduced earnings, higher debt relative to assets ratio, inability to pay mortgage and bills, meeting governmental guidelines for poverty status, and worry about financials resources going forward due to the turbulent nature of the economy. past work has shown that economic hardship is related to behavioral health problems, including psychological disorders, addictive behavior, physical health problems, and interpersonal dysfunction in adults and children (k. j. conger et al., 2012; sareen, afifi, mcmillan, & asmundson, 2011) . for instance, economic adversity has been linked to reduced social competence and elevated physiological markers of stress (k. e. bolger, patterson, thompson, & kupersmidt, 1995; evans & english, 2002) . further, economic hardship is related to selfregulation capacity and the corresponding difficulty in dealing with additional responsibilities. for example, past work has found limited socioeconomic resources are related to harsher parenting behavior and greater substance use (r. d. conger & donnellan, 2007) . the negative effects may be particularly profound when economic hardship is severe or chronic (dearing, mccartney, & taylor, 2001; magnuson & duncan, 2002) . the totality of worsening economic conditions for individuals and families in the larger context of an uncertain economic future are apt to be related to elevations in anxiety, stress, and depression as well as other negative emotional states (e.g., anger, frustration, fatigue; newland, crnic, cox, & mills-koonce, 2013) . such emotional symptoms and problems are likely to be related to elevations in substance use and other maladaptive behavior (e.g., less supportive interpersonal behavior, less affection) and j o u r n a l p r e -p r o o f may exacerbate chronic health conditions. other work has found that these processes also disrupt social interconnections (scaramella, sohr-preston, callahan, & mirabile, 2008) . primary care givers who have children home from school, are unlikely to be able to work at their full capacity even with added flexibility in schedules. although certain occupations have decreased activity, many have not. therefore, it could be expected that for individuals with added responsibilities of educating their children at home occupational stress may be greater compared to those without such responsibilities. further, it is possible that the accumulation of occupational responsibilities that are not addressed for persons with additional educational responsibilities will accumulate and make it more challenging to recover when going back to 'normal,' resulting in a greater degree of occupational stress. grappling with lower socioeconomic states related to covid-19 will, for certain segments of the population, offer an additional psychological challenge. indeed, past work has repeatedly documented that lower socioeconomic status is related to adverse health outcomes for chronic illness and mortality rates (adler et al., 1994; adler, boyce, chesney, folkman, & syme, 1993) . moreover, harms faced by people who cannot afford not to work in dangerous settings can exacerbate the psychological and health risk associated with coid-19. further essential workers are more apt to be persons of color (handerson, mccullough, & treuhaft, 2020) . certain groups will be more likely to recover than others, which past work indicates is related to poorer health outcomes even at higher socioeconomic levels (kraus, borhani, & franti, 1980) . moreover, research has found that lower socioeconomic persons experience more chronic stress and negative life events (stansfeld, north, white, & marmot, 1995) . additionally, lower socioeconomic status is related to cognitive biases for threat (chen & matthews, 2001) , which engender greater degrees of interpersonal conflict and heightened negative emotional states j o u r n a l p r e -p r o o f (matthews et al., 2000; stansfeld, head, & marmot, 1997) . it would be expected that such negative emotional experiences will be related to maintained direct relations with poorer health behavior and health outcomes (mcewen & stellar, 1993) . in fact, research has consistently found that lower socioeconomic status is related to greater degrees of anxiety, stress, and depression when compared to those higher in socioeconomic status (mcleod & kessler, 1990) . this heightened stress reactivity may be at least in part attributable to having fewer resources. consequently, those struggling with a lower socioeconomic status due to covd-19 may be more contexts in which they must utilize their emotional resources and be less likely to be in a sociocultural context wherein such resources can be replenished (holahan, moos, holahan, & cronkite, 1999) . this perspective is in line with past work that has found that when persons are exposed to chronic stress, emotional resources are challenged, and there is a greater risk for future emotional distress (n. bolger & zuckerman, 1995; ensel & lin, 1991) . there is broad band evidence that significant health disparities exist for persons of racial/ethnic minority in the u.s. and beyond prior to covid-19 for psychological, addictive behavior, and health behavior as well as chronic illness. for example, african american/black individuals experience a disproportionate burden in disease morbidity, mortality, disability, and injury (mechanic, 2005; mensah, mokdad, ford, greenlund, & croft, 2005) . indeed, african american/black individuals remain significantly and consistently more at risk for early death than do similar non-latinx white individuals (williams, neighbors, & jackson, 2003; williams, yu, jackson, & anderson, 1997) ; overall early death rates of african american/black individuals are comparable to those observed among non-latinx whites in the u.s. decades ago (levine et al., 2016; williams & jackson, 2005) . differences in prevalence and rate of growth of chronic illness are not accounted for solely by j o u r n a l p r e -p r o o f exposure to lower income environments (franks, muennig, lubetkin, & jia, 2006) . indeed, social determinants of health (e.g., racism; krieger & sidney, 1996) , addictive behavior (e.g., tobacco use; sakuma et al., 2015) , and stress represent robust and consistent factors related to health inequalities among african american/black individuals and those from other underrepresented racial/ethnic groups. the covid-19 pandemic has appeared to strike racial and ethnic minority populations (e.g., african american/black) hard and with possible longerterm consequences. for example, less access to health care services for chronic illness, addictive behavior, and mental illness could exacerbate covid-19 related symptoms or promote a greater degree of stress-related burden associated with the pandemic (e.g., worry that loved ones, if infected, cannot access care). consequently, addictive behaviors (e.g., smoking, alcohol misuse) and health behaviors (e.g., disrupted sleep, emotional eating) may be used in the short-term to cope with such covid-19 related stress, increasing the longer-term risk for more severe negative emotional symptoms and health complaints (e.g., pain) and chronic health problems (e.g., obesity). additionally, situations characterized by mass fear and confusion, such as the current pandemic, also can elicit a human instinct to resolve the confusion and mitigate the fear by identifying a culprit for the introduction or spread of the disease (bard, verger, & hubert, 1997; bromet, 2011) . asian american persons are one group that has been singled out as responsible for the covid-19. the misdirection of fear and/or anger related to covid-19 toward a racial or ethnic group instead of the disease, however, can perpetuate fear and contribute to racism and stigma. several reports have already documented the rise in violent crimes and discrimination experienced by asian american persons related to covid-19 beliefs (e. liu, 2020) . covid-19 specific language, such as referring to covid-19 as 'the chinese virus,' has created a platform j o u r n a l p r e -p r o o f to propagate stigma and discrimination towards asian americans. it is likely that stigma and discrimination experienced by asian americans in response to covid-19 will increase emotional distress, coping-oriented addictive behavior, and may alter health behavior or exacerbate chronic illness. it would also be remiss to not call explicit attention to the fact that societies marked by greater economic and social inequality experience far more medical, psychological, and social pathology than do societies where such wealth inequalities are less pronounced (wilkinson & pickett, 2006 . further, such adverse effects occur across social classes, not merely among the most disadvantaged. yet, the adverse effects of economic (and thus social) inequality hurt everyone, although the poorest or most marginalized are affected the most (pickett, kelly, brunner, lobstein, & wilkinson, 2005; wilkinson & pickett, 2008) . there are far-reaching implications for psychological health, addictive behavior, and health behavior from a developmental perspective. for children, despite covid-19 appearing to have less severe symptoms and lower mortality rates than other age groups, are among the highest risk groups (sinha et al., 2020; zimmermann & curtis, 2020) . estimates suggests that there are over 1 billion children not in school (cluver et al., 2020) . the economic impact of covid-19 will likely be related to greater risk for children to be utilized to offset such financial hardship (e.g., selling merchandise on the street, forced begging for food and goods) and be a more likely to be abused (campbell, 2020) . for example, it is possible that children will be more likely to be used for child labor and be exploited for sexual behavioral and experience corresponding risk for sexual disease and pregnancy as well as serious psychological distress. interpersonal violence and child abuse will affect children at a significant rate, especially under j o u r n a l p r e -p r o o f conditions wherein there is no oversight from educational systems due to quarantine. world health organizations are already predicting an increase in children who will be orphaned and exposed to abuse and neglect (cluver et al., 2020) . child abuse is less likely to be detected during the covid-19 pandemic because the reduction or lack of child protection agencies monitoring cases, and teachers less able to detect signs of abuse. further, children who received meals at school through government programs such as the national school lunch program may now no longer have access to nutritious food, which can negatively impact their development. the lack of structure from schooling and missed education will have a lasting impact on well-being and apt to be related to increased anxiety, depression, and stress about educational attainment and progress going forward (van lancker & parolin, 2020) . although on-line school may help offset some of these challenges, disparities will exist for those who are most vulnerable, including those who lack internet access or cannot afford technology. older children and young adults may be more likely to drop out of school to help offset family needs. children and youth also may be engaging in more on-line behavior in general or due to emotional distress (e.g., loneliness due to social isolation) and be increasing the chance for solicitation from others who prey on their emotional vulnerabilities (peterman et al., 2020) . lacking access to physical activity due to quarantine protocols may reduce fitness levels and immunological response as well as decrease psychological wellbeing (rundle, park, herbstman, kinsey, & wang, 2020) . children and youth in juvenile systems, such as orphanages, already were exposed to high density living conditions and often lack access to proper medical or psychological care. the covid-19 pandemic is likely to place pressure on such systems (e.g., more children) and the physical environments of these settings may be amenable to the spread of infection. likewise, refugee or otherwise displaced children and youth often live-in high-density environments j o u r n a l p r e -p r o o f wherein social distancing is challenging if not impossible. further, lack of access in these settings to cleaning supplies and water can catalyze the spread of covid-19 or even the basic fear of acquiring the virus. to the extent the covid-19 challenges the medical system, it is possible other forms of medical care necessary for child welfare (e.g., routine exams, immunizations) will be reduced, as was the case during other pandemics such as ebola (mupere, kaducu, & yoti, 2001) . collectively, covid-19 places an enormous stress on children and youth, placing them at an increased risk for psychological disturbances and physical health vulnerability (j. j. liu, bao, huang, shi, & lu, 2020) . covid-19 also will affect ranges of the lifespan, including adults and older adults. the well-publicized health risks for older adults place an obvious psychological and health pressure on this group. older adults are among the most likely to have a chronic illness (e.g., diabetes, cancer, cardiovascular disease) and consequently they maintain an increased vulnerability to deteriorating health and death from covid-19. however, even in the absence of exposure to the virus, the fear and worry about contracting the disease is apt to be significant for this group, especially when in homecare facilities such as nursing homes or hospitals (armitage & nellums, 2020) . this group also is at significant risk for lacking transportation for food, which could challenge the quality of nutrition and have a negative effect in immunological function. similarly, older adults are among the least physical active groups, which again, will have the potential for decreasing psychological wellbeing and immunity. although not specific to older adults, the potential for disruption in grief and loss of others also is a significant psychological stressor. during the pandemic, regular methods of grieving such as funerals have been limited if not all together impossible. the inability to grieve with others or as traditionally done may spur escalation in psychological distress (e.g., sadness, j o u r n a l p r e -p r o o f depression) and complicate the grief process (wallace, wladkowski, gibson, & white, 2020) . to the extent that grief is impaired, individuals may engage in maladaptive addictive behaviors (e.g., alcohol misuse) to cope with the aversive experiences. similar types of emotional reactions may occur when parents are separated from their children due to quarantine protocols and disruptions in travel (e.g., cannot travel to see children located in another region). there are several individual difference factors at a psychological level of analysis that will place people at an increased or decreased risk for psychological problems, addiction, and poor health behavior, and chronic illness during and after the pandemic. research over the past few decades has theorized and found consistent empirical support for emotional symptoms and disorders as well as addictive behavior being explained by individual differences in transdiagnostic processes (sauer-zavala et al., 2012) . transdiagnostic factors may contribute to onset, maintenance, and exacerbation of emotional symptomatology and addictive and health behavior. a core aspect of transdiagnostic models is that they seek to identify basic processes underlying multiple, usually comorbid, psychopathologies or addictive behavior. one set of transdiagnostic factors relevant to covid-19 may be those that are "reactive" vulnerabilities; that is, individual differences that reflect a heightened emotional response to stressful stimuli. such vulnerabilities influence emotion experience by enhancing or diminishing the normative response to emotion stimuli and states, resulting in an excess or deficit, respectively, beyond typical emotional functioning; or altering the type of response to emotion stimuli and states (gratz & roemer, 2004; reiss, 1991; zvolensky, bernstein, & vujanovic, 2011) . in both instances, such reactive processes may be maladaptive because they serve to j o u r n a l p r e -p r o o f reinforce the intensity and frequency of future emotional symptoms. for example, when faced with negative emotion states, individuals with an emotional vulnerability factor that limits their capacity to handle distress may be more apt to execute behaviors that preclude habituation to negative emotion states, which could ultimately increase the intensity of future negative affect and solidify beliefs and learned responses that interfere capacity to adaptively respond to distress. to illustrate, a transdiagnostic factor that may be especially relevant to covid-19 related stress responsivity, substance use, and physical health is anxiety sensitivity (taylor, 2014) . anxiety sensitivity is a malleable, cognitive-affective factor reflecting the tendency to respond to interoceptive distress with anxiety (mcnally, 1989) . anxiety sensitivity is related to, yet distinct from, negative affectivity and trait anxiety (keough, riccardi, timpano, mitchell, & schmidt, 2010) . anxiety sensitivity has demonstrated racial/ethnic, gender, age, and time invariance (ebesutani, mcleish, luberto, young, & maack, 2014; farris et al., 2015; jardin et al., 2018) . given covid-19 can produce physical sensations and even when not infected, covid-related stress can elicit a range of interoceptive sensations, persons higher in anxiety sensitivity may be more be emotional reactive to such stimuli and engage in behavior to dampen stress symptoms (e.g., using tobacco, alcohol). for example, persons may interpret the onset of aversive bodily sensations (e.g., runny nose, cough, fever) as intolerable or catastrophic, exacerbating the experience of such interoceptive symptoms. further, interoceptive symptoms might be particularly salient to persons with higher anxiety sensitivity who are prone to health inequalities (e.g., racial/ethnic minorities, persons in financial stress), as they may be more apt to perceive these internal sensations as uncontrollable because resources to regulate symptoms (i.e., adaptive cognitive and behavioral skills) are likely diminished due to chronic stress exposure j o u r n a l p r e -p r o o f (e.g., low socioeconomic status, discrimination). in turn, persons higher in anxiety sensitivity may be motivated to use substances to reduce emotional and interoceptive distress, elevating their chance for physical illness and compromised immune system function. although this illustrative example represents only one of many possible transdiagnostic amplifying factors, it draws attention to the fact that individual differences in psychological processes are apt to play a central role in the relation between covid-19 related stress and mental health, addictive behavior, health behavior, and chronic illness. individual difference factors also may play roles in offering resilience to covid-19 related stress. that is, individual differences may contribute to the likelihood of a resilient response to covid-19 in the short and long term. thus, in addition to the many situational and contextual factors, individual difference factors will likely shape the level of resiliency to covid-19 pandemic. here, it is likely individual difference factors that de-amplify stress responses will play a central role in offsetting relative risk for psychological, addictive, and health behaviors problems and exacerbation of chronic illness (pidgeon & keye, 2014) . as with affect amplifying factors, such as anxiety sensitivity, there most certainly is a range of factors of potential importance, including flexible coping repertoires, mindfulness, self-efficacy, selfcompassion, and proneness to experience positive affect. to illustrate, individual difference in the capacity to accept difficult covid-19 related stress may offset the potential escalation of anxiety, stress, and depression and mitigate the need for addictive or unhealthy behaviors (e.g., emotional eating) to delimit aversive internal experiences (ranzijn & luszcz, 1999) . consequently, the corresponding risk for health complaints or worsening of chronic health conditions can be offset. indeed, there is a large theoretical and empirical literature that suggests the capacity to accept difficult emotions experiences is related to psychological well-being and j o u r n a l p r e -p r o o f adaptation. for example, one of the reasons meditative practice is related to decreased stress is via change emotional acceptance (teasdale et al., 2002) . this type of work has robust implications in efforts to intervene on covid-19 related stress in the immediate context and for those that struggle to regain stability and growth in the future in terms of mental health, addictive behavior, and health behavior. despite the present lack of systematic empirical work on covid-19 in terms of behavioral health problems, there is good theoretical basis from past scientific work to hypothesize that covid-19 related stress burden, due to a myriad of sources, may play a major vulnerability role in terms of mental health, addictive disorders, and health behaviors as well as chronic illness. for some, the stress-related burden of covid-19 may elicit fundamental changes in risk potential and serve as a fertile basis for future behavioral health problems. for others, the ability to adapt to covd-19 will offer a different course; one that is characterized by greater stability, speed of recovery, and growth. further, it is important to recognize that the adaptation process to covid-19 related stress is apt to be non-linear in many instances. that is, contextual factors (e.g., future life stressors, access to social support) can influence the degree of risk for future problems. research described in this essay provides a basis to develop a theoretical model that could be used to evaluate covid-19 related stress burden on psychological, addictive, and health behaviour problems. we therefore begin this section by briefly outlining a general model that can be used as a heuristic for understanding the complex issues at hand. see figure 1 for a graphical depiction of the model. in general, we predict individual differences in affect amplifying and de-amplifying factors will predict the course of psychological, addictive behavior j o u r n a l p r e -p r o o f and health behavior and chronic illness even when considering differences in exposure to covid-19 experiences (e.g., time of quarantine, acquisition of virus). we would predict, based on past work that transdiagnostic affect amplifying factors will influence addictive and health behaviour, which in turn, will increase (or decrease if de-amplifying) the risk of chronic illness and psychological problems and their comorbidity. further, we can expect that this type of perspective will be moderated by daily stress in the future and access to stress-dampening resources (e.g., social support). accordingly, certain subgroups more prone to greater and more chronic stress, such as first responders and racial/ethnic minorities and orphaned children, may be particularly vulnerable. this conceptual model predicts that the associations which exist between are reciprocal and dynamic. although the model offered here is purposively general and is offered only as a heuristic, it is presumed that there is, in fact, specificity between specific affect amplifying and deamplifying factors, moderators, mediators, and various forms of psychological and chronic illness. that is, a specific type of individual difference factor like anxiety sensitivity is linked to a particular type of problem (e.g., anxiety disorder, worsening of a chronic respiratory illness, severity of hazardous drinking) via a specified mediating process (e.g., smoking, sleep disruption) in the context of certain moderating variables (e.g., higher levels of covid-19 stress burden). the core idea being that the underlying mechanism in this hypothetical example may be quite different from that explaining other problems. the above theoretical model requires empirical testing, and if it is confirmed, one next logical step would be to intervene in it to reduce the burden of mental health, addictive disorders, poor health behaviours, and chronic health conditions related to covid-19 stress burden. ideally, this type of intervention approach would target the root of the pathway, including affect j o u r n a l p r e -p r o o f amplifying (i.e., decreasing levels) and de-amplifying (i.e., promoting growth). however, intervention efforts sit in the fact that the healthcare system will continue to shift and adapt to treatment delivery, including the uptake of digital health technologies. digital health, including mobile health (mhealth), telemedicine/telehealth, and health information technology (e.g., mobile phones, wearable sensors), can be used to develop scalable interventions to promote adherence public health guidelines for mitigating the spread of covid-19. they also can be combined with greater attention to affect amplifying (i.e., decreasing levels) and de-amplifying (i.e., promoting growth) factors that govern many psychological, addictive, and health behaviour processes. here, there is great opportunity for growth of digital health interventions to offer standalone clinical grade therapeutic tactics and as an adjunct to face-to-face interventions. this type of work can close the gap in access to care and offer evidence-based interventions to large segment of society. for example, digital interventions can be used to combat resistance to public health measures at the level of individuals and institutions with a consideration of individual difference factors that affect emotional and behavioral self-regulation. indeed, the public's response to public health measures is itself a potential risk and protective factor for many of the psychological, addictive, and health behavior problems reviewed in this essay. the public health impact of covid-19 on psychological symptoms and disorders, addiction, and health behavior is substantial and ongoing. there is a need for financial and social investment in research to better understand how covid-19 affects the onset, maintenance, and relapse potential for some of the most common, costly, and chronic behavioral health conditions in the general population. further, there is a need for the study of the role of psychological processes, addictive behavior, and health behavior in terms of the onset and maintenance of j o u r n a l p r e -p r o o f covid-19 infection and stress burden. there most certainly will be a demand for preventative and intervention efforts for managing the impact of covid-19 among individuals with elevated negative mood symptoms and disorders, addictive behavior, and certain health behaviors (e.g., sleep disorders) and chronic illness. this work is important to offset the current and projected burden to personal, system, and societal entities, and for providing a theoretical and empirical knowledge base for future pandemics. we presented a heuristic model, which posits that covid-19 related stress and mood, addictive, and health behavior may, in fact, exacerbate each other via several distinct mechanisms. future research in this emerging area has the potential to refine both theory and application with respect to covid-19 and its relation to affect, addiction, and health behavior as well as chronic disease. j o u r n a l p r e -p r o o f • the public health impact of covid-19 on psychological symptoms and disorders, addiction, and health behavior is substantial and ongoing • an integrative covid-19 stress-based model could be used to guide research focused on the stress-related burden of the pandemic • this work could provide a theoretical and empirical knowledge base for future pandemics j o u r n a l p r e -p r o o f how covid-19 may increase domestic 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potential conflicts of interest and to significant financial contributions to this work zvolensky receives personal fees from elsevier, guilford press, and is supported by grants from nih he receives research support from nih, texas higher education coordinating board, rebuild texas and greater houston community fund. he receives travel support and honorarium from iocdf for training in ocd treatment schmidt is supported by the military suicide research consortium (msrc), department of defense, and visn 19 mental illness research, education, and clinical center buckner receives funding from the u.s. department of health & human services' graduate psychology education (gpe) program (grant d40hp33350) smits reports grants from cancer prevention and research institute of texas; personal fees from big health, ltd., personal fees from aptinyx, inc., personal fees from elsevier vujanovic receives book royalties from routledge press and is supported, in part cleirigh is supported by grants from the nih and the centers for disease control and prevention we confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed he/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. we confirm that we have provided a current, correct email address which is accessible by the corresponding author and which has been configured to accept email from mjzvolen@central key: cord-336599-r8xgnz87 authors: yaacoub, jean-paul a.; salman, ola; noura, hassan n.; kaaniche, nesrine; chehab, ali; malli, mohamad title: cyber-physical systems security: limitations, issues and future trends date: 2020-07-08 journal: microprocess microsyst doi: 10.1016/j.micpro.2020.103201 sha: doc_id: 336599 cord_uid: r8xgnz87 typically, cyber-physical systems (cps) involve various interconnected systems, which can monitor and manipulate real objects and processes. they are closely related to internet of things (iot) systems, except that cps focuses on the interaction between physical, networking and computation processes. their integration with iot led to a new cps aspect, the internet of cyber-physical things (iocpt). the fast and significant evolution of cps affects various aspects in people’s way of life and enables a wider range of services and applications including e-health, smart homes, e-commerce, etc. however, interconnecting the cyber and physical worlds gives rise to new dangerous security challenges. consequently, cps security has attracted the attention of both researchers and industries. this paper surveys the main aspects of cps and the corresponding applications, technologies, and standards. moreover, cps security vulnerabilities, threats and attacks are reviewed, while the key issues and challenges are identified. additionally, the existing security measures are presented and analyzed while identifying their main limitations. finally, several suggestions and recommendations are proposed benefiting from the lessons learned throughout this comprehensive review. cyber physical systems (cps) are designated as essential components of the industrial internet of things (iiot), and they are supposed to play a key role in industry v4.0. cps enables smart applications and services to operate accurately and in real-time. they are based on the integration of cyber and physical systems, which exchange various types of data and sensitive information in a real-time manner [1] . the development of cps is being carried out by researchers and manufacturers alike [2] . given that cps and industry v4.0 offer a significant economic potential [3] , the german gross value will be boosted by a cumulative of 267 billion euros by 2025 upon the introduction of cps into industry v4.0 [4] . a cps is identified as a network of embedded systems that interact with physical input and output. in other words, cps consists of the combination of various interconnected systems with the ability to monitor and manipulate real iotrelated objects and processes. cps includes three main central components: sensors, aggregators and actuators. moreover, cps systems can sense the surrounding environment, with the ability to adapt and control the physical world [5] . this is mainly attributed to their flexibility and capability to change the run-time of system(s) process(es) through the use of realtime computing [6] . in fact, cps systems are being used in multiple domains (see fig. 1 ), and embedded in different systems such as power transmission systems, communication systems, agricultural/ecological systems, military systems [7] , [8] , and autonomous systems (drones, robotics, autonomous cars, etc.) [9] , [10] . that, in addition to medical care domains to enhance the medical services [11] . moreover, cps can be used in supply chain management to enable echo-friendly, transient, cost efficient, and safe manufacturing process. despite their numerous advantages, cps systems are prone to various cyber and/or physical security threats, attacks and challenges. this is due to their heterogeneous nature, their reliance on private and sensitive data, and their large scale deployment. as such, intentional or accidental exposures of these systems can result into catastrophic effects, which makes it critical to put in place robust security measures. however, this could lead to unacceptable network overhead, especially in terms of latency. also, zero-day vulnerabilities should be minimized with constant software, applications and operating system updates. recently, several research works addressed the different security aspects of cps: the different cps security goals were listed and discussed in [12] , [13] , [14] , [15] ; maintaining cps security was presented in [16] ; cps security challenges and issues were presented in [17] , [18] ; some of the security issues were reviewed, including big data security [19] , [20] , iot storage issues [21] , and operating system vulnerabilities [22] ; several security and privacy solutions using cryptographic algorithms and protocols were discussed in [23] , [24] . however, none of the existing works presented a comprehensive view of cps security in terms of threats, vulnerabilities, and attacks based on the targeted domain (cyber, physical, or hybrid). hence, this paper presents a detailed overview of the existing cyber, physical and hybrid attacks, and their security solutions including cryptographic and non-cryptographic ones. • cyber-physical attacks are presented in relation to the targeted cyber and/or physical system/device, and the corresponding vulnerabilities of each such domain. • risk assessment: a qualitative risk assessment method is presented to evaluate the risk and exposure levels for each cps system, while proposing suitable security countermeasures. • security measures and their limitations are discussed and analyzed, including recent cryptographic and noncryptographic solutions. • forensics solutions are also presented and discussed about securely extracting evidence and thus, to improve forensics investigations. • lessons: various lessons are learnt throughout this survey including how to protect real-time data/information communication among resource-constrained cps devices, and how to achieve protection of cps security goals such as confidentiality, integrity, availability and authentication. • suggestions & recommendations are presented about how to mitigate and overcome various cyber, physical and hybrid threats, vulnerabilities, attacks, challenges and issues for a safe cps environment. aside from the introduction, this paper is divided into six main sections as follows. section ii presents some background about cps including their layers, components, and models. section iii discusses and details the key cps threats, attacks and vulnerabilities in addition to listing and describing several real-case cps attacks, and the main persistent challenges and issues. section v assesses and evaluates the risks associated with cps security attacks, especially in a qualitative risk assessment manner. section v presents and analyzes the main cps security solutions including cryptographic, noncryptographic, and forensics ones. section vi highlights the lessons learnt throughout this study. section vii provides key suggestions and recommendations for a safe and secure cps environment. section viii concludes the presented work. in this section, we present the cps architecture, its main layers and components, as well as the main cps models. the architecture of cps systems consists of different layers and components, which rely on different communication protocols and technologies to communicate among each other across the different layers. 1) cps layers: the cps architecture consists of three main layers, the perception layer, transmission layer, and application layer, which are presented and described in fig. 2 . the analysis of the security issues at the various cps layers is based on the work in [25] . • perception layer: it is also known as either the recognition or the sensing layer [26] . it includes equipment such as sensors, actuators, aggregators, radio-frequency identification (rfid) tags, global positioning systems (gps) along with various other devices. these devices collect real-time data in order to monitor, track and interpret the physical world [27] . examples of such collected data include electrical consumption, heat, location, chemistry, and biology, in addition to sound and light signals [28] , depending on the sensors' type [29] . these sensors generate real-time data within wide and local network domains, before being aggregated and analyzed by the application layer. moreover, securing actuators depends on authorized sources to ensure that both feedback and control commands are error-free and protected [30] . generally, increasing the security level requires an endto-end encryption scheme at each layer [31] . therefore, heavyweight computations and large memory requirements would be introduced [32] . in this context, there is a need for the design of efficient and lightweight security protocols, which take into consideration the devices capabilities and the security requirements. • transmission layer: it is also known as the transport layer or network layer, and it is the second cps layer [29] . this layer interchanges and processes data between the perception and application layers. data transmission and interaction is achieved through the internet for this purpose, various protocols are used to address the increase in the number of internet-connected devices, such as the internet protocol version 6 (ipv6) [33] . this layer also ensures data routing and transmission using cloud computing platforms, routing devices, switching and internet gateways, firewalls and intrusion detection/prevention systems (ids/ips) [34] , [35] . before outsourcing data contents, it is essential to secure their transmission to prevent intrusions and malicious attacks including malware, malicious code injection [36] , denial of service/distributed denial of service (dos/ddos), eavesdropping, and unauthorised access attacks [37] . this introduces a challenge, especially for resource-constrained devices due to the imposed overhead in terms of the required processing and power resources [38] . • application layer: it is the third and most interactive layer. it processes the received information from the data transmission layer and issues commands, which are executed by the physical units including sensors and actuators [39] . this is done by implementing complex decision-making algorithms based on the aggregated data [40] . moreover, this layer receives and processes information from the perception layer before determining the rightly invoked automated actions [29] . in fact, cloud computing, middleware, and data mining algorithms are used to manage the data at this layer [41] . protecting and preserving privacy requires protecting private data from being leaked. the most known protective approaches include anonymization, data masking (camouflage) [42] , [43] , privacy-preserving, and secret sharing [31] . moreover, this layer also requires a strong multi-factor authentication process to prevent unauthorised access and escalation of privilege [44] . due to the increase in the number of internet-connected devices, the size of the generated data has become a significant issue [21] . therefore, securing big data calls for efficient protection techniques to process huge amounts of data in a timely and efficient manner [45] . 2) cps components: cps components are used for sensing information [5] , or for controlling signals (fig. 3) . in this regard, cps components are classified into two main categories: sensing components (sc) that collect and sense information, and controlling components (cc) that monitor and control signals. • sensing components: are primarily located at the perception layer and consist of sensors that collect data/information and forward them to aggregators. then, this data/information is sent to the actuators for further analysis to ensure accurate decision making. in the following, we list the main cps sensing components. -sensors: collect and record real-world data following a correlation process named "calibration", to assess the correctness of the collected data [46] . sensing data is essential since the decisions that will be made are based on the analysis of this data. -aggregators: are primarily located at the transmission layer (i.e routers, switches and gateways) to process the received data/information from sensors, before issuing the corresponding decision(s). in fact, data aggregation is based on the collected information about a specific target, where this information is gathered and summarized following a statistical analysis. online analytical processing (olap) is a prime data aggregation type used as an online reporting mechanism for processing information [46] . -actuators: are located at the application layer to make the information visible to the surrounding environment based on the decisions made by the aggregators. since actuators highly depend on other network nodes, then each action performed by the cps relies on an earlier data aggregation sequence [5] . also in terms of operations, actuators process electrical signals as input and generate physical actions as output [46] . • controlling components: are used to control signals and they play a key role in signal control, monitoring and management to achieve higher levels of accuracy and protection against malicious attacks or accidents, mainly signal jamming, noise and interference. as a result, the reliance on programmable logic controllers (plcs) and distributed control system (dcss) along with their components (i.e programmable automation controller (pac) [47] , operational technology/information tech-nology (ot/it) [48] , control loop/server [49] , and human-machine interface (hmi)/graphical user interface (gui) [50] ) has become highly essential. next, we list the different types of control systems that are used in cps systems: • programmable logic controllers (plc): were initially developed to replace hard-wired relays, and are considered as industrial digital computers that control the manufacturing processes such as robotic devices performance and/or fault diagnosis processing; hence achieving better flexibility and resiliency. • distributed control systems (dcs): are computerized control systems that allow the autonomous controllers' distribution throughout the system using a central operator supervisory control. as a result of the remote monitoring and supervision process, the dcs's reliability is increased, whilst its installation cost is reduced. in some cases, dcs can be similar to supervisory control and data acquisition (scada) systems. • remote terminal units (rtu): or "remote telemetry unit" [51] , are electronic devices controlled by a microprocessor such as the master terminal unit (mtu) [52] . unlike the plc, they do not support any control loop nor control algorithm(s). thus, making them more suitable for wireless communications over wider geographical telemetry areas. rtu's main task is to interface scada to the physical object(s) using a supervisory messaging system that controls these objects through the system's transmission of telemetry data. in fact, both rtus and plcs use a small computerized "artificial brain" (central processing unit (cpu)) to process inputs and outputs from sensing devices and pumping equip-ment [53] ; hence using ieds (intelligent electronic devices) to transmit data flow or trigger an alarm in case of any intrusion. table i presents a comparison of the common points and differences between plcs and rtus. concerning the relation between components and layers, it can be seen that sensing components are mainly deployed at the perception and transmission layers, while the controlling components are deployed at the application layer. cps models can be divided into three main types: • timed actor cps: this model focuses on the functional aspects based on behaviour and correctness, along with the non-functional aspects that are based on performance and timing. a theory was introduced in [54] with a functional and classical refinement that restricts certain behaviour set, improving efficiency while reducing complexity. the main focus is on the refinement based on the "earlier-the-better" principle since it offers the ability to identify deterministic abstractions of non-deterministic systems [55] . in fact, these time-deterministic models are less prone to state explosion problems, with the ability to derive analytical bounds easier [56] . • event-based cps: in such models, an event must be sensed and detected by the proper cps components, before the actuation decisions are made. however, individual component timing constraints vary depending on the non-deterministic system delay, which is caused by the different cps actions including sensing, actuating, communication and computing [57] . in [58] , hu et al. stated that time constraints can be handled through the use of an event-based approach, which uses cps events to ensure the system's communication, computation, and control processes. this allows the cps to be more suitable and more useful for spatio-temporal information. • lattice-based event model in [59] , the cps events are represented according to the event type, along with the internal and external event attributes. if these events are combined, they can be used to define a spatio-temporal property of any given event, while also identifying all the components that were observing the event. • hybrid-based cps model hybrid cps systems are heterogeneous systems that are made up of two distinct interactive system types, continuous state (physical dynamic systems) and discrete-state (discrete computing systems) [60] , [61] . both development and evolution depend on the response of discrete transient events represented by finite state machines, and the the dynamic behaviour represented by differential/difference equation(s) [62] . unlike other cps models, hybrid cps is interconnected via a network, which makes it prone to delays. moreover, hybrid cps systems do not support any hierarchical modeling, and are not suitable for modeling concurrent systems. hence, hybrid systems modeling challenges caused by cps were discussed by benveniste et al. in [63] . in fact, cps system network latency issues were addressed and solved by kumar et al. using a real-time hybrid authentication method [64] , while a configurable real-time hybrid structural testing for cps was presented by tidwell et al. in [65] . finally, an event driven monitoring of cps based on hybrid automata was presented by jianhui in [66] . in a similar manner to most networking systems, security services were not incorporated into cps systems by design, leaving the door open for various vulnerabilities and threats to be leveraged by attackers to launch security attacks. this is also due to the heterogeneous nature of cps devices since they operate in different iot domains and communicate using different technologies and protocols. cps security threats can be classified as cyber or physical threats, as explained below, and if combined, these can result into cyber-physical threats. 1) cyber threats: the main attention on industrial iot security was highly focused on cyber threats rather than physical threats for many reasons, as cited in [18] . this includes the electrical grid evolution into an advanced metering infrastructure (ami), which resulted into the rise of newly unknown cyber threats aside from scada vulnerabilities [67] , [68] , [69] . electronic attacks are now easier to launch from any device, unlike physical attacks that require physical presence and physical tools. moreover, the smart meter interfacing and interconnection with other meters in the near-me area network (nan) and home area network (han) increase its exposure to various remote threats. finally, electronic attacks are difficult to mitigate and overcome in the absence of the right prevention and defensive countermeasures. for further details on cyber threat intelligence, a brief survey of cps security approaches was presented in [14] . for further information about cyber security threats, more details can be found in [70] , [71] . since cyber security is not limited to a single aspect, it can be considered from different perspectives, such as: • centring information: which requires protecting the data flow during the storage phase, transmission phase, and even the processing phase. • oriented function: which requires integrating the cyberphysical components in the overall cps. • oriented threat: which impacts data confidentiality, integrity, availability, and accountability [70] . the above issues make cps systems prone to: • wireless exploitation: it requires knowledge of the system's structure and thus, exploiting its wireless capabilities to gain remote access or control over a system or possibly disrupt the system's operations. this causes collision and/or loss of control [72] . • jamming: in this case, attackers usually aim at changing the device's state and the expected operations to cause sold with plc-like features digital computers designed for output arrangements and multiple inputs electronic device controlled by a microprocessor automates electro-mechanical processes interfaces scada physical objects physical media with process, relays, motion control and networking uses supervisory system messages to control objects does support control loops and algorithms does not support control loops and algorithms immune to electrical noise, resistant to vibration low to null immunity against electrical noise and vibration suitable for local geographical areas suitable for wider geographical telemetry areas mainly iec standards wired/wireless communications damage by launching waves of de-authentication or wireless jamming signals, which would result into denial of device and system services [73] . • reconnaissance: an example of such a threat is where intelligence agencies continuously perform operations targeting a nation's computational intelligence (ci) and industrial control system (ics) mainly through a malware spread [74] . this results in violating data confidentiality due to the limitation of traditional defenses [75] , [76] . • remote access: this is mainly done by trying to gain remote access to the cps infrastructure, for example, causing disturbances, financial losses, blackouts, as well as industrial data theft and industrial espionage [77] . moreover, havex trojans are among the most dangerous malware against icss, as they can be weaponized and used as part of cyber-warfare campaign management against a nation's cps [78] . • disclosure of information: hackers can disclose any private/personal information through the interception of communication traffic using wireless hacking tools [16] , violating both privacy and confidentiality [79] . • unauthorised access: attackers try to gain an unauthorized access through either a logical or physical network breach and to retrieve important data, leading to a privacy breach [80] . • interception: hackers can intercept private conversations through the exploitation of already existing or new vulnerabilities leading to another type of privacy and confidentiality breach [72] . • gps exploitation: hackers can track a device or even a car by exploiting (gps) navigation systems, resulting in a location privacy violation [81] , [72] . • information gathering: software manufacturers covertly gather files and audit logs stored on any given device in order to sell this huge amount of personal information for marketing and commercial purposes in an illegal manner. 2) physical threats: cps systems are recently evolving into the industrial domain by introducing an advanced metering infrastructure (ami), and neighbourhood area networks (nans), along with data meter management systems to maintain the robustness of cps in industrial domains [82] . in fact, physical threats might be classified according to the following three factors: are well protected. this is due to the fact that these stations are well-manned and well-guarded based on the implementation of access controls, authorisation and authentication mechanisms such as usernames and passwords, access cards, biometrics and video surveillance. however, the main concern is related to the less protected power-generating sub-stations since transmission lines are vulnerable to sabotage attacks and disruption. in fact, smart meters are also vulnerable to a number of threats as explained in [83] . to address this problem, smart meters must be tamper-resistant by relying on outage detection or even host-based intrusion detection. however, it is almost impossible to prevent physical tampering or theft by adversaries (such as advanced persistent threats (apts)), except that it is possible to mitigate the risk and reduce its impact. • loss: the most worrying scenario is having more than a single substation failure caused by a malicious attacker. in case of a severe damage in the smart grid, a total blackout of major metropolitan areas may occur for several hours [84] . a real-case scenario includes the cascading blackout that managed to hit the u.s. on august 14th, 2003 [85] , caused by the people liberation army (pla), which is a chinese politically-motivated group [86] . • repair: it can be based on a self-healing process [87] , which is based on the ability to either sense faults or disruptions, whilst isolating the problem and sending alerts to the corresponding control system to automatically reconfigure the back-up resources in order to continuously provide the necessary service. the aim is to ensure a fast recovery in as short of a time as possible. however, critical components do suffer from either a lack or a limited backup capability. therefore, self-healing can respond faster to a severe damage. some of the threats associated with cps systems include: • spoofing: it consists of masquerading the identity of a trusted entity by a malicious unknown source. in this case, attackers are capable of spoofing sensors, for example, by sending misleading and/or false measurements to the control center. • sabotage: sabotage consists of intercepting the legal communication traffic and redirecting it to malicious third party or disrupting the communication process. for example, attackers can sabotage physically exposed cps components across the power grid, to cause a service disruption or even denial of service that leads to either total or partial blackout. • service disruption or denial: attackers are capable of physically tampering with any device to disrupt a service or to change the configuration. this has serious effects, especially in the case of medical applications. • tracking: since devices are physically exposed, an attacker can gain access to a given device, and/or even attach a malicious device or track the legal ones. in the following, we present the main cps vulnerabilities that can be targeted by the above-mentioned threats. a vulnerability is identified as a security gap that can be exploited for industrial espionage purposes (reconnaissance or active attacks). hence, a vulnerability assessment includes the identification and analysis of the available cps weaknesses, while also identifying appropriate corrective and preventive actions to reduce, mitigate or even eliminate any vulnerability [88] . in fact, cps vulnerabilities are divided into three main categories: • network vulnerabilities: include weaknesses of the protective security measures, in addition to compromising open wired/wireless communication and connections, including man-in-the-middle, eavesdropping, replay, sniffing, spoofing and communication-stack (network/transport/application layer) [89] , back-doors [90] , dos/ddos and packet manipulation attacks [91] . • platform vulnerabilities: include hardware, software, configuration, and database vulnerabilities [36] . • management vulnerabilities: include lack of security guidelines, procedures and policies. vulnerabilities occur due to many reasons. however, there are three main causes of vulnerabilities: • assumption and isolation: it is based on the "security by obscurity" trend in most cps designs. therefore, the focus here is to design a reliable and safe system, taking into consideration the implementation of necessary security services, without assuming that systems are isolated from the outside world. • heterogeneity: cps systems include heterogeneous third party components which are integrated to build cps applications. this has resulted in cps becoming a multivendor system, where each product is prone to different security problems [93] . • usb usage: this is a main cause of cps vulnerabilities, such as the case of the stuxnet attack that targeted iranian power plants, since the malware is inside the usb. upon plugging it, the malware spread across several devices through exploitation and replication. • bad practice: is primarily related to a bad coding/weak skills that lead to the code to execute infinite loops, or to become too easy to be modified by a given attacker. • spying: cps systems are also prone to spying/surveillance attacks, mainly by using spyware (malware) types that gain a stealthy access and remain undetected for years with the main task to eavesdrop, steal and gather sensitive/confidential data and information. • homogeneity: similar cyber-physical system types suffer from the same vulnerabilities, which once exploited, can affect all the devices within their vicinity, a prime example is the stuxnet worm attack on iranian nuclear power plants [94] . • suspicious employees: can intentionally or inadvertently damage or harm cps devices, by sabotaging and modifying the coding language, or granting remote access to hackers through the opening of closed ports or plugging in an infected usb/device. thus, cps vulnerabilities can be of three types, including cyber, physical, and when combined, they result into a cyberphysical threat. 1) cyber vulnerabilities: since ics heavily relies on open standard protocols including inter-control center communications protocol (iccp) [95] and transmission control protocol/internet protocol (tcp/ip) [96] , ics applications are prone to security attacks. in fact, iccp suffers from a critical buffer overflow vulnerability [89] and also lacks the basic security measures [97] . in fact, the remote procedure call (rpc) protocol [98] and icss are prone to various vulnerabilities including the stuxnet (1 & 2) [99] , [100] , [101] and duqu malware (1.0, 1.5 & 2.0) attack types [102] , [103] , [104] , gauss malware [105] , [106] , [102] , and red october malware [107] , [108] , as well as shamoon malware (1, 2 & 3) [109] , [110] , [111] , mahdi malware [112] , [113] , [114] , and slammer worm [115] . open/non-secure wired/wireless communications such as ethernet are vulnerable to interception, sniffing, eavesdropping, wiretapping and wardialing and wardriving attacks [116] , [117] , [118] and meet-in-the-middle attacks [119] . short-range wireless communications are also vulnerable, since they can be captured, analysed, damaged, deleted or even manipulated by insiders [120] . moreover, employees' connected devices to ics wireless network, if not secure, are prone to botnet, remote access trojan and rootkit attacks, where their devices will be remotely controlled by an attacker [121] . long-range wireless communications are vulnerable to eavesdropping, replay attacks, and unauthorized access attacks. yet, sql injection remains the most web-related vulnerability since attackers can access any server database without authorization through the injection of a malicious code that keeps on running endlessly once executed without the user's knowledge [122] . since many medical devices heavily rely on wireless communications, they are prone to a large number of wireless attacks including jamming, modification and replay attacks due to the lack of encryption. moreover, gps and the device's microphone are now becoming a tracking tool, allowing the identification of the target's location, or intercepting the in-car conversations through eavesdropping [13] . by default, ics relies on modbus and dnp3 protocols to monitor and send control commands to sensors and actuators. in [16] , humayed et al. stated that the modbus protocol lacks basic security measures such as encryption, authentication and authorization. this has made it prone to eavesdropping, wiretapping, and port-scan [123] , with the risk of the controller being spoofed through false data injection [124] . the dnp3 protocol is also prone to the same vulnerabilities and attacks, with one main difference which is the integration of cyclic redundancy check (crc) as an integrity measure [125] . moreover, windows server services were vulnerable to remote code execution [99] , with more attacks being achieved through the exploitation of buffer overflow vulnerabilities in any running operating system (os). moreover, power system infrastructure of smart grids is prone to the same vulnerabilities as ics, modbus and dnp3, since they are based on the same protocols. as a result, iec 61850 protocol was introduced in substations' communications, which lack security properties and are prone to eavesdropping attacks. therefore, leading to interference attacks [126] , or false information injection attacks [127] . in [128] , santamarta et al. analysed the available documentation of smart meters, and located a "factory login" account used to perform basic configurations. this gives the user full control over a smart meter and leads to power disruption, wrong decision making and targeting neighbouring smart meters within the same network. in addition, many devices are prone to battery exhausting attacks [73] . gollakota et al. [129] and halperin et al. [130] exploited the implantable cardioverter defibrillator (icd) wireless vulnerabilities through injection attacks. the authors also showed that smart cars are vulnerable to various attack types. in [131] , radcliffe, revealed another vulnerability with continuous glucose monitoring (cgm) devices being vulnerable to replay attacks. the cgm device was spoofed with the injection of incorrect values. this is due to the fact that security considerations were not made when the smart cars were designed [132] . in fact, the controller area network (can) protocol suffers from many vulnerabilities, which if exploited could result in attacks against smart cars. this will increase the likelihood of a dos attack [133] . a tire-pressure monitoring system (tpms) is also vulnerable to eavesdropping and spoofing due to the lack of encryption [134] . in addition, adaptive cruise control (acc), which forms a part of the can network can be directly exploited [13] . in fact, a well-equipped attacker is able to interrupt acc sensors' operations by adding noise or spoofing. thus, controlling the car by either reducing, increasing its speed or even causing collisions. 2) physical vulnerabilities: physical tampering may result into misleading data in cyber-physical components. in fact, physical attacks with cyber impact were studied in [135] . the physical exposure of ics components is classified as a vulnerability due to the insufficient physical security provided to these components. thus, making them prone to physical tampering, alteration, modification or even sabotage. cps field devices (i.e smart grids, power grids, supply chains etc.) are prone to the same ics vulnerabilities since a large number of physical components is exposed without physical security, making them prone to physical destruction. therefore, in [136] , mo et al. stressed on detection and prevention solutions. in [16] , humayed et al. stated that medical devices are vulnerable to physical access along with the possibility of installing malware into them, or even modifying the device's configurations, risking the patient's health. moreover, a physical access to any medical device is also a vulnerability since an attacker can retrieve the device's serial number to launch targeted attacks [131] . as listed above, cps systems suffer from various vulnerabilities making them prone to different types of attacks, which are discussed next. in this section, we present the different types of attacks that target the different aspects of cps systems, including cyber and physical ones: 1) physical attacks: physical attacks were more active in past years, especially against industrial cps systems [137] , [138] . many of these attacks were already presented in [139] . nonetheless, this paper presents a broader range of physical attack types: • infected items: this includes infected cds, usbs, devices and drives such as the case of the stuxnet worm [140] , which upon their insertion into a cyberphysical device, a covert malware is installed containing a malicious software. • abuse of privilege: this attack occurs when rogue or unsatisfied employees access the server rooms and installation areas within the cps domain. this allows them to insert a rogue usb for infection through the installation of malicious malware/code or as keystroke, or to capture confidential data. • wire cuts/taps/dialing: since communication lines including telephony and wi-fi of many cyber-physical headquarters (hqs) are still physically visible, attackers can cut the wires or wiretap into them to intercept the communicated data [117] . • fake identity: this attack occurs when attackers masquerade themselves as legitimate employees, with enough experience to fool the others. they mainly act as cleaners to gain an easier access and better interaction with other employees. a prime example of that is australia's maroochy water breach in 2000 [141] . • stalkers: these are usually legal employees who act curious (with malicious intents) by being on the shoulder of cps administrators and engineers to acquire their credentials to blackmail or sell them to other competing cps organisations. • cctv camera interception: this includes intercepting the footage of closed-circuit television cameras that are securing entry and key points within cps areas. this can be done by distorting the signals of cameras, cutting off the communication wires, deleting the footage, gaining access to the remote control and monitoring area, etc., before performing a physical attack in an undetected manner. • key-card hijacking: this includes cloning legitimate cards that are stolen from employees, or creating lookalike genuine copies to gain full/partial access and to compromise the cps domain. • physical breach: this attack requires gaining an illegal physical access to the system, mainly through a physical breach such as the case of the springfield pumping station in 2011 [142] , a backdoor such as the case of us georgia water treatment plant in 2013 [143] , or an exploited security gap such as the case of the canadian telvent company in 2012 [144] . this allows an attacker to damage and shut-down network-connected manufacturing systems and cps devices, resulting into loss of availability and productivity. • malicious third party software provider: the main purpose of this attack is to target the company's cps by compromising the legitimate "industrial control systems" software, such as the case of the georgia nuclear power plant shutdown in 2008 [145] . this includes replacing legitimate files in their repositories with a malware that will be installed to offer remote access functionalities to control or compromise a given system. • abuse of privilege: is mainly led by insiders or "whistleblowers" to perform or help perform a (cyber)-attack from within. such high privilege grants them the ability to conduct these attacks by exposing valuable knowledge on cps systems' vulnerabilities and weaknesses. this abuse of privilege can take many forms. -physical tampering: including gaining unauthorised or masqueraded authorised access to restricted areas to damage cps systems, devices, modify their operational mode, inject malicious data/information or steal confidential documents. -unauthorised activities: are based on performing suspicious tasks, such as opening/closing pumping stations, increasing/decreasing power voltage, opening closed ports, communicating with an external entity, network traffic redirection or information leakage. • social engineering: can take many deceptive forms [91] such as reverse engineering (impersonating a techysavvy), baiting (selling malicious usbs or software), tailgating (following authorised personnel) or quid pro quo (impersonating technical support teams), and is based on the art of manipulating people (either mentally or emotionally) to reveal confidential information by manipulating their emotions to gain their trust to reveal sensitive information related to a cps, plc or ics system. recently, cps systems became the new target of hackers for espionage, sabotage, warfare, terrorism, and service theft [146] , mainly as part of cyber-warfare [147] , cybercrimes [148] , [149] , (cyber)-terrorism [150] , [151] , [152] , (cyber)-sabotage [153] (such as cyber-attacks against estonia in 2007 [154] , and georgia in 2008 [155] ), or (cyber)espionage [156] , [157] . the lack of (cyber)-security revealed a serious issue with possibly drastic effects [12] , especially in countries like lebanon [158] , [159] . 2) cyber attacks: in recent years, there was a rise in the rate of cyber-attacks targeting cps and iocpt with very devastating consequences. according to current studies carried out by [160] , [161] , cps is highly prone to malicious code injection attacks [162] and code-reuse attacks [163] , along with fake data injection attacks [164] , zero-control data attacks [165] , and finally control-flow attestation (c-flat) attacks [160] . such attacks can result into a total blackout targeting cps industrial devices and systems as presented in table ii. • eavesdropping: eavesdropping includes the interception of non-secure cps network traffic to obtain sensitive information (passwords, usernames, or any other cps information). eavesdropping can take two main forms:passive by listening to cps network message transmission, and active by probing, scanning or tampering the message by claiming to be a legitimate source. • cross-site scripting: or xss occurs when third-party web resources are used to run malicious scripts in the targeted victim's web browser (mainly a targeted cps engineer, contractor, workers, etc. ) by injecting malicious coding script into a website's database. xss can achieve session hijacking, and in some cases, can log key strokes along and remotely accesses a victim's machine. • sql injection: or sqli targets cps database-driven websites to read and/or modify sensitive data, along possibly executing administrative operations such as database shutdown, especially when cps systems are still relying on sql for data management [166] . • password cracking: aim to target the authenticity of cps users [167] , [168] (mainly engineers and managers) by trying to crack their passwords using bruteforce [169] , dictionary [170] (mitigated by using key exchange [171] ), rainbow table [172] , birthday (mitigated by hashing) [173] or online/offline password guessing attacks [174] to gain access to the password database, or to the incoming/outgoing network traffic. therefore, it is important to prevent such escalation from taking place [175] , [176] . • phishing: has many types such as e-mail phishing, vishing, spear phishing or whaling that target some or all cps users (such as engineers, specialists, businessmen, chief executive officers (ceos), chief operations officers (coo), or/and chief financial officers (cfo)), through impersonation of business colleagues or service providers. • replay: includes intercepting transmitted/received packets between icss, rtus, and plcs through impersonation to cause delays that affect cps's real-time operations and affect their availability. in some cases, these intercepted packets can be modified, which would seriously hinder normal operations. • dos/ddos: dos attacks target the cyber-physical system resources and are launched from a large number of locally infected devices. ddos attacks are usually exploited by botnets, whereby a large number of infected devices simultaneously launch a ddos attack from different geo-graphical locations. dos attacks can take many forms (i.e blackhole [177] , teardrop [178] ), while ddos can take the following forms (i.e ping-of-death [179] , smurf [180] and black energy series (be-1, be-2 and be-3 [181] , [182] , [183] ), all targeting cps systems. -tcp syn flood: exploits the tcp handshake process by constantly sending requests without responding back to the server, causing the server to constantly allocate space awaiting a reply [184] . this leads to a buffer overflow and causes the cyberphysical system to crash. • malicious third party: includes software that covertly exploit data aggregation network and compromises them, mainly using botnets, trojans or worms to infiltrate information through a cps encrypted channel from an internal system (i.e plc, ics or rtu) through the reliance on trusted third party in disguise, to a botnet commandand-control server. thus, targeting cpss [185] and amis [186] . • watering-hole attack: the attacker scans for any cyberphysical security weakness. once a weakness is identified, the chosen cps website will be manipulated by a "watering hole", where a malware will delivered by exploiting the targeted cps system mainly through backdoor, rootkits or zero-day exploit [187] . • malware: is used to compromise cps devices in order to steal/leak data, harm devices or bypass access control systems. the malware can take many forms, however, the main forms that target cps are briefly listed and presented in the following. -botnets: this includes exploiting cps devices vulnerabilities to turn them into bots or zombies, mainly to conduct hardly-traceable ddos attacks (i.e ramnit (2015) [188] , mirai (2016) [189] , smominru botnet (2017) [188] , mootbot (2020) [190] , wild-pressure and victorygate (2020).) -trojan: is a disguised malware that seems legitimate and tricks users to download it. upon download, the trojan infects the device and offers a remote access to steal data credentials and monitor users activities. this also includes remote access trojans which in turn, can be used to turn a device into a bot (i.e turla (2008) [191] , minipanzer/megapanzer (2009) [192] , gh0st rat (2009) [193] , shylock (2011) [194] , coreflood (2011) [195] , darkcornet (2012) [196] , memz (2016) [197] , tinybanker (2016) [198] and banking.br android botnet (2020)). -virus: it can replicate and spread to other devices through human/non-human intervention. viruses spread by attaching themselves to other executable codes and programs to harm cps devices and steal information. -worms: spread by exploiting operating system vulnerabilities to harm host networks by carrying payloads to steal, modify and delete data, or overload to web-servers (aside stuxnet, flame and duqu, i.e acode red/code red ii (2001) [199] , nimda (2001) [200] , triton (2017 [201] )). -rootkit: is designed to remotely and covertly access or control a computer to execute files, access/steal information or modify system configurations (i.e moonlight maze (1999) [202] , and blackhole exploit kit (2012) [203] ). -polymorphic malware: constantly and frequently changes its identifiable to evade being detected to become unrecognizable against any pattern-matching detection technique. -spyware: is a malicious software covertly installed on a device without the user or authorization knowledge, for spying purposes (e.g surveillance, reconnaissance, or scanning). in fact, they can be used for future cyber-attack purposes (i.e projectsauron (2011) [204] , dark caracal (2012) [205] , red october (2013) [107] , warriorpride (2014) [206] , fin-fisher (2014) [207] , and covid-19 spyware.) -ransomware: is a malicious software that holds and encrypts cps data as a ransom by exploiting cps vulnerabilities, targeting oil refineries, power grids [208] , manufacturing facilities, medical centers and encrypting all data-backups until a ransom has been paid. a prime example of that is the siskey (2016) (2019) and ekans (2020) ransomware [211] , [212] , [213] , [214] . • side-channel: is based on the information gained from the implemented cps system such as timing information, power consumption and electromagnetic leaks that can be exploited. for this reason, some of the most infamous cyber-attacks deserve being mentioned (table ii) . moreover, for further details, you can refer to [139] . in fact, do et al. presented a much more detailed attack description as early as 1980s in [142] . however, this paper aims to classify the occurrence of these attacks as early as 2000 and based on, but not limited to, political, religious, and criminal motives. after reviewing the main cps attacks, it is essential to assess their associated risks to design the convenient countermeasures. in the next section, the risks associated with the different cps security attacks are evaluated. given the different threats, attacks and vulnerabilities that the cps domain suffers from, it is important to highlight the main failures than cps systems suffer from. these failures can either be minor (limited damage) or major (severe damage). in fact, further details can be found in [222] , where avizienis et al. presented a well-defined and detailed explanation in this regards. • content failure: means that the content of the delivered information is inaccurate, which would result into some functional system failure. content failure can be either numerical or non-numerical (i.e alphabets, graphics, sounds or colours). • timing failure: means that the timing of information delivery (transmission/receiving) is delayed or interrupted (received/transmitted too early or too late). this would affect the decision making process and may cause data management issues. • sensors failure: means that the sensors are no longer functioning properly, and would seriously hinder the decision making process due to misinformation, or bringing a cps system to a sudden halt. a similar case occurred in 2005, at taum sauk hydroelectric power station [216] . • silent failure: occurs when there is no message sent or received in a distributed system. • babbling failure: occurs when the information is delivered, causing the system to malfunction and to operate in a babbling manner. • budget failure: occurs when the cost of implementing a cyber-physical system outweighs the budget set, before ever reaching the testing level. this is mainly caused by poor planning. • schedule failure: occurs when the schedule set for planning, testing and evaluating a given cps is not achieved due to further upgrades, additional testing, or inadequacy for users needs. • service failure: occurs when having an error propagates through the service interface and affects its decision making or/and normal performance ability. this failure can either cause a partial or full cps system failure either temporarily or permanently. • consistent/inconsistent failures: a consistent failure occurs when a given service is identically perceived by all cps users. an inconsistent failure takes place when all cps users differently perceive an incorrect service (i.e bohrbugs, mandelbugs, heisenbugs and byzantine failures) [223] . evaluating risks is essential to assess the risk's economic impact of an attack on any cps system, before managing it. such management is based on assessing and analysing the risk before mitigating it, then deploying the right security measures according to the level of severity and risk impact (see fig. 4 ). risk management is implemented in order to identify, analyse, rank, evaluate, plan and monitor any possible risk through risk assessment. • identifying risks: identification is based on uncovering and recognising risks that can negatively affect a project/project outcome and describing it [224] . • analysing risks: risks likelihood and consequence must be determined once they are identified, to understand the nature of a risk. • ranking risks: risks rank is evaluated according to the risk magnitude, based on the combination of both risk likelihood and consequence in case it occurred. • evaluating risks: based on their ranks, risks are either deemed as acceptable or require serious treatment and urgent attention. • planning risks response: highest ranked risks are assessed to treat, modify and mitigate them to once again achieve an acceptable risk level. therefore, risk mitigation strategies are created, along with the deployment of preventive and contingency plans. • monitoring and reviewing risks: risks are constantly monitored, tracked and reviewed. in case of any suspicious activity, these risks are mitigated before any serious threat occurs. risk assessment is implemented to minimize the impact of a given attack [225] . in fact, risks are evaluated based on calculating the average loss in each occurring event [226] . additionally, several risk assessment methods, as well as various techniques to secure cps were revealed in [25] . in fact, since most studies are focused on securing enterprise systems in order to assess risks, security became an emerging issue that imposes a serious risk on cps [227] . as a result in [228] , [229] , lu et al. presented an adequate risk assessment method. the main security focus was based on transferring it from risk assessment, to computer risk assessment (cra), to network risk assessment (nra) with a heavy reliance on the internet [230] . asset identification: is also important, since it is a resource value that can either be tangible, or intangible that impacts daily transactions and services [231] . in fact, cps assets can be divided between cyber assets, physical assets, and cyber-physical assets. finally, since asset quantization is estimated from both direct and indirect economic losses [232] , it is important to determine the asset value (av). risk is assessed based on its possible impact on cps systems. it is divided into three main types: • high impact: in case the risk has occurred, this can result in devastating and damaging effects on cps systems. it is used to evaluate and mitigate persistent advanced threats [233] . • medium impact: in case of its occurrence, the impact is less severe. however, it also imposes a serious threat against cps. it is used to evaluate and mitigate advanced threats [234] . • low impact: in case this risk has occurred, its impact is not severe, nor has damaging effects. as a result, its impact is very limited and can be easily mitigated. it is used to evaluate and mitigate basic threats [235] . risk mitigation requires the adaptation and implementation of a well-built management strategy in addition to cyber and physical security in order to counter-espionage, theft, or/and terrorist attacks. such a mitigation model also requires, data security and protection, as well as anti-counterfeit and supply chain risk management [236] . these models should also be supported by both forensic and recovery plans. this can help in analyzing cyber-attacks whilst coordinating and cooperating with the responsible agencies to identify external cyber-attack vectors [237] . therefore, preventive, detective, repressive and corrective logical security measures can be adopted. as a result, a qualitative risk assessment table is presented (see table iii the cost of security attacks can take many forms, and the main ones are highlighted as follows: • delays: cps systems may be prone to service delays, which may affect their performance and render them inactive (blackout, burnout) until the issue is sorted either through maintenance or back up. • affected performance: system delays due to a malicious (cyber-attack)/non-malicious (accident) event can gradually affect the cps performance and cause it to operate in an abnormal manner which can seriously affect the decision making process. • additional spending: may be required to tackle the advanced persistent threat attempts and zero-day attacks, which require additional spending in terms of security protection in a defense-in-depth manner. • loss of life: can be the result of flooding, radioactivity, fire or electric shock due to hazardous or intentional acts. • disclosure of information: can affect cps businesses and business trades and put the privacy of users at risk of having their personal information being exposed. before proceeding any further, it is important to classify cps components as critical, moderate and non-critical, to identify the risk of an event occurrence (malicious/hazard) along its impact to define the proper security measures (basic, standard or advanced), as seen in fig. 5 . while adopting all possible security measures might be costly in all terms (i.e. complexity, financial cost, delay, etc.), risk management is key for selecting the convenient security solutions. in the next section, the different security solutions proposed to defend the security issues are reviewed. while these security solutions aim at preventing, detecting or correcting system damage, the cps forensics aim at knowing the system issues causes, which help in reducing and preventing future attacks. thus, the main cps forensics solutions are also reviewed. securing cps is not a straightforward task. for this reason, various existing solutions are mentioned and discussed in this section. already existing testing tools are also introduced. all of these schemes are presented to protect cps domains against attacks that target the confidentiality, integrity, availability, authentication and privacy of both data and systems as seen in fig. 6 . according to national institute of standards and technology (nist) guidelines [243] , [244] , ensuring trust between iot and cps, should consist of various multi-factors. this is due to both iot and cps systems relying on safety, security, privacy, consistency, dependability, resiliency, reliability, interaction and coordination, all of which are combined to form a well-designed and trustworthy system. if this condition is satisfied, a perfect cps mechanism is achieved. as a result, several cps testing tools were used to evaluate the security of industrial control devices upon their development (see table iv) . for further details, these tools are explained in [245] . moreover, several security certifications are also discussed, reviewed, analysed and compared according to their different aspects [245] (see table v) . in the following, the main cps security requirements are defined and discussed. • privacy: in cps, a huge data collection process is constantly taking place, and this is what most people are not aware of [256] , [257] . therefore, a person has the right to access his own data, along with being given the right to know what type of data is being collected about them by data collectors, and to whom these data is being given or sold to. however, this also requires preventing the illegal/unauthorised access to the user's personal data and their information disclosure [258] , [259] . • dependability: intelligent physical world (ipw) ensures that the cps adaptive behaviour is achieved to bring a higher dependability and ensure the right quality of service (qos) through the adoption of fault-tolerance mechanisms in a timely manner. dependability includes two other qualities, safety and reliability. safety is often an objective defined in terms of the organisation's [243] . this is due to the negative impact of cybersecurity risks, where vulnerabilities can be compromised and exploited by a hacker, or due to cps failure. hence, safety is of a high concern for iot, cps and (internet of cyber-physical things) iocpt users alike. while reliability is based on the ability to adapt to changing conditions to overcome and recover from any possible disruption either based on cyber or/and physical attacks led by adversaries, in addition to natural disasters [243] . physical systems rely on timing and proper functionality. however, in case of any possible mismatch, unreliability and uncertainty can cause problems and disruptions for cps services. therefore, maintaining a high reliability requires reducing the uncertainty levels. in fact, it is also recommended to implement error-correction algorithms to sort electronic components imperfect reliability [260] . as a result, rajamaki et al. in [260] stated that cps behaviour can be predictable through the implementation and use of artificial intelligence or/and even machine learning (ml) schemes. this allows the prediction of the so called "next-time system state". • resiliency: cps must be resilient to overcome accidents and malicious attacks. therefore, cps logical and physical systems are prone to cyber security vulnerabilities from a security aspect. this included the demonstration of carshark software tools that control a car in [133] , along with the successful design of a virus in 2010 which attacked siemens plant-control systems [261] , along with how hackers broke into the united states federal aviation administration (us faa) air traffic control system in 2009 [262] . resiliency is achieved by each cps component in a base architecture (ba) presented in [263] , where each communication and physical connection path between elements is granted access by the ba's connectors. this requires the ba system to know and identify every possible path, while overcoming any connection disruption. moreover, in case the elements were inconsistent, a multi-view editor will be deployed to make corrections. • interaction and coordination: are essential to maintain an all-time operational cps security. in [58] , hu et al. stated that cps interaction and coordination between cyber and physical system elements are a key aspect. in fact, the main physical world characteristics are based on the constant system change over time. however, the cyber world characteristics are based on sequence series with no temporal semantics. moreover, two basic approaches are presented to study and analyse this problem. these approaches are based on the "cyberizing" the physical (ctp) aspect through the introduction of cyber-properties and interfaces into physical systems, and "physicalizing" the cyber (ptc) where cyber-software components are to be represented in real-time [264] . • operational security (opsec): operational security (opsec) was introduced in 1988 to ensure physical security, information security, and personnel security [265] through careful planning, risk assessment and risk management [266] . its primary task is to ensure operational effectiveness by denying any adversary access to public/private information; hence controlling information and observable actions about a given cyber-physical system, especially in hostile environments/areas [265] . one of its key benefits is providing means to develop cost-effective security measures to overcome a given threat. to achieve this task, opsec involves five main steps: -critical information identification: includes identifying which information, if targeted, can effectively degrade a cps's operational effectiveness or place its potential organizational success at risk, and develop an initial plan to protect it. -threat analysis: includes determining an adversary's potential and capabilities to gather, process, analyze, and use the needed information. -vulnerability analysis: includes studying the weaknesses of a given cyber-physical system and the strengths of an adversary. thus, building a possible view over how a potential adversary might exploit this security gap to perform a security breach. -risk assessment: risks are assessed based on the threat and vulnerability levels combined, depending on how high or how low these levels are. risk assessment levels include evaluating the cost of implementing the right security measures by ensuring a trade-off between the effective cost and benefit balance. -appropriate application countermeasures: once the trade-off is achieved in the earlier phase, the appropriate countermeasures are then developed to offer the best protection of cps against these ongoing threats in terms of feasibility, cost, and effectiveness. • system hardening: system hardening can be used to defend a wider range of threats. therefore, it is highly recommended to isolate critical applications that lack the proper security measures, from any os that is not trusted in order to boost the iocpt and cpt security. in [267] , shepherd et al. analysed different trustcomputing technologies along with their applications in the cps domain. according to [268] , such analysis included a trusted platform module (tpm), trusted execution environments (tee), secure elements (se), and encrypted execution environment (e3), to increase the os's integrity. moreover, the authors' work in [269] has successfully achieved a higher security level in the presence of untrustworthy components. this allowed the improvement of cps by enhancing system's integrity. however, if the graph-based optimization was combined with parameters, it can provide a reasoning basis to ensure an overall system integrity [270] . therefore, it is essential to set the right privileges (task-based, role-based, rulebased, etc..) and strong password complexity policies in order to enhance the security level. moreover, this also includes getting rid of old unused accounts and open yet unused ports to reduce the exposure to remote wireless attacks. as a result, cps nature must be considered before achieving any design. in [136] , mo et al. presented a cyber-physical security by combining systems-theoretic with cyber-physical security controls. the adoption of security measures has many benefits when it comes to protecting cps components, layers and domains. however, despite these advantages, cps systems are impacted by the application of these security measures, which can be summarized as follows: • reduced performance: security measures can partially or fully affect the performance of a given cps, in the absence of careful consideration for a balanced securityperformance trade-off. this can affect normal operations and requires more human interventions to manually assign services and domains. • higher power consumption: is a serious issue, especially for resource-constrained and battery-limited cps end devices. a higher power consumption means a shorter lifespan and a higher cost to maintain their availability. • transmission delays: transmitted/received data is prone to delays due to the additional encryption process that is being added to thwart passive/active eavesdropping and sniffing attacks. despite the protective advantage that is offers, this is unacceptable in a real-time cps systems. • higher cost: higher security levels are associated with higher computational costs, which are not limited to the initial capital spending phase, but also include training, update, and operational phases. • compatibility issues: some cps systems are not compatible with the employed security measures and vice versa. this can be due to the software in-use, firmware, operating system, etc. • operational security delays: upon the deployment of any security service, there is a training phase that precedes the full operational security mode, and during which the service is temporarily ineffective or basic and thus, prone to attacks. maintaining a secure cps environment is not an easy task due to the constant increase of challenges, integration issues and limitation of the existing solutions including the lack of security, privacy and accuracy. nonetheless, this can be mitigated through different means including cryptographic and non-cryptographic solutions as seen in fig. 7 . • safety critical: in such a cps type, an attack can lead to loss of life or to chronic deadly diseases, with significant damage to the environment such as fire, floods, radioactivity (e.g. chernobyl in 1986 and fukushima in 2011) incidents [271] , [272] . • mission critical: for this type of cps, an attack can result into a fatal/non-fatal, total/partial failure of a cps to achieve its objectives [273] . • business critical: in such a cps type, an attack can result into huge financial and economic losses, damaged reputation and loss of cps contractors and clients. • security critical: for this type of cps, an attack can result into a security breach of the cyber-physical system (security gap, exploitable vulnerability, rootkits, backdoors, etc.). cryptographic measures are mainly employed to secure the communication channel from active/passive attacks, along any unauthorized access and interception, especially in scada systems [274] . in fact, traditional cryptography approaches based on utilizing ciphers and hash function are not easily applied to cps including iocpt due to power and size constraints. as a result, the main focus should be limited to data security alone, instead it should maintain and ensure the efficiency of the overall system process along. therefore, various solutions were presented. in [23] kocabas et al. conducted their own survey which was dedicated to conventional and emerging encryption schemes which could be employed to offer secure data storage and sharing. in [24] , lai et al. reviewed and discussed prominent cryptographic authentication and encryption methods [275] to secure distributed energy resources (der) systems, while providing recommendations on applying cryptography to der systems. in [276] , ding et al. presented an overview of recent advances on security control and attack detection of industrial cps, especially against denial-of-service, replay, and deception attacks. in [15] , sklavos et al. presented a tutorial that discusses the implementation efficiency of communications confidentiality, user authentication, data integrity and services availability, along attacks and modern threats with their countermeasures. many solutions were presented to maintain a secure cps environment by fulfilling its main security goals. in [277] , adam et. al. presented a novel framework to understand cyber-attacks and cps risks. their framework offers a novel approach to ensure a comprehensive study of cps attack elements, including the attacker and his objectives, cyber exploitation, control-theoretic and physical system properties. in [232] , stouffer et al. provided a comprehensive ics security guideline that is related to technical controls including intrusion detection systems (ids), access controls (ac), firewalls, and operational controls including training, awareness and personnel security. in [97] , security experts were able to gain the employees' credentials due to their lack of awareness and training, using phishing and social engineering techniques through a simulated attack. in [34] , sommestad et al. conducted a keyword mining comparison, and concluded that the main focus was either on operational controls, or technical controls only. in [278] , sharma et al. presented a novel multi-level network security evaluation scheme (nses) that represent five different levels of security. therefore, providing a holistic view over whether nses is suitable for wireless sensor networks (wsn) security for iot/cps/iocpt applications. nses offers recommendation for network administrators on early design phases to achieve the right security needs. as a result, this paper classifies these solutions in terms of them fulfilling one of the following security goals: • confidentiality: securing cps communication lines is essential. as a result, various cryptographic solutions were presented. in [279] , the authors presented a solution based on the use of compression techniques before being encrypted. their solution reduces the overhead and mitigates the problem. since, lightweight cryptography became the centre of attention with various lightweight block ciphers being presented by different authors, including an ultra-lightweight block cipher by bogdanov et al. [280] and a low-latency block cipher for pervasive computing applications [281] . this was due to their lowcost and low-latency with the ability to provide cryptographic blocks for any resource constrained, normal, industrial, or even medical devices. in [282] , shahzad, et al. suggested the installation of encryption-decryption modules at both ends of non-secure modbus communication to protect its connection from confidentiality attacks. thus, requiring an additional overhead to convert plaintexts into ciphertexts and vice versa. in [283] , the american gas association (aga) presented its aga-12 standard to provide "bump-in-the-wire" encryption services for cps, but at the expense of large latency overheard [284] . in [ [296] . ssu is complementary to the existing siem architectures, and it can transparently intercept its communication control channels along with its physical process input/output lines to constantly assess both security and operational status of plc or rtu. another approach was also presented in [297] , by asem et. al to overcome mitm, replay and command modification attacks by providing an encryption level for the transferred packets, along with the use of hardware cipher models. in [298] , cao et al. presented a layered approach with the aim of protecting sensitive data. their techniques relied on hash chains that provide a layered protection for both high and low security levels zones along with a lightweight key management mechanism. thus, preventing attackers from intercepting data from a higher security level zone. therefore, ics applications vendors should work on releasing compatible versions of their applications to ensure that the ics operators will not resort to older versions of vulnerable os [22] . their presented approach revealed the ineffectiveness of interception, injection and denial of service attacks, along with the ability of their openplc project to overcome man-in-the-middle attacks through data encryption, without interfering with its own real-time characteristics. • authentication: authentication is the first line of defense that should be well-built, designed and maintained [302] , [303] , [259] , [304] . as a result, in [130] , halperin et al. presented a public key-exchange authentication mechanism to prevent unauthorized parties from gaining access. their mechanism relies on external radio frequency rather than batteries as an energy source. in fact, out-ofband authentication were deployed in certain wearable devices, where the authentication mechanism uses additional channels including audio and visual channels [73] . on the other hand, medical cps (mcps) biometrics, including mainly heart rates and blood pressure [305] , can possibly be used to generate a key to encrypt and secure the body sensor network communication [73] . in [ • privacy preserving preserving the privacy of users' big data is not an easy task. as a result, various privacy preserving techniques were presented to solve this issue including differential privacy and homomorphic encryption. -differential privacy: limits the disclosure of private real-time big-data and information during its transmission. in [311] , keshk et al. studied the feature reduction role along privacy protection levels using independent component analysis (ica) as a technique on big power cps data. results revealed that ica is more secure without breaching confidential data and offers a better privacy preservation and data utility. in [312] , j. feng et al. presented a lightweight privacy-preserving high-order bi-lanczos scheme in integrated edge-fog-cloud architectural paradigm for big data processing. user's privacy is achieved using an homomorphic cryptosystem, while computation overheads are offloaded using privacy-preserving tensor protocols. in [313] , ye et al. presented a secure and efficient outsourcing differential privacy (dp) scheme to solve data providers issues related to being vulnerable to privacy attacks. in [314] , zhang et al. presented a practical lightweight identity-based proxy-oriented outsourcing with public auditing scheme in cloudbased mcps, by using elliptic curve cryptography to achieve storage correctness guarantee and proxyoriented privacy-preserving property. -homomorphic encryption: for a better data confidentiality and privacy protection, homomorphic encryption techniques were adopted. in [315] , zhang et al. presented a secure estimation based on kalman filtering (sekf) using a multiplicative homomorphic encryption scheme with a modified decryption algorithm to reduce network overhead and enhance the confidentiality of the communicated data. in [316] , kim et al. a fully homomorphic encryption (fhe) as an advanced cryptographic scheme to directly enable arithmetic operations on the encrypted variables without decryption. moreover, a tree-based computation of sequential matrix multiplication is introduced to slow down the decrease of the lifespan. in [317] , min et al. presented a parallel fully homomorphic encryption algorithm that supports floatingpoint numbers to achieve an efficient ciphertext operation without decryption. results revealed that the ability to limited application problems while meeting the efficient homomorphic encryption requirements in cloud computing environment. many noncryptographic solutions were also presented to mitigate and eliminate any possible cyber-attack or malicious event. this was done by implementing intrusion detection systems (ids), firewalls and honeypots. as a result, various solutions presented by various authors are mentioned and discussed. various ids methodology types are available due to the availability of different network configurations [318] . each ids methodology is characterised by its own advantages and drawbacks when it comes to detection, configuration, cost, and their placement in the network. in [268] , almohri et al. stated that various research activities were implemented to detect attacks against the cps. these attacks are split into two main models. physics-based model, which defines normal cps operations in cps through anomaly detection. cyber-based model which is used in order to recognize potential attacks as listed in [319] , [320] . in fact, existing approaches were mainly designed to detect specific attacks against specific applications, including unmanned aerial vehicles (uav) [321] , industrial control processes [322] , and smart grids [323] . in [324] , zimmer et al. exploited the possibility of a worst case execution time, through obtaining information using a static application analysis in order to detect malicious code injection attacks in cps. in [325] , mitchell et al. analysed a behaviour-rule specification-based technique to employ ids mainly in medical cps. the authors also presented the transformation of behaviour rules in a state machine, which can detect any suspicious deviation initiated from any medical device behaviour specification. -intrusion detection system placement: ids can be placed at the border router of any given iot network, in one or many given hosts, or in every physical object to ensure the required detection of attacks. simultaneously, ids may be able to generate a communication overhead between the lln (low power lossy networks) nodes and the border router due to the ids ability to frequently query the network state. in fact in [326] , zarpel at al. described three main ids placement strategies (see fig. 8 ): fig. 8 : ids structure * distributed ids: d-idss are being employed in every physical lln object, whilst being optimized in each resource-constrained node. therefore, a lightweight distributed ids was presented. in [327] , oh et al. identified a lightweight algorithm matching the attack signatures, and the packet payloads, while suggesting other techniques that require less matching numbers to detect any possible attack. in [328] , lee et al. suggested their own lightweight method that allows them to monitor a node's energy consumption by assigning nodes to monitor their neighbours in the distributed placement. these nodes are defined as "watchdogs". in [329] , cervantes et al., presented a solution called "intrusion detection of sinkhole attacks on ipv6 over low -power wireless personal area networks (6lowpan) for iot" (inti), which combines their concepts of trust and reputation with the watchdogs nodes to mainly detect and mitigate sinkhole attacks. this included the node's role possibly changing every time a network is reconfigured or an attack event has occurred. * centralized ids: c-ids is mainly deployed in centralized components. this allows all data to be gathered and transmitted by the lln to the internet across the border. therefore, centralised ids can analyse all of the exchanged traffic between the lln and the internet. in fact, it is not enough to only detect attacks involving nodes within the lln, since it is difficult to monitor each node during an occurring attack [330] . in [331] , cho et al. presented their solution which is based on analysing all the packets that pass through the border router between physical and network domains. however, the main task is based on how to overcome a botnet attack. in [332] , [333] , kasinathan et al. deployed a centralized placement that allows them to take into consideration the possibility of overcoming dos attacks, where in case of a dos attack, the ids data transmission would not be affected. in [334] , wallgren et al. employed their centralized approach which is placed in the border router to detect the attacks that target the physical domain. * hybrid ids: h-ids utilizes both concepts of centralized and distributed placements, by combining their advantages and overcoming their drawbacks. the initial approach allows the network to be organised into clusters with the main node of each cluster being able to host an ids instance before taking the responsibility for monitoring other neighbouring nodes. therefore, hybrid ids placements can be designed in order to consume more resources than a distributed ids placement. in [335] , le et al. followed the same approach, through the use of a hybrid placement using a relatively small number of "watchdogs" nodes covering the network. this offered them the ability to sniff the communication of its surrounding neighbours in order to indicate whether a node was compromised or not. therefore, reducing the communication overhead. in [336] , le et al. also managed to organize the network into smaller clusters with a cluster head for each, using the same number of nodes. this allowed an ids instance to be placed in each cluster head, with each cluster member reporting its own related information and other neighbours related information to the cluster head. in the second approach, ids modules were placed in, both the border router and other network nodes with the presence of a central component. in [337] , raza et al. presented their own ids named as svelte, where the border router hosts are given the task of processing intensive ids modules that are responsible for detecting any intrusion attempt by analysing the routing protocol low-power and lossy device's (rpl) network data. based on pongle et al.'s work [338] , network nodes were responsible for any detectable changes in their neighbourhood. moreover, network nodes were also responsible for sending information about their surrounding neighbours to their centralized module which is deployed in the border router having the main assigned responsibility of storing and analysing data. thus, making it easier to detect and intrusion while identifying attacks in their early stages. in [339] , thanigaivelan et al. presented an ids, which allocates different responsibilities to the network nodes and also to the router's border. thus, ensuring a cooperative combined work amongst them, with the ids module monitoring neighbouring nodes, detecting any intrusion attempt, and sending notifications to the ids modules. -intrusion detection methods: the four main ids methods are signature-based, anomaly-based, behaviour-based and hybrid based. in fact in [326] , these methods were presented, while testing methods and techniques were classified into five main categories, depending on their detection mechanism . * signature based: such a detection technique is very fast and easy to configure. however, it is only effective for detecting known threats. thus, showing a high weakness against unknown threats mainly polymorphic malwares and crypting services. despite its limited capability, signature based ids is very accurate, and also very effective at detecting known threats, with an easy way to understand mechanism. however, this approach is ineffective against the detection of both new and variants of known attacks, due to their matching signature remaining unknown, and constantly updating its signature patches [340] , [341] . in [327] , oh et al.'s aimed to reduce the computational cost by comparing attack signatures and packet payloads. in [342] , liu et al. presented a signaturebased ids that employs an "artificial immune system" (ais) mechanism with detectors being modelled as immune cells with an ability to classify any datagram as malicious or non-malicious according to the matching signature. such approach can evolve into the adaptation ability new conditions in new environments that are being monitored. in [332] , kasinathan et al. integrated a signature-based ids into the network framework, with the objective of being able to detect dos attacks against 6lowpan-based networks. this ids was implemented through the adaptation of "suricata4" used for 6lowpan networks, with the main objective of reducing the false alarm rate. in [333] , kasinathan et al. presented a signaturebased approach as an extension of their presented approach in [332] . * behaviour based: behaviour based can be classified as a set of rules and thresholds implemented to define the expected behaviour of the network's components including both nodes and protocols. this approach is capable of detecting any intrusion as soon as the network behaviour deviates from its original behaviour. behaviour-based acts in the same way as the anomaly-based detection with a slight difference from specification-based systems where a human expert is needed to manually define each specification rule. thus, providing a lower false-positive rate than the anomaly based detection [343] , [344] . therefore, there will be no need for any training phase, since they are implemented to operate instantly. however, such an approach is not fit for all scenarios, and may become time consuming and error prone. in [345] , misra et al. presented their new approach to protect the iot middleware from ddos attacks, by triggering an alert whenever the request number exceeds the threshold line. in [335] , le et al. presented a different specification-based approach, aimed at detecting rpl attacks [346] , by specifying the rpl behaviour through network monitoring operation and malicious action detection. in [336] , le et al.'s work was extended. their experimentation resulted in a high true-positive rate, where false positive rates were low throughout their experimentation, whilst also causing an energy overhead compared to a typical rpl network as stated in [326] . in [347] , amaral et al. presented a specification-based ids that grants the network administrator the ability to create and maintain rules in order to detect any potential attack. whenever the rule is violated, the ids would right away send an alert to the event management system (ems) that correlates these alerts for different available nodes in a given network. the success of misra et al. [345] and amaral et al. [347] approaches highly relied on the expertise of the network administrator, as well as his experience and skills combined. therefore, in case of any wrong specifications, it will cause an excessively high false-positive rate and/or a high false-negative rate, leading to a possibly serious risk that threatens the network's security. * anomaly based: this type compares system's activities instantly with the ability to generate an alert whenever a deviation from normal behaviour is detected. however, such a detection method suffers from a high false positive rate [343] , [348] , [349] . in [331] , cho et al. presented a botnet detection scheme using the anomaly-based method, by computing an average for each three metrics composing the normal behaviour profile. this was achieved before the system monitors the network's traffic and raises the alert whenever a metric violates the already defined computed averages. in [350] , gupta et al. presented their own architecture for a wireless ids, by applying the necessary computational intelligence algorithms which are used in order to a construct normal profile behaviour. moreover, a distinct normal behaviour profile will be implemented for each different ip address being assigned. in [328] , lee et al. suggested that energy consumption should be classified as parameter in order to be used in analyzing each node's behaviour. thus, defining a regular energy consumption model for each mesh-under routing scheme and route-over routing scheme, where each node will monitor its own energy consumption. in case the node deviates, the ids classifies the node as malicious and removes it. in [351] , summerville et al. successfully managed to develop a deep-packet anomaly detection approach aimed at reducing the run on resource constrained iot devices, by using a bit-pattern matching technique which performs a feature selection. in their experimental evaluation, they used internet enabled devices against four main attack types (including sqli, worms, etc..), and results have shown low false-positive rates. in [339] , thanigaivelan et al. successfully introduced an iot distributed internal anomaly detection system, that monitors the node's data rate and packet size. moreover , in [338] pongle and chavan presented an ids that is designed specifically in order to detect wormhole attacks in iot devices, in addition to presenting three main algorithms to detect network anomalies. as a result, their experiment revealed that the system has achieved a true positive rate of 94% when tested against wormhole detection, whilst scoring an 87% when it came to detecting both, the attack, and the attacker launching it. in [352] , k. demertzis et al. presented an advanced spiking one-class anomaly detection framework (soccadf) based on the evolving spiking neural network algorithm. this algorithm implements a one-class classification methodology in an innovative applicable way, due to it being exclusively trained with data to characterise normal ics operations. moreover, this algorithm can detect any divergence in behaviours and abnormalities that are associated with apt attacks. the authors stated that soccadf is highly suitable for difficult problems, and applications with a huge amount of data. according to their results, the authors stated that soccadf has a better performance at a very fast learning speed, with higher accuracy, reliability, and efficiency, and it outperforms the other approaches. * radio-frequency based: in [353] , stone et al. presented a radio-frequency based anomaly detection method for programmable logic controllers in the critical infrastructure [354] . their experimental results have demonstrated that the use of a single collected waveform response provides sufficient separability to enable the differentiation between anomalous and normal operational conditions. however, in case of using multi-time domain waveform response, their performance significantly degrades. to solve this problem, the authors presented anomaly detection method based on rf fingerprint feature retrieved from the waveform amplitude, phase, and frequency response to ensure a qualitative differentiation between an anomalous and normal operating conditions. in [355] , stone et al. also presented an rf-based methodology to detect anomalous programmable logic controller behaviours with a superior timedomain rf emissions performance. the cincinnati bell any distance (cbad) approach reached a threat agent detection and response (tadr) detection rate higher than 90% benchmark realised at an signal power ratio (snr) higher or equal to 0 db. despite these results, this approach is prone to rf noise, signal degradation and coding loops. in [356] , stephen et al. presented a timing-based side channel analysis technique to help control system operators in detecting any firmware and ladder logic programs modification to the programmable logic controllers. this approach allows a field device to be fingerprinted upon deployment to create an supplicate baseline fingerprint. various fingerprints of the device are taken and compared to the baseline in order to detect and alert operators of both intentional and unintentional modifications in programmable logic controllers. * hybrid based: it is based on using a specification-based techniques of signature-based, and anomaly-based detection in order to maximize their advantage whilst minimizing their drawbacks. in [337] , raza et al. presented a hybrid ids known as svelte which offers the right trade-off between storage cost of signature-based methods, and computational cost of anomalybased methods. in [357] , krimmling et al. tested their anomaly and signature-based ids using the ids evaluation framework that they presented. their results revealed the failure of each approach in detecting certain attacks alone. as a result, the authors combined these approaches to cover and detect a wider attack range. in [329] it is not enough to encrypt, detect and protect against passive and active attacks. in fact, aside from identifying the source of the attack, it is also important to know how the attack was performed despite of the challenges [372] . hence, there an urgent need for the forensics domain to enhance the forensics tools and techniques to retrieve and analyze logs of events that took place before, during and after the incident. in fact, cps forensic analysis is still in its early stages of development, due to the ics specialized nature along with its proprietary and poorly documented protocols [373] . in [374] , awad et al. surveyed the digital forensics applied to scada systems and covered the challenges that surround them. therefore, presenting the current state-of-the-art device and networkspecific tools. in [375] , grispos et al. presented a forensicby-design framework that ensure the integration of forensics principles and concepts in mcps. in [376] , h. al-khateeb et al. shed a light on a new approach where a blockchainbased chain-of-custody may be simultaneously established to the generated preidentified data (data of interest) by an iot device. in [377] , chan et al. described a novel security block method for detecting memory variable changes that may affect the integrity of programmable logic controllers and efficiently and effectively enhancing security and forensics. this is done by by adding monitoring and logging mechanisms to plcs. therefore, ensuring faster anomaly detection with higher accuracy, less overhead and adjustable impact. in [378] , ahmadi et al. presented a federated blockchain (bc) model that achieves forensic-readiness by establishing a digital chain-of-custody (coc) and a cps collaborative environment to qualify as digital witnesses (dw) to support post-incident investigations. in [379] , parry et al. presented a high speed hardware-software network forensics tool that was specifically designed for capturing and replaying data traffic in scada systems. experimental results guaranteed preserving the original packet ordering with improvement in data capture and replay capabilities. in [380] , cebe et al. presented a blockchain infrastructure by integrating a vehicular public key infrastructure (vpki) to achieve membership establishment and privacy along a fragmented ledger related to detailed vehicular data. moreover, identities pseudonyms were used to preserve users' privacy. in [381] , p. taveras presented a high level software application that detects critical situations like abnormal changes of sensor reads and traffic over the communication channel, mainly. therefore, helping by improving critical infrastructure protection and providing appropriate scada forensics tools for incident response and forensics analysis. in [382] , ahmed et. al. presented a testbed of three ipps (industrial physical processes) using real-world industrial equipment including plc. the authors stated that their presented testbed is useful in cyber-security, education (scada systems) and forensics research including plc analysis and programming. moreover, their testbed includes fully functional physical processes which are deemed very essential for both research and pedagogical efforts. in [383] , yau and chow presented a novel methodology which logs relevant memory address values, that are being used by programmable logic controller programs, in addition to their timestamps. this methodology can be extremely valuable in a forensic investigation in case of an ics incident. this is realized by applying machine learning techniques to the logged data in order to identify any anomalous programmable logic controller operation. in [384] saman et. al. combined symbolic execution with model checking to analyse any malicious plc code bound injection. their combined approach can also be used for forensic purposes including the identification of the areas where the code injection took place, along with which part of the code caused its execution. in [385] , mcminn et al. presented a firmware verification tool used for the forensics analysis of trials of the altered firmware codes to gain unauthorised access over ics networks. such verification is achieved either though the analysis of the plc's captured data to check whether the plc's firmware is modified or not. in [386] , kleinmann et al. presented an accurate ids that utilizes a deterministic finite automaton that models the network traffic with a 99.26% accuracy, after analysing and observing the highly periodic network traffic of siemens s7 plc. in [387] , saranyan et al. provided a comprehensive forensic analysis of network traffic generated by the pccc (programmable controller communication commands) protocol, and also presented prototype tool that extracts updates of the programmable logic and crucial configuration information. authors also stated that their proof-of-concept tool, "cutter", which is capable of parsing the content of pccc messages, extracts and presents digital artifacts in a human-readable form such as simple mail transfer protocol (smtp) configuration. moreover, the smtp configuration can be retrieved from the network log and can be parsed, too. in [377] , chan et. al. presented a novel security block method that enhances ics security and forensics by adding monitoring and logging mechanisms to plcs, and ics's key components. their results demonstrated that their approach increased the anomaly detection range, speed and accuracy with a slight performance impact and a reduced network overhead. thus, ensuring a more enhanced, efficient and effective forensic investigation procedure. in [388] , yua et al. described the design and implementation of a novel plc logging system. to overcome the inadequacy of information in forensics investigations, their logging system is used to extract data from siemens s7 communications protocol traffic. this logging system also helps in recording the evidence based on the exchanged data between the plc and other network devices. thus, providing key information about the attack source, actions and timelines. the choice of simatic s7 plc is due to their widespread use [389] and successful exploitation by insidious stuxnet malware. in [390] , chan et al. focused on the logging mechanism of a siemens plc, including the siemens total integrated automation portal v13 program (siemens tia portal, known as siemens step-7). the author's methodology performs an effective and practical forensics analysis of the plc. moreover, it focuses on siemens plc along with an installed computer workstation with the siemens tia portal (previously targeted by stuxnet). during the evaluation and analysis of the existing presented security solutions, several limitations can be deduced, presented and discussed as follows: • asymmetric cryptography: introduces overhead in terms of latency and resources. the asymmetric nature of certain cryptographic work [285] , [292] leaves cps's real-time communication prone to network latency and overhead due to delays in the encryption/decryption process. • weak device/user authentication scheme: many of the presented authentication techniques [130] , [73] , [306] , [308] are not very suitable for a secure appliance, due to the lack of multi-factor authentication schemes to protect cps systems from unauthorised users and access. • cps forensics field: are still prone to many challenges including the lack of tools, skills and responses against any potential anti-forensics activity [372] , [373] . • inefficient honeypot & deception system: despite of the recently proposed techniques in [366] , [368] , [370] , [371] , there are no appropriate honeypot techniques that can be specifically adopted to protect cps systems, especially in the wake of industry v4.0. • lack of firewall protection: firewall solutions including [358] , [359] are not very applicable and suitable for employment into the cps domain, nor they offer an effective protection. the best solution requires dynamic firewalls, as well as application and next generation firewall types. • inefficient intrusion detection systems: despite the availability of various ids types such as anomalybased [352] , behaviour-based [345] and signaturebased [333] , these are generally applied within iot-based domains and not specifically designed to protect cps systems. to secure cps, many lessons were learnt as how to maintain and achieve their required security goals. among such lessons: 1) maintaining security services: new lightweight cryptographic solutions are required to secure cps and iocpt in real-time operations but with minimum computational complexity. these cryptographic solutions can help ensure the following security services: • confidentiality: there is a need for a new class of lightweight block or stream cipher algorithms to secure cps resource-constrained real-time communications. recently, a new approach was presented, and it is based on the dynamic key-dependent cipher structure and it requires two or one iteration with few operations [391] , [392] , [393] , [394] . a set of these solutions can be applied at the physical layer [395] , [393] , [394] . • message/device integrity: this includes the protection of cps data and devices' integrity from any physical/logical alteration(s). this can be done by ensuring that the operating system, applications, and software are securely designed and without any flaws to prevent tampering, with strong cryptographic hash functions (sha256, sha384 and sha512). in this end, a new lightweight hash function was presented in [396] and it requires a single round compared to the existing ones. • device/data availability: requires the need for computational resources along with verified backups, and a self-healing ability of cps in such a way to recover immediately from availability attack types. also, maintaining data availability is as necessary [397] , and this can be done by defining a multi-secure connection [398] [403] . 2) strong device/user authentication: an efficient device/user mutual multi-factor authentication scheme is necessary,along with enhancing verification and identification phases based on attribute access-control privileges (least-privilege) to ensure non-repudiation and stronger accountability. 3) protecting digital evidences: this is highly important since most of the advanced attacks focus on eliminating any source of evidence that traces back to the attack source, such as the case of shamoon, duqu, flame and stuxnet malware types [404] , [109] , [75] . furthermore, modern digital forensics solutions should define new countermeasures to preserve digital forensics logs. 4) enhancing security policy: in many cases, cps attacks occurred by insiders (by accident or on purpose). accordingly, all employees must undergo a screening process before recruitment, and have their privileges suspended outside working hours and monitored their actions in the case of advanced tasks. this means that cps security policy should be contain new rules to limit access and to reduce the potential damage. 5) smart cooperation with non-cryptographic solutions: intrusion detection systems should be hybrid in all terms and should be coordinated in an efficient manner with firewalls and dynamic honeypot systems. 6) enforcing compliance: by respecting users' privacy through ensuring data access regulatory compliance that processes cps's big data via clouds, especially when stored by utility providers (trusted third party (ttp)) to prevent any data leakage and users privacy violations. therefore, maintaining a suitable trade-off between users privacy and systems' security and performance, while also ensuring firmer accountability measures [405] , [406] . 7) achieving trade-off: is essential for maintaining systems' availability, safety and security [407] , [408] . therefore, such a trade-off must be achieved based on the combination of these three key requirements while taking into consideration available budget and cost requirements in terms of risk assessment: • availability & safety: both features are linked together since issues related to the safety of a cps system also affect its operational availability. to ensure this trade-off, verified back-ups of computational devices must always be considered in the planning phase, as a second line of defense to handle any sudden service/system disruption (power cuts, blackouts, pumping stoppage), or maintenance (updates, renovation, installation, etc. different security measures could be adopted and enhanced to enhance the protection against various threats and attacks. these include: • prioritization & classification: of critical cps components and assets before assessing, managing and analysing risks to ensure the proper budget spending on the right choice of security measures (basic, standard or advanced) in accordance to their costs compared to the likelihood of the occurrence of a given incident and its impact. • careful financial planning & management: must be conducted in terms of available budget and needed costs/resources to protect critical/non-critical cps assets and components. • lightweight dynamic key dependent cryptographic algorithms: these solutions can be used to to ensure several security services such as message confidentiality, integrity and authentication, which are mandatory during any secure cps communications. this can be done by using new generation of cryptographic algorithms, which were presented in [392] , [409] , [410] . the advantage of these solutions that it can reach a good balance between security and performance level. the robustness against attacks were proved since a dynamic key is used per message (or a set of messages; depend of application constraints and requirements). moreover, this dynamic key is used to produce a set of cryptographic primitives and update cryptographic primitives. this means different ciphertext can be obtained for the same plaintext since different cryptographic primitives are used. while, the effectiveness is validates since these algorithms require only one round iteration and uses simple operations in addition to avoid diffusion operation. the new generation of these cryptographic algorithms reduce the required latency, resources and computation overhead, which help cps devices to preserve better their main functionalities. • defining privileges: this should be considered as the most suitable access control policy, which assigns permissions and rights depending on the users' roles/tasks/attributes when it comes to accessing cps, and removing these access rights upon completing the task or upon the employee's leave. this also includes the use of the least privilege policy. therefore, the definition of privilege should be done based on attribute based access control (abac), where policies combined with attributes specify access authorizations. note that abac makes access control decisions based on boolean conditions of attribute values. it provides a high level of granularity, which is necessary to make cps control access scheme more secure. • strong entity multi-factor authentication: unfortunately, entity authentication schemes that are based on a single factor of authentication (you have, you know, you do or you are) are not resistant enough against authentication attacks, which are increasingly becoming more dangerous. the first line of defense in any system is the entity authentication scheme since any entity authentication attack can lead to confidentiality, integrity and/or availability attack. recently, the concept of multi-factor authentication was applied by combining two or more factors: 1) "you are" which includes device fingerprint, user fingerprint, hand geometry, iris scan, retina scan, etc., and 2) "you have" which includes cryptographic keys to increase its robustness against authentication attacks such as the ones described in [411] , [412] . this mechanism should be an essential requirement in cps systems, in addition to the use of the geographical location. the advantage of these solutions is their ability to reduce false positives, and to complicate the authentication attacks since several factors should be broken instead of one. consequently, this limits the access only to authorised entities and personnel (devices/users). • strong password & dynamic hashing process: passwords are considered as the "you know" authentication factor. however, several attacks such as rainbow and hash table attacks can be applied. in order to prevent them from occurring, after a periodic interval, passwords must be re-hashed with a new dynamic nonce for each user. moreover, a secure cryptographic hash function should be used such as sha-3 and sha-2 (variant 512). this avoids birthday attacks and reduces rainbow/hash table attacks. • secure and protected audit: can be done by using an audit manager system that collects and stores logs in a distributed system. a possible solution that can be applied in this context was presented recently in [413] . this limits any insider attempt against a cyber-physical system and it preserves the digital evidence of internal and external attacks to trace them back. • enhanced non-cryptographic solutions: require the need for hybrid ids/ips systems or ai-based ids/ips (using machine learning algorithms), along with advanced firewalls (i.e application and next generation firewalls) [414] , and dynamic honeypots [415] to prevent any future security breach based on a vulnerability exploit. this can be done by employing lightweight ids/ips and especially the anomaly-based ones. in fact, one should select the anomaly detection algorithm according to the cps device constraints, which can be statistical for limited ones or based on machine algorithm, such as random forest, for powerful cps devices. on the other hand, signature-based techniques can be applied at the gateway (gw) where all network traffic can be analyzed. • secure & verified backups: this is essential to maintain the cps data availability and to avoid data destruction or alteration by ensuring robustness against dos/ddos and ransowmare attacks, especially that such attacks may result in total blackouts as in the case of the us. this can be done by using lightweight data protection solutions such as the ones presented in [399] . • forensic efforts: are essential to retrieve the traces of any occurring attack. also, new solutions against antiforensic techniques should be introduced to preserve any digital evidence [413] . this is realized by recovering logs and monitoring network and system behaviour, which can successfully limit various reconnaissance attempts. however, the newly introduced forensics tools must be compatible with different cps devices' software/hardware, especially resource constrained devices, and must also be resistant against anti-forensics attempts. • enhanced incident response: includes the ability to identify, alert and respond to a given incident. moreover, incident recovery and incident investigation plans should be put in place to mitigate attacks. this provides protection against non-intentional technical and operational failures (power shortage, blackout) through backup plans, and from intentional failures (cyber-attacks), through cert (computer emergency response) [416] , csirt (computer security incident response) [417] , and ircf (incident response and computer forensics) teams [418] , [419] . as such, cps scientists and engineers must undergo further education and training to ensure an enhanced and efficient cyber, physical and computational environment with secure computing and communications. • real time monitoring: running real-time systems using specialised forensics or non-forensics tools and methods is essential to prevent any cyber-physical system accidental or non-accidental failure. this enables constant checking and monitoring of cps devices' behaviour and hence, the detection of any cyber-attack attempt in its early stages. • security check: and employee screening must be done for each employee before and during the job to eliminate and contain any possible insider/whistle-blower attempt. therefore, signing agreements [420] such as non-disclosure agreement (nda), confidentiality agreement (ca), confidential disclosure agreement (cda), proprietary information agreement (pia) or secrecy agreement (sa) is highly recommended. such security checks are essential especially in critical areas such as nuclear power plants [421] . • periodic employee training: includes periodic awareness training of ics and plc employees on the best cyber-security practices based on their level and knowledge, with the ability to detect any suspicious behaviour or activity. moreover, employees must be trained over various security threats and wrong practices such as avoiding the installation of any software update, how to counter social-engineering and phishing attempts, while also maintaining accountability in case of wrong doings. • periodic pen testing & vulnerability assessment: must be maintained in a periodic manner to enforce system auditing, detecting threats, and mitigating them in a real-time manner before they are discovered and exploited by an attacker under the zero-day exploit conditions. • periodic risk assessment: must also be enforced to study the likelihood and impact of a given risk against a critical/non-critical cyber-physical system based on a qualitative or/and quantitative risk assessment and a cost-benefit analysis (cba), to classify the risk based on acceptable/non-acceptable level and to mitigate it as early as possible. • up-to-date systems: cyber-physical systems must be kept up-to-date in terms of software, firmware and hardware through constant verified patches and updates [422] . moreover, such systems must be secured at different levels of their implementations (layered protection), with the ability to mitigate and tackle a given attack to reduce its impact and prevent further escalation and damage. furthermore, usb ports must be physically and logically removed to prevent any payload injection, and plc systems behaviour and activities must be constantly monitored for any suspicious/abnormal behaviour [422] . • ai security solutions: artificial intelligence is used in ids/ips anomaly detection schemes or in "you are" or "you do" entity authentication schemes. in fact, ai is now being considered as a game-changing solution against a variety of cyber-physical attacks targeting cps systems, devices and communication points. despite the time consuming process of training an ai system, the accuracy of detection and prevention are much higher than any human intervention. recent advancements in machine learning, and especially in deep learning, can make cps systems more secure, robust and resistant against cyber-physical attacks. • defense in-depth: most of the existing solutions offer protection against a single attack aspect or a security requirement. instead, there is need for a multi-purpose security solution that ensures the best protection at each operational layer (perception, transmission and application) of cps. for example, the two most known international standards for functional safety in the automotive industry, the iso 26262 [423] and iec 61508/edition2 [424] , [425] should be respected and applied. this ensures a safe cps implementation based on the functional safety, which includes the safety integrity level (sil) basics [426] which in turn, rely on the probability of failure on demand (pofod) and the risk reduction factor (rrf) to ensure a much more accurate and efficient hazard and risk analysis (hra) [426] , [424] , mainly in the electronic control units (ecu) [427] , [428] ). • cps security & privacy life-cycle: finally, to sum up this work, our paper presents a combined operational and functional safety/security (ofss) life-cycle that ensures a successful and safe cps employment as seen in fig. 9 ). this framework is derived from iso 26262 and iec 61508/edition2 protocols and their approach towards ensuring the cps functional safety/security. the framework consists of six main phases: -phase 1: devising a plan to design a cps system by following a well-defined time-table and schedule in accordance to the needed budget and corresponding costs. this also requires the assistance of humans (businessmen, engineers, workers, etc.) and nonhuman assets (vehicles, machines, etc.). -phase 2: requires a careful risk and hazard analysis, which consists of a proper risk management and asset classification, as well as the mutual connection between the two to ensure an accurate decision-making over the adoption of the right security measures/counter-measures. -phase 3: defines the right functional safety, security and dependability requirements along their key components/mechanisms that are essential to mitigate a risk/hazard and to reduce their likelihood and impact in case of their occurrence. -phase 4: consists of evaluating the performance of cps in terms of the recently introduced functional safety, security and dependability measures in an operational manner where a performance management and analysis will be conducted to ensure a proper/mutual security-performance, safetyperformance and dependability-performance tradeoffs. -phase 5: once the performance is evaluated, the cyber-physical system is tested and validated to detect any remaining software/hardware bug, security gap, or performance issue to apply the required modifications before being commissioned. if the testing is unsuccessful, the process restarts again to find where the issue took place. if successful, the cps will head towards further commissioning before being officially deployed. -phase 6: upon successful testing, the deployed cps system will undergo a trial phase to evaluate its operational status, while monitoring its behaviour and performance before becoming fully operational. cps systems are key components of industry v4.0, and they are already transforming how humans interact with the physical environment by integrating it with the cyber world. the aim of implementing cps systems, either within or outside iot (iocpt), is to enhance the products' quality and systems' availability and reliability. however, cps systems suffer from various security and privacy issues that can degrade their reliability, safety, efficiency, and possibly hindering their wide deployment. in this paper, we first overview all components within cps systems and their interconnections including iot systems, and we focus on the main cps security threats, vulnerabilities and attacks, as related to the components and communication protocols being used. then, we discuss and analyze the recently available cps security solutions, which can be categorized as cryptographic and non-cryptographic solutions. next, we 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computing the safety integrity level (sil) for turbo machinery protection electronic control unit us patent 9,036,026. declare the following financial interests/personal relationships which may be considered as potential competing interests: jean-paul yaacoub is a master student in the department of electrical and lebanon. hassan noura is a research associate in the department of electrical and computer engineering at the american university of beirut (aub), lebanon. nesrine kaaniche is lecturer in cybersecurity and expert in cryptographic solutions at the university of salford, school of computing ali chehab is a professor in the department of electrical and key: cord-332181-k90i33gp authors: degeling, chris; kerridge, ian title: hendra in the news: public policy meets public morality in times of zoonotic uncertainty date: 2012-12-29 journal: soc sci med doi: 10.1016/j.socscimed.2012.12.024 sha: doc_id: 332181 cord_uid: k90i33gp public discourses have influence on policymaking for emerging health issues. media representations of unfolding events, scientific uncertainty, and real and perceived risks shape public acceptance of health policy and therefore policy outcomes. to characterize and track views in popular circulation on the causes, consequences and appropriate policy responses to the emergence of hendra virus as a zoonotic risk, this study examines coverage of this issue in australian mass media for the period 2007–2011. results demonstrate the predominant explanation for the emergence of hendra became the encroachment of flying fox populations on human settlement. depictions of scientific uncertainty as to whom and what was at risk from hendra virus promoted the view that flying foxes were a direct risk to human health. descriptions of the best strategy to address hendra have become polarized between recognized health authorities advocating individualized behaviour changes to limit risk exposure; versus populist calls for flying fox control and eradication. less than a quarter of news reports describe the ecological determinants of emerging infectious disease or upstream policy solutions. because flying foxes rather than horses were increasingly represented as the proximal source of human infection, existing policies of flying fox protection became equated with government inaction; the plight of those affected by flying foxes representative of a moral failure. these findings illustrate the potential for health communications for emerging infectious disease risks to become entangled in other political agendas, with implications for the public's likelihood of supporting public policy and risk management strategies that require behavioural change or seek to address the ecological drivers of incidence. hendra virus is a zoonosis e which means it can be transmitted across species boundaries from its natural host (flying foxes or fruit bats) to cause infection and disease in domestic animals and people. emerging bat-borne infections such as hendra are a pressing global public health concern (wong, lau, woo, & yuen, 2007) . hendra is highly lethal to humans and endemic in australian flying fox populations. like other new and re-emerging infectious diseases, changes in the incidence and cross-species transmissibility of hendra are likely to hinge on the ecological impacts of natural events and human activities (jones et al., 2008) . indeed it is clear that hendra has 'spilled' over from flying fox populations into horses, and then people and pet dogs through their increasingly intense interaction in rural and peri-urban areas. importantly, the impacts of these interactions are bi-directional; anything that induces 'stress' in flying foxes is thought to amplify viral shedding into the environment (parrish et al., 2008) . efforts to disrupt flying-fox encroachment on human settlement, therefore, are likely to increase the risk of human infection. current hopes of prevention rest on the development of a vaccine for horses, the only confirmed intermediate host for hendra transmission to humans. in the interim, public health responses to hendra have focussed on education and behaviour modification amongst high-risk groups such as veterinarians, horse owners and people who work in equine industries, and the institution of disease surveillance and quarantine measures involving both human and animal health sectors (adamson, marich, & roth, 2011) . since hendra virus first emerged in 1994 there have only been four human deaths and seven human infections. however concerns in australia about the risks to human health escalated sharply in 2011 when outbreaks in horses occurred over a greater geographic area and at a far higher frequency than past 'hendra seasons' (field, crameri, kung, & wang, 2012) . concern about the risks posed by the bat-borne virus were further heightened by the subsequent and unexpected discovery of a pet dog with a naturally acquired infection (tapim & withey, 2011) . many australians, particularly those living in regional areas, already consider flying foxes to be a noisy and unhygienic pest. towns and city suburbs in north-eastern parts of the country can find themselves 'under siege' from large groups of roosting 'fruit bats' e with these 'camps' or colonies sometimes comprised of several thousand individuals. aside from the impacts of noise and faeces, flying fox colonies can 'fly in and feed' on commercial orchards causing significant economic losses for fruit growers. for this reason there has been a longstanding practice of shooting flying foxes and disrupting their colonies with sirens, smoke bombs and helicopters to deter them from congregating in agricultural and residential areas. whereas in the past diseases of wild animals were thought to pose limited risk to humans, the connection between human activity e particularly changes in land use e and changes in patterns of infectious disease is becoming increasingly clear (newell et al., 2005) . the urbanisation of coastal habitats is thought to have had a number of effects on flying fox populations in eastern australia e restricting access to their normal foods and forcing them to both turn to, and increasingly rely on, commercial orchards and urban gardens for sustenance (plowright et al., 2008) . and because food is scarce flying foxes are also less inclined to migrate, leading to the formation of permanent camps in agricultural and residential areas. these effects are also exacerbated by natural events that further limit the availability of natural and horticultural food resources, such as cyclones and floods (plowright et al., 2011) . as large groups of flying foxes congregate in and around human settlements this gives the impression that the population is thriving, whereas this is more a result of reduction in their natural habitat, and several species of flying foxes are, in fact, vulnerable to extinction (welbergen, klose, markus, & eby, 2008) . for this reason, since 1986 in nsw and 1994 in queensland, flying foxes camps have been legally protected from human interference to try and rehabilitate the population. in 2008 the queensland government took the further step of refusing all applications by farmers for permits to shoot flying foxes to protect their crops, both on ecological grounds and because attempts to break up established camps may be counterproductive. it was argued that any measures that stressed flying foxes would increase the risk of hendra spilling over into horses; and dispersing specific camps would likely be ineffective as there would be nothing to stop the colony re-establishing itself nearby, and once again in conflict with human settlement. thus, what was designed to be legislation to protect a vulnerable species of native animal became a policy instrument with which to try and limit zoonotic risk exposure. this transition from conservation-focussed environmental policy to public health policy has been incremental, such that the policy aim was not to solve either problem but manage areas of emerging concern. yet as people directly affected by flying foxes have struggled to 'live with' the growing throngs of unwelcome neighbours, many have come to believe that by protecting flying fox populations and advocating the adoption of low risk behaviours towards them, governments and health authorities have put the health and welfare of another species above that of human populations. experiences with bovine spongiform encephalopathy (bse) and severe acute respiratory syndrome (sars) indicate that policymaking for a new zoonotic disease is always difficult and prone to polarising different stakeholders in affected communities (phillips, bridgeman, & ferguson-smith, 2000; singer et al., 2003) . a key feature in matters surrounding animal disease control is that radically different policy responses e such as wholesale culling or vaccination e can typically be presented as plausible points of intervention. for this reason decisions surrounding what should be done about new or pressing zoonotic risks are often contested, and finding the right balance between over-caution, laissez-faire approaches, and determining the weight given to different socioeconomic factors can be difficult. for example a lack of due diligence can expose the population to the risk of infection for far longer than necessary, as was the case with bse. conversely, the overzealous application of the precautionary principle can destroy the livelihood of a population, impact its food supply, limit development, and entrench or exacerbate socioeconomic disadvantage (world health organization, 2004) . furthermore, when the zoonotic risk is new, attempts to explain the choice of policy are likely to be further complicated by uncertainty regarding the precise risk of infection, the drivers of disease emergence, and the measures needed to control the risk of infection. therefore public support for policies that disrupt people's lives and communities or place precautionary limits on the development of natural resources might depend on their understanding of the causes and risks of zoonotic outbreaks, their trust in government agencies, and the likely consequences for them of different public health responses. in this regard news media are an important source of information for the public (brodie, hamel, altman, blendon, & benson, 2003) , particularly with regard to the complex relationship between the environment and human health and with regards to the risk posed by animals. for not only does the media reflect the issues that concern people, it also impacts upon the issues the public thinks about, and the criteria through which they think about them e influencing people's understanding of what is at stake, of who or what is to blame, of who is at risk, and of what can be done to address the situation (entman, 1993; scheufele, 2000) . in this regard, while individual journalists my privilege independence, accuracy and balance, media organisations are rarely neutral and can both influence public opinion themselves, or be used by industry, politicians and interests groups to influence public perception of particular issues and/or promote their own ends (callaghan & schnell, 2001; terkildsen, schnell, & ling, 1998) . therefore the effects of how the media chooses to raise to public prominence and then 'frame' events and opinions surrounding a new health issue such as an emerging zoonosis can be recursive. for example because elected officials, politicians and policy advisors are responsive to public opinion, public perceptions about the causes of a disease threat like hendra virus might influence the level of public support for specific health policies, and, thereby, ongoing political debate (gollust, lantz, & ubel, 2009; harrabin, coote, & allen, 2003) . in this paper we analyse representations in the australian media of the causes and consequences of the emergence of hendra as a zoonotic risk, focussing on how the unavoidable uncertainty about its causes and likely consequences shaped perceptions of the health policies put in place in the attempt to mitigate the risk of human infection. in short we seek to examine media representations of an infectious threat within a broader policy context. because flying foxes are a highly visible, widespread and relatively novel source of infectious risk for humans, the emergence of hendra virus presents an opportunity to track and compare media representations of disease 'events', health policy goals, political discourses and public opinions in ways that are difficult for noncommunicable diseases. in this our research is consistent with other reports examining media portrayals of the health risk and scientific and policy uncertainty associated with contested environmental exposures (mayer, 2012) and emerging infectious diseases (eids) (daku, gibbs, & heymann, 2012; hilton & hunt, 2011; washer, 2010) . to identify australian media coverage of issues surrounding the emergence of hendra virus, the database factiva was searched using the following terms as textwords: (hendra virus) or (flying fox*) or (fruit bat*) for the period 1 january 2007 through 31 december 2011. a news filter limiting content to the region of australia was then applied identifying more than 10,000 items. because we were focussing on representations of hendra and associated public policy, further subject filters were applied to restrict the sample to political and general news, limiting the corpus to just over 6000 articles. full-text reports from 9 news media sources from areas affected by hendra virus outbreaks were then downloaded. the sample includes 2 national media organizations . pretesting confirmed that this search strategy would produce a larger and more heterogeneous sample of news reports, while still including coverage that focussed more narrowly on specific zoonotic events. from the resulting corpus of 1383 articles we discarded 43 duplicates and 356 reports that were not immediately relevant to hendra virus or flying fox populations (such as those that refer to the zip-line apparatus known as a 'flying-fox' or businesses or products with 'flying fox' in the title), after which 984 unique articles remained to be analysed. the media sample was then read, catalogued manually, and cross-compared by the lead author in order to identify and track prominent concepts, differences, and themes. next, both authors manually cross-coded a pilot sample (n ¼ 40) of the media corpus for specific types of content to confirm and to extend the preliminary thematic analysis. articles then were coded for: mention of horses, flying foxes/fruit bats or hendra virus mention of debates about flying fox control report of distal ecological causes (loss of natural habitat) for the emergence of hendra virus or the possibility of viral mutation mention of ignorance about hendra virus amongst scientists, healthcare providers or members of the public reference to government inaction as a factor contributing to the hendra problem reference to people's health and welfare not being high enough on the political agenda. these codes were both emergent and informed by similar media analyses (for example gollust & lantz, 2009; washer, 2004) . because hendra events tend to occur seasonally (from winterspring), the calendar year was chosen as the unit of analysis. the results from coding were then tabulated in matrix form, cross referenced and displayed visually as descriptive statistics in charts to aid interpretation. regular discussions among the authors served to generate additional enquires and to validate insights as they emerged. this approach is consistent with ethnographic content analysis, a qualitative research method for interpreting documents within the context of their use, which enables researchers to generate insights about how documents promote particular ways of understanding, interpreting and responding to an issue or event such as the emergence of a new disease from both numerical and narrative data (altheide, 1987) . with these concepts and types of content in mind, our analysis of the 984 articles proceeded through several cycles of immersion and crystallization of insights e a research process comprised of repeated readings and comparisons across and between newssources, discussions amongst the authors, periods of testing of alternate explanations, and then re-immersion within the research materials (lecompte & schensul, 1999) . coverage of issues surrounding hendra virus and flying fox populations in the media sample more than doubled in 2008, then plateaued before rising sharply in 2011 (table 1 ). this two-phase pattern can be attributed to the tragic deaths from hendra virus of the veterinarians ben cuneen [2008] and alister rodgers [2009] ) report on debate about flying fox control does mention hendra virus 0 6 (3.6) 13 (7.7) 9 (5.5) 90 (20.5) report suggests that people's welfare is not high enough on the political agenda 4 (9.1) 6 (3.6) 8 (4.7) 6 (3.7) 47 (10.1) report suggests that 'government' inaction is contributing to the problem 3 (6.8) 5 (3.0) 1 (0.6) 9 (5.5) 38 (8.6) during the one or two outbreaks that occurred in each of these years; and to the unprecedented number and geographic spread of hendra events in 2011. table 1 shows the results of cross coding for types of content and the frequency with which specific constellations of information appear each year in the media sources sampled. given that flying foxes were first identified as the natural host of hendra virus in 1996 (young et al., 1996) it is surprising to find that until 2011, the media paid little attention to the link between hendra virus and flying fox populations. in previous years reports about flying foxes tended not to mention hendra, but focussed on the impact of flying fox populations on horticultural enterprises and residential areas. in these reports first hand testimony and events on the ground were used to framepublic perceptions of this animal's protected status, and the bureaucratic and 'hands off' approach of the government agencies to this issue. at the same time reports that are primarily about hendra virus during this period typically focus on 'unfolding' zoonotic outbreaks, suspected cases of hendra infection, quarantine orders, human exposure and disease, experimental treatments, and the impacts of these incidents on individuals. it is not until the unprecedented number of hendra outbreaks in 2011 that the relationship between hendra virus infection and contact with flying foxes becomes an item of sustained interest in our media sample. in 2011 with 17 zoonotic events across two states, 21 dead horses, and upwards of 70 people potentially exposed to the virus through their dealings with sick and dying animals, discussions about the potential role of flying foxes as hendra carriers became firmly established as a central part of the media discourse. although the relative prominence given to different types of nonhuman animal changed across the years sampled. by 2011 news about hendra virus and flying foxes suddenly began to be described in reference to each other in the majority of news reports (table 1) . the nonhuman species most often linked to hendra virus in the media sample was the horse, both as a victim of zoonotic outbreaks and as the intermediate host for human infection (see fig. 2 ) . as the link between hendra and flying foxes was given greater prominence in the media, representations of the position and status of flying foxes and horses also began to change. an article in the sydney morning herald in 2009 provides a typical example of the more cautious approach taken in the earlier years sampled: hendra is not highly contagious but is very often fatal. carried by fruit bats, it infects horses, which can then transmit the disease to humans through bodily fluids. (marriner, 2009, p.2) in this quote flying foxes are identified as the source of the virus and the role of horses as intermediate hosts is well defined, as is the mode of transmission for human infection. at this stage the media are at pains to make it clear that hendra virus is a fatal and devastating disease of horses that can, on occasion, infect and kill people who work in equine industries. flying foxes are not portrayed as an immediate or direct risk to human health but as an environmental factor, they are to be understood as the inadvertent reservoir of equine infection. although horses continue to be a feature of hendra news stories, by 2011 it was not uncommon for some subtle distinctions in the natural history of the disease to be dispensed with. rather than intermediate hosts, horses began to be portrayed as victims of a dangerous 'bat-borne' disease; their role as intermediate hosts is implied rather than explicitly stated, as shown by this 2011 report in the australian: the outbreak of hendra virus that has killed six horses and exposed 26 people to infection has reached the outskirts of brisbane and is the most virulent in the known history of the fruit bat-borne disease. (barrett, 2011a, p.3) at the same time as the media start to problematize the role of flying foxes in hendra outbreaks column inches begin to be devoted to identifying the source of each equine case. reports begin to note forensically significant details, often with direct quotes from the investigating scientists, much in the same way a crime reporter might ask a detective to profile a likely suspect and then "set the scene" of a murder. "the infected horse was grazing in a small paddock containing flowering and fruiting trees, where flying foxes were active." ("national snapshot: almost 50 waiting for hendra results," 2011, p.14) these descriptions of 'place' resonate closely with public health recommendations given to horse owners to place feeding bins and water troughs under cover and keep their horses out of paddocks with flowering or fruiting trees, if possible. yet translating this advice into practice sometimes only served to increase people's sense of anxiety and powerlessness, and their anger with the government. for example one property owner in gayndah told the courier-mail: "the head vet of queensland is saying, 'keep your horses away from the bats'. well, i'm doing that but the bats aren't keeping away from my horses" mrs robertson said. "fifty thousand infected bats are pooping on my horses, their grass and their water every day." (robertson & hall, 2011, p.8) portrayals of uncertainty, risk, and the drivers of incidence public acknowledgement of scientific uncertainty about hendra virus was also a feature of the media coverage in 2011, heightening the sense that events were out of control (table 1 ). in previous years, statements about expert uncertainty were either general reflections about the lack of knowledge of how horses acquired the virus, or they had a sharp clinical focus e describing how little experience health professions had in dealing with human hendra infections. the former were typically framed as a matter of scientific curiosity, the later a matter of critical urgency that had immediate impact on people's lives. but during 2011 the media spotlight on hendra returned to unanswered questions surrounding the health and management of other species. even as scientists and veterinarians were described as being "baffled" by hendra virus, they were required to publically speculate on two issues: the implications of finding a pet dog with a naturally acquired infection, and theorise as to why there were so many equine cases that year. that scientists interviewed by the media appeared to be taken aback by the discovery of the canine case drew this response from the queensland premier, at the time, anna bligh: "the scientists themselves are being very honest with us. they're telling us that science does not fully understand every part of this disease. we, as human beings, have had to cope with that in our past, we've conquered diseases before, i believe we will conquer this one." (miles, macdonald, & helbig, 2011, p.2) throughout the same period members of the public were increasingly portrayed as being forced to deal with the effects and risks of hendra outbreaks with inadequate information about the disease. reflecting the statements of the experts, the concerns of the public expressed in the media were, for the most part, articulated around what people should do to protect themselves and their animals from hendra events, particularly as pet dogs now appeared to catch the disease, and therefore might be a risk to humans. as reports emerged that the infected dog had been destroyed and the media sought to highlight existing scientific literature that showed that dogs, cats and guinea pigs could be infected with the virus under "controlled" laboratory conditions, repeated assurances by health authorities that there was minimal risk of catching hendra from animals other than horses began to wear thin. with this single canine infection, in the words of one reporter: "the bats' presence has become all the more sinister". (macdonald, 2011, p.5) despite increasing attention to the link between hendra virus and flying fox populations, for the most part media reports of the hendra outbreak in 2011 infrequently gave any consideration to nonproximal factors for disease emergence. while earlier reports, in 2007 and 2010, regularly pointed to land clearing and environmental events such as prolonged drought, floods and cyclones as explanations for flying foxes congregating in residential and agricultural areas, and approximately one in four articles describe habitat loss as inevitably increasing the risk of hendra jumping species, there is a clear and precipitous decline in such reports in 2011. of the 440 reports analysed from 2011, only one in 10 has any mention of these types of ecological drivers for disease emergence or the increasing prevalence of hendra outbreaks (table 1) . indeed by 2011 the media focus is almost always on events 'as they happen' e the vast majority of reports doing little more than point to the presence of flying foxes and horses in the same locality as the most important characteristic of a causal story of disease or of public health risk. finally cross-coding the media sample revealed that issues surrounding the risk of hendra virus to human health became a dominant feature of reports that specifically address, or at least in some way refer to, the continuing controversy about the control of flying fox populations (fig. 2) . while the frequency with which media reports describe the level of dissatisfaction with the government's policy of flying fox protection remains much the same from 2010 onwards, in 2011 heightened uncertainty about who and what was at risk from hendra virus increasingly became a factor of some importance to assessments of the queensland government's response to the unfolding situation. as the lack of knowledge about hendra virus became an increasingly prominent feature of debates about what should be done about the encroachment of flying fox populations on human settlement and agriculture, so did assertions in the media by members of the public and politicians that concern for the health and welfare of people affected be flying foxes was being ignored in deference to the interests of another species. in 2011 key features of the justification for the policy of not moving or culling flying foxes increasingly became contested in the media e particularly the claim that flying fox numbers were in decline and the claim that attempts to disperse flying fox colonies would spread the disease. for those wanting to repeal protective legislation, assertions that flying fox numbers were not falling could be backed up by simple first hand observation. people just had to come to affected areas and look for themselves. what they would find, according to the mayor of charters towers, was: "these bats aren't endangered, they are in plague numbers and more and more communities are feeling the effects of bat infestation." (gilham, 2011, p.5) proponents of policy change to protect the public against batborne diseases also dismissed in the media claims that culling or dispersing flying foxes would spread hendra virus. even as the premier or a government spokespersons re-iterated publically that they would: "respond to the outbreak of hendra virus on the basis of the best-informed science that we can access" (barrett, 2011b, p.7) , what constituted evidence became a point of contention. those seeking to remove protections told the media that current policies were based on a set of (unproven or unsound) assumptions. in support of this, scientists themselves, as is their fashion, acknowledged the limits of scientific certainty e noting that they did not know how horses caught the virus, and that they lacked incontestable proof that disrupting bat colonies would lead to its spread e something admitted by the chief veterinarian of queensland (to the significant discomfort of the previous labor government). in contrast, politicians supporting the 'rights' of land-owners to government protection from flying foxes, such as the independent member of parliament, bob katter, were able to tell press conferences that fruit bats had been removed from towns for years before the current ban without causing an outbreak. and of claims by scientists, health authorities and government spokesperson that these types of interventions could heighten zoonotic risks, katter noted in the townsville bulletin: "if you were looking for a more stupid claim you couldn't find it. we've got empirical evidence on our side, all they've got is conjecture on theirs". (galloway, 2011, p.15) a prominent advocate for bat culling known for his theatrical turn of phrase, one week earlier katter framed the deeper issues in the following terms in the courier-mail: "if it comes to a choice of our children dying or us going out there and killing flying foxes, then i have a very grave moral problem about not going out there and killing the flying foxes," mr katter said. (miles, helbig, & michael, 2011, p.11) pointedly, a number of other politicians even claimed that calls by scientist and the government for more research on hendra was further evidence that current policies put the needs of flying foxes above the health and welfare of 'real' people: "why don't we, as an immediate first response, reduce flying fox numbers? . why is the government throwing money at research, which will not protect families now?" ("hendra virus claims another victim," 2011, p. 3) the newsworthiness of the hendra outbreak in 2011 and the growing sense of uncertainty expressed by those charged with managing the situation created a media forum in which previously distinct health and environmental issues related to flying foxes became redefined as one and the same problem. consequently, even as a large pool of research funding was announced for projects related to protecting people and communities from hendra virus, this only served to highlight the absence of direct government action. this study employs ethnographic methods to evaluate news coverage of hendra virus and flying foxes in australia. past studies indicate the australian media have a tendency to use alarmist headlines in matters relating to infectious disease (holland, blood, imison, chapman, & fogarty, 2012) . nonetheless our impression is that the australian news media did not 'over-hype' the risks posed by hendra virus; a finding that echoes uk media coverage of the recent swine flu event (hilton & hunt, 2011) . what is noteworthy however was the way politicians, interest groups and other 'policy entrepreneurs' used the media to challenge the established policy community surrounding public health, animal disease control and wildlife management to put controlling flying fox populations higher on the public agenda (kingdon, 2011) . as the number of hendra outbreaks increased in 2011, the values and expertise of public health officials, epidemiologists, wildlife ecologists and environmentalists were questioned, as was their current choice of actions. several features of how hendra outbreaks and debates about flying fox population control were reported in the media permitted opponents of the current policies and practices to reframe the issues, recast debate about what types of actions needed to be taken, and then prime the public as to how these actions could and should be justified in the face of imperfect scientific knowledge. media representation of hendra virus enabled the issue to become not simply a policy or public health issue e but a moral one. by this we mean the discourse surrounding hendra virus and flying fox populations became a debate about what is and should be valued, what is important and worth protecting, and, more broadly, what is the 'right' thing to do. throughout the period sampled media reports increasingly depict the encroachment of flying foxes on human settlement as being the source of the hendra problem. thus while horses remained a risk to human health, rather than being the intermediate host they become fellow victims of the disease. in contrast, the role of flying foxes in hendra transmission and disease ecology becomes increasingly prominent in media coverage, as shown by fig. 1 . as a species they were stigmatized and pathologized. news media increasingly depicted flying foxes as an invasive plague, both reflecting and potentially re-enforcing community sentiment that they are unhygienic disease carrying vermin. and ecological drivers that bring these native wild animals into increasing contact with human settlement, such as land clearing, were increasingly backgrounded. the small number of articles that did identify distal causes for emergent disease neither suggest, nor reflect upon, the relationship between human activities and novel zoonotic events as being a point for plausible preventive interventions. in contrast to the number of reports that advocate some form of control for flying fox populations, only a handful of reports raise the possibility completely removing horses from flying fox habitats as a possible solution. instead by emphasising proximal causes, flying foxes become increasingly blamed for the emergence of poorly understood and increasingly unpredictable emerging zoonotic disease. only a handful of reports offer any attempt to describe the implications of habitat loss for planning policy and disease prevention. this pattern of media reports externalising the origins and threats posed by new infectious diseases is, of course, not unique, but is consistent with media representations of other zoonoses and emerging infectious diseases (eids) (joffe, 2011) . unlike previous studies of zoonotic events such as sars or swine flu, where the strength of the human-to-human link dominates media representations of risk, in the case of hendra virus the role of nonhuman animals in disease emergence was the most salient feature. rather than being characterised and understood as a consequence of modernity and globalisation e such as is said to be the case for other eids (washer, 2010) e the threat posed to human interests by another species of animal became the dominant 'frame' in the media. as was also the case in news reporting about issues surrounding other late 20th century diseases, analysis and critique of the policies, actions and inactions of the government eventually become a central part of the causal story, and, thereby, of increasing moral significance. against this background calls for further research, and for nuanced responses to hendra virus that took account of human, animal, and ecological factors only seemed to reinforce the idea being put forward in the media by opponents of the current policy responses that scientists and environmentalists, rather than the concerns and plight of the very people at risk of disease, were dictating the terms of flying fox and hendra management strategies. questions in the media about the value orientations of those in authority offered an alternative framework through which their actions could be judged, potentially eroding public trust in the government and their stated commitment to evidence-based policymaking. according to this view, the risk of hendra virus was not voluntarily assumed by affected individuals, but forced on them by current government policies. such causal stories, of course, tend to have far greater political potency than discourses reflective of aetiological uncertainty as harmful consequences are viewed as being the product of human intentions, rather than the products of chance (stone, 1997) . in policy terms, the unprecedented number of outbreaks in 2011 seems to have served as a "focussing event" that raised the public visibility of both hendra virus and flying fox management and made them a pressing public health issue (birkland, 1998; kingdon, 2011) . the policy rationale of seeking to protect and promote the collective interest was poorly represented in the media; the focus instead was on the immediate impacts on individuals and discrete communities. in these terms the costs of current protections for flying foxes were being borne by an increasingly visible and vocal segment of the population; the benefits were diffuse, unpredictable, unrecognised by the electorate, and therefore difficult to defend politically (oliver, 2006) . as the amount of coverage of hendra related issues escalated throughout 2011, government spokespersons began to struggle to frame the terms of the debate. those charged with providing information to the public fell into the trap of emphasising the scientific aspects of the health threat, rather than the real world implications. from a public health perspective, the message then became that hendra virus and flying foxes presented a serious but unquantifiable risk to human health, and, as a consequence of the government's cautious and "hands off approach", an imminent threat to communities. at the heart of this transition, media portrayals of scientific uncertainty, moral ambiguity and inconsistencies in descriptions of the government's policy position became linked to a wider political discourse surrounding the control of flying fox populations. opponents of current policies were able to use the media to point to how government legislation was protecting flying foxes, while discounting the implicit policy goals of limiting the environmental drivers of hendra risk exposure. in these terms opponents of the current policies were able to appeal to a set of established norms, tropes and 'rhetorics' for rescue in public health interventions, creating a moral weight for action against flying fox populations in ways that economic arguments and environmental policies had not. as novel zoonotic events such as canine infection remained unexplained, hendra virus and the increasing presence of flying foxes in residential and horticultural areas increasingly became portrayed as a pressing moral issue that required a moral, rather than a scientific solution. against the government's scientific uncertainty and apparent inaction in deference to what they thought was likely to happen in the future, their political opposition offered moral certainty and direct immediate action. people's livelihoods and their 'way of life' were being sacrificed for the good of another species of animal: one that posed a threat to human heath. for the safety and wellbeing of humans, particularly those being forced to live in and around flying foxes, had to be prioritised over the welfare of another species of animal, irrespective of whether interventions intended to resolve their health risks and promote their wellbeing actually did so. this research has several limitations. first given our focus on reactions in selected news media to zoonotic events, health communications and public policy, we were not able to capture the nuance that a broader analysis of press releases, policy documents and the grey literature on hendra virus and flying fox population control would illuminate. second we did not seek to include the political leanings, funding relationships and commercial affiliations of the news organisations examined in the analysis. in this regard australia, and especially queensland, does not have a competitive and diverse media market. ownership of news media is highly concentrated. aside from the news provided by the government funded national broadcaster, the abc, many major towns and cites are served by only one newspaper. this may have coloured how statements by member of the public, politicians, scientists and other experts were framed and presented in the media. finally our focus was on hendra virus in australia. without further research it is doubtful our findings can be generalised to the coverage of other bat-borne emergent zoonotic diseases such as nipah virus in malaysia and bangladesh or sars-like corona virus in south-east asia. what this study reveals is the extent to which the media can be used to construct the risks of hendra virus not as a scientific problem but as a moral question; that is, a problem that requires moral solutions. given that any government measure aimed at protecting public health involves moral judgements that are legitimated through political processes (leichter, 2003; oliver, 2006) , the infectious risk posed by wild animals to agricultural production and human populations is undoubtedly both a political and a moral issue. but the moral dimensions of this issue, and the development of policy responses to it, are deeply contested and heavily influenced by media representations of the link between human health, animals and the environment. our findings illustrate the potential for health communications around emerging infectious disease risks to become entangled in other political agendas and conflict with widely held human values, with implications for the public's likelihood of supporting public policy and risk management strategies that require behavioural change or seek to address the ecological drivers of incidence. more broadly, our research illustrates the value of methodologies from the social sciences to expand the relevance of the one world one health public health agenda to reflect lived realities and the needs of communities. one health in nsw: coordination of human an animal sector management of zoonoses of public health significance deadliest hendra closer to capital. the australian. canbera: act news limited row over bat culling as another horse dies. the australian. canbera focusing events, mobilization, and agenda setting health news and the american public assessing the democratic debate: how the news media frame elite policy discourse. political communication representations of mdr and xdr-tb in south african newspapers framing: toward clarification of a fractured paradigm ecological aspects of hendra virus katter's threat to sue state cyclone yasi: the recovery victim feels sorry for bat the polarizing effect of news media messages about the social determinants of health health in the news: risk, reporting and media influence hendra virus claims another victim uk newspapers' representations of the 2009e10 outbreak of swine flu: one health scare not over-hyped by the media risk, expert uncertainty, and australian news media: public and private faces of expert opinion during the 2009 swine flu pandemic public apprehension of emerging infectious diseases: are changes afoot? global trends in emerging infectious diseases agendas, aletrnatives, and public policies analyzing and interpreting ethnographic data evil habits" and "personal choices": assigning responsibility for health in the 20th century bats out of hell e amid the stench, noise and threat of disease, these residents say they're living a nightmare. the courier-mail deadly virus could spread here. the sydney morning herald relax and take a deep breath': print media coverage of asthma and air pollution in the united states family's hendra heartache goes on e son's pet dog faces a death sentence. the courier-mail national snapshot: almost 50 waiting for hendra results2011 a conceptual template for integrative humaneenvironment research the politics of public health policy cross-species virus transmission and the emergence of new epidemic diseases the bse inquiry. london: stationery office reproduction and nutritional stress are risk factors for hendra virus infection in little red flying foxes (pteropus scapulatus) urban habituation, ecological connectivity and epidemic dampening: the emergence of hendra virus from flying foxes (pteropus spp to cull or not to cull is the burning question. the courier-mail agenda-setting, priming, and framing revisited: another look at cognitive effects of political communication policy paradox: the art of political decision making hendra dog case sparks crisis meeting. abc news interest groups, the media, and policy debate formation: an analysis of message structure, rhetoric, and source cues representations of sars in the british newspapers emerging infectious diseases and society climate change and the effects of temperature extremes on australian flying-foxes bats as a continuing source of emerging infections in humans. reviews in medical virology, 17, 67e91. world health organization serologic evidence for the presence in pteropus bats of a paramyxovirus related to equine morbillivirus funding for this research was provided by the nhmrc centre for research excellence in critical and emerging infectious disease. chris degeling's position at the centre for values, ethics and the law in medicine at sydney university is part funded by a grant from alberta innovates e health solutions awarded to melanie rock. sources of funding had no involvement in design, data collection, analysis or drafting of this article. key: cord-004894-75w35fkd authors: nan title: abstract date: 2006-06-14 journal: eur j epidemiol doi: 10.1007/s10654-006-9021-1 sha: doc_id: 4894 cord_uid: 75w35fkd nan the organisers of the european congress of epidemiology 2006, the board of the netherlands epidemiological society, and the board of the european epidemiology federation of the international epidemiological association (iea-eef) welcome you to utrecht, the netherlands, for this iea-eef congress. epidemiology is a medical discipline that is focussed on principles and methods of research on causes, diagnosis and prognosis of disease, and establishing the benefits and risks of treatment and prevention. epidemiological research has proven its importance by contributions to the understanding the origins and consequences of diseases, and has made major contributions to the management diseases and improvement of health in-patients and populations. this meeting provides a major opportunity to affirm the scientific and societal contributions of epidemiological research in health care practice, both in clinical medicine and in public health. during this meeting major current health care problems are addressed alongside methodological issues, and the opportunities and challenges in approaching them are explored. the exchange of ideas will foster existing co-operation and stimulate new collaborations across countries and cultures. the goal of this meeting is to promote the highest scientific quality of the presentations and display advanced achievements in epidemiological research. our aim is to offer a comprehensive and educational programme in the field of epidemiological research in health care and public health, and create room for discussions on contemporary methods and innovations from the perspective of policy makers, professionals and patients. above all, we want to stimulate open interaction among the congress participants. your presence in utrecht is key to an outstanding scientific meeting. the european congress of epidemiology 2006 is organised by epidemiologists of utrecht university, under the auspices of the iea-eef, and in collaboration with the netherlands epidemiological society. utrecht university, founded in 1634, is the largest university in the netherlands and harbours the largest academic teaching hospital in the netherlands. the epidemiologists from utrecht university work in the faculties of medicine, veterinary medicine, pharmacy and biology. the current meeting was announced through national societies, taking advantage of their newsletters and of the iea-eef newsletter. in addition, avoiding the costs and disadvantages of the traditional journal advertisements and leaflets, information about the congress was disseminated via an internet mailing list of epidemiologists, which was compiled from, among other, the meeting in porto in 2004, the european young epidemiologist network (http://higiene.med.up.pt/eye/) and several institutions and departments. many of the procedures followed this year were based on or directly borrowed from the stimulating iea-eef congress in porto in 2004. publication in an international journal of large circulation of the congress programme and abstracts selected for oral and poster presentation, signifies the commitment of the organisers towards all colleagues that decided to present their original work at our meeting, and is intended to promote our discipline and to further stimulate the quality of the scientific work of european epidemiologists. and methods to the objectives and quality of its description; presentation of results; importance of the topic; and originality. a final rating was given on a 0-10 point scale. the two junior epidemiologists independently evaluated each abstract. based on ratings of the juniors, the senior epidemiologist gave a final abstract rating. the senior reviewer decided when juniors disagreed, and harnessed against untoward extreme judgements of the juniors. based on the judgement by the seniors abstracts with a final rating of 6 or higher were accepted for presentation. next, in order to shape the scientific programme according to scientific and professional topics and issues of interest for epidemiologists, members of the scientific programme committee grouped the accepted abstracts in major thematic clusters. for these, topics, keywords and title words were used. within each cluster, abstracts with a final rating of 8 or higher, as well as abstracts featuring innovative epidemiological approaches were prioritised to be programmed as an oral presentation. the 642 submitted abstracts had an average final rating of 6 (sd=1). in total 148 abstracts (23%) with a final rating of 5 or lower were rejected. because of the thematic programming some abstracts with a final rating of 8 or higher will be presented as posters, while few with a final rating of 7 are programmed as oral presentation. there were 345 abstracts (54%) accepted and programmed for poster presentation; each poster will be displayed for a full day. in total 149 abstracts (23%) are accepted for oral presentation. these are programmed in 29 parallel sessions. based on the topics of their abstracts the oral sessions were arranged into 7 themes, notably epidemiology of diseases, methods clinical & population research, burden of disease, high risk populations, growth and development, public health strategies, translational epidemiology. sessions from one theme never are programmed parallel. in table 1 we present the submitted and accepted abstracts (oral or poster) according to the distribution of country of origin. in table 2 submitted abstracts are displayed according to their topic, as classified by the authors using the topic long list of the submission form. the scientific programme committee convened in a telephone meeting by the end of the summer of 2005 and decided on the above programming process. the scientific programme committee was informed on the result of the programming process by the end of april 2006. fifteen abstracts were submitted for the eye session work in progress. of these 3 abstracts were selected for oral presentation and thereby nominated for the eye award. in total, 10 abstracts were submitted in relation to the student award, of which 6 were programmed for oral presentation and thus nominated. during the congress authors of poster presentations may name themselves as candidate for the poster award. during the closing ceremony the winners of the student award 2006 and the poster award 2006 will be announced. these awards are an initiative of the netherlands epidemiological society that will fund them in 2006. according to the iea rules expenses of congress participation for applicants from low-income countries will be covered. the board of the iea-eef will select a maximum of 10 candidates; their travel and registration expenses will be (partly) covered from the congress budget. in order to stimulate participation form as many as possible junior researchers and young epidemiologists the congress budget covers registration fee reduction for undergraduate (msc) participants and eye members. this also holds for the registration fee reduction of iea-eef members and nes members. it is 11 years ago (1995) that the iea regional european meeting was held in the hague, the marcon 348 wei 352 leray 353 gehring 354 leray 356 spallek 362 greving 367 laan 372 brussee 379 brussee 383 mayde groot 385 hoefman 386 goettsch 387 posters ordered by abstract number 11 olawuyi 19 de vries 21 uotinen 22 smits 26 gimeno 28 houben 29 de vries 30 de vries 31 ten berg 34 diaconu 36 diaconu 46 streppel 47 belo 48 sauvaget 51 koopman 71 kilsztajn 76 pembrey 81 schmidt 85 kretzschmar 102 scholtens 109 defraye 116 medronho 117 eljedi 124 van de garde 127 mello 128 hosper 129 feleus 134 bayingana 135 de wit 139 stolk 169 teixeira 171 teixeira 175 verhoef 180 capon 185 de boer 186 lazarevska 198 terschu¨ren 201 khosravi boroujeni 202 molag 208 mikolajczyk 209 luijsterburg 216 stolk 219 mirabelli 236 barreto 242 curzio 262 pereira 268 van gageldonk-lafeber 284 van nispen 287 roobol 294 mokkink 295 rava 303 haukka 304 jansen 307 de kraker 313 bogers 322 donalisio 325 behrens 329 borders 332 melis 347 pac 364 muller 365 van den hooven 369 van der sande 373 van den berg 395 novoa 410 van den boogaard 411 vannoord 412 koedijk 414 kuczerowska 420 giorgi rossi 432 vannoord 433 baussano 434 agabiti 457 bierma-zeinstra 460 van wier 464 faustini 465 jarrin 477 juhl 484 miguel 485 maira 497 lindert 508 van den berg 509 mierzejewska 520 fonseca cardoso 525 martens 536 cotton 539 corte 542 ursoniu 544 vernic 545 boer 563 ruskamp 568 szurkowska 572 bijkerk 574 fonseca cardoso 576 mazur 595 ahrens 598 dijkstra 600 ajdacic-gross 603 ajdacic-gross 604 lucas 607 santos 634 gielkens-sijstermans 639 tobi 643 de kraker proteomics and genomics are supposed to be related to epidemiology and clinical medicine, among other because of the putative diagnostic usefulness of proteomics and genomics tests. hence, clinical and sometimes even public health applications are promised by basic sciences. it is debated whether such promises and subsequent expectation are fulfilled. what are at meaningful and consequential examples of current findings in proteomics, genomics and similar approaches in biomedical research? are they different from the ''classic'' tools and frameworks of clinical epidemiology? in the context of proteomics and genomics, etiologic studies, primary prevention, epidemiological surveillance and public health are concerned with the influence of environmental exposures on gene expression and on the accumulation of genetic alterations. proponents and advocates of proteomics and genomics have suggested that their products can yield clinically useful findings, e.g., for early diagnosis, for prognosis, for therapeutic monitoring, without always needing to identify the proteins, peptides or other 'biomarkers' at stake. do we feel comfortable with this ''black-box'' reasoning, i.e. do we question the role of pathophysiological and mechanistic reasoning in clinical medicine? how much sense does it make for epidemiology to play with and scrutinize proteomics and genomics approaches in epidemiology and clinical medicine? what are at present (and in the near future) the main biological, clinical and public health implications of current findings in these research fields? in this plenary session these and other questions regarding the place and role of proteomics and genomics in clinical epidemiological research are discussed from different perspectives. infection diseases: beneficial or disaster for man? infectious diseases pose an increasing risk to human and animal health. they lead to increasing mortality, in contrast to the situation fifty years ago when new control measures still provided hope of overcoming many problems in the future. improved hygiene, better socio-economic circumstances, vaccination and use of antibiotics has led to a gradual decline of tuberculosis, rheumatic fever, measles and mumps in western societies over the last five decades. paradoxically, absence of exposure to infectious agents has a major impact as well. the decline in infectious disease risk is accompanied by a gradual increase of allergic and autoimmune diseases and this association is believed to be causal. exposure to infectious agents from early on in life can markedly boost an individual's natural resistance and hence influence the individual's reaction to future exposure to both biological and non-biological antigens. in this plenary session we want to emphasise both aspects of the effect of infectious agents on human and animal health. evidence based medicine in health care practice and epidemiological research p. glasziou & l. bonneux evidence-based medicine is defined as the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. proponents of evidence-based medicine maintain that coming form a tradition of pathophysiological rationale and rather unsystematic clinical experience, clinical disciplines should summarize and use evidence concerning their practices, by using principles of critical appraisal and quantitative clinical reasoning. for this they should convert clinical information needs into answerable questions, locate the available evidence, critically appraise that evidence for its validity and usefulness, and apply the results of the best available evidence in practice. applying the principles of evidence-based medicine implies improvement of the effectiveness and efficiency of health care. therefore, evidence-based medicine has commonalties with clinical medical and epidemiological research. for integration of evidence-based medicine into health care practice the challenge is to translate knowledge from clinical medical and epidemiological research, for example in up to date practice guidelines. the limitations of using evidence alone to make decisions are evident. the importance of the values and preference judgments that are implicit in every clinical management decision are also evident. critics of evidence based medicine argue that applying best available research evidence in practice in order to improve the effectiveness and efficiency of health care contradicts with the importance of the values and preference judgments in clinical management decisions. in this plenary session we want to contrast these and other viewpoints on evidence based medicine in health care practice. statistical topics i: missing data prof. dr. t. stijnen this workshop will be an educational lecture on missing data by professor stijnen from the department of epidemiology and biostatistics of the erasmus mc rotterdam, the netherlands. every clinical or epidemiological study suffers from the problem of missing data. in practice mostly simple solutions are chosen, such as restricting the analysis to individuals without missing data or imputing missing values by the mean value of the individuals with observed data. it is not always realised that these simple approaches can lead to considerable bias in the estimates and standard errors of the parameters of interest. in the last 10 to 15 years much research has been done to better methods for dealing with missing values. in this workshop first an overview will be given of the methods that are available and their advantages and disadvantages will be discussed. most attention will be given to multiple imputation, to date generally considered as the best method for dealing with missing values. also the available software in important statistical packages such as spss and sas will be shortly discussed. prof. dr. b. van hout suppose that one wants to know how often individuals have a certain characteristic, and suppose that one doesn't have any knowledge -any knowledge at all -how often this is the case. now, suppose that one starts by checking 10 individuals and only finds 1 individual with this characteristic. than the probability that the 11' th individual has the characteristic is 1/6. the fact that this is not 1/10 (although it will be close to that if the numbers of observations increase) may be counter-intuitive. it will become less so, when realising how it is obtained from the formal integration of the new information with the complete uncertainty beforehand. this formal integration, with a prior indicating that it is as likely to be 1/100 as it is to be 50/100 as it is 99/100, and with 9 negative and 1 positive observation -is by way of bayes rule. the italian mathematician, actuary, and bayesian, bruno de finetti (1906 -1985 , estimated that it would take until the year 2020 for the bayesian view of statistics to completely prevail. the purpose of this workshop is to not only convince the attendants that this is appealing outlook but also to aid the workshop participants in realising this prediction. after a first introduction of the work of reverend bayes, a number of practical examples are presented and the attendant is introduced in the use of win-bugs. a first example -introducing the notion of noninformative priors -concerns a random effects logistic regression analysis. second, the use of informative priors, is illustrated (in contrast with non-informative priors) using an analysis of differences in quality of life as observed in a randomised clinical trial. it will be shown how taking account of such prior information changes the results as well as showing how such information may increase the power of the study. in a third example, it will be shown how winbugs offers a powerful and flexible tool to estimate rather complex multi-level models in a relatively easy way and how to discriminate between various models. within this presentation some survival techniques (or stress control techniques) will be presented for when winbugs starts to spit out obscure error-codes without giving the researcher any clue where to search for the reason behind these errors. communicating research to the public h. van maanen, prof. dr. ir. d. kromhout, a. aarts most researchers will at some point in their career face difficulties in communicating research results to the public. whereas most scientific publications will pass by the larger public in silence, now and then a publication provokes profound interest of popular press. interest from the general public should be regarded as positive. after all, public money is put into research and a researcher has a societal responsibility of spreading new knowledge. however, often, general press interest is regarded upon as negative by the researcher. the messages get shortened, distorted or ridiculed. whose responsibility is this misunderstanding between press and researchers? should a researcher foresee press reaction and what can be done to prevent negative consequences? is the press responsible background and relevance: patients with a carotid artery stenosis, including those with an asymptomatic or moderate stenosis, have a considerable risk of ischemic stroke. identification of risk factors for cerebrovascular disease in these patients may improve risk profiling and guide new treatment strategies. objectives and question: we cross-sectionally investigated whether carotid stiffness is associated with previous ischemic stroke or tia in patients with a carotid artery stenosis of at least 50%. design and methods: patients were selected from the second manifestations of arterial disease (smart) study, a cohort study among patients with manifest vascular disease or vascular risk factors. arterial stiffness, measured as change in lumen diameter of the common carotid arteries during the cardiac cycle, forms part of the vascular screening performed at baseline. the first 420 participants with a stenosis of minimally 50% in at least one of the internal carotid arteries measured by duplex scanning were included in this study. logistic regression analysis was used to determine the relation between arterial stiffness and previous ischemic stroke or tia. results: the risk of ischemic stroke or tia in the highest quartile (stiffest arteries) relative to the lowest quartile was 2.1 (95% ci 1.1-4.1). these findings were adjusted for age, sex, systolic blood pressure, minimal diameter of the carotid artery and degree of carotid artery stenosis. conclusion and discussion: in-patients with a ‡50% carotid artery stenosis, increased common carotid stiffness is associated with previous ischemic stroke and tia. measurement of carotid stiffness may improve selection of high-risk patients eligible for carotid endarterectomy and may guide new treatment strategies. background (and relevance): patients with advanced renal insufficiency are at increased risk for adverse cardiovascular disease (cvd) outcomes. objectives and question: the aim was to establish whether impaired renal function is an independent predictor of cvd and death in an unselected high-risk population with cvd. design and methods: the study was performed in 2784 patients with cvd. primary outcomes were all vascular events and all cause death. during a median follow-up of 39 months, 291 patients had a vascular event (10%) and 266 patients died (9.5%). results: the adjusted hazard ratio (hr) of an estimated glomerular filtration rate <60 vs >90 ml/min per 1.73 m2 was 1.8 (95% ci 1. 2-2.7) for vascular events and 1.4 (95% ci 0.9-2.2) for all cause death. for stroke as a separate outcome it was 2.7 (95% ci 1. 2-5.8) . subgroup analysis according to vascular disease at presentation or the risk factors hypertension, diabetes and albuminuria had no influence on the hr's. conclusion and discussion: renal insufficiency is an independent risk factor for adverse cvd events in patients with a history of vascular disease. renal function was a particularly important factor in predicting stroke. the presence of other risk factors hypertension, diabetes or albuminuria had no influence on the impact of renal function alone. background and relevance: patients with hypertension have an increased case-fatality during acute mi. coronary collateral (cc) circulation has been proposed to reduce the risk of death during acute ischemia. objectives and question: we determined whether and to which degree high blood pressure (bp) affects the presence and extent of cc-circulation. design and methods: cross-sectional study in 237 patients (84% males), admitted for elective coronary angioplasty between january 1998 and july 2002. collaterals were graded with rentrop's classification (grade 0 -3). ccpresence was defined as rentrop-grade ‡1. bp was measured twice with an inflatable cuff-manometer in seated position. pulse pressure was calculated by systolic blood pressure (sbp) )diastolic blood pressure (dbp). mean arterial pressure was calculated by dbp + 1/3*(sbp-dbp). systolic hypertension was defined by a reading ‡140 mmhg. we used logistic regression with adjustment for putative confounders. results: sbp (odds ratio (or) 0.86 per 10 mmhg; 95% confidence-interval (ci) 0.73-1.00), dbp (or 0.67 per 10 mmhg; 95% ci 0.49-0.93), mean arterial pressure (or 0.73 per 10 mmhg; 95% ci 0.56-0.94), systolic hypertension (or 0.49; 95% ci 0.26-0.94), and antihypertensive treatment (or 0.53; 95% ci 0.27-1.02), each were inversely associated with the presence of cc's. also, among patients with cc's, there was a graded, significant inverse relation between levels of sbp, levels of pulse pressure, and collateral extent. conclusion and discussion: there is an inverse relationship between bp and the presence and extent of cc-circulation in patients with ischemic heart disease. background and relevance: silent brain infarcts are associated with decreased cognitive function in the general population. objectives and question: we examined whether this relation also exists in patients with symptomatic arterial disease. furthermore, we compared cognitive function of patients with stroke or tia, with cognitive function of patients with symptomatic arterial disease at other sites in the arterial tree. design and methods: an extensive screening was done in 336 consecutive patients participating in the second manifestations of arterial disease (smart) study, including a neuropsychological test. inclusion diagnoses were cerebrovascular disease, symptomatic coronary artery disease, peripheral arterial disease, or abdominal aortic aneurysm. mri examination was performed to assess the presence of silent infarcts in patients without symptomatic cerebrovascular disease. the patients were assigned to one of three categories according to their patient history and inclusion diagnosis: no stroke or tia, no silent infarcts (n = 220; mean age 57 years); no stroke or tia, but silent infarcts present (n = 33; mean age 65 years); stroke or tia at background and relevance: patients with manifest vascular disease are at high risk of a new vascular event or death. modification of classical risk factors is often not successful. objectives and question: we determined whether the extra care of a nurse practitioner (np) could be beneficial to the cardiovascular risk profile of high-risk patients. design and methods: randomised controlled trial based on the zelen design. 236 patients with manifestations of a vascular disease and who had ‡2 modifiable vascular risk factors were prerandomised to receive treatment by a np plus usual care or usual care alone. after 1 year, risk factors were re-measured. primary endpoint was achievement of treatment goals for risk factors. results: of the pre-randomised patients, 95 of 119 (80%) in the intervention group and 80 of 117 (68%) in the control group participated in the study. after a mean follow-up of 14 months, the patients in the intervention group achieved significantly more treatment goals than did the patients in the control group (systolic blood pressure 63% versus 37%, total cholesterol 79% vs 61%, ldl-cholesterol 88% vs 67%, and bmi 38% vs 24%). medication use was increased in both groups and no differences were found in patients' quality of life (sf-36) at followup. conclusion and discussion: treatment delivered by nps, in addition to a vascular risk factor screening and prevention program, resulted in a better management of vascular risk factors compared to usual care alone in vascular patients after 1 year follow-up. were used as non-invasive markers of vascular damage and adjusted for age and sex if appropriate. results: the prevalence of the metabolic syndrome in the study population was 45%. in pad patients this was 57%; in chd patients 40%, in stroke patients 43% and in aaa patients 45%. patients with the metabolic syndrome had an increased mean imt (0.98 vs. 0.92 mm, p-value <0.01), more often a decreased abpi (14% vs. 10%, p-value 0.06) and increased prevalence of albuminuria (20% vs. 15%, p-value 0.03) compared to patients without this syndrome. an increase in the number of components of the metabolic syndrome was associated with an increase in mean imt (p-value for trend <0.001), lower abpi (p-value for trend < 0.01) and higher prevalence albuminuria (p-value for trend < 0.01). conclusion and discussion: in patients with manifest vascular disease the presence of the metabolic syndrome is associated with advanced vascular damage. background (and relevance): in patients with type 2 diabetes the progression of atherosclerosis is accelerated, as observed by the high incidence of cardiovascular events. objectives (and question): to estimate the influence of location and extent of vascular disease on new cardiovascular events in type 2 diabetes patients. design and methods: diabetes patients (n = 669), mean age 59 years, with and without prior vascular disease were followed through 1996-2004 (mean follow-up 3 years). patients with vascular disease (n = 399) were classified according to symptomatic vascular location, and number (extent) of locations. we analyzed occurrence of new (non)-fatal cardiovascular events using cox proportional hazards models and kaplan-meier analysis. results: multivariate-adjusted hazard ratios (hrs) were comparable in diabetes patients with cerebrovascular disease (hr 3.2; 95% ci 1.3-7.4), coronary heart disease (hr 3.3; 1.5-7.1) and peripheral arterial disease (hr 2.6; 1.1-6.3), compared to those without vascular disease. multivariate-adjusted hr was 2.7; (1. 3-5.9 ) in patients with one vascular location and 4.8; (2.1-10.9) in those with ‡2 locations. the 3-year risks were respectively 11.6% (7.4-15.7) and 26.7% (16. 8-36.7) . conclusion and discussion: diabetes patients with prior vascular disease have an increased risk of cardiovascular events, irrespective of symptomatic vascular location. cardiovascular risk increased with the number of locations. data emphasize the necessity of early and aggressive treatment of cardiovascular risk factors in diabetes patients. background (and relevance): despite recent advances in medical treatment, cardiovascular disease (cvd) is still health problem number one in western societies. a multifactorial approach with the aid of nurse practitioners (nps) is beneficial for achieving treatment goals and reducing events in patients with manifest cvd. objectives (and question): in the self-management of vascular patients activated by internet and nurses (spain) pilot study, we want to implement and test a secure personalized website with additional treatment and coaching of a np for hypertension, hyperlipidemia, diabetes mellitus, smoking and obesity in patients with clinical manifestations of cvd. design and methods: 50 interesting patients are going to use the secure patient-specific website. before the use of the web-application, risk factors are measured. realistic treatment goal(s) for elevated risk factors based on current guidelines are made and appointments how to achieve the treatment goal(s) are determined between the patients and the np in a face to face contact. patients can enter his/ her own weight or a new blood pressure measurement for instance, besides the regular exchange information with the responding np through e-mail messages. the np personally replies as quick as possible and gives regular but protocol driven feedback and support to the patient. the risk factors are remeasured after six months. conclusion and discussion: the spain study is aimed to implement and test a patient specific website. secondary outcome is the change in cardiovascular risk profile. the pre-post measurements of risk factors and the amount of corresponding e-mail messages between the patient and the np enhances the feasibility of this innovative way of risk factor management. background (and relevance): modification of vascular risk factors has been shown to be effective in reducing mortality and morbidity in patients with symptomatic atherosclerosis. nevertheless, reduction of risk factors in clinical practice is difficult to achieve and maintain. objectives (and question): in the risk management in utrecht and leiden evaluation (rule) study, a prospective, comparative study, we assess the effects of a multidisciplinary vascular screening program on improvement of the cardiovascular risk profile and to compare this to a setting without such a program that provides current standard practice in patients referred for cardiovascular disorders. design and methods: patients with diabetes mellitus, coronary artery disease, cerebrovascular disease, or peripheral arterial disease (150 per disease category in each hospital) referred by the general practitioner will be enrolled, started january 2005. at the umcu, patients need to be enrolled in the vascular screening program or will be identified through the hospital registration system. at the lumc patients will be identified through the hospital registration system. risk factors will be measured in the two hospitals at baseline and one year after their initial visit. a risk function will be developed for this population based on data of the whole cohort. analysis will be performed on the two comparison groups as a whole, and on subgroups per disease category. changes in risk factors will be assessed with linear or logistic regression procedures, adjusting for differences in baseline characteristics between groups. conclusion and discussion: the rule study is aimed to evaluate the added value of a systematic hospital based vascular screening program on risk factor management in patients at high risk for vascular diseases. background: signs of early cerebral damage are frequently seen on mri scans in elderly people. they are related to future manifest cerebrovascular disease and cognitive deterioration. cardiovascular risk factors can only partially explain their presence and progression. evidence that inflammation is involved in atherogenesis continues to accumulate. chronic infections can act as an inflammatory stimulus. it is possible that subclinical inflammation and chronic infections play a role in the pathogenesis of early cerebral damage. objectives (and question): to unravel the role of inflammation and chronic infection in the occurrence and progression of early cerebral damage in patients with manifest vascular disease. design and methods: 1200 participants of the smart study with manifest vascular disease underwent an mr investigation of the brain between may 2001 and december 2005. starting in january of 2006 all patients are invited for a second mr of the brain after an average follow-up period of four years. both at baseline and after follow-up all cardiovascular risk factors are measured and blood samples are stored to assess levels of inflammatory biomarkers and antibodies against several pathogens. occurrence and progression of early cerebral damage is assessed by measuring the volume of white matter lesions, the number of silent brain infarctions, cerebral atrophy, aberrant metabolic ratios measured with mr spectroscopy and cognitive function at baseline and after follow-up. the relation between inflammation, chronic infection and the occurrence and progression of early cerebral damage will be investigated using both crosssectional and longitudinal analysis. abstract 13 monocyte chemoattractant protein 1 (mcp-1) polymorphism and susceptibility for coro-nary collaterals j.j. regieli 1,2 , j. koerselman 2 , ng sunanto 1,2 , m. entius 1 , p.p. de jaegere 1 , y. van der graaf 2 , d.e. grobbee 2 , p.a. doevendans 1 1 heart lung institute, dept of cardiology 2 clinical epidemiology, julius center for health sciences and primary care, utrecht, netherlands background (and relevance): collateral formation is an important beneficial condition during an acute ischemic event. a marked interindividual variability in high risk patients is seen, but at present the basis for this variability is unclear and can not be explained solely by environmental factors. a genetic factor might be present that could influence coronary collateral formation. objectives (and question): we have analyzed the association between a single nucleotide polymorphism in mcp-1 and the formation of coronary collaterals in patients admitted for angioplasty. mcp-1 has been suggested to play an important role in collateral development. design and methods: this study involved 226 caucasian patients who were admitted for coronary angioplasty. coronary collateral development was defined angiographically as rentropgrade ‡1. polymorphisms in the promoter region of mcp-1 ()2518) were identified by pcr and allele specific restriction digestion. this method allows identification of individuals with either aa, ag or gg at mcp-1 position )2518. statistical analysis was performed using a x2-test, unconditional logistic regression, likelihood ration and a wald's test. results: we could genotype 224 of the 226 patients. coronary collaterals (rentropgrade >1) were found in 84 patients. the allele frequency for aa, ag and gg was 53.1%, 40.2% and 6.7%, respectively. the dis-tribution of mcp-1 genotypes in subjects without collaterals was in hardy weinberg equilibrium. we found that individuals with g allele (24%) were more likely to have collaterals than those with homozygous aa (or 1.66, 95% ci 0.96 to 2.87) adjusted for potential confounders. linear regression shows that the allele g increased the likelihood for collateral presence with a factor 1.41. conclusion and discussion: this study provides evidence for a role for genetic variation of mcp-1 gene in the occurrence of coronary collaterals in high risk patients. 2001 until september 2003 patients with recently established clinically manifest atherosclerotic disease with >2 modifiable vascular risk factors were selected for the study. the mean self-efficacy scores were calculated for vascular risk factors (age, sex, vascular disease, weight, diabetes mellitus, smoking behavior, hypercholesterolemia, hypertension, and hyperhomocysteinemia). results: diabetes, overweight, and smoking, but none of the other risk factors, were significantly associated with the level of self-efficacy in these patients. patients with diabetes had lower self-efficacy scores (3.0) for exercise and controlling weight (3.7) than patients without diabetes (4.2 p = 0.05) and (4.1 p = 0.01) respectively. overweight patients scored low on controlling weight (3.8 and 3.5 p<0.001) and choosing healthy food (3.7 and 3.3 p = 0.01) than patients who were on a healthy weight (4.3 and 4.0). conclusion and discussion: patients with vascular diseases appear to have high levels of self-efficacy regarding medication use (4.8), exercise (4.1), and controlling weight (4.0). in patients with diabetes, overweight and in smokers, self efficacy levels were lower. practice implications: in nursing care and research on developing self-efficacy based interventions, lower self-efficacy levels can be taken into account for specific vascular patient groups. background (and relevance): little is known about the role of serum uric acid in the metabolic syndrome and increased risk of cardiovascular disease. we investigated the association between uric acid levels and the metabolic syndrome in a population of patients with manifest vascular diseases and whether serum uric acid levels conveyed an increased risk for cardiovascular disease in patients with the metabolic syndrome. design and methods: this is a nested case-cohort study of 431 patients originating from the second manifestations of arterial disease (smart) study. all patients had manifest vascular diseases, constituting peripheral artery disease, cerebral ischemia, coronary artery disease and abdominal aortic aneurysm. analyzing the relationship of serum uric acid with the metabolic syndrome, age, sex, creatinine clearance, alcohol and diuretics were considered as confounders. investigating the relationship of serum uric acid levels with the risk for cardiovascular disease, values were adjusted for age and sex. results: the metabolic syndrome was present in 50% of the patients. serum uric acid levels in 214 patients with metabolic syndrome were higher compared to 217 patients without (0.36 ± 0.08 mmol/l vs. 0.32 ± 0.09 mmol/l). serum uric acid concentrations increased with the number of components of the metabolic syndrome (0.30 mmol/l to 0.38 mmol/l) adjusted for age, sex, creatinine clearance, alcohol and use of diuretics. increased serum uric acid concentrations showed to be independently associated with the occurrence of cardiovascular events in patients without the metabolic syndrome (age en sex adjusted hr: 1.9, 95% ci 0. 9-3.9) , contrary to patients with the metabolic syndrome (adjusted hr: 1.3, 95% ci 0.6 -2.7). conclusion: elevated serum uric acid levels are strongly associated with the metabolic syndrome, yet are not linked to an increased risk for cardiovascular disease in patients with the metabolic syndrome. however, in patients without the metabolic syndrome elevated serum uric acid levels are associated with increased risk for cardiovascular disease. the objective of this study is to investigate the overall and combined role of late-life depression, prolonged psychosocial stress exposure, and stress hormones in the etiology of hippocampal atrophy and cognitive decline. design and methods: as part of the smart study, 1200 participants with manifest vascular disease underwent an mri of the brain between may 2001 and december 2005. in a subsample of 800 subjects, cognitive function and depressed mood were assessed. starting in january 2006, all patients are invited for a follow-up mri of the brain. at this follow-up measurement, minor and major depression, hypothalamic-pituitary-adrenal (hpa) axis function indicated by salivary cortisol, psychosocial stress exposure indicated by stressful life events early and later in life, and cognitive functioning will also be assessed. the independent and combined effects of late-life depression, (change in) hpa-axis activity, and psychosocial stress exposure on risk of hippocampal atrophy and cognitive decline will be estimated with regression analysis techniques adjusting for potential confounders. introduction the netherlands epidemiological society advocates according to good epidemiological practice, that research with sound research questions and good methodology should be adequately published independent of the research outcomes. although reporting bias in clinical trials is fully acknowledged, failure to report outcomes or selective reporting of outcomes in non-clinical trial epidemiological studies is less well known, but most likely occurs as well. in this mini-symposium the netherlands epidemiological society wants to give attention to this phenomenon of not publishing research outcomes, to encourage publication of all outcomes of adequate research. different scopes to this subject will be addressed: the background, an example of occurrence, initiatives to possibly avoid it and an editor's point of view. selective reporting of outcomes in clinical studies (reporting bias) has been described to occur frequently. therefore a registration of clinical trials is started which enables to address this problem in the future since occurrence of not publishing negative or adverse outcomes can be investigated with this registration. in non-clinical epidemiological studies the failure to report outcomes or selective reporting of outcomes most likely occurs as well, but is less studied and reported. again studies with negative outcomes or no associations are the ones most likely not to be reported. the most important obstacles for not publishing no or negative associations are tradition and priorities of researchers and journals. the reviewers might play a role in this as well. the netherlands epidemiological society advocates according to good epidemiological practice, that research with sound research questions and good methodology should be adequately published independent of the research outcomes. however, reality occurs not to be accordingly. therefore we would like to give attention to this phenomenon of not publishing research outcomes in non-trial-based epidemiological studies, to encourage publication of all outcomes of adequate research. in this mini-symposium, firstly the effects of failure or selective publishing of outcomes on subsequent meta-analysis in a non-clinical research setting will be demonstrated. afterwards, initiatives to promote and improve publication of observational epidemiological research will be addressed, the editor's point of view on this phenomenon will be given and finally concluding remarks will be given. background: there are several reasons for suspecting reporting bias in time-series studies of air pollution. such bias could lead to false conclusions concerning causal associations or inflate estimates of health impact. objectives: to examine time-series results for evidence of publication and lag selection bias. design and methods: all published time-series studies were identified and relevant data extracted into a relational database. effect estimates were adjusted to an increment of 10lg/m 3 . publication bias was investigated using funnel plots and two statistical methods (begg, egger). adjusted summary estimates were calculated using the ''trim and fill'' method. the effect of lag selection was investigated using data on mortality from 90 us cities and from a european multi-centre panel study of children. results: there was evidence of publication bias in a number of pollutant-outcome analyses. adjustment reduced the summary estimates by up to 20%. selection of the most significant lag increased estimates by over 100% compared with a fixed lag. conclusion and discussion: publication and lag selection bias occurs in these studies but significant associations remain. presentation and publication of time-series results should be standardised. background: selective non-publication of study outcomes hampers the critical appraisal and appropriate interpretation of available evidence. its existence could be shown empirically in clinical trials. observational research often uses an exploratory approach rather than testing specific hypotheses. results of multiple data analyses may be selected based on their direction and significance. objectives: to improve the quality of reporting of observational studies. to help avoid selective non-publication of study outcomes. methods: ''strengthening the reporting of observational studies in epidemiology (strobe)'' is an international multidisciplinary initiative that currently develops a checklist of items recommended for the reporting of observational studies (http:// www.strobe-statement.org). results: strobe recommends to avoid selective reporting of 'positive' or 'significant' study results and to base the interpretation on main results rather than on results of secondary analyses. discussion: strobe cannot prevent data dredging, but it promotes transparency at the publication stage. for instance, if multiple statistical analyses were performed in a large dataset to identify new exposure-outcome associations, authors should give details and not only report significant associations. strobe could have a ''feedback effect'' on study quality since, ideally, researchers think ahead when a study is planned and consider points that are essential for later publication. good publishing practice begins with researchers considering (1) whether an intended study can bring added value, irrespective its result, (2) and whether its methodology is valid to pick up positive and negative outcomes equally well. when reporting (3) they should adequately discuss the significance of a negative result (4) and be as eager to publish negative results as positive ones. as to editors, intentional bias in relation to study results is considered editorial malpractice, whatever its motivation. unintentional bias may be more frequent but will not easily be noticed, also by editors. editorial responsibility implies several levels (accepting for review, choice of reviewers, assess their reviews, decision making, and a repeated process in case of resubmission). various designs for process evaluation can be considered. evaluation will be more difficult for journals with few professional support. collaboration between journals can help, and may also avoid 'self evaluation bias'. in line with registering of randomized trials, registers for observational study protocols could facilitate monitoring for bias and searching unpublished results. but practicalities, methodological requirements, and bureaucratic burden should not be underestimated. in principle, in an era of electronic publishing every study can be made widely accessible widely also if not 'accepted', by editors or authors themselves. however, this would need huge changes in culture of authoring and reading, editorial practice, publishing business, and scientific openness. background: high circulating levels of insulin-like growth factor-i (igf-i), a mitogenic and anti-apoptotic peptide, have been associated with increased risk of several cancer types. objective: to study circulating levels of igf-i and igf binding protein-3 (igfbp-3) in relation to ovarian cancer risk. design and methods: within the european prospective investigation into cancer and nutrition (epic), we compared levels of igf-i and igfbp-3 measured in blood samples collected at baseline in 214 women who subsequently developed ovarian cancer (37 women diagnosed before age 50) and 388 controls. results: the risk of developing ovarian cancer before age 50 ('premenopausal' was increased among women in the middle or top tertiles of igf-i, compared to the lowest tertile: or = 2.69 [95% ci: 0.87 8.35 ], and or = 3.20 [95% ci: 1.01 -10.2], respectively (p trend = 0.06). results were adjusted for bmi, previous hormone use, fertility problems and parity. adjustment for igfbp-3 levels slightly attenuated relative risks. in older women we observed no association between igf-i, igfbp-3 and ovarian cancer risk. discussion and conclusion: in agreement with the only other prospective study in this field (lukanova et al, int j cancer, 2002) , our results indicate that high circulating igf-i levels may increase the risk of premenopausal ovarian cancer. background: the proportion of glandular and stromal tissue in the breast (percent breast density) is a strong breast cancer risk factor. insulin-like growth factor 1 (igf-1) is hypothesized to influence breast cancer risk by increasing breast density. objectives: we studied the relation between premenopausal circulating igf-1 levels and changes in breast density over menopause. design and methods: mammograms and blood samples of 684 premenopausal participants of the prospect-epic cohort were collected at baseline. a second mammogram was collected after these women became postmenopausal. we determined serum igf-1 levels. mammographic density was assessed using a computer-assisted method. changes in percent density over menopause were calculated for quartiles of igf-1, using linear regression, adjusted for age and bmi. results: premenopausal percent density was not associated with igf-1 levels (mean percent density 0.43 in all quartiles). however, women in the highest igf-1 quartile showed less decrease in percent density over menopause (1st quartile: )0.094 vs 4th quartile: )0.059, p-trend = 0.02). this was mostly explained by a stronger decrease of total breast size in women with high igf-1 levels. conclusion and discussion: women with high igf-1 levels show a lower decrease of percent density over menopause than those with low igf-1 levels. background: body mass index (bmi) has been found to be associated with risk of colon cancer in men, whereas weaker associations have been reported for women. reasons for this discrepancy are unclear but may be related to fat distribution or use of hormone replacement therapy (hrt) in women. objective: to examine the association between anthropometry and risk of colon cancer in men and women. design and methods: during 6.1 years of followup, we identified 984 cases of colon cancer among 368,277 subjects free of cancer at baseline from 9 european countries. results: bmi was significantly related to colon cancer risk in men (rr per kg/ m2, 1.05; 95%-ci 1.02-1.08) but not in women (rr 1.02; 1.00-1.04; p interaction = 0.04), whereas waist-hip-ratio (whr) was equally strong related to risk in both genders (rr per 0.1, men, 1.24; 95%-ci 1.05-1.46; women, 1.24; 1.10-1.39; p interaction = 0.92). the positive association for whr was not apparent among postmenopausal women who used hrt. conclusions: abdominal obesity is an equally strong risk factor for colon cancer in both sexes and whr is a disease predictor superior to bmi in women. the association may vary depending on hrt use in postmenopausal women; however, these findings require confirmation in future studies. background: fruits and vegetables are thought to protect against colorectal cancer. recent cohort studies, however, have not been able to show a protective effect. patients & methods: the relationship between consumption of vegetables and fruit and the incidence of colorectal cancer within epic was examined among 453,158 subjects of whom 1808 developed colorectal cancer. a multivariate cox proportional hazard model was used to determine adjusted cancer risk estimates. a calibration method based on standardized 24-hour dietary recalls was used to correct for measurement errors. results: after adjustment for potential confounding and exclusion of the first two years of follow-up, the results suggest that consumption of vegetables and fruits is weakly, inversely associated with risk of colorectal cancer (hr 1.00, 0.85, 0.85, 0.86, 0.79, for quintiles of intake, 95% ci upper quintile 0.65-0.97, p-trend 0.06), with each 100 gram daily increase in vegetables and fruit associated with a statistically borderline significant 3% reduction in colorectal cancer risk (hr 0.97; 0.94-1.00). linear calibration strengthened this effect. further subgroup analyses will be presented. conclusion: findings within epic support the hypothesis that increased consumption of fruits and vegetables may protect against colorectal cancer risk. a diverse consumption of vegetables and fruit may influence the risk of gastric and oesophageal cancer. diet diversity scores (dds) were calculated within the epic cohort data from >520,000 subjects in 10 european countries. four scores, counting the number of ffq-based food-items usually eaten at least once in two weeks, were calculated to represent the diversity in the overall vegetable and/or fruit consumption. after an average follow-up of 6.1 years, 400 incident cases of gastric and oesophageal cancer were observed. cox proportional hazard models were used to compute tertile specific risks, stratified by follow-up duration, gender and centre and adjusted for total consumption of vegetables and fruit and potential confounders.preliminary findings suggest that, compared to individuals who eat from only 5 or less vegetable sub-groups, individuals who usually eat from eight different subgroups, have a reduced gastric cancer risk (hr 0.68; 95% ci 0.45-1.05). in comparison to all others, individuals who usually eat only the same fruit may experience an elevated risk (hr 1.34; 95% ci 0.95-1.89). these findings from the epic study suggest that a diverse consumption of vegetables may reduce gastric and oesophageal cancer risk. subjects with a very low diversity in fruit consumption may experience higher risk. g. steindorf 1 , l. friedenreich 2 , j. linseisen 1 , p. vineis 3 , e. riboli 3 for the epic group 1 german cancer research center, heidelberg, germany 2 alberta cancer board, alberta, canada 3 imperial college london, great-britain background: previous research on physical activity and lung cancer risk, conducted predominantly in males, has yielded inconsistent results. objectives: we examined this relationship among 416,277 men and women from the epic-cohort. design and methods: during 6.3 years of follow-up we identified 607 men and 476 women with incident primary lung cancer. detailed information on recreational, household and occupational physical activity, smoking habits, and diet was assessed. relative risks (rr) were estimated using cox regression. results: we did not observe an inverse association between occupational, recreational or household physical activity and lung cancer risk either in males or in females. we found a modest reduction in lung cancer risk associated with sports in males and cycling in females. for occupational physical activity, lung cancer risk was increased for unemployed men (rr = 1.55; 95% confidence interval 1.18-2.03) and men with standing occupations (rr = 1.34; 1.01-1.78) compared with sitting professions. conclusion: our study shows no convincing protective associations of physical activity with lung cancer risk. discussion: it may be speculated that the elevated risks for occupational physical activity could reflect the higher probability that manual workers are exposed to industrial carcinogens compared to workers having sitting/office jobs. purposes: epidemiological research almost always means using data and, increasingly, human tissue as well. the use of these resources is not free but is subject to various regulations, which differ in the european countries on several important aspects. usually these regulations have been determined without involvement of active epidemiological researchers or patient organisations. this workshop will address the issues involved in these regulations in the european context. it will serve the following purposes: -to provide arguments and tools and to exchange best practices for a way out of the regulatory labyrinths especially in cross european research projects; -to provide a platform for epidemiologists and patient groups to discuss their concerns about impediments for epidemiological research with other parties, like data protection authorities. targeted audience: the mini symposium is primarily meant for epidemiologists, but provides an excellent opportunity to meet and discuss with other stakeholders, like from patient groups, data protection authorities, the european commission etc. as well. therefore program allows for extra time for discussion. the other stakeholders will be explicitly invited. a special 'day ticket' is available to satellite symposium epidemiology and the seventh eu research framework over the last few years the seventh eu research framework has been drafted. it is now rapidly moving towards the first calls for proposals. previous eu research programmes and frameworks have been criticised because they are considered to include too few possibilities for epidemiological research and public health research. this satellite-symposium will provide an outline of the research framework and inform researchers about the current state of affairs of the seventh eu research framework. special focus will be on the possibilities for epidemiology and public health research. 30-14.35 welcome by our host prof. jan willem coebergh, rotterdam, introduction, international and national regulations on the use of data and tissue or research in europe, different approaches to: evert-ben van veen l.l.m. (medlawconsult, the netherlands) -'identifiability' of data -consent for using data and tissue for research the tubafrost code of conduct to exchange data and tissue across europe. 14. 50-15.05 data and tissuebanking for research in denmark: a liberal approach the danish approach to use patient data for epidemiological research, cooperation of the danish data protection authority, the danish act of 2004 to use anonymous but coded tissue for research based on an opt-out system, first experiences hans storm ph.d. (copenhagen, denmark) 15. 05-15.20 estonian data protection act: a disaster for epidemiology the story of the birth of the act, implementing the european data protection directive and of its consequences reveal political and administrative incapability resulting in gradual vanishing of register-based epidemiological research. background: non-invasive assessment of atherosclerosis is important. most of the evidence of coronary calcium has been based on images obtained by electron beam ct (ebct). current data suggest that ebct and multi-slice ct (msct) give comparable results. since msct is more widely available than ebct, information on its reproducibility is relevant. objective: to assess inter-scan reproducibility of msct and to evaluate whether reproducibility is affected by different measurement protocols, slice thickness, cardiovascular risk factors and technical variables. design: cross-sectional study. materials and methods: the study population comprised 76 healthy postmenopausal women. coronary calcium was assessed in these women twice at two separate visits using msct (philips mx 8000 idt 16). images were made using 1.5 and 3.0 mm slice thickness. the agatston, volume and mass scores were assessed. reproducibility was determined by mean differences, absolute mean differences and intra-class correlation coefficients (iccc). results: the reproducibility of coronary calcium measurements between scans was excellent with iccc of > 0.98, and small mean and absolute mean differences. reproducibilility was similar for 1.5 as for 3.0 mm slices, and equal for agatston, volume and mass measurements. conclusion: inter-scan reproducibilility of msct is excellent, irrespective of slice thickness and type of calcium parameter. background: it has been suggested that the incidence of colorectal cancer is associated with socioeconomic status (ses). the major part of this association may be explained by known lifestyle risk factors such as dietary habits. objective: to explore the association between diet and ses measured at area-based level. methods: the data for this analysis were taken from a multi-centre case-control study conducted to investigate the association between some environmental, genetic factors and colorectal cancer incidence. the townsend scores (as deprivation index) were categorized into fifths. a linear regression analysis was used to estimate difference in mean of each continuous variable of diet by deprivation fifth. results: the mean of processed meat consumption in the most deprived area was higher compared to the mean of that in the most affluent areas (mean difference = 5.5, 95% ci: 3.94, 7.05). by contrast, the mean of vegetables and fruits consumption in the most deprived areas was lower than that in the affluent areas. conclusion: our findings suggest that lifestyle factors are likely to be related to ses. thus any relation between ses and colorectal cancer may direct us to seek for the role of different life style factors in aetiology of this cancer. background: the reason for the apparent decline in semen quality during the past 50 years is still unexplained. objective: to investigate the effect of exposure to cigarette smoke in utero on the semen quality in the male offspring. design and methods: in this prospective follow-up study, 350 adult sons of mothers, who during pregnancy provided information about smoking and other lifestyle factors, are sampled in six strata according to prenatal tobacco smoke exposure. each man provides a semen sample, a blood sample, and answers a questionnaire, which is collected in a mobile laboratory. external quality assessment of semen analysis is performed twice a year. results: until now, a total of 265 men have been included. the participation rate is 52%. the percentage of men with decreased sperm concentration (<20 mill/ml) is 23%. the unadjusted median (25-75% percentile) sperm concentration in the non-exposed group (n = 90) is 49 (23-86) mill/ml compared to 33 (12-63) mill/ml among men exposed to >19 cigarettes per day in fetal life (n = 26 aim: to estimate the prevalence of overweight and obesity, and their effects in physical activity (pa) levels of portuguese children and adolescents aged 10-18 years. methods: the sample comprises 12669 subjects (6489 females-6180 males) attending basic/secondary schools. the prevalence of overweight and obesity was calculated using body mass index (bmi), and the cut-off points suggested by cole et al. (2000) . pa was assessed with the baecke et al. (1982) questionnaire. proportions were compared using chi-square tests and means by anova. results and conclusions: overall, 17.1% were overweight (females = 16.4%; males = 17.8%) and 3.3% were obese (females = 3.0%; males = 3.6%). prevalence was similar across age and gender. bmi changed with age (p<0.001), and a significant interaction between age and gender was found (p = 0.001): whereas bmi in males increased with aging, in females increased up to 16 years and stabilized onwards. males showed significantly higher values of pa (p<0.001). both genders had a tendency to increase their pa until 16-17 years. a significant interaction between age and gender (p = 0.006) points out different gender patterns across age: pa increased with aging in males but in females started to decline after 16 years. no significant differences in pa were found between normal weight, overweight and obese subjects (p = 0.352). background: atherosclerosis is an inflammatory process. however, the relation between inflammatory markers and extent and progression of atherosclerosis remains unclear. objectives: we studied the association between c-reactive protein (crp) and 5 established measures of atherosclerosis. design and methods: within the rotterdam study, a population-based cohort of 7,983 persons over age 55, we measured crp, carotid plaque and intima-media thickness (imt), abdominal artery calcification, ankle-brachial index (abi) and coronary calcification. using ancova, we investigated the relation between crp and extent of atherosclerosis. we studied the association between progression of extra coronary atherosclerosis (mean follow-up period: 6.4 years) and crp using multinomial regression analysis. results: crp levels were positively related to all measures of atherosclerosis, but the relation was weaker for measures based on detection of calcification only. crp levels were associated with severe progression of carotid plaque (multivariable adjusted odds ratio: 1.5, 95% ci: 0.9-2.5), imt (1.7, 1.0-2.8) and abi (1.7, 1.1-2.6). no relation was observed with progression of abdominal artery calcification. conclusion and discussion: crp is related to extent and progression of atherosclerosis. the relation seems weaker for measures based on detection of calcification only, indicating that calcification of plaques might attenuate the inflammatory process. background: maternal stress during pregnancy has been reported to have an adverse influence on fetal growth. the terrorist attacks of september 11, 2001 on the united states have provoked feelings of insecurity and stress worldwide. objective: our aim was to test the hypothesis that maternal exposure to these acts of terrorism via the media had an unfavourable influence on mean birth weight in the netherlands. design and methods: in a prospective cohort study, we compared birth weights of 1885 dutch neonates who were in utero during the attacks with those of 1258 neonates who were in utero exactly 1 year later. results: in the exposed group, birth weight was lower than in the non-exposed group (difference, 48 g, 95%ci 13.6, 82.9, p = 0.006). the difference in birth weight could not be explained by tobacco use, maternal age, parity or other potential confounders, nor by shorter pregnancy durations. conclusion: these results provide evidence supporting the hypothesis that exposure of dutch pregnant women to the september 11 events via the media has had an adverse effect on the birth weight of their offspring. objective: asian studies suggested potential reduction in the risk of pneumonia among patients with stroke on ace-inhibitor therapy. because of the high risk of pneumonia in patients with diabetes we aimed to assess the effects of ace-inhibitors on the occurrence of pneumonia in a general, ambulatory population of diabetic patients. methods: a case-control study was performed nested in 142,175 patients with diabetes. cases were defined as patients with a first diagnosis of pneumonia. for each case, up to 4 controls were matched by age, gender, practice, and index date. current ace-inhibitor use was defined within a time-window encompassing the index date. results: ace-inhibitors were used in 12.7% of 4,719 cases and in 13,7% of 15,322 matched controls (crude or: 0.92, 95% ci 0.82 to 1.01). after adjusting for potential confounders, ace-inhibitor therapy was associated with a reduction in pneumonia risk (adjusted or: 0.72, 95% ci 0.64 to 0.80). the association was consistent among different relevant subgroups (stroke, heart failure, and pulmonary diseases) and showed a strong dose-effect relationship (p<0.001). conclusions: use of ace-inhibitors was significantly associated with reduced pneumonia risk and may apart from blood pressure lowering properties be useful in prevention of respiratory infections in patients with diabetes. background: progressive decline in serum levels of testosterone occurs with normal aging in both men and women. this is paralleled by a decrease in physical performance and muscle strength, which may lead to disability, institutionalization and mortality. objective. we examined whether low levels of testosterone were associated with three-year decline in physical performance and muscle strength in two population-based samples of older men and women. methods: data were available for 623 men in the longitudinal aging study amsterdam (lasa) and 1172 men and 1278 women in the health, aging, and body composition (health abc) study. levels of total testosterone and free testosterone were determined at baseline. physical performance and grip strength were measured at baseline and after three years. results: total and free testosterone were not associated with change in physical performance or muscle strength in men. in women, low levels of total testosterone (<=20 ng/dl) increased the risk of decline in physical performance (p = 0.03), and low levels of free testosterone (<2 pg/ ml) of decline in muscle strength (p = 0.03). conclusion: low levels of total and free testosterone were associated with decline in physical performance and muscle strength in older women, but not in older men. background: obesity and physical inactivity are key determinants of insulin resistance, and chronic hyperinsulinemia may mediate their effects on endometrial cancer (ec) risk. aim: to examine the relationships between prediagnostic serum concentrations of cpeptide, igf binding protein (igfbp)-1 and igfbp-2, and ec risk. methods: we conducted a case-control study nested within the epic prospective cohort study, including 286 incident cases of ec, in pre-and post-menopausal women, and 555 matched control subjects. odds ratios (or) and 95% confidence intervals (ci) were calculated using conditional logistic regression models. results: in fasting women (>6 h since last meal), serum levels of c-peptide, igfbp-1 and igfbp-2 were not related to risk. however, in nonfasting women (6 h or less since last meal), ec risk increased with increasing serum levels of c-peptide ( background: tobacco is the single most preventable cause of death in the world today. tobacco use primarily begins in early adolescent. objective: to estimate the prevalence and evaluate factors associated with smoking among high school going adolescents in karachi, pakistan. methods: a school based cross sectional survey was conducted in three towns of karachi from january through may 2003. two-stage cluster sampling stratified on school types was employed to select schools and students. self-reported smoking status of school going adolescents was our main outcome in analysis. results: prevalence of smoking (30 days) among adolescents was 13.7%. multiple logistic regression model showed that after adjustment for age, ethnicity and place of residence, being student of a government school (or=1.6; 95% ci: 1.0-2.7), parental smoking (or = 1.7; 95% ci: 1.1 -2.8), uncle (or = 1.7; 95% ci: 1. 2-2.8) , peer smoking (or = 6.2; 95% ci: 3.9 -9.9) and spending leisure time outside home (or = 3.9; 95% ci 1. 2-13.2) were significantly associated with adolescents smoking. conclusion: a 13.7% prevalence of smoking among school going adolescents and influence of parents and peers in initiating smoking in this age group warrant the need for effective tobacco control in the country especially among the adolescents. background: individual patient data meta-analyses (ipd-ma) have been proposed to improve subgroup analyses that may provide clinically relevant information. nevertheles, comparison of the effect estimates of ipd-ma and meta-analyses of published data (map) are lacking. objective: to compare main and subgroup effect estimates of ipd-ma and map. methods: an extended literature search was performed to identify all ipd-ma of randomized controlled trials, followed by a related article search to identify maps with a similar domain, objective, and outcome. data were extracted regarding number of trials, number of subgroups, effect measure, effect estimate and their confidence intervals. results: in total 16 ipd-ma and 18 map could be included in the analysis. twentyfive main effect estimates could be compared; of which 22 were in the same direction. although over 100 subgroups were studied in both ipd-ma and map, only 18 effect estimates could be compared; 17 were in the same direction. subgroup analyses in map most often related to trial characteristics, whereas subgroup analyses in ipd-ma were related to patient characteristics. conclusion: comparable ipd-ma and map report similar main and subgroup effect estimates. however, ipd-ma more often study subgroups based on patient characteristics, and thus provide more clinically relevant information. patients with diabetes have an increased risk of a complicated course of community-acquired lower respiratory tract infections. although influenza vaccination is recommended for these persons, vaccination levels remain too low because of conflicting evidence regarding potential benefits. as part of the prisma nested casecontrol study among 75,000 persons recommended for vaccination, we studied the effectiveness of single and repeat influenza vaccination in the subgroup of adult diabetic population (9, 238) during the 1999-2000 influenza a epidemic. case patients were hospitalized for diabetes, acute respiratory or cardiovascular events, or died and controls were sampled from the baseline cohort. after control for age, gender, health insurance, prior health care, medication use and co-morbid conditions logistic regression analysis showed that the occurrence of any complication (131 hospitalizations, 61 deaths) was reduced by 56% (95% confidence interval 36% to 70%). vaccine effectiveness was similar for those who received the vaccine for the first time and for those who received an earlier influenza vaccination. although we did not perform virological analysis or distinguish type i from type ii diabetes we conclude that patients with diabetes benefit substantially from influenza vaccination independent of whether they received the vaccine for the first time or received earlier influenza vaccinations. background: construction workers are at risk of developing silicosis. regular medical evaluations to detect silicosis preferably in the pre-clinical phase are needed. objectives: to identify the presence or absence of silicosis by developing an easy to use diagnostic model for pneumoconiosis from simple questionnaires and spirometry. design and methods: multiple logistic regression analysis was done in 1291 dutch construction workers, using chest x-ray indicative for pneumoconiosis (ilo profusion category > 1/1) as the reference standard (prevalence 2.9%). model calibration was assessed with graph and the hoshmer-lemeshow goodness of fit test; discriminative ability using area under receiver operating characteristic curve (auc); and internal validity using bootstrapping procedure. results: age > 40 years, current smoking, high exposure job title, working > 15 years in the construction industry, 'feeling unhealthy', and standardized residual fev1 below )1.0 were selected as predictors. the diagnostic model showed a good calibration (p = 0.5) and discriminative ability (auc 0.81; 95% ci 0.74 to 0.85). internal validity was reasonable (correction factor of 0.82 and optimism corrected auc of 0.76). conclusions: and discussion: our diagnostic model for silicosis showed reasonable performance and internal validity. to apply the model with confidence, external validation before application in a new working population is recommended. background: artemisinin based combination therapy (act) reduces microscopic gametocytaemia, the malaria parasite stage responsible for transmission from man to mosquito. as a result, act is expected to reduce the burden of disease in african populations. however, molecular techniques recently revealed high prevalences of gametocytaemia below the microscopic threshold. our objective was to determine the importance of sub-microscopic gametocytaemia after act treatment. methods: kenyan children (n=528) aged 6 months -10 years were randomised to four treatment regimens. gametocytaemia was determined by microscopy and pfs25 real-time nucleic acid sequence-based amplification (qt-nasba). transmission was determined by membrane feedings. findings: gametocyte prevalence at enrolment was 89.4% (219/245) as determined by pfs25 qt-nasba and decreased after treatment with act. membrane feedings in randomly selected children revealed that the proportion of infectious children was up to fourfold higher than expected when based on microscopy. act did not significantly reduce the proportion of infectious children but merely the proportion of infected mosquitoes. interpretation: sub-microscopic gametocyte densities are common after treatment and contribute considerably to mosquito infection. our novel approach indicates that the effect of act on malaria transmission is much smaller than previously suggested. these findings are sobering for future interventions aiming to reduce malaria transmission. background: adequate folate intake may be important in the prevention of breast cancer. factors linked to folate metabolism may be relevant to its protective role. objectives: to investigate the association between folate intake and breast cancer risk among postmenopausal women and evaluate the interaction with alcohol and vitamin b12 intake. methods: a prospective cohort analysis of folate intake among 62,739 postmenopausal women from the e3n french cohort who completed a validated food frequency questionnaire in 1993 was conducted. during 9 years follow-up 1,814 cases of pathology-confirmed breast cancer were documented through followup questionnaires. nutrient intakes were categorized in quintiles and energy-adjusted using the regression-residual method. cox modelderived relative risks (rr) were adjusted for known risk factors for breast cancer. results: the multivariate rr comparing the extreme quintiles of folate intake was 0.76 (95% ci 0.65-0.88; p-trend=0.005). after stratification, the association was observed only among women whose alcohol consumption was above the median (=6.2 g/day) and among women who consumed =6.5lg/day of vitamin b12. however, tests for interaction were not significant. conclusions: in this population, high intakes of folate were associated with decreased breast cancer risk; alcohol and vitamin b12 intake may modify the observed inverse association. background: the simultaneous rise in the prevalence of obesity and atopy in children has prompted suggestions that obesity might be a causal factor in the inception of atopic diseases. objective: we investigated the possible role of ponderal index (kg/m 3 ) as marker for fatness at birth in early childhood atopic dermatitis (ad) in a prospective birth cohort study. methods: between november 2000 and november 2001, mothers and their newborns were recruited after delivery at the university of ulm, germany. active follow-up was performed at the age of 12 months. results: for 872 (82%) of the 1066 children included at baseline, information on physician reported diagnosis of ad was obtained during follow-up. incidence of ad was 12.4% at the age of one year. mean ponderal index at birth was 24.7 kg/m 3 . risk for ad was higher among children with high ponderal index at birth (adjusted or for children within the third and fourth compared to children within the second quartile of ponderal index: 2.14; 95% ci 1. respectively) background: the relationship between duration of breastfeeding and risk of childhood overweight remains inconclusive, possibly in part caused by using never breastfeeding mothers as the reference category. objectives: we assessed the association between duration of breastfeeding and childhood overweight among ever breastfed children within a prospective birth cohort study. methods: between november 2000 and november 2001 all mothers and their newborns were recruited after delivery at the university of ulm, germany. active follow-up was performed at age 24 months. results: among 855 children (80% of 1066 children included at baseline) with available body mass index at age two 72 (8.4%) were overweight. whereas 76 children (8.9%) were never breastfed, 533 (62.3%) were breastfed for at least six months, and 322 (37.7%) were exclusively breastfed for at least six months. compared to children who were exclusively breastfed less than three months, the adjusted or for overweight was 0.8 (95% ci 0.4; 1.5) in children who were exclusively breastfed for at least three but less than six months and 0.4 (95% ci 0.2; 0.9) in children who were exclusively breastfed for at least six months. conclusion: these results highlight the importance of prolonged breastfeeding in the prevention of overweight in children. background: in africa, hiv and feeding practices influence child mortality. exclusive breastfeeding for 6 months (bf6) and formula feeding (ff) when affordable are two who recommendations for safe feeding. objective: we estimated the proportion and the number of children saved with each recommendation at population level. design and methods: data on 31 sub-saharan countries were analysed. we considered saved a child remaining hiv-free and alive after two years of life. a spreadsheet model based on a decision tree for risk assessment was used to calculate this number according to six scenarios that combine the two recommendations without and with promotion then with promotion and group education. results: whatever the country, the number of children saved with bf6 would be higher than with ff. overall, without promotion, 52 315 ( background: farming has been associated with respiratory symptoms as well as protection against atopy. effects of different farming practices on respiratory health in adults have rarely been studied. objectives: we studied associations between farming practices and hay fever and current asthma in organic and conventional farmers. design and methods this cross-sectional study evaluated questionnaire data of 1205 conventional and 593 organic farmers. associations between health effects and farm exposures were assessed by logistic regression. results: organic farmers reported slightly more hay fever than conventional farmers (9.3% versus 6.9%, p = 0.07). however, organic farming was no independent determinant for hay fever in multivariate models including farming practices and potential confounders. livestock farmers who grew up on a farm had a five-fold lower prevalence of hay fever than crop farmers without farm childhood (or 0.2, 95% ci 0.1-0.5). use of disinfectants containing quaternary ammonium compounds was positively related to hay fever (or 2.4, 95% ci 1.1-5.1). no effects of farming practices were found for asthma. conclusion and discussion: our study adds to the evidence that a farm childhood in combination with current livestock farming protects against allergic disorders. this effect was found for both organic and conventional farmers. background: although a body mass index (bmi) above 25 kg/m 2 is clearly associated with an increase in mortality in the general population, the meaning of high levels of bmi among physically heavily working men is less clear. methods: we assessed the association between bmi and mortality in a cohort of 19513 male construction workers, aged 25-64 years, who underwent an occupational health examination in wu¨rttemberg (germany) during 1986-1992 and who were followed over a 10 years period. covariates considered in the proportional hazard regression analysis included age, nationality, smoking status, alcohol consumption, and comorbidity. results: during the follow-up 802 deaths occurred. there was a strong u-shaped association between bmi and all-cause mortality, which was lowest for bmi levels between 25 and 35 kg/m 2 . this pattern persisted after exclusion of the first years of follow-up and control for multiple covariates. compared with men with a bmi < 25.0 kg/m 2 , the relative mortality was 0.76 (95% confidence interval: 0,64-0,91), 0.75 (0.59-0.97) and 1.00 (0.62-1.62) for bmi ranges 25-29.9, 30-34.9 and = 35.0 kg/m 2 . conclusion and discussion: bmi levels commonly considered to reflect overweight or moderate obesity in the general population may be associated with reduced mortality in physically heavily working men. background: colonoscopy with removal of polyps may strongly reduce colorectal cancer (crc) incidence and mortality. empirical evidence for optimal schedules for surveillance is limited. objective. to assess risk of proximal and distal crc after colonoscopy with polypectomy. design and methods: history and results of colonoscopies were obtained from 540 cases and 614 controls in a population-based case-control study in germany. risk of proximal and distal crc according to time since colonoscopy was compared to risk of subjects without previous colonoscopy. results: subjects with previous detection and removal of polyps had a much lower risk of crc within four years after colonoscopy (adjusted odds ratio 0.38, 95% confidence interval 0.18-0.78), and a similar risk as those without colonoscopy in the long run. within four years after colonoscopy, risk was particularly low if only single or small adenomas were detected. most cancers occurring after polypectomy were located in the proximal colon, even if polyps were found in the sigma or rectum only. conclusion and discussion: our results support suggestions that surveillance colonoscopy after removal of single and small adenomas may be deferred to five years and that surveillance should include the entire colorectum even if only distal polyps are detected. background: a population-based early detection programme for breast cancer has been in progress in finland since 1987. recently, detailed information about actual screening invitation schemes in 1987 -2001 has become available in electronic form, which enables more specific modeling of breast cancer incidence. objectives: to present a methodology for taking into account historical municipality-specific schemes of mass screening when constructing predictions for breast cancer incidence. to provide predictions for numbers of new cancer cases and incidence rates according to alternative future screening policies. methods: observed municipality-specific screening invitation schemes in finland during 1987-2001 were linked together with breast cancer data. the incidence rate during the observation period was analyzed using poisson regression, and this was done separately for localized and nonlocalized cancers. for modeling, the screening programme was divided into seven different phases. alternative screening scenarios for future mass-screening practices in finland were created and an appropriate model for incidence prediction was defined. results and conclusion: expanding the screening programme would increase the incidence of localized breast cancers; the biggest increase would be obtained by expanding from women aged 50-59 to 50-69. the impacts of changes in the screening practices on predictions for non-localized cancers would be minor. background: new screening technologies are implemented to routine screening in increasing numbers, with limited evidence on their effectiveness. randomised evaluation of new technologies is encouraged but rarely done. objective: to evaluate in a randomised design whether the effectiveness of an organised cervical screening programme can be improved by means of new technologies. methods: since 1999 150,000-170,000 women have been invited annually to a randomised multi-arm trial ran within the finnish organised cervical screening programme. the invited women are randomly allocated to three study arms of different primary screening tests: conventional cytology, automation-assisted cytology and, since 2003, human papillomavirus (hpv) testing. up to 2005, we have gathered information on 185,000 screening visits in the automation-assisted arm and 4,653 in the hpv arm, and we have compared the results to conventional screening. results: automation-assistance resulted in a slightly increased detection of precancers, but the efficacy based on interval cancers is not known. results on hpv screening suggest higher detection of precancers and cancers compared to conventional screening. conclusion: evidence of higher effectiveness of new screening technologies is needed, especially when changing the existing screening programmes. the multi-arm trial shows how these technologies can be implemented to routine in a controlled manner. introduction: nodules and goitres are important risk factors for thyroid cancer. as the number of diagnosed cases of thyroid cancer is increasing, the incidence of such risk factors has been assessed in a french cohort of adults. methods: the su.vi.max (supple´mentation en vitamines et mine´raux antioxydants) cohort study included 12741 middle-aged adults followed-up during eight years. incident cases of goitres and nodules have been identified retrospectively by scheduled clinical examinations and spontaneous consultations by the participants. cox proportional hazards modeling was used to identify factors associated to thyroid diseases. results: finally, 160 incident cases of nodules and goitres were identified among 4,002 subjects free of thyroid diseases at inclusion. after an average follow-up of 7 years, the incidence of goitres and nodules was 2.2% in 45-60 year old men, 4.9% in 35-44 year old women and 7.4% in 45-60 year old women. identified associated factors were age, low urinary thiocyanate level and oral contraceptive use in women, and high urinary thiocyanate level and low urinary iodine level in men. conclusion: estimated incidences are consistent with those observed in other countries. the protective role of urinary thiocyanate in both men and women and, in women, oral contraceptives deserve further investigation. background: various statistical methods for outbreak detection in hospital settings have been proposed in the literature. usually validation of those methods is difficult, because the long time series of data needed for testing the methods are not available. modeling is a tool to overcome that difficulty. objectives: to use model generated data for testing sensitivity and specificity of different outbreak detection methods. methods: we developed a simple stochastic model for a process of importation and transmission of infection in small populations (hospital wards). we applied different statistical outbreak detection methods described in the literature to the generated time series of diagnosis data and calculated and the sensitivity and specificity of different methods. results: we present roc curves for the different methods and show how they depend on the underlying model parameters. we discuss how sensitivity and specificity measures depend on the degree of underdiagnosis, on the ratio of admitted colonised patients to colonisation resulting from transmission in the hospital, and on the frequency of testing patients for colonisation. conclusions: modeling can be a useful tool for evaluating statistical methods of outbreak detection especially in situation where real data is scarce or its quality questionable. associated with higher mammographic density and breast pain, has been increased which has bearing on screening performance. objective: we compared the screening performance for women aged 49-69 years with dense and lucent breast patterns in two time periods and studied the possible interaction with use of hrt. methods: data were collected from a dutch regional screening programme for women referred in 1994-1995 (n = 642) and 2001-2002 (n = 107) . in addition, we sampled controls for both periods that were not referred (n = 1927 and n = 212 resp.) and women diagnosed with an interval cancer. mammograms were digitised and computer-assisted methods used to measure mammographic density. among other parameters, sensitivity was calculated to describe screening performance. results: screening performance has improved slightly, but the difference between dense and lucent breast patterns still exists (e.g. sensitivity 62% vs. 78%). hrt use has increased; sensitivity was particularly low (38%) in the group of women with dense breast patterns on hrt. discussion: in conclusion, the detrimental effect of breast density and the interaction with hrt on screening performance warrants further research with enlargement of the catchment area, more referred women, interval cancers and controls. background: population based association studies might lead to false-positive results if possibly underlying population structure is not adequately accounted for. to assess the nature of the population structure some kind of cluster analysis has to be carried out. we investigated the use of self-organizing maps (soms) for this purpose. objectives: the two main questions concern identification of an either discrete or an admixed population structure and identification of the number of subpopulations involved in forming the structured population under investigation. design and methods: we simulated data sets with different population models and included varying informative marker and map sizes. sample sizes ranged from 200 to 2400 individuals. results: we found that a discrete structure can easily be accessed by soms. a near to perfect assignment of individuals to their population of origin can be obtained. for an admixed population structure though, soms do not lead to reasonable results. here, even the correct number of subpopulations involved can not be identified. conclusion: in conclusion, soms can be an alternative to a model-based cluster analysis if the researcher assumes a discrete structure but should not be applied if an admixed structure is likely. background: little is known about the combined effect of duration of breastfeeding, sucking habits and malocclusion in the primary dentition. objectives: we studied the association of breastfeeding and non-nutritive sucking habits on malocclusion on the primary dentition. design and methods: a cross-sectional study nested in a birth cohort was carried out in pelotas, brazil. a random sample of 359 children aged 6 was examined and their mothers interviewed. the foster and hamilton criteria were used to define anterior open bite (aob) and posterior cross bite (pcb). information regarding breastfeeding and non-nutritive sucking habits was collected from birth to 6 years-old. poisson's regression analysis was used. results: non-nutritive sucking habits between 12 months and 4 years of age (pr3.5 [2.3;5.4] ) and digital sucking at 6 years of age (pr1.5[1.1;2.1]) were risk factors for aob. breastfeeding for less than 9 months (pr7.6[1.5; 39.5] ) and the regular use of a pacifier between 12 months and 4 years of age (pr7.5[1.3;44.3]) were the risk factors for pcb. for pcb an interaction was identified between lack of breastfeeding and the use of a pacifier. conclusion: lack of breastfeeding and longer non-nutritive sucking habits during early childhood were the main risk factors for malocclusion in primary dentition. background: recent, dramatic coronary heart disease (chd) mortality increases in beijing, can be mostly explained by adverse changes in risk factors, particularly total cholesterol and diabetes. it is important for policy making to predict the impact of future changes in risk factors on chd mortality trends. objective: to assess the potential impact of changes in risk factors on numbers of chd deaths in beijing from 1999 to 2010, to provide evidence for future chd strategies. design: the previously validated impact model was used to estimate the chd deaths expected in 2010 a) if recent risk factor trends continue or b) if levels of risk factors reduce. results: continuation of current risk factor trends will result in a 48% increase in chd deaths by 2010, (almost half being attributable to increases in total cholesterol levels). even optimistically assuming a 1% annual decrease in risk factors, chd deaths would still rise by 21% because of population ageing. conclusion: a substantial increase in chd deaths in beijing may be expected by 2010. this will reflect worsening risk factors compounded by demographic trends. population ageing in china will play an important role in the future, irrespective of any improvements in risk factor profiles. background: since smoking cessation is more likely during pregnancy than at other times, interventions to maintain quitting postpartum may give the best opportunity for a long-time abstinence. it is still not clear what kind of advice or counseling should be given to help prevent the relapse postpartum. objectives: to identify the factors, which predispose women to smoking relapse after delivery. design and methods: the cohort study was conducted in 2004 and 2005 in public maternity units in lodz, poland. the study population consisted of pregnant women between 32-36 weeks of pregnancy who have quit smoking no later than three months prior to participation in the study. smoking status was verified using saliva cotinine level. women were interviewed twice: during pregnancy and three months after delivery. results: within three months after delivery about half of women relapsed into smoking. the final model identified the following risk factors for smoking relapse: having partner and friends who smoke, quitting smoking in late pregnancy, and negative experiences after quitting smoking such as dissatisfaction with weight, nervousness, irritation, loosing pleasure. conclusion. this study advanced the knowledge of the factors that determine smoking relapse after delivery and provided preliminary data for future interventions. introduction: it remains difficult to predict the effect of an particular antihypertensive drug in an individual patient and pharmacogenetics might optimise this. objective: to investigate whether the association between use of angiotensin converting enzyme (ace)-inhibitors or ß-blockers and the risk of stroke or myocardial infarction (mi) is modified by the t-allele of the angiotensinogen m235t polymorphism. methods: data were used from the rotterdam study, a population-based prospective cohort study. in total, 4093 subjects with hypertension were included from july 1st, 1991 onwards. follow-up ended at the diagnosis of mi or stroke, death, or the end of study period (january 1st, 2002) . the drug-gene interaction and the risk of mi/stroke was determined with a cox proportional hazard model (adjusted for each drug class as time-dependent covariates). results: the interaction between current use of ace-inhibitors and the angiotensinogen m235t polymorphism increased the risk of mi (synergy index (si) = 4.00; 95% ci:1.32-12.11) and non-significant increased risk of stroke (si = 1.83; 95% ci:0.95-3.54). no interaction was found between current use of ß-blockers and the agt m235t polymorphism on the risk of mi or stroke. conclusion: subjects with at least one copy of the 235t allele of the agt gene might have less benefit from ace-inhibitor therapy. [2.4-6.9 ] to 1.5 [1.1-2.1] in those without ms-idf and 1.9 [1.5-2.6] with ms-idf. ms-ncep had no effect. conclusion and discussion: although cardiovascular disease was self-reported, we conclude that the higher prevalence of cardiovascular disease is partly accounted for by marked differences in the prevalence of metabolic syndrome. the ms-idf criteria seem better for defining metabolic syndrome in ethnic groups than the ms-ncep criteria. background: selenium is an essential trace mineral with antioxidant properties. objective: to perform meta-analyses of the association of selenium levels with coronary heart disease (chd) endpoints in observational studies and the efficacy of selenium supplements in preventing chd in randomized controlled trials. methods: we searched medline and the cochrane library from 1966 through 2005. relative risk (rr) estimates were pooled using an inversevariance weighted random-effects model. for observational studies reporting three or more categories of exposure we conducted a dose-response meta-analysis. results: twenty-five observational studies and 6 clinical trials met our inclusion criteria. the pooled rr comparing the highest to the lowest categories of selenium levels was 0.85 (95% confidence interval 0.74-0.99) in cohort studies and 0.43 (0.29-0.66) in case-control studies. in dose-response models, a 50% increase in selenium levels was associated with a 24% (7-38%) reduced risk of coronary events. in randomized trials, the rr comparing participants taking selenium supplements to those taking placebo was 0.90 (0.75-1.09). conclusion: selenium levels were inversely associated with the risk of chd in observational studies. the randomized trials findings are still inconclusive. these results require confirmation in randomised controlled trials. currently, selenium supplements should not be recommended for cardiovascular prevention. 140 background propensity score analysis (psa) can be used to reduce confounding bias in pharmacoepidemiologic studies of the effectiveness and safety of drugs. however, confidence intervals may be falsely precise because psa ignores uncertainty in the estimated propensity scores. objectives: we propose a new statistical analysis technique called bayesian propensity score analysis (bpsa). the method uses bayesian modelling with the propensity score as a latent variable. our question is: does bpsa yield improved interval estimation of treatment effects compared to psa? our objective is: to implement bpsa using computer programs and investigate the performance of bpsa compared to psa. design and methods: we investigated bpsa using monte carlo simulations. synthetic datasets, of sample size n = 250, 1000, 4000, were simulated by computer. the datasets were analyzed using bpsa and psa and we estimated the coverage probability of 80% credible intervals. results the estimated coverage probabilities ranged from 78% to 84% for bpsa, and from 42% to 82% for psa, with simulation standard errors less than 2%. background: several factors associated with low birth weight, such as smoking and body mass index (bmi) do not explain all ethnic differences. this study investigates the effects of working conditions on birth weight among different ethnic groups. methods: questionnaire data, filled in 2 weeks after prenatal screening, was used from the amsterdam born children and their development (abcd) study (all pregnant women in amsterdam [7/1/03-7/3/04 (n = 12.381), response 8267 (67%)]. ethnicity (country of birth). was dichotomised into dutch and non-dutch. working conditions were: weekly working hours, weekly hours standing/walking, physical load and job-strain (karasek-model). only singleton deliveries with pregnancy duration = 37 weeks were included. results: although only 39.4% of the non-dutch women worked during first trimester (79.6% of the dutch women), they reported significantly more physical load (15.1% vs 9.0%), more hours standing/walking (10.6% vs 6.3%) and more high job-strain (10.2 vs 5.7). linear regression revealed that only high job-strain lowered significantly birth weight (non-dutch: 159 gram and dutch: 75 gram). after adjusting for confounders (gender, parity, smoking, maternal length, maternal bmi and education), this was only significant in the non-dutch group (112 vs. 30 gram). conclusion: job-strain has more effect on birth weight in non-dutch compared to dutch women. background: in 2004 panama population was estimated in 3.2 million habitants, from which three millions lived in malaria endemic areas. until january 26 1998 malaria control activities were accomplished under a vertical structure. objective: to evaluate the evolution of malaria control in panama, before and after the decentralization of the malaria program. design and methods: average (standard deviation) of the program indexes are described for the last decades. the correlation between positive smears index and per capita cost of the program is analyze. results: in the 1960's the average (standard deviation) positive smears index per 100 habitants was 3.3% (1.8); in the 1970's: 0.4% (0.5); in the 1980's: 0.13% (0.1); in the 1990's: 0.32% (0.2); and in the first five years of 2000: 1.7% (1.1). after the decentralization of the program was accomplished in 1998, the positive smears index increased 5.3 fold. the average per capita cost involved in malaria control activities per decade ranged between 0.19 y 1.25 us dollars and presented a determination coefficient of 0.42 in the reduction of the positive smears index. discussion: the decentralization had significant detrimental implications in the control program capabilities. background: notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in vietnam in general (69/100,000 population). this study assessed whether this is explained by low case detection. objective: to assess the prevalence and case detection of new smear-positive pulmonary tuberculosis among adults with a prolonged cough in central mountainous vietnam. design and methods: a house-to-house survey of adults 15 years or older was carried out in 12 randomly selected districts in three mountainous provinces in central vietnam in 2003. three sputum specimens were microscopically examined of persons reporting a cough of 3 weeks or longer. results: the survey included 68,946 persons with a response of 95%. a cough of 3 weeks or longer was reported by 1,298 (1.9% 95% ci 1. 8-2.2) persons. of these, 18 were sputum smear-positive of whom 2 had had anti-tuberculosis treatment. the prevalence of new smear-positive tuberculosis was 27/100,000 population (95% ci 11-44/100,000 population). the patient diagnostic rate was 1.6 per person-year, suggesting that the case notification rate as defined by who was 76%. conclusion: low tuberculosis notification rates in mountainous vietnam are probably due to low tuberculosis incidence. explanations for low incidence at high altitude need to be studied. background: although patients with type 2 diabetes (dm2) have an increased risk of urinary tract infections (utis), not much is known about predictors of a complicated course. objective: this study aims to develop a prediction rule for complicated utis in dm2 patients in primary care. design and methods: we conducted a 12-month prospective cohort study, including dm2 patients aged 45 years or older from the second dutch national survey of general practice. the combined outcome measure was defined as the occurrence of recurrent cystitis, or an episode of acute pyelonephritis or prostatitis. results: of the 6,343 dm2 patients 46% was male and mean age was 67 years (sd 11). incidence of the outcome was 3 per 100 patient years (n = 179). predictors were age, male sex, number of physician contacts, incontinence of urine, cerebro vascular disease or dementia and renal disease. the area under the receiver-operating curve (auc) was 0.77 (95% ci 0.73 to 0.80). subgroup analyses for gender showed no differences. there is an increased early postoperative mortality (operation risk) after elective surgery. this mortality is normally associated with cardiovascular events, such as deep venous thrombosis, pulmonary embolism, and ischemic heart diseases. our objective was to quantify the magnitude of the increased mortality and how long the mortality after an operation persists. we focused on the early postoperative mortality after surgery for total knee and total hip replacements from the national registries in australia and norway, which cover more than 95% of all operations in the two nations. only osteoarthritis patients between 50 and 80 years of age were included. a total of 244.275 patients remained for analyses. smoothed intensity curves were calculated for the early postoperative period. effects of risk factors were studied using a nonparametric proportional hazards model. the mortality was highest immediately after the operation ($1 deaths per 10.000 patients per day), and it decreased until the 3rd postoperative week. the mortality was virtually the same for both nations and both joints. mortality increased with age and was higher for males than for females. a possible reduction of early postoperative mortality is plausible for the immediate postoperative period, and no longer than the 3rd postoperative week. background/objectives: single, modifiable risk factors for stroke have been extensively studied before, but their combined effects were rarely investigated. aim of the present study was to assess single and joint effects of risk factors on stroke and transitoric ischemic attack (tia) incidence in the european prospective investigation into cancer and nutrition (epic)-potsdam study. methods: among 25538 participants aged 35-65 years at baseline 100 total stroke cases and 112 tia cases occurred during 4.3 years of follow-up. relative risks (rr) for stroke and tia related to risk factors were estimated using cox proportional hazard models. results: after adjustment for potential confounders rr for ischemic stroke associated with hypertension was 2.32 (95% ci, 1.35-3.99) and for tia 1.14 (95% ci 0.76-1.71). the highest rr for ischemic stroke (rr 5.12, 95% ci 1.49-17.6, p trend<0.0001) and tia (rr 3.08, 95% ci 1.00-9.44, p trend=0.024) were observed among participants with 4 or 5 modifiable risk factors. 58.5 % of ischemic strokes and 26.2% of tia cases were attributable to hypertension, diabetes mellitus, high alcohol consumption, hyperlipidemia, and smoking. conclusion: almost 60% of ischemic stroke cases could be explained by classical modifiable risk factors. however, only one in four tia cases was attributable to those risk factors. background: the investigation of genetic factors is gaining importance in epidemi-ology. most relevant from a public health perspective are complex diseases that are characterised by complex pathways involving gene-gene-and gene-environment-interactions. the identification of such pathways requires sophisticated statistical methods that are still in their infancy. due to their ability in describing complex association structures, directed graphs may represent a suitable means for modelling complex causal pathways. objectives: we present a study plan to investigate the appropriateness for using directed graphs for modelling complex pathways in association stud-ies. design and methods: graphical models and artificial neural networks will be investigated using simulation studies and real data and their advantages and disadvantages of the respective ap-proaches summed up. furthermore, it is planned to construct a hybrid model exploiting the strengths of either model type. results and conclusions: the part of the project that concerns graphical models is being funded and ongoing. first results of a simulation study have been obtained and will be presented and discussed. a second project is currently being applied for. this shall cover the investigation of neural networks and the construction of the hybrid model. this study investigates variations in mortality from 'avoidable' causes among migrants in the netherlands in comparison with the native dutch population. data were obtained from population and mortality registries in the period 1995-2000. we compared mortality rates for selected 'avoidable' conditions for turkish, moroccan, surinamese and antillean/aruban groups to native dutch. we found slightly elevated risk in total 'avoidable' mortality for migrant populations (rr = 1.13). higher risks of death among migrants were observed from almost all infectious diseases (most rr>3.00) and several chronic conditions including asthma, diabetes and cerebro-vascular disorders (most rr>1.70). migrant women experienced a higher risk of death from maternity-related conditions (rr = 3.37). surinamese and antillean/ aruban population had a higher mortality risk (rr = 1.65 and 1.31 respectively), while turkish and moroccans experienced a lower risk of death (rr = 0.93 and 0.77 respectively) from all 'avoidable' conditions compared to native dutch. control for demographic and socioeconomic factors explained a substantial part of ethnic differences in 'avoidable' mortality. conclusion: compared to native dutch, total 'avoidable' mortality was slightly elevated for all migrants combined. mortality risks varied greatly by cause of death and ethnicity. the substantial differences in mortality for a few 'avoidable' conditions suggest opportunities for improvement within specific areas of the healthcare system. warmblood horses scored by the jury as having uneven feet will never pass yearly selection sales of the royal dutch warmblood studbook (kwpn).to evaluate whether the undesired trait 'uneven feet' influences performance, databases of kwpn (n = 62234 horses) and knhs (n = 16015 show jumpers, n = 24269 dressage horses) were linked through the unique number of each registered horse. using a proc glm model of sas was investigated whether uneven feet had effects on age at first start and highest performance level. elite show jumpers with uneven feet start at 7.2 years and dressage horses 9.4 years of age, which is a significant difference (p<0.05) with elite even feet horses (8.0 respectively 9.0 years). at their maximum level of performance horses with even feet linearly scored in show jumping 31.1 at regular and 116.8 at elite level (29.0 resp. 105.7 with uneven feet), while in dressage horses scores were 38.0 at regular and 139.7 at elite level (35.5 resp. 136.7 with uneven feet).the conformational trait 'uneven feet' appears to have a significant effect on age at first start, while horses with even feet demonstrate a higher maximal performance than horses with uneven feet. objectives: to identify children with acute otitis media (aom) who might benefit more from treatment with antibiotics. methods: an individual patient data meta-analysis (ipdma) on six randomized trials (n = 1643 children). to preclude multiple testing, we first performed a prognostic study in which predictors of poor outcome were identified. subsequently, interactions between these predictors and treatment were studied by fixed effect logistic regression analyses. only if a significant interaction term was found, stratified analyses were performed to quantify the effect in each subgroup. results: interactions were found for: age and bilateral aom, and otorrhea. in children less than 2 years with bilateral aom, a rate difference (rd) of )25% (95% ci )30; )20%) was found, whereas in children aged 2 years or older with unilateral aom the rd was )4% (95% ci )6; )2%). in children with and without otorrhea the rd were )36% (95% ci )45; )27%), and )14% (95% ci )17%; )11%). conclusion: although there still are many areas in which ipdma can be improved, using individual patient data appear to have many advantages especially in identifying subgroups. in our example, antibiotics are beneficial in children aged less than 2 years with bilateral aom, and in children with otorrhea. major injuries, such as fractures, are known to increase the risk of venous thrombosis (vt). however, little is known of the risk caused by minor injuries, such as ankle sprains. we studied the risk of vt after minor injury in a population-based case-control study of risk factors for vt, the mega-study. consecutive patients, enrolled via anticoagulation clinics, and control subjects, consisting both of partners of patients and randomly selected control subjects, were asked to participate and filled in a questionnaire. participants with cancer, recent plastercasts, surgery or bedrest were excluded from the current analyses. 270 out of 2207 patients (12.2%) and 200 out of 4467 controls (4.5%) had suffered from a minor injury resulting in a three-fold increased risk of vt (odds ratio adjusted for age and sex 3.2; 95% confidence interval 2.7-3.9) compared to those without injury. the risk was highest in the first month after injury and was no longer increased after 3 months. injuries located in the leg increased the risk five-fold, while those located in other body parts did not increase the risk. these results show that minor injuries in the leg increase the risk of vt. this effect appears to be temporary and mainly local. introduction: in southeast asia, dengue was considered a childhood disease. in the americas, this disease occurs predominantly in older age groups, indicating the need for studies to investigate the immune status of the child population, since the presence of antibodies against a serotype of this virus is a risk factor for dengue hemorrhagic fever (dhf). objective: to evaluate the seroprevalence and seroincidence of dengue in children living in salvador, bahia, brazil. methods: a prospective study was carried out in a sample of children of 0-3 years by performing sequential serological surveys (igg/ dengue). results: seroprevalence in 625 children was 26.6%. a second survey (n = 289 seronegative children) detected an incidence of 33.2% and no difference was found between males and females or according to factors socioeconomic analyzed. conclusion and discussion: these results show that, in brazil, the dengue virus circulates actively in the initial years of life, indicating that children are also at great risk of developing dhf. it is possible that in this age group, dengue infections are mistaken for other febrile conditions, and that there are more inapparent infections in this age group. therefore, epidemiological surveillance and medical care services should be aware of the risk of dhf in children. since 1996, in the comprehensive cancer centre limburg (cccl) region, all women aged 30-60 years are invited to participate in the cervical cancer screening programme once every five years. we had the unique opportunity to link data from the cervical screening programme and the cancer registry. we studied individual pap smear testing and participation in the screening programme preceding the diagnosis of cervical cancer. all invasive cases of cervical cancer of women aged 30-60 years in the period 1996-2003 were selected. subgroups were based on results of the pap smear and invitation and participation in the screening programme. time interval between screening and detection of tumours was calculated. in 1996-2003, the non-response rate was 18%. in total, 211 invasive cervical cancer cases were detected of which 54 were screening and 32 interval carcinomas. in the group of women who were invited but did not participate and women who were not invited, respectively 64 and 61 tumours were detected. these tumours had a higher stage compared to screening carcinomas. in the cccl region, more and higher stage tumours were found in women who did not participate in the screening compared to women with screening tumours. background: pcr for mycobacterium tuberculosis (mtb) has already proved to be a useful tool for the diagnosis and investigation of molecular epidemiology. objectives: evaluation of pcr assay for detection of mycobacterium tuberculosis dna as a diagnostic aid in cutaneous tuberculosis. design and methods: thirty paraffinembedded samples belonging to 28 patients were analyzed for acid fast bacilli. dna was extracted from tissue sections and pcr was performed using specific primers based on is 6110 repeated gene sequence of mtb. results: two of the tissue samples were positive for acid fast bacilli (afb). pcr was positive in eight samples from six patients. amongst them, two were suspected of having lupus vulgaris confirmed histopathologically, whom their entire tests were positive. accounting histopathology as gold standard, the sensitivity of pcr in this study was determined as 75%. conclusion: from 8 cases of skin tuberculosis diagnosed by histopathology, 6 were positive by pcr technique, which shows the priority of previous method to molecular technique. discussion: pcr assay can be used for rapid detection of mtb from cutaneous tuberculosis cases, particularly when staining for afb is negative and there is a lack of growth on culture or when fresh material has not been collected for culture. background: recent epidemiological studies used automated oscillometric blood pressure (aod) devices that systematically measure higher blood pressure values than random zero sphygmomanometer devices (rzs) hampering the comparability of the blood pressure values between these studies. we applied both a random zero and an automated oscillometric blood pressure device in a randomized order in an ongoing cohort study. objectives: the aim of this analysis was to compare the blood pressure values by device and to develop a conversion algorithm for the estimation of blood pressure values from one device to the other. methods: within a randomized subset of 2365 subjects aged 45-75 years, each subject was measured three times by each device (hawskley random zero and omron hem-705cp) in a randomized order. results: the mean difference (aod-rzs) between the devices was 3.9 mmhg and 2.6 mmhg for the systolic and diastolic blood pressure respectively. linear regression models including age, sex, and blood pressure level can be used to convert rzs blood pressure values to aod blood pressure values and vice versa. conclusions: the results may help to better compare blood pressure values of epidemiological studies that used different blood pressure devices. a form was used to collect relevant perinatal clinical data, as part of a european (mosaic) and italian (action) project. the main outcomes were mortality and a variable combining mortality and severe morbidity at discharge. the cox proportional hazards and logistic regression models were used, respectively, for the two outcomes. results: twenty-two of percent of vpbs were among fbms. comparing to control group, the percentage of babies below 28 weeks and plurality was statistically significant higher among babies of fbms: 52% vs. 41.7 and 28.3% vs. 16.0%. adjusting for potential confounders, no association for mortality among immigrant group was found, whereas a slightly excess of morbidity-mortality was observed (odd ratio, 1.36; 95% cis 0.99-1.88). conclusions: the high proportion of vpbs among fbms and the slight excess observed in morbidity and mortality indicate the need to improve the health care delivery for the immigrant population. background: high-risk newborns have excess mortality, morbidity and use of health services. objectives: to describe re-hospitalizations after discharge from an italian region. design and methods: the population study consisted of all births with <32 weeks' gestation discharged alive from the twelve neonatal intensive care units in lazio region during 2003. the perinatal clinical data was collected as part of a european project (mosaic). we used the regional hospital discharge database to find hospital admissions within 12 months, using tax code for record linkage. data were analyzed through logistic regression for re-hospitalization. results: the study group included 361 children; among these, 111 (30.7%) were re-hospitalized; overall, 206 readmission were observed. the median total length of stay for re-admissions was 5 d. the two most common reasons for re-hospitalization were respiratory (37.8%) and gastrointestinal (16.5%) disorders. the presence of a severe morbidity at discharge (odd ratio 2.03: 95% cis 1.20-3.42) and male sex (odd ratio 1.97; 95% cis 1.24-3.15) predicted re-hospitalization in multivariate model. conclusions: almost one out three preterm infants was re-hospitalized in the first 12 months. readmissions after initial hospitalization for a very preterm birth could be a sensitive indicator of quality of follow-up strategies in high risk newborns. background: self-medication with antibiotics may lead to inappropriate use and increase the risk of selection of resistant bacteria. in europe the prevalence varies from 1/1000 to 210/1000 respondents. self-medication may be triggered by experience with prescribed antibiotics. we investigated whether in european countries prescribed use was associated with self-medication with antibiotics. methods: a population survey was conducted in 19 european countries with 15548 respondents completing the questionnaire. multivariate logistic regression analysis was used to study the relationship between prescribed use and self-medication (both actual and intended) in general, for a specific symptom/disease or a specific antibiotic. results: prescribed use was associated with selfmedication, with stronger effect in northern/western europe (odds ratio 7.6, 95% ci 4.2-13.6) than in southern (2.1, 1.2-3.6) and eastern europe (1.9, 1.3-2.7). prescribing of a specific antibiotic increased the probability of self-medication with the same antibiotic. prescribing for a specific symptom/disease increased the likelihood of self-medication for the same symptom/disease. the use of prescribed antibiotics and actual self-medication were both determinants of intended self-medication in general and for specific symptoms/diseases. conclusions: routine prescribing of antibiotics increases the risk of self-medication with antibiotics for similar ailments, both through the use of leftovers and buying antibiotics directly from pharmacies. background: in 2003 the american national kidney foundation published a guideline based on opinion and observational studies which recommends tight control of serum calcium, phosphorus and calcium-phosphorus product levels in dialysis patients. objectives: within the context of this guideline, we explored associations of these plasma concentrations with cardiovascular mortality risk in incident dialysis patients. design and methods: in necosad, a prospective multi-centre cohort study in the netherlands, we included 1629 consecutive patients new on haemodialysis or peritoneal dialysis between 1997 and 2004. risks were estimated using adjusted time-dependent cox regression models. results: mean age was 60±15 years, 61% was male, and 64% was treated with haemodialysis. cardiovascular mortality risk was significantly higher in haemodialysis patients (hr: 1.5; 95% ci: 1.1 to 2.1) and in peritoneal dialysis patients (hr: 2.4; 1.3 to 4.2) with elevated plasma phosphorus levels when compared to patients who met the target. in addition, having elevated plasma calcium-phosphorus product concentrations increased cardiovascular mortality risk in haemodialysis (hr: 1.5; 1.1 to 2.1) and in peritoneal dialysis patients (hr: 2.2; 1.3 to 3.8). conclusion: application of the current guideline in clinical practice is warranted since it reduces cardiovascular mortality risk in haemodialysis and peritoneal dialysis patients in the netherlands. background: urologists are increasingly confronted with requests for early detection of prostate cancer in men from hereditary prostate cancer (hpc) families. however, little is known about the benefit of early detection among men at increased risk. objectives: we studied the effect of biennial screening with psa in unaffected men from hpc families, aged 50-70 years, on surrogate endpoints (test and tumour characteristics). methods: the netherlands foundation for the detection of hereditary tumours holds information on approximately 140 hpc families. here, 172 nonaffected men from these families were included and invited for psa testing every 2 years. we collected data on screening history and complications related to screening. results: in the first round, serum psa was elevated (3 ng/ml or greater) in 39 of 172 men screened (23%). further diagnostic assessment revealed 14 patients with prostate cancer (8.1%). compared to population-based prostate cancer screening trials, the referral rate is equal but the detection rate is twice as high. discussion: in conclusion, the results of prostate cancer screening trials will not be directly applicable to screening in hpc families. the balance between costs, side-effects and potential benefits of screening when applied to a high-risk population will have to be assessed separately. background: in industrialized countries occupational tuberculosis among health care workers (hcws) is re-emerging as a public health priority. to prevent and control tuberculosis transmission in nosocomial settings, public health agencies have issued specific guidelines. turin, the capital of the piedmont region in italy, is experiencing a worrying rise of tuberculosis incidence. here, hcws are increasingly exposed to the risk of nosocomial tuberculosis transmission. objectives: a) to estimate the sex-and age-adjusted annual rate of tuberculosis infection (arti) (per 100 person-years [%py]) among the hcws, as indicated by tuberculin skin test conversion (tst) conversion, b) to identify occupational factors associated with significant variations in the arti, c) to investigate the efficacy of the regional preventive guidelines. design and methods: multivariate survival analysis on tst conversion data from a dynamic cohort of 2185 hcws in turin, between 1998 and 2004. results: the overall estimated arti was 2.4 (95% ci: 1.9-3.0) %py. the risk of tst conversion significantly differed among workplaces, occupations, and age of hcws. the guidelines implementation was associated with an arti reductions of 1.35 (95% ci: 1.33-1.27) %py. conclusions: we identify occupational risk categories for targeting surveillance and prevention measures and assessed the efficacy of the local guidelines. background: a positive family history (fh) of breast cancer is an established risk factor for the disease. screening for breast cancer in israel is recommended annually for positive-fh women aged = 40 y and biennially for average-risk women aged 50-74 y. objective: to assess the effect of having a positive breast cancer fh on performing screening mammography in israeli women. methods: a cross-sectional survey based on a random sample of the israeli population. the study population consists of 1,605 women aged 40-74 y and telephone interviews were used. logistic regression models identified variables associated with mammography performance. results: a positive fh for breast cancer was reported by 153 (9.5%) participants. performing a mammogram in the previous year was reported by 43.1% and 24.7% of the positive and negative fh subgroups, respectively (p<0.0001). rates increased with age. among positive fh participants, being married was the only significant correlate for a mammogram in the previous year. conclusions: over 60% and around 55% of high-risk women aged 40-49 y and = 50 y, respectively, are inadequately screened for breast cancer. screening rates are suboptimal in average-risk women too. discussion: national efforts should concentrate on increasing awareness and breast cancer screening rates. to evaluate the association between infertility, infertility treatments and breast cancer risk. methods: a historical prospective cohort with 5,788 women who attended 5 israeli infertility centers between 1964 and 1984. their medical charts were abstracted. breast cancer incidence was determined through linkage with the national cancer registry. standardized incidence ratios (sirs) and 95% confidence intervals were computed by comparing observed cancer rates to those expected in the general population. additionally, in order to control for known risk factors, a casecontrol study nested within the cohort was carried out as well based on telephone interviews with breast cancer cases and controls matched by 1:2 ratio. results: compared to 115.2 expected breast cancer cases, 131 were observed (sir = 1.1;non-significant). risk for breast cancer was higher for women treated with clomiphene citrate (sir = 1.4; 95% ci 1.0-1.8). similar results were noted when treated and untreated women were compared, and when multivariate models were applied. in the nested case-control study, higher cycle index and treatment with clomiphene citrate were associated with significantly higher risk for breast cancer. conclusions: clomiphene citrate may be associated with higher breast cancer risk. smoking is a strong risk factor for arterial disease. some consider smoking also as a risk factor for venous thrombosis, while the results of studies investigating the relationship are inconsistent. therefore, we evaluated smoking as a risk factor for venous thrombosis in the multiple environmental and genetic assessment of risk factors for venous thrombosis (mega) study, a large population-based case-control study. consecutive patients with a first venous thrombosis were included from six anticoagulation clinics. using a random-digit-dialing method a control group was recruited in the same geographical area. all participants completed a questionnaire including questions on smoking habits. persons with known malignancies were excluded from the analyses, leading to a total of 4086 patients and 2567 controls. current and former smoking resulted in a small increased risk of venous thrombosis (ors adjusted for age, sex and bmi) (or-current:1.5 ci95:1.3-1.7, or-former:1.2 ci95:1.0-1.4). an increasing amount and duration of smoking was associated with an increase in risk. the highest risk was found among young (lowest tertile:18 to 41 yrs) current smokers; twenty or more pack-years resulted in a 3.3-fold increased risk (ci95:2.2-5.0). in conclusion, smoking results in a small increased risk of venous thrombosis, with the greatest relative effect among young heavy smokers. objective: to explore whether the observed association between silica exposure and lung cancer was confounded by exposure to other occupational carcinogens, we conducted a nested case-control-study among a cohort of male workers in 29 chinese mines and potteries. methods: 511 lung cancer cases and 1879 matched controls were selected. exposure to respirable silica as well as relevant occupational confounders were evaluated quantitatively based on historical industrial hygiene data. the relationship between silica exposure and lung cancer mortality was analyzed by conditional logistic regression analysis adjusted for exposure to arsenic, polycyclic aromatic hydrocarbons (pahs), radon, and smoking habit. results: in a crude analysis adjusted for smoking only, a significant trend of increasing risk of lung cancer with exposure to silica was found for tin, copper/iron miners, and pottery workers. however, after the relevant occupational confounders were adjusted, no association can be observed between silica exposure and lung cancer mortality (pro mg/m3-year increase of silica exposure: or = 1.01, 95% ci: 0.99 -1.02). conclusion: our results suggest that, the observed excess risk of lung cancer among silica exposed chinese workers is more likely due to exposure to other occupational carcinogens such as arsenic and pahs rather than due to exposure to respirable silica. background: modelling studies have shown that lifestyle interventions for adults with a high risk of developing diabetes are costeffective. objective: to explore the cost-effectiveness of lifestyle interventions for adults with low or moderate risk of developing diabetes. design and methods: the short-term effects of both a community-based lifestyle program for the general population and a lifestyle intervention for obese adults on diabetes risk factors were estimated from international literature. intervention costs were based on dutch projects. the rivm chronic diseases model was used to estimate long-term health effects and disease costs. costeffectiveness was evaluated from a health care perspective with a time horizon of 70 years. results: intervention costs needed to prevent one case of diabetes in 20 years range from 1,000 to 5,000 euro for the community program and from 5,000 to 21,000 euro for the intervention for obese adults. cost-effectiveness was 3,000 to 3,500 euro per quality adjusted life-year for the community program and 3,500 to 5,500 for the lifestyle intervention. conclusion: a lifestyle intervention for obese adults produces larger individual health benefits then a community program but, on a population level, health gains are more expensively achieved. both lifestyle interventions are cost-effective. background: in barcelona, the proportion of foreign-born patients with tuberculosis (tb) raised from 12.8% in 1999 to 35,2% in 2004. objective: to determine differences in infection by country of origin among contacts investigated by the tb programme in barcelona from 2000-2004. design and methods: data were collected on 1198 cases and their 4638 contacts. generalized estimating equations were used to obtain the risk of infection (or and 95% ci) to account for potential correlation among contacts. results: contacts of foreign born cases were more infected than contacts of natives patients (41% vs 20%, p<0.001) factors related to infection among contacts of foreign cases were inner city residency (or:1.8,95% ci: 1.2-2.8) and sputum smear positivity of the case (or:1.9,95% ci: 1. 2-2.8) and male contact (or:1.4,95% ci: 1.0-1.9), but not daily contact (or:1.1,95% ci:0.8-1.6) among natives cases, inner city residency (or:2.0,95% ci: 1.2-3.2), sputum smear positivity (or:2.2,95% ci: 1.5-3.1) and daily exposure (or:2.3,95% ci: 1.7-2.9) increased risk of infection. conclusion: contacts immigrant tb cases have a higher risk of infection than contacts of natives cases, however daily exposure to an immigrant case was not associated with a greater risk of infection. this could be explained by the higher prevalence of tb infection in their country of origin. background: an inverse association between birthweight and subsequent coronary heart disease (chd) has been widely reported but has not been formally quantified. we therefore conducted a systematic review of the association between birthweight and chd. design and methods: seventeen studies including a total of 144,794 singletons that had reported quantitative or qualitative estimates of the association between birthweight and chd by october 2005 were identified. additional data from two unpublished studies of 3801 individuals were also included. in total, the analyses included data on 4210 non-fatal and 3308 fatal coronary heart disease events in 147,009 individuals. results: the mean weighted estimate for the association between birthweight and chd incidence was 0.84 (95% ci 0.81-0.88) per kg of birthweight. overall, there was no significant heterogeneity between studies (p = 0.09) or evidence of publication bias (begg test p = 0.3). fifteen studies were able to adjust for some measure of socioeconomic position, but such adjustment did not materially influence the association: 0.85 (95% ci 0.81-0.90). discussion: these findings are consistent with one kilogram higher birthweight being associated with 10-20% lower risk of subsequent chd, but the causal nature of this association remains uncertain and its direct relevance to public health is likely to be small. objective: diabetes has been reported to be associated with a greater coronary hazard among women compared with men with diabetes. we quantified the coronary risk associated with diabetes by sex by conducting a meta-analysis of prospective cohort studies. methods: studies reporting estimates of the relative risk for fatal coronary heart disease (chd) comparing those with and without diabetes, for both men and women were included. results: 37 studies of type-2 diabetes and chd among 447,064 individuals were identified. the summary relative risk for fatal chd, diabetes versus not, was significantly greater among women than men: 3.50 (95% ci 2.70 to 4.53) versus 2.06 (95% ci 1.81 to 2.34), p<0.0001. after excluding eight studies that had only adjusted for age, the sex risk difference was substantially reduced, but still highly significant (p = 0.003). the pooled ratio of the relative risks (female: male) from the 29 multiple-adjusted studies was 1.46 (95% ci 1.14 to 1.88). conclusions: the relative risk for fatal chd associated with diabetes is 50% higher in women than in men. more adverse cardiovascular risk profiles among women with diabetes, combined with possible treatment disparities that favour men, may explain the greater excess coronary risk associated with diabetes in women. background: malaria in sri lanka is strongly seasonal and often of epidemic nature. the incidence has lowered in recent years which increased the relevance of epidemic forecasting for better targeting control resources. objectives: to establish the spatio/temporal correlation of precipitation and malaria incidence for use in forecasting. design and methods: de-trended long term (1972 de-trended long term ( -2001 monthly time series of malaria incidence at district level were regressed in a poisson regression against rainfall and temperature at several lags. results: in the north and east of sri lanka, malaria seasonality is strongly positively correlated to rainfall seasonality (malaria lagging one or two months behind rainfall). however, in the south west, no significant (negative) correlation was found. also in the hill country, no significant correlation was observed. conclusion and discussion: despite high correlations, it still remains to be explored to what extent rainfall can be a used as a predictor (in time) of malaria. observed correlation could simply be due to two cyclical seasonal patterns running in parallel, without causal relationship. e.g. similarly, strong correlations were found between temperature and malaria seasonality at 9 months time lag in northern districts, but causality is biologically implausible. background: few studies assessed the excess burden of acute respiratory tract infections (rti) among preschool children in primary care during viral seasons. objective: to determine the excess of rti in preschool children in primary care attributable to influenza and respiratory syncytial virus (rsv). methods: we performed a retrospective cohort study including all children aged 0-5 years registered in the database of the utrecht general practitioner (gp) network. during 1998 during -2002 , gps recorded episodes of acute rti. surveillance data of influenza and rsv were obtained from the weekly sentinel system of the dutch working group on clinical virology. viral seasons and base-line period were defined as the weeks with respectively more than 5% and less than 1% of the yearly number of isolates of influenza or rsv. results: on average 329 episodes of rti were recorded per 1,000 child years (95% ci:321-337). notably more consults for rti occurred during influenza-season (rr 1.74, 95% ci:1.63-1.86) and rsv-season (rr 2.27, 95% ci:2.14-2.42) as compared to base-line period, especially in children younger than two years of age. conclusion: substantial excess rates of rti were demonstrated among preschool children in primary care during influenza-season and particularly during rsvseason, notably in the younger age group. background: many cancer patients who have already survived some time want to know about their prognosis, given the precondition that they are still alive. objective: we described and interpreted population-based conditional 5-year relative survival rates for cancer patients. methods: the longstanding eindhoven cancer registry collects data on all patients with newly diagnosed cancer in the southeastern part of the netherlands (2.4 million inhabitants). patients aged 25-74 years, diagnosed between 1985 and 2002 and followed up until january 1, 2005 were included. conditional 5-year relative survival was computed for every additional year survived. results: for many tumours conditional 5-year relative survival approached 90-100% after having survived 5-10 years. however, for stomach cancer and hodgkin's lymphoma conditional 5-year relative survival increased to only 80-90% and for lung cancer and non-hodgkin's lymphoma it did not exceed 70-80%. initial differences in survival at diagnosis between age and stage groups disappeared after having survived for 5-10 years. conclusion: prognosis for patients with cancer changes with each year survived and for most tumours patients can considered to be cured after a certain period of time. however, for stomach cancer, lymphoma's and lung cancer the odds for death remains elevated compared to the general population. background: systematic review with meta-analysis, now regarded as 'best evidence', depends on availability of primary trials and on completeness of review. whilst reviewers have attempted to assess publication bias, relatively little attention has been given to selection bias by reviewers. method: systematic reviews of three cardiology treatments, that used common search terms, were compared for inclusion/exclusion of primary trials, pooled measures of principal outcomes and conclusions. results: in one treatment, reviews included 18, 11, 19, 28, 27 and 35 trials. there was little overlap: of 35 trials in the last review only 5, 4, 6, 13 and 3 were included by others. reported summary effects ranged from (most effective to least significant); mortality relative risk 0.29 (0.12, 0.70) in 4 trials to 0.96 (0.85, 1.09) in 23, and in one morbidity measure; standardised mean difference from 0.28 (0.10, 0.47) in 11 trials (822 patients) to 0.01 ()0.02, 0.04) in 10 (3960 patients). reviewers' conclusions ranged from 'highly effective' to 'no evidence of effect'. conclusions: these examples illustrate strong selection bias in published meta-analyses. post hoc review contravenes one important principal of science 'first the hypothesis, then the test'. selection bias by reviewers may affect 'evidence' more than does publication bias. in the context of a large population based german case control study examining the effects of hormone therapy (ht) on breast cancer risk, we conducted a validation study comparing ht prescription data with participants' self-reports for data quality assurance. included were 224 cases and 225 controls aged 50-74 years, stratified by age and hormone use. study participants provided detailed information on ht use to trained interviewers, while gynecologists provided prescription data via telephone or fax. data were compared using proportion of agreement, kappa, intraclass correlation coefficient (icc), and descriptive statistics. overall agreement for ever/never use was 88.2%, while agreement for ever/never use by type of ht was 80.6%, 80.3%, and 90.5% for mono-estrogen, cyclical, and continuous combined therapy, respectively. icc for duration was high (0.82 (95% ci: 0.77-0.85)), as were the iccs for age at first and last use (0.88(95% ci: 0.85-0.91) and 0.98 (95% ci: 0.97-0.98), respectively). comparison of exact brand name resulted in perfect agreement for 50.2% of participants, partial agreement for 29.3%, and no agreement for 20.7%. higher education and shorter length of recall were associated with better agreement. agreement was not differential by disease status. in conclusion, these self-reported ht data corresponded well with gynecologists' reports. background: legionnaires' disease (ld) is a pneumonia of low incidence. however, the impact of an outbreak can be substantial. objective: to stop a possible outbreak at an early stage, an outbreak detection programme was installed in the netherlands and evaluated after two years. design: the programme was installed nationally and consisted of sampling and controlling of potential sources to which ld patients had been exposed during their incubation period. potential sources were considered to be true sources of infection if two or more ld patients (cluster) had visited them, or if available patients' and environmental strains were indistinguishable by amplified fragment length polymorphism genotyping. all 39 municipal health services of the netherlands participated in the study. the regional public health laboratory kennemerland sampled potential sources and cultured samples for legionella spp. results: rapid sampling and genotyping as well as cluster recognition helped to target control measures. despite these measures, two small outbreaks were only stopped after renewal of the water system. the combination of genotyping and cluster recognition lead to 29 of 190 (15%) patient-source associations. conclusion and discussion: systematic sampling and cluster recognition can contribute to ld outbreak detection and control. this programme can cost-effectively lead to secondary prevention. -up (1990-2002) , 1896 primary invasive breast cancers occurred. results: compared with hrt never-use, use of estrogen alone was associated with a significant 1.4-fold increased risk. the association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: while there was no increase in risk with estrogen-progesterone (rr 1.0 [0.8-1.3]), estrogen-dydrogesterone was associated with a significant 1.3-fold increase, and estrogen combined with other synthetic progestins with a significant 1.8-fold increase. although the latter type of hrt involves a variety of different progestins, their associations with breast cancer risk did not differ significantly from one another. rrs did not vary significantly according to the route of estrogen administration (oral or transdermal/percutaneous). conclusion and discussion: progesterone rather than synthetic progestins may be preferred when an opposed estrogen therapy is to be prescribed. additional results on estrogen-progesterone are needed. background: although survival of hodgkin's lymphoma (hl) is high (>85%), treatment may cause long-term side-effects like premature menopause. objectives: to assess therapy-related risk factors for premature menopause (age <40) following hl. design and methods: we conducted a cohort-study among 387 female 5year hl-survivors, aged <31 at diagnose and treated between 1965 and 1995. patients were followed from first treatment until june 2001, menopause, death, or age 40. cumulative dose of various chemotherapeutic agents as well as radiation fields were studied as risk factors for premature menopause. cox-regression was used to adjust for age, year of treatment, smoking, bmi, and oral contraceptive-use. results: after a median follow-up of 11.4 years, 130 (34%) women reached premature menopause. overall 20 women (5%) were treated with chemotherapy only, 115 (30%) with radiotherapy only and 252 (65%) with both radio-and chemotherapy. exposure to procarbazine ), cyclophosphamide (hr 3.6 [2.1-5.9] ) and irradiation of the ovaries ]) were associated with significant increased risks for premature menopause. for procarbazine a dose-response relation was observed. procarbazine-use has decreased over time. conclusion: to decrease the risk for premature menopause after hl, procarbazine and cyclophosphamide exposure should be minimized and ovarian irradiation should be avoided. background: casale is an italian town where a large asbestos cement plant was active for decades. previous studies found increased risk for mesothelioma in residents, suggesting a decreasing spatial trend with distance from the plant. objective: to analyse the spatial variation of risk in casale and the surrounding area ($100,000 inhabitants) focussing on non-occupationally exposed individuals. design/methods: population-based case-control study including pleural mesotheliomas diagnosed between 1987 and 1993. information on the 97 cases and 250 controls comprised lifelong residential and occupational history of subjects and their relatives. nonparametric tests of clustering were used to evaluate spatial aggregation. parametric spatial models based on distance between the longest-lasting subject residence (excluding the last 20 years before diagnosis) and the source enabled estimation of risk gradient. results: mesothelioma risk appeared higher in an area of roughly 9-11 km radius from the source. spatial clustering was statistically significant (p = 0.003) and several clusters of cases were identified within casale. risk was highly related to the distance from the source; the best fitting model was the exponential decay with threshold. conclusion/discussion: asbestos pollution has increased dramatically the risk of mesothelioma in the area around casale. risk decreases slowly with the square of distance from the plant. malaria control programmes targeting malaria transmission from man to mosquito can have a large impact of malaria morbidity and mortality. to successfully interrupt transmission, a thorough understanding of disease and transmission parameters is essential. our objective was to map malaria transmission and analyse microenvironmental factors influencing this transmission in order to select high risk areas where transmission reducing interventions can be introduced. each house in the village msitu-wa-tembo was mapped and censused. transmission intensity was estimated from weekly mosquito catches. malaria cases identified through passive case detection were mapped by residence using gis software and the incidence of cases by season and distance to river were calculated. the distribution of malaria cases showed a clear seasonal pattern with the majority of cases during the rainy season (chisquare = 62.3, p<0.001). living further away from the river (p = 0.04) was the most notable independent protective factor for malaria infection. transmission intensity was estimated at 3.4 (95% ci 0.7 -9.9) infectious bites per person per year. we show that malaria in the study area is restricted to a short transmission season. spatial clustering of cases indicates that interventions should be planned in the area closest to the river, prior and during the rainy season. background: the effectiveness of influenza vaccination of elders has been subject of some dispute. its impact on health inequalities also demands epidemiological assessments, as health interventions may affect early and most intensely better-off social strata. objectives: to compare pneumonia and influenza (p&i) mortality of elders (aged 65 or more years old) before and after the onset of a largescale scheme of vaccination in sao paulo, brazil. methods: official information on deaths and population allowed the study of p&i mortality at the inner-city area level. rates related to the period 1998 to 2002, during which vaccination coverage ranked higher than 60% of elders were compared with figures related to the precedent period (1993) (1994) (1995) (1996) (1997) . the appraisal of mortality decrease used a geo-referred model for regression analysis. results: overall p&i mortality reduced 26.3% after vaccination. also the number of outbreaks, the excess of deaths during epidemic weeks, and the proportional p&i mortality ratio reduced significantly after vaccination. besides having higher prior levels of p&i deaths, deprived areas of the city presented a higher proportional decrease of mortality. conclusion: influenza vaccination contributed for an overall reduction of p&i mortality, while reducing the gap in the experience of disease among social strata. background: alcohol's first metabolite, acetaldehyde, may trigger aberrations in dna which predispose to developing colorectal cancer (crc) through several distinct pathways. our objective was to study associations between alcohol consumption and the risk of crc, according to two pathways characterized by mutations in apc and k-ras genes, and absence of hmlh1 expression. methods: in the netherlands cohort study, 120,852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer in 1986. case-cohort analyses were conducted using 575 crc cases with complete data after 7.3 years of follow-up, excluding the first 2.3 years. gender-specific adjusted incidence rate ratios (rr) and 95% confidence intervals (ci) were estimated. results: neither total alcohol, nor beer, wine or liquor consumption was clearly associated with the risk of colorectal tumors lacking hmlh1 expression or harboring a truncating apc mutation and/or an activating k-ras mutation. in men and women, total alcohol consumption above 30 g/day was associated with an increased risk of crc harboring a truncating apc and/or activating k-ras mutation, though not statistically significant. (rr:1.37 (95% ci: 0.8-2.5) in men, rr: 1.88 (95% ci: 0.8-4.6) in women). in conclusion, alcohol consumption is not involved in the studied pathways leading to crc. background: educational level is commonly used to identify social groups with increased prevalence of smoking. other indicators of socioeconomic status (ses) might however be more discriminatory. objective: this study examines to what extent smoking behaviour is related to other ses indicators, such as labour market position and financial situation. methods: data derived from the european household panel, which includes data on smoking for 11 european countries. we selected data for 101,312 respondents aged 25-60 years. the association between ses indicators and smoking prevalence was examined through logistic regression analyses. results: preliminary results show that, in univariate analysis, all selected ses indicators were associated with smoking. higher rates of smoking in lower social groups were observed in all countries, except for women in some mediterranean countries. in multivariate analyses, education retained an independent effect on smoking. no strong effect was observed for labour market position (occupational class, employment status) or for income. however, smoking prevalence was strongly related to economic deprivation and housing tenure. conclusion: these results suggest that different aspects of people's ses affect their smoking behaviour. interventions that aim to tackle smoking among high-risk groups should identify risk groups in terms of both education and material deprivation. objective: we investigated time trends in overweight and leisure time physical activities (ltpa) in the netherlands since 1980. intra-national differences were examined stratified for sex, age and urbanisation degree. design and methods: we used a random sample from the health interview survey of about 140 000 respondents, aged 20-to-69 years. self-reported data on weight, height and demographic characteristics were gathered through interviews (yearly) and data on ltpa were collected by selfadministered questionnaires . linear regression was performed for trend analyses. results: during 1981-2004, mean body mass index (bmi) increased by 1.0 kg/m2 (p = 0.001). trends were similar across sex and urbanisation degrees. in 20-to-39 year old women, mean bmi increased more (1.7 kg/m2; p = 0.05) than in older women. concerning ltpa, no clear trend was observed during 1990 observed during -97 and 2001 observed during -04. however, in 2001 year old women spent $ 150 min/wk less on ltpa compared to older women, while this difference was smaller during 1990-97. conclusions: mean bmi increased more in younger women, which is consistent with the observation that this group spent less time on ltpa during recent years. although the overall increase in overweight could no´t be explained by trends in ltpa, physical activity interventions should target the younger women. background: prediction rules combine patient characteristics and test results to predict the presence of an outcome (diagnosis) or the occurrence of an outcome (prognosis) for individual patients. when prediction rules show poor performance in new patients, investigators often develop a new rule, ignoring the prior information available in the original rule. recently, several updating methods have been proposed that consider both prior information and information of the new patients. objectives: to compare five updating methods (that vary in extensiveness) for an existing prediction rule that preoperatively predicts the risk of severe postoperative pain (spp). design and methods: the rule was tested and updated on a validation set of 752 new surgical patients (274 (36%) with spp). we estimated the discrimination (the ability to discriminate between patients with and without spp) and calibration (the agreement between the predicted risks and observed frequencies of spp) of the five updated rules in 283 other patients (100 (35%) with spp). results: simple updating methods showed similar effects on calibration and discrimination as the more complex methods. discussion and conclusion: when the performance of a prediction rule in new patients is poor, a simple updating method can be applied to improve the predictive accuracy. about two million ethnic germans (aussiedler) have resettled in germany since 1990. analyses with a yet incomplete follow-up of a cohort of aussiedler showed a different mortality compared to russia and germany. objectives: we investigated whether the mortality pattern changed after a complete follow-up and whether residential mobility after resettlement has an effect on mortality. we established a cohort of 34393 aussiedler who moved to germany between 1990 and 2001. we calculated smr for all causes, external causes, cardiovascular deaths and cancer in comparison to german rates. results: with a complete follow-up, the cohort accumulated 248798 person years. overall, 1726 deaths were observed (smr 0.85, 95% ci: 0.81-0.89). smr for all external causes, all cancer and cardiovascular deaths were 0.84, 0.85 and 0.79, respectively. increased number of moves within germany was associated with increased mortality. conclusion and discussion: the mortality in the cohort is surprisingly low, in particular for cardiovascular deaths. there is a mortality disadvantage from external causes and for some selected cancers. this disadvantage is however not as large as would be expected if aussiedler were representative of the general population in fsu countries. mobility as an indicator for a lesser integration will be discussed. background: breast cancer screening (bcs) provides an opportunity to analyze the relationship between lymph node involvement (ln), the most important prognostic factor, and biological and time dependent characteristics. objective: our aim was to assess those characteristics that are associated with ln in a cohort of screen-detected breast cancers. methods: observational population study of all invasive cancers within stage i-iiia detected from 1996 to 2002 through a bcs program in catalonia (spain). age, tumor size, histological grade, ln status and screening episode (prevalent or incident) were analyzed. pearson chi-square or fisher's exact test, mann-whitney test and stratified analyses were applied, as well as multiple logistic regression techniques. results: twenty nine percent (95% ci 21.7-35.4%) out of 168 invasive cancers had ln and 37.5% were prevalent cancers. in the bivariate analysis, tumor size and age were strongly associated to ln (p< 0.010) while grade was related to ln only in incident cancers (p = 0.027). grade was associated with tumor size (p = 0.005) and with screening episode (p = 0.013). adjusting for screening episode and grade, age and tumor size were independent predictors of ln. conclusion: in conclusion, age and tumor size are independent predictors of ln. grade emerges as an important biological factor in incident cancers. background: the evidence regarding the association between smoking and cognitive function in the elderly is inconsistent. objectives: to examine the association between smoking and cognitive function in the elderly. design and methods: in 2003, all 740 participants of a population-based cohort study aged 70 years or older were eligible for a telephone interview on cognitive function using validated instruments, such as the telephone interview of cognitive status (tics). information on smoking history was available from questionnaires administered in 2002. we estimated the odds ratios (or) of cognitive impairment (below 25th percentile) and the corresponding 95% confidence intervals (ci) by means of logistic regression adjusting for age, sex, alcohol consumption, body mass index, physical exercise, educational level, depressive symptoms and co-morbidity. results: in total, 465 participants were interviewed and had complete information on smoking history. former smokers had a lower prevalence of cognitive impairment (oradjusted = 0.61;95% ci:0.33-1.13) compared with never smokers, but not current smokers (oradjusted = 0.96;95% ci:0.34-2.70). conclusion: there is no association between current smoking and cognitive impairment in the elderly. discussion: the lack of association between current smoking and cognitive impairment is in line with previous non-prospective studies. the inverse association with former smoking might be due to smoking cessation associated with co-morbidities. background: many studies have reported late effects of treatment in childhood cancer survivors. most studies, however, focused on only one late effect or suffered from incomplete follow-up. objectives: we assessed the total burden of adverse events (ae), and determined treatment-related risk factors for the development of various aes. methods: the study cohort included 1362 5-year survivors, treated in the emma childrens hospital amc in the netherlands between 1966-1996. aes were graded for severity by one reviewer according to the common terminology criteria adverse events version 3.0. results: medical follow-up data were complete for 94.3% 5-year survivors. median follow-up time was 18 years. almost 75% of survivors had one or more aes, and 24.6% had even 5 or more aes. of patients treated with rt alone, 55% had a high or severe burden of aes, while this was only 15% in patients treated with ct alone. radiotherapy (rt) was associated with the highest risk to develop an ae of at least grade 2, and was also associated with a greater risk to develop a medium to severe ae burden. conclusions: survivors are at increased risk for many health problems that may adversely affect their quality of life and long-term survival. background: studies in the past demonstrated that multifaceted interventions could enhance the quality of diabetes care. however many of these studies showed methodological flaws as no corrections were made for patient case-mix and clustering or a nonrandomised design was used. objective: to assess the efficacy of a multifaceted intervention to implement diabetes shared care guidelines. methods: a cluster randomised controlled trial of 2097 patients with type 2 diabetes was conducted at 40 general practises (n = 1714) and one outpatient clinic (n = 383). in primary care, facilitators analysed barriers to change, introduced structured care, gave feedback and trained practice staff. at the outpatient clinic, an abstract of the guidelines was distributed. case-mix differences such as duration of diabetes, education, co-morbidity and quality of life were taken into account. results: in primary care, more patients in the intervention group were seen on a three monthly basis (85.7% versus 69.4%, p<0.001) and their hba1c was statistically significant lower (6.9±0.9 versus 7.0±0.1, p<0.01). however, significance was lost after correction for case-mix (p = 0.6). change in blood pressure and total cholesterol was not significant. we were unable to demonstrate any change in secondary care. conclusion: multifaceted implementation did improve the process of care but left cardiovascular risk unchanged. background: we have performed a meta-analysis including 43 studies on the diagnostic accuracy of mr-mammography in patients referred for further characterization of suspicious breast lesions. using the bivariate diagnostic meta-analysis approach we found an overall sensitivity and specificity of 0.90 and 0.73, respectively. the aim of the present analysis was to detect heterogeneity between studies. materials and methods: seventeen study and population characteristics were separately included in the bivariate model to compare sensitivity and specificity between strata of the characteristics. results: both sensitivity and specificity were higher in studies performed in the united states compared to non-united states studies. both estimates were also higher if two criteria for malignancy were used instead of one or three. only specificity was affected by the prevalence of cancer: specificity was highest in studies with the lowest prevalence of cancer in the study population. furthermore, specificity was affected by whether the radiologist was blinded for clinical information: specificity was higher if there was no blinding. conclusions: variation between studies was notably present across studies in country of publication, the number of criteria for malignancy, the prevalence of cancer and whether the observers were blinded for clinical information. objective: the aim of this project is to explore variation in three candidate genes involved in cholesterol metabolism in relation to risk of acute coronary syndrome (acs), and to investigate whether dietary fat intake modifies inherent genetic risks. study population: a case-cohort study is designed within the danish 'diet, cancer and health' study population. a total of 1500 cases of acs have been identified among 57,053 men and women who participated in a baseline examination between 1993-1997 when they were aged 50-64 years. a random sample of 1500 participants will serve as 'control' population. exposures: all participants have filled out a detailed 192-item food frequency questionnaire and a questionnaire concerning lifestyle factors. participants were asked to provide a blood sample. candidate genes for acs have been selected among those involved in cholesterol transport (atp-binding cassette transporter a1, cholesterol-ester transfer protein, and acyl-coa:cholesterol acyltransferase 2). five single nucleotide polymorphisms (snps) will be genotyped within each gene. snps will be selected among those with demonstrated functional importance, as assessed in public databases. methods: statistical analyses of association between genetic variation in the three chosen genes and risk of acs. explorations of methods to evaluate biological interaction will be of particular focus. background: c-reactive protein (crp) has been shown to be associated with type 2 diabetes mellitus. it is unclear whether the association is completely explained by obesity. objective: to examine whether crp is associated with diabetes independent of obesity. design and methods: we measured baseline characteristics and serum crp in 5954 non-diabetic participants of the rotterdam study and followed them for a mean of 9.8 years. cox regression was used to estimate the hazard ratio. in addition, we performed a meta-analysis on 10 published studies. results: during follow-up, 658 participants developed diabetes. serum crp was significantly and positively associated with the risk to develop diabetes. the risk estimates attenuated but remained statistically significant after adjustment for obesity indexes. age, sex and body mass index (bmi) adjusted hazard ratios (95% ci) were 1.90(1.43-2.52) for the fourth quartile, 1.66(1.25-2.20) for the third quartile, and 1.51(1.16-2.01) for the second quartile of serum crp compared to the first quartile. in the meta-analysis, weighed age, sex, and bmi adjusted risk ratio was 1.44(1.16-1.78), for the highest crp category (>2.6 mg/l) compared to the reference category (<0.5 mg/l). conclusion: our findings shows that the association of serum crp with diabetes is independent of obesity. background: effectiveness of screening can be predicted by episode sensitivity, which is estimated by interval cancers following a screen. full-field digital or cr plate mammography are increasingly introduced into mammography screening. objectives: to develop a design to compare performance and validity between screen-film and digital mammography in a breast cancer screening program. methods: interval cancer incidence was estimated by linking 721 000 screening visits from 1991-2001 at an individual level to the files of the cancer registry in finland. these data was used to estimate the study size requirements for analyzing differences in episode sensitivity between screen-film and digital mammography in a randomized setting. results: the two-year cumulative incidence of interval cancers per 100 000 screening visits was estimated to be 300. to allow the maximum acceptable difference in the episode sensitivity between screenfilm and digital arm to be 20% (80% power, 0.05 significance level, 1:1 randomization ratio, 85% attendance rate), approximately 240 000 women need to be invited. conclusion: only fairly large differences in the episode sensitivity can be explored within a single randomized study. in order to reduce the degree of non-inferiority between the screen-film and digital mammography, meta-analyses or pooled analyses with other randomized data are needed. session: socio-economic status and migrants presentation: oral. background: tackling urban/rural inequalities in health has been identified as a substantial challenge in reforming health system in lithuania. objectives: to assess mortality trends from major causes of death of the lithuanian urban and rural populations throughout the period of 1994-2004. methods: information on major causes of death (cardiovascular diseases, cancers, external causes, and respiratory diseases) of lithuanian urban and rural populations from 1994 to 2004 was obtained from lithuanian department of statistics. mortality rates were age-standardized, using european standard. mortality trends were explored using the logarithmic regression analysis. results: overall mortality of lithuanian urban and rural populations was decreasing statistically significantly during 1994-2004. more considerable decrease was observed in urban areas where mortality declined by 1.7% per year in males and 2.2% in females, compare to the decline by 1.2% in males and 1.7% in females in rural areas. the most notable urban/rural differences in mortality trends with unfavourable situation in rural areas were estimated in mortality from stoke, breast cancer in females, and external causes of death (traffic accidents and suicides). background: recent studies indicate that depression plays an important role in the occurrence of cardiovascular diseases (cvd). underlying mechanisms are not well understood. objectives: we investigated whether low intake of omega-3 fatty acids (fas) is a common cause for depression and cvd. methods: the zutphen elderly study is a prospective cohort study conducted in the netherlands. depressive symptoms were measured with the zung scale in 332 men, aged 70-90 years, and free from cvd and diabetes in 1990. dietary factors were assessed with a cross-check dietary history method. results: compared to high intake (= 156.2 mg/d), low intake (<58.9 mg/d) of omega-3 fas, adjusted for demographics and cvd risk factors, was associated with an increased risk of depressive symptoms (or 2.20; 95% ci 1.06-4.58) at baseline, and non-significantly with 10-year cvd mortality (hr 1.14; 95% ci 0.67-1.95). the adjusted hr for a 5-point increase in depressive symptoms for cvd mortality was 1.13 (95% ci 1.01-1.26), and did not change after additional adjustment for omega-3 fas. conclusion: low intake of omega-3 fas may increase the risk of depression. our results, however, do not support the hypothesis that low intake of omega-3 fas explains the relation between depression and increased risk of cvd. background: during the last decades the incidence of metabolic syndrome has risen dramatically. several studies have shown beneficial effects of nut and seed intake on components of this syndrome. the relationship with prevalence of metabolic syndrome has not yet been examined. objectives: we studied the relation between nut and seed intake and metabolic syndrome in coronary patients. design and methods: presence of metabolic syndrome (according to international diabetes federation definition) was assessed in 904 stable myocardial infarction patients (77% men) aged 60-80 years, as part of the alpha omega trial. dietary data were collected by food-frequency questionnaire. results: the prevalence of metabolic syndrome was 42%. median nut and seed intake was 3.82 g/day (interquartile range, 1.53-8.33 g/day). intake of nuts and seeds was inversely associated with the metabolic syndrome (prevalence ratio: 0.84; 95% confidence interval: 0.59-1.19, for >10 g/day versus <1 g/day), after adjustment for age, gender, dietary and lifestyle factors. the prevalence of metabolic syndrome was 31% lower (p = 0.050) in men with a high nut and seed intake compared to men with a low intake, after adjustment for confounders. conclusion and discussion: intake of nuts and seeds may reduce the risk of metabolic syndrome in stable coronary patients. background: in epidemiology, interaction is often assessed by adding a product term to the regression model. in linear regression the regression coefficient of the product term refers to additive interaction. however, in logistic regression it refers to multiplicative interaction. rothman has argued that interaction as departure from additivity better reflects biological interaction. hosmer and lemeshow presented a method to quantify additive interaction and its confidence interval (ci) between two dichotomous determinants using logistic regression. objective: our objective was to provide an estimation method for additive interaction between continuous determinants. methods and results: from the abovementioned literature we derived the formulas to quantify additive interaction and its ci between one continuous and one dichotomous determinant and between two continuous determinants using logistic regression. to illustrate the theory, data of the utrecht health project were used, with age and body mass index as risk factors for diastolic blood pressure. conclusions: this paper will help epidemiologists to estimate interaction as departure from additivity. to facilitate its use, we developed a spreadsheet, which will become freely available at our website. background: the incidences of acute myocardial infarction (ami) and ischemic stroke (is) in finland have been among highest in the world. accurate geo-referenced epidemiological data in finland provides unique possibilities for ecological studies using bayesian spatial models. objectives: examine sex-specific geographical patterns and temporal variation of ami and is. design and methods: ami (n = 205,213) and is (n = 115,383) cases in 1991-2003 in finland, localized at the time of diagnosis according to the place of residence address using map coordinates. cases and population were aggregated to 10 km x10 km grids. full bayesian conditional autoregressive models (car) were used for studying the geographic incidence patterns. results: the incidence patterns of ami and is showed on average 70% (95% ci 50-85%) common geographic variation and significantly the rest of the variation was disease specific. there was no significant difference between sexes. the patterns of high-risk areas have persisted over the years and the pattern of is showed more annual random fluctuations. conclusions: although ami and is showed rather similar and temporally stable patterns, significant part of the spatial variation was disease specific. further studies are needed for finding the reasons for disease specific geographical variation. most studies addressing socio-economic inequalities in health services use fail to take into account the disease the patient is suffering from. the objective of this study is to compare possible socioeconomic differences in the use of ambulatory care between 2 distinct patient groups: diabetics and patients with migraine. data was obtained from the belgian health interview surveys 1997, 2001 and 2004. in total 4381 patients with self reported diabetes or migraine were identified. in a multilevel analysis the probability of a contact and the volume of contacts with the general practitioner and/or the specialist were studied for both groups in relation to educational attainment and income. adjustment was made for age, sex, subjective health and comorbidity at the individual level, and doctors' density and region at district level. no socio-economic differences were observed among diabetic patients. among patients with migraine we observed a higher probability of specialist contacts in higher income groups (or 1,6;95% ci 1,1-2,4) and higher educated persons (or 1,6;95% ci 1,2-2,2), while lower educated persons tend to report more visits with the general practitioner. to correctly interpret socio-economic differences in the use of health services there is need to take into account information on the patient's type of disease. background: the suitability of non-randomised studies to assess effects of interventions has been debated for a long time, mainly because of the risk of confounding by indication. choices in the design and analytical phase of non-randomised studies determine the ability to control for such confounding, but have not been systematically compared yet. objective: the aim of the study will be to quantify the role of design and analytical factors on confounding in non-randomised studies. design and methods: a meta-regression analysis will be conducted, based on 41 cohort and 8 case-control studies analysed in a recent cochrane review on influenza vaccine effectiveness against hospitalisation or death in the elderly. primary outcome will be the degree of confounding as measured by the difference between the reported effect estimate (odds ratios or relative risks) and the best available estimate (nichol, unpublished data) . design factors that will be considered include study design, matching, restriction and availability of confounders. statistical techniques that will be evaluated include multivariate regression analysis with adjustment for confounders, stratification and, if available, propensity scores. results the rsults will be used to develop a generic guideline with recommendations how to prevent confounding by indication in non-randomised effect studies. the wreckage of the oil tanker prestige in november 2002 produced a heavy contamination of the coast of galicia (spain). we studied relationships between participation in clean-up work and respiratory symptoms in local fishermen. questionnaires including details of clean-up activities and respiratory symptoms were distributed among associates of 38 fishermen's cooperatives, with postal and telephone follow-up. statistical associations were evaluated using multiple logistic regression analyses, adjusted for sex, age, and smoking status. between january 2004 and february 2005, information was obtained from 6,780 fishermen (response rate 76%). sixty-three percent had participated in clean-up operations. lower respiratory tract symptoms were more prevalent in clean-up workers (odds ratio (or) 1.73; 95% confidence interval 1.54-1.94). the risk increased when the number of exposed days, number of hours per day, or number of activities increased (p for linear trend <0.0001). the excess risk decreased when more time had elapsed since last exposure (or 1.45 (1.28-1.64) and 2.16 (1.91-2.45) for more and less than 17 months, respectively; p for interaction <0.05). in conclusion, fishermen who participated in the clean-up work of the prestige oil spill show a prolonged dosedependent increased prevalence of respiratory symptoms one to two years after the beginning of the spill. background. hpv testing has been proposed for cervical cancer screening. objectives: evaluating the protection provided by hpv testing at long intervals vs. cytology every third year. methods: randomised controlled trial conventional arm: conventional cytology. experimental arm: in phase 1 hpv and liquid-based cytology. hpv-positive cytology-negatives referred for colposcopy if age 35-60, for repeat after one year if age 25-34. in phase 2 hpv alone. positives referred for colposcopy independently of age. endpoint: histologically confirmed cervical intraepithelial neoplasia (cin) grade 2 or more. results: overall 94,323 women were randomised. preliminary data at recruitment are presented. overall, among women aged 35-60 years relative sensitivity of hpv versus conventional cytology was 1.43 (95% c.i. 1.09-1.88) and relative positive predictive (ppv) value was 0.59 (95% c.i. 0.45-0.76). among women aged 25-34 relative sensitivity of hpv vs. conventional cytology was 1.58 (95% c.i. 1.03-2.44) during phase 1 but 3.79 (95% c.i. 2.26-6.35) during phase 2. conclusions: hpv testing increased cross-sectional sensitivity, but reduced ppv. in younger women data suggest that direct referral of hpv-positives to colposcopy results in relevant overdiagnosis of regressive lesions. measuring detection rate of cin at the following screening round will allow studying overdiagnosis and the possibility of longer screening intervals. background: plant lignans are present in foods such as whole grains, seeds, fruits and vegetables, and beverages. they are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone. enterolignans possess several biological activities whereby they may influence carcinogenesis. objective: to study the association between plasma enterolignans and the risk of colorectal adenomas. colorectal adenomas are considered to be precursors of colorectal cancer. design and method: the case-control study included 532 cases with at least one histologically confirmed colorectal adenoma and 503 controls with no history of any type of adenoma. associations between plasma enterolignans and colorectal adenomas were analyzed by logistic regression. results: associations were stronger for incident than for prevalent cases. when only incident cases (n = 262) were included, high compared to low enterodiol plasma concentrations were associated with a reduction in colorectal adenoma risk after adjustment for confounding variables. enterodiol odds ratios (95% ci) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), 0.53 (0.32-0.88) with a significant trend (p = 0.01) through the quartiles. although enterolactone plasma concentrations were 10fold higher, enterolactone's reduction in risk was not statistically significant (p for trend = 0.09). conclusion: we observed a substantial reduction in colorectal adenoma risk among subjects with high plasma concentrations of enterolignans, in particular enterodiol. background: smoking is a risk factor for tuberculosis diseases. recently the question was raised if smoking also increases the risk of tuberculosis infection. objective: to assess the influence of environmental tobacco smoke (ets) exposure in the household on tuberculosis infection in children. design and methods: a crosssectional community survey was done and information on 1373 children was obtained. tuberculosis infection was determined with a tuberculin skin test (tst) (cut-off 10 mm) and information on smoking habits was obtained from all adult household members. univariate and multivariate analyses were performed, and odds ratio (or) was adjusted for the presence of a tb contact in the household, crowding and age of the child. results: ets was a risk factor for tuberculosis infection (or: 1.92, 95% ci: 1.27 -2.92) when all children with a tst read between two and five days were included. the adjusted or was 1.64 (95% ci: 1.03 -2.61). in dwellings were a tuberculosis case had lived the association was strongest (adjusted or 5.67, 95% ci: 1.26 -25.65). conclusion and discussion: ets exposure seems to be a risk factor for tuberculosis infection in children. this is of great concern considering the high prevalence of smoking and tuberculosis in developing countries. background and objective: to implement a simulation model to analyze demand and waiting time (wt) for knee arthroplasty and to compare a waiting list prioritization system (ps) with the usual first-in, first-out (fifo) system. methods: parameters for the conceptual model were estimated using administrative data and specific studies. a discrete-event simulation model was implemented to perform 5-year simulations. the benefit of applying the ps was calculated as the difference in wt weighted by priority score between disciplines, for all cases who entered the waiting list. results: wt for patients operated under the fifo discipline was homogeneous (standard deviation (sd) between 1.3-1.7 months) with mean 18.7. wt under the ps had higher variability (sd between 10.6-11.6) and was positively skewed, with mean 7.6 months and 10% of cases over 24 months. when wt was weighted by priority score, the ps saved 6.6 months (95% ci 6.4-6.9) on average. the ps was favorable for patients with priority scores over 50, but penalized those with lower priority scores. conclusions: management of the waiting list for knee arthroplasty through a ps was globally more effective than through fifo, although patients with low priority scores were penalized with higher waiting times. background: we developed a probabilistic linkage procedure for the linking of readmissions of newborns from the dutch paediatrician registry (lnr). 15% of all newborns (30.000) are admitted to a neonatal ward. the main problems were the unknown number of readmissions per child and the identification of admissions of twins. objective: to validate our linking procedure in a double blinded study. design and methods: a random sample of admissions from 200 children from the linked file has been validated by the caregivers, using the original medical records. results: response was 97%. for admissions of singletons the linkage contained no errors except for the small uncertain area of the linkage. for admissions of multiple births a high error rate was found. conclusion and discussion: we successfully linked the admissions of singleton newborns with the developed probabilistic linking algorithm. for multiple births we did not succeed in constructing valid admission histories due to too low data quality of twin membership variables. validation showed alternative solutions for linking twin admissions. we strongly recommend that linkage results should always be externally validated. background: salmonella typhimurium definitive phage type (dt) 104 has emerged as an important pathogen in the last two decades. a 10-fold increase in cases in the netherlands during september-november 2005 prompted an outbreak investigation. objective: the objective was to identify the source of infection to enable preventive measures. methods: a subset of outbreak isolates was typed by molecular means. in a case-control study, cases (n = 109) and matched population controls (n = 411) were invited to complete self-administered questionnaires. results: the molecular typing corroborated the clonality of the isolates. the molecular type was similar to that of a recent s. typhimurium dt104 outbreak in denmark associated with imported beef. the incriminated shipment was traced after having been distributed sequentially through several eu member states. sampling of the beef identified s. typhimurium dt104 of the same molecular type as the outbreak isolates. cases were more likely than controls to have eaten a particular raw beef product. conclusions: our preliminary results are consistent with this s. typhimurium dt104 outbreak being caused by contaminated beef. our findings underline the importance of european collaboration, traceability of consumer products and a need for timely intervention into distribution chains. background: heavy-metals may affect newborns. some of them are presenting tobacco smoke. objectives: to estimate cord-blood levels of mercury, arsenic, lead and cadmium in newborns in 2 areas in madrid, and to assess the relationship with maternal tobacco exposure. design and methods: bio-madrid study obtained 115 cord-blood samples from recruited trios (mother/father/ newborn). cold-vapor atomic absorption spectrophotometry (aas) was used to measure mercury and graphite-furnace aas for the other metals. mothers answered a questionnaire including tobacco exposure. median, means and standard errors were calculated and logistic regression used to estimate or. results: median levels for mercury and lead were 7.5 mg/l and 13.7 mg/l. arsenic and cadmium were undetectable in 82% and 47 % of samples. preliminar analysis showed a significant association of maternal tobacco exposure and levels of arsenic (or:3.59;95% ci:1. 11-11.55 ), cadmium (or:2.24;95% ci:1.04-4.79), and lead (or:3.83;95% ci:1.41-10.36). smoking in pregnancy was associated to arsenic (or:3.90;95% ci:1.17-12.96), while passive exposure was more related to lead (or:3.61;95% ci:1.26-4.79) and cadmium (or:2.06;95% ci:0.91-4.97). conclusion: madrid newborns have high cord-blood levels of mercury. tobacco exposure in pregnancy might increase levels of arsenic, cadmium and lead. background: road traffic accidents (rta) are the leading cause of death for young. rta police reports provide no health information other then the number of deaths and injured, while health databases have no information on the accident dynamics. the integration of the two databases would allows to better describe the phenomenon. nevertheless, the absence of common identification variables through the lists makes the deterministic record linkage (rl) impossible. objective: to test feasibility of a probabilistic rl between rta and health information when personal identifiers are lacking. methods: health information came from the rta integrated surveillance for the year 2000. it integrates data from ed visits, hospital discharges and deaths certificates. a deterministic rl was performed with 149 police reports, where the name and age of deceased were present. results of the deterministic rl was then used as gold standard to evaluate the performance of the probabilistic one. results: the deterministic rl resulted in 141 (94.6%) linked records. the probabilistic rl, where the name was omitted, was capable to correctly identify 130 (87.2%). conclusions: performance of the probabilistic rl was good. further work is needed to develop strategies for the use of this approach in the complete datasets. background: overweight constitutes a major public health problem. the prevalence of overweight is unequally distributed between socioeconomic groups. risk group identification, therefore, may enhance the efficiency of interventions. objectives: to identify which socioeconomic variable best predicts overweight in european populations: education, occupation or income. design: european community household panel data were obtained for 9 countries (n = 52,855). overweight was defined as a body mass index >= 25 kg/m2. uni-and multivariate logistic regression analyses were employed to predict overweight in relationship to socioeconomic indicators. results: major socioeconomic differences in overweight were observed, especially for women. for both sexes, a low educational attainment was the strongest predictor of overweight. after control for confounders and the other socioeconomic predictors, the income gradient was either absent or positive (men) or negative (women) in most countries. similar patterns were found for occupational level. for women, inequalities in overweight were generally greater in southern european countries. conversely, for men, differences were generally greater in other european countries. conclusion: across europe, educational attainment most strongly predicts overweight. therefore, obesity interventions should target adults and children with lower levels of education. background: because incidence and prevalence of most chronic diseases rise with age, their burden will increase in ageing populations. we report the increase in prevalence of myocardial infarction (mi), stroke (cva), diabetes type ii (dm) and copd based on the demographic changes in the netherlands. in addition, for mi and dm the effect of a rise in overweight was calculated. methods: calculations were made for the period 2005-2025 with a dynamic multi-state transition model and demographic projections of the cbs. results: based on ageing alone, between 2005 and 2025 prevalence of dm will rise from 550.000 to 870.000 (+58%), prevalence of mi from 310.000 to 365.000 (+18%), stroke prevalence from 185.000 to 290.000 (+57%) and copd prevalence from 55 455.000 to 540.000 (+19%). a continuation of the dutch (rising) trend in overweight prevalence would in 2025 lead to about 940.000 diabetics (+70%). a trend resulting in american levels would lead to over 1 million diabetics (+90%), while the impact on mi was much smaller: about 375.000 (+20%) in 2025. conclusion: the burden of chronic disease will substantially increase in the near future. a rising prevalence of overweight has an impact especially on the future prevalence of diabetes background: there has been increasing concern about the effects of environmental endocrine disruptors (eeds) on human reproductive health. eeds include various industrial chemicals, as well as dietary phyto-estrogens. intra-uterine exposures to eeds are hypothesized to disturb normal foetal development of male reproductive organs and specifically, to increase the risk of cryptorchidism, hypospadias, testicular cancer, and a reduced sperm quality in offspring. objective: to study the associations between maternal and paternal exposures to eeds and the risks of cryptorchidism, hypospadias, testicular cancer and reduced sperm quality. design and methods: these associations are studied using a case-referent design. in the first phase of the study, we collected questionnaire data of the parents of 231 cases with cryptorchidism, 329 cases with hypospadias and 742 referent children. in the second phase, we will focus on the health effects at adult age: testicular cancer and reduced sperm quality. in both phases, we will attempt to estimate the total eed exposure of parents of cases and referents at time of pregnancy through an exposure-assessment model in which various sources of exposure, e.g. environment, occupation, leisure time activities and nutrition, are combined. in addition, we will measure hormone receptor activity in blood. background: eleven percent of the pharmacotherapeutic budget is spent on acid-suppressive drugs (asd); 3% of patients are chronic user. most of these indications are not conform to dyspepsia guidelines. objectives: we evaluated the implementation of an asd rationalisation protocol among chronic users, and analysed effects on volume and costs. method: in a cohort study 2871 patients from 158 gp's with protocol were compared to a control group of 8120 patients from 267 gp's without. prescription data of 2002-2004 were extracted from agis health database. a log-linear regression model compared standardised outcomes of number of patients that stopped or reduced asd (>50%) and of prescription volume and costs. results: gp's and patients in both groups were comparable. 7% in the intervention group had stopped; 6% in the control group (p<0.01). the volume had decreased in another 11% of patients; 8% in control group (p<0.001). compared to the baseline data in the control group (100%) the adjusted or of volume in the intervention group was 98.2%. the total costs adjusted or was 97.5%. the implementation significantly reduced the number of chronic users, and substantially dropped volume and costs. active intervention from insurance companies can stimulate rationalisation of prescription. background/objective: today, 20% of lung cancers are resectable (stage i/ii). 5-year survival is therefore low (15%). spiral computed tomography (ct) screening detects more lung cancers than chest x-ray. it is unknown if this will translate into a lung cancer mortality reduction. the nelson trial investigates whether 16detector multi-slice ct reduces lung cancer mortality with at least 25% compared to no screening. we present baseline screening results. methods: a questionnaire was sent to 550,000 men and women. of the 150,000 respondents, 30,500 high-risk current and former smokers were invited. until december 22, 2005, 15,530 of them gave informed consent and were randomised (1:1) in a screen arm (ct in year 1, 2 and 4) and control arm (no screening). data will be linked with the cancer registry and statistics netherlands to determine cancer mortality and incidence. results: of the first 5,700 baseline ct examinations 82% was negative (ct after one year), 16% indeterminate (ct after 3 months) and 2% positive (referral pulmonologist). seventy percent of detected tumours were resectable. conclusion/discussion: ct screening detects a high percentage of early stage lung cancers. it is estimated that the nelson trial is sufficiently large to demonstrate a 25% lung cancer mortality reduction or more. background: due to diagnostic dilemmas in childhood asthma, drug treatment of young children with asthmatic complaints often serves as a trial treatment. objective: to obtain more insight into patterns and continuation of asthma medication in children during the first 4 years of life. design: prospective birth cohort study methods: within the prevention and incidence of asthma and mite allergy (piama) study (n = 3,291 children) we identified 125 children using asthma medication in their first year of life. results: about 80% of children receiving asthma medication before the age of one, discontinued use during follow-up. continuation of therapy was associated with male gender (adjusted odds ratio [aor] 3.6, 95% confidence interval [ci]: 1.6-8.2), a diagnosis of asthma (aor 2.9, 95% ci: 1.3-6.3) and receiving combination or controller therapy (aor 2,6, 95% ci: 1.1-6.1). conclusion: patterns of medication use in preschool children support the notion that both beta2-agonist and inhaled corticosteroids are often used as trial medication, since 80% discontinues. the observed association between continuation of therapy and both an early diagnosis of asthma and a prescription for controller therapy suggests that, despite of diagnostic dilemmas, children in apparent need of prolonged asthma therapy are identified at this very early age. background: this study explored the differences in birthweight between infants of first and second generation immigrants and infants of dutch women, and to what extent maternal, fetal and environmental characteristics could explain these differences. method: during 15 months all pregnant women in amsterdam attending their first prenatel screening were asked to fill out a questionnaire (sociodemographic status, lifestyle) as part of the amsterdam born children and their development (abcd)-study; 8267 women (67%) responded. only singleton deliveries with pregnancy duration = 37 weeks were included (n = 7209). results: infants of all first and second generation immigrant groups (surinam, the antilles, turkey, morocco, ghana, other countries) had lower birthweights (range: 3227-3529 gram) than dutch infants (3548 gram). linear regression revealed that, adjusted for maternal height, weight, age, parity, smoking, marital status, gestational age and gender, infants of surinamese women (1st and 2nd generation), antillean and ghanaian women (both 1st generation) were still lighter than dutch infants (93.7, 166.7, 113.1, and 128.0 grams respectively; p<0.05). conclusion: adjusted for maternal, fetal and environmental characteristics infants of some immigrant groups had substantial lower birthweights than infants of dutch women. other factors (like genetics, culture) can possibly explain these differences. introduction: missing data is frequently seen in cost-effectiveness analyses (ceas). we applied multiple imputation (mi) combined with bootstrapping in a cea. objective: to examine the effect of two new methodological procedures of combining mi and bootstrapping in a cea with missing data. methods: from a trial we used direct health and non-health care costs and indirect costs, kinesiophobia and work absence data assessed over 12 months. mi was applied by multivariate imputation by chained equations (mice) and non-parametric bootstrapping was used. observed case analyses (oca), where analyses were conducted on the data without missings, were compared with complete case analysis (cca) and with analyses when mi and bootstrapping were combined after 10 to 30% of cost and effect data were omitted. results: by the cca effect and cost estimates shifted from negative to positive and cost-effectiveness planes and acceptability curves were biased compared to the oca. the methods of combining mi and bootstrapping generated good cost and effect estimates and the cost-effectiveness planes and acceptability curves were almost identical to the oca. conclusion: on basis of our study results we recommend to use the combined application of mi and bootstrapping in data sets with missingness in costs and effects. background: since the 1980s, coronary heart disease (chd) mortality rates have halved with approximately 50% of this decrease being attributable to medical and surgical treatments. objective: this study examined the cost-effectiveness of specific chd treatments. design and methods: the impact chd model was used to calculate the number of life-years-gained (lyg) by specific cardiology interventions given in 2000, and followed over ten years. this previously validated model integrates data on patient numbers, median survival in specific groups, treatment uptake, effectiveness and costs of specific interventions. cost-effectiveness ratios were generated as costs per lyg for each specific intervention. results: in 2000, medical and surgical treatments together prevented or postponed approximately 1,635 chd deaths in patients aged 25-84 years; this generated approximately 13,645 extra life years. aspirin and beta-blockers for secondary prevention of myocardial infarction and heart failure, and spironolactone for heart failure all appeared highly cost-effective (<e1,500 per lyg). less cost effective, however, were revascularisation for chronic angina (cabg surgery e12,970 and angioplasty e14,865 per lyg), or statins for primary prevention (e11,475 per lyg) or for community patients with angina (e11,220 per lyg). conclusions: cost effectiveness ratios generally favoured simple medical treatments for myocardial infarction, secondary prevention, and heart failure. objective: is population-based primary prevention more favourable than secondary prevention (risk factor reduction in coronary heart disease (chd) patients)? methods: the previously validated im-pact model was used to integrate data describing chd patient numbers, specific treatment uptake levels, trends in major risk factors, and the mortality benefits of these risk factor changes in healthy people and in chd patients. results: approximately 2,530 fewer deaths were attributable to reductions in the three major risk factors between 1985 and 2000. declining smoking prevalence resulted in approximately 685 fewer deaths: 395 in healthy people and 290 in known chd patients. decreasing population total cholesterol concentrations resulted in approximately 1,340 fewer deaths attributable to dietary changes (1,250 in healthy people and 90 in chd patients) plus 265 fewer deaths attributable to statin treatment (45 in people without chd and 220 in chd patients). decreasing mean population blood pressure resulted in approximately 170 fewer deaths attributable to secular falls in blood pressure (150 in healthy people and 20 in chd patients) plus approximately 70 fewer deaths attributable to antihypertensive treatments in people without chd. conclusions: compared with secondary prevention (620 fewer deaths), primary prevention (1,910 fewer deaths) achieved a three-fold larger reduction in chd deaths. background: carotenoid intake has been positively associated with plasma concentrations in different populations. however, the influence of body mass index (bmi) on this association is mostly unknown. objectives: we explored the relationship between intake of carotenoids and vitamin c, and their plasma concentrations by bmi categories in spanish elderly people. desgin/methods: a dietary interview using a 135-item food-frequency questionnaire was conducted with 240 men and 293 women, 65 and older, participating in the eureye study in spain. blood samples were collected for measurement of carotenoids and vitamin c. correlation coefficients (r) between energy adjusted nutrient intakes and plasma concentrations were calculated by categories of bmi, adjusting for sex, age and smoking. results: significant correlations between acarotene, ß-carotene, lycopene, ß-cryptoxanthin and vitamin c intakes, and plasma concentrations were observed, r=0.21;0.19;0.17;0.20,0.41, respectively (p<0.05). correlations for carotenoids changed substantially by bmi categories, with the highest correlations for a-carotene, ß-carotene, and, to a lesser extension, ß-cryptoxanthin and lycopene, in subjects with bmi<25 (0.39;0.34;0.25;0.22 respectively), and the lowest, in subjects with bmi=30 (0.08;0.19;0.18;0.19 respectively). correlations for vitamin c remained unchanged by bmi. conclusions: our data suggest that carotenoids in plasma may be good markers of dietary intake in elderly subjects with lower bmi. background: reduced heart rate variability (hrv) is associated with an increased mortality, morbidity and worse prognosis of cardiovascular diseases (cvd). there is a lack of population-based data to examine the distribution of hrv, its association with cardiovascular risk factors (cvrf), and its role as a potential mediator of the effect of established risk factors on cvd. objective: to study the distribution of hrv and its association with cvrf in an elderly eastern german population. design and methods: this analysis is based on data of 1336 participants (45-83 years) of an ongoing cross-sectional study. time-and frequency-domain measures of hrv were computed. their association with cvrf was determined by linear regression modelling. results: age-and heart rate-adjusted standard deviation of the durations of nn intervals and high frequency power was significantly higher in women. significant inverse associations of timeand frequency-domain hrv with anthropometric parameters, triglycerides, blood pressure, prevalent diabetes and age were observed in both sexes. there was a graded inverse association of hrv with age except for the oldest age-group. discussion/conclusion: established cvrf are associated with a reduced hrv. therefore reduced hrv could be a mediator between cvrf and cvd, which will be examined in a follow-up study. background: aalen's model and cox's proportional hazard model postulate different relationship between hazard and covariates and the subject matter seldom suggests which of the models are to be preferred. actually the assumption of constant effects, either additive or multiplicative, may be incorrect especially in cancer survival analysis. objectives: the aim of the study is to analyse survival for a breast cancer cohort where typical prognostic factors lack of proportionality. design and methods: the cohort consists of 2700 invasive breast cancer cases from turin cancer registry within a high resolution study in co-operation with the breast cancer screening program, diagnosed from 1997 through 2000, aged 40-79. an additive-multiplicative cox-aalen model with age at diagnosis, categorized tumour size (t) and nodal status (n) is fitted. results: the prognostic role of age at diagnosis, t and n are confirmed. proportionality assumption holds only for age (hazard ratio = 1.03, p-value<0.0001). t, particularly the category referring to 'extended to chest wall or skin' versus 'less than 2 cm', has a significant time-varying effect (p-value = 0.02) after 12 months since diagnosis. discussion: more flexible regression tools than cox model which is routinely used for analyzing cancer survival are needed. cox-aalen proves to be an appealing alternative. background: the major software packages for meta-analysis of causal -notably intervention -research are generally too expensive for developing countries. moreover, interactive educational software for students and teachers is largely unavailable. we recently developed the 'mix' program, an easy-to-maintain, interactive, and educational meta-analysis add-in for excel, available as free download at http://www.mix-for-meta-analysis.info. objectives: to formally establish whether the program's numerical and graphical output is comprehensive and accurate enough for scientific standards. design and methods: the study was designed as a software validation. data sets, primarily intervention studies, with substantially different features were analyzed by three investigators with mix and stata, using the latter program as golden standard. additionally, a feature (software options) comparison was made with modern programs for meta-analysis, such as cma 2.0, metawin 2.1, weasyma 2.2, and revman 4.2. results: the results of the validation project will be fully reported at the congress. preliminary results indicate that the mix program's output is comparable to stata output. it distinguishes itself from other software by the variety of graphical output, the excel-based interface, and free availability. conclusion and discussion: the mix program appears to provide valid output and may be an attractive, feature-rich alternative to existing meta-analysis software. background: an ankle-arm index (aai) <0.9 of systolic blood pressure (sbp) as marker of peripheral arterial disease is a predictor of coronary and carotid artery disease. the present gold standard examination with doppler-ultrasound and sphygmomanometric cuff is subject to observer bias and requires intensive training. for epidemiologic studies, valid and easy-to-use examination methods are needed. objective: to validate the easy-to-use omron hem-705cp for sbp measurements in the ankle and for aai determination in epidemiologic studies. design/methods: in a population-based sample of 112 subjects (45-80 years), arm and ankle sbp measurements by the omron hem-705cp and corresponding aai were compared with those using a hand-held doppler and sphygmomanometric cuff. bland-altman plots of sbp and aai differences, validation criteria for use in clinical practice and diagnostic values for the detection of an aai<0.9 were employed. results: omron measured higher sbp than doppler. sbp and aai differences increasing towards higher sbp levels. specificity, sensitivity and negative predictive value for the detection of aai<0.9 were >99% (positive predictive value was 67%). conclusion: omron fails the validation criteria for ankle sbp measurement. however, the ease of use of the device could outweigh the inaccuracy if used as a screening tool for aai<0,9 in epidemiologic studies. background: associations exist between: 1) parental birth weight and child birth weight; 2) birth weight and adult psychopathology; and 3) maternal psychopathology during pregnancy and birth weight of the child. this study is the first to combine those associations. objective: to investigate the different pathways from parental birth weight and parental psychopathology to child birth weight in one model. design and methods: depression and anxiety scores on 6,507 mothers and 4,764 fathers during 20 weeks pregnancy and birth weights from 6,116 children were available. path analyses with standardized regression coefficients were used to evaluate the different effects. results: in the unadjusted path analyses significant effects existed between: maternal (r = .17) and paternal birth weight (r = .13) and child birth weight; maternal birth weight and maternal depression (r=).05) and anxiety (r=).06); and maternal depression (r = .06) and anxiety (r = .06) and child birth weight. after adjustment for confounders, only maternal (r = .10) and paternal (r = .08) birth weight and maternal depression (r=).02) remained significantly related to child birth weight. conclusion after adjustment maternal depression, and not anxiety, remained significantly related to child birth weight. discussion future research should focus on the different mechanisms of maternal anxiety and depression on child birth weight. background: most patients with peripheral arterial disease (pad) die from coronary artery disease (cad). non-invasive cardiac imaging can assess the presence of coronary atherosclerosis and/or cardiac ischemia. screening in combination with more aggressive treatment may improve prognosis. objective: to evaluate whether a non-invasive cardiac imaging algorithm, followed by treatment will reduce the 5-year-risk of cardiovascular events in pad patients free from cardiac symptoms. design and methods: this is a multicenter randomized controlled clinical trial. patients with intermittent claudication and no history of cad are eligible. one group will undergo computed tomography (ct) calcium scoring. the other group will undergo ct calcium scoring and ct angiography (cta) of the coronary arteries. patients in the latter group will be scheduled for a dobutamine stress magnetic resonance imaging (dsmr) test to assess cardiac ischemia, unless a stenosis of the left main (lm) coronary artery (or its equivalent) was found on cta. patients with cardiac ischemia or a lm/lm-equivalent stenosis will be referred to a cardiologist, who will decide on further (interventional) treatment. patients are followed for 5 years. conclusion: this study assesses the value of non-invasive cardiac imaging to reduce the risk of cardiovascular events in patients with pad free from cardiac symptoms. background: hpv is the main risk factor for cervical cancer and also a necessary cause for it. participation rates in cervical cancer screening are low in some countries and soon hpv vaccination will be available. objectives: aim of this systematic review was to collect and analyze published data on knowledge about hpv. design and methods: a medline search was performed for publications on knowledge about hpv as a risk factor for cervical cancer and other issues of hpv infection. results: of individual studies were stratified by age of study population, country of origin, study size, publication year and response proportion. heterogeneity was described. results: knowledge between 27 included studies varied substantially. thirteen to 57% (closed question) and 0.6 to 1.9% (open question) of the participants knew about hpv as a risk factor for cervical cancer. women had consistently better knowledge on hpv than men. there was confusion of hpv with other sexually transmitted diseases. conclusion and discussion: studies were very heterogeneous, thus making comparison difficult. knowledge about hpv infections depended on the type of question used, gender of the participants and their professional background. education of the general public on hpv infections needs improvement, specially men should also be addressed. background: influenza outbreaks in hospitals and nursing homes are characterized by high attack rates and severe complications. knowledge of the virus' specific transmission dynamics in healthcare institutions is scarce but essential to develop cost-effective strategies. objective: to follow and model the spread of influenza in two hospital departments and to quantify the contributions of the several possible transmission pathways. methods: an observational prospective cohort study is performed on the departments of internal medicine & infectious diseases and pulmonary diseases of the umc utrecht during the 2006 influenza season. all patients and regular medical staff are checked daily on the presence of fever and cough, the most accurate symptoms of influenza infection. nose-throat swabs are taken for pcr analysis for both symptomatic individuals and a sample of asymptomatic individuals. to determine transmission, contact patterns are observed between patients and visitors and patients and medical staff. results/discussion: spatial and temporal data of influenza cases will be combined with contact data in a mathematical model to quantify the main transmission pathways. among others the model can be used to predict the effect of vaccination of the medical staff which is not yet common practice in the studied hospital. background: the long term maternal sequelae of stillbirths is unknown. objectives: to assess whether women who experienced stillbirths have an excess risk of long term mortality. study design: cohort study. methods: we traced jewish women from the jerusalem perinatal study, a population-based database of all births to west jerusalem residents (1964 -1976 who gave birth at least twice during the study period, using unique identity numbers. we compared the survival to 31-12-2004 of women who had at least one stillbirth (n = 569) to that of women who had only live births (n = 24108) using cox proportional hazards models. results: during a median follow up of 36.2 years, 77 (13.5%) mothers with stillbirths died compared to 1,483 (6.2%) unexposed women; crude hazard ratio (hr) 2.15 (95% ci: 1.71-2.70). the mortality risk remained significantly increased after adjustments for sociodemo-graphic variables, maternal diseases, placental abruption and preeclampsia (hr: 1.42, 95% ci: 1.12-1.80). stillbirth was associated with increased risk of death from cardiovascular (adjusted hr:1.95, 0.99-3.84), circulatory (1.77, 1.07-2.92) and genitourinary (4.59, 1.41-14.91) causes. conclusions: the finding of increased mortality among mothers of stillbirths joins the growing body of evidence demonstrating long term sequelae of obstetric events. future studies should elucidate the mechanisms underlying these associations. resilience is one of the essential characteristics of successful ageing. however, very little is known about the determinants of resilience in old age. our objectives were to identify resilience in the english longitudinal study of ageing (elsa) and to investigate social and psychological factors determining it. the study design was a crosssectional analysis of wave 1 of elsa. using structural equation modelling, we identified resilience as a latent variable indicated by high quality of life in the face of six adversities: ageing, limiting long-standing illness, disability, depression, perceived poverty and social isolation and we regressed it on social and psychological factors. the latent variable model for resilience showed a highly significant degree of fit (weighted root mean square resid-ual=0.035). determinants of resilience included good quality of relationships with spouse (p = 0.002), family (p = 0.028), and friends (p< 0.001), good neighbourhood (p<0.001), high level of social participation (p<0.001), involvement in leisure activities (p = 0.003); perception of not being old (p<0.001); optimism (p = 0.041), and high subjective probability of survival to an older age (p<0.001). we concluded that resilience in old age was as much a matter of social engagement, networks and context as of individual disposition. implications of this on health policy are discussed. background: there is extensive literature concluding that ses is inversely related to obesity in developed countries. several studies in developing populations however reported curvilinear or positive association between ses and obesity. objectives: to assess the social distribution of obesity in men and women in 3 middle-income countries of eastern and central europe with different level of economic development. methods: random population samples aged 45-69 years from poland, russia and czech republic were examined between 2002-2005 as baseline for prospective cohort study. we used body-mass index (bmi) and waist/hip ratio (whr) as obesity measures. we compared age-adjusted bmi and whr for men and women by educational levels in all 3 countries. results: the data collection was concluded in summer 2005. we collected data from about 29,000 subjects. lower ses increased obesity risk in women in all 3 countries (the strongest gradient in the czech republic and the lowest in russia), and in czech men. there was no ses gradient in bmi in polish men and positive association between education and bmi in russian men. conclusions: our findings strongly agree with previous literature showing that the association between ses status and obesity is strongly influenced by overall level of country economic development. background: inaccurate measurements of body weight, height and waist circumference will lead to an inaccurate assessment of body composition, and thus of the general health of a population. objectives: to assess the accuracy of self-reported body weight, height and waist-circumference in a dutch overweight working population. design and methods: bland and altman methods were used to examine the individual agreement between self-reported and measured body weight and height in 1298 overweight workers (67% male; mean age 43.9 +/) 8.6 years; mean body mass index [bmi] 29.5 +/) 3.4 kg/m2). the accuracy of self-reported waistcircumference was assessed in a subgroup of 250 persons (70% male; mean age 44.1 +/) 9.2 years; mean bmi 29.6 +/) 3.0 kg/ m2), for whom both measured and self-reported waist circumference was available. results: body weight was underreported by a mean (standard deviation) of 1.4 (1.9) kg, body height was on average over-reported by 0.7 (1.5) cm. bmi was on average underreported by 0.68 (0.8) kg/m2. waist-circumference was overreported by 1.1 (4.0) cm. the overall degree of error from selfreporting was between 0.4 and 2.3%. conclusion and discussion: self-reported anthropometrics seem satisfactorily accurate for the assessment of general health in a middle-aged overweight working population. the incidence of breast cancer and the prevalence of metabolic syndrome are increasing rapidly in chile, but this relationship is still debated. the goal of this study is to assess the association between metabolic syndrome and breast cancer before and after menopause. a hospital based case-control study was conducted in chile during 2005. 170 cases with histologically confirmed breast cancer and 170 age matched controls with normal mammography were identified. metabolic syndrome was defined by atpiii and serum lipids, glucose, blood pressure and waist circumference were measured by trained nurses. data of potential confounders such as, obesity, socioeconomic status, exercise and diet were obtained by anthropometric measures and a questionnaire. odds ratios (ors) and 95% confidence intervals (cis) were estimated by conditional logistic regression stratified by menopause. in postmenopausal women, a significant increase risk of breast cancer was observed in women with metabolic syndrome (or = 1.90, 95% ci = 1.00-3.60). the elements of metabolic syndrome strongly associated were high levels of glucose and hypertension. in conclusion, postmenopausal women with metabolic syndrome had 90% of excess risk of breast cancer. these findings support the theory that there is a different risk profile of breast cancer after and before menopause. background: physical exercise during pregnancy has numerous beneficial effects on maternal and foetal health. it may, however, affect early foetal survival negatively. objectives: to examine the association between physical exercise and spontaneous abortion in a cohort study. design and methods: in total, 92,721 women recruited to the danish national birth cohort in early pregnancy, provided information on amount and type of exercise during pregnancy and on possible confounding factors. 3,187 women experienced foetal death before 23 gestational weeks. hazard ratios for spontaneous abortion in four periods of pregnancy ()10, 11-14, 15-18, and 19-22 weeks) according to amount (min/week) and type of exercise, respectively, were estimated using cox regression. various sensitivity analyses to reveal distortion of the results from selection forces and information bias were made. results: the hazard ratios of spontaneous abortion increased stepwise with amount of physical exercise and were largest in the earlier periods of pregnancy (hrweek11-14 = 3.4 (ci 2.7-4.3) for 420 min/week, compared to no exercise). weight bearing types of exercise were strongest associated with abortion, while swimming showed no association. these results remained stable, although attenuated, in the sensitivity analyses. discussion: handling of unexpected findings that furthermore challenge official public health messages will be discussed. hemodialysis (hd) patients with a low body mass index (bmi) have an increased mortality risk, but bmi changes over time on dialysis treatment. we studied the association between changes in bmi and all-cause mortality in a cohort of incident hd patients. patients were followed until death or censoring for a maximum follow-up of 7 years. bmi was measured every 6 months and changes in bmi were calculated over each 6-mo period. with a time-dependent cox regression analysis, hazard ratios (hr) were calculated for these 6-mo changes on subsequent mortality from all causes, adjusted for the mean bmi of each 6-mo period, age, sex and comorbidity. 712 men and 494 women were included (age: 64?14 years, bmi: 25.1?4.6 kg/m2, 7-y mortality: 75%). a loss of bmi>5% was independently associated with an increased mortality risk (hr: 1.83, 95%-ci: 1.41-2.37), while a loss of 1-5% showed no difference (hr: 0.89, 0.69-1.14) compared to no change in bmi ()1% to +1% change). a gain in bmi of 1-5% showed beneficial (hr: 0.67, 0.51-0.88), while a gain of bmi>5% was not associated with a survival advantage (hr: 1.02, 0.69-1.50). in conclusion, hd patients with a decreasing bmi have an increased risk of all-cause mortality. background: within the tripss-2 project, impact of clinical guidelines (gl) on venous thromboembolism (vte) prophylaxis was evaluated in a large italian hospital. gl were effective in increasing the appropriateness of prophylaxis and in reducing vte. objectives: we performed a cost-effectiveness analysis by using a decision-tree model to estimate the impact of the adopted gl on costs and benefits. design and methods: a decision-tree model compared prophylaxis cost and effects before and after gl implementation. four risk profiles were identified (low, medium, high, very high). possible outcomes were: no event, major bleeding, asymptomatic vte, symptomatic vte and fatal pulmonary embolism. vte patients risk and probability of receiving prophylaxis were defined using data from the previous survey. outcome probabilities were assumed from literature. tariffs and hospital figures were used for costing the events. results: gl introduction reduced the average cost per patient from e 190 to 165 ()13%) with an increase in terms of event free patients (+4%). results are particularly relevant in the very high risk group. conclusion: the implementation of locally adapted gl may lead to a gain in terms of costs and effects, in particular for patients at highest vte risk. background: assisted reproductive techniques are used to overcome infertility. one reason of success is the use of ovarian stimulation. objectives: compare two ovarian stimulation protocols, gonadotropin-releasing hormone agonists/antagonists, assessing laboratorial and clinical outcomes, to provide proper therapy option. identify significant predictors of clinical pregnancy and ovarian response. design and methods: retrospective study (agonist cycles, 203; antagonist cycles, 177) including ivf/intracytoplasmic sperm injection cycles. multiple logistic and regression models, with fractional polynomial method were used. results: antagonist group exhibited lower length of stimulation and dose of recombinant follicle stimulating hormone (rfsh), higher number of retrieved and fertilized oocytes, and embryos. agonist group presented thicker endometrium, better fertilization, implantation and clinical pregnancy rates. clinical pregnancy has shown positive correlation with endometrial thickness and use of agonist; negative correlation with age and number of previous attempts. retrieved oocytes shown positive correlation with estradiol on day of human chorionic gonadotrophin (hcg) and use of antagonist; negative correlation with rfsh dose. conclusion: patients from antagonist group are more likely to get more oocytes and quality embryos, despite those from agonist group are more likely to get pregnant. background: prevalence studies of the metabolic syndrome require fasting blood samples and are therefore lacking in many countries including germany. objectives: to narrow the incertitude resulting from extrapolation of international prevalence estimates, with a sensitivity analysis of the prevalence of the metabolic syndrome in germany using a nationally representative but partially non-fasting sample. methods: stepwise analysis of the german health examination survey 1998, using the national cholesterol education program (ncep) criteria, hemoglobin a1c (hba1c), non-fasting triglycerides and fasting time. results: among 6666 participants aged 18-79 years, the metabolic syndrome prevalence was (i) 13.6% with 13.3% inconclusive cases using the unmodified ncep criteria, (ii) 17.6% with 9.4% inconclusive cases using hba1c > 6.1% if fasting glucose was missing, (iii) 23.8% with 0.6% inconclusive cases when additionally using non-fasting triglycerides = 75th percentile stratified by fasting time, and (iv) 21.2% to 23.8% with <1% inconclusive cases using different cutoffs (hba1c 6.1%, non-fasting triglycerides 200 and 250 mg/dl). discussion: despite a lower prevalence of obesity in germany compared to the us, the prevalence of the metabolic syndrome is likely to be in the same order of magnitude. this analysis may help promote healthy life styles by stressing the high prevalence of interrelated cardiovascular risk factors. background: epidemiologic studies that directly examine fruits and vegetables (f&v) consumption and other lifestyle factors in relation to weight gain are sparse. objective: we examined the associations between the f&v intake and 10-y weight gain among spanish adult people. design/methods: the study was conducted with a sub-sample of 214 healthy people aged 15 y and over at baseline in 1994, who participated in a population-based nutrition survey in valencia-spain. data on diet, lifestyle factors and body weight (direct measurement) were obtained in 1994 and 2004. information on weight gain was available for 187 participants in 2004. results: during the 10-y period, participants tended to gain on average 4.61 kg (median = 3.6 kg). in multivariate analyses, participants with the highest tertile of f&v intake at baseline had a 65% of lower risk of gaining =3.6 kg compared with those who had the lowest intake tertile after adjustment for sex, age, education, smoking, tv-viewing, bmi, and energy intake (or = 0.35;95% ci:0.15 0.84;p-fortrend = 0.02). for every 100 g/d increase in f&v intake, the or was reduced by 14% (or = 0.86;0.75-0.99;p-trend=0.036). tvviewing at baseline was positively associated with weight gain, or for-1 h-increase=1.32 (1.01-1.71;p-trend=0.04). conclusions: our findings suggest that a high f&v intake and low tv-viewing may reduce weight gain among adults. background: diabetic patients develop more readily atherosclerosis thus showing greatly increased risk for cardiovascular disease. objective: the heinz nixdorf recall-study is a prospective cohort-study designed to assess the prognostic value of new risk stratification methods. here we examined the association between diabetes, previously unknown hyperglycemia and the degree of coronary calcification (cac). methods: a population-based sample of 4,814 men and women aged 45-74 years was recruited from three german cities between 2000-2003. baseline examination included amongst others a detailed medical history, blood analyses and electron-beam tomography. we calculated adjusted prevalence ratios (pr), adjusting for age, smoking, bmi and 95%-confidence intervals (95% ci) with log-linear binomial regression. results: the prevalence of diabetes is 8.4% (men: 9.8%, women: 6.7%), for hyperglycemia 5.7% (men: 8.1%, women: 3.4%). prevalence ratio for cac in male diabetics without overt coronary heart disease is 1.87 (95% ci: 1.28-2.72), for those with hyperglycemia 1.62 (1.09-2.46). in women the association is even stronger: 2.62 (1.78-3.87) with diabetes, 1.92 (1.11-3.31) with hyperglycemia. conclusion: the data support the concept of regarding diabetic patients as being in a high risk category meaning >20% hard events in 10 years. furthermore, even persons with elevated blood glucose levels already show higher levels of coronary calcification. background: birth weight is associated with health in infancy and later in life. socioeconomic inequality in birth weight is an important marker of current and future population health inequality. objective: to examine the effect of maternal education on birth weight, low birth weight (lbw, birth weight<2,500 g), and small for gestational age (sga) background: in clinical practice patient data are obtained gradually and health care practitioners tune prognostic information according to available data. prognostic research does not always reproduce this sequential acquisition of data: instead, 'worst', discharge or aggregate data are often used. objective: to estimate prognostic performance of sequentially updated models. methods: cohortstudy of all very-low-birth-weight-babies (<1500 g) admitted to the study neonatal icu <2 days after birth (984 eligible from 1991 to 2002) and followed-up until 2 years old (7.8% lost-to-follow-up). main outcomes: disabling cerebral palsy at 2 years (37, 3.8%) or death (194, 19 .7% )95% in the first 4 weeks). main prognostic determinants: neonatal cerebral lesions identified with cranial ultrasound (us) exams performed per protocol on days 2, 7, 28 and at discharge. logistic regression models were updated with data available at these different moments in time during admission. results: at days 2, 7 and 28 respectively, main predictor (severe parenchymal lesion) adjusted odds ratio: 18, 31 and 37; us model c-statistic: 0.69, 0.75 and 0.80. discussion: prognostic models performance in neonatal patients improved from inception to discharge, particularly for identification of the high risk category. time of data acquisition should be considered when comparing prognostic instruments. in epidemiological longitudinal studies one is often interested in the analysis of time patterns of censored history data. for example, how regular a medication is used or how often someone is depressed. our goal is to develop a method to analyse time patterns of censored data. one of the tools in longitudinal studies is a nonhomogeneous markov chain model with discrete time moments and categorical state space (for example, use of various medications). suppose we are interested only in the time pattern of appearance of a particular state which is in fact a certain epidemiological event under study. for this purpose we construct a new homogeneous markov chain associated with this event. the states of this markov chain are the time moments of the original nonhomogeneous markov chain. using the new transition matrix and standard tools from markov chain theory we can derive the probabilities of occurence of that epidemiological event during various time periods (including ones with gaps). for example, probabilities of cumulative use of medication during any time period. in conclusion, the proposed approach based on markov chain model provides a new way of data representation and analysis which is easy to interpret in practical applications. background: tuberculosis (tb) cases that belong to a cluster of the same mycobacterium tuberculosis dna fingerprint are assumed to be consequence of recent transmission. targeting interventions to fast growing clusters may be an efficient way of interrupting transmission in outbreaks. objective: to assess predictors for large growing clusters compared to clusters that remain small within a 2 years period. design and method out of the 10567 culture confirmed tb patients diagnosed between 1993 and 2004, 4783 (45%) had unique fingerprints while 5784 were part of a cluster. of the clustered cases 673 were in a small (2 to 4 cases within the first 2 years) and 83 in a large cluster (more than 4 cases within the first 2 years). results independent risk factors for being a case within the first 2 years of a large cluster were non-dutch nationality (or = 6.38 95% ci [1. 38-29.55 background: passive smoking causes adverse health outcomes such as lung cancer or coronary heart disease (chd). the burden of passive smoking on a population level is currently unclear and depends on several assumptions. we investigated the public health impact of passive smoking in germany. methods: we computed attributable mortality risks due to environmental tobacco smoke (ets). we considered lung cancer, chd, stroke, copd and sudden infant death. frequency of passive smoking was derived from the national german health survey. sensitivity analyses were performed using different definitions of exposure to passive smoking. results: in total, 3301 deaths every year in germany are estimated to be caused by exposure to passive smoking at home (women 2293, men 1008). most of these deaths are due to chd (2148) and stroke (774). additional consideration of passive smoking at workplace increased the number of deaths to 3864. considering any exposure to passive smoking and also active smokers who report exposure to passive smoking increased the number of deaths further. conclusions: passive smoking has an important impact on mortality in germany. even the most conservative estimate using exposure to ets at home led to a substantial number of deaths related to passive smoking. des daughters have a strongly increased risk of clear-cell adenocarcinoma of the vagina and cervix (ccac) at a young age. longterm health problems, however, are still unknown. we studied incidence of cancer, other than ccac, in a prospective cohort of des daughters (desnet project). in 2000 13,674 questionnaires were sent to des daughters registered at the des center in utrecht. also, informed consent was asked for linkage with disease registries. for this analysis, data of 12,219 responders and nonresponders were linked to palga, the dutch nationwide network and registry of histo-and cytopathology. mean age at the end of follow-up was 41.7 years. a total of 244 incident cancers occurred. increased standardized incidence rates (sir) were found for vaginal/vulvar cancers (sir = 4.1, 95% confidence interval (95% ci) 1.4-9.7), melanoma (sir = 1.9, 95% ci 1.4-2.6)) and breast cancer (sir=1.2, 95% ci 1.0-1.4) as compared to the general population. no increased risk was found for invasive cervical cancer, possibly due to effective screening. results for breast and cervical cancer are consistent with the sparse literature. the risk of melanoma might be due to surveillance bias. future analyses will include non-invasive cervical cancer, stage specific sirs for melanoma and adjustment for confounding (sister control group) for breast cancer. background: contact tracing plays an important role in the control of emerging infectious diseases in both human and farm animal populations, but little is known yet about its effectiveness. here we investigate in a generic setting for well-mixed populations the dependence of tracing effectiveness on the probability that a contact is traced, the possibility of iteratively tracing yet asymptomatic infectives, and delays in the tracing process. methods and findings: we investigate contact tracing in a mathematical model of an emerging epidemic, incorporating a flexible infectivity function and incubation period distribution. we consider isolation of symptomatic infected as the basic scenario, and determine the critical tracing probability (needed for effective control) in relation to two infectious disease parameters: the reproduction ratio under isolation and the duration of latent period relative to the incubation period. the effect of tracing delays is considered, as is the possibility of single-step tracing vs. iterative tracing of quarantined invectives. finally, the model is used to assess the likely success of tracing for influenza, smallpox, sars, and foot-and-mouth disease epidemics. conclusions: we conclude that single-step contact tracing can be effective for infections with a relatively long latent period or a large variation in incubation period, thus enabling backwards tracing of super spreading individuals. the sensitivity to changes in the tracing delay varies greatly, but small increases may have major consequences for effectiveness. if single-step tracing is on the brink of being effective, iterative tracing can help, but otherwise it will not improve much. we conclude that contact tracing will not be effective for influenza pandemics, only partially for fmd epidemics, and very effective for smallpox and sars epidemics. abstract: infections of highly pathogenic h5n1 avian influenza in humans underline the need for tracking of the ability of these viruses to spread among humans. here we propose a method of analysing outbreak data that allows determination of whether and to what extent transmission in a household has occurred after an introduction from the animal reservoir. in particular, it distinguishes between onward transmission from humans that were infected from the animal reservoir (primary human-to-human transmission) and onward transmission from humans who were themselves infected by humans (secondary human-to-human transmission). the method is applied to data from an epidemiological study of an outbreak of highly pathogenic avian influenza (h7n7) in the netherlands in 2003. we contrast a number of models that differ with respect to the assumptions on primary versus secondary human-to-human transmission. session: mathematical modelling of infectious diseases presentation: oral. usually models for the spread of an infection in a population are based on the assumption of a randomly mixing population, where every individual may contact every other individual. however, the assumption of random mixing seems to be unrealistic, therefore one may also want to consider epidemics on (social) networks. connections in the network are possible contacts, e.g. if we consider sexually transmitted diseases and ignore all spread by other than sexual ways, the connections are only between people that may have intercourse with each other. in this talk i will compare the basic reproduction ratio, r0 and the probability of a major outbreak of network models and for randomly mixing populations. furthermore, i will discuss which properties of the network are important and how they can be incorporated in the model. in this talk a reproductive power model is proposed that incorporates the following points met when an epidemic disease outbreak is modeled statistically: 1) the dependence of the data is handled with a non-homogeneous birth process. 2) the first stage of the outbreak is described with an epidemic sir model. soon control measures will start to influence the process. these measures are in addition to the natural epidemic removal process. the prevalence is related to the censored infection times in such a way that the distribution function, and therefore the survival function, satisfies approximately the first equation of the sir model. this leads in a natural way to the burr-family of distributions. 3) the non-homogeneous birth process handles the fact that in practice, with some delay, it is the infected that are registered and not the susceptibles. 4) finally the ending of the epidemic caused by the measures taken is incorporated by modifying the survival function with a finalsize parameter in the same way as is done in long-term survival models. this method is applied to the dutch classical swine individual and area (municipality) measures of income, marital and employment status were obtained. there were 9,011 suicides and 180,220 controls. after controlling for compositional effects, ecological associations of increased suicide risk with declining area levels of employment and income and increasing levels of people living alone were much attenuated. individual-level associations with these risk factors were little changed when controlling for contextual effects. we found no consistent evidence that associations with individual level risk factors differed depending on the areas characteristics (cross-level interactions). this analysis suggests the ecological associations reported in previous studies are likely to be due in greater part to the characteristics of the residents in those areas than area-influences on risk, rather than to contextual effects. were found to be at higher risk. risk was significantly greater in women whose first full-term pregnancy was at age 30 or more (or 7.79, ). in addition, more than 5 full-term pregnancies would be expected to correlate with an increase in the risk (x2 111.12, p<0.05). in multivariate analysis, history of breast feeding is a significant factor in decreasing risk (or 0.68, 95% ci 0. 12-0.97 the euregion meuse-rhine (emr) is an area with different regions, regarding language, culture and law. organisations and institutions received frequently signals about an increasing and region-related consumption of addictive drugs and risky behaviour of adolescents. as a reaction 11 institutions from 4 regions of the emr started a cross-border cooperation project 'risky behaviour adolescents in the emr'. the partners intend to improve the efficiency of prevention programmes by investigating the prevalence and pre-conditional aspects related to risky behaviour, and creating conditions for best-practice-public-health. the project included two phases: study. two cross-border (epidemiological) studies where realized: a quantitative study of the prevalence of risky behaviour (46000 pupils) and a qualitative study mapped preconditional aspects of risky behaviour and possibilities to preventive programmes. implementation. this served bringing about recommendations on policy level as well as on prevention level. during this phase the planning and realisation of cross-border preventionprogrammes and activities started. there is region-related variance of prevalence in risky-behaviour of adolescents in de emr. also there are essential differences in legislation and regulation, (tolerated) policy, prevention structures, political and organizational priorities and social acceptance toward stimulants. cross-border studies and cooperation between institutions have resulted in best-practice-projects in (border) areas of the emr. abstract background: beta-blockers increase bone strenght in mice and may reduce fracture risk in humans. therefore, we hypothesized that inhaled beta-2 agonists may increase risk of hip fracture. objective: to determine the association between daily dose of beta-2 agonist use and risk of hip fractures. methods: a case-control study was conducted among adults who were enrolled in the dutch phar-mo database (n = 950,000). cases (n = 6,763) were patients with a first hip fracture. the date of the fracture was the index date. four controls were matched by age, gender and region. we adjusted our analyses for 10 indicators of asthma/copd severity, and for disease and drug history. results: low daily doses (dds) (<400 ug albuterol eq.) of beta2-agonists (crude or 1.2, 95% ci 0.8-1.8) did not increase risk of hip fracture, in contrast to high dds (>1600 ug albuterol eq., crude or 2.0, 95% ci 0.1.5-2.7). after extensive adjustment for indicators of the severity of the underlying disease, (including corticosteroid intake), fracture risk in the high dd group decreased to 1.5 (95% ci 1.1-2.1). conclusions: high dds of beta-2 agonists are linked to increased risk of hip fracture. extensive adjustments for the severity of the underlying disease is important when evaluating this association. abstract salivary nitrate arises from ingested nitrate and is the main source of gastric nitrite, a precursor of carcinogenic n-nitroso compounds. we examinated the nitrate and nitrite levels in saliva of children who used private wells for their drinking water supply. saliva was collected in the morning, from 150 children aged 7-16 years. control group (n = 50) drank water containing 0.03-15.5 mg/l (milligrams/litre) nitrate. exposure groups consisting of subjects (n = 50) who used private wells with nitrate levels in drinking water below 50 mg/l (mean ± standard deviation 20.05 ± 11.42 mg/l) and above 50 mg/l (n = 50) (141.32±80.56 mg/l) respectively. the nitrate and nitrite of saliva samples was determined by high performance liquid chromatographs method. the values of nitrate in saliva samples from exposed groups ranged between 4.57 to 25.94 mg/l (15.33±8.88 mg/l). for control groups, the levels of 0.89 to 14.57 mg/l (7.18±4.54 mg/l) were registered. no differences between levels of salivary nitrite from control and exposed groups were found. regression analysis on water nitrate concentrations and salivary nitrate showed significant correlations. in conclusion, we estimate that salivary nitrate may be used as biomarkers of human exposure to nitrate. abstract disinfection of public drinking water supplies produces trihalomethanes. epidemiological studies have associated chlorinated disinfection by-products with cancer, reproductive and developmental effects. we studied the levels of trihalomethanes (chloroform, dibromochloromethane, bromodichloromethane, bromoform) in drinking water delivered to the population living in some urban areas (n=20). the water samples (n=150) were analysed using gas chromatographic method. assessment of exposure to trihalomethanes in tap water has been on monitoring data collected over 2-12 months periods and that we averaged over entire water system. analytical data revealed that total trihalomethanes levels were higher in the summer: mean ± standard deviation 72.07±42.88lg/l (micrograms/litre). these organic compounds were present in the end of distribution networks (9.87±5.87lg/l). it is noted that, sometimes, we found high concentrations of chloroform exceeding the sanitary norm (100lg/l) in tap water (maximum value 41.65lg/l). results of sampling programs showed stronger correlations between chlorine and trihalomethanes value (correlation coefficient r = 0.821 to 0.952, credible 95%interval). in conclusion, the population drank water with the law concentration of trihalomethanes, especially chloroform. abstract objective: to determine the validity of a performance-based assessment of knee function, dynaport[rsymbol] kneetest (dpkt), in first-time consulters with non-traumatic knee complaints in general practice. methods: patients consulting for nontraumatic knee pain in general practice aged 18 years and older were enrolled in the study. at baseline and 6-months follow-up knee function was assessed by questionnaires and the dpkt; a physical examination was also performed at baseline. hypothesis testing assessed cross-sectional and longitudinal validity of the dpkt. results: a total of 87 patients were included for dpkt of which 86 were available for analysis. the studied population included 44 women (51.2%), median age was 54 (range 18-81) years. at follow-up, 77 patients (89.5%) were available for dpkt. only 3 out of 11 (27%) predetermined hypotheses concerning cross-sectional and longitudinal validity were confirmed. comparison of the general practice and secondary care population showed a major difference in baseline characteristics, dynaport knee score, internal consistency and hypotheses confirmation concerning the construct validity. conclusion: the validity of the dpkt could not be demonstrated for first-time consulters with non-traumatic knee complaints in general practice. measurement instruments developed and validated in secondary care are not automatically also valid in primary care setting. abstract although animal studies have described the protective effects of dietary factors supplemented before radiation exposure, little is known about the lifestyle effects after radiation exposure on radiation damage and cancer risks in human. the purpose of this study is to clarify whether lifestyle can modify the effects of radiation exposure on cancer risk. a cohort of 40,000 japanese atomic-bomb survivors, for whom radiation dose estimates were currently available, had their lifestyle assessed in 1980. they were followed during 20 years for cancer incidence. the combined effect of smoking, drinking, diet and radiation exposure on cancer risk was examined in additive and multiplicative models. combined effects of a diet rich in fruit and vegetables and ionizing radiation exposure resulted in a lower cancer risk as compared to those with a diet poor in fruit and vegetables and exposed to radiation. similarly, those exposed to radiation and who never drink alcohol or never smoke tobacco presented a lower oesophagus cancer risk than those exposed to radiation and who currently drink alcohol or smoke tobacco. there was no evidence to reject either the additive or the multiplicative model. a healthy lifestyle seems beneficial to persons exposed to radiation in reducing their cancer risks. abstract background: clinical trials have shown significant reduction in major adverse cardiac events (mace) following implantation of sirolimus-eluting (ses) vs. bare-metal stents (bms) for coronary artery disease (cad). objective: to evaluate long-term clinical outcomes and economic implications of ses vs. bms in usual care. methods: in this prospective intervention study, cad patients were treated with bms or ses (sequential control design). standardized patient and physician questionnaires 3, 6, and 12 months following implantation documented mace, disease-related costs and patient quality of life (qol). results: 602 patients treated with ses (mean age 63±9, 87% male), 295 with bms (mean age 65±10, 79% male). there were no significant baseline differences in cardiovascular risk factors and severity of cad. after 12 months, 18% ses vs. 30% bms patients had suffered mace (p<0.05). initial hospital costs were higher with ses than with bms, but respective 12month follow-up direct and indirect costs were lower (5,052±642 vs. 6,052±590 euro and 753±459 vs. 2,013±422 euro, p = ns). overall, disease-related costs were similar in both groups (ses 11, 765±827, bms 11, 826±760, p = ns) . differences in qol were not significant. conclusions: as in clinical trials, ses patients experienced significantly fewer mace than bms patients during 12-month follow-up with similar overall costs and qol. abstract background: meta-analyses that use individual patient data (ipd-ma) rather than published data have been proposed as an improvement in subgroup-analyses. objective: to study 1) whether and how often ipd-ma are used to perform subgroup-analyses 2) whether the methodology used for subgroup-analyses differs between ipd-ma and meta-analyses of published data (map) methods: ipd-ma were identified in pubmed. related article search was used to identify map on the same objective. metaanalyses not performing subgroup-analysis were excluded from further analyses. differences between ipd-ma and map were analysed, reasons for discrepancies were described. we recently developed a simple diagnostic rule (including 7 history and physical findings plus d-dimer assay results) to safely exclude the presence of deep vein thrombosis (dvt) without the need for referral in primary care patients suspected of dvt. when applied to new patients, the performance of any (diagnostic or prognostic) prediction rule tends to be lower than expected based on the original study results. therefore, rules need to be tested on their generalizability. the aim was to determine the generalizability of the rule. in this cross-sectional study, 532 primary care patients with suspicion of dvt were prospectively identified. the 8 rule items were obtained from each patient plus ultrasonography as reference standard. the accuracy of the rule was quantified on its discriminative performance, sensitivity, specificity, negative predictive value, and negative likelihood ratio, with accompanying 95% confidence interval. dvt could be safely excluded in 21% (23% in the original study) of the patients, without referral. none of these patients had dvt (0.7% in the derivation population). in conclusion, the rule appears to be a safe diagnostic tool for excluding dvt in patients suspected of dvt in primary care. abstract background: long-term exposure to very low concentrations of asbestos in the environment and relation to incidence of mesothelioma contributes to insight into the dose-response relationship and public health policy. aim: to describe regional differences in the occurrence mesothelioma in the netherlands in relation to the occurrence in the asbestos polluted area around goor and to determine whether the increased incidence of pleural mesothelioma among women in this area could be attributed to environmental exposure to asbestos. methods: mesothelioma cases were selected in the period 1989-2002 from the netherlands cancer register (n = 4781). for the women in the region goor (n = 30) exposure to asbestos due to occupation, household or environment was verified from the medical files, the general practitioner and next-of-kin for cases. results: in goor the incidence of pleural mesothelioma among women was 5-fold increased compared with the netherlands and among men 2fold. of the additional 19 cases among women, 11 cases were attributed to the environmental asbestos pollution and in 4 cases this was the most likely cause. the average cumulative asbestos exposure was estimated at 0.1 fiber-years. . temporal trends and gender differences were investigated by random slope analysis. variance was expressed using median odds ratio (mor). results: ohcs appeared to be more relevant than administrative areas for understanding physicians' propensity to follow prescription guidelines (mor_ohc = 2.7 and mor_aa = 1.5). conclusion and discussion: as expected, the intervention increased prevalence and decreased variance, but at the end of the observation period practice variation remained high. these results may reflect inefficient therapeutic traditions, and suggest that more intensive interventions may be necessary to promote rational statin prescription. abstract background: mortality rates in ska˚ne, sweden have decreased in recent years. if this decline has been similar for different geographical areas have not been examined closely. objectives: we wanted to illustrate trends and geographical inequities in all cause mortality between the 33 municipalities in ska˚ne, sweden from 1970 to 2000. we also aimed to explore the application of multilevel regression analysis (mlra) in our study, since it is a relatively new methodology when describing mortality rates. design and methods: we used linear mlra with years at the first level and municipalities at the second to model direct age-standardized rates. temporal trends were examined by random slope analysis. variance across time was expressed using intra-class correlation (icc). results: the municipality level was very relevant for understanding temporal differences in mortality rates (icc = 26 %). in average, mortality decreased by 34/10 ù 4 along the study period but this trend varied considerably between municipalities, geographical inequalities along the years were u-shaped with lowest variance in the 80s (var = 26). conclusion: mortality has decreased in ska˚ne but municipality differences are increasing again. mlra is a useful technique for modelling mortality trends and variation among geographical areas. abstract background: ozone has adverse health effects but it is not clear who is most susceptible. objective: identification of individuals with increased ozone susceptibility. methods: daily visits for lower respiratory symptoms (lrs) in 6 general practitioner (gp) offices in the north of the netherlands (1989-2000, 38000 patients) were related to daily ozone levels in summer. ozone effects were estimated for patients with asthma, copd, atopic dermatitis, and cardiovascular diseases (cvd) and compared to effects in patients without these diseases. generalized additive models adjusting for trend, weekday, temperature, and pollen counts were used. results: the mean daily number of lrs-visits in summer in the gp-offices varied from 1.3 to 8.5. mean (sd) 8-hour maximum ozone level was 62.6 (30.5) lg/m3. rrs (95% ci) for a 90lg/m3 increase (from 5th to 95th percentile) in the mean of lag 0 to 4 of ozone for patients with/ without disease are: abstract asthma is a costly health condition, its economic effect is greater than that estimated for aids and tuberculosis together. following global initiative for asthma recommendations that require more data about the burden of asthma, we have determined the cost of this illness from 1998-2002. an epidemiological approach based on population studies was made to estimate global as well as direct and indirect costs. data were obtained mainly from the national health ministry database, the national statistics institute of spain and the national health survey. the costs were averaged and adjusted to 2002 e. we have found a global burden (including private medicine) of 920 million e. indirect and direct costs account for 35,4 and 64,6%.the largest components within direct costs were pharmaceutical (29.6%), primary health care systems (8,4%), hospital admissions (5.2%) and hospital non-emergency ambulatory visits (3.2%). within indirect costs, total cessation of work days (19.4%), permanent labour incapacity (8.5%) and early mortality (3.1%) costs were the main components. pharmaceutical cost is the first component as in most studies from developed countries, followed by primary health care systems unlike some reports that consider hospital admissions in second place. finally, direct costs represent 1.3% of the total health care expenditure. abstract background: it is well known that fair phenotypical characteristics are a risk factor for cutaneous melanoma. the aim of our study was to investigate the analogous associations between phenotypical characteristics and uveal melanoma. design/methods: in our casecontrol study we compared incident uveal melamom patients with population controls to evaluate the role of phenotypical characteristics like iris-, hair-and skin color and other risk factors in the pathogenesis of this tumor. a total of 455 patients and 827 controls matched on sex, age and region were interviewed. conditional logistic regression was used to calculate odds ratio (or) and 95% confidence intervals (95% ci). results: risk of uveal melanoma was increased among people with light iris color (or = 1.9 95% ci 1.4-2.7) and light skin color was slightly associated with an increased risk of uveal melanoma (or 1.4 95% 1.1-1.4). hair color, tanning ability, burning tendency and freckles as a child showed no increased risk. results of the combined analysis of eye-and hair color, burning tendency and freckles showed that only light iris color was clearly associated with uveal melanoma risk. conclusion: among potential phenotypical risk factors only light iris-and skin color were identified as risk factor for uveal melanoma. abstract background: between-study variation in estimates of the risk of hcv mother-to-child transmission (mtct) and associated risk factors may be due to methodological differences or changes in population characteristics over time. objective: to investigate the effect of sample size and time on risk factors for mtct of hcv. design and methods: heterogeneity was assessed before pooling data. logistic regression estimated odds ratios for risk factors. results: the three studies included 1633 mother-child pairs born between 1992 and 1998, 346 born between 1986 and 2000, and 1758 between 1999 and 2003 . there was no evidence of heterogeneity of the estimates for maternal hcv/hiv co-infection and mode of delivery (q = 2.16, p = 0.34 and q = 1.42, p = 0.49, respectively). in pooled analysis the proportion of hcv/hiv co-infected mothers significantly decreased from 54% before 1994 to 10% since 2002 (p<0.00001). the pooled adjusted odds ratios for maternal hcv/hiv co-infection and elective caesarean section delivery were 2.80 (95%ci 1.99-3.95), p<0.001 and 1.11 (95%ci 0.79-1.57), p = 0.53 respectively. there was no evidence that the effect of risk factors for mtct changed over time. conclusion: although certain risk factors have become less common, their effect on mtct of hcv has not changed substantially over time. abstract background: the need to gain insight into prevailing eating pattrerns and their health effects is evident. objective: to identify dietary patterns and their relationship with total mortality in dutch older women. methods: principal components analysis on 22 food groups was used to identify dietary patterns among 5,427 women (60-69 y) included in the dutch epic-elderly cohort (follow-up $8.2 y). mortality ratios for three major principle components were assessed using cox proportional hazard analysis. results: the most relevant principal components were a 'mediterranean-like' pattern (high in vegetable oils, pasta/rice, sauces, fish, and wine), a 'traditional dutch dinner' pattern (high in meat, potatoes, vegetables, and alcoholic beverages) and a 'healthy traditional' pattern (high in vegetables, fruit, non-alcoholic drinks, dairy products, and potatoes). in 44,667 person years 277 deaths occurred. independent of age, education, and other life style factors only the 'healthy traditional' pattern score was associated with a lower mortality rate, women in the highest tertile experienced a 30 percent reduced mortality risk. conclusion: from this study a healthy traditional dutch diet, rather than a mediterranean diet, appears beneficial for longevity and feasible for health promotion. this diet is comparable to other reported 'healthy' or 'prudent' diets that have been shown to be protective. parents of 413 (aged 0-4) and 294 (aged 5-15) children were sent a questionnaire, as were 113 adolescents (aged 10-15). to assess validity, generic outcome instruments were included (infant toddler quality of life questionnaire (itqol) or the child health questionnaire (chq) and the euroqol-5d). response rate was 48-53%. internal consistency of hobq and boq-scales was good (cronbach's alpha's >0.7 in all but two scales). test-retest results showed no differences in 70-92% of scales. high correlations between hobq-and boq-scales and conceptually equivalent generic outcome instruments were found. the majority of hobq (7/10) and boq scales (11/12) showed significant differences between children with a long versus short length of stay. the dutch hobq and boq can be used to evaluate functional outcome after burns in children. the study estimated caesarean section rates and odds ratios for caesarean section in association with maternal characteristics in both public and private sectors; and maternal mortality associated with mode of delivery in the public sector, adjusted for hypertension, other disorders, problems and complications, as well as maternal age. results: the caesarean section rate was 32.9% in the public sector, and 80.4% in the private sector. the odd ratio for caesarean section was 2.6 (95%ci: 2.6-2.7) for women with 12 or more years of education. the odd ratio for maternal mortality associated with caesarean section in the public sector was 3.3 (95%ci:2.6-4.3). conclusion and discussion: sao paulo presented high caesarean section rates. caesarean section compared to vaginal delivery in the public sector presented higher risk for mortality even when adjusted for hypertension, other disorders, problems and complications, as well as maternal age. we show that serious bias in questionnaires can be revealed by bland-altman methods but may remain undetected by correlation coefficients. we refute the argument that correlation coefficients properly investigate whether questionnaires rank subjects sufficiently well. conclusions: the commonly used correlation approach can yield misleading conclusions in validation studies. a more frequent and proper use of the bland-altman methods would be desirable to improve epidemiological data quality. abstract screening performance relies on quality and efficiency of protocols and guidelines for screening and follow-up. evidence of low attendance rates, over-screening of young women and low smear specificity gathered by the early 1990's in the dutch cervical cancer screening program called for an improvement. several protocols and guidelines were redefined in 1996, with emphasis on assuring that these would be adhered to. we assessed improvement since 1996 by changes in various indicators: coverage rates, follow-up compliance and number of smears. information on all cervix uteri tests in the netherlands registered until 31st march 2004 was retrieved from the nationwide registry of histo-and cytopathology (palga). five-year coverage rate in the age group 30-60 years rose to 77%. the percentage of screened women in follow-up decreased from 19% to 3%. fourteen percent more women with abnormal smears were followed-up, and the time spent in follow-up decreased. a 20% decrease in the annual number of smears made was observed, especially among young women. in conclusion, the 1996 changes in protocols and guidelines, and their implementation have increased coverage and efficiency of screening, and decreased the screening-induced negative side effects. similar measures can be used to improve other mass screening programmes. abstract background: it is common knowledge that in low endemic countries the main transmission route of hepatitis b infection is sexual contact, while in high endemic regions it is perinatal transmission and horizontal household transmission in early childhood. objectives: to get insight into what determines the main transmission route in different regions. design and methods: we used a formula for the basic reproduction number r0 for hepatitis b in a population stratified by age and sexual activity to investigate under which conditions r0 > 1. using data extracted from the literature we investigated how r0 depends on fertility rates, rates of horizontal childhood transmission and sexual partner change rates. results: we identified conditions on the mean offspring number and the transmission probabilities for which perinatal and horizontal childhood transmission alone ensures that r0 > 1. those transmission routes are then dominant, because of the high probability for children to become chronic carriers. sexual transmission dominates if fertility is too low to be the driving force of transmission. conclusion: in regions with high fertility rates hepatitis b can establish itself on a high level of prevalence driven by perinatal and horizontal childhood transmission. therefore, demographic changes can influence hepatitis b transmission routes. abstract background: the artificial oestrogen diethylstilboestrol is known to be fetotoxic. thus, intrauterine exposure to other artificial sex hormones may increase the risk of fetal death. objective: to study if use of oral contraceptive 4 months prior to or during pregnancy is associated to an increased risk of fetal death. design and methods: a cohort study of 92 719 pregnant women who were recruited into the danish national birth cohort during the years 1996-2002 and interviewed about exposures during pregnancy, either during the first part of their pregnancy (n = 90 167) or following a fetal loss (n = 2552). cox regression analyses with delayed entry were used to estimate the risk of fetal death. results: in total 1102 (1.2%) women took oral contraceptives during pregnancy. use of combined oestrogen and progesterone oral contraceptives (coc) or progesterone only oral contraceptives (poc) during pregnancy were not associated with increased hazard ratios of fetal death compared to non-users, hr 1.01 (95% ci 0.71-1.45) and hr 1.37 (95% ci 0.65-2.89) respectively. neither use of coc nor poc prior to pregnancy was associated with fetal death. conclusion: use of oral contraceptive 4 months prior to conception or during pregnancy is not related to an increased risk of fetal death. abstract background: few studies have been performed to assess if water fluoridation reduces social inequalities among groups of different socioeconomic status, and none of them was conducted in developing countries. objectives: to assess socioeconomic differences between brazilians towns with and without water fluoridation, and to compare dental caries indices among socioeconomic strata in fluoridated and non-fluoridated areas. design and methods: a countrywide survey of oral health performed in 2002-3 and comprising 34,550 children aged 12 years provided information about dental caries indices in 249 brazilian towns. socioeconomic indices, the coverage and the fluoride status of the water supply network of participating towns were also appraised. multivariate regression models were performed. inequalities in dental outcomes were compared in towns with and without fluoridated tap water. results: better-off towns tended to present a higher coverage by the water supply network, and were more inclined to add fluoride. fluoridated tap water was associated with an overall improved profile of caries, concurrent with an expressively larger inequality in the distribution of dental disease. conclusion: suppressing inequalities in the distribution of dental caries requires an expanded access to fluoridated tap water; a strategy that can be effective to foster further reductions in caries indices. objective: to investigate the role of family socioeconomic trajectories from childhood to adolescence on dental caries and associated behavioural factors. design and methods: a population-based birth cohort was carried out in pelotas, brazil. a sample (n=888) of the population of subjects born in 1982 were dentally examined and interviewed at aged 15. dental caries index, care index, toothbrushing, flossing, and pattern of utilization of dental services were the outcomes. these measures were compared among four different family income trajectories. results: adolescents who were always poor showed, in general, a worse dental caries profile, whilst adolescents who never were poor had a better dental caries profile. adolescents who had moved from poverty in childhood to nonpoverty in adolescence and those who had moved from non-poverty in childhood to poverty in adolescence had similar dental profiles to those who were always poor except for pattern of utilization of dental services which was higher in the first group. conclusion: poverty in at least one stage of the lifespan has a harmful effect on dental caries, oral behaviours and utilization of dental services. we assessed contextual and individual determinants of dental caries in the brazilian context. a country-wide survey of oral health informed the dental status of 34,550 twelve-year-old schoolchildren living in 250 towns in 2003. a multilevel model fitted the adjustment of untreated caries prevalence to individual (socio-demographic characteristics of examined children) and contextual (geographic characteristics of participating towns) covariates. being black (or = 1.6; 95% ci: 1.5-1.7), living in rural areas (or = 1.9; 1.7-2.0) and studying in public schools (or = 1.7; 1.6-1.9) increased the odds of having untreated decayed teeth. the multilevel model identified the fluoride status of water supplies (ß=)0.3), the proportion of households linked to the water network (ß=)0.3) and the human development index (ß=)0.2) as town-level covariates of caries experience. better-off brazilian regions presented an improved profile of dental health, besides having a less unequal distribution of dental treatment needs between blacks and whites, rural and urban areas, and public and private schools. dental caries experience is prone to socio-demographic and geographic inequalities. monitoring contrasts in dental health outcomes is relevant for programming socially appropriate interventions aimed both at overall improvements and at the targeting of resources for groups of population presenting higher levels of needs. abstract background: ultraviolet radiation (uvr) is the main cause of nonmelanoma skin cancer but has been hypothesised to protect against development of prostate cancer (pc). if this is true, skin cancer patients should have lower pc incidence than the general population. objectives: to study the incidence of pc after a diagnosis of skin cancer. design methods: using the eindhoven cancer registry, a cohort of male skin cancer patients diagnosed since 1970 (2565 squamous cell carcinoma (scc), 9295 basal cell carcinoma (bcc) and 1419 melanoma (cm)) was followed up for incidence of invasive pc. observed incidence rates of pc amongst skin cancer patients were compared to those in the reference population, resulting in standardised incidence ratios (sir). results: scc (sir 0.88 (95%ci: 0.64; 1.2)) and bcc (sir 0.79 (95%ci: 0.65;0.94)) showed a decreased incidence of pc, cm did not. patients with bccs occurring in the chronically sun-exposed head and neck area (sir 0.79 (95%ci: 0.64; 0.97) had significantly lower pc incidence rates. conclusion discussion: although numbers of scc and cm were too small to obtain unequivocal results, this study partly supports the hypothesis that uvr protects against pc and also illustrate that cm patients are different from nmsc patients in several aspects. abstract introduction: hypo-and hyperthyroidism have been associated to various symptoms and metabolic dysfunctions in men and women. incidences of these diseases have been estimated in a cohort of middle-aged adults in france. methods: the su.vi.max (sup-ple´mentation en vitamines et mine´raux antioxydants) cohort study included 12741 volunteers followed-up for eight years since 1994-1995. the incidence of hypo-and hyperthyroidism was estimated retrospectively from scheduled questionnaires and the data transmitted by the subjects during their follow-up. factors associated to incident cases have been identified by cox proportional hazards models. results: among the 5166 subjects free of thyroid dysfunction at inclusion, 95 incident cases were identified. after an average follow-up of 7.5 years, the incidence of hyper-and hypothyroidism was 0.5% in men, 2.3% in 35-44 year old women, and 3.6% in 45-60 year old women. no associated factor was identified in men. in women, age and alcohol consumption (>15 grams/day) increased the risk of hypo-or hyperthyroidism, while a high urinary thiocyanate level in 1994-1995 would be a protective factor. conclusion: the incidences of hypo and hyperthyroidism observed in our study as well as the associated risk factors found are in agreement with the data of studies performed in other countries. abstract background: lung cancer is the most frequent malignant neoplasm world-wide. in 2000, the number of new lung cancer cases was estimated at 1.2 million, which makes over 12% of all new cases of neoplasm registered all round the globe. it is also the leading cause of cancer deaths. objective: the objective of this paper is to provide a systematic review of life-related factors for lung cancer risk. methods: data sources were medline from january 1950 to december 2005, title in the field. search terms included: lung cancer, tobacco smoke, education, diet, alcohol consumption or physical activity terms. book chapters, monographs, relevant news reports, and web material were also reviewed to find articles. results: the results of the literature review suggest that smoking is a major, unquestionable factor of lung cancer risk. exposure to environmental tobacco smoke (ets) and education could also play a role in the occurrence of the disease. diet, alcohol consumption and physical activity level are other important but less extended determinants of lung cancer. conclusions: effective prevention programs against some of the life style-related factors for lung cancer, especially against smoking must be developed to minimize potential health risks and prevent the future cost of health. stedendriehoek twente and south (n = 179), additional data (co-morbidity, complications after surgery and follow-up) were gathered. cox-regression analyses were used. results: the proportion resections declined from 80% of patients <60 to 30% of patients aged > = 80 years, whereas primary radiotherapy increased from 7% to 36%. in the two regions 25 patients (14%) underwent resection. co-morbid conditions did not influence the choice of the therapy. 75% had complications. postoperative mortality was 20%. in multivariate analysis, only treatment had an independent effect.two year survival was 58% for patients undergoing surgical resection and 27% for those receiving radiotherapy (p<0.05). conclusion: number of co-morbid conditions did not influence choice of treatment, postoperative complications, and survival in patients with nsclc > = 80 years. the epidemiology of oesophageal cancer has changed in recent decades. the incidence has increased sharply, mainly comprising men, adenocarcinoma and tumours of the lower third of the oesophagus. the eurocare study suggested large variation in survival between european countries, primarily related to early mortality. to study potential explanations, we compared data from the rotterdam and thames cancer registry. computer records from 18,320 patients diagnosed with oesophageal cancer in the period 1993-2003 were analysed by age, gender, histological type, tumour subsite, period and region. there was a large variation in resection rates between the two regions, 31% for rotterdam versus 14% for thames (p<0.001). resection rates were higher for men, younger patients, adenocarcinoma and distal tumours. postoperative mortality (pom) was defined as death within 30 days of surgery and was 7.4% on average. pom increased with age from 3.3% for patients younger than 60 years to 12.6% for patients older than 70 years. pom was significantly lower in high-volume hospitals (>20 operations per year), 8.7% versus 2.4% (p<0.001). this study shows a large variation in treatment practice between the netherlands and the united kingdom. potential explanations will need to be studied in detail. abstract russia has experienced tremendous decline in life expectancy after break up of the ussr. surprisingly, im has also been decreasing. less is known on the structure of im in different regions of russia. the official im data may be underestimated partly due to misreporting early neonatal deaths (end) as stillbirths (sb). end/sb ratio considerably exceeding 1:1 indicates misreporting. we present the trends and structure of im in arkhangelsk oblast (ao), north-west russia from 1980 to 2004 as obtained from the regional statistical committee. im decreased from 22.3 to 10.1 per 1000 live births. cause-specific death rates (per 100,000) decreased from 251 to 7.0 for infectious diseases, from 745 to 56 for respiratory causes, from 141 to 56 for traumas, from 384 to 285 for inborn abnormalities but did not change for conditions of the perinatal period (501 in both 1980 and 2004) . the end/sb ratio increased from 1 to 1.5. in 2004, im from infections and respiratory causes in the ao are much lower than in russia in general. the degree of misreporting end as sb in the ao is lower than in russia in general. other potential sources of underestimation of im in russia will be discussed. abstract background: epidemiological studies that investigated malocclusion and different physical aspects in adolescents are rare in the literature. objective: we studied the impact of malocclusion on adolescents' self-image regardless of other physical aspects. design and methods: a cross-sectional study nested in a cohort study was carried out, in pelotas, brazil. a random sample of 900 15 yearsold adolescents was selected. the world health organization (1987) criteria were used to define malocclusion. interviews about self-reported skin colour and appearance satisfaction were administered. the body mass index was calculated. gender, birth weight and socioeconomic characteristics were obtained from the birth phase of the cohort study. poisson regression models were performed. results: the prevalence of moderate or severe malocclusion was 31.6% [95%ci 28.5; 34.7] in the whole sample without significant difference between boys and girls. a higher statistically significant difference of appearance dissatisfaction was identified in girls (46.5%) than in boys (29.8%). a positive association between malocclusion and appearance dissatisfaction was observed only in girls, after adjusting for other physical and socioeconomic characteristics. conclusions: malocclusion influenced appearance dissatisfaction only in young women. abstract background: factors for healthy aging with good functional capacity and those which increase the risk of death and disability need to be identified. objectives: we studied the prevalence of low functional capacity and its associations in a small city in southern brazil. design and methods: a population based cross sectional study was carried out with a random sample size of 345 elderly people. a home-applied questionnaire including socioeconomic, demographic, house conditions, socioeconomic self-perception characteristics was applied. the low functional capacity was defined as the difficulty in the performance of 6 or more activities or inability to carry out 3 of those activities according to scale proposed by rikli and jones. descriptive statistics, association using chi-square test as well as the multiple logistic regression analysis were performed. abstract introduction: assessment of trichiuriasis spatial distribution is important to evaluate sanitation conditions. our objective was to identify risk areas for the trichuris trichiura infection. methods: cross sectional study was held in 19 census tracts of duque de caxias county, rio de janeiro, brazil. collection and analysis of fecal specimens and a standardize questionnaire were carry out in order to evaluate socio-economic and sanitation conditions in a sample of 1,546 children between 1 and 9 years old. geoestatistics techniques were used to identify risk areas for trichiuriasis. results: the mean age of the studied population was 4.4 years old, which 52% were females and 48% were males. the prevalence of trichuris trichiura in the sample was 17%. children whose mothers studied for 4 years or less had odds ratio (or) = 1.9 than children whose mothers studied for more than 4 years old. children who were living in houses without water supply had or = 2.6 comparing to children living in houses with water supply. the spatial analysis identified risk areas for infection. conclusion: the results show association between socio-economic conditions and the proliferation of trichuris trichiura infection. the identification of risk areas can guide efficient actions to combat the disease. abstract background: refuge life and diabetes mellitus can affect the healthrelated quality of life (hrqol). objective: to assess how both aspects influence hrqol of the diabetic refugees in gaza strip. methods: overall 591 subjects filled a self-administered questionnaire including world health organization quality of life questionnaire (whoqol-bref) and some socio-demographic information. the sample consisted of three frequency matched groups for gender and sex, 197 each. first group were refugees with diabetes mellitus, second refugees without diabetes and third diabetes patients with no refugee history. the response rate was 87% on average. global score consisting of all four domains of who-qol-bref was dichotomized by the value of 50 and logistic regression was used for the analysis. results: crude odds ratios (or) for lower quality of life were 17.2 (95% ci 10.4-28.3) for diabetes refugees compared to diabetes non-refugees and 19.4 (11.7-32. 2) compared to non-diabetes refugees. after adjusting for age, gender, education, employment, income status and number of persons depending on the respondents or was 11.2 (6.1-20.5) and 35.3 (17.7-70.4), respectively. additionally, adjusting for length of diabetes and complications reduced the or to 5.6 (2.4-13.4) for diabetes refugees compared to diabetes non-refugees. conclusion: quality of life is highly reduced in refugees with diabetes. abstract background: pesticides have a significant public health benefit by increasing food production productivity and decreasing diseases. on the other hand, public concern has been raised about the potential health effects of the exposure to pesticides on the developing fetus and child. objectives: to review the available literature to find an epidemiological studies dealing with the exposure to pesticides and children health. design and methods: epidemiological studies were identified during search of the literature basis. following health effects were taking into account: adverse reproductive and developmental disorders, childhood cancer, neurodevelopmental effects and the role of pesticides as endocrine disrupters. results: pesticides were associated with wide range of reproductive disorders. the association between exposure to pesticides and the risk of childhood cancer and neurodevelopmental effects was found in several studies. epidemiological studies have been limited by luck of specific pesticide exposure, exposure based on job title, small size of examined groups. conclusions: in the light of existing although still limited evidence of adverse effects of pesticide exposure it is necessary to reduce the exposure. the literature review suggests a great need to increase awareness of people who are occupationally or environmentally exposed to pesticides about its potential negative influence on their children. in order to match local health policy more with the needs of citizens, the municipal health service utrecht started the project 'demand-orientated prevention policy'. one of the aims was to explore the needs of the utrecht citizens. the local health survey from 2003 contained questions about needs of information and support with regard to disorders and lifestyle. do these questions about needs give other results compared to questions about prevalence of health problems? in total 2284 utrecht citizens aged 16 to 54 years returned the health questionnaire (response rate 55%). most needs were observed on subjects concerning overweight and mental problems, and were higher among women, moroccans, turks, low educated people and citizens of deprived areas. the prevalence of disorders and unhealthy lifestyles did not correlate well to the needs (majority correlation coefficients: <0,30). most striking, of the utrecht population 30% were smokers and 20% excessive alcohol drinkers, while needs related to these topics were low. furthermore, higher needs among specific groups did not always correspond to higher prevalences of related health problems in these groups. these results show the importance of including questions about needs in a health survey, because they add additional information to questions about prevalences. abstract background: recent studies associated statin therapy with better outcome in patients with pneumonia. because of an increased risk of pneumonia in patients with diabetes we aimed to assess the effects of statin use on pneumonia occurrence in diabetic patients managed in primary care. methods: we performed a case-control study nested in 142,174 patients with diabetes. cases were defined as patients with a diagnosis of pneumonia. for each case, up to 4 controls were matched by age, gender, practice, and index date. patients were classified as current statin user when the index date was between the start and end date of statin therapy. results: statins were currently used in 1.1 % of 4,719 cases and in 2.1% of 15,322 controls (crude or: 0.51, 95% ci 0.37-0.68). after adjusting for potential confounders, statin therapy was associated with a 51% reduction in pneumonia risk (adjusted or: 0.49, 95% ci 0.35-0.68). the association was consistent among relevant subgroups (stroke, heart failure, and pulmonary diseases) and independent of age or use of other prescription drugs. conclusions: use of statins was significantly associated with reduced pneumonia risk in diabetic patients and may apart from lipid lowering properties be useful in prevention of respiratory infections. abstract introduction: cigarette smoking is the most important risk factor for copd development. therefore, smoking cessation is the best preventive measure. aim: to determine the beneficial effect of smoking cessation on copd development. methods: incidence of copd (gold stage > = 1) was studied in smokers without copd who quitted or continued smoking during 25 yr of followup. we performed logistic regression analyses on pairs of observations. correlations within a subject and time, and time between 2 successive surveys were taken into account. abstract objectives: to describe the prevalence and severity of dental caries in adolescents of the city of porto, portugal, and to assess socioeconomic and behavioral covariates of dental caries experience. methods: a sample of 700 thirteen-year-old schoolchildren underwent dental examination. results from the dental examination were linked to anthropometric information and to data supplied by two structured questionnaires assessing nutritional factors, sociodemographic characteristics and behaviors related to health promotion. dental caries was appraised in terms of the dmft index, and two dichotomous outcomes, one assessing the prevalence of dental caries (dmft = 1); the other assessing the prevalence of a high level of dental caries (dmft = 4). results: consuming soft drinks derived from cola two or more times per week, attending a public school, being girl and having parents with low educational attainment were identified as risk factors both for having dental caries and for having a high level of dental caries. conclusion: the improvement of oral health status in the portuguese context demands the implementation of polices to reduce the frequency of sugar intake, and could benefit from an overall and longstanding expansion of education in society. abstract background: migrant mortality does not conform to a single pattern of convergence towards rates in the host population. to better understand how migrant mortality will develop, there is a need to further investigate how the underlying behavioural determinants change following migration. objective: we studied whether behavioural risk factors among two generations of migrants converge towards the behaviour in the host population. design and methods: cross-sectional interview-data were used including 299 moroccan and 476 turkish migrants, aged 15-30. questions were asked about smoking, alcohol consumption, physical inactivity and weight/height. age-adjusted prevalence rates among first and second generation migrants were compared with prevalence rates in the host population. results: converging trends were found for smoking, physical inactivity and overweight. for example, we found a higher prevalence of physical inactivity in first generation turkish women as compared to ethnic dutch (or = 1.78(1.22-2.62)), whereas among second generation no differences were found (or = 0.82(0.57-1.17)). however, this trend was not found in all subgroups. additionally, alcohol consumption remained low in all subgroups and did not converge. conclusion and discussion: behavioural risk factors in two generations of migrants seem to converge towards the prevalence rates in the host population. although, some groups and risk factors showed a deviant pattern. abstract background/relevance: arm-neck-shoulder complaints are common in general practice. for referral in these complaints, only guidelines exist for shoulder complaints and epicondylitis. besides, other factors can be important. objective: what factors are associated with referral to physiotherapy or specialist in non-traumatic armneck-shoulder complaints in general practice, during the first consultation? design/methods: 31 general practitioners (gps) recruited consulters with new arm, neck or shoulder complaints. data on complaint-, patient-, gp-characteristics and management were collected. the diagnosis was categorised into: shoulder specific, epicondylitis, other specific or non-specific. multilevel analyses (adjustment for treating gp) were executed in procgenmod to assess associated variables (p<0.05). results: during the first consultation, 23% was referred for physiotherapy and 5% for specialist care. indicators of reference to physiotherapy were: long duration of complaint, recurrent complaint and gp located in a little/not urbanised area. while having shoulder specific or other specific diagnoses was negatively associated. indicators of reference to specialist care were: having other specific diagnosis, long duration of complaint, musculoskeletal co-morbidity, functional limitations and consulting a less experienced gp. conclusion/discussion: most referrals were to physiotherapy and only a minority to specialist care. mainly diagnosis and other complaint variables indicate on 'who goes where'. besides gp-characteristics can play a role. abstract background: the ruhr area has for 170 years been a synonym for a me´gapolis of heavy industry with a high population density. presently, 40% of the population of the state of north rhine-westphalia live there, i.e. more than five million people. objectives: for the first time, social and health indicators of nrw's health indicator set were brought together for this me´gapolis area. design and methods: new standard tables were constructed for the central area of 'ruhr-city' including seven cities with more than 2000 inhabitants/km2 and the peripheral zone with eight districts and cities. for the pilot phase, four socio-demographic and four health indicators were recalculated. comparability of the figures was achieved by age standardization. the results obtained were submitted to a significance test by identifying 95% confidence intervals. results: the centre of 'ruhr-city' is characterised by elderly, unemployed, foreign, low-income citizens living closely together. infant mortality lies above nrw's average, male life expectancy is 1.34 years lower and female life expectancy 0.90 years lower than life expectancy in nrw (without 'ruhr-city'). several avoidable deaths' rate in the ruhr area are significantly higher than the average in nrw. specific intervention strategies are required to improve the health status in 'ruhr-city'. abstract background: general practitioners (gps) have a fundamental role to play in tobacco control, since they reach a high percentage of the target population. objectives: to evaluate specific strategies to enhance promotion of smoking cessation in general practice. design and methods in a cluster-randomized trial, 82 medical practices were randomized following a 2·2 factorial design. 577 patients aged 36-75 years who smoked at least 10 cigarettes per day (irrespective of their intention to stop smoking) were recruited. the intervention included (ti) the provision of a two-hour physician group training in smoking cessation methods plus direct physician payments for every participant not smoking 12 months after recruitment; and (tm) provision of the same training plus direct participant reimbursements for pharmacy costs associated with nicotine replacement therapy or bupropion treatment. results: in the mixed logistic regression model, no effect was identified for intervention ti (odds ratio (or) = 1.26, 95% confidence interval (ci) 0.65-2.43), but intervention tm strongly increased the odds of cessation (or = 4.77, 95% ci 2.03-11.22). conclusion and discussion: the cost-free provision of effective medication along with improved training opportunities for gps may be an effective measure to enhance smoking cessation promotion in general practice. in europe, little research on international comparison of health surveys has been accomplished, despite a growing interest in this field. smoking prevalence is chosen to explore data comparability. we aim to illustrate methodological problems encountered when comparing data from health surveys and investigate international variations in smoking behaviour. we examined a sample 89.754 individuals aged 16 and more, from six european health surveys performed in 2000-2002. problems met during the comparisons are described. we took the example of current smoking as an indicator allowing a valid comparison of the prevalences. the differences in age and sex distribution between countries were adjusted through direct standardisation. additionally, multivariate analysis will assess variations in current smoking between countries, when controlling for sex, age, and educational level. methodological problems concern comparability of socioeconomic variables. the percentage of current smokers varies from 29% to 43%. smoking patterns observed by age groups, sexes and educational level are similar, although rates per country differ. further results will determine if the variations in smoking related to socioeconomic status are alike. this international comparison of health surveys highlights methodological problems encountered when comparing data of several countries. furthermore, variations in smoking may call for adaptations in public health programs. from research it appears that adolescent alcohol use in the achterhoek is much higher than in the rest of the netherlands and rapidly increasing. excessive alcohol use has consequences for health and society. parents play an important role in preventing excessive adolescent alcohol use, but are not aware of the problem and consequences. for this reasons the municipalities in the achterhoek launch an alcohol moderation programme, starting with a regional media campaign to increase problem awareness among parents. the objective of this study is to assess the impact of this media campaign in the achterhoek. three successive independent cross-sectional telephone surveys, interviewing approximately 350 respondents each, will be conducted before, during and after the campaign. respondents will be questioned on knowledge and awareness of excessive adolescent alcohol use, its consequences and the role child raising can play. also the reach and appreciation of the different activities of the campaign will be investigated. results: of the surveys before and during the implementation will be known by may 2006. with these first findings the unawareness of the problem among parents and partly the reach and appreciation of the campaign can be assessed. abstract background: obesity is a growing problem, increasingly so in children and adolescents. overweight is partly 'programmed' during pregnancy, but few comprehensive studies looked prospectively into the changes of body composition and metabolic factors from birth. objectives: the aim of the population-based birth-cohort study within gecko is to study the etiology and prognosis of overweight and the metabolic syndrome during childhood. design and methods: the gecko drenthe will be a population based observational birth-cohort study, which includes all children born from april 2006 to april 2007 in drenthe, one of the northern provinces of the netherlands. during the first year of life, the study includes repeated questionnaires, extensive anthropometric measurements and blood measurements at birth (cord blood) and at the age of eleven months. results: the number of babies born in the drenthe province is about 5.500 per year. the results from a feasibility study conducted in february 2006 will be presented. conclusion: gecko drenthe is a unique project that will contribute to the understanding of the development of obesity in childhood and its tracking into adulthood. this will enable early identification of children at risk and opens the way for timely and tailored preventive interventions. abstract background: tunisia is facing an epidemiologic transition with the extension of chronic diseases that share common risk factors. obesity is a leading risk factor and happens to occur frequently in early life. objective: to study the prevalence and the risk factors of obesity and overweight among urban schoolchildren in sousse, tunisia. methods: cross sectional study of a tunisian sample of schoolchildren aged between 13 and 17 years living in the urban area of sousse, tunisia. a representative sample of 1600 school children selected by multistage cluster sampling procedure. measurements: weight and height, blood pressure measured by electronic system, fasting blood lipids. questionnaire assessment was used for family history of cardiovascular disease, smoking habits, physical activity and diet. abstract background: quality of life (qol) measurements are acknowledged as very important in the evaluation of health care. objectives: we studied the validity and the reliability of the hungarian version of the whoqol-bref among people living in small settlements. method: a questionnaire-based cross-sectional study was conducted in a representative sample (n = 814) of persons aged 35 years and over in south-east-hungary, in 2004. data were analysed by the spss 13.0. the internal consistency was evaluated using cronbach's alpha; for comparison of the qol scores amongst the various groups the two-tailed t-tests were used; convergent validity was assessed by spearman coefficients. results: the male:female ratio was 48.3 to 51.7%, and the average age 59.68 (sd:14.37) years. the domain scores were 14.14 (sd:3.08) for the physical, 14.19 (sd:2.42) for psychological, 14.15 (sd:3.03) for the social, and 14.01 (sd:2.08) for the environment domains. the cronbach's alpha values ranged from 0.73 to 0.87 across domains. the whoqol-bref seemed to be suitable to distinguish healthy and unhealthy people. the scores for all domains correlated with the self-evaluated health, and overall quality of life (p<0.01). conclusion: our study supported that the whoqol-bref provided a valid, reasonable and useful determination of the qol of people living in hungarian villages. abstract background: further than a cardiovascular disease, arterial hypertension (aht) is the main cardiovascular risk factor. in spain, the aht prevalence reaches 47%, placed in the third position after germany and finland in affecters percentage. although its high morbi-mortality, the aht is a forecast factor. the treatment's objective (pharmacological and life style modifications) of hypertensive patients is not only to reduce blood pressure levels to optimum levels but also to treat all modifiable vascular risk factors. objective: economic impact evaluation of direct costs due to aht pathology (cie9-mc 401-405) in spain in 2003, according to autonomous region. design and methods: descriptive and transversal study of costs estimation in the period between january to december 2003 in spain according to autonomous region. the study is based on data available from the national health ministry database and the national statistics institute of spain. results: the national health service assigned 2000 million e to aht treatment. 73,4% of the total cost is owe to pharmaceutical service expenses, 23,2% to primary health care and a 3,4% to hospital admissions. conclusion and discussion: the costs generated by aht are mainly due to the pharmaceutical service. the costs distribution is modified according to the geographical region. abstract background: over the last decades, for low-stage cervical cancer less surgical treatment and for high-stage cervical cancer chemoradiotherapy was recommended in the national guidelines. objectives: to describe changes and variation in treatment and survival in cervical cancer in the regions of the comprehensive cancer centre stedendriehoek twente (cccst) and south (cccs) in the netherlands. design and methods. 1736 newly diagnosed cervical cancer cases were selected from both cancer registries in the period 1989-2002. patient characteristics, tumour characteristics, treatment and follow-up data were collected from the medical records. results: in figo stages ia2-ib2 the percentage hysterectomy decreased from 90% in 1989 -1993 to 77% in 1999 -2002 (p<.05) and survival improved comparing 1989 -1993 with 1999 -2002 . figo stages iii-ivb had mostly received radiotherapy only (60%). no differences in survival between years of diagnosis were found. in the cccs-region more chemoradiotherapy was given in these stages (11% versus 5% in the cccst-region in the whole period). conclusion and discussion:. abstract background: the reason for the increased prevalence of depression in type 2 diabetes (dm2) is unknown. objective: we investigated whether depression is associated with metabolic dysregulation or that depression is rather a consequence of having dm2. methods: baseline data of the utrecht health project were used. subjects with cardiovascular disease were excluded. 4,203 subjects (age: 38.0 +/) 12) were classified into four mutually exclusive categories: normal fasting plasma glucose (fpg < 5.6 mmol/l), impaired fpg (> = 5.6 and < 7.0 mmol/l), undiagnosed dm2 (fpg > = 7.0 mmol/l), and diagnosed dm2. depression was defined as either a score of 25 or more on the depression subscale of the symptom check list-90 or use of antidepressants. results: subjects with impaired fasting glucose and undiagnosed dm2 had no increased prevalence of depression. diagnosed dm2 patients had an increased prevalence of depression (or = 2.11 (1.08-4.11)) after adjustment for gender, age, body mass index, smoking, alcohol consumption, physical activity, education level and number of chronic diseases. conclusions: our findings suggest that depression is not related to disturbed glucose homeostasis. the increased risk of depression in diagnosed dm2 only, suggests that depression is rather a consequence of the psychosocial burden of diabetes. abstract background: breast-conserving surgery (bcs) followed by radiotherapy (bcs-rt) is a safe treatment option for the large majority of patients with tumours less than 5 cm. aim: the use of bcs and bcs-rt in pt1 (?2 cm) and pt2-tumours (2-5 cm) was investigated in the netherlands in the period 1990 and 2001. methods: from the netherlands cancer registry patients were selected with invasive pt1 (?2.0 cm) or pt2 (2.1-5.0 cm) tumours, without metastasis at time of diagnosis. trends in the use of bcs and rt after bcs were determined for different age groups and regions. results: in the period 1990-2001 52,937 pt1-tumours and 36,285 pt2-tumours were diagnosed. the %bcs in pt1-tumours increased in all age groups. it remained lowest in patients 80 years and older (32% in 2001). in pt2-tumours a decrease was observed in patients 80 years and older (from 23% to 17% in 2001). in both pt1 and pt2tumours the %bcs-rt increased in patients 80 years and older to respectively 59% and 44%. between regions and hospitals large differences were seen in %bcs and %bcs-rt. conclusion: multidisciplinary treatment planning, based on specific guidelines, and patient education could increase the use of bcs combined with rt in all age groups. abstract this is a follow-up study on the adverse health effects associated with pesticide exposure among cut-flower farmers. survey questionnaires and detailed physical and laboratory examinations were administered to 114 and 102 respondents, respectively, to determine pesticide exposure, work and safety practices, and cholinesterase levels. results showed that pesticide application was the most frequent activity associated with pesticide exposure, and entry was mostly ocular and dermal. majority of those exposed were symptomatic. on physical examination, 90 or 88.2 % of those examined were found to have abnormal peak expiratory flow rate (pefr). eighty-two percent had abnormal temperature, followed by abnormal general survey findings (e.g. cardiorespiratory distress). 51% had cholinesterase levels below the mean value of 0.7 ? ph/hour, and 25.5% exhibited a more than 10% depression in the level of rbc cholinesterase. certain hematological parameters were also abnormal, namely hemoglobin, hematocrit, and eosinophil count. using pearson's r, factors strongly associated with illness due to pesticides include using a contaminated piece of fabric to wipe sweat off (p.=0.01) and reusing pesticide containers to store water (p.=0.01). the greatest adverse effect of those exposed is an abnormal cholinesterase level which confirms earlier studies on the effect of pesticides on the body. objectives: this pair-study was performed to find out the rate of spontaneous abortions in female workers exposed to organic solvents from the wood-processing industry. methods: the level of organic solvents was assessed within the workplaces during a 10year period. 366 exposed female workers from the wood-processing industry were examined. the occupational and non-occupational data associated with their fertility were obtained by applying a standard epidemiological computed questionnaire. the reference group consisted of female workers non-exposed to hypo-fertilizing agents, residing in the same locality. the rate of spontaneous abortions was evaluated in both groups as an epidemiological fertility indicator. results: within the studied period, the organic solvents levels exceeded several time the maximal admissible concentrations in all workplaces. the long-term exposure to organic solvents caused a significant increase in rate of spontaneous abortions compared to the reference group (p<0.05). the majority of abortions (85%) have happened in the first trimester of pregnancy. conclusions: the long-term exposure to organic solvents may cause low fertility on female workers because of the spontaneous abortions. it is advised to reduce the organic solvents level in the air of all workplaces, as well as to stop working the pregnant women in exposure to organic solvents. abstract introduction: rio de janeiro city (rj) presents a fast aging of the population with changes in morbi-mortality. cardiovascular diseases are the first cause of death in elderly population. more than a half of ischemic heart diseases (ihd) cases occur in aged people (> 60 years old). objective: describe the spatial distribution of ihd mortality in the elderly population in rj and associations with socio-demographics variables. methods: data were gathered from information on mortality system of the ministry of health and the 2000 demographic census of the foundation of the brazilian institute for geography and statistics. the geographic distributions of the standardized coefficient of mortality due to ihd and socio-demographics variables, by districts, in 2000 were analyzed in arcgis 8.0. spatial autocorrelation of ihd was assessed by the moran and geary indices. a conditional autoregressive model was used to evaluate the association between idh and socio-demographics variables. results: association between idh mortality and income, educational level, family type and to possess computer, videocassette and microwave was found. conclusion: spatial analysis of the idh mortality and socio-demographics factors influence are fundamental to subsidize more efficient public policies in sense to prevention and control of this important injury of health. abstract purpose: to evaluate the prognostic impact of isolated loco-regional recurrences on metastatic progression among women treated for invasive stage i or ii breast cancer (within phase iii trials concerning the optimal management of breast cancer). patients and methods: the study population consisted of 3,602 women primary surgically treated for early stage breast cancer, enrolled in eortc trials 10801, 10854, or 10902, by breast conservation (55%) and mastectomy (45%) with long time of follow-up (median: 10.2 range: 0. 2-17.4 ). data were analysed in a multi-state model by using multivariate cox regression models, including a state-dependent covariate. results: after the incidence of the loco-regional recurrence, a positive nodal status at baseline is a significant prognostic risk factor for distant metastases. the effects of the young ages at diagnosis and larger tumour size, become less significant after the incidence of loco-regional recurrences. the presence of a locoregional recurrence in itself is a significant prognostic risk factor for distant metastases after loco-regional recurrences. the effect of the time to the loco-regional recurrence is not a significant prognostic factor. conclusion: the presence of local recurrence is an important risk factor for outcome in patients with early breast cancer. abstract background: the relationship between the antral follicles and ovarian reserve tests (ort) to determine ovarian response in ivf is extensively studied. we studied the role of follicle size distribution in the response on the various orts in a large group of subfertile patients. methods: in a prospective cohort study, female patients were included if they had regular ovulatory cycles, subfertility for >12 months, > = 1 ovary and > = 1 patent ovarian tube. antral follicles were counted by ultrasound and blood was collected for fsh, including a clomiphene challenge test (ccct), inhibin b, and estradiol before and after administration of puregon [rsymbol] . (efort test). statistical analysis was performed using spss 12.0 for windows. results: of 740 eligible patients, 489 participated. mean age was 32.6 years and mean duration of subfertility was 21.7 months. age, baseline fsh, ccct and efort correlated with the number of small follicles (2-5 mm) but not with large follicles (6-10 mm). regression analysis confirmed that the number of small follicles and average follicle size contributed to ovarian response after correction for age, while large follicles did not. conclusion: small antral follicles are responsible for the hormonal response in ort and may be suitable to predict ovarian response in ivf. abstract background: dengue epidemics account annually for several million cases and deaths worldwide. the high endemic level of dengue fever and its hemorrhagic form (dhf) correlates to extensive house infestation by aedes aegypti and multiple viral serotype human infection. objective: to describe dengue incidence evolutionary patterns and spatial distribution in brazil. methods: it is a review study that analyzed serial case reports registered since 1981 until 2003. results: it was shown that defined epidemic waves followed the introduction of every serotype (den 1 to 3) , and reduction in susceptible people possibly responded for downward case frequency. conclusions and discussion: an incremental expansion of affected areas and increasing occurrence of dhf with high lethality were noted in recent years. in contrast, efforts based solely on chemical vectorial combat have been insufficient. moreover, some evidence demonstrated that educational action do not permanently modify population habits. in this regard it was stated that while vaccine is not available, further dengue control would depend on potential results gathered from basic interdisciplinary research and intervention evaluation studies, integrating environmental changes, community participation and education, epidemiological and virological surveillance, and strategic technological innovations aimed to stop transmission. abstract background: patient participation in treatment decisions can have positive effects on patient satisfaction, compliance and health outcomes. objectives: study objectives were to examine attitudes regarding participation in decision-making among psoriasis patients and to evaluate the effect of a decision-aid for discussing treatment options. methods: a 'quasi experiment' was conducted in a large dermatological hospital in italy: a questionnaire evaluating the decision-making process and knowledge on treatments was selfcompleted by a consecutive sample of 231 psoriasis patients after routine clinical practice and by a second sample of 171 patients exposed to a decision-board. results: in routine clinical practice 67.9% of patients wanted to be involved in treatment decisions, 28.4% wanted to leave decisions entirely to the doctor and 3.7% preferred making decisions alone. 17.9% and 25.3% of the control and decision-board group had good knowledge level. at multivariate analysis good knowledge on treatments increased the likelihood of preferring an active role (or = 2.21; 95%ci 1.3-3.9; p = 0.006). the decision-board only marginally improved patient knowledge and doctor-patient communication. conclusion and discussion: in conclusion, large proportions of patients want to participate in decision-making, but insufficient knowledge can represent a barrier. further research is needed for developing effective instruments for improving patient knowledge and participation. abstract background: the only available means of controlling infections caused by the dengue virus is the elimination of its principal urban vector (aedes aegypti). brazil has been implementing programs to fight the mosquito; however, since the 1980's the geographic range of infestation has been expanding steadily, resulting in increased circulation of the virus. objective: to evaluate the effectiveness of the dengue control actions that have been implemented in the city of salvador. methods: prospective design, serologic inquiries were made in a sample population of residents of 30 urban 'sentinel areas'.the seroprevalence and one year seroincidence of dengue are estimated and the relationship between intensity of viral circulation and the standards of living and vector density is analysed. results: there were high overall seroprevalence (67.7%) and seroincidence (70.6%) for the circulating serotypes (denv-1 and denv-2). the effectiveness of control measures appears to be low, and although a preventable fraction of 29.7% was found, the incidence of infections in these areas was still very high (55.4%). conclusions and discussions: it is necessary to revise the technical and operational strategies of the infection control program in order to attain infestation levels that are low enough to interrupt the circulation of the dengue virus. this study investigates the difference in cancer mortality risks between migrant groups and the native dutch population, and determines the extent of convergence of cancer mortality risks according to migrants' generation, age at migration and duration of residence. data were obtained from the national population & mortality registries in the period 1995-2000 (75860 person years, 173461 cancer deaths). we used poisson regression to compare the cancer mortality rates of migrants originating from turkey, morocco, surinam, netherlands antilles/aruba to the rates for the native dutch. results: all-cancer mortality among all migrant groups combined was significantly lower compared to the native dutch population (rr=0.55 ci: 0.52-0.58). mortality rates for all cancers combined were higher among 2nd generation migrants, among those with younger age at migration, and those with longer duration of residence. this effect was particularly pronounced in lung cancer and colorectal cancer. for most cancers, mortality among 2nd generation migrants remained lower compared to the native dutch population. surinamese migrants showed the most consistent pattern of convergence of cancer mortality. conclusions: the generally low risk of cancer mortality for migrants showed some degree of convergence but the cancer mortality rates did not yet reach the levels of the native dutch population. abstract background: legionnaires' disease (ld) is a notifiable disease in the netherlands. ld cases are reported to authorities for national surveillance. supplementary, a national ld outbreak detection program (odp) is installed in the netherlands. these two registration systems have their own information exchange process and databases. objectives: surveillance systems are known to suffer from incompleteness of reported data. co-existence of two databases creates the opportunity to investigate accuracy and reliability in a national surveillance system. design and methods: comparison was made between the outcome 'diagnosis by culture' in both databases and physical presence of legionella strains in laboratories for 174 patients. accuracy is described using the parameters sensitivity and correctness. for reliability, cohen's kappa coefficient (?) was applied. results: accuracy and reliability were significantly higher in the odp database, but not optimal in both databases when compared to data in laboratories. the odp database was moderately reliable (? = 0.56; 95%ci 0.43-0.69), the surveillance database slightly (? = 0.14; 95%ci 0.02-0.27). conclusion: our findings suggest that diagnostic notification data concerning ld patients are most accurate and reliable when derived directly from diagnostic laboratories. discussion: involvement of data-entry persons in outbreak detection results in higher reliability. unreliable data may have considerable consequences during outbreaks of ld. the aim of the study was to investigate the medical students' plans to emigrate, quantify the scale of migration in the near future and to build a profile of the possible emigrants. data were collected based on anonymous questionnaire delivered to random group of 367 medical students (katowice). we used the binary logistic regression and multivariate analysis to identify the differences between groups preferring to go abroad or stay in poland. 85% respondents confirmed that considerate the emigration; 35.3% of them declared they are very likely to move and further 10.7% is certain. 23,9% of those considering emigration confirmed having taken practical steps towards moving. binary logistic regression showed no difference between people who were certain or almost certain to go and those who were not considering going for most baseline characteristics: hometown size, socio economic background and having family tradition of the medical profession (p = 0.19). only marks' mean differentiates between the two groups: 4.01 for those who will definitely stay vs 3.7 for students who will definitely move (p = 0.02). the multivariate analysis gave similar results. conclusions: most of the students consider the emigration, but the declarations of will to departure are more frequent among those with the worse marks. abstract background: falls incidence in home resident elderly people varies from 30% to 40%. falls induce loss of self-sufficiency and increase mortality and morbidity. objectives: to evaluate falls incidence and risk factors in a group of general practice elderly patients. design : prospective cohort study with 1 year follow-up methods: eight hundreds elderly (>75 years) were visited by 18 practitioners for a baseline assessment. information on current pathologies and previous falls in the last six months was collected. functional status was evaluated using: short portable mental state questionnaire, geriatric depression scale, activities of daily living (adl), instrumental activities of daily living, total mobility tinetti score. falls were monitored through 2 phone-interviews at 6 and 12 months. data were analyzed through logistic regression. results: twenty-eight percent of the elderly fell in the whole period. sixty percent of falls were not reported to the practitioner. independent predictors for falls were adl score (adl<5: or = 1.88; 95% ci 1.04-3.38) and previous falls (or = 1.60; 95% ci 1.02-1.52). tinetti score was significantly associated to falls only in univariate analysis. conclusions: practitioners can play a key-role in identifying at-risk subjects and managing prevention interventions. falls monitoring and a continuous practice of comprehensive geriatric assessment should be encouraged. abstract background: oral health represents an important indicator of health status. socio-economic barriers to oral care among elderly are considerable. in the lazio region, a public health program for oral rehabilitation was implemented to offer dentures to elderly people with social security. objectives: to compare hospitalisation between elderly enrolled in the program and a control group. design and methods: for each elderly enrolled in the program living in rome, three controls, matched for sex and age, were selected from rome municipality register. hospital admissions in the two-year period before enrollment were traced by record-linkage with the hospital discharge register. results: totally, 2,935 admissions occurred. the annual admissions rate was 218 per 1000 elderly among controls and 329 in the program group (incidence rate ratio: irr = 1.50; 95% ci 1.40-1.63). when comparing diagnosis-specific rates, significant excesses were observed in the program group for respiratory diseases ( abstract background: herpes simplex virus (hsv) type 1 and 2 are important viral sexually transmitted diseases (sti) and can cause significant morbidity. in the netherlands, data about prevalences in the general population are hampered. objective: description of the seroprevalences of hsv-1 and hsv-2 and associated factors in the netherlands. design and methods: a population based serum bank survey in the netherlands with an age-stratified sample was used (1995) (1996) . antibodies against hsv-1 and hsv-2 were determined using elisa. a questionnaire was used to get information on demographics and risk factors. a logistic regression adjusting for age and full multiple regression were done to establish risk factors. results: questionnaires and sera were available for 7166 persons. both hsv-1 and hsv-2 seroprevalence increased with age. seroprevalence of hsv-1 was 59.5% and was amongst others associated with female sex and being divorced. seroprevalence of hsv-2 was 8.4% and was amongst others associated with being divorced and a history of sti. conclusion: seroprevalence is higher in certain groups like teenagers, women, divorced people and those with a history of sti. prevention should be focused on those groups. more research is needed on prevention methods, which can be used in the netherlands, like screening or vaccination. abstract background: frequently, statistically significant prognostic factors are reported with suggestions that patient management should be modified. however, the clinical relevance of such factors is rarely quantified. objectives: we evaluated the accuracy of predicting the need for invasive treatment among bph patients managed conservatively with alpha1-blockers. methods: information on eight prognostic factors was collected from 280 patients treated with alpha1-blockers. with phm regression coefficients a risk score for retreatment was calculated for each patient. the analyses were repeated on 1000 groups of 280 patients sampled from the original case series. these bootstrap results were compared to the original results. results: three significant predictors of retreatment were identified. the 20% of patients with the highest risk score had an 18-month risk of retreatment of only 20%. analyses of less than half of all the bootstrap samples resulted in the same three significant prognostic factors. the 20% of patients with the highest risk score in each of the 1000 samples experienced a highly variable risk of retreatment of 0% to 42%. conclusions: four of the five high risk patients would be overtreated with a modified policy. internal validation procedures may warn against the invalid translation of statistical significance into clinical relevance. background: e-cadherin expression is frequently lost in human epithelium derived cancers, including bladder cancer. for two genetic polymorphisms in the region of the e-cadherin gene (cdh1) promoter, a reduced transcription has been reported: a c/a single nucleotide polymorphism (snp) and a g/ga snp at 160 bp and 347 bp, respectively, upstream of the transcriptional start site. objective: we studied the association between both polymorphisms and the risk of bladder cancer. methods: 174 patients with bladder cancer and 326 population controls were genotyped for the )160 c/ a and the )347 g/ga promoter polymorphisms using pcr-rflp. results: a significantly increased risk for bladder cancer was found for a allele carriers compared to the homozygous c allele carriers (or 1.58; 95% ci: 1.06-2.35). the risk for the heterozygous and homozygous a allele carriers, was increased approximately 1.5 and 2-fold, respectively. the association was stronger for more aggressive tumors. we did not find any association between the )347 g/ga snp and bladder cancer. conclusion: this study indicates that the )160 c/a snp in the e-cadherin gene promoter is a low-penetrance susceptibility factor for bladder cancer. background: health problems, whether somatic, psychiatric or accident-related cluster within persons. the study of allostatic load as a unifying theme (salut) aims to identify risk factors that are shared by different pathologies and that could explain this clustering. studying patients with repetitive injuries might be helpful to identify risk factors that are shared by accident-related and other health problems. objectives: to study injury characteristics in repetitive injury (ri) patients as compared to single injury (si) patients. methods: the presented study included 196 ri patients and 558 si patients. medical records provided information about injury characteristics and patients were asked for possible causes and context. results: ri patients suffered significantly more from contusions than si patients (25% vs 16%). regarding the context, si patients were significantly more injured in traffic (28% vs 23%). in both groups most injuries were attributed to 'mere bad luck' (ri 44%, si 49%), closely followed by 'clumsiness or inattention' (ri 39%, si 44%). ri patients pointed out aggression or substance misuse significantly more often than si patients (17% vs 7%). conclusion: ri patients seem to have more 'at risk' behavior (i.e. aggression, impulsivity), which will increase their risk for psychiatric health problems. abstract background: breastfeeding may have a protective effect on infant eczema. bias as a result of methodological problems may explain the controversial scientific evidence. objective: we studied the association between duration of breastfeeding and eczema when taking into account the possible influence of reverse causation. design and methods: information on breastfeeding, determinants and outcomes at age one year was collected by repeated questionnaires in 2834 mother infant-pairs participating in the koala study (535 cases of eczema). to avoid reverse causation, a periodspecific-analysis was performed in which only 'at risk' infants were considered. results: no statistically significant association between the duration of breastfeeding (>12 weeks versus formula feeding) and the risk of eczema in the first year was found (or 2.07 95%ci 0.69-6.22). after excluding from the analysis all breastfed infants with symptoms of eczema reported in the same period as breastfeeding, also no statistical significant association was found for the duration of breastfeeding and eczema between 4 and 12 months (or 1.45 95%ci 0.34-6.25). conclusion and discussion: in conclusion, no evidence was found for a protective effect of breastfeeding duration on eczema. this conclusion was strengthened by risk period-specific-analysis which made the influence of reverse causation unlikely. abstract background: the internet can be used to meet health information needs, provide social support, and deliver health services. the anonymity of the internet offers benefits for people with mental health problems, who often feel stigmatized when seeking help from traditional sources. objectives: to identify the prevalence of internet use for physical and mental health information among the uk population. to investigate the relationship of internet use with current psychological status. to identify the relative importance of the internet as a source of mental health information. design and methods: self-completion questionnaire survey of a random sample of the uk population (n = 1800). questions included demographic characteristics, health status (general health questionnaire), and use of the internet and other information sources. results: 59% of internet users had sought health information online, and 18% had sought mental health information. use was higher among those with current psychological problems. only 12% of respondents identified the internet as one of the most accurate sources of mental health information, compared with 24% who identified it as one of the sources they would use. conclusions: health service providers must recognise the increasing use of the internet in healthcare, even though it is not always regarded as being accurate. abstract old age is a significant risk factor for falls. approximately 45% of people older than 80 are falling at least once a year, mostly in the own homes. resulting hip fractures cause at least partial immobility in 40-50% of the affected persons. almost 20% are sent to nursing homes afterwards. in mecklenburg-west pomerania, ageing of the population proceeds particularly fast. to prevent falls and the loss of independent living a falls prevention module was integrated in a community-bbased study conducted in cooperation with a general practitioner (gp). in the patients homes' a trained nurse performed a test to estimate the falls risk of each patient and a consultation how to reduce risk, e.g. eye sight check, gymnastic exercise. in the feasibility study 11 (55%) out of 20 patients (average age 74 years), agreed to a visiting of each room of their homes in search for tripping dangers. the evaluation was assisted by a standardized, computer-based documentation. the prevention module received a considerable acceptance despite the extensive home visiting. within one month the patients started to transfer advice into practice. during the first follow up visits of the nurse three patients reported e.g. to have started gymnastics and/or wear stable shoes. abstract background: the emergence of drug resistant m. tuberculosis (mtb) is an increasing problem in both developed and developing countries. objectives: investigation of isoniazid (inh) and rifampin (rif) susceptibility patterns among mtb isolates from patients. design and methods: in total 80 sputum samples were collected. smears were prepared for acid fast staining and all the isolates were identified as m. tuberculosis by preliminary cultural and biochemical tests. the isolates were examined for inh and rifampin resistance using conventional mic method and pcr technique by using specific inh (kat g) and rifampin (rpo b) resistant primers. results: seven isolates were resistant to both inh and rifampin by mic method. in pcr technique, 5 and 6 out of 7 above mentioned strains showed resistant to inh and rifampin respectively. coclusion: the epidemiology of drug resistance is 8.7% in region of study which is significant. discussion: conventional mic method despite being time consuming is more sensitive for evaluation of drug resistance, however, pcr as a rapid and sensitive technique is recommended additionally to conventional method for having quicker results to start treatment and disease control management. abstract background and objectives: we studied in literature which design characteristics of food frequency questionnaires (ffqs) influence their validity to assess both absolute and relative levels of energy intake in adults with western food habits, and to rank them according to these intakes. this information is required in harmonizing ffqs for multi centre studies. design and methods: we performed a review of studies investigating the validity or reproducibility of ffqs, published since 1980. the included studies validated ffqs against doubly labeled water (for energy expenditure) as a gold standard, or against food records or 24 hour recalls for assessing relative validity (for energy intake). the design characteristics we studied were the number of food items, the reference period, the administration mode, and inclusion of portion size questions. results: and conclusion: for this review we included 35 articles representing the validation of 37 questionnaires. three questionnaires were validated against dlw, ten against urinary n and 25 against 24-hour recalls or food records. in conclusion a positive linear relationship (r = 0.57, p<0.0001) was observed between the number of items on the ffq and the reported mean energy intake. details about the influence of other design characteristics on validity will be discussed at the conference. abstract background: high ethanol intake may increase the risk of lung cancer. objectives: to examine the association of ethanol intake with lung cancer in epic. design and methods: information on baseline and past alcohol consumption, lifetime tobacco smoking, diet, and anthropometrics of 478,590 participants was collected between 1992 and 2000. cox proportional hazard regression was used to examine the association of ethanol intake at recruitment (1119 cases) and mean lifelong ethanol intake (878 cases) with lung cancer. results: non-consumers at recruitment had a higher lung cancer risk than low consumers (0.1-4.9 g/day) [hr = 1.22, 95% ci 0.99-1.50]. lung cancer risk was lower for moderate ethanol intake at recruitment (5.0-14.9 g/day) compared with low intake (hr = 0.76, 95% ci 0.63-0.90); no association was seen for higher intake. compared with lifelong low consumers, lifelong non-consumers did not have a higher lung cancer risk (hr = 1.01, 95% ci 0.67, 1.50) but lifelong moderate consumers had a lower risk (hr = 0.80, 95% ci: 0.66-0.97). lung cancer risk tended to increase with increasing lifelong ethanol intake (=60 vs. 0.1-4.9 g/ day hr = 1.29, 95% ci: 0.93-1.74). conclusion: while lung cancer risk was lower for moderate compared with low ethanol intake in this study, high lifelong ethanol intake might increase the risk. abstract background: one of the hypotheses to explain the increasing prevalence of atopic diseases (eczema, allergy and asthma) is imbalance between dietary intake of omega-6 and omega-3 fatty acids. objectives: we evaluated the role of perinatal fatty acid (fa) supply from mother to child in the early development of atopy. design and methods: fa composition of breast milk was used as a marker of maternal fa intake and placental and lactational fa supply. breast milk was sampled 1 months postpartum from 312 mother-infant pairs in the koala birth cohort study, the netherlands. the infants were followed for atopic symptoms (repeated questionnaires on eczema and wheezing) and sensitisation at age 2 (specific serum ige against major allergens). multivariate logistic regression analysis was used to adjust for confounding factors. results: high levels of omega-3 long chain polyunsaturated fas were associated with lower incidence of eczema in the first year (odds ratio for the highest vs lowest quintile 0.31, 95% confidence interval 0.12-0.81; trend over quintiles p = 0.007). wheeze and sensitisation were not associated with breast milk fa composition. conclusion and discussion: the results support the omega-6/3 hypothesis. we suggest that anti-inflammatory activity of omega-3 eicosanoid mediators is involved but not allergic sensitisation. abstract background: acute myocardial infarction (ami) is among the main causes of death in italy and is characterized by high fatality associated with a fast course of the disease. consequently timeliness and appropriateness of the first treatment are paramount for a positive recovery. objectives: investigate the differences among italian regions of ami first treatment and in-hospital deaths. design and methods: following the theoretical care pathway (from onset of ami to hospitalization and recovery or death), regional in-hospital deaths are decomposed into the contributions of attack rate, hospitalization and in-hospital fatality. hospital discharges, death and population data are provided by the official statistics. results: generally in northern and central regions there is an excess of observed in-hospital deaths, while the opposite occurs in southern regions. conclusion: in northern and central regions the decomposition method suggests a more frequent and severe illness, generally accompanied by a higher availability of hospitals; exceptions are lombardia and lazio, where some inefficiencies in the hospital system are highlighted. in most southern regions the decomposition confirms a less frequent and less severe illness; exceptions are campania and sicilia, where only the less severe patients reach the hospital and then recover, while the others die before reaching the hospital. abstract background: atherosclerotic lesions have typical histological and histochemical compositions at different stages of their natural history. the more advanced atherosclerotic lesions contain calcification. objective: we examined the prevalence of and associations between calcification in the coronary arteries, aortic arch and carotid arteries assessed by multislice computed tomography (msct). methods: this study was part of the rotterdam study,a population-based study of subjects aged 55 years and over. calcification was measured and quantified in 600 subjects. correlation coefficients were computed using spearman's correlation coefficients. results: the prevalence of calcification increased with age throughout the vascular bed. in subjects aged 80 and over, up to 100% of men had calcification in the coronary arteries and up to 100% of women had calcification in the aortic arch. in men, the strongest correlation was found between calcification in the aortic arch and the carotid arteries (r=0.60, p<0.001). in women, the relations were somewhat lower, the strongest correlation was found between calcification in the coronary arteries and the carotid arteries (r = 0.47, p<0.001). conclusion and discussion: in conclusion, the prevalence of calcification was generally high and increased with increasing age. the study confirms the presence of strong correlations between atherosclerosis in different vessel beds. abstract background: health status deteriorates with age and can be affected by transition from active work to retirement. objective: to assess the effect of retirement on age related deterioration of health. methods: secondary analysis of the german health survey (bundesgesundheitssurvey 1998) and california health interview survey (chis 2003) . subjective health was assessed by a single question regarding respondent's health status from 1 = excellent to 5 = poor. locally weighted regression was used for exploratory analysis and b-splines for the effect estimation in regression models. results: subjective health decreased in an obviously non-linear manner with age. in both cases the decrease could be reasonably approximated by two linear segments, however the pattern was different in the german and california sample. in germany, the change point of the slope describing deterioration of health was located at 59. abstract objective: to assess the effectiveness of physiotherapy compared to general practitioners' care alone, in patients with acute sciatica. design, setting and patients: a randomised clinical trial in primary care with a 12-months follow-up period. 135 patients with acute sciatica (recruited 2003 -2004) were randomised in two groups: 1) intervention group received physiotherapy (active exercises), and 2) control group received general practitioners' care only. main outcome measures the primary outcome was patients' global perceived effect. secondary outcomes were severity of leg and back pain, severity of disability, general health and absence from work. the outcomes were measured at 3, 6, 12 and 52 weeks after randomisation. results: at 3 months follow-up, 70% of the intervention group and 62% of the control group reported improvement (rr 1.1; 95% ci 0.9 to 1.5). at 12 months follow-up, 79% of the intervention group and 56% of the control group reported improvement (rr 1.4; 95% ci 1.1; 1.8). no significant differences in secondary outcomes were found at short-term or long-term follow-up. conclusion: at 12 months follow-up, evidence was found that physiotherapy added to general practitioners' care is more effective in the treatment of patients with acute sciatica than general practitioners' care alone. abstract background: only little is known about the epidemiology of skin melanoma in the baltic states. objectives: the aim of this study was to provide insights into the epidemiology of skin melanoma in lithuania by analyzing population-based incidence and mortality (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002) time trends and relative survival based on 3485 skin melanoma. methods: we calculated age-standardized incidence and mortality rates (cases per 100,000) using the european standard population and calculated period estimates of relative survival. for the period 1993-2002, 76% of all registered cases were checked by reviews of the medical charts. results: about 97% of the 2013 cases of the period 1993-2002 were reported to the cancer registry indicating a high quality of cancer registration of skin melanoma in lithuania. the incidence rates increased from 1978 (men: 1.7, women: 2.3) to 2002 (men: 5.0, women: 7.0). mortality rates increased from 1990 (men: 1.2, women: 1.7) to 2002 (men: 2.3, women: 2.2). relative 5-year relative survival rates among men were 10% lower than among women. the overall difference in survival is mainly due to a more favorable survival among women aged 60-74 years. conclusions: overall prognosis is less favorable among men most likely due to diagnoses at later stages. abstract background: only little is known about the epidemiology of skin melanoma in the baltic states. objectives: the aim of this study was to provide insights into the epidemiology of skin melanoma in lithuania by analyzing population-based incidence and mortality (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002) time trends and relative survival based on 3485 skin melanoma. methods: we calculated age-standardized incidence and mortality rates (cases per 100,000) using the european standard population and calculated period estimates of relative survival. for the period 1993-2002, 76% of all registered cases were checked by reviews of the medical charts. results: about 97% of the 2013 cases of the period 1993-2002 were reported to the cancer registry indicating a high quality of cancer registration of skin melanoma in lithuania. the incidence rates increased from 1978 (men: 1.7, women: 2.3) to 2002 (men: 5.0, women: 7.0). mortality rates increased from 1990 (men: 1.2, women: 1.7) to 2002 (men: 2.3, women: 2.2). relative 5-year relative survival rates among men were 10% lower than among women. the overall difference in survival is mainly due to a more favorable survival among women aged 60-74 years. conclusions: overall prognosis is less favorable among men most likely due to diagnoses at later stages. abstract background: multifactorial diseases share many risk factors, genetic as well as environmental. to investigate the unresolved issues on etiology of and individual susceptibility to multifactorial diseases, the research focus must move from single determinantoutcome relations to modification of universal risk factors. objectives: the aim of the lifelines project is to study universal risk factors and their modifiers for multifactorial diseases. modifiers can be categorized into factors that determine the effect of the studied risk factor (eg gen-expression), those that determine the expression of the studied outcome (eg previous disease), and generic factors that determine the baseline risk for multifactorial diseases (eg age). design and methods: lifelines is carried out in a representative sample of 165.000 participants from the northern provinces of the netherlands. apart from questionnaires and clinical measurements, a biobank is constructed (blood, urine, dna). lifelines will employ a three-generation family design (proband design with relatives), which has statistical advantages, enables unique possibilities to study social characteristics, and offers practical benefits. conclusion: lifelines will contribute to the understanding of how disease-overriding risk factors are modified to influence the individual susceptibility to multifactorial diseases, not only at one stage of life but cumulatively over time: the lifeline. abstract background: obesity-related mortality is a major public health problem, but few studies have been conducted on severely obese individuals. objectives: we assessed long-term mortality in treatment-seeking, severely obese persons. design and methods: we enrolled 4837 persons in six centres for obesity treatment in four italian regions, with body mass index (bmi) at first visit => 40 kg/m2 and age => 18. after exclusion of duplicate registrations and persons with missing personal or clinical data, 4662 persons were followed up; as 164 (3.5%) could not be traced, 4498 persons (972 men, 3526 women) were retained for analysis. results: there were 484 (153 men, 331 women) deaths; the standardized mortality ratios (smrs) and 95% confidence intervals were 278 (236-326) among men and 210 (188-234) among women. mortality increased with increasing bmi, but the trend was not monotonic in men. lower smrs were observed among persons recruited more recently. excess mortality was inversely related to age attained at follow-up. conclusions and discussion: the harmful, long-term potential of severe obesity we documented confirms observations from studies carried out in different nutritional contexts. the decrease in mortality among most recently recruited persons may reflect better treatment of obesity and of its complications. abstract background: in finland, every cancer patient should have equal access to high quality care provided by the public sector. therefore no regional differences in survival should be observed. objectives: the aim of the study was to find any regional differences in survival, and to elaborate whether possible differences could be explained, e.g., by differences in distributions of prognostic factors. design and methods: the study material consisted of 159,000 patients diagnosed in 1993 to 2000 with cancer at one of the 15 major primary sites. the common closing date was 31 dec. 2001. finland was divided into five university hospital regions. stage, age at diagnosis and sex were used as prognostic factors. the relative survival rates for calendar period window, 1998-2001, were tabulated using period method and modelled. results: survival differences between the regions were not significant for most primary sites. for some sites, the differences disappeared in the modelling phase after adjusting for the prognostic factors. for a few of the primary sites (e.g., carcinoma of the ovary), regional differences remained after modelling. conclusion: we were able to highlight certain regional survival differences. ways to improve the equity of cancer care will be considered in collaboration with the oncological community. abstract background: the prevalence of cardiovascular disease (cvd) is extremely high in dialysis patients. disordered mineral metabolism, including hyperphosphatemia and hypercalcaemia, contributes to the development of cvd in these patients. objectives: to assess associations between plasma calcium, phosphorus and calciumphosphorus product levels and risk of cvd-related hospitalization in incident dialysis patients. design and methods: in necosad, a prospective multi-centre cohort study in the netherlands, we included 1629 consecutive patients new on haemodialysis or peritoneal dialysis between 1997 and 2004. risks were estimated using adjusted time-dependent cox regression modeling. results: mean age was 60±15 years, 61% was male, and 64% was treated with haemodialysis. cvd was the cause of hospitalization in 159 haemodialysis patients (26% of hospitalizations) and in 60 peritoneal dialysis patients (22%). most common cardiovascular morbidities were peripheral vascular disease and coronary artery disease in both patient groups. in haemodialysis patients risk of cvd-related hospitalization increased with elevated plasma calcium (hazard ratio: 1.8; 95% ci: 1.1 to 2.9) and calcium-phosphorus product levels (1.8; 95% ci: 1.2 to 2.7). in peritoneal dialysis patients, we observed similar effects that were not statistically significant. conclusion: tight control of plasma calcium and calcium-phosphorus product levels might prevent cvd-related hospitalizations in dialysis patients. abstract background: nurses are at health risk due to the nature of their work. analysis of morbidity among nurses was conducted to provide insight concerning the relationship between their occupational exposure and health response. methods: self reported medical history, was collected from an israeli female-nurses cohort (n = 395, 50+ years old) and their siblings (n = 180, age matched +/)7 years) using a structured questionnaire. to compare disease occurrence between the two groups we used chi-square tests and hazard ratio (hr) was calculated by cox-regression to account for age of onset. results: cardiovascular diseases were more frequent among the nurses compared to the controls: heart diseases 14.2% vs. 6.1, p = .0052 (hr=2.02, p = .0329); hypertension 43.8% vs. 23.3%, p<.0001 (hr=1.78, p = .0008). the frequency of hyperlipidemia was 40.3% among the nurses, and only 12.2% among the controls. (hr=3.31,p = .0001). for the following chronic diseases the occurrence were significantly higher among the nurses and the hrs were significantly higher than 1: thyroid, hr=2.21; liver, hr=10.37. total cancer and diabetes rates were similar in the groups (hr$1). conclusions: the results suggest an association between working as a nurse and the existence of risk factors for cardiovascular diseases. the specific related determinants of their work should be further evaluated. abstract background: early referral (er) to a nephrologist and arteriovenous fistulae as first vascular access (va) reduce negative outcomes in chronic dialysis patients (cdp). objectives: to evaluate the effect of nephrologist referral timing and type of the first va on mortality. design and methods: prospective cohort study of 2260 incident cdp notified to lazio dialysis registry (italy) in 2002-2004. late referral (lr) was a patient not referred to nephrologists within 6 months before starting dialysis. we dichotomized va as fistulae versus catheters. to estimate mortality hazard ratios (hr) a multivariate cox model was performed. results: we observed 22.3% lr subjects and 24.8% catheters as first va; proportion of catheters was 41.2% vs. 20.1% (p<0.001) for lr and er, respectively. we found a higher mortality hr for patient with a catheter as first va both for er (hr = 1.58; 95%c.i. = 1.22-2.06) and lr (hr = 2.56; 95%c.i. = 1.92-3.43); the interaction between referral and va was slight significant (p = 0.13). conclusions: the originality of our study was to investigate the influence of nephrologist referral timing and va on cdp mortality using a population registry, area-based: we found that a catheter as first va has an independent effect for mortality and modifies the effect of referral timing on this outcome. abstract patients with idiopathic venous thrombosis (vt) without known genetic risk factors but with a positive family history might carry yet unknown genetic defects. to determine the role of unknown hereditary factors in unexplained vt we calculated the risk associated with family history. in the multiple environmental and genetic assessment of risk factors for vt (mega) study, a large population-based case-control study, we collected blood samples and questionnaires on acquired risk factors (surgery, immobilisation, malignancy, pregnancy and hormone use) and family history of 2463 patients and 2926 control subjects. overall, positive family history was associated with an increased risk of vt (or (95% ci): 2.4 (2.0-2.9)), especially in the absence of acquired risk factors (or (95% ci): 2.8 (2.2-3.6) ). among participants without acquired factors but with a positive family history, prothrombotic defects (factor v leiden, prothrombin 20210a, protein c or protein s deficiency) were identified in 80 out of 236 (34%) patients compared to 22 out of 143 (15%) control subjects. after excluding participants with acquired or prothrombotic defects, family history persisted as a risk factor (or (95% ci): 2.4 (1.7-3.3)). in conclusion, a substantial fraction of thrombotic events is unexplained. family history remains an important predictor of vt. abstract background: alcohol may have a beneficial effect on coronary heart disease (chd) through elevation of high-density lipoprotein cholesterol (hdlc) or other alterations in blood lipids. data on alcohol consumption and blood lipids in coronary patients are scarce. objectives: to assess whether alcohol consumption and intake of specific types of beverages are associated with blood lipids in older subjects with chd. design and methods: blood lipids (total cholesterol, hdlc, ldl cholesterol, triglycerides) were measured in 1052 myocardial infarction patients aged 60-80 years (78% male), as part of the alpha omega trial. intake of alcoholic beverages, total ethanol and macro and micronutrients were assessed by food-frequency questionnaire. results: seventy percent of the subjects used lipidlowering medication. mean total cholesterol was 5.14 mmol/l and hdlc was 1.28 mmol/l. in men but not in women, ethanol intake was positively associated with hdlc (difference of 0.095 mmol/l for =15 g/d vs. 0 g/d, p = 0.022) after adjustment for diet, lifestyle, and chd risk factors. also, liquor consumption was weakly positively associated with hdlc in men (p = 0.042). conclusion and discussion: moderate alcohol consumption may elevate hdlc in (treated) myocardial infarction patients. this is probably due to ethanol and not to other beneficial substances in alcoholic beverages. session: posters session 3: july 1 2006 presentation: poster. abstract objective: early detection and diagnosis of silicosis among dust exposed workers is based mainly on the presence of rounded opacities on radiographs. it is thus important to examine how reliable the radiographic findings are in comparison to pathological findings. methods: a systematic literature search via medline was conducted. validity of silicosis detection and its influence on risk estimation in epidemiology was evaluated in a sensitivity analysis. results: 4 studies on comparison between radiographic and pathological findings of silicosis were identified. the sensitivity of radiographic diagnosis of silicosis (ilo 1/1) varied between 39% and 71%, and specifity between 60% and 99%. under the realistic assumption of silicosis prevalence between 2% and 8% in dust exposed workers, 23% to 56% of silicosis identified may be falsely diagnosed. the sensitivity analysis indicates that invalid diagnostics alone may lead to the finding of an increased risk of lung cancer among patients with silicosis. it may also lead to findings of 1% to 4% of radiographic silicosis even when there is no case of silicosis. however, the risk of silicosis could also be underestimated if the prevalence of silicosis exceeds 10%. conclusion: epidemiological studies based on patients with silicosis should be interpreted with caution. abstract introduction: epidemics of dengue occurring in various countries have stimulated investigators to seek innovative ways of improving current knowledge on the issue. objective: to identify the characteristics of spatial-temporal diffusion of the first dengue epidemic in a major brazilian city (salvador, bahia). methods: notified cases of dengue in salvador in 1995 were georeferenced according to census sector (cs) and by epidemiological week. kernel density estimation was used to identify the spatial diffusion pattern. results: of the 2006 cs in the city, cases of dengue were registered in 1400 (70%). spatial distribution showed that in 1995 practically the entire city had been affected by the virus, with a greater concentration of cases in the western region, comprising cs of high population density and predominantly horizontal dwellings. conclusion and discussion: the pattern found showed characteristics of a contagious diffusion process. it was possible to identify the epicenter of the epidemic from which propagation initiated. the speed of progression suggested that even if a rapid intervention was initiated to reduce the vector population, it would probably have little effect in reducing the incidence of the disease. this finding confirms the need for new studies to develop novel technology for prevention of this disease. abstract background: knowing the size of drug user hidden populations in a community is important to plan and evaluate public health interventions. objectives: the aim of this study was to estimate the prevalence of opiate and cocaine users in liguria region by using the covariate capture-recapture method applied to four data sources. methods: we performed a cross-sectional study in the resident population aged 15-54 years (780.995 people at 2001 census). during 2002 individual cases identified as opiate or cocaine primary users were flagged by four sources (drug dependence services, social service at prefectures, therapeutic communities, hospital discharges). poisson regression models were fitted, adjusting for dependence among sources and for heterogeneity in catchability among categories of the two examined covariates: age (15-29 and 30-54 years) and gender. results: the prevalence of opiate or cocaine users was 2,0% (95% c.i., 1,5 -2,8%) and 2,1% (95% c.i.= 0,6 -8,5%) respectively. conclusions: the estimated prevalence of opiate and cocaine users is consistent with that found in inner london: 1.6% and 1.9% respectively (hickman m.,2004; hope v.d., 2005) . the covariate capture-recapture method applied to four data sources allowed identifying a large cocaine-using population and resulted appropriate to determine drug user hidden populations. abstract background: in 2002-2004 we performed a population based diabetes screening programme. objectives: to investigate whether the yield of screening is influenced by gp and practice characteristics. methods: a questionnaire containing items on the gp (age, gender, employment, specialty in diabetes, applying insulin therapy) and the practice (setting, location, number of patients from ethnic minority groups, specific diabetes clinic, involvement of practice assistant and practice nurse in diabetes care, cooperation with a diabetes nurse) was sent to 106 general practitioners (gps) in 79 practices in the southwestern region of the netherlands. multiple linear regression analysis was performed. outcome measure was the ratio screen detected diabetic patients/known diabetic patients per practice (sdm/kdm). results: sdm/kdm was independently associated with higher age of the gp (regression coefficient 0.20; 95% confidence interval 0.07 to 0.34), urban location ()4.60; )6.41 to )2.78) and involvement of the practice assistant in diabetes care (2.27; 0.49 to 4.06) . conclusion: a lower yield of screening, assumably reflecting a lower prevalence of undiagnosed diabetes, was found in practices of younger gps and in urban practices. a lower yield was not associated with an appropriate practice organization nor with a specialty of the gp in diabetes. session: posters session 3: july 1 2006 presentation: poster. background: since few years increased incidence rates for childhood cancer were reported from industrialized countries. these findings were discussed controversial, because increases could be caused by changing of potential risk factors. objectives: the question is: are observed increasing rates due to actual changes in incidence rates or mainly caused by changes in registration practice or artefacts? methods: for europe, data from the accis project (pooled data from 32 european population-based cancer registries, performed at iarc, lyon; responsible: e. steliarova-foucher) (1978) (1979) (1980) (1981) (1982) (1983) (1984) (1985) (1986) (1987) (1988) (1989) (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) , and for germany, data of the german childhood cancer registry available from1980 onwards were used. results: accis data (based on 75,000 cases) show significantly increased data with an overall average annual percentage change of about 1 % and it is seen for mainly all diagnostic subgroups. for germany, increases are seen for neuroblastoma (due to screening programmes) and brain tumours (due to improved registration). for acute leukaemia the observed increase is explained by changes in classification. conclusion and discussion: the increased incidence for europe can only partly be explained by registration artefacts or improved diagnostic methods. the observed patterns suggest that an actual change exists. in germany, from 1980 till now the observed increased rates could be explained by artefacts. abstract suicide is the fourth most common cause of death among working age finns. among men socioeconomic status is strongly and inversely associated with suicide mortality, but little is known about socioeconomic differences in female suicide. we studied the direct and indirect effects of different socioeconomic indicators -education, occupation-based social class and income -on suicide among finnish women aged 25-64. also the effect of main economic activity was studied. we used individual level data from the 1990 census linked to the death register for the years 1991-2001. altogether over 14 million person-years were included and 2137 suicides were committed. age-adjusted rii conducted using poissonregression model was 1.72 (95% ci 1.47-2.03) for education, 1.97 (1.68-2.30) for social class and 2.13 (1.82-2.49) for income. however, almost all of the effect of education was mediated by social class. fifteen per cent of social class was explained by education and 40 per cent was mediated by income. the effect of income on suicide was mainly explained by economic activity. in conclusion, net of other indicators occupation-based social class is a strong determinant of socioeconomic differences in female suicide mortality, and actions aimed at preventing female suicide should target this group. abstract c-reactive protein levels (crp) in the range between 1 and 5 mg/ l independently predict the risk of future cardiovascular events. besides being a marker of atherosclerotic processes, high-normal crp levels may also be a sign of a more pronounced response to everyday inflammatory stimuli. the aim of our study is to assess the association between response to everyday stimuli and the risk of myocardial infarction. we will perform a population based case-control study including a total of 600 persons. cases (n = 100) are first myocardial infarction (mi) patients. controls (n = 100) are partners of the patients. offspring of the mi patients (n = 200) are included because disease activity and the use of medication by the mi patients may influence the inflammatory response. in order to assess the inflammatory response in mi patients the mean genetically determined inflammatory response in the offspring will be assessed and used as a measure for the inflammatory response in the mi patients. the offspring is free of disease and medication use. partners of the offspring (n = 200) are the controls for the offspring. influvac vaccine will be given to assess crp concentration, i.e. inflammatory response, before and after the vaccination. abstract background:. ischemic heart disease risk may be influenced by long-term exposure to electromagnetic fields (emf) in vulnerable subjects, but epidemiological data is inconsistent. objectives: we studied whether the long-term occupational exposure to emf is related to an increased myocardial infarction (mi) risk. design and methods: we conducted a prospective case-control study, which involved 1042 mi cases and 2341 controls. emf exposure in 48 cases and 63 controls was assessed subjectively. the effect of emf exposure on mi risk was estimated using multivariate logistic regression. results: after adjustment for age, smoking, blood pressure, body mass index and psychological stress the odds ratios for emf exposure <10 years was 2.74; 95 % ci 0.62-12.07, for emf exposure 10-20 years -2.08; 95 % ci 0.91-4.76 and for emf exposure >20 years -2.05; 95 % ci 1.24-3.39. conclusion: longterm occupational exposure to emf may increase the risk of mi. our crude estimates of emf exposure might have impact on excess risk because of nondifferential misclassification in assigning exposure. abstract background: it has been suggested that noise exposure is associated with ischemic heart disease risk, but epidemiological evidence is still limited. objectives: we studied whether road traffic noise exposure increases the risk of myocardial infarction (mi). design and methods: we conducted population-based prospective casecontrol study, which involved 1042 mi cases and 2341 controls. we measured traffic-related noise levels at the 117 electoral districts and linked these levels to residential addresses. we used multiple logistic regression to assess effect of noise exposure on mi risk. results: after adjustment for age, smoking, blood pressure, body mass index, and psychological stress the risk of mi was higher for the men exposed to 70-75 dba ( background: some studies have suggested that patients, depressed following acute myocardial infarction (mi), experience poorer survival. however, i) other studies show no significant association, when adjusted for recognized prognostic indicators and ii) some 'natural' responses to mi may be recorded in questionnaires as indicators of depression. method: depression was assessed in mi patients, by interview on two measures (gwb and sf36) 1-2 weeks after discharge, clinical data were abstracted from patients' medical records and vital status was assessed at 2-4 years. survivals of depressed, marginally depressed and normal patients were calculated by kaplan meier method and comparisons made by log rank and cox proportional hazard modelling. results: crude survival at 3 years in 2137 patients was higher for depressed and marginally depressed (13%) than for normals (10%), although not significantly. in multivariate analysis, four patient characteristics contributed significantly to survival: age (p<0.001), previous mi (<0.001), diabetes (<0.001) and sex (<0.05): other potential explanatory variables, including hypertension, infarct severity and depression were excluded by the model. abstract background: the low coronary heart disease (chd) incidence in southern europe could result in lower low density lipoprotein cholesterol oxidation (oxldl). objective. the aim of this study was to compare oxldl levels in chd patients from several european countries. methods: a cross-sectional multicenter study included 796 stable chd male subjects aged 25 to 74 years from northen (finland and sweden), central (germany), and southern europe (greece and spain). lipid peroxidation was determined by plasma oxldl. results: the score of adherence to mediterranean diet, antioxidant intake, alcohol intake, and lipid profile were significantly associated with oxldl. oxldl levels were higher in northern (60.9 u/l) than in centre (54.4 u/l) and southern populations (53.8 u/l), p = 0.01, in the adjusted models. the probability of northern europe to have the highest oxldl levels was 95.5%, and 98.9, % in logarithm of triglyceride-adjusted and fully adjusted models, respectively. the probability of this order to hold after adjustment for country was 78.4%. conclusion: a gradient on lipoperoxidation from north to central and southern europe is very likely to exist, and parallels that observed in the chd mortality, and incidence rates. southern populations may have more favourable environmental factors against oxidation than northern europe. abstract background: whereas socioeconomic status (ses) has been established as a risk factor for a range of adverse health outcomes, little literature exists examining socio-economic inequalities in the prevalence of congenital anomalies. objectives: to investigate the relationship between the ses and the risk of specific congenital anomalies, such as neural tube defects (ntd), oral clefts (oc) and down's syndrome (ds). design and methods: a total of 485 cases of congenital anomaly and 970 non-malformed control births were collected between 2002 and 2003 from the italian archive of the certificates of delivery care. as a measure of ses, cases and controls were given a value for a 4 level deprivation index. data were analysed using a logistic regression model. results: we found 31 cases of dtn, 287 cases of sof and 167 cases of ds. the risk of having a baby with ntd was significantly higher for women of low ses (or = 2.7;c.i.: 1.1-7. 3), as well as for oc (or = 1.7; c.i.:1.3-2.3). no significant evidence for ses variation was found for ds. conclusion and discussion: our data suggest risk factors linked to ses, such as nutritional factors, lifestyle, and access to health services, may play a role in the occurrence of some malformations. abstract background: general practitioners (gp) are well-regarded by their patients and have the opportunity to play an active role in providing cessation advice. objectives: this study was run to examine whether a public health programme based on a carefully adapted programme of continuing education can increase gps' use of cessation advice and increase the success rates of such advice. methods: the particular context due to a randomization of gp leads us to consider a cluster randomization trial. marginal models, estimated by gee and mixed generalized linear models are used for this type of design. results: the cessation rate is relatively high for all smokers enrolled in the trial (n = 1075): a total of 313 smokers were ex-smokers at one year (29.1%). patients who were seen by trained gps were more likely to successfully stop smoking than those seen by the control gps (31.3% vs 24.4%). motivated subjects, aged over 40, lower had anxiety scores, and confidence in their ability to stop smoking, were predictive of successful cessation at one year follow-up. conclusions: cluster analysis indicated that factors important to successful cessation in this population of smokers are factors commonly found to influence cessation. abstract background: and purpose conventional meta-analysis showed no difference in primary outcome for coronary bypass surgery without (offpump) or with (onpump) the heart-lung machine. secondary outcome parameters such as transfusion requirements or hospitalization days favored offpump surgery. combined individual data analysis improves precision of effect estimates and allows accurate subgroup analyses. objective: our objective is to obtain accurate effect estimates for stroke, myocardial infarction, or death, after offpump versus onpump surgery, by meta-analysis on pooled individual patient data. method and results: bibliographic database search identified eleven large trials (>100 patients). the obtained data for 9 trials data included 1933 patients. primary endpoint was composite (n = 117), secondary endpoints were death (n = 34), stroke (n = 24) and myocardial infarction (n = 75). hazard ratio for event-free survival after offpump vs onpump (95% ci) was: composite endpoint 0.94(0.66;1.36), death 1.12(0.57;2.20) myocardial infarction 1.07(0.68;1.69), stroke 0.84(0.38;1.88). after stratification for diabetes, gender and age the results slightly favored offpump for high-risk groups. hazard ratios remained not statistically significant. conclusion: no clinical or statistical significant differences were found for any endpoint or subgroup. offpump coronary bypass surgery is at least equal to conventional coronary bypass surgery. offpump surgery therefore is a justifiable option for cardiac surgeons for cardiac bypass surgery. in 1996-1997 an outbreak of pertussis occurred, mostly among vaccinated children. since then the incidence has remained high. therefore, a fifth dose with acellular booster vaccine for 4-yearolds was introduced in october 2001. the impact of this vaccination on the age-specific pertussis incidence was assessed. mandatory notifications and hospitalisations were analysed for 2002-2004 and compared with previous years. surveillance data show 'epidemic' increases of pertussis in 1996, 1999, 2001 and 2004 . the total incidence/100,000 in 2004 (59.8) was higher than in the previous epidemic year 2001 (50.0). nevertheless, the incidence of notifications and hospitalisations in the age-groups targeted for the booster-vaccination had decreased with respectively 72% and 86% compared to 2001. in contrast, the incidence in adolescents and adults almost doubled. unlike other countries that introduced a pre-school booster, the incidence of hospitalised infants <6 months also decreased (31% compared with 2001). as expected, the booster-vaccination for 4-year-olds has decreased the incidence among the target-population itself. more importantly, the decreased incidence among infants <6 months suggests that transmission from siblings to infants has also decreased. in further exploration of the impact of additional vaccination strategies (such as boostering of adolescents and/or adults) this effect should not be ignored. abstract acute respiratory infections (ari) are responsible for considerable morbidity in the community, but little is known about the presence of respiratory pathogens in asymptomatic individuals. we hypothesized that asymptomatic persons could have a sub clinical infection and so act as a source of transmission. between 2000 and 2003 all patients with ari who visited their sentinel general practitioner were reported to estimate the incidence of ari in dutch general practices. a random selection of them (cases) and an equal number of asymptomatic persons visiting for other complaints (controls) were included in a case-control study. nose/ throat swabs of participants were tested for a broad range of pathogens. the overall incidence of ari was 545 per 10,000 person years, suggesting that in the dutch population an estimated 900,000 persons annually consult their general practitioner for respiratory complaints. viruses were detected in 58% of the cases, ?-haemolytic streptococci group a in 11% and mixed infections in 3%. besides, pathogens were detected in approximately 30% of controls, particularly in the youngest age groups. this study confirms that most ari are viral and supports the reserved policy of prescribing antibiotics. furthermore, we demonstrated that asymptomatic persons might be a neglected source of transmission. abstract background: the baking and flour producing industries in the netherlands agreed on developing a health surveillance system to reduce the burden of and improve prognosis of occupational allergic diseases. objectives: to develop and validate a diagnostic model for sensitization to wheat and fungal amylase allergens, as triage instrument to detect occupational allergic diseases. design and methods: a diagnostic regression model was developed in 391 bakers from a cross-sectional study with ige serology to wheat and or amylase allergens as the reference standard. model calibration was assessed with hoshmer-lemeshow goodness of fit test; discriminative ability using area under receiver operating characteristic curve (auc); and internal validity using bootstrapping procedure. external validation was conducted in 200 other bakers. results: the diagnostic model consisted of four questionnaire items (history of asthma, rhinitis, conjunctivitis, and work-related allergic symptom) showed good calibration (p = 0.7) and discriminative ability (auc 0.73; 95% ci 0.67 to 0.79). internal validity was reasonable (correction factor of 0.85 and optimism corrected auc of 0.70). external validation showed good calibration (p = 0.9) and discriminative ability (auc 0.73; 95% ci 0.63 to 0.83). conclusions and discussion: this easily applicable diagnostic model for sensitization to flour and enzymes shows reasonable diagnostic accuracy and external validation. abstract background: in the netherlands the baking and flour producing industries (3,000 small bakeries, 80 industrial bakeries, and 50 flour manufactures) agreed to reduce the high rate (up to 30%) of occupational related allergic diseases. objectives: to conduct health surveillance for early detection of occupational allergic diseases by implementing a diagnostic model as triage instrument. design and methods: in the preparation phase, a validated diagnostic regression model for sensitization to wheat and or a-amylase allergens was converted into score chart for use in occupational health practice. two cut off points of the sum scores were selected based on diagnostic accuracy properties. in the first phase, a questionnaire including the diagnostic predictors from the model was applied in 10.000 bakers. surveillance simulation was done in 4194 bakers recently enrolled in the surveillance. workers with high questionnaire scores were referred for advanced medical examination. results: implementing the diagnostic questionnaire model yielded 59%, 23%, and 18% bakers in the low, intermediate, and high score groups. workers with high scores showed the highest percentage of occupational allergic diseases. conclusions and discussion: with proper cut off points for referral, the diagnostic model could serve as triage instrument in health surveillance to early detect occupational allergic diseases. abstract background: the prevalence of cardiovascular risk factors in spain is high but myocardial infarction incidence is lower than in other countries. objective: to determine the role of basic lipid profile on coronary heart disease (chd) incidence in spain. methods: a cohort of 5,732 healthy spanish individuals aged 35 to 74 years was followed for 5 years. the end-points were fatal and non-fatal myocardial infarction, and angina. results: the 180 participants who developed a coronary end-point were significantly older (62 vs 56), more often diabetic (30% vs 16%), smoker (39% vs 24%) and hypertensive (65% vs 44%) than the rest, and their average total and hdl-cholesterols (mg/dl) were: 233 vs 232 (ns) and 47 vs 54, (p<0.001), respectively. chd incidence among individuals with low hdl levels (<40 in men/<46 in women) was higher than in the rest: 11.7&aeyear-1 vs 7.3&aeyear-1 (p<0.05) in men, and 8.8&aeyear-1 vs 3.2&aeyear-1 (p<0.001) in women. hdl-cholesterol was the only lipid related variable significantly associated with chd: hazard ratio for 1 mg/dl increase was 0.98 (95% ci:0.96-0.99) in men, and 0.96 (95% ci:0.93-0.98) in women, after adjusting for classical risk factors. conclusion: hdl-cholesterol is the only classical lipid variable associated with chd incidence in spain. abstract background: it is widely recognized that health service interventions may reduce infant mortality/imr rate which usually occurs alongside with economic growth. however, there are reports showing that imr decrease under adverse economic and social conditions, indicating the presence of other unknown determinants. objective: this study aims to analyze temporal tendency of infant mortality in brazil during a recent period (1980 to 1998) of economic crisis. methods: temporal series study using data from the mortality information system, censuses (ibge) and epidemiological information (funasa). applying arima -autoregressive integrated moving average, it was described series parameters and, spearman correlation coefficients were used to evaluate the association between infant mortality coefficient and some determinants. results: the infant mortality showed a declining tendency ()59.3%) and strong correlation to the majority of the indicators analyzed. however, only correlation between infant mortality coefficient and total fecundity and birth rates differed significantly within decades. conclusions/discussion: fecundity variation was responsible to the persistence of mortality decline during the eighties. in the next period those indicators of life conditions, mostly health care, could be more important. abstract background: across european union (eu) member states, considerable variation exists in the structure and performance of surveillance systems for communicable disease prevention and control. objectives: the study aims to support the improvement of surveillance systems of communicable diseases in europe while using benchmarking for the comparison of national surveillance systems. design and methods: surveillance systems from england & wales, finland, france, germany, hungary and the netherlands were described and analysed. benchmarking processes were performed with selected criteria (e.g. case definitions, early warning systems). after the description of benchmarks, best practices were identified and described. results: the six countries have in general wellfunctioning communicable disease control and prevention systems. nevertheless, different strengths and weaknesses in could be identified. practical examples for best practice from various surveillance systems demonstrated fields for improvement. conclusion and discussion: benchmarking national surveillance systems is applicable as a new tool for the comparison of communicable disease control in europe. a gold standard of surveillance systems in various countries is very difficult to achieve because of heterogeneity (e.g. in disease burden, personal and financial resources). however, to improve the quality of surveillance systems across europe, it will be useful to benchmark surveillance systems of all eu member states. abstract background: therapeutic decisions in osteoarthritis (oa) often involve trade-offs between accepting risks of side effects and gaining pain relief. data about the risk levels patients are willing to accept are limited. objectives: to determine patients' maximum acceptable risk levels (marls) for different adverse effects from typical oa medications and to identify the predictors of these risk attitudes. design and methods: marls were measured with a probabilistic threshold technique for different levels of pain relief. baseline pain and risk levels were controlled for in a 2x2 factorial design. clinical and sociodemographic characteristics were assessed using a selfadministered questionnaire. results: for 196 subjects, marls distributions were skewed, and varied by level of pain relief, type of adverse effect, and baseline risk level. given a 0% baseline risk, for a 2-point (0-10 scale) pain benefit the mean (median) marls were 3.0% (0%) for heart attack/stroke; 5.7% (0%) for stomach bleed; 13.4% (4.5%) for hypertension; and 23.4% (10.5%) for dyspepsia. most clinical and sociodemographic factors were not associated with marls. conclusion: subjects were willing to trade substantial risks of side effects for pain benefits. this study provides new data on risk acceptability in oa patients that could be incorporated into practice guidelines for physicians. background: several independent studies have shown that single genetic determinants of platelet aggregation are associated with increased ihd risk. objectives: to study the effects of clustering prothombotic (genetic) determinants on the prediction of ihd risk. design and methods: the study is based on a cohort of 17,357 women, aged 49 to 70 years, who were followed from 1993 to 1999. during this period, there were 200 women with registered ihd (icd9 410-414) . a nested case cohort analysis was performed to study the relation of plasma levels vwf and fibrinogen, blood group genotype and prothrombotic mutations in the gene of a2b1, gpvi, gpib and aiibb3 to ihd. results: blood group ab, high vwf concentrations and high fibrinogen concentrations were associated with increased incidence of acute ihd. when the effects of blood group ab/o genotype, plasma levels fibrinogen and vwf were clustered with a score, there was a convincing relationship between a high prothrombotic score and increased incidence of acute ihd: the full-adjusted hr (95% confidence interval) was 3.2 (1.4-6.7) for women with the highest score when the lowest score was taken as reference. conclusions: clustering of prothrombotic markers is a major determinant of increased incidence of acute ihd. abstract background: studies have revealed heart rate variability (hrv) was a predictor of hypertension; however its 24h-recording has not been analysed with the 24-hour ambulatory blood pressure. objective: we studied the relationship between hrv and blood pressure. methods: hrv and blood pressure were measured by 24-hour ambulatory recordings, in randomly selected population without evidence of heart disease. cross-sectional analyses were conducted in 571 women and 372 men (mean age: 65.64±0.79). hrv values, measured by the standard deviation of rr intervals (sdnn), were compared after logarithmic transformation between the blood pressure levels (135/85 mmhg), using analysis of variance. stepwise multiple-regression was performed to assess on sdnn the cumulative effects of systolic and diastolic blood pressure, clinical obesity, fasting glycaemia, c-reative protein, treatments, smoking and alcohol consumption. results: sdnn was lower in hypertensive men and women (p<0.05), independently of drug treatments. after adjustment for factors associated with hypertension, sdnn was no more associated with hypertension, but with obesity, glycaemia and c-reative protein in both genders. sdnn was negatively associated with diastolic blood pressure in men (p = 0.03) in the multivariate approach. conclusion: whereas blood pressure levels were not related to the sdnn in the multivariate analysis, diastolic blood pressure contributed to sdnn in men. it has been proposed that n-3 fatty acids may protect against the development of allergic disease, while n-6 fatty acids may promote its development. in the piama (prevention and incidence of asthma and mite allergy) study we investigated associations between breast milk fatty acid composition of 158 allergic and 107 non allergic mothers and allergic disease (doctor diagnosed asthma, eczema or hay fever) in their children at the age of 1 year and at the age of 4 years. in children of allergic mothers prevalences of allergic disease at age 1 and at age 4 were relatively high if the breast milk they consumed had a low content (wt%) of n-3 fatty acids and particularly of n-3 long chain polyunsaturates (lcps), a low content of trans fatty acids, or a low ratio of n-3lcps/n-6lcps. the strongest predictor of allergic disease was a low breast milk n-3lcps/n-6lcps ratio (odds ratios (95% ci) of lowest vs highest tertile, adjusted for maternal age, parity and education: 2.80 (1.07 to 7.28) for allergic disease at age 1 and 2.86 (1.09 to 7.52) for allergic disease at age 4). in children of non allergic mothers no statistically significant associations were observed. abstract background/relevance: to find out about the appropriateness of using two vision related quality of life instruments to measure outcome of visually impaired elderly in a mono-and multidisciplinary rehabilitation centre. objective/design: to evaluate sensitivity of the vision quality of life core measure (vcm1) and the low vision quality of life questionnaire (lvqol) to measure changes in vision related quality of life in a non-randomised followup study. methods: visually impaired patients (n=319) recruited from 4 ophthalmology departments administered questionnaires at baseline (2000) (2001) (2002) (2003) , 3 months and 1 year after rehabilitation. person measures were analysed using rasch analyses for polytomous rating scales. results: paired sample t-tests for the vcm1 showed improvement at 3 months (p = 0.02; effect size = 0.12 and p = 0.003; effect size=0.15) for the monodisciplinary and the multidisciplinary groups respectively. at 1 year only the multidisciplinary group showed improvement on the vcm1 (p = 0.03; effect size = 0.12). on the lvqol, no significant improvement or deterioration was found for both groups. discussion: although, vcm1 showed improvement in vision related quality of life over time, the effect sizes appeared to be quite small. we conclude that both instruments lack sensitivity to measure changes. another explanation is that rehabilitation did not contribute to quality of life improvements. abstract background: the natural history of asthma severity is poorly known. objective: to investigate prognostic factors of asthma severity. methods: all current asthmatics identified in 1991/93 in the european community respiratory health survey were followed up and their severity was assessed in 2002 by using the global initiative for asthma categorization (n = 856). asthma severity was related to baseline/follow-up potential determinants by a multinomial logistic model, using intermittent asthmatics as reference category for relative risk ratios (rrr). results: patients in the lowest/highest levels of severity at baseline had an 80% likelihood of remaining in a similar level. severe persistent had a poorer fev1%predicted at baseline, higher ige levels (rrr=2.06;95% ci:1.38-3.06), higher prevalence of chronic cough/phlegm (4.90;2.18-11.02) than intermittent asthmatics. moderate persistent showed similar associations. mild persistent were similar to intermittent asthmatics, although the former showed a poorer control of symptoms than the latter. subjects in remission had a lower probability of an increase in bmi than current asthmatics (0.86;0.75-0.97). allergic rhinitis, smoking, respiratory infections in childhood were not associated with severity. conclusion: asthma severity is a relatively stable condition, at least for patients at the two extremes of the severity spectrum. high ige levels and persistent cough/phlegm are strong markers of moderate/severe asthma. abstract background: thyroid cancer (tc) has a low, yet growing, incidence in spain. ionizing radiation is the only well established risk factor. objectives: this study sought to depict the municipal distribution of tc mortality in spain and to argue about possible risk factors. design and methods: posterior distribution of relative risk for tc was computed using a single bayesian spatial model covering all municipal areas of spain (8, 077) . maps were plotted depicting standardised mortality ratios, smoothed municipal relative risk (rr) using the besag, york and mollie`model, and the distribution of the posterior probability that rr>1. results: from 1989 to 1998 a total of 2,538 tc deaths were registered in 1,041 municipalities. there was a higher risk of death in some areas of canary islands, galicia and asturias. abstract igf-i is an important growth factor associated with increased breast cancer risk in epidemiological and experimental studies. lycopene intake has been associated with decreased cancer risk. although some data indicate that lycopene can influence the igfsystem, this has never been extensively tested in humans. the purpose of this study is to evaluate the effects of a lycopene intervention on the circulating igf-system in women with an increased risk of breast cancer. we conducted a randomized, placebo-controlled cross-over intervention study on the effects of lycopene supplementation (30 mg/day, 2 months) in pre-menopausal women with 1) history of breast cancer (n = 29) and 2) high familial breast cancer risk (n = 47). drop-out rate was 21%. mean igf-i and igfbp-3 concentrations after placebo were 175.8±51.2 ng/ml and 2.54±0.42 mg/ml respectively. lycopene supplementation did not significantly alter serum total igf-i (mean lycopene effect: )1.4 ng/ml; 95% ci: )8. 2-5.4 ) and igfbp-3 ()0.002 mg/ml; )0.052-0.056) concentrations. dietary energy and macronutrient intake, physical activity, body weight, and serum lycopene concentrations were assessed, and are currently under evaluation. in conclusion, this study shows that 2 months lycopene supplementation has no effect on serum igf-system components in a high risk population for breast cancer. abstract introduction: patients who experience burden during diagnostic tests may disrupt these tests. the aim was to describe the perception of melanoma patients with lymph node metastases of the diagnostic tests. methods: patients were requested to complete a self-administrated questionnaire. experienced levels of embarrassment, discomfort and anxiety were calculated, as well as (total) scores for each burden. the non-parametric friedman test for related samples was used to see if there was a difference in burden. results: the questionnaire was completed by 34 patients; response rate was 87%. overall satisfaction was high. in total 26% felt embarrassment, 27% discomfort and 39% anxiety. overall, 31% felt some kind of burden. there was no difference in anxiety between the three tests. however, patients experienced more embarrassment and discomfort during the pet (positron emission tomography) scan (p = 0.027 and p = 0.002). conclusion: overall levels of burden were low. however, patients experienced more embarrassment and discomfort during the pet scan, possibly as a result of lying immobile for a long time. the accuracy, costs and patients upstaged will probably be the most important to determine the additional value of fdg-pet and ct, but it is reassuring to know that only few patients experience severe or extreme burden. abstract gastric cancer (gc) is the second most frequent cause of cancer death in lithuania. some intercultural aspects of diet that is related to the outcome could be the risk factors of the disease. the objective of the study was to assess an associations between risk of gc and dietary factors. a case-control study included 379 cases with diagnose of gc and 1137 controls that were cancer and gastric diseases free. a questionnaire used to collect information on possible risk factors. the odds ratios (or) and 95% confidence intervals (ci) estimated by the conditional logistic regression model. after controlling for possible confounders that were associated with gc, use of salted meat (or = 2.21; 95% ci = 1.43-3.42; >1-2 times/week vs. almost never) smoked meat (or = 1.79; 95% ci = 1.23-2.60; >1-4 times/week vs. less), smoked fish (or = 1.70; 95% ci = 1.13-2.53; >1-2 times/week vs. less) was associated with increased risk of gc. higher risk of gc was associated with frequent use of butter, eggs and noodles. while frequent consumption of carrots, cabbages, broccolis, tomatoes, garlic, beans decreased the risk significantly. the data support a role of salt processed food and some animal foods in increasing the risk of gc and plant foods in reducing the risk of the disease. abstract background: standards for the evaluation of measurement properties of health status measurement instruments (hsmi), including explicit criteria for what constitutes good measurement properties, are lacking. nevertheless, many systematic reviews have been performed to compare and select hsmi, using different criteria to judge the measurement properties. objectives: (1) to determine which measurement properties are reported in systematic reviews of hsmi and how these properties are defined, (2) which standards are used to define how measurement properties should be assessed, and (3) which criteria are defined for good measurement properties. methods: a systematic literature search was performed in pubmed, embase and psychlit. articles were included if they met the following inclusion criteria: (1) systematic review, (2) hsmi were reviewed, and (3) the purpose of the review is to identify all measurement instruments assessing (an aspect of) health status and to report on the clinimetric properties of these hsmi. two independent reviewers selected the articles. a standardised data-extraction form was used. preliminary results: 103 systematic reviews were included. conclusions: large variability in standards and criteria used for evaluating measurement properties was found. this review can serve as basis for reaching consensus on standards and criteria for evaluating measurement properties of hsmi. abstract residential exposure to nitrogen dioxide is an air quality indicator and could be very useful to assess the effects of air pollution on respiratory diseases. the present study aims at developing a model to predict residential exposure to no2, combining data from questionnaires and from local monitoring stations (ms). in the italian centres of verona, torino and pavia, participating in ecrhs-ii, no2 concentrations were measured using passive samplers (ps-no2) placed outside the kitchen of 340 subjects for 14 days. simultaneously, average no2 concentrations were collected from all the mss of the three centres (ms-no2). a multiple regression model was set up with ps-no2 concentrations as response variable and questionnaire information and ms-no2 concentrations as predictors. the model minimizing the root mean square error (rmse), obtained from a ten fold cross validation, was selected. the model with the best predictive ability (rmse=12.20), had as predictors: ms-no2 concentrations, season of the survey, centre, type of building, self-reported intensity of heavy vehicle traffic. the correlation coefficient between predictive and observed values was 0.79 (95% ci: 0.75-0.83). in conclusion, this preliminary analysis suggests that the combination of questionnaire information and routine data from the mss could be useful to predict the residential exposure to no2. abstract background: currently only 18% of dutch mothers comply with the who recommendation to give exclusive breastfeeding for at least six months. therefore, the dutch authorities consider policies on breastfeeding. objectives: quantification of the health effect of several breastfeeding policies. methods: a systematic literature search of published epidemiological studies conducted in the general 'western' population. based on this overview a model is developed. the model simulates incidences of 11 diseases of mother and child depending on the duration that mothers breastfeed. each policy corresponds to a distribution in the duration of breastfeeding. the health effects of each policy are compared to the present situation. results: breastfeeding has beneficial health effects on both the short and the long term for mother and child. the longer the duration of breastfeeding, the larger is the effect. most public health gain is achieved by introducing breastfeeding to all newborns rather than through a policy focusing just on extending the lactation period of women already breastfeeding. conclusion: breastfeeding has positive health effects. policy should focus preferentially on encouraging all mothers to start with breastfeeding. abstract background: constant increase of international trade and travel activities has risen the significance of pandemic infectious diseases worldwide. the 2002/2003 sars outbreak rapidly spread from china to 28 countries, from which 9 were located in europe. in order to control and prevent pandemic infections in europe, systematic and effective public health preparation by every member state is essential. method: supported by the european commission, surveys focusing on national sars (september 2003) and influenza (october 2005) preparedness were accomplished. a descriptive analysis was undertaken to identify differences in european infectious disease policies. results: guidelines and guidance for disease management were well established in most european countries. however, the application of control measures, like e.g. measures for mass gatherings or public information policies, had varied among member states. discussion: the results show that european countries are aware of preparing for pandemic infections. yet, the effectiveness of certain control measures is analysed insufficiently. further research and detailed knowledge about factors influencing international spread of diseases is required. 'hazard analysis of critical control points' (haccp) will be applied to evaluate national health response in order to provide comprehensive data for recommendations to european pandemic preparedness. abstract background: influenza is still an important problem for public health. knowing its space-time evolution is of special interest in order to carry out prevention plans. objectives: to analyze the geographical diffusion of the epidemic wave in extremadura. methods: the influenza incidence absolute rates in every town have been calculated, according to the registered cases per week in the compulsory disease declaration system. continuous maps have been represented using a geographical interpolation method (inverse distance weighting (idw) was applied with weighting exponents of 2). results: the 2004/05 season began in the 40th week of 2004, with a small influenza incidence. there have been concrete cases in those towns until the 46th week. punctual areas diffusion in the north and southwest of the region between the 46th and the 51st weeks. the highest incidence appeared between the 52nd week of 2004 and the 3rd of 2005. influenza cases started to decrease in the northwest and north of the region from the 3rd week of 2005, till the 10th week, when most of the cases were found in the southwest. conclusion: there is a space-time diffusion of influenza, due to the higher population density. we propose to analyze these data combining temperature information. abstract background: acute lower respiratory tract infection (lrti) can cause various complications leading to morbidity and mortality notably among elderly patients. antibiotics are often given to prevent complications. to minimise costs and bacterial resistance, antibiotics are only recommended in case of pneumonia or in patients at serious risk for serious complications. objective: we assessed the course of illness of lrtis among dutch elderly primary care patients and assessed whether gps were inclined to prescribe antibiotics more readily to patients at risk for complications. methods: we retrospectively analysed medical data from 3,166 episodes of lrti among patients? 65 years of age presenting in primary care to describe the course of illness. the relation between prescriptions of antibiotics and patients with risk factors for a complicated course was assessed by means of multivariate logistic regression. results: in episodes of acute bronchitis antibiotics were more readily prescribed to patients aged 90 years or older. in exacerbations of copd or asthma gps favoured antibiotics in male patients and when diabetes, neurological disease or dementia was present. conclusion: gp's do not take all high risk conditions into account when prescribing antibiotics to patients with lrti despite recommendations of national guidelines. abstract background: the putative association between antidepressant treatment and increased suicidal behaviour has been under debate. objectives: to estimate the risk of suicide, attempted suicide, and overall mortality during antidepressant treatments. design and methods: study cohort consisted all subjects without non-affective psychosis, hospitalized due to a suicide attempt during the years 1997 -2003 , followed up by using nationwide registers. main outcome were completed suicides, attempted suicides, and mortality. main explanatory variable was antidepressant usage. results: 470 suicides, 4411 suicide attempts and 1263 deaths were observed. when the effect of background variables was taken into account, the risk of suicide attempts was increased markedly during antidepressant treatment (rr for selective serotonin reuptake inhibitors or ssri 1.34, 1.19-1.50) compared with no antidepressants. however, the risk of completed suicides was not increased. a lower mortality was observed during ssri use (rr 0.67, 0.54-0.84), which was mainly attributable to decrease in cardiovascular deaths. conclusion and discussion: in this suicidal high risk cohort the use of any antidepressant is associated with an increased risk of suicide attempts, but not with the increased risk of completed suicide. antidepressants and, especially, ssri use is associated with a substantial decrease in cardiovascular deaths and overall mortality. abstract background: the quattro study is a rct on the effectiveness of intensified preventive care in primary health care centres in deprived neighbourhoods. additional qualitative research on the execution of interventions in primary care was considered necessary for the explanation of differences in effectiveness. objectives: our question was: can we understand rct outcomes better with qualitative research? design and methods: an ethnographic design was used. in their daily work we observed 2 researchers for 8 months 2 days a week, and 4 practice nurses for 5 days each. two other practice nurses were interviewed. all transcribed observations were analysed thematically. results: from the rct showed differences in effectiveness among the centres and that intensified preventive care provided no additional effect compared to structural physical measurements. ethnographic results show that these differences are due to variations in execution of the intervention among the centres. conclusion: in conclusion ethnographic analysis showed that differences in execution of intervention lead to differences in rct outcomes. the rct conclusion 'no additional effect' is problematic. discussion as variations in primary care influence a rcts' execution they create methodological problems for research. to what extent can additional qualitative research improve rct research. abstract background: acute myocardial infarction is the most important cause of morbidity from ischemic heart disease (ihd) and is the leading cause of death in the western world. objectives: to assess the benefits and harms of 'dan shen' compound for acute myocardial infarction. methods: we searched the cochrane controlled trials register on the cochrane library, medline, embase, chinese biomedical database and the chinese cochrane centre controlled trials register. we included randomized controlled studies lasting at least 7 days. main results: eleven studies with 1196 participants in total were included. seven studies compared the mortality in routine treatment plus 'dan shen' compound and single routine treatment. one trial compared the arrhythmia in routine treatment plus 'dan shen' compound injection and single routine treatment. two trials compared the revascularization in routine treatment plus 'dan shen' compound injection and single routine treatment. conclusions: evidence is insufficient to recommend the routine use of 'dan shen' compound because of the small number of included studies and their low quality. no well designed randomized controlled trials with adequate power to provide a more definitive answer have been conducted. in addition, the safety of 'dan shen' compound is unproven, though adverse events were rarely reported. abstract antimicrobial resistance is emerging. to identify the scope of this threat and to be able to take proper actions and evaluate these, monitoring is essential. the remit of earss is to maintain a comprehensive surveillance system that provides comparable and validated data on the prevalence and spread of major invasive bacteria with clinically and epidemiologically relevant antimicrobial resistance in europe. since 2000, earss collects routine antimicrobial susceptibility test (ast) results of invasive isolates of five indicator bacteria, tested according to standard protocols. in 2004, ast results for 80,000 isolates were provided by 800 laboratories, serving 1200 hospitals, covering 100 million inhabitants in 30 countries. through a biannual questionnaire denominator information was collected. the quality of ast results of laboratories was evaluated by the yearly external quality assessment. currently, earss includes all member and candidate states (29) of the european union, plus israel, bosnia, bulgaria and turkey. participating hospitals treat a wide range of patients and laboratory results are of sufficient validity. earss identified antimicrobial resistance time trends and found a steady increase for most pathogen-compound combinations. in conclusion, earss is a comprehensive system with sufficient quality to show that antimicrobial resistance is increasing in europe and threatens health-care outcomes. abstract introduction: since chloroform has been detected in drinking waters, the number of studies has increased to identify the presence of trihalomethanes (thms) in drinking waters, as well as to establish the possible effects they may have population health. objectives: to determine thms levels in the water distributing network in the city of valencia. design and methods: over a one-year period, 16 points of the drinking water distributing netowrk have undergone sampling at 1 week intervals. the concentration of these pollutants was determined by gas chromatography. results: our results showed greater concentrations of the species substituted by chlorine and bromine atoms (dichlorobromomethane and dibromochloromethane) in the range of 10-20z lg/l for both, 0-10 lg/l for trichloromethane and between 0-5 lg/l for tribromomethane. an increase in thms concentration was observed in those points near the sea, although they did not exceed the legal limit of 100lg/l. conclusion: we established two areas of concentration of these species in water: high and average, according to their proximity to the sea. abstract background: childhood cancer survivors are known to be at increased risk for second malignancies. objectives: we studied longterm risk of second malignancy in 5-year survivors, according to therapy and follow-up interval. methods: the risk of second malignancies was assessed in 1368 5-year survivors of childhood cancer treated in the emma children's hospital amc in amsterdam and compared with incidence in the general population of the netherlands. complete follow-up till at least january 2001 was obtained for 91.9% of the patients. the median follow-up time was 16.8. results: sixty second malignancies were observed against 5.4 expected, yielding a standardized incidence ratio (sir) of ). the absolute excess risk (aer) was 3.2 per 1,000 persons per year. the sir appeared to stabilize after 15 years of follow-up, but the absolute excess risk increased with longer follow-up (aer follow-up > = 25 years of 8.24). patients who were treated with radiotherapy experienced the greatest increase of risk. conclusions: in view of the quickly increasing background rate of cancer with ageing of the cohort, it is concerning that even after more than 20 years of follow-up the sir is still increased, as is the absolute excess risk. the chek2*1100delc germline variant has been shown to increase susceptibility for breast cancer and could have an impact on breast cancer survival. this study aimed to determine the proportion of chek2*1100delc germline mutation carriers, and breast cancer survival and tumor characteristics, compared to non-carriers in an unselected (for family history) breast cancer cohort. women with invasive mammary carcinoma, aged <50 years and diagnosed in several dutch hospitals between 1973 and 1995, were included. for all patients, paraffin embedded tissue blocks were collected for dna isolation (normal tissue), and subsequent mutation analyses, and tumor revision. in 1479 breast cancer patients, 54 (3.7%) chek2*1100delc carriers were detected. chek2*1100delc tumors characteristics, treatment and patient stage did not differ from those of non-carriers. chek2*1100delc carriers had 2 times increased risk of developing a second breast cancer compared to non-carriers. with a mean follow up of 10 years, chek2*1100delc carriers had worse recurrence free and breast cancer specific survival than non-carriers. in conclusion, this study indicates a worse breast cancer outcome in chek2*1100-delc carriers compared to non-carriers. the extension of the presence of the chek2*1100delc germline mutation warrants research into therapy interaction and possibly into screening of premenopausal breast cancer patients. abstract background: for primary or secondary prevention (e.g. myocardial infarction) hormone therapy (ht) is no longer recommended in postmenopausal women. however, physicians commonly prescribe ht to climacteric women as a treatment of hot flashes/night sweats. objective: to assess efficacy and adverse reactions of ht in climacteric women with hot flashes (including night sweats). methods: for our systematic review (sr), we searched databases (medline, embase, cochrane) for randomized controlled trials, other srs and meta-analyses, published 1999 to 2004. the quality of the studies was assessed using checklists corresponding to the study type. results: we identified 18 studies of good/excellent quality. they included predominantly caucasian women and lasted 3-12 months. in all studies, ht showed a reduction of 75-95% in the number of hot flashes, which was significantly better than placebo. most common adverse events of ht were uterine bleeding and breast pain/tenderness. cardiovascular diseases and neoplasms were reported only sporadically. conclusions: ht is highly effective in treating hot flashes in climacteric women. however, to assess serious adverse events longer studies (including also non-caucasian women) are needed, as there are only sparse data available. abstract igf-i is an important growth factor, and has been associated with increased colorectal cancer risk in both prospective epidemiological and experimental studies. however, it is largely unknown which lifestyle factors are related to circulating levels of the igf-system. studies investigating the effect of isoflavones on the igf-system have thus far been conflicting. the purpose of this study was to evaluate the effects of isoflavones on the circulating igf-system in men with high colorectal cancer risk. we conducted a randomized, placebo-controlled, cross-over study on the effect of a 2-month isoflavone supplementation (80 mg/day) on igf levels in 40 men with a family history of colorectal cancer or a personal history of colorectal adenomas. dropout rate was 5%, and all but 3 men were more than 80% compliant. isoflavones supplementation did not significantly alter serum total igf-i ()1.6%; 95%ci: )9.3 -6.1) and igf binding protein 3 (+0.7%, 95%ci: )3.5 -4.8) concentrations. other covariables, e.g. dietary energy and macronutrient intake, physical activity, and body weight, are currently under evaluation. in conclusion, this study shows that a 2-month isoflavone supplementation has no effect on serum igf-system components in men with high colorectal cancer risk. abstract background/objective: eurociss-european cardiovascular indicators surveillance set project, funded under the health monitoring programme of european commission, aims developing health indicators and recommendations for monitoring cardiovascular diseases (cvd). methods: prioritise cvd according to their importance in public health; identify morbidity and mortality indicators; develop data collection and harmonizing recommendations; describe data collection, validation procedures and discuss their comparability. population (geographical area, age, gender), methods (case definition, icd codes), procedures (record linkage, validation), morbidity indicators (attack rate, incidence, case fatality) collected by questionnaire. results: the main outcome was the inventory of acute myocardial infarction (ami) populationbased registers in the 18 european partner countries: 8 countries have no register, 10 regional, 4 of which also national. registers differ for: icd codes (only ami or also acute and subacute ischemic forms), ages (35-64, 35-74, all) , record linkage (probabilistic, personal identification number), calendar years, validation (monica, esc/acc diagnostic criteria). differences make morbidity indicators difficult to compare. conclusion: new diagnostic criteria led to a more exhaustive definition of myocardial necrosis as acute coronary syndrome (acs). given the high burden of ami/acs, efforts are needed to implement population-based registers in all countries. application of recommended indicators, validated through standardized methodology, will provide reliable, valid and comparable data. abstract objective: the objective of this paper was to compare and discuss the use of odd ratios and prevalence ratios using real data with complex sampling design. method: we carried out a cross-sectional study using data obtained from a two-stage stratified cluster sample from a study conducted in 2001-2002 (n = 1,958) . odds ratios and prevalence ratios were obtained by unconditional logistic regression and poisson regression, respectively, for later comparison using the stata statistical package (v. 7.0). confidence intervals and design effects were considered in the evaluation of the precision of estimates. two outcomes of a cross-sectional study with different prevalence were evaluates: vaccination against influenza (66.1%) and self-referred lung disease (6.9%). results: in the high-prevalence scenario, using prevalence ratios the estimates were more conservative and we found narrower confidence intervals. in the low-prevalence scenario, we found no important differences between the estimates and standard errors obtained using the two techniques. discussion: however, it is the researcher's task to choose which technique and measure to use for each set of data, since this choice must remain within the scope of epidemiology. abstract background: in italy coronary heart disease chd mortality has been falling since the 1970s. objective: to examine how much of the fall between 1980 and 2000 could be attributed to trends in risk factors, medical and surgical treatments. methods: a validated model was used to combine and analyse data on uptake and effectiveness of cardiological treatments and risk factor trends. published trials, meta-analyses, official statistics, longitudinal studies, surveys are main data sources. results: chd mortality fell by 41% in men and 43% in women aged 25-84; 42,930 fewer deaths in 2000. approximately half mortality fall was attributed to treatments in patients and half to population changes in risk factors: in men, mainly improvements in cholesterol (39%) and smoking (33%) rather than blood pressure (6%). in women 1/3 mortality fall attributable to improvements in cholesterol (31%) and blood pressure (5%); adverse trends in smoking ()14%). adverse trends also in bmi ()2% in both genders) and diabetes ()4% in men; )0.5% in women). conclusion: half chd mortality fall was attributable to risk factors reductions, principally cholesterol in men and women and smoking in men; in women rising smoking rates generated substantial additional deaths. a comprehensive strategy promoting primary prevention is needed. objective: to investigate the efficacy of ni in the post exposure prophylaxis (pep), i.e. in persons who had contact with an influenza case. design and methods: we conducted a systematic electronic data base review for the period between 1999 and 2004. studies were selected and graded by two independent reviewers. the proportion of influenza-positive patients was chosen as primary outcome. for all analyses fixed effect models were used. weighted relative risks (rr) and 95% confidence intervals (ci) were calculated on an intention-to-treat basis. results: 5 randomized controlled trials (n=3,663) were included in the analysis. zanamivir and oseltamivir were effective against an infection with influenza (rr=0.23, 95% ci 0.15-0.36 and rr=0.20, 95% ci 0.11-0.34, respectively). prophylactic efficacy was comparable in the subgroup of persons who had contact with an index case with lab-confirmed influenza (4 studies, all ni, rr=0.18, 95% ci 0.12-0.28). conclusions: the available evidence suggests that ni are effective in the pep of influenza. discussion: results have to be interpreted with caution when transferred into general medical practice because study populations mainly included young and healthy adults without chronic diseases. abstract an important risk factor of breast cancer, mammographic breast density (mbd) is inversely associated with reproductive factors (age at first childbirth, and lactating). as pregnancy and lactating are highly correlated, whether this decline is induced by pregnancy or lactating is still unclear. we hypothesize that lactation reduces mbd independent of age at first pregnancy and parity. a study was done on 4051 women in the third sub-cohort of the dom project who had complete data regarding lactating, dy, had a child but varied by duration of lactating. multiple logistic regression analysis was done using dy (yes/ no) as outcome variable. explanatory variables added into the model were age, bmi, parity and age at first childbirth. a significant univariate relation was seen between lactating of the first child and dy. or 0.83 (ci 95% 0.73; 0.94). adjusted for explanatory variables, the or changed to 0.89 (ci 95% 0.73; 1.08). lactating seems to contribute independently to the reduction of mbd over and above pregnancy itself. given the limitations of the dichotomous dy ratio scores, additional studies will address which part; either glandular mass or fat tissue is responsible for the observed relation which will be measured from mammograms to be digitized. abstract background: alcohol consumption is common, but little is known about whether drinking patterns vary across geographic regions. objectives: to examine potential disparities in alcohol consumption across census regions and urban, suburban, and rural areas of the united states. design and methods: the data source was the national epidemiologic survey on alcohol and related conditions, an in-person interview of approximately 43,000 adults. the prevalence of abstinence and, among drinkers, the prevalences of heavy and daily drinking were calculated by census region and metropolitan status. multivariate logistic regression analyses were conducted to test for differences in abstinence and per drinker consumption after controlling for confounders. results: the odds of abstinence, heavy, and daily drinking varied widely across geographic areas. additional analyses stratified by census region revealed that rural residents in the south and northeast as well as urban residents in the northeast had higher odds of abstinence. rural residents in the midwest had higher odds of heavy drinking. conclusion and discussion: heavy alcohol consumption is of particular concern among drinkers living in the rural areas of the united states, particularly the rural midwest. other nations should consider testing for similar differences as they implement policies to promote safe alcohol consumption. abstract background: long-term exposure to particulate air pollution (pm) has been suggested to accelerate atherogenesis. objective: we examined the relationship between long-term exposure to traffic emissions and the degree of coronary artery calcification (cac), a measure of atherosclerosis. methods: in a population based, crosssectional study, distances between participants' home addresses and major roads were calculated with a geographic information system. annual mean pm2.5-exposure at the residence was derived from a small scale geostatistical model. cac, assessed by electronbeam computer tomography, was modelled with linear regression by proximity to major roads, controlling for background pm2.5air pollution and individual level risk factors. results: of 4424 participants 499 lived within 150 m of a major road. background-pm2.5 ranged from 16.1 to 26.8 lg/m3 (mean 22.8). mean cacvalues were strongly dependent on age, sex and smoking status. reducing the distance to major roads by 50% leads to increases in cac by 10.1% (95%ci 0.6-20.5%) in the unadjusted model and 5,5% (95%ci )2. 2-13.8 ) in the adjusted model. stronger effects (adjusted model) were seen in men (7,4%, 95%ci )3.9-20.1) and male non-smokers (10,5%, 95%ci )3.2-13.0). conclusions: this study provides epidemiologic evidence that long-term exposure to traffic emissions is an important risk factor for coronary calcification. abstract background: this polymorphism has been associated risk factor levels and in one study with a reduced risk of acute myocardial infarction (ami). yet, the risk relation has not been confirmed. objectives: we investigated the role of this polymorphism on occurrence of ami, coronary heart disease (chd) and stroke in healthy dutch women. design and methods: a case-cohort study in a prospective cohort of 15236 initially healthy dutch from1993 until january 1st 2000. results: we applied a cox proportional hazards model with an estimation procedure adapted for case-cohort designs. a lower ami (n=71) risk was found among carriers of the ala allele (n=364) compared with those with the more common pro12pro genotype (hazard ratio=0.51; 95% ci, 0.26 to 1.00). no relation was found for chd (n=211;hr 0.82; 95% ci, 0.58-1.17) and for stroke (n=74;hr 1.41; 95% ci, 0.85-2.33). in our data little evidence was found for a relation between pparg2 and risk factors. conclusion and discussion: this study shows the pro12ala polymorphism in pparg2 gene is modestly related to a reduced risk of ami in our study. no statistically significant relation was found for chd and stroke. abstract background: pseudo cluster randomization was used in a services evaluation trial because individual randomization risked contamination and cluster randomization risked selection bias due to expected treatment arm preferences of recruiting general practitioners (gps). gps were randomized in two groups. depending on this randomization, participants were randomized in majority to one study arm: intervention:control/80:20 or intervention:control/ 20:80. objectives: to evaluate internal validity of pseudo cluster randomization. have gps treatment arm preferences? what is the effect on allocation concealment and selection bias? design and methods: we compared the baseline characteristics of participants to study selection bias. using a questionnaire, gps indicated their treatment arm preferences on a visual analogue scale (vas) and the allocation proportions they believed were used to allocate their patients over treatment arms. results: gps preferred allocation to the intervention (vas 14.5 (sd 15.6); 0-100: 0 indicates strongly favoring the intervention arm). after recruitment 67% of gps estimated a randomization ratio of 50:50 was used. the participants showed no relevant differences at baseline. conclusion and discussion: gps profoundly preferred allocation to the intervention group. few indications of allocation disclosure or selection bias were found in the dutch easycare trial. pseudo cluster randomization proofs to be a valid randomization method. abstract background: epidemiological studies rely on self-reporting to acquire data on participants, although such data are often limited in reliability. the aim here is to assess nuclear magnetic resonance (nmr) based metabonomics for evaluation of self-reported data on paracetamol use. method: four in-depth 24-hour dietary recalls and two timed 24-hour urine collections were obtained for each participant in the intermap study. a 600 mhz 1h nmr spectrum was acquired for each urine specimen (n = 9,943). training and test sets involved two strata, i.e., paracetamol metabolites yes or no in the urine spectra, selected from all 17 population samples by a principal component analysis model. the partial least squares-discriminant analysis (pls-da) model based on a training set of 110 samples was validated by test set (n = 620). the model correctly predicted stratum for 575 of 587 samples (98%) after removal of 33 outliers not fitting the model, sensitivity 95.4%, specificity 100%. this model was used to predict paracetamol status in all intermap specimens. it identified 384 participants (8.2%) who underreported analgesic use, of whom 63 underreported analgesic use in both clinical visits. conclusion: nmr-based metabonomics can be used as a tool to enhance reliability of self-reported data. abstract background: in patients with asthma, the decline in forced expiratory volume in one second (fev1) is accelerated compared with non-asthmatics. objective: to investigate long-term prognostic factors of fev1 change in asthmatics from the general population. methods: a cohort of 667 asthmatics (20-44 years-old) was identified in the frame of the european community respiratory health survey (1991/93), and followed up in 1998/2002. spirometry was performed on both occasions. the annual fev1 decrease (?fev1) was analysed by multi-level regression models, according to age, sex, height, bmi, occupation, familiarity of asthma, hospitalization for asthma (baseline factors); cumulative time of inhaled corticosteroid (ics) use and annual weight gain during the follow-up; lifetime pack-years smoked. results: when adjusting for all covariates, ics use for >2 years significantly reduced ?fev1, with respect to non-users, of 10.4(95%ci: 1.6-19.2) ml/year. ?fev1 was 9.9(0.5-19.4) ml/year lower in women than in men. it increased by 0.7(0.2-1.2) ml/year for every additional year in patient age and by 7.2(3.3-11.0) ml/year for every additional kg/year in the rate of weight gain. conclusion: long-term ics use (>2 years) seems to be associated with a reduced ?fev1 over a 9-year followup. body weight gain seems a crucial factor in determining lung function decrease in asthmatics. abstract background: effectiveness of screening can be predicted by episode sensitivity, which is estimated by interval cancers following a screen. full-field digital or cr plate mammography are increasingly introduced into mammography screening. objectives: to develop a design to compare performance and validity between screen-film and digital mammography in a breast cancer screening program. methods: interval cancer incidence was estimated by linking 721 000 screening visits from 1991-2001 at an individual level to the files of the cancer registry in finland. these data were used to estimate the study size requirements for analyzing differences in episode sensitivity between screen-film and digital mammography in a randomized setting. results: the two-year cumulative incidence of interval cancers per 100 000 screening visits was estimated to be 300. to allow the maximum acceptable difference in the episode sensitivity between screen-film and digital arm to be 20% (80% power, 0.05 significance level, 1:1 randomization ratio, 85% attendance rate), approximately 240 000 women need to be invited. conclusion: only fairly large differences in the episode sensitivity can be explored within a single randomized study. in order to reduce the degree of non-inferiority between the screen-film and digital mammography, meta-analyses or pooled analyses with other randomized data are needed. according to the literature up to 70% of colorectal cancers worldwide is preventable by dietary change. however the results of the epidemiologic studies are not consistent across the countries. the objective of the study is to evaluate the role of dietary nutrients on colorectal cancer risk in poland. the hospital-based case-control study was carried out in 2000-2003. in total, 239 histologically confirmed cancer cases and 548 controls were recruited. adjustment for age, sex, education, marital status, multivitamin use, alcohol consumption, cigarette smoking, family history and energy consumption was done by logistic regression model. low tertile of daily intake in the control group was defined as a reference level. the lower colorectal cancer risk was found in cases with high daily intake of dietary fiber (or = 0,62; 95%ci: 0,42-0,91) and vitamin e (or = 0,67; 95%ci: 0,46-0,99). on the other hand, an increased risk for high monosaccharides consumption was observed. the risk pattern wasn't changed after additional adjustment for physical activity and body mass index. the results of the present study support the protective role of dietary fiber and some antyoxidative vitamins in the etiology of colorectal cancer. additionally they suggest that high consumption of monosaccharides may lead to elevated risk of investigated cancers. abstract assessment of nutrition is very difficult in every population, but in children there's additional question if child can properly recognize and recall foods that have been eaten. the aim of this study was to assess if dietary recall administered to adolescents can be used in epidemiological studies on nutrition. subjects were 100 children, 9-15 years old, and they caretakers. 24-h recall was used to evaluate children's nutrition. both, child and caretaker were asked to recall all products, drinks and dishes eaten by child during the day before recall. the statistical analyses were done separately for each meal. we have noticed statistically significant differenced for intake of energy and almost all nutrients from the lunch. the observed spearman rank correlation coefficients between child and his caretaker ranged from 0.39 for vitamin c up to 0.71 for intake of carbohydrates. only calcium intake (146.16 vs. 123.52 mg/day) differentiated groups for the breakfast and b-carotene for the supper. the study showed that the recall with adolescents could be helpful source of data for the research in the population aspect. however, one shouldn't use such data for the examination of the individual nutritional habit of children, especially information about dinner can be biased. abstract background: acute bronchitis is one of the most common diagnoses made by primary care physicians. in addition to antibiotics, chinese medicinal herbs may be a potential medicine of choice. objectives: this review aims to summarize the existing evidence of comparative effectiveness and safety of chinese medicinal herbs for treating uncomplicated acute bronchitis. methods: we searched the cochrane central register of controlled trials, medline, embase, chinese biomedical database and etc. we included randomised controlled trials comparing chinese medicinal herbs with placebo, antibiotics or other western medicine for treating uncomplicated acute bronchitis. at least two authors extracted data and assessed trial quality. main results: four trials reported the time to improvement of cough, fever, and rales; two trials reported the proportion of patients with improved signs and symptoms; thirteen trials analyzed the data of global assessments of improvement. one trial reported the adverse effect during treatment. conclusions: there is insufficient quality data to recommend the routine use of chinese herbs for acute bronchitis. the benefit found in individual studies and this systematic review could be due to publication bias and study design limitations. in addition, the safety of chinese herbs is unknown, though adverse events are rarely reported. design and methods: patients with a definite ms and classified as dead or alive at 1st january 2004 were included in this retrospective observational study. influence of demographic and clinical variables was assessed with kaplan meier and cox methods. standardised mortality ratios were computed to compare patients' mortality with the french general population. results: a total of 1935 patients were included (623 men, 1322 women). the mean age at ms onset was 31 +/) 10 years and the mean follow-up duration was 15 +/) 9 years (29260 patients-years). by 2004, 85 deaths occurred (3 per 1000 patients-years). male gender, progressive course, polysymptomatic onset and high relapse rate were related to a worse prognosis. ms did not increase the number of deaths in our cohort compared to the general french population (75 expected), except for highly disabled patients (58 observed, 18 expected). conclusion: this study gave precise insights on mortality in multiple sclerosis in west france. mattress dust. methods: we performed nested case-control studies within ongoing birth cohort studies in germany, the netherlands, and sweden and selected approximately 180 sensitised and 180 non-sensitised children per country. we measured levels of bacterial endotoxin, ß(1->3)-glucans, and fungal extracellular polysaccharides (eps) in dust samples collected on the children's mattresses. results: combined across countries, higher amounts of dust and higher endotoxin, ß(1->3)-glucans, and eps loads of mattress dust were associated with a significantly decreased risk of sensitization to inhalant allergens, but not food allergens. after mutual adjustment, only the protective effect of the amount of mattress dust remained significant [odds ratio (95% confidence interval) 0.57 (0.39-0.84)]. conclusion: higher amounts of mattress dust might decrease the risk of allergic sensitization to inhalant allergens. the effect might be partly attributable to endotoxin, ß(1->3)-glucans, and eps. it is not possible to distinguish with certainty, which component relates to the effect, since microbial agents loads are highly correlated with amount of dust and with each other. abstract background: postmenopausal hormone therapy (ht) increases mammographic density, a strong breast cancer risk factor, but effects vary across women. objective: to investigate whether the effect of ht use on changes in mammographic density is modified by polymorphisms in the estrogen (esr1) and progesterone receptor (pgr) genes. design and methods: information on ht use, dna and two consecutive mammograms were obtained from 795 ht users and 781 never ht users of the dutch prospect-epic and the english epic-norfolk cohorts. mammographic density was assessed using a computer-assisted method. changes in density between mammograms before and during ht use were analyzed using linear regression. results: a difference in percent density change between ht users and never users was seen in women with the esr1 pvuii pp or pp genotype (2.24%; p<0.01), but not in those with the pp genotype (0.90%; p = 0.47). similar effects were observed for the esr1 xbai and the pgr +331 g/a polymorphisms. the pgr progins polymorphism did not appear to make women more susceptible to the effects of ht use. discussion and conclusion: our results suggest that specific polymorphisms in the esr1 and pgr genes may make women more susceptible to the effects of ht use on mammographic density. abstract background: there is a paucity of data on the cancer risk of turkish migrant children in germany. objectives: to identify cancer cases of turkish origin in the german childhood cancer registry (gccr) and to compare the relative incidence of individual cancers among turkish and non-turkish children. design and methods: we used a name algorithm to identify children of turkish origin among the 37,259 cancer cases below 15 years of age registered since 1980. we calculated proportional cancer incidence ratios (pcir) stratified for sex and time period. results: the name algorithm performed well (high sensitivity and specificity), and 1774 turkish childhood cancers were identified. overall, the relative frequency of tumours among turkish and non-turkish children is similar. there are specific sites and cancers for which pcirs are different; these will be reported during the conference. conclusion: our study is the first to show differences in the relative frequency of cancers among turkish and non-turkish children in germany. discussion: case control studies could help to explain whether observed differences in the relative frequency of cancers are due to differences in genetic disposition, lifestyle or socio-economic status. mutations in the netherlands cohort study on diet and cancer. data from 120,852 participants, 528 cases and 4,176 subcohort members were analysed from a follow-up period between 2.3 to 7.3 years after baseline. adjusted gender-specific incidence rate ratios (rr) and 95% confidence intervals (ci) were calculated over tertiles of folate intake in case-cohort analyses. high folate intake did not reduce overall colon cancer risk. however, in men only, it was inversely associated with apc[csymbol] colon tumours (rr 0.58, 95% ci 0.32-1.05 for the highest versus the lowest tertile of folate intake), but positively associated with apc+ colon tumours (highest vs. lowest tertile: rr 2.77, ci 1.29-5.95). folate intake was neither associated with overall rectum cancer risk, nor with rectum cancer when apc mutation status was accounted for. we observed opposite associations between folate intake and colon cancer risk with or without apc mutations in men, which may implicate a distinct mutated apc pathway mediated by folate intake in men. abstract background and objectives: ten years after completion of the first serum bank of the general population to evaluate the long-term effects of the national immunisation programme (nip) a new serum collection is desirable. the objective is to provide insight into age-specific estimates of the immunity to childhood diseases and estimates of the incidence of infectious diseases with a frequent sub clinical course. design and methods: a two-stage cluster sampling technique was used to draw a nationwide sample. in each of five geographic regions, eight municipalities were randomly selected proportionally to their size. within each municipality, an age-stratified sample of 380 individuals (0-79 yr) will be drawn from the population register. in addition eight municipalities will be selected with lower immunization coverage to obtain insight into the immune status of persons who often refuse vaccination on religious grounds. furthermore over sampling of migrants will be performed to study whether their immune status is satisfactory. participants will be asked to fill in a questionnaire and to allow blood to be taken. extra blood will be taken for a genetic study. results and conclusion: the design of a population-based serum collection aimed at the establishment of a representative serum bank will be presented. abstract background: during the last decade, the standard of diabetes care evolved to require more intensive management focussing on multiple cardiovascular risk factors. treatment decisions for lipidlowering drugs should be based on cholesterol and blood pressure levels. objectives: to investigate the influence of hba1c, blood pressure and cholesterol levels on subsequent intensification of lipid-lowering therapy between 1998-2004. design and methods: we conducted a prospective cohort study including 2,373 type 2 diabetes patients who had at least two consecutive annual visits to a diabetes nurse. treatment intensification was measured by comparing drug regimes per year, and defined as initiation of a new drug class or dose increase of an existing drug. results: between 1998-2004, the prevalence of lipid-lowering drug use increased from 12% to 39%. rates of intensification of lipid-lowering therapy remained low in poorly controlled patients (12% to 28%;tc/hdl ratio>6). intensification of lipid-lowering therapy was only associated with tc/hdl ratio (age-adjusted or = 1.6;95%ci 1.5-1.7) and this association became slightly stronger over time. blood pressure was not found to be a predictor of the intensification of lipid-lowering therapy (or = 1.0). conclusion: hypercholesterolemia management intensified between 1998-2004, but therapy intensification was only triggered by elevated cholesterol levels. more attention for multifactorial risk assessment is needed. abstract background: there are no standard severity measures that can classify the range of illness and disease seen in general practice. objectives: to validate new scales of morbidity severity against age, gender, deprivation and poor physical function. design and methods: in a cross-sectional design, morbidity data for consulters in a 12-month period was linked to their physical function status . there were 9003 english older consulters (50 years +) and 7753 dutch consulters (18 years +). consulters for 116 morbidities classified on four gp-defined ordinal scales of severity ('chronicity', 'time course', 'health care use' and 'patient impact on activities of daily living') were compared to consulters for morbidity other than the 116, by age-groups, gender, and dichotomised deprivation and physical function scores. results: for both countries, on all scales, there was an increasing association between morbidity severity and older ages, female gender, more deprivation (minimum p<0.05) and poor physical function (all trends p<0.001). the estimates for categories, for example, within the 'chronicity' scale was ordered as follows: 'acute' (unadjusted odds ratio 1.4), 'acute-on-chronic' (1.8), 'chronic' (2.2) and 'life-threatening' (5.4). conclusions: new validated measures of morbidity severity indicate physical health status and offer the potential to optimise general practice care. hospitalization or death. calibration and discriminative capacity were estimated. results: among 445 episodes of lrti in elderly patients with dm, 68 endpoints occurred (attack rate 15%). reliability of the model was good (goodness-of-fit test p = 0.54). the discriminative properties of the original rule was acceptable (area under the receiver-operating curve (auc): 0.79, 95% ci: 0.72 to 0.86). conclusion: the prediction rule for the probability of hospitalization or death derived from an unselected elderly population with lrti appeared to have acceptable discriminative properties in diabetes patients and can be used to target management of these common diseases. confounding by indication is a major threat to the validity of nonrandomized studies on treatment effects. we quantified such confounding in a cohort study on the effect of statin therapy on acute respiratory disease (ard) during influenza epidemics in the umc utrecht general practitioner research database among persons aged > = 50 years. the primary endpoint was a composite of pneumonia or prednisolone-treated ard during epidemic, non-epidemic and summer seasons. to quantify confounding, we obtained unadjusted and adjusted estimates of associations for outcome and control events. in all, 22,638 persons provided 130,558 persons-periods, statin therapy was used in 5.3% and in 3,333 person-periods an outcome event occurred. without adjustments, statin therapy was not associated with the primary endpoint during influenza epidemics (relative risk [rr] 1.02; 95% confidence interval [95%ci]: 0.83-1.25). after applying multivariable generalized estimating equations (gee) and propensity score analysis the rrs were 0.72 (95% ci: 0.57-0.90) and 0.69 (95% ci: 0.59-0.89). the findings were consistent across relevant strata. in non-epidemic influenza and summer seasons the rr approached 1.0 while statin therapy was not associated with control event rates. observed confounding in the association between statin therapy and acute respiratory outcomes during influenza epidemics masked a potential benefit of more than 30%. abstract background: despite several advances in the treatment of schizophrenia, the currently available pharmacotherapy does not change the course of illness or prevent functional deterioration in a substantial number of patients. therefore, research efforts into alternative or adjuvant treatment options are needed. in this project, called the 'aspirine trial', we investigate the effect of the antiinflammatory drug acetylsalicylic acid as an add-on to regular antipsychotic therapy on the symptoms of schizophrenia. objectives: to objective is to study the efficacy of acetylsalicylic acid in schizophrenia on positive and negative psychotic symptoms, immune parameters and cognitive functions. design and methods: a randomized placebo controlled double-blind add-on trial of 80 inpatients and outpatients with schizophrenia, schizophreniform or schizoaffective disorder is performed. patients are 1:1 randomized to either 3 months 1000 mg acetylsalicylic acid per day or 3 months placebo, in addition to their regular antipsychotic treatment. all patients receive pantoprazole treatment for gastroprotection. participants are recruited from various major psychiatric hospitals in the netherlands. the outcomes of this study are 3-month change in psychotic and negative symptom severity, cognitive function, and several immunological parameters. status around 45 participants have been randomized. no interim analysis was planned. abstract background: congenital cmv infection is the most prevalent congenital infection worldwide. epidemiology and outcome are known to vary with socio-economic background, but few data are available on epidemiology and outcome in a developing country, where the overall burden of infectious diseases is high. objective: to determine prevalence, riskfactors and outcome of congenital cmv infection in an environment with high infectious disease burden methods: as part of an ongoing birth cohort study, baby and maternal samples were collected at birth, and tested with an inhouse pcr for the presence of cmv. standardised clinical assessment were performed by a paediatrician. placental malaria was also assessed. follow-up is ongoing till the age of 5 years. preliminary results: the prevalence of congenital cmv infection was 36/700 (5.1%). the infected children were more often first born babies (47.4% vs 21.5%, p<0.001). while no seasonality was observed, placental malaria was more prevalent among congenitally infected children (25.0% vs 11.3%,p = 0.04). there were no symptomatic babies detected. conclusion: this prevalence of congenital cmv is much higher than reported in industrialised countries, in the absence of obvious clinical pathology. further follow up is needed to assess impact on response to vaccinations, growth, and morbidities. of wheeze or cough at night in the first 3 years. data on respiratory symptoms and dda were collected by yearly questionnaires. in total, 193 symptomatic children with and 916 without an early dda were included in the study population. results: fifty-one percent of the children with and 29% of the children without an early dda had persistent respiratory symptoms at age 6. persistence of symptoms was associated with parental atopy, eczema, nose symptoms without a cold, or a combination of wheeze and cough in the first 3 years. conclusions: monitoring the course of symptoms in children with risk factors for persistent symptoms, irrespective of a diagnosis of asthma, may contribute to early recognition and treatment of asthma. little is known about the response mechanisms of survivors of disasters. objective: to examine selective non-response and to investigate whether attrition has biased the prevalence estimates among survivors of a disaster. design and methods: a longitudinal study was performed after the explosion of a fireworks depot in enschede, the netherlands. survivors completed a questionnaire 3 weeks (t1), 18 months (t2) and 4 years post-disaster (t3). prevalence estimates resulting from multiple imputation were compared with estimates resulting from complete case analysis. results: non-response differed between native dutch and nonwestern immigrant survivors. for example, native dutch survivors who participate at t1 only were more likely to have health problems at t1 such as depression than native dutch who participated at all three waves (or = 1.9, 95% ci: 1. 2-2.9) . in contrast, immigrants who participated at t1 only were less likely to have depression at t1 (or = 0.2, 95% ci: 0.1-0.6). conclusion and discussion: among native dutch survivors, the imputed estimates of t3 health problems tended to underestimated than the complete case estimates. the imputed t3 estimates among immigrants were unaffected or somewhat overestimated than the complete case estimates. multiple imputation is a useful statistical technique to examine whether selective non-response has biased the prevalence estimates. session: posters session 3: july 1 2006 presentation: poster. background: several epidemiologic studies have shown decreased colon cancer risk in physically active individuals. objectives: this review provides an update of the epidemiologic evidence for the association between physical activity and colon cancer risk. we also explored whether study quality explains discrepancies in results between different studies. methods: we included cohort (male n = 16; female n = 10) and case-control studies (male n = 13; female n = 12) that assessed total or leisure time activities in relation to colon cancer risk. we developed a specific methodological quality scoring system for this review. due to the large heterogeneity between studies, we refrained from statistical pooling. results: in males, the cohort and case-control studies lead to different conclusions: the case-control studies provide strong evidence for a decreased colon cancer risk in the physically active while the evidence in the cohort studies is inconclusive. these discrepant findings can be attributed to either misclassification bias in cohort or selection bias in case-control studies. in females, the small number of high quality cohort studies precludes a conclusion and the case-control studies indicate an inverse association. conclusion: this review indicates a possible association of physical activity and reduction of colon cancer risk in both sexes but the evidence is not yet convincing. abstract background/objectives: radiotherapy after lumpectomy is commonly applied to reduce recurrence of breast cancer but may cause acute and late side effects. we determined predictive factors for the development of late toxicity in a prospective study of breast cancer patients. methods: late toxicity was assessed using the rtog/ eortc classification among 418 women receiving radiotherapy following lumpectomy after a mean follow-up time of 51 months. predictors of late toxicity were modelled using cox regression in relation to observation time, adjusting for age, bmi and biologically effective dose in the maximum at the skin. results: 133 (31.8%) patients presented with telangiectasia and 28 (6.7%) patients with fibrosis. we observed a strong association between development of telangiectasia and fibrosis (p<0.01). increasing patient age was a risk factor for telangiectasia and fibrosis (p for trend 0.02 and 0.04, respectively). boost therapy (hazard ratio (hr) 4.2, 95% ci 1.7-10.7) and acute skin toxicity (hr 1.6, 95% ci 1.0-2.6) significantly increased risk of telangiectasia. risk of fibrosis was elevated among patients with atopic diseases (hr 2.2, 95% ci 1.0-4.7). discussion: our study revealed several risk factors for late complications of radiotherapy. further understanding of differences in response to irradiation may enable individualized treatment and improve cosmetic outcome. doctor-diagnosed asthma and respiratory symptoms (age 6) were available for 311 (rint) and 125 (no) children. results: the discriminative capacities of rint and exhaled no were statistically significant for the prediction of doctor-diagnosed asthma, wheeze (rint only) and shortness of breath (rint only). due to the low prevalence of disease in this general population sample, the positive predictive values of both individual tests were low. however, the positive predictive value of the combination of increased rint (cutoff 1.05 kpa.l-1.second) and exhaled no (cut-off 10 ppb) was 38% for the prediction of doctor-diagnosed asthma, with a negative predictive value of 97%. combinations of rint or exhaled no with atopy of the child showed similar results. conclusions: the combination of rint, exhaled no and atopy may be useful to identify high-risk children, for monitoring the course of their symptoms and to facilitate early detection of asthma. abstract background: in 1992 a cargo aircraft crashed into apartment buildings in amsterdam, killing 43 people, and destroying 266 apartments. an extensive, troublesome aftermath followed with rumours on toxic exposures and health consequences. objectives: we studied the long-term physical health effects of occupational exposure to this disaster among professional assistance workers. design and methods: in this historical cohort study we compared the 334 firefighters and 834 police officers who were occupationally exposed to this disaster (i.e. who reported one or more disasterrelated tasks) with their nonexposed colleagues (n = 194, and n = 634, respectively), using regression models adjusted for background characteristics. data collection took place from january 2000 to march 2002, and included various clinical blood and urine parameters (including blood count and kidney function), and questionnaire data on occupational exposure, physical symptoms, and background characteristics. the overall response rate was 71%. results: exposed workers reported various physical symptoms (including fatigue, skin and musculoskeletal symptoms) significantly more often than their nonexposed colleagues. in contrast, no consistent significant differences between exposed and nonexposed workers were found regarding clinical blood and urine parameters. discussion and conclusion: this epidemiological study demonstrates that professional assistance workers involved in a disaster are at risk for long-term unexplained physical symptoms. abstract background and objectives: recent studies indicate that women with cosmetic breast implants have significantly increased risk of suicide. reasons for elevated risk are not known. it is suggested that women with cosmetic breast implants differ in their characteristics and have more mental problems than women of general population. aim of this study was to find out possible associations between physical or mental health and postoperative quality of life among finnish women with cosmetic breast implants. design and methods: information was collected from patient records of 685 women and structured questionnaires mailed to 470 women of the same cohort. data was analysed by using pearson chi square testing and logistic regression modelling. results: although effects of implantation on postoperative quality of life in different areas were mainly reported as positive or neutral, 12 % of the women reported decreased state of health. postoperative dissatisfaction and decreased quality of life were significantly associated with diagnoses of depression (p = 0.01) and local complication called capsular contracture (p<0.001). conclusion: our results are consistent with previous results finding most of the cosmetic breast surgery patients satisfied after implantation. however, this study brings new information on associations between depression, capsular contracture and decreased quality of life. abstract cancer and its treatments often produce significant persistent morbidities that reduce quality of life (qol) in cancer survivors. research indicates that both, physical exercise and psycho-education might enhance qol. therefore, we developed a 12-week multidisciplinary rehabilitation program that combines physical training with psycho-education. the aim of the present multicenter study is to determine the effect of multidisciplinary rehabilitation on qol as compared to no treatment and, additionally, to physical training alone. furthermore, we will explore which variables are related to successful outcome (socio-demographic, disease related, physiological, psychological and environmental characteristics). 225 participants are needed to detect a medium effect. at present, 170 cancer survivors are randomised to either the multidisciplinary or physical rehabilitation program or a 6-month waiting list control group. outcome assessment will take place before, halfway, directly after, 3 and 9 months following the intervention by means of questionnaires. physical activity will be measured before, halfway and directly after rehabilitation using maximal and submaximal cycle ergometer testing and muscle strength measurement. effectiveness of multidisciplinary rehabilitation will be determined by analysing changes between groups from baseline to post-intervention using multiple linear and logistic regression. positive evaluation of multidisciplinary rehabilitation may lead to implementation in usual care. continuous event recorders (cer) have proven to be successful in diagnosing causes of palpitations but may affect patient qol and increase anxiety. objectives: determine qol and anxiety in patients presenting with palpitations, and to evaluate the burden of the cer on qol and anxiety in patients presenting to the general practitioner. methods: randomized clinical trial in general practice. the short form-36 (sf-36) and state-trait anxiety inventory (stai) were administered at study inclusion, 6-weeks and 6months. results: at baseline, patients with palpitations (n = 226) reported lower qol and more anxiety than a healthy population for both males and females. there were no differences between the cer arm and usual gp care at 6-weeks. at 6-months the usual care group (n = 92) showed minimal qol improvement and less anxiety compared to the cer group (n = 103). type of diagnosis did not account for any of these reported differences. conclusion: anxiety decreases and qol increases in both groups at 6-weeks and 6-month follow-up. hence it is a safe and effective diagnostic tool, which is applicable for all patients with palpitations in the general practice. abstract background: clinical benefits of statin therapy are accepted, but their safety profiles have been under scrutiny, particularly for the most recently introduced statin, rosuvastatin, relating to serious adverse events involving muscle, kidney and liver. objective: to study the association between statin use and the incidence of hospitalizations for rhabdomyolysis, myopathy, acute renal failure and hepatic impairment (outcome events) in real life. methods: in 2003 and 2004, 10,147 incident rosuvastatin users, 37,396 incident other statin users and 99,935 patients without statin prescriptions from the pharmo database of >2 million dutch residents were included in a retrospective cohort study. potential cases of hospitalization for myopathy, rhabdomyolysis, acute renal failure or hepatic impairment were identified using icd-9-cm codes and validated using hospital records. results: there were 26 validated outcome events in the three cohorts including one case each of myopathy (other statin group) and rhabdomyolysis (non-treated group). there were no significant differences in the incidence of outcome events between rosuvastatin and other statin users. discussion: this study indicated that the number of outcome events is less than 1 per 3000 person years. rosuvastatin does not lead to an increased incidence of rhabdomyolysis, myopathy, acute renal failure and hepatic impairment compared to other statins. the aim: the aim of the study was to assess the influence of insulin resistance (ir) on the coronary artery disease (cad) occurrence in middle aged women with normal glucose tolerance (ngt) material and methods: in 1998-2000 year 986 women aged 35-55, participants of the polish multicenter study on diabetes epidemiology were examined. anthropometric, biochemical (fasting lipids, fasting and after glucose load plasma glucose and insulin) and blood pressure determinations were performed . ir was defined as the matsuda index (irmatsuda) below the lower quartile of the irmatsuda distribution in ngt population the questionnaire examination of the lifestyle, present and past diseases was performed. results: ir was observed in 31 % of all examined women and in 17.9% with ngt. cad was diagnosed in 10, 3% of all examined women and in 6,9% of those with ngt. the relative risk of cad related to ir in ngt and normotensive women was 2,90 (95% ci:1,07-7,88) (p<0.05). regular menstruation was observed in 41,1% of cad women. irmatsuda was not different for cad menstruating and non menstruating women (respectively 9,31±1,01 and 9,70±1,68). conclusion: in middle aged, normotensive and normal glucose tolerant women ir seems to be an important risk factor of cad abstract background: in germany, primary prevention at population level is provided by general practitioners (gp). little is known about gps' strategies to identify patients at high risk for vascular diseases using standardised risk scores. objectives: we studied gp attitudes and current practice in using risk scores. methods-a cross-sectional survey was conducted among 744 gps in north rhine-westphalia, germany, using mailed self-administered questionnaires on attitudes and current practice in identification of patients at high risk for vascular diseases. results: in 2005, 350 gps participated in the study. 69.0% of gps stated to know the framingham-score, 81.3% the procam-score and 29.4% the score-score. 47.4% of gps reported regular use of standardised risk scores to identify patients at high risk for vascular diseases, most frequently procam-score (79.7%), followed by score-score (6.8%) and framingham-score (6.8%). main reasons for not using standardised risk scores were assumed rigid assessment of individual patients' risk profile (51.9%), time-consuming appliance (35.2%) and higher confidence in own work experience (17.3%). conclusion: use of standardised risk scores to identify patients at high risk for vascular diseases is common among gps in germany. however, more educational work might be useful to strengthen gps' belief in the flexible appliance of standardised risk scores in medical practice. among epilepsy patients than in general population, but effects of specific antiepileptic drugs on birth rate are not well known. objectives: to estimate birth rate in epilepsy patients on aed treatment or without aeds and in a population-based reference cohort without epilepsy. design and methods: patients (n = 20, 101) with reimbursement for aeds for the first time between 1985 and 1994 and information on their aed use, were identified from the databases of social insurance institution of finland. reference cohort without epilepsy (n = 29,828) and information on live births were identified from the finnish population register centre. the analyses were performed using poisson regression modelling. results:birth rate was decreased in epilepsy patients in relation to reference cohort without epilepsy in both genders regardless of aed use. in relation to untreated patients, women on any of the aeds had non-significantly lower birth rates. among men, birth rate was decreased in men on oxcarbazepine (rr = 0.52, 95% ci = 0.32,0.84), but was not clearly lower among those on carbamazepine (rr = 0.86,95% ci = 0.66,1.13) or valproate (rr = 0.78,95% ci = 0.55,1.11) when compared to untreated patients. conclusion: our results suggest that birth rate is decreased among epilepsy patients on aeds, more so in men. abstract background: hereditary hemochromatosis (hh), characterised by excessive iron absorption, subsequent iron storage and progressive clinical features, can when diagnosed at an early stage be successfully treated. high prevalence of the c282y-mutation on the hfe-gene in the hh patient population may motivate genetic screening. objectives: in first-degree relatives of c282y-homozygotes we studied the gender and age -related biochemical penetrance of hfe-genotype to define a high-risk population eligible for screening. design and methods: one-thousand-six first-degree family members of 280 probands with clinically overt hfe-related hh from five medical centres in the netherlands were approached. data on levels of serum iron parameters and hfe-genotype were collected. elevation of serum ferritin was defined using the centre-specific normal-values by age and gender. results: among the 610 participating relatives, highest serum iron parameters were found in male c282y-homozygous siblings aged >55 years: 97% had elevated levels of serum ferritin. generally, male gender and increased age are related with higher iron values. discussion and conclusion: genetic screening for hh is most relevant in male and elderly first-degree relatives of patients with clinically overt hfe-related hh, enabling regular investigations of iron parameters in homozygous individuals. abstract background: nosocomial infection causes increased hospital morbidity and mortality rates. although handwashing is known to be the most important action in its prevention, adherence of health care workers to recommended hand hygiene procedures is extremely poor. objective: evaluation of compliance of hand hygiene recommendations in health care workers of a tertiary hospital in barcelona after a course on hand hygiene was given to all nurses in the hospital during the previous year. methods: by means of nondeclared observation, compliance (handwashing or disinfecting, not solely glove exchange) of recommendations given by the center for disease control related to opportunities for hand hygiene was registered, in procedures of diverse risk level for infection, both in physicians and nurses. results: in 1288 opportunities for hand hygiene carried out by 254 health care workers compliance of recommendations was 19.9%. adherence differed between wards (68.9% in intensive care units, 17.8% in medical wards and 4.3% in surgical wards) and slightly between health care workers (21.4% in physicians, 19.2% in nurses). discussion: in conclusion, after one year of an intervention on education, adherence to hand hygiene recommendations is very low. these results enhance the need of reconsidering the type of interventions implemented. type of comorbidity affects qol most. objectives: we studied whether qol differed in subjects with dm with and without comorbidities. in addition, we determined differences in type of comorbidity. design and methods: cross-sectional data of 193 dm patients, participants of a population-based dutch monitoring project on risk factors for chronic disease (morgen) were analyzed. qol was measured by the short form 36. we compared the means of 8 subdimensions for dm patients with one comorbidity (cardiovascular diseases (cvd), musculoskeletal diseases (msd) and asthma/copd) to dm patients without this comorbidity, by regression analyses adjusted for age and sex. results: the prevalences of cvd, msd and asthma/copd were 17.1%, 26.4%, and 46.6%. all comorbidities were associated with lower qol, especially for physical functioning. the mean difference (95% ci) was 13. abstract background: the extent or increase of ueds is suggested repeatedly, but never before the scientific literature was systematic studied. objectives: a systematic appraisal of the worldwide incidence and prevalence rates of upper extremity disorders (ueds) available in scientific literature was executed to gauge the range of these estimates in various countries and to determine whether the rates are increasing in time. design and methods: studies that recruited at least 500 people, collected data by using questionnaires, interviews and/or physical examinations, and reported incidence or prevalence rates of the whole upper-extremity including neck, were included. results: no studies were found with regard to the incidence of ueds and 13 studies that reported prevalence rates of ueds were included. the point prevalence ranged from 1.6-53%; the 12months prevalence ranged from 2.3-41%. one study reported on the lifetime prevalence (29%). we did not find evidence of a clear increasing or decreasing pattern over time. it was not possible to pool the date, because the definitions used for ueds differed enormously. conclusions: there are substantial differences in reported prevalence rates on ueds. main reason for this is the absence of a universally accepted way of labelling or defining ueds. abstract background: the absolute number of women diagnosed with breast cancer increased from 7,899 in 1989 to 11,687 in 2003 in the netherlands. likewise, the age standardized rate increased from 100.1 to 120.7 per 100,000 women. besides the current screening programme, changes in risk profile could be a reason for the increased incidence. objective: we studied the changes in breast cancer risk factors for women in nijmegen. methods: in the regional screening programme in nijmegen, almost 20,000 women aged 35-64 years filled in a questionnaire about risk factors in [1975] [1976] . similar questions were applied in the nijmegen biomedical study in 2002, where 2345 women of 35-64 year participated. the median age in both studies was 50 years. results: the frequency of a first-degree relative with breast cancer was 9.9% and 11.1% in 1975 and 2002, respectively . none of the other risk factors, as the age of women at 1st birth (26.3% respectively 27.1%), nulliparity (19.2% resp. 20.6%), age at menarche (13.1% resp. 13.2%), age at menopause (47.2% resp. 49.2%) and obesity (11.9% resp. 11 .4%), changed in time. conclusion: the distribution of risk factors hardly changed, and is unlikely to explain the rise in breast cancer incidence from 1989 onwards. abstract background: a single electronic clinical history system has been developed in the bac (basque autonomous community) for general use for all health centres, thus making it possible to collect information online on acute health problems as well as chronic ailments. method: the prevalence of diabetes, high blood pressure and copd (chronic obstructive pulmonary disease) was estimated using icd-9-cm diagnosis performed by primary care physicians. an estimate was also made of the prevalence of cholesterolemia based on the results of analyses requested by physicians. results: in 2004, 441,097 patients (out of a total population of 2,082,587) were assessed for serum cholesterol levels. based on this highly representative sample, it was estimated that 13.3% had serum cholesterol levels above 250 mg/dl. the prevalence of diabetes mellitus in people over the age of 29 was 6.4%. the prevalence of high blood pressure in people over 13 was 25%. discussion: the primary care database makes it possible to access information on problems related to chronic illnesses. knowing the prevalence of diabetes patients enables doctors to analyse all aspects related to services used by the diabetic population. it also makes it possible to monitor analytical data in real time and evaluate health service outcomes. examinations were used to asses risk factors for diabetes. cases (n = 101) were matched on age and sex to controls (n = 709) who were not treated with antidiabetic drugs. logistic regression was used to calculate odds ratios (or). results: the or of incident diabetes for acei-use versus non-acei use was 3.63 (95%ci :1.93-6.88). for ace dd homozygotes the or was 0.57 (95%ci:0.07-4.47) and for ace-i allele carriers 5.72 (95%ci:2.77-11.81). the interaction or was 10.05 (95%ci:1.13-89.38). the agt and at1r genotypes did not modify the association between acei use and diabetes. abstract background: lignans have antioxidant and estrogen-like activity, and may therefore lower cardiovascular and cancer risk. objective: we have investigated whether intake of four plant lignans (lariciresinol, pinoresinol, secoisolariciresinol, matairesinol) was inversely associated with coronary heart disease (chd), cardiovascular diseases (cvd), cancer, and all-cause mortality. design: the zutphen elderly study is a prospective cohort study in which 570 men aged 64-84y were followed for 15 years. lignan intake was estimated using a recently developed database, and related to mortality using cox proportional hazards analysis. results: median total lignan intake in 1985 was 977lg/d. beverages such as tea and wine, vegetables, bread, and fruits were the major lignan sources. total lignan intake was not related to mortality. however, matairesinol was inversely associated with chd, cvd, cancer, and all-cause mortality. multivariate adjusted rrs (95% ci) per sd increase in intake were 0.72 (0.53-0.98) for chd, 0.83 (0.69-1.00) for cvd, 0.81 (0.65-1.00) for cancer, and 0.86 (0.76-0.97) for allcause mortality. conclusions: total lignan intake was not associated with mortality. the intake of matairesinol was inversely associated with mortality from chd, cvd, cancer, and all-causes. we can not rule out that this is due to an associated factor, such as wine consumption. abstract despite the drastic increase in the amount of research into neighbourhood-level contextual effects on health, studies contrasting these effects between different domains of health within one contextual setting are strikingly sparse. in this study we use multilevel logistic regression models to estimate the existence of neighbourhood-level variations of physical health functioning (pcs) and mental well-being (ghq) in the helsinki metropolitan area and assess the causes of these differences. the individual-level data are based on a health-survey of 40-60 year old employees of the city of helsinki (n = 4313, response rate 68%). the metropolitan area is divided into 53 neighbourhoods, which are characterised using a number of area-level indicators (e.g. unemployment rate). our results show moderate but systematic negative effect of indicators of neighbourhood deprivation on physical functioning, whereas for mental health the effect is absent. these effects were strongest for proportion of manual workers; odds ratio for poor physical functioning was 0.8 for respondents living in areas with low proportion of manual workers. part of this effect was mediated by differences in health behaviour. analyses on cross-level interactions show that individual-level socioeconomic differences in physical health are smallest in most deprived areas, somewhat contradicting the results of earlier studies. abstract background: the second-eye cataract surgery is beneficial, nevertheless, there is a considerable proportion of unmet needs. objective: to estimate the proportion of second-eye cataract surgery in the public health system of catalonia, and explore differences in utilisation by patients' gender, age, and region of residence. methods: a total of 154,215 senile cataract surgeries performed between 1999 and 2002 were included. proportions observed were adjusted through independent logarithmic regression models for each study factor. results: the proportion of second-eye surgery showed an increasing trend (r2 59.4%) from 23.8% (95% ci 21.6; 26.1) in november 2000 to 32.5% (95% ci 31.4; 33.6) in december 2002, and its projection to 5 years was 35,7% (95% ci 33.6; 37.7). the proportion of second-eye surgery was 2% (95% ci 0.9; 3.1) greater in women than in men. patients 80 years or older had a lowest proportion (20.7%; 95% ic 20.2; 21.3), which nevertheless increased during the period, unlike that of patients aged less than 60 years. differences among regions were moderate and decreased throughout the period. conclusions: if the observed trends persist, there will be a substantial proportion of unmet need for bilateral surgery. we predict greater use of second-eye surgery by older patients. abstract background: persistence with bisphosphonates is suboptimal which could limit prevention of fractures in daily practice. objectives: to investigate the effect of long term persistent bisphosphonate usage on the risk of osteoporotic fractures. methods: the pharmo database, including drug-dispensing and hospital discharge records for > two million subjects in the netherlands, was used to identify new female bisphosphonate users >50 years from jan '96 -jun '03. persistence with bisphosphonates was determined using the method of catalan. a nested matched case-control study was performed. cases had a first hospitalization for an osteoporotic fracture (index-date). controls were matched 10:1 to cases on year of inclusion and received a random index-date. the association with fracturerisk was assessed for one and two year persistent bisphosphonate use prior to the index-date. analyses were adjusted for di fferences in patient characteristics. results: 14,760 bisphosphonate users were identified and 541 had a hospitalization for osteoporotic fracture during follow-up. one year persistent bisphosphonate use resulted in a 26% lower fracture rate (or 0.74; 95% ci 0.57-0.95) whereas two year persistent use resulted in a 32% lower rate (or 0.68; 95% ci 0.47-0.96). conclusion and discussion: these results emphasize the importance of persistent bisphosphonate usage to obtain maximal protective effect of treatment. abstract background: in 1997 the who recommended all countries to add hepatitis b (hbv) vaccination to their national immunization programs. the netherlands is a low hbv endemic country and therefore adopted a vaccination policy targeted towards high-risk groups. methods: during 2004, epidemiological data and blood samples were collected from all reported patients with an acute hbv infection. a fragment of the s-gene was sequenced and phylogenetically analysed to clarify transmission patterns between risk groups. results: of 295 hbv cases reported, 60% was infected through sexual contact (34% homo-/bisexual, 23% heterosexual). for 158 patients samples were available for genotyping. phylogenetic analysis identified 6 genotypes: a(64%), b(3%), c(3%), d(21%), e(5%) and f(4%). of men who have sex with men (msm), 86% were infected with genotype a. among heterosexuals, all genotypes were found. in many cases, genotypes b-f were direct or indirect related to countries abroad. only 1 injecting drug user was found (genotype a). conclusion: genotype a is predominant in the netherlands, including most of the msm. migrant hbv carriers play an important role in the dutch hbv epidemic. genotyping provides insight into the spread of hbv among highrisk groups. this information will be used to evaluate the vaccination policy in the netherlands. abstract background: excess weight might affect the perception of both physical and mental health in women. objective: to examine the relationship between body mass index (bmi) and hrqol in women aged 18-to 60-year-old in a rural zone of galicia. design and methods: population-based cross-sectional study covering 1321 women, personally interviewed, from 14 villages. hrqol was assessed with sf-36 questionnaire, through personal interviews. each scale of sf-36 was dichotomised in suboptimal or optimal hrqol using previously defined cut-offs. odds ratios (or) obtained from logistic regression summarize the relationship of bmi with each scale, adjusting for sociodemographic variables, sedentary leisuretime, number of chronic diseases and sleeping hours. results: a 14.7% of women were obese (bmi = 30 kg/m2) and 31.2% overweight 9 kg/m2) . frequency of suboptimal physical function was higher among overweight women (adjusted or:1.76; 95% ci:1.27-2.45) and obesity (adjusted or:2.10;95% ci:1.40-3.16). furthermore, obese women had higher frequency of suboptimal scores on the general health scale (adjusted or:1.64; 95% ci:1.10-2.44). no differences were observed regarding mental health scores among women with different bmi categories. conclusion: in women from rural villages, overweight is associated with worse hrqol in physical function and general health. abstract background: pneumococcal vaccination among elderly is recommended in several western countries. objectives: we estimate the cost-effectiveness of a hypothetical vaccination campaign among the 65+ general population in lazio region (italy). methods: a cohort was followed during a 5 years timeframe. we estimated the incidence of invasive pneumococcal disease, in absence of vaccine, based on actual surveillance and hospital data. the avoided deaths and cases have been estimated from literature according to trial results. health expenditures included: costs of vaccine program, inpatient and some outpatient costs. cost-effectiveness was expressed as net healthcare costs per episode averted and life-year gained (lyg) and was estimated at baseline and in deterministic and stochastic sensitivity analyses. all parameters were age-specific and varied according to literature data. results: at baseline net costs per event averted and lyg at 2001 prices were, respectively, e34,681 (95% ci: e28,699-e42,929) and 23,361 (95% ci: e16,419-e38,297). in the sensitivity analysis, bacteraemic pneumonia incidence and vaccine effectiveness increased the net cost per lyg by 131% and 218% in the worst-case scenario, and decreased it to e4,249 in the best-case. conclusions: the intervention was not cost saving. the uncertainties concerning invasive pneumococcal disease incidence and vaccine effectiveness make the cost-effectiveness estimates instable. spain 1989 -1998 abstract background: spatial data analysis can detect possible sources of heterogeneity in spatial distribution of incidence and mortality of diseases. moreover small area studies have greater capacity to detect local effects linked to environmental exposures. objective: to estimate the patterns of cancer mortality at municipal level in spain using smoothing techniques in a single spatial model. design and methods: cases were deaths due to cancer, registered at a municipal level nation-wide for the period 1989-1998. expected cases for each town were calculated using overall spanish mortality rates and standard mortality ratios were computed. to plot the maps, smoothed municipal relative risks were calculated using besag york and mollie`model and markov chain monte carlo simulation methods. as an example maps for stomach and lung cancer neoplasms are shown. results: it was possible to obtain the posterior distribution of relative risk by a single spatial model including 8077 towns and the 46398 adjacencies. maps showed the singular patterns for both cancer locations. conclusion: the municipal atlas allows to avoid edge local effects, improving the detection of spatial patterns. discussion: bayesian modelling is a very efficient way to detect spatial heterogeneity by cancer and other causes of death. abstract background: little is known about the impact of socioeconomic status (ses) on outcomes of surgical care. objectives: we estimated the association between ses and outcomes of selected complex elective surgical procedures. methods: using hospital discharge registries (icd-ix-cm codes) of milan, bologna, turin and rome we identified patients undergoing cardiovascular operations (coronary artery bypass grafting, valve replacement, carotid endarterectomy, repair of unruptured thoracic aorta aneurysm) (n = 20,194) and cancer resections (pancreatectomy, oesophagectomy, liver resection, pneumonectomy, pelvic evisceration) (n = 2,300) in four italian cities, 1997-2000. an area-based income index was calculated. post-operative mortality (in-hospital or within 30 days) was the outcome. logistic regression adjusted for gender, age, residence, comorbidities, concurrent and previous surgeries. results: high income patients were older and had fewer comorbidities. mortality varied by surgery type (cabg 4,1%, valve 7,5%, endartectomy 1,2%, aorta aneurysm 10,2%, cancer 6.7%). low income patients were more likely to die after cabg (or = 1. abstract background: an important medical problem of renal transplant patients who receive immunosuppression therapy, is the development of a malignancy during the long term follow-up. however, existing studies are not in agreement over whether patients who undergo renal transplantation have an increased risk of melanoma. objective: the aim of this study was to determine the incidence of melanoma in renal transplantation patients in the northern part of the netherlands. methods: we linked a cohort of 1125 patients who received a renal transplantation in the university medical centre groningen between 1989 and 2003 with the cancer registry of the comprehensive cancer centre north-netherlands, to identify all melanoma patients in this cohort. results: only 1 patient developed a melanoma following the renal transplantation; no significant increase in the risk of melanoma was found. conclusion: although several epidemiologic studies have shown that the risk of melanoma is increased in renal transplantation patients who receive immunosuppression therapy to prevent allograft rejection, this increased risk was not found in the present study. the lower level of immunosuppressive agents given in the netherlands might be responsible for this low incidence. abstract background: socio-economic health inequalities are usually studied for self-reported income, although the validity of self-reports is uncertain. objectives: to compare self-reports of income by respondents to health surveys with their income according to tax registries, and determine to what extent choice of income measure influences the health-income relation. methods: around 22.000 respondents from the dutch permanent survey on living conditions were linked to data from dutch tax and housing registries of 2001. both self-reported and registry-based measures of household equivalent income were calculated and divided into deciles. the association with less than good self-assessed health was studied using prevalence rates and odds ratios. results: around 18% of the respondents did not report their income. around 27% reported an income 3 deciles lower or higher than the actual income value. the relation between income and health was influenced by choice of income measure. larger health inequalities were observed with selfreports compared to registry-based measures. while a linear healthincome relation was found using self-reported income, a curvilinear relation (with the worst health in the second lowest deciles) was observed for registry-based income. conclusion: choice of the income source has a major influence on the health-income relation that is found in inequality research. abstract background: while many health problems are known to affect immigrant groups more than the native dutch population, little is known about health differences within immigrant groups. objectives: to determine the association between self assessed health and socioeconomic status (ses) among people of turkish, moroccan, surinamese and antillean origin. methods: data were obtained from a social survey held among immigrants 20-59 years in the netherlands, with almost 2000 respondents per immigrant group. ses differences in the prevalence of 'poor' self-assessed health were measured using prevalence rate ratios estimated with regression techniques. results: within each immigrant group, poor health was much more common among those with low ses. the health of women was related to their educational level, occupational position, household income, financial situation and (to a lesser extent) their parents' education. similar relationships were observed for men, except that income was the strongest predictor of poor health. the health differences were about as large as those known for the native dutch population. conclusion and discussion: migrant groups are not homogenous. also within these groups, low ses is related to poor general health. in order to identify subgroups where most health problems occur, different socioeconomic indictors should be used. abstract background: genetic damage quantification can be considered as biomarker of exposure to genotoxic agents and as early-effect biomarker regarding cancer risk. objectives: to assess genetic damage in newborns and its relationship with anthropometrical, sociodemographic variables, maternal tobacco consumption and pollution perception. design and methods: the bio-madrid study recruited 150 trios (mother/father/newborn) from 2 areas in madrid to assess the impact of pollutants in humans. parents answered a questionnaire about socio-economic characteristics, pregnancy, life-style and perception of pollution. genetic damage in newborns were measured with the micronucleus(mn) test in peripheral lymphocytes poisson regression models were fitted using mn frequency per 1000 binucleated cells as dependent variable. explanatory variables included sex, parents age, tobacco, area and reported pollution level. results: the mean frequency of mn was 3.94 per 1000 (range:2-10). no differences were found regarding area, sex and maternal tobacco consumption. mn frequency was higher in underweighted newborns and in those residing near heavy traffic roads. in recent years minimally invasive surgery procedures underwent rapid diffusion and laparoscopic cholecystectomy has been among the first to be introduced. after its advent, increasing rates of overall and laparoscopic cholecystectomy have been observed in many countries. we evaluated the effect of the introduction of laparoscopic procedure on the rates of cholecystectomy in friuli venezia giulia region, performing a retrospective study. from regional hospitals discharge data we selected all records with procedure code of laparoscopic (icd 9 cm: 5123) or open (5122) cholecystectomy and diagnosis of uncomplicated cholelithiasis (icd 9 cm: 574.0; 574.1; 574, 2) or cholecystitis (575,0; 575,1), in any field, from 1993 to 2004. in the 12 year study period, the number of overall cholecystectomies increased from 1546 to 2039 (+31,9%), mainly for the relevant increase of laparoscopic interventions from 3 procedures, (0,2% of overall cholecystectomies), to 1697 (83,2%). rates of laparoscopic cholecystectomies increased from 0,1 to 46,8 per 100 admitted patients with diagnosis of cholelithiasis or cholecystitis. the introduction of laparoscopic cholecystectomies was followed not only by a shift towards laparoscopically performed interventions but also by an increase in overall cholecystectomies in friuli venezia giulia region. abstract background: although a diminished doses scheme of 7-valent pneumococcal conjugate vaccination (pcv7) may offer protection against invasive pneumococcal disease, it might affect pneumococcal carriage and herd immunity. long term memory has to be evaluated. objective: to compare the influence of a 3 and 2-doses pcv7-vaccination scheme on pneumococcal carriage, transmission, herd immunity and anti-pneumococcal antibody levels. methods: in a prospective, randomized, controlled trial infants are randomly allocated to receive pcv7 at ages 2 and 4 months; ages 2, 4 and 11 months and the age of 24 months only. nasopharyngeal (np) swabs are regularly obtained from infants and family members. the np swabs are cultured by conventional methods and pneumococcal serotypes are determined by quellung reaction. antibody levels are obtained at 12 and 24 months from 80 infants in group i and ii and from 30 infants in group iii. one thousand infants are needed to detect a 10% difference in pneumococcal carriage (a = 0.05, ß = 0.80) between the three groups. results: so far, 852 infants have been included. preliminary results show that prior to vaccination pneumococcal carriage was 16%. conclusion: this trial will provide insight into the effects of a diminished dose scheme on herd immunity and long-term antipneumococcal antibody development. abstract background: oil-spills cause important environmental damages and acute health problems on affected populations. objectives: to assess the impact of the prestige oil-spill in the hrqol of the exposed population. design and methods: we selected 1350 residents in coastal areas heavily affected by the oil-spill and 1350 residents in unaffected inland villages through random sampling, stratified by age and sex. hrqol was measured with the sf-36 questionnaire in personal interviews. individual exposure was also explored. mean differences in sf-36 scores >3 points were considered 'clinically relevant'. odds ratios (or) summarized the association between area of residence (coast vs inland) and suboptimum hrqol (lower than percentile 25th), adjusting for possible confounders. results: neither clinically relevant nor statistically significant differences were observed in most of the sf-36 scales regarding place of residence or individual exposure. worse scores (inland = 79,2; coast = 75,9; p<0,001) abstract background: patient comorbidities are usually measured and controlled in health care outcome research. hypertension is one of the most commonly used comorbidity measures. objectives: this study aims to assess underreporting of hypertension in ami patients, and to analyze the impact of coding practices among italian regions or hospitals' type. methods: a cohort of ami hospitalisations in italy from november 2002 to october 2003 was selected. 4820 patients with a previous hospital admission reporting a diagnosis of complicated hypertension within the preceding 22 months were studied. a logistic model was constructed. both crude and adjusted probability of reporting a hypertension in ami admissions, depending from the number of diagnosis fields compiled in discharge abstracts, and presence of other diseases were estimated. results: in 57.9% of patients hypertension was not reported. probability of reporting hypertension increased with the number of compiled diagnosis fields (adjusted ors range: 1.50-2.17). there were no significant differences among italian regions, while private hospitals' reporting was less accurate. disorders of lipoid metabolism were more probably coded with hypertension (adjusted or: 4.37). conclusions: information from both ami and previous hospitali-sations would be needed to include hypertension in a comorbidity measure. abstract background: the angiotensin converting enzyme inhibitors (acei) should be considered the standard initial treatment of the systolic heart failure. this treatment is not recommended in patients with hypotension, although figures of systolic blood pressure around 85-90 mmhg during the treatment are allowed if the patient remains asymptomatic. objectives: to know the proportion of patients with systolic heart failure receiving treatment with acei, and the proportion of these patients with signs oh hypotension. design and methods: the electronic clinical records of all the patients diagnosed of systolic heart failure were reviewed. the electronic information system covers a 60% of the population of the basque country, approximately. diagnosis of heart failure was defined as the presence of any of the following cie-9 codes: 428 or 402.11 or 402.91. to evaluate the blood pressure, the last available determination was considered. results: out of 9464 patients with left heart failure, 4108 (43.4%) have been prescribed acei. among the 328 patients with blood pressure lower than 85mmhg (systolic) or than 60mmhg (diastolic), 163 (49.7%) were also receiving this treatment. conclusions: acei are clearly underprescribed in the basque country for the treatment of heart failure. attention should be given to the group at risk of hypotension. abstract background: epidemiologic studies have shown an association between c-reactive protein (crp) and cardiovascular endpoints in population samples. methods: in a longitudinal study of 1006 myocardial infarction (mi) survivors, crp was measured repeatedly (up to 8 times) within a period of 13 months. data on disease history and life style were collected at baseline. we examined the association between different variables and the level of crp using a random effects model. results: in total 5835 crp samples were collected in athens, augsburg, barcelona, helsinki, rome and stockholm. mean levels of crp were 2.6, 2.4, 3.4, 2.0, 2.5, 2.8 [mg/l] respectively. body mass index (bmi) and chronic bronchitis (ever diagnosed) had the largest effect on crp (38% (for 5 kg/m 2 ) and 32% change from the mean level, respectively, p<0.05). age classes showed a cubic function with a minimum at ages 50 to 60. glycosylated hemoglobin (hba1c) <6.5% as a measure of long-term blood glucose control and being male were found to be protective ()21% and )17% respectively, p<0.05). conclusion: it was shown that bmi and history of bronchitis are important in predicting the level of crp. other variables, like alcohol intake, play a minor role in this large sample of mi patients. abstract background: during the last decades a remarkable increase in incidence rates of malignant lymphoma was seen. although some reasons are known or suspect underlying risk factors are not well understood. objectives: we studied the influence of medical radiation (x-ray, radiotherapy and szintigraphy) on the risk of malignant lymphoma. methods: we analysed data from a population-based case-control study with 710 incident lymphoma cases in germany from 1999-2003. after informed consent cases were pair-matched with controls recruited from registration office by age, gender and study region. data was collected in a personal interview. we analysed data using conditional logistic regression. results: the linear model shows an or = 0.99/msv due to x-ray exposure and or = 0.63 (95%-ci = 0.5-0.79) comparing higher with lower exposure. radiotherapy shows an or = 0.76 (n = 31 cases). there is no association between all lymphomas and szintigraphies but in the subgroup containing multiple myeloma, cll, malt-and marginalcell lymphoma we found an or = 1.86 (95%-ci = 1.02-3.40) in the multivariate model. discussion: no excess risk was observed for x-ray examinations. ionising radiation may increase risk for specific lymphoma subgroups. however, it should be noted that numbers in the subgroups are small and that radiation dose may be somehow inaccurate as no measures were available. abstract background: varus-alignment (bow-leggedness) is assumed to correlate with knee osteoarthritis (oa), but it is unknown whether varus-alignment precedes the oa or whether varus-alignment is a result of oa. objective: to assess the relationship between varusalignment and the development, as well as progression, of knee oa. methods: 1,501 participants in the rotterdam study were selected. knee oa at baseline and at follow-up (mean follow-up 6.6 years) was defined as kellgren & lawrence (k&l) grade 3 2, and progression of oa as an increase of 3 1 k&l degree. alignment was measured by the femoro-tibial angle on baseline radiographs. multivariable logistic regression for repeated measurements was used. results: of 2,664 knees, 35.2% showed normal alignment, 64.3% varus-alignment, and 0.5% valgus-alignment. comparison of high varus-alignment versus normal, low and mediate varus-alignment together, showed a two-fold increase in the development of knee oa. (or = 1.83; 95%ci = 1.17-2.85). the risk of progression was higher in the high varus group compared to the normal, low and mediate varus group (or = 2.53; 95%ci = 1.04-6.19). stratification for overweight gave similar odds ratio's in the overweight group, but weaker odds ratio's in the non-overweight group. conclusion: a higher value of varus-alignment is associated with the onset and progression of knee oa. abstract background: echocardiographic image quality in copd patients can be hampered by hyperinflated lungs. cardiovascular magnetic resonance imaging (cmr) may overcome this problem and provides accurate and reproducible information about the heart without geometric assumptions. objective: to determine the value of easily assessable cmr parameters compared to other diagnostic tests in identifying heart failure (hf) in copd patients. design and methods: participants were recruited from a cohort of 405 copd patients = 65 years. a panel established the diagnosis of hf during consensus meetings using all diagnostic information, including echocardiography. in a nested case-control study design, 37 copd patients with hf (cases) and a random sample of 41 copd patients without hf (controls) received cmr. the diagnostic value of cmr for diagnosing hf was quantified using univariate and multivariate logistic modelling and roc-area analyses. results: four easily assessable cmr measurements had significantly more added diagnostic value beyond clinical items (roc-area 0.91) than amino-terminal pro b-type natriuretic peptide (roc-area 0.80) or electrocardiography (roc-area 0.77). a 'cmr model' without clinical items had an roc-area of 0.88. conclusion: cmr has excellent capacities to establish a diagnosis of heart failure in copd patients and could be an alternative for echocardiography in this group of patients. abstract background: the prevalence of overweight (i.e, body mass index [bmi] > = 25 kg/m2) is increasing. new approaches to address this problem are needed. objectives: 1) to assess the effectiveness of distance counseling (i.e., by phone and e-mail/internet) on body weight and bmi, in an overweight working population. 2) to assess differences in effectiveness of the two communication methods. design and methods: 1386 overweight employees (67% male; mean age 43.9±8.6 years; mean bmi 29.6±3.5 kg/m2) were randomized to a control group receiving general information on overweight and lifestyle (n = 460), a phone based intervention group (n = 462) and an internet based intervention group (n = 464). the intervention took 6 months and used a cognitive behavioral approach, addressing physical activity and diet. the primary outcome measures, body weight and bmi, were measured at baseline and at six months. statistical analyses were performed with multiple linear regression. results: the intervention groups (i.e., phone and e-mail combined) lost 1.5 kg (bmi reduced by 0.5 kg/m2) over the control group (p = 0.000). the phone group lost 0.5 kg more than the internet group (p = 0.179). abstract objective: although an inverse gradient education-mortality has been shown in the general population, little is known about this trend in groups with higher risks of death.we examine differences in mortality by education and hiv-status among injecting drug users (idus) before and after introduction of highly active antiretroviral therapy (haart) in 1997. methods: communitybased cohort study of idus recruited in 3 aids prevention centres (1987) (1988) (1989) (1990) (1991) (1992) (1993) (1994) (1995) (1996) abstract background: pancreatic cancer is an aggressive cancer with low survival time, with health-related quality of life (hrqol) being of major importance. objectives: the aim of our study was to assess both generic and disease-specific hrqol in patients with pancreatic cancer. methods: patients with suspected pancreatic cancer were consecutively included at admission to the hospital. hrqol was determined with the disease-specific european organization for research and treatment of cancer (eortc) health status instrument and generic euroqol (eq-5d). results: a total of 57 patients (mean age 62 years ±11, 49% men) were admitted with suspected pancreatic cancer. of these patients, 45 (79%) had pancreatic cancer confirmed as final diagnosis. hrqol was significantly impaired in patients with pancreatic cancer for most eortc and eq-5d scales in comparison to norm populations. the ed-5d visual analogue scale (vas) and utility values were significantly correlated to the five functional scales, to the global health scale and to some but not all of the eortc symptom scales/items. conclusions: hrqol was severely impaired in patients with pancreatic cancer. there was a significant correlation between most eortc and eq-5d scales. our results may facilitate further economic evaluations and aid health policy makers in resource allocation. abstract background: organised violence has health impact both on those who experience the violence directly and indirectly. the numbers of people affected by mass violence is alarming. substantial knowledge on the long-term health impact of organized violence is of importance for public health and for epidemiology. objectives: to investigate research results of long term mental health impact of organised violence. design and methods: a search of papers for the keywords genocide, organised violence, transgenerational effects, mental health was carried out in pubmed, science citation index and psychinfo. results: the systematic review on the long-term health impact of genocide showed that exposure to organised violence has an impact on mental health. methodological strenghts and weaknesses varied between studies. the found mental health consequences were associated with the country of research and the time of study. overall data showed organised violence has transgenerational impact on mental health of individuals and societies. conclusion: longitudinal studies have to be carried out to get further insight into the long-term health effects of organised violence. discussion: research results on mental health effects of organised violence have to be analysed in the context of changing concepts of illness. overweight is increasing and associated with various health problems. there are no well-structured primary care programs for overweight available in the netherlands. therefore, we developed a 12-month multidisciplinary treatment program in a primary care setting. the aim of the present study is to determine the feasibility and efficacy of a multidisciplinary treatment program on weight loss and risk profile in an adult overweight population. hundred participants of the utrecht health project are randomised to either a dietetic group or a dietetic plus physiotherapy group. the control group consist of another 50 participants recruited from the utrecht health project and receives routine health care. body weight, waist circumference, blood pressure, serum levels, energy-intake and physical activity are measured at baseline, halfway and at the end of the treatment program. feasibility of the treatment program is assessed by response, compliance and program-associated costs and workload. efficacy is determined by analysing changes in outcome measures between groups over time using t-tests and anova repeated measurements. the treatment program is considered effective with at least a 5% difference in mean weight change over time between groups. positive evaluation of the multidisciplinary treatment program for overweight may lead to implementation in routine primary health care. abstract background: examining patient's quality of life (qol) before icu admission will permit to compare and analyze its relation with other variables. objectives: analyze qol of patients admitted to a surgical icu before admission and study its relation with baseline characteristics and outcome. design and methods: the study was observational and prospective in a surgical icu, enrolling all patients admitted between november 2004 and april 2005. baseline characteristics of patients, history of co morbidities and quality of life survey score (qolss) were recorded. assessment of the relation between each variable or outcome and the total score of qolss was performed by multiple linear regression. results: total qolss demonstrated worse qol in patients with hypertension, cerebrovascular disease, renal insufficiency, severely ill (as measured by saps and asa physical status), and in older patients. there was no relation between qol and longer icu los. conclusions: preadmission qol correlates with age, severity of illness, comorbidities and mortality rates but is an able to predict longer icu stay. discussion: qolss appears to be a good indicator of outcome and severity of illness. abstract background: transient loss of consciousness (tloc) has a cumulative lifetime incidence of 35%, and can be caused by various disorders. objectives: to assess the yield and accuracy of initial evaluation (standardized history, physical examination and ecg), performed by attending physicians in patients with tloc, using follow-up as a gold standard. design and methods: adult patients presenting with tloc to the academic medical centre between february 2000 and may 2002 were included. after initial evaluation physicians made a certain, likely or no initial diagnosis. when no diagnosis was made additional cardiological testing, expert history taking and autonomic function testing were performed. the final diagnosis, after 2 years follow-up, was determined by an expert committee. results: 503 patients were included. after initial evaluation, 24% of the patients were diagnosed with a certain and 40% with a likely cause for their episodes. overall diagnostic accuracy was 91% (95%ci 88-94%); 96% (95%ci 91-98%) for the certain diagnoses and 88% (95%ci 83-92%) for the likely diagnoses. conclusion and discussion: attending physicians make a diagnosis in 64% of patients with tloc after initial evaluation, with high accuracy. the use of abundant additional testing can be avoided in many patients. abstract background: the possibility of an influenza pandemic is one of the major public health challenges of today. risk perceptions among the general public may be important for successful public health measures to better control an outbreak situation. objectives: we investigated risk perception and efficacy beliefs related to an influenza pandemic in the general population in 8 countries in europe and asia. design and methods: telephone interviews were conducted in 2005. risk perception of an influenza pandemic was measured on a 5-point scale and outcome-and self-efficacy on a 4point scale (low-high). the differences in risk perception by country, sex and age were assessed with a general linear model including interaction effects. results: 3,403 persons were interviewed. the mean risk perception of flu was 3.14 and was significantly higher in europe (3.21) compared to asia (3.03) (p<0.001) and higher in women (3.23) than men (3.02) (p<0.001). outcome-and self-efficacy were lower in europe than asia. conclusion: in europe higher risk perceptions and lower efficacy beliefs were found as compared to asia. in developing preparedness plans for an influenza pandemic specific attention should therefore be paid to risk communication and how perceived self-efficacy can be increased. abstract background: increased survival of patients with cf has prompted interest towards their hrqol. objectives: 1.to measure hrqol and its predictors in cf patients cared for at the bambino gesuc hildren's hospital in rome; 2. to assess the psychometric properties of the italian version of the cf specific hrqol instrument (cystic fibrosis questionnaire, cfq). design and methods: crosssectional survey. all cf patients aged 7 years or more were asked to complete the cfq (age-specific format). psychological distress was assessed through standardized questionnaires in patients (achenbach and general health questionnaire, ghq) and their parents (ghq and sf-36). results: one-hundred-eighteen patients (58 males, 60 females, age range 7 to 39 years) participated in the study (response rate 97%). internal consistency of cfq was satisfactory (cronbach alpha from 0.60 to 0.88); all item-test correlation were greater than 0.40. average cfq standardized scores were very good in all domains (>70 on a 0-100 scale), except perceived burden of treatments (57) and degree of socialization (45). multiple regression analysis was performed to identify factors associated with different hrqol dimensions. conclusion: support interventions for these patients should concentrate on finding a balance between need to prevent infections and promotions of adequate, age-appropriate social interactions. abstract background: the metabolic syndrome (metsyn) -a clustering of metabolic risk factors with diabetes and cardiovascular diseases as the primary clinical outcomes -is thought to be highly prevalent with an enormous impact on public health. to date, consistent data in germany are missing. objective: the study was conducted to examine the prevalence of the metsyn (according to ncap atp iii-definition) among german patients in primary care. methods: the german-wide cross-sectional study run two weeks in october 2005 with 1503 randomly selected general practitioners included. blood glucose and serum lipids were analyzed, waist circumference and blood pressure assessed, data on smoking, dietary and exercise habits, regional and sociodemographic characteristics collected. abstract background: excessive infant crying is a common and often stress inducing problem than can ultimately result in child abuse. from previous research is known that maternal depression during pregnancy is related to excessive crying, but so far little attention is paid to paternal depression. objective: we studied whether paternal depression is independently associated to excessive infant crying. design and methods: in a prospective multiethnic population-based study we obtained depression scores of 3,451 mothers and 2,606 fathers at 20 weeks pregnancy using the brief symptom inventory, and information on crying behaviour of 2,747 infants at 2 months. we used logistic regression analyses in which we adjusted for depression of the mother, level of education, smoking and alcohol use. results: paternal depressive symptomatology was related to the widely used wessel's criteria for excessive crying (adusted odds ratio 2.34, 1.22 -4.49). conclusion: our findings indicate that paternal depressive symptomatology might be a risk factor for excessive infant crying. discussion genetic as well as other direct (e.g. interaction between father and child) or indirect (e.g. marital distress or poor circumstances) mechanisms could explain the found association. abstract background: in studying genetic background of congenital anomalies the comparison of affected cases to non-affected controls is popular method. investigation of case-parent triads uses observation of cases and their parents exclusively. methods: both casecontrol approach and log-linear case-parent triads model were implemented to spina bifida (sb) cases and their parents (61 triads) and 267 controls in analysis of impact of the c667t and a1298c mthfr polymorphisms on occurrence of sb. results: observed frequencies for 677tt genotype were 11,5% in sb children, 6,6% in mothers, 9,8% in fathers, 8,6% in controls and for 1298cc genotype were 4,9% of sb children, 4,9% of mothers, 11,5% of fathers and 7,9% of controls. both genotype frequencies in sb triads did not differ significantly from controls. case-control approach showed nonsignificant increase in risk of having sb for 677t allele carriers either in homozygous (or = 1,7) or heterozygous form (or = 1,2) and for 1298c allele carriers in heterozygous form (or = 1,3). log-linear model revealed significant relative risk of sb in children with both 677tt and ct genotype (rr = 3,77 and rr = 2,37 respectively). child's genotype at a1298c and mother's genotypes did not contribute to the risk. conclusions: caseparent triads approach adds new information regarding impact of parental imprinting on congenital anomalies. abstract background: previous studies showed an association of autonomic dysfunction with coronary heart disease (chd) and with depression as well as an association of depression with chd. however, there is limited information on autonomic dysfunction as potential mediator of the adverse effect of depression on chd. objectives: to examine the role of autonomic dysfunction as a potential mediator of the association of depression with chd. design/ methods: we used data of 1309 participants aged 45-83 years of the ongoing population-based cross-sectional carla study (54% male). time-and frequency-domain parameters of heart rate variability (hrv) as a marker of autonomic dysfunction were calculated. prevalent myocardial infarction (mi) was defined as selfreported physician-diagnosed mi or diagnostic minnesota code in the electrocardiogram. depression was defined based on the cesd-depression scale. logistic regression was used to assess associations between depression, hrv and mi. results: in ageadjusted logistic regression models, there was no statistically significant association of hrv with depression, of depression with mi, or of hrv with mi in men and women. discussion/conclusion: the present analyses do not support the hypothesis of an intermediate role of autonomic dysfunction on the causal path from depression to chd. abstract background: hypertension is an established risk factor for cardiovascular disease. however, prevalence of untreated or uncontrolled hypertension is often high (even in populations at high risk). objectives: to assess the prevalence of untreated and of uncontrolled hypertension in an elderly east german population. design and methods preliminary data of a cross-sectional, populationbased examination of 1556 men and women aged 45-83 years were analysed. systolic (sbp) and diastolic blood pressure (dbp) were measured and physician-diagnosed hypertension and use of antihypertensive drugs were recorded. prevalence of hypertension was calculated according to age and sex. results: of all participants, 78.5 % were hypertensive (81.8 % of men, 74.8 % of women). of these, 29.7 % were untreated, 43.8 % treated but uncontrolled, and 26.6 % controlled. women were more often properly treated than men. the prevalence of untreated hypertension was highest in men aged 45-55 years (60.9 %) and lowest in men and women aged > = 75 years (12.6 %). uncontrolled hypertension increases with age in both sexes. conclusion and discussion: in this elderly population, there is a high prevalence of untreated and uncontrolled hypertension. higher awareness in the population and among physicians is needed to prevent sequelae such as cardiovascular disease. abstract background: exposure to pesticides is a potential risk factor for subfertility, which can be measured by time-to-pregnancy (ttp). as female greenhouse workers constitute a major group of workers exposed to pesticides at childbearing age, a study was performed among these and a non-exposed group of female workers. objectives: to measure the effects of pesticide exposure on time-topregnancy. design and methods: data were collected through postal questionnaires with detailed questions on ttp, lifestyle factors, and work tasks (e.g. application of pesticides, re-entry activities, and work hours) during six months prior to conception of the most recent pregnancy. associations between ttp and exposure to pesticides were studied in cox's proportional hazards models among 398 female greenhouse workers and 524 referents. results: the initial fecundability ratio (fradjusted) for greenhouse workers versus referents was 1.11 (95%ci: 0.96-1.29). this fr proved to be biased by the reproductively unhealthy worker effect. restricting the analyses to fulltime workers only gave an fradjusted of 0.89 (95%ci: 0.67-1.19). among primigravidous greenhouse workers, an association was observed between prolonged ttp and gathering flowers (fr = 0.46, 95%ci: 0.18-1.19). conclusion and discussion: this study adds some evidence to the hypothesis of adverse effects of pesticide exposure on time-topregnancy, but more research is needed. abstract background: hfe-related hereditary hemochromatosis (hh) is an iron overload disease for which screening is recommended to prevent morbidity and mortality. however, discussion has risen on the clinical penetrance of the hfe-gene mutations. objective: in the present study the morbidity and mortality of families with hferelated hh is compared to a normal population. methods: c282yhomozygous probands with clinically overt hfe-related hh and their first-degree relatives filled in a questionnaire on health, diseases and mortality among relatives. laboratory results on serum iron parameters and hfe-genotype were collected. the self-reported morbidity, family mortality and laboratory results were compared with an age and gender matched subpopulation of the nijmegen biomedical study (nbs), a population-based survey conducted in the eastern part of the netherlands. results: twohundred-twenty-eight probands and 743 first-degree relatives participated in the hefas. serum iron parameters were significantly elevated in the hefas population compared to the nbs controls. also, the morbidity within hefas families was significantly increased for fatigue, hypertension, liver disease, myocardial infarction, osteoporosis and rheumatism. mortality among siblings, children and parents of hefas probands and nbs participants was similar. discussion: the substantially elevated morbidity within hefas families justifies further exploration for a family cascade screening program for hh in the netherlands. abstract objectives: to evaluate awareness levels and effectiveness of warning labels in cigarette packs, among portuguese students enrolled in the 7th to the 12th grades. design and methods: a cross sectional-study was carried out in may (2004) in a high school population (7th-12th grades) in the north of portugal (n = 1005). a confidential self-reported questionnaire was administered. warning labels effectiveness was evaluated by changes in smoking behaviour and cigarette consuption, during the period between june/2003 (before the implementation of the tobacco warnings labels in portugal) and may/2004. continuous variables were compared by the t-test for paired samples and kruskal-wallis test. crude and adjusted odds ratios and confidential intervals were calculated by logistic regression analysis. results: the majority of students (71.8%) have a high level of awareness about warning labels content. this knowledge was significantly associated with school grade and current smoking status. none of these variables was significantly associated with changes in smoking behaviour. although not reaching statistic significance, the majority of teenagers (75.4%) increased or kept their smoking pattern. awareness level was not associated with smoking prevalence or consumption decreases. conclusions: current warning labels are ineffective in changing smoking behaviour among portuguese adolescents. abstract background: injuries are an important cause of morbidity. the presence of pre-existing chronic conditions (pecs) have been shown to be associated with higher mortality. objectives: aim of this study is to evaluate the association between pecs and risk of death in elder trauma patients. methods: an injury surveillance, based on the integration between emergency, hospital, and mortality databases of lazio region, year 2000, was used. patients were the elder people visited at the emergency departments, and hospitalised. pecs were evaluated on the basis of the charlson comorbidity index (cci). to measure the effect of pecs on the probability of death, we used logistic regression. results: 8145 patients were admitted to the hospital. the 17.9% of the injured subjects were affected by one or more chronic conditions. risk of death for non urgent and urgent patients increased at increasing cci score abstract background: c-reactive protein (crp) was shown to predict prognosis in heart failure (hf). objective: to assess variability of crp over time in patients with stable hf. methods: we measured high-sensitivity crp (hscrp) 3 times (3-week intervals) in patients with stable hf. patients whose hscrp was >1 mg/dl or whose clinical status deteriorated were excluded. two consecutive hscrp measurements were available for 50 patients: 37 men, mean(sd) age 69.6(11.9) years, 82% depressed left ventricular systolic function. forty-four patients had a third measurement. using the cutoff point of 0.3mg/dl for prediction of adverse cardiac events we assessed the proportion of patients who changed risk category. results: median(p25-p75) baseline hscrp was 0.19mg/dl(0.12-0.34). hscrp varied largely particularly for higher levels. the 5th and 95th percentiles of differences between first two measurements were )0.20mg/dl and +0.55mg/dl. correlation coefficient between these measurements: 0.55, p<0.001. eleven (22%) patients changed risk category, kappa = 0.53, p<0.001. among patients whose first two measurements were concordant, 16.7% changed category in third measurement, kappa = 0.65, p<0.001. conclusion: large variability in hscrp in stable hf may decrease the validity of risk stratification based on single measurements. it remains to be demonstrated whether the pattern of change over time adds predictive value in hf patients. abstract background: instrumental variables can be used to adjust for confounding in observational studies. this method has not yet been applied with censored survival outcomes. objectives: to show how instrumental variables can be combined with survival analysis. design and methods: in a sample of 415 patients with type-1 diabetes who started renal-replacement therapy in the netherlands between 1985 and 1996, the effect of pancreas-kidney transplantation versus kidney transplantation on mortality was analyzed using region as the instrumental variable. because the hospital could not be chosen with this type of transplantation, patients can be assumed to be naturally randomized across hospitals. we calculated an adjusted difference in survival probabilities for every time point including the appropriate confidence interval (ci95%). results: the 5-year difference in survival probabilities between the two transplantation methods, adjusted for measured and unmeasured confounders, was 0.37 (ci95%: 0.18-0.57) favoring the pancreas-kidney transplantation. this is substantially larger than the intention-to-treat estimate of 0.13 (ci95%: 0.01-0.25) where policies are compared. conclusion and discussion: instrumental variables are not restricted to uncensored data, but can also be used with a censored survival outcome. hazard ratios with this method have not yet been developed. the strong assumptions of this technique apply similarly with survival outcomes. 11.2] . sir of coronary heart disease was 5.7 [95%ci: 4.8-6.7] and remained significantly increased up to 30 years of follow-up. cox regression analysis showed a 3.2-fold (95% ci, 1.6-6.4) increased risk of congestive heart failure after anthracyclines and a 5.3-fold (95% ci, 1.6-16.8) increased risk of coronary heart disease after radiotherapy to the mediastinum. conclusion: the incidence of several cardiac diseases was strongly increased after treatment for hl, even after prolonged follow-up. anthracyclines increased the risk of congestive heart failure and radiotherapy to the mediastinum increased the risk of coronary heart disease. abstract background: the concept of reproductive health is emerging as an essential need for health development. objectives: to know the opinions of parents, teachers and students about education of reproductive health issues to students of mid and high schools. design and methods: focus group discussions (fgd) as a qualitative research was chosen. a series of 24 group discussions with participation of 162 persons (64 students, 50 teachers, and 48 parents) was held. each group had included 6 to 9 persons. results: all the participants noted to a true need in education of puberty health in order to provide essentials for pre-adolescent students to adopt the psycho-and somatic changes of puberty. however, a few fathers and a group of mothers believed that education of family planning is not suitable for students. a need for education of aids and marital problems for students was the major concern in all groups. the female students emphasized a need for programming counseling in pre-marital period. conclusion: essentials in puberty health, family planning, aids and marital problems should be provided in mid-and high schools in order to narrow the knowledge gap of the students. abstract background: the association between social support and hypertension in pregnancy remains controversial. objective: the objective of this study was to investigate whether level of social support is a protective factor against preeclampsia and eclampsia. design and methods: a case-control study was carried out in a public high-risk maternity hospital in rio de janeiro, brazil. between july 2003-may 2004, all 225 cases, identified at diagnosis, and 459 controls, matched on gestational age, were included in the study. participants were interviewed about clinical history, socio-demographic and psychosocial characteristics. the principal exposure was the level of social support available during the pregnancy, using the medical outcomes study scale. adjusted odds ratios were estimated using multivariate conditional logistic regression. results: multiparous women with a higher level of social support had a lower risk of presenting with preeclampsia and eclampsia (or = 0.7), although this association was not statistically significant (95% ci 0.4-1.2). in primiparous women, a higher level of social support was seen amongst cases (or = 2.1; 95% ci 1.5-2.9). an interaction between level of social support and stressful life events was not identified. these results contribute to increased knowledge of the relationship between preeclampsia and psychosocial factors in low-income pregnant and puerperal women. abstract background: current case-definitions for cfs/me are designed for clinical-use and not appropriate for health needs assessment. a robust epidemiological case-definition is crucial in order to achieve rational allocation of resources to improve service provision for people with cfs/me. objectives: to identify the clinical features that distinguish people with cfs/me from those with other forms of chronic fatigue and to develop a reliable epidemiological case-definition. methods-primary care patient data for unexplained chronic fatigue was assessed for symptoms, exclusionary and comorbid conditions and demographic characteristics. 101 cases were assigned to disease and non-disease groups by three members of the chief medical officer's working group on cfs/me (reliability-cronbach's alpha 0.644). results: preliminary multivariate analyses were conducted and classification and regression tree analysis included a 10-fold cross-validation approach to prevent over fitting. the results suggested that there were at least four strong discriminating variables for cfs/ me with 'post-exertional malaise' being the strongest predictor. risk and classification tables showed an overall correct classification rate of 81.2%. conclusion: the analyses demonstrated that the application of the combination of the four discriminating variables (the defacto epidemiological case-definition) and predefined comorbid conditions had the ability to differentiate between cfs/me and non-cfs/me cases. abstract background: infection with high-risk human papillomavirus (hpv) is a necessary cause for cervical cancer. vaccines against the most common types (hpv16, hpv18) are being developed. relatively little is known about factors associated with hpv16 or hpv18 infection. we investigated associations between lifestyle factors and hpv16 and hpv18 infection. methods: 5031 uk women aged 20-59 years with a recent abnormal cervical smear underwent hpv testing and completed a lifestyle questionnaire. hpv16 and hpv18 status was determined using type-specific pcrs. associations between lifestyle factors and hpv status were assessed by multivariate logistic regression models. results: 16.5% (95%ci 15.4%-17.6%) of women were hpv16-positive. 8.6% (95% ci 7.9%-9.5%) were hpv18-positive. for both types, the proportion testing positive decreased with increasing age, and increased with increasing grade of cytological abnormality. after adjusting for these factors, significant associations remained between (i) hpv16 and marital, employment, and smoking status and (ii) hpv18 and marital status and contraceptive pill use. gravidity, ethnicity, barrier contraceptive use and socio-economic status were not related to either type. conclusions we identified modest associations between several lifestyle factors and hpv16 and hpv18. studies of this type help elucidate hpv natural history in different populations and will inform development of future vaccine delivery programmes. in ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. we set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men. we recruited 237 men with serum testosterone levels below 17 nmol/l and ages 60-80 years. they were randomized to either four capsules of 40 mg testosterone undecanoate (tu) or placebo daily for 26 weeks. primary endpoints are functional mobility and quality of life. secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. effects on prostate, liver and hematological parameters will be studied with respect to safety. measure of effect will be the difference in change from baseline visit to final visit between tu and placebo. we will study whether the effect of tu differs across subgroups of baseline waist girth, testosterone level, age, and level of outcome under study. at baseline, mean age, bmi and testosterone levels were 67 (yrs), 27 (kg/m2) and 13.x (nmol/l), respectively. abstract at a student population, the carie's prevalence was 56,28%. objectives: to evaluate the efficiency between two types of oral health education programmes and the adherence towards tooth brushing. study design: case control study: 333 youngsters took part, 134 in the case group. an health education programme was carried out in 8 schools and included two types of strategies: a participative strategy (learning based on the colouring of the dental plaque) towards a case group; and a traditional strategy (oral expository method) towards a control group. during the outcome of the programmes, the oral health condition evaluation was done through cpo index, the adherence towards tooth brushing and the (iho's) oral hygiene index. results: in the initial dental exam the (iho) average was of 1,60. three months after the application of the oral health programme, there was a general decrease in the average of iho's to 1,30. discussion and conclusion: in the case group the decrease was higher: 0,36 to 0,20. the students submitted to a session of oral health education based on the colouring of the dental plaque showed an lower iho's average and higher knowledge. this can be due to the teaching session being more active, participative and demonstrative. abstract background: violence perpetuated by adolescents is a major problem in many societies. objectives: the aim of this study is to examine high school students' violent behaviour and to identify predictors. design and methods: a cross-sectional study was conducted in timis county, romania between may-june 2004. the sample consisted of 149 randomly selected classes, stratified proportionally according to grades 9-12, high school profile, urban and rural environment. the students completed a self administered questionnaire in their classroom. a weighting factor was applied to each student record to adjust for non-response and for the varying probabilities of selection. results: a total of 2908 students were included in the survey. during the last 12 months, 24.3% of adolescents got mixed into a physical fight outside school and 14.5% on school property. abstract background: drug use by adolescents has become an increasing public health problem in many countries. objectives: the aim of this study is to identify prevalence of drug use and to examine high school students' perceived risks of substance use. design and methods: a cross-sectional study was conducted in timis county, romania between may-june 2004. the sample consisted of 149 randomly selected classes, stratified proportionally according to grades 9-12, high school profile, urban and rural environment. the students completed a self administered questionnaire in their classroom. eighteen items regarding illicit drug use suggesting different intensity of use were listed. the response categories were 'no risk', 'slight risk', 'moderate risk', 'great risk' and 'don't know'. results: a total of 2908 students were included in the survey. the lifetime prevalence of any illicit drug was 5.3%. significant beliefs associated with drug use are: trying marijuana once or twice (p<0.001), smoking marijuana occasionally (p = 0.003), trying lsd once or twice (p = 0.035), trying cocaine once or twice (p = 0.001), trying heroine once or twice (p = 0.002). conclusion: the overall drug use prevalence is small. however, use of some drugs once or twice is not seen as a very risky behaviour. abstract background: the health ombudsman service was created in ceara´, brazil, in 1991, with the objective of receiving user opinions about public services. objectives: to describe user profiles, evaluating their satisfaction with health services and the ombudsman service itself. design and methods: a transversal and exploratory study with a random sample of 292 users who had used the service in the last three months. the data were analyzed with the epi info program. results: women were those who used the service most (74.1%). the users sought the service for complaints (64.7%), guidance (12.3%) and commendation (11.5%). users made the following complaints about health services: lack of care (57.8%), poor assistance (52.0%) lack of medication (8.6%). in relation to the ombudsman service, the following failures were mentioned: lack of autonomy (14.7%), delay in solving problems (8.0%) and few ombudsmen (6.6%). conclusion: participation of the population in use of the serviced is small. the service does not satisfy the expectations of users, it is necessary to publicize the service and try to establish an effective partnership between users and ombudsmen so that the population finds in the ombudsman service an instrument to put into effect social control and improve the quality of health services. in chile, the rates of breast cancer and diabetes have dramatically increased in the last decade. the role of insulin resistance in the development of breast cancer, however, remains unexplored. we conducted a hospital-based case-control to assess the relationship of insulin resistance (ir) and breast cancer in chilean pre and postmenopausal women. we compared 175 women, 33-86 y, with incident breast cancer diagnosed by biopsy and 209 controls with normal mammography. insulin and glucose were measured in blood and ir was calculated by homeostasis model assessment method. anthropometric measurements and socio-demographic and behavioural data were also collected. odds ratios (ors) and 95% confidence intervals (cis) were estimated by multivariate logistic regression. the risk of breast cancer increased with age. ir was significantly associated to breast cancer in postmenopausal women (or = 2.03, 95%ci = 1.11-3.74), but not in premenopausal (p>0.05). socioeconomic status and smoking appeared as important risk factors for breast cancer. obesity was not associated with breast cancer at any age (p>0.05). in these women, ir increased the risk of breast cancer only after menopause. overall, these results suggest a different risk pattern for breast cancer before and after menopause. keywords: insulin resistance; breast cancer; chile. abstract background: previous european community health indicators (echi) projects have proposed a shortlist of 82 indicators as a common conceptual structure for health information. the european community health indicators and monitoring (echim) is a 3-year project to develop and implement health indicators and to develop health monitoring. objectives: our aim is to assess the availability and comparability of the echi-shortlist indicators in european countries. methods: four widely used health indicators i) perceived general health ii-iii) prevalence of any and certain chronic diseases or conditions iv) limitations in activities of daily living (adl) were evaluated. our evaluation of available sources for these indicators is based on the european health interview & health examination surveys database (171 surveys in chile, breast cancer, obesity and sedentary behaviour rates are increasing. the role of specific nutrients and exercise in the risk of breast cancer remains unclear. the aim of the present study was to evaluate the role of fruits and vegetables intake and physical activity in the prevention of breast cancer. we undertook an age matched case-control study. cases were 170 women with breast cancer histologically confirmed and controls were 170 women with normal mammography, admitted to the same hospital. a structured questionnaire was used to obtain dietary information and measurement of physical activity was obtained from the international physical activity questionnaire. odds ratios (ors) and 95% confidence intervals (cis) were estimated by conditional logistic regression adjusted by obesity, socioeconomic status and smoking habit. a significant association was found with fruit intake (or = 0.57, 95%ci = 0.35-0.94). the consumption of vegetables (or = 0.91, 95%ci = 0.80-1.04), moderate (or = 1.00, 95%ci = 0.62-1.59) and high physical activity (or = 1.13, 95%ci = 0.51-2.50) were not observed as protective factors. in conclusion, the consumption of fruit is protective in breast cancer. these findings need to be replicated at chile to support the role of diet and physical activity in breast cancer and subsequence contribution in public health policy. keywords: diet; physical activity; breast cancer; chile. the role of trace elements in pathogenesis of liver cirrhosis and its complications is still not clearly understood. serum concentrations of zinc, copper, manganese and magnesium were determinated in 100 patients with alcoholic liver cirrhosis and 50 healthy subjects by means of plasma sequential spectrophotometer. serum levels of zinc were significantly lower (median 0.77 vs 11.0lmol/l, p = 0.001) in patients with liver cirrhosis in comparison to controls. serum levels of copper were significantly higher in patients with liver cirrhosis (23.71 vs 13.32lmol/l, p<0.001) as well as manganese (4.60 vs 0.02lmol/l, p = 0.001). concentration of magnesium was not significantly different between patients with liver cirrhosis and controls (0.94 vs 0.88 mmol/l, p = 0.060). there was no difference in trace elements concentrations between child-pugh groups. zinc level was significantly lower in patients with hepatic encephalopathy in comparison to cirrhotic patients without encephalopathy (0.60 vs 0.96lmol/l, p = 0.020). manganese was significantly higher in cirrhotic patients with ascites in comparison to those without ascites (6.05 vs 2.60lmol/l, p = 0.039). correction of trace elements concentrations might have beneficial effect on complications and maybe progression of liver cirrhosis. it would be recommendable to provide analyzis of trace elements as a routine. abstract background: respiratory tract infections (rti) are very common in childhood and knowledge of pathogenesis and risk factors is required for effective prevention. objective: to investigate the association between early atopic symptoms and occurrence of recurrent rti during first 4 years of life. design and methods: in the prospective prevention and incidence of asthma and mite allergy birth cohort study, 4146 children were followed from birth to the age of 4 years. information on atopic symptoms, potential confounders, and effect modifiers like passive smoking, daycare attendance and presence of siblings was collected at ages 3 months and 1 year by parental questionnaires. information on rti was collected at ages 1, 2, 3, and 4 years. results: children with early atopic symptoms, i.e. itchy skin rash and/or eczema or doctordiagnosed cow's milk allergy at 1 year of age had a slightly higher risk to develop recurrent rti (aor 1.20 (0.83-1.73); and 1.98 (1.06-3.70), respectively). the association between atopic symptoms and recurrent rti was stronger in children whose mother smoked during pregnancy and who had siblings (aor 4. 12 (1.47-11.49) the aim : the aim of the study was to assess the relative risk (rr) of obesity and abdominal fat distribution on the insulin resistance (ir), diabetes, hyperlipidemia and hypertension in polish population. materials and methods: 6000 subjects at age 35-75, were randomized and invited to the study. in 2838 participants anthropometric and blood pressure examination was performed. fasting lipids, fasting and after glucose load glucose and insulin were determined. ir was defined as the upper quartile of the homa-ir distribution for the normal glucose tolerant population. results: overweight and obesity was observed in 39,7% and 25,1% of subjects. visceral obesity was found in 2143 subjects (88,9%-men and 73,4%-women). rr of ir in obesity was 3,94 (95% ci:3,09-5,04), for obese subjects at age below 45 was 6,6 (95% ci:3,6-12,0). in men with visceral obesity rr of ir was the highest for men aged below 55. rr of diabetes was increasing with the increase of body weight, in obese subjects with abdominal fat distribution was 2,88 (95%ci:2,20-3,79). the same was observed for the hypertension and hyperlipidemia. conclusions: obesity and the abdominal fat distribution seems to be an important risk factor of ir, diabetes, hypertension, hiperlipidemia, especially in the younger age groups. abstract background: age as an effect modifier in cardiovascular risk remains unclear. objective: to evaluate age-related differences in the effect of risk factors for acute myocardial infarction (ami). methods: in a population-based case-control study, with data collected by trained interviewers, 696 consecutive male cases of first myocardial infarction (participation rate 98%) and 867 randomly selected male control dwellers (participation rate 70%) were compared. effect-measure modification was evaluated by the statistical significance of a product term of each independent variable with age. unconditional logistic regression was used to estimate ors in each age stratum (<46 years/>45 years). results: there was a statistically significant interaction between education (>9 vs. <5 years), sports practice, diabetes and age: the adjusted (education, ami family history, dyslipidemia, hypertension, diabetes, angina, waist circumference, sports practice, alcohol and caffeine consumption, and energy intake) ors (95%ci) were respectively 0.16 (0.07-0.33), 0.76 (0.45-1.28) and 8.35 (1.64-42.6 ) in younger, and 0.46 (0.30-0.69), 0.36 (0.24-0.52) and 1.84 (1.08-3.16) in older participants. conclusions: in males, age has a significant interaction with education, sports practice and diabetes in the occurrence of ami. the effect is evident in the magnitude but not in the direction of the association. abstract there are few studies on the role of diet in lung cancer etiology. thus, we calculated both, squamous cell and small cell carcinoma risks in relation to the frequency of consumption of vegetables, cooked meat, fish and butter in silesian male in industrial area of poland. in the case-control study, the studied population comprised 237 men with squamous cell carcinoma and 122 men with small cell carcinoma, and 649 healthy controls. multivariate logistic regression was employed to calculate lung cancer risk in the relation to simultaneous influence of dietary factors. the relative risk was adjusted for age and smoking. we observed a significant decrease in lung cancer risk related to more frequent consumption of raw vegetables, cooked meat and fish. however, stronger protective effect was reported for squamous cell carcinoma. frequent fish consumption significantly decreases the risk especially in cigarette smokers. the frequent consumption of pickles lowers squamous cell carcinoma risk in all cases but small cell carcinoma risk only in smokers. the presence of butter, cooked meat, fish and vegetables in diet significantly decreases the lung cancer risk especially in smokers. the association between diet and lung cancer risk is more pronounced for squamous cell carcinoma. abstract background: in functional disease research selection mechanisms need to be studied to assure external validity of trial results. objective: we compared demographic and disease-specific characteristics, history, co-morbidity and psychosocial factors of patients diagnosed, approached and randomised for a clinical trial analysing the efficacy of fibre therapy in irritable bowel syndrome (ibs). design and methods: in primary care 1078 patients were diagnosed with ibs by their gp in the past two years. characteristics were compared between (1) randomised patients (n = 108); (2) patients who did not give their informed consent (n = 235); (3) patients who decided not to participate (n = 270); and (4) those not responding to the mailing (n = 465). results: the groups showed no significance differences in age and gender (74% females, mean age 41 years, s.d. 12). patients consulting their gp for the trial compared to patients not attending their gp showed significant more severe ibs symptoms, more abdominal pain during the previous three months, and a longer history of ibs (p<0,001). patients randomised have more comorbidity (p = 0,001). conclusion and discussion: patients included in this ibs trial differ from no participating and excluded patients mainly in ibs symptomatology, history and comorbidity. this may affect the external validity of the trial results. abstract objectives: to evaluate smoking prevalence among teenagers and identify associated social-behavioral factors. study design and methods: a cross sectional-study was carried out in may (2004) in high school population (7th-12th grades) in the north of portugal (n = 1005). a confidential self-reported questionnaire was administered. crude and adjusted odds ratios and confidence intervals were calculated by logistic regression analysis. results: overall smoking prevalence was 19.5% (boys = 26.1%; girls = 14.6%) (or = 2.06; ci 95% = 1.50-2.83; p<0.001). smoking prevalence was significantly and positively associated with gender, smoking parents, school failure and school grade; in the group of students with smoking relatives, smoking was significantly associated with parents who smoke near the student (or = 4.32; ci 95% = 2.41-7.74; p<0.001); in the group of the secondary grade (10th-12th grades) smoking was significantly associated with belonging to 'non science-courses' (or = 1.81; ci 95% = 1.18-2.78; p = 0.007). conclusions: smoking is a growing problem among portuguese adolescents, increasing with age, prevailing among males, although major increases have been documented in the female population. parents' behaviours and habits have an important impact in their children's smoking behaviour. school failure is also an important factor associated with smoking. there is a need for further prevention programmes that should include families and consider students' social environment. abstract background: social environment of school can contribute to etiology of health behaviors. objective: to evaluate the role of school context for substance abuse in youth. design: a cross-sectional study was carried out in 2005, using self-completed classroomadministered questionnaire. subjects: from a representative sample of 2893 students, a sub-sample of 1880 students was selected (including 85/130 classes with at least 15 persons without missing data)*. methods: substance abuse was measured by: tobacco smoking at present, episodes of drunkenness and marijuana use in the lifetime. overall index was created as main independent variable, ranging 0-9 (cronbach's alpha = 0.71). class membership, type of school, gender, place of domicile, and school climate were included as contextual variables, measured on individual or group level. results: on individual level, the mean index was equal to 3.5 (sd = 2.9), and ranged from 3.1 in general comprehensive schools to 4.6 in basic vocational schools and from 1.0 to 7.4 for separated classes. about 16.3% of total variance in this index may be attributed to differences between classes. conclusion: individual differences in substance abuse in youth could be partly explained by factors at school level. * project no 2 po5d 064 27. abstract background: rates of c-section in brazil are very high, 33.8% in 2004. brazil illustrates an extreme example of medicalization of birth. c-section, as any major surgery, increases the risk of morbidity, which can persist long after discharge from hospital. objectives: to investigate how social, reproductive, prenatal care and delivery factors interact after hospital discharge, influencing post partum complications. design and methods: a cross-sectional study of 200 women gathered information through home interviews and clinical examination during post-partum. a hierarchical logistic regression model of factors associated with post-partum complications was applied. results: physical and emotional post partum complications were almost twice as high among women having c-section. most of this effect were associated with lower socioeconomic conditions which influences, were mainly explained by longer duration of delivery (even in the presence of medical indications), and less social support when returning home. conclusion: risk of c-section complications is higher among women from the lower socioeconomic strata. social inequalities mediate the association between type of delivery and postpartum complications. discussion: c-section complications should be taken into account when decisions concerning type of delivery are made. social support after birth, from the public health sector, has to be provided for women in socioeconomic deprivation. the relationship between unemployment and increased mortality was previously reported in western countries. the aim of this study was to assess the influence of the changes in unemployment rate on survival in general population in northern poland at the time of economic transition. to analyze the association between the unemployment and risk of death we collected survival data from 62736 death certificates and data on rates of unemployment from 8 regions of gdansk county from period 1991-1996. kaplan-meier method and cox proportional hazard model were used in univariate and multivariate analysis. a change of unemployment (percentage) in the year of death in the area of residence, sex and educational level (6 categories) were included into multivariate analysis. the change of unemployment rate was associated with significantly worse overall survival: hazard ratio 1.02 95% confidence interval 1.016 to 1.024. the highest risk associated with the change of unemployment in the area of residence was for death from congenital defects (hazard ratio 1.16 95% confidence interval 1.04 to 1.3) and for death from cardiovascular diseases (hazard ratio 1.036 95% confidence interval 1.032 to 1.042 abstract background: there is no evidence from randomized trials as to whether or not educational interventions improve voluntary reporting systems in terms of quantity or quality. objectives: evaluation of the effectiveness of educational outreach visits aimed at improving adverse drug reaction (adr) reporting by physicians design and methods: cluster-randomized controlled trial covering all health system physicians in northern portugal. four spatialclusters assigned to intervention group (n = 1388) received outreach visits tailored to training needs detected in previous study and 11 clusters were assigned to the control (n = 5063). the main was the total number of reported adr; the second was the number of serious, unexpected, high-causality and new-drug-related adr. a follow-up was conducted for a period of 30 months. results: the intervention increased reports as follows: total adr, 9.7-fold (p<0.0001); serious adr, 6.1-fold (p = 0.001); high-causality adr, 8.5-fold (p<0.001); unexpected adr, 32.6-fold (p<0.001); and newdrug-related adr, 8.2-fold (p = 0.002). the intervention had its maximum effect during the first four months (23.3-fold increase, p<0.001), yet the effect was nonetheless maintained over the four 4month periods post-intervention (p = 0.06). discussion and conclusion: physician training based on academic detailing visits improves reporting quality and quantity. this type of intervention could result in sizeable improvements in voluntary reporting in many countries. there were no evidence of differences in absolute indications between the years. conclusion: most of the increase in rates in the period may be attributable to relative and non-medical indications. discussion policies to promote rational use of c-sections should take into account the role played by obstetrician's convenience and the increased medicalization of birth on cesarean rates. abstract background: the changing environment has led to unhealthy dietary habits and low physical activity of children resulting in overweight/obesity and related comorbid conditions. objective: idefics is a five-year multilevel epidemiological approach proposed under the sixth eu framework to counteract the threatening epidemic of diet-and lifestyle-induced morbidity by evidence-based interventions. design and methods: a population-based cohort of 17.000 children 2 to 10 years old will be established in nine european countries to investigate the aetiology of these diseases. culturally adapted multi-component intervention strategies will be developed, implemented and evaluated prospectively. results: idefics compares regional, ethnic and sex-specific distributions of the above disorders and their key risk factors in children within europe. the impact of sensory perception, genetic polymorphisms and the role of internal/external triggers of food choice and children's consumer behaviour are elucidated. risk profile inventories for children susceptible to obesity and its co-morbid conditions are identified. based on controlled intervention studies an evidencebased set of guidelines for health promotion and disease prevention is developed. conclusions: provision of effective intervention modules, easy to implement in larger populations, may reduce future obesity related disease incidence. discussion: transfer of feasible guidelines into practice requires involvement of health professionals, stakeholders and consumers. abstract background: non-medically indicated cesarean deliveries increase morbidity and health care costs. brazil has one of the highest rates of caesarean sections in the world. variations in rates are positively associated with socioeconomic status. objectives: to investigate factors associated with cesarean sections in public and private sector wards in south brazil. design and methods: cross sectional data from post partum interviews and clinical records of 216 consecutive deliveries (112 in the main public and 104 in a private maternity) was analyzed using logistic regression. results: multiple regression showed privately insured women having much higher cesarean rates than those delivering in public sector wards (or = 9.4; ci95%: 4.5-32.6). obstetricians individual rates varied from 38%-100%. doctors working in both, public and private sectors had a higher rates of cesarean in private wards (p<0.01). wanting and having a cesarean was significantly more common among privately insured women. conclusion: women from wealthier families are at higher risk of cesarean, particularly those willing this type of delivery and whose obstetrician works in the private sector. discussion: women potentially at lower clinical risk are more like to have a caesarean. the obstetricians' role and women's preferences must be further investigated to tackle this problem. abstract background: in the netherlands, bcg-vaccination is offered to immigrant children and children of immigrant parents in order to prevent severe tuberculosis. the effectiveness of this policy has never been studied. objectives: assessing the effectiveness of the bcg-vaccination policy in the netherlands. design and methods: we used data on the size of the risk population per year (from statistics netherlands), number of children with meningitis or miliary tuberculosis in the risk population per year, and vaccination status of those cases (from the netherlands tuberculosis register) over the period 1996-2003. we estimated the vaccine efficacy and annual risk of acquiring meningitis or miliary tuberculosis by log-linear modelling and treating the vaccination coverage as missing data. results: in the period 1996-2003 13 cases of meningitis or miliary tuberculosis were registered. the risk for unvaccinated to children to acquire such a serious tuberculosis infection was 4.54 (95%ci 2.26-9.62) per 100000 per year; the reduction in risk for vaccinated children was 81% (95%ci 31-94%). conclusion and discussion: this means that, discounting future effects with 4%, a 1088 (95%ci: 560-2500) extra children should be vaccinated to prevent one extra case of meningitis or miliary tuberculosis. given that bcg-vaccination is relatively inexpensive, the current policy could even be cost-saving. abstract background: psychotic symptom experiences in the general population are frequent and often longlasting. objectives: the zurich cohort study offered the opportunity of differentiating the patterns of psychotic experiences over a span of 20 years. design and methods: the zurich study is based on a stratified community sample of 591 persons born in 1958 (women) and 1959 (men). the data were collected at six time points since 1979. we examined variables from two subscales of the scl-90-r -'paranoid ideation' and 'psychoticism' -using factor analysis, cluster analysis and polytomous logistic regression. results: two new subscales were derived representing 'thought disorders' and 'schizotypal signs'. continously high symptom load on one of these subscales (both subscales) was found in 7% (1.7%) of the population. cannabis use was the best predictor of continuously high symptom load in the 'thought disorders' subscale, whereas several variables representing adversity in childhood / youth were associated with continuously high symptom load in the 'schizotypal signs' subscale. conclusion and discussion: psychotic experiences can be divided at least in two different syndromes -thought disorders and schizotypal signs. despite similar longitudinal course patterns and also similar outcomes these syndromes rely on different risk factors, thus possibly defining separate pathways to psychosis. abstract background: the reasons for the rise in asthma and allergies remain unclear. to identify influential factors several european birth cohort studies on asthma and allergic diseases have been initiated since 1985. objective: the aim of one work package within the global allergy and asthma european network (ga2len), sponsored by the european commission, was to identify and compare european birth cohorts specifically designed to examine asthma and allergic diseases. methods: for each study, we collected detailed information (mostly by personal visits) regarding recruitment process, study setting, follow-up rates, subjective/objective outcomes and exposure parameters. results: by june 2005, we assessed 18 european birth cohort studies on asthma and allergic diseases. the largest 5 recruited over 3000 children each. most studies determined specific immunoglobulin e levels to various allergens or used the isaac questionnaire for evaluation of asthma or allergic rhinitis symptoms. however, the assessment of other objective and subjective outcomes (e.g. lung function or definitions of eczema) were rather heterogeneous across the studies. conclusions due to the unique cooperation within the ga2len project a common database was established containing study characteristics of european birth cohorts on asthma and allergic diseases. the possibility to pool data and perform meta-analyses is currently being evaluated. abstract background: birth weight is an important marker of health in infancy and health trajectories later in life. social inequality in birth weight is a key component in population health inequalities. objective: to comparatively study social inequality in birth weight in denmark, finland, norway, and sweden from 1980 to 2005. design and methods as part of the nordic collaborative project on health and social inequality in early life (norchase), register-based data covering all births in all involved countries 1980-2005 was linked with national registries on parental socioeconomic position, covering a host of different markers including income, education and occupation. also, nested cohort studies provide opportunity to test hypotheses of mediation. results: preliminary results show that the social inequality in birth weight, small for gestational age, and low birth weight has increased in denmark through out the period. also, preliminary results from finland, norway and sweden will be presented. discussion: crosscountry comparisons pose several methodological challenges. these challenges include characterizing the societal context of each country so as to correctly interpret inter-country differences in social gradients, along with dealing with differences in the data collection methods and classification schemes used by different national registries. also, strategies for influencing policy will be discussed. abstract background: modifying the availability of suicide methods is a major issue in suicide prevention. objectives: we investigated changes in the proportion of firearm suicides in western countries since the 1980's, and their relation to the change of legislation and regulatory measures. design and methods: data from previous publications, from the who mortality database, and from the international crime victims survey (icvs) were used in a multilevel analysis. results: multilevel modeling of longitudinal data confirmed the effect of the proportion of households owning firearms on firearm suicide rates. several countries stand out with an obvious decline in firearm suicides since the 1980s: norway, united kingdom, canada, australia, and new zealand. in all of these countries legislative measures have been introduced which led to a decrease in the proportion of households owning firearms. conclusion and discussion: the spread of firearms is a main determinant of the proportion of firearm suicides. legislative measures restricting the availability of firearms are a promising option in suicide prevention. abstract background: fatigue is a non-specific but frequent symptom in a number of conditions, for which correlates are unclear. objectives: to estimate socio-demographic and clinical factors determining the magnitude of fatigue. methods: as part of a follow-up evaluation of a cohort of urban portuguese adults, socio-demographic and clinical variables for 563 consecutive participants were collected through personal interview. lifetime history of chronic disease diagnosis was inquired (depression, cancer, cardiovascular, rheumatic, and respiratory conditions), anthropometry was measured, and haemoglobin determined. krupp's 9-item fatigue severity scale was applied and severe fatigue defined as mean score over 4. mean age (sd) was 62.3 (9.9) and 58.8% of participants were females. logistic regression was used to compute adjusted odds ratios, and attributable fractions were estimated using the formula ar = 1-s(?j/orj). results: adjusted for age and clinical conditions, female gender (or = 1.56, 95%ci: 1.08-2.26) and education (under 5-years schooling: or = 1.61, 95%ci: 1.10-2.34) were associated with severe fatigue. obesity (or = 1.87, 95%ci: 1.21-2.90) and diagnosed cardiovascular disease (or = 2.23, 95%ci: 1.28-3.90) also increased fatigue. attributable fractions were 21.1% for gender, 14.2% for education, 9.8% for obesity, and 10.9% for cardiovascular disease. conclusion: gender and education have large impact on severe fatigue, and, to a lesser extent, obesity and cardiovascular disease. abstract introduction: analysis of infant mortality allows identification of death contributing factors and assessment of child health care quality. objective: to study characteristics of infant and fetal mortality using data from a committee for prevention of maternal and infant mortality, in sobral, brazil. methods: all cases of infant deaths between 2002 and 2004 were analyzed. medical records were reviewed and mothers, interviewed. using a tool to identify preventable deaths (seade classification -brazil) the committee characterized causes of death. meetings with governmental groups involved in family health care took place to identify death contributing factors. results: in 2002, infant mortality decreased from 29.7 to 18.9. in the next 2 years there was an increase from 23.1 to 26.6. the increase in 2003 was due to respiratory illnesses. in 2004, was due to diarrhea. analysis of preventable deaths indicated a reduction from 32 to 20 deaths that could have been prevented by adequate gestational care, and an increase in preventable deaths by early diagnosis and treatment. conclusion: pre-natal and delivery care improved whereas care for children less than 1 yr old worsened. analysis of death causes allowed a reduction of infant mortality rate to 16.44 abstract objective: to identify dietary patterns and its association with metabolic syndrome. design and methods: we evaluated 2166 noninstitutionalised adults. diet was assessed using a semi-quantitative dietary frequency questionnaire, and dietary patterns were identified using principal components analysis followed by cluster analysis (k-means method) with bootstrapping (choosing the clusters presenting the lowest intra-cluster variance). metabolic syndrome (mets) was defined according to the ncep-atp-iii. results: the overall prevalence of metabolic syndrome was 20.6%. in the population sample 4 clusters were identified in females -1.healthy, 2.milk/soup; 3.fast food; 4.wine/low calories; and 4 in males -1.milk/carbohydrates; 2. codfish/soup; 3.fast food; 4.low calories. in males, using milk/carbohydrates as the reference and adjusting for age and education, high blood pressure (or = 1.72; 95%ci:1.04-2.85) and high triglycerides (or = 1.61;95%ci:1.00-2.60) were associated with the fast food pattern, and low calories pattern presented higher frequency of high blood pressure (or = 1.61; 95%ci:1.01-2.55). in females, after age and education adjustment, no significant association was found either with metabolic syndrome or its individual features and the dietary patterns identified. conclusion: we found no specific dietary pattern associated with an increased prevalence of metabolic syndrome. however, a fast food diet was significantly more frequent in males with dyslipidemia and high blood pressure. abstract aim: to determine the prevalence of stress urinary incontinence (sui) before, during pregnancy and following childbirth, and also to analyse the impact of a health education campaign about sui prevention, following childbirth in viana district, portugal. methods: participants (n = 336), interviewed during hospitalization, after birth and two months later at health centres, were divided into two groups: a first group of non-exposed and a second exposed to a health education campaign. this second group was encouraged to perform an exercise programme and given a 'suiprevention-treatment' brochure, approved by the regional health authority. results: sui prevalence was 5.4%(95%ci: 3.0-7.8) before pregnancy, 51.5%(95%ci: 46.1-56.9) during pregnancy and 10.2(95%ci: 6.8-13.7) four weeks after birth. less than half of the women with sui sought help from healthcare professionals. statistical significant differences were found between groups: sui knowledge level and practice of pelvic floor muscles re-education exercises were higher in the exposed group (2.6 and 5.1 times, respectively). conclusions: sui affects a great number of women but only a small percentage reveals it. this campaign improved women knowledge and modified their else behaviors. healthcare professionals must be aware of this reality, providing an early and continuous intervention that would optimise the verified benefits of this campaign. abstract background: social inequalities have been associated with poorer developmental outcomes, but little is known about the role of the area of residence. objectives: examine whether the housing infrastructure of the area modifies the effect of socio-economic conditions of the families on child development. design and methods: community-based survey of 3052 under-fives in southern brazil applied hierarchical multi-level linear regression to investigate determinants of child development, measured by a score from the denver developmental screening test. results: in multivariable models, the mean score of child development increased with maternal and paternal education and work qualification, family income and better housing and was higher when the mother was in paid work (all p<0.001). paternal education had an effect in areas of lower housing quality only; the effect of occupational status and income in these areas were twice as large as in better-provided areas (likelihood test for all interactions p<0.05). this model explained 37% of the variation in developmental score between the areas of residence. conclusion: the housing quality and sanitation of the area modified the effects of socioeconomic conditions on child development. discussion: housing and sanitation programs are potentially beneficial to decrease the negative effect of social disadvantage on child development. abstract background: it is known that both genetic and environmental factors are involved in the early development of type1 diabetes (t1d), and that incidence varies geographically. however we still need to explain why there is variation in incidence. objectives: in order to better understand the role of non-genetic factors, we decided to examine whether prevalence of newborns with high risk genotypes or islet autoantibodies varies geographically. design and methods: the analysis was performed on a cohort of 29912 newborns born to non-diabetic mothers, between september 2000 and august 2004, who were included in diabetes prediction in ska˚ne study (dipis) in sweden. neighbourhoods were defined by administrative boundaries and variation in prevalence was investigated using multi-level regression analysis. results: we observed that prevalence of newborns with islet autoantibodies differed across the 33 municipalities of ska˚ne (s = 0.16, p <0.01), with highest prevalence found in wealthy urban areas. however there was no observed difference in the prevalence of newborns with high risk genes. conclusion and discussion: newborns born with autoantibodies to islet antigens appear to cluster by region. we suggest that non-genetic factors during pregnancy may explain some of the geographical variation in the incidence of t1d. abstract background: risk assessment is a science-based discipline used for decision making and regulatory purposes, such as setting acceptable exposure limits. estimation of risks attributed to exposure to chemical substances are traditionally mainly the domain of toxicology. it is recognized, however, that human, epidemiologic data, if available, are to be preferred to data from laboratory animal experiments. objectives: how can epidemiologic data be used for (quantitative) risk assessment? results: we described a framework to conduct quantitative risk assessment based on epidemiological studies. important features of the process include a weight-of-theevidence approach, estimation of the optimal exposure-risk function by fitting a regression model to the epidemiological data, estimation of uncertainty introduced by potential biases and missing information in the epidemiological studies, and calculation of excess lifetime risk through a life table to take into account competing risks. sensitivity analyses are a useful tool to evaluate the impact of assumptions and the variability of the underlying data. conclusion and discussion: many types of epidemiologic data, ranging from published, sometimes incomplete data to detailed individual data, can be used for risk assessment. epidemiologists should better facilitate such use of their data, however. abstract background: high-virulence h. pylori (hp) strains and smoking increase the risk of gastric precancerous lesions. its association with specific types of intestinal metaplasia (im) in infected subjects may clarify gastric carcinogenesis pathways. objectives: to quantify the association between types of im and infection with highvirulence hp strains (simultaneously caga+, vacas1 and va-cam1) and current smoking. design and methods: male volunteers (n = 201) underwent gastroscopy and completed a self-administered questionnaire. participants were classified based on mucin expression patterns in biopsy specimens (antrum, body and incisura). hp vaca and caga were directly genotyped by pcr/reverse hybridization. data were analysed using multinomial logistic regression (reference: normal/superficial gastritis), models including hp virulence, smoking and age. results: high-virulence strains increased the risk of all im types (complete: or = 3.08, 95%ci:1.20-7.89; incomplete: or = 9.23, 95%ci:2.20-38.72; mixed: or = 6.27, 95%ci:2.55-15.43) but smoking was only associated with an increased risk of complete im (or = 2.99 95%ci:1.15-7.78). compared to non-smokers infected with lowvirulent strains, infection with the high-virulence hp increased the risk of im similarly for smokers (or = 11.00, 95%ci:3.59-33.71) and non-smokers (or = 9.65 95%ci:3.82-24.40). conclusion: gastric precancerous lesions, with different potential for progression, are differentially modulated by hp virulence and smoking. the risk of im associated with high-virulence hp is not further increased by smoking. abstract background: in may 1999, the portuguese government created the basic urgency units (buu). these buu must attend at least 40.000 persons, be open 24 hours per day, and be at maximum 60 minutes of distance to all the users. objectives: determine the optimal location of buu, considering the existing health centers, in the viseu district, north portugal. methods: from a matrix of distances between population and health centers an accessibility index was created (sum of distances traveled by population to reach a buu). the location-allocation models were used to create simulations based on p-median model, maximal covering location problem (mclp) and set covering location problem (sclp). the solutions were ranked by weighting the variables of accessibility (50%), number of doctors in the health centers (5%), equipments (20%), distance/time (20%) and total number of buu (5%). results: the best solution has 3 buu, 89 doctors, attends 59 000 users and the accessibility index is 8.859 km. conclusions: it was proved that it is impossible to attend all the criterion for creation of a buu. in some areas with low population density, to sum at least 40 000 persons in a buu, the travel time is necessarily more than 1 hour. background: a prospective observational study of fatigue in staff working a 10 day/5 off/8 night/5 off roster of 12 hour shifts was conducted at a fly-in/fly-out fertilizer mine in remote northern australia. objectives: to determine whether fatigue in staff increased: from the start compared to the finish of shift; with the number of consecutive shifts; and from day-compared to nightshift. methods: data of sleep diaries, the mackworth clock test and the swedish occupational fatigue inventory were obtained at the start and finish of each shift from august to november 2004. results: a total of 51 staff participated in the study. reaction times, sleepiness and lack of energy scores were highest at the finish of nights 1 to 4. the reaction times increased significantly at both the start and finish of day 8 onwards, and at the finish of night 7. reaction times and lack of motivation were highest during nightshift. conclusions: from the above results, a disturbed diurnal rhythm and decreased motivation during night-shift; and a roster of more than eight consecutive shifts can be inferred as the primary contributors to staff fatigue. discussion: the implications for changes to workplace practices and environment will be discussed. the aim of this survey was to assess the impact of a meta-analysis comparing resurfacing with nonresurfacing of the patella on the daily practice of experts. participants in this study were 87 experts which had participated in a previous survey on personal preferences regarding patella resurfacing. these experts in the field of patella resurfacing were identified by a thorough search of medline, an internet search (with googletm search engine), and personal references from the identified experts. participants of the 'knee arthroplasty trial' (kat) in the united kingdom were also included. two surveys were sent to the participants, one before and one after the publication of the meta-analysis. the response rate is 39 questionnaires or 45%. the vast majority of responders are not persuaded to change change their practice after reading the metaanalysis. this is only in part due to the fact that best evidence and practice coincide. other reasons given are methodology related, an observation which is shared by the authors of the review, which force the orthopedic community to improve its research methodology. reasons such as 'i do not believe in meta-analysis' either demands a fundamental discussion or demands the reader to take evidence based medicine more seriously. abstract background: patients with type 2 diabetes (dm2) have a 2-3 fold increased risk of cardiovascular disease. delegating routine tasks and computerized decision support systems (cdss) such as diabetes care protocol (dcp) may improve treatment of cardiovascular risk factors hba1c, blood pressure and cholesterol. dcp includes consultation-hours exclusively scheduled for dm2 patients, rigorous delegation of routine tasks in diabetes care to trained paramedics, and software to support medical management. objective: to investigate the effects of dcp, used by practice assistants, on the risk of coronary heart disease for patients with dm2. design and methods: in an open-label pragmatic trial in 72 general practices with 7893 patients, hba1, blood pressure and cholesterol were examined before and prospectively one year after implementation of dcp. the primary outcome was the change in the 10 year ukpds coronary heart disease (chd) risk estimate. results: the median 10 year ukpds chd risk estimate improved significantly from 21.7% to 19.0%. hba1 decreased from 7.2% to 6.9%, systolic blood pressure from 148.4 to 144.0 mmhg and total cholesterol from 5.1 to 4.7 mmol/l. (all p<0.01). conclusion: delegating routine task in diabetes care to trained paramedics and using cdss improves the cardiovascular risk of dm2 patients. tuberculosis in exposed immigrants by tuberculin skin test, ifn-g tests and epidemiologic abstract background: currently immigrants in western countries are only investigated for active tuberculosis (tb) by use of a chest x-ray. recent latent tuberculosis infection (ltbi) is hard to diagnose in this specific population because the only available test method, the tuberculin skin test (tst), has a low positive predictive value (ppv). recently interferon-gamma (ifn-g) tests have become available that measure cellular responses to specific m. tuberculosis antigens and might have a better ppv. objective: to determine the predictive value of tst and two different ifn-g tests combined with epidemiological characteristics for developing active tb in immigrants who are close contacts of smear positive tb patients. methods in this prospective cohort study 800 close contacts will be included. demographic characteristics and exposure data are investigated. beside their normal examination they will all have a tst. two different ifn-g tests will be done in those with a tst induration of ?5 mm. these contacts will be followed for 2 years to determine the occurrence of tb. results since april 2005, 13 municipal health services have started with the inclusion. preliminary results on the predictive value of tst, both ifn-g tests and epidemiological characteristics will be presented. abstract background: different factors contribute to the quality of ed (emergency department) care of an injured patient. objective: determine factors influencing the disagreement between er diagnoses and those assigned at hospital admission in injuried patients, and evaluate if disagreement between the diagnoses could have worsened the outcome. methods: all the er visits of the 60 emergency departments of lazio region for unintentional injuries followed by hospitalisation in 2000. concordant diagnoses were established on the basis of the barell matrix cells. logistic regression was used to assess the role of individual and er care factors on the probability of concordance. a logistic regression where death within 30 days was the outcome and concordance the determinant was uses. results: 22,892 injury er visits were considered. in 62.2% cases, the er and discharge diagnoses were concordant. higher concordance was found with increasing age and less urgent cases. factors influencing concordance were: the hour of the visit, er level, initial outcome, length of stay in hospital. patients who had non concordant diagnoses had a 30% higher probability of death. conclusions: a correct diagnosis at first contact with the emergency room is associated with lower mortality. methods: a cohort of consecutive patients treated for secondary peritonitis were sent the posttraumatic stress syndrome inventory (ptss-10) and impact of events scale-revised (ies-r) 4-10 years following their surgery for secondary peritonitis. results: from the 278 patients operated upon between 1994 and 2000, questionnaires were sent to the 131 long-term survivors of which 88% responded (n = 101). ptsd-related symptoms were found in 17% of patients by both questionnaires. patients admitted to icu (n = 39) were significantly older, with higher apache-ii scores, but reported similar ptsd symptomology scores compared to non-icu patients (n = 61). traumatic memories during icu and hospital-stay were most predictive for higher scores. adverse memories did not occur more often in the icu group than in the hospital-ward group conclusions: longterm ptsdrelated symptoms in patients with secondary peritonitis were very barthé lé my 53 c cabanas ruiz-carrillo 429 de la cruz den boon jimé nez-moleó n mü ller-nordhorn 36 national evaluation team 436 279 rich-edwards in the netherlands. design and methods we used the populationbased databases of the netherlands cancer registry, the eindhoven cancer registry (ecr) and the central bureau of statistics. patients from the ecr were followed until 1-1-2005 for vital status and relative survival was calculated. results: the number of breast cancer cases increased from 7900 in 1989 to 11.500 in 2003, an annual increase of 1.3% (p<0.001). the death rate decreased 1,4% annually (p<0.001), which resulted in 3400 deaths in 2003. the relative 5-yr survival was less than 50% for patients diagnosed in the seventies, this increased to over 80% for patient diagnosed since 2000, patients with stage i disease even have a 96% 5-yr relative survival. conclusion: the alarming increase in breast cancer incidence is accompanied with a serious improvement in survival rates. this results in a large number of women (ever) diagnosed with breast cancer, about 119,000 in 2005 of whom 80% demand some kind of medical care. abstract background: nine % of the population in the netherlands belongs to non-western ethnic minorities. perceived health is worse and health care use different from dutch natives. objectives. which factors are associated with ethnic differences in self-rated health? which factors are associated with differences in utilisation of gp care? methods: during one year all contacts with gps were registered. adult surinam, antillean, turkish, moroccan and dutch responders were included (total n: 10.252). we performed multivariate analyses of determinants of self-rated health and on the number of contacts with gps. results: self-rated health differ from native dutch: surinam/antillean (or 2.4) and turkish/moroccan patients (or 4.7/3.8) , especially in turkish/moroccan females. more turks visit the gps at least once a year (or 1.5). less surinamese (or 0.5) and antillean patients (or 0.9) visit their gps than the dutch do. people from ethnic minorities in good health visit their gps more often (3.9 -4.4 consults per year vs. 3.4). incidence rates of acute respiratory infections and chest complaints were significantly higher than in the dutch. conclusions: ethnicity is independently associated with self-rated health. higher use of gp-care by ethnic minorities in good health, points towards possible inappropriate use of resources. the future: do they fulfil it? first results of the limburg youth monitoring project abstract background: incidence of coronary heart disease (chd) and stroke can be estimated from local, population-based registers. it is unclear, to what extent local register data are applicable on a nationwide level. therefore, we compared german register data with estimates derived with who global burden of disease (gbd) method. methods: incidence of chd and stroke was computed with the gbd method using official german mortality statistics and prevalences from the german national health survey. results were compared to estimates from the kora/monica augsburg register (chd) and the erlangen stroke project in southern germany. results: gbd estimates and register data showed good agreement: chd (age group 25-74 years) 155,862 (gbd) versus 159,245 (register) and stroke (all ages) 157,104 versus 167, 892 incident cases per year. chd incidence among all age groups was estimated with the gbd method to be 250,000 per year (no register data available). chd incidence in men and stroke incidence in women were underestimated with the gbd method as compared to register data. conclusions: gbd method is a useful tool to estimate incidence of chd and stroke. the computed estimates may be seen as lower limit for incidence data. differences between gbd estimates and register data are discussed. abstract background: children with mental retardation (mr) are a vulnerable not much studied population. objectives: to investigate psychopharmacotherapy in children with mr and to examine possible factors associated with psychopharmacotherapy. methods: participants were recruited through all facilities for children with mental retardation in friesland, the netherlands, resulting in 865 participants, 4-18 years old, including all levels of mental retardation. the dbc and the pdd-mrs were used to assess general behavior problems and pervasive developmental disorders (pdd). information on medication was collected through a parent-interview. logistic regression was used to investigate the relationship between the psychotropic drug use and the factors dbc, pdd, housing, age, gender and level of mr. results: 10% of the participants used psychotropic medication. main factors associated with receiving psychopharmacotherapy were pdd (or 2.31) and dbc score (or 1.03). living away from home and mr-level also played a role whereas gender and age did not. dbc score was associated with clonidine, stimulants and anti-psychotics. pdd was the main factor associated with anti-psychotics use (or 5.7). discussion: psychopharmacotherapy is especially prevalent among children with mr and comorbid pdd and general behavior problems. although many psychotropic drugs are used off-label, specific drugs were associated with specific psychiatric or behavior problems. abstract background: increased survival in children with cancer has raised interest on the quality-of-life of long-term survivors. objective: to compare educational outcomes of adult survivors of childhood cancer and healthy controls. methods: retrospective cohort study including a sample of adult survivors (495) treated for childhood cancer in the three existing italian paediatric research hospitals. controls (501) were selected among siblings, relatives or friends of survivors. when these controls were not available, a search was carried out in the same area of residence of the survivors though random digit dialling. data collection was carried out through a telephone-administered structured questionnaire. results: significantly more survivors than controls needed school support (adjusted odds ratio -oradj-1.61, 95% ci 1.22-2.13); failed at least a grade after disease onset (oradj 1.46, 95% ci 1.09-1.97); achieved a lower educational level (oradj 1.77, 95% ci 1.27-2.45) and did not reach an educational level higher than their parents' (oradj 1.66, 95% ci 1.19-2.32). subject's age, sex, parents' education and area of residence were taken into account as possible confounders. conclusions: these findings suggest the need to provide appropriate school support to children treated for childhood cancer. abstract background: in italy supplementation with folic acid (fa) in the periconceptional period to prevent congenital malformations (cms) is quite low. the national health institute has recently launched (2005) a programme to improve awareness about the role of fa in reducing the risk of serious defects also by providing 0.4 mg fa tablets free of charge to women planning a pregnancy. objectives: we analysed cms that are or may be sensitive to fa supplementation in order to establish an adequate baseline to allow a fa impact assessment in the next years and to investigate spatial differences among cms registries, time trends and time-space interactions. design and methods data collected over 1996-2003 by the italian registries members of eurocat and icbdsr on births and induced abortions with neural tube defects, ano-rectal atresia, omphalocele, oral clefts, cardiovascular, limb reduction and urinary system defects. results: all the cms showed statistically significant differences among registries with the exception of ano-rectal atresia. the majority of cms by registry showed stable or increasing trends over time. conclusions results show the importance of fa intake during the periconceptional period. differences among registries indicate also the need of having a baseline for each registry to follow trends over time. abstract country-specific resistance proportions are more biased by variable sampling and ascertainment procedures than incidence rates. within the european antimicrobial resistance surveillance system (earss) resistance incidence rates and proportions can be calculated. in this study, the association between antimicrobial resistance incidence rates and proportions and the possible effect of differential sampling of blood cultures was investigated. in 2004, earss collected routine antimicrobial susceptibility test data from invasive s. aureus isolates, tested according to standard protocols. via a questionnaire denominator information was collected. the spearman correlation coefficient and linear regression were used for statistical analysis. this year, 735 of 1205 hospitals and 483 of 758 laboratories from 28 of 30 earss countries responded to the questionnaire. they reported of, overall, 18,729 s. aureus isolates. in the different countries, mrsa proportions ranged from <1% to 40% and incidence rates per 1,000 patient days from 0.26ae10-2 to 19.29ae10-2. overall, the proportions and rates highly correlated. blood culturing rates only influenced the relationship between mrsa resistance proportions and incidence rates for eastern european countries. in conclusion, resistance proportions seem to be very similar to resistance incidence rates, in the case of mrsa. nevertheless, this relationship appears to be dependent of some level of blood culturing. . key: cord-272727-a5ngjuyz authors: bertsimas, d.; boussioux, l.; cory wright, r.; delarue, a.; digalakis, v.; jacquillat, a.; lahlou kitane, d.; lukin, g.; li, m. l.; mingardi, l.; nohadani, o.; orfanoudaki, a.; papalexopoulos, t.; paskov, i.; pauphilet, j.; skali lami, o.; stellato, b.; tazi bouardi, h.; villalobos carballo, k.; wiberg, h.; zeng, c. title: from predictions to prescriptions: a data-drivenresponse to covid-19 date: 2020-06-29 journal: nan doi: 10.1101/2020.06.26.20141127 sha: doc_id: 272727 cord_uid: a5ngjuyz the covid-19 pandemic has created unprecedented challenges worldwide. strained healthcare providers make difficult decisions on patient triage, treatment and care management on a daily basis. policy makers have imposed social distancing measures to slow the disease, at a steep economic price. we design analytical tools to support these decisions and combat the pandemic. specifically, we propose a comprehensive data-driven approach to understand the clinical characteristics of covid-19, predict its mortality, forecast its evolution, and ultimately alleviate its impact. by leveraging cohort-level clinical data, patient-level hospital data, and census-level epidemiological data, we develop an integrated four-step approach, combining descriptive, predictive and prescriptive analytics. first, we aggregate hundreds of clinical studies into the most comprehensive database on covid-19 to paint a new macroscopic picture of the disease. second, we build personalized calculators to predict the risk of infection and mortality as a function of demographics, symptoms, comorbidities, and lab values. third, we develop a novel epidemiological model to project the pandemic's spread and inform social distancing policies. fourth, we propose an optimization model to reallocate ventilators and alleviate shortages. our results have been used at the clinical level by several hospitals to triage patients, guide care management, plan icu capacity, and re-distribute ventilators. at the policy level, they are currently supporting safe back-to-work policies at a major institution and equitable vaccine distribution planning at a major pharmaceutical company, and have been integrated into the us center for disease control's pandemic forecast. america is applying our infection risk calculator to determine 97 how employees can safely return to work. a major hospital 98 system in the united states planned its intensive care unit 99 (icu) capacity based on our forecasts, and leveraged our opti-100 mization results to allocate ventilators across hospitals when 101 the number of cases was rising. our epidemiological predic-102 tions are used by a major pharmaceutical company to design 103 a vaccine distribution strategy that can contain future phases 104 of the pandemic. they have also been incorporated into the 105 us center for disease control's forecasts (7). early responses to the covid-19 pandemic have been in-108 hibited by the lack of available data on patient outcomes. 109 individual centers released reports summarizing patient char-110 acteristics. yet, this decentralized e ort makes it di cult to 111 construct a cohesive picture of the pandemic. to address this problem, we construct a database that ag-113 gregates demographics, comorbidities, symptoms, laboratory 114 blood test results ("lab values", henceforth) and clinical out-115 comes from 160 clinical studies released between december 116 2019 and may 2020-made available on our website for broader 117 use. the database contains information on 133,600 covid-19 118 patients (3.13% of the global covid-19 patients as of may 119 12, 2020), spanning mainly europe (81, 207 patients), asia 120 (19, 418 patients) and north america (23, 279 patients). to 121 our knowledge, this is the largest dataset on covid-19. a. data aggregation. each study was read by an mit re-123 searcher, who transcribed numerical data from the manuscript. 124 the appendix reports the main transcription assumptions. each row in the database corresponds to a cohort of 126 patients-some papers study a single cohort, whereas oth-127 ers study several cohorts or sub-cohorts. each column reports 128 cohort-level statistics on demographics (e.g., average age, gen-129 der breakdown), comorbidities (e.g., prevalence of diabetes, 130 hypertension), symptoms (e.g., prevalence of fever, cough), 131 treatments (e.g., prevalence of antibiotics, intubation), lab 132 values (e.g., average lymphocyte count), and clinical outcomes 133 (e.g., average hospital length of stay, mortality rate). we also 134 track whether the cohort comprises "mild" or "severe" patients 135 (mild and severe cohorts are only a subset of the data). due to the pandemic's urgency, many papers were published 137 before all patients in a cohort were discharged or deceased. ac-138 cordingly, we estimate the mortality rate from discharged and 139 deceased patients only (referred to as "projected mortality"). using a similar nomenclature, figure 2a d. discussion and impact. our database is the largest avail-184 able source of clinical information on covid-19 assembled 185 to date. as such, it provides new insights on common symp-186 toms and the drivers of the disease's severity. ultimately, this 187 database can support guidelines from health organizations, 188 and contribute to ongoing clinical research on the disease. another benefit of this database is its geographical reach. 190 results highlight disparities in patients' symptoms across 191 regions. these disparities may stem from (i) di erent reporting 192 criteria; (ii) di erent treatments; (iii) disparate impacts across 193 di erent ethnic groups; and (iv) mutations of the virus since 194 it first appeared in china. this information contributes to 195 early evidence on covid-19 mutations (14, 15) and on its 196 disparate e ects on di erent ethnic groups (16, 17). the insights derived from this descriptive analysis highlight 203 the need for personalized data-driven clinical indicators. yet, 204 our population-level database cannot be leveraged directly 205 to support decision-making at the patient level. we have 206 therefore initiated a multi-institution collaboration to collect 207 electronic medical records from covid-19 patients and de-208 velop clinical risk calculators. these calculators, presented in 209 the next section, are informed by several of our descriptive 210 insights. notably, the disparities between severe patients and 211 the rest of the patient population inform the choice of the fea-212 tures included in our mortality risk calculator. moreover, the 213 geographic disparities suggest that data from asia may be less 214 predictive when building infection or mortality risk calculators 215 designed for patients in europe or north america-motivating 216 our use of data from europe. throughout the covid-19 crisis, physicians have made dif-219 ficult triage and care management decisions on a daily basis. 220 oftentimes, these decisions could only rely on small-scale 221 clinical tests, each requiring significant time, personnel and 222 equipment and thus cannot be easily replicated. once the 223 burden on "hot spots" has ebbed, hospitals began to aggregate 224 rich data on covid-19 patients. this data o ers opportu-225 nities to develop algorithmic risk calculators for large-scale 226 decision support-ultimately facilitating a more proactive and 227 data-driven strategy to combat the disease globally. 228 we have established a patient-level database of thousands of 229 covid-19 hospital admissions. using state-of-the-art machine 230 learning methods, we develop a mortality risk calculator and an 231 infection risk calculator. together, these two risk assessments 232 provide screening tools to support critical care management 233 decisions, spanning patient triage, hospital admissions, bed 234 assignment and testing prioritization. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 29, 2020. . table 1 . count and prevalence of symptoms among covid-19 patients, in aggregate, broken down into mild/severe patients, and broken down per continent (asia, europe, north america). mild and severe patients only form a subset of the data, and so do patients from asia, europe and north america. a "-" indicates that fewer than 100 patients in a subpopulation reported on this symptom. all patients discriminative ability of the proposed models. we report in 286 the appendix average results across all random data partitions. 287 we also report in the appendix threshold-based metrics, 308 † hm hospitals patients were not included since no negative case data was available. c. discussion and impact. the models with lab values provide 309 algorithmic screening tools that can deliver covid-19 risk 310 predictions using common clinical features. in a constrained 311 healthcare system or in a clinic without access to advanced 312 diagnostics, clinicians can use these models to rapidly identify 313 high-risk patients to support triage and treatment decisions. the models without lab values o er an even simpler tool 315 that could be used outside of a clinical setting. in strained 316 healthcare systems, it can be di cult for patients to obtain 317 direct advice from providers. our tool could serve as a pre-318 screening step to identify personalized infection risk-without 319 visiting a testing facility. while the exclusion of lab values 320 reduces the auc (especially for infection), these calculators 321 still achieve strong predictive performance. our models provide insights into risk factors and biomark-323 ers related to covid-19 infection and mortality. our results 324 suggest that the main indicators of mortality risk are age, 325 bun, crp, ast, and low oxygen saturation. these findings 326 validate several population-level insights from section 1 and 327 are in agreement with clinical studies: prevalence of shortness 328 of breath (23), elevated levels of crp as an inflammatory 329 marker (24, 25), and elevated ast levels due to liver dysfunc-330 tion in severe covid-19 cases (11, 26). turning to infection risk, the main indicators are crp, 332 leukocytes, calcium, ast, and temperature. these findings 333 are also in agreement with clinical reports: an elevated crp 334 generally indicates an early sign of infection and implies lung 335 lesions from covid-19 (27), elevated levels of leukocytes 336 suggest cytokine release syndrome caused by sars-cov-2 337 virus (28), and lowered levels of serum calcium signal higher 338 rate of organ injury and septic shock (29) . since our findings 339 agree with clinical observations, our calculators can be used 340 to support clinical decision making-although they are not 341 intended to substitute clinical diagnostic or medical expertise. 342 when lab values are not available, the widely accepted 343 risk factors of age, oxygen saturation, temperature, and heart 344 rate become the key indicators for both risk calculators. we 345 observe that mortality risk is higher for male patients (blue in 346 figure 3b ) than for female patients (red), confirming clinical 347 reports (30, 31). an elevated respiratory frequency becomes 348 an important predictor of infection, as reported in (32). these 349 findings suggest that demographics and vitals provide valuable 350 information in the absence of lab values. however, when lab 351 values are available, these other features become secondary. a limitation of the current mortality model is that it does 353 not take into account medication and treatments during hos-354 pitalization. we intend to incorporate these in future research 355 to make these models more actionable. furthermore, these 356 models aim to reveal associations between risks and patient 357 characteristics but are not designed to establish causality. overall, we have developed data-driven calculators that 359 allow physicians and patients to assess mortality and infection 360 risks in order to guide care management-especially with 361 scarce healthcare resources. these calculators are being used 362 by several hospitals within the asst cremona system to 363 support triage and treatment decisions-alleviating the toll of 364 the pandemic. our infection calculator also supports safety 365 protocols for banco de credito del peru, the largest bank in 366 peru, to determine how employees can return to work. the inverse tangent function provides a concave-convex re-404 lationship, capturing three phases of government response. 405 in phase i, most activities continue normally as people 406 adjust their behavior. in phase ii, the infection rate 407 declines sharply as policies are implemented. in phase 408 iii, the decline in the infection rate reaches saturation. 409 the parameters t0 and k can be respectively thought of 410 as the start date and the strength of the response. ultimately, delphi involves 13 parameters that define 412 the transition rates between the 11 states. we calibrate six of 413 them from our clinical outcomes database (section 1). using 414 of the pandemic (7). it has also been used by the hartford healthcare system-the major hospital system in connecticut, 472 us-to plan its icu capacity, and by a major pharmaceutical 473 company to design a vaccine distribution strategy that can 474 most e ectively contain the next phases of the pandemic. b. delphi-presc: toward re-opening society. to inform the 476 relaxation of social distancing policies, we link policies to the 477 infection rate using machine learning. specifically, we predict 478 the values of "(t), obtained from the fitting procedure of 479 delphi-pred. for simplicity and interpretability, we consider 480 a simple model based on regression trees (35) and restrict the 481 independent variables to the policies in place. we classify 482 policies based on whether they restrict mass gatherings, school 483 and/or other activities (referred to as "others", and including 484 business closures, severe travel limitations and/or closing of 485 non-essential services). we define a set of seven mutually 486 exclusive and collectively exhaustive policies observed in the 487 us data: (i) no measure; (ii) restrict mass gatherings; (iii) 488 restrict others; (iv) authorize schools, restrict mass gatherings 489 and others; (v) restrict mass gatherings and schools; (vi) 490 restrict mass gatherings, schools and others; and (vii) stay-491 at-home. 492 we report the regression tree in the appendix, obtained 493 from state-level data in the united states. this model achieves 494 an out-of-sample r 2 of 0.8, suggesting a good fit to the data. 495 as expected, more stringent policies lead to lower values of 496 "(t). the results also provide comparisons between various 497 policies-for instance, school closures seem to induce a stronger 498 reduction in the infection rate than restricting "other" activ-499 ities. more importantly, the model quantifies the impact of 500 each policy on the infection rate. we then use these results 501 to predict the value of "(t) as a function of the policies (see 502 appendix for details), and simulate the spread of the disease 503 as states progressively loosen social distancing policies. 504 figure 4d plots the projected case count in the state of new 505 york (ny), for di erent policies (we report a similar plot for 506 the death count in the appendix). note that the stringency of 507 the policies has a significant impact on the pandemic's spread 508 and ultimate toll. for instance, relaxing all social distancing 509 policies on may 12 can increase the cumulative number of 510 cases in ny by up to 25% by september. using a similar nomenclature, figure 4e shows the case 512 count if all social distancing policies are relaxed on may 12 vs. 513 may 26. note that the timing of the policies also has a strong 514 impact: a two-week delay in re-opening society can greatly 515 reduce a resurgence in ny. the road back to a new normal is not straightforward: 517 results suggest that the disease's spread is highly sensitive to 518 both the intensity and the timing of social distancing policies. 519 as governments grapple with an evolving pandemic, delphi-520 presc can be a useful tool to explore alternative scenarios and 521 ensure that critical decisions are supported with data. we model ventilator pooling as a multi-period resource 565 allocation over s states and d days. the model takes as input 566 ventilator demand in state s and day d, denoted as v s,d , as 567 well as parameters capturing the surge supply from the federal 568 government and the extent of inter-state collaboration. we 569 formulate an optimization problem that decides on the number 570 of ventilators transferred from state s to state s õ on day d, 571 and on the number of ventilators allocated from the federal 572 government to state s on day d. we propose a bi-objective 573 formulation. the first objective is to minimize ventilator-day 574 shortages; for robustness, we consider both projected shortages 575 (based on demand forecasts) and worst-case shortages (includ-576 ing a bu er in the demand estimates). the second objective 577 is to minimize inter-state transfers, to limit the operational 578 and political costs of inter-state coordination. mixed-integer 579 optimization provides modeling flexibility to capture spatial-580 temporal dynamics and the trade-o s between these various 581 objectives. we report the mathematical formulation of the 582 model, along with the key assumptions, in the appendix. put on a ventilator, which we use to estimate the demand for 589 ventilators. we also obtain the average length of stay from 590 our clinical outcomes database (figure 2 ). we discuss these trade-o s further in the appendix. a similar model has been developed to support the re-626 distribution of ventilators across hospitals within the hartford 627 healthcare system in connecticut-using county-level fore-628 casts of ventilator demand obtained from delphi-pred. this 629 model has been used by a collection of hospitals in the united 630 states to align ventilator supply with projected demand at a 631 time where the pandemic was on the rise. looking ahead, the proposed model can support the alloca-633 tion of critical resources in the next phases of the pandemic-634 spanning ventilators, medicines, personal protective equipment 635 etc. since epidemics do not peak in each state at the same 636 time, states whose infection peak has already passed or lies 637 weeks ahead can help other states facing immediate shortages 638 at little costs to their constituents. inter-state transfers of 639 ventilators occurred in isolated fashion through april 2020; 640 our model proposes an automated decision-making tool to 641 support these decisions systematically. as our results show, 642 proactive coordination and resource pooling can significantly 643 reduce shortages-thus increasing the number of patients that 644 can be treated without resorting to extreme clinical recourse 645 with side e ects (such as splitting ventilators). this paper proposes a comprehensive data-driven approach to 648 address several core challenges faced by healthcare providers 649 and policy makers in the midst of the covid-19 pandemic. 650 we have gathered and aggregated data from hundreds of clini-651 dimitris bertsimas et al. pnas | may 26, 2020 | vol. xxx | no. xx | 9 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june 29, 2020. . cal studies, electronic health records, and census reports. we sophia xing and cynthia zheng from 672 our extended team for helpful discussions persistence of coronaviruses on inanimate sur-674 faces and its inactivation with biocidal agents high contagiousness and rapid spread of severe acute respiratory 676 how will country-based 680 mitigation measures influence the course of the covid-19 epidemic? economic effects of coronavirus outbreak (covid-19) on the world economy. 683 available at ssrn the global macroeconomic impacts of covid-19: seven scenarios. 685 cama work covid-19 forecasts check if you have coronavirus symptoms 694 clinical characteristics of coronavirus disease 2019 in china clinical characteristics of covid-19 in factors associated with hospitalization and critical illness among 4,103 701 patients with covid-19 disease in new york city phylogenetic network analysis of sars-cov-2 703 genomes an 81 nucleotide deletion in sars-cov-2 orf7a identified from sentinel 705 surveillance in arizona hospitalization rates and characteristics of patients hospitalized with laboratory-707 confirmed coronavirus disease 2019-covid-net, 14 states racial and ethnic disparities in sars-cov-2 pandemic: analysis of a covid-19 710 observational registry for a diverse us metropolitan population positive rt-pcr test results in patients recovered from covid-19 missing value estimation methods for dna microarrays xgboost: a scalable tree boosting system in proceedings of the 22nd 716 acm sigkdd international conference on knowledge discovery and data mining a unified approach to interpreting model predictions in advances in 719 neural information processing systems 30 from local explanations to global understanding with explainable ai for 722 trees unique epidemiological and clinical features of the emerg-724 ing 2019 novel coronavirus pneumonia (covid-19) implicate special control measures the covid-19 epidemic chest ct features of covid-19 in rome, italy clinical features of patients infected with 2019 novel coronavirus in wuhan, 730 china c-reactive protein levels in the early stage of covid-19 covid-19 infection: the perspectives on immune responses serum calcium as a biomarker of clinical severity and prognosis in patients with 735 coronavirus disease 2019: a retrospective cross-sectional study covid-19: risk factors for severe disease and death neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in 738 hospitalized patients with covid-19 clinical course and risk factors for mortality of adult inpatients with covid-19 in 740 china: a retrospective cohort study. the lancet projecting the transmission dy-742 namics of sars-cov-2 through the postpandemic period classification and regression trees effects of prone positioning on lung protection in patients with acute 748 the standard of care of patients with ards: ventilatory settings and rescue 751 therapies for refractory hypoxemia intubation and ventilation amid the covid-19 outbreakwuhan's experience critical supply shortages-the need for ventilators and per-755 sonal protective equipment during the covid-19 pandemic stockpiling ventilators for influenza pandemics a model of supply-chain decisions for 759 resource sharing with an application to ventilator allocation to combat covid-19